Novel compound and pharmaceutical composition comprising same as active ingredient

Abstract

The present invention relates to a novel compound which modulates the function and differentiation of a cytoskeleton involved in pulmonary fibrosis and thus can be used for preparing a medicament capable of treating related diseases. It has been determined that: the novel compound according to the present invention or a pharmaceutically acceptable salt thereof has an effect of modulating actin polymerization required for cytoskeleton formation; and the expression of alpha-SMA and F-actin, which are main factors causing fibrosis, is effectively inhibited in human lung tissue-derived fibroblasts (MRC5). Furthermore, it has been determined that when activated macrophages are treated with the compounds, the level of inflammation of inflammatory cytokines caused by the macrophages is reduced. Therefore, the novel compound according to the present invention is expected to be effectively used in the prevention and treatment of diseases associated with pulmonary fibrosis as a preparation having an effect of inhibiting or reducing 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.

[0002] This application claims priority to and the benefit of 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, the disclosures of which are incorporated herein by reference in their entireties. Background Art

[0003] Idiopathic pulmonary fibrosis (IPF) is a disease of chronic progression of fibrosis of the lung parenchyma, and is characterized in that immune cells infiltrate into the alveolar wall, induce fibrosis and cause serious structural changes in lung tissue, resulting in a gradual decline in lung function. If the fibrosis of the lung parenchyma continues to progress due to IPF, respiratory failure may occur and even lead to death. However, due to the lack of an effective therapeutic agent, IPF is a highly lethal disease, with a 5-year survival rate after diagnosis being less than 40%, and a 10-year survival rate being less than 15%. Currently, pirfenidone (Pirfenidone) and nintedanib (nintedanib) used as therapeutic agents for pulmonary fibrosis clinically have been approved by the U.S. FDA, but show a low therapeutic effect, wherein showing that the lung function improvement rate is only about 10%. In addition, two therapeutic agents do not show significant differences in terms of life expectancy after extending the patient's diagnosis. Therefore, it is necessary to develop a therapeutic agent for pulmonary fibrosis by a new mechanism.

[0004] In damaged tissues, inflammatory proteins such as TGF-β and TNF-α are produced and secreted outside the cells, causing functional and structural changes in the cytoskeleton and a healing process. Under normal conditions, after the healing process, inflammatory proteins and accumulated extracellular matrix (ECM) are reduced, and a recovery process occurs, but under pathological conditions, the accumulation of secreted ECM continues without normal recovery. This is one of the main mechanisms causing fibrosis. Cells cause changes in gene expression, cell morphology, and cytoskeleton through changes in intracellular signaling (mechanical transduction) and intercellular interactions, and then respond to external physical stimuli. These cellular changes serve as an important driving force for cell movement and cell surface remodeling. When damaged tissue cannot be restored to its original state by repeated abnormal healing processes due to the continuous influx of various external factors, the damaged tissue is converted into fibrotic tissue.

[0005] Epithelial-mesenchymal transition (EMT) and fibroblast-myofibroblast transformation (FMT) are the key mechanisms causing pulmonary fibrosis. In the damaged tissue of alveoli, inflammatory cytokine TGF-β is secreted, and in the activated epithelial layer, EMT is due to the decomposition of the cell connective tissue caused by inflammatory signals and is produced, and epithelial cells are converted into fibroblasts. In addition, when the fibroblasts present in the subepithelial layer receive mechanical and physical damage from external stimuli, stress fibers are expressed via mechanical transduction pathways. In addition, it is effectively activated by the cytokines that cause fibrosis, and fibroblasts are converted into myofibroblasts by FMT. The change of cytoskeleton occurs from the above process. Cytoskeleton is composed of microtubules, actin microfilaments and intermediate filaments, and not only maintains the skeletal structure of cells, but also plays various roles such as cell movement and interaction with the external environment. Among them, actin filaments are microfilaments composed of globular actin (G-actin) as a monomer and filamentous actin (F-actin) as a polymeric filament, and are involved in the movement of cells such as lamellipodia or filopodia, and are also very important in cell transformation (EMT and FMT) caused by external mechanical stimulation. Cell transformation is achieved by changes in the cytoskeleton, and one of the factors causing changes in the cytoskeleton is actin polymerization.

[0006] The control of cytoskeleton changes is very important in pulmonary fibrosis, and abnormal pulmonary fibrosis mechanism can be improved by controlling actin polymerization. Cell controls cell mobility and forms stress fibers to cause cytoskeleton remodeling by actin polymerization, and the target protein involved is actin binding protein. As one of target proteins, Arp2 / 3 complex acts on nucleation in each step of controlling cytoskeleton mobility, and is used to form filament branches, and is composed of 7 subunits (Arp2, Arp3, ARPC1, ARPC2, ARPC3, ARPC4 and ARPC5). Here, Arp2 / 3 complex affects the amplification of actin filaments by actin branching, and is relevant to the speed of the actin network formed in fibroblasts. Therefore, cell transformation can be controlled by controlling the function of Arp2 / 3 complex to suppress the change of actin network and cytoskeleton due to actin polymerization.

[0007] Pulmonary fibrosis occurs between the tissue and blood vessels around the alveoli, and in particular, IPF is a disease in which tissue gradually hardens due to the ECM accumulation caused by myofibroblasts. This disease causes the contraction of myofibroblasts induced by changes in the cytoskeleton of fibroblasts, thereby causing tissue hardening and decreased lung respiratory function. The change of the cytoskeleton is related to the activity of myofibroblasts, and the key biomarker for the activity of myofibroblasts is known to be α-smooth muscle actin (α-SMA). Recent research results reveal that when fibroblasts derived from IPF are treated with cytokine TGF-β, α-SMA expression increases. Therefore, the sign of the activity of the myofibroblasts involved in fibrosis is α-SMA expression. According to previous research results, the improvement of cell transformation by controlling the cytoskeleton is considered to be a mechanism for treating IPF. Therefore, it is intended to develop a medicine for treating various fibrosis-related diseases (including IPF) by developing a material for controlling the function of the actin polymerization Arp2 / 3 complex involved in controlling cytoskeleton changes. Summary of the Invention

[0008] [Technical Issues]

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

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

[0011] [Chemical Formula 1]

[0012]

[0013] The present invention also aims to provide a pharmaceutical composition for preventing or treating diseases related to pulmonary fibrosis, which comprises the compound, its stereoisomers or pharmaceutically acceptable salts thereof as an active ingredient.

[0014] The present invention also aims to provide a kit for preventing or treating diseases related to pulmonary fibrosis, comprising the composition.

[0015] However, the technical problems to be solved by the present invention are not limited to the above problems, and a person skilled in the art will fully understand other problems not described herein based on the following description.

[0016] The related technical documents of the present invention are as follows:

[0017] (Non-patent document 001) Cold Spring Harb. Perspect. Biol. 8, a018226 (2016)

[0018] (Non-patent document 002) J. Clin. Invest. 119, 1420-1428 (2009).

[0019] (Non-patent document 003) Front. Bioeng. Biotechnol. 8, 609653 (2020).

[0020] (Non-Patent Document 004) Cancers 13, 1882 (2021)

[0021] (Non-patent document 005) Mol. Biol. Cell 12, 2730-2741 (2001)

[0022] (Non-patent document 006) Am J. Physiol. Lung. Cell. Mol. Physiol. 315, L59-L65 (2018)

[0023] (Non-patent document 007) Mol. Biol. Cell 24, 2861-2875 (2013)

[0024] (Non-patent document 008) Front.Pharmacol.5,00051(2014)

[0025] (Non-patent document 009) Br. J. Pharmacol. 179, 125-140 (2022)

[0026] [Technical solution]

[0027] The present invention provides a compound represented by the following Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0028] [Chemical Formula 1]

[0029]

[0030] (In Chemical Formula 1,

[0031] X1 to X4 can each independently be N or C;

[0032] Y can be N, S, or O;

[0033] R1 can be C1-C 10 Alkyl, C3-C 20 Cycloalkyl, C2-C 20Heterocycloalkyl, 3- to 10-membered cyclic aromatic group, 3- to 10-membered heterocyclic aromatic group, -CO-(C1-C6 alkyl) or -CO-(halogen-substituted or unsubstituted C6-C6 12 aryl), and

[0034] At least one H of R1 may be substituted with halogen, cyano, or unsubstituted C6-C 12 Aryl or halogen substituted or unsubstituted C5-C 12 heteroaryl substitution;

[0035] When all of X1 to X4 are C, R2 may be hydrogen, halogen, or C1-C5 alkyl, and when one or more of X1 to X4 is N, R2 may be hydrogen;

[0036] R3 and R4 may be linked to each other to form a 5-membered or 6-membered ring, wherein at least one H in the ring may be substituted by -OH, -NH2, dimethylamine, -NH-(C1-C5 alkyl), -NH-(C1-C5 alkoxy), -NH-COCH3, -NH-SO2CH3, C1-C5 alkyl or C1-C5 alkoxy, and

[0037] When R3 and R4 do not form a ring, R4 can be hydrogen or C1-C5 alkyl, and R3 can be 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 heterocyclic aromatic group), at least one H of R3 may be substituted by -OH, C1-C5 alkyl, acetyl, C1-C5 alkoxy, -COCF3 or -SO2CH3, and

[0038] The heterocycloalkyl group, heterocyclic group and heteroaryl group each independently contain one or more heteroatoms selected from the group consisting of N, O, P and S.

[0039] In another embodiment of the present invention, R3 and R4 may be connected to each other to form a 5-membered or 6-membered heterocycloalkyl group containing one or two N atoms in the ring, wherein Y is N. At least one H in the 5-membered or 6-membered heterocycloalkyl group 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 the present invention is not limited thereto.

[0040] In another embodiment of the present invention, R1 can be a 6-membered cyclic aromatic group, a 6-membered heterocyclic aromatic group, -CH2-aryl, -CH2-heteroaryl, a 6-membered cycloalkyl group, a 6-membered heterocycloalkyl group, -CO-aryl or -CO-(C4-C5 alkyl), wherein the 6-membered heterocyclic aromatic group can contain at least one N, and the 6-membered heterocycloalkyl group can contain at least one O. At least one H of R1 can be substituted or unsubstituted C6-C5 alkyl, cyano, halogen or halogen. 12 Aryl or halogen substituted or unsubstituted C5-C 12 The present invention is not limited to heteroaryl substitution.

[0041] In yet another embodiment of the present invention, the compound represented by Chemical Formula 1 may be any one selected from the group consisting of the following compounds, but the present invention is not limited thereto:

[0042] (1) (R)-6-fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0043] (2) (R)-6-fluoro-4-(4-fluorophenyl)-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0044] (3) (R)-6-fluoro-4-(4-fluorophenyl)-N-(1-isopropylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0045] (4) (R)-6-fluoro-4-(4-fluorophenyl)-N-(1-isobutylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0046] (5) (R)-6-fluoro-4-(4-fluorophenyl)-N-(1-(2,2,2-trifluoroacetyl)pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0047] (6) (R)-N-(1-acetylpyrrolidin-3-yl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0048] (7) (R)-6-fluoro-4-(4-fluorophenyl)-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0049] (8) (S)-6-Fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0050] (9) (S)-6-Fluoro-4-(4-fluorophenyl)-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0051] (10) (S)-6-Fluoro-4-(4-fluorophenyl)-N-(1-isopropylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0052] (11) (S)-(3-aminopyrrolidin-1-yl)(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone;

[0053] (12) (S)-(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-(methylamino)pyrrolidin-1-yl)methanone;

[0054] (13) (S)-(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-(isobutylamino)pyrrolidin-1-yl)methanone;

[0055] (14) (S)-(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-(isopropylamino)pyrrolidin-1-yl)methanone;

[0056] (15) (S)-N-(1-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)acetamide;

[0057] (16) (S)-N-(1-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)methanesulfonamide;

[0058] (17) (S)-6-Fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0059] (18) (R)-6-fluoro-4-(4-fluorophenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0060] (19) (R)-6-fluoro-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0061] (20) (R)-6-fluoro-4-(4-fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0062] (21) (R)-6-fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0063] (22) (R)-6-fluoro-4-(4-fluorophenyl)-N-((1-methylpyrrolidin-2-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0064] (23) (R)-6-fluoro-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-2-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0065] (24) (R)-6-fluoro-4-(4-fluorophenyl)-N-((1-isobutylpyrrolidin-2-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0066] (25) (S)-6-Fluoro-4-(4-fluorophenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0067] (26) (S)-6-Fluoro-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0068] (27) (S)-6-Fluoro-4-(4-fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0069] (28) N-(cyclopropylmethyl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0070] (29) 6-Fluoro-4-(4-fluorophenyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0071] (30) 6-fluoro-4-(4-fluorophenyl)-N-(1-methylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0072] (31) 6-Fluoro-4-(4-fluorophenyl)-N-(1-isopropylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0073] (32) 6-Fluoro-4-(4-fluorophenyl)-N-(1-isobutylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0074] (33) 6-fluoro-4-(4-fluorophenyl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0075] (34) 6-Fluoro-4-(4-fluorophenyl)-N-(methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0076] (35) 6-fluoro-4-(4-fluorophenyl)-N-((1-isobutylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0077] (36) 6-fluoro-4-(4-fluorophenyl)-N-((1-isopropylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0078] (37) N-((1H-imidazole-4-)methyl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0079] (38) 6-Fluoro-4-(4-fluorophenyl)-N-(pyrazin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0080] (39) (R)-(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-hydroxypyrrolidin-1-yl)methanone;

[0081] (40)(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-methoxypyrrolidin-1-yl)methanone;

[0082] (41) N-(azetidin-3-yl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0083] (42) 6-Fluoro-4-(4-fluorophenyl)-N-(1-isopropylazetidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0084] (43) 6-Fluoro-4-(4-fluorophenyl)-N-(1-isobutylazetidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0085] (44) N-(1-acetylazetidin-3-yl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0086] (45) 6-fluoro-4-(4-fluorophenyl)-N-((1-methylazetidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0087] (46) 6-fluoro-4-(4-fluorophenyl)-N-((1-isopropylazetidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0088] (47) 6-fluoro-4-(4-fluorophenyl)-N-((1-isobutylazetidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0089] (48) 6-Fluoro-4-(4-fluorophenyl)-N-((tetrahydrofuran-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0090] (49) (S)-4-(4-Fluorophenyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0091] (50) 4-(4-Fluorophenyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0092] (51) (S)-4-(4-Fluorophenyl)-N-(tetrahydrofuran-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0093] (52) 4-(4-Fluorophenyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0094] (53) (S)-4-(4-Fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0095] (54) (R)-4-(4-Fluorophenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0096] (55) (R)-4-(4-Fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0097] (56) (R)-4-(4-Fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0098] (57) (R)-4-(4-fluorophenyl)-N-(pyrrolidin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0099] (58) (S)-4-(4-Fluorophenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0100] (59) (S)-4-(4-Fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0101] (60) (S)-4-(4-Fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0102] (61) 4-(4-Fluorophenyl)-N-((1-isobutylazetidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0103] (62) 4-(4-Fluorophenyl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0104] (63) 4-(4-Fluorophenyl)-N-((1-isopropylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0105] (64) 4-(4-Fluorophenyl)-N-((1-isobutylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0106] (65) (R)-6-Fluoro-4-phenyl-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0107] (66)(4-(2-chlorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(piperidin-1-yl)methanone;

[0108] (67) 4-(2-chlorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(pyrrolidin-1-yl)methanone;

[0109] (68)(4-(2-chlorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(4-methylpiperazin-1-yl)methanone;

[0110] (69) (S)-N-(1-isopropylpyrrolidin-3-yl)-4-(pyridin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0111] (70) (R)-N-(1-acetylpyrrolidin-3-yl)-4-(pyridin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0112] (71) (S)-4-(pyridin-2-yl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0113] (72) (R)-4-(pyridin-2-yl)-N-(pyrrolidin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0114] (73) (R)-4-(pyridin-3-yl)-N-(tetrahydrofuran-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0115] (74) N-(cyclopropylmethyl)-4-(pyridin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0116] (75) (R)-4-(5-fluoropyridin-2-yl)-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0117] (76) (R)-4-(5-fluoropyridin-2-yl)-N-(1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0118] (77) 4-(5-fluoropyridin-2-yl)-N-(1-methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0119] (78) (S)-(3-aminopyrrolidin-1-yl)(4-(5-fluoropyridin-2-yl)-3,4-dihydroquinoxaline-1(2H)-methanone;

[0120] (79) (S)-4-(4-cyanophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0121] (80) (S)-4-(pyrazin-2-yl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0122] (81) (S)-N-(1-isopropylpyrrolidin-3-yl)-4-(pyrazin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0123] (82) N-(1-isobutylpiperidin-4-yl)-4-(pyrazin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0124] (83) N-(1-isopropylpiperidin-4-yl)-4-(pyrazin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0125] (84) (R)-4-Benzyl-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0126] (85) (S)-(3-aminopyrrolidin-1-yl)(4-benzyl-3,4-dihydroquinoxalin-1(2H)-yl)methanone;

[0127] (86) (S)-(4-Benzyl-3,4-dihydroquinoxalin-1(2H)-yl)(3-(methylamino)pyrrolidin-1-yl)methanone;

[0128] (87) (R)-4-(2-fluorobenzyl)-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0129] (88) 4-(2-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0130] (89) 4-(2-Fluorobenzyl)-N-((1-methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0131] (90) (R)-4-(2-fluorobenzyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0132] (91) (R)-4-(4-fluorobenzyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0133] (92) (R)-4-(4-fluorobenzyl)-N-(1-isopropylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0134] (93) 4-(4-Fluorobenzyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0135] (94) 4-(4-Fluorobenzyl)-N-(1-isopropylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0136] (95) (R)-4-(4-chlorobenzyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0137] (96) (S)-(3-(Isobutylamino)pyrrolidin-1-yl)(4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone;

[0138] (97) (S)-(3-(dimethylamino)pyrrolidin-1-yl)(4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone;

[0139] (98) (R)-4-(pyridin-2-ylmethyl)-N-(tetrahydrofuran-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0140] (99) N-(oxetan-3-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0141] (100) 4-(pyridin-2-ylmethyl)-N-((tetrahydrofuran-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0142] (101) 4-(pyridin-2-ylmethyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0143] (102) N-(cyclopropylmethyl)-4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0144] (103)(4-(4-Fluorophenyl)-3,4-dihydropyrido[3,4-b]pyrazin-1(2H)-yl)(3-hydroxypyrrolidin-1-yl)methanone;

[0145] (104) (R)-4-cyclohexyl-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0146] (105) (R)-4-cyclohexyl-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0147] (106) (R)-4-cyclohexyl-N-(1-isobutylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0148] (107)(4-cyclohexyl-3,4-dihydroquinoxalin-1(2H)-yl)(4-methylpiperazin-1-yl)methanone;

[0149] (108)(4-cyclohexyl-3,4-dihydroquinoxalin-1(2H)-yl)(pyrrolidin-1-yl)methanone;

[0150] (109)(4-cyclohexyl-3,4-dihydroquinoxalin-1(2H)-yl)(piperidin-1-yl)methanone;

[0151] (110) (R)-N-(1-methylpyrrolidin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0152] (111) (R)-N-(1-isobutylpyrrolidin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0153] (112) (S)-(3-aminopyrrolidin-1-yl)(4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone;

[0154] (113) (S)-(3-(dimethylamino)pyrrolidin-1-yl)(4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone;

[0155] (114) 4-Benzoyl-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0156] (115) (S)-4-Benzoyl-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0157] (116) (R)-4-Benzoyl-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0158] (117) (S)-4-(2-fluorobenzoyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0159] (118) (R)-4-(2-fluorobenzoyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0160] (119) (R)-4-(3-fluorobenzoyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0161] (120) (S)-4-(3-fluorobenzoyl)-N-(pyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0162] (121) (R)-4-(3-fluorobenzoyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0163] (122) (S)-4-(4-Fluorobenzoyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0164] (123) (R)-4-(4-Fluorobenzoyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0165] (124) 4-(4-Fluorobenzoyl-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0166] (125) 4-(3-methylbutyryl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0167] (126) 4-(3-methylbutanoyl)-N-((1-methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0168] (127) N-((1-isobutylpiperidin-4-yl)methyl)-4-(3-methylbutanoyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0169] (128) (R)-4-(3-methylbutanoyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide;

[0170] (129) (R)-4-(3,3-dimethylbutanoyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; and

[0171] (130) 4-(3,3-Dimethylbutanoyl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0172] In addition, the present invention also provides a pharmaceutical composition for preventing or treating diseases related to pulmonary fibrosis, the composition comprising the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0173] In addition, the present invention also provides a method for preventing or treating diseases related to pulmonary fibrosis, which comprises administering a compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0174] In addition, the present invention also provides use of the compound represented by Chemical Formula 1, its stereoisomers, or pharmaceutically acceptable salts thereof for preventing or treating diseases related to pulmonary fibrosis.

[0175] In addition, the present invention also provides use of the compound represented by Chemical Formula 1, its stereoisomers or pharmaceutically acceptable salts thereof in the preparation of a medicament for preventing or treating diseases related to pulmonary fibrosis.

[0176] In one embodiment of the present invention, the composition can inhibit actin aggregation, but the present invention is not limited thereto.

[0177] In another embodiment of the present invention, the composition can inhibit the level or activity of inflammatory cytokines, but the present invention is not limited thereto.

[0178] In yet another embodiment of the present invention, the composition can reduce 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 the present invention is not limited thereto.

[0179] In another embodiment 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, cryptogenic organizing pneumonia, respiratory bronchiolitis-associated interstitial lung disease, acute interstitial pneumonia, lymphointerstitial pneumonia, idiopathic pleural pulmonary fibroelastosis, and chronic obstructive pulmonary disease (COPD), but the present invention is not limited thereto.

[0180] In yet another embodiment of the present invention, the pulmonary fibrosis-related disease may be a pulmonary fibrosis-related disease accompanied by excessive activation of actin polymerization, but the present invention is not limited thereto.

[0181] In addition, the present invention also provides a kit for preventing or treating pulmonary fibrosis, the kit comprising the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; or a composition.

[0182] In addition, the present invention also provides a pharmaceutical composition for inhibiting pulmonary fibrosis and / or pulmonary inflammation, the composition comprising the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0183] In addition, the present invention also provides a method for inhibiting or improving pulmonary fibrosis and / or pulmonary inflammation, which comprises administering a compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0184] In addition, the present invention also provides use of the compound represented by Chemical Formula 1, its stereoisomers, or pharmaceutically acceptable salts thereof for inhibiting pulmonary fibrosis and / or pulmonary inflammation.

[0185] In addition, the present invention also provides use of the compound represented by Chemical Formula 1, its stereoisomers or pharmaceutically acceptable salts thereof in the preparation of a medicament for inhibiting or improving pulmonary fibrosis and / or pulmonary inflammation.

[0186] [Beneficial effects]

[0187] The present invention relates to a novel compound that can be used to prepare a drug that can treat related diseases by regulating the function and differentiation of the cytoskeleton involved in the process of pulmonary fibrosis. It is confirmed that the novel compound according to the present invention or a pharmaceutically acceptable salt thereof is effective in controlling the actin polymerization required to form the cytoskeleton, and the expression of α-SMA and F-actin, which are the main pathogenic factors of fibrosis in fibroblasts derived from lung tissue, is effectively inhibited. In addition, it is confirmed that when activated macrophages are treated with the compound, the level of inflammatory cytokines produced by the macrophages is significantly reduced. Therefore, the novel compound according to the present invention is expected to be used as a drug that effectively inhibits or improves pulmonary fibrosis and can be used to prevent and treat various pulmonary fibrosis-related diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0188] Figure 1a Shown are the results of inducing actin polymerization after treating actin monomers with the compounds of the present invention and then measuring actin polymerization activity to confirm the actin polymerization inhibitory activity of the compounds according to the present invention.

[0189] Figure 1b Shown are the results of inducing actin polymerization after treating actin monomers with the compounds of the present invention, and then measuring relative fluorescence units (RFUs) to confirm the actin polymerization inhibitory activity of the compounds according to the present invention.

[0190] Figures 2a to 2d Shown are high-resolution images using a confocal microscope (which confirm the expression levels of lung fibrosis biomarkers such as α-SMA and F-actin) after human lung tissue-derived fibroblasts (MRC5) were treated with DMSO, the compound of the present invention, CK-666 (actin polymerization inhibitor) or nintedanib and then treated with TGF-β1 to induce fibrosis, as well as quantitative results confirming the lung fibrosis inhibitory effect of the compound according to the present invention ( Figure 2a and Figure 2b , images of intracellular α-SMA and quantitative results of α-SMA levels; Figure 2c and Figure 2d , images of intracellular F-actin and quantification of F-actin levels).

[0191] Figure 3 The results show the results of measuring the level of IL-6 protein secreted in vitro after treatment with or without the compound of the present invention while inducing THP-1 differentiation into M1 macrophages to confirm the inhibitory effect of pulmonary fibrosis caused by the anti-inflammatory action of the compound according to the present invention. DETAILED DESCRIPTION

[0192] The present invention, which relates to a novel compound, has been accomplished by confirming that the compound is effective not only in regulating abnormal formation of the cytoskeleton but also in inhibiting the production of pulmonary fibrosis-related factors (including α-SMA) by inhibiting actin polymerization.

[0193] Specifically, in one embodiment of the present invention, a novel compound according to the present invention was prepared (Experimental Example 1).

[0194] In another embodiment of the present invention, as a result of inducing actin polymerization after treating actin monomers with the compound according to the present invention, it was confirmed that the actin polymerization activity was significantly reduced by the above compound, thereby indicating that the compound has an excellent actin polymerization inhibitory effect (Experimental Example 2).

[0195] In another embodiment of the present invention, as a result of measuring changes in the levels of fibrosis-related factors such as α-SMA and F-actin by treating MRC5 with the compound according to the present invention, it was confirmed that the levels of major biomarkers of pulmonary fibrosis, such as α-SMA and F-actin, were significantly reduced by treatment with the compound of the present invention (Experimental Example 3).

[0196] In yet 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).

[0197] In another embodiment of the present invention, as a result of observing the production and secretion levels of IL-6, a major fibrosis-inducing factor, after treatment of activated macrophages with the compound according to the present invention, it was confirmed that the IL-6 level was significantly reduced by treatment with the compound according to the present invention (Experimental Example 5).

[0198] The above results confirm that the novel compound according to the present invention can effectively inhibit pulmonary fibrosis inducing factor, and the present invention is expected to be applied in the treatment of various pulmonary fibrosis-related diseases.

[0199] Hereinafter, the present invention will be described in detail.

[0200] The present invention provides a compound represented by the following Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0201] [Chemical Formula 1]

[0202]

[0203] (In Chemical Formula 1,

[0204] X1 to X4 can each independently be N or C;

[0205] Y can be N, S, or O;

[0206] R1 can be C1-C 10 Alkyl, C3-C 20 Cycloalkyl, C2-C 20 Heterocycloalkyl, 3- to 10-membered cyclic aromatic group, 3- to 10-membered heterocyclic aromatic group, -CO-(C1-C6 alkyl) or -CO-(halogen-substituted or unsubstituted C6-C6 12 aryl), and

[0207] At least one H of R1 may be substituted with halogen, cyano, or unsubstituted C6-C 12 Aryl or halogen substituted or unsubstituted C5-C 12 heteroaryl substitution;

[0208] When all of X1 to X4 are C, R2 may be hydrogen, halogen or C1-C5 alkyl, and when one or more of X1 to X4 are N, R2 may be hydrogen (i.e., when one or more of X1 to X4 are N, R2 is hydrogen, which is bound to X n(except N). In other words, when one or more of X1 to X4 is N, H of the ring formed by X1 to X4 is unsubstituted);

[0209] R3 and R4 may be linked to each other to form a 5-membered or 6-membered ring, wherein at least one H in the ring is substituted by -OH, -NH2, dimethylamine, -NH-(C1-C5 alkyl), -NH-(C1-C5 alkoxy), -NH-COCH3, -NH-SO2CH3, C1-C5 alkyl or C1-C5 alkoxy, and

[0210] When R3 and R4 do not form a ring, R4 can be hydrogen or C1-C5 alkyl, and R3 can be 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 heterocyclic aromatic group), at least one H of R3 may be substituted by -OH, C1-C5 alkyl, acetyl, C1-C5 alkoxy, -COCF3 or -SO2CH3; and

[0211] The heterocycloalkyl, heterocyclic and heteroaryl groups each independently contain one or more heteroatoms selected from the group consisting of N, O, P and S.

[0212] Here, -CO-(C1-C6 alkyl) refers to a C1-C6 alkyl group connected to CO. For example, when R1 is -CO-(C1-C6 alkyl), it means that the C1-C6 alkyl group is connected to a nitrogen (N) atom via CO.

[0213] In the present invention, when R3 and R4 are connected to form a 5-membered or 6-membered ring, it means that R3 and R4 are connected to each other via another atom to form a cyclic structure. The ring can be formed by a single bond, multiple bonds (double bonds, triple bonds, etc.) or a combination thereof (i.e., including both cycloalkyl and cyclic aromatic groups), a ring composed entirely of C atoms, or a heterocyclic group having one or more heteroatoms. Preferably, when R3 and R4 are connected to form a 5-membered or 6-membered ring, R3 and R4 are both C.

[0214] In one embodiment of the invention, R3 and R4 are connected to each other and form 5 yuan or 6 yuan of heterocycloalkyl, which includes one or two N atoms in this ring.Here, Y can be N, but the invention is not limited to this.In addition, in the 5 yuan or 6 yuan of heterocycloalkyl formed by R3 and R4, at least one H can be replaced by-OH,-NH2, dimethylamine,-NH-(C1-C5 alkyl),-NH-(C1-C5 alkoxy),-NH-COCH3,-NH-SO2CH3, C1-C5 alkyl or C1-C5 alkoxy, but the invention is not limited to this.

[0215] In another embodiment of the present invention, R1 can be a 6-membered cyclic aromatic group (e.g., aryl), a 6-membered heterocyclic aromatic group (e.g., heteroaryl), -CH2-aryl, -CH2-heteroaryl, a 6-membered cycloalkyl group, a 6-membered heterocycloalkyl group, -CO-aryl or -CO-(C4-C5 alkyl), wherein the 6-membered heterocyclic aromatic group contains at least one N, and the 6-membered heterocycloalkyl group can contain at least one O, but the present invention is not limited thereto. In addition, at least one H of R1 can be substituted or unsubstituted C6-C5 alkyl, halogen, cyano, halogen or substituted C6-C5 alkyl. 12 Aryl or halogen substituted or unsubstituted C5-C 12 The present invention is not limited to heteroaryl substitution.

[0216] In another embodiment of the present invention, when R3 and R4 do not form a ring, R4 can be hydrogen or C1-C5 alkyl, and R3 can be -CH2-(C3-C6 cycloalkyl), -CH2-(C2-C6 heterocycloalkyl) or -CH2-(3 to 6 membered heterocyclic aromatic groups). Here, the heterocycloalkyl can be a 4 to 6 membered heterocycloalkyl with one or two N or O atoms, and the heterocyclic aromatic group can be a 5 or 6 membered heterocyclic aromatic group with one or two N atoms, but the present invention is not limited thereto.

[0217] In one embodiment of the present invention, the compound may be represented by the following Chemical Formula 1-1, but the present invention is not limited thereto:

[0218] [Chemical Formula 1-1]

[0219]

[0220] (In Chemical Formula 1-1,

[0221] X1 to X4 are each independently N or C;

[0222] Z1 to Z6 are each independently N, O or C;

[0223] R 1a is hydrogen, halogen or cyano;

[0224] R2 is hydrogen, halogen or C1-C5 alkyl;

[0225] R3 is C1-C 10 Alkyl, C3-C 10 Cycloalkyl, C2-C 10heterocycloalkyl, -CH2-(C3-C6 cycloalkyl), -CH2-(C2-C6 heterocycloalkyl) or -CH2-(3- to 6-membered heterocyclic aromatic group), wherein at least one H of R3 may be substituted by -OH, C1-C5 alkyl, acetyl, C1-C5 alkoxy, -COCF3 or -SO2CH3; and

[0226] R4 is hydrogen or C1-C5 alkyl,

[0227] wherein the heterocycloalkyl group and the heterocyclic group each independently contain one or more heteroatoms selected from the group consisting of N, O, P and S.

[0228] In Chemical Formula 1-1, a solid line and a dotted line (i.e. ) indicates that two atoms are connected by a single or double bond.

[0229] Preferably, the compound may be any one of the compounds shown in Table 1 below, but the present invention is not limited thereto.

[0230] Throughout the specification, functional groups may be written with "-group" omitted.

[0231] In the present invention, "halogen" includes F, Cl, Br or I.

[0232] In the present invention, "alkyl" refers to a fully saturated branched or unbranched (or straight or linear) hydrocarbon. In addition, the alkyl group according to the present invention includes a straight or branched hydrocarbon containing a hydrocarbon ring group at the end or in the middle. In the present invention, the alkyl group can be C1-C 20 、C1-C 15 、C1-C 12 、C1-C 10 , C1-C8, C1-C6, C1-C5 or C1-C3 alkyl, but the present invention is not limited thereto. Alkyl groups are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, Neopentyl, Isopentyl In one embodiment of the present invention, "alkyl" may be an aminoalkyl or a haloalkyl. "Aminoalkyl" may refer to an alkyl group in which at least one H is replaced by an N atom (e.g., -NH-(C1-C5 alkyl)), and "haloalkyl" may refer to an alkyl group in which at least one H is replaced by a halogen atom.

[0233] The compounds according to the present invention may contain an alkoxy group. In the present invention, "alkoxy" refers to an alkyl group (-OR) bonded to a single oxygen atom. In the present invention, an alkoxy group may be a C1-C 10 , C1-C8, C1-C6, C1-C5, C1-C3 or C1-C2 alkoxy, but the present invention is not limited thereto. Alkoxy may refer to, for example, methoxy, ethoxy, phenoxy or butoxy.

[0234] In the present invention, "acetyl" refers to a monovalent atomic group (CH3CO-) consisting of a methyl group (-CH3) and a carbonyl group (C=O), and "halogen-substituted acetyl" means that one or more hydrogen atoms of the acetyl group are substituted by a halogen atom. For example, in the present invention, "halogen-substituted acetyl" may be a trifluoroacetyl group (-COCF3).

[0235] In the present invention, "sulfonyl" refers to a divalent atomic group (-SO2-) consisting of two O atoms and one S atom. Preferably, the sulfonyl group is C1-C 10 An alkylsulfonyl group may be an alkyl group bonded to an alkyl group. For example, the sulfonyl group may be a methylsulfonyl group bonded to a methyl group.

[0236] In the present invention, "amino" refers to a functional group (-NH2) in which hydrogen is bonded to a nitrogen atom.

[0237] The compounds according to the present invention may contain cyclic substituents (e.g., cycloalkyl groups, aryl groups, etc.) having single bonds, multiple bonds (double bonds, triple bonds, etc.) or combinations thereof. That is, the compounds according to the present invention may contain (hetero)cyclic groups having single bonds and / or multiple bonds.

[0238] In the present invention, "cycloalkyl" refers to a saturated or partially unsaturated cyclic non-aromatic hydrocarbon group. In the present invention, cycloalkyl can be C3-C 20 、C3-C 15 、C3-C 12 、C3-C 10In some embodiments, the cycloalkyl group may be a C3-C8, C3-C6 or C3-C5 cycloalkyl, but the present invention is not limited thereto. In other words, the cycloalkyl group may be, for example, a cyclopropyl, a cyclobutyl, a cyclopentyl, a cyclohexyl, a cyclohexenyl, a cycloheptyl, a cycloheptenyl, a cyclooctyl or a cyclooctenyl. In the present invention, "cycloalkyl" includes "bicycloalkyl" or "tricycloalkyl". Unless otherwise indicated, the term "bicycloalkyl" or "tricycloalkyl" refers to a structure consisting of two or more cycloalkyl moieties having two or more common atoms. In addition, the cycloalkyl group may be a polycyclic ring.

[0239] In the present invention, " heterocycloalkyl " refers to a cyclic hydrocarbon group that also includes one or more heteroatoms in addition to carbon atoms in the ring. Heteroatoms can be one or more selected from the group consisting of N, O, P and S. In one embodiment of the invention, heterocycloalkyl can be a cyclic amine (cyclic amine) or a heterocyclic amine (heterocyclicamine) containing an N atom, and is preferably a 3- to 6-membered cyclic amine. For example, heterocycloalkyl can be selected from the group consisting of piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, pyrrolopyrazinyl and azetidinyl. Alternatively, heterocycloalkyl can be a 4- to 6-membered cyclic group with one or more O atoms. In the present invention, heterocycloalkyl includes " diheterocycloalkyl ". Diheterocycloalkyl is composed of two or more rings with two or more common atoms, and one or more of the two or more rings are heterocycloalkyl.

[0240] In the present invention, "aryl" refers to an aromatic system (aromatic ring) containing one or more rings, which is used alone or in combination, and also includes a group in which an aromatic ring is fused with one or more carbon rings. In the present invention, aryl can be C3-C 20 、C3-C 15 、C3-C 12 、C3-C 10 "Aryl" may be, for example, phenyl, benzyl, naphthyl or tetrahydronaphthyl, but the present invention is not limited thereto. Aryl includes heteroaryl.

[0241] In the present invention, "heteroaryl" refers to a monocyclic or bicyclic organic compound that contains one or more heteroatoms in addition to carbon atoms in its ring. The heteroatom can 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 at least one N (i.e., at least one C constituting the ring is replaced by N). Alternatively, in the present invention, the heteroaryl may be an aromatic amine. In another embodiment of the present invention, the heteroaryl may contain one to three, one or two, or one N atom.

[0242] The aryl and heteroaryl groups (aromatic rings) according to the present invention may include, for example, phenyl, biphenyl, benzyl, benzoyl, benzidine, toluoyl, thienyl, furyl, naphthyl, imidazolyl (imidazole), pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, pyranyl, pyrazinyl, pyrrolinyl, pyridyl (pyridyl ), piperazinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiadiazolyl, triazolyl, indolyl, azaindolyl, indazolyl, azaindazolylbenzimidazolyl, benzofuranyl, benzothiophenyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adeninyl, quinolinyl, isoquinolinyl, naphthyl, tetrahydronaphthyl and isomers thereof.

[0243] Alternatively, the compound according to the present invention may include a polycyclic ring consisting of a plurality of rings joined together. Specifically, a polycyclic ring refers to a substituent in which two or more rings are formed with a linear angled or tightly packed structure. For example, the compound may include a polycyclic ring (i.e., a polycyclic ring with 2 to 5 rings) with 2 to 5 ring combinations, a polycyclic ring with 2 to 4 ring combinations, or a polycyclic ring with 2 or 3 ring combinations. The individual rings constituting the polycyclic ring may be any ring known in the art, as well as the rings disclosed in the specification. For example, the ring may be a 3, 4, 5, 6, 10-membered ring or a combination thereof, and preferably one or more 5-membered and / or 6-membered rings. In addition, the individual rings constituting the polycyclic ring may consist only of a single bond, or may include multiple bonds (double bonds, triple bonds, etc.). The individual rings constituting the polycyclic ring may be the same or different from each other. For example, the rings may each independently be a cycloalkyl, a heterocycloalkyl, a 3- to 10-membered cyclic aromatic group, or a 3- to 10-membered heterocyclic aromatic group.

[0244] Alternatively, the compound according to the present invention may include a heterocyclic group. Ring may include a single bond or multiple bonds (double bonds, triple bonds, etc.). In one embodiment of the invention, the heterocyclic group may include one or more heteroatoms selected from the group consisting of N, O, and S.

[0245] In the present invention, "cyclic aromatic group" refers to a substituent in which carbon compounds are combined in a ring shape through unsaturated bonds (such as double bonds), single electron pairs or empty orbitals. In addition, "heterocyclic aromatic group" refers to a heterocyclic group having two or more different types of ring atoms in an aromatic ring. In the present invention, the (hetero)cyclic aromatic group can be a 3-10-membered, 3-8-membered, 3-6-membered, 3-5-membered, 4-6-membered, 4- or 5-membered, or 5- or 6-membered (hetero)cyclic group, but the present invention is not limited thereto.

[0246] In the present invention, the substituent having a heteroatom (heterocyclic group, heterocycloalkyl group, heteroaryl group and other types of heterocyclic groups) may contain one or more heteroatoms in its main chain structure. For example, the substituent having a heteroatom may contain 1 to 5, 1 to 4, 1 to 3, 1 or 2 or 1 heteroatom, but the present invention is not limited thereto.

[0247] In the present invention, the term "substituted" in "substituted or unsubstituted" refers to that when forming a derivative, one or more hydrogen atoms in an organic compound are replaced by introducing another atomic group, and substituent refers to the atomic group introduced. That is, in the present invention, replacing any group refers to that one or more hydrogen atoms of a corresponding functional group are replaced by other atomic groups. In the present invention, in each functional group (alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy or acetyl), one or more hydrogen atoms can be each independently replaced by different atomic groups. In the present invention, "substituted" includes monosubstituted, disubstituted, trisubstituted or tetrasubstituted.

[0248] In the present invention, unless otherwise specified, "substituted or unsubstituted" may mean that at least one hydrogen (H) atom is substituted or unsubstituted by a different functional group. For example, "halogen substituted or unsubstituted C3-C 10 "Aryl" may refer to C3-C 10 The aryl group is unsubstituted, or at least one H group of the aryl group is substituted by halogen.

[0249] In the present invention, the term "isomer" refers to a compound having the same molecular formula but having different ways of connecting or spatially arranging the constituent atoms within the molecule. Isomers include, for example, structural isomers and stereoisomers. Stereoisomers can be diastereomers or enantiomers. An enantiomer refers to an isomer that does not overlap with its mirror image (such as the relationship between the left hand and the right hand), and is also referred to as an optical isomer. Enantiomers are classified as R (Rectus: clockwise) and S (Sinister: counterclockwise) when there are four or more different substituents at the chiral center carbon. Diastereomers refer to stereoisomers that are not mirror images, and can be classified as cis (cis)-trans (trans) isomers due to different atomic spatial arrangements.

[0250] In the present invention, the term "pharmaceutically acceptable salts" includes all salts derived from pharmaceutically acceptable inorganic acids, organic acids or bases.

[0251] As used herein, the term "pharmaceutically acceptable" refers to compounds or compositions that are suitable for use in contact with the tissues of subjects (e.g., humans) without excessive toxicity, irritation, allergic response, or other problems or complications due to a reasonable benefit / risk ratio, and are included within the scope of sound medical judgment.

[0252] Examples of suitable acids can 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, p-toluenesulfonic acid, tartaric acid, (+)-L-tartaric acid, di-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, decanoic acid, hexanoic acid, octanoic acid, cinnamic acid, cyclamic acid, dodecylsulfonic acid 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, α-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 Palmitic acid L-Pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, tannic acid, thiocyanic acid, camphorsulfonic acid and undecanoic acid. 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). Alternatively, the acid addition salt can be prepared by heating equimolar amounts of the compound and the acid or alcohol in water and evaporating or drying the mixture, or filtering the precipitated salt with suction.

[0253] Salts derived from suitable bases may include, but are not limited to, alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), and ammonium. Alkali 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 undissolved compound salt, and then evaporating the dried filtrate. Here, as metal salts, in particular, sodium, potassium, or calcium salts are pharmaceutically suitable, and corresponding silver salts can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0254] The scope of the compounds of the present invention may include not only pharmaceutically acceptable salts but also all isomers, hydrates and solvates, which can be prepared by conventional methods.

[0255] In addition, the present invention provides a pharmaceutical composition for preventing or treating pulmonary fibrosis-related diseases, comprising the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0256] In the present invention, "pulmonary fibrosis-related diseases" include all diseases directly or indirectly caused by pulmonary fibrosis, including pulmonary fibrosis. Fibrosis refers to a phenomenon in which connective tissue forms within tissues as activated fibroblasts secrete extracellular matrix (including collagen). Fibrosis helps wound healing by forming scar tissue, but if connective tissue accumulates excessively, it may paralyze the normal structure and function of the corresponding organ.

[0257] In some embodiments, the present invention relates to a group of lung fibrosis associated diseases, wherein the lung fibrosis associated diseases are selected from the group consisting of pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), desquamative interstitial pneumonia, nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, respiratory bronchiolitis-associated interstitial lung disease, acute interstitial pneumonia, lymphocytic interstitial pneumonia, idiopathic pleural pulmonary parenchymal fibroelastosis and chronic obstructive pulmonary disease (COPD), but the present invention is not limited thereto. Any disease with lung fibrosis or that can be caused directly or indirectly by lung fibrosis is included without limitation. Preferably, in the present invention, lung fibrosis associated diseases are accompanied by the hyperactivation of actin polymerization. In another embodiment of the present invention, lung fibrosis associated diseases may relate to the overactivation or overexpression of α-SMA, F-actin and / or IL-6.

[0258] In the present invention, "pulmonary fibrosis" is a respiratory disease that causes difficulty breathing due to the hardening of lung tissue, and specifically refers to a condition in which the normal lung structure is destroyed and hardened due to excessive accumulation of fibrous connective tissue in the lungs. As fibrosis in the lungs progresses, the lung walls thicken and the amount of oxygen supplied to the blood decreases, leading to shortness of breath. The most common type of pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF), and the main symptom is shortness of breath during exercise. For IPF treatment, nintedanib, an anti-fibrotic drug, has been used, but the known therapeutic effect is only 10%.

[0259] In the present invention, the composition can inhibit actin polymerization. Actin includes F-actin. The inhibition of actin polymerization can be carried out by functional inhibition of actin binding proteins such as Arp2 / 3 complex. Actin filaments are assembled from actin monomers through actin polymerization (which hydrolyzes ATP to ADP). Although actin polymerization is necessary for controlling cell movement, excessive actin polymerization promotes the expression of α-smooth muscle actin (α-SMA) protein and induces the activation of myofibroblasts (a heterogeneous cell group composed of cells that promote fibrosis), thereby leading to tissue fibrosis. The inventors have confirmed through specific experiments that the compound according to the present invention can effectively inhibit actin polymerization, and therefore can fundamentally treat and alleviate pulmonary fibrosis.

[0260] In addition, in the present invention, the composition can inhibit the level or activity of inflammatory cytokines. Inflammatory cytokines can be produced and secreted by macrophages. The inflammatory cytokine can be IL-6, but the present invention is not limited thereto. IL-6 is a cytokine that participates in B cell differentiation, T cell activation and inflammatory response and particularly induces pulmonary fibrosis. When pulmonary fibrosis occurs, an acute or chronic inflammatory response will first occur. During the inflammatory response, inflammatory cells including macrophages are activated and secrete inflammatory cytokines such as IL-6, IL-1β and TNF-α, and these cytokines can damage tissues, cause fibroblast proliferation, accumulate ECM and promote pulmonary fibrosis.

[0261] In addition, in the present invention, the feature of the composition is to reduce the level of one or more proteins selected from the group consisting of α-SMA, COL1A1, COL4A1, fibronectin, F-actin and IL-6. These proteins are biomarkers for pulmonary fibrosis, and in particular, "α-SMA" protein is a marker for activated myofibroblasts (which are the main effector cells of pulmonary fibrosis). The inventors have confirmed through specific embodiments that, compared with conventional pulmonary fibrosis therapeutic agent nintedanib, the compound according to the present invention shows an excellent effect of suppressing the α-SMA expression in fibroblasts, thereby showing that compared with nintedanib, the compound according to the present invention has an excellent effect of suppressing pulmonary fibrosis.

[0262] The content of the compound 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, and the condition of the patient, and can be, for example, 0.0001 to 99.9% by weight or 0.001 to 50% by weight based on the total weight of the composition, but the present invention is not limited thereto. The content ratio is a value based on the dry content after removing the solvent.

[0263] The pharmaceutical composition according to the present invention may further comprise suitable carriers, adjuvants and diluents, which are commonly used in the preparation of pharmaceutical compositions. The adjuvants may be, for example, one or more selected from the group consisting of diluents, binders, disintegrants, lubricants, adsorbents, humectants, film coating materials and controlled release additives.

[0264] The pharmaceutical composition according to the present invention can be formulated into tablets, sustained-release tablets, enteric-coated tablets, sublingual tablets, lozenges, 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, lemonade or external preparations such as aromatic water, oils, spirits, tinctures, inhalants, elixirs, injections, perfusions, sterile injection solutions, eye drops, plasters, lotions, pastes, sprays, patches or aerosols according to conventional methods, and external preparations can be formulated into creams, gels, patches, sprays, ointments, plasters, lotions, liniments, pastes or papules.

[0265] The carriers, excipients and diluents that may be included in the pharmaceutical composition according to the present invention may include lactose, dextrose, sucrose, oligosaccharides, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil.

[0266] When formulated, the composition according to the present invention can be prepared using commonly used diluents or excipients such as fillers, thickeners, binders, wetting agents, disintegrants and surfactants.

[0267] The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. "Pharmaceutically effective amount" as used herein refers to an amount sufficient to treat a disease with a reasonable benefit / risk ratio suitable for medical treatment, and an effective dose can be determined by parameters (including the type and severity of the patient's disease, drug activity, sensitivity to the drug, administration time, route of administration, and excretion rate), duration of treatment, and concurrently used drugs, as well as other parameters well known in the medical field.

[0268] The pharmaceutical compositions of the present invention can be administered alone or in combination with other therapeutic agents, sequentially or simultaneously with conventional therapeutic agents, or in single or multiple doses. Taking into account all the above-mentioned parameters, it is important to achieve the maximum effect at the minimum dose without side effects, and such dosage can be easily determined by a person of ordinary skill in the art.

[0269] The pharmaceutical composition of the present invention can be administered to a subject via various routes. All routes of administration are contemplated, and the pharmaceutical composition of the present invention can be administered, for example, by oral administration, subcutaneous injection, intraperitoneal administration, intravenous, intramuscular or intrathecal injection, sublingual administration, buccal administration, rectal insertion, vaginal insertion, ophthalmic administration, ear administration, nasal administration, inhalation, oral or nasal spray, dermal administration, or transdermal administration.

[0270] The pharmaceutical composition of the present invention is determined according to the kind of drug as an active ingredient and various relevant parameters such as the disease to be treated, administration route, patient's age, sex, weight and severity of the disease.

[0271] In the present invention, "subject" refers to a subject in need of disease treatment, and more specifically, refers to a mammal such as a human or non-human primate, mouse, rat, dog, cat, horse or cow.

[0272] In the present invention, "administering" means providing a given composition of the present invention to a subject by any appropriate method.

[0273] In the present invention, "prevention" refers to all actions involved in inhibiting or delaying the onset of a desired disease, "treatment" refers to all actions involved in improving or beneficially changing a desired disease and its metabolic abnormalities by administering a pharmaceutical composition according to the present invention, and "alleviation" refers to all actions involved in reducing parameters associated with a desired disease (such as the severity of symptoms) by administering a composition according to the present invention.

[0274] In addition, the present invention provides a kit for preventing or treating pulmonary fibrosis, which comprises a composition according to the present invention. In the present invention, "kit" refers to a combination of materials and devices for preventing or treating pulmonary fibrosis using a compound according to the present invention, and is not limited to a specific form. The kit according to the present invention may not only comprise a compound according to the present invention for preventing and / or treating pulmonary fibrosis, but may also comprise one or more types of components, solutions or devices suitable for preventing, alleviating or treating the disease. In addition, the kit may further comprise instructions describing information related to the compound of the present invention.

[0275] Throughout the specification, when a part "comprises" a component, unless otherwise expressly stated, it means that it may also include other components rather than excluding components. As used herein, the terms "about" or "substantially" are used with respect to numerical values ​​or approximate numerical values ​​when presenting the allowable manufacturing and material tolerances inherent in the meaning. These terms are used to prevent unscrupulous infringers from improperly using the disclosure in which the exact or absolute values ​​are quoted to assist in understanding the present invention.

[0276] Throughout the specification, the term "combination thereof" contained in a Markush-type expression refers to a mixture or combination of one or more selected from the group consisting of the ingredients described in the Markush-type expression, i.e., a mixture or combination of one or more selected from the group consisting of these components.

[0277] Hereinafter, preferred embodiments will be presented to enable the present invention to be better understood. However, the following embodiments are provided only for easier understanding of the present invention, and the contents of the present invention are not limited to the following embodiments.

[0278] [Experimental example]

[0279] Experimental Example 1. Preparation of compounds

[0280] [Reaction Scheme 1]

[0281]

[0282] <Preparation method a> Preparation of 7-fluoro-1-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline

[0283] The 7-fluoro-1-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline according to the present invention was prepared according to the following Preparation Examples a-1 to a-4.

[0284] <Preparation Example a-1> Preparation of 5-fluoro-N-(4-fluorophenyl)-2-nitroaniline

[0285] A 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 cooled to room temperature. After the reaction was terminated by adding water, the reaction solution was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO 4 , filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a n-hexane / ethyl acetate mixture to prepare 5-fluoro-N-(4-fluorophenyl)-2-nitroaniline.

[0286] Yellow solid (yield: 63%); 1 H NMR (400MHz, CDCl3) δ9.54 (s, 1H), 8.26 (dd, J = 9.4, 6.3Hz, 1H), 7.27-7.23 (m, 2H), 7.18-7.13(m,2H),6.63(dd,J=11.3,2.7Hz,1H),6.48(ddd,1H,J=9.5,6.9,2.7Hz).

[0287] <Preparation Example a-2> 5-Fluoro-N 1 Preparation of -(4-fluorophenyl)benzene-1,2-diamine

[0288] A mixture of 5-fluoro-N-(4-fluorophenyl)-2-nitroaniline (4.0 g, 15.98 mmol) and tin(II) chloride dihydrate (10.8 g, 47.96 mmol) obtained in Preparation Example a-1 was dissolved in ethyl acetate (32 mL) and stirred at 90° C. for 5 hours. The reaction solution was cooled to room temperature, poured into water, neutralized with a 10 M NaOH aqueous solution, and then extracted with ethyl acetate. The organic layer was washed with salt water, dried over MgSO , filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a n-hexane / ethyl acetate mixture to prepare 5-fluoro-N-(4-fluorophenyl)-2-nitroaniline. 1 -(4-fluorophenyl)benzene-1,2-diamine.

[0289] Orange solid (yield: 56%); 1 H NMR (400MHz, CDCl3) δ7.00-6.94(m,2H),6.86-6.82(m,2H),6.79(dd,J=10.0,2.9Hz, 1H), 6.70 (dd, J=8.6, 5.9Hz, 1H), 6.64-6.59 (m, 1H), 5.27 (s, 1H), 3.49 (s, 2H); LC / MS ESI(+):220.6(M+1).

[0290] <Preparation Example a-3> Preparation of 7-fluoro-1-(4-fluorophenyl)quinoxaline-2,3(1H,4H)-dione

[0291] The 5-fluoro-N 1 7-(4-Fluorophenyl)benzene-1,2-diamine (3.0 g, 14.83 mmol) was dissolved in diethyl oxalate (130 mL, 89.00 mmol) and stirred at 160° C. for 24 hours. The reaction solution was cooled to room temperature, filtered, and dried to prepare 7-fluoro-1-(4-fluorophenyl)quinoxaline-2,3(1H,4H)-dione.

[0292] Ivory solid (yield: 68%); 1 LC / MS ESI(+): 274.9(M+1).

[0293] <Preparation Example a-4> Preparation of 7-fluoro-1-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline

[0294] Borane-THF complex (1M) (22mL, 21.88mmol) is slowly added to a solution of 7-fluoro-1-(4-fluorophenyl)quinoxaline-2,3(1H,4H)-dione (2.0g, 7.29mmol) obtained in Preparation Example a-3 dissolved in THF (14mL) 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 the reaction product was neutralized with a saturated NaHCO3 aqueous 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 n-hexane / ethyl acetate mixture to prepare 7-fluoro-1-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline.

[0295] Light purple solid (yield: 72%); 1 H LC / MS ESI(+):246.8(M+1).

[0296] [Reaction Scheme 2]

[0297]

[0298] <Preparation Example a-5> Preparation of tert-butyl (R)-3-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate

[0299] The 7-fluoro-1-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline (200 mg, 0.81 mmol) obtained in Preparation Example a-4 was dissolved in dichloromethane (1.6 mL), TEA (0.23 mL, 1.62 mmol) and triphosgene (120 mg, 0.41 mmol) were slowly added at 0 ° C, and then 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 terminating the reaction by adding water to the reaction solution, 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 an n-hexane / ethyl acetate mixture to prepare (R)-tert-butyl 3-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate.

[0300] Light yellow solid (yield: 96%); 1 H NMR (400MHz, CDCl3) δ7.24-7.20(m,2H),7.16-7.10(m,2H),7.05(dd,J=8.9,5.6Hz,1H),6.41-6.39(m,1H),6.25(dd,J=11.3,2.7Hz,1H),5.25(dd,J=6 .7Hz,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).

[0301] <Example 1> Synthesis of (R)-6-fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0302] (R) -3- (6- fluoro -4- (4- fluorophenyl) -1,2,3,4- tetrahydroquinoxaline -1- formamido) tert-butyl pyrrolidine -1- carboxylate (300 mg, 0.65 mmol) obtained in Preparation Example a-5 was dissolved in dichloromethane (1.3 mL), TFA (0.5 mL, 6.54 mmol) was added, and the resulting solution was stirred at room temperature for 24 hours. After terminating the reaction by adding water to the reaction solution, 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 mixture of n-hexane / ethyl acetate to synthesize (R) -6- fluoro -4- (4- fluorophenyl) -N- (pyrrolidin-3-yl) -3,4- dihydroquinoxaline -1 (2H) - formamide.

[0303] Yellow solid (yield: 47%); 1 H NMR (400MHz, CD3OD) δ7.34-7.29(m,2H),7.24-7.16(m,3H),6.45-6.40(m,1H),6.17(dd,J=11.3,2.7Hz,1H),4.29-4.23(m,1H),3.88-3.82(m,2 H),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).

[0304] Example 2: Synthesis of (R)-6-fluoro-4-(4-fluorophenyl)-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0305] The (R) -6- fluoro- 4- (4- fluorophenyl) -N- (pyrrolidin-3-yl) -3,4- dihydroquinoxaline -1 (2H) -methane amide (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 resulting solution was stirred at room temperature for 1 hour. After terminating the reaction by adding water to the reaction solution, 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) -6- fluoro- 4- (4- fluorophenyl) -N- (1- methylpyrrolidin-3-yl) -3,4- dihydroquinoxaline -1 (2H) -methane amide.

[0306] Yellow oil (yield: 73%); 1 H NMR (400MHz, CDCl3) δ7.25-7.20(m,2H),7.16-7.09(m,3H),6.42-6.38(m,1H),6.2 4(dd,J=11.5,2.9Hz,1H),5.55(d,J=6.7Hz,1H),4.47-4.38(m,1H),4.01-3.95(m,1 H),3.87-3.81(m,1H),3.60(t,J=5.1Hz,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).

[0307] Example 3: Synthesis of (R)-6-fluoro-4-(4-fluorophenyl)-N-(1-isopropylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0308] (R)-6-fluoro-4-(4-fluorophenyl)-N-(1-isopropylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 2, except that acetone was used instead of formaldehyde.

[0309] Yellow oil (yield: 32%); 1H NMR (400MHz, CDCl3) δ7.25-7.20(m,2H),7.16-7.09(m,3H),6.43-6.39(m,1H) ,6.25(dd,J=11.3,2.7Hz,1H),5.85-5.74(m,1H),4.49-4.38(m,1H),4.00-3.9 4(m,1H),3.89-3.83(m,1H),3.61(t,J=5.1Hz,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=6.5Hz,6H); LC / MS ESI(+):401.1(M+1).

[0310] Example 4: Synthesis of (R)-6-fluoro-4-(4-fluorophenyl)-N-(1-isobutylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0311] (R)-6-fluoro-4-(4-fluorophenyl)-N-(1-isobutylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 2, except that isobutyraldehyde was used instead of acetone.

[0312] Yellow oil (yield: 72%); 1 H NMR (400MHz, CDCl3) δ7.25-7.20(m,2H),7.15-7.09(m,3H),6.41-6.37(m,1H), 6.25(dd,J=11.3,2.7Hz,1H),5.73-5.57(m,1H),4.42-4.32(m,1H),3.97-3.86( m,2H),3.60(t,J=5.1Hz,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=6.3,2.7Hz,6H); LC / MS ESI(+):414.8(M+1).

[0313] Example 5: Synthesis of (R)-6-fluoro-4-(4-fluorophenyl)-N-(1-(2,2,2-trifluoroacetyl)pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0314] The (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 dichloromethane (1.0 mL), and TEA (-30.0 μL, 0.21 mmol) and trifluoroacetic anhydride (30.0 μL, 0.21 mmol) were added, and the resulting solution was stirred at 0 ° C for 30 minutes. The reaction solution was neutralized with a saturated NaHCO3 aqueous 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 a dichloromethane / methanol mixture, thereby synthesizing (R)-6-fluoro-4-(4-fluorophenyl)-N-(1-(2,2,2-trifluoroacetyl)pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0315] White solid (yield: 45%); 1 H NMR (400MHz, CDCl3) δ7.24-7.21(m,2H),7.17-7.11(m,2H),7.03(dd,J=8.6,5.9Hz,1H),6.43-6.37(m,1H),6.26(dd,J=11.3,2.7Hz,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).

