Novel indoleamine-2,3-dioxygenase inhibitor, method for producing the same, and pharmaceutical composition containing the same

Abstract

The present invention provides a novel compound having a cyclohexyl-(alkyl- or cycloalkyl-substituted)ethylene-amino-heteroaryl moiety or a pharma- ceutically acceptable salt thereof, a method for preparing the compound, a pharmaceutical composition containing the compound, and use of the compound. The compound or a pharma- ceutically acceptable salt thereof not only has excellent inhibitory activity against indoleamine-2,3-dioxygenase (IDO), but also shows a remarkably high in vivo exposure upon oral administration. Therefore, the compound or a pharma- ceutically acceptable salt thereof can be usefully applied to the prevention or treatment of various diseases associated with IDO.

Description

[Technical Field]

[0001] The present invention relates to novel compounds having inhibitory activity against indoleamine-2,3-dioxygenase (IDO), namely derivatives having a cyclohexyl-(alkyl-substituted or cycloalkyl-substituted)ethylene-amino-heteroaryl moiety or pharmaceutically acceptable salts thereof, methods for producing the same, pharmaceutical compositions containing the same, and uses thereof. [Background technology]

[0002] The rapid growth of cancer stems from its ability to evade attack by the immune system. Tryptophan has been reported to play a crucial role in cancer immune evasion (Opitz, CA et al. Nature 478, 197-203 (2011)). In particular, the complex interactions between cancer cells and immune cells are one of the key factors determining the survival and death of early cancer cells. The pathways that cancer cells use to evade attack by immune cells are related to immunosuppressive pathways. Recently, the degradation process of tryptophan by indoleamine-2,3-dioxygenase (IDO) and the role of the resulting kynurenine have attracted attention.

[0003] Tryptophan is an essential amino acid for cell proliferation and survival. Indoleamine-2,3-dioxygenase (commonly called "IDO-1") is an intracellular heme-containing enzyme that catalyzes the first rate-limiting step in the breakdown of tryptophan to N-formyl-kynurenine. IDO acts on the metabolism of L-tryptophan, breaking it down to N-formyl-kynurenine, which is then metabolized at various stages to produce nicotinamide adenine dinucleotide (NAD+). Tryptophan catabolites produced from N-formyl-kynurenine, such as kynurenine, are known to be cytotoxic to T cells. Therefore, IDO inhibits the activity of immune cells, including T cells, through various mechanisms by depleting tryptophan and generating kynurenine (Mellor, AL & Munn, DH Nature Rev. Immunol. 8, 74-80 (2008), Fallarino, F., Gizzi, S., Mosci, P., Gronmann, U. & Puccetti, P. Curr. Drug Metab. 8, 209-216 (2007)). IDO is also distributed in dendritic cells and regulatory B cells (and cancer cells), and acts on these cells to suppress the immune system's ability to recognize and attack cancer cells. Thus, overexpression of IDO leads to increased resistance of the tumor microenvironment, resulting in the proliferation of cancer tissue.

[0004] It has been reported that elevated IDO expression is associated with a poor prognosis in cancer patients (Uyttenhove, C. et al. Nature Med. 9, 1269-1274 (2003)). Studies using IDO gene knockout mice have confirmed that IDO plays an important role in immune tolerance and inflammatory carcinogenesis (Muller, AJ, Mandik-Nayak, L. & Prendergast, GC Immunotherapy 2, 293-297 (2010); Muller, AJ et al. Proc. Natl Acad. Sci. USA 105, 17073-17078 (2008)). In particular, it has been reported that the use of IDO inhibitors as adjunctive therapy improves the efficacy of immunochemotherapy, radiotherapy, and anti-cancer vaccines (Muller, AJ, DuHadaway, JB, Donover, PS, Sutanto-Ward, E. & Prendergast, GC Nature Med. 11, 312-319 (2005)). Furthermore, it has been reported that the potent effect of the anti-cancer drug imatinib (Gleevec) against solid gastrointestinal stromal tumors is due to IDO inhibition (Balachandran, VP et al. Nature Med. 17, 1094-1100 (2011)).

[0005] Therefore, IDO inhibitors can effectively inhibit cancer metastasis and proliferation. Furthermore, IDO inhibitors can be effectively applied to the treatment and prevention of viral infections and autoimmune diseases such as rheumatoid arthritis. In addition, IDO inhibitors can be used to activate T cells during pregnancy, malignant tumors, or virus-induced T cell suppression. Although the mechanism of action is not fully understood, IDO inhibitors are expected to be applicable to the treatment of patients with neuropsychiatric disorders and conditions such as depression. For example, International Publication No. WO2016 / 073770 and International Publication No. WO2018 / 039512 disclose compounds having inhibitory activity against indoleamine-2,3-dioxygenase and pharmaceutical compositions containing the same. [Overview of the project] [Problems that the invention aims to solve]

[0006] The inventors have found that derivatives having a cyclohexyl-(alkyl-substituted or cycloalkyl-substituted)ethylene-amino-heteroaryl moiety or pharmaceutically acceptable salts thereof not only exhibit excellent inhibitory activity against indoleamine-2,3-dioxygenase, but also show remarkably high in vivo exposure levels upon oral administration. Therefore, these derivatives or pharmaceutically acceptable salts thereof can be usefully applied to prevent or treat various IDO-related diseases, such as proliferative disorders including cancer, viral infections, and / or autoimmune diseases.

[0007] Accordingly, the present invention provides a derivative having the cyclohexyl-(alkyl-substituted or cycloalkyl-substituted)ethylene-amino-heteroaryl moiety or a pharmaceutically acceptable salt thereof, a method for producing the same, a pharmaceutical composition containing the same, and the use thereof. [Means for solving the problem]

[0008] One embodiment of the present invention provides a derivative having a cyclohexyl-(alkyl-substituted or cycloalkyl-substituted)ethylene-amino-heteroaryl moiety or a pharmaceutically acceptable salt thereof.

[0009] Another embodiment of the present invention provides a method for producing a derivative having the cyclohexyl-(alkyl-substituted or cycloalkyl-substituted)ethylene-amino-heteroaryl moiety or a pharmaceutically acceptable salt thereof.

[0010] In yet another aspect of the present invention, a pharmaceutical composition is provided comprising a derivative having the cyclohexyl-(alkyl-substituted or cycloalkyl-substituted)ethylene-amino-heteroaryl moiety or a pharmaceutically acceptable salt thereof as an active ingredient.

[0011] In yet another aspect of the present invention, a therapeutic method is provided, comprising administering a derivative having the cyclohexyl-(alkyl-substituted or cycloalkyl-substituted)ethylene-amino-heteroaryl moiety or a pharmaceutically acceptable salt thereof.

[0012] In yet another aspect of the present invention, the use of a derivative having the cyclohexyl-(alkyl-substituted or cycloalkyl-substituted)ethylene-amino-heteroaryl moiety or a pharmaceutically acceptable salt thereof is provided for the production of a drug for inhibiting indoleamine-2,3-dioxygenase. [Effects of the Invention]

[0013] The present invention has revealed that derivatives having a cyclohexyl-(alkyl-substituted or cycloalkyl-substituted)ethylene-amino-heteroaryl moiety or pharmaceutically acceptable salts thereof not only exhibit excellent inhibitory activity against indoleamine-2,3-dioxygenase, but also show remarkably high in vivo exposure levels upon oral administration. Therefore, the compounds according to the present invention or pharmaceutically acceptable salts thereof can be usefully applied to prevent or treat various diseases associated with indoleamine-2,3-dioxygenase, such as proliferative disorders including cancer, viral infections, and / or autoimmune diseases. [Brief explanation of the drawing]

[0014] [Figure 1] The blood concentration profiles obtained by orally administering the compound of the present invention and the control substance (BMS-986205) to rats are shown. [Modes for carrying out the invention]

[0015] The present invention provides a compound or salt thereof that has excellent inhibitory activity against indoleamine-2,3-dioxygenase, i.e., the compound of chemical formula 1 or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R is a C1-C6 alkyl group or C3-C 10 It is a cycloalkyl group, A is a heteroaryl group selected from the group consisting of quinazolinyl, 2H-chromen-2-onyl, benzothiazolyl, benzoxazolyl, thiazolopyridinyl, oxazolopyridinyl, isoquinolinyl, and phthalazinyl, and the heteroaryl group may be substituted with one or two substituents selected from the group consisting of halogen, C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, halogeno-C1-C6 alkoxy, trifluoromethoxy, and cyano.

[0016] In one embodiment of the present invention, R may be methyl, ethyl, or cyclopropyl.

[0017] In another embodiment of the present invention, A may be a substituted or unsubstituted quinazolinyl group, preferably a quinazolinyl group substituted with one or two substituents selected from the group consisting of halogens, C1-C6 alkyls, trifluoromethyls, C1-C6 alkoxys, trifluoromethoxys, and cyanos. For example, A may have the structure of the following chemical formula 1a. [ka] In the formula, R 11 and R 12 R is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, halogeno-C1-C6 alkoxy, trifluoromethoxy, and cyano, 13 R may be hydrogen or a halogen. In one embodiment, R 13 This can be hydrogen, Cl, or F.

[0018] In yet another embodiment of the present invention, A may be a substituted or unsubstituted 2H-chromen-2-on-yl group, preferably a 2H-chromen-2-on-yl group substituted with one or two halogens. For example, A may have the structure of Chemical Formula 1b below. [Chemical Formula] In the formula, R 21 and R 22 are each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, halogeno-C1-C6 alkoxy, trifluoromethoxy, and cyano.

[0019] In yet another embodiment of the present invention, A may be a substituted or unsubstituted benzothiazolyl group, preferably a benzothiazolyl group substituted with one or two substituents selected from the group consisting of halogen and C1-C6 alkoxy. For example, A may have the structure of Chemical Formula 1c below. [Chemical Formula] In the formula, R 31 and R 32 are each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, halogeno-C1-C6 alkoxy, trifluoromethoxy, and cyano.

[0020] In yet another embodiment of the present invention, A may be a substituted or unsubstituted thiazolopyridinyl group, preferably a thiazolopyridinyl group optionally substituted with halogen or C1-C6 alkoxy. For example, A may have the structure of Chemical Formula 1d-1 or 1d-2 below. [Chemical Formula] [Chemical Formula] In the formula, R 41 and R 42 These are independently selected from the group consisting of hydrogen, halogens, C1-C6 alkyl groups, trifluoromethyl groups, C1-C6 alkoxy groups, halogeno-C1-C6 alkoxy groups, trifluoromethoxy groups, and cyano groups.

[0021] In yet another embodiment of the present invention, A may be a substituted or unsubstituted benzoxazolyl group, and preferably a benzoxazolyl group that is substituted with one or two substituents selected from the group consisting of halogens, C1-C6 alkoxys, and halogeno-C1-C6 alkoxys. For example, A may have the structure of the following chemical formula 1e. [ka] In the formula, R 51 and R 52 These are independently selected from the group consisting of hydrogen, halogens, C1-C6 alkyl groups, trifluoromethyl groups, C1-C6 alkoxy groups, halogeno-C1-C6 alkoxy groups, trifluoromethoxy groups, and cyano groups.

[0022] In yet another embodiment of the present invention, A may be a substituted or unsubstituted oxazolopyridinyl group, and preferably an oxazolopyridinyl group that is substituted with a halogen. For example, A may have the structure of the following chemical formula 1f-1 or 1f-2. [ka] [ka] In the formula, R 61 and R 62 These are independently selected from the group consisting of hydrogen, halogens, C1-C6 alkyl groups, trifluoromethyl groups, C1-C6 alkoxy groups, halogeno-C1-C6 alkoxy groups, trifluoromethoxy groups, and cyano groups.

[0023] In yet another embodiment of the present invention, A may be a substituted or unsubstituted isoquinolinyl group, preferably a halogen-substituted isoquinolinyl group. For example, A may have the structure of the following chemical formula 1g. [ka] In the formula, R 71 and R 72 These are independently selected from the group consisting of hydrogen, halogens, C1-C6 alkyl groups, trifluoromethyl groups, C1-C6 alkoxy groups, halogeno-C1-C6 alkoxy groups, trifluoromethoxy groups, and cyano groups.

[0024] In yet another embodiment of the present invention, A may be a substituted or unsubstituted phthalazinyl group, preferably a halogen-substituted phthalazinyl group. For example, A may have the structure of the following chemical formula 1h. [ka] In the formula, R 81 and R 82 These are independently selected from the group consisting of hydrogen, halogens, C1-C6 alkyl groups, trifluoromethyl groups, C1-C6 alkoxy groups, halogeno-C1-C6 alkoxy groups, trifluoromethoxy groups, and cyano groups.

[0025] In this specification, if a heteroaryl is substituted with two halogens, those halogens may be the same or different. If a heteroaryl is substituted with two C1-C6 alkyl groups, those C1-C6 alkyl groups may be the same or different. If a heteroaryl is substituted with two C1-C6 alkoxy groups, those C1-C6 alkoxy groups may be the same or different. If a heteroaryl is substituted with two halogeno-C1-C6 alkoxy groups, those halogeno-C1-C6 alkoxy groups may be the same or different.

[0026] In compounds of chemical formula 1 or pharmaceutically acceptable salts thereof, preferred compounds include compounds selected from the group consisting of the following or pharmaceutically acceptable salts thereof: 4-(((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)quinazoline-7-carbonitrile; 7-Bromo-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 7-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 7-Chloro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 7-Bromo-4-(((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one; 7-Chloro-4-(((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one; 6-Bromo-4-(((R)-1-((Trans)-4-(6-Fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-Cromen-2-one; 7-Chloro-4-(((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one; 7-Bromo-4-(((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one; 7-Chloro-3-fluoro-4-(((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one; 7-Bromo-3-fluoro-4-(((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one; 7-Bromo-3-fluoro-4-(((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one; 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazole-2-amine; N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-6-methoxybenzo[d]thiazole-2-amine; N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)butan-2-yl)-6-methoxybenzo[d]thiazole-2-amine; N-((S)-1-cyclopropyl-2-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)ethyl)-6-methoxybenzo[d]thiazole-2-amine; 4,6-Difluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazole-2-amine; 7-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazole-2-amine; 6-Ethoxy-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazole-2-amine; 6-Ethoxy-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)butan-2-yl)benzo[d]thiazole-2-amine; N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)thiazolo[4,5-b]pyridine-2-amine; N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-5-methoxythiazolo[5,4-b]pyridine-2-amine; 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)thiazolo[4,5-b]pyridine-2-amine; N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-6-methoxybenzo[d]oxazole-2-amine; 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)butan-2-yl)benzo[d]oxazole-2-amine; 4-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; 6-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)oxazolo[5,4-b]pyridine-2-amine; 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)oxazolo[4,5-b]pyridine-2-amine; N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)oxazolo[4,5-b]pyridine-2-amine; 6-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)isoquinoline-1-amine; 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)isoquinoline-1-amine; 4-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazole-2-amine; 5-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; 7-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; 2-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)phthalazine-1-amine; 2,7-Dichloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 2,7-Dichloro-N-((R)-1-((Trans)-4-(6-Fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)Quinazoline-4-amine; 7-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-6-methoxybenzo[d]oxazole-2-amine; 6-Chloro-5-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; 6-Ethoxy-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; 6-(2-fluoroethoxy)-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; 6,7-Dichloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; 6,7-Difluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; 2-Chloro-6-fluoro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 2,6-Dichloro-N-((R)-1-((Trans)-4-(6-Fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)Quinazoline-4-amine; 2-Chloro-8-fluoro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 2,8-Dichloro-N-((R)-1-((Trans)-4-(6-Fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)Quinazoline-4-amine; 2-Chloro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-8-methoxyquinazoline-4-amine; 2-Chloro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-8-(trifluoromethoxy)quinazoline-4-amine; 2-Chloro-7-fluoro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 2-Chloro-4-(((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)quinazoline-7-carbonitrile; 7-Bromo-2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 2-Chloro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-7-methylquinazoline-4-amine; 2-Chloro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-7-(trifluoromethyl)quinazoline-4-amine; 2-Chloro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-7-methoxyquinazoline-4-amine; 2-Chloro-6-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 2,6-Dichloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 2-Chloro-7-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 2-Chloro-4-(((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)quinazoline-7-carbonitrile; 7-Bromo-2-chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 2-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-7-methylquinazoline-4-amine; 2-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-7-(trifluoromethyl)quinazoline-4-amine; 2-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-7-methoxyquinazoline-4-amine; 2,8-Dichloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 2-Chloro-8-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 2-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-8-methoxyquinazoline-4-amine; and 2-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-8-(trifluoromethoxy)quinazoline-4-amine.

[0027] Among compounds of chemical formula 1 or pharmaceutically acceptable salts thereof, more preferred compounds include compounds selected from the group consisting of the following or pharmaceutically acceptable salts thereof: 7-Bromo-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 7-Bromo-4-(((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one; 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)butan-2-yl)benzo[d]oxazole-2-amine; 4-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; 6-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; and 6,7-Difluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine.

[0028] Among compounds of chemical formula 1 or pharmaceutically acceptable salts thereof, particularly preferred compounds include 6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine or pharmaceutically acceptable salts thereof.

[0029] Compounds of chemical formula 1 or their pharmaceutically acceptable salts may have substituents containing chiral atoms, and geometric isomers via cyclohexyl may exist. That is, compounds of chemical formula 1 or their pharmaceutically acceptable salts may be in the form of cis- or trans-geometric isomers, (R)- or (S)-optical isomers, or racemic mixtures (RS). Therefore, unless otherwise specified, compounds of chemical formula 1 or their pharmaceutically acceptable salts include cis- or trans-geometric isomers, (R)- or (S)-optical isomers, and racemic mixtures (RS).

[0030] The compound of Chemical Formula 1 of the present invention may also be in the form of a pharmaceutically acceptable salt. The salt may be in the form of a conventional acid addition salt, for example, a salt derived from an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, or nitric acid; and a salt derived from an organic acid such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, citric acid, maleic acid, malonic acid, methanesulfonic acid, tartaric acid, malic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxybenzoic acid, fumaric acid, p-toluenesulfonic acid, oxalic acid, or trifluoroacetic acid. Furthermore, the salt may also be in the form of a conventional metal salt, for example, a salt derived from a metal such as lithium, sodium, potassium, magnesium, or calcium. Acid addition salts or metal salts can be prepared according to conventional methods.

[0031] The present invention includes, within its scope, a method for producing a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0032] For example, the compound of chemical formula 1 or a pharmaceutically acceptable salt thereof according to the present invention can be produced by a manufacturing method comprising the steps of: reacting the compound of chemical formula 2 or a salt thereof with the compound of chemical formula 3 to obtain the compound of chemical formula 1; and optionally, converting the compound of chemical formula 1 into its pharmaceutically acceptable salt: [ka] <Chemical formula 3> XA In the formula, R and A are the same as defined above, and X is a halogen.

[0033] The compound of chemical formula 3 is commercially available. The coupling reaction between the compound of chemical formula 2 or its salt (e.g., hydrochloride) and the compound of chemical formula 3 may be carried out in the presence of a base and a solvent. Examples of bases include cesium carbonate, potassium carbonate, sodium carbonate, and triethylamine, and examples of solvents include organic solvents such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, ethanol, or isopropyl alcohol. The reaction may also be carried out at room temperature to 100°C.

[0034] The compound of Chemical Formula 2 or its salts are novel compounds and can be usefully used as intermediates in the production of derivatives having a cyclohexyl-(alkyl-substituted or cycloalkyl-substituted)ethylene-amino-heteroaryl moiety or pharmaceutically acceptable salts thereof (i.e., compounds of Chemical Formula 1 or their pharmaceutically acceptable salts) according to the present invention. Therefore, the present invention includes, within its scope, compounds of Chemical Formula 2 or their salts. Examples of salts of the compound of Chemical Formula 2 include acid addition salts such as hydrochloride salts.

[0035] For example, a compound of chemical formula 2a (R=methyl) may be prepared according to the following reaction formula 1. [ka]

[0036] The compound of chemical formula 5 may also be prepared by the Suzuki reaction of the compound of chemical formula 4 (commercially available) with 4-chloro-6-fluoroquinoline. The reaction may be carried out using a palladium catalyst such as palladium(II) acetate (Pd(OAc)2), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), tetrakis(triphenylphosphine)palladium(O) (Pd(PPh3)4), or [1,1'-bis(diphenylphosphinoferocene)]dichloropalladium(II) (Pd(dppf)Cl2). In addition, the reaction may be carried out in the presence of a ligand and a base in addition to the palladium catalyst. Examples of ligands include (S)-2,2'-bis(diphenylphosphin)-1,1'-binaphthyl (BINAP), 1,1'-bis(diphenylphosphin)ferrocene (dppf), and tri(o-tolyl)phosphine (P(o-Tol)3). Examples of bases include inorganic bases such as cesium carbonate (Cs2CO3), sodium carbonate (Na2CO3), potassium carbonate (K2CO3), potassium fluoride (KF), cesium fluoride (CsF), sodium hydroxide (NaOH), potassium phosphate (K3PO4), sodium tert-butoxide (tert-BuONa), and potassium tert-butoxide (tert-BuOK). The reaction may be carried out in a nonpolar organic solvent such as benzene or toluene, or in a polar organic solvent such as 1,4-dioxane, tetrahydrofuran, acetonitrile, 1,2-dimethoxyethane, or N,N-dimethylformamide, at 50°C to 150°C, preferably 80°C to 110°C. Other reaction conditions, including reaction time, may be determined according to known methods for the Suzuki reaction (Barbara Czako and Laszlo Kurti, STRATEGIC APPLICATIONS of NAMED REACTIONS in ORGANIC SYNTHESIS, 2005).

[0037] The reduction of the compound of chemical formula 5 may be carried out using palladium / carbon in an organic solvent such as ethyl acetate or methanol. The reduction may also be carried out at room temperature using hydrogen.

[0038] The reduction of the compound of chemical formula 6 may be carried out using lithium aluminum hydride in an organic solvent such as tetrahydrofuran or dichloromethane. This reduction may typically be carried out at -78°C to room temperature.

[0039] The oxidation of the compound of chemical formula 7 may be carried out using an oxidizing agent in an organic solvent such as ethyl acetate or dichloromethane. This oxidation may usually be carried out at 0°C to room temperature.

[0040] The compound of chemical formula 9 may also be prepared by condensing the compound of chemical formula 8 with (S)-(-)-2-methyl-2-propanesulfinamide. The condensation may be carried out in an organic solvent such as ethyl acetate, dichloromethane, or tetrahydrofuran, in the presence of a Lewis acid catalyst such as titanium(IV) isopropoxide or titanium(IV) epoxide. The reaction may be carried out at -78°C to room temperature.

[0041] The compound of chemical formula 10 may be prepared by reacting the compound of chemical formula 9 with an alkyl Grignard reagent. Furthermore, the compound of chemical formula 2a or its salt (e.g., hydrochloride) may be obtained by deprotection of the compound of chemical formula 10. This deprotection may be carried out according to known methods (Theodora W. Greene and Peter GM Wuts, Protective groups in organic synthesis, 3rd Ed., 1999). For example, this deprotection may be carried out at room temperature in an organic solvent such as dichloromethane, 1,4-dioxane, or ethyl acetate, using a trifluoroacetic acid solution or a hydrochloric acid solution.

[0042] The derivative having a cyclohexyl-(alkyl-substituted or cycloalkyl-substituted)ethylene-amino-heteroaryl moiety according to the present invention, or a pharmaceutically acceptable salt thereof (i.e., the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof), exhibits excellent inhibitory activity against indoleamine-2,3-dioxygenase (IDO). Furthermore, the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof shows remarkably high in vivo exposure when administered orally. The inventors conducted studies on changes in biomarkers and pharmacokinetics in a subcutaneous MC38 colorectal cancer model of C57BL / 6 mice. After oral administration for 1 day, the group administered with the compound of the present invention showed a significant decrease in kynurenine levels in plasma and tumor tissue compared to the vehicle group and the positive control group (BMS-986205, Epacadostat). After oral administration for 3 days, the group administered with the compound of the present invention showed a significant decrease in kynurenine levels in plasma and tumor tissue. In particular, in the group administered with the specific compound of the present invention for 3 days, kynurenine levels in plasma and tumor tissue were almost completely reduced. Therefore, the compound of chemical formula 1 or its pharmaceutically acceptable salt can be usefully applied for the prevention or treatment of various diseases associated with IDO.

[0043] Accordingly, the present invention includes, within its scope, pharmaceutical compositions for inhibiting indoleamine-2,3-dioxygenase, comprising a therapeutically effective amount of the compound of chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. In one embodiment, the present invention provides a pharmaceutical composition for preventing or treating IDO-related diseases such as viral infections; autoimmune diseases (e.g., rheumatoid arthritis); cancers (e.g., melanoma, pancreatic cancer, prostate cancer, brain cancer); or neuropsychiatric disorders (e.g., depression), comprising a therapeutically effective amount of the compound of chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0044] The pharmaceutical composition of the present invention may contain pharmaceutically acceptable carriers such as diluents, disintegrants, sweeteners, lubricants, or flavoring agents commonly used in the art. The pharmaceutical composition can be formulated according to conventional methods into oral dosage forms such as tablets, capsules, powders, granules, suspensions, emulsions, or syrups; or into parenteral dosage forms such as topical solutions, topical suspensions, topical emulsions, gels (e.g., ointments), inhalants, sprays, or injections. Various dosage forms are possible, such as single-dose or multi-dose forms.

[0045] The pharmaceutical composition of the present invention may, for example, contain a diluent (e.g., lactose, corn starch, etc.); a lubricant (e.g., magnesium stearate); an emulsifier; a suspending agent; a stabilizer; and / or an isotonic agent. Optionally, the composition may further contain a sweetener and / or a flavoring agent.

[0046] The compositions of the present invention may be administered orally, or parenterally, including by routes of administration such as inhalation, intravenous, intraperitoneal, subcutaneous, rectal, and topical application. Accordingly, the compositions of the present invention can be formulated in various forms such as tablets, capsules, aqueous solutions, or suspensions. For oral tablets, carriers such as lactose and corn starch, and lubricants such as magnesium stearate are commonly used. For oral capsules, lactose and / or dried corn starch can be used as diluents. If an aqueous suspension for oral administration is required, emulsifiers and / or suspending agents can be incorporated into the active ingredient. Specific sweeteners and / or flavorings may be used as needed. For intramuscular, intraperitoneal, subcutaneous, and intravenous administration, it is usually necessary to prepare a sterile solution of the active ingredient and buffer it by appropriately adjusting the pH of the solution. For intravenous administration, it is necessary to adjust the total concentration of the solute to make the formulation isotonic. The compositions of the present invention can be in the form of an aqueous solution containing a pharmaceutically acceptable carrier, such as physiological saline with a pH of 7.4. This solution can be introduced into the patient's muscle bloodstream via local bolus injection.

[0047] The compound of chemical formula 1 or a pharmaceutically acceptable salt thereof may be administered to the patient in a therapeutically effective dose ranging from approximately 5 mg / kg to approximately 50 mg / kg per day, preferably from approximately 10 mg / kg to approximately 20 mg / kg per day, either as a single dose or multiple doses. Of course, the aforementioned dose may be adjusted depending on the patient's age, weight, sensitivity, symptoms, or the activity of the compound.

[0048] Within its scope, the present invention includes a method for inhibiting indoleamine-2,3-dioxygenase in mammals, comprising administering a therapeutically effective amount of the compound of chemical formula 1 or a pharmaceutically acceptable salt thereof to a mammal in need. In one embodiment, the present invention provides a method for treating indoleamine-2,3-dioxygenase-related diseases such as viral infections; autoimmune diseases (e.g., rheumatoid arthritis); cancers (e.g., melanoma, pancreatic cancer, prostate cancer, brain cancer); or neuropsychiatric disorders (e.g., depression), comprising administering a therapeutically effective amount of the compound of chemical formula 1 or a pharmaceutically acceptable salt thereof to a mammal in need.

[0049] The present invention also provides the use of a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof for producing agents for inhibiting indoleamine-2,3-dioxygenase in mammals. In one embodiment, the present invention provides the use of a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof for producing agents for preventing or treating diseases associated with indoleamine-2,3-dioxygenase, such as viral infections; autoimmune diseases (e.g., rheumatoid arthritis); cancers (e.g., melanoma, pancreatic cancer, prostate cancer, brain cancer); or neuropsychiatric disorders (e.g., depression). [Examples]

[0050] The following examples and test examples are for illustrative purposes only and do not limit the scope of the present invention.

[0051] The compounds prepared in the following examples were analyzed as follows: Nuclear magnetic resonance (NMR) spectroscopy was performed using a Bruker 400 MHz spectrometer, and chemical shifts were analyzed in ppm units. Column chromatography was performed using silica gel (Merck, 70-230 mesh) (WCStill, J. Org. Chem., 43, 2923, 1978). Each starting material is a known compound, which was synthesized according to the literature or commercially purchased, for example, from Sigma-Aldrich.

[0052] Manufacturing Example 1: (R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride [ka]

[0053] Step 1: Ethyl 2-(4-(6-fluoroquinoline-4-yl)cyclohexa-3-en-1-yl)acetate [ka] Ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexa-3-en-1-yl) acetate (5.83 g), 4-chloro-6-fluoroquinoline (3.00 g), and sodium carbonate (5.35 g) were dissolved in a mixed solvent of 1,4-dioxane (30 ml) and water (30 ml). [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) (675 mg) was added to the solution and stirred overnight at 95°C. After concentrating the reaction mixture, ethyl acetate was added. The mixture was washed with distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a yellow residue. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1, v / v) to obtain 4.40 g of the title compound as a white solid. (Yield: 82.4%) 1H-NMR (CDCl3) δ 8.79 (d, 1H), 8.10 (t, 1H), 7.61 (d, 1H), 7.51 (t, 1H), 7.18 (d, 1H), 5.81 (s, 1H), 4.18 (q, 2H), 2.51-2.28 (m, 7H), 2.02 (m, 2H), 1.58 (m, 1H), 1.28 (t, 3H)

[0054] Step 2: Ethyl 2-(4-(6-fluoroquinoline-4-yl)cyclohexyl)acetate [ka] The methanol solution (30 ml) containing ethyl 2-(4-(6-fluoroquinoline-4-yl)cyclohexa-3-en-1-yl) acetate (4.40 g), 10% Pd / C (440 mg), and acetic acid (0.16 ml) prepared in step 1 was stirred under a hydrogen atmosphere for 12 hours. After drying the reaction mixture, it was filtered. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1, v / v) to obtain 4.17 g of the title compound as a white solid. (Yield: 94.2%) 1 H-NMR (CDCl3) δ 8.80 (s, 1H), 8.11 (t, 1H), 7.65 (d, 1H), 7.46 (t, 1H), 7.30 (d, 1H), 4.16 (q, 2H), 3.21-3.06 (m, 1H), 2.49 (s, 1H), 2.30 (d, 1H), 2.04-1.72 (m, 7H), 1.62 (q, 1H), 1.37-1.24 (m, 4H)

[0055] Step 3: 2-(4-(6-fluoroquinoline-4-yl)cyclohexyl)ethane-1-ol [ka] A solution of ethyl 2-(4-(6-fluoroquinoline-4-yl)cyclohexyl)acetate (2.27 g) prepared in step 2 was stirred in tetrahydrofuran (24 ml) at 0°C for 10 minutes, and then lithium aluminum hydride (355 mg) was gradually added. The reaction mixture was stirred at room temperature for 6 hours. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. After recovering the two stereoisomers identified by TLC, the compound was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 2, v / v) to obtain 1.53 g of the title compound as a white solid. (Yield: 73.2%) 1 H-NMR (DMSO-d6) δ 8.77 (d, 1H), 8.06 (t, 1H), 7.89 (d, 1H), 7.62 (t, 1H), 7.35 (d, 1H), 4.63 (t, 1 / 2 H), 4.39 (t, 1 / 2 H), 3.47 (q, 2H), 3.20 (t, 1 / 2 H), 3.12 (t, 1 / 2 H), 1.87-1.72 (m, 4H), 1.50-1.36 (m, 4H), 1.21-1.14 (q, 2H)

[0056] Step 4: 2-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)acetaldehyde [ka] A solution of 2-(4-(6-fluoroquinoline-4-yl)cyclohexyl)ethane-1-ol (15.14 g) prepared in step 3 was stirred in dichloromethane (185 ml) at 0°C for 30 minutes, and then Dess-Martin oxidizing agent (35.2 g) was gradually added. The reaction mixture was stirred at room temperature for 5 hours. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. Of the two stereoisomers identified by TLC, the lower one was purified by silica gel column chromatography (n-hexane / ethyl acetate = 3 / 1, v / v) to obtain 8.72 g of the title compound as a white solid. (Yield: 57.9%) 1 H-NMR (CDCl3) δ 9.82 (s, 1H), 8.81 (d, 1H), 8.12 (t, 1H), 7.64 (d, 1H), 7.48 (t, 1H), 7.31 (d, 1H), 3.22 (t, 1H), 2.61 (s, 3H), 1.93-1.67 (m, 8H)

[0057] Step 5: (S)-N-(2-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)ethylidene)-2-methylpropane-2-sulfinamide [ka] The solution of 2-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)acetaldehyde (4.50 g) and (S)-(-)-2-methyl-2-propanesulfinamide (4.02 g) prepared in step 4 was stirred in dichloromethane (55 ml) at 0°C for 10 minutes, after which titanium(IV) isopropoxide (9.82 ml) was gradually added. The reaction mixture was stirred at room temperature for 8 hours. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 1, v / v) to obtain 5.22 g of the title compound as a white solid. (Yield: 84.0%) 1 H-NMR (CDCl3) δ 8.82 (1H, d), 8.14-8.10 (m, 2H), 7.64 (d, 1H), 7.46 (t, 1H), 7.33 (d, 1H), 3.22 (t, 1H), 2.72 (t, 2H), 2.04 (s, 1H), 1.95-1.68 (m, 8H), 1.21 (s, 9H)

[0058] Step 6: (R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride [ka] A solution of (S)-N-(2-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)ethylidene)-2-methylpropane-2-sulfinamide (2.54 g) prepared in step 5 was stirred in dichloromethane (23 ml) at 0°C for 10 minutes, and then a solution of methylmagnesium bromide in diethyl ether (3.0 M, 4.6 ml) was gradually added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was stopped by adding a saturated ammonium chloride solution to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The obtained substance was dissolved in ethyl acetate (25 ml), and then a solution of 1,4-dioxane in hydrochloric acid (4 N, 2 ml) was gradually added. The reaction mixture was stirred at room temperature for 8 hours. The resulting solid was filtered under reduced pressure and washed with ethyl acetate to obtain 1.67 g of the title compound as a white solid. (Yield: 86.0%) 1 H-NMR (DMSO-d6) δ 9.23 (d, 1H), 8.56 (t, 1H), 8.42 (d, 1H), 8.27 (s, 2H), 8.08 (t, 2H), 3.63 (s, 1H), 3.19 (s, 1H), 2.11 (m, 11H), 1.26 (d, 3H)

[0059] Manufacturing Example 2: (R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)butan-2-amine hydrochloride [ka] Using a tetrahydrofuran solution (2.0 M, 1.3 ml) of ethylmagnesium bromide instead of a diethyl ether solution of methylmagnesium bromide, 276 mg of the title compound was prepared as a white solid following the same procedure as in Preparation Example 1. (Yield: 86.0%) 1 H-NMR (DMSO-d6) δ 9.21 (d, 1H), 8.57 (q, 1H), 8.40 (d, 1H), 8.26 (s, 2H), 8.08 (q, 2H), 3.61 (s, 1H), 3.01 (s, 1H), 2.00-1.62 (m, 13H), 0.95 (t, 3H)

[0060] Manufacturing Example 3: (S)-1-Cyclopropyl-2-((cis)-4-(6-Fluoroquinoline-4-yl)cyclohexyl)ethane-1-amine hydrochloride [ka] Using a tetrahydrofuran solution (1.0 M, 1.3 ml) of cyclopropylmagnesium bromide instead of a diethyl ether solution of methylmagnesium bromide, 298 mg of the title compound was prepared as a white solid following the same procedure as in Preparation Example 1. (Yield: 71.4%) 1 H-NMR (DMSO-d6) δ 9.22 (d, 1H), 8.58 (q, 1H), 8.43 (d, 1H), 8.30 (s, 2H), 8.09 (t, 2H), 3.64 (s, 1H), 2.43 (s, 1H), 2.17 (s, 2H), 1.99-1.68 (m, 9H), 0.94 (s, 1H), 0.63-0.37 (m, 4H)

[0061] Manufacturing Example 4: (R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride

[0062] Step 1: 2-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)acetaldehyde [ka] A solution of 2-(4-(6-fluoroquinoline-4-yl)cyclohexyl)ethane-1-ol (15.14 g), prepared in step 3 of Preparation Example 1, was stirred in dichloromethane (185 ml) at 0°C for 30 minutes, after which Dess-Martin oxidizing agent (35.2 g) was gradually added. The reaction mixture was stirred at room temperature for 5 hours. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. Of the two stereoisomers identified by TLC from the resulting residue, the upper substance was purified by silica gel column chromatography (n-hexane / ethyl acetate = 3 / 1, v / v) to obtain 5.48 g of the labeled compound as a white solid. (Yield: 36.5%) 1 H-NMR (CDCl3) δ 9.84 (s, 1H), 8.83 (d, 1H), 8.12 (dd, 1H), 7.67 (dd, 1H), 7.49 (dd, 1H), 7.30 (d, 1H), 3.19-3.13 (dt, 1H), 2.46 (dd, 2H), 2.11-2.00 (m, 5H), 1.71-1.61 (m, 2H), 1.41-1.31 (m, 2H)

[0063] Step 2: (S)-N-(2-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)ethylidene)-2-methylpropane-2-sulfinamide [ka] A solution of 2-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)acetaldehyde (3.00 g) and (S)-(-)-2-methyl-2-propanesulfinamide (1.61 g) prepared in Step 1 was stirred in tetrahydrofuran (40 ml) at 0°C for 10 minutes, after which titanium(IV) isopropoxide (6.55 ml) was gradually added. The reaction mixture was stirred at room temperature for 8 hours. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 1, v / v) to obtain 4.1 g of the title compound as a white solid. (Yield: 99.0%) 1 H-NMR (CDCl3) δ 8.82(d, 1H), 8.13(dd, 1H), 7.65(dd, 1H), 7.48(dd, 1H), 7.30(d, 1H), 3.20-3.14(dt, 1H), 2.56( dd, 2H), 2.08-2.02(m, 4H), 1.96-1.91(m, 1H), 1.67-1.58(m, 2H), 1.43-1.33(m, 2H), 1.22(s, 9H)

[0064] Step 3: (R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride [ka] Using (S)-N-(2-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)ethylidene)-2-methylpropane-2-sulfinamide (3.2 g) prepared in step 2 instead of (S)-N-(2-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)ethylidene)-2-methylpropane-2-sulfinamide) prepared in step 2, 1.9 g of the title compound was prepared as a white solid following the same procedure as in step 6 of Preparation Example 1. (Yield: 68.9%) 1H-NMR (DMSO-d6) δ 9.12 (d, 1H), 8.47 (q, 1H), 8.34 (d, 1H), 8.17 (s, 2H), 8.00 (t, 1H), 7.84 (d, 1H), 3.54 (t, 1H), 3.28 (s, 1H), 1.95-1.84 (m, 4H), 1.66-1.26 (m, 7H), 1.24 (d, 3H)

[0065] Example 1: 4-(((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)quinazoline-7-carbonitrile A solution of (R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride (30 mg), 4-chloroquinazoline-7-carbonitrile (19 mg), and triethylamine (23.3 μl) prepared in Preparation Example 1 was refluxed in ethanol (1.0 ml) at 90°C for 4 hours. The reaction mixture was concentrated under reduced pressure. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 1, v / v) to obtain 12.2 mg of the title compound as a white solid. (Yield: 33.2%) 1 H-NMR (CDCl3) δ 8.80 (d, 1H), 8.71 (s, 1H), 8.17 (s, 1H), 8.12 (t, 1H), 7.86 (d, 1H), 7.67-7.60 (m, 2H), 7.47 (t, 1H), 7.31 (d, 1H), 5.82 (d, 1H), 4.67-4.64 (m, 1H), 3.22 (s, 1H), 2.03 (s, 1H), 1.92-1.73 (m, 10H), 1.39 (d, 3H)

[0066] Example 2: 7-Bromo-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine A solution of (R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride (120 mg), 7-bromo-4-chloroquinazoline (117.6 mg), and triethylamine (155.4 μl) prepared in Preparation Example 1 was refluxed in ethanol (1.0 ml) at 90°C for 4 hours. The reaction mixture was concentrated under reduced pressure. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 1, v / v) to obtain 113.0 mg of the title compound as a white solid. (Yield: 61.6%) 1 H-NMR (CDCl3) δ 8.80 (d, 1H), 8.63 (s, 1H), 8.11 (t, 1H), 8.01 (s, 1H), 7.65 (d, 1H), 7.57 (dd, 2H), 7.46 (t, 1H), 7.31 (s, 1H), 5.60 (d, 1H), 4.66-4.61 (m, 1H), 3.20 (s, 1H), 2.03 (s, 1H), 1.89-1.71 (m, 10H), 1.37 (d, 3H)

[0067] Example 3: 7-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine A solution of (R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride (57.5 mg), 4,7-dichloroquinazoline (50 mg), and triethylamine (23.3 μl) prepared in Preparation Example 1 was refluxed in ethanol (1.0 ml) at 90°C for 4 hours. The reaction mixture was concentrated under reduced pressure. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 1, v / v) to obtain 52.2 mg of the title compound as a white solid. (Yield: 46.3%) 1 H-NMR (CDCl3) δ 8.80 (d, 1H), 8.64 (s, 1H), 8.12-8.10 (m, 1H), 7.84 (s, 1H), 7.67-7.63 (m, 2H), 7.48-7.42 (m, 2H), 7.31 (s, 1H), 5.43 (m, 1H), 4.64-4.62 (m, 1H), 3.21 (m, 1H) 1.86-1.44 (m, 11H), 1.38 (d, 3H)

[0068] Example 4: 7-Chloro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine A solution of (R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride (130 mg), 4,7-dichloroquinazoline (180.7 mg), and triethylamine (190 μl) prepared in Preparation Example 4 was refluxed in ethanol (1.0 ml) at 90°C for 4 hours. The reaction mixture was concentrated under reduced pressure. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 1, v / v) to obtain 45.2 mg of the title compound as a white solid. (Yield: 34.8%) 1 H-NMR (CDCl3) δ 8.78 (d, 1H), 8.65 (s, 1H), 8.12-8.08 (m, 1H), 7.84 (s, 1H), 7.66-7.63 (m, 2H), 7.48-7.42 (m, 2H), 7.24 (d, 1H), 5.44 (m, 1H), 4.72 (m, 1H), 3.18-3.12 (m, 1H), 2.11 (d, 1H), 2.05-2.00 (m, 3H), 1.70-1.53 ​​(m, 7H), 1.38 (d, 3H)

[0069] Example 5: 7-Bromo-4-(((R)-1-((Trans)-4-(6-Fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-Cromen-2-one A solution of (R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride (30 mg), 7-bromo-4-chloro-2H-chromen-2-one (25.9 mg), and triethylamine (40.0 μl) in ethanol (1.0 ml) was refluxed at 90°C for 4 hours. The reaction mixture was concentrated under reduced pressure. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 1, v / v) to obtain 23.2 mg of the title compound as a white solid. (Yield: 43.8%) 1 H-NMR (CDCl3) δ:8.78 (d, 1H), 8.12-8.10 (m, 1H), 7.65 (dd, 1H), 7.50-7.41 (m, 4H), 7.27 (s, 1H), 5.35 (s, 1H), 5.15 (d, 1H), 3.78-3.72 (m, 1H), 3.18-3.10 (m, 1H), 2.10-1.89 (m, H), 1.86-1.44 (m, 5H), 1.40-1.18 (m, 9H)

[0070] Example 6: 7-Chloro-4-(((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one A solution of (R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride (30 mg), 4,7-dichloro-2H-chromen-2-one (45.1 mg), and triethylamine (40.0 μl) in ethanol (1.0 ml) was refluxed at 90°C for 4 hours. The reaction mixture was concentrated under reduced pressure. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 1, v / v) to obtain 11.0 mg of the title compound as a white solid. (Yield: 22.6%) 1 H-NMR (CDCl3) δ 8.78 (d, 1H), 8.13-8.09 (m, 1H), 7.66-7.63 (d, 1H), 7.50-7.40 (m, 2H), 7.35 (s, 1H), 7.26-7.24 (m, 2H), 5.35 (s, 1H), 4.96 (d, 1H), 3.82-3.78 (m, 1H), 3.18-3.12 (m, 1H), 2.08-2.04 (m, 4H), 1.75 (m, 1H), 1.63-1.56 (m, 4H), 1.38 (d, 3H)

[0071] Example 7: 6-bromo-4-(((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one A solution of (R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride (80.8 mg), 6-bromo-4-chloro-2H-chromen-2-one (50 mg), and triethylamine (23.3 μl) in ethanol (1.0 ml) was refluxed at 90°C for 4 hours. The reaction mixture was concentrated under reduced pressure. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 1, v / v) to obtain 54.3 mg of the title compound as a white solid. (Yield: 55.3%) 1 H-NMR (CDCl3) δ 8.81 (d, 1H), 8.26 (t, 1H), 7.71-7.60 (m, 3H), 7.52 (t, 1H), 7.34 (d, 1H), 7.23 (t, 1H), 5.38 (s, 1H), 5.04 (d, 1H), 3.83-3.78 (m, 1H), 3.19 (t, 1H), 2.12-1.98 (m, 4H), 1.77 (t, 1H), 1.64-1.55 (m, 4H), 1.38-1.22 (m, 5H)

[0072] Example 8: 7-Chloro-4-(((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one A solution of (R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride (30 mg), 4,7-dichloro-2H-chromen-2-one (45.1 mg), and triethylamine (40.0 μl) in ethanol (1.0 ml) was refluxed at 90°C for 4 hours. The reaction mixture was concentrated under reduced pressure. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 1, v / v) to obtain 5.5 mg of the title compound as a white solid. (Yield: 11.3%) 1 H-NMR (CDCl3) δ 8.80 (d, 1H), 8.13-8.10 (m, 1H), 7.66-7.63 (d, 1H), 7.50-7.45 (m, 1H), 7.39-7.31 (m, 3H), 7.26-7.24 (m, 1H), 5.35 (s, 1H), 4.88 (d, 1H), 3.74-3.70 (m, 1H), 3.23-3.20 (m, 1H), 2.04-2.00 (m, 1H), 1.88-1.64 (m, 10H), 1.36 (d, 3H)

[0073] Example 9: 7-Bromo-4-(((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one A solution of (R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride (30 mg), 7-bromo-4-chloro-2H-chromen-2-one (25.9 mg), and triethylamine (40.0 μl) in ethanol (1.0 ml) was refluxed at 90°C for 4 hours. The reaction mixture was concentrated under reduced pressure. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 1, v / v) to obtain 19.5 mg of the title compound as a white solid. (Yield: 36.0%) 1 H-NMR (CDCl3) δ 8.80 (d, 1H), 8,13-8.10 (dd, 1H), 7.64 (dd, 1H), 7.50-7.44 (m, 2H), 7.38 (s, 2H), 7.31 (d, 1H), 5.35 (s, 1H), 5.10 (d, 1H), 3.74-3.68 (m, 1H), 3.22-3.20 (m, 1H), 2.07-1.97 (m, 1H), 1.92-1.65 (m, 10H), 1.35 (d, 3H), 1.25 (s, 2H)

[0074] Example 10: 7-Chloro-3-fluoro-4-(((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one 100 mg of 7-chloro-4-(((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one hydrochloride, prepared in Example 6, was dissolved in a mixed solvent of methanol (1.0 ml) and acetonitrile (1.0 ml). The reaction mixture was stirred at -10°C for 10 minutes, and then Selectfluor (83.4 mg) was gradually added. The reaction mixture was stirred at -10°C for 10 minutes, and then stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. Water was added to the reaction mixture to stop the reaction, and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 1, v / v) to obtain 5.2 mg of the title compound as a white solid. (Yield: 84.0%) 1 H-NMR (CDCl3) δ 8.79 (d, 1H), 8.11 (t, 1H), 7.05 (t, 1H), 7.47-7.26 (m, 5H), 4.35 (d, 2H), 3.74 (m, 1H), 3.20-3.09 (m, 1H), 2.11-1.96 (m, 4H), 1.88-1.82 (m, 1H), 1.75-1.49 (m, 4H), 1.46-1.32 (m, 5H)

[0075] Example 11: 7-Bromo-3-fluoro-4-(((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one 7-bromo-4-(((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one (68 mg), prepared in Example 9, was dissolved in a mixed solvent of methanol (1.0 ml) and acetonitrile (1.0 ml). The reaction mixture was stirred at -10°C for 10 minutes, and then Selectfluor (77.7 mg) was gradually added. The reaction mixture was stirred at -10°C for 10 minutes, and then stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 1, v / v) to obtain 61.0 mg of the title compound as a white solid. (Yield: 86.4%) 1 H-NMR (CDCl3) δ 8.80 (d, 1H), 8.11 (t, 1H), 7.65 (d, 1H), 7.51-7.26 (m, 4H), 6.98 (s, 1H), 4.48 (d, 1H), 4.26-4.22 (m, 1H), 3.27-3.16 (m, 1H), 2.27 (s, 1H), 2.05 (s, 2H), 1.91-1.64 (m, 8H), 1.38 (d, 3H)

[0076] Example 12: 7-Bromo-3-fluoro-4-(((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one 7-bromo-4-(((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one (100 mg), prepared in Example 5, was dissolved in a mixed solvent of methanol (1.0 ml) and acetonitrile (1.0 ml). The reaction mixture was stirred at -10°C for 10 minutes, and then Selectfluor (83.4 mg) was gradually added. The reaction mixture was stirred at -10°C for 10 minutes, and then stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 1, v / v) to obtain 16.0 mg of the title compound as a white solid. (Yield: 58.9%) 1 H-NMR (CDCl3) δ 8.79 (d, 1H), 8.13-8.09 (m, 1H), 7.65 (d, 1H), 7.52 (s, 1H), 7.49-7.44 (m, 2H), 7.36 (d, 2H), 4.42-4.33 (m, 2H), 3.15 (t, 1H), 2.04-1.99 (m, 4H), 1.72-1.51 (m, 7H), 1.36 (d, 3H)

[0077] Example 13: 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazole-2-amine (R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride (150 mg) and 2,6-dichloro-1,3-benzothiazole (22 mg), prepared in Preparation Example 1, were dissolved in N-methyl-2-pyrrolidone (1.0 ml), and then N,N-diisopropylethylamine (55 μl) was gradually added. The reaction mixture was stirred in a microwave reactor (180 °C, 1200 W) for 2 hours and then cooled to room temperature. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 1, v / v) to obtain 10.7 mg of the title compound as a white solid. (Yield: 22.5%) 1 H-NMR (CDCl3) δ 8.78 (d, 1H), 8.13-8.10(m, 1H), 7.64(d, 1H), 7.54 (s, 1H), 7.48-7.39(m, 2H), 7.28-7.23(m, 2H), 5.48(m, 1H), 3.84(m, 1H), 3.12(m, 1H), 2.04(s, 2H), 1.80-1.49(m, 8H), 1.36(d, 3H)

[0078] Example 14: N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-6-methoxybenzo[d]thiazole-2-amine Using 2-chloro-6-methoxy-1,3-benzothiazole (21 mg) instead of 2,6-dichloro-1,3-benzothiazole, 5.2 mg of the title compound was prepared following the same procedure as in Example 13. (Yield: 11.0%) 1H-NMR (CDCl3) δ 8.78 (d, 1H), 8.13-8.09 (m, 1H), 7.65 (d, 1H), 7.48-7.41 (m, 2H), 7.30 (d, 1H), 7.13 (s, 1H), 6.88 (d, 1H), 5.04 (m, 1H), 3.82-3.78 (m, 4H), 3.21-3.19 (m, 1H), 2.08-2.04 (m, 1H), 1.81-1.51 (m, 10H), 1.38 (d, 3H)

[0079] Example 15: N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)butan-2-yl)-6-methoxybenzo[d]thiazole-2-amine (R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)butan-2-amine hydrochloride (35.5 mg) and 2-chloro-6-methoxy-1,3-benzothiazole (30 mg), prepared in Preparation Example 2, were dissolved in N-methyl-2-pyrrolidone (1.0 ml), and then N,N-diisopropylethylamine (78.5 μl) was gradually added. The reaction mixture was stirred in a microwave reactor (180 °C, 1200 W) for 2 hours and then cooled to room temperature. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 1, v / v) to obtain 22 mg of the title compound as a white solid. (Yield: 31.6%) 1 H-NMR (CDCl3) δ 8.77 (d, 1H), 8.10 (t, 1H), 7.65 (d, 1H), 7.45 (t, 1H), 7.39 (d, 1H), 7.30-7.23 (m, 1H), 7.12 (s, 1H), 6.88 (d, 1H), 5.21 (s, 1H), 3.81 (s, 3H), 3.61 (d, 1H), 3.20-3.08 (m, 1H), 2.04 (s, 1H), 1.85-1.53 ​​(m, 10H), 1.34-1.24 (m, 2H), 1.01 (t, 3H)

[0080] Example 16: N-((S)-1-cyclopropyl-2-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)ethyl)-6-methoxybenzo[d]thiazole-2-amine (S)-1-cyclopropyl-2-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)ethane-1-amine hydrochloride (36.7 mg) and 2-chloro-6-methoxy-1,3-benzothiazole (30 mg), prepared in Preparation Example 3, were dissolved in N-methyl-2-pyrrolidone (1.0 ml), and then N,N-diisopropylethylamine (78.5 μl) was gradually added. The reaction mixture was stirred in a microwave reactor (180 °C, 1200 W) for 2 hours and then cooled to room temperature. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 1, v / v) to obtain 27.3 mg of the title compound as a white solid. (Yield: 38.2%) 1 H-NMR (CDCl3) δ 8.77 (d, 1H), 8.10 (t, 1H), 7.65 (d, 1H), 7.46 (t, 1H), 7.40 (d, 1H), 7.39-7.23 (m, 1H), 7.12 (s, 1H), 6.88 (d, 1H), 5.19 (s, 1H), 3.81 (s, 3H), 3.33-3.09 (m, 2H), 2.04-1.53 ​​(m, 10H), 0.97 (t, 1H), 0.61-0.34 (m, 4H)

[0081] Example 17: 4,6-Difluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazole-2-amine (R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride (34 mg), 2-chloro-4,6-difluorobenzothiazole (21.3 mg), and copper(I) iodide (6 mg), prepared in Preparation Example 1, were dissolved in dimethyl sulfoxide (1.0 ml), and then potassium carbonate (43 mg) was added. The reaction mixture was stirred in a microwave reactor (100°C, 600 W) for 3 hours and then cooled to room temperature. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with aqueous ammonia and brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 2, v / v) to obtain 25 mg of the title compound as a white solid. (Yield: 52.4%) 1 H-NMR (CDCl3) δ 8.79 (s, 1H), 8.12 (t, 1H), 7.64 (d, 1H), 7.46 (t, 1H), 7.27 (d, 1H), 7.11 (d, 1H), 6.83 (t, 1H), 5.81 (d, 1H), 3.85-3.72 (m, 1H), 3.25-3.10 (m, 1H), 2.05 (s, 2H), 1.86-1.58 (m, 9H), 1.36 (d, 3H)

[0082] Example 18: 7-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazole-2-amine Using 2,7-dichlorobenzo[d]thiazole (21.3 mg) instead of 2-chloro-4,6-difluorobenzothiazole, 18.4 mg of the title compound was prepared following the same procedure as in Example 17. (Yield: 38.7%) 1H-NMR (CDCl3) δ 8.78 (s, 1H), 8.13-8.10 (m, 1H), 7.64 (d, 1H), 7.45 (t, 1H), 7.39 (d, 1H), 7.28-7.21 (m, 2H), 7.06 (d, 1H), 5.72 (s, 1H), 3.84-3.83 (m, 1H), 3.18 (t, 1H), 2.04 (s, 2H), 1.80-1.66 (m, 9H), 1.38 (d, 3H)

[0083] Example 19: 6-Ethoxy-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazole-2-amine (R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride (20 mg), 2-chloro-6-ethoxy-1,3-benzothiazole (23 mg), and copper(I) iodