Novel compounds and pharmaceutical compositions containing the same as an active ingredient

Abstract

The present invention relates to a novel compound useful for the production of a medicament capable of treating related diseases by regulating the function and differentiation of the cytoskeleton involved in the pulmonary fibrosis process. The novel compound according to the present invention or a pharmaceutically acceptable salt thereof has been confirmed to have an effect of regulating actin polymerization necessary for the formation of the cytoskeleton, and has been confirmed to effectively suppress the expression of α-SMA and F-actin, which are the main causative factors of fibrosis, in fibroblasts (MRC5) derived from human lung tissue. In addition, when the compound is treated with activated macrophages, it has been confirmed that the level of inflammatory cytokines by macrophages decreases. Therefore, the novel compound according to the present invention is expected to be usefully utilized for the prevention and treatment of pulmonary fibrosis-related diseases as a formulation having an effect of suppressing or improving pulmonary fibrosis.

Description

Technical Field

[0001] The present invention relates to a novel compound and a pharmaceutical composition containing the same as an active ingredient, etc.

[0002] The present invention claims priority based on Korean Patent Application No. 10-2022-0070989 filed on June 10, 2022, and Korean Patent Application No. 10-2023-0074884 filed on June 12, 2023, and all the contents disclosed in the specifications and drawings of the applications are incorporated herein by reference.

Background Art

[0003] Idiopathic Pulmonary Fibrosis (IPF) is a disease in which fibrosis of the lung parenchyma of unknown cause progresses chronically. Chronic inflammatory cells penetrate the alveolar wall to induce fibrosis, causing profound structural changes in lung tissue and gradually decreasing lung function. When fibrosis of the lung parenchyma continues due to idiopathic pulmonary fibrosis, respiratory failure may occur and lead to death. However, there is no effective treatment method, the 5-year survival rate after diagnosis is less than 40%, the 10-year survival rate is less than 15%, and it is a disease with a very high fatality rate. As drugs for treating pulmonary fibrosis currently used clinically, pirfenidone and nintedanib are used under the approval of the US Food and Drug Administration (FDA), but they show a low treatment effect with only about a 10% improvement in lung function. In addition, neither of the two therapeutic agents shows a significant difference in extending the life expectancy of patients after diagnosis. Therefore, the development of a therapeutic agent for pulmonary fibrosis through a new mechanism is required.

[0004] In damaged tissues, inflammatory proteins such as TGF-β and TNF-α are produced and secreted extracellularly, which causes functional and structural changes in the cytoskeleton, and the healing process proceeds. However, in a normal state, once the healing process is over, the inflammatory proteins and the accumulated extracellular matrix proteins (ECM) decrease, and the recovery procedure occurs. In a pathological state, the recovery procedure does not proceed, and the accumulation of the secreted extracellular matrix proteins continues. This is one of the main mechanisms causing fibrosis. Cells respond to external physical stimuli by causing changes in gene expression, cell morphology, and cytoskeleton through intracellular mechanotransduction and changes in cell-cell interaction. Such changes in the cytoskeleton are an important driving force for causing cell movement and remodeling of the cell surface. When damage caused by various external causes cannot be restored to its original state through healing and recovery, the damaged tissue is converted into a process of fibrosis.

[0005] Epithelial-mesenchymal transition (EMT) and fibroblast-myofibroblast transition (FMT) are the main mechanisms underlying pulmonary fibrosis. In damaged alveolar tissues, the inflammatory cytokine TGF-β is secreted, and in the activated epithelial layer, EMT occurs due to the breakdown of cell adhesion tissues by inflammatory signals, and epithelial cells are converted into fibroblasts. In addition, fibroblasts present in the subepithelial layer, when subjected to mechanical and physical damage by external stimuli, express stress fibers and the like through the mechanotransduction pathway. Then, they are effectively activated by cytokines that cause fibrosis, and fibroblasts are converted into myofibroblasts by FMT. Such a process leads to changes in the cytoskeleton. The cytoskeleton is composed of microtubules, actin microfilaments, and intermediate filaments, and it not only maintains the skeletal structure of cells but also plays various roles such as cell movement and the interaction between cells and the external environment. Among these, actin microfilaments are fine filaments composed of the monomeric globular actin (G-actin) and the polymeric filament of globular actin, filamentous actin (F-actin), and are involved in cell motility such as lamellipodia and filopodia, and are also very importantly related to cell modification (EMT and FMT) by external mechanical stimuli. Thus, cell modification is carried out by changes in the cytoskeleton, and one of the factors causing this is the actin polymerization stage.

[0006] The regulation of cytoskeletal changes is important in the process of pulmonary fibrosis, and in particular, the mechanism of abnormal pulmonary fibrosis can be improved by regulating the actin polymerization reaction. Cells regulate cell motility through the actin polymerization reaction or form stress fibers and cause skeletal changes, and in this case, the target proteins involved are actin binding proteins. One of the target proteins, the Arp2 / 3 complex, acts on the nucleation stage among various stages of regulating cytoskeletal motility, plays a role in creating filament branches, and is composed of seven subunits (Arp2, Arp3, ARPC1, ARPC2, ARPC3, ARPC4, ARPC5). At this time, the Arp2 / 3 complex affects the amplification of actin microfilaments through the formation of actin branches and is related to the actin network formation rate in fibroblasts. Therefore, cell modification can be regulated by suppressing the changes in the actin network and cytoskeleton caused by the actin polymerization reaction through the regulation of the function of the Arp2 / 3 complex.

[0007] Pulmonary fibrosis is a disease that occurs between the tissues surrounding the alveoli and blood vessels. Especially in the case of idiopathic pulmonary fibrosis, progressive tissue hardening occurs due to the accumulation of ECM by myofibroblasts. This disease is induced by the contraction of myofibroblasts induced by changes in the cytoskeleton of cells such as fibroblasts. As a result, tissue hardening is induced, and the respiratory function of the lungs is reduced. Changes in the cytoskeleton are related to the activity of myofibroblasts, and it is known that the main biomarker for the activity of myofibroblasts is associated with the expression of α-smooth muscle actin (α-SMA). According to recent research results, there is a report that when fibroblasts derived from idiopathic pulmonary fibrosis are treated with the fibrosis-inducing cytokine TGF-β, the expression of α-SMA increases. Therefore, the activity of myofibroblasts related to pulmonary fibrosis is characterized by the expression of α-SMA. From such previous research results, it is judged that the improvement of cell modification by regulating the cytoskeleton is a mechanism that can treat idiopathic pulmonary fibrosis. Therefore, drugs for treating various pulmonary fibrosis-related diseases including idiopathic pulmonary fibrosis are to be developed from the development of substances that regulate the function of the Arp2 / 3 complex related to the actin polymerization reaction that regulates changes in the cytoskeleton.

Prior Art Documents

Patent Documents

[0008]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Summary of the Invention

Problems to be Solved by the Invention

[0009] The present invention has been devised to solve the above problems, and the inventors have developed a novel compound that can treat cytoskeleton-related diseases such as pulmonary fibrosis by suppressing pulmonary fibrosis factors and inflammatory factors and regulating actin polymerization reaction, thereby completing the present invention.

[0010] Therefore, the main object of the present invention is to provide a compound represented by the following Chemical Formula 1, its stereoisomer, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1]

[0011]

Chemical Structure

[0012] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating pulmonary fibrosis-related diseases, which contains the above compound, its stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0013]

[0014] Still another object of the present invention is to provide a kit for preventing or treating pulmonary fibrosis-related diseases, which contains the above composition.However, the technical problems to be achieved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those having ordinary knowledge in the technical field to which the present invention pertains from the following description.

Means for Solving the Problems

[0015] The present invention provides a compound represented by the following Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1]

[0016]

Chem.

[0017] (In the above Chemical Formula 1, X1 to X4 are each independently N or C; Y is N, S, or O; R1 is C1-C 10 alkyl, C3-C 20 cycloalkyl, C2-C 20 heterocycloalkyl, a 3- to 10-membered aromatic ring group, a 3- to 10-membered aromatic heterocyclic group, -CO-(C1-C6 alkyl), or -CO-(aryl substituted or unsubstituted with halogen and having C6-C 12 ), and one or more H of the above R1 may be substituted with halogen, a cyano group, aryl having C6-C 12 substituted or unsubstituted with halogen, or heteroaryl having C5-C 12 substituted or unsubstituted with halogen; when all of X1 to X4 are C, R2 is hydrogen, halogen, or C1-C5 alkyl, and when one or more of X1 to X4 are N, R2 is hydrogen; R3 and R4 can be linked to each other to form a 5- or 6-membered ring, where the ring may have one or more H atoms substituted with -OH, -NH2, dimethylamine, -NH-(C1-C5 alkyl), -NH-(C1-C5 alkoxy), -NH-COCH3, -NH-SO2CH3, C1-C5 alkyl, or C1-C5 alkoxy. When R3 and R4 do not form a ring, R4 is hydrogen or C1-C5 alkyl, and R3 is C1-C 10 alkyl, C3-C 10 cycloalkyl, C2-C 10 heterocycloalkyl, -CH2-(C3-C6 cycloalkyl), -CH2-(C2-C6 heterocycloalkyl), or -CH2-(3- to 6-membered aromatic heterocyclic group), and one or more H atoms of the R3 may be substituted with -OH, C1-C5 alkyl, acetyl, C1-C5 alkoxy, -COCF3, or -SO2CH3; The heterocycloalkyl, heterocyclic group, and heteroaryl each independently contain one or more heteroatoms selected from the group consisting of N, O, P, and S. In another embodiment of the present invention, R3 and R4 are linked to each other to form a 5- or 6-membered heterocycloalkyl, and the 5- or 6-membered heterocycloalkyl contains 1 to 2 N atoms in its ring. At this time, Y is N, and the 5- or 6-membered heterocycloalkyl formed by R3 and R4 may have one or more H atoms substituted with -OH, -NH2, dimethylamine, -NH-(C1-C5 alkyl), -NH-(C1-C5 alkoxy), -NH-COCH3, -NH-SO2CH3, C1-C5 alkyl, or C1-C5 alkoxy, but is not limited thereto. In still another embodiment of the present invention, R1 is a 6-membered aromatic ring group, a 6-membered aromatic heterocyclic group, -CH2-aryl, -CH2-heteroaryl, 6-membered cycloalkyl, 6-membered heterocycloalkyl, -CO-aryl, or -CO-(C4-C5 alkyl), wherein the 6-membered aromatic heterocyclic group contains one or more Ns, the 6-membered heterocycloalkyl contains one or more Os, and one or more Hs of the R1 are halogen, a cyano group, aryl substituted or unsubstituted with halogen, or C5-C 12 aryl substituted or unsubstituted with halogen, or C5-C 12 heteroaryl substituted or unsubstituted with halogen, but is not limited thereto. In still another embodiment of the present invention, the compound represented by Chemical Formula 1 may be any one selected from the group consisting of, but not limited to: (1) (R)-6-Fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (2) (R)-6-Fluoro-4-(4-fluorophenyl)-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (3) (R)-6-Fluoro-4-(4-fluorophenyl)-N-(1-isopropylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (4) (R)-6-Fluoro-4-(4-fluorophenyl)-N-(1-isobutylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (5) (R)-6-Fluoro-4-(4-fluorophenyl)-N-(1-(2,2,2-trifluoroacetyl)pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (6) (R)-N-(1-acetylpyrrolidin-3-yl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (7)(R)-6-Fluoro-4-(4-fluorophenyl)-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (8)(S)-6-Fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (9)(S)-6-Fluoro-4-(4-fluorophenyl)-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (10)(S)-6-Fluoro-4-(4-fluorophenyl)-N-(1-isopropylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (11)(S)-(3-Aminopyrrolidin-1-yl)(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone; (12)(S)-(6-Fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-(methylamino)pyrrolidin-1-yl)methanone; (13)(S)-(6-Fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-(isobutylamino)pyrrolidin-1-yl)methanone; (14)(S)-(6-Fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-(isopropylamino)pyrrolidin-1-yl)methanone; (15)(S)-N-(1-(6-Fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)acetamide; (16)(S)-N-(1-(6-Fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)methanesulfonamide; (17) (S)-6-Fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (18) (R)-6-Fluoro-4-(4-fluorophenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (19) (R)-6-Fluoro-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (20) (R)-6-Fluoro-4-(4-fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (21) (R)-6-Fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (22) (R)-6-Fluoro-4-(4-fluorophenyl)-N-((1-methylpyrrolidin-2-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (23) (R)-6-Fluoro-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-2-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (24) (R)-6-Fluoro-4-(4-fluorophenyl)-N-((1-isobutylpyrrolidin-2-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (25) (S)-6-Fluoro-4-(4-fluorophenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (26) (S)-6-Fluoro-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (27) (S)-6-Fluoro-4-(4-fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (28) N-(Cyclopropylmethyl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (29) 6-Fluoro-4-(4-fluorophenyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (30) 6-Fluoro-4-(4-fluorophenyl)-N-(1-methylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (31) 6-Fluoro-4-(4-fluorophenyl)-N-(1-isopropylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (32) 6-Fluoro-4-(4-fluorophenyl)-N-(1-isobutylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (33) 6-Fluoro-4-(4-fluorophenyl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (34) 6-Fluoro-4-(4-fluorophenyl)-N-(methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (35) 6-Fluoro-4-(4-fluorophenyl)-N-((1-isobutylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (36) 6-Fluoro-4-(4-fluorophenyl)-N-((1-isopropylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (37) N-((1H-Imidazol-4-yl)methyl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (38)6-Fluoro-4-(4-fluorophenyl)-N-(pyrazin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (39)(R)-(6-Fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-hydroxypyrrolidin-1-yl)methanone; (40)(6-Fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-methoxypyrrolidin-1-yl)methanone; (41)N-(Azetidin-3-yl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (42)6-Fluoro-4-(4-fluorophenyl)-N-(1-isopropylazetidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (43)6-Fluoro-4-(4-fluorophenyl)-N-(1-isobutylazetidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (44)N-(1-Acetylazetidin-3-yl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (45)6-Fluoro-4-(4-fluorophenyl)-N-((1-methylazetidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (46)6-Fluoro-4-(4-fluorophenyl)-N-((1-isopropylazetidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (47)6-Fluoro-4-(4-fluorophenyl)-N-((1-isobutylazetidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (48)6-Fluoro-4-(4-fluorophenyl)-N-((tetrahydrofuran-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (49) (S)-4-(4-Fluorophenyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (50) 4-(4-Fluorophenyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (51) (S)-4-(4-Fluorophenyl)-N-(tetrahydrofuran-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (52) 4-(4-Fluorophenyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (53) (S)-4-(4-Fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (54) (R)-4-(4-Fluorophenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (55) (R)-4-(4-Fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (56) (R)-4-(4-Fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (57) (R)-4-(4-Fluorophenyl)-N-(pyrrolidin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (58) (S)-4-(4-Fluorophenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (59) (S)-4-(4-Fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (60)(S)-4-(4-Fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (61)4-(4-Fluorophenyl)-N-((1-isobutylazetidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (62)4-(4-Fluorophenyl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (63)4-(4-Fluorophenyl)-N-((1-isopropylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (64)4-(4-Fluorophenyl)-N-((1-isobutylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (65)(R)-6-Fluoro-4-phenyl-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (66)(4-(2-Chlorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(piperidin-1-yl)methanone; (67)4-(2-Chlorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(pyrrolidin-1-yl)methanone; (68)(4-(2-Chlorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(4-methylpiperazin-1-yl)methanone; (69)(S)-N-(1-Isopropylpyrrolidin-3-yl)-4-(pyridin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (70)(R)-N-(1-Acetylpyrrolidin-3-yl)-4-(pyridin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (71)(S)-4-(Pyridin-2-yl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (72)(R)-4-(Pyridin-2-yl)-N-(pyrrolidin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (73)(R)-4-(Pyridin-3-yl)-N-(tetrahydrofuran-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (74)N-(Cyclopropylmethyl)-4-(pyridin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (75)(R)-4-(5-Fluoropyridin-2-yl)-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (76)(R)-4-(5-Fluoropyridin-2-yl)-N-(1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (77)4-(5-Fluoropyridin-2-yl)-N-(1-methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (78)(S)-(3-Aminopyrrolidin-1-yl)(4-(5-fluoropyridin-2-yl)-3,4-dihydroquinoxaline-1(2H)-methanone; (79)(S)-4-(4-Cyanophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (80)(S)-4-(Pyrazin-2-yl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (81)(S)-N-(1-Isopropylpyrrolidin-3-yl)-4-(pyrazin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (82)N-(1-Isobutylpiperidin-4-yl)-4-(pyrazin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (83)N-(1-Isopropylpiperidin-4-yl)-4-(pyrazin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (84) (R)-4-Benzyl-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (85) (S)-(3-Aminopyrrolidin-1-yl)(4-benzyl-3,4-dihydroquinoxalin-1(2H)-yl)methanone; (86) (S)-(4-Benzyl-3,4-dihydroquinoxalin-1(2H)-yl)(3-(methylamino)pyrrolidin-1-yl)methanone; (87) (R)-4-(2-Fluorobenzyl)-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (88) 4-(2-Fluorobenzyl)-N-(1-methylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (89) 4-(2-Fluorobenzyl)-N-((1-methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (90) (R)-4-(2-Fluorobenzyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (91) (R)-4-(4-Fluorobenzyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (92) (R)-4-(4-Fluorobenzyl)-N-(1-isopropylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (93) 4-(4-Fluorobenzyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (94) 4-(4-Fluorobenzyl)-N-(1-isopropylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (95) (R)-4-(4-Chlorobenzyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (96)(S)-(3-(Isobutylamino)pyrrolidin-1-yl)(4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone; (97)(S)-(3-(Dimethylamino)pyrrolidin-1-yl)(4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone; (98)(R)-4-(Pyridin-2-ylmethyl)-N-(tetrahydrofuran-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (99)N-(Oxetan-3-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (100)4-(Pyridin-2-ylmethyl)-N-((tetrahydrofuran-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (101)4-(Pyridin-2-ylmethyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (102)N-(Cyclopropylmethyl)-4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (103)(4-(4-Fluorophenyl)-3,4-dihydropyrido[3,4-b]pyrazin-1(2H)-yl)(3-hydroxypyrrolidin-1-yl)methanone; (104)(R)-4-Cyclohexyl-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (105)(R)-4-Cyclohexyl-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (106)(R)-4-Cyclohexyl-N-(1-isobutylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (107)(4-Cyclohexyl-3,4-dihydroquinoxalin-1(2H)-yl)(4-methylpiperazin-1-yl)methanone; (108) (4-Cyclohexyl-3,4-dihydroquinoxalin-1(2H)-yl)(pyrrolidin-1-yl)methanone; (109) (4-Cyclohexyl-3,4-dihydroquinoxalin-1(2H)-yl)(piperidin-1-yl)methanone; (110) (R)-N-(1-Methylpyrrolidin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (111) (R)-N-(1-Isobutylpyrrolidin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (112) (S)-(3-Aminopyrrolidin-1-yl)(4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone; (113) (S)-(3-(Dimethylamino)pyrrolidin-1-yl)(4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone; (114) 4-Benzoyl-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (115) (S)-4-Benzoyl-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (116) (R)-4-Benzoyl-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (117) (S)-4-(2-Fluorobenzoyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (118) (R)-4-(2-Fluorobenzoyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (119) (R)-4-(3-Fluorobenzoyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (120) (S)-4-(3-Fluorobenzoyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (121) (R)-4-(3-Fluorobenzoyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (122) (S)-4-(4-Fluorobenzoyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (123) (R)-4-(4-Fluorobenzoyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (124) 4-(4-Fluorobenzoyl-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (125) 4-(3-Methylbutanoyl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (126) 4-(3-Methylbutanoyl)-N-((1-methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (127) N-((1-Isobutylpiperidin-4-yl)methyl)-4-(3-methylbutanoyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (128) (R)-4-(3-Methylbutanoyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (129) (R)-4-(3,3-Dimethylbutanoyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; and (130) 4-(3,3-Dimethylbutanoyl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0018] The present invention also provides a pharmaceutical composition for preventing or treating a pulmonary fibrosis-related disease, comprising, as an active ingredient, the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0019] The present invention also provides a pharmaceutical composition for preventing or treating a pulmonary fibrosis-related disease, comprising the step of administering to an individual in need thereof the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0020] The present invention also provides the use of the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for preventing or treating a pulmonary fibrosis-related disease. The present invention also provides the use of the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for manufacturing a medicament for preventing or treating a pulmonary fibrosis-related disease.

[0021] In one embodiment of the present invention, the composition may suppress actin polymerization, but is not limited thereto.

[0022] In another embodiment of the present invention, the composition may suppress the level or activity of inflammatory cytokines, but is not limited thereto.

[0023] In still another embodiment of the present invention, the composition may decrease the level or activity of one or more proteins selected from the group consisting of α-SMA, COL1A1, COL4A1, fibronectin, F-actin, and IL-6, but is not limited thereto.

[0024] In still other embodiments of the present invention, the pulmonary fibrosis-related disease may be one or more selected from the group consisting of pulmonary fibrosis, idiopathic pulmonary fibrosis, desquamative interstitial pneumonia, nonspecific interstitial pneumonia, latent organizing pneumonia, respiratory bronchiolitis-associated interstitial lung disease, acute interstitial pneumonia, lymphocytic interstitial pneumonia, idiopathic pulmonary parenchymal fibroelastosis, and chronic obstructive pulmonary disease (COPD), but is not limited thereto.

[0025] In still other embodiments of the present invention, the pulmonary fibrosis-related disease may be for the treatment of a pulmonary fibrosis-related disease accompanied by hyperactivation of actin polymerization, but is not limited thereto.

[0026] In addition, the present invention provides a kit for preventing or treating pulmonary fibrosis, comprising the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; or the composition.

[0027] In addition, the present invention provides a pharmaceutical composition for suppressing pulmonary fibrosis and / or pulmonary inflammation, comprising the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0028] Furthermore, the present invention provides a method for suppressing or improving pulmonary fibrosis and / or pulmonary inflammation, comprising the step of administering to an individual in need thereof the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0029] Furthermore, the present invention provides the use of the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for suppressing pulmonary fibrosis and / or pulmonary inflammation.

[0030] Furthermore, the present invention provides the use of the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of an agent for suppressing or improving pulmonary fibrosis and / or pulmonary inflammation.

Advantages of the Invention

[0031] The present invention relates to a novel compound useful for the production of a medicament capable of treating related diseases by regulating the function and differentiation of the cytoskeleton involved in the process of pulmonary fibrosis. The novel compound according to the present invention or a pharmaceutically acceptable salt thereof has been confirmed to have an effect of regulating actin polymerization necessary for the formation of the cytoskeleton, and has been confirmed to effectively suppress the expression of α-SMA and F-actin, which are the main causative factors of fibrosis, in fibroblasts derived from lung tissue. In addition, when the compound is treated with activated macrophages, it has been confirmed that the level of inflammatory cytokines by macrophages is significantly reduced. Therefore, the novel compound according to the present invention is expected to be usefully utilized for the prevention and treatment of various pulmonary fibrosis-related diseases as a preparation having an effect of suppressing or improving pulmonary fibrosis.

Brief Description of the Drawings

[0032]

Fig. 1a

Fig. 1b

Figs. 2a-2d

Fig. 3

Mode for Carrying Out the Invention

[0033] The present invention relates to a novel compound. It has been confirmed that by suppressing the actin polymerization reaction, the compound can not only regulate the formation of abnormal cytoskeletons but also has the effect of suppressing the production of pulmonary fibrosis-related factors including α-SMA, and thus the present invention has been completed.

[0034] Specifically, in one embodiment of the present invention, a novel compound according to the present invention was produced (Experimental Example 1). In another embodiment of the present invention, after treating the compound according to the present invention with actin monomers and then inducing the actin polymerization reaction, as a result, the actin polymerization activity was significantly decreased by the compound, and it was confirmed that the compound has an excellent actin polymerization reaction inhibitory effect (Experimental Example 2).

[0035] In still another embodiment of the present invention, the compound according to the present invention was treated with MRC5, and the changes in the levels of α-SMA and F-actin, which are fibrosis-related factors, were measured. As a result, it was confirmed that the levels of α-SMA and F-actin, which are the main biomarkers of pulmonary fibrosis, were significantly decreased by the treatment with the compound of the present invention (Experimental Example 3).

[0036] In still another embodiment of the present invention, as a result of verifying the α-SMA inhibitory effect of the compound according to the present invention, it was confirmed that the compound can effectively inhibit the protein expression of α-SMA in MRC5 (Experimental Example 4).

[0037] In still other embodiments of the present invention, after treating the compound according to the present invention with activated macrophages, the levels of production and secretion of IL-6, which is a major fibrogenic factor, were observed. As a result, it was confirmed that the level of IL-6 was significantly decreased by the treatment with the compound of the present invention (Experimental Example 5).

[0038] The above results prove that the novel compound according to the present invention can effectively suppress the lung fibrosis inducing factor, and the present invention is expected to be widely used in the treatment fields of various diseases related to lung fibrosis.

[0039] Hereinafter, the present invention will be specifically described. The present invention provides a compound represented by the following Chemical Formula 1, its stereoisomers, or pharmaceutically acceptable salts thereof: [Chemical Formula 1]

[0040]

Chemical Structure

[0041] (In the above Chemical Formula 1, X1 to X4 are each independently N or C; Y is N, S, or O; R1 is C1-C 10 alkyl, C3-C 20 cycloalkyl, C2-C 20 heterocycloalkyl, a 3- to 10-membered aromatic ring group, a 3- to 10-membered aromatic heterocyclic group, -CO-(C1-C6 alkyl), or -CO-(aryl substituted or unsubstituted with halogen and having 6 to 12 carbon atoms), and one or more H of the above R1 may be substituted with halogen, a cyano group, aryl having 6 to 12 carbon atoms substituted or unsubstituted with halogen, or heteroaryl having 5 to 12 carbon atoms substituted or unsubstituted with halogen; When all of X1 to X4 are C, R2 is hydrogen, halogen, or C1-C5 alkyl; when one or more of X1 to X4 is N, R2 is hydrogen (that is, when one or more of X1 to X4 is N, R2 is not N and is bonded to X n and is hydrogen. In other words, when one or more of X1 to X4 is N, the H of the ring formed by X1 to X4 is not substituted); R3 and R4 can be linked to each other to form a 5- or 6-membered ring. At this time, the ring may have one or more H substituted with -OH, -NH2, dimethylamine, -NH-(C1-C5 alkyl), -NH-(C1-C5 alkoxy), -NH-COCH3, -NH-SO2CH3, C1-C5 alkyl, C1-C5 alkoxy, When R3 and R4 do not form a ring, R4 is hydrogen or C1-C5 alkyl, and R3 is C1-C 10 alkyl, C3-C 10 cycloalkyl, C2-C 10 heterocycloalkyl, -CH2-(C3-C6 cycloalkyl), -CH2-(C2-C6 heterocycloalkyl), or -CH2-(3- to 6-membered aromatic heterocyclic group). One or more H of the said R3 may be substituted with -OH, C1-C5 alkyl, acetyl, C1-C5 alkoxy, -COCF3, or -SO2CH3; The heterocycloalkyl, heterocyclic group, and heteroaryl each independently contain one or more heteroatoms selected from the group consisting of N, O, P, and S.) Here, the -CO-(C1-C6 alkyl) means a C1-C6 alkyl linked to CO. For example, when R1 is -CO-(C1-C6 alkyl), it means a C1-C6 alkyl linked to a nitrogen atom (N) via CO. In the present invention, the statement that R3 and R4 are linked to each other to form a 5- or 6-membered ring means that R3 and R4 are linked to each other through other atoms to form a ring structure. The ring may consist of single bonds, multiple bonds (double bonds, triple bonds, etc.), or combinations thereof (i.e., including all cycloalkyls and aromatic rings), may be a ring consisting entirely of C, or may be a heterocyclic group containing one or more heteroatoms. Preferably, when R3 and R4 are linked to each other to form a 5- or 6-membered ring, R3 and R4 are both C. In one embodiment of the present invention, R3 and R4 are linked to each other to form a 5- or 6-membered heterocycloalkyl, and the 5- or 6-membered heterocycloalkyl contains 1 to 2 N atoms in its ring. At this time, Y may be N, but is not limited thereto. Further, one or more H atoms of the 5- or 6-membered heterocycloalkyl formed by R3 and R4 may be substituted with -OH, -NH2, dimethylamine, -NH-(C1-C5 alkyl), -NH-(C1-C5 alkoxy), -NH-COCH3, -NH-SO2CH3, C1-C5 alkyl, or C1-C5 alkoxy, but is not limited thereto. In another embodiment of the present invention, R1 is a 6-membered aromatic ring group (e.g., aryl), a 6-membered aromatic heterocyclic group (e.g., heteroaryl), -CH2-aryl, -CH2-heteroaryl, a 6-membered cycloalkyl, a 6-membered heterocycloalkyl, -CO-aryl, or -CO-(C4-C5 alkyl), where the 6-membered aromatic heterocyclic group contains one or more N atoms, and the 6-membered heterocycloalkyl may contain one or more O atoms, but is not limited thereto. Further, one or more H atoms of R1 may be substituted with a halogen, a cyano group, an aryl substituted or unsubstituted with a halogen and having 6 to C 12 or a heteroaryl substituted or unsubstituted with a halogen and having 5 to C 12 but is not limited thereto. In still another embodiment of the present invention, when R3 and R4 do not form a ring, R4 is hydrogen or C1-C5 alkyl, and R3 can be -CH2-(C3-C6 cycloalkyl), -CH2-(C2-C6 heterocycloalkyl), or -CH2-(3- to 6-membered aromatic heterocyclic group). Here, the heterocycloalkyl may be a 4- to 6-membered heterocycloalkyl containing 1 to 2 N or O, and the aromatic heterocyclic group may be a 5- or 6-membered aromatic heterocyclic group containing 1 to 2 N, but is not limited thereto. In one embodiment of the present invention, the compound may be represented by the following Chemical Formula 1-1, but is not limited thereto: [Chemical Formula 1-1]

[0042]

Chemical Formula

[0043] (In Chemical Formula 1-1, X1 to X4 are each independently N or C; Z1 to Z6 are each independently N, O, or C; R 1a is hydrogen, a halogen, or a cyano group; R2 is hydrogen, a halogen, or C1-C5 alkyl; R3 is C1-C 10 alkyl, C3-C 10 cycloalkyl, C2-C 10 heterocycloalkyl, -CH2-(C3-C6 cycloalkyl), -CH2-(C2-C6 heterocycloalkyl), or -CH2-(3- to 6-membered aromatic heterocyclic group), and one or more H of R3 may be substituted with -OH, C1-C5 alkyl, acetyl, C1-C5 alkoxy, -COCF3, or -SO2CH3; R4 is hydrogen or C1-C5 alkyl; The heterocycloalkyl and heteroaryl groups each independently contain one or more heteroatoms selected from the group consisting of N, O, P, and S.) In Chemical Formula 1-1, one solid line and one dotted line (i.e.,

[0044]

Chemical formula

[0045] ) means that two atoms can be linked by a single bond or a double bond.) Preferably, the compound may be any one of the compounds shown in Table 1 below, but is not limited thereto.)

[0046] Throughout this specification, a functional group can be denoted by omitting “-group”.

[0047] In the present invention, “halogen” includes F, Cl, Br, I, etc.)

[0048] In the present invention, “alkyl” means a fully saturated branched or unbranched (or straight-chain or linear) hydrocarbon. Also, the alkyl according to the present invention includes a linear or branched hydrocarbon containing a hydrocarbon ring group at the terminal or in the middle. In the present invention, the alkyl is C1-C 20 , C1-C 15 , C1-C 12 , C1-C 10, C1-C8, C1-C6, C1-C5, C1-C4, or C1-C3 alkyl, which may be, but is not limited to, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, iso-amyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, or n-heptyl. In one embodiment of the present invention, the alkyl may be aminoalkyl or haloalkyl. The "aminoalkyl" may mean an alkyl group in which one or more H atoms are replaced by N atoms (e.g., -NH-(C1-C5 alkyl)), and the "haloalkyl" means an alkyl group in which one or more H atoms are replaced by halogen atoms.

[0049] The compound according to the present invention may contain an alkoxy group. In the present invention, "alkoxy" means an alkyl singly bonded to an oxygen atom (-O-R). In the present invention, the alkoxy may be C1-C 10 , C1-C8, C1-C6, C1-C5, C1-C3 or C1-C2 alkoxy, which may be, but is not limited to, for example, methoxy, ethoxy, phenoxy, butoxy, etc. In the present invention, "acetyl" refers to a monovalent atomic group (CH3CO-) composed of a methyl group (-CH3) and a carbonyl group (C=O), and "acetyl substituted with halogen" means that one or more hydrogen atoms of acetyl are replaced by halogen. For example, in the present invention, acetyl substituted with halogen may be trifluoroacetyl (-COCF3).

[0050] In the present invention, "sulfonyl" means a divalent atomic group (-SO2-) composed of two O atoms and one S atom. Preferably, the sulfonyl is an alkylsulfonyl to which an alkyl group of C1-C 10 is bonded. For example, the sulfonyl may be methylsulfonyl to which a methyl group is bonded. In the present invention, "amino" refers to a functional group (-NH2) in which hydrogen is bonded to a nitrogen atom.

[0051] The compounds according to the present invention may contain a cyclic substituent (e.g., cycloalkyl group, aryl group, etc.) including a single bond, multiple bonds (double bond, triple bond, etc.), or a combination thereof. That is, the compounds according to the present invention may contain a (hetero)cycle group having a single bond and / or multiple bonds.

[0052] In the present invention, "cycloalkyl" means a saturated or partially unsaturated non-aromatic cyclic hydrocarbon group. In the present invention, the cycloalkyl is C3-C 20 、C3-C 15 、C3-C 12 、C3-C 10 、which may be cycloalkyl of C3-C8, C3-C6, or C3-C5, but is not limited thereto. As specific examples, the cycloalkyl group includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, etc. In the present invention, cycloalkyl includes "bicycloalkyl" or "tricycloalkyl". The terms "bicycloalkyl" or "tricycloalkyl" mean a structure composed of two or more cycloalkyl moieties having two or more atoms in common, unless otherwise indicated. Also, the cycloalkyl group may be a polycyclic ring.

[0053] In the present invention, "heterocycloalkyl" means a cyclic hydrocarbon group containing one or more heteroatoms in addition to carbon atoms in the ring. The heteroatom(s) can be one or more selected from the group consisting of N, O, P, and S. In one embodiment of the present invention, the heterocycloalkyl may be a cyclic amine or a heterocyclic amine containing an N atom, preferably a 3- to 6-membered cyclic amine. For example, the heterocycloalkyl can be selected from the group consisting of piperidine, pyrrolidine, morpholine, piperazine, pyrrolopyrazine, and azetidine. Alternatively, the heterocycloalkyl can be a 4- to 6-membered ring group containing one or more O atoms. In the present invention, heterocycloalkyl includes "biheterocycloalkyl". The biheterocycloalkyl consists of two or more rings having two or more atoms in common, meaning that one or more of the two or more rings is a heterocycloalkyl.

[0054] In the present invention, "aryl" means an aromatic system containing one or more rings, used alone or in combination, and also includes a group in which an aromatic ring is fused to one or more carbocyclic rings. In the present invention, the aryl is C3-C 20 、C3-C 15 、C3-C 12 、C3-C 10 、C3-C8, or C3-C6 aryl, but is not limited thereto. The aryl means, for example, phenyl, benzyl, naphthyl, or tetrahydronaphthyl, but is not limited thereto. The aryl includes heteroaryl.

[0055] In the present invention, "heteroaryl" means a monocyclic or bicyclic organic compound containing one or more heteroatoms in addition to carbon atoms in the ring. The heteroatom may be one or more selected from the group consisting of N, O, P, and S. In one embodiment of the present invention, the heteroaryl may contain one or more N's (i.e., one or more C's constituting the ring are substituted with N). Also, in the present invention, heteroaryl may be an aromatic amine. In another embodiment of the present invention, the heteroaryl may contain 1 to 3, 1 to 2, or 1 N atom.

[0056] The aryl and heteroaryl (aromatic ring) according to the present invention include, as non-limiting examples, phenyl, biphenyl, benzyl, benzoyl, benzidine, toluyl, thienyl, furyl, naphthyl, pyrimidine, imidazolyl (imidazole), pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, pyranyl, pyrazinyl, pyrrolinyl, pyridinyl (pyridyl), piperazinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiadiazolyl, triazolyl, indolyl, azaindolyl, indazolyl, azaindazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzoisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adeninyl, quinolinyl, isoquinolinyl, naphthalenyl, tetrahydronaphthyl, and isomers thereof.

[0057] In addition, the compound according to the present invention may contain a polycyclic ring in which a plurality of rings are bonded. Specifically, the polycyclic ring means a substituent in which two or more rings are linearly angled or have a dense structure. For example, the compound may contain a polycyclic ring to which 2 to 5 ring groups are bonded (that is, a polycyclic ring of 2 to 5 rings), a polycyclic ring to which 2 to 4 ring groups are bonded, or a polycyclic ring to which 2 to 3 ring groups are bonded. Each ring group constituting the polycyclic ring may include all ring groups known in the art as well as the ring groups described in this specification. For example, the ring group may be composed of a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 10-membered ring, or a combination thereof, and preferably may be composed of a 5-membered ring and / or a 6-membered ring. In addition, each ring group constituting the polycyclic ring group may consist only of a single bond or may include a multiple bond (double bond, triple bond, etc.). Each ring group constituting the polycyclic ring may be of the same or different types from each other. For example, the ring groups may each independently be a cycloalkyl, a heterocycloalkyl, an aromatic ring group of 3 to 10 members, or an aromatic heterocyclic group of 3 to 10 members.

[0058] In addition, the compound according to the present invention may contain a heterocyclic group. The ring group may include a single bond or a multiple bond (double bond, triple bond, etc.). In one embodiment of the present invention, the heterocyclic group may include one or more heteroatoms selected from the group consisting of N, O, and S.

[0059] In the present invention, the "aromatic ring group" means a substituent in which a carbon compound is cyclically bonded by an unsaturated bond (for example, a double bond), a lone pair of electrons, an empty orbital, or the like. The "aromatic heterocyclic group" means a heterocyclic group in which the types of elements constituting the ring in an aromatic ring are two or more. In the present invention, the aromatic (hetero) ring group may be a (hetero) ring group of 3 to 10 members, 3 to 8 members, 3 to 6 members, 3 to 5 members, 4 to 6 members, 4 to 5 members, or 5 to 6 members, but is not limited thereto.

[0060] In the present invention, a substituent containing a heteroatom (heterocyclic group, heterocycloalkyl group, heteroaryl group, and various other heterocyclic groups, etc.) may contain one or more heteroatoms in its skeletal structure. For example, the substituent containing a heteroatom may contain 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 heteroatom, but is not limited thereto.

[0061] In the present invention, the term "substituted or unsubstituted" in "substituted or unsubstituted" means that when one or more hydrogen atoms in an organic compound are substituted with other atomic groups to form a derivative, they are introduced in place of the hydrogen atoms, and the substituent refers to the introduced atomic group. That is, in the present invention, when any functional group is substituted, it means that one or more hydrogen atoms of the functional group are replaced with other atomic groups. In the present invention, each functional group (alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, acetyl, etc.) may independently have one or more hydrogen atoms substituted with other atomic groups. In the present invention, "substituted" includes single substitution, double substitution, triple substitution, quadruple substitution, etc.

[0062] In the present invention, unless otherwise specified, "substituted or unsubstituted" means that one or more H (hydrogen atoms) are substituted or unsubstituted with other functional groups. For example, "a C3-C 10 aryl group substituted or unsubstituted with a halogen" means that the C3-C 10 aryl group is unsubstituted, or one or more H of the aryl group are substituted with a halogen.

[0063] In the present invention, the term "isomer" refers to a compound having the same molecular formula but different in the connection mode or spatial arrangement of constituent atoms within the molecule. Isomers include, for example, structural isomers and stereoisomers. The stereoisomers can be diastereomers or enantiomers. Enantiomers refer to isomers that do not overlap with the mirror image like the relationship between the left hand and the right hand, and are also called optical isomers. Enantiomers are classified into R (Rectus: clockwise) and S (Sinister: counterclockwise) when four or more substituents on the chiral center carbon are different from each other. Diastereomers refer to stereoisomers that are not in a mirror image relationship and are divided into cis-trans with different spatial arrangements of atoms.

[0064] In the present invention, the term "pharmaceutically acceptable salt" includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases.

[0065] As used herein, the term "pharmaceutically acceptable" means a compound or composition that has a reasonable benefit / risk ratio without excessive toxicity, irritation, allergic reaction or other problems or complications, is suitable for use in contact with the tissues of a subject (e.g., human), and is within the scope of sound medical judgment.

[0066] Examples of suitable acids include hydrochloric acid, bromic acid, sulfuric acid, nitric acid, perchloric acid, hydroiodic acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, (+)-L-tartaric acid, acetic acid, trichloroacetic acid or trifluoroacetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphorsulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, galactaric acid, gentisic acid, glucoheptanoic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, a-oxo-glutaric acid, hippuric acid, (+)-L-lactic acid, (+-)-DL-lactic acid, lactobionic acid, (-)-L-malic acid, (+-)-DL-mandelic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, gluconic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, benzenesulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, palmitoleic acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, tannic acid, thiocyanic acid, camcillic acid, and undecylic acid, etc. The acid addition salts can be prepared by conventional methods, for example, by dissolving the compound in an excess of aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Also, the same molar amounts of the compound and the acid or alcohol in water can be heated and then the mixture can be evaporated to dryness or the precipitated salt can be suction filtered to produce it.

[0067] Salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium, and ammonium. Alkali metal or alkaline earth metal salts can be obtained, for example, by dissolving the compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound, and then evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to produce sodium, potassium or calcium salts as metal salts in particular, and the corresponding silver salts can be obtained by reacting the alkali metal or alkaline earth metal salts with a suitable silver salt (e.g., silver nitrate).

[0068] The scope of the compounds of the present invention may include not only pharmaceutically acceptable salts, but also all isomers, hydrates and solvates that can be produced by ordinary methods.

[0069] The present invention also provides a pharmaceutical composition for preventing or treating a pulmonary fibrosis-related disease, comprising, as an active ingredient, a compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0070] In the present invention, "pulmonary fibrosis-related diseases" include all diseases directly or indirectly induced by pulmonary fibrosis, and diseases accompanied by pulmonary fibrosis may also be included. Fibrosis refers to a phenomenon in which extracellular matrix containing collagen etc. is secreted by activated fibroblasts and connective tissue is formed in the tissue. Fibrosis contributes to the process of forming scar tissue etc. to recover from wounds, but when connective tissue accumulates excessively, it can paralyze the normal structure and function of the organ.

[0071] Specifically, the pulmonary fibrosis-related disease may be one or more selected from the group consisting of pulmonary fibrosis, idiopathic pulmonary fibrosis, desquamative interstitial pneumonia, non-specific interstitial pneumonia, latent organizing pneumonia, respiratory bronchiolitis-associated interstitial lung disease, acute interstitial pneumonia, lymphocytic interstitial pneumonia, idiopathic pulmonary parenchymal fibroelastosis, and chronic obstructive pulmonary disease (COPD), but is not limited thereto, and any disease that presents with pulmonary fibrosis or can be directly or indirectly induced by pulmonary fibrosis is included without limitation. Preferably, in the present invention, the pulmonary fibrosis-related disease may preferably be accompanied by hyperactivation of actin polymerization. In another embodiment of the present invention, the pulmonary fibrosis-related disease may be accompanied by hyperactivation or overexpression of α-SMA, F-actin, and / or IL-6.

[0072] In the present invention, "pulmonary fibrosis" refers to a respiratory disease in which lung tissue hardens and causes respiratory impairment. Specifically, it means a state in which excessive accumulation of fibrous connective tissue occurs in the lungs, and the normal lung structure is destroyed and hardened. The phenomenon in which fibrous connective tissue is excessively formed in an organ in this way is called fibrosis. When fibrosis progresses in the lungs, the walls of the lungs thicken, the amount of oxygen supplied to the blood decreases, and shortness of breath and the like occur. The most common type of pulmonary fibrosis is idiopathic pulmonary fibrosis of unknown cause, which has dyspnea during exercise as the main symptom. Nintedanib, an antifibrotic agent, is used in the treatment of idiopathic pulmonary fibrosis, but the treatment effect is known to be only 10%.

[0073] In the present invention, the composition may suppress actin polymerization. The actin includes F-actin. The suppression of actin polymerization may be achieved through the suppression of the function of the Arp2 / 3 complex, which is an actin-binding protein. Actin filaments are assembled from actin monomers through an actin polymerization reaction that hydrolyzes ATP to ADP. Actin polymerization is necessary for the regulation of cell motility, but excessive actin polymerization can promote the expression of α-SMA, induce the activation of myofibroblasts, which are a heterogeneous cell population composed of fibrosis-promoting cells, and cause tissue fibrosis. The inventors of the present invention confirmed through specific experiments that the compound according to the present invention can effectively suppress actin polymerization, and thus can fundamentally treat and improve pulmonary fibrosis.

[0074] Also, in the present invention, the composition can suppress the level or activity of inflammatory cytokines. The inflammatory cytokines may be those produced and secreted by macrophages. The inflammatory cytokine may be, but is not limited to, IL-6. IL-6 is involved in B cell differentiation, T cell activation, and inflammatory reactions, and is a cytokine that particularly induces pulmonary fibrosis. When pulmonary fibrosis occurs, an acute or chronic inflammatory reaction precedes, but during the inflammatory reaction, inflammatory cells including macrophages are activated, and inflammatory cytokines such as IL-6, IL-1β, and TNF-α are secreted. These cytokines promote pulmonary fibrosis by damaging tissues to proliferate fibroblasts and accumulating ECM.

[0075] In addition, in the present invention, the composition is characterized by reducing the level of one or more proteins selected from the group consisting of α-SMA, COL1A1, COL4A1, fibronectin, F-actin, and IL-6. The protein is a biomarker of pulmonary fibrosis. In particular, the "α-SMA" protein is a marker of activated myofibroblasts, which are the main effector cells of pulmonary fibrosis. The inventors confirmed through specific examples that the compound according to the present invention is superior to nintedanib, which is a conventional therapeutic agent for pulmonary fibrosis, in terms of the inhibitory effect on α-SMA expression in fibroblasts. This indicates that the compound according to the present invention is superior to nintedanib in terms of the inhibitory effect on pulmonary fibrosis.

[0076] The content of the compound of the present invention in the composition of the present invention can be appropriately adjusted according to the symptoms of the disease, the degree of progression of the symptoms, the condition of the patient, etc. For example, it may be 0.0001 to 99.9% by weight, or 0.001 to 50% by weight based on the total weight of the composition, but it is not limited thereto. The ratio of the content is a value based on the dry weight after removing the solvent. The pharmaceutical composition according to the present invention may further contain suitable carriers, excipients, and diluents commonly used in the manufacture of pharmaceutical compositions. The excipient may be, for example, one or more selected from the group consisting of diluents, binders, disintegrants, lubricants, adsorbents, humectants, film-coating substances, and release control type additives.

[0077] The pharmaceutical composition according to the present invention can be formulated and used in the form of tablets, sustained-release tablets, enteric-coated tablets, sublingual tablets, troches, pills, capsules, hard capsules, soft capsules, sustained-release capsules, enteric-coated capsules, granules, sustained-release granules, enteric-coated granules, powders, dry extracts, liquids, suspensions, soft extracts, fluid extracts, lemonades, aromatic waters, emulsions, spirits, tinctures, inhalants, elixirs, injections, perfusion fluids, sterile injection solutions, eye drops, plasters, lotions, pastes, sprays, patches, or external preparations such as aerosols, etc. The external preparation can have a dosage form such as cream, gel, patch, spray, ointment, plaster, lotion, liniment, paste or cataplasm, etc.

[0078] Examples of carriers, excipients and diluents that can be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharides, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. When formulating, it is usually prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc.

[0079] The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dosage level may be determined by factors such as the type and severity of the patient's disease, the activity of the drug, drug sensitivity, administration time, administration route and excretion ratio, treatment period, factors including co-administered drugs, and other factors well known in the medical field.

[0080] The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent, may be administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered by single or multiple administrations. It is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects in consideration of all the above-described elements, and this may be easily determined by a person having ordinary skill in the art to which the present invention pertains.

[0081] The pharmaceutical composition of the present invention may be administered to an individual by various routes. Although all modes of administration can be anticipated, for example, it may be administered by oral administration, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, injection into the perispinal space (intradural), sublingual administration, buccal mucosal administration, rectal insertion, vaginal insertion, ocular administration, ear administration, nasal administration, inhalation, spraying through the mouth or nose, skin administration, transdermal administration, etc. The pharmaceutical composition of the present invention is determined by the type of the drug as the active ingredient, together with various related factors such as the disease to be treated, the administration route, the age, sex, weight of the patient, and the severity of the disease. In the present invention, "individual" means a subject in need of treatment for a disease, and more specifically, means mammals such as humans or non-human primates, mice, rats, dogs, cats, horses, and cows.

[0082] In the present invention, "administration" means providing a predetermined composition of the present invention to an individual by any appropriate method.

[0083] In the present invention, "prevention" means all acts of suppressing or delaying the onset of a target disease, "treatment" means all acts in which the target disease and the metabolic disorder symptoms caused thereby are improved or beneficially changed by administration of the pharmaceutical composition according to the present invention, and "improvement" means all acts of reducing parameters related to the target disease, such as the degree of symptoms, by administration of the composition according to the present invention.

[0084] In addition, the present invention provides a kit for preventing or treating pulmonary fibrosis, which contains the composition according to the present invention. In the present invention, the "Kit" means a combination of substances or devices for preventing or treating pulmonary fibrosis using the compound according to the present invention, and there is no limitation on the specific form. The kit according to the present invention may contain, in addition to the compound according to the present invention, one or more other component compositions, solutions or devices suitable for preventing, improving or treating the disease in order to prevent and / or treat pulmonary fibrosis. Further, the kit may further contain an instruction manual or an instruction sheet on which information related to the compound of the present invention is described.

[0085] Throughout the specification of the present invention, when any part states that any component "comprises", this means, unless otherwise stated to the contrary, that it does not exclude other components, but may further include other components. Terms such as "about" and "substantially" used throughout the specification of the present invention are used in the sense of the numerical value or a value close to the numerical value when manufacturing and material tolerances inherent in the stated meaning are presented, and are used to prevent unscrupulous infringers from improperly using the disclosure in which exact or absolute numerical values are described in order to assist in the understanding of the present invention.

[0086] Throughout the specification of the present invention, the term "these combinations" included in the Markush-type expressions means one or more mixtures or combinations selected from the group consisting of the components described in the Markush-type expressions, and means including at least one selected from the group consisting of the components.

[0087] Hereinafter, preferred examples are presented to assist in the understanding of the present invention. However, the following examples are only provided to more easily understand the present invention, and the content of the present invention is not limited by the following examples.

Examples

[0088] [Experimental Examples] Experimental Example 1. Production of Compound [Reaction Formula 1] [Chem.]

[0089] <Production Method a> Production of 7-Fluoro-1-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline 7-Fluoro-1-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline according to the present invention was produced through the processes of the following Production Examples a-1 to a-4.

[0090] <Production Example a-1> Production of 5-Fluoro-N-(4-fluorophenyl)-2-nitroaniline A mixed solution of 2,4-difluoro-1-nitrobenzene (4.0 g, 25.14 mmol) and 4-fluoroaniline (2.8 g, 25.14 mmol) was stirred at 130 °C for 24 hours and then cooled to room temperature. After adding water to the reaction solution to terminate the reaction, it was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce 5-fluoro-N-(4-fluorophenyl)-2-nitroaniline.

[0091] Yellow solid (yield 63%); 1 1H NMR (400 MHz, CDCl3) δ 9.54 (s, 1H), 8.26 (dd, J = 9.4, 6.3 Hz, 1H), 7.27 - 7.23 (m, 2H), 7.18 - 7.13 (m, 2H), 6.63 (dd, J = 11.3, 2.7 Hz, 1H), 6.48 (ddd, 1H, J = 9.5, 6.9, 2.7 Hz).

[0092] <Production Example a-2> 5-Fluoro-N 1 -(4-fluorophenyl)benzene-1,2-diamine production The mixture of 5-fluoro-N-(4-fluorophenyl)-2-nitroaniline (4.0 g, 15.98 mmol) obtained in Production Example a-1 and tin(II) chloride dihydrate (10.8 g, 47.96 mmol) dissolved in ethyl acetate (32 mL) was stirred at 90 °C for 5 hours. After the reaction solution was cooled to room temperature, it was added to water, neutralized with 10 M aqueous NaOH solution, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce 5-fluoro-N 1 -(4-fluorophenyl)benzene-1,2-diamine. Orange solid (yield 56%); 1 1H NMR (400 MHz, CDCl3) δ 7.00 - 6.94 (m, 2H), 6.86 - 6.82 (m, 2H), 6.79 (dd, J = 10.0, 2.9 Hz, 1H), 6.70 (dd, J = 8.6, 5.9 Hz, 1H), 6.64 - 6.59 (m, 1H), 5.27 (s, 1H), 3.49 (s, 2H); LC / MS ESI(+): 220.6 (M + 1).

[0093] <Production Example a-3> Production of 7-fluoro-1-(4-fluorophenyl)quinoxaline-2,3(1H,4H)-dione 5-Fluoro-N 1 -(4-fluorophenyl)benzene-1,2-diamine (3.0 g, 14.83 mmol) was dissolved in diethyl oxalate (130 mL, 89.00 mmol), and then stirred at 160 °C for 24 hours. After the reaction solution was cooled to room temperature, the reaction solution was filtered and dried to produce 7-fluoro-1-(4-fluorophenyl)quinoxaline-2,3(1H,4H)-dione. Ivory solid (yield 68%); 11H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 7.47 (d, J = 6.7 Hz, 4H), 7.23 (dd, J = 8.8, 5.3 Hz, 1H), 7.05 - 7.00 (m, 1H), 6.08 (dd, J = 10.4, 2.5 Hz, 1H); LC / MS ESI(+): 274.9 (M+1).

[0094] <Production Example a-4> Production of 7-Fluoro-1-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline To a solution of 7-fluoro-1-(4-fluorophenyl)quinoxaline-2,3(1H,4H)-dione (2.0 g, 7.29 mmol) obtained in Production Example a-3 in THF (14 mL), borane-THF complex (1 M) (22 mL, 21.88 mmol) was slowly added at room temperature, and then the mixture was stirred at 65 °C for 16 hours. After the reaction solution was cooled to room temperature, water was added to terminate the reaction, and then it was neutralized with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce 7-fluoro-1-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline. Light purple solid (yield 72%); 1 1H NMR (400 MHz, CDCl3) δ 7.21 - 7.16 (m, 2H), 7.09 - 7.03 (m, 2H), 6.49 (dd, J = 8.6, 5.5 Hz, 1H), 6.36 - 6.27 (m, 2H), 3.66 - 3.63 (m, 2H), 3.46 - 3.44 (m, 2H); LC / MS ESI(+): 246.8 (M+1).

[0095] [Reaction Formula 2] [Chemical Formula]

[0096] <Production Example a-5>Production of tert-butyl (R)-3-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide)pyrrolidine-1-carboxylate 7-Fluoro-1-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline (200 mg, 0.81 mmol) obtained in Production Example a-4 was dissolved in dichloromethane (1.6 mL), and TEA (0.23 mL, 1.62 mmol) and triphosgene (120 mg, 0.41 mmol) were slowly added at 0 °C and stirred at 0 °C for 1 hour. TEA (0.23 mL, 1.62 mmol) and (R)-(+)-1-Boc-3-aminopyrrolidine (0.16 mL, 0.97 mmol) were added to the reaction solution and stirred at room temperature for 3 hours. After adding water to the reaction solution to terminate the reaction, it was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce tert-butyl (R)-3-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide)pyrrolidine-1-carboxylate.

[0097] Light yellow solid (yield 96%); 1 1H NMR (400 MHz, CDCl3) δ 7.24 - 7.20 (m, 2H), 7.16 - 7.10 (m, 2H), 7.05 (dd, J = 8.9, 5.6 Hz, 1H), 6.41 - 6.39 (m, 1H), 6.25 (dd, J = 11.3, 2.7 Hz, 1H), 5.25 (dd, J = 6.7 Hz, 1H), 4.41 (brs, 1H), 3.95 - 3.88 (m, 2H), 3.68 - 3.60 (m, 3H), 3.45 - 3.40 (m, 2H), 3.18 (brs, 1H), 2.20 - 2.14 (m, 1H), 1.85 - 1.75 (m, 1H), 1.46 (s, 9H).

[0098] <Example 1>Synthesis of (R)-6-fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Tert-butyl (R)-3-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide) pyrrolidine-1-carboxylate (300 mg, 0.65 mmol) obtained in Production Example a-5 was dissolved in dichloromethane (1.3 mL), TFA (0.5 mL, 6.54 mmol) was added, and the mixture was stirred at room temperature for 24 hours. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to synthesize (R)-6-fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0099] Yellow solid (yield 47%); 1 1H NMR (400 MHz, CD3OD) δ 7.34 - 7.29 (m, 2H), 7.24 - 7.16 (m, 3H), 6.45 - 6.40 (m, 1H), 6.17 (dd, J = 11.3, 2.7 Hz, 1H), 4.29 - 4.23 (m, 1H), 3.88 - 3.82 (m, 2H), 3.68 - 3.60 (m, 2H), 3.14 - 3.08 (m, 1H), 3.06 - 2.99 (m, 1H), 2.91 - 2.85 (m, 1H), 2.81 - 2.73 (m, 1H), 2.19 - 2.10 (m, 1H), 1.74 - 1.66 (m, 1H); LC / MS ESI(+): 359.1 (M+1).

[0100] <Example 2>Synthesis of (R)-6-fluoro-4-(4-fluorophenyl)-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (R)-6-Fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (50 mg, 0.14 mmol) obtained in Example 1 was dissolved in methanol (1.0 mL), sodium triacetoxyborohydride (59 mg, 0.27 mmol) and formaldehyde (20.0 μL, 0.56 mmol) were added, and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction mixture to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize (R)-6-fluoro-4-(4-fluorophenyl)-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0101] Yellow oil (yield 73%); 1 1H NMR (400 MHz, CDCl3) δ 7.25 - 7.20 (m, 2H), 7.16 - 7.09 (m, 3H), 6.42 - 6.38 (m, 1H), 6.24 (dd, J = 11.5, 2.9 Hz, 1H), 5.55 (d, J = 6.7 Hz, 1H), 4.47 - 4.38 (m, 1H), 4.01 - 3.95 (m, 1H), 3.87 - 3.81 (m, 1H), 3.60 (t, J = 5.1 Hz, 2H), 2.91 - 2.82 (m, 1H), 2.71 - 2.69 (m, 1H), 2.60 - 2.56 (m, 1H), 2.41 - 2.30 (m, 4H), 2.28 - 2.21 (m, 1H), 1.66 - 1.57 (m, 1H); LC / MS ESI(+): 373.1 (M + 1).

[0102] <Example 3>Synthesis of (R)-6-Fluoro-4-(4-fluorophenyl)-N-(1-isopropylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide Although it was carried out in the same manner as in Example 2, (R)-6-fluoro-4-(4-fluorophenyl)-N-(1-isopropylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized using acetone instead of formaldehyde.

[0103] Yellow oil (yield 32%); 1 1H NMR (400 MHz, CDCl3) δ 7.25 - 7.20 (m, 2H), 7.16 - 7.09 (m, 3H), 6.43 - 6.39 (m, 1H), 6.25 (dd, J = 11.3, 2.7 Hz, 1H), 5.85 - 5.74 (m, 1H), 4.49 - 4.38 (m, 1H), 4.00 - 3.94 (m, 1H), 3.89 - 3.83 (m, 1H), 3.61 (t, J = 5.1 Hz, 2H), 3.05 - 2.95 (m, 1H), 2.86 - 2.73 (m, 2H), 2.54 - 2.26 (m, 3H), 1.74 - 1.63 (m, 1H), 1.13 (t, J = 6.5 Hz, 6H); LC / MS ESI(+): 401.1 (M + 1).

[0104] <Example 4>Synthesis of (R)-6-fluoro-4-(4-fluorophenyl)-N-(1-isobutylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide Although it was carried out in the same manner as in Example 2, (R)-6-fluoro-4-(4-fluorophenyl)-N-(1-isobutylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized using isobutyl aldehyde instead of acetone.

[0105] Yellow oil (yield 72%); 11H NMR (400 MHz, CDCl3) δ 7.25 - 7.20 (m, 2H), 7.15 - 7.09 (m, 3H), 6.41 - 6.37 (m, 1H), 6.25 (dd, J = 11.3, 2.7 Hz, 1H), 5.73 - 5.57 (m, 1H), 4.42 - 4.32 (m, 1H), 3.97 - 3.86 (m, 2H), 3.60 (t, J = 5.1 Hz, 2H), 2.92 - 2.80 (m, 1H), 2.67 - 2.56 (m, 1H), 2.53 - 2.42 (m, 1H), 2.29 - 2.14 (m, 4H), 1.76 - 1.58 (m, 2H), 0.90 (dd, J = 6.3, 2.7 Hz, 6H); LC / MS ESI(+): 414.8 (M + 1).

[0106] <Example 5>Synthesis of (R)-6-Fluoro-4-(4-fluorophenyl)-N-(1-(2,2,2-trifluoroacetyl)pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Dissolve (R)-6-Fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (50 mg, 0.14 mmol) obtained in Example 1 in dichloromethane (1.0 mL), add TEA (-30.0 μL, 0.21 mmol) and trifluoroacetic anhydride (30.0 μL, 0.21 mmol), and stir at 0 °C for 30 minutes. After neutralizing the reaction solution with saturated aqueous NaHCO3, extract with ethyl acetate. Wash the organic layer with brine, dry over MgSO4, filter, and then concentrate under reduced pressure. Purify the obtained residue by silica column chromatography using a dichloromethane / methanol mixture to synthesize (R)-6-Fluoro-4-(4-fluorophenyl)-N-(1-(2,2,2-trifluoroacetyl)pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide.

[0107] White solid (yield 45%); 11H NMR (400 MHz, CDCl3) δ 7.24 - 7.21 (m, 2H), 7.17 - 7.11 (m, 2H), 7.03 (dd, J = 8.6, 5.9 Hz, 1H), 6.43 - 6.37 (m, 1H), 6.26 (dd, J = 11.3, 2.7 Hz, 1H), 5.30 - 5.21 (m, 1H), 4.54 - 4.45 (m, 1H), 4.01 - 3.86 (m, 3H), 3.79 - 3.72 (m, 1H), 3.71 - 3.61 (m, 3H), 3.58 - 3.43 (m, 1H), 2.40 - 2.22 (m, 1H), 2.06 - 1.82 (m, 1H); LC / MS ESI(+): 454.9 (M+1).

[0108] <Example 6> Synthesis of (R)-N-(1-acetylpyrrolidin-3-yl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The (R)-6-fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (50 mg, 0.14 mmol) obtained in Example 1 was dissolved in THF (1.4 mL), and TEA (20.0 μL, 0.14 mmol) and acetyl chloride (10.0 μL, 0.15 mmol) were added, followed by stirring at room temperature for 1 hour and 30 minutes. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize (R)-N-(1-acetylpyrrolidin-3-yl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide.

[0109] Yellow solid (yield 50%); 11H NMR (400 MHz, CDCl3) δ 7.25 - 7.19 (m, 2H), 7.16 - 7.10 (m, 2H), 7.07 - 7.01 (m, 2H), 6.43 - 6.36 (m, 1H), 6.28 - 6.23 (m, 1H), 5.29 - 5.22 (m, 1H), 4.49 - 4.41 (m, 1H), 4.01 - 3.93 (m, 1H), 3.89 - 3.75 (m, 2H), 3.64 - 3.60 (m, 2H), 3.57 - 3.49 (m, 2H), 3.36 - 3.26 (m, 1H), 2.34 - 2.15 (m, 1H), 2.05 (d, J = 3.1 Hz, 3H), 2.01 - 1.74 (m, 1H); LC / MS ESI(+): 401.0 (M + 1).

[0110] <Example 7>Synthesis of (R)-6-Fluoro-4-(4-fluorophenyl)-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although carried out in the same manner as in Example 6, (R)-6-Fluoro-4-(4-fluorophenyl)-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide was synthesized using methanesulfonyl chloride instead of acetyl chloride.

[0111] Ivory solid (yield 49%); 1 1H NMR (400 MHz, CDCl3) δ 7.24 - 7.20 (m, 2H), 7.16 - 7.06 (m, 3H), 6.44 - 6.39 (m, 1H), 6.25 (dd, J = 11.3, 2.7 Hz, 1H), 5.37 (d, J = 7.0 Hz, 1H), 4.51 - 4.43 (m, 1H), 3.97 - 3.85 (m, 2H), 3.62 (t, J = 5.3 Hz, 2H), 3.57 - 3.49 (m, 2H), 3.37 - 3.30 (m, 2H), 2.86 (s, 3H), 2.33 - 2.23 (m, 1H), 1.98 - 1.87 (m, 1H); LC / MS ESI(+): 436.9 (M + 1).

[0112] [Reaction Scheme 3] [Chemical Formula]

[0113] <Production Example a-6> Production of tert-butyl (S)-3-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide)pyrrolidine-1-carboxylate Although carried out in the same manner as in Production Example a-5, tert-butyl (S)-3-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide)pyrrolidine-1-carboxylate was produced using (S)-(-)-1-Boc-3-aminopyrrolidine instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[0114] White solid (yield 71%); 1 H NMR (400 MHz, CDCl3) δ 7.25 - 7.20 (m, 2H), 7.17 - 7.10 (m, 2H), 7.08 - 7.02 (m, 1H), 6.44 - 6.35 (m, 1H), 6.26 (dd, J = 11.3, 2.7 Hz, 1H), 5.25 (d, J = 7.6 Hz, 1H), 4.48 - 4.35 (m, 1H), 4.02 - 3.81 (m, 2H), 3.70 - 3.59 (m, 3H), 3.49 - 3.35 (m, 2H), 3.23 - 3.12 (m, 1H), 2.25 - 2.12 (m, 1H), 1.89 - 1.72 (m, 1H), 1.46 (s, 9H).

[0115] <Example 8> Synthesis of (S)-6-fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide The Boc group of tert-butyl (S)-3-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide)pyrrolidine-1-carboxylate obtained in Production Example a-6 was deprotected with TFA to synthesize (S)-6-fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0116] White solid (yield 65%);1 1H NMR (400 MHz, CDCl3) δ 7.25 - 7.19 (m, 2H), 7.16 - 7.08 (m, 3H), 6.43 - 6.38 (m, 1H), 6.25 (dd, J = 11.3, 2.7 Hz, 1H), 5.35 (d, J = 6.7 Hz, 1H), 4.36 - 4.29 (m, 1H), 3.97 - 3.86 (m, 2H), 3.63 - 3.59 (m, 2H), 3.22 - 3.17 (m, 1H), 3.07 - 3.01 (m, 1H), 2.97 - 2.90 (m, 1H), 2.82 - 2.78 (m, 1H), 2.22 - 2.13 (m, 2H), 1.63 - 1.55 (m, 1H); LC / MS ESI(+): 359.0 (M + 1).

[0117] <Example 9> Synthesis of (S)-6-Fluoro-4-(4-fluorophenyl)-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Dissolve (S)-6-Fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (1.0 equivalent) obtained in Example 8 in dichloromethane (0.3 M), add sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents), and stir at room temperature for 1 hour. After adding water to the reaction solution to terminate the reaction, extract with dichloromethane. Wash the organic layer with brine, dry over MgSO4, filter, and concentrate under reduced pressure. Purify the obtained residue by silica column chromatography using a dichloromethane / methanol mixture to synthesize (S)-6-Fluoro-4-(4-fluorophenyl)-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide.

[0118] Yellow oil (yield 32%); 11H NMR (400 MHz, CDCl3) δ 7.25 - 7.20 (m, 2H), 7.16 - 7.09 (m, 3H), 6.42 - 6.38 (m, 1H), 6.24 (dd, J = 11.3, 2.7 Hz, 1H), 5.48 (d, J = 7.4 Hz, 1H), 4.42 - 4.35 (m, 1H), 4.02 - 3.96 (m, 1H), 3.87 - 3.81 (m, 1H), 3.62 - 3.59 (m, 2H), 2.85 - 2.80 (m, 1H), 2.66 - 2.61 (m, 1H), 2.58 - 2.54 (m, 1H), 2.39 - 2.31 (m, 4H), 2.25 - 2.19 (m, 1H), 1.63 - 1.56 (m, 1H); LC / MS ESI(+): 373.0 (M + 1).

[0119] <Example 10>Synthesis of (S)-6-Fluoro-4-(4-fluorophenyl)-N-(1-isopropylpyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although carried out in the same manner as in Example 2, (S)-6-Fluoro-4-(4-fluorophenyl)-N-(1-isopropylpyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide was synthesized using acetone instead of formaldehyde.

[0120] Yellow oil (yield 64%); 1 1H NMR (400 MHz, CDCl3) δ 7.25 - 7.20 (m, 2H), 7.16 - 7.08 (m, 3H), 6.42 - 6.37 (m, 1H), 6.25 (dd, J = 11.3, 2.7 Hz, 1H), 5.48 (d, J = 7.4 Hz, 1H), 4.41 - 4.34 (m, 1H), 4.00 - 3.94 (m, 1H), 3.89 - 3.83 (m, 1H), 3.62 - 3.59 (m, 2H), 2.91 - 2.84 (m, 1H), 2.73 - 2.64 (m, 2H), 2.37 - 2.26 (m, 3H), 1.62 - 1.54 (m, 1H), 1.08 (t, J = 6.5 Hz, 6H); LC / MS ESI(+): 401.0 (M + 1).

[0121] [Reaction Scheme 4] [Chemical Formula]

[0122] <Production Example a-7>Production of tert-butyl (S)-(1-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)carbamate Although carried out in the same manner as in Production Example a-5, tert-butyl (S)-(1-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)carbamate was produced using (S)-(-)-3-(Boc-amino)pyrrolidine instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[0123] White solid (yield 93%); 1 H NMR (400 MHz, CD3OD) δ 7.36 - 7.27 (m, 2H), 7.22 - 7.13 (m, 2H), 6.93 - 6.85 (m, 1H), 6.44 - 6.34 (m, 1H), 6.20 - 6.12 (m, 1H), 4.06 - 3.99 (m, 1H), 3.86 - 3.67 (m, 4H), 3.57 - 3.37 (m, 3H), 3.25 - 3.16 (m, 1H), 2.14 - 1.99 (m, 1H), 1.91 - 1.78 (m, 1H), 1.42 (s, 9H).

[0124] <Example 11>Synthesis of (S)-(3-aminopyrrolidin-1-yl)(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone The Boc group of tert-butyl (S)-(1-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)carbamate obtained in Production Example a-7 was deprotected with TFA to synthesize (S)-(3-aminopyrrolidin-1-yl)(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone.

[0125] White solid (yield 49%); 11H NMR (400 MHz, CDCl3) δ 7.25 - 7.17 (m, 2H), 7.14 - 7.06 (m, 2H), 6.92 - 6.84 (m, 1H), 6.43 - 6.33 (m, 1H), 6.30 - 6.22 (m, 1H), 3.93 - 3.76 (m, 2H), 3.76 - 3.68 (m, 2H), 3.61 - 3.47 (m, 3H), 3.47 - 3.36 (m, 2H), 3.07 - 3.03 (m, 1H), 2.11 - 1.99 (m, 1H), 1.72 - 1.59 (m, 1H); LC / MS ESI(+): 358.6 (M+1).

[0126] <Production Example a-8> Production of tert-butyl (S)-(1-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)(methyl)carbamate Dissolve tert-butyl (S)-(1-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)carbamate (60.0 mg, 0.13 mmol) obtained in Production Example a-7 in THF (0.5 mL), add NaH (6.3 mg, 0.26 mmol) and iodomethane (22.2 mg, 0.16 mmol), and stir at room temperature for 5 hours. After adding water to the reaction solution to terminate the reaction, extract with dichloromethane. Wash the organic layer with brine, dry over MgSO4, filter, and then concentrate under reduced pressure. Purify the obtained residue by silica column chromatography using an n-hexane / ethyl acetate mixture to produce tert-butyl (S)-(1-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)(methyl)carbamate.

[0127] White solid (yield 81%); 11H NMR (400 MHz, CDCl3) δ 7.28 - 7.18 (m, 2H), 7.15 - 7.06 (m, 2H), 6.92 - 6.84 (m, 1H), 6.42 - 6.33 (m, 1H), 6.30 - 6.22 (m, 1H), 4.10 - 4.03 (m, 1H), 3.78 - 3.66 (m, 2H), 3.66 - 3.57 (m, 1H), 3.53 - 3.34 (m, 3H), 3.28 - 3.16 (m, 1H), 2.76 (s, 3H), 2.04 - 1.86 (m, 2H), 1.45 (s, 9H).

[0128] <Example 12> Synthesis of (S)-(6-Fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-methylamino)pyrrolidin-1-yl)methanone The Boc group of tert-butyl (S)-(1-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)(methyl)carbamate obtained in Production Example a-8 was deprotected with TFA to synthesize (S)-(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-methylamino)pyrrolidin-1-yl)methanone.

[0129] Ivory solid (yield 80%); 1 1H NMR (400 MHz, CD3OD) δ 7.35 - 7.27 (m, 2H), 7.23 - 7.14 (m, 2H), 6.98 - 6.90 (m, 1H), 6.44 - 6.35 (m, 1H), 6.22 - 6.14 (m, 1H), 3.94 - 3.80 (m, 1H), 3.78 - 3.66 (m, 5H), 3.59 - 3.41 (m, 3H), 2.68 (s, 3H), 2.41 - 2.25 (m, 1H), 2.08 - 1.93 (m, 1H); LC / MS ESI(+): 372.7 (M+1).

[0130] [Reaction Scheme 5] [Chemical Formula]

[0131] <Example 13>Synthesis of (S)-(6-Fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-(isobutylamino)pyrrolidin-1-yl)methanone (S)-(3-Aminopyrrolidin-1-yl)(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone (1.0 equivalent) obtained in Example 11 was dissolved in dichloromethane (0.3 M), and sodium triacetoxyborohydride (1.5 equivalents) and isobutyraldehyde (2.0 equivalents) were added, followed by stirring at room temperature for 1 hour. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize (S)-(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-(isobutylamino)pyrrolidin-1-yl)methanone.

[0132] Colorless oil (yield 50%); 1 1H NMR (400 MHz, CDCl3) δ 7.25 - 7.17 (m, 2H), 7.15 - 7.06 (m, 2H), 6.91 - 6.83 (m, 1H), 6.41 - 6.32 (m, 1H), 6.30 - 6.22 (m, 1H), 3.92 - 3.82 (m, 1H), 3.82 - 3.75 (m, 1H), 3.74 - 3.67 (m, 2H), 3.58 - 3.44 (m, 2H), 3.44 - 3.33 (m, 1H), 3.33 - 3.24 (m, 1H), 3.17 - 3.04 (m, 1H), 2.47 - 2.33 (m, 2H), 2.10 - 1.98 (m, 1H), 1.76 - 1.62 (m, 2H), 1.25 (s, 1H), 0.90 (d, J = 6.7 Hz, 6H); LC / MS ESI(+): 414.7 (M + 1).

[0133] <Example 14>Synthesis of (S)-(6-Fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-(isopropylamino)pyrrolidin-1-yl)methanone Although it was carried out in the same manner as in Example 13, (S)-(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-(isopropylamino)pyrrolidin-1-yl)methanone was synthesized using acetone instead of isobutyl aldehyde.

[0134] Light yellow oil (yield 46%); 1 1H NMR (400 MHz, CDCl3) δ 7.24 - 7.17 (m, 2H), 7.15 - 7.05 (m, 2H), 6.91 - 6.83 (m, 1H), 6.42 - 6.32 (m, 1H), 6.29 - 6.21 (m, 1H), 4.00 - 3.88 (m, 1H), 3.77 - 3.65 (m, 3H), 3.61 - 3.46 (m, 2H), 3.46 - 3.34 (m, 2H), 3.10 - 3.01 (m, 1H), 2.93 - 2.81 (m, 1H), 2.17 - 2.06 (m, 1H), 1.74 - 1.60 (m, 1H), 1.25 (s, 1H), 1.06 (dd, J = 8.3, 6.2 Hz, 6H); LC / MS ESI(+): 400.7 (M + 1).

[0135] <Example 15>Synthesis of (S)-N-(1-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)acetamide The (S)-(3-aminopyrrolidin-1-yl)(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone (1.0 equivalent) obtained in Example 11 was dissolved in THF (0.3 M), and TEA (2.5 equivalents) and acetyl chloride (1.8 equivalents) were added, followed by stirring at room temperature for 4 hours and 30 minutes. After adding water to the reaction solution to terminate the reaction, it was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize (S)-N-(1-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)acetamide.

[0136] White solid (yield 68%); 1 H NMR (400 MHz, CD3OD) δ 7.25 - 7.06 (m, 4H), 6.91 - 6.83 (m, 1H), 6.41 - 6.32 (m, 1H), 6.28 - 6.20 (m, 1H), 5.48 (d, J = 7.2 Hz, 1H), 4.49 - 4.37 (m, 1H), 3.94 - 3.84 (m, 1H), 3.84 - 3.75 (m, 1H), 3.74 - 3.66 (m, 2H), 3.61 - 3.52 (m, 1H), 3.52 - 3.41 (m, 2H), 3.13 (dd, J = 11.3, 5.2 Hz, 1H), 2.23 - 2.11 (m, 1H), 1.97 (s, 3H), 1.87 - 1.74 (m, 1H); LC / MS ESI(+): 400.7 (M + 1).

[0137] <Example 16>Synthesis of (S)-N-(1-(6-Fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)methanesulfonamide Although carried out in the same manner as in Example 15, (S)-N-(1-(6-Fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)methanesulfonamide was synthesized using methanesulfonyl chloride instead of acetyl chloride.

[0138] White solid (yield 66%); 1 H NMR (400 MHz, CDCl3) δ 7.25 - 7.18 (m, 2H), 7.16 - 7.07 (m, 2H), 6.91 - 6.83 (m, 1H), 6.42 - 6.33 (m, 1H), 6.29 - 6.21 (m, 1H), 4.40 (d, J = 7.3 Hz, 1H), 4.09 - 3.98 (m, 1H), 3.93 - 3.77 (m, 2H), 3.76 - 3.69 (m, 2H), 3.65 - 3.56 (m, 1H), 3.56 - 3.36 (m, 2H), 3.35 - 3.26 (m, 1H), 2.99 (s, 3H), 2.27 - 2.15 (m, 1H), 1.97 - 1.84 (m, 1H); LC / MS ESI(+): 436.6 (M + 1).

[0139] [Reaction Scheme 6] [Chem.]

[0140] <Production Example a-9> Production of tert-butyl (R)-3-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate Although carried out in the same manner as in Production Example a-5, tert-butyl (R)-3-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate was produced using (R)-1-Boc-3-(aminomethyl)pyrrolidine instead of (R)-(+)-1-Boc-3-aminopyrrolidine. White solid (yield 90%); 1 1H NMR (400 MHz, CDCl3) δ 7.25 - 7.03 (m, 5H), 6.47 - 6.34 (m, 1H), 6.30 - 6.19 (m, 1H), 5.40 - 5.28 (m, 1H), 3.98 - 3.83 (m, 2H), 3.66 - 3.57 (m, 2H), 3.56 - 3.35 (m, 3H), 3.34 - 3.23 (m, 2H), 3.10 - 2.94 (m, 1H), 2.53 - 2.30 (m, 1H), 2.06 - 1.87 (m, 1H), 1.71 - 1.52 (m, 1H), 1.44 (s, 9H).

[0141] <Example 17> Synthesis of (S)-6-fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide The Boc group of tert-butyl (R)-3-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate obtained in Production Example a-9 was deprotected with TFA to synthesize (S)-6-fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide. White solid (yield 46%); 1 1H NMR (400 MHz, CDCl3) δ 7.25 - 5 - 7.05 (m, 5H), 6.47 - 6.36 (m, 1H), 6.28 - 6.20 (m, 1H), 5.74 - 5.66 (m, 1H), 4.03 - 3.82 (m, 2H), 3.68 - 3.56 (m, 2H), 3.47 - 3.24 (m, 5H), 3.22 - 3.08 (m, 1H), 2.75 - 2.60 (m, 1H), 2.29 - 1.99 (m, 2H), 1.86 - 1.71 (m, 1H); LC / MS ESI(+): 373.2 (M+1).

[0142] <Example 18>Synthesis of (R)-6-Fluoro-4-(4-fluorophenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The (S)-6-Fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (1.0 equivalent) obtained in Example 17 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to synthesize (R)-6-Fluoro-4-(4-fluorophenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. White solid (yield 40%); 11H NMR (400 MHz, CDCl3) δ 7.25 - 7.06 (m, 5H), 6.47 - 6.37 (m, 1H), 6.29 - 6.21 (m, 1H), 5.91 (brs, 1H), 3.99 - 3.83 (m, 2H), 3.69 - 3.52 (m, 2H), 3.42 - 3.26 (m, 2H), 3.06 - 2.83 (m, 2H), 2.82 - 2.58 (m, 3H), 2.50 (s, 3H), 2.23 - 2.06 (m, 1H), 1.80 - 1.63 (m, 1H); LC / MS ESI(+): 387.2 (M + 1).

[0143] <Example 19> Synthesis of (R)-6-Fluoro-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although carried out in the same manner as in Example 18, (R)-6-Fluoro-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide was synthesized using acetone instead of formaldehyde. Yellow solid (yield 64%); 1 1H NMR (400 MHz, CDCl3) δ 7.255 - 7.07 (m, 5H), 6.46 - 6.37 (m, 1H), 6.31 - 6.19 (m, 1H), 5.83 (brs, 1H), 4.03 - 3.92 (m, 1H), 3.90 - 3.79 (m, 1H), 3.70 - 3.53 (m, 2H), 3.42 - 3.27 (m, 2H), 3.15 - 2.81 (m, 3H), 2.81 - 2.48 (m, 3H), 2.19 - 2.01 (m, 1H), 1.78 - 1.62 (m, 1H), 1.24 - 1.11 (m, 6H); LC / MS ESI(+): 415.2 (M + 1).

[0144] <Example 20> Synthesis of (R)-6-Fluoro-4-(4-fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although it was carried out in the same manner as in Example 18, (R)-6-fluoro-4-(4-fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide was synthesized using isobutylaldehyde instead of formaldehyde. White solid (yield 64%); 1 1H NMR (400 MHz, CD3OD) δ 7.37 - 7.14 (m, 5H), 6.50 - 6.40 (m, 1H), 6.26 - 6.16 (m, 1H), 3.96 - 3.77 (m, 2H), 3.70 - 3.59 (m, 2H), 3.28 (dd, J = 6.8, 1.7 Hz, 2H), 3.20 - 2.96 (m, 3H), 2.89 - 2.65 (m, 3H), 2.64 - 2.52 (m, 1H), 2.19 - 2.04 (m, 1H), 1.99 - 1.84 (m, 1H), 1.80 - 1.66 (m, 1H), 0.97 (dd, J = 6.6, 4.6 Hz, 6H); LC / MS ESI(+): 429.2 (M+1).

[0145] [Reaction Scheme 7]

Chemical Structure

[0146] <Production Example a-10> Production of tert-butyl (R)-2-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide)methyl)pyrrolidine-1-carboxylate Although it was carried out in the same manner as in Production Example a-5, tert-butyl (R)-2-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide)methyl)pyrrolidine-1-carboxylate was produced using (R)-1-Boc-2-(aminomethyl)pyrrolidine instead of (R)-(+)-1-Boc-3-aminopyrrolidine. White solid (yield 90%); 11H NMR (400 MHz, CD3OD) δ 7.37 - 7.10 (m, 5H), 6.51 - 6.37 (m, 1H), 6.25 - 6.11 (m, 1H), 4.02 - 3.91 (m, 1H), 3.90 - 3.77 (m, 2H), 3.69 - 3.59 (m, 2H), 3.51 - 3.33 (m, 3H), 3.29 - 3.14 (m, 1H), 2.01 - 1.71 (m, 4H), 1.55 - 1.34 (m, 9H).

[0147] <Example 21> Synthesis of (R)-6-Fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The Boc group of tert-butyl (R)-2-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide)methyl)pyrrolidine-1-carboxylate obtained in Production Example a-10 was deprotected with TFA to synthesize (R)-6-fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Pale yellow solid (yield 53%); 1 1H NMR (400 MHz, CD3OD) δ 7.38 - 7.13 (m, 5H), 6.53 - 6.37 (m, 1H), 6.26 - 6.14 (m, 1H), 3.98 - 3.82 (m, 2H), 3.78 - 3.70 (m, 1H), 3.70 - 3.64 (m, 2H), 3.58 - 3.41 (m, 2H), 3.39 - 3.33 (m, 1H), 3.29 - 3.23 (m, 1H), 2.23 - 1.93 (m, 3H), 1.87 - 1.72 (m, 1H); LC / MS ESI(+): 373.2 (M+1).

[0148] <Example 22> Synthesis of (R)-6-Fluoro-4-(4-fluorophenyl)-N-((1-methylpyrrolidin-2-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (R)-6-Fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (1.0 eq) obtained in Example 21 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 eq) and formaldehyde (2.0 eq) were added, and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction mixture to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to synthesize (R)-6-fluoro-4-(4-fluorophenyl)-N-((1-methylpyrrolidin-2-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Light yellow solid (yield 23%); 1 1H NMR (400 MHz, CD3OD) δ 7.38 - 7.16 (m, 5H), 6.46 (ddd, J = 8.8, 8.0, 2.8 Hz, 1H), 6.20 (dd, J = 11.4, 2.8 Hz, 1H), 3.94 - 3.85 (m, 2H), 3.72 - 3.64 (m, 2H), 3.50 - 3.42 (m, 2H), 3.41 - 3.34 (m, 1H), 2.99 (brs, 1H), 2.77 - 2.59 (m, 4H), 2.17 - 2.05 (m, 1H), 2.02 - 1.89 (m, 1H), 1.88 - 1.69 (m, 2H); LC / MS ESI(+): 387.2 (M+1).

[0149] <Example 23>Synthesis of (R)-6-Fluoro-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-2-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although carried out in the same manner as in Example 22, (R)-6-fluoro-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-2-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide was synthesized using acetone instead of formaldehyde. White solid (yield 51%); 11H NMR (400 MHz, CD3OD) δ 7.37 - 7.16 (m, 5H), 6.47 (ddd, J = 8.8, 8.0, 2.8 Hz, 1H), 6.21 (dd, J = 11.4, 2.8 Hz, 1H), 4.04 - 3.79 (m, 2H), 3.73 - 3.63 (m, 2H), 3.62 - 3.36 (m, 4H), 3.31 - 3.19 (m, 1H), 3.01 (brs, 1H), 2.20 - 1.77 (m, 4H), 1.39 - 1.18 (m, 6H); LC / MS ESI(+): 415.2 (M+1).

[0150] <Example 24>Synthesis of (R)-6-Fluoro-4-(4-fluorophenyl)-N-((1-isobutylpyrrolidin-2-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although carried out in the same manner as in Example 22, (R)-6-Fluoro-4-(4-fluorophenyl)-N-((1-isobutylpyrrolidin-2-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide was synthesized using isobutylaldehyde instead of formaldehyde. Pale yellow oil (yield 49%); 1 1H NMR (400 MHz, CD3OD) δ 7.35 - 7.14 (m, 5H), 6.48 - 6.39 (m, 1H), 6.23 - 6.15 (m, 1H), 4.10 - 4.00 (m, 1H), 3.77 - 3.66 (m, 1H), 3.66 - 3.56 (m, 2H), 3.46 - 3.38 (m, 1H), 3.29 - 3.02 (m, 2H), 2.66 (brs, 1H), 2.38 (brs, 1H), 2.29 - 2.06 (m, 2H), 2.03 - 1.88 (m, 1H), 1.86 - 1.53 (m, 4H), 0.98 - 0.83 (m, 3H), 0.82 - 0.65 (m, 3H); LC / MS ESI(+): 429.2 (M+1).

[0151] [Reaction Scheme 8] [Chemical Formula]

[0152] <Production Example a-11>Production of tert-butyl (S)-3-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate Although carried out in the same manner as in Production Example a-5, tert-butyl (S)-3-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate was produced using (S)-1-Boc-3-(aminomethyl)pyrrolidine instead of (R)-(+)-1-Boc-3-aminopyrrolidine. White solid (yield 91%); 1 1H NMR (400 MHz, CDCl3) δ 7.25 - 57.02 (m, 5H), 6.45 - 6.36 (m, 1H), 6.29 - 6.21 (m, 1H), 5.41 - 5.26 (m, 1H), 3.98 - 3.84 (m, 2H), 3.60 (t, J = 5.2 Hz, 2H), 3.55 - 3.35 (m, 3H), 3.35 - 3.25 (m, 2H), 3.09 - 2.93 (m, 1H), 2.49 - 2.37 (m, 1H), 2.02 - 1.92 (m, 1H), 1.68 - 1.54 (m, 1H), 1.45 (s, 9H).

[0153] <Production Example a-12>Production of (R)-6-fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide The Boc group of tert-butyl (S)-3-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate obtained in Production Example a-11 was deprotected with TFA to produce (R)-6-fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide. Light yellow solid (yield 28%); 11H NMR (400 MHz, CDCl3) δ 7.25 - 7.04 (m, 5H), 6.45 - 6.36 (m, 1H), 6.28 - 6.20 (m, 1H), 5.67 (t, J = 6.0 Hz, 1H), 4.01 - 3.82 (m, 2H), 3.67 - 3.53 (m, 2H), 3.47 - 3.24 (m, 6H), 3.20 - 3.08 (m, 1H), 2.73 - 2.61 (m, 1H), 2.20 - 2.07 (m, 1H), 1.85 - 1.72 (m, 1H); LC / MS ESI(+): 373.2 (M + 1).

[0154] <Example 25> Synthesis of (S)-6-Fluoro-4-(4-fluorophenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The (R)-6-fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (1.0 equivalent) obtained in Production Example a-12 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to synthesize (S)-6-fluoro-4-(4-fluorophenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Yellow solid (yield 33%); 11H NMR (400 MHz, CD3OD) δ 7.38 - 7.15 (m, 5H), 6.51 - 6.39 (m, 1H), 6.20 (dd, J = 11.4, 2.8 Hz, 1H), 3.96 - 3.80 (m, 2H), 3.74 - 3.57 (m, 2H), 3.42 - 3.33 (m, 1H), 3.31 - 3.21 (m, 3H), 3.09 - 2.99 (m, 1H), 2.84 (s, 3H), 2.78 - 2.62 (m, 1H), 2.30 - 2.13 (m, 1H), 1.89 - 1.76 (m, 1H), 1.37 - 1.31 (m, 1H); LC / MS ESI(+): 387.2 (M + 1).

[0155] <Example 26>Synthesis of (S)-6-Fluoro-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although carried out in the same manner as in Example 25 above, (S)-6-Fluoro-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide was synthesized using acetone instead of formaldehyde. White solid (yield 41%); 1 1H NMR (400 MHz, CD3OD) δ 7.38 - 7.14 (m, 5H), 6.51 - 6.40 (m, 1H), 6.27 - 6.15 (m, 1H), 3.94 - 3.81 (m, 2H), 3.72 - 3.60 (m, 2H), 3.57 - 3.46 (m, 1H), 3.46 - 3.33 (m, 4H), 3.14 (brs, 1H), 2.76 - 2.60 (m, 1H), 2.27 - 2.14 (m, 1H), 1.90 - 1.76 (m, 1H), 1.38 (d, J = 6.5 Hz, 6H), 1.35 - 1.25 (m, 1H); LC / MS ESI(+): 415.2 (M + 1).

[0156] <Example 27>Synthesis of (S)-6-Fluoro-4-(4-fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although carried out in the same manner as in Example 25, (S)-6-fluoro-4-(4-fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized using isobutylaldehyde instead of formaldehyde. White solid (yield 54%); 1 1H NMR (400 MHz, CD3OD) δ 7.38 - 7.14 (m, 5H), 6.50 - 6.41 (m, 1H), 6.20 (dd, J = 11.4, 2.8 Hz, 1H), 3.97 - 3.77 (m, 2H), 3.74 - 3.56 (m, 2H), 3.30 - 3.24 (m, 2H), 3.18 (brs, 2H), 3.04 - 2.87 (m, 1H), 2.86 - 2.72 (m, 2H), 2.71 - 2.57 (m, 1H), 2.22 - 2.08 (m, 1H), 2.05 - 1.88 (m, 1H), 1.85 - 1.71 (m, 1H), 1.39 - 1.22 (m, 1H), 1.00 (dd, J = 6.6, 2.6 Hz, 6H); LC / MS ESI(+): 429.2 (M + 1).

[0157] [Reaction Scheme 9]

Chemical Formula

[0158] [Example 28] Synthesis of N-(cyclopropylmethyl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide Although carried out in the same manner as in Production Example a-5, N-(cyclopropylmethyl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized using cyclopropylmethylamine instead of (R)-(+)-1-Boc-3-aminopyrrolidine. White solid (yield 57%); 11H NMR (400 MHz, CDCl3) δ 7.25 - 7.08 (m, 5H), 6.49 - 6.35 (m, 1H), 6.26 (dd, J = 11.4, 2.8 Hz, 1H), 5.37 - 5.30 (m, 1H), 3.96 - 3.89 (m, 2H), 3.65 - 3.58 (m, 2H), 3.21 - 3.10 (m, 2H), 1.06 - 0.91 (m, 1H), 0.56 - 0.44 (m, 2H), 0.27 - 0.15 (m, 2H); LC / MS ESI(+): 344.2 (M+1).

[0159] [Reaction Scheme 10] [Chemical Formula]

[0160] [Production Example a-13] Production of tert-Butyl 4-(6-Fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)piperidine-1-carboxylate Although carried out in the same manner as in Production Example a-5, tert-Butyl 4-(6-Fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)piperidine-1-carboxylate was produced using 1-Boc-4-aminopiperidine instead of (R)-(+)-1-Boc-3-aminopyrrolidine. White solid (yield 73%); 1 1H NMR (400 MHz, CDCl3) δ 7.24 - 7.20 (m, 2H), 7.16 - 7.09 (m, 2H), 7.07 (dd, J = 8.6, 5.9 Hz, 1H), 6.40 (d, J = 2.7 Hz, 1H), 6.26 (dd, J = 11.3, 2.7 Hz, 1H), 5.11 (d, J = 7.8 Hz, 1H), 4.08 - 3.96 (m, 2H), 3.61 (t, J = 5.1 Hz, 2H), 2.96 - 2.84 (m, 2H), 1.99 - 1.91 (m, 2H), 1.45 (s, 9H), 1.35 - 1.26 (m, 2H).

[0161] <Example 29>Synthesis of 6-Fluoro-4-(4-fluorophenyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The Boc group of tert-butyl 4-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide)piperidine-1-carboxylate obtained in Production Example a-13 was deprotected with TFA to synthesize 6-fluoro-4-(4-fluorophenyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. White solid (yield 90%); 1 1H NMR (400 MHz, CDCl3) δ 7.25 - 7.18 (m, 2H), 7.16 - 7.08 (m, 3H), 6.43 - 6.38 (m, 1H), 6.26 (dd, J = 11.3, 2.7 Hz, 1H), 5.14 (d, J = 7.8 Hz, 1H), 3.92 (t, J = 5.1 Hz, 2H), 3.87 - 3.77 (m, 1H), 3.62 (t, J = 5.1 Hz, 2H), 3.09 - 3.04 (m, 2H), 2.75 - 2.69 (m, 2H), 2.01 - 1.91 (m, 3H), 1.36 - 1.27 (m, 2H); LC / MS ESI(+): 373.0 (M+1).

[0162] <Example 30>Synthesis of 6-Fluoro-4-(4-fluorophenyl)-N-(1-methylpiperidin-4-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (6-Fluoro-4-(4-fluorophenyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (1.0 equivalent) obtained in Example 29 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to synthesize 6-fluoro-4-(4-fluorophenyl)-N-(1-methylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.) White solid (yield 48%); 1 1H NMR (400 MHz, CDCl3) δ 7.24 - 7.21 (m, 2H), 7.15 - 7.06 (m, 3H), 6.43 - 6.38 (m, 1H), 6.26 (dd, J = 11.3, 2.7 Hz, 1H), 5.11 (d, J = 7.4 Hz, 1H), 3.91 (t, J = 5.1 Hz, 1H), 3.80 - 3.72 (m, 1H), 3.61 (t, J = 5.1 Hz, 1H), 2.90 - 2.77 (m, 2H), 2.33 (s, 3H), 2.26 - 2.14 (m, 2H), 2.05 - 1.95 (m, 2H), 1.59 - 1.48 (m, 2H); LC / MS ESI(+): 387.0 (M+1).

[0163] (Example 31) Synthesis of 6-Fluoro-4-(4-fluorophenyl)-N-(1-isopropylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide Although carried out in the same manner as in Example 30, 6-Fluoro-4-(4-fluorophenyl)-N-(1-isopropylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized using acetone instead of formaldehyde. White solid (yield 45%); 11H NMR (400 MHz, CDCl3) δ 7.24 - 7.21 (m, 2H), 7.16 - 7.06 (m, 3H), 6.40 - 6.35 (m, 1H), 6.26 (dd, J = 11.3, 2.7 Hz, 1H), 5.15 (d, J = 7.8 Hz, 1H), 3.91 (t, J = 5.1 Hz, 2H), 3.81 - 3.70 (m, 1H), 3.60 (t, J = 5.1 Hz, 2H), 2.97 - 2.83 (m, 3H), 2.41 - 2.32 (m, 2H), 2.05 - 2.00 (m, 2H), 1.62 - 1.45 (m, 2H), 1.09 (d, J = 6.7 Hz, 6H); LC / MS ESI(+): 415.0 (M+1).

[0164] <Example 32>Synthesis of 6-Fluoro-4-(4-fluorophenyl)-N-(1-isobutylpiperidin-4-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although carried out in the same manner as in Example 30, 6-Fluoro-4-(4-fluorophenyl)-N-(1-isobutylpiperidin-4-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide was synthesized using isobutylaldehyde instead of formaldehyde. White solid (yield 40%); 1 1H-NMR (400 MHz, CDCl3) δ 7.24 - 7.21 (m, 2H), 7.16 - 7.06 (m, 3H), 6.43 - 6.38 (m, 1H), 6.26 (dd, J = 11.3, 2.7 Hz, 1H), 5.21 (d, J = 7.8 Hz, 1H), 3.91 (t, J = 5.1 Hz, 2H), 3.85 - 3.75 (m, 1H), 3.61 (t, J = 5.1 Hz, 2H), 3.09 - 2.96 (m, 1H), 2.35 - 2.20 (m, 4H), 2.07 - 1.95 (m, 5H), 1.94 - 1.81 (m, 1H), 0.94 (d, J = 6.7 Hz, 6H); LC / MS ESI(+): 428.9 (M+1).

[0165] [Reaction Scheme 11]

Chemical Structure

[0166] <Production Example a-14>Production of tert-butyl 4-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate Although carried out in the same manner as in Production Example a-5, tert-butyl 4-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate was produced using 1-Boc-4-(aminomethyl)piperidine instead of (R)-(+)-1-Boc-3-aminopyrrolidine. White solid (yield 95%); 1 H NMR (400 MHz, CD3OD) δ 7.37 - 7.25 (m, 2H), 7.24 - 7.13 (m, 3H), 6.45 (ddd, J = 8.9, 8.0, 2.8 Hz, 1H), 6.20 (dd, J = 11.4, 2.8 Hz, 1H), 4.17 - 3.99 (m, 2H), 3.94 - 3.81 (m, 2H), 3.71 - 3.60 (m, 2H), 3.12 (d, J = 6.6 Hz, 2H), 2.75 (brs, 2H), 1.83 - 1.63 (m, 3H), 1.46 (s, 9H), 1.21 - 1.01 (m, 2H).

[0167] <Example 33>Synthesis of 6-fluoro-4-(4-fluorophenyl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide The Boc group of tert-butyl 4-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate obtained in Production Example a-14 was deprotected with TFA to synthesize 6-fluoro-4-(4-fluorophenyl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide. White solid (yield 80%); 11H NMR (400 MHz, CD3OD) δ 7.37 - 7.27 (m, 2H), 7.25 - 7.15 (m, 3H), 6.45 (ddd, J = 8.8, 8.0, 2.8 Hz, 1H), 6.20 (dd, J = 11.4, 2.8 Hz, 1H), 3.86 (dd, J = 5.8, 4.5 Hz, 2H), 3.64 (dd, J = 5.8, 4.5 Hz, 2H), 3.17 - 3.09 (m, 3H), 3.09 - 3.01 (m, 1H), 2.67 - 2.55 (m, 2H), 1.78 - 1.62 (m, 3H), 1.27 - 1.12 (m, 2H); LC / MS ESI(+): 387.1 (M + 1).

[0168] <Example 34>Synthesis of 6-Fluoro-4-(4-fluorophenyl)-N-((1-methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The 6-fluoro-4-(4-fluorophenyl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (1.0 equivalent) obtained in Example 33 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction solution to terminate the reaction, it was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to synthesize 6-fluoro-4-(4-fluorophenyl)-N-((1-methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. White solid (yield 68%); 11H NMR (400 MHz, CD3OD) δ 7.37 - 7.27 (m, 2H), 7.25 - 7.15 (m, 3H), 6.50 - 6.41 (m, 1H), 6.24 - 6.16 (m, 1H), 3.86 (dd, J = 5.8, 4.5 Hz, 2H), 3.64 (dd, J = 5.8, 4.5 Hz, 2H), 3.14 (d, J = 6.7 Hz, 2H), 3.09 (d, J = 11.7 Hz, 2H), 2.46 (s, 3H), 2.39 - 2.28 (m, 2H), 1.87 - 1.76 (m, 2H), 1.74 - 1.58 (m, 1H), 1.46 - 1.26 (m, 2H); LC / MS ESI(+): 401.2 (M + 1).

[0169] <Example 35> Synthesis of 6-Fluoro-4-(4-fluorophenyl)-N-((1-isobutylpiperidin-4-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although carried out in the same manner as in Example 34, 6-Fluoro-4-(4-fluorophenyl)-N-((1-isobutylpiperidin-4-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide was synthesized using isobutylaldehyde instead of formaldehyde. White solid (yield 46%); 1 1H NMR (400 MHz, CDCl3) δ 7.26 - 77.07 (m, 5H), 6.47 - 6.38 (m, 1H), 6.29 - 6.21 (m, 1H), 5.45 - 5.32 (m, 1H), 3.94 - 3.87 (m, 2H), 3.64 - 3.57 (m, 2H), 3.38 - 2.93 (m, 3H), 2.78 - 2.19 (m, 3H), 2.17 - 1.88 (m, 2H), 1.87 - 1.37 (m, 6H), 1.15 - 0.89 (m, 6H); LC / MS ESI(+): 443.2 (M + 1).

[0170] <Example 36> Synthesis of 6-Fluoro-4-(4-fluorophenyl)-N-((1-isopropylpiperidin-4-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although carried out in the same manner as in Example 34, 6-fluoro-4-(4-fluorophenyl)-N-((1-isopropylpiperidin-4-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide was synthesized using acetone instead of formaldehyde. White solid (yield 67%); 1 1H NMR (400 MHz, CD3OD) δ 7.37 - 7.15 (m, 5H), 6.50 - 6.41 (m, 1H), 6.25 - 6.17 (m, 1H), 3.86 (dd, J = 5.8, 4.5 Hz, 2H), 3.64 (dd, J = 5.8, 4.6 Hz, 2H), 3.22 (d, J = 12.0 Hz, 2H), 3.16 (d, J = 6.7 Hz, 3H), 2.65 (t, J = 12.1 Hz, 2H), 1.97 - 1.83 (m, 2H), 1.82 - 1.65 (m, 1H), 1.51 - 1.35 (m, 2H), 1.23 (d, J = 6.6 Hz, 6H); LC / MS ESI(+): 429.2 (M+1).

[0171] [Reaction Scheme 12] [Chemical Formula]

[0172] [Example 37] Synthesis of N-((1H-imidazol-4-yl)methyl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although carried out in the same manner as in Production Example a-5, N-((1H-imidazol-4-yl)methyl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide was synthesized using (1H-imidazol-4-yl)methanamine hydrochloride instead of (R)-(+)-1-Boc-3-aminopyrrolidine. Light yellow solid (yield 11%); 11H NMR (400 MHz, CD3OD) δ 7.61 (s, 1H), 7.33 - 7.28 (m, 2H), 7.23 - 7.15 (m, 3H), 6.96 (s, 1H), 6.44 - 6.39 (m, 1H), 6.17 (dd, J = 11.3, 2.7 Hz, 1H), 4.34 (s, 2H), 3.87 (t, J = 5.1 Hz, 2H), 3.63 (t, J = 5.1 Hz, 2H); LC / MS ESI(+): 370.0 (M+1).

[0173] <Example 38> Synthesis of 6-Fluoro-4-(4-fluorophenyl)-N-(pyrazin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although carried out in the same manner as Production Example a-5, 6-Fluoro-4-(4-fluorophenyl)-N-(pyrazin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide was synthesized using 4-(aminomethyl)pyrimidine instead of (R)-(+)-1-Boc-3-aminopyrrolidine. Ivory solid (yield 61%); 1 1H-NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.68 (d, J = 5.2 Hz, 1H), 7.33 (d, J = 5.5 Hz, 1H), 7.30 - 7.27 (m, 1H), 7.25 - 7.21 (m, 2H), 7.17 - 7.11 (m, 2H), 6.49 - 6.44 (m, 1H), 6.33 - 6.26 (m, 2H) 4.59 (d, J = 5.5 Hz, 1H), 3.96 (t, J = 5.1 Hz, 1H), 3.64 (t, J = 5.1 Hz, 1H); LC / MS ESI(+): 381.9 (M+1).

[0174] [Reaction Scheme 13]

Chemical Formula

[0175] <Example 39> Synthesis of (6-Fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-hydroxypyrrolidin-1-yl)methanone Although carried out in the same manner as Production Example a-5, (6-Fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-hydroxypyrrolidin-1-yl)methanone was synthesized using 3-pyrrolidinol instead of (R)-(+)-1-Boc-3-aminopyrrolidine. Ivory solid (yield 89%); 1 1H NMR (400 MHz, CDCl3) δ 7.24 - 7.19 (m, 2H), 7.14 - 7.08 (m, 2H), 6.90 (dd, J = 8.6, 5.9 Hz, 1H), 6.41 - 6.36 (m, 1H), 6.27 (dd, J = 11.3, 2.7 Hz, 1H), 5.48 (d, J = 7.4 Hz, 1H), 4.47 (brs, 1H), 4.07 - 4.02 (m, 1H), 3.76 - 3.70 (m, 2H), 3.69 - 3.53 (m, 3H), 3.45 - 3.39 (m, 1H), 3.34 - 3.31 (m, 1H), 2.03 - 1.89 (m, 2H), 1.76 (d, J = 3.5 Hz, 1H); LC / MS ESI(+): 360.0 (M+1).

[0176] <Example 40>Synthesis of (6-Fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-methoxypyrrolidin-1-yl)methanone The (6-Fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-hydroxypyrrolidin-1-yl)methanone (1.0 equivalent) obtained in Example 39 was dissolved in THF (0.3 M), and NaH (2.0 equivalents) and iodomethane (1.2 equivalents) were added, followed by stirring at room temperature for 2 hours. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize (6-Fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-methoxypyrrolidin-1-yl)methanone. Yellow oil (yield 96%); 11H NMR (400 MHz, CDCl3) δ 7.24 - 7.19 (m, 2H), 7.13 - 7.07 (m, 2H), 6.89 (dd, J = 9.0, 5.9 Hz, 1H), 6.41 - 6.36 (m, 1H), 6.26 (dd, J = 11.0, 2.7 Hz, 1H), 4.04 - 3.99 (m, 1H), 3.95 - 3.90 (m, 1H), 3.75 - 3.70 (m, 2H), 3.68 - 3.61 (m, 1H), 3.53 - 3.46 (m, 2H), 3.44 - 3.36 (m, 2H), 3.32 (s, 3H), 2.05 - 1.97 (m, 1H), 1.94 - 1.85 (m, 1H); LC / MS ESI(+): 374.0 (M+1).

[0177] [Reaction Scheme 14] [Chemical Formula]

[0178] [Production Example a-15] Production of tert-Butyl 3-(6-Fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)azetidine-1-carboxylate Although carried out in the same manner as in Production Example a-5, tert-Butyl 3-(6-Fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)azetidine-1-carboxylate was produced using 1-Boc-3-aminoazetidine instead of (R)-(+)-1-Boc-3-aminopyrrolidine. White solid (yield 94%); 1 1H NMR (400 MHz, CDCl3) δ 7.25 - 7.20 (m, 2H), 7.17 - 7.09 (m, 3H), 6.47 - 6.41 (m, 1H), 6.26 (dd, J = 11.3, 2.7 Hz, 1H), 5.56 (d, J = 6.7 Hz, 1H), 4.63 - 4.54 (m, 1H), 4.26 - 4.24 (m, 2H), 3.92 (t, J = 4.9 Hz, 2H), 3.73 - 3.71 (m, 2H), 3.62 (t, J = 5.1 Hz, 2H), 1.44 (s, 9H).

[0179] <Example 41>Synthesis of N-(azetidin-3-yl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The Boc group of tert-butyl 3-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxalin-1-carboxamido)azetidine-1-carboxylate obtained in Production Example a-15 was deprotected with TFA to synthesize N-(azetidin-3-yl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. White solid (yield 43%); 1 1H NMR (400 MHz, CDCl3) δ 7.25 - 7.20 (m, 2H), 7.17 - 7.11 (m, 3H), 6.46 - 6.41 (m, 1H), 6.26 (dd, J = 11.3, 2.7 Hz, 1H), 5.91 (d, J = 7.4 Hz, 1H), 4.79 - 4.70 (m, 1H), 4.10 - 4.06 (m, 2H), 3.92 (t, J = 5.3 Hz, 2H), 3.74 - 3.65 (m, 2H), 3.62 (t, J = 5.1 Hz, 2H); LC / MS ESI(+): 345.0 (M+1).

[0180] <Example 42>Synthesis of 6-fluoro-4-(4-fluorophenyl)-N-(1-isopropylazetidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide N-(Azetidin-3-yl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (1.0 equivalent) obtained in Example 41 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 equivalents) and acetone (2.0 equivalents) were added, and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to synthesize 6-fluoro-4-(4-fluorophenyl)-N-((1-methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. White solid (yield 39%); 1 1H NMR (400 MHz, CDCl3) δ 7.25 - 7.21 (m, 2H), 7.16 - 7.10 (m, 3H), 6.45 - 6.40 (m, 5H), 6.25 (dd, J = 11.3, 2.7 Hz, 1H), 5.94 - 5.67 (m, 1H), 4.54 - 4.45 (m, 1H), 3.91 (t, J = 5.1 Hz, 2H), 3.75 - 3.68 (m, 2H), 3.62 (t, J = 5.1 Hz, 2H), 3.26 - 3.03 (m, 4H) 2.54 - 2.37 (m, 2H), 0.99 (d, J = 6.3 Hz, 6H); LC / MS ESI(+): 387.2 (M+1).

[0181] <Example 43> Synthesis of 6-fluoro-4-(4-fluorophenyl)-N-(1-isobutylazetidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although carried out in the same manner as in Example 42 above, 6-fluoro-4-(4-fluorophenyl)-N-(1-isobutylazetidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide was synthesized using isobutyl aldehyde instead of acetone. White solid (yield 56%); 11H NMR (400 MHz, CDCl3) δ 7.25 - 7.21 (m, 2H), 7.16 - 7.11 (m, 3H), 6.45 - 6.41 (m, 1H), 6.26 (dd, J = 11.3, 2.7 Hz, 1H), 5.59 - 5.47 (m, 1H), 4.54 - 4.46 (m, 1H), 3.91 (t, J = 5.1 Hz, 2H), 3.69 - 3.63 (m, 2H), 3.62 (t, J = 5.1 Hz, 2H), 2.95 - 2.80 (m, 2H), 2.25 (d, J = 7.0 Hz, 2H), 1.63 - 1.53 (m, 1H), 0.87 (d, J = 6.7 Hz, 6H); LC / MS ESI(+): 401.2 (M+1).

[0182] <Example 44>Synthesis of N-(1-acetylazetidin-3-yl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The N-(azetidin-3-yl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (1.0 equivalent) obtained in Example 41 was dissolved in THF (0.3 M), and TEA (2.5 equivalents) and acetyl chloride (1.8 equivalents) were added, and the mixture was stirred at room temperature for 4 hours and 30 minutes. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize N-(1-acetylazetidin-3-yl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. White solid (yield 37%); 11H NMR (400 MHz, CDCl3) δ 7.25 - 7.20 (m, 2H), 7.17 - 7.11 (m, 3H), 6.46 - 6.42 (m, 1H), 6.27 (dd, J = 11.3, 2.7 Hz, 1H), 5.59 (d, J = 6.7 Hz, 1H), 4.67 - 4.59 (m, 1H), 4.47 - 4.43 (m, 1H), 4.35 - 4.30 (m, 1H), 3.97 - 3.88 (m, 3H), 3.81 - 3.77 (m, 1H), 3.63 (t, J = 5.1 Hz, 2H), 1.88 (s, 3H); LC / MS ESI(+): 387.1 (M+1).

[0183] [Reaction Scheme 15] [Chemical Formula]

[0184] <Production Example a-16>Production of tert-butyl 3-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)azetidine-1-carboxylate Although carried out in the same manner as in Production Example a-5, tert-butyl 3-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)azetidine-1-carboxylate was produced using 1-Boc-3-(aminomethyl)azetidine instead of (R)-(+)-1-Boc-3-aminopyrrolidine. White solid (yield 81%); 1 1H NMR (400 MHz, CD3OD) δ 7.36 - 7.28 (m, 2H), 7.26 - 7.11 (m, 3H), 6.51 - 6.40 (m, 1H), 6.19 (dd, J = 11.4, 2.8 Hz, 1H), 3.98 (dd, J = 8.5, 8.5 Hz, 2H), 3.87 (brs, 2H), 3.77 - 3.67 (m, 2H), 3.66 - 3.61 (m, 2H), 3.41 (d, J = 6.3 Hz, 2H), 2.87 - 2.71 (m, 1H), 1.44 (s, 9H).

[0185] <Example 45>Synthesis of 6-Fluoro-4-(4-fluorophenyl)-N-((1-methylazetidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide tert-Butyl 3-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide)methyl)azetidine-1-carboxylate (1.0 equivalent) obtained in Production Example a-16 was dissolved in dichloromethane (0.3 M), TFA (10 equivalents) was added, and the mixture was stirred at room temperature for 24 hours. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The resulting concentrated solution was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The resulting residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to synthesize 6-fluoro-4-(4-fluorophenyl)-N-((1-methylazetidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Ivory-colored solid (yield 2%); 1 H NMR (400 MHz, CD3OD) δ 7.36 - 7.27 (m, 2H), 7.26 - 7.16 (m, 3H), 6.45 (ddd, J = 8.8, 8.0, 2.8 Hz, 1H), 6.20 (dd, J = 11.4, 2.8 Hz, 1H), 4.20 - 4.08 (m, 2H), 4.03 - 3.92 (m, 2H), 3.87 (dd, J = 5.9, 4.5 Hz, 2H), 3.65 (dd, J = 5.8, 4.6 Hz, 2H), 3.42 (d, J = 6.5 Hz, 2H), 3.18 - 3.01 (m, 1H), 2.88 (s, 3H); LC / MS ESI(+): 373.1 (M + 1).

[0186] <Example 46>Synthesis of 6-Fluoro-4-(4-fluorophenyl)-N-((1-isopropylazetidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although carried out in the same manner as in Example 45, 6-Fluoro-4-(4-fluorophenyl)-N-((1-isopropylazetidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide was synthesized using acetone instead of formaldehyde. White solid (yield 25%); 1 1H NMR (400 MHz, CD3OD) δ 7.36 - 7.25 (m, 2H), 7.24 - 7.14 (m, 3H), 6.45 (ddd, J = 8.8, 8.0, 2.8 Hz, 1H), 6.20 (dd, J = 11.4, 2.8 Hz, 1H), 3.86 (dd, J = 5.8, 4.5 Hz, 2H), 3.76 - 3.60 (m, 4H), 3.37 (d, J = 6.5 Hz, 2H), 3.33 (brs, 1H), 2.84 - 2.71 (m, 2H), 1.39 - 1.22 (m, 1H), 1.04 (d, J = 6.3 Hz, 6H); LC / MS ESI(+): 401.2 (M+1).

[0187] <Example 47>Synthesis of 6-Fluoro-4-(4-fluorophenyl)-N-((1-isobutylazetidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although carried out in the same manner as in Example 45, 6-Fluoro-4-(4-fluorophenyl)-N-((1-isobutylazetidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide was synthesized using isobutylaldehyde instead of formaldehyde. White solid (yield 27%); 11H NMR (400 MHz, CD3OD) δ 7.36 - 7.26 (m, 2H), 7.25 - 7.14 (m, 3H), 6.45 (ddd, J = 8.9, 8.0, 2.8 Hz, 1H), 6.20 (dd, J = 11.4, 2.8 Hz, 1H), 3.86 (dd, J = 5.8, 4.5 Hz, 2H), 3.76 (dd, J = 8.2, 1.6 Hz, 2H), 3.64 (dd, J = 5.8, 4.6 Hz, 2H), 3.47 - 3.35 (m, 4H), 2.96 - 2.81 (m, 1H), 2.62 (d, J = 7.1 Hz, 2H), 1.84 - 1.69 (m, 1H), 0.93 (d, J = 6.7 Hz, 6H); LC / MS ESI(+): 415.2 (M + 1).

[0188] [Reaction Scheme 16] [Chem.]

[0189] [Example 48] Synthesis of 6-Fluoro-4-(4-fluorophenyl)-N-((tetrahydrofuran-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although carried out in the same manner as in Production Example a-5, 6-Fluoro-4-(4-fluorophenyl)-N-((tetrahydrofuran-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide was synthesized using (tetrahydrofuran-3-yl)methanamine instead of (R)-(+)-1-Boc-3-aminopyrrolidine. White solid (yield 57%); 11H NMR (400 MHz, CDCl3) δ 7.26 - 7.17 (m, 2H), 7.16 - 7.05 (m, 3H), 6.41 (ddd, J = 8.7, 7.7, 2.8 Hz, 1H), 6.26 (dd, J = 11.4, 2.8 Hz, 1H), 5.46 - 5.33 (m, 1H), 3.96 - 3.90 (m, 2H), 3.89 - 3.69 (m, 3H), 3.64 - 3.58 (m, 2H), 3.57 - 3.50 (m, 1H), 3.39 - 3.21 (m, 2H), 2.59 - 2.44 (m, 1H), 2.10 - 1.97 (m, 1H), 1.70 - 1.58 (m, 1H); LC / MS ESI(+): 374.2 (M+1).

[0190] [Reaction Formula 17] [Chemical Formula]

[0191] [Production Method b] Production of 1-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline 1-(4-Fluorophenyl)-1,2,3,4-tetrahydroquinoxaline according to the present invention was produced through the processes of the following Production Examples b-1 to b-4.

[0192] [Production Example b-1] Production of N-(4-fluorophenyl)-2-nitroaniline Although carried out in the same manner as in Production Example a-1 above, N-(4-fluorophenyl)-2-nitroaniline was produced using 1-fluoro-2-nitrobenzene instead of 2,4-difluoro-1-nitrobenzene. Yellow solid (yield 30%); 1 1H NMR (400 MHz, CDCl3) δ 9.40 (s, 1H), 8.21 (dd, J = 8.6, 1.6 Hz, 1H), 7.38 - 7.34 (m, 1H), 7.27 - 7.22 (m, 2H), 7.15 - 7.09 (m, 2H), 7.05 (dd, J = 8.6, 1.2 Hz, 1H), 6.77 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H).

[0193] [Production Example b-2] N 1Production of -(4-Fluorophenyl)benzene-1,2-diamine Although carried out in the same manner as Production Example a-2, N-(4-fluorophenyl)-2-nitroaniline obtained in Production Example b-1 was used instead of 5-fluoro-N-(4-fluorophenyl)-2-nitroaniline to produce N 1 -(4-Fluorophenyl)benzene-1,2-diamine. Orange solid (yield 61%); 1 H NMR (400 MHz, CDCl3) δ 7.06 (dd, J = 7.8, 1.2 Hz, 1H), 7.01 (td, J = 7.6, 1.2 Hz, 1H), 6.95 - 6.89 (m, 2H), 6.81 (dd, J = 7.8, 1.2 Hz, 1H), 6.79 - 6.73 (m. 1H), 6.73 - 6.67 (m, 2H), 5.09 (s, 1H), 3.74 (s, 2H); LC / MS ESI(+): 202.6 (M + 1).

[0194] <Production Example b-3>Production of 1-(4-Fluorophenyl)quinoxaline-2,3(1H,4H)-dione Although carried out in the same manner as Production Example a-3, N 1 -phenylbenzene-1,2-diamine was replaced with N-(4-fluorophenyl)benzene-1,2-diamine obtained in Production Example b-2 to produce 1-(4-fluorophenyl)quinoxaline-2,3(1H,4H)-dione. 1 1 White solid (yield 81%); 1 H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 7.45 (d, 4H, J = 6.7 Hz), 7.24 - 7.19 (m, 1H), 7.16 - 7.10 (m, 1H), 7.00 - 6.96 (m, 1H), 6.32 (dd, J = 8.2, 0.8 Hz, 1H); LC / MS ESI(+): 256.6 (M + 1).

[0195] <Production Example b-4>Production of 1-(4-Fluorophenyl)-1,2,3,4-tetrahydroquinoxaline Although it was carried out in the same manner as in Production Example a-4, 1-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline was produced using 1-(4-fluorophenyl)quinoxaline-2,3(1H,4H)-dione obtained in Production Example b-3 instead of 7-fluoro-1-phenylquinoxaline-2,3(1H,4H)-dione. Brown solid (yield 38%); 1 1H NMR (400 MHz, CDCl3) δ 7.18 - 7.13 (m, 2H), 7.05 - 6.99 (m, 2H), 6.70 - 6.53 (m, 4H), 3.66 - 3.64 (m, 2H), 3.48 - 3.45 (m, 2H); LC / MS ESI(+): 228.8 (M+1).

[0196] [Reaction Scheme 18]

Chemical Structure

[0197] [Production Example b-5] Production of tert-butyl (S)-3-(4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate 1-(4-Fluorophenyl)-1,2,3,4-tetrahydroquinoxaline (200 mg, 0.88 mmol) obtained in Production Example b-4 was dissolved in dichloromethane (8.0 mL), and TEA (0.5 mL, 3.50 mmol) and triphosgene (156 mg, 0.53 mmol) were slowly added at 0 °C, followed by stirring at 0 °C for 1 hour. TEA (0.5 mL, 3.50 mmol) and (S)-(-)-1-Boc-3-aminopyrrolidine (0.2 mL, 1.31 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After adding water to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce tert-butyl (S)-3-(4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate. Yellow oil (yield 98%); 1 H NMR (400 MHz, CDCl3) δ 7.25 - 7.19 (m, 2H), 7.15 - 7.07 (m, 3H), 6.94 - 6.86 (m, 1H), 6.74 - 6.68 (m, 1H), 6.65 - 6.59 (m, 1H), 5.38 (d, J = 6.9 Hz, 1H), 4.45 - 4.40 (m, 1H), 3.99 - 3.90 (m, 2H), 3.71 - 3.61 (m, 3H), 3.44 - 3.39 (m, 2H), 3.21 - 3.15 (m, 1H), 2.19 - 2.15 (m, 1H), 1.83 - 1.79 (m, 1H), 1.46 (s, 9H).

[0198] <Example 49>Synthesis of (S)-4-(4-Fluorophenyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The tert-butyl (S)-3-(4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxalin-1-carboxamido)pyrrolidine-1-carboxylate (100 mg, 0.23 mmol) obtained in Production Example b-5 was dissolved in dichloromethane (0.7 mL), TFA (170.0 μL, 2.27 mmol) was added, and the mixture was stirred at room temperature for 24 hours. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to synthesize (S)-4-(4-fluorophenyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. White solid (yield 31%); 11H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.27 - 7.18 (m, 3H), 7.12 - 7.03 (m, 2H), 6.91 - 6.83 (m, 1H), 6.76 - 6.68 (m, 1H), 6.62 (d, J = 8.1 Hz, 1H), 6.30 (d, J = 7.2 Hz, 1H), 4.62 - 4.57 (m, 1H), 3.93 (t, J = 5.0 Hz, 2H), 3.64 (t, J = 5.2 Hz, 2H), 3.36 - 3.22 (m, 2H), 3.21 - 3.09 (m, 2H), 2.38 - 2.24 (m, 1H), 2.00 - 1.95 (m, 1H); LC / MS ESI(+): 341.0 (M+1).

[0199] [Reaction Scheme 19] [Chem.]

[0200] [Production Example b-6] Production of tert-butyl 4-(4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)piperidine-1-carboxylate Although carried out in the same manner as in Production Example b-5, tert-butyl 4-(4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)piperidine-1-carboxylate was synthesized using 1-Boc-4-aminopiperidine instead of (S)-(-)-1-Boc-3-aminopyrrolidine. White solid (yield 85%); 1 1H NMR (400 MHz, CDCl3) δ 7.24 - 7.19 (m, 2H), 7.16 - 7.07 (m, 3H), 6.93 - 6.86 (m, 1H), 6.73 - 6.69 (m, 1H), 6.62 (d, J = 8.2 Hz, 1H), 5.23 (d, J = 7.4 Hz, 1H), 4.09 - 3.82 (m, 5H), 3.63 (t, J = 5.1 Hz, 1H), 2.97 - 2.85 (m, 2H), 2.00 - 1.90 (m, 2H), 1.45 (s, 9H), 1.37 - 1.24 (m, 2H).

[0201] <Example 50>Synthesis of 4-(4-Fluorophenyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide The Boc group of tert-butyl 4-(4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)piperidine-1-carboxylate obtained in Production Example b-5 was deprotected with TFA to synthesize 4-(4-fluorophenyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide. White solid (yield 49%); 1 1H NMR (400 MHz, CDCl3) δ 7.24 - 7.15 (m, 3H), 7.12 - 7.06 (m, 2H), 6.92 - 6.86 (m, 1H), 6.74 - 6.69 (m, 1H), 6.63 (d, J = 8.2 Hz, 1H), 5.25 (d, J = 7.8 Hz, 1H), 3.94 (t, J = 5.3 Hz, 1H), 3.87 - 3.79 (m, 1H), 3.63 (t, J = 5.1 Hz, 1H), 3.08 - 2.99 (m, 2H), 2.75 - 2.65 (m, 2H), 2.02 - 1.93 (m, 2H), 1.36 - 1.23 (m, 2H); LC / MS ESI(+): 355.1 (M + 1).

[0202] [Reaction Scheme 20]

Chemical formula

[0203] <Example 51>Synthesis of (S)-4-(4-Fluorophenyl)-N-(tetrahydrofuran-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide Although carried out in the same manner as in Production Example b-5, (S)-4-(4-fluorophenyl)-N-(tetrahydrofuran-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized using (S)-3-aminotetrahydrofuran instead of (S)-(-)-1-Boc-3-aminopyrrolidine. Brown solid (yield 67%); 11H NMR (400 MHz, CDCl3) δ 7.25 - 7.20 (m, 2H), 7.16 (dd, J = 7.9, 1.5 Hz, 1H), 7.13 - 7.07 (m, 2H), 6.90 (ddd, J = 8.4, 7.2, 1.5 Hz, 1H), 6.75 - 6.70 (m, 1H), 6.62 (dd, J = 8.3, 1.3 Hz, 1H), 5.48 (d, J = 6.9 Hz, 1H), 4.52 - 4.46 (m, 1H), 4.01 - 3.85 (m, 4H), 3.81 - 3.76 (m, 1H), 3.70 - 3.66 (m, 1H), 3.64 (t, J = 5.2 Hz, 1H), 2.32 - 2.24 (m, 1H), 1.82 - 1.77 (m, 1H); LC / MS ESI(+): 342.2 (M + 1).

[0204] <Example 52>Synthesis of 4-(4-Fluorophenyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide Although carried out in the same manner as Production Example b-5, 4-(4-Fluorophenyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized using 4-aminomethyltetrahydropyran instead of (S)-(-)-1-Boc-3-aminopyrrolidine. Pale yellow solid (yield 74%); 1 1H NMR (400 MHz, CDCl3) δ 7.25 - 7.21 (m, 3H), 7.15 - 7.09 (m, 2H), 6.95 - 6.91 (m, 1H), 6.79 - 6.74 (m, 1H), 6.66 (dd, J = 8.3, 1.3 Hz, 1H), 5.48 (t, J = 5.8 Hz, 1H), 4.03 - 3.94 (m, 4H), 3.67 - 3.64 (m, 2H), 3.44 - 3.37 (m, 2H), 3.21 (t, J = 6.4 Hz, 1H), 1.87 - 1.76 (m, 1H), 1.65 - 1.62 (m, 2H), 1.40 - 1.29 (m, 2H); LC / MS ESI(+): 370.2 (M + 1). [Reaction Scheme 21]

Chemical Formula

[0205] <Production Example b-7> Production of tert-butyl (R)-3-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate Although carried out in the same manner as in Production Example b-5, tert-butyl (R)-3-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate was produced using (R)-1-Boc-3-(aminomethyl)pyrrolidine instead of (S)-(-)-1-Boc-3-aminopyrrolidine. White solid (yield 91%); 1 1H NMR (400 MHz, CDCl3) δ 7.25 - 7.12 (m, 3H), 7.11 - 7.03 (m, 2H), 6.95 - 6.85 (m, 1H), 6.77 - 6.69 (m, 1H), 6.65 - 6.58 (m, 1H), 5.46 (t, J = 5.9 Hz, 1H), 4.01 - 3.86 (m, 2H), 3.62 (t, J = 5.2 Hz, 2H), 3.56 - 3.34 (m, 3H), 3.33 - 3.25 (m, 2H), 3.08 - 2.94 (m, 1H), 2.51 - 2.37 (m, 1H), 2.02 - 1.91 (m, 1H), 1.67 - 1.54 (m, 1H), 1.45 (s, 9H).

[0206] <Example 53> Synthesis of (S)-4-(4-fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The Boc group of tert-butyl (R)-3-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate obtained in Production Example b-7 was deprotected with TFA to synthesize (S)-4-(4-fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. White solid (yield 56.4%); 11H NMR (400 MHz, CDCl3) δ 7.24 - 7.18 (m, 2H), 7.17 (dd, J = 7.9, 1.6 Hz, 1H), 7.13 - 7.05 (m, 2H), 6.94 - 6.86 (m, 1H), 6.77 - 6.69 (m, 1H), 6.62 (dd, J = 8.3, 1.4 Hz, 1H), 5.65 (t, J = 5.7 Hz, 1H), 3.93 (t, J = 5.2 Hz, 2H), 3.63 (t, J = 5.1 Hz, 2H), 3.53 - 3.34 (m, 1H), 3.33 - 3.22 (m, 2H), 3.21 - 3.12 (m, 2H), 3.11 - 3.01 (m, 1H), 2.89 - 2.79 (m, 1H), 2.53 - 2.41 (m, 1H), 2.05 - 1.95 (m, 1H), 1.65 - 1.52 (m, 1H); LC / MS ESI(+): 355.2 (M + 1).

[0207] <Example 54> Synthesis of (R)-4-(4-Fluorophenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Dissolve the (S)-4-(4-fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (80 mg, 0.23 mmol) obtained in Example 53 in dichloromethane (1.0 mL), add sodium triacetoxyborohydride (62 mg, 0.29 mmol) and formaldehyde (19.8 μL, 0.25 mmol), and stir at room temperature for 3 hours. After adding water to the reaction solution to terminate the reaction, extract with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to synthesize (R)-4-(4-fluorophenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Light yellow oil (yield 76.9%); 11H NMR (400 MHz, CDCl3) δ 7.24 - 7.03 (m, 5H), 6.93 - 6.83 (m, 1H), 6.76 - 6.68 (m, 1H), 6.62 (dd, J = 8.3, 1.4 Hz, 1H), 4.05 - 3.94 (m, 1H), 3.93 - 3.82 (m, 1H), 3.63 (t, J = 5.2 Hz, 2H), 3.39 - 3.19 (m, 2H), 2.75 - 2.64 (m, 1H), 2.63 - 2.54 (m, 1H), 2.53 - 2.39 (m, 3H), 2.31 (s, 3H), 2.10 - 1.96 (m, 1H), 1.64 - 1.51 (m, 1H); LC / MS ESI(+): 369.2 (M + 1).

[0208] <Example 55>Synthesis of (R)-4-(4-Fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although carried out in the same manner as in Example 54, (R)-4-(4-Fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide was synthesized using acetone instead of formaldehyde. Light yellow oil (yield 56.9%); 1 1H NMR (400 MHz, CDCl3) δ 7.25 - 7.14 (m, 3H), 7.12 - 7.01 (m, 2H), 6.92 - 6.82 (m, 1H), 6.76 - 6.69 (m, 1H), 6.63 (dd, J = 8.3, 1.4 Hz, 1H), 5.95 (t, J = 5.1 Hz, 1H), 4.09 - 4.00 (m, 1H), 3.83 (ddd, J = 13.1, 6.2, 4.6 Hz, 1H), 3.65 - 3.61 (m, 2H), 3.36 - 3.21 (m, 2H), 2.69 - 2.58 (m, 2H), 2.51 (q, J = 6.6 Hz, 1H), 2.44 - 2.32 (m, 2H), 2.30 - 2.23 (m, 1H), 2.03 - 1.90 (m, 1H), 1.60 - 1.43 (m, 1H), 0.99 (dd, J = 9.8, 6.3 Hz, 6H); LC / MS ESI(+): 397.2 (M + 1).

[0209] <Example 56>Synthesis of (R)-4-(4-Fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although carried out in the same manner as in Example 54, (R)-4-(4-Fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide was synthesized using isobutylaldehyde instead of formaldehyde. Light yellow oil (yield 91.7%); 1 1H NMR (400 MHz, CDCl3) δ 7.27 - 7.04 (m, 5H), 6.95 - 6.83 (m, 1H), 6.78 - 6.67 (m, 1H), 6.63 (dd, J = 8.3, 1.4 Hz, 1H), 6.10 (s, 1H), 4.24 - 4.12 (m, 1H), 3.83 - 3.69 (m, 1H), 3.68 - 3.59 (m, 2H), 3.42 - 3.22 (m, 2H), 2.83 - 2.62 (m, 1H), 2.61 - 2.30 (m, 5H), 2.23 - 2.10 (m, 1H), 2.09 - 1.93 (m, 1H), 1.76 - 1.50 (m, 2H), 0.94 - 0.67 (m, 6H); LC / MS ESI(+): 411.2 (M + 1). [Reaction Scheme 22] [Chemical Formula]

[0210] <Production Example b-8>Production of tert-Butyl (R)-2-((4-(4-Fluorophenyl)-1,2,3,4-tetrahydroquinoxalin-1-carboxamide)methyl)pyrrolidine-1-carboxylate Although carried out in the same manner as in Production Example b-5, tert-Butyl (R)-2-((4-(4-Fluorophenyl)-1,2,3,4-tetrahydroquinoxalin-1-carboxamide)methyl)pyrrolidine-1-carboxylate was produced using (R)-1-Boc-2-(aminomethyl)pyrrolidine instead of (S)-(-)-1-Boc-3-aminopyrrolidine. Light yellow solid (yield 93%); 11H NMR (400 MHz, CDCl3) δ 7.35 - 7.26 (m, 1H), 7.23 - 7.18 (m, 2H), 7.13 - 7.00 (m, 2H), 6.94 - 6.83 (m, 1H), 6.78 - 6.68 (m, 1H), 6.62 (d, J = 8.1 Hz, 1H), 6.40 (brs, 1H), 4.04 - 3.83 (m, 3H), 3.65 - 3.62 (m, 2H), 3.55 - 3.41 (m, 1H), 3.40 - 3.20 (m, 3H), 2.00 - 1.75 (m, 4H), 1.40 (s, 9H).

[0211] <Example 57> Synthesis of (R)-4-(4-Fluorophenyl)-N-(pyrrolidin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Using the product obtained in Production Example b-8, the Boc group of tert-butyl (R)-2-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate was deprotected with TFA to synthesize (R)-4-(4-fluorophenyl)-N-(pyrrolidin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Yellow oil (yield 65%); 1 1H NMR (400 MHz, CDCl3) δ 7.24 - 7.19 (m, 3H), 7.12 - 7.06 (m, 2H), 6.91 - 6.87 (m, 1H), 6.75 - 6.70 (m, 1H), 6.62 (dd, J = 8.3, 1.3 Hz, 1H), 5.86 - 5.78 (m, 1H), 3.98 - 3.92 (m, 2H), 3.67 - 3.61 (m, 2H), 3.42 - 3.32 (m, 2H), 3.19 - 3.12 (m, 1H), 2.97 - 2.86 (m, 2H), 2.17 (brs, 1H), 1.94 - 1.85 (m, 1H), 1.82 - 1.68 (m, 2H), 1.46 - 1.40 (m, 1H); LC / MS ESI(+): 355.2 (M+1). [Reaction Scheme 23] [Chemical Formula]

[0212] <Production Example b-9> Production of tert-butyl (R)-3-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate Although carried out in the same manner as in Production Example b-5, tert-butyl (R)-3-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate was produced using (R)-1-Boc-3-(aminomethyl)pyrrolidine instead of (S)-(-)-1-Boc-3-aminopyrrolidine. White solid (yield 70%); 1 1H NMR (400 MHz, CDCl3) δ 7.24 - 7.20 (m, 2H), 7.17 - 7.07 (m, 3H), 6.95 - 6.87 (m, 1H), 6.76 - 6.71 (m, 1H), 6.66 - 6.60 (m, 1H), 5.50 - 5.43 (m, 1H), 4.01 - 3.88 (m, 2H), 3.63 (t, J = 5.1 Hz, 2H), 3.55 - 3.16 (m, 5H), 3.06 - 2.97 (m, 1H), 2.50 - 2.38 (m, 1H), 2.03 - 1.93 (m, 1H), 1.67 - 1.58 (m, 1H), 1.46 (s, 9H). <Production Example b-10> Production of (R)-4-(4-fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The Boc group of tert-butyl (R)-3-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate obtained in Production Example b-9 was deprotected with TFA to produce (R)-4-(4-fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. White solid (yield 70%); 11H NMR (400 MHz, CDCl3) δ 7.22 - 7.17 (m, 3H), 7.12 - 7.06 (m, 2H), 6.91 - 6.87 (m, 1H), 6.75 - 6.70 (m, 1H), 6.62 (dd, J = 8.3, 1.3 Hz, 1H), 5.69 (t, J = 5.4 Hz, 1H), 3.92 (t, J = 5.1 Hz, 2H), 3.62 (t, J = 5.1 Hz, 2H), 3.31 - 3.24 (m, 2H), 3.15 - 3.09 (m, 2H), 3.05 - 2.98 (m, 1H), 2.81 - 2.77 (m, 1H), 2.45 - 2.36 (m, 1H), 2.01 - 1.91 (m, 1H), 1.57 - 1.48 (m, 1H); LC / MS ESI(+): 355.2 (M + 1). <Example 58>Synthesis of (S)-4-(4-Fluorophenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The (R)-4-(4-Fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (1.0 equivalent) obtained in Production Example b-10 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize (S)-4-(4-Fluorophenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Yellow oil (yield 67%); 11H NMR (400 MHz, CDCl3) δ 7.23 - 7.17 (m, 3H), 7.13 - 7.07 (m, 2H), 6.91 - 6.87 (m, 1H), 6.74 - 6.70 (m, 1H), 6.63 (dd, J = 8.3, 1.3 Hz, 1H), 6.10 - 6.00 (m, 1H), 4.03 - 3.97 (m, 1H), 3.91 - 3.85 (m, 1H), 3.63 (t, J = 5.1 Hz, 2H), 3.35 - 3.23 (m, 2H), 2.65 - 2.59 (m, 1H), 2.55 - 2.50 (m, 1H), 2.48 - 2.34 (m, 3H), 2.25 (s, 3H), 2.05 - 1.96 (m, 1H), 1.58 - 1.51 (m, 1H); LC / MS ESI(+): 369.3 (M + 1). <Example 59>Synthesis of (S)-4-(4-Fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although carried out in the same manner as in Example 58, (S)-4-(4-Fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide was synthesized using acetone instead of formaldehyde. Colorless oil (yield 71%); 1 1H NMR (400 MHz, CDCl3) δ 7.23 - 7.17 (m, 3H), 7.12 - 7.05 (m, 2H), 6.90 - 6.85 (m, 1H), 6.74 - 6.70 (m, 1H), 6.63 (dd, J = 8.3, 1.3 Hz, 1H), 5.99 - 5.92 (m, 1H), 4.08 - 4.02 (m, 1H), 3.86 - 3.80 (m, 1H), 3.65 - 3.62 (m, 2H), 3.36 - 3.24 (m, 2H), 2.67 - 2.61 (m, 2H), 2.54 - 2.48 (m, 1H), 2.45 - 2.34 (m, 2H), 2.30 - 2.24 (m, 1H), 2.02 - 1.94 (m, 1H), 1.58 - 1.49 (m, 1H), 0.99 (dd, J = 9.8, 6.4 Hz, 6H); LC / MS ESI(+): 397.3 (M + 1). <Example 60>Synthesis of (S)-4-(4-Fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although carried out in the same manner as in Example 58, (S)-4-(4-Fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide was synthesized using isobutylaldehyde instead of formaldehyde. Colorless oil (yield 69%); 1 1H NMR (400 MHz, CDCl3) δ 7.23 - 7.17 (m, 3H), 7.12 - 7.05 (m, 2H), 6.90 - 6.85 (m, 1H), 6.74 - 6.69 (m, 1H), 6.61 (dd, J = 8.3, 1.3 Hz, 1H), 6.10 (brs, 1H), 4.21 - 4.14 (m, 1H), 3.76 - 3.68 (m, 1H), 3.65 - 3.61 (m, 2H), 3.36 - 3.24 (m, 2H), 2.69 - 2.64 (m, 1H), 2.50 - 2.29 (m, 4H), 2.17 - 1.93 (m, 3H), 1.70 - 1.51 (m, 3H), 0.81 (d, J = 6.6 Hz, 3H), 0.73 (d, J = 6.6 Hz, 3H); LC / MS ESI(+): 411.3 (M + 1). [Reaction Scheme 24]

Chemical Formula

[0213] <Production Example b-11>Production of tert-Butyl 3-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxalin-1-carboxamide)methyl)azetidine-1-carboxylate Although carried out in the same manner as in Production Example b-5, tert-Butyl 3-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxalin-1-carboxamide)methyl)azetidine-1-carboxylate was produced using 1-Boc-3-(aminomethyl)azetidine instead of (S)-(-)-1-Boc-3-aminopyrrolidine. Light yellow solid (yield 92%); 1HNMR (400 MHz, CDCl3) δ 7.26 - 7.20 (m, 2H), 7.17 - 7.09 (m, 3H), 6.95 - 6.90 (m, 1H), 6.77 - 6.72 (m, 1H), 6.64 (dd, J = 8.3, 1.3 Hz, 1H), 5.58 - 5.54 (m, 1H), 4.04 - 4.00 (m, 2H), 3.98 - 3.95 (m, 2H), 3.69 - 3.62 (m, 4H), 3.54 - 3.45 (m, 2H), 2.84 - 2.74 (m, 1H), 1.46 (s, 9H). <Example 61>Synthesis of 4-(4-Fluorophenyl)-N-((1-isobutylazetidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide tert-Butyl 3-((4-(4-Fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide)methyl)azetidine-1-carboxylate (1.0 equivalent) obtained in Production Example b-11 was dissolved in dichloromethane (0.3 M), TFA (10.0 equivalents) was added, and the mixture was stirred at room temperature for 24 hours. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained concentrated solution was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 equivalents) and isobutyl aldehyde (2.0 equivalents) were added, and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize 4-(4-fluorophenyl)-N-((1-isobutylazetidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Colorless oil (yield 19%); 11H NMR (400 MHz, CDCl3) δ 7.24 - 7.18 (m, 3H), 7.12 - 7.05 (m, 2H), 6.90 - 6.86 (m, 1H), 6.73 - 6.69 (m, 1H), 6.62 (dd, J = 8.3, 1.3 Hz, 1H), 5.85 (t, J = 5.2 Hz, 1H), 3.69 - 3.65 (m, 2H), 3.64 - 3.62 (m, 2H), 3.44 (t, J = 5.7 Hz, 2H), 3.31 - 3.27 (m, 2H), 2.91 - 2.88 (m, 2H), 2.69 - 2.59 (m, 1H), 2.17 (d, J = 7.1 Hz, 2H), 1.58 - 1.48 (m, 1H), 0.81 (d, J = 6.6 Hz, 6H); LC / MS ESI(+): 396.5 (M+1). [Reaction Scheme 25] [Chem.]

[0214] <Production Example b-12> Production of tert-butyl 4-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate Although carried out in the same manner as in Production Example b-5, tert-butyl 4-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate was produced using 1-Boc-4-(aminomethyl)piperidine instead of (S)-(-)-1-Boc-3-aminopyrrolidine. White solid (yield 67%); 1 1H NMR (400 MHz, CDCl3) δ 7.22 - 7.16 (m, 3H), 7.12 - 7.07 (m, 2H), 6.95 - 6.87 (m, 1H), 6.77 - 6.70 (m, 1H), 6.65 - 6.61 (m, 1H), 5.47 - 5.42 (m, 1H), 4.18 - 4.06 (m, 2H), 3.94 (t, J = 4.4 Hz, 2H), 3.63 (t, J = 5.1 Hz, 2H), 3.17 (t, J = 5.4 Hz, 2H), 2.76 - 2.62 (m, 2H), 1.72 - 1.65 (m, 3H), 1.45 (s, 9H), 1.18 - 1.08 (m, 2H). <Example 62>Synthesis of 4-(4-Fluorophenyl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The Boc group of tert-butyl 4-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide)methyl)piperidine-1-carboxylate obtained in Production Example b-12 was deprotected with TFA to synthesize 4-(4-fluorophenyl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. White solid (yield 96%); 1 1H NMR (400 MHz, CDCl3) δ 7.23 - 7.17 (m, 3H), 7.12 - 7.07 (m, 2H), 6.93 - 6.88 (m, 1H), 6.76 - 6.72 (m, 1H), 6.66 (dd, J = 8.3, 1.3 Hz, 1H), 5.45 (t, J = 5.9 Hz, 2H), 3.96 - 3.93 (m, 2H), 3.64 - 3.62 (m, 2H), 3.18 - 3.09 (m, 4H), 2.65 - 2.58 (m, 2H), 2.15 - 1.98 (m, 2H), 1.74 - 1.62 (m, 3H), 1.24 - 1.11 (m, 2H); LC / MS ESI(+): 369.2 (M + 1). <Example 63>Synthesis of 4-(4-Fluorophenyl)-N-((1-isopropylpiperidin-4-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide 4-(4-Fluorophenyl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (1.0 eq) obtained in Example 62 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 eq) and acetone (2.0 eq) were added, and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction mixture to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize 4-(4-fluorophenyl)-N-((1-isopropylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide. Light yellow solid (yield 81%); 1 1H NMR (400 MHz, CDCl3) δ 7.23 - 7.17 (m, 3H), 7.12 - 7.07 (m, 2H), 6.92 - 6.88 (m, 1H), 6.75 - 6.71 (m, 1H), 6.63 (dd, J = 8.3, 1.3 Hz, 1H), 5.44 (t, J = 5.7 Hz, 1H), 3.96 - 3.93 (m, 2H), 3.64 - 3.62 (m, 2H), 3.17 (t, J = 6.3 Hz, 2H), 2.92 - 2.85 (m, 2H), 2.75 - 2.65 (m, 1H), 2.16 - 2.06 (m, 2H), 2.05 - 1.67 (m, 2H), 1.58 - 1.47 (m, 1H), 1.32 - 1.20 (m, 2H), 1.03 (d, J = 6.6 Hz, 6H); LC / MS ESI(+): 411.3 (M+1). <Example 64> Synthesis of 4-(4-Fluorophenyl)-N-((1-isobutylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide Although carried out in the same manner as in Example 63, 4-(4-fluorophenyl)-N-((1-isobutylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized using isobutyl aldehyde instead of acetone. Light yellow solid (yield 69%); 11H NMR (400 MHz, CDCl3) δ 7.23 - 7.17 (m, 3H), 7.12 - 7.07 (m, 2H), 6.92 - 6.88 (m, 1H), 6.75 - 6.71 (m, 1H), 6.63 (dd, J = 8.3, 1.3 Hz, 1H), 5.43 (t, J = 5.8 Hz, 1H), 3.96 - 3.93 (m, 2H), 3.64 - 3.62 (m, 2H), 3.17 (t, J = 6.3 Hz, 2H), 2.89 - 2.83 (m, 2H), 2.05 (d, J = 7.4 Hz, 2H), 1.88 - 1.81 (m, 2H), 1.80 - 1.74 (m, 1H), 1.64 - 1.61 (m, 2H), 1.57 - 1.45 (m, 1H), 1.32 - 1.22 (m, 2H), 0.88 (d, J = 6.5 Hz, 6H); LC / MS ESI(+): 425.3 (M + 1). [Reaction Formula 26] [Chemical Formula]

[0215] <Production Method c> Production of 7-Fluoro-1-phenyl-1,2,3,4-tetrahydroquinoxaline The 7-fluoro-1-phenyl-1,2,3,4-tetrahydroquinoxaline according to the present invention was synthesized through the processes of the following Production Examples c-1 to c-4. <Production Example c-1> Production of 5-Fluoro-2-nitro-N-phenylaniline A mixed solution of 2,4-difluoro-1-nitrobenzene (1.0 equivalent) and aniline (1.0 equivalent) was stirred at 130 °C for 24 hours and then cooled to room temperature. After adding water to the reaction solution to terminate the reaction, it was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce 5-fluoro-2-nitro-N-phenylaniline. Yellow solid (yield 63%); 11H NMR (400 MHz, CDCl3) δ 9.65 (s, 1H), 8.26 (dd, J = 9.4, 5.9 Hz, 1H), 7.448 - 7.43 (m, 2H), 7.31 - 7.26 (m, 3H), 6.80 (dd, J = 11.3, 2.3 Hz, 1H), 6.48 (ddd, J = 9.5, 6.9, 2.7 Hz, 1H). <Production Example c-2> 5-Fluoro-N 1 -Phenylbenzene-1,2-diamine Production A mixed solution prepared by dissolving 5-fluoro-2-nitro-N-phenylaniline (1.0 equivalent) and tin(II) chloride dihydrate (3.0 equivalents) in ethyl acetate (0.5 M) was stirred at 90 °C for 5 hours. After cooling the reaction solution to room temperature, it was poured into water, neutralized with 10 M aqueous NaOH solution, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce 5-fluoro-N 1 -Phenylbenzene-1,2-diamine. Brown oil (yield 86%); 1H NMR (400 MHz, CDCl3) δ 7.28 - 7.24 (m, 2H), 6.93 - 6.86 (m, 3H), 6.75 - 6.71 (m, 1H), 6.69 - 6.64 (m, 1H), 5.34 (s, 1H), 3.89 (s, 2H); LC / MS ESI(+): 202.7 (M+1). <Production Example c-3> 7-Fluoro-1-phenylquinoxaline-2,3(1H,4H)-dione Production A reaction solution prepared by dissolving 5-fluoro-N 1 -Phenylbenzene-1,2-diamine (1.0 equivalent) in diethyl oxalate (6.0 equivalents) was stirred at 160 °C for 24 hours. After cooling the reaction solution to room temperature, the reaction solution was filtered and dried to produce 7-fluoro-1-phenylquinoxaline-2,3(1H,4H)-dione. White solid (yield 86%); 11H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 7.64 - 7.54 (m, 3H), 7.40 - 7.38 (m, 2H), 7.22 (dd, J = 8.8, 5.3 Hz, 1H), 7.04 - 6.68 (m, 1H), 5.99 (dd, J = 10.2, 2.7 Hz, 1H); LC / MS ESI(+): 256.6 (M + 1). <Production Example c-4> Production of 7-Fluoro-1-phenyl-1,2,3,4-tetrahydroquinoxaline To a solution of 7-fluoro-1-phenylquinoxaline-2,3(1H,4H)-dione (1.0 equivalent) obtained in Production Example c-3 dissolved in THF (0.5 M), borane-THF complex (1 M) (3.0 equivalents) was slowly added at room temperature, and then the mixture was stirred at 65 °C for 16 hours. After the reaction solution was cooled to room temperature, water was added to terminate the reaction, and then it was neutralized with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce 7-fluoro-1-phenyl-1,2,3,4-tetrahydroquinoxaline. Brown solid (yield 38%); 1 1H NMR (400 MHz, CDCl3) δ 7.38 - 7.34 (m, 2H), 7.25 - 7.20 (m, 2H), 7.13 - 7.09 (m, 1H), 6.52 - 6.46 (m, 2H), 6.39 - 6.33 (m, 1H), 3.71 - 3.68 (m, 2H), 3.46 - 3.44 (m, 2H); LC / MS ESI(+): 228.9 (M + 1). <Example 65> Synthesis of (R)-6-Fluoro-4-phenyl-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide 7-Fluoro-1-phenyl-1,2,3,4-tetrahydroquinoxaline (120 mg, 0.52 mmol) obtained in Production Example c-4 was dissolved in dichloromethane (5.0 mL), and TEA (220.0 μL, 1.57 mmol) and triphosgene (78 mg, 0.26 mmol) were slowly added at 0 °C, followed by stirring at 0 °C for 1 hour. TEA (220.0 μL, 1.57 mmol) and (R)-(+)-1-Boc-3-aminopyrrolidine (0.16 mL, 0.97 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The obtained concentrated solution was dissolved in dichloromethane (2.0 mL), TFA (490.0 μL, 5.20 mmol) was added, and the mixture was stirred at room temperature for 24 hours. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was used to synthesize (R)-6-fluoro-4-phenyl-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide using an n-hexane / ethyl acetate mixture. White solid (yield 60.6%); 1 1H NMR (400 MHz, CDCl3) δ 7.49 - 7.32 (m, 2H), 7.25 - 7.19 (m, 3H), 7.13 - 7.09 (m, 1H), 6.43 - 6.33 (m, 2H), 5.39 (s, 1H), 4.35 - 4.31 (m, 1H), 3.92 - 3.88 (m, 2H), 3.66 - 3.62 (m, 2H), 3.25 - 3.20 (m, 1H), 3.06 (s, 1H), 3.02 - 2.90 (m, 1H), 2.89 - 2.70 (m, 1H), 2.21 - 2.12 (m, 1H), 1.91 - 1.87 (m, 1H), 1.69 - 1.50 (m, 1H); LC / MS ESI(+): 341.0 (M + 1). [Reaction Formula 27] [Chemical Formula]

[0216] [Production Method d] Production of Chlorosubstituted Phenyl or Pyridine-1,2,3,4-tetrahydroquinoxaline The chloro-substituted phenyl or pyridine-1,2,3,4-tetrahydroquinoxaline according to the present invention was produced through the processes of Production Examples d-1 to d-11 below. <Production Example d-1> Production of tert-butyl 3,4-dihydroquinoxaline-1(2H)-carboxylate To a mixed solution of 1,2,3,4-tetrahydroquinoxaline (10.8 g, 80.48 mmol) and di-tert-butyl dicarbonate (18.5 mL, 80.48 mmol) dissolved in THF (200 mL), an aqueous 0.02 M NaOH solution (50 mL) was added, and the mixture was stirred at room temperature for 24 hours. After concentrating the reaction solution under reduced pressure, it was extracted with dichloromethane. The organic layer was dried over MgSO 4 4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce tert-butyl 3,4-dihydroquinoxaline-1(2H)-carboxylate. Yellow solid (yield 94%); 1 1H NMR (400 MHz, DMSO-d6) δ 7.29 (d, J = 8.1 Hz, 1H), 6.79 (ddd, J = 8.5, 7.2, 1.5 Hz, 1H), 6.54 (dd, J = 8.0, 1.5 Hz, 1H), 6.45 (ddd, J = 8.5, 7.2, 1.5 Hz, 1H), 6.01 (s, 1H), 3.60 - 3.53 (m, 2H), 3.27 - 3.20 (m, 2H), 1.44 (s, 9H). <Production Example d-2> Production of tert-butyl 4-benzyl-3,4-dihydroquinoxaline-1(2H)-carboxylate To a mixed solution of tert-butyl 3,4-dihydroquinoxaline-1(2H)-carboxylate (2.0 g, 8.54 mmol) obtained in Production Example d-1 and DIPEA (4.4 g, 34.15 mmol) dissolved in DMF (15.0 mL), benzyl bromide (1.7 g, 10.24 mmol) was added, and the mixture was stirred at 130 °C for 2 hours. After the reaction solution was cooled to room temperature, it was poured into water and extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce tert-butyl 4-benzyl-3,4-dihydroquinoxaline-1(2H)-carboxylate. Brown oil (yield 98.9%); 1 1H NMR (400 MHz, CD3CN) δ 7.40 - 7.29 (m, 3H), 7.28 - 7.19 (m, 3H), 6.84 (ddd, J = 8.6, 7.3, 1.6 Hz, 1H), 6.62 - 6.51 (m, 2H), 4.53 (s, 2H), 3.80 - 3.73 (m, 2H), 3.48 - 3.41 (m, 2H), 1.47 (s, 9H). <Production Example d-3> Production of 1-benzyl-1,2,3,4-tetrahydroquinoxaline To a mixed solution of tert-butyl 4-benzyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (2.7 g, 8.40 mmol) obtained in Production Example d-2 and TFA (6.4 mL, 84.00 mmol) dissolved in (15.0 mL), the mixture was stirred at room temperature for 12 hours. After completion of the reaction, toluene was added to the reaction solution, and the mixture was concentrated under reduced pressure. Then, water was added and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce 1-benzyl-1,2,3,4-tetrahydroquinoxaline. Brown solid (yield 80%); 11H NMR (400 MHz, CD3CN) δ 7.37 - 7.19 (m, 5H), 6.47 - 6.39 (m, 4H), 4.41 (s, 2H), 4.29 (brs, 1H), 3.37 (s, 4H); LC / MS ESI(+): 225.2 (M + 1). <Production Example d-4> Production of 1-benzyl-4-(2-chlorophenyl)-1,2,3,4-tetrahydroquinoxaline Dissolve 1-benzyl-1,2,3,4-tetrahydroquinoxaline (1.0 equivalent), sodium butoxide (2.0 equivalents), and 1-chloro-2-iodobenzene (3.0 equivalents) obtained in Production Example d-3 in toluene (0.3 M) sufficiently. Slowly add a mixed solution of Pd2dba (0.05 equivalent) and Xphos (0.15 equivalent) dissolved in toluene (0.6 M) heated at 110 °C for 5 minutes to the reaction solution, and stir at 110 °C for 15 hours. Cool to room temperature, filter the reaction solution through a celite pad, add water, and extract with dichloromethane. Dry the organic layer over MgSO4, filter, and then concentrate under reduced pressure. Purify the obtained residue by silica column chromatography using an n-hexane / ethyl acetate mixture to produce 1-benzyl-4-(2-chlorophenyl)-1,2,3,4-tetrahydroquinoxaline. Colorless oil (yield 99%); 1 1H NMR (400 MHz, DMSO-d6) δ 7.57 (dd, J = 8.0, 1.4 Hz, 1H), 7.47 - 7.31 (m, 6H), 7.30 - 7.21 (m, 2H), 6.61 - 6.49 (m, 2H), 6.37 (dd, J = 7.4, 1.9 Hz, 1H), 5.99 (dd, J = 8.0, 0.9 Hz, 1H), 3.72 - 3.59 (m, 2H), 3.57 - 3.42 (m, 2H); LC / MS ESI(+): 335.1 (M + 1). <Production Example d-5> Production of 1-benzyl-4-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline Although carried out in the same manner as in Production Example d-4, 1-benzyl-4-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline was produced using 2-bromopyridine instead of 1-chloro-2-iodobenzene. Yellow solid (yield 73%); 11H NMR (400 MHz, DMSO-d6) δ 8.22 (dd, J = 5.1, 1.2 Hz, 1H), 7.53 (ddd, J = 8.7, 6.9, 1.9 Hz, 1H), 7.35 - 7.19 (m, 5H), 7.15 (dd, J = 7.8, 1.6 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.86 (ddd, J = 8.6, 7.3, 1.5 Hz, 1H), 6.77 (dd, J = 7.0, 5.5 Hz, 1H), 6.70 (dd, J = 8.2, 1.2 Hz, 1H), 6.60 - 6.53 (m, 1H), 4.65 - 4.50 (m, 2H), 4.10 - 4.02 (m, 2H), 3.40 (t, J = 5.1 Hz, 2H); LC / MS ESI(+): 302.2 (M + 1). <Production Example d-6> Production of 1-Benzyl-4-(pyridin-3-yl)-1,2,3,4-tetrahydroquinoxaline Although carried out in the same manner as in Production Example d-4, 1-Benzyl-4-(pyridin-3-yl)-1,2,3,4-tetrahydroquinoxaline was produced using 3-iodopyridine instead of 1-chloro-2-iodobenzene. Yellow oil (yield 100%); 1 1H NMR (400 MHz, CD3CN) δ 8.46 (d, J = 2.7 Hz, 1H), 8.19 (dd, J = 4.7, 1.2 Hz, 1H), 7.50 (ddd, J = 8.4, 2.9, 1.6 Hz, 1H), 7.40 - 7.31 (m, 4H), 7.30 - 7.24 (m, 2H), 6.82 (dd, J = 8.2, 1.6 Hz, 1H), 6.78 - 6.72 (m, 1H), 6.70 - 6.65 (m, 1H), 6.55 - 6.49 (m, 1H), 4.57 (s, 2H), 3.80 - 3.74 (m, 2H), 3.52 - 3.46 (m, 2H); LC / MS ESI(+): 302.2 (M + 1). <Production Example d-7> Production of 1-Benzyl-4-(pyridin-4-yl)-1,2,3,4-tetrahydroquinoxaline Although carried out in the same manner as in Production Example d-4, 1-Benzyl-4-(pyridin-4-yl)-1,2,3,4-tetrahydroquinoxaline was produced using 4-iodopyridine instead of 1-chloro-2-iodobenzene. Red oil (yield 100%); 11H NMR (400 MHz, DMSO-d6) δ 8.26 - 8.19 (m, 2H), 7.31 (dd, J = 8.1, 6.8 Hz, 2H), 7.26 - 7.18 (m, 3H), 7.09 (dd, J = 7.9, 1.5 Hz, 1H), 7.05 - 6.99 (m, 2H), 6.89 (ddd, J = 8.6, 7.2, 1.5 Hz, 1H), 6.73 (dd, J = 8.3, 1.3 Hz, 1H), 6.62 - 6.53 (m, 1H), 4.56 (s, 2H), 3.84 (q, J = 5.9 Hz, 2H), 3.40 (t, J = 5.1 Hz, 2H); LC / MS ESI(+): 302.2 (M + 1). <Production Example d-8> Production of 1-(2-chlorophenyl)-1,2,3,4-tetrahydroquinoxaline A mixed solution of 1-benzyl-4-(2-chlorophenyl)-1,2,3,4-tetrahydroquinoxaline (1.0 equivalent) obtained in Production Example d-4 and Pd(OH)2 (0.6 equivalent) dissolved in MeOH / THF (v / v = 2:1, 0.3 M) was stirred at room temperature for 3 hours under hydrogen gas conditions. The reaction solution was filtered through a celite pad, water was added, and extraction was performed with dichloromethane. The organic layer was dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate / mixture to produce 1-(2-chlorophenyl)-1,2,3,4-tetrahydroquinoxaline. Gray solid (yield 62%); 1 1H NMR (400 MHz, DMSO-d6) δ 7.55 (dd, J = 8.0, 1.4 Hz, 1H), 7.43 - 7.35 (m, 1H), 7.34 - 7.30 (m, 1H), 7.28 - 7.21 (m, 1H), 6.54 - 6.49 (m, 2H), 6.31 (ddd, J = 8.2, 5.1, 3.5 Hz, 1H), 5.96 (d, J = 7.8 Hz, 1H), 3.54 - 3.46 (m, 2H), 3.35 (dd, J = 4.9, 2.2 Hz, 2H); LC / MS ESI(+): 245.1 (M + 1). <Production Example d-9> Production of 1-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline Although it was carried out in the same manner as Production Example d-8, 1-benzyl-4-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline obtained in Production Example d-5 was used instead of 1-benzyl-4-(2-chlorophenyl)-1,2,3,4-tetrahydroquinoxaline to produce 1-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline. Yellow solid (yield 78.2%); 1 H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 4.1 Hz, 1H), 7.42 (ddd, J = 8.5, 7.1, 2.0 Hz, 1H), 7.22 (dd, J = 8.4, 1.5 Hz, 1H), 7.16 (d, J = 8.5 Hz, 1H), 6.93 - 6.83 (m, 1H), 6.70 (ddd, J = 7.1, 4.9, 1.0 Hz, 1H), 6.67 - 6.55 (m, 2H), 4.08 (t, J = 4.8 Hz, 2H), 3.99 (brs, 1H), 3.41 (t, J = 4.8 Hz, 2H); LC / MS ESI(+): 212.2 (M+1). <Production Example d-10> Production of 1-(pyridin-3-yl)-1,2,3,4-tetrahydroquinoxaline Although it was carried out in the same manner as Production Example d-8, 1-benzyl-4-(pyridin-3-yl)-1,2,3,4-tetrahydroquinoxaline obtained in Production Example d-6 was used instead of 1-benzyl-4-(2-chlorophenyl)-1,2,3,4-tetrahydroquinoxaline to produce 1-(pyridin-3-yl)-1,2,3,4-tetrahydroquinoxaline. Brown oil (yield 83.1%); 1 H NMR (400 MHz, CD3CN) δ 8.45 (d, J = 2.7 Hz, 1H), 8.17 (dd, J = 4.7, 1.6 Hz, 1H), 7.50 (ddd, J = 8.3, 2.8, 1.8 Hz, 1H), 7.26 (dd, J = 8.2, 4.7 Hz, 1H), 6.81 - 6.71 (m, 2H), 6.66 - 6.61 (m, 1H), 6.54 - 6.47 (m, 1H), 4.63 (brs, 1H), 3.68 - 3.63 (m, 2H), 3.39 - 3.34 (m, 2H); LC / MS ESI(+): 212.2 (M+1). <Production Example d-11>Production of 1-(pyridin-4-yl)-1,2,3,4-tetrahydroquinoxaline Although carried out in the same manner as in Production Example d-8, 1-(pyridin-4-yl)-1,2,3,4-tetrahydroquinoxaline obtained in Production Example d-7 was used instead of 1-benzyl-4-(2-chlorophenyl)-1,2,3,4-tetrahydroquinoxaline to produce 1-(pyridin-4-yl)-1,2,3,4-tetrahydroquinoxaline. Yellow solid (yield 76.7%); 1 1H NMR (400 MHz, DMSO-d6) δ 8.25 - 8.18 (m, 2H), 7.06 - 7.00 (m, 3H), 6.85 (ddd, J = 8.4, 7.2, 1.4 Hz, 1H), 6.65 (dd, J = 8.1, 1.5 Hz, 1H), 6.50 (ddd, J = 8.0, 7.2, 1.5 Hz, 1H), 6.09 (s, 1H), 3.70 - 3.63 (m, 2H), 3.29 - 3.21 (m, 2H); LC / MS ESI(+): 212.1 (M+1). [Reaction Formula 28]

Chemical Structure

[0217] <Example 66>Synthesis of (4-(2-chlorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(piperidin-1-yl)methanone 1-(2-Chlorophenyl)-1,2,3,4-tetrahydroquinoxaline (1.0 eq) obtained in Production Example d-8 was dissolved in dichloromethane (0.3 M), and TEA (3.0 eq) and triphosgene (0.6 eq) were slowly added at 0 °C, followed by stirring at 0 °C for 1 hour. TEA (2.0 eq) and piperidine (1.2 eq) were added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After adding water to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to synthesize (4-(2-chlorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(piperidin-1-yl)methanone. Light yellow oil (yield 34.8%); 1 1H NMR (400 MHz, CDCl3) δ 7.55 - 7.48 (m, 1H), 7.36 - 7.31 (m, 2H), 7.26 - 7.21 (m, 1H), 7.02 (dd, J = 8.0, 1.6 Hz, 1H), 6.77 - 6.70 (m, 1H), 6.69 - 6.62 (m, 1H), 6.21 (dd, J = 8.0, 1.5 Hz, 1H), 3.84 (t, J = 5.0 Hz, 2H), 3.69 (t, J = 4.1 Hz, 2H), 3.38 - 3.31 (m, 4H), 1.61 - 1.48 (m, 6H); LC / MS ESI(+): 342.2 (M + 1). <Example 67>Synthesis of (4-(2-chlorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(pyrrolidin-1-yl)methanone Although carried out in the same manner as in Example 66, (4-(2-chlorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(pyrrolidin-1-yl)methanone was synthesized using pyrrolidine instead of piperidine. Light yellow oil (yield 54.5%); 11H NMR (400 MHz, CDCl3) δ 7.54 - 7.49 (m, 1H), 7.36 - 7.32 (m, 2H), 7.28 - 7.26 (m, 1H), 6.95 (dd, J = 7.9, 1.6 Hz, 1H), 6.77 - 6.70 (m, 1H), 6.69 - 6.63 (m, 1H), 6.19 (dd, J = 8.0, 1.5 Hz, 1H), 3.90 (t, J = 5.1 Hz, 2H), 3.75 - 3.69 (m, 2H), 3.40 - 3.33 (m, 4H), 1.89 - 1.78 (m, 4H); LC / MS ESI(+): 356.2 (M + 1). <Example 68>Synthesis of (4-(2-Chlorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(4-methylpiperazin-1-yl)methanone Although carried out in the same manner as in Example 66, (4-(2-Chlorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(4-methylpiperazin-1-yl)methanone was synthesized using N-methylpiperazine instead of piperidine. Light yellow oil (yield 51.6%); 1 1H NMR (400 MHz, CDCl3) δ 7.53 - 7.48 (m, 1H), 7.40 - 7.26 (m, 3H), 7.05 (dd, J = 8.0, 1.6 Hz, 1H), 6.80 - 6.71 (m, 1H), 6.70 - 6.62 (m, 1H), 6.20 (dd, J = 8.1, 1.5 Hz, 1H), 3.87 (t, J = 5.0 Hz, 2H), 3.70 (t, J = 4.3 Hz, 2H), 3.46 - 3.39 (m, 4H), 2.38 (t, J = 5.1 Hz, 5H), 2.29 (s, 3H); LC / MS ESI(+): 371.2 (M + 1). [Reaction Scheme 29] [Chemical Formula]

[0218] <Production Example d-12>Production of tert-Butyl (S)-3-(4-(Pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate 1-(Pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline (1.0 equivalent) obtained in Production Example d-9 was dissolved in dichloromethane (0.3 M), and TEA (3.0 equivalents) and triphosgene (0.6 equivalent) were slowly added at 0 °C and stirred at 0 °C for 1 hour. TEA (2.0 equivalents) and (S)-(-)-1-Boc-3-aminopyrrolidine (1.2 equivalents) were added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After adding water to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce tert-butyl (S)-3-(4-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate. White solid (yield 97%); 1 1H NMR (400 MHz, CD3OD) δ 8.25 - 8.24 (m, 1H), 7.67 - 7.62 (m, 1H), 7.45 (dd, J = 8.3, 1.3 Hz, 1H), 7.34 - 7.32 (m, 1H), 7.24 - 7.19 (m, 1H), 7.10 - 7.01 (m, 2H), 6.92 (ddd, J = 7.3, 5.0, 0.9 Hz, 1H), 4.34 - 4.28 (m, 1H), 4.02 - 3.97 (m, 2H), 3.92 - 3.84 (m, 2H), 3.65 - 3.59 (m, 1H), 3.49 - 3.36 (m, 2H), 3.24 - 3.20 (m, 1H), 2.20 - 2.11 (m, 1H), 1.95 - 1.87 (m, 1H), 1.47 (s, 9H). <Production Example d-13> Production of (S)-4-(pyridin-2-yl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The Boc group of tert-butyl (S)-3-(4-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate obtained in Production Example d-12 was deprotected with TFA to produce (S)-4-(pyridin-2-yl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. White solid (yield 48%); 1 1H NMR (400 MHz, CDCl3) δ 8.32 - 8.30 (m, 1H), 7.56 - 7.51 (m, 1H), 7.47 (dd, J = 8.1, 1.4 Hz, 1H), 7.33 (dd, J = 7.9, 1.5 Hz, 1H), 7.16 - 7.15 (m, 1H), 7.08 - 7.03 (m, 1H), 7.01 - 6.94 (m, 1H), 6.84 (ddd, J = 7.2, 4.9, 0.8 Hz, 1H), 5.34 (d, J = 6.9 Hz, 1H), 4.36 - 4.28 (m, 1H), 4.03 - 3.94 (m, 4H), 3.19 - 3.14 (m, 1H), 3.05 - 2.99 (m, 1H), 2.95 - 2.88 (m, 1H), 2.80 - 2.76 (m, 1H), 2.46 (brs, 1H), 2.19 - 2.10 (m, 1H), 1.63 - 1.55 (m, 1H); LC / MS ESI(+): 324.2 (M+1). <Example 69>Synthesis of (S)-N-(1-Isopropylpyrrolidin-3-yl)-4-(pyridin-2-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The (S)-4-(pyridin-2-yl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (1.0 equivalent) obtained in Production Example d-13 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 equivalents) and acetone (2.0 equivalents) were added, and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize (S)-N-(1-isopropylpyrrolidin-3-yl)-4-(pyridin-2-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Pale yellow oil (yield 48%); 11H NMR (400 MHz, CD3OD) δ 8.25 - 8.21 (m, 1H), 7.64 - 7.58 (m, 1H), 7.48 - 7.46 (m, 1H), 7.34 - 7.31 (m, 1H), 7.22 - 7.18 (m, 1H), 7.10 - 7.01 (m, 2H), 6.90 (ddd, J = 7.2, 5.1, 0.9 Hz, 1H), 4.37 - 4.30 (m, 1H), 3.99 - 3.95 (m, 2H), 3.93 - 3.80 (m, 2H), 2.90 - 2.81 (m, 2H), 2.62 - 2.59 (m, 1H), 2.54 - 2.48 (m, 1H), 2.45 - 2.39 (m, 1H), 2.32 - 2.23 (m, 1H), 1.71 - 1.63 (m, 1H), 1.10 (t, J = 7.1, 6.6 Hz, 6H); LC / MS ESI(+): 366.3 (M + 1). [Reaction Formula 30] [Chemical Formula]

[0219] <Production Example d-14>Production of tert-butyl (R)-3-(4-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate Although carried out in the same manner as in Production Example d-12, tert-butyl (R)-3-((4-pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate was produced using (R)-(+)-1-Boc-3-aminopyrrolidine instead of (S)-(-)-1-Boc-3-aminopyrrolidine. Light yellow oil (yield 89%); 11H NMR (400 MHz, CDCl3) δ 8.33 - 8.27 (m, 1H), 7.58 - 7.49 (m, 1H), 7.46 (dd, J = 8.2, 1.4 Hz, 1H), 7.28 - 7.22 (m, 1H), 7.18 - 7.11 (m, 1H), 7.10 - 7.02 (m, 1H), 6.99 - 6.93 (m, 1H), 6.87 - 6.80 (m, 1H), 5.20 (d, J = 6.7 Hz, 1H), 4.38 (s, 1H), 4.02 - 3.97 (m, 2H), 3.66 - 3.58 (m, 1H), 3.42 - 3.35 (m, 3H), 3.13 (s, 1H), 1.45 - 1.41 (m, 12H); LC / MS ESI(+): 424.1 (M + 1). <Production Example d-15> Production of (R)-4-(pyridin-2-yl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The Boc group of tert-butyl (R)-3-((4-pyridin-2-yl)-1,2,3,4-tetrahydroquinoxalin-1-carboxamido)methyl)pyrrolidine-1-carboxylate obtained in Production Example d-14 was deprotected with TFA to produce (R)-4-(pyridin-2-yl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Ivory-colored solid (yield 99%); 1 1H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 10.33 (s, 1H), 8.35 - 8.16 (m, 1H), 7.99 - 7.94 (m, 1H), 7.67 - 7.60 (m, 1H), 7.56 - 7.48 (m, 1H), 7.47 - 7.36 (m, 4H), 7.26 - 7.14 (m, 1H), 5.10 - 4.71 (m, 1H), 2.32 (d, J = 12.3 Hz, 1H), 1.32 - 1.19 (m, 1H), 1.03 (d, J = 6.7 Hz, 6H), 0.90 - 0.81 (m, 1H); LC / MS ESI(+): 324.1 (M + 1). <Example 70> Synthesis of (R)-N-(1-acetylpyrrolidin-3-yl)-4-(pyridin-2-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (R)-4-(Pyridin-2-yl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (1.0 equiv) obtained in Production Example d-15 was dissolved in THF (0.3 M), and TEA (1.0 equiv) and acetyl chloride (1.1 equiv) were added, followed by stirring at room temperature for 1 hour and 30 minutes. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize (R)-N-(1-acetylpyrrolidin-3-yl)-4-(pyridin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide. Ivory solid (yield 45%); 1 H NMR (400 MHz, CDCl3) δ 8.33 - 8.27 (m, 1H), 7.58 - 7.43 (m, 2H), 7.28 - 7.20 (m, 1H), 7.18 - 7.02 (m, 2H), 7.01 - 6.90 (m, 1H), 6.88 - 6.80 (m, 1H), 5.23 (d, J = 6.2 Hz, 1H), 4.47 - 4.37 (m, 1H), 4.04 - 3.93 (m, 3H), 3.82 - 3.68 (m, 1H), 3.56 - 3.44 (m, 2H), 3.33 - 3.22 (m, 1H), 2.20 - 2.10 (m, 1H), 2.02 (d, J = 9.0 Hz, 3H), 1.83 - 1.70 (m, 1H), 1.28 - 1.20 (m, 1H); LC / MS ESI(+): 366.1 (M + 1). [Reaction Scheme 31] [Chemical Formula]

[0220] <Production Example d-16> Production of tert-butyl (R)-3-((4-pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate Although it was carried out in the same manner as in Production Example d-12, tert-butyl (R)-3-((4-pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate was produced using (R)-1-Boc-3-(aminomethyl)pyrrolidine instead of (R)-(+)-1-Boc-3-aminopyrrolidine. Yellow oil (yield 100%); 1 1H NMR (400 MHz, CD3OD) δ 8.24 (ddd, J = 5.0, 2.0, 0.9 Hz, 1H), 7.62 (ddd, J = 8.5, 7.2, 2.0 Hz, 1H), 7.47 - 7.40 (m, 1H), 7.37 - 7.30 (m, 1H), 7.23 - 7.16 (m, 1H), 7.13 - 7.00 (m, 2H), 6.90 (ddd, J = 7.2, 5.0, 0.9 Hz, 1H), 4.02 - 3.95 (m, 2H), 3.93 - 3.81 (m, 2H), 3.47 - 3.35 (m, 2H), 3.30 - 3.13 (m, 2H), 3.08 - 2.98 (m, 1H), 2.50 - 2.35 (m, 1H), 2.02 - 1.86 (m, 1H), 1.71 - 1.56 (m, 1H), 1.44 (s, 9H); LC / MS ESI(+): 438.0 (M+1). <Example 71>Synthesis of (S)-4-(pyridin-2-yl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The Boc group of tert-butyl (R)-3-((4-pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate obtained in Production Example d-16 was deprotected with TFA to synthesize (S)-4-(pyridin-2-yl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Yellow oil (yield 100%); 11H NMR (400 MHz, CD3OD) δ 8.27 - 8.21 (m, 1H), 7.64 (ddd, J = 8.5, 7.2, 2.0 Hz, 1H), 7.48 - 7.41 (m, 1H), 7.39 - 7.31 (m, 1H), 7.23 - 7.16 (m, 1H), 7.14 - 7.01 (m, 3H), 6.92 (ddd, J = 7.2, 5.0, 0.9 Hz, 1H), 4.07 - 3.95 (m, 2H), 3.92 - 3.84 (m, 2H), 3.38 - 3.33 (m, 2H), 3.29 - 3.18 (m, 3H), 3.02 - 2.93 (m, 1H), 2.65 - 2.49 (m, 1H), 2.16 - 2.01 (m, 1H), 1.81 - 1.67 (m, 1H); LC / MS ESI(+): 338.0 (M + 1). [Reaction Formula 32] [Chemical Formula]

[0221] <Production Example d - 17> Production of tert - butyl (R) - 2 - ((4 - pyridin - 2 - yl) - 1,2,3,4 - tetrahydroquinoxaline - 1 - carboxamido)methyl)pyrrolidine - 1 - carboxylate Although carried out in the same manner as in Production Example d - 12, tert - butyl (R) - 3 - ((4 - pyridin - 2 - yl) - 1,2,3,4 - tetrahydroquinoxaline - 1 - carboxamido)methyl)pyrrolidine - 1 - carboxylate was produced using (R) - 1 - Boc - 2 - (aminomethyl)pyrrolidine instead of (S) - (-) - 1 - Boc - 3 - aminopyrrolidine. Yellow oil (yield 100%); 1 1H NMR (400 MHz, CDCl3) δ 8.32 - 8.26 (m, 1H), 7.61 - 7.56 (m, 1H), 7.50 - 7.42 (m, 1H), 7.40 - 7.36 (m, 1H), 7.18 - 7.11 (m, 1H), 7.05 - 6.99 (m, 2H), 6.81 - 6.75 (m, 1H), 6.59 - 6.54 (m, 1H), 4.10 - 3.83 (m, 4H), 3.46 - 3.19 (m, 3H), 2.03 - 1.66 (m, 4H), 1.40 (s, 9H); LC / MS ESI(+): 438.0 (M + 1). <Example 72>Synthesis of (R)-4-(pyridin-2-yl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The Boc group of tert-butyl (R)-3-((4-pyridin-2-yl)-1,2,3,4-tetrahydroquinoxalin-1-carboxamido)methyl)pyrrolidine-1-carboxylate obtained in Production Example d-17 was deprotected with TFA to synthesize (R)-4-(pyridin-2-yl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Yellow oil (yield 100%); 1 1H NMR (400 MHz, CD3OD) δ 8.24 (ddd, J = 5.0, 2.0, 0.9 Hz, 1H), 7.64 (ddd, J = 8.5, 7.2, 2.0 Hz, 1H), 7.50 (dd, J = 8.0, 1.6 Hz, 1H), 7.36 (dd, J = 8.0, 1.5 Hz, 1H), 7.20 (dd, J = 8.5, 0.9 Hz, 1H), 7.15 - 7.00 (m, 3H), 6.92 (ddd, J = 7.2, 5.0, 0.9 Hz, 1H), 4.04 - 3.98 (m, 2H), 3.95 - 3.89 (m, 2H), 3.73 - 3.61 (m, 1H), 3.53 - 3.41 (m, 2H), 3.28 - 3.15 (m, 2H), 2.16 - 1.90 (m, 3H), 1.81 - 1.69 (m, 1H); LC / MS ESI(+): 338.0 (M+1). [Reaction Formula 33]

Chemical Structure

[0222] <Example 73>Synthesis of (R)-4-(pyridin-3-yl)-N-(tetrahydrofuran-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide 1-(Pyridin-3-yl)-1,2,3,4-tetrahydroquinoxaline (1.0 eq) obtained in the above Production Example d-10 was dissolved in dichloromethane (0.3 M), and TEA (3.0 eq) and triphosgene (0.6 eq) were slowly added at 0 °C, followed by stirring at 0 °C for 1 hour. TEA (2.0 eq) and (R)-3-aminotetrahydrofuran (1.2 eq) were added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After adding water to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to synthesize (R)-4-(pyridin-3-yl)-N-(tetrahydrofuran-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide. Yellow solid (yield 97%); 1 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 2.4 Hz, 1H), 8.41 (dd, J = 4.8, 1.4 Hz, 1H), 7.61 - 7.58 (m, 1H), 7.34 - 7.31 (m, 1H), 7.24 - 7.20 (m, 1H), 6.98 - 6.93 (m, 1H), 6.84 - 6.82 (m, 2H), 5.45 (d, J = 6.9 Hz, 1H), 4.53 - 4.46 (m, 1H), 4.03 - 3.84 (m, 4H), 3.82 - 3.67 (m, 4H), 2.33 - 2.24 (m, 1H), 1.84 - 1.76 (m, 1H); LC / MS ESI(+): 325.0 (M + 1). [Reaction Scheme 34] [Chemical Formula]

[0223] <Example 74> Synthesis of N-(Cyclopropylmethyl)-4-(pyridin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide 1-(Pyridin-3-yl)-1,2,3,4-tetrahydroquinoxaline (1.0 equiv) obtained in the above Production Example d-11 was dissolved in dichloromethane (0.3 M), and TEA (3.0 equiv) and triphosgene (0.6 equiv) were slowly added at 0 °C, followed by stirring at 0 °C for 1 h. TEA (2.0 equiv) and cyclopropylmethylamine (1.2 equiv) were added to the reaction mixture, and the mixture was stirred at room temperature for 3 h. After adding water to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to synthesize N-(cyclopropylmethyl)-4-(pyridin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide. Light yellow solid (yield 37%); 1 1H NMR (400 MHz, CDCl3) δ 8.40 - 8.34 (m, 2H), 7.43 - 7.40 (m, 1H), 7.39 - 7.36 (m, 1H), 7.14 - 7.10 (m, 1H), 7.07 - 7.03 (m, 3H), 5.28 - 5.24 (m, 1H), 4.00 - 3.97 (m, 2H), 3.84 - 3.80 (m, 2H), 3.14 (dd, J = 7.1, 5.4 Hz, 1H), 1.01 - 0.91 (m, 1H), 0.51 - 0.46 (m, 2H), 0.20 - 0.16 (m, 2H); LC / MS ESI(+) : 309.1 (M + 1). [Reaction Scheme 35] [Chemical Formula]

[0224] <Production Method e> Production of Halogen-Substituted Pyridine, Cyano Phenyl or Pyrazine-1,2,3,4-tetrahydroquinoxaline The halogen-substituted pyridine, cyano phenyl or pyrazine-1,2,3,4-tetrahydroquinoxaline according to the present invention was produced through the processes of the following Production Examples e-1 to e-6. <Production Example e-1> Production of tert-Butyl 4-(5-Fluoropyridin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate Tert-butyl 3,4-dihydroquinoxaline-1(2H)-carboxylate (1.0 eq) obtained in the above Production Example d-1, sodium butoxide (2.0 eq), and 5-fluoro-2-bromopyridine (3.0 eq) are completely dissolved in toluene (0.3 M). A mixed solution of Pd2dba (0.05 eq) and Xphos (0.15 eq) dissolved in toluene (0.6 M) and heated at 110 °C for 5 minutes is slowly added to the reaction solution, and the mixture is stirred at 110 °C for 15 hours. The reaction solution is cooled to room temperature, filtered through a celite pad, water is added, and the mixture is extracted with dichloromethane. The organic layer is dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue is purified by silica column chromatography using an n-hexane / ethyl acetate / mixture to produce tert-butyl 4-(5-fluoropyridin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate. Red oil (yield 93%); 1 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 3.0 Hz, 1H), 7.79 (s, 1H), 7.25 - 7.20 (m, 2H), 7.19 - 7.12 (m, 1H), 7.03 - 6.92 (m, 2H), 4.06 - 3.99 (m, 2H), 3.91 - 3.83 (m, 2H), 1.53 (s, 9H); LC / MS ESI(+): 330.1 (M + 1). <Production Example e-2> Production of tert-butyl 4-(4-cyanophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate Although carried out in the same manner as in the above Production Example e-1, tert-butyl 4-(4-cyanophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate was produced using 4-iodobenzonitrile instead of 2-bromo-3-fluoropyridine. Yellow solid (yield 89%); 1 1H NMR (400 MHz, CD3OD) δ 7.68 - 7.61 (m, 1H), 7.61 - 7.54 (m, 2H), 7.32 - 7.24 (m, 2H), 7.17 - 7.08 (m, 1H), 7.03 - 6.91 (m, 2H), 3.90 - 3.77 (m, 4H), 1.50 (s, 9H). <Production Example e-3>Production of tert-butyl 4-(pyrazin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate Although carried out in the same manner as in Production Example e-1, tert-butyl 4-(pyrazin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate was produced using 2-chloropyrazine instead of 2-bromo-3-fluoropyridine. Orange solid (yield 85%); 1 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 1.6 Hz, 1H), 8.16 (dd, J = 2.7, 1.5 Hz, 1H), 7.98 (d, J = 2.7 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.40 - 7.34 (m, 1H), 7.12 - 7.00 (m, 2H), 4.12 - 4.04 (m, 2H), 3.93 - 3.86 (m, 2H), 1.53 (s, 9H). <Production Example e-4>Production of 1-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline The Boc group of tert-butyl 4-(5-fluoropyridin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate obtained in Production Example e-1 was deprotected with TFA to produce 1-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline. Red oil (yield 91%); 1 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 3.0 Hz, 1H), 7.23 - 7.09 (m, 3H), 6.92 - 6.83 (m, 1H), 6.69 - 6.59 (m, 2H), 4.07 - 3.89 (m, 3H), 3.43 - 3.37 (m, 2H); LC / MS ESI(+): 230.1 (M + 1). <Production Example e-5>Production of 4-(3,4-dihydroquinoxalin-1(2H)-yl)benzonitrile The Boc group of tert-butyl 4-(4-cyanophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate obtained in Production Example e-2 was deprotected with TFA to produce 4-(3,4-dihydroquinoxalin-1(2H)-yl)benzonitrile. Yellow solid (yield 89%); 1 1H NMR (400 MHz, CD3OD) δ 7.56 - 7.47 (m, 2H), 7.24 - 7.14 (m, 2H), 7.01 - 6.94 (m, 1H), 6.85 - 6.76 (m, 1H), 6.69 - 6.62 (m, 1H), 6.57 - 6.48 (m, 1H), 3.74 - 3.67 (m, 2H), 3.35 - 3.28 (m, 2H); LC / MS ESI(+): 236.1 (M+1). <Production Example e-6> Production of 1-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinoxaline The Boc group of tert-butyl 4-(pyrazin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate obtained in Production Example e-3 was deprotected with TFA to produce 1-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinoxaline. Yellow oil (yield 88%); 1 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 1.6 Hz, 1H), 8.13 (dd, J = 2.7, 1.6 Hz, 1H), 7.92 (d, J = 2.7 Hz, 1H), 7.26 - 7.21 (m, 1H), 6.99 - 6.89 (m, 1H), 6.72 - 6.63 (m, 2H), 4.11 - 4.01 (m, 3H), 3.48 - 3.40 (m, 2H); LC / MS ESI(+): 230.1 (M+1). [Reaction Formula 36] [Chemical Formula]

[0225] <Production Example e-7> Production of tert-butyl (R)-3-(4-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate 1-(5-Fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline (1.0 eq) obtained in Production Example e-4 was dissolved in dichloromethane (0.3 M), and TEA (3.0 eq) and triphosgene (0.6 eq) were slowly added at 0 °C, followed by stirring at 0 °C for 1 hour. TEA (2.0 eq) and (R)-(+)-1-Boc-3-aminopyrrolidine (1.2 eq) were added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce tert-butyl (R)-3-(4-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate. Light yellow solid (yield 95.5%); 1 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 3.0 Hz, 1H), 7.39 - 7.28 (m, 2H), 7.26 - 7.13 (m, 2H), 7.10 - 7.02 (m, 1H), 6.99 - 6.90 (m, 1H), 5.27 - 5.19 (m, 1H), 4.49 - 4.31 (m, 1H), 4.01 - 3.87 (m, 4H), 3.68 - 3.59 (m, 1H), 3.47 - 3.33 (m, 2H), 3.22 - 3.08 (m, 1H), 2.22 - 2.09 (m, 1H), 1.89 - 1.70 (m, 1H), 1.45 (s, 9H); LC / MS ESI(+): 442.2 (M+1). <Production Example e-8> Production of (R)-4-(5-fluoropyridin-2-yl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The Boc group of tert-butyl (R)-3-(4-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate obtained in Production Example e-7 was deprotected with TFA to produce (R)-4-(5-fluoropyridin-2-yl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Light yellow solid (yield 68.9%); 1 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 3.0 Hz, 1H), 7.38 - 7.28 (m, 3H), 7.16 (dd, J = 9.1, 3.6 Hz, 1H), 7.09 - 7.00 (m, 1H), 6.98 - 6.91 (m, 1H), 5.31 (d, J = 6.9 Hz, 1H), 4.37 - 4.25 (m, 1H), 4.02 - 3.88 (m, 4H), 3.16 (dd, J = 11.3, 6.5 Hz, 1H), 3.06 - 2.96 (m, 1H), 2.95 - 2.85 (m, 1H), 2.77 (dd, J = 11.3, 4.0 Hz, 1H), 2.20 - 2.09 (m, 1H), 2.01 (s, 1H), 1.63 - 1.53 (m, 1H); LC / MS ESI(+): 342.2 (M + 1). <Example 75>Synthesis of (R)-4-(5-Fluoropyridin-2-yl)-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide Dissolve (R)-4-(5-Fluoropyridin-2-yl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (1.0 equivalent) obtained in Production Example e-8 in dichloromethane (0.3 M), add sodium triacetoxyborohydride (1.3 equivalents) and formaldehyde (1.1 equivalents), and stir at room temperature for 3 hours. After adding water to the reaction solution to terminate the reaction, it was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize (R)-4-(5-Fluoropyridin-2-yl)-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide. Light yellow oil (yield 85.6%); 11H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 3.0 Hz, 1H), 7.36 - 7.31 (m, 2H), 7.31 - 7.27 (m, 1H), 7.20 - 7.14 (m, 1H), 7.06 - 7.00 (m, 1H), 6.98 - 6.92 (m, 1H), 5.44 (d, J = 7.7 Hz, 1H), 4.46 - 4.31 (m, 1H), 4.03 - 3.82 (m, 4H), 2.83 - 2.74 (m, 1H), 2.61 - 2.48 (m, 2H), 2.37 - 2.26 (m, 4H), 2.25 - 2.14 (m, 1H), 1.64 - 1.51 (m, 1H); LC / MS ESI(+): 356.2 (M + 1). [Reaction Formula 37] [Chemical Formula]

[0226] <Production Example e-9> Production of tert-butyl (R)-3-((4-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate Although carried out in the same manner as in Production Example e-7, tert-butyl (R)-3-((4-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate was produced using (R)-1-Boc-3-(aminomethyl)pyrrolidine instead of (R)-(+)-1-Boc-3-aminopyrrolidine. White solid (yield 87.5%); 1 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 3.0 Hz, 1H), 7.40 - 7.27 (m, 3H), 7.20 - 7.03 (m, 2H), 6.99 - 6.93 (m, 1H), 5.33 - 5.28 (m, 1H), 4.00 - 3.90 (m, 4H), 3.55 - 3.32 (m, 2H), 3.31 - 3.21 (m, 2H), 3.20 - 3.09 (m, 1H), 3.06 - 2.92 (m, 1H), 2.44 - 2.37 (m, 1H), 2.01 - 1.89 (m, 1H), 1.64 (s, 1H), 1.45 (s, 9H); LC / MS ESI(+): 456.2 (M + 1). <Production Example e-10>Production of (S)-4-(5-Fluoropyridin-2-yl)-N-(1-pyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The Boc group of tert-butyl (R)-3-((4-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxalin-1-carboxamide)methyl)pyrrolidine-1-carboxylate obtained in Production Example e-9 was deprotected with TFA to produce (S)-4-(5-fluoropyridin-2-yl)-N-(1-pyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Light yellow solid (yield 83.1%); 1 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 3.0 Hz, 1H), 7.38 - 7.27 (m, 3H), 7.18 - 7.12 (m, 1H), 7.08 - 7.02 (m, 1H), 6.98 - 6.93 (m, 1H), 5.49 (t, J = 5.5 Hz, 1H), 3.97 - 3.92 (m, 4H), 3.31 - 3.20 (m, 2H), 3.04 - 2.97 (m, 2H), 2.93 - 2.84 (m, 1H), 2.70 - 2.61 (m, 1H), 2.37 - 2.29 (m, 2H), 1.96 - 1.83 (m, 1H), 1.52 - 1.37 (m, 1H); LC / MS ESI(+): 356.2 (M+1). <Example 76>Synthesis of (R)-4-(5-Fluoropyridin-2-yl)-N-(1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (S)-4-(5-Fluoropyridin-2-yl)-N-(1-pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (1.0 eq) obtained in Production Example e-10 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.3 eq) and formaldehyde (1.1 eq) were added, and the mixture was stirred at room temperature for 3 hours. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize (R)-4-(5-fluoropyridin-2-yl)-N-(1-methylpyrrolidin-3-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Light yellow oil (yield 83.7%); 1 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 3.0 Hz, 1H), 7.37 - 7.31 (m, 2H), 7.30 - 7.27 (m, 1H), 7.18 - 7.10 (m, 1H), 7.07 - 7.00 (m, 1H), 6.99 - 6.91 (m, 1H), 6.06 - 6.02 (m, 1H), 4.07 - 3.77 (m, 4H), 3.33 - 3.18 (m, 2H), 2.67 - 2.57 (m, 1H), 2.48 - 2.34 (m, 3H), 2.34 - 2.24 (m, 1H), 2.04 - 1.91 (m, 1H), 1.57 - 1.47 (m, 1H); LC / MS ESI(+): 370.3 (M + 1). [Reaction Scheme 38] [Chemical Formula]

[0227] <Production Example e-11> Production of tert-butyl 4-((4-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide)methyl)piperidine-1-carboxylate Although carried out in the same manner as Production Example e-7, tert-butyl 4-(((4-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate was produced using 1-Boc-4-(aminomethyl)piperidine instead of (R)-(+)-1-Boc-3-aminopyrrolidine. White solid (yield 88.4%); 1 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 3.0 Hz, 1H), 7.40 - 7.27 (m, 3H), 7.18 - 7.11 (m, 1H), 7.07 (ddd, J = 8.2, 7.3, 1.6 Hz, 1H), 7.00 - 6.94 (m, H), 5.32 - 5.25 (m, 1H), 4.16 - 4.03 (m, 2H), 3.97 - 3.92 (m, 4H), 3.20 - 3.06 (m, 2H), 2.75 - 2.55 (m, 2H), 1.68 - 1.62 (m, 3H), 1.44 (s, 9H), 1.18 - 1.02 (m, 2H); LC / MS ESI(+): 470.2 (M+1). <Production Example e-12> Production of 4-(5-fluoropyridin-2-yl)-N-(1-piperidin-4-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The Boc group of tert-butyl 4-(((4-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate obtained in Production Example e-11 was deprotected with TFA to produce (4-(5-fluoropyridin-2-yl)-N-(1-piperidin-4-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Light yellow solid (yield 78.8%); 11H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 3.0 Hz, 1H), 7.39 - 7.27 (m, 3H), 7.19 - 7.11 (m, 1H), 7.10 - 7.03 (m, 1H), 7.00 - 6.93 (m, 1H), 5.32 - 5.24 (m, 1H), 3.97 - 3.92 (m, 4H), 3.17 - 3.04 (m, 4H), 2.64 - 2.50 (m, 2H), 2.15 - 2.10 (m, 1H), 1.73 - 1.54 (m, 3H), 1.23 - 1.07 (m, 2H); LC / MS ESI(+): 370.2 (M+1). <Example 77>Synthesis of 4-(5-Fluoropyridin-2-yl)-N-(1-methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Dissolve 4-(5-Fluoropyridin-2-yl)-N-(1-piperidin-4-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (1.0 equivalent), obtained in Production Example e-12, in dichloromethane (0.3 M), add sodium triacetoxyborohydride (1.3 equivalents) and formaldehyde (1.1 equivalents), and stir at room temperature for 3 hours. After adding water to the reaction solution to terminate the reaction, extract with dichloromethane. Wash the organic layer with brine, dry over MgSO4, filter, and then concentrate under reduced pressure. Purify the obtained residue by silica column chromatography using a dichloromethane / methanol mixture to synthesize 4-(5-Fluoropyridin-2-yl)-N-(1-methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. White solid (yield 88.5%); 11H NMR (400 MHz, CDCl3) δ 8.19 - 8.17 (m, 1H), 7.36 (dd, J = 8.2, 1.4 Hz, 1H), 7.34 - 7.27 (m, 2H), 7.18 - 7.12 (m, 1H), 7.09 - 7.03 (m, 1H), 7.00 - 6.93 (m, 1H), 5.31 - 5.21 (m, 1H), 3.97 - 3.92 (m, 4H), 3.19 - 3.11 (m, 2H), 2.87 - 2.78 (m, 2H), 2.25 (s, 3H), 1.94 - 1.83 (m, 2H), 1.70 - 1.66 (m, 2H), 1.55 - 1.41 (m, 1H), 1.33 - 1.19 (m, 2H); LC / MS ESI(+): 384.3 (M + 1). [Reaction Formula 39] [Chemical Formula]

[0228] <Production Example e - 13>Production of tert - butyl (S)-(1-(4-(5 - fluoropyridin - 2 - yl)-1,2,3,4 - tetrahydroquinoxaline - 1 - carbonyl)pyrrolidin - 3 - yl)carbamate Although carried out in the same manner as in Production Example e - 7, tert - butyl (S)-(1-(4-(5 - fluoropyridin - 2 - yl)-1,2,3,4 - tetrahydroquinoxaline - 1 - carbonyl)pyrrolidin - 3 - yl)carbamate was produced using (S)-(-)-3-(Boc - amino)pyrrolidine instead of (R)-(+)-1 - Boc - 3 - aminopyrrolidine. White solid (yield 98.4%); 1 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 3.0 Hz, 1H), 7.36 - 7.29 (m, 1H), 7.25 - 7.21 (m, 1H), 7.18 - 7.11 (m, 1H), 7.06 - 6.98 (m, 1H), 6.97 - 6.90 (m, 2H), 4.20 - 4.06 (m, 1H), 4.05 - 3.96 (m, 2H), 3.91 - 3.77 (m, 2H), 3.58 - 3.29 (m, 4H), 3.14 - 3.05 (m, 1H), 2.13 - 2.06 (m, 1H), 1.82 - 1.73 (m, 1H), 1.39 (s, 9H); LC / MS ESI(+): 456.3 (M + 1). <Example 78> Synthesis of (S)-(3-aminopyrrolidin-1-yl)(4-(5-fluoropyridin-2-yl)-3,4-dihydroquinoxalin-1(2H)-methanone The Boc group of tert-butyl (S)-(1-(4-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)carbamate obtained in Production Example e-13 was deprotected with TFA to synthesize (S)-(3-aminopyrrolidin-1-yl)(4-(5-fluoropyridin-2-yl)-3,4-dihydroquinoxalin-1(2H)-methanone. White solid (yield 71.5%); 1 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 3.0 Hz, 1H), 7.36 - 7.28 (m, 1H), 7.26 - 7.20 (m, 1H), 7.14 (dd, J = 9.2, 3.6 Hz, 1H), 7.07 - 7.01 (m, 1H), 6.97 - 6.90 (m, 2H), 4.01 (t, J = 6.3 Hz, 2H), 3.92 - 3.75 (m, 2H), 3.58 - 3.31 (m, 4H), 3.00 (dd, J = 10.3, 4.5 Hz, 1H), 2.07 - 1.97 (m, 1H), 1.68 - 1.55 (m, 1H), 1.33 - 1.27 (m, 2H); LC / MS ESI(+): 342.2 (M+1). [Reaction Formula 40]

Chemical Formula

[0229] <Production Example e-14> Production of tert-butyl (R)-3-((4-(4-cyanophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate 4-(3,4-Dihydroquinoxalin-1(2H)-yl)benzonitrile (1.0 eq) obtained in Production Example e-5 was dissolved in dichloromethane (0.3 M), and TEA (3.0 eq) and triphosgene (0.6 eq) were slowly added at 0 °C, followed by stirring at 0 °C for 1 hour. TEA (2.0 eq) and (R)-1-Boc-3-(aminomethyl)pyrrolidine (1.2 eq) were added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After adding water to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize tert-butyl (R)-3-(((4-(4-cyanophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate). Ivory-colored solid (yield 91%); 1 H NMR (400 MHz, CD3OD) δ 7.63 - 7.54 (m, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.35 - 7.27 (m, 2H), 7.22 (dd, J = 7.9, 1.7 Hz, 1H), 7.12 - 6.98 (m, 2H), 3.93 - 3.78 (m, 4H), 3.44 - 3.32 (m, 2H), 3.29 - 3.10 (m, 3H), 3.05 - 2.95 (m, 1H), 2.46 - 2.34 (m, 1H), 1.99 - 1.86 (m, 1H), 1.69 - 1.54 (m, 1H), 1.42 (d, J = 5.2 Hz, 9H). <Example 79>Synthesis of (S)-4-(4-Cyanophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The Boc group of tert-butyl (R)-3-(((4-(4-cyanophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate) obtained in Production Example e-14 was deprotected with TFA to synthesize (S)-4-(4-cyanophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Ivory-colored solid (yield 17%); 11H NMR (400 MHz, CD3OD) δ 7.67 - 7.56 (m, 2H), 7.44 - 7.36 (m, 1H), 7.35 - 7.28 (m, 2H), 7.26 - 7.20 (m, 1H), 7.12 - 6.99 (m, 2H), 3.94 - 3.79 (m, 4H), 3.24 - 3.08 (m, 2H), 2.99 - 2.78 (m, 3H), 2.58 (dd, J = 11.2, 6.5 Hz, 1H), 2.43 - 2.27 (m, 1H), 1.94 - 1.81 (m, 1H), 1.52 - 1.39 (m, 1H); LC / MS ESI(+): 362.1 (M+1). [Reaction Formula 41] [Chemical Formula]

[0230] <Production Example e-15> Production of tert-butyl (S)-3-(4-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate Dissolve 1-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinoxaline (1.0 equivalent) obtained in Production Example e-6 in dichloromethane (0.3 M), and slowly add TEA (3.0 equivalents) and triphosgene (0.6 equivalent) at 0 °C, and stir at 0 °C for 1 hour. Add TEA (2.0 equivalents) and (S)-(-)-1-Boc-3-aminopyrrolidine (1.2 equivalents) to the reaction solution, and stir at room temperature for 3 hours. After adding water to the reaction solution to terminate the reaction, extract with dichloromethane. Wash the organic layer with brine, dry over MgSO4, filter, and then concentrate under reduced pressure. Purify the obtained residue by silica column chromatography using an n-hexane / ethyl acetate mixture to produce tert-butyl (S)-3-(4-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate. Light yellow solid (yield 87.6%); 11H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 1.5 Hz, 1H), 8.21 (dd, J = 2.6, 1.5 Hz, 1H), 8.05 (d, J = 2.7 Hz, 1H), 7.54 (dd, J = 8.1, 1.5 Hz, 1H), 7.32 (dd, J = 7.9, 1.6 Hz, 1H), 7.19 - 7.02 (m, 2H), 5.18 (d, J = 6.7 Hz, 1H), 4.40 (s, 1H), 4.07 - 3.91 (m, 4H), 3.65 (t, J = 9.4 Hz, 1H), 3.47 - 3.32 (m, 2H), 3.24 - 3.11 (m, 1H), 2.23 - 2.07 (m, 1H), 1.80 (s, 1H), 1.45 (s, 9H); LC / MS ESI(+): 425.2 (M + 1). <Example 80> Synthesis of (S)-4-(Pyrazin-2-yl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The Boc group of tert-butyl (S)-3-(4-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate obtained in Production Example e-15 was deprotected with TFA to synthesize (S)-4-(pyrazin-2-yl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Ivory-colored solid (yield 76.9%); 1 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 1.5 Hz, 1H), 8.20 (dd, J = 2.7, 1.6 Hz, 1H), 8.03 (d, J = 2.7 Hz, 1H), 7.51 (dd, J = 7.9, 1.6 Hz, 1H), 7.37 (dd, J = 7.8, 1.7 Hz, 1H), 7.16 - 7.01 (m, 2H), 5.29 (d, J = 6.9 Hz, 1H), 4.38 - 4.26 (m, 1H), 4.05 - 4.00 (m, 2H), 4.00 - 3.91 (m, 2H), 3.20 - 3.12 (m, 1H), 3.07 - 2.97 (m, 1H), 2.96 - 2.85 (m, 1H), 2.82 - 2.74 (m, 1H), 2.24 - 2.08 (m, 1H), 2.01 - 1.98 (m, 1H), 1.65 - 1.52 (m, 1H); LC / MS ESI(+): 325.1 (M + 1). <Example 81>Synthesis of (S)-N-(1-Isopropylpyrrolidin-3-yl)-4-(pyrazin-2-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The (S)-4-(pyrazin-2-yl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (1.0 equivalent) obtained in Example 80 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 equivalents) and acetone (2.0 equivalents) were added, and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize (S)-N-(1-isopropylpyrrolidin-3-yl)-4-(pyrazin-2-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Yellow solid (yield 64.6%); 1 1H NMR (400 MHz, CH3CN) δ 8.62 (d, J = 1.6 Hz, 1H), 8.20 (dd, J = 2.7, 1.5 Hz, 1H), 8.03 (d, J = 2.6 Hz, 1H), 7.50 (dd, J = 7.9, 1.6 Hz, 1H), 7.39 (dd, J = 7.7, 1.8 Hz, 1H), 7.15 - 7.01 (m, 2H), 5.43 (d, J = 7.6 Hz, 1H), 4.44 - 4.33 (m, 1H), 4.05 - 3.90 (m, 4H), 2.90 - 2.79 (m, 1H), 2.73 - 2.60 (m, 2H), 2.39 - 2.21 (m, 3H), 1.65 - 1.51 (m, 1H), 1.09 - 1.01 (m, 6H); LC / MS ESI(+): 367.2 (M + 1). [Reaction Scheme 42]

Chemical formula

[0231] <Production Example e-16>Production of tert-Butyl (4-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide) Piperidine-1-carboxylate Although it was carried out in the same manner as Production Example e-15, tert-butyl (4-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide) piperidine-1-carboxylate was produced using 1-Boc-4-aminopiperidine instead of (S)-(-)-1-Boc-3-aminopyrrolidine. Light yellow solid (yield 85.3%); 1 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 1.5 Hz, 1H), 8.21 (dd, J = 2.7, 1.5 Hz, 1H), 8.04 (d, J = 2.6 Hz, 1H), 7.53 (dd, J = 8.1, 1.5 Hz, 1H), 7.34 (dd, J = 7.8, 1.6 Hz, 1H), 7.17 - 7.02 (m, 2H), 5.03 (d, J = 7.6 Hz, 1H), 4.17 - 3.93 (m, 6H), 3.92 - 3.78 (m, 1H), 2.87 (t, J = 12.9 Hz, 1H), 1.99 - 1.88 (m, 2H), 1.44 (s, 9H), 1.35 - 1.21 (m, 2H); LC / MS ESI(+): 425.2. <Production Example e-17>Production of N-(1-piperidin-4-yl)-4-(pyrazin-2-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The Boc group of tert-butyl (4-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide) piperidine-1-carboxylate obtained in Production Example e-16 was deprotected with TFA to produce N-(1-piperidin-4-yl)-4-(pyrazin-2-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Light yellow solid (yield 84.0%); 11H NMR (400 MHz, CDCl3) δ 8.60 (dd, J = 1.5, 0.4 Hz, 1H), 8.20 (dd, J = 2.7, 1.5 Hz, 1H), 8.04 (dd, J = 2.7, 0.4 Hz, 1H), 7.56 - 7.48 (m, 1H), 7.40 - 7.32 (m, 1H), 7.17 - 7.02 (m, 2H), 5.06 (d, J = 7.7 Hz, 1H), 4.06 - 3.92 (m, 4H), 3.87 - 3.73 (m, 1H), 3.09 - 2.99 (m, 2H), 2.75 - 2.63 (m, 2H), 2.02 - 1.92 (m, 2H), 1.67 - 1.64 (m, 1H), 1.36 - 1.22 (m, 2H); LC / MS ESI(+): 339.2 (M+1). <Example 82>Synthesis of N-(1-Isobutylpiperidin-4-yl)-4-(pyrazin-2-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Dissolve N-(1-Piperidin-4-yl)-4-(pyrazin-2-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (1.0 equivalent) obtained in Production Example e-17 in dichloromethane (0.3 M), add sodium triacetoxyborohydride (1.5 equivalents) and isobutyraldehyde (2.0 equivalents), and stir at room temperature for 1 hour. After adding water to the reaction solution to terminate the reaction, it was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize N-(1-Isobutylpiperidin-4-yl)-4-(pyrazin-2-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Light yellow solid (yield 81.8%); 11H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 1.5 Hz, 1H), 8.20 (dd, J = 2.6, 1.5 Hz, 1H), 8.03 (d, J = 2.6 Hz, 1H), 7.52 (dd, J = 8.0, 1.5 Hz, 1H), 7.36 (dd, J = 7.9, 1.6 Hz, 1H), 7.16 - 7.02 (m, 2H), 5.05 (d, J = 7.7 Hz, 1H), 4.06 - 4.00 (m, 2H), 4.00 - 3.93 (m, 2H), 3.78 - 3.64 (m, 1H), 2.72 (d, J = 10.9 Hz, 2H), 2.09 - 1.97 (m, 4H), 1.96 - 1.86 (m, 2H), 1.80 - 1.66 (m, 1H), 1.50 - 1.35 (m, 2H), 0.86 (d, J = 6.5 Hz, 6H); LC / MS ESI(+): 395.3 (M + 1). <Example 83>Synthesis of N-(1-Isopropylpiperidin-4-yl)-4-(pyrazin-2-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although carried out in the same manner as in Example 82, N-(1-Isopropylpiperidin-4-yl)-4-(pyrazin-2-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide was synthesized using acetone instead of isobutyraldehyde. Pale yellow solid (yield 81.6%); 1 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 1.6 Hz, 1H), 8.20 (dd, J = 2.6, 1.5 Hz, 1H), 8.03 (d, J = 2.6 Hz, 1H), 7.52 (dd, J = 8.1, 1.4 Hz, 1H), 7.35 (dd, J = 7.9, 1.6 Hz, 1H), 7.15 - 7.00 (m, 2H), 5.05 (d, J = 7.7 Hz, 1H), 4.06 - 3.92 (m, 4H), 3.77 - 3.63 (m, 1H), 2.78 (d, J = 11.9 Hz, 2H), 2.74 - 2.63 (m, 1H), 2.25 (t, J = 2.6 Hz, 2H), 2.04 - 1.94 (m, 2H), 1.48 - 1.34 (m, 2H), 1.02 (d, J = 6.6 Hz, 6H); LC / MS ESI(+): 381.3 (M + 1). [Reaction Scheme 43]

Chemical Structure

[0232] <Production method f> Production of benzyl or halogen-substituted benzyl-1,2,3,4-tetrahydroquinoxaline The benzyl or halogen-substituted benzyl-1,2,3,4-tetrahydroquinoxaline according to the present invention was produced through the processes of the following Production Examples f-1 to f-6. <Production Example f-1> Production of tert-butyl 4-(2-fluorobenzyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate Although carried out in the same manner as in Production Example d-2, tert-butyl 4-(2-fluorobenzyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate was produced using 2-fluorobenzyl bromide instead of benzyl bromide. Yellow oil (yield 90%); 1 H NMR (400 MHz, CDCl3) δ 7.57 - 7.41 (m, 1H), 7.32 - 7.17 (m, 2H), 7.16 - 7.05 (m, 2H), 6.98 - 6.90 (m, 1H), 6.72 - 6.58 (m, 2H), 4.59 (s, 2H), 3.91 - 3.84 (m, 2H), 3.49 (dd, J = 5.7, 4.5 Hz, 2H), 1.55 (s, 9H). <Production Example f-2> Production of tert-butyl 4-(4-fluorobenzyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate Although carried out in the same manner as in Production Example d-2, tert-butyl 4-(4-fluorobenzyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate was produced using 2-fluorobenzyl bromide instead of benzyl bromide. Yellow oil (yield 95%); 1 H NMR (400 MHz, CDCl3) δ 7.53 - 7.45 (m, 1H), 7.28 - 7.18 (m, 2H), 7.09 - 6.99 (m, 2H), 7.03 - 6.90 (m, 1H), 6.73 - 6.59 (m, 2H), 4.51 (d, J = 1.3 Hz, 2H), 3.89 - 3.82 (m, 2H), 3.51 - 3.40 (m, 2H), 1.55 (s, 9H). <Production Example f-3>Production of tert-Butyl 4-(4-Chlorobenzyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate Although carried out in the same manner as in Production Example d-2, tert-Butyl 4-(3-Chlorobenzyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate was produced using 4-Chlorobenzyl bromide instead of Benzyl bromide. Light yellow oil (yield 100%); 1 H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.1 Hz, 1H), 7.31 - 7.27 (m, 2H), 7.21 - 7.15 (m, 2H), 6.91 (ddd, J = 8.1, 7.3, 1.5 Hz, 1H), 6.66 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 6.58 (dd, J = 8.3, 1.3 Hz, 1H), 4.48 (s, 2H), 3.87 - 3.80 (m, 2H), 3.45 - 3.38 (m, 2H), 1.53 (s, 9H). <Production Example f-4>Production of 1-(2-Fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline The Boc group of tert-Butyl 4-(2-Fluorobenzyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate obtained in Production Example f-1 was deprotected with TFA to produce 1-(2-Fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline. Gray solid (yield 96%); 1 H NMR (400 MHz, CD3OD) δ 7.37 - 7.22 (m, 2H), 7.15 - 7.06 (m, 2H), 6.61 - 6.44 (m, 4H), 4.50 (s, 2H), 3.47 - 3.34 (m, 4H); LC / MS ESI(+): 243.1 (M). <Production Example f-5>Production of 1-(4-Fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline The Boc group of tert-Butyl 4-(4-Fluorobenzyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate obtained in Production Example f-2 was deprotected with TFA to produce 1-(2-Fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline. Light brown solid (yield 93%); 1 1H NMR (400 MHz, CD3OD) δ 7.37 - 7.28 (m, 2H), 7.10 - 6.99 (m, 2H), 6.60 - 6.45 (m, 4H), 4.42 (s, 2H), 3.42 - 3.33 (m, 4H); LC / MS ESI(+): 243.1 (M). <Production Example f-6> Production of 1-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinoxaline The Boc group of tert-butyl 4-(3-chlorobenzyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate obtained in Production Example f-3 was deprotected with TFA to produce 1-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinoxaline. Light brown oil (yield 94%); 1 1H NMR (400 MHz, DMSO-d6) δ 7.42 - 7.32 (m, 2H), 7.31 - 7.26 (m, 2H), 6.47 - 6.32 (m, 4H), 5.48 (s, 1H), 4.38 (s, 2H), 3.30 (d, J = 1.5 Hz, 4H); LC / MS ESI(+): 258.0 (M). [Reaction Formula 44] [Chemical Formula]

[0233] <Production Example f-7> Production of tert-butyl (R)-3-(4-benzyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate Dissolve 1-benzyl-1,2,3,4-tetrahydroquinoxaline (1.0 eq) obtained in Production Example d-3 in dichloromethane (0.3 M), slowly add TEA (3.0 eq) and triphosgene (0.6 eq) at 0 °C, and stir at 0 °C for 1 hour. Add TEA (2.0 eq) and (R)-(+)-1-Boc-3-aminopyrrolidine (1.2 eq) to the reaction solution, and stir at room temperature for 3 hours. After adding water to the reaction solution to terminate the reaction, extract with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce tert-butyl (R)-3-(4-benzyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate. Brown solid (yield 100%); 1 1H NMR (400 MHz, CDCl3) δ 7.36 - 7.27 (m, 2H), 7.25 - 7.17 (m, 2H), 7.08 (d, J = 7.8 Hz, 1H), 7.00 - 6.94 (m, 1H), 6.71 - 6.59 (m, 2H), 5.34 (d, J = 6.9 Hz, 1H), 5.08 - 5.03 (m, 2H), 4.56 (s, 2H), 4.49 - 4.35 (m, 1H), 3.95 - 3.75 (m, 2H), 3.73 - 3.52 (m, 1H), 3.46 - 3.31 (m, 2H), 3.20 - 3.04 (m, 1H), 2.24 - 2.02 (m, 1H), 1.94 - 1.64 (m, 1H), 1.51 - 1.48 (m, 1H), 1.45 (s, 9H). <Example 84>Synthesis of (R)-4-benzyl-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide A mixture of tert-butyl (R)-3-(4-benzyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate (1.0 equivalent) obtained in Production Example f-7 and TFA (10.0 equivalents) dissolved in dichloromethane (0.5 M) was stirred at room temperature for 12 hours. After completion of the reaction, toluene was added to the reaction solution, and the mixture was concentrated under reduced pressure. Then, water was added, and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to synthesize (R)-4-benzyl-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide. Yellow solid (yield 49%); 1 1H NMR (400 MHz, CDCl3) δ 7.36 - 7.27 (m, 3H), 7.25 - 7.18 (m, 3H), 7.15 - 7.09 (m, 1H), 6.97 (ddd, J = 8.6, 7.3, 1.6 Hz, 1H), 6.70 - 6.61 (m, 2H), 5.41 (d, J = 6.8 Hz, 1H), 4.55 (s, 2H), 4.37 - 4.25 (m, 1H), 3.94 - 3.78 (m, 2H), 3.47 - 3.40 (m, 2H), 3.23 - 3.14 (m, 1H), 3.07 - 2.88 (m, 2H), 2.80 - 2.72 (m, 1H), 2.25 - 2.08 (m, 1H), 1.64 - 1.51 (m, 1H); LC / MS ESI(+): 337.1 (M + 1). [Reaction Scheme 45] [Chemical Formula]

[0234] <Example 85>Synthesis of (S)-(3-aminopyrrolidin-1-yl)(4-benzyl-3,4-dihydroquinoxalin-1(2H)-yl)methanone 1-Benzyl-1,2,3,4-tetrahydroquinoxaline (1.0 eq) obtained in Production Example d-3 was dissolved in dichloromethane (0.4 M), and TEA (3.0 eq) and triphosgene (0.6 eq) were slowly added at 0 °C, followed by stirring at 0 °C for 1 hour. TEA (2.0 eq) and (S)-(-)-3-(Boc-amino)pyrrolidine (1.2 eq) were added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained concentrated solution was dissolved in dichloromethane (0.5 M), TFA (10.0 eq) was added, and the mixture was stirred at room temperature for 24 hours. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to synthesize (S)-(3-aminopyrrolidin-1-yl)(4-benzyl-3,4-dihydroquinoxalin-1(2H)-yl)methanone. Yellow oil (yield 23%); 1 1H NMR (400 MHz, CD3OD) δ 7.36 - 7.15 (m, 5H), 6.90 - 6.74 (m, 2H), 6.68 - 6.52 (m, 2H), 4.54 (s, 2H), 3.80 - 3.59 (m, 2H), 3.57 - 3.31 (m, 6H), 3.06 - 2.95 (m, 1H), 2.10 - 1.95 (m, 1H), 1.73 - 1.59 (m, 1H); LC / MS ESI(+): 337.0 (M + 1). <Example 86>Synthesis of (S)-(4-benzyl-3,4-dihydroquinoxalin-1(2H)-yl)(3-(methylamino)pyrrolidin-1-yl)methanone The 1-benzyl-1,2,3,4-tetrahydroquinoxaline (1.0 equivalent) obtained in Production Example d-3 was dissolved in dichloromethane (0.3 M), and TEA (3.0 equivalents) and triphosgene (0.6 equivalent) were slowly added at 0 °C, followed by stirring at 0 °C for 1 hour. TEA (2.0 equivalents) and (S)-(-)-3-(Boc-amino)pyrrolidine (1.2 equivalents) were added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After adding water to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The ivory-colored solid obtained was dissolved in THF (0.3 M), NaH (1.5 equivalents) and iodomethane (1.0 equivalent) were added, and the mixture was stirred at room temperature for 3 hours. After adding water to terminate the reaction, the mixture was extracted with dichloromethane, washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The light brown oil obtained was dissolved in dichloromethane (0.5 M), TFA (10.0 equivalents) was added, and the mixture was stirred at room temperature for 3 hours. After adding water to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The residue obtained was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to synthesize (S)-(4-benzyl-3,4-dihydroquinoxalin-1(2H)-yl)(3-(methylamino)pyrrolidin-1-yl)methanone. Yellow oil (yield 47%); 1 1H NMR (400 MHz, CD3OD) δ 7.35 - 7.16 (m, 5H), 6.86 - 6.76 (m, 2H), 6.67 - 6.52 (m, 2H), 4.55 (s, 2H), 3.80 - 3.70 (m, 1H), 3.68 - 3.59 (m, 1H), 3.58 - 3.40 (m, 4H), 3.39 - 3.33 (m, 1H), 3.21 - 3.06 (m, 2H), 2.31 (s, 3H), 2.12 - 2.01 (m, 1H), 1.76 - 1.63 (m, 1H); LC / MS ESI(+): 351.3 (M+1). [Reaction Scheme 46] [Chemical Formula]

[0235] <Production Example f-8>Production of tert-butyl (R)-3-(4-(2-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide)pyrrolidine-1-carboxylate 1-(2-Fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline (1.0 equivalent) obtained in Production Example f-4 was dissolved in dichloromethane (0.3 M), and TEA (3.0 equivalents) and triphosgene (0.6 equivalent) were slowly added at 0 °C, followed by stirring at 0 °C for 1 hour. TEA (2.0 equivalents) and (R)-(+)-1-Boc-3-aminopyrrolidine (1.2 equivalents) were added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After adding water to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce tert-butyl (R)-3-(4-(2-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide)pyrrolidine-1-carboxylate. White solid (yield 98%); 1 1H NMR (400 MHz, CDCl3) δ 7.32 - 7.22 (m, 1H), 7.20 - 7.05 (m, 5H), 7.05 - 6.96 (m, 1H), 6.72 - 6.65 (m, 2H), 5.36 (d, J = 6.9 Hz, 1H), 4.62 (s, 2H), 4.46 - 4.39 (m, 1H), 3.95 - 3.86 (m, 3H), 3.67 (d, J = 7.2 Hz, 1H), 3.51 - 3.37 (m, 3H), 3.23 - 3.10 (m, 1H), 1.85 - 1.72 (m, 1H), 1.48 (s, 9H). <Production Example f-9>Production of (R)-4-(2-fluorobenzyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide The Boc group of tert-butyl (R)-3-(4-(2-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide)pyrrolidine-1-carboxylate obtained in Production Example f-8 was deprotected with TFA to produce (R)-4-(2-fluorobenzyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide. White solid (yield 98%); 1 1H NMR (400 MHz, CDCl3) δ 7.32 - 7.21 (m, 1H), 7.15 - 7.05 (m, 3H), 7.05 - 6.94 (m, 1H), 6.73 - 6.59 (m, 2H), 5.55 (d, J = 6.7 Hz, 1H), 4.61 (s, 2H), 4.44 - 4.32 (m, 1H), 3.98 - 3.81 (m, 2H), 3.46 (dt, J = 9.2, 5.2 Hz, 2H), 3.34 - 3.25 (m, 1H), 3.24 - 3.13 (m, 1H), 3.11 - 2.92 (m, 2H), 2.65 - 2.54 (m, 1H), 2.26 - 2.17 (m, 1H), 1.79 - 1.55 (m, 1H); LC / MS ESI(+): 355.2 (M + 1). <Example 87>Synthesis of (R)-4-(2-fluorobenzyl)-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (R)-4-(2-Fluorobenzyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (1.0 equivalent) obtained in Production Example f-9 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize (R)-4-(2-fluorobenzyl)-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide. Light yellow oil (yield 81%); 11H NMR (400 MHz, CDCl3) δ 7.32 - 7.21 (m, 1H), 7.19 - 7.03 (m, 4H), 7.02 - 6.94 (m, 1H), 6.72 - 6.62 (m, 2H), 5.54 (d, J = 7.5 Hz, 1H), 4.61 (s, 2H), 4.48 - 4.36 (m, 1H), 4.01 - 3.91 (m, 1H), 3.90 - 3.78 (m, 1H), 3.46 (t, J = 5.2 Hz, 2H), 2.82 - 2.73 (m, 1H), 2.65 - 2.53 (m, 2H), 2.41 - 2.20 (m, 5H), 1.64 - 1.51 (m, 1H); LC / MS ESI(+): 369.3 (M + 1). [Reaction Scheme 47] [Chem.]

[0236] <Production Example f - 10> Production of tert - butyl 4-(4-(2 - fluorobenzyl)-1,2,3,4 - tetrahydroquinoxaline - 1 - carboxamido)piperidine - 1 - carboxylate Although carried out in the same manner as in Production Example f - 8, tert - butyl 4-(4-(2 - fluorobenzyl)-1,2,3,4 - tetrahydroquinoxaline - 1 - carboxamido)piperidine - 1 - carboxylate was produced using 1 - Boc - 4 - aminopiperidine instead of (R)-(+)-1 - Boc - 3 - aminopyrrolidine. White solid (yield 98%); 1 1H NMR (400 MHz, CDCl3) δ 7.32 - 7.21 (m, 1H), 7.17 - 6.96 (m, 5H), 6.72 - 6.63 (m, 2H), 5.21 (d, J = 7.7 Hz, 1H), 4.62 (s, 2H), 4.00 (s, 2H), 3.95 - 3.82 (m, 3H), 3.47 (t, J = 5.2 Hz, 2H), 2.97 - 2.86 (m, 2H), 2.00 - 1.91 (m, 2H), 1.47 (s, 9H), 1.38 - 1.23 (m, 2H). <Production Example f - 11> Production of 4-(2 - fluorobenzyl)-N-(piperidin - 4 - yl)-3,4 - dihydroquinoxaline - 1(2H)-carboxamide The Boc group of tert-butyl 4-(4-(2-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide)piperidine-1-carboxylate obtained in the above Production Example f-10 was deprotected with TFA to produce 4-(2-fluorobenzyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide. White solid (yield 97%); 1 1H NMR (400 MHz, CDCl3) δ 7.36 - 7.21 (m, 1H), 7.19 - 7.04 (m, 4H), 7.04 - 6.96 (m, 1H), 6.72 - 6.64 (m, 2H), 5.24 (d, J = 7.8 Hz, 1H), 4.62 (s, 2H), 3.90 (dd, J = 6.5, 3.9 Hz, 2H), 3.88 - 3.76 (m, 1H), 3.47 (t, J = 5.2 Hz, 2H), 3.11 - 3.01 (m, 2H), 2.78 - 2.67 (m, 2H), 2.04 - 1.94 (m, 2H), 1.37 - 1.23 (m, 3H); LC / MS ESI(+): 369.1 (M + 1). <Example 88>Synthesis of 4-(2-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide 4-(2-Fluorobenzyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (1.0 equivalent) obtained in the above Production Example f-11 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize 4-(2-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide. White solid (yield 90%); 11H NMR (400 MHz, CDCl3) δ 7.32 - 7.21 (m, 1H), 7.19 - 6.96 (m, 5H), 6.71 - 6.63 (m, 2H), 5.22 (d, J = 7.8 Hz, 1H), 4.62 (s, 2H), 3.90 (t, J = 5.2 Hz, 2H), 3.81 - 3.65 (m, 1H), 3.47 (t, J = 5.2 Hz, 2H), 2.77 - 2.70 (m, 2H), 2.28 (s, 3H), 2.18 - 2.08 (m, 2H), 2.03 - 1.93 (m, 2H), 1.53 - 1.37 (m, 2H); LC / MS ESI(+): 383.3 (M + 1). [Reaction Scheme 48] [Chem.]

[0237] <Production Example f - 12> Production of tert - butyl 4 - ((4 - (2 - fluorobenzyl)-1,2,3,4 - tetrahydroquinoxaline - 1 - carboxamido)methyl)piperidine - 1 - carboxylate Although carried out in the same manner as in Production Example f - 8, tert - butyl 4 - ((4 - (2 - fluorobenzyl)-1,2,3,4 - tetrahydroquinoxaline - 1 - carboxamido)methyl)piperidine - 1 - carboxylate was produced using 1 - Boc - 4 - (aminomethyl)piperidine instead of (R)-(+)-1 - Boc - 3 - aminopyrrolidine. Yellow oil (yield 99%); 1 1H NMR (400 MHz, CDCl3) δ 7.32 - 7.21 (m, 1H), 7.19 - 6.98 (m, 5H), 6.74 - 6.65 (m, 2H), 5.43 (t, J = 6.0 Hz, 1H), 4.62 (s, 2H), 3.90 (t, J = 5.1 Hz, 2H), 3.47 (t, J = 5.2 Hz, 2H), 3.17 (s, 2H), 2.70 (s, 2H), 1.83 - 1.55 (m, 4H), 1.47 (s, 9H), 1.21 - 1.06 (m, 2H), 0.95 - 0.79 (m, 1H). <Production Example f - 13> Production of 4 - (2 - fluorobenzyl)-N - (piperidin - 4 - ylmethyl)-3,4 - dihydroquinoxalin - 1(2H)-carboxamide The Boc group of tert-butyl 4-((4-(2-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate obtained in Production Example f-12 was deprotected with TFA to produce 4-(2-fluorobenzyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide. Light yellow solid (yield 81%); 1 1H NMR (400 MHz, CDCl3) δ 7.19 - 7.12 (m, 2H), 7.10 - 7.06 (m, 2H), 7.03 - 6.98 (m, 1H), 6.74 - 6.64 (m, 2H), 5.50 - 5.38 (m, 1H), 7.32 - 7.21 (m, 1H), 4.62 (s, 2H), 3.90 (td, J = 5.2, 2.8 Hz, 2H), 3.29 (d, J = 4.1 Hz, 1H), 3.21 - 3.13 (m, 2H), 3.07 - 2.96 (m, 1H), 2.79 - 2.67 (m, 2H), 2.03 - 1.93 (m, 1H), 1.84 - 0.76 (m, 2H), 1.79 - 1.62 (m, 1H), 1.60 - 1.34 (m, 2H), 1.32 - 1.18 (m, 1H), 0.94 - 0.77 (m, 1H); LC / MS ESI(+): 383.1 (M + 1). <Example 89> Synthesis of 4-(2-fluorobenzyl)-N-((1-methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide 4-(2-Fluorobenzyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (1.0 equivalent) obtained in Production Example f-13 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize 4-(2-fluorobenzyl)-N-((1-methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide. Light yellow oil (yield 85%); 1 H NMR (400 MHz, CDCl3) δ 7.32 - 7.21 (m, 1H), 7.19 - 7.06 (m, 4H), 7.05 - 6.97 (m, 1H), 6.74 - 6.64 (m, 2H), 5.43 (t, J = 6.0 Hz, 1H), 4.62 (s, 2H), 3.90 (dd, J = 6.6, 3.8 Hz, 2H), 3.47 (t, J = 5.2 Hz, 2H), 3.18 (t, J = 6.3 Hz, 2H), 2.91 - 2.82 (m, 2H), 2.28 (s, 3H), 1.98 - 1.87 (m, 2H), 1.71 (s, 1H), 1.60 - 1.44 (m, 1H), 1.38 - 1.22 (m, 3H); LC / MS ESI(+): 397.3 (M + 1). [Reaction formula 49] [Chemical formula]

[0238] <Production example f - 14> Production of tert - butyl (R)-3 - ((4 - (2 - fluorobenzyl)-1,2,3,4 - tetrahydroquinoxaline - 1 - carboxamido)methyl)pyrrolidine - 1 - carboxylate Although carried out in the same manner as in Production example f - 8, tert - butyl (R)-3 - ((4 - (2 - fluorobenzyl)-1,2,3,4 - tetrahydroquinoxaline - 1 - carboxamido)methyl)pyrrolidine - 1 - carboxylate was produced using (S)-1 - Boc - 3 - (aminomethyl)pyrrolidine instead of (R)-(+)-1 - Boc - 3 - aminopyrrolidine. Light yellow solid (yield 98%); 11H NMR (400 MHz, CDCl3) δ 7.32 - 7.21 (m, 1H), 7.18 - 7.11 (m, 2H), 7.11 - 7.05 (m, 2H), 7.05 - 6.97 (m, 1H), 6.74 - 6.65 (m, 2H), 5.44 (t, J = 5.6 Hz, 1H), 4.62 (s, 2H), 3.97 - 3.87 (m, 2H), 3.58 - 3.40 (m, 3H), 3.40 - 3.14 (m, 2H), 3.09 - 2.95 (m, 1H), 2.44 (s, 1H), 2.02 - 1.94 (m, 1H), 1.73 - 1.51 (m, 1H), 1.50 - 1.46 (m, 10H), 0.95 - 0.74 (m, 1H). <Production Example f - 15> Production of (S)-4-(2-fluorobenzyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The Boc group of tert-butyl (R)-3-((4-(2-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide)methyl)pyrrolidine-1-carboxylate obtained in Production Example f - 14 was deprotected with TFA to produce (S)-4-(2-fluorobenzyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Light yellow solid (yield 89%); 1 1H NMR (400 MHz, CDCl3) δ 7.32 - 7.21 (m, 1H), 7.18 - 7.13 (m, 2H), 7.11 - 7.04 (m, 2H), 7.04 - 6.94 (m, 1H), 6.73 - 6.61 (m, 2H), 5.62 (t, J = 5.8 Hz, 1H), 4.60 (d, J = 8.1 Hz, 2H), 3.89 (t, J = 5.2 Hz, 2H), 3.46 (t, J = 5.1 Hz, 2H), 3.31 - 3.23 (m, 2H), 3.27 - 3.10 (m, 2H), 3.14 - 3.00 (m, 1H), 2.90 - 2.81 (m, 1H), 2.53 - 2.44 (m, 1H), 2.44 - 2.27 (m, 1H), 2.10 - 1.86 (m, 1H), 1.66 - 1.44 (m, 1H); LC / MS ESI(+): 369.1 (M + 1). <Example 90>Synthesis of (R)-4-(2-Fluorobenzyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Dissolve (S)-4-(2-Fluorobenzyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (1.0 equivalent) obtained in Production Example f-15 in dichloromethane (0.3 M), add sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents), and stir at room temperature for 1 hour. After adding water to the reaction solution to terminate the reaction, it was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize (R)-4-(2-Fluorobenzyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Light yellow oil (yield 85%); 1 1H NMR (400 MHz, CDCl3) δ 7.32 - 7.21 (m, 1H), 7.20 - 7.04 (m, 3H), 7.03 - 6.95 (m, 2H), 6.75 - 6.63 (m, 2H), 6.05 - 5.98 (m, 1H), 4.62 (s, 2H), 4.02 - 3.92 (m, 1H), 3.91 - 3.78 (m, 1H), 3.47 (dd, J = 5.9, 4.6 Hz, 2H), 3.36 - 3.21 (m, 2H), 2.65 - 2.31 (m, 5H), 2.24 (s, 3H), 2.06 - 1.93 (m, 1H), 1.60 - 1.45 (m, 1H); LC / MS ESI(+): 383.3 (M + 1). [Reaction Scheme 50] [Chemical Formula]

[0239] <Production Example f-16>Production of tert-Butyl (R)-3-(4-(4-Fluorobenzyl)-1,2,3,4-tetrahydroquinoxalin-1-carboxamide)pyrrolidine-1-carboxylate 1-(4-Fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline (1.0 eq.) obtained in Production Example f-5 was dissolved in dichloromethane (0.3 M), and TEA (3.0 eq.) and triphosgene (0.6 eq.) were slowly added at 0 °C, followed by stirring at 0 °C for 1 hour. TEA (2.0 eq.) and (R)-(+)-1-Boc-3-aminopyrrolidine (1.2 eq.) were added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After adding water to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce tert-butyl (R)-3-(4-(4-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate. White solid (yield 94%); 1 1H NMR (400 MHz, CDCl3) δ 7.23 - 7.07 (m, 3H), 7.06 - 6.94 (m, 3H), 6.72 - 6.65 (m, 2H), 5.38 - 5.30 (m, 2H), 4.54 (s, 2H), 4.44 - 4.40 (m, 1H), 4.03 - 3.77 (m, 3H), 3.66 (d, J = 6.9 Hz, 1H), 3.44 (t, J = 5.2 Hz, 3H), 3.16 (s, 1H), 1.50 - 1.45 (m, 10H). <Example 91>Synthesis of (R)-4-(4-Fluorobenzyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The Boc group of tert-butyl (R)-3-(4-(4-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate obtained in Production Example f-14 was deprotected with TFA to synthesize (R)-4-(4-fluorobenzyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. White solid (yield 94%); 11H NMR (400 MHz, CDCl3) δ 7.27 - 7.13 (m, 3H), 7.11 - 6.93 (m, 3H), 6.74 - 6.67 (m, 1H), 6.70 - 6.60 (m, 1H), 5.76 (d, J = 6.4 Hz, 1H), 4.54 - 4.47 (m, 2H), 3.96 - 3.76 (m, 2H), 3.48 - 3.36 (m, 3H), 3.30 - 3.19 (m, 2H), 2.64 (d, J = 5.0 Hz, 1H), 2.44 - 2.18 (m, 1H), 1.69 - 1.55 (m, 1H), 0.94 - 0.79 (m, 2H); LC / MS ESI(+): 355.1 (M+1). <Example 92>Synthesis of (R)-4-(4-Fluorobenzyl)-N-(1-isopropylpyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The (R)-4-(4-Fluorobenzyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (1.0 equiv) obtained in Example 91 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 equiv) and acetone (2.0 equiv) were added, and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction solution to terminate the reaction, extraction was performed with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize (R)-4-(4-Fluorobenzyl)-N-(1-isopropylpyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Pale yellow oil (yield 78%); 11H NMR (400 MHz, CDCl3) δ 7.23 - 7.13 (m, 3H), 7.10 - 6.94 (m, 3H), 6.72 - 6.63 (m, 2H), 5.55 (d, J = 7.7 Hz, 1H), 4.53 (s, 2H), 4.00 - 3.89 (m, 1H), 3.89 - 3.78 (m, 1H), 3.42 (t, J = 5.2 Hz, 2H), 2.85 (td, J = 8.3, 3.4 Hz, 1H), 2.79 - 2.71 (m, 1H), 2.66 - 2.54 (m, 1H), 2.42 - 2.19 (m, 4H), 1.63 - 1.51 (m, 1H), 1.09 (dd, J = 6.3, 5.2 Hz, 6H); LC / MS ESI(+): 397.3 (M + 1). [Reaction Scheme 51] [Chem.]

[0240] <Production Example f - 17>Production of tert - butyl 4-(4-(4 - fluorobenzyl)-1,2,3,4 - tetrahydroquinoxaline - 1 - carboxamido)piperidine - 1 - carboxylate Dissolve 1-(4 - fluorobenzyl)-1,2,3,4 - tetrahydroquinoxaline (1.0 equivalent) obtained in Production Example f - 5 in dichloromethane (0.3 M), and slowly add TEA (3.0 equivalents) and triphosgene (0.6 equivalent) at 0 °C, then stir at 0 °C for 1 hour. Add TEA (2.0 equivalents) and 1 - Boc - 4 - aminopiperidine (1.2 equivalents) to the reaction solution, and stir at room temperature for 3 hours. After adding water to terminate the reaction, extract with dichloromethane. Wash the organic layer with brine, dry over MgSO4, filter, and then concentrate under reduced pressure. Purify the obtained residue by silica column chromatography using an n - hexane / ethyl acetate mixture to produce tert - butyl 4-(4-(4 - fluorobenzyl)-1,2,3,4 - tetrahydroquinoxaline - 1 - carboxamido)piperidine - 1 - carboxylate. White solid (yield 80%); 11H NMR (400 MHz, CDCl3) δ 7.23 - 7.10 (m, 3H), 7.08 - 6.95 (m, 3H), 6.72 - 6.63 (m, 2H), 4.54 (s, 2H), 4.08 - 3.78 (m, 6H), 3.43 (t, J = 5.2 Hz, 2H), 2.96 - 2.86 (m, 2H), 2.00 - 1.90 (m, 2H), 1.47 (s, 9H), 1.37 - 1.23 (m, 2H). <Example 93> Synthesis of 4-(4-Fluorobenzyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The Boc group of tert-butyl (4-(4-(4-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)piperidine-1-carboxylate obtained in Production Example f-17 was deprotected with TFA to synthesize 4-(4-fluorobenzyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. White solid (yield 90%); 1 1H NMR (400 MHz, CDCl3) δ 7.23 - 7.08 (m, 3H), 7.06 - 6.95 (m, 3H), 6.73 - 6.62 (m, 2H), 5.29 - 5.19 (m, 1H), 4.54 (s, 2H), 3.97 - 3.83 (m, 3H), 3.37 - 3.27 (m, 1H), 2.94 - 2.82 (m, 3H), 2.14 (s, 1H), 1.98 - 1.91 (m, 1H), 1.75 - 1.55 (m, 2H), 1.48 - 1.25 (m, 1H), 0.94 - 0.79 (m, 2H); LC / MS ESI(+): 369.3 (M+1). <Example 94> Synthesis of 4-(4-Fluorobenzyl)-N-(1-isopropylpiperidin-4-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Dissolve 4-(4-fluorobenzyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (1.0 equiv), obtained in Example 93, in dichloromethane (0.3 M), add sodium triacetoxyborohydride (1.5 equiv) and acetone (2.0 equiv), and stir at room temperature for 1 hour. After adding water to the reaction mixture to terminate the reaction, extract with dichloromethane. Wash the organic layer with brine, dry over MgSO4, filter, and concentrate under reduced pressure. Purify the obtained residue by silica column chromatography using a dichloromethane / methanol mixture to synthesize 4-(4-fluorobenzyl)-N-(1-isopropylpiperidin-4-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. Pale yellow oil (yield 58%); 1 1H NMR (400 MHz, CDCl3) δ 7.23 - 7.10 (m, 3H), 7.08 - 6.95 (m, 3H), 6.71 - 6.60 (m, 2H), 5.23 (d, J = 7.9 Hz, 1H), 4.53 (s, 2H), 3.88 (dd, J = 6.2, 4.2 Hz, 2H), 3.81 - 3.67 (m, 1H), 3.43 (t, J = 5.2 Hz, 2H), 2.83 - 2.66 (m, 3H), 2.34 - 2.23 (m, 2H), 2.05 - 1.95 (m, 2H), 1.49 - 1.35 (m, 2H), 1.05 (d, J = 6.5 Hz, 6H); LC / MS ESI(+): 411.3 (M + 1). [Reaction Scheme 52]

Chemical Formula

[0241] <Production Example f-18> Production of tert-butyl (R)-3-(4-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide)pyrrolidine-1-carboxylate 1-(4-Chlorobenzyl)-1,2,3,4-tetrahydroquinoxaline (1.0 equivalent) obtained in the above Production Example f-6 was dissolved in dichloromethane (0.3 M), and TEA (3.0 equivalents) and triphosgene (0.6 equivalent) were slowly added at 0 °C, followed by stirring at 0 °C for 1 hour. TEA (2.0 equivalents) and (R)-(+)-1-Boc-3-aminopyrrolidine (1.2 equivalents) were added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce tert-butyl (R)-3-(4-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate. Brown oil (yield 82%); 1 1H NMR (400 MHz, CDCl3) δ 7.32 - 7.27 (m, 2H), 7.14 (d, J = 8.3 Hz, 2H), 7.09 (d, J = 7.8 Hz, 1H), 7.02 - 6.94 (m, 1H), 6.69 - 6.60 (m, 2H), 5.32 (d, J = 6.9 Hz, 1H), 4.51 (s, 2H), 4.46 - 4.35 (m, 1H), 3.95 - 3.76 (m, 2H), 3.67 (d, J = 15.3 Hz, 1H), 3.49 - 3.28 (m, 4H), 3.24 - 3.10 (m, 1H), 2.22 - 2.11 (m, 1H), 1.91 - 1.68 (m, 1H), 1.45 (s, 9H). <Example 95>Synthesis of (R)-4-(4-chlorobenzyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The Boc group of tert-butyl (R)-3-(4-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate obtained in the above Production Example f-18 was deprotected with TFA to synthesize (R)-4-(4-chlorobenzyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. White solid (yield 27%); 11H NMR (400 MHz, CDCl3) δ 7.31 - 7.27 (m, 2H), 7.17 - 7.12 (m, 3H), 7.00 - 6.94 (m, 1H), 6.70 - 6.57 (m, 2H), 5.50 (d, J = 6.7 Hz, 1H), 4.50 (s, 2H), 4.41 - 4.28 (m, 1H), 3.93 - 3.78 (m, 2H), 3.44 - 3.38 (m, 2H), 3.28 - 3.21 (m, 1H), 3.19 - 3.09 (m, 1H), 3.05 - 2.97 (m, 1H), 2.93 - 2.87 (m, 1H), 2.26 - 2.14 (m, 2H), 1.74 - 1.61 (m, 1H); LC / MS ESI(+): 371.3 (M + 1). [Reaction Scheme 53] [Chem.]

[0242] [Production Method g] Production of 1-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroquinoxaline 1-(Pyridin-2-ylmethyl)-1,2,3,4-tetrahydroquinoxaline according to the present invention was produced through the process of Production Example g-1 below. [Production Example g-1] Production of 1-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroquinoxaline The tert-butyl 3,4-dihydroquinoxaline-1(2H)-carboxylate (3.5 g, 14.94 mmol) obtained in Production Example d-1 was dissolved in THF (25.0 mL), and 2-(bromomethyl)pyridine hydrobromide (5.3 g, 20.91 mmol), DIPEA (11.6 g, 89.63 mmol) and NaOH (1.2 g, 29.88 mmol) were added, followed by stirring at room temperature for 1 hour. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained concentrated solution was dissolved in dichloromethane (20.0 mL), TFA (10.3 mL, 134.76 mmol) was added, and the mixture was stirred at room temperature for 24 hours. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce 1-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroquinoxaline. Light brown solid (yield 86.7%); 1 1H NMR (400 MHz, CD3CN) δ 8.54 - 8.47 (m, 1H), 7.68 - 7.59 (m, 1H), 7.29 - 7.22 (m, 1H), 7.21 - 7.12 (m, 1H), 6.47 - 6.35 (m, 3H), 6.34 - 6.27 (m, 1H), 4.46 (s, 2H), 4.29 (brs, 1H), 3.50 - 3.43 (m, 5H); LC / MS ESI(+): 226.1 (M+1). [Reaction Scheme 54] [Chemical Formula]

[0243] <Production Example g-2> Production of (S)-(3-aminopyrrolidin-1-yl)(4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone 1-(Pyridin-2-ylmethyl)-1,2,3,4-tetrahydroquinoxaline (1.0 eq) obtained in the above Production Example g-1 was dissolved in dichloromethane (0.4 M), and TEA (3.0 eq) and triphosgene (0.6 eq) were slowly added at 0 °C, followed by stirring at 0 °C for 1 hour. TEA (2.0 eq) and (S)-(-)-3-(Boc-amino) (1.2 eq) were added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained concentrated solution was dissolved in dichloromethane (0.3 M), TFA (10 eq) was added, and the mixture was stirred at room temperature for 3 hours. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to synthesize (S)-(3-aminopyrrolidin-1-yl)(4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone. Yellow oil (yield 70%); 1 1H NMR (400 MHz, CD3OD) δ 8.53 - 8.45 (m, 1H), 7.79 - 7.70 (m, 1H), 7.33 - 7.24 (m, 2H), 6.87 - 6.80 (m, 1H), 6.79 - 6.72 (m, 1H), 6.62 - 6.53 (m, 1H), 6.52 - 6.45 (m, 1H), 4.65 - 4.59 (m, 2H), 3.82 - 3.71 (m, 1H), 3.70 - 3.64 (m, 1H), 3.63 - 3.55 (m, 2H), 3.54 - 3.32 (m, 4H), 3.10 - 2.94 (m, 1H), 2.09 - 1.96 (m, 1H), 1.73 - 1.60 (m, 1H); LC / MS ESI(+): 338.2 (M + 1). <Example 96>Synthesis of (S)-(3-(isobutylamino)pyrrolidin-1-yl)(4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone (S)-(3-Aminopyrrolidin-1-yl)(4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone (1.0 equivalent) obtained in Production Example g-2 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 equivalents) and isobutyraldehyde (2.0 equivalents) were added, and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize (S)-(3-(isobutylamino)pyrrolidin-1-yl)(4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone. Pale yellow oil (yield 71%); 1 1H NMR (400 MHz, CD3OD) δ 8.55 - 8.42 (m, 1H), 7.78 - 7.69 (m, 1H), 7.32 - 7.23 (m, 2H), 6.86 - 6.79 (m, 1H), 6.78 - 6.71 (m, 1H), 6.61 - 6.52 (m, 1H), 6.52 - 6.45 (m, 1H), 4.61 (d, J = 4.3 Hz, 2H), 3.88 - 3.77 (m, 1H), 3.69 - 3.52 (m, 3H), 3.51 - 3.40 (m, 2H), 3.39 - 3.29 (m, 1H), 3.26 - 3.17 (m, 1H), 3.13 - 3.04 (m, 1H), 2.42 - 2.25 (m, 2H), 2.12 - 1.98 (m, 1H), 1.76 - 1.61 (m, 2H), 0.96 - 0.81 (dd, J = 6.6, 1.0 Hz, 6H); LC / MS ESI(+): 394.3 (M+1). <Example 97>Synthesis of (S)-(3-(dimethylamino)pyrrolidin-1-yl)(4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone Although carried out in the same manner as in Example 96 above, (S)-(3-(dimethylamino)pyrrolidin-1-yl)(4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone was synthesized using formaldehyde instead of isobutyraldehyde. Pale yellow oil (yield 53%); 1 1H NMR (400 MHz, CD3OD) δ 8.53 - 8.46 (m, 1H), 7.78 - 7.69 (m, 1H), 7.33 - 7.24 (m, 2H), 6.86 - 6.74 (m, 2H), 6.62 - 6.53 (m, 1H), 6.52 - 6.47 (m, 1H), 4.75 - 4.53 (m, 2H), 4.02 - 3.93 (m, 1H), 3.73 - 3.62 (m, 1H), 3.61 - 3.52 (m, 1H), 3.54 - 3.31 (m, 4H), 3.19 - 3.10 (m, 1H), 2.80 - 2.67 (m, 1H), 2.21 (s, 6H), 2.19 - 2.02 (m, 1H), 1.78 - 1.63 (m, 1H); LC / MS ESI(+): 366.3 (M+1). [Reaction Scheme 55] [Chem.]

[0244] <Example 98>Synthesis of (R)-4-(pyridin-2-ylmethyl)-N-(tetrahydrofuran-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide 1-(Pyridin-2-ylmethyl)-1,2,3,4-tetrahydroquinoxaline (1.0 eq) obtained in Production Example g-1 was dissolved in dichloromethane (0.3 M), and TEA (3.0 eq) and triphosgene (0.6 eq) were slowly added at 0 °C and stirred at 0 °C for 1 hour. TEA (2.0 eq) and (S)-3-aminotetrahydrofuran (1.2 eq) were added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After adding water to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to synthesize (R)-4-(pyridin-2-ylmethyl)-N-(tetrahydrofuran-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide. Ivory solid (yield 52%); 11H NMR (400 MHz, CD3OD) δ 8.55 - 8.49 (m, 1H), 7.77 (dd, J = 7.7, 1.8 Hz, 1H), 7.36 - 7.27 (m, 2H), 7.19 (dd, J = 7.9, 1.5 Hz, 1H), 6.93 (dd, J = 7.4, 1.6 Hz, 1H), 6.71 - 6.58 (m, 2H), 4.67 (s, 2H), 4.41 - 4.31 (m, 1H), 3.94 - 3.82 (m, 4H), 3.81 - 3.73 (m, 1H), 3.67 - 3.60 (m, 1H), 3.54 (t, J = 4.7 Hz, 2H), 2.30 - 2.16 (m, 1H), 1.94 - 1.79 (m, 1H); LC / MS ESI(+): 339.2 (M + 1). <Example 99>Synthesis of N-(oxetan-3-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although carried out in the same manner as in Example 98, N-(oxetan-3-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide was synthesized using 3-oxetanamine instead of (S)-3-aminotetrahydrofuran. White solid (yield 77%); 1 1H NMR (400 MHz, CD3CN) δ 8.55 - 8.48 (m, 1H), 7.64 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H), 7.24 - 7.15 (m, 3H), 6.90 (ddd, J = 8.3, 7.4, 1.6 Hz, 1H), 6.67 - 6.58 (m, 2H), 6.02 (d, J = 6.6 Hz, 1H), 4.92 - 4.77 (m, 1H), 4.75 - 4.66 (m, 2H), 4.60 (s, 2H), 4.49 - 4.39 (m, 2H), 3.78 - 3.71 (m, 2H), 3.52 - 3.45 (m, 2H); LC / MS ESI(+): 325.1 (M + 1). <Example 100>Synthesis of 4-(pyridin-2-ylmethyl)-N-((tetrahydrofuran-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although carried out in the same manner as in Example 98, 4-(pyridin-2-ylmethyl)-N-((tetrahydrofuran-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized using (tetrahydrofuran-3-yl)methanamine instead of (S)-3-aminotetrahydrofuran. White solid (yield 51%); 1 1H NMR (400 MHz, CDCl3) δ 8.59 (dd, J = 4.9, 0.9 Hz, 1H), 7.61 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H), 7.23 - 7.09 (m, 3H), 6.98 (ddd, J = 8.3, 7.4, 1.5 Hz, 1H), 6.71 - 6.60 (m, 2H), 5.47 (t, J = 5.8 Hz, 1H), 4.65 (s, 2H), 3.97 - 3.88 (m, 2H), 3.87 - 3.68 (m, 3H), 3.60 - 3.48 (m, 3H), 3.37 - 3.19 (m, 2H), 2.60 - 2.44 (m, 1H), 2.09 - 1.96 (m, 1H), 1.75 - 1.59 (m, 1H); LC / MS ESI(+): 353.2 (M+1). <Example 101>Synthesis of 4-(pyridin-2-ylmethyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide Although carried out in the same manner as in Example 98, 4-(pyridin-2-ylmethyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized using 4-aminomethyltetrahydropyran instead of (S)-3-aminotetrahydrofuran. Ivory solid (yield 84%); 11H NMR (400 MHz, CD3CN) δ 8.49 (dd, J = 4.9, 1.0 Hz, 1H), 7.62 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H), 7.23 - 7.08 (m, 3H), 6.88 (ddd, J = 8.6, 7.3, 1.6 Hz, 1H), 6.64 - 6.55 (m, 2H), 5.67 - 5.49 (m, 1H), 4.58 (s, 2H), 3.88 - 3.79 (m, 2H), 3.74 (dd, J = 5.8, 4.5 Hz, 2H), 3.46 (dd, J = 5.7, 4.5 Hz, 2H), 3.27 (ddd, J = 11.8, 11.8, 2.2 Hz, 2H), 3.02 (dd, J = 6.8, 6.0 Hz, 2H), 1.74 - 1.58 (m, 1H), 1.56 - 1.45 (m, 2H), 1.22 - 1.07 (m, 2H); LC / MS ESI(+): 367.2 (M + 1). <Example 102>Synthesis of N-(Cyclopropylmethyl)-4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide Although carried out in the same manner as in Example 98, N-(Cyclopropylmethyl)-4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide was synthesized using cyclopropylmethanamine instead of (S)-3-aminotetrahydrofuran. Light yellow solid (yield 68%); 1 1H NMR (400 MHz, CD3OD) δ 8.52 (dd, J = 4.9, 0.9 Hz, 1H), 7.76 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H), 7.34 - 7.23 (m, 2H), 7.19 (dd, J = 7.9, 1.5 Hz, 1H), 6.94 (ddd, J = 8.3, 7.4, 1.6 Hz, 1H), 6.67 (ddd, J = 7.6, 7.5, 1.3 Hz, 1H), 6.61 (dd, J = 8.3, 1.3 Hz, 1H), 4.66 (s, 2H), 3.84 (dd, J = 5.7, 4.6 Hz, 2H), 3.54 (dd, J = 5.8, 4.6 Hz, 2H), 3.09 (d, J = 6.9 Hz, 2H), 1.10 - 0.95 (m, 1H), 0.53 - 0.41 (m, 2H), 0.25 - 0.16 (m, 2H); LC / MS ESI(+): 323.2 (M + 1). [Reaction Scheme 56] [Chemical formula]

[0245] <Production Method h> Production of 4-(4-Fluorophenyl)-1,2,3,4-tetrahydropyrido[3,4-b]pyrazine 4-(4-Fluorophenyl)-1,2,3,4-tetrahydropyrido[3,4-b]pyrazine according to the present invention was produced through the processes of the following Production Examples h-1 to h-4. <Production Example h-1> Production of 3-((4-Fluorophenyl)amino)-4-nitropyridine 1-oxide A mixed solution obtained by dissolving 3-fluoro-4-nitropyridine 1-oxide (5.0 g, 31.6 mmol) and 4-fluoroaniline (10.5 g, 94.9 mmol) in pyridine (28 mL) was stirred at 70 °C for 1 hour and then cooled to room temperature. EtOH (30 mL) was added to the reaction solution, and the formed precipitate was washed with EtOH and filtered to produce 3-((4-fluorophenyl)amino)-4-nitropyridine 1-oxide. Orange solid (yield 90.3%); 1 H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.13 - 8.07 (m, 1H), 7.65 - 7.60 (m, 2H), 7.46 - 7.40 (m, 2H), 7.36 - 7.27 (m, 2H); LC / MS ESI(+): 250.0 (M + 1). <Production Example h-2> Production of N3-(4-Fluorophenyl)pyridine-3,4-diamine Fe powder (9.4 g, 168.0 mmol) was added to a mixed solution obtained by dissolving 3-((4-fluorophenyl)amino)-4-nitropyridine 1-oxide (7.0 g, 28.1 mmol) obtained in the above Production Example h-1 in AcOH / H2O (4:1 = v / v, 50 mL), and the mixture was stirred at 100 °C for 3 hours. After the reaction solution was cooled to room temperature, it was filtered through a celite pad, adjusted to pH 12 with 10 M aqueous NaOH solution, and then extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure to produce N3-(4-fluorophenyl)pyridine-3,4-diamine. Purple oil (yield 68.4%); 1 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.85 (d, J = 5.4 Hz, 1H), 7.16 (s, 1H), 7.02 - 6.91 (m, 2H), 6.66 - 6.56 (m, 3H), 5.65 (s, 2H); LC / MS ESI(+): 204.0 (M+1). <Production Example h-3> Production of 4-(4-fluorophenyl)pyrido[3,4-b]pyrazine-2,3(1H,4H)-dione The N3-(4-fluorophenyl)pyridine-3,4-diamine (3.9 g, 19.2 mmol) obtained in Production Example h-2 was dissolved in diethyl oxalate (7.8 mL, 57.6 mmol), and then stirred at 160 °C for 24 hours. After the reaction solution was cooled to room temperature, EtOH was added, and the formed precipitate was washed with EtOH, filtered, and dried to produce 4-(4-fluorophenyl)pyrido[3,4-b]pyrazine-2,3(1H,4H)-dione. White solid (yield 69.7%); 1 1H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 8.23 (d, J = 5.3 Hz, 1H), 7.53 - 7.46 (m, 5H), 7.16 (d, J = 5.3 Hz, 1H); LC / MS ESI(+): 258.0 (M+1). <Production Example h-4> Production of 4-(4-fluorophenyl)-1,2,3,4-tetrahydropyrido[3,4-b]pyrazine A solution of 4-(4-fluorophenyl)pyrido[3,4-b]pyrazine-2,3(1H,4H)-dione (1.0 g, 3.89 mmol) obtained in Production Example h-3 in THF (30 mL) was slowly added with borane-THF complex (1 M) (23.3 mL, 23.3 mmol) at room temperature, and then stirred at 65 °C for 16 hours. After the reaction solution was cooled to room temperature, water was added to terminate the reaction, and then neutralized with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to produce 4-(4-fluorophenyl)-1,2,3,4-tetrahydropyrido[3,4-b]pyrazine. White solid (yield 43.1%); 1 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 5.3 Hz, 2H), 7.18 - 7.09 (m, 2H), 7.08 - 6.99 (m, 2H), 6.42 (d, J = 5.3 Hz, 1H), 4.38 (s, 1H), 3.65 - 3.58 (m, 2H), 3.55 - 3.46 (m, 2H); LC / MS ESI(+): 230.0 (M + 1). <Example 103>Synthesis of (4-(4-fluorophenyl)-3,4-dihydropyrido[3,4-b]pyrazin-1(2H)-yl)(3-hydroxypyrrolidin-1-yl)methanone 4-(4-Fluorophenyl)-1,2,3,4-tetrahydropyrido[3,4-b]pyrazine (300 mg, 0.13 mmol) obtained in the above Production Example h-4 was dissolved in dichloromethane (1.0 mL), and TEA (36.5 μL, 0.26 mmol) and triphosgene (23.3 mg, 1.62 mmol) were slowly added at 0 °C, followed by stirring at 0 °C for 1 hour. TEA (36.5 μL, 0.26 mmol) and pyrrolidin-3-ol (12.8 μL, 0.16 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to synthesize (4-(4-fluorophenyl)-3,4-dihydropyrido[3,4-b]pyrazin-1(2H)-yl)(3-hydroxypyrrolidin-1-yl)methanone. Yellow solid (yield 33%); 1 1H NMR (400 MHz, CDCl3) δ 7.89 - 7.84 (m, 2H), 7.24 - 7.16 (m, 2H), 7.15 - 7.05 (m, 2H), 6.82 (d, J = 5.4 Hz, 1H), 4.55 - 4.49 (m, 1H), 3.95 - 3.86 (m, 1H), 3.77 - 3.57 (m, 5H), 3.55 - 3.38 (m, 2H), 2.10 - 1.91 (m, 3H); LC / MS ESI(+) : 343.0 (M+1). [Reaction Scheme 57] [Chemical Formula]

[0246] <Production Method i> Production of 1-cyclohexyl-1,2,3,4-tetrahydroquinoxaline 1-Cyclohexyl-1,2,3,4-tetrahydroquinoxaline according to the present invention was synthesized through the processes of the following Production Examples i-1 to i-4. <Production Example i-1> Production of N-cyclohexyl-2-nitroaniline A solution of 1-fluoro-2-nitrobenzene (1 g, 7.09 mmol) and cyclohexylamine (1.0 mL, 8.50 mmol) was stirred at 110 °C for 6 hours and then cooled to room temperature. After adding water to the reaction solution to terminate the reaction, it was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce N-cyclohexyl-2-nitroaniline. Orange solid (yield 99%); 1 1H NMR (400 MHz, CDCl3) δ 8.20 - 8.08 (m, 2H), 7.42 - 7.36 (m, 1H), 6.86 (d, J = 8.6 Hz, 1H), 6.59 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 3.55 - 3.48 (m, 1H), 2.10 - 2.01 (m, 2H), 1.85 - 1.76 (m, 2H), 1.70 - 1.62 (m, 1H), 1.48 - 1.25 (m, 6H); LC / MS ESI(+): 221.1 (M + 1). <Production Example i-2> N 1 Production of N-cyclohexylbenzene-1,2-diamine N-cyclohexyl-2-nitroaniline (1.6 g, 7.04 mmol) obtained in the above Production Example i-1 was dissolved in EtOAc / MeOH (1:3 = v / v, 20 mL), then 10% Pd / C (74 mg, 0.70 mmol) was added, and it was stirred at room temperature for 6 hours under hydrogen gas conditions. The reaction solution was filtered through a Celite pad and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce N 1 -cyclohexylbenzene-1,2-diamine. Brown oil (yield 86%); 11H NMR (400 MHz, CDCl3) δ 6.83 - 6.77 (m, 1H), 6.74 - 6.70 (m, 1H), 6.69 - 6.62 (m, 2H), 3.27 - 3.19 (m, 4H), 2.10 - 2.06 (m, 2H), 1.82 - 1.73 (m, 2H), 1.69 - 1.62 (m, 1H), 1.45 - 1.32 (m, 2H), 1.29 - 1.16 (m, 3H); LC / MS ESI(+): 191.2 (M + 1). <Production Example i-3> Production of 1-Cyclohexylquinoxaline-2,3(1H,4H)-dione The N obtained in Production Example i-2 1 A reaction solution prepared by dissolving N-cyclohexylbenzene-1,2-diamine (1.0 g, 5.26 mmol) in diethyl oxalate (4.3 mL, 31.53 mmol) was stirred at 130 °C for 2 hours. After the reaction solution was cooled to room temperature, the reaction solution was filtered and dried to produce 1-cyclohexylquinoxaline-2,3(1H,4H)-dione. Gray solid (yield 80%); 1 1H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H), 7.65 - 7.56 (m, 1H), 7.19 - 7.13 (m, 3H), 4.58 - 4.39 (m, 1H), 2.47 - 2.37 (m, 2H), 1.85 - 1.79 (m, 2H), 1.74 - 1.62 (m, 3H), 1.51 - 1.38 (m, 2H), 1.31 - 1.16 (m, 1H); LC / MS ESI(+): 245.1 (M + 1). <Production Example i-4> Production of 1-Cyclohexyl-1,2,3,4-tetrahydroquinoxaline A solution of 1-cyclohexylquinoxaline-2,3(1H,4H)-dione (980 mg, 4.01 mmol) obtained in Production Example i-3 in THF (7.0 mL) was slowly added with borane-THF complex (1 M) (24 mL, 24.07 mmol) at room temperature, and then stirred at 65 °C for 16 hours. After the reaction solution was cooled to room temperature, water was added to terminate the reaction, and then neutralized with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce 1-cyclohexyl-1,2,3,4-tetrahydroquinoxaline. Orange oil (yield 91%); 1 1H NMR (400 MHz, CDCl3) δ 6.70 - 6.60 (m, 2H), 6.55 - 6.47 (m, 2H), 3.61 - 3.49 (m, 1H), 3.44 - 3.35 (m, 2H), 3.34 - 3.24 (m, 2H), 1.92 - 1.78 (m, 4H), 1.76 - 1.66 (m, 1H), 1.50 - 1.31 (m, 4H), 1.22 - 1.07 (m, 1H); LC / MS ESI(+): 217.2 (M+1). [Reaction Scheme 58]

Chemical Formula

[0247] <Production Example i-5> Production of tert-butyl (R)-3-(4-cyclohexyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate 1-Cyclohexyl-1,2,3,4-tetrahydroquinoxaline (1.0 eq) obtained in Production Example i-4 was dissolved in dichloromethane (0.3 M), and TEA (3.0 eq) and triphosgene (0.6 eq) were slowly added at 0 °C, followed by stirring at 0 °C for 1 hour. TEA (2.0 eq) and (R)-(+)-1-Boc-3-aminopyrrolidine (1.2 eq) were added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After adding water to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce tert-butyl (R)-3-(4-cyclohexyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate. White solid (yield 85%); 1 1H NMR (400 MHz, CDCl3) δ 7.10 - 7.03 (m, 2H), 6.82 - 6.77 (m, 1H), 6.64 - 6.56 (m, 1H), 5.31 - 5.27 (m, 1H), 4.46 - 4.34 (m, 1H), 3.85 - 3.60 (m, 4H), 3.46 - 3.30 (m, 4H), 3.19 - 3.10 (m, 1H), 2.20 - 2.10 (m, 1H), 1.91 - 1.70 (m, 6H), 1.52 - 1.37 (m, 13H), 1.23 - 1.12 (m, 1H). <Example 104>Synthesis of (R)-4-Cyclohexyl-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The Boc group of tert-butyl (R)-3-(4-cyclohexyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate obtained in Production Example i-5 was deprotected with TFA to synthesize (R)-4-cyclohexyl-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. White solid (yield 67%); 11H NMR (400 MHz, CDCl3) δ 7.11 - 7.03 (m, 2H), 6.80 - 6.78 (m, 1H), 6.64 - 6.58 (m, 1H), 5.39 (d, J = 6.8 Hz, 1H), 4.34 - 4.25 (m, 1H), 3.78 - 3.71 (m, 2H), 3.67 - 3.59 (m, 1H), 3.31 (t, J = 5.4 Hz, 2H), 3.23 - 3.18 (m, 1H), 3.08 - 3.02 (m, 1H), 2.98 - 2.92 (m, 1H), 2.82 - 2.78 (m, 1H), 2.21 - 2.12 (m, 1H), 1.91 - 1.82 (m, 4H), 1.75 - 1.71 (m, 1H), 1.65 - 1.55 (m, 1H), 1.52 - 1.35 (m, 4H), 1.23 - 1.12 (m, 1H); LC / MS ESI(+): 329.3 (M + 1). <Example 105>Synthesis of (R)-4-Cyclohexyl-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide The (R)-4-cyclohexyl-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (1.0 equivalent) obtained in Example 104 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.3 equivalents) and formaldehyde (1.1 equivalents) were added, and the mixture was stirred at room temperature for 3 hours. After adding water to the reaction solution to terminate the reaction, it was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize (R)-4-cyclohexyl-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide. Ivory solid (yield 43%); 11H NMR (400 MHz, CDCl3) δ 7.11 (dd, J = 7.8, 1.6 Hz, 1H), 7.07 - 7.02 (m, 1H), 6.79 - 6.76 (m, 1H), 6.64 - 6.59 (m, 1H), 5.48 (d, J = 7.4 Hz, 1H), 4.43 - 4.35 (m, 1H), 3.83 - 3.77 (m, 1H), 3.71 - 3.60 (m, 2H), 3.33 - 3.28 (m, 2H), 2.77 - 2.72 (m, 1H), 2.63 - 2.59 (m, 1H), 2.55 - 2.51 (m, 1H), 2.34 - 2.22 (m, 5H), 1.90 - 1.82 (m, 4H), 1.75 - 1.72 (m, 1H), 1.58 - 1.52 (m, 1H), 1.49 - 1.37 (m, 4H), 1.21 - 1.14 (m, 1H); LC / MS ESI(+): 343.3 (M + 1). <Example 106>Synthesis of (R)-4-Cyclohexyl-N-(1-isobutylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide Although carried out in the same manner as in Example 105, (R)-4-Cyclohexyl-N-(1-isobutylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized using isobutylaldehyde instead of formaldehyde. White solid (yield 46%); 1 1H NMR (400 MHz, CDCl3) δ 7.09 (dd, J = 7.8, 1.5 Hz, 1H), 7.05 - 7.00 (m, 1H), 6.77 - 6.75 (m, 1H), 6.61 - 6.57 (m, 1H), 5.59 (d, J = 8.0 Hz, 1H), 4.37 - 4.30 (m, 1H), 3.78 - 3.66 (m, 2H), 3.64 - 3.58 (m, 1H), 3.28 (t, J = 5.3 Hz, 1H), 2.77 - 2.72 (m, 1H), 2.53 - 2.46 (m, 2H), 2.25 - 2.11 (m, 4H), 1.88 - 1.79 (m, 4H), 1.74 - 1.64 (m, 2H), 1.54 - 1.32 (m, 5H), 1.21 - 1.10 (m, 1H), 0.87 (dd, J = 6.6, 3.9 Hz, 6H); LC / MS ESI(+): 385.4 (M + 1). [Reaction Scheme 59] [Chemical Formula]

[0248] <Example 107>Synthesis of (4-Cyclohexyl-3,4-dihydroquinoxalin-1(2H)-yl)(4-methylpiperazin-1-yl)methanone Although carried out in the same manner as in Production Example i-5, (4-Cyclohexyl-3,4-dihydroquinoxalin-1(2H)-yl)(4-methylpiperazin-1-yl)methanone was synthesized using 1-methylpiperazine instead of (R)-(+)-1-Boc-3-aminopyrrolidine. Brown oil (yield 81%); 1 H NMR (400 MHz, CDCl3) δ 6.96 (dd, J = 7.9, 1.5 Hz, 1H), 6.93 - 6.89 (m, 1H), 6.72 - 6.70 (m, 1H), 6.59 - 6.63 (m, 1H), 3.65 - 3.57 (m, 3H), 3.38 - 3.33 (m, 6H), 2.26 - 2.33 (m, 4H), 2.28 (s, 3H), 1.89 - 1.81 (m, 4H), 1.73 - 1.70 (m, 1H), 1.50 - 1.33 (m, 4H), 1.17 - 1.13 (m, 1H); LC / MS ESI(+): 343.3 (M+1). <Example 108>Synthesis of (4-Cyclohexyl-3,4-dihydroquinoxalin-1(2H)-yl)(pyrrolidin-1-yl)methanone Although carried out in the same manner as in Production Example i-5, (4-Cyclohexyl-3,4-dihydroquinoxalin-1(2H)-yl)(pyrrolidin-1-yl)methanone was synthesized using pyrrolidine instead of (R)-(+)-1-Boc-3-aminopyrrolidine. Ivory solid (yield 54%); 11H NMR (400 MHz, CDCl3) δ 6.91 - 6.84 (m, 2H), 6.70 - 6.68 (m, 1H), 6.57 - 6.53 (m, 1H), 3.67 (t, J = 5.4 Hz, 2H), 3.63 - 3.57 (m, 1H), 3.37 (t, J = 5.3 Hz, 2H), 3.28 - 3.25 (m, 4H), 1.88 - 1.76 (m, 8H), 1.73 - 1.69 (m, 1H), 1.51 - 1.33 (m, 4H), 1.21 - 1.10 (m, 1H); LC / MS ESI(+): 314.3 (M + 1). <Example 109>Synthesis of (4 - cyclohexyl - 3,4 - dihydroquinoxalin - 1(2H) - yl)(piperidin - 1 - yl)methanone Although carried out in the same manner as in Production Example i - 5, (4 - cyclohexyl - 3,4 - dihydroquinoxalin - 1(2H) - yl)(piperidin - 1 - yl)methanone was synthesized using piperidine instead of (R)-(+)-1 - Boc - 3 - aminopyrrolidine. Red oil (yield 80%); 1 1H NMR (400 MHz, CDCl3) δ 6.94 - 6.87 (m, 2H), 6.71 - 6.69 (m, 1H), 6.58 - 6.53 (m, 1H), 3.62 - 3.58 (m, 3H), 3.36 (t, J = 5.3 Hz, 2H), 3.27 - 3.24 (m, 4H), 1.88 - 1.82 (m, 4H), 1.73 - 1.69 (m, 1H), 1.55 - 1.36 (m, 10H), 1.21 - 1.11 (m, 1H); LC / MS ESI(+): 328.0 (M + 1). [Reaction Scheme 60] [Chemical Formula]

[0249] <Production Method j>Production of 1 - (tetrahydro - 2H - pyran - 4 - yl)-1,2,3,4 - tetrahydroquinoxaline 1 - (tetrahydro - 2H - pyran - 4 - yl)-1,2,3,4 - tetrahydroquinoxaline according to the present invention was synthesized through the processes of Production Examples j - 1 to j - 4 below. <Production Example i - 1>Production of N - (2 - nitrophenyl)tetrahydro - 2H - pyran - 4 - amine A solution of 1-fluoro-2-nitrobenzene (1.0 equivalent) and tetrahydro-2H-pyran-4-amine (1.2 equivalents) was stirred at 110 °C for 6 hours and then cooled to room temperature. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce N-(2-nitrophenyl)tetrahydro-2H-pyran-4-amine. Orange solid (yield 91%); 1 1H NMR (400 MHz, CDCl3) δ 8.25 - 8.18 (m, 1H), 8.12 (s, 1H), 7.49 - 7.40 (m, 1H), 6.93 - 6.86 (m, 1H), 6.72 - 6.63 (m, 1H), 4.10 - 4.00 (m, 2H), 3.83 - 3.70 (m, 1H), 3.65 - 3.54 (m, 2H), 2.16 - 2.04 (m, 2H), 1.78 - 1.63 (m, 2H); LC / MS ESI(+): 223.1 (M + 1). <Production Example j-2> N 1 -tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine Production N-(2-nitrophenyl)tetrahydro-2H-pyran-4-amine (1.0 equivalent) obtained in Production Example j-1 was dissolved in EtOAc / MeOH (1:3 = v / v, 20 mL), then 10% Pd / C (0.2 equivalent) was added, and the mixture was stirred at room temperature for 6 hours under hydrogen gas conditions. The reaction solution was filtered through a Celite pad and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce N 1 -tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine. Brown solid (yield 91%); 11H NMR (400 MHz, CDCl3) δ 6.86 - 6.80 (m, 1H), 6.79 - 6.68 (m, 3H), 4.08 - 3.99 (m, 2H), 3.61 - 3.43 (m, 3H), 3.37 (s, 2H), 3.27 (s, 1H), 2.12 - 2.01 (m, 2H), 1.62 - 1.48 (m, 2H); LC / MS ESI(+): 193.2 (M + 1). <Production Example j-3> Production of 1-(tetrahydro-2H-pyran-4-yl)hydroquinoxaline-2,3-dione The N obtained in Production Example j-2 1 -tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine (1.0 equivalent) was dissolved in diethyl oxalate (6.0 equivalents), and the reaction solution was stirred at 130 °C for 2 hours. After cooling the reaction solution to room temperature, the reaction solution was filtered and dried to produce 1-(tetrahydro-2H-pyran-4-yl)hydroquinoxaline-2,3-dione. Brown solid (yield 70%); 1 1H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 7.78 - 7.57 (m, 1H), 7.25 - 7.13 (m, 3H), 4.31 - 4.21 (m, 3H), 2.79 - 2.64 (m, 2H), 1.66 - 1.57 (m, 2H), 1.10 - 1.02 (m, 2H); LC / MS ESI(+): 247.1 (M + 1). <Production Example j-4> Production of 1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoxaline A solution of 1-(tetrahydro-2H-pyran-4-yl)hydroxyquinoxaline-2,3-dione (1.0 eq) obtained in Production Example j-3 in THF was slowly added with borane-THF complex (1.0 M) (6.0 eq) at room temperature, and then stirred at 65 °C for 16 hours. After the reaction solution was cooled to room temperature, water was added to terminate the reaction, and then neutralized with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce 1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoxaline. White solid (yield 79%); 1 1H NMR (400 MHz, CD3OD) δ 6.77 - 6.70 (m, 1H), 6.67 - 6.46 (m, 3H), 4.09 - 4.01 (m, 2H), 3.93 - 3.81 (m, 1H), 3.62 - 3.51 (m, 2H), 3.34 - 3.29 (m, 3H), 3.28 - 3.25 (m, 2H), 1.94 - 1.77 (m, 2H), 1.76 - 1.66 (m, 2H); LC / MS ESI(+): 219.2 (M+1). [Reaction Scheme 61]

Chemical Formula

[0250] <Production Example j-5> Production of tert-butyl (R)-3-(4-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate 1-(Tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoxaline (1.0 eq) obtained in Production Example j-4 was dissolved in dichloromethane (0.3 M), and TEA (3.0 eq) and triphosgene (0.6 eq) were slowly added at 0 °C, followed by stirring at 0 °C for 1 hour. TEA (2.0 eq) and (R)-(+)-1-Boc-3-aminopyrrolidine (1.2 eq) were added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After adding water to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce tert-butyl (R)-3-(4-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate. White solid (yield 94.3%); 1 1H NMR (400 MHz, CDCl3) δ 7.10 - 7.02 (m, 2H), 6.85 - 6.77 (m, 1H), 6.68 - 6.58 (m, 1H), 5.27 (d, J = 6.8 Hz, 1H), 4.46 - 4.32 (m, 1H), 4.12 - 4.04 (m, 2H), 3.94 - 3.83 (m, 1H), 3.82 - 3.74 (m, 1H), 3.73 - 3.58 (m, 1H), 3.57 - 3.46 (m, 2H), 3.45 - 3.23 (m, 5H), 3.16 - 3.09 (m, 1H), 2.17 - 2.10 (m, 1H), 1.93 - 1.79 (m, 2H), 1.74 - 1.66 (m, 2H), 1.44 (s, 9H); LC / MS ESI(+): 431.2 (M+1). <Production Example j-6> Production of (R)-N-(Pyrrolidin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide The Boc group of tert-butyl (R)-3-(4-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide) pyrrolidine-1-carboxylate obtained in the above Production Example j-5 was deprotected with TFA to produce (R)-N-(pyrrolidin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide. White solid (yield 84.3%); 1 H NMR (400 MHz, CDCl3) δ 7.13 (dd, J = 7.8, 1.6 Hz, 1H), 7.08 - 7.03 (m, 1H), 6.86 - 6.78 (m, 1H), 6.67 - 6.61 (m, 1H), 5.44 (d, J = 6.7 Hz, 1H), 4.40 - 4.28 (m, 1H), 4.11 - 4.05 (m, 2H), 3.92 - 3.79 (m, 1H), 3.78 - 3.63 (m, 2H), 3.55 - 3.47 (m, 2H), 3.34 - 3.18 (m, 4H), 3.17 - 3.05 (m, 1H), 3.04 - 2.96 (m, 1H), 2.92 - 2.86 (m, 1H), 2.24 - 2.11 (m, 1H), 1.95 - 1.77 (m, 2H), 1.76 - 1.57 (m, 3H); LC / MS ESI(+): 331.2 (M + 1). <Example 110>Synthesis of (R)-N-(1-methylpyrrolidin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (R)-N-(Pyrrolidin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (1.0 eq) obtained in Production Example j-6 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.3 eq) and formaldehyde (1.1 eq) were added, and the mixture was stirred at room temperature for 3 hours. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize (R)-N-(1-methylpyrrolidin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide. Light yellow oil (yield 82.5); 1 1H NMR (400 MHz, CDCl3) δ 7.11 (dd, J = 7.8, 1.6 Hz, 1H), 7.08 - 6.98 (m, 1H), 6.79 (dd, J = 8.3, 1.1 Hz, 1H), 6.67 - 6.59 (m, 1H), 5.44 (d, J = 7.5 Hz, 1H), 4.42 - 4.30 (m, 1H), 4.13 - 4.04 (m, 2H), 3.94 - 3.77 (m, 2H), 3.74 - 3.62 (m, 1H), 3.56 - 3.45 (m, 2H), 3.35 - 3.22 (m, 2H), 2.79 - 2.69 (m, 1H), 2.60 - 2.49 (m, 2H), 2.35 - 2.26 (m, 4H), 2.25 - 2.16 (m, 1H), 1.93 - 1.77 (m, 2H), 1.75 - 1.72 (m, 2H), 1.59 - 1.46 (m, 1H); LC / MS ESI(+): 345.2 (M + 1). <Example 111>Synthesis of (R)-N-(1-isobutylpyrrolidin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide Although carried out in the same manner as in Example 110, (R)-N-(1-isobutylpyrrolidin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized using isobutylaldehyde instead of formaldehyde. Pale yellow oil (yield 86.3%); 1 H NMR (400 MHz, CDCl3) δ 7.11 (dd, J = 7.8, 1.6 Hz, 1H), 7.07 - 6.98 (m, 1H), 6.83 - 6.76 (m, 1H), 6.67 - 6.58 (m, 1H), 5.59 (d, J = 7.9 Hz, 1H), 4.39 - 4.28 (m, 1H), 4.13 - 4.04 (m, 2H), 3.95 - 3.83 (m, 1H), 3.83 - 3.67 (m, 2H), 3.51 (t, J = 2.1 Hz, 2H), 3.29 (t, J = 5.3 Hz, 2H), 2.82 - 2.71 (m, 1H), 2.56 - 2.49 (m, 1H), 2.49 - 2.41 (m, 1H), 2.27 - 2.08 (m, 4H), 1.93 - 1.78 (m, 2H), 1.76 - 1.67 (m, 3H), 1.59 - 1.48 (m, 1H), 0.92 - 0.80 (m, 6H); LC / MS ESI(+): 387.3 (M + 1). [Reaction Scheme 62] [Chemical formula]

[0251] <Production Example j - 7> Production of tert - butyl (S)-(1-(4-(tetrahydro - 2H - pyran - 4 - yl)-1,2,3,4 - tetrahydroquinoxaline - 1 - carboxamido)pyrrolidin - 3 - yl)carbamate Although carried out in the same manner as in Production Example j - 5, tert - butyl (S)-(1-(4-(tetrahydro - 2H - pyran - 4 - yl)-1,2,3,4 - tetrahydroquinoxaline - 1 - carboxamido)pyrrolidin - 3 - yl)carbamate was produced using (S)-( - )-3-(Boc - amino)pyrrolidine instead of (R)-(+)-1 - Boc - 3 - aminopyrrolidine. Ivory solid (yield 90.2%); 11H NMR (400 MHz, CDCl3) δ 6.96 - 6.88 (m, 1H), 6.86 (dd, J = 7.9, 1.5 Hz, 1H), 6.77 - 6.70 (m, 1H), 6.64 - 6.55 (m, 1H), 4.60 - 4.47 (m, 1H), 4.15 - 4.06 (m, 3H), 3.91 - 3.81 (m, 1H), 3.68 (t, J = 4.5 Hz, 2H), 3.57 - 3.29 (m, 6H), 3.09 - 3.01 (m, 1H), 2.13 - 2.03 (m, 1H), 1.95 - 1.79 (m, 2H), 1.77 - 1.71 (m, 3H), 1.42 (s, 9H); LC / MS ESI(+): 431.2 (M + 1). <Example 112> Synthesis of (S)-(3-Aminopyrrolidin-1-yl)(4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone The Boc group of tert-butyl (S)-(1-(4-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidin-3-yl)carbamate obtained in Production Example j-7 was deprotected with TFA to synthesize (S)-(3-aminopyrrolidin-1-yl)(4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone. Light yellow oil (yield 69.7%); 1 1H NMR (400 MHz, CDCl3) δ 6.96 - 6.85 (m, 2H), 6.76 - 6.71 (m, 1H), 6.65 - 6.55 (m, 1H), 4.13 - 4.04 (m, 2H), 3.86 (t, J = 3.9 Hz, 1H), 3.78 - 3.69 (m, 1H), 3.68 - 3.56 (m, 1H), 3.56 - 3.41 (m, 5H), 3.41 - 3.26 (m, 3H), 3.03 - 2.89 (m, 1H), 2.07 - 1.95 (m, 1H), 1.93 - 1.78 (m, 2H), 1.78 - 1.69 (m, 2H), 1.67 - 1.54 (m, 1H), 1.44 - 1.37 (m, 2H); LC / MS ESI(+): 331.2 (M + 1). <Example 113>Synthesis of (S)-(3-(dimethylamino)pyrrolidin-1-yl)(4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone (S)-(3-Aminopyrrolidin-1-yl)(4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone (95.0 mg, 0.29 mmol) obtained in Example 114 was dissolved in dichloromethane (3.0 mL), sodium triacetoxyborohydride (182.8 mg, 0.86 mmol) and formaldehyde (69.1 μL, 0.86 mmol) were added, and the mixture was stirred at room temperature for 4 hours. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize (S)-(3-(dimethylamino)pyrrolidin-1-yl)(4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone. Light yellow oil (yield 16.5%); 1 1H NMR (400 MHz, CDCl3) δ 6.94 - 6.83 (m, 2H), 6.73 (dd, J = 8.1, 1.2 Hz, 1H), 6.63 - 6.55 (m, 1H), 4.09 (d, J = 1.5 Hz, 2H), 4.03 - 3.94 (m, 1H), 3.92 - 3.83 (m, 1H), 3.58 - 3.43 (m, 3H), 3.42 - 3.25 (m, 5H), 3.15 (dd, J = 10.7, 8.9 Hz, 1H), 2.68 - 2.56 (m, 1H), 2.20 (s, 6H), 2.05 - 1.95 (m, 1H), 1.94 - 1.78 (m, 2H), 1.77 - 1.67 (m, 3H); LC / MS ESI(+): 359.3 (M + 1). [Reaction Scheme 63] [Chemical Formula]

[0252] <Production Method k>Production of (3,4-dihydroquinoxalin-1(2H)-yl)(phenyl)methanone or halogen-substituted (3,4-dihydroquinoxalin-1(2H)-yl)(phenyl)methanone The (3,4-dihydroquinoxalin-1(2H)-yl)(phenyl)methanone or halogen-substituted (3,4-dihydroquinoxalin-1(2H)-yl)(phenyl)methanone according to the present invention was synthesized through the processes of Production Examples k-1 to k-8 below. <Production Example k-1>Production of tert-butyl 4-benzoyl-3,4-dihydroquinoxalin-1(2H)-carboxylate The tert-butyl 3,4-dihydroquinoxalin-1(2H)-carboxylate (473 mg, 2.02 mmol) obtained in Production Example d-1 was dissolved in THF (20 mL), benzoyl chloride (117 μL, 1.01 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After adding water to the reaction solution to terminate the reaction, it was neutralized with a saturated NaHCO3 aqueous solution and extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a hexane / ethyl acetate mixture to produce tert-butyl 4-benzoyl-3,4-dihydroquinoxalin-1(2H)-carboxylate. Yellow oil (yield 100%); 1 1H NMR (400 MHz, CDCl3) δ 7.92 - 7.83 (m, 1H), 7.45 - 7.34 (m, 3H), 7.31 - 7.26 (m, 2H), 7.05 (d, J = 1.6 Hz, 1H), 6.73 (s, 1H), 6.65 - 6.54 (m, 1H), 4.09 - 4.02 (m, 2H), 3.98 - 3.91 (m, 2H), 1.57 (s, 9H). <Production Example k-2>Production of tert-butyl 4-(2-fluorobenzoyl)-3,4-dihydroquinoxalin-1(2H)-carboxylate Although carried out in the same manner as in Production Example k-1, tert-butyl 4-(2-fluorobenzoyl)-3,4-dihydroquinoxalin-1(2H)-carboxylate was produced using 2-fluorobenzoyl chloride instead of benzoyl chloride. Colorless oil (yield 84%); 1 1H NMR (400 MHz, CDCl3) δ 7.96 - 7.82 (m, 1H), 7.51 - 7.45 (m, 1H), 7.42 - 7.32 (m, 1H), 7.22 - 7.15 (m, 1H), 7.13 - 7.07 (m, 1H), 7.02 - 6.89 (m, 1H), 6.85 - 6.40 (m, 2H), 4.12 - 3.95 (m, 4H), 1.57 (s, 9H). <Production Example k-3> Production of tert-Butyl 4-(3-Fluorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate Although carried out in the same manner as in Production Example k-1, tert-Butyl 4-(3-Fluorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate was produced using 3-Fluorobenzoyl chloride instead of Benzoyl chloride. Colorless oil (yield 72%); 1 1H NMR (400 MHz, CDCl3) δ 7.93 - 7.83 (m, 1H), 7.25 - 7.21 (m, 1H), 7.20 - 7.16 (m, 1H), 7.15 - 7.12 (m, 1H), 7.11 - 7.06 (m, 2H), 6.80 - 6.78 (m, 1H), 6.65 - 6.55 (m, 1H), 4.08 - 4.03 (m, 2H), 3.97 - 3.93 (m, 2H), 1.57 (s, 9H). <Production Example k-4> Production of tert-Butyl 4-(4-Fluorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate Although carried out in the same manner as in Production Example k-1, tert-Butyl 4-(4-Fluorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate was produced using 4-Fluorobenzoyl chloride instead of Benzoyl chloride. Colorless oil (yield 93%); 11H NMR (400 MHz, CDCl3) δ 7.95 - 7.85 (m, 1H), 7.46 - 7.41 (m, 2H), 7.10 - 7.05 (m, 1H), 7.01 - 6.94 (m, 2H), 6.77 - 6.73 (m, 1H), 6.57 - 6.50 (m, 1H), 4.08 - 4.05 (m, 2H), 3.97 - 3.93 (m, 2H), 1.57 (s, 9H). <Production Example k-5> Production of (3,4-dihydroquinoxalin-1(2H)-yl)(phenyl)methanone The Boc group of tert-butyl 4-benzoyl-3,4-dihydroquinoxalin-1(2H)-carboxylate obtained in Production Example k-1 was deprotected with TFA to produce (3,4-dihydroquinoxalin-1(2H)-yl)(phenyl)methanone. Light yellow oil (yield 92%); 1 1H NMR (400 MHz, CDCl3) δ 7.49 - 7.35 (m, 3H), 7.34 - 7.28 (m, 2H), 6.91 - 6.83 (m, 1H), 6.59 (dd, J = 8.0, 0.9 Hz, 2H), 6.40 - 6.34 (m, 1H), 4.07 (brs, 1H), 3.98 (t, J = 5.1 Hz, 2H), 3.56 (t, J = 5.1 Hz, 2H); LC / MS ESI(+): 239.1 (M+1). <Production Example k-6> Production of (3,4-dihydroquinoxalin-1(2H)-yl)(2-fluorophenyl)methanone The Boc group of tert-butyl 4-(2-fluorobenzoyl)-3,4-dihydroquinoxalin-1(2H)-carboxylate obtained in Production Example k-2 was deprotected with TFA to produce (3,4-dihydroquinoxalin-1(2H)-yl)(2-fluorophenyl)methanone. White solid (yield 87%); 1 1H NMR (400 MHz, CDCl3) δ 7.52 - 7.46 (m, 1H), 7.42 - 7.28 (m, 1H), 7.24 - 7.12 (m, 1H), 7.05 - 6.75 (m, 2H), 6.58 (d, J = 7.9 Hz, 1H), 6.42 - 6.17 (m, 1H), 4.50 - 3.87 (m, 2H), 3.80 - 3.20 (m, 3H); LC / MS ESI(+): 257.1 (M+1). <Production Example k-7>Production of (3,4-Dihydroquinoxalin-1(2H)-yl)(3-fluorophenyl)methanone The Boc group of tert-butyl 4-(3-fluorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate obtained in Production Example k-3 was deprotected with TFA to produce (3,4-dihydroquinoxalin-1(2H)-yl)(3-fluorophenyl)methanone. White solid (yield 87%); 1 1H NMR (400 MHz, CDCl3) δ 7.30 - 7.27 (m, 1H), 7.21 - 7.16 (m, 2H), 7.09 - 7.05 (m, 1H), 6.92 - 6.87 (m, 1H), 6.68 - 6.45 (m, 2H), 6.44 - 6.30 (m, 1H), 4.12 (brs, 1H), 3.97 (t, J = 4.9 Hz, 2H), 3.62 - 3.50 (m, 2H); LC / MS ESI(+): 257.1 (M+1). <Production Example k-8>Production of (3,4-Dihydroquinoxalin-1(2H)-yl)(4-fluorophenyl)methanone The Boc group of tert-butyl 4-(4-fluorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate obtained in Production Example k-4 was deprotected with TFA to produce (3,4-dihydroquinoxalin-1(2H)-yl)(4-fluorophenyl)methanone. White solid (yield 93%); 1 1H NMR (400 MHz, CDCl3) δ 7.48 - 7.44 (m, 1H), 7.01 - 6.96 (m, 2H), 6.90 - 6.85 (m, 1H), 6.65 - 6.45 (m, 2H), 6.38 - 6.34 (m, 1H), 4.14 (brs, 1H), 3.98 - 3.96 (m, 2H), 3.56 (t, J = 4.9 Hz, 2H); LC / MS ESI(+): 257.1 (M+1). [Reaction Scheme 64]

Chemical Formula

[0253] <Production Example k-9>Production of tert-Butyl 4-((4-benzoyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate The (3,4-dihydroquinoxalin-1(2H)-yl)(phenyl)methanone (1.0 equivalent) obtained in Production Example k-5 was dissolved in dichloromethane (0.3 M), and TEA (3.0 equivalents) and triphosgene (0.6 equivalent) were slowly added at 0 °C, followed by stirring at 0 °C for 1 hour. TEA (2.0 equivalents) and 1-Boc-4-(aminomethyl)piperidine (1.2 equivalents) were added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce tert-butyl 4-((4-benzoyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate. White solid (yield 90%); 1 1H NMR (400 MHz, CDCl3) δ 7.43 - 7.40 (m, 4H), 7.35 - 7.31 (m, 2H), 7.15 - 7.10 (m, 1H), 6.94 - 6.85 (m, 2H), 5.33 - 5.31 (m, 1H), 4.22 - 4.04 (m, 4H), 4.03 - 3.96 (m, 2H), 3.30 - 3.17 (m, 2H), 2.80 - 2.65 (m, 2H), 1.80 - 1.70 (m, 3H), 1.47 (s, 9H), 1.22 - 1.14 (m, 2H). <Example 114>Synthesis of 4-Benzoyl-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide The Boc group of tert-butyl 4-((4-benzoyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate obtained in Production Example k-9 was deprotected with TFA to synthesize 4-benzoyl-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide. White solid (yield 67%);1 1H NMR (400 MHz, CD3OD) δ 7.55 - 7.53 (m, 1H), 7.43 - 7.39 (m, 3H), 7.34 - 7.30 (m, 2H), 7.14 - 7.10 (m, 1H), 6.84 - 6.79 (m, 1H), 6.68 (d, 1H, J = 7.9 Hz), 4.08 - 4.05 (m, 2H), 3.93 - 3.89 (m, 2H), 3.17 - 3.10 (m, 4H), 2.69 - 2.62 (m, 2H), 1.81 - 1.74 (m, 3H), 1.32 - 1.21 (m, 2H); LC / MS ESI(+): 379.3 (M + 1). [Reaction Formula 65] [Chem.]

[0254] [Production Example k - 10] Production of tert - butyl (R)-3 - ((4 - benzoyl - 1,2,3,4 - tetrahydroquinoxaline - 1 - carboxamido)methyl)pyrrolidine - 1 - carboxylate Although carried out in the same manner as in Production Example k - 9, tert - butyl (R)-3 - ((4 - benzoyl - 1,2,3,4 - tetrahydroquinoxaline - 1 - carboxamido)methyl)pyrrolidine - 1 - carboxylate was produced using (R)-1 - Boc - 3 - (aminomethyl)pyrrolidine instead of 1 - Boc - 4 - (aminomethyl)piperidine. White solid (yield 94%); 1 1H NMR (400 MHz, CDCl3) δ 7.42 - 7.38 (m, 4H), 7.34 - 7.31 (m, 2H), 7.15 - 7.07 (m, 1H), 6.95 - 6.80 (m, 2H), 5.39 - 5.27 (m, 1H), 4.07 - 4.03 (m, 2H), 4.00 - 3.94 (m, 2H), 3.59 - 3.18 (m, 5H), 3.12 - 2.99 (m, 1H), 2.56 - 2.42 (m, 1H), 2.05 - 1.97 (m, 1H), 1.72 - 1.60 (m, 1H), 1.46 (s, 9H). [Example 115] Synthesis of (S)-4 - benzoyl - N - (pyrrolidin - 3 - ylmethyl)-3,4 - dihydroquinoxalin - 1(2H)-carboxamide The Boc group of tert-butyl (R)-3-((4-benzoyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate obtained in the above Production Example k-10 was deprotected with TFA to synthesize (S)-4-benzoyl-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide. White solid (yield 92%); 1 1H NMR (400 MHz, CD3OD) δ 7.56 (dd, J = 8.3, 1.1 Hz, 1H), 7.48 - 7.42 (m, 3H), 7.37 - 7.33 (m, 2H), 7.18 - 7.13 (m, 1H), 6.87 - 6.83 (m, 1H), 6.75 - 6.65 (m, 1H), 4.11 - 4.07 (m, 2H), 3.96 - 3.91 (m, 2H), 3.36 - 3.30 (m, 1H), 3.27 - 3.19 (m, 2H), 3.14 - 3.07 (m, 1H), 3.91 - 2.85 (m, 1H), 2.62 - 2.53 (m, 1H), 2.13 - 2.06 (m, 1H), 1.75 - 1.66 (m, 1H); LC / MS ESI(+): 365.2 (M+1). <Example 116>Synthesis of (R)-4-benzoyl-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (S)-4-Benzoyl-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (1.0 equivalent) obtained in the above Example 115 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize (R)-4-benzoyl-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide. White solid (yield 82%); 11H NMR (400 MHz, CD3OD) δ 7.52 (dd, J = 8.2, 1.2 Hz, 1H), 7.45 - 7.39 (m, 3H), 7.34 - 7.30 (m, 2H), 7.15 - 7.10 (m, 1H), 6.84 - 6.80 (m, 1H), 6.68 (d, J = 7.9 Hz, 1H), 4.08 - 4.04 (m, 2H), 3.92 - 3.89 (m, 2H), 3.26 (d, J = 7.1 Hz, 2H), 2.79 - 2.74 (m, 1H), 2.65 - 2.61 (m, 2H), 2.58 - 2.52 (m, 1H), 2.43 - 2.39 (m, 1H), 2.36 (s, 3H), 2.07 - 2.00 (m, 1H), 1.65 - 1.58 (m, 1H); LC / MS ESI(+): 379.1 (M + 1). [Reaction Scheme 66] [Chem.]

[0255] <Production Example k-11> Production of tert-butyl (R)-3-((4-(2-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate Dissolve (3,4-dihydroquinoxalin-1(2H)-yl)(2-fluorophenyl)methanone (1.0 equivalent), obtained in Production Example k-6, in dichloromethane (0.3 M), and slowly add TEA (3.0 equivalents) and triphosgene (0.6 equivalent) at 0 °C, then stir at 0 °C for 1 hour. Add TEA (2.0 equivalents) and (R)-1-Boc-3-(aminomethyl)pyrrolidine (1.2 equivalents) to the reaction solution, and stir at room temperature for 3 hours. After adding water to terminate the reaction, extract with dichloromethane. Wash the organic layer with brine, dry over MgSO4, filter, and then concentrate under reduced pressure. Purify the obtained residue by silica column chromatography using an n-hexane / ethyl acetate mixture to produce tert-butyl (R)-3-((4-(2-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate. White solid (yield 97%); 11H NMR (400 MHz, CDCl3) δ 7.65 - 7.55 (m, 1H), 7.42 - 7.31 (m, 2H), 7.25 - 7.22 (m, 1H), 7.15 - 7.11 (m, 1H), 6.95 - 6.75 (m, 3H), 5.25 - 5.15 (m, 1H), 4.10 - 3.90 (m, 4H), 3.55 - 3.40 (m, 3H), 3.35 - 3.25 (m, 2H), 3.10 - 2.95 (m, 1H), 2.50 - 2.40 (m, 1H), 2.04 - 1.95 (m, 1H), 1.70 - 1.55 (m, 1H), 1.45 (s, 9H). <Example 117> Synthesis of (S)-4-(2-Fluorobenzoyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The Boc group of tert-butyl (R)-3-((4-(2-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide)methyl)pyrrolidine-1-carboxylate obtained in Production Example k-11 was deprotected with TFA to synthesize (S)-4-(2-fluorobenzoyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. White solid (yield 71%); 1 1H NMR (400 MHz, CD3OD) δ 7.54 - 7.43 (m, 3H), 7.26 - 7.23 (m, 1H), 7.17 - 7.13 (m, 1H), 7.09 - 6.91 (m, 1H), 6.90 - 6.50 (m, 2H), 4.19 - 4.00 (m, 2H), 3.98 - 3.85 (m, 2H), 3.28 - 3.24 (m, 2H), 3.15 - 3.09 (m, 2H), 3.04 - 2.97 (m, 1H), 2.80 - 2.76 (m, 1H), 2.53 - 2.46 (m, 1H), 2.05 - 1.96 (m, 1H), 1.66 - 1.57 (m, 1H); LC / MS ESI(+): 383.3 (M+1). <Example 118> Synthesis of (R)-4-(2-Fluorobenzoyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (S)-4-(2-Fluorobenzoyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (1.0 eq) obtained in Example 117 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 eq) and formaldehyde (2.0 eq) were added, and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction mixture to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture to synthesize (R)-4-(2-fluorobenzoyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. White solid (yield 76%); 1 1H NMR (400 MHz, CD3OD) δ 7.52 - 7.42 (m, 3H), 7.26 - 7.22 (m, 1H), 7.16 - 7.12 (m, 1H), 7.09 - 6.91 (m, 1H), 6.90 - 6.50 (m, 2H), 4.15 - 3.96 (m, 2H), 3.95 - 3.82 (m, 2H), 3.25 (d, J = 7.0 Hz, 2H), 2.78 - 2.73 (m, 1H), 2.66 - 2.61 (m, 2H), 2.59 - 2.52 (m, 1H), 2.43 - 2.39 (m, 1H), 2.36 (s, 3H), 2.07 - 1.98 (m, 1H), 1.65 - 1.56 (m, 1H); LC / MS ESI(+): 397.3 (M + 1). [Reaction Scheme 67] [Chemical Formula]

[0256] <Production Example k-12> Production of tert-butyl (R)-3-(4-(3-fluorobenzoyl)-1,2,3,4-tetrahydroquinoxalin-1-carboxamide)pyrrolidine-1-carboxylate The 3,4-dihydroquinoxalin-1(2H)-yl)(3-fluorophenyl)methanone (1.0 equivalent) obtained in Production Example k-7 was dissolved in dichloromethane (0.3 M), and TEA (3.0 equivalents) and triphosgene (0.6 equivalent) were slowly added at 0 °C and stirred at 0 °C for 1 hour. TEA (2.0 equivalents) and (R)-(+)-1-Boc-3-aminopyrrolidine (1.2 equivalents) were added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After adding water to the reaction solution to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to produce tert-butyl (R)-3-(4-(3-fluorobenzoyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate. White solid (yield 96%); 1 1H NMR (400 MHz, CD3OD) δ 7.58 (d, J = 8.0 Hz, 1H), 7.40 - 7.34 (m, 1H), 7.25 - 7.20 (m, 3H), 7.18 - 7.13 (m, 1H), 6.87 - 6.83 (m, 1H), 6.73 (d, J = 7.5 Hz, 1H), 4.42 - 4.37 (m, 1H), 4.09 - 4.05 (m, 2H), 3.95 - 3.92 (m, 2H), 3.72 - 3.66 (m, 1H), 3.54 - 3.46 (m, 1H), 3.45 - 3.37 (m, 1H), 3.30 - 3.27 (m, 1H), 2.27 - 2.18 (m, 1H), 2.02 - 1.98 (m, 1H), 1.48 (s, 9H). <Example 119>Synthesis of (R)-4-(3-fluorobenzoyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The Boc group of tert-butyl (R)-3-(4-(3-fluorobenzoyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate obtained in Production Example k-12 was deprotected with TFA to synthesize (R)-4-(3-fluorobenzoyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. White solid (yield 67%); 1 1H NMR (400 MHz, CD3OD) δ 7.63 - 7.61 (m, 1H), 7.40 - 7.35 (m, 1H), 7.26 - 7.14 (m, 4H), 6.88 - 6.84 (m, 1H), 6.74 (d, J = 7.6 Hz, 1H), 4.41 - 4.35 (m, 1H), 4.15 - 4.03 (m, 2H), 3.96 - 3.91 (m, 2H), 3.30 - 3.21 (m, 2H), 3.09 - 2.97 (m, 2H), 2.31 - 2.23 (m, 1H), 1.97 - 1.88 (m, 1H); LC / MS ESI(+): 369.3 (M + 1). [Reaction Scheme 68] [Chem.]

[0257] [Production Example k - 13] Production of tert - butyl (R)-3 - ((4-(3 - fluorophenyl)-1,2,3,4 - tetrahydroquinoxaline - 1 - carboxamido)methyl)pyrrolidine - 1 - carboxylate Dissolve (3,4 - dihydroquinoxalin - 1(2H)-yl)(3 - fluorophenyl)methanone (1.0 equivalent), obtained in Production Example k - 7, in dichloromethane (0.3 M), and slowly add TEA (3.0 equivalents) and triphosgene (0.6 equivalent) at 0 °C, then stir at 0 °C for 1 hour. Add TEA (2.0 equivalents) and (R)-1 - Boc - 3 - (aminomethyl)pyrrolidine (1.2 equivalents) to the reaction solution, and stir at room temperature for 3 hours. After adding water to terminate the reaction, extract with dichloromethane. Wash the organic layer with brine, dry over MgSO4, filter, and then concentrate under reduced pressure. Purify the obtained residue by silica column chromatography using an n - hexane / ethyl acetate mixture to produce tert - butyl (R)-3 - ((4-(3 - fluorophenyl)-1,2,3,4 - tetrahydroquinoxaline - 1 - carboxamido)methyl)pyrrolidine - 1 - carboxylate. White solid (yield 97%); 11H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 7.9 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.18 - 7.07 (m, 4H), 6.96 - 6.80 (m, 2H), 5.35 - 5.27 (m, 1H), 4.07 - 4.03 (m, 2H), 4.01 - 3.94 (m, 2H), 3.57 - 3.39 (m, 3H), 3.38 - 3.18 (m, 2H), 3.12 - 2.99 (m, 1H), 2.53 - 2.43 (m, 1H), 2.04 - 1.95 (m, 1H), 1.72 - 1.61 (m, 1H), 1.45 (s, 9H). <Example 120> Synthesis of (S)-4-(3-Fluorobenzoyl)-N-(pyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide The Boc group of tert-butyl (R)-3-((4-(3-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamide)methyl)pyrrolidine-1-carboxylate obtained in Production Example k-13 was deprotected with TFA to synthesize (S)-4-(3-fluorobenzoyl)-N-(pyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide. White solid (yield 82%); 1 1H NMR (400 MHz, CD3OD) δ 7.57 - 7.52 (m, 1H), 7.37 - 7.31 (m, 1H), 7.21 - 7.13 (m, 4H), 6.88 - 6.83 (m, 1H), 6.72 (d, J = 7.6 Hz, 1H), 4.08 - 4.02 (m, 2H), 3.93 - 3.87 (m, 2H), 3.33 - 3.22 (m, 1H), 3.19 - 3.13 (m, 2H), 3.06 - 3.00 (m, 1H), 2.83 - 2.77 (m, 1H), 2.56 - 2.46 (m, 1H), 2.08 - 1.96 (m, 1H), 1.68 - 1.57 (m, 1H); LC / MS ESI(+): 383.3 (M+1). <Example 121> Synthesis of (R)-4-(3-Fluorobenzoyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (S)-4-(3-Fluorobenzoyl)-N-(pyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide (1.0 equiv) obtained in Example 120 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 equiv) and formaldehyde (2.0 equiv) were added, and the mixture was stirred at room temperature for 1 hour. After adding water to the reaction mixture to terminate the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with brine...

Claims

1. A compound represented by the following Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] 【Chemical 1】 (In the above Chemical Formula 1, X １ ~X ４ is, independently of one another, N or C; Y is N, S, or O; R １ is an alkyl of C １ -C １０ a cycloalkyl of C ３ -C ２０ a heterocycloalkyl of C ２ -C ２０ a 3- to 10-membered aromatic ring group, a 3- to 10-membered aromatic heterocyclic group, -CO-(C １ -C ６ alkyl), or -CO-(aryl of C ６ -C １２ substituted or unsubstituted with halogen), and Said R １ One or more Hs of are halogen, cyano group, C substituted or unsubstituted with halogen ６ -C １２ aryl of, or C substituted or unsubstituted with halogen ５ -C １２ may be substituted with heteroaryl of; X １ ~X ４ When all of them are C, R ２ is hydrogen, halogen, or C １ -C ５ alkyl, and when one or more of X １ ~X ４ are N, R ２ is hydrogen; R ３ and R ４ are connected to each other and can form a 5- or 6-membered ring, where the ring may have one or more H replaced by -OH, -NH ２ , dimethylamine, -NH-(C １ -C ５ alkyl), -NH-(C １ -C ５ alkoxy), -NH-COCH ３ , -NH-SO ２ CH ３ , C １ -C ５ alkyl, or C １ -C ５ alkoxy, and may be substituted R ３ and R ４ do not form a ring, R ４ is hydrogen or C １ -C ５ alkyl, R ３ is C １ -C １０ alkyl, C ３ -C １０ cycloalkyl, C ２ -C １０ heterocycloalkyl, -CH ２ -(C ３ -C ６ cycloalkyl), -CH ２ -(C ２ -C ６ heterocycloalkyl), or -CH ２ -(3- to 6-membered aromatic heterocyclic group), and one or more H of said R ３ may be substituted with -OH, C １ -C ５ alkyl, acetyl, C １ -C ５ alkoxy, -COCF ３ or -SO ２ CH ３ ; The heterocycloalkyl, heterocyclic group, and heteroaryl each independently contain one or more heteroatoms selected from the group consisting of N, O, P, and S.)

2. Said R ３ and R ４ are linked to each other to form a 5- or 6-membered heterocycloalkyl, and the 5- or 6-membered heterocycloalkyl contains 1 to 2 N's in its ring. At this time, Y is N, Said R ３ and R ４ formed 5- or 6-membered heterocycloalkyl may have one or more H replaced by -OH, -NH ２ , dimethylamine, -NH-(C １ -C ５ alkyl), -NH-(C １ -C ５ alkoxy), -NH-COCH ３ , -NH-SO ２ CH ３ , C １ -C ５ alkyl, or C １ -C ５ alkoxy, and the compound according to claim 1, its stereoisomers, or its pharmaceutically acceptable salts.

3. R １ is a 6-membered aromatic ring group, 6-membered aromatic heterocyclic group, -CH ２ -aryl, -CH ２ -heteroaryl, 6-membered cycloalkyl, 6-membered heterocycloalkyl, -CO-aryl, or -CO-(C ４ -C ５ alkyl), where the 6-membered aromatic heterocyclic group contains one or more Ns, and the 6-membered heterocycloalkyl contains one or more Os. The foregoing R １ One or more Hs of which may be substituted by halogen, cyano group, C ６ -C １２ aryl, or C ５ -C １２ heteroaryl, each of which may be substituted or unsubstituted by halogen, the compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt.

4. The compound represented by the above Chemical Formula 1 is any one selected from the group consisting of the following, the enantiomer thereof, the diastereomer thereof, or a pharmaceutically acceptable salt thereof: (1) (R)-6-Fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (2) (R)-6-Fluoro-4-(4-fluorophenyl)-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (3) (R)-6-Fluoro-4-(4-fluorophenyl)-N-(1-isopropylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (4) (R)-6-Fluoro-4-(4-fluorophenyl)-N-(1-isobutylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (5) (R)-6-Fluoro-4-(4-fluorophenyl)-N-(1-(2,2,2-trifluoroacetyl)pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (6) (R)-N-(1-acetylpyrrolidin-3-yl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (7) (R)-6-Fluoro-4-(4-fluorophenyl)-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (8) (S)-6-Fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (9) (S)-6-Fluoro-4-(4-fluorophenyl)-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (10) (S)-6-Fluoro-4-(4-fluorophenyl)-N-(1-isopropylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (11) (S)-(3-Aminopyrrolidin-1-yl)(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone; (12) (S)-(6-Fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-(methylamino)pyrrolidin-1-yl)methanone; (13) (S)-(6-Fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-(isobutylamino)pyrrolidin-1-yl)methanone; (14) (S)-(6-Fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-(isopropylamino)pyrrolidin-1-yl)methanone; (15) (S)-N-(1-(6-Fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)acetamide; (16) (S)-N-(1-(6-Fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)methanesulfonamide; (17) (S)-6-Fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (18) (R)-6-Fluoro-4-(4-fluorophenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (19) (R)-6-Fluoro-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (20) (R)-6-Fluoro-4-(4-fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (21) (R)-6-Fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (22) (R)-6-Fluoro-4-(4-fluorophenyl)-N-(((1-methylpyrrolidin-2-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (23) (R)-6-Fluoro-4-(4-fluorophenyl)-N-(((1-isopropylpyrrolidin-2-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (24) (R)-6-Fluoro-4-(4-fluorophenyl)-N-(((1-isobutylpyrrolidin-2-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (25) (S)-6-Fluoro-4-(4-fluorophenyl)-N-(((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (26) (S)-6-Fluoro-4-(4-fluorophenyl)-N-(((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (27) (S)-6-Fluoro-4-(4-fluorophenyl)-N-(((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (28) N-(Cyclopropylmethyl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (29) 6-Fluoro-4-(4-fluorophenyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (30) 6-Fluoro-4-(4-fluorophenyl)-N-(1-methylpiperidin-4-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (31) 6-Fluoro-4-(4-fluorophenyl)-N-(1-isopropylpiperidin-4-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (32) 6-Fluoro-4-(4-fluorophenyl)-N-(1-isobutylpiperidin-4-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (33) 6-Fluoro-4-(4-fluorophenyl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (34) 6-Fluoro-4-(4-fluorophenyl)-N-((methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (35) 6-Fluoro-4-(4-fluorophenyl)-N-(((1-isobutylpiperidin-4-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (36) 6-Fluoro-4-(4-fluorophenyl)-N-(((1-isopropylpiperidin-4-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (37) N-(((1H-imidazol-4-yl)methyl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (38) 6-Fluoro-4-(4-fluorophenyl)-N-(pyrazin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (39) (R)-(6-Fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-hydroxypyrrolidin-1-yl)methanone; (40) (6-Fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-methoxypyrrolidin-1-yl)methanone; (41) N-(azetidin-3-yl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (42) 6-Fluoro-4-(4-fluorophenyl)-N-(1-isopropylazetidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (43) 6-Fluoro-4-(4-fluorophenyl)-N-(1-isobutylazetidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (44) N-(1-acetylazetidin-3-yl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (45) 6-Fluoro-4-(4-fluorophenyl)-N-(((1-methylazetidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (46) 6-Fluoro-4-(4-fluorophenyl)-N-(((1-isopropylazetidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (47) 6-Fluoro-4-(4-fluorophenyl)-N-(((1-isobutylazetidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (48) 6-Fluoro-4-(4-fluorophenyl)-N-(((tetrahydrofuran-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (49) (S)-4-(4-Fluorophenyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (50) 4-(4-Fluorophenyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (51) (S)-4-(4-Fluorophenyl)-N-(tetrahydrofuran-3-yl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (52) 4-(4-Fluorophenyl)-N-(((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (53) (S)-4-(4-Fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (54) (R)-4-(4-Fluorophenyl)-N-(((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (55) (R)-4-(4-Fluorophenyl)-N-(((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (56) (R)-4-(4-Fluorophenyl)-N-(((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (57) (R)-4-(4-Fluorophenyl)-N-(pyrrolidin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (58) (S)-4-(4-Fluorophenyl)-N-(((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxalin-1(2H)-carboxamide; (59) (S)-4-(4-Fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (60) (S)-4-(4-Fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (61) 4-(4-Fluorophenyl)-N-((1-isobutylazetidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (62) 4-(4-Fluorophenyl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (63) 4-(4-Fluorophenyl)-N-((1-isopropylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (64) 4-(4-Fluorophenyl)-N-((1-isobutylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (65) (R)-6-Fluoro-4-phenyl-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (66) (4-(2-Chlorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(piperidin-1-yl)methanone; (67) 4-(2-Chlorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(pyrrolidin-1-yl)methanone; (68) (4-(2-Chlorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(4-methylpiperazin-1-yl)methanone; (69) (S)-N-(1-Isopropylpyrrolidin-3-yl)-4-(pyridin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (70) (R)-N-(1-Acetylpyrrolidin-3-yl)-4-(pyridin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (71) (S)-4-(Pyridin-2-yl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (72) (R)-4-(Pyridin-2-yl)-N-(pyrrolidin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (73) (R)-4-(Pyridin-3-yl)-N-(tetrahydrofuran-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (74) N-(Cyclopropylmethyl)-4-(pyridin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (75) (R)-4-(5-Fluoropyridin-2-yl)-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (76) (R)-4-(5-Fluoropyridin-2-yl)-N-(1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (77) 4-(5-Fluoropyridin-2-yl)-N-(1-methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (78) (S)-(3-Aminopyrrolidin-1-yl)(4-(5-fluoropyridin-2-yl)-3,4-dihydroquinoxaline-1(2H)-methanone; (79) (S)-4-(4-Cyanophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (80) (S)-4-(Pyrazin-2-yl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (81) (S)-N-(1-Isopropylpyrrolidin-3-yl)-4-(pyrazin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (82) N-(1-Isobutylpiperidin-4-yl)-4-(pyrazin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (83) N-(1-Isopropylpiperidin-4-yl)-4-(pyrazin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (84) (R)-4-Benzyl-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (85) (S)-(3-Aminopyrrolidin-1-yl)(4-benzyl-3,4-dihydroquinoxaline-1(2H)-yl)methanone; (86) (S)-(4-Benzyl-3,4-dihydroquinoxaline-1(2H)-yl)(3-(methylamino)pyrrolidin-1-yl)methanone; (87) (R)-4-(2-Fluorobenzyl)-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (88) 4-(2-Fluorobenzyl)-N-(1-methylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (89) 4-(2-Fluorobenzyl)-N-((1-methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (90) (R)-4-(2-Fluorobenzyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (91) (R)-4-(4-Fluorobenzyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (92) (R)-4-(4-Fluorobenzyl)-N-(1-isopropylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (93) 4-(4-Fluorobenzyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (94) 4-(4-Fluorobenzyl)-N-(1-isopropylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (95) (R)-4-(4-Chlorobenzyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (96) (S)-(3-(Isobutylamino)pyrrolidin-1-yl)(4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone; (97) (S)-(3-(Dimethylamino)pyrrolidin-1-yl)(4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone; (98) (R)-4-(Pyridin-2-ylmethyl)-N-(tetrahydrofuran-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (99) N-(Oxetan-3-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (100) 4-(Pyridin-2-ylmethyl)-N-((tetrahydrofuran-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (101) 4-(Pyridin-2-ylmethyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (102) N-(Cyclopropylmethyl)-4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (103) (4-(4-Fluorophenyl)-3,4-dihydropyrido[3,4-b]pyrazin-1(2H)-yl)(3-hydroxypyrrolidin-1-yl)methanone; (104) (R)-4-Cyclohexyl-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (105) (R)-4-Cyclohexyl-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (106) (R)-4-Cyclohexyl-N-(1-isobutylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (107) (4-Cyclohexyl-3,4-dihydroquinoxaline-1(2H)-yl)(4-methylpiperazin-1-yl)methanone; (108) (4-Cyclohexyl-3,4-dihydroquinoxaline-1(2H)-yl)(pyrrolidin-1-yl)methanone; (109) (4-Cyclohexyl-3,4-dihydroquinoxaline-1(2H)-yl)(piperidin-1-yl)methanone; (110) (R)-N-(1-methylpyrrolidin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (111) (R)-N-(1-isobutylpyrrolidin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (112) (S)-(3-Aminopyrrolidin-1-yl)(4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxaline-1(2H)-yl)methanone; (113) (S)-(3-(Dimethylamino)pyrrolidin-1-yl)(4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone; (114) 4-Benzoyl-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (115) (S)-4-Benzoyl-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (116) (R)-4-Benzoyl-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (117) (S)-4-(2-Fluorobenzoyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (118) (R)-4-(2-Fluorobenzoyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (119) (R)-4-(3-Fluorobenzoyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (120) (S)-4-(3-Fluorobenzoyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (121) (R)-4-(3-Fluorobenzoyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (122) (S)-4-(4-Fluorobenzoyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (123) (R)-4-(4-Fluorobenzoyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (124) 4-(4-Fluorobenzoyl-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (125) 4-(3-Methylbutanoyl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (126) 4-(3-Methylbutanoyl)-N-((1-methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (127) N-((1-Isobutylpiperidin-4-yl)methyl)-4-(3-methylbutanoyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (128) (R)-4-(3-Methylbutanoyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (129) (R)-4-(3,3-Dimethylbutanoyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; and (130) 4-(3,3-Dimethylbutanoyl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide. (Claim 5) A pharmaceutical composition for the prevention or treatment of a disease associated with pulmonary fibrosis, comprising, as an active ingredient, the compound represented by Chemical Formula 1 according to Claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. (Claim 6) The pharmaceutical composition for the prevention or treatment of a disease associated with pulmonary fibrosis according to Claim 5, wherein the composition suppresses actin polymerization. (Claim 7) The pharmaceutical composition for the prevention or treatment of a disease associated with pulmonary fibrosis according to Claim 5, wherein the composition suppresses the level or activity of inflammatory cytokines. (Claim 8) The pharmaceutical composition for the prevention or treatment of a disease associated with pulmonary fibrosis according to Claim 5, wherein the composition decreases the level or activity of one or more proteins selected from the group consisting of α-SMA, F-actin, and IL-6. (Claim 9) The pharmaceutical composition for the prevention or treatment of a disease associated with pulmonary fibrosis according to Claim 5, wherein the disease associated with pulmonary fibrosis is one or more selected from the group consisting of pulmonary fibrosis, idiopathic pulmonary fibrosis, desquamative interstitial pneumonia, nonspecific interstitial pneumonia, latent organizing pneumonia, respiratory bronchiolitis-associated interstitial lung disease, acute interstitial pneumonia, lymphocytic interstitial pneumonia, idiopathic pulmonary parenchymal fibroelastosis, and chronic obstructive pulmonary disease (COPD). (Claim 10) The pharmaceutical composition for the prevention or treatment of a disease associated with pulmonary fibrosis according to Claim 5, wherein the disease associated with pulmonary fibrosis is for the treatment of a disease associated with pulmonary fibrosis accompanied by overactivation of actin polymerization. (Claim 11) A kit for preventing or treating a lung fibrosis-related disease, comprising the composition according to any one of claims 5 to 10.

12. A method for preventing or treating a lung fibrosis-related disease, comprising administering to an individual in need thereof the compound represented by Chemical Formula 1 according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

13. Use of the compound represented by Chemical Formula 1 according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing or treating a lung fibrosis-related disease.

14. Use of the compound represented by Chemical Formula 1 according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for preventing or treating a lung fibrosis-related disease.

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