[0316] Example 6: Synthesis of (R)-N-(1-acetylpyrrolidin-3-yl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0317] The (R) -6- fluoro- 4- (4- fluorophenyl) -N- (pyrrolidin-3-yl) -3,4- dihydroquinoxaline -1 (2H) -methane amide (50 mg, 0.14 mmol) obtained in Example 1 was dissolved in THF (1.4 mL), TEA (20.0 μL, 0.14 mmol) and acetyl chloride (10.0 μL, 0.15 mmol) were added, and the resulting solution was stirred at room temperature for 1.5 hours. After terminating the reaction by adding water to the reaction solution, 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) -N- (1- acetylpyrrolidin-3-yl) -6- fluoro- 4- (4- fluorophenyl) -3,4- dihydroquinoxaline -1 (2H) -methane amide.

[0318] Yellow solid (yield: 50%); 1 H NMR (400MHz, CDCl3) δ7.25-7.19(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),4.0 1-3.93(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=3.1Hz,3H),2.01-1.74(m,1H); LC / MS ESI(+):401.0(M+1).

[0319] Example 7: Synthesis of (R)-6-fluoro-4-(4-fluorophenyl)-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0320] (R)-6-fluoro-4-(4-fluorophenyl)-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 6, except that methanesulfonyl chloride was used instead of acetyl chloride.

[0321] Ivory solid (yield: 49%); 1H NMR (400MHz, CDCl3) δ7.24-7.20(m,2H),7.16-7.06(m,3H),6.44-6.39(m,1H),6.25(dd,J=11.3,2.7Hz,1H),5.37(d,J=7.0Hz,1H),4.51-4.43( m,1H),3.97-3.85(m,2H),3.62(t,J=5.3Hz,2H),3.57-3.49(m,2H),3.3 7-3.30(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).

[0322] [Reaction Scheme 3]

[0323]

[0324] <Preparation Example a-6> Preparation of tert-butyl (S)-3-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate

[0325] (S)-tert-butyl 3-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate was prepared in the same manner as in Preparation Example a-5, except that (S)-(-)-1-Boc-3-aminopyrrolidine was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[0326] White solid (yield: 71%); 1 H NMR (400MHz, CDCl3) δ7.25-7.20(m,2H),7.17-7.10(m,2H),7.08-7.02(m,1H),6.44-6.35(m,1H),6.26(dd,J=11.3,2.7Hz,1H),5.25(d,J=7.6Hz,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).

[0327] Example 8: Synthesis of (S)-6-fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0328] The Boc group of tert-butyl (S)-3-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate obtained in Preparation Example a-6 was deprotected with TFA, thereby synthesizing (S)-6-fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0329] White solid (yield: 65%); 1 H NMR (400MHz, CDCl3) δ7.25-7.19(m,2H),7.16-7.08(m,3H),6.43-6.38(m,1H ),6.25(dd,J=11.3,2.7Hz,1H),5.35(d,J=6.7Hz,1H),4.36-4.29(m,1H),3.9 7-3.86(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).

[0330] Example 9: Synthesis of (S)-6-fluoro-4-(4-fluorophenyl)-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0331] (S) -6- fluoro-4- (4- fluorophenyl) -N- (pyrrolidin-3-yl) -3,4- dihydroquinoxaline -1 (2H) - carboxamide (1.0 equivalent) obtained in Example 8 was dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After terminating the reaction by adding water to the reaction solution, 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 (S) -6- fluoro-4- (4- fluorophenyl) -N- (1-methylpyrrolidin-3-yl) -3,4- dihydroquinoxaline -1 (2H) - carboxamide.

[0332] Yellow oil (yield: 32%); 1H NMR (400MHz, CDCl3) δ7.25-7.20(m,2H),7.16-7.09(m,3H),6.42-6.38(m,1H),6. 24(dd,J=11.3,2.7Hz,1H),5.48(d,J=7.4Hz,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).

[0333] Example 10: Synthesis of (S)-6-fluoro-4-(4-fluorophenyl)-N-(1-isopropylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0334] (S)-6-fluoro-4-(4-fluorophenyl)-N-(1-isopropylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 2, except that acetone was used instead of formaldehyde.

[0335] Yellow oil (yield: 64%); 1 H NMR (400MHz, CDCl3) δ7.25-7.20(m,2H),7.16-7.08(m,3H),6.42-6.37(m,1H) ,6.25(dd,J=11.3,2.7Hz,1H),5.48(d,J=7.4Hz,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=6.5Hz,6H); LC / MS ESI(+):401.0(M+1).

[0336] [Reaction Scheme 4]

[0337]

[0338] <Preparation Example a-7> Preparation of tert-butyl (S)-(1-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)carbamate

[0339] (S)-tert-butyl(1-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)carbamate was prepared in the same manner as in Preparation Example a-5, except that (S)-(-)-3-(Boc-amino)pyrrolidine was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[0340] White solid (yield: 93%); 1 H NMR (400MHz, CD3OD) δ7.36-7.27(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).

[0341] Example 11: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-yl)methanone

[0342] 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 Preparation Example a-7 was deprotected with TFA, thereby synthesizing (S)-(3-aminopyrrolidin-1-yl)(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-yl)methanone.

[0343] White solid (yield: 49%); 1 H NMR (400MHz, CDCl3) δ7.25-7.17(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 LC / MS ESI(+): 358.6(M+1).

[0344] <Preparation Example a-8> Preparation of tert-butyl (S)-(1-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)(methyl)carbamate

[0345] The (S)-(1-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)t-butyl carbamate (60.0 mg, 0.13 mmol) obtained in Preparation Example a-7 was dissolved in THF (0.5 mL), NaH (6.3 mg, 0.26 mmol) and iodomethane (22.2 mg, 0.16 mmol) were added, and the resulting solution was stirred at room temperature for 5 hours. After terminating the reaction by adding water to the reaction solution, 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 an n-hexane / ethyl acetate mixture to prepare tert-butyl (S)-(1-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)(methyl)carbamate.

[0346] White solid (yield: 81%); 1 H NMR (400MHz, CDCl3) δ7.28-7.18(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).

[0347] Example 12: Synthesis of (S)-(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-yl)(3-(methylamino)pyrrolidin-1-yl)methanone

[0348] 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 Preparation Example a-8 was deprotected with TFA, thereby synthesizing (S)-(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-yl)(3-(methylamino)pyrrolidin-1-yl)methanone.

[0349] Ivory solid (yield: 80%);1 H NMR (400MHz, CD3OD) δ7.35-7.27(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),3.94-3.8 0(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 / MSESI(+): 372.7(M+1).

[0350] [Reaction Scheme 5]

[0351]

[0352] Example 13: Synthesis of (S)-(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-yl)(3-(isobutylamino)pyrrolidin-1-yl)methanone

[0353] (S)-(3-aminopyrrolidin-1-yl)(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-yl)methanone (1.0 equivalent) obtained in Example 11 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 equivalents) and isobutyraldehyde (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After the reaction was terminated by adding water to the reaction solution, 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, thereby synthesizing (S)-(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-yl)(3-(isobutylamino)pyrrolidin-1-yl)methanone.

[0354] Colorless oil (yield: 50%); 1H NMR (400MHz, CDCl3) δ7.25-7.17(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=6.7Hz,6H); LC / MS ESI(+): 414.7(M+1).

[0355] Example 14: Synthesis of (S)-(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-yl)(3-(isopropylamino)pyrrolidin-1-yl)methanone

[0356] (S)-(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(3-(isopropylamino)pyrrolidin-1-yl)methanone was synthesized in the same manner as in Example 13, except that acetone was used instead of isobutyraldehyde.

[0357] Light yellow oil (yield: 46%); 1 H NMR (400MHz, CDCl3) δ7.24-7.17(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),3.6 1-3.46(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=8.3,6.2Hz,6H); LC / MS ESI(+):400.7(M+1).

[0358] Example 15: Synthesis of (S)-N-(1-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)acetamide

[0359] (S)-(3-aminopyrrolidin-1-yl)(6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-yl)methanone (1.0 equivalent) obtained in Example 11 was dissolved in THF (0.3 M), TEA (2.5 equivalents) and acetyl chloride (1.8 equivalents) were added, and the resulting solution was stirred at room temperature for 4.5 hours. After the reaction was terminated by adding water to the reaction solution, 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, thereby synthesizing (S)-N-(1-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)acetamide.

[0360] White solid (yield: 68%); 1 H NMR(400MHz,CD3OD)δ7.25-7.06(m,4H),6.91-6.83(m,1H),6.41-6.32(m,1H),6.28-6 .20(m,1H),5.48(d,J=7.2Hz,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=11.3,5.2H z,1H),2.23-2.11(m,1H),1.97(s,3H),1.87-1.74(m,1H); LC / MSESI(+): 400.7(M+1).

[0361] Example 16: Synthesis of (S)-N-(1-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)methanesulfonamide

[0362] (S)—N-(1-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)methanesulfonamide was synthesized in the same manner as in Example 15, except that methanesulfonyl chloride was used instead of acetyl chloride.

[0363] White solid (yield: 66%); 1H NMR (400MHz, CDCl3) δ7.25-7.18(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=7.3Hz,1H),4.09-3.98(m,1 H),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).

[0364] [Reaction Scheme 6]

[0365]

[0366] <Preparation Example a-9> Preparation of tert-butyl (R)-3-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate

[0367] (R)-tert-butyl 3-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate was prepared in the same manner as in Preparation Example a-5, except that (R)-1-Boc-3-(aminomethyl)pyrrolidine was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[0368] White solid (yield: 90%); 1 H NMR (400MHz, CDCl3) δ7.25-7.03(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).

[0369] Example 17: Synthesis of (S)-6-fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0370] 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 Preparation Example a-9 was deprotected with TFA, thereby synthesizing (S)-6-fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0371] White solid (yield: 46%); 1 H NMR (400MHz, CDCl3) δ7.25-5-7.05(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).

[0372] Example 18: Synthesis of (R)-6-fluoro-4-(4-fluorophenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0373] (S) -6- fluoro-4- (4-fluorophenyl) -N- (pyrrolidin-3-ylmethyl) -3,4- dihydroquinoxaline -1 (2H) - carboxamide (1.0 equivalent) obtained in Example 17 was dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After terminating the reaction by adding water to the reaction solution, 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 n-hexane / ethyl acetate mixture to synthesize (R) -6- fluoro-4- (4-fluorophenyl) -N- ((1-methylpyrrolidin-3-yl) methyl) -3,4- dihydroquinoxaline -1 (2H) - carboxamide.

[0374] White solid (yield: 40%); 1H NMR (400MHz, CDCl3) δ7.25-7.7.06(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).

[0375] Example 19: Synthesis of (R)-6-fluoro-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0376] (R)-6-fluoro-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 18, except that acetone was used instead of formaldehyde.

[0377] Yellow solid (yield: 64%); 1 H NMR (400MHz, CDCl3) δ7.255-7.07(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).

[0378] Example 20: Synthesis of (R)-6-fluoro-4-(4-fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0379] (R)-6-fluoro-4-(4-fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 18, except that isobutyraldehyde was used instead of formaldehyde.

[0380] White solid (yield: 64%); 1H NMR (400MHz, CD3OD) δ7.37-7.14(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=6.8,1.7Hz,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=6.6,4.6Hz,6H); LC / MS ESI(+): 429.2(M+1).

[0381] [Reaction Scheme 7]

[0382]

[0383] <Preparation Example a-10> Preparation of tert-butyl (R)-2-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate

[0384] (R)-2-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester was prepared in the same manner as in Preparation Example a-5, except that (R)-1-Boc-2-(aminomethyl)pyrrolidine was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[0385] White solid (yield: 90%); 1 H NMR (400MHz, CD3OD) δ7.37-7.10(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).

[0386] Example 21: Synthesis of (R)-6-fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0387] The Boc group of tert-butyl (R)-2-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate obtained in Preparation Example a-10 was deprotected with TFA, thereby synthesizing (R)-6-fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0388] Light yellow solid (yield: 53%); 1 H NMR (400MHz, CD3OD) δ7.38-7.13(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).

[0389] Example 22: Synthesis of (R)-6-fluoro-4-(4-fluorophenyl)-N-((1-methylpyrrolidin-2-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0390] (R) -6- fluoro-4- (4-fluorophenyl) -N- (pyrrolidin-2-ylmethyl) -3,4- dihydroquinoxaline -1 (2H) - carboxamide (1.0 equivalent) obtained in Example 21 was dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After terminating the reaction by adding water to the reaction solution, 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 mixture of n-hexane / ethyl acetate to synthesize (R) -6- fluoro-4- (4-fluorophenyl) -N- ((1-methylpyrrolidin-2-yl) methyl) -3,4- dihydroquinoxaline -1 (2H) - carboxamide.

[0391] Light yellow solid (yield: 23%); 1H NMR (400MHz, CD3OD) δ7.38--7.16(m,5H),6.46(ddd,J=8.8,8.0,2.8Hz,1H),6.20(dd,J=11.4,2.8Hz,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).

[0392] Example 23: Synthesis of (R)-6-fluoro-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-2-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0393] (R)-6-fluoro-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-2-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 22, except that acetone was used instead of formaldehyde.

[0394] White solid (yield: 51%); 1 H NMR (400MHz, CD3OD) δ7.37-7.16(m,5H),6.47(ddd,J=8.8,8.0,2.8Hz,1H),6.21(dd,J=11.4,2.8Hz,1H),4.04-3.79(m,2 LC / MS ESI(+): 415.2(M+1).

[0395] Example 24: Synthesis of (R)-6-fluoro-4-(4-fluorophenyl)-N-((1-isobutylpyrrolidin-2-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0396] (R)-6-fluoro-4-(4-fluorophenyl)-N-((1-isobutylpyrrolidin-2-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 22, except that isobutyraldehyde was used instead of formaldehyde.

[0397] Light yellow oil (yield: 49%); 1H NMR(400MHz,CD3OD)δ7.35-7.14(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).

[0398] [Reaction Scheme 8]

[0399]

[0400] <Preparation Example a-11> Preparation of tert-butyl (S)-3-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate

[0401] (S)-tert-butyl 3-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate was prepared in the same manner as in Preparation Example a-5, except that (S)-1-Boc-3-(aminomethyl)pyrrolidine was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[0402] White solid (yield: 91%); 1 H NMR (400MHz, CDCl3) δ7.25-57.02(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=5.2H z,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).

[0403] <Preparation Example a-12> Preparation of (R)-6-fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0404] 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 Preparation Example a-11 was deprotected with TFA to prepare (R)-6-fluoro-4-(4-fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0405] Light yellow solid (yield: 28%); 1 H NMR (400MHz, CDCl3) δ7.25-7.04(m,5H),6.45-6.36(m,1H),6.28-6.20(m,1H),5.67(t,J=6.0Hz,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).

[0406] Example 25: Synthesis of (S)-6-fluoro-4-(4-fluorophenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0407] The (R) -6- fluoro-4- (4- fluorophenyl) -N- (pyrrolidin-3-ylmethyl) -3,4- dihydroquinoxaline -1 (2H) -methane amide (1.0 equivalent) obtained in Preparation Example a-12 was dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After terminating the reaction by adding water to the reaction solution, 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 mixture of n-hexane / ethyl acetate to synthesize (S) -6- fluoro-4- (4- fluorophenyl) -N- ((1- methylpyrrolidin-3-yl) methyl) -3,4- dihydroquinoxaline -1 (2H) -methane amide.

[0408] Yellow solid (yield: 33%); 1H NMR (400MHz, CD3OD) δ7.38-7.15(m,5H),6.51-6.39(m,1H),6.20(dd,J=11.4,2.8Hz,1H),3.96-3.80(m,2H),3.74-3.57(m,2H),3.42-3.33( LC / MS ESI(+): 387.2(M+1).

[0409] Example 26: Synthesis of (S)-6-fluoro-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0410] (S)-6-fluoro-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 25, except that acetone was used instead of formaldehyde.

[0411] White solid (yield: 41%); 1 H NMR (400MHz, CD3OD) δ7.38-7.14(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=6.5Hz,6H),1.35-1.25(m,1H); LC / MS ESI(+): 415.2(M+1).

[0412] Example 27: Synthesis of (S)-6-fluoro-4-(4-fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0413] (S)-6-fluoro-4-(4-fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 25, except that isobutyraldehyde was used instead of formaldehyde.

[0414] White solid (yield: 54%); 1 H NMR (400MHz, CD3OD) δ7.38-7.14(m,5H),6.50-6.41(m,1H),6.20(dd,J=11.4,2.8H z,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=6.6,2.6Hz,6H); LC / MS ESI(+): 429.2(M+1).

[0415] [Reaction Scheme 9]

[0416]

[0417] Example 28 Synthesis of N-(cyclopropylmethyl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0418] N-(Cyclopropylmethyl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Preparation Example a-5, except that cyclopropylmethylamine was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[0419] White solid (yield: 57%); 1 H NMR (400MHz, CDCl3) δ7.25-7.08(m,5H),6.49-6.35(m,1H),6.26(dd,J=11.4,2.8Hz,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).

[0420] [Reaction Scheme 10]

[0421]

[0422] <Preparation Example a-13> Preparation of tert-butyl 4-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)piperidine-1-carboxylate

[0423] Tert-butyl 4-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)piperidine-1-carboxylate was prepared in the same manner as in Preparation a-5, except that 1-Boc-4-aminopiperidine was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[0424] White solid (yield: 73%); 1 H NMR (400MHz, CDCl3) δ7.24-7.20(m,2H),7.16-7.09(m,2H),7.07(dd,J=8.6,5.9Hz,1H),6.40(d,J=2.7Hz,1H),6.26(dd,J=11.3,2.7Hz,1 H),5.11(d,J=7.8Hz,1H),4.08-3.96(m,2H),3.61(t,J=5.1Hz,2H),2.96-2.84(m,2H),1.99-1.91(m,2H),1.45(s,9H),1.35-1.26(m,2H).

[0425] <Example 29> Synthesis of 6-fluoro-4-(4-fluorophenyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0426] The Boc group of tert-butyl 4-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)piperidine-1-carboxylate obtained in Preparation Example a-13 was deprotected with TFA, thereby synthesizing 6-fluoro-4-(4-fluorophenyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0427] White solid (yield: 90%); 1H NMR (400MHz, CDCl3) δ7.25-7.18(m,2H),7.16-7.08(m,3H),6.43-6.38(m,1H),6.26(dd,J=11.3,2.7Hz,1H),5.14(d,J=7.8Hz,1H),3.92(t ,J=5.1Hz,2H),3.87-3.77(m,1H),3.62(t,J=5.1Hz,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).

[0428] <Example 30> Synthesis of 6-fluoro-4-(4-fluorophenyl)-N-(1-methylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0429] The 6-fluoro-4-(4-fluorophenyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-formamide (1.0 equivalent) obtained in Example 29 was dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After terminating the reaction by adding water to the reaction solution, 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 n-hexane / ethyl acetate mixture to synthesize 6-fluoro-4-(4-fluorophenyl)-N-(1-methylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-formamide.

[0430] White solid (yield: 48%); 1 H NMR (400MHz, CDCl3) δ7.24-7.21(m,2H),7.15-7.06(m,3H),6.43-6.38(m,1H),6.26(dd,J=11.3,2.7Hz,1H),5.11(d,J=7.4Hz,1H),3.91(t,J=5.1 Hz,1H),3.80-3.72(m,1H),3.61(t,J=5.1Hz,1H),2.90-2.77(m,2H),2.3 3(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).

[0431] <Example 31> Synthesis of 6-fluoro-4-(4-fluorophenyl)-N-(1-isopropylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0432] 6-Fluoro-4-(4-fluorophenyl)-N-(1-isopropylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 30, except that acetone was used instead of formaldehyde.

[0433] White solid (yield: 45%); 1 H NMR (400MHz, CDCl3) δ7.24-7.21(m,2H),7.16-7.06(m,3H),6.40-6.35(m,1 H),6.26(dd,J=11.3,2.7Hz,1H),5.15(d,J=7.8Hz,1H),3.91(t,J=5.1Hz,2 H),3.81-3.70(m,1H),3.60(t,J=5.1Hz,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=6.7Hz,6H); LC / MS ESI(+): 415.0(M+1).

[0434] <Example 32> Synthesis of 6-fluoro-4-(4-fluorophenyl)-N-(1-isobutylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0435] 6-Fluoro-4-(4-fluorophenyl)-N-(1-isobutylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 30, except that isobutyraldehyde was used instead of formaldehyde.

[0436] White solid (yield: 40%); 1H-NMR (400MHz, CDCl3) δ7.24-7.21(m,2H),7.16-7.06(m,3H),6.43-6.38(m ,1H),6.26(dd,J=11.3,2.7Hz,1H),5.21(d,J=7.8Hz,1H),3.91(t,J=5.1Hz, 2H),3.85-3.75(m,1H),3.61(t,J=5.1Hz,2H),3.09-2.96(m,1H),2.35-2.2 0(m,4H),2.07-1.95(m,5H),1.94-1.81(m,1H),0.94(d,J=6.7Hz,6H); LC / MS ESI(+): 428.9(M+1).

[0437] [Reaction Scheme 11]

[0438]

[0439] <Preparation Example a-14> Preparation of tert-butyl 4-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate

[0440] Tert-butyl 4-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate was prepared in the same manner as in Preparation a-5, except that 1-Boc-4-(aminomethyl)piperidine was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[0441] White solid (yield: 95%); 1 H NMR (400MHz, CD3OD) δ7.37-7.25(m,2H),7.24-7.13(m,3H),6.45(ddd,J=8.9,8.0,2.8Hz,1H),6.20(dd,J=11.4,2.8Hz,1H),4.17-3.99 (m,2H),3.94-3.81(m,2H),3.71-3.60(m,2H),3.12(d,J=6.6Hz,2H),2.75(brs,2H),1.83-1.63(m,3H),1.46(s,9H),1.21-1.01(m,2H).

[0442] <Example 33> Synthesis of 6-fluoro-4-(4-fluorophenyl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0443] 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 Preparation Example a-14 was deprotected with TFA, thereby synthesizing 6-fluoro-4-(4-fluorophenyl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0444] White solid (yield: 80%); 1 H NMR (400MHz, CD3OD) δ7.37-7.27(m,2H),7.25-7.15(m,3H),6.45(ddd,J=8.8,8.0,2.8Hz,1H),6.20(dd,J=11.4,2.8Hz,1H),3.86(dd,J=5.8, 4.5Hz,2H),3.64(dd,J=5.8,4.5Hz,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).

[0445] <Example 34> Synthesis of 6-fluoro-4-(4-fluorophenyl)-N-((1-methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0446] The 6-fluoro-4-(4-fluorophenyl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-formamide (1.0 equivalent) obtained in Example 33 was dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After terminating the reaction by adding water to the reaction solution, 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 mixture of n-hexane / ethyl acetate to synthesize 6-fluoro-4-(4-fluorophenyl)-N-((1-methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-formamide.

[0447] White solid (yield: 68%); 1H NMR (400MHz, CD3OD) δ7.37-7.27(m,2H),7.25-7.15(m,3H),6.50-6.41(m,1H),6.24-6.16(m,1H),3.86(dd,J=5.8,4.5Hz,2H),3.64(dd,J=5.8,4.5H z,2H),3.14(d,J=6.7Hz,2H),3.09(d,J=11.7Hz,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).

[0448] <Example 35> Synthesis of 6-fluoro-4-(4-fluorophenyl)-N-((1-isobutylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0449] 6-Fluoro-4-(4-fluorophenyl)-N-((1-isobutylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 34, except that isobutyraldehyde was used instead of formaldehyde.

[0450] White solid (yield: 46%); 1 H NMR (400MHz, CDCl3) δ7.26-77.07(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 / MSESI(+): 443.2(M+1).

[0451] <Example 36> Synthesis of 6-fluoro-4-(4-fluorophenyl)-N-((1-isopropylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0452] 6-Fluoro-4-(4-fluorophenyl)-N-((1-isopropylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 34, except that acetone was used instead of formaldehyde.

[0453] White solid (yield: 67%); 1H NMR (400MHz, CD3OD) δ7.37-7.15(m,5H),6.50-6.41(m,1H),6.25-6.17(m,1H),3.86(dd,J=5.8,4.5Hz,2H),3.64(dd,J=5.8,4.6Hz,2H),3.22(d,J =12.0Hz,2H),3.16(d,J=6.7Hz,3H),2.65(t,J=12.1Hz,2H),1.97-1.83( m,2H),1.82-1.65(m,1H),1.51-1.35(m,2H),1.23(d,J=6.6Hz,6H); LC / MS ESI(+): 429.2(M+1).

[0454] [Reaction Scheme 12]

[0455]

[0456] Example 37 Synthesis of N-((1H-imidazole-4-)methyl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0457] N-((1H-imidazole-4-yl)methyl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Preparation Example a-5, except that (1H-imidazol-4-yl)methanamine hydrochloride was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[0458] Light yellow solid (yield: 11%); 1 H NMR(400MHz,CD3OD)δ7.61(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=11.3,2.7Hz,1H),4.34(s,2H),3.87(t,J=5.1Hz,2H),3.63(t,J=5.1Hz,2H); LC / MS ESI(+): 370.0(M+1).

[0459] <Example 38> Synthesis of 6-fluoro-4-(4-fluorophenyl)-N-(pyrazin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0460] 6-Fluoro-4-(4-fluorophenyl)-N-(pyrazin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Preparation Example a-5, except that 4-(aminomethyl)pyrimidine was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[0461] Ivory solid (yield: 61%); 1 H-NMR (400MHz, CDCl3) δ9.14(s,1H),8.68(d,J=5.2Hz,1H),7.33(d,J=5.5Hz,1H),7.30-7.27(m,1H),7.25-7.21(m,2H),7.17 LC / MS ESI(+): 381.9(M+1).

[0462] [Reaction Scheme 13]

[0463]

[0464] <Example 39> Synthesis of (6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-yl)(3-hydroxypyrrolidin-1-yl)methanone

[0465] (6-Fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-yl)(3-hydroxypyrrolidin-1-yl)methanone was synthesized in the same manner as in Preparation Example a-5, except that 3-pyrrolidinol was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[0466] Ivory solid (yield: 89%); 1H NMR (400MHz, CDCl3) δ7.24-7.19(m,2H),7.14-7.08(m,2H),6.90(dd,J=8.6,5.9Hz,1 H),6.41-6.36(m,1H),6.27(dd,J=11.3,2.7Hz,1H),5.48(d,J=7.4Hz,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 = 3.5Hz, 1H); LC / MSESI (+): 360.0 (M+1).

[0467] <Example 40> Synthesis of (6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-yl)(3-methoxypyrrolidin-1-yl)methanone

[0468] (6-Fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-yl)(3-hydroxypyrrolidin-1-yl)methanone (1.0 equiv.) obtained in Example 39 was dissolved in THF (0.3 M), NaH (2.0 equiv.) and iodomethane (1.2 equiv.) were added, and the resulting solution was stirred at room temperature for 2 hours. After the reaction was terminated by adding water, the reaction solution 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 (6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-yl)(3-methoxypyrrolidin-1-yl)methanone.

[0469] Yellow oil (yield: 96%); 1 H NMR (400MHz, CDCl3) δ7.24-7.19(m,2H),7.13-7.07(m,2H),6.89(dd,J=9.0, 5.9Hz,1H),6.41-6.36(m,1H),6.26(dd,J=11.0,2.7Hz,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).

[0470] [Reaction Scheme 14]

[0471]

[0472] <Preparation Example a-15> Preparation of tert-butyl 3-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)azetidine-1-carboxylate

[0473] Tert-butyl 3-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)azetidine-1-carboxylate was prepared in the same manner as in Preparation Example a-5, except that 1-Boc-3-aminoazetidine was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[0474] White solid (yield: 94%); 1 H NMR (400MHz, CDCl3) δ7.25-7.20(m,2H),7.17-7.09(m,3H),6.47-6.41(m,1H),6.26(dd,J=11.3,2.7Hz,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=4.9Hz,2H),3.73-3.71(m,2H),3.62(t,J=5.1Hz,2H),1.44(s,9H).

[0475] <Example 41> Synthesis of N-(azetidin-3-yl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0476] The Boc group of tert-butyl 3-(6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)azetidine-1-carboxylate obtained in Preparation Example a-15 was deprotected with TFA to synthesize N-(azetidin-3-yl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0477] White solid (yield: 43%); 1H NMR (400MHz, CDCl3) δ7.25-7.20(m,2H),7.17-7.11(m,3H),6.46-6.41(m,1H),6.26(dd,J=11.3,2.7Hz,1H),5.91(d,J= 7.4Hz,1H),4.79-4.70(m,1H),4.10-4.06(m,2H),3.92(t,J=5.3Hz,2H),3.74-3.65(m,2H),3.62(t,J=5.1Hz,2H); LC / MS ESI(+): 345.0(M+1).

[0478] <Example 42> Synthesis of 6-fluoro-4-(4-fluorophenyl)-N-(1-isopropylazetidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0479] The N- (azetidine -3- bases) -6- fluoro- 4- (4- fluorophenyl) -3,4- dihydroquinoxaline -1 (2H) -methane amide (1.0 equivalents) obtained in Example 41 is dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.5 equivalents) and acetone (2.0 equivalents) are added, and the resulting solution is stirred at room temperature for 1 hour. After the reaction is terminated by adding water, the reaction solution is extracted with dichloromethane. The organic layer is washed with salt water, dried with MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue is purified by silica column chromatography utilizing a mixture of n-hexane / ethyl acetate, thus synthesizing 6- fluoro- 4- (4- fluorophenyl) -N- ((1- methylpiperidin-4-yl) methyl) -3,4- dihydroquinoxaline -1 (2H) -methane amide.

[0480] White solid (yield: 39%); 1 H NMR (400MHz, CDCl3) δ7.25-7.21(m,2H),7.16-7.10(m,3H),6.45-6.40(m,5H),6.25(dd,J=11.3,2.7Hz,1H),5.94-5.67(m,1H),4.54-4.45 LC / MS ESI(+): 387.2(M+1).

[0481] <Example 43> Synthesis of 6-fluoro-4-(4-fluorophenyl)-N-(1-isobutylazetidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0482] 6-Fluoro-4-(4-fluorophenyl)-N-(1-isobutylazetidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 42, except that isobutyraldehyde was used instead of acetone.

[0483] White solid (yield: 56%); 1 H NMR (400MHz, CDCl3) δ7.25-7.21(m,2H),7.16-7.11(m,3H),6.45-6.41(m,1 H),6.26(dd,J=11.3,2.7Hz,1H),5.59-5.47(m,1H),4.54-4.46(m,1H),3.9 1(t,J=5.1Hz,2H),3.69-3.63(m,2H),3.62(t,J=5.1Hz,2H),2.95-2.80(m, 2H), 2.25 (d, J = 7.0Hz, 2H), 1.63-1.53 ​​(m, 1H), 0.87 (d, J = 6.7Hz, 6H); LC / MS ESI(+): 401.2(M+1).

[0484] <Example 44> Synthesis of N-(1-acetylazetidin-3-yl)-6-fluoro-4-(4-fluorophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0485] The N- (azetidine -3- bases) -6- fluoro- 4- (4- fluorophenyl) -3,4- dihydroquinoxaline -1 (2H) -methane amide (1.0 equivalents) obtained in Example 41 was dissolved in THF (0.3M), TEA (2.5 equivalents) and acetyl chloride (1.8 equivalents) were added, and the resulting solution was stirred at room temperature for 4.5 hours. After the reaction was terminated by adding water, the reaction solution was extracted with dichloromethane. The organic layer was washed with brine, dried with MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a dichloromethane / methanol mixture, thereby synthesizing N- (1- acetylazetidine -3- bases) -6- fluoro- 4- (4- fluorophenyl) -3,4- dihydroquinoxaline -1 (2H) -methane amide.

[0486] White solid (yield: 37%); 1H NMR (400MHz, CDCl3) δ7.25-7.20(m,2H),7.17-7.11(m,3H),6.46-6.42(m,1H),6.27(dd,J=11.3,2.7Hz,1H),5.59(d,J=6.7Hz,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=5.1Hz,2H),1.88(s,3H); LC / MS ESI(+): 387.1(M+1).

[0487] [Reaction Scheme 15]

[0488]

[0489] <Preparation Example a-16> Preparation of tert-butyl 3-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)azetidine-1-carboxylate

[0490] Tert-butyl 3-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)azetidine-1-carboxylate was prepared in the same manner as in Preparation Example a-5, except that 1-Boc-3-(aminomethyl)azetidine was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[0491] White solid (yield: 81%); 1 H NMR (400MHz, CD3OD) δ7.36-7.28(m,2H),7.26-7.11(m,3H),6.51-6.40(m,1H),6.19(dd,J=11.4,2.8Hz,1H),3.98(dd,J=8. 5,8.5Hz,2H),3.87(brs,2H),3.77-3.67(m,2H),3.66-3.61(m,2H),3.41(d,J=6.3Hz,2H),2.87-2.71(m,1H),1.44(s,9H).

[0492] <Example 45> Synthesis of 6-fluoro-4-(4-fluorophenyl)-N-((1-methylazetidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0493] 3-((6-fluoro-4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-formamido)methyl)azetidine-1-carboxylic acid tert-butyl ester (1.0 equivalents) obtained in Preparation Example a-16 was dissolved in dichloromethane (0.3M), TFA (10 equivalents) was added, and the resulting solution was stirred at room temperature for 24 hours. After the reaction was terminated by adding water, the reaction solution was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained concentrate was dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After the reaction was terminated by adding water, the reaction solution 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, thereby synthesizing 6-fluoro-4-(4-fluorophenyl)-N-((1-methylazetidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0494] Ivory solid (yield: 2%); 1 H NMR (400MHz, CD3OD) δ7.36-7.27(m,2H),7.26-7.16(m,3H),6.45(ddd,J=8.8,8.0,2.8Hz,1H),6.20(dd,J=11.4,2.8Hz,1H),4.20-4.08(m,2 LC / MS ESI(+): 373.1(M+1).

[0495] <Example 46> Synthesis of 6-fluoro-4-(4-fluorophenyl)-N-((1-isopropylazetidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0496] 6-Fluoro-4-(4-fluorophenyl)-N-((1-isopropylazetidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 45, except that acetone was used instead of formaldehyde.

[0497] White solid (yield: 25%); 1H NMR (400MHz, CD3OD) δ7.36-7.25(m,2H),7.24-7.14(m,3H),6.45(ddd,J=8.8,8.0,2.8Hz,1H),6.20(dd,J=11.4,2.8Hz,1H),3.86(dd,J=5. 8,4.5Hz,2H),3.76-3.60(m,4H),3.37(d,J=6.5Hz,2H),3.33(brs,1H),2.84-2.71(m,2H),1.39-1.22(m,1H),1.04(d,J=6.3Hz,6H); LC / MS ESI(+): 401.2(M+1).

[0498] <Example 47> Synthesis of 6-fluoro-4-(4-fluorophenyl)-N-((1-isobutylazetidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0499] 6-Fluoro-4-(4-fluorophenyl)-N-((1-isobutylazetidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 45, except that isobutyraldehyde was used instead of formaldehyde.

[0500] White solid (yield: 27%); 1 H NMR (400MHz, CD3OD) δ7.36-7.26(m,2H),7.25-7.14(m,3H),6.45(ddd,J=8.9,8.0,2. 8Hz, 1H), 6.20 (dd, J=11.4, 2.8Hz, 1H), 3.86 (dd, J=5.8, 4.5Hz, 2H), 3.76 (dd, J=8.2, 1.6Hz,2H),3.64(dd,J=5.8,4.6Hz,2H),3.47-3.35(m,4H),2.96-2.81(m,1H),2.62( d, J=7.1Hz, 2H), 1.84-1.69 (m, 1H), 0.93 (d, J=6.7Hz, 6H); LC / MSESI(+): 415.2(M+1).

[0501] [Reaction Scheme 16]

[0502]

[0503] <Example 48> Synthesis of 6-fluoro-4-(4-fluorophenyl)-N-((tetrahydrofuran-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0504] 6-Fluoro-4-(4-fluorophenyl)-N-((tetrahydrofuran-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Preparation Example a-5, except that (tetrahydrofuran-3-yl)methanamine was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[0505] White solid (yield: 57%); 1 H NMR (400MHz, CDCl3) δ7.26-7.17(m,2H),7.16-7.05(m,3H),6.41(ddd,J=8. 7,7.7,2.8Hz,1H),6.26(dd,J=11.4,2.8Hz,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).

[0506] [Reaction Scheme 17]

[0507]

[0508] <Preparation method b> Preparation of 1-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline

[0509] The 1-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline according to the present invention was prepared by the following Preparation Examples b-1 to b-4.

[0510] <Preparation Example b-1> Preparation of N-(4-fluorophenyl)-2-nitroaniline

[0511] N-(4-Fluorophenyl)-2-nitroaniline was prepared in the same manner as in Preparation Example a-1, except that 1-fluoro-2-nitrobenzene was used instead of 2,4-difluoro-1-nitrobenzene.

[0512] Yellow solid (yield: 30%); 1 H NMR (400MHz, CDCl3) δ9.40 (s, 1H), 8.21 (dd, J = 8.6, 1.6Hz, 1H), 7.38-7.34 (m, 1H), 7.27-7.2 2(m,2H),7.15-7.09(m,2H),7.05(dd,J=8.6,1.2Hz,1H),6.77(ddd,J=8.4,6.8,1.2Hz,1H).

[0513] Preparation Example b-2> N 1 Preparation of -(4-fluorophenyl)benzene-1,2-diamine

[0514] N-(4-fluorophenyl)-2-nitroaniline was prepared in the same manner as in Preparation Example a-2, except that N-(4-fluorophenyl)-2-nitroaniline obtained in Preparation Example b-1 was used instead of 5-fluoro-N-(4-fluorophenyl)-2-nitroaniline. 1 -(4-fluorophenyl)benzene-1,2-diamine.

[0515] Orange solid (yield: 61%); 1 H NMR (400MHz, CDCl3) δ7.06 (dd, J=7.8, 1.2Hz, 1H), 7.01 (td, J=7.6, 1.2Hz, 1H), 6.95-6.89 (m, 2H), 6.81(dd,J=7.8,1.2Hz,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).

[0516] <Preparation Example b-3> Preparation of 1-(4-fluorophenyl)quinoxaline-2,3(1H,4H)-dione

[0517] In addition to using the N obtained in Preparation Example b-2 1 -(4-Fluorophenyl)benzene-1,2-diamine instead of 5-fluoro-N 1 1-(4-Fluorophenyl)quinoxaline-2,3(1H,4H)-dione was prepared in the same manner as in Preparation Example a-3 except for 1-phenylbenzene-1,2-diamine.

[0518] White solid (yield: 81%); 1 H LC / MS ESI(+): 256.6(M+1).

[0519] <Preparation Example b-4> Preparation of 1-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline

[0520] 1-(4-Fluorophenyl)-1,2,3,4-tetrahydroquinoxaline was obtained in the same manner as in Preparation Example a-4, except that 1-(4-fluorophenyl)quinoxaline-2,3(1H,4H)-dione obtained in Preparation Example b-3 was used instead of 7-fluoro-1-phenylquinoxaline-2,3(1H,4H)-dione.

[0521] Brown solid (yield: 38%); 1 H NMR (400MHz, CDCl3) δ7.18-7.13(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).

[0522] [Reaction Scheme 18]

[0523]

[0524] Preparation Example b-5 Preparation of tert-butyl (S)-3-(4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate

[0525] 1- (4- fluorophenyl) -1,2,3,4- tetrahydroquinoxaline (200mg, 0.88mmol) obtained in Preparation Example b-4 was dissolved in dichloromethane (8.0mL), TEA (0.5mL, 3.50mmol) and triphosgene (156mg, 0.53mmol) were slowly added at 0°C, and the resulting solution was stirred at 0°C for 1 hour. TEA (0.5mL, 3.50mmol) and (S) -(-) -1-Boc-3- aminopyrrolidine (0.2mL, 1.31mmol) were added, and the resulting solution was stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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, thereby synthesizing (S)-tert-butyl 3-(4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate.

[0526] Yellow oil (yield: 98%); 1H NMR (400MHz, CDCl3) δ7.25-7.19(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=6.9Hz,1H),4.4 5-4.40(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).

[0527] Example 49: Synthesis of (S)-4-(4-fluorophenyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0528] (S) -3- (4- (4- fluorophenyl) -1,2,3,4- tetrahydroquinoxaline -1- formamido) tert-butyl pyrrolidine -1- carboxylate (100 mg, 0.23 mmol) obtained in Preparation Example b-5 was dissolved in dichloromethane (0.7 mL), TFA (-170.030.0 μL, 2.27 mmol) was added, and the resulting solution was stirred at room temperature for 24 hours. After the reaction was terminated by adding water, the reaction solution 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 mixture of n-hexane / ethyl acetate to synthesize (S) -4- (4- fluorophenyl) -N- (pyrrolidin-3-yl) -3,4- dihydroquinoxaline -1 (2H) -carboxamide.

[0529] White solid (yield: 31%); 1 H NMR(400MHz, CDCl3)δ8.12(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=8.1Hz,1H),6.30(d,J=7.2Hz, 1H),4.62-4.57(m,1H),3.93(t,J=5.0Hz,2H),3.64(t,J=5.2Hz,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).

[0530] [Reaction Scheme 19]

[0531]

[0532] Preparation Example b-6 Preparation of tert-butyl 4-(4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)piperidine-1-carboxylate

[0533] tert-Butyl 4-(4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)piperidine-1-carboxylate was synthesized in the same manner as in Preparation Example b-5, except that 1-Boc-4-aminopiperidine was used instead of (S)-(-)-1-Boc-3-aminopyrrolidine.

[0534] White solid (yield: 85%); 1 H NMR (400MHz, CDCl3) δ7.24-7.19(m,2H),7.16-7.07(m,3H),6.93-6.86(m,1H),6.73-6.69(m,1H),6.62(d,J=8.2Hz,1H),5.23(d ,J=7.4Hz,1H),4.09-3.82(m,5H),3.63(t,J=5.1Hz,1H),2.97-2.85(m,2H),2.00-1.90(m,2H),1.45(s,9H),1.37-1.24(m,2H).

[0535] <Example 50> Synthesis of 4-(4-fluorophenyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0536] The Boc group of tert-butyl 4-(4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)piperidine-1-carboxylate obtained in Preparation Example b-6 was deprotected with TFA to synthesize 4-(4-fluorophenyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0537] White solid (yield: 49%); 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).

[0538] [Reaction Scheme 20]

[0539]

[0540] Example 51: Synthesis of (S)-4-(4-fluorophenyl)-N-(tetrahydrofuran-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0541] (S)-4-(4-Fluorophenyl)-N-(tetrahydrofuran-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Preparation Example b-5, except that (S)-3-aminotetrahydrofuran was used instead of (S)-(-)-1-Boc-3-aminopyrrolidine.

[0542] Brown solid (yield: 67%); 1 H NMR (400MHz, CDCl3) δ7.25-7.20(m,2H),7.16(dd,J=7.9,1.5Hz,1H),7.13-7.07(m, 2H),6.90(ddd,J=8.4,7.2,1.5Hz,1H),6.75-6.70(m,1H),6.62(dd,J=8.3,1.3Hz,1H ),5.48(d,J=6.9Hz,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=5.2Hz,1H),2.32-2.24(m,1H),1.82-1.77(m,1H); LC / MS ESI(+): 342.2(M+1).

[0543] <Example 52> Synthesis of 4-(4-fluorophenyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0544] 4-(4-Fluorophenyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Preparation Example b-5, except that 4-aminomethyltetrahydropyran was used instead of (S)-(-)-1-Boc-3-aminopyrrolidine.

[0545] Light yellow solid (yield: 74%); 1 H NMR (400MHz, CDCl3) δ7.25-7.21(m,3H),7.15-7.09(m,2H),6.95-6.91(m,1H),6.79-6.74(m,1H),6.66(dd,J=8.3,1.3Hz,1H),5.48(t,J=5.8Hz,1 H),4.03-3.94(m,4H),3.67-3.64(m,2H),3.44-3.37(m,2H),3.21(t,J=6 .4Hz,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).

[0546] [Reaction Scheme 21]

[0547]

[0548] Preparation Example b-7 Preparation of tert-butyl (R)-3-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate

[0549] (R)-tert-butyl 3-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate was prepared in the same manner as in Preparation Example b-5, except that (R)-1-Boc-3-(aminomethyl)pyrrolidine was used instead of (S)-(-)-1-Boc-3-aminopyrrolidine.

[0550] White solid (yield: 91%); 1H NMR (400MHz, CDCl3) δ7.25-7.12(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=5.9Hz,1H),4.01-3.86(m, 2H),3.62(t,J=5.2Hz,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).

[0551] Example 53: Synthesis of (S)-4-(4-fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0552] The Boc group of (R)-3-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester obtained in Preparation Example b-7 was deprotected with TFA to synthesize (S)-4-(4-fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0553] White solid (yield: 56.4%); 1 H NMR (400MHz, CDCl3) δ7.24-7.18(m,2H),7.17(dd,J=7.9,1.6Hz,1H),7.13-7.05(m,2H),6.94-6 .86(m,1H),6.77-6.69(m,1H),6.62(dd,J=8.3,1.4Hz,1H),5.65(t,J=5.7Hz,1H),3.93(t,J=5. 2Hz,2H),3.63(t,J=5.1Hz,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).

[0554] Example 54: Synthesis of (R)-4-(4-fluorophenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0555] (S) -4- (4- fluorophenyl) -N- (pyrrolidin-3-ylmethyl) -3,4- dihydroquinoxaline -1 (2H) -methane amide (80 mg, 0.23 mmol) obtained in Example 53 was dissolved in dichloromethane (1.0 mL), sodium triacetoxyborohydride (62 mg, 0.29 mmol) and formaldehyde (19.8 μL, 0.25 mmol) were added, and the resulting solution was stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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 mixture of n-hexane / ethyl acetate to prepare (R) -4- (4- fluorophenyl) -N- ((1- methylpyrrolidin-3-yl) methyl) -3,4- dihydroquinoxaline -1 (2H) -methane amide.

[0556] Light yellow oil (yield: 76.9%); 1 H NMR (400MHz, CDCl3) δ7.24-7.03(m,5H),6.93-6.83(m,1H),6.76-6.68(m,1 H),6.62(dd,J=8.3,1.4Hz,1H),4.05-3.94(m,1H),3.93-3.82(m,1H),3.63 (t,J=5.2Hz,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).

[0557] Example 55: Synthesis of (R)-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0558] (R)-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 54, except that acetone was used instead of formaldehyde.

[0559] Pale yellow oil (yield: 56.9%); 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, 4.6H z,1H),3.65-3.61(m,2H),3.36-3.21(m,2H),2.69-2.58(m,2H),2.51(q,J=6.6Hz,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=9.8,6.3Hz,6H);LC / MS ESI(+): 397.2(M+1).

[0560] Example 56: Synthesis of (R)-4-(4-fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0561] (R)-4-(4-fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 54, except that isobutyraldehyde was used instead of formaldehyde.

[0562] Light yellow oil (yield: 91.7%); 1 H NMR (400MHz, CDCl3) δ7.27-7.04(m,5H),6.95-6.83(m,1H),6.78-6.67(m,1H),6.63( dd,J=8.3,1.4Hz,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 / MSESI(+): 411.2(M+1).

[0563] [Reaction Scheme 22]

[0564]

[0565] Preparation Example b-8 Preparation of (R)-2-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0566] (R)-tert-butyl 2-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate was prepared in the same manner as in Preparation Example b-5, except that (R)-1-Boc-2-(aminomethyl)pyrrolidine was used instead of (S)-(-)-1-Boc-3-aminopyrrolidine.

[0567] Light yellow solid (yield: 93%); 1 H NMR (400MHz, CDCl3) δ7.35-7.26(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).

[0568] Example 57: Synthesis of (R)-4-(4-fluorophenyl)-N-(pyrrolidin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0569] The Boc group of tert-butyl (R)-2-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate obtained in Preparation Example b-8 was deprotected with TFA to synthesize (R)-4-(4-fluorophenyl)-N-(pyrrolidin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0570] Yellow oil (yield: 65%); 1H NMR (400MHz, CDCl3) δ7.24-7.19(m,3H),7.12-7.06(m,2H),6.91-6.87(m,1H),6 .75-6.70(m,1H),6.62(dd,J=8.3,1.3Hz,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).

[0571] [Reaction Scheme 23]

[0572]

[0573] Preparation Example b-9 Preparation of tert-butyl (R)-3-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate

[0574] (R)-tert-butyl 3-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate was prepared in the same manner as in Preparation Example b-5, except that (R)-1-Boc-3-(aminomethyl)pyrrolidine was used instead of (S)-(-)-1-Boc-3-aminopyrrolidine.

[0575] White solid (yield: 70%); 1 H NMR (400MHz, CDCl3) δ7.24-7.20(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=5.1Hz,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).

[0576] Preparation Example b-10 Preparation of (R)-4-(4-fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0577] The Boc group of tert-butyl (R)-3-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate obtained in Preparation Example b-9 was deprotected with TFA to prepare (R)-4-(4-fluorophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0578] White solid (yield: 70%); 1 H NMR (400MHz, CDCl3) δ7.22-7.17(m,3H),7.12-7.06(m,2H),6.91-6.87(m,1H),6.75 -6.70(m,1H),6.62(dd,J=8.3,1.3Hz,1H),5.69(t,J=5.4Hz,1H),3.92(t,J=5.1Hz, 2H),3.62(t,J=5.1Hz,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).

[0579] Example 58: Synthesis of (S)-4-(4-fluorophenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0580] The (R) -4- (4- fluorophenyl) -N- (pyrrolidin-3-ylmethyl) -3,4- dihydroquinoxaline -1 (2H) - carboxamide (1.0 equivalent) obtained in Preparation Example b-10 was dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After the reaction was terminated by adding water, the reaction solution 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- dihydroquinoxaline -1 (2H) - carboxamide.

[0581] Yellow oil (yield: 67%); 1H NMR (400MHz, CDCl3) δ7.23-7.17(m,3H),7.13-7.07(m,2H),6.91-6.87(m,1H),6.74- 6.70(m,1H),6.63(dd,J=8.3,1.3Hz,1H),6.10-6.00(m,1H),4.03-3.97(m,1H),3.91 -3.85(m,1H),3.63(t,J=5.1Hz,2H),3.35-3.23(m,2H),2.65-2.59(m,1H),2.55-2.5 0(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).

[0582] Example 59: Synthesis of (S)-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0583] (S)-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 58, except that acetone was used instead of formaldehyde.

[0584] Colorless oil (yield: 71%); 1 H NMR (400MHz, CDCl3) δ7.23-7.17(m,3H),7.12-7.05(m,2H),6.90-6.85(m,1H),6.74-6.70(m ,1H),6.63(dd,J=8.3,1.3Hz,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=9.8,6.4Hz,6H); LC / MS ESI(+): 397.3(M+1).

[0585] Example 60: Synthesis of (S)-4-(4-fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0586] (S)-4-(4-fluorophenyl)-N-((1-isobutylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 58, except that isobutyraldehyde was used instead of formaldehyde.

[0587] Colorless oil (yield: 69%); 1 H NMR (400MHz, CDCl3) δ7.23-7.17(m,3H),7.12-7.05(m,2H),6.90-6.85(m,1H),6.74-6 .69(m,1H),6.61(dd,J=8.3,1.3Hz,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=6.6Hz,3H),0.73(d,J=6.6Hz,3H); LC / MS ESI(+): 411.3(M+1).

[0588] [Reaction Scheme 24]

[0589]

[0590] <Preparation Example b-11> Preparation of tert-butyl 3-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)azetidine-1-carboxylate

[0591] Tert-butyl 3-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)azetidine-1-carboxylate was prepared in the same manner as in Preparation Example b-5, except that 1-Boc-3-(aminomethyl)azetidine was used instead of (S)-(-)-1-Boc-3-aminopyrrolidine.

[0592] Light yellow solid (yield: 92%); 1HNMR (400MHz, CDCl3) δ7.26-7.20(m,2H),7.17-7.09(m,3H),6.95-6.90(m,1H),6.77-6.72(m,1H),6.64(dd,J=8.3,1.3Hz,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).

[0593] <Example 61> Synthesis of 4-(4-fluorophenyl)-N-((1-isobutylazetidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0594] tert-Butyl 3-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-formamido)methyl)azetidine-1-carboxylate (1.0 equivalents) obtained in Preparation Example b-11 was dissolved in dichloromethane (0.3M), TFA (10.0 equivalents) was added, and the resulting solution was stirred at room temperature for 24 hours. After the reaction was terminated by adding water, the reaction solution was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained concentrate was dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.5 equivalents) and isobutyraldehyde (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After the reaction was terminated by adding water, the reaction solution 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, thereby synthesizing 4-(4-fluorophenyl)-N-((1-isobutylazetidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0595] Colorless oil (yield: 19%); 1H NMR (400MHz, CDCl3) δ7.24-7.18 (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, 1.3Hz, 1H), 5.85 (t, J = 5.2Hz, 1H), 3.69-3.65 (m, 2H), 3.64-3.62(m,2H),3.44(t,J=5.7Hz,2H),3.31-3.27(m,2H),2.91-2.88(m,2H),2.69 -2.59(m,1H),2.17(d,J=7.1Hz,2H),1.58-1.48(m,1H),0.81(d,J=6.6Hz,6H); LC / MS ESI(+): 396.5(M+1).

[0596] [Reaction Scheme 25]

[0597]

[0598] Preparation Example b-12 Preparation of tert-butyl 4-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate

[0599] Tert-butyl 4-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate was prepared in the same manner as in Preparation Example b-5, except that 1-Boc-4-(aminomethyl)piperidine was used instead of (S)-(-)-1-Boc-3-aminopyrrolidine.

[0600] White solid (yield: 67%); 1 H NMR (400MHz, CDCl3) δ7.22-7.16(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=4.4Hz,2H),3.63(t,J=5.1Hz,2H),3.17(t,J=5.4Hz,2 H),2.76-2.62(m,2H),1.72-1.65(m,3H),1.45(s,9H),1.18-1.08(m,2H).

[0601] <Example 62> Synthesis of 4-(4-fluorophenyl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0602] The Boc group of tert-butyl 4-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate obtained in Preparation Example b-12 was deprotected with TFA to synthesize 4-(4-fluorophenyl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0603] White solid (yield: 96%); 1 H NMR (400MHz, CDCl3) δ7.23-7.17(m,3H),7.12-7.07(m,2H),6.93-6.88(m,1H),6.76-6.72(m,1H),6.66(dd,J=8.3,1.3Hz,1H),5.45(t,J=5.9Hz, 2H),3.96-3.93(m,2H),3.64-3.62(m,2H),3.18-3.09(m,4H),2.65-2.5 8(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).

[0604] <Example 63> Synthesis of 4-(4-fluorophenyl)-N-((1-isopropylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0605] 4-(4-Fluorophenyl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (1.0 equivalent) obtained in Example 62 was dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.5 equivalents) and acetone (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After the reaction was terminated by adding water, the reaction solution 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-(4-fluorophenyl)-N-((1-isopropylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0606] Light yellow solid (yield: 81%); 1H NMR (400MHz, CDCl3) δ7.23-7.17(m,3H),7.12-7.07(m,2H),6.92-6.88(m,1H),6.75-6.7 1(m,1H),6.63(dd,J=8.3,1.3Hz,1H),5.44(t,J=5.7Hz,1H),3.96-3.93(m,2H),3.64-3. 62(m,2H),3.17(t,J=6.3Hz,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=6.6Hz,6H); LC / MS ESI(+): 411.3(M+1).

[0607] Example 64: Synthesis of 4-(4-fluorophenyl)-N-((1-isobutylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0608] 4-(4-fluorophenyl)-N-((1-isobutylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 63, except that isobutyraldehyde was used instead of acetone.

[0609] Light yellow solid (yield: 69%); 1 H NMR (400MHz, CDCl3) δ7.23-7.17(m,3H),7.12-7.07(m,2H),6.92-6.88(m,1H),6.75-6.71(m, 1H),6.63(dd,J=8.3,1.3Hz,1H),5.43(t,J=5.8Hz,1H),3.96-3.93(m,2H),3.64-3.62(m,2H), 3.17(t,J=6.3Hz,2H),2.89-2.83(m,2H),2.05(d,J=7.4Hz,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=6.5Hz,6H); LC / MS ESI(+): 425.3(M+1).

[0610] [Reaction Scheme 26]

[0611]

[0612] <Preparation Method c> Preparation of 7-fluoro-1-phenyl-1,2,3,4-tetrahydroquinoxaline

[0613] 7-Fluoro-1-phenyl-1,2,3,4-tetrahydroquinoxaline according to the present invention was synthesized by the following Preparation Examples c-1 to c-4.

[0614] <Preparation Example c-1> Preparation of 5-fluoro-2-nitro-N-phenylaniline

[0615] A 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 the reaction was terminated by adding water, the reaction solution was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO 4 , filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a n-hexane / ethyl acetate mixture to prepare 5-fluoro-2-nitro-N-phenylaniline.

[0616] Yellow solid (yield: 63%); 1 H NMR (400MHz, CDCl3) δ9.65 (s, 1H), 8.26 (dd, J = 9.4, 5.9Hz, 1H), 7.448-7.43 (m, 2H), 7.31-7.26(m,3H),6.80(dd,J=11.3,2.3Hz,1H),6.48(ddd,J=9.5,6.9,2.7Hz,1H).

[0617] <Preparation Example c-2> 5-Fluoro-N 1 Preparation of phenylbenzene-1,2-diamine

[0618] The mixed solution of 5-fluoro-2-nitro-N-phenylaniline (1.0 equivalent) and tin chloride (II) dihydrate (3.0 equivalent) obtained in Preparation Example c-1 was dissolved in ethyl acetate (0.5M) and stirred for 5 hours at 90°C. After the reaction solution was cooled to room temperature, it was poured into water, neutralized with a 10M NaOH aqueous solution, and then extracted with ethyl acetate. The organic layer was washed with salt water, dried with MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography utilizing a n-hexane / ethyl acetate mixture to prepare 5-fluoro-N-phenylaniline. 1 -phenylbenzene-1,2-diamine.

[0619] Brown oil (yield: 86%); 1LC / MS ESI(+):202.7(M+1).

[0620] <Preparation Example c-3> Preparation of 7-fluoro-1-phenylquinoxaline-2,3(1H,4H)-dione

[0621] The 5-fluoro-N 1 A reaction solution of 1-phenylbenzene-1,2-diamine (1.0 equivalent) dissolved in diethyl oxalate (6.0 equivalent) was stirred at 160° C. for 24 hours. The reaction solution was cooled to room temperature, filtered, and dried to prepare 7-fluoro-1-phenylquinoxaline-2,3(1H,4H)-dione.

[0622] White solid (yield: 86%); 1 H NMR(400MHz,DMSO-d6)δ12.11(s,1H),7.64-7.54(m,3H),7.40-7.38(m,2H),7.2 2(dd,J=8.8,5.3Hz,1H),7.04-6.68(m,1H),5.99(dd,J=10.2,2.7Hz,1H); LC / MS ESI(+): 256.6(M+1).

[0623] <Preparation Example c-4> Preparation of 7-fluoro-1-phenyl-1,2,3,4-tetrahydroquinoxaline

[0624] Borane-THF complex (1M) (3.0 equivalents) is slowly added to a solution of 7-fluoro-1-phenylquinoxaline-2,3 (1H, 4H)-dione (1.0 equivalents) obtained in Preparation Example c-3 dissolved in THF (0.5M) at room temperature and stirred at 65°C for 16 hours. After the reaction solution was cooled to room temperature, water was added to terminate the reaction, and the reaction solution was neutralized with a saturated NaHCO3 aqueous 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 n-hexane / ethyl acetate mixture to prepare 7-fluoro-1-phenyl-1,2,3,4-tetrahydroquinoxaline.

[0625] Brown solid (yield: 38%); 1H NMR (400MHz, CDCl3) δ7.38-7.34(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).

[0626] Example 65: Synthesis of (R)-6-fluoro-4-phenyl-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0627] The 7-fluoro-1-phenyl-1,2,3,4-tetrahydroquinoxaline (120 mg, 0.52 mmol) obtained in preparation example c-4 was dissolved in dichloromethane (5.0 mL), TEA (220.0 μL, 1.57 mmol) and triphosgene (78 mg, 0.26 mmol) were slowly added at 0 ° C, and the resulting solution was stirred 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 then stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution was extracted with dichloromethane. The obtained concentrate was dissolved in dichloromethane (2.0 mL), TFA (-490.0 μL, 5.20 mmol) was added, and the resulting solution was stirred at room temperature for 24 hours. After the reaction was terminated by adding water, the reaction solution was extracted with dichloromethane. The organic layer was washed with salt water, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a n-hexane / ethyl acetate mixture to synthesize (R)-6-fluoro-4-phenyl-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-methaneamide.

[0628] White solid (yield: 60.6%); 1H NMR (400MHz, CDCl3) δ7.49-7.32(m,2H),7.25-7.19(m,3H),7.13-7.09(m,1 H),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).

[0629] [Reaction Scheme 27]

[0630]

[0631] <Preparation Method d> Preparation of Chloro-substituted Phenyl or Pyridine-1,2,3,4-tetrahydroquinoxaline

[0632] The chloro-substituted phenyl or pyridine-1,2,3,4-tetrahydroquinoxaline according to the present invention was prepared by the following Preparation Examples d-1 to d-11.

[0633] <Preparation Example d-1> Preparation of tert-butyl 3,4-dihydroquinoxaline-1(2H)-carboxylate

[0634] 0.02M NaOH aqueous solution (50mL) is added to a mixed solution of 1,2,3,4-tetrahydroquinoxaline (10.8g, 80.48mmol) and di-tert-butyl dicarbonate (18.5mL, 80.48mmol) dissolved in THF (200mL), and stirred at room temperature for 24 hours. The reaction solution is concentrated under reduced pressure, then extracted with dichloromethane. The organic layer is dried with MgSO4, filtered, then concentrated under reduced pressure. The obtained residue is purified by silica column chromatography utilizing n-hexane / ethyl acetate mixture, thus preparing 3,4-dihydroquinoxaline-1 (2H)-tert-butyl formates.

[0635] Yellow solid (yield: 94%); 1H NMR (400MHz, DMSO-d6) δ7.29(d,J=8.1Hz,1H),6.79(ddd,J=8.5,7.2,1.5Hz,1H),6.54(dd,J=8.0,1.5Hz ,1H),6.45(ddd,J=8.5,7.2,1.5Hz,1H),6.01(s,1H),3.60-3.53(m,2H),3.27-3.20(m,2H),1.44(s,9H).

[0636] <Preparation Example d-2> Preparation of tert-butyl 4-benzyl-3,4-dihydroquinoxaline-1(2H)-carboxylate

[0637] Benzyl bromide (1.7 g, 10.24 mmol) was added to a mixture solution of tert-butyl 3,4-dihydroquinoxaline-1 (2H)-formate (2.0 g, 8.54 mmol) and DIPEA (4.4 g, 34.15 mmol) obtained in Preparation Example d-1, dissolved in DMF (15.0 mL), and stirred at 130 ° C for 2 hours. The reaction solution was cooled to room temperature, 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 a mixture of n-hexane / ethyl acetate to prepare tert-butyl 4-benzyl-3,4-dihydroquinoxaline-1 (2H)-formate.

[0638] Brown oil (yield: 98.9%); 1 H NMR (400MHz, CD3CN) δ7.40-7.29(m,3H),7.28--7.19(m,3H),6.84(ddd,J=8.6,7.3,1.6Hz ,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).

[0639] <Preparation Example d-3> Preparation of 1-benzyl-1,2,3,4-tetrahydroquinoxaline

[0640] A mixture solution of tert-butyl 4-benzyl-3,4-dihydroquinoxaline-1(2H)-formate (2.7 g, 8.40 mmol) and TFA (6.4 mL, 84.00 mmol) obtained in Preparation Example d-2 was dissolved in (15.0 mL) and stirred at room temperature for 12 hours. After the reaction, the reaction solution was concentrated under reduced pressure by adding toluene, water was added, and the resulting solution 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 mixture of n-hexane / ethyl acetate to prepare 1-benzyl-1,2,3,4-tetrahydroquinoxaline.

[0641] Brown solid (yield: 80%); 1 H NMR (400MHz, CD3CN) δ7.37-7.19(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).

[0642] <Preparation Example d-4> Preparation of 1-benzyl-4-(2-chlorophenyl)-1,2,3,4-tetrahydroquinoxaline

[0643] 1-benzyl-1,2,3,4-tetrahydroquinoxaline (1.0 equivalent), sodium butoxide (2.0 equivalent) and 1-chloro-2-iodobenzene (3.0 equivalent) obtained in Preparation Example d-3 were fully dissolved in toluene (0.3M). A mixed solution of Pd2dba (0.05 equivalent) and Xphos (0.15 equivalent) dissolved in toluene (0.6M) (which had been heated at 110°C for 5 minutes) was slowly added to the reaction solution and then stirred at 110°C for 15 hours. After cooling to room temperature, the reaction solution was filtered through a diatomaceous earth pad, water was added, and the resulting solution was extracted with dichloromethane. The organic layer was dried with MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a mixture of n-hexane / ethyl acetate to prepare 1-benzyl-4-(2-chlorophenyl)-1,2,3,4-tetrahydroquinoxaline.

[0644] Colorless oil (yield: 99%); 1H NMR(400MHz, DMSO-d6)δ7.57(dd,J=8.0,1.4Hz,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, 1.9Hz, 1H), 5.99 (dd, J=8.0, 0.9Hz, 1H), 3.72-3.59 (m, 2H), 3.57-3.42 (m, 2H); LC / MS ESI(+): 335.1(M+1).

[0645] <Preparation Example d-5> Preparation of 1-benzyl-4-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline

[0646] 1-Benzyl-4-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline was prepared in the same manner as in Preparation Example d-4, except that 2-bromopyridine was used instead of 1-chloro-2-iodobenzene.

[0647] Yellow solid (yield: 73%); 1 H NMR (400MHz, DMSO-d6) δ8.22(dd,J=5.1,1.2Hz,1H),7.53(ddd,J=8.7,6.9,1.9Hz,1 H),7.35-7.19(m,5H),7.15(dd,J=7.8,1.6Hz,1H),7.03(d,J=8.6Hz,1H),6.86(ddd ,J=8.6,7.3,1.5Hz,1H),6.77(dd,J=7.0,5.5Hz,1H),6.70(dd,J=8.2,1.2Hz,1H),6 .60-6.53(m,1H),4.65-4.50(m,2H),4.10-4.02(m,2H),3.40(t,J=5.1Hz,2H); LC / MS ESI(+): 302.2(M+1).

[0648] <Preparation Example d-6> Preparation of 1-benzyl-4-(pyridin-3-yl)-1,2,3,4-tetrahydroquinoxaline

[0649] 1-Benzyl-4-(pyridin-3-yl)-1,2,3,4-tetrahydroquinoxaline was prepared in the same manner as in Preparation Example d-4, except that 3-iodopyridine was used instead of 1-chloro-2-iodobenzene.

[0650] Yellow oil (yield: 100%); 1H NMR (400MHz, CD3CN) δ8.46(d,J=2.7Hz,1H),8.19(dd,J=4.7,1.2Hz,1H),7.50(ddd,J=8.4,2.9,1.6Hz,1H),7.40-7.31(m,4H),7.30-7.24(m,2H) ,6.82(dd,J=8.2,1.6Hz,1H),6.78-6.72(m,1H),6.70-6.65(m,1H),6.5 5-6.49(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).

[0651] <Preparation Example d-7> Preparation of 1-benzyl-4-(pyridin-4-yl)-1,2,3,4-tetrahydroquinoxaline

[0652] 1-Benzyl-4-(pyridin-4-yl)-1,2,3,4-tetrahydroquinoxaline was prepared in the same manner as in Preparation Example d-4, except that 4-iodopyridine was used instead of 1-chloro-2-iodobenzene.

[0653] Red oil (yield: 100%); 1 H NMR (400MHz, DMSO-d6) δ8.26-8.19(m,2H),7.31(dd,J=8.1,6.8Hz,2H),7.26-7.18(m,3H),7.09(dd,J=7.9,1.5Hz,1H),7.05-6.99(m,2H),6.8 9(ddd,J=8.6,7.2,1.5Hz,1H),6.73(dd,J=8.3,1.3Hz,1H),6.62-6.53(m,1H),4.56(s,2H),3.84(q,J=5.9Hz,2H),3.40(t,J=5.1Hz,2H); LC / MS ESI(+): 302.2(M+1).

[0654] <Preparation Example d-8> Preparation of 1-(2-chlorophenyl)-1,2,3,4-tetrahydroquinoxaline

[0655] A mixed solution of 1-benzyl-4-(2-chlorophenyl)-1,2,3,4-tetrahydroquinoxaline (1.0 equivalent) obtained in Preparation Example d-4 and Pd(OH)2 (0.6 equivalent) was dissolved in MeOH / THF (v / v=2:1, 0.3M) and stirred at room temperature under hydrogen for 3 hours. The reaction solution was filtered through a celite pad, water was added, and the resulting solution was extracted 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 a n-hexane / ethyl acetate mixture to prepare 1-(2-chlorophenyl)-1,2,3,4-tetrahydroquinoxaline.

[0656] Gray solid (yield: 62%); 1 H NMR(400MHz, DMSO-d6)δ7.55(dd,J=8.0,1.4Hz,1H),7.43-7.35(m,1H),7.34-7.30(m,1H),7.28-7.21(m,1H),6.54-6.4 9(m,2H),6.31(ddd,J=8.2,5.1,3.5Hz,1H),5.96(d,J=7.8Hz,1H),3.54-3.46(m,2H),3.35(dd,J=4.9,2.2Hz,2H); LC / MS ESI(+): 245.1(M+1).

[0657] <Preparation Example d-9> Preparation of 1-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline

[0658] 1-(Pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline was prepared in the same manner as in Preparation Example d-8, except that 1-benzyl-4-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline obtained in Preparation Example d-5 was used instead of 1-benzyl-4-(2-chlorophenyl)-1,2,3,4-tetrahydroquinoxaline.

[0659] Yellow solid (yield: 78.2%); 1H NMR (400MHz, CDCl3) δ8.26(d,J=4.1Hz,1H),7.42(ddd,J=8.5,7.1,2.0Hz,1H),7.22(dd,J=8.4,1.5Hz,1H),7.16(d,J=8.5Hz,1H),6.93 LC / MS ESI(+):212.2(M+1).

[0660] <Preparation Example d-10> Preparation of 1-(pyridin-3-yl)-1,2,3,4-tetrahydroquinoxaline

[0661] 1-(Pyridin-3-yl)-1,2,3,4-tetrahydroquinoxaline was prepared in the same manner as in Preparation Example d-8, except that 1-benzyl-4-(pyridin-3-yl)-1,2,3,4-tetrahydroquinoxaline obtained in Preparation Example d-6 was used instead of 1-benzyl-4-(2-chlorophenyl)-1,2,3,4-tetrahydroquinoxaline.

[0662] Brown oil (yield: 83.1%); 1 H NMR (400MHz, CD3CN) δ8.45(d,J=2.7Hz,1H),8.17(dd,J=4.7,1.6Hz,1H),7.50(ddd,J=8.3,2.8,1.8Hz,1H),7.26(dd,J=8.2,4. 7Hz,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).

[0663] <Preparation Example d-11> Preparation of 1-(pyridin-4-yl)-1,2,3,4-tetrahydroquinoxaline

[0664] 1-(Pyridin-4-yl)-1,2,3,4-tetrahydroquinoxaline was prepared in the same manner as in Preparation Example d-8, except that 1-benzyl-4-(pyridin-4-yl)-1,2,3,4-tetrahydroquinoxaline obtained in Preparation Example d-7 was used instead of 1-benzyl-4-(2-chlorophenyl)-1,2,3,4-tetrahydroquinoxaline.

[0665] Yellow solid (yield: 76.7%); 1H NMR (400MHz, DMSO-d6) δ8.25-8.18(m,2H),7.06-7.00(m,3H),6.85(ddd,J=8.4,7.2,1.4Hz,1H),6.65(dd,J= 8.1,1.5Hz,1H),6.50(ddd,J=8.0,7.2,1.5Hz,1H),6.09(s,1H),3.70-3.63(m,2H),3.29-3.21(m,2H); LC / MS ESI(+): 212.1(M+1).

[0666] [Reaction Scheme 28]

[0667]

[0668] Example 66: Synthesis of (4-(2-chlorophenyl)-3,4-dihydroquinoxaline-1(2H)-yl)(piperidin-1-yl)methanone

[0669] 1- (2- chlorophenyl) -1,2,3,4- tetrahydroquinoxaline (1.0 equivalent) obtained in Preparation Example d-8 was dissolved in dichloromethane (0.3M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0 ° C, and the resulting solution was stirred at 0 ° C for 1 hour. TEA (2.0 equivalents) and piperidine (1.2 equivalents) were added to the reaction solution, and then stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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 mixture of n-hexane / ethyl acetate to synthesize (4- (2- chlorophenyl) -3,4- dihydroquinoxaline -1 (2H) -yl) (piperidin-1-yl) ketone.

[0670] Light yellow oil (yield: 34.8%); 1 H NMR (400MHz, CDCl3) δ7.55-7.48(m,1H),7.36-7.31(m,2H),7.26-7.21(m,1H),7.02(dd,J=8.0,1.6Hz,1H),6.77-6.70(m,1H),6.69 LC / MS ESI(+): 342.2(M+1).

[0671] <Example 67> Synthesis of (4-(2-chlorophenyl)-3,4-dihydroquinoxaline-1(2H)-yl)(pyrrolidin-1-yl)methanone

[0672] (4-(2-chlorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(pyrrolidin-1-yl)methanone was synthesized in the same manner as in Example 66, except that pyrrolidine was used instead of piperidine.

[0673] Light yellow oil (yield: 54.5%); 1 H NMR (400MHz, CDCl3) δ7.54-7.49(m,1H),7.36-7.32(m,2H),7.28-7.26(m,1H),6.95(dd,J=7.9,1.6Hz,1H),6.77-6.70(m,1H),6.6 9-6.63(m,1H),6.19(dd,J=8.0,1.5Hz,1H),3.90(t,J=5.1Hz,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).

[0674] Example 68: Synthesis of (4-(2-chlorophenyl)-3,4-dihydroquinoxaline-1(2H)-yl)(4-methylpiperazin-1-yl)methanone

[0675] (4-(2-chlorophenyl)-3,4-dihydroquinoxalin-1(2H)-yl)(4-methylpiperazin-1-yl)methanone was synthesized in the same manner as in Example 66, except that N-methylpiperazine was used instead of piperidine.

[0676] Light yellow oil (yield: 51.6%); 1 H NMR (400MHz, CDCl3) δ7.53-7.48(m,1H),7.40-7.26(m,3H),7.05(dd,J=8.0,1.6Hz,1H),6.80-6.71(m,1H),6.70-6.62(m,1H),6.2 0(dd,J=8.1,1.5Hz,1H),3.87(t,J=5.0Hz,2H),3.70(t,J=4.3Hz,2H),3.46-3.39(m,4H),2.38(t,J=5.1Hz,5H),2.29(s,3H); LC / MS ESI(+): 371.2(M+1).

[0677] [Reaction Scheme 29]

[0678]

[0679] <Preparation Example d-12> Preparation of (S)-3-(4-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylic acid tert-butyl ester

[0680] 1- (pyridin-2-yl) -1,2,3,4-tetrahydroquinoxaline (1.0 equivalent) obtained in Preparation Example d-9 was dissolved in dichloromethane (0.3 M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0 ° C, and the resulting solution was 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 stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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 prepare (S)-tert-butyl 3-(4-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate.

[0681] White solid (yield: 97%); 1 H NMR (400MHz, CD3OD) δ8.25-8.24(m,1H),7.67-7.62(m,1H),7.45(dd,J=8.3,1.3Hz,1H ),7.34-7.32(m,1H),7.24-7.19(m,1H),7.10-7.01(m,2H),6.92(ddd,J=7.3,5.0,0.9H z,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).

[0682] Preparation Example d-13 Preparation of (S)-4-(pyridin-2-yl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0683] The Boc group of (S)-3-(4-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylic acid tert-butyl ester obtained in Preparation Example d-12 was deprotected with TFA to prepare (S)-4-(pyridin-2-yl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0684] White solid (yield: 48%); 1 H NMR (400MHz, CDCl3) δ8.32-8.30(m,1H),7.56-7.51(m,1H),7.47(dd,J=8.1,1.4Hz,1H),7.33(dd,J=7 .9,1.5Hz,1H),7.16-7.15(m,1H),7.08-7.03(m,1H),7.01-6.94(m,1H),6.84(ddd,J=7.2,4.9,0.8Hz ,1H),5.34(d,J=6.9Hz,1H),4.36-4.28(m,1H),4.03-3.94(m,4H),3.19-3.14(m,1H),3.05-2.99(m,1 LC / MS ESI(+): 324.2(M+1).

[0685] Example 69: Synthesis of (S)-N-(1-isopropylpyrrolidin-3-yl)-4-(pyridin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0686] (S) -4- (pyridin-2-yl) -N- (pyrrolidin-3-yl) -3,4- dihydroquinoxaline -1 (2H) -carboxamide (1.0 equivalent) obtained in Preparation Example d-13 was dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.5 equivalents) and acetone (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After the reaction was terminated by adding water, the reaction solution 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- dihydroquinoxaline -1 (2H) -carboxamide.

[0687] Light yellow oil (yield: 48%); 1H NMR (400MHz, CD3OD) δ8.25-8.21(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=7.2,5.1,0.9Hz,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,1 LC / MS ESI(+): 366.3(M+1).

[0688] [Reaction Scheme 30]

[0689]

[0690] <Preparation Example d-14> Preparation of (R)-3-(4-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylic acid tert-butyl ester

[0691] (R)-tert-butyl 3-((4-pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate was prepared in the same manner as in Preparation Example d-12, except that (R)-(+)-1-Boc-3-aminopyrrolidine was used instead of (S)-(-)-1-Boc-3-aminopyrrolidine.

[0692] Light yellow oil (yield: 89%); 1 H NMR (400MHz, CDCl3) δ8.33-8.27(m,1H),7.58-7.49(m,1H),7.46(dd,J=8.2,1. 4Hz,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=6.7Hz,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).

[0693] <Preparation Example d-15> Preparation of (R)-4-(pyridin-2-yl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0694] 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 Preparation Example d-14 was deprotected with TFA to prepare (R)-4-(pyridin-2-yl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0695] Ivory solid (yield: 99%); 1 H NMR(400MHz,DMSO-d6)δ13.04(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),7.47-7.3 6(m,4H),7.26-7.14(m,1H),5.10-4.71(m,1H),2.32(d,J=12.3Hz,1H),1.32-1.19(m,1H),1.03(d,J=6.7Hz,6H),0.90-0.81(m,1H); LC / MS ESI(+): 324.1(M+1).

[0696] Example 70: Synthesis of (R)-N-(1-acetylpyrrolidin-3-yl)-4-(pyridin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0697] (R) -4- (pyridin-2-yl) -N- (pyrrolidin-3-yl) -3,4- dihydroquinoxaline -1 (2H) -methane amide (1.0 equivalent) obtained in Preparation Example d-15 was dissolved in THF (0.3M), TEA (1.0 equivalent) and acetyl chloride (1.1 equivalent) were added, and the resulting solution was stirred at room temperature for 1.5 hours. After the reaction was terminated by adding water, the reaction solution 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) -methane amide.

[0698] Ivory solid (yield: 45%); 1H NMR (400MHz, CDCl3) δ8.33-8.27(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=6.2Hz,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=9.0Hz,3H),1.83-1.70(m,1H),1.28-1.20(m,1H); LC / MS ESI(+): 366.1(M+1).

[0699] [Reaction Scheme 31]

[0700]

[0701] Preparation Example d-16 Preparation of tert-butyl (R)-3-((4-pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate

[0702] (R)-tert-Butyl 3-((4-pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate was prepared in the same manner as in Preparation Example d-12, except that (R)-1-Boc-3-(aminomethyl)pyrrolidine was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[0703] Yellow oil (yield: 100%); 1H NMR (400MHz, CD3OD) δ8.24 (ddd, J=5.0, 2.0, 0.9Hz, 1H), 7.62 (ddd, J=8.5, 7.2, 2.0Hz, 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 .0,0.9Hz,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).

[0704] Example 71: Synthesis of (S)-4-(pyridin-2-yl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0705] 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 Preparation Example d-16 was deprotected with TFA to synthesize (S)-4-(pyridin-2-yl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0706] Yellow oil (yield: 100%); 1 H NMR(400MHz CD3OD)δ8.27-8.21(m,1H),7.64(ddd,J=8.5,7.2,2.0Hz,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=7.2,5.0,0.9H z,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).

[0707] [Reaction Scheme 32]

[0708]

[0709] Preparation Example d-17 Preparation of (R)-2-((4-pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0710] (R)-tert-butyl 3-((4-pyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate was prepared in the same manner as in Preparation Example d-12, except that (R)-1-Boc-2-(aminomethyl)pyrrolidine was used instead of (S)-(-)-1-Boc-3-aminopyrrolidine.

[0711] Yellow oil (yield: 100%); 1 H NMR (400MHz, CDCl3) δ8.32-8.26(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).

[0712] Example 72: Synthesis of (R)-4-(pyridin-2-yl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0713] 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 Preparation Example d-17 was deprotected with TFA to synthesize (R)-4-(pyridin-2-yl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0714] Yellow oil (yield: 100%); 1H NMR(400MHz,CD3OD)δ8.24(ddd,J=5.0,2.0,0.9Hz,1H),7.64(ddd,J=8.5,7.2,2.0Hz,1H),7 .50(dd,J=8.0,1.6Hz,1H),7.36(dd,J=8.0,1.5Hz,1H),7.20(dd,J=8.5,0.9Hz,1H),7.15-7. 00(m,3H),6.92(ddd,J=7.2,5.0,0.9Hz,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).

[0715] [Reaction Scheme 33]

[0716]

[0717] <Example 73>Synthesis of (R)-4-(pyridin-3-yl)-N-(tetrahydrofuran-3-yl)-3,4-dihydroquinoxaline-1(2H)-formamide 1-(pyridin-3-yl)-1,2,3,4-tetrahydroquinoxaline (1.0 equivalent) obtained in Preparation Example d-10 was dissolved in dichloromethane (0.3M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0°C, and the resulting solution was stirred at 0°C for 1 hour. TEA (2.0 equivalents) and (R)-3-aminotetrahydrofuran (1.2 equivalents) were added to the reaction solution and stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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, thereby synthesizing (R)-4-(pyridin-3-yl)-N-(tetrahydrofuran-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0718] Yellow solid (yield: 97%); 1H NMR (400MHz, CDCl3) δ8.58(d,J=2.4Hz,1H),8.41(dd,J=4.8,1.4Hz,1H),7.61-7.58(m,1H),7.34-7.31(m,1H),7.24-7.20(m,1H),6.98-6.93(m,1 H),6.84-6.82(m,2H),5.45(d,J=6.9Hz,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).

[0719] [Reaction Scheme 34]

[0720]

[0721] <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 equivalent) obtained in Preparation Example d-11 was dissolved in dichloromethane (0.3M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0°C, and the resulting solution was stirred at 0°C for 1 hour. TEA (2.0 equivalents) and cyclopropylmethylamine (1.2 equivalents) were added to the reaction solution and stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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, thereby synthesizing N-(cyclopropylmethyl)-4-(pyridin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0722] Light yellow solid (yield: 37%); 1 H NMR (400MHz, CDCl3) δ8.40-8.34(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,1 LC / MS ESI(+): 309.1(M+1).

[0723] [Reaction Scheme 35]

[0724]

[0725] Preparation Method e> Preparation of Halogen-Substituted Pyridine, Cyanophenyl or Pyrazine-1,2,3,4-Tetrahydroquinoxaline

[0726] The halogen-substituted pyridine, cyanophenyl or pyrazine-1,2,3,4-tetrahydroquinoxaline according to the present invention is prepared by the following Preparations e-1 to e-6.

[0727] <Preparation Example e-1> Preparation of tert-butyl 4-(5-fluoropyridin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate

[0728] The tert-butyl 3,4-dihydroquinoxaline-1 (2H)-formate (1.0 equivalent), sodium butoxide (2.0 equivalents) and 5-fluoro-2-bromopyridine (3.0 equivalents) obtained in Preparation Example d-1 were fully dissolved in toluene (0.3M). A mixed solution (which had been heated at 110°C for 5 minutes) in which Pd2 dba (0.05 equivalents) and Xphos (0.15 equivalents) were dissolved in toluene (0.6M) was slowly added to the reaction solution and stirred at 110°C for 15 hours. After cooling to room temperature, the reaction solution was filtered through a diatomaceous earth pad, water was added, and the resulting solution was extracted with dichloromethane. The organic layer was dried with MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture, thereby preparing tert-butyl 4-(5-fluoropyridin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate.

[0729] Red oil (yield: 93%); 1 H NMR (400MHz, CDCl3) δ8.14 (d, J = 3.0Hz, 1H), 7.79 (s, 1H), 7.25-7.20 (m, 2H), 7.19-7.1 2(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).

[0730] <Preparation Example e-2> Preparation of tert-butyl 4-(4-cyanophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate

[0731] tert-Butyl 4-(4-cyanophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate was prepared in the same manner as in Preparation Example e-1, except that 4-iodobenzonitrile was used instead of 2-bromo-3-fluoropyridine.

[0732] Yellow solid (yield: 89%); 1 H NMR(400MHz,CD3OD)δ7.68-7.61(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).

[0733] <Preparation Example e-3> Preparation of tert-butyl 4-(pyrazin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate

[0734] tert-Butyl 4-(pyrazin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate was prepared in the same manner as in Preparation Example e-1, except that 2-chloropyrazine was used instead of 2-bromo-3-fluoropyridine.

[0735] Orange solid (yield: 85%); 1 H NMR (400MHz, CDCl3) δ8.59(d,J=1.6Hz,1H),8.16(dd,J=2.7,1.5Hz,1H),7.98(d,J=2.7Hz,1H),7.84(d, J=8.0Hz,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).

[0736] <Preparation Example e-4> Preparation of 1-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline

[0737] The Boc group of tert-butyl 4-(5-fluoropyridin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate obtained in Preparation Example e-1 was deprotected with TFA to prepare 1-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline.

[0738] Red oil (yield: 91%); 1LC / MS ESI(+): 230.1(M+1).

[0739] <Preparation Example e-5> Preparation of 4-(3,4-dihydroquinoxaline-1(2H)-yl)benzonitrile

[0740] The Boc group of tert-butyl 4-(4-cyanophenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate obtained in Preparation Example e-2 was deprotected with TFA to prepare 4-(3,4-dihydroquinoxalin-1(2H)-yl)benzonitrile.

[0741] Yellow solid (yield: 89%); 1 H NMR(400MHz,CD3OD)δ7.56-7.47(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).

[0742] <Preparation Example e-6> Preparation of 1-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinoxaline

[0743] The Boc group of tert-butyl 4-(pyrazin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate obtained in Preparation Example e-3 was deprotected with TFA to prepare 1-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinoxaline.

[0744] Yellow oil (yield: 88%); 1 H NMR (400MHz, CDCl3) δ8.60(d,J=1.6Hz,1H),8.13(dd,J=2.7,1.6Hz,1H),7.92(d,J=2.7Hz,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).

[0745] [Reaction Scheme 36]

[0746]

[0747] Preparation Example e-7 Preparation of (R)-3-(4-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylic acid tert-butyl ester

[0748] 1- (5-fluoropyridin-2-yl) -1,2,3,4-tetrahydroquinoxaline (1.0 equivalent) obtained in Preparation Example e-4 was dissolved in dichloromethane (0.3M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0 ° C, and the resulting solution was 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 stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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 prepare (R)-tert-butyl 3-(4-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate.

[0749] Light yellow solid (yield: 95.5%); 1 H NMR (400MHz, CDCl3) δ8.18(d,J=3.0Hz,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).

[0750] Preparation Example e-8 Preparation of (R)-4-(5-fluoropyridin-2-yl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0751] The Boc group of (R)-3-(4-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylic acid tert-butyl ester obtained in Preparation Example e-7 was deprotected with TFA to prepare (R)-4-(5-fluoropyridin-2-yl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0752] Light yellow solid (yield: 68.9%); 1 H NMR(400MHz, CDCl3)δ8.17(d,J=3.0Hz,1H),7.38-7.28(m,3H),7.16(dd,J=9.1,3.6Hz ,1H),7.09-7.00(m,1H),6.98-6.91(m,1H),5.31(d,J=6.9Hz,1H),4.37-4.25(m,1H),4 .02-3.88(m,4H),3.16(dd,J=11.3,6.5Hz,1H),3.06-2.96(m,1H),2.95-2.85(m,1H), 2.77(dd,J=11.3,4.0Hz,1H),2.20-2.09(m,1H),2.01(s,1H),1.63-1.53(m,1H); LC / MS ESI(+): 342.2(M+1).

[0753] Example 75: Synthesis of (R)-4-(5-fluoropyridin-2-yl)-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0754] (R) -4- (5- fluoropyridin-2-yl) -N- (pyrrolidin-3-yl) -3,4- dihydroquinoxaline -1 (2H) -methane amide (1.0 equivalent) obtained in Preparation Example e-8 was dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.3 equivalents) and formaldehyde (1.1 equivalents) were added, and the resulting solution was stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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) -methane amide.

[0755] Light yellow oil (yield: 85.6%); 1H NMR (400MHz, CDCl3) δ8.17 (d, J = 3.0Hz, 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= 7.7Hz,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).

[0756] [Reaction Scheme 37]

[0757]

[0758] Preparation Example e-9 Preparation of (R)-tert-Butyl 3-((4-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate

[0759] (R)-3-((4-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester was prepared in the same manner as in Preparation Example e-7, except that (R)-1-Boc-3-(aminomethyl)pyrrolidine was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[0760] White solid (yield: 87.5%); 1 H NMR (400MHz, CDCl3) δ8.18 (d, J = 3.0Hz, 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), 3.5 5-3.32(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).

[0761] Preparation Example e-10 Preparation of (S)-4-(5-fluoropyridin-2-yl)-N-(1-pyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0762] The Boc group of (R)-3-((4-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester obtained in Preparation Example e-9 was deprotected with TFA to prepare (S)-4-(5-fluoropyridin-2-yl)-N-(1-pyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0763] Light yellow solid (yield: 83.1%); 1 H NMR (400MHz, CDCl3) δ8.17 (d, J = 3.0Hz, 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=5.5Hz,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).

[0764] Example 76: Synthesis of (R)-4-(5-fluoropyridin-2-yl)-N-(1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0765] (S) -4- (5- fluoropyridin-2-yl) -N- (1- pyrrolidin-3-yl) methyl) -3,4- dihydroquinoxaline -1 (2H) - carboxamide (1.0 equivalent) obtained in Preparation Example e-10 was dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.3 equivalents) and formaldehyde (1.1 equivalents) were added, and the resulting solution was stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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) methyl) -3,4- dihydroquinoxaline -1 (2H) - carboxamide.

[0766] Light yellow oil (yield: 83.7%); 1H NMR (400MHz, CDCl3) δ8.18 (d, J = 3.0Hz, 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),6.06-6.0 2(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).

[0767] [Reaction Scheme 38]

[0768]

[0769] Preparation Example e-11 Preparation of tert-butyl 4-((4-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate

[0770] Tert-butyl 4-((4-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate was prepared in the same manner as in Preparation Example e-7, except that 1-Boc-4-(aminomethyl)piperidine was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[0771] White solid (yield: 88.4%); 1 H NMR (400MHz, CDCl3) δ8.18(d,J=3.0Hz,1H),7.40-7.27(m,3H),7.18-7.11(m,1H),7.07(ddd,J=8.2,7.3,1.6Hz,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),2.7 5-2.55(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).

[0772] Preparation Example e-12 Preparation of 4-(5-fluoropyridin-2-yl)-N-(1-piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0773] 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 Preparation Example e-11 was deprotected with TFA to prepare 4-(5-fluoropyridin-2-yl)-N-(1-piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0774] Light yellow solid (yield: 78.8%); 1 H NMR (400MHz, CDCl3) δ8.17(d,J=3.0Hz,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),5.32-5.2 4(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).

[0775] Example 77 Synthesis of 4-(5-fluoropyridin-2-yl)-N-(1-methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0776] 4- (5- fluoropyridin-2-yl) -N- (1- piperidin-4-ylmethyl) -3,4- dihydroquinoxaline -1 (2H) - carboxamide (1.0 equivalent) obtained in Preparation Example e-12 was dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.3 equivalents) and formaldehyde (1.1 equivalents) were added, and the resulting solution was stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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- (5- fluoropyridin-2-yl) -N- (1- methylpiperidin-4-yl) methyl) -3,4- dihydroquinoxaline -1 (2H) - carboxamide.

[0777] White solid (yield: 88.5%); 1H NMR (400MHz, CDCl3) δ8.19-8.17 (m, 1H), 7.36 (dd, J = 8.2, 1.4Hz, 1H), 7.34-7.2 7(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).

[0778] [Reaction Scheme 39]

[0779]

[0780] Preparation Example e-13 Preparation of tert-butyl (S)-(1-(4-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)carbamate

[0781] (S)-tert-butyl (1-(4-(5-fluoropyridin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyrrolidin-3-yl)carbamate was prepared in the same manner as in Preparation Example e-7, except that (S)-(-)-3-(Boc-amino)pyrrolidine was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[0782] White solid (yield: 98.4%); 1 H NMR (400MHz, CDCl3) δ8.15 (d, J = 3.0Hz, 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).

[0783] Example 78: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(4-(5-fluoropyridin-2-yl)-3,4-dihydroquinoxaline-1(2H)-methanone

[0784] 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 Preparation Example e-13 was deprotected with TFA to synthesize (S)-(3-aminopyrrolidin-1-yl)(4-(5-fluoropyridin-2-yl)-3,4-dihydroquinoxaline-1(2H)-methanone.

[0785] White solid (yield: 71.5%); 1 H NMR (400MHz, CDCl3) δ8.15 (d, J = 3.0Hz, 1H), 7.36-7.28 (m, 1H), 7.26-7.20 ( m,1H),7.14(dd,J=9.2,3.6Hz,1H),7.07-7.01(m,1H),6.97-6.90(m,2H),4. 01(t,J=6.3Hz,2H),3.92-3.75(m,2H),3.58-3.31(m,4H),3.00(dd,J=10.3 ,4.5Hz,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).

[0786] [Reaction Scheme 40]

[0787]

[0788] Preparation Example e-14 Preparation of tert-butyl (R)-3-((4-(4-cyanophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate

[0789] 4-(3,4-dihydroquinoxaline-1(2H)-yl)benzonitrile (1.0 equivalent) obtained in Preparation Example e-5 was dissolved in dichloromethane (0.3M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0°C, and the resulting solution was stirred at 0°C for 1 hour. TEA (2.0 equivalents) and (R)-1-Boc-3-(aminomethyl)pyrrolidine (1.2 equivalents) were added to the reaction solution and stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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, thereby synthesizing tert-butyl (R)-3-((4-(4-cyanophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate.

[0790] Ivory solid (yield: 91%); 1 H NMR (400MHz, CD3OD) δ7.63-7.54(m,2H),7.39(d,J=8.0Hz,1H),7.35-7.27(m,2H),7.22(dd,J=7.9,1.7Hz,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=5.2Hz,9H).

[0791] Example 79: Synthesis of (S)-4-(4-cyanophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0792] The Boc group of tert-butyl (R)-3-((4-(4-cyanophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate obtained in Preparation Example e-14 was deprotected with TFA to synthesize (S)-4-(4-cyanophenyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0793] Ivory solid (yield: 17%); 1H NMR (400MHz, CD3OD) δ7.67-7.56(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 LC / MS ESI(+): 362.1(M+1).

[0794] [Reaction Scheme 41]

[0795]

[0796] Preparation Example e-15 Preparation of (S)-tert-Butyl 3-(4-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate

[0797] 1- (Pyrazin-2-yl) -1,2,3,4-tetrahydroquinoxaline (1.0 equivalent) obtained in Preparation Example e-6 was dissolved in dichloromethane (0.3M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0°C, and the resulting solution was 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 stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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 prepare (S)-tert-butyl 3-(4-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate.

[0798] Light yellow solid (yield: 87.6%); 1H NMR (400MHz, CDCl3) δ8.61 (d, J=1.5Hz, 1H), 8.21 (dd, J=2.6, 1.5Hz, 1H) 8.05 (d, J=2 .7Hz,1H),7.54(dd,J=8.1,1.5Hz,1H),7.32(dd,J=7.9,1.6Hz,1H),7.19-7.02(m,2H ),5.18(d,J=6.7Hz,1H),4.40(s,1H),4.07-3.91(m,4H),3.65(t,J=9.4Hz,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).

[0799] Example 80: Synthesis of (S)-4-(pyrazin-2-yl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0800] The Boc group of (S)-3-(4-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylic acid tert-butyl ester obtained in Preparation Example e-15 was deprotected with TFA to synthesize (S)-4-(pyrazin-2-yl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0801] Ivory solid (yield: 76.9%); 1 H NMR (400MHz, CDCl3) δ8.60(d,J=1.5Hz,1H),8.20(dd,J=2.7,1.6Hz,1H),8.03(d,J=2.7Hz,1H),7. 51(dd,J=7.9,1.6Hz,1H),7.37(dd,J=7.8,1.7Hz,1H),7.16-7.01(m,2H),5.29(d,J=6.9Hz,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),2.9 6-2.85(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).

[0802] Example 81: Synthesis of (S)-N-(1-isopropylpyrrolidin-3-yl)-4-(pyrazin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0803] (S) -4- (pyrazine-2-yl) -N- (pyrrolidin-3-yl) -3,4- dihydroquinoxaline -1 (2H) -carboxamide (1.0 equivalent) obtained in Example 80 was dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.5 equivalents) and acetone (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After the reaction was terminated by adding water, the reaction solution 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- (pyrazine-2-yl) -3,4- dihydroquinoxaline -1 (2H) -carboxamide.

[0804] Yellow solid (yield: 64.6%); 1 H NMR (400MHz, CH3CN) δ8.62 (d, J=1.6Hz, 1H), 8.20 (dd, J=2.7, 1.5Hz, 1H), 8.03 (d, J= 2.6Hz,1H),7.50(dd,J=7.9,1.6Hz,1H),7.39(dd,J=7.7,1.8Hz,1H),7.15-7.01(m, 2H),5.43(d,J=7.6Hz,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).

[0805] [Reaction Scheme 42]

[0806]

[0807] Preparation Example e-16 Preparation of tert-butyl (4-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)piperidine-1-carboxylate

[0808] Tert-butyl (4-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)piperidine-1-carboxylate was prepared in the same manner as in Preparation Example e-15, except that 1-Boc-4-aminopiperidine was used instead of (S)-(-)-1-Boc-3-aminopyrrolidine.

[0809] Light yellow solid (yield: 85.3%); 1 H NMR(400MHz, CDCl3) δ8.59(d,J=1.5Hz,1H),8.21(dd,J=2.7,1.5Hz,1H),8.04(d,J =2.6Hz,1H),7.53(dd,J=8.1,1.5Hz,1H),7.34(dd,J=7.8,1.6Hz,1H),7.17-7.02( m,2H),5.03(d,J=7.6Hz,1H),4.17-3.93(m,6H),3.92-3.78(m,1H),2.87(t,J=12. 9Hz,1H),1.99-1.88(m,2H),1.44(s,9H),1.35-1.21(m,2H); LC / MSESI(+): 425.2.

[0810] Preparation Example e-17 Preparation of N-(1-piperidin-4-yl)-4-(pyrazin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0811] The Boc group of tert-butyl (4-(pyrazin-2-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)piperidine-1-carboxylate prepared in Preparation Example e-16 was deprotected with TFA to prepare N-(1-piperidin-4-yl)-4-(pyrazin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0812] Light yellow solid (yield: 84.0%); 1 H NMR (400MHz, CDCl3) δ8.60 (dd, J=1.5, 0.4Hz, 1H), 8.20 (dd, J=2.7, 1.5Hz, 1H), 8. 04(dd,J=2.7,0.4Hz,1H),7.56-7.48(m,1H),7.40-7.32(m,1H),7.17-7.02(m,2H) ,5.06(d,J=7.7Hz,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).

[0813] <Example 82> Synthesis of N-(1-isobutylpiperidin-4-yl)-4-(pyrazin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0814] The N-(1-piperidin-4-yl)-4-(pyrazine-2-yl)-3,4-dihydroquinoxaline-1(2H)-formamide (1.0 equivalent) obtained in Preparation Example e-17 was dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.5 equivalents) and isobutyraldehyde (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After the reaction was terminated by adding water, the reaction solution 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-(pyrazine-2-yl)-3,4-dihydroquinoxaline-1(2H)-formamide.

[0815] Light yellow solid (yield: 81.8%) 1 H NMR(400MHz, CDCl3) δ8.60(d,J=1.5Hz,1H),8.20(dd,J=2.6,1.5Hz,1H),8.03(d,J=2.6Hz,1H) ,7.52(dd,J=8.0,1.5Hz,1H),7.36(dd,J=7.9,1.6Hz,1H),7.16-7.02(m,2H),5.05(d,J=7.7Hz, 1H),4.06-4.00(m,2H),4.00-3.93(m,2H),3.78-3.64(m,1H),2.72(d,J=10.9Hz,2H),2.09-1.9 7(m,4H),1.96-1.86(m,2H),1.80-1.66(m,1H),1.50-1.35(m,2H),0.86(d,J=6.5Hz,6H); LC / MS ESI(+): 395.3(M+1).

[0816] <Example 83> Synthesis of N-(1-isopropylpiperidin-4-yl)-4-(pyrazin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0817] N-(1-isopropylpiperidin-4-yl)-4-(pyrazin-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 82, except that acetone was used instead of isobutyraldehyde.

[0818] Light yellow solid (yield: 81.6%); 1H NMR (400MHz, CDCl3) δ8.59 (d, J=1.6Hz, 1H), 8.20 (dd, J=2.6, 1.5Hz, 1H), 8.03 (d, J=2.6Hz, 1H),7.52(dd,J=8.1,1.4Hz,1H),7.35(dd,J=7.9,1.6Hz,1H),7.15-7.00(m,2H),5.05(d,J= 7.7Hz,1H),4.06-3.92(m,4H),3.77-3.63(m,1H),2.78(d,J=11.9Hz,2H),2.74-2.63(m,1H ),2.25(t,J=2.6Hz,2H),2.04-1.94(m,2H),1.48-1.34(m,2H),1.02(d,J=6.6Hz,6H); LC / MS ESI(+): 381.3(M+1).

[0819] [Reaction Scheme 43]

[0820]

[0821] <Preparation method f> Preparation of benzyl or halogen-substituted benzyl-1,2,3,4-tetrahydroquinoxaline

[0822] The benzyl- or halogen-substituted benzyl-1,2,3,4-tetrahydroquinoxaline according to the present invention was prepared by the following Preparation Examples f-1 to f-6.

[0823] <Preparation Example f-1> Preparation of tert-butyl 4-(2-fluorobenzyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate

[0824] tert-Butyl 4-(2-fluorobenzyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate was prepared in the same manner as in Preparation Example d-2, except that 2-fluorobenzyl bromide was used instead of benzyl bromide.

[0825] Yellow oil (yield: 90%); 1 H NMR (400MHz, CDCl3) δ7.57-7.41(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, 4.5Hz, 2H), 1.55 (s, 9H).

[0826] <Preparation Example f-2> Preparation of tert-butyl 4-(4-fluorobenzyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate

[0827] tert-Butyl 4-(4-fluorobenzyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate was prepared in the same manner as in Preparation Example d-2, except that 2-fluorobenzyl bromide was used instead of benzyl bromide.

[0828] Yellow oil (yield: 95%); 1 H NMR (400MHz, CDCl3) δ7.53-7.45(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 = 1.3Hz, 2H), 3.89-3.82 (m, 2H), 3.51-3.40 (m, 2H), 1.55 (s, 9H).

[0829] <Preparation Example f-3> Preparation of tert-butyl 4-(4-chlorobenzyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate

[0830] tert-Butyl 4-(3-chlorobenzyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate was prepared in the same manner as in Preparation Example d-2, except that 4-chlorobenzyl bromide was used instead of benzyl bromide.

[0831] Light yellow oil (yield: 100%); 1 H NMR (400MHz, CDCl3) δ7.48 (d, J=8.1Hz, 1H), 7.31-7.27 (m, 2H), 7.21-7.15 (m, 2H), 6.91 (ddd, J=8.1, 7.3, 1.5Hz, 1H), 6.66 (ddd,J=8.4,7.2,1.3Hz,1H),6.58(dd,J=8.3,1.3Hz,1H),4.48(s,2H),3.87-3.80(m,2H),3.45-3.38(m,2H),1.53(s,9H).

[0832] <Preparation Example f-4> Preparation of 1-(2-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline

[0833] The Boc group of tert-butyl 4-(2-fluorobenzyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate obtained in Preparation Example f-1 was deprotected with TFA to prepare 1-(2-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline.

[0834] Gray solid (yield: 96%); 1H NMR (400MHz, CD3OD) δ7.37-7.22(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).

[0835] <Preparation Example f-5> Preparation of 1-(4-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline

[0836] The Boc group of tert-butyl 4-(4-fluorobenzyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate obtained in Preparation Example f-2 was deprotected with TFA to prepare 1-(2-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline.

[0837] Light brown solid (yield: 93%); 1 H NMR (400MHz, CD3OD) δ7.37-7.28(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).

[0838] <Preparation Example f-6> Preparation of 1-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinoxaline

[0839] The Boc group of tert-butyl 4-(3-chlorobenzyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate obtained in Preparation Example f-3 was deprotected with TFA to prepare 1-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinoxaline.

[0840] Light brown oil (yield: 94%); 1 H NMR(400MHz,DMSO-d6)δ7.42-7.32(m,2H),7.31-7.26(m,2H),6.47-6.32(m,4 H), 5.48 (s, 1H), 4.38 (s, 2H), 3.30 (d, J = 1.5Hz, 4H); LC / MSESI (+): 258.0 (M).

[0841] [Reaction Scheme 44]

[0842]

[0843] <Preparation Example f-7> Preparation of (R)-3-(4-benzyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylic acid tert-butyl ester

[0844] 1-Benzyl-1,2,3,4-tetrahydroquinoxaline (1.0 equivalent) obtained in Preparation Example d-3 was dissolved in dichloromethane (0.3M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0°C, and the resulting solution was 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 stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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 mixture of n-hexane / ethyl acetate to prepare (R)-3-(4-benzyl-1,2,3,4-tetrahydroquinoxaline-1-formamido)pyrrolidine-1-carboxylic acid tert-butyl ester.

[0845] Brown solid (yield: 100%); 1 H NMR (400MHz, CDCl3) δ7.36-7.27(m,2H),7.25-7.17(m,2H),7.08(d,J=7.8Hz,1H),7. 00-6.94(m,1H),6.71-6.59(m,2H),5.34(d,J=6.9Hz,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),3.2 0-3.04(m,1H),2.24-2.02(m,1H),1.94-1.64(m,1H),1.51-1.48(m,1H),1.45(s,9H).

[0846] <Example 84> Synthesis of (R)-4-benzyl-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0847] A mixed solution of (R) -3- (4-benzyl -1,2,3,4- tetrahydroquinoxaline -1- formamido) pyrrolidine -1- carboxylic acid tert-butyl ester (1.0 equivalents) and TFA (10.0 equivalents) obtained in Preparation Example f-7 was dissolved in dichloromethane (0.5M) and stirred at room temperature for 12 hours. After the reaction, the reaction solution was concentrated under reduced pressure by adding toluene, water was added, and the resulting solution 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 mixture of n-hexane / ethyl acetate to synthesize (R) -4-benzyl -N- (pyrrolidin-3-yl) -3,4- dihydroquinoxaline -1 (2H) -formamide.

[0848] Yellow solid (yield: 49%); 1 H NMR (400MHz, CDCl3) δ7.36-7.27(m,3H),7.25-7.18(m,3H),7.15-7.09(m,1H),6. 97(ddd,J=8.6,7.3,1.6Hz,1H),6.70-6.61(m,2H),5.41(d,J=6.8Hz,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).

[0849] [Reaction Scheme 45]

[0850]

[0851] Example 85: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(4-benzyl-3,4-dihydroquinoxaline-1(2H)-yl)methanone

[0852] 1-Benzyl-1,2,3,4-tetrahydroquinoxaline (1.0 equivalent) obtained in Preparation Example d-3 was dissolved in dichloromethane (0.4M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0°C, and the resulting solution was stirred 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 stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained concentrate was dissolved in dichloromethane (0.5M), TFA (10.0 equivalents) was added and stirred at room temperature for 24 hours. After the reaction was terminated by adding water, the reaction solution was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO 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 synthesize (S)-(3-aminopyrrolidin-1-yl)(4-benzyl-3,4-dihydroquinoxaline-1(2H)-yl)methanone.

[0853] Yellow oil (yield: 23%); 1H NMR (400MHz, CD3OD) δ7.36-7.15(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).

[0854] Example 86: Synthesis of (S)-(4-benzyl-3,4-dihydroquinoxaline-1(2H)-yl)(3-(methylamino)pyrrolidin-1-yl)methanone

[0855] 1-Benzyl-1,2,3,4-tetrahydroquinoxaline (1.0 equivalent) obtained in Preparation Example d-3 was dissolved in dichloromethane (0.3 M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0 ° C, and the resulting solution was stirred 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 stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution was extracted with dichloromethane. The ivory solid obtained by washing the organic layer with brine, drying it with MgSO4, filtering it, and then concentrating it under reduced pressure was dissolved in THF (0.3 M), NaH (1.5 equivalents) and iodomethane (1.0 equivalents) were added, and the resulting solution was stirred at room temperature for 3 hours. After the reaction is stopped by adding water, the reaction solution is extracted with dichloromethane, washed with salt water, and MgSO is dried, filtered, and under reduced pressure concentrated. The light brown oil obtained is dissolved in dichloromethane (0.5M), TFA (10.0 equivalent) is added and stirred at room temperature for 3 hours, and after the reaction is stopped by adding water, extracted with dichloromethane. The organic layer is washed with salt water, and MgSO is dried, filtered, and under reduced pressure concentrated. The residue obtained is purified by the silica column chromatography utilizing normal hexane / ethyl acetate mixture, thus synthesizing (S)-(4-benzyl-3,4-dihydroquinoxaline-1 (2H)-yl) (3-(methylamino) pyrrolidin-1-yl) ketone.

[0856] Yellow oil (yield: 47%); 1H NMR (400MHz, CD3OD) δ7.35-7.16(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 LC / MS ESI(+): 351.3(M+1).

[0857] [Reaction Scheme 46]

[0858]

[0859] Preparation Example f-8 Preparation of (R)-3-(4-(2-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylic acid tert-butyl ester

[0860] 1- (2- fluorobenzyl) -1,2,3,4- tetrahydroquinoxaline (1.0 equivalent) obtained in Preparation Example f-4 was dissolved in dichloromethane (0.3 M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0 ° C, and the resulting solution was 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 stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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, thereby preparing (R)-tert-butyl 3-(4-(2-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate.

[0861] White solid (yield: 98%); 1 H NMR (400MHz, CDCl3) δ7.32-7.22(m,1H),7.20-7.05(m,5H),7.05-6.96(m,1H),6.72-6.65(m,2H),5.36(d,J=6.9Hz,1H),4.62(s,2H) ,4.46-4.39(m,1H),3.95-3.86(m,3H),3.67(d,J=7.2Hz,1H),3.51-3.37(m,3H),3.23-3.10(m,1H),1.85-1.72(m,1H),1.48(s,9H).

[0862] Preparation Example f-9 Preparation of (R)-4-(2-fluorobenzyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0863] The Boc group of (R)-3-(4-(2-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylic acid tert-butyl ester obtained in Preparation Example f-8 was deprotected with TFA to prepare (R)-4-(2-fluorobenzyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0864] White solid (yield: 98%); 1 H NMR (400MHz, CDCl3) δ7.32-7.21(m,1H),7.15-7.05(m,3H),7.05-6.94(m,1H),6 .73-6.59(m,2H),5.55(d,J=6.7Hz,1H),4.61(s,2H),4.44-4.32(m,1H),3.98-3 .81(m,2H),3.46(dt,J=9.2,5.2Hz,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).

[0865] Example 87: Synthesis of (R)-4-(2-fluorobenzyl)-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0866] The (R) -4- (2- fluorobenzyl) -N- (pyrrolidin-3-yl) -3,4- dihydroquinoxaline -1 (2H) - carboxamide (1.0 equivalent) obtained in Preparation Example f-9 was dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After the reaction was terminated by adding water, the reaction solution 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.

[0867] Light yellow oil (yield: 81%);1 H NMR (400MHz, CDCl3) δ7.32-7.21(m,1H),7.19-7.03(m,4H),7.02-6.94(m, 1H),6.72-6.62(m,2H),5.54(d,J=7.5Hz,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=5.2Hz,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).

[0868] [Reaction Scheme 47]

[0869]

[0870] <Preparation Example f-10> Preparation of tert-butyl 4-(4-(2-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)piperidine-1-carboxylate

[0871] tert-Butyl 4-(4-(2-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)piperidine-1-carboxylate was prepared in the same manner as in Preparation Example f-8, except that 1-Boc-4-aminopiperidine was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[0872] White solid (yield: 98%); 1 H NMR (400MHz, CDCl3) δ7.32-7.21(m,1H),7.17-6.96(m,5H),6.72-6.63(m,2H),5.21(d,J=7.7Hz,1H),4.62(s,2H),4.00 (s,2H),3.95-3.82(m,3H),3.47(t,J=5.2Hz,2H),2.97-2.86(m,2H),2.00-1.91(m,2H),1.47(s,9H),1.38-1.23(m,2H).

[0873] <Preparation Example f-11> Preparation of 4-(2-fluorobenzyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0874] The Boc group of tert-butyl 4-(4-(2-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)piperidine-1-carboxylate obtained in Preparation Example f-10 was deprotected with TFA to prepare 4-(2-fluorobenzyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0875] White solid (yield: 97%); 1 H NMR (400MHz, CDCl3) δ7.36-7.21(m,1H),7.19-7.04(m,4H),7.04-6.96(m,1H),6.72-6.64(m,2H),5.24(d,J=7.8Hz,1H),4.62(s,2H),3.90(dd, LC / MS ESI(+): 369.1(M+1).

[0876] <Example 88> Synthesis of 4-(2-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0877] 4-(2-fluorobenzyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-formamide (1.0 equivalent) obtained in Preparation Example f-11 was dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After the reaction was terminated by adding water, the reaction solution 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)-3,4-dihydroquinoxaline-1(2H)-formamide.

[0878] White solid (yield: 90%); 1H NMR (400MHz, CDCl3) δ7.32-7.21(m,1H),7.19-6.96(m,5H),6.71-6.63(m,2H),5.22(d,J=7.8Hz,1H),4.62(s,2H),3.90(t,J=5.2Hz,2H), 3.81-3.65(m,1H),3.47(t,J=5.2Hz,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).

[0879] [Reaction Scheme 48]

[0880]

[0881] Preparation Example f-12 Preparation of tert-butyl 4-((4-(2-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate

[0882] Tert-butyl 4-((4-(2-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate was prepared in the same manner as in Preparation Example f-8, except that 1-Boc-4-(aminomethyl)piperidine was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[0883] Yellow oil (yield: 99%); 1 H NMR (400MHz, CDCl3) δ7.32-7.21(m,1H),7.19-6.98(m,5H),6.74-6.65(m,2H),5.43(t,J=6.0Hz,1H),4.62(s,2H),3.90(t,J=5. 1Hz,2H),3.47(t,J=5.2Hz,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).

[0884] <Preparation Example f-13> Preparation of 4-(2-fluorobenzyl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0885] The Boc group of tert-butyl 4-((4-(2-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate obtained in Preparation Example f-12 was deprotected with TFA to prepare 4-(2-fluorobenzyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0886] Light yellow solid (yield: 81%); 1 H NMR (400MHz, CDCl3) δ7.19-7.12(m,2H),7.10-7.06(m,2H),7.03-6.98(m,1H),6.74-6.64(m,2 H),5.50-5.38(m,1H),7.32-7.21(m,1H),4.62(s,2H),3.90(td,J=5.2,2.8Hz,2H),3.29(d,J= 4.1Hz,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- .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).

[0887] <Example 89> Synthesis of 4-(2-fluorobenzyl)-N-((1-methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0888] The 4-(2-fluorobenzyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-formamide (1.0 equivalent) obtained in Preparation Example f-13 was dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After terminating the reaction by adding water to the reaction solution, 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 4-(2-fluorobenzyl)-N-((1-methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-formamide.

[0889] Light yellow oil (yield: 85%); 1H NMR (400MHz, CDCl3) δ7.32-7.21(m,1H),7.19-7.06(m,4H),7.05-6.97(m,1H),6.74 -6.64(m,2H),5.43(t,J=6.0Hz,1H),4.62(s,2H),3.90(dd,J=6.6,3.8Hz,2H),3.47( t,J=5.2Hz,2H),3.18(t,J=6.3Hz,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 / MSESI(+): 397.3(M+1).

[0890] [Reaction Scheme 49]

[0891]

[0892] Preparation Example f-14 Preparation of (R)-tert-Butyl 3-((4-(2-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate

[0893] (R)-tert-butyl 3-((4-(2-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate was prepared in the same manner as in Preparation Example f-8, except that (S)-1-Boc-3-(aminomethyl)pyrrolidine was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[0894] Light yellow solid (yield: 98%); 1 H NMR (400MHz, CDCl3) δ7.32-7.21(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=5.6Hz,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).

[0895] Preparation Example f-15 Preparation of (S)-4-(2-fluorobenzyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0896] The Boc group of (R)-3-((4-(2-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester obtained in Preparation Example f-14 was deprotected with TFA to prepare (S)-4-(2-fluorobenzyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0897] Light yellow solid (yield: 89%); 1 H NMR (400MHz, CDCl3) δ7.32-7.21(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=5.8Hz,1H),4.60(d,J=8.1Hz,2H),3.89(t,J=5.2Hz,2H ),3.46(t,J=5.1Hz,2H),3.31-3.23(m,2H),3.27-3.10(m,2H),3.14-3.00(m,1H),2.90-2.8 1(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).

[0898] Example 90: Synthesis of (R)-4-(2-fluorobenzyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0899] (S) -4- (2- fluorobenzyl) -N- (pyrrolidin-3-ylmethyl) -3,4- dihydroquinoxaline -1 (2H) - carboxamide (1.0 equivalent) obtained in Preparation Example f-15 was dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After the reaction was terminated by adding water, the reaction solution 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- dihydroquinoxaline -1 (2H) - carboxamide.

[0900] Light yellow oil (yield: 85%); 1 H NMR (400MHz, CDCl3) δ7.32-7.21(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,1 H),3.91-3.78(m,1H),3.47(dd,J=5.9,4.6Hz,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).

[0901] [Reaction Scheme 50]

[0902]

[0903] Preparation Example f-16 Preparation of (R)-3-(4-(4-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylic acid tert-butyl ester

[0904] 1- (4- fluorobenzyl) -1,2,3,4- tetrahydroquinoxaline (1.0 equivalent) obtained in Preparation Example f-5 was dissolved in dichloromethane (0.3 M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0 ° C, and the resulting solution was 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 stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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 prepare (R)-tert-butyl 3-(4-(4-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate.

[0905] White solid (yield: 94%); 1H NMR (400MHz, CDCl3) δ7.23-7.07(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=6.9Hz,1H),3.44(t,J=5.2Hz,3H),3.16(s,1H),1.50-1.45(m,10H).

[0906] Example 91: Synthesis of (R)-4-(4-fluorobenzyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0907] The Boc group of (R)-3-(4-(4-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylic acid tert-butyl ester obtained in Preparation Example f-14 was deprotected with TFA to synthesize (R)-4-(4-fluorobenzyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0908] White solid (yield: 94%); 1 H NMR (400MHz, CDCl3) δ7.27-7.13(m,3H),7.11-6.93(m,3H),6.74-6.67(m,1H),6.70-6.60(m,1H),5.76(d,J=6.4Hz,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).

[0909] Example 92: Synthesis of (R)-4-(4-fluorobenzyl)-N-(1-isopropylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0910] (R) -4- (4- fluorobenzyl) -N- (pyrrolidin-3-yl) -3,4- dihydroquinoxaline -1 (2H) - carboxamide (1.0 equivalent) obtained in Example 91 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 equivalents) and acetone (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After the reaction was terminated by adding water, the reaction solution 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- (4- fluorobenzyl) -N- (1-isopropylpyrrolidin-3-yl) -3,4- dihydroquinoxaline -1 (2H) - carboxamide.

[0911] Light yellow oil (yield: 78%); 1 H NMR (400MHz, CDCl3) δ7.23-7.13(m,3H),7.10-6.94(m,3H),6.72-6.63(m,2H), 5.55(d,J=7.7Hz,1H),4.53(s,2H),4.00-3.89(m,1H),3.89-3.78(m,1H),3.42 (t,J=5.2Hz,2H),2.85(td,J=8.3,3.4Hz,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=6.3,5.2Hz,6H); LC / MS ESI(+):397.3(M+1).

[0912] [Reaction Scheme 51]

[0913]

[0914] Preparation Example f-17 Preparation of tert-butyl 4-(4-(4-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)piperidine-1-carboxylate

[0915] 1- (4- fluorobenzyl) -1,2,3,4- tetrahydroquinoxaline (1.0 equivalent) obtained in Preparation Example f-5 was dissolved in dichloromethane (0.3M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0 ° C, and the resulting solution was stirred at 0 ° C for 1 hour. TEA (2.0 equivalents) and 1-Boc-4-aminopiperidine (1.2 equivalents) were added to the reaction solution, and the resulting solution was stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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 mixture of n-hexane / ethyl acetate to prepare tert-butyl 4- (4- (4- fluorobenzyl) -1,2,3,4- tetrahydroquinoxaline -1- formamido) piperidine -1-carboxylate.

[0916] White solid (yield: 80%); 1 H NMR (400MHz, CDCl3) δ7.23-7.10(m,3H),7.08-6.95(m,3H),6.72-6.63(m,2H),4.54(s,2H),4.08-3.7 8(m,6H),3.43(t,J=5.2Hz,2H),2.96-2.86(m,2H),2.00-1.90(m,2H),1.47(s,9H),1.37-1.23(m,2H).

[0917] <Example 93> Synthesis of 4-(4-fluorobenzyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0918] The Boc group of tert-butyl 4-(4-(4-fluorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)piperidine-1-carboxylate obtained in Preparation Example f-17 was deprotected with TFA to synthesize 4-(4-fluorobenzyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0919] White solid (yield: 90%); 1H NMR (400MHz, CDCl3) δ7.23-7.08(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).

[0920] <Example 94> Synthesis of 4-(4-fluorobenzyl)-N-(1-isopropylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0921] 4-(4-Fluorobenzyl)-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (1.0 equivalent) obtained in Example 93 was dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.5 equivalents) and acetone (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After the reaction was terminated by adding water, the reaction solution 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-(4-fluorobenzyl)-N-(1-isopropylpiperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0922] Light yellow oil (yield: 58%); 1 H NMR (400MHz, CDCl3) δ7.23-7.10(m,3H),7.08-6.95(m,3H),6.71-6.60(m,2H),5.23(d,J=7.9Hz,1H),4.53(s,2H),3.88(dd,J=6.2,4.2Hz,2H),3 .81-3.67(m,1H),3.43(t,J=5.2Hz,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=6.5Hz,6H); LC / MS ESI(+): 411.3(M+1).

[0923] [Reaction Scheme 52]

[0924]

[0925] Preparation Example f-18 Preparation of (R)-3-(4-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylic acid tert-butyl ester

[0926] 1- (4-chlorobenzyl) -1,2,3,4-tetrahydroquinoxaline (1.0 equivalent) obtained in Preparation Example f-6 was dissolved in dichloromethane (0.3M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0 ° C, and the resulting solution was 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 resulting solution was stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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 prepare (R)-tert-butyl 3-(4-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate.

[0927] Brown oil (yield: 82%); 1 H NMR (400MHz, CDCl3) δ7.32-7.27(m,2H),7.14(d,J=8.3Hz,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=6.9Hz,1H),4.51(s, 2H),4.46-4.35(m,1H),3.95-3.76(m,2H),3.67(d,J=15.3Hz,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).

[0928] Example 95: Synthesis of (R)-4-(4-chlorobenzyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0929] The Boc group of (R)-3-(4-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylic acid tert-butyl ester obtained in Preparation Example f-18 was deprotected with TFA to synthesize (R)-4-(4-chlorobenzyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0930] White solid (yield: 27%); 1 H NMR (400MHz, CDCl3) δ7.31-7.27(m,2H),7.17-7.12(m,3H),7.00-6.94(m,1H) ,6.70-6.57(m,2H),5.50(d,J=6.7Hz,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),3.0 5-2.97(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).

[0931] [Reaction Scheme 53]

[0932]

[0933] <Preparation Method g> Preparation of 1-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroquinoxaline

[0934] The 1-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroquinoxaline according to the present invention was prepared by the following Preparation Example g-1.

[0935] <Preparation Example g-1> Preparation of 1-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroquinoxaline

[0936] 3,4-dihydroquinoxaline-1 (2H) -tert-butyl formate (3.5 g, 14.94 mmol) obtained in Preparation Example d-1 was dissolved in THF (25.0 mL), 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 and stirred at room temperature for 1 hour. After the reaction was terminated by adding water, the reaction solution was extracted with dichloromethane. The organic layer was washed with brine, dried with MgSO4, filtered, and then concentrated under reduced pressure. The obtained concentrate was dissolved in dichloromethane (20.0 mL), TFA (10.3 mL, 134.76 mmol) was added and stirred at room temperature for 24 hours. After the reaction was terminated by adding water, the reaction solution was extracted with dichloromethane. The organic layer was washed with brine, dried with MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture, thereby preparing 1-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroquinoxaline.

[0937] Light brown solid (yield: 86.7%); 1 H NMR(400MHz,CD3CN)δ8.54-8.47(m,1H),7.68-7.59(m,1H),7.29-7.22(m,1H),7.21-7.12(m,1 H),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).

[0938] [Reaction Scheme 54]

[0939]

[0940] Preparation Example g-2 Preparation of (S)-(3-aminopyrrolidin-1-yl)(4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-yl)methanone

[0941] 1-(Pyridin-2-ylmethyl)-1,2,3,4-tetrahydroquinoxaline (1.0 equivalent) obtained in Preparation Example g-1 was dissolved in dichloromethane (0.4M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0°C, and the resulting solution was stirred 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 resulting solution was stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and then concentrated under reduced pressure. The obtained concentrate was dissolved in dichloromethane (0.3M), TFA (10 equivalents) was added to the reaction solution, and the resulting solution was stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO 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 synthesize (S)-(3-aminopyrrolidin-1-yl)(4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-yl)methanone.

[0942] Yellow oil (yield: 70%); 1H NMR(400MHz,CD3OD)δ8.53-8.45(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),3.5 4-3.32(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).

[0943] Example 96: Synthesis of (S)-(3-(Isobutylamino)pyrrolidin-1-yl)(4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-yl)methanone

[0944] (S)-(3-aminopyrrolidin-1-yl)(4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-yl)methanone (1.0 equivalent) obtained in Preparation Example g-2 was dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.5 equivalents) and isobutyraldehyde (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After the reaction was terminated by adding water, the reaction solution 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, thereby synthesizing (S)-(3-(isobutylamino)pyrrolidin-1-yl)(4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-yl)methanone.

[0945] Light yellow oil (yield: 71%); 1H NMR(400MHz,CD3OD)δ8.55-8.42(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=4.3Hz,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=6.6,1.0Hz,6H); LC / MS ESI(+): 394.3(M+1).

[0946] Example 97: Synthesis of (S)-(3-(dimethylamino)pyrrolidin-1-yl)(4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-yl)methanone

[0947] (S)-(3-(dimethylamino)pyrrolidin-1-yl)(4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone was synthesized in the same manner as in Example 96, except that formaldehyde was used instead of isobutyraldehyde.

[0948] Light yellow oil (yield: 53%); 1 H NMR(400MHz,CD3OD)δ8.53-8.46(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).

[0949] [Reaction Scheme 55]

[0950]

[0951] Example 98: Synthesis of (R)-4-(pyridin-2-ylmethyl)-N-(tetrahydrofuran-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0952] 1- (pyridin-2-ylmethyl) -1,2,3,4-tetrahydroquinoxaline (1.0 equivalent) obtained in Preparation Example g-1 was dissolved in dichloromethane (0.3M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0°C, and the resulting solution was stirred at 0°C for 1 hour. TEA (2.0 equivalents) and (S) -3-aminotetrahydrofuran (1.2 equivalents) were added to the reaction solution, and the resulting solution was stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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, thereby synthesizing (R)-4-(pyridin-2-ylmethyl)-N-(tetrahydrofuran-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0953] Ivory solid (yield: 52%); 1 H NMR(400MHz,CD3OD)δ8.55-8.49(m,1H),7.77(dd,J=7.7,1.8Hz,1H),7.36-7.27(m,2 H),7.19(dd,J=7.9,1.5Hz,1H),6.93(dd,J=7.4,1.6Hz,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=4.7Hz,2H),2.30-2.16(m,1H),1.94-1.79(m,1H); LC / MSESI(+): 339.2(M+1).

[0954] <Example 99> Synthesis of N-(oxetane-3-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0955] N-(oxetan-3-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 98, except that 3-axetanamine was used instead of (S)-3-aminotetrahydrofuran.

[0956] White solid (yield: 77%); 1H NMR (400MHz, CD3CN) δ8.55-8.48(m,1H),7.64(ddd,J=7.7,7.7,1.8Hz,1H),7.24-7.15(m,3H),6.90(ddd,J=8.3,7.4,1.6Hz,1H),6.67-6.58(m ,2H),6.02(d,J=6.6Hz,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).

[0957] <Example 100> Synthesis of 4-(pyridin-2-ylmethyl)-N-((tetrahydrofuran-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0958] 4-(Pyridin-2-ylmethyl)-N-((tetrahydrofuran-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 98, except that (tetrahydrofuran-3-yl)methanamine was used instead of (S)-3-aminotetrahydrofuran.

[0959] White solid (yield: 51%); 1 H NMR (400MHz, CDCl3) δ8.59 (dd, J=4.9, 0.9Hz, 1H), 7.61 (ddd, J=7.7, 7.7, 1.8Hz, 1H ),7.23-7.09(m,3H),6.98(ddd,J=8.3,7.4,1.5Hz,1H),6.71-6.60(m,2H),5.47(t, J=5.8Hz,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).

[0960] Example 101: Synthesis of 4-(pyridin-2-ylmethyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0961] 4-(Pyridin-2-ylmethyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 98, except that 4-aminomethyltetrahydropyran was used instead of (S)-3-aminotetrahydrofuran.

[0962] Ivory solid (yield: 84%); 1 H NMR(400MHz,CD3CN)δ8.49(dd,J=4.9,1.0Hz,1H),7.62(ddd,J=7.7,7.7,1.8Hz,1H),7.23-7.08(m ,3H),6.88(ddd,J=8.6,7.3,1.6Hz,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=5.8,4.5Hz,2H),3.46(dd,J=5.7,4.5Hz,2H),3.27(ddd,J=11.8,11.8,2.2H z,2H),3.02(dd,J=6.8,6.0Hz,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).

[0963] Example 102 Synthesis of N-(cyclopropylmethyl)-4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[0964] N-(Cyclopropylmethyl)-4-(pyridin-2-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 98, except that cyclopropylmethylamine was used instead of (S)-3-aminotetrahydrofuran.

[0965] Light yellow solid (yield: 68%); 1H NMR (400MHz, CD3OD) δ8.52(dd,J=4.9,0.9Hz,1H),7.76(ddd,J=7.7,7.7,1.8Hz,1H),7.34-7.23( m,2H),7.19(dd,J=7.9,1.5Hz,1H),6.94(ddd,J=8.3,7.4,1.6Hz,1H),6.67(ddd,J=7.6,7.5,1.3 Hz,1H),6.61(dd,J=8.3,1.3Hz,1H),4.66(s,2H),3.84(dd,J=5.7,4.6Hz,2H),3.54(dd,J=5.8,4 .6Hz,2H),3.09(d,J=6.9Hz,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).

[0966] [Reaction Scheme 56]

[0967]

[0968] <Preparation Method h> Preparation of 4-(4-fluorophenyl)-1,2,3,4-tetrahydropyrido[3,4-b]pyrazine

[0969] The 4-(4-fluorophenyl)-1,2,3,4-tetrahydropyrido[3,4-b]pyrazine according to the present invention was prepared by the following Preparation Examples h-1 to h-4.

[0970] <Preparation Example h-1> Preparation of 3-((4-fluorophenyl)amino)-4-nitropyridine-1-oxide

[0971] A mixed solution in which 3-fluoro-4-nitropyridine 1-oxide (5.0 g, 31.6 mmol) and 4-fluoroaniline (10.5 g, 94.9 mmol) were dissolved in pyridine (28 mL) was stirred at 70° C. for 1 hour and cooled to room temperature. The precipitate generated by adding EtOH (30 mL) to the reaction solution was washed with EtOH and filtered to prepare 3-((4-fluorophenyl)amino)-4-nitropyridine-1-oxide.

[0972] Orange solid (yield: 90.3%); 1 H NMR (400MHz, DMSO-d6) δ9.56(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).

[0973] <Preparation Example h-2> Preparation of N3-(4-fluorophenyl)pyridine-3,4-diamine

[0974] Fe powder (9.4g, 168.0mmol) is added to 3-((4-fluorophenyl) amino)-4-nitropyridine-1-oxide (7.0g, 28.1mmol) obtained in preparation example h-1 and is dissolved in AcOH / H in a mixed solution in O (4:1=v / v, 50mL) and stirred at 100 DEG C for 3 hours. After the reaction solution is cooled to room temperature, it is filtered through a diatomaceous earth pad, adjusted to pH 12 with a 10M NaOH aqueous solution, and extracted with ethyl acetate. The organic layer obtained is washed with salt water, dried over MgSO, filtered, and concentrated under reduced pressure to prepare N3-(4-fluorophenyl) pyridine-3,4-diamine.

[0975] Purple oil (yield: 68.4%); 1 LC / MS ESI(+):204.0(M+1).

[0976] <Preparation Example h-3> Preparation of 4-(4-fluorophenyl)pyrido[3,4-b]pyrazine-2,3(1H,4H)-dione

[0977] N3-(4-fluorophenyl)pyridine-3,4-diamine (3.9 g, 19.2 mmol) obtained in Preparation Example h-2 was dissolved in diethyl oxalate (7.8 mL, 57.6 mmol) and stirred at 160° C. for 24 hours. The precipitate generated by cooling the reaction solution to room temperature and adding EtOH was washed with EtOH, filtered, and dried to prepare 4-(4-fluorophenyl)pyrido[3,4-b]pyrazine-2,3(1H,4H)-dione.

[0978] White solid (yield: 69.7%); 1 H NMR (400MHz, DMSO-d6) δ 12.37 (s, 1H), 8.23 ​​(d, J = 5.3Hz, 1H), 7.53-7.46 (m, 5H), 7.16 (d, J = 5.3Hz, 1H); LC / MS ESI (+): 258.0 (M+1).

[0979] <Preparation Example h-4> Preparation of 4-(4-fluorophenyl)-1,2,3,4-tetrahydropyrido[3,4-b]pyrazine

[0980] Borane-THF complex (1M) (23.3mL, 23.3mmol) is slowly added to a solution of 4-(4-fluorophenyl)pyrido[3,4-b]pyrazine-2,3(1H,4H)-dione (1.0g, 3.89mmol) obtained in Preparation Example h-3 dissolved in THF (30mL) at room temperature and stirred at 65°C for 16 hours. After the reaction solution was cooled to room temperature, water was added to terminate the reaction, and the reaction product was neutralized with a saturated NaHCO3 aqueous 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 prepare 4-(4-fluorophenyl)-1,2,3,4-tetrahydropyrido[3,4-b]pyrazine.

[0981] White solid (yield: 43.1%); 1 H NMR (400MHz, CDCl3) δ7.80 (d, J = 5.3Hz, 2H), 7.18-7.09 (m, 2H), 7.08-6.99 (m, 2H) ,6.42(d,J=5.3Hz,1H),4.38(s,1H),3.65-3.58(m,2H),3.55-3.46(m,2H); LC / MS ESI(+):230.0(M+1).

[0982] <Example 103> Synthesis of (4-(4-fluorophenyl)-3,4-dihydropyrido[3,4-b]pyrazin-1(2H)-yl)(3-hydroxypyrrolidin-1-yl)methanone

[0983] 4- (4- fluorophenyl) -1,2,3,4- tetrahydropyrido [3,4-b] pyrazine (300 mg, 0.13 mmol) obtained in preparation example h-4 was dissolved in dichloromethane (1.0 mL), TEA (36.5 μL, 0.26 mmol) and triphosgene (23.3 mg, 1.62 mmol) were slowly added at 0 ° C, and the resulting solution was stirred at 0 ° C for 1 hour. TEA (36.5 μL, 0.26 mmol) and pyrrolidine -3-ol (12.8 μL, 0.16 mmol) were added to the reaction solution and stirred at room temperature for 1 hour. After the reaction was terminated by adding water, the reaction solution was extracted with dichloromethane. The organic layer was washed with brine, dried with MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture, thereby synthesizing (4-(4-fluorophenyl)-3,4-dihydropyrido[3,4-b]pyrazin-1(2H)-yl)(3-hydroxypyrrolidin-1-yl)methanone.

[0984] Yellow solid (yield: 33%); 1 H NMR (400MHz, CDCl3) δ7.89-7.84(m,2H),7.24-7.16(m,2H),7.15-7.05(m,2H),6.82(d,J=5.4Hz,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).

[0985] [Reaction Scheme 57]

[0986]

[0987] <Preparation Method i> Preparation of 1-cyclohexyl-1,2,3,4-tetrahydroquinoxaline

[0988] The 1-cyclohexyl-1,2,3,4-tetrahydroquinoxaline according to the present invention was synthesized by the following Preparation Examples i-1 to i-4.

[0989] <Preparation Example i-1> Preparation of N-cyclohexyl-2-nitroaniline

[0990] 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 cooled to room temperature. After the reaction was terminated by adding water, the reaction solution was extracted with dichloromethane. The organic layer was washed with salt water, dried over MgSO , filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a n-hexane / ethyl acetate mixture to prepare N-cyclohexyl-2-nitroaniline.

[0991] Orange solid (yield: 99%); 1 H NMR (400MHz, CDCl3) δ8.20-8.08(m,2H),7.42-7.36(m,1H),6.86(d,J=8.6Hz,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).

[0992] <Preparation Example i-2> N 1 Preparation of cyclohexylbenzene-1,2-diamine

[0993] The N-cyclohexyl-2-nitroaniline (1.6 g, 7.04 mmol) obtained in Preparation Example i-1 was dissolved in EtOAc / MeOH (1:3=v / v, 20 mL), 10% Pd / C (74 mg, 0.70 mmol) was added, and the resulting solution was stirred for 6 hours at room temperature under hydrogen conditions. The reaction solution was filtered through a diatomaceous earth pad and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography utilizing a n-hexane / ethyl acetate mixture, thus preparing N 1 -cyclohexylbenzene-1,2-diamine.

[0994] Brown oil (yield: 86%); 1 H NMR (400MHz, CDCl3) δ6.83-6.77(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).

[0995] <Preparation Example i-3> Preparation of 1-cyclohexylquinoxaline-2,3(1H,4H)-dione

[0996] The N obtained in Preparation Example i-2 1 A reaction solution of 1-cyclohexylbenzene-1,2-diamine (1.0 g, 5.26 mmol) dissolved 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, it was filtered and dried to prepare 1-cyclohexylquinoxaline-2,3(1H,4H)-dione.

[0997] Gray solid (yield: 80%); 1 H NMR(400MHz,DMSO-d6)δ11.96(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).

[0998] <Preparation Example i-4> Preparation of 1-cyclohexyl-1,2,3,4-tetrahydroquinoxaline

[0999] Borane-THF complex (1M) (24mL, 24.07mmol) is slowly added to a solution of 1-cyclohexylquinoxaline-2,3 (1H, 4H) -dione (980mg, 4.01mmol) obtained in Preparation Example i-3 dissolved in THF (7.0mL) 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 the reaction product was neutralized with a saturated NaHCO3 aqueous 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 n-hexane / ethyl acetate mixture to prepare 1-cyclohexyl-1,2,3,4-tetrahydroquinoxaline.

[1000] Orange oil (yield: 91%); 1 H NMR (400MHz, CDCl3) δ6.70-6.60(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).

[1001] [Reaction Scheme 58]

[1002]

[1003] <Preparation Example i-5> Preparation of (R)-3-(4-cyclohexyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylic acid tert-butyl ester

[1004] 1-cyclohexyl-1,2,3,4-tetrahydroquinoxaline (1.0 equivalent) obtained in Preparation Example i-4 was dissolved in dichloromethane (0.3M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0°C, and the resulting solution was 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 resulting solution was stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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 prepare (R)-tert-butyl 3-(4-cyclohexyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate.

[1005] White solid (yield: 85%); 1 H NMR (400MHz, CDCl3) δ7.10-7.03(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).

[1006] Example 104: Synthesis of (R)-4-cyclohexyl-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[1007] The Boc group of tert-butyl (R)-3-(4-cyclohexyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate obtained in Preparation Example i-5 was deprotected with TFA to synthesize (R)-4-cyclohexyl-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[1008] White solid (yield: 67%); 1H NMR (400MHz, CDCl3) δ7.11-7.03(m,2H),6.80-6.78(m,1H),6.64-6.58(m,1H),5.39(d,J=6.8H z,1H),4.34-4.25(m,1H),3.78-3.71(m,2H),3.67-3.59(m,1H),3.31(t,J=5.4Hz,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).

[1009] <Example 105> Synthesis of (R)-4-cyclohexyl-N-(1-methylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[1010] (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 resulting solution was stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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.

[1011] Ivory solid (yield: 43%); 1H NMR (400MHz, CDCl3) δ7.11 (dd, J=7.8, 1.6Hz, 1H), 7.07-7.02 (m, 1H), 6.79-6.76 (m, 1H), 6.64-6 .59(m,1H),5.48(d,J=7.4Hz,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).

[1012] Example 106: Synthesis of (R)-4-cyclohexyl-N-(1-isobutylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[1013] (R)-4-cyclohexyl-N-(1-isobutylpyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 105, except that isobutyraldehyde was used instead of formaldehyde.

[1014] White solid (yield: 46%); 1 H NMR (400MHz, CDCl3) δ7.09 (dd, J=7.8, 1.5Hz, 1H), 7.05-7.00 (m, 1H), 6.77-6.75 (m, 1H), 6.61- 6.57(m,1H),5.59(d,J=8.0Hz,1H),4.37-4.30(m,1H),3.78-3.66(m,2H),3.64-3.58(m,1H),3 .28(t,J=5.3Hz,1H),2.77-2.72(m,1H),2.53-2.46(m,2H),2.25-2.11(m,4H),1.88-1.79(m,4 LC / MS ESI(+): 385.4(M+1).

[1015] [Reaction Scheme 59]

[1016]

[1017] Example 107 Synthesis of (4-cyclohexyl-3,4-dihydroquinoxaline-1(2H)-yl)(4-methylpiperazin-1-yl)methanone

[1018] (4-Cyclohexyl-3,4-dihydroquinoxaline-1(2H)-yl)(4-methylpiperazin-1-yl)methanone was synthesized in the same manner as in Preparation Example i-5, except that 1-methylpiperazine was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[1019] Brown oil (yield: 81%); 1 H NMR (400MHz, CDCl3) δ6.96 (dd, J=7.9, 1.5Hz, 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), 3.3 8-3.33(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).

[1020] <Example 108> Synthesis of (4-cyclohexyl-3,4-dihydroquinoxaline-1(2H)-yl)(pyrrolidin-1-yl)methanone

[1021] (4-cyclohexyl-3,4-dihydroquinoxalin-1(2H)-yl)(pyrrolidin-1-yl)methanone was synthesized in the same manner as in Preparation Example i-5, except that pyrrolidine was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[1022] Ivory solid (yield: 54%); 1 H NMR (400MHz, CDCl3) δ6.91-6.84(m,2H),6.70-6.68(m,1H),6.57-6.53(m,1H),3.67(t,J=5.4Hz,2H),3.63-3.57(m,1H),3 .37(t,J=5.3Hz,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).

[1023] <Example 109> Synthesis of (4-cyclohexyl-3,4-dihydroquinoxaline-1(2H)-yl)(piperidin-1-yl)methanone

[1024] (4-cyclohexyl-3,4-dihydroquinoxalin-1(2H)-yl)(piperidin-1-yl)methanone was synthesized in the same manner as in Preparation Example i-5, except that piperidine was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[1025] Red oil (yield: 80%); 1 H NMR (400MHz, CDCl3) δ6.94-6.87(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. 3Hz,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).

[1026] [Reaction Scheme 60]

[1027]

[1028] <Preparation Method j> Preparation of 1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoxaline

[1029] 1-(Tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoxaline according to the present invention was synthesized by the following Preparation Examples j-1 to j-4.

[1030] <Preparation Example j-1> Preparation of N-(2-nitrophenyl)tetrahydro-2H-pyran-4-amine

[1031] A solution in which 1-fluoro-2-nitrobenzene (1.0 equivalent) and tetrahydro-2H-pyran-4-amine (1.2 equivalents) were mixed was stirred at 110° C. for 6 hours and cooled to room temperature. After the reaction was terminated by adding water, the reaction solution was extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO , filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using an n-hexane / ethyl acetate mixture to prepare N-(2-nitrophenyl)tetrahydro-2H-pyran-4-amine.

[1032] Orange solid (yield: 91%); 1H NMR (400MHz, CDCl3) δ8.25-8.18(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).

[1033] <Preparation Example j-2> N 1 Preparation of 2-tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine

[1034] The N-(2-nitrophenyl)tetrahydro-2H-pyran-4-amine (1.0 equivalent) obtained in Preparation Example j-1 was dissolved in EtOAc / MeOH (1:3=v / v, 20 mL), 10% Pd / C (0.2 equivalent) was added, and stirred for 6 hours under hydrogen at room temperature. 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 a n-hexane / ethyl acetate mixture, thereby preparing N 1 -tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine.

[1035] Brown solid (yield: 91%); 1 H NMR (400MHz, CDCl3) δ6.86-6.80(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).

[1036] <Preparation Example j-3> Preparation of 1-(tetrahydro-2H-pyran-4-yl)hydroquinoxaline-2,3-dione

[1037] The N obtained in Preparation Example j-2 1 A reaction solution of 1-(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine (1.0 equivalent) dissolved in diethyl oxalate (6.0 equivalent) was stirred at 130° C. for 2 hours. After cooling the reaction solution to room temperature, the reaction solution was filtered and dried to prepare 1-(tetrahydro-2H-pyran-4-yl)hydroquinoxaline-2,3-dione.

[1038] Brown solid (yield: 70%);1 H NMR(400MHz,DMSO-d6)δ11.99(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).

[1039] <Preparation Example j-4> Preparation of 1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoxaline

[1040] Borane-THF complex (1.0 M) (6.0 equivalents) was slowly added to a solution of 1-(tetrahydro-2H-pyran-4-yl) hydroquinoxaline-2,3-dione (1.0 equivalents) obtained in Preparation Example j-3 dissolved in THF at room temperature and stirred at 65 ° C for 16 hours. After the reaction solution was cooled to room temperature, water was added to terminate the reaction, and the reaction product was neutralized with a saturated NaHCO3 aqueous 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 n-hexane / ethyl acetate mixture to prepare 1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoxaline.

[1041] White solid (yield: 79%); 1 H NMR(400MHz,CD3OD)δ6.77-6.70(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).

[1042] [Reaction Scheme 61]

[1043]

[1044] Preparation Example j-5 Preparation of (R)-3-(4-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylic acid tert-butyl ester

[1045] 1- (tetrahydro -2H- pyran -4- bases) -1,2,3,4- tetrahydroquinoxaline (1.0 equivalent) obtained in Preparation Example j-4 was dissolved in dichloromethane (0.3M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0 ° C, and the resulting solution was 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 resulting solution was stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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 prepare (R)-tert-butyl 3-(4-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate.

[1046] White solid (yield: 94.3%); 1 H NMR (400MHz, CDCl3) δ7.10-7.02(m,2H),6.85-6.77(m,1H),6.68-6.58(m,1H),5.2 7(d,J=6.8Hz,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).

[1047] Preparation Example j-6 Preparation of (R)-N-(pyrrolidin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[1048] The Boc group of (R)-3-(4-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylic acid tert-butyl ester obtained in Preparation Example j-5 was deprotected with TFA to prepare (R)-N-(pyrrolidin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[1049] White solid (yield: 84.3%); 1H NMR (400MHz, CDCl3) δ7.13 (dd, J=7.8, 1.6Hz, 1H), 7.08-7.03 (m, 1H), 6.86-6.78 (m, 1H), 6. 67-6.61(m,1H),5.44(d,J=6.7Hz,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),3.04-2.9 6(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).

[1050] Example 110: Synthesis of (R)-N-(1-methylpyrrolidin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[1051] (R) -N- (pyrrolidin-3-yl) -4- (tetrahydro -2H- pyran -4-yl) -3,4- dihydroquinoxaline -1 (2H) -carboxamide (1.0 equivalent) obtained in Preparation Example j-6 was dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.3 equivalents) and formaldehyde (1.1 equivalents) were added, and the resulting solution was stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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.

[1052] Light yellow oil (yield: 82.5%); 1H NMR (400MHz, CDCl3) δ7.11 (dd, J=7.8, 1.6Hz, 1H), 7.08-6.98 (m, 1H), 6.79 (dd, J=8.3, 1.1Hz, 1H), 6.67-6.59(m,1H),5.44(d,J=7.5Hz,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).

[1053] Example 111: Synthesis of (R)-N-(1-isobutylpyrrolidin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[1054] (R)-N-(1-isobutylpyrrolidin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide was synthesized in the same manner as in Example 110, except that isobutyraldehyde was used instead of formaldehyde.

[1055] Light yellow oil (yield: 86.3%); 1 H NMR (400MHz, CDCl3) δ7.11 (dd, J=7.8, 1.6Hz, 1H), 7.07-6.98 (m, 1H), 6.83-6.76 (m, 1H), 6.67-6.58 (m, 1H),5.59(d,J=7.9Hz,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=2.1Hz,2H),3.29(t,J=5.3Hz,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).

[1056] [Reaction Scheme 62]

[1057]

[1058] Preparation Example j-7 Preparation of (S)-(1-(4-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidin-3-yl)carbamic acid tert-butyl ester

[1059] (S)-tert-butyl(1-(4-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidin-3-yl)carbamate was prepared in the same manner as in Preparation Example j-5, except that (S)-(-)-3-(Boc-amino)pyrrolidine was used instead of (R)-(+)-1-Boc-3-aminopyrrolidine.

[1060] Ivory solid (yield: 90.2%); 1 H NMR(400MHz, CDCl3)δ6.96-6.88(m,1H),6.86(dd,J=7.9,1.5Hz,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=4.5Hz,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).

[1061] Example 112: Synthesis of (S)-(3-aminopyrrolidin-1-yl)(4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxaline-1(2H)-yl)methanone

[1062] 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 Preparation Example j-7 was deprotected with TFA to synthesize (S)-(3-aminopyrrolidin-1-yl)(4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxaline-1(2H)-yl)methanone.

[1063] Light yellow oil (yield: 69.7%); 1H NMR (400MHz, CDCl3) δ6.96-6.85(m,2H),6.76-6.71(m,1H),6.65-6.55(m,1H),4.13- 4.04(m,2H),3.86(t,J=3.9Hz,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 / MSESI(+): 331.2(M+1).

[1064] Example 113 Synthesis of (S)-(3-(dimethylamino)pyrrolidin-1-yl)(4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxaline-1(2H)-yl)methanone

[1065] (S)-(3-aminopyrrolidin-1-yl)(4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxaline-1(2H)-yl)methanone (95.0 mg, 0.29 mmol) obtained in Example 112 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 resulting solution was stirred at room temperature for 4 hours. After the reaction was terminated by adding water, the reaction solution 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, thereby synthesizing (S)-(3-(dimethylamino)pyrrolidin-1-yl)(4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinoxalin-1(2H)-yl)methanone.

[1066] Light yellow oil (yield: 16.5%); 1H NMR (400MHz, CDCl3) δ6.94-6.83 (m, 2H), 6.73 (dd, J = 8.1, 1.2Hz, 1H), 6.63-6. 55(m,1H),4.09(d,J=1.5Hz,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=10.7,8.9Hz,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).

[1067] [Reaction Scheme 63]

[1068]

[1069] <Preparation Method k> Preparation of (3,4-dihydroquinoxaline-1(2H)-yl)(phenyl)methanone or halogen-substituted (3,4-dihydroquinoxaline-1(2H)-yl)(phenyl)methanone

[1070] 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 by the following Preparation Examples k-1 to k-8.

[1071] <Preparation Example k-1> Preparation of tert-butyl 4-benzoyl-3,4-dihydroquinoxaline-1(2H)-carboxylate

[1072] 3,4-dihydroquinoxaline-1 (2H)-tert-butyl formate (473 mg, 2.02 mmol) obtained in Preparation Example d-1 was dissolved in THF (20 mL), benzoyl chloride (117 μL, 1.01 mmol) was added, and the resulting solution was stirred at room temperature for 3 hours. The reaction was terminated by adding water to the reaction solution, and the resulting solution was neutralized with a saturated NaHCO3 aqueous solution and extracted with dichloromethane. The organic layer was washed with brine, dried with MgSO4, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a hexane / ethyl acetate mixture to prepare 4-benzoyl-3,4-dihydroquinoxaline-1 (2H)-tert-butyl formate.

[1073] Yellow oil (yield: 100%); 1H NMR (400MHz, CDCl3) δ7.92-7.83(m,1H),7.45-7.34(m,3H),7.31-7.26(m,2H),7.05(d,J=1. 6Hz,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).

[1074] <Preparation Example k-2> Preparation of tert-butyl 4-(2-fluorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate

[1075] tert-Butyl 4-(2-fluorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate was prepared in the same manner as in Preparation Example k-1, except that 2-fluorobenzoyl chloride was used instead of benzoyl chloride.

[1076] Colorless oil (yield: 84%); 1 H NMR (400MHz, CDCl3) δ7.96-7.82(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).

[1077] <Preparation Example k-3> Preparation of tert-butyl 4-(3-fluorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate

[1078] tert-Butyl 4-(3-fluorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate was prepared in the same manner as in Preparation Example k-1, except that 3-fluorobenzoyl chloride was used instead of benzoyl chloride.

[1079] Colorless oil (yield: 72%); 1 H NMR (400MHz, CDCl3) δ7.93-7.83(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).

[1080] <Preparation Example k-4> Preparation of tert-butyl 4-(4-fluorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate

[1081] tert-Butyl 4-(4-fluorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate was prepared in the same manner as in Preparation Example k-1, except that 4-fluorobenzoyl chloride was used instead of benzoyl chloride.

[1082] Colorless oil (yield: 93%); 1 H NMR (400MHz, CDCl3) δ7.95-7.85(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).

[1083] <Preparation Example k-5> Preparation of (3,4-dihydroquinoxaline-1(2H)-yl)(phenyl)methanone

[1084] The Boc group of tert-butyl 4-benzoyl-3,4-dihydroquinoxaline-1(2H)-carboxylate obtained in Preparation Example k-1 was deprotected with TFA to prepare (3,4-dihydroquinoxalin-1(2H)-yl)(phenyl)methanone.

[1085] Light yellow oil (yield: 92%); 1 H NMR (400MHz, CDCl3) δ7.49-7.35(m,3H),7.34-7.28(m,2H),6.91-6.83(m,1H),6.59(dd,J=8.0,0 .9Hz,2H),6.40-6.34(m,1H),4.07(brs,1H),3.98(t,J=5.1Hz,2H),3.56(t,J=5.1Hz,2H); LC / MS ESI(+): 239.1(M+1).

[1086] <Preparation Example k-6> Preparation of (3,4-dihydroquinoxaline-1(2H)-yl)(2-fluorophenyl)methanone

[1087] The Boc group of tert-butyl 4-(2-fluorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate obtained in Preparation Example k-2 was deprotected with TFA to prepare (3,4-dihydroquinoxalin-1(2H)-yl)(2-fluorophenyl)methanone.

[1088] White solid (yield: 87%); 1H NMR (400MHz, CDCl3) δ7.52-7.46(m,1H),7.42-7.28(m,1H),7.24-7.12(m,1H),7.05-6.75(m ,2H),6.58(d,J=7.9Hz,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).

[1089] <Preparation Example k-7> Preparation of (3,4-dihydroquinoxaline-1(2H)-yl)(3-fluorophenyl)methanone

[1090] The Boc group of tert-butyl 4-(3-fluorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate obtained in Preparation Example k-3 was deprotected with TFA to prepare (3,4-dihydroquinoxalin-1(2H)-yl)(3-fluorophenyl)methanone.

[1091] White solid (yield: 87%); 1 H NMR (400MHz, CDCl3) δ7.30-7.27(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=4.9Hz,2H),3.62-3.50(m,2H); LC / MS ESI(+):257.1(M+1).

[1092] <Preparation Example k-8> Preparation of (3,4-dihydroquinoxaline-1(2H)-yl)(4-fluorophenyl)methanone

[1093] The Boc group of tert-butyl 4-(4-fluorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate obtained in Preparation Example k-4 was deprotected with TFA to prepare (3,4-dihydroquinoxalin-1(2H)-yl)(4-fluorophenyl)methanone.

[1094] White solid (yield: 93%); 1 H NMR (400MHz, CDCl3) δ7.48-7.44(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=4.9Hz,2H); LC / MS ESI(+):257.1(M+1).

[1095] [Reaction Scheme 64]

[1096]

[1097] <Preparation Example k-9> Preparation of tert-butyl 4-((4-benzoyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate

[1098] (3,4-dihydroquinoxaline-1(2H)-yl)(phenyl)methanone (1.0 equivalent) obtained in Preparation Example k-5 was dissolved in dichloromethane (0.3M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0°C, and the resulting solution was stirred 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 resulting solution was stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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 mixture of n-hexane / ethyl acetate to prepare tert-butyl 4-((4-benzoyl-1,2,3,4-tetrahydroquinoxaline-1-formamido)methyl)piperidine-1-carboxylate.

[1099] White solid (yield: 90%); 1 H NMR (400MHz, CDCl3) δ7.43-7.40(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).

[1100] <Example 114> Synthesis of 4-benzoyl-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[1101] The Boc group of tert-butyl 4-((4-benzoyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate obtained in Preparation Example k-9 was deprotected with TFA to synthesize 4-benzoyl-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[1102] White solid (yield: 67%);1 H NMR (400MHz, CD3OD) δ7.55-7.53(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 =7.9Hz),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).

[1103] [Reaction Scheme 65]

[1104]

[1105] Preparation Example k-10 Preparation of (R)-tert-Butyl 3-((4-benzoyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate

[1106] (R)-tert-butyl 3-((4-benzoyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate was prepared in the same manner as in Preparation Example k-9, except that (R)-1-Boc-3-(aminomethyl)pyrrolidine was used instead of 1-Boc-4-(aminomethyl)piperidine.

[1107] White solid (yield: 94%); 1 H NMR (400MHz, CDCl3) δ7.42-7.38(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).

[1108] <Example 115> Synthesis of (S)-4-benzoyl-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[1109] The Boc group of tert-butyl (R)-3-((4-benzoyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate obtained in Preparation Example k-10 was deprotected with TFA to synthesize (S)-4-benzoyl-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[1110] White solid (yield: 92%); 1 H NMR(400MHz,CD3OD)δ7.56(dd,J=8.3,1.1Hz,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 / MSESI(+): 365.2(M+1).

[1111] Example 116: Synthesis of (R)-4-benzoyl-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[1112] (S) -4-benzoyl -N- (pyrrolidin-3-ylmethyl) -3,4- dihydroquinoxaline -1 (2H) -carboxamide (1.0 equivalent) obtained in Example 115 was dissolved in dichloromethane (0.3M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After the reaction was terminated by adding water, the reaction solution 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.

[1113] White solid (yield: 82%); 1H NMR(400MHz,CD3OD)δ7.52(dd,J=8.2,1.2Hz,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=7.9Hz,1H),4.08-4.04(m,2H),3.9 2-3.89(m,2H),3.26(d,J=7.1Hz,2H),2.79-2.74(m,1H),2.65-2.61(m,2H),2.58-2.5 2(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).

[1114] [Reaction Scheme 66]

[1115]

[1116] Preparation Example k-11 Preparation of tert-butyl (R)-3-((4-(2-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate

[1117] (3,4-dihydroquinoxaline-1(2H)-yl)(2-fluorophenyl)methanone (1.0 equivalent) obtained in Preparation Example k-6 was dissolved in dichloromethane (0.3M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0°C, and the resulting solution was stirred at 0°C for 1 hour. TEA (2.0 equivalents) and (R)-1-Boc-3-(aminomethyl)pyrrolidine (1.2 equivalents) were added to the reaction solution, and the resulting solution was stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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 prepare (R)-tert-butyl 3-((4-(2-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate.

[1118] White solid (yield: 97%); 1H NMR (400MHz, CDCl3) δ7.65-7.55(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).

[1119] Example 117 Synthesis of (S)-4-(2-fluorobenzoyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[1120] The Boc group of (R)-3-((4-(2-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester obtained in Preparation Example k-11 was deprotected with TFA to synthesize (S)-4-(2-fluorobenzoyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[1121] White solid (yield: 71%); 1 H NMR(400MHz,CD3OD)δ7.54-7.43(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).

[1122] Example 118: Synthesis of (R)-4-(2-fluorobenzoyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[1123] (S) -4- (2-fluorobenzoyl) -N- (pyrrolidin-3-ylmethyl) -3,4- dihydroquinoxaline -1 (2H) -carboxamide (1.0 equivalent) obtained in Example 117 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After the reaction was terminated by adding water, the reaction solution 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-fluorobenzoyl) -N- ((1-methylpyrrolidin-3-yl) methyl) -3,4- dihydroquinoxaline -1 (2H) -carboxamide.

[1124] White solid (yield: 76%); 1 H NMR(400MHz,CD3OD)δ7.52-7.42(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=7.0Hz,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).

[1125] [Reaction Scheme 67]

[1126]

[1127] Preparation Example k-12 Preparation of (R)-tert-Butyl 3-(4-(3-fluorobenzoyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate

[1128] 3,4-Dihydroquinoxaline-1(2H)-yl)(3-fluorophenyl)methanone (1.0 equivalent) obtained in Preparation Example k-7 was dissolved in dichloromethane (0.3M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0°C, and the resulting solution was 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 resulting solution was stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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 prepare (R)-tert-butyl 3-(4-(3-fluorobenzoyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylate.

[1129] White solid (yield: 96%); 1 H NMR (400MHz, CD3OD) δ7.58 (d, J=8.0Hz, 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=7.5Hz,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).

[1130] Example 119: Synthesis of (R)-4-(3-fluorobenzoyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[1131] The Boc group of (R)-3-(4-(3-fluorobenzoyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)pyrrolidine-1-carboxylic acid tert-butyl ester obtained in Preparation Example k-12 was deprotected with TFA to synthesize (R)-4-(3-fluorobenzoyl)-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[1132] White solid (yield: 67%); 1H NMR (400MHz, CD3OD) δ7.63-7.61(m,1H),7.40-7.35(m,1H),7.26-7.14(m,4H),6.88-6.84(m,1H),6.74(d,J=7.6Hz,1H),4.41-4.3 5(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).

[1133] [Reaction Scheme 68]

[1134]

[1135] Preparation Example k-13 Preparation of (R)-tert-Butyl 3-((4-(3-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate

[1136] (3,4-dihydroquinoxaline-1(2H)-yl)(3-fluorophenyl)methanone (1.0 equivalent) obtained in Preparation Example k-7 was dissolved in dichloromethane (0.3M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0°C, and the resulting solution was stirred at 0°C for 1 hour. TEA (2.0 equivalents) and (R)-1-Boc-3-(aminomethyl)pyrrolidine (1.2 equivalents) were added to the reaction solution, and the resulting solution was stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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 prepare (R)-tert-butyl 3-((4-(3-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate.

[1137] White solid (yield: 97%); 1H NMR (400MHz, CDCl3) δ7.40 (d, J = 7.9Hz, 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), 4.0 1-3.94(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).

[1138] Example 120: Synthesis of (S)-4-(3-fluorobenzoyl)-N-(pyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[1139] The Boc group of (R)-3-((4-(3-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester obtained in Preparation Example k-13 was deprotected with TFA to synthesize (S)-4-(3-fluorobenzoyl)-N-(pyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[1140] White solid (yield: 82%); 1 H NMR(400MHz,CD3OD)δ7.57-7.52(m,1H),7.37-7.31(m,1H),7.21-7.13(m, 4H),6.88-6.83(m,1H),6.72(d,J=7.6Hz,1H),4.08-4.02(m,2H),3.93-3.8 7(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).

[1141] Example 121: Synthesis of (R)-4-(3-fluorobenzoyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[1142] (S) -4- (3- fluorobenzoyl) -N- (pyrrolidin-3-yl) methyl) -3,4- dihydroquinoxaline -1 (2H) - carboxamide (1.0 equivalent) obtained in Example 120 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After the reaction was terminated by adding water, the reaction solution 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- (3- fluorobenzoyl) -N- ((1- methylpyrrolidin-3-yl) methyl) -3,4- dihydroquinoxaline -1 (2H) - carboxamide.

[1143] White solid (yield: 76%); 1 H NMR(400MHz,CD3OD)δ7.54-7.51(m,1H),7.37-7.31(m,1H),7.20-7.13(m,4H), 6.87-6.83(m,1H),6.71(d,J=7.9Hz,1H),4.08-4.04(m,2H),3.92-3.89(m,2H) ,3.26(d,J=7.0Hz,2H),2.78-2.74(m,1H),2.65-2.61(m,2H),2.59-2.52(m,1H ),2.43-2.39(m,1H),2.36(s,3H),2.08-1.99(m,1H),1.65-1.57(m,1H); LC / MS ESI(+):397.2(M+1).

[1144] [Reaction Scheme 69]

[1145]

[1146] Preparation Example k-14 Preparation of (R)-tert-Butyl 3-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate

[1147] (3,4-dihydroquinoxaline-1(2H)-yl)(4-fluorophenyl)methanone (1.0 equivalent) obtained in Preparation Example k-8 was dissolved in dichloromethane (0.3M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0°C, and the resulting solution was stirred at 0°C for 1 hour. TEA (2.0 equivalents) and (R)-1-Boc-3-(aminomethyl)pyrrolidine (1.2 equivalents) were added to the reaction solution, and the resulting solution was stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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 prepare (R)-tert-butyl 3-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylate.

[1148] White solid (yield: 53%); 1 H NMR (400MHz, CDCl3) δ7.45-7.40(m,3H),7.17-7.11(m,1H),7.06-6.99(m,2 H),6.95-6.87(m,1H),6.85-6.73(m,1H),5.40-5.25(m,1H),4.10-4.05(m, 2H),4.02-3.95(m,2H),3.60-3.40(m,3H),3.39-3.30(m,2H),3.15-2.99(m ,1H),2.57-2.43(m,1H),2.05-1.98(m,1H),1.71-1.62(m,1H),1.48(s,9H).

[1149] Example 122: Synthesis of (S)-4-(4-fluorobenzoyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[1150] The Boc group of (R)-3-((4-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester obtained in Preparation Example k-14 was deprotected with TFA to synthesize (S)-4-(4-fluorobenzoyl)-N-(pyrrolidin-3-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[1151] White solid (yield: 96%); 1H NMR(400MHz,CD3OD)δ7.56-7.53(m,1H),7.48-7.43(m,2H),7.16-7.12(m,1H), 7.08-7.02(m,2H),6.88-6.83(m,1H),6.67(d,J=7.9Hz,1H),4.08-4.04(m,2H), 3.93-3.89(m,2H),3.29-3.23(m,2H),3.15-3.07(m,2H),3.02-2.96(m,1H),2. 79-2.74(m,1H),2.55-2.44(m,1H),2.05-1.97(m,1H),1.66-1.57(m,1H); LC / MS ESI(+):383.3(M+1).

[1152] Example 123 Synthesis of (R)-4-(4-fluorobenzoyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[1153] (S) -4- (4- fluorobenzoyl) -N- (pyrrolidin-3-ylmethyl) -3,4- dihydroquinoxaline -1 (2H) - carboxamide (1.0 equivalent) obtained in Example 122 was dissolved in dichloromethane (0.3 M), sodium triacetoxyborohydride (1.5 equivalents) and formaldehyde (2.0 equivalents) were added, and the resulting solution was stirred at room temperature for 1 hour. After the reaction was terminated by adding water, the reaction solution 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- (4- fluorobenzoyl) -N- ((1-methylpyrrolidin-3-yl) methyl) -3,4- dihydroquinoxaline -1 (2H) - carboxamide.

[1154] White solid (yield: 82%); 1H NMR (400MHz, CD3OD) δ7.53 (dd, J=8.1, 1.1Hz, 1H), 7.48-7.43 (m, 2H), 7.16-7.12 (m, 1H ),7.07-7.02(m,2H),6.87-6.83(m,1H),6.66(d,J=7.9Hz,1H),4.08-4.04(m,2H),3.9 2-3.89(m,2H),3.26(d,J=7.1Hz,2H),2.77-2.73(m,1H),2.63-2.60(m,2H),2.58-2.5 2(m,1H),2.41-2.37(m,1H),2.36(s,3H),2.08-1.99(m,1H),1.65-1.56(m,1H); LC / MS ESI(+): 397.2(M+1).

[1155] [Reaction Scheme 70]

[1156]

[1157] Preparation Example k-15 Preparation of tert-butyl 4-(4-(4-fluorobenzoyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)piperidine-1-carboxylate

[1158] (3,4-dihydroquinoxaline-1(2H)-yl)(4-fluorophenyl)methanone (1.0 equivalent) obtained in Preparation Example k-8 was dissolved in dichloromethane (0.3M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0°C, and the resulting solution was stirred at 0°C for 1 hour. TEA (2.0 equivalents) and 1-Boc-4-aminopiperidine (1.2 equivalents) were added to the reaction solution, and the resulting solution was stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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 mixture of n-hexane / ethyl acetate to prepare tert-butyl 4-(4-(4-fluorobenzoyl)-1,2,3,4-tetrahydroquinoxaline-1-formamido)piperidine-1-carboxylate.

[1159] White solid (yield: 96%); 1H NMR (400MHz, CDCl3) δ7.44-7.38(m,3H),7.14-7.08(m,1H),7.03-6.98(m,2H),6.91-6.86(m,1H),6.81-6.76(m,1H ), 5.03 (d, J = 7.6Hz, 1H), 4.07-3.93 (m, 7H), 2.93-2.87 (m, 2H), 2.02-1.98 (m, 2H), 1.46 (s, 9H), 1.39-1.29 (m, 2H).

[1160] <Example 124> Synthesis of 4-(4-fluorobenzoyl-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[1161] The Boc group of tert-butyl 4-(4-(4-fluorobenzoyl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)piperidine-1-carboxylate obtained in Preparation Example k-15 was deprotected with TFA to synthesize 4-(4-fluorobenzoyl-N-(piperidin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[1162] White solid (yield: 87%); 1 H NMR (400MHz, CD3OD) δ7.55(dd,J=8.3,1.1Hz,1H),7.50-7.45(m,2H),7.14-7.10(m,1H),7.09-7.03(m,2H),6.85-6.81(m,1H),6.66(d,J=7.9Hz, 1H),4.07-4.04(m,2H),3.92-3.89(m,2H),3.83-3.74(m,1H),3.14-3.0 8(m,2H),2.74-2.68(m,2H),2.01-1.93(m,2H),1.57-1.47(m,2H); LC / MS ESI(+): 383.3(M+1).

[1163] [Reaction Scheme 71]

[1164]

[1165] <Preparation Method 1> Preparation of 1-(3,4-dihydroquinoxaline-1(2H)-yl)-3-methylbutan-1-one

[1166] 1-(3,4-dihydroquinoxalin-1(2H)-yl)-3-methylbutan-1-one according to the present invention was synthesized by the following Preparation Examples 1-1 to 1-2.

[1167] Preparation Example 1-1 Preparation of 1-(4-benzyl-3,4-dihydroquinoxalin-1(2H)-yl)-3-methylbutan-1-one

[1168] The 1-benzyl-1,2,3,4-tetrahydroquinoxaline (1.0 equivalent) obtained in Preparation Example d-3 was dissolved in THF (0.3M), isovaleryl chloride (1.5 equivalents) and triethylamine (2.0 equivalents) were slowly added at 0°C, and the resulting solution was stirred for 1.5 hours. After the reaction was terminated by adding water, the reaction solution 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 mixture of n-hexane / ethyl acetate to prepare 1- (4-benzyl-3,4-dihydroquinoxaline-1 (2H) -yl) -3-methylbutan-1-one.

[1169] Colorless oil (yield: 100%); 1 H NMR (400MHz, CD3CN) δ7.38-7.30(m,2H),7.29-7.02(m,4H),7.01-6.92(m,1H),6.68(d,J=8.2Hz,1H),6.62(dd,J=7.6,7.6H LC / MS ESI(+): 309.3(M+1).

[1170] Preparation Example 1-2 Preparation of 1-(3,4-dihydroquinoxaline-1(2H)-yl)-3-methylbutan-1-one

[1171] 1-(4-benzyl-3,4-dihydroquinoxaline-1(2H)-yl)-3-methylbutan-1-one (1.0 equivalent) obtained in Preparation Example 1-1 was dissolved in MeOH / THF (v / v=2:1, 0.4M), 10% Pd / C (0.5 equivalent) was added, and the resulting solution was stirred at room temperature under hydrogen conditions for 1.5 hours. The reaction solution was filtered through a celite pad and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography using a n-hexane / ethyl acetate mixture to prepare 1-(3,4-dihydroquinoxaline-1(2H)-yl)-3-methylbutan-1-one.

[1172] Yellow solid (yield: 92.5%); 1H NMR(400MHz,CD3CN)δ7.21-6.88(m,2H),6.68-6.53(m,2H),4.78(brs,1H),3.77-3.66( m,2H),3.42-3.31(m,2H),2.42(d,J=7.0Hz,2H),2.10-2.02(m,1H),0.89(s,6H); LC / MS ESI(+): 219.1(M+1).

[1173] [Reaction Scheme 72]

[1174]

[1175] Preparation Example 1-3 Preparation of tert-butyl 4-((4-(3-methylbutyryl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate

[1176] 1- (3,4-dihydroquinoxaline-1 (2H) -yl) -3-methylbutan-1-one (1.0 equivalent) obtained in Preparation Example 1-2 was dissolved in dichloromethane (0.3M), TEA (3.0 equivalents) and triphosgene (0.6 equivalents) were slowly added at 0°C, and the resulting solution was stirred 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 resulting solution was stirred at room temperature for 3 hours. After the reaction was terminated by adding water, the reaction solution 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 prepare tert-butyl 4-((4-(3-methylbutyryl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate.

[1177] White solid (yield: 93%); 1 H NMR(400MHz,CD3OD)δ7.62-7.46(m,1H),7.46-7.18(m,2H),7.17-7.05(m,1H), 4.11-3.98(m,2H),3.92(dd,J=6.4,6.4Hz,2H),3.76(dd,J=6.4,6.4Hz,2H),3. 07(d,J=6.6Hz,2H),2.69(brs,2H),2.42(d,J=7.2Hz,2H),2.12-1.95(m,1H),1 .76-1.59(m,3H),1.42(s,9H),1.13-0.97(m,2H),0.93-0.69(d,J=6.2Hz,6H).

[1178] <Example 125> Synthesis of 4-(3-methylbutyryl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[1179] The Boc group of tert-butyl 4-((4-(3-methylbutyryl)-1,2,3,4-tetrahydroquinoxaline-1-carboxamido)methyl)piperidine-1-carboxylate obtained in Preparation Example 1-3 was deprotected with TFA to synthesize 4-(3-methylbutyryl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[1180] Ivory solid (yield: 95%); 1 H NMR(400MHz,CD3OD)δ7.55(d,J=8.1Hz,1H),7.47-7.19(m,2H),7.18-7.09(m ,1H),3.92(dd,J=6.4,6.4Hz,2H),3.77(dd,J=6.4,6.4Hz,2H),3.07(d,J=6.4 Hz,2H),3.06-2.93(m,2H),2.59-2.48(m,2H),2.43(d,J=7.2Hz,2H),2.13-1. 96(m,1H),1.73-1.58(m,3H),1.21-1.05(m,2H),0.83(d,J=6.2Hz,6H); LC / MS ESI(+):359.0(M+1).

[1181] <Example 126> Synthesis of 4-(3-methylbutyryl)-N-((1-methylpiperidin-4-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide

[1182] 4-(3-methylbutyryl)-N-(piperidin-4-ylmethyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (1.0 equivalent) obtained in Example 125 was dissolved in dichloro...

Claims

1. A compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical formula 1] (In 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, 3- to 10-membered cyclic aromatic group, 3- to 10-membered heterocyclic aromatic group, -CO-(C1-C6 alkyl) or -CO-(halogen substituted or unsubstituted C6-C 12 aryl), and At least one of the H groups of R1 is substituted with halogen, cyano, or halogen-substituted or unsubstituted C6-C 12 Aryl or halogen substituted or unsubstituted C5-C 12 heteroaryl substitution; 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 is N, R2 is hydrogen; R3 and R4 are connected to each other to form a 5-membered or 6-membered ring, wherein at least one H in the ring is substituted by -OH, -NH2, dimethylamine, -NH-(C1-C5 alkyl), -NH-(C1-C5 alkoxy), -NH-COCH3, -NH-SO2CH3, C1-C5 alkyl or C1-C5 alkoxy, and 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 heterocyclic aromatic group), at least one H of R3 is substituted by -OH, C1-C5 alkyl, acetyl, C1-C5 alkoxy, -COCF3 or -SO2CH3; and The heterocycloalkyl, heterocyclic group and heteroaryl group each independently contain one or more heteroatoms selected from the group consisting of N, O, P and S.

2. The compound according to claim 1, wherein R3 and R4 are linked to each other to form a 5- or 6-membered heterocycloalkyl group containing one or two N atoms in the ring, wherein Y is N, and At least one H in the 5-membered or 6-membered heterocycloalkyl formed by R3 and R4 is substituted by -OH, -NH2, dimethylamine, -NH-(C1-C5 alkyl), -NH-(C1-C5 alkoxy), -NH-COCH3, -NH-SO2CH3, C1-C5 alkyl or C1-C5 alkoxy.

3. The compound according to claim 1, wherein R1 is a 6-membered cyclic aromatic group, a 6-membered heterocyclic aromatic group, -CH2-aryl, -CH2-heteroaryl, a 6-membered cycloalkyl group, a 6-membered heterocycloalkyl group, -CO-aryl or -CO-(C4-C5 alkyl), wherein the 6-membered heterocyclic aromatic group contains at least one N, and the 6-membered heterocycloalkyl group contains at least one O, and At least one of the H groups of R1 is substituted with halogen, cyano, or halogen-substituted or unsubstituted C6-C 12 Aryl or halogen substituted or unsubstituted C5-C 12 Heteroaryl substitution.

4. The compound according to claim 1, wherein the compound represented by Chemical Formula 1 is any one selected from the group consisting of the following compounds: (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-dihydroquinoxaline-1(2H)-carboxamide; (23) (R)-6-Fluoro-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-2-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (24) (R)-6-Fluoro-4-(4-fluorophenyl)-N-((1-isobutylpyrrolidin-2-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (25) (S)-6-Fluoro-4-(4-fluorophenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (26) (S)-6-Fluoro-4-(4-fluorophenyl)-N-((1-isopropylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-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-imidazole-4-)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-yl)methyl)-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-methylbutyryl)-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-methylbutyryl)-N-((1-methylpyrrolidin-3-yl)methyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; (129) (R)-4-(3,3-dimethylbutyryl)-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.

5. A pharmaceutical composition for preventing or treating a disease related to pulmonary fibrosis, comprising the compound represented by Chemical Formula 1 according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

6. The pharmaceutical composition according to claim 5, wherein the composition inhibits actin polymerization.

7. The pharmaceutical composition of claim 5, wherein the composition inhibits the level or activity of inflammatory cytokines.

8. The pharmaceutical composition according to claim 5, wherein the composition reduces the level or activity of one or more proteins selected from the group consisting of α-SMA, F-actin and IL-6.

9. The pharmaceutical composition of claim 5, wherein the pulmonary fibrosis-related disease is one or more selected from the group consisting of pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), desquamative interstitial pneumonia, nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, respiratory bronchiolitis-associated interstitial lung disease, acute interstitial pneumonia, lymphocytic interstitial pneumonia, idiopathic pleural pulmonary parenchymal fibroelastosis, and chronic obstructive pulmonary disease (COPD). 10 . The pharmaceutical composition according to claim 5 , wherein the pulmonary fibrosis-related disease is a pulmonary fibrosis-related disease accompanied by excessive activation of actin polymerization.

11. A kit for preventing or treating diseases related to pulmonary fibrosis, comprising the composition according to any one of claims 5 to 10.

12. A method for preventing or treating a disease related to pulmonary fibrosis, comprising: The compound represented by Chemical Formula 1 according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof.

13. Use of the compound represented by Chemical Formula 1 according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating diseases related to pulmonary fibrosis. 14 . Use of the compound represented by Chemical Formula 1 according to claim 1 , its stereoisomer or a pharmaceutically acceptable salt thereof for preventing or treating diseases related to pulmonary fibrosis.

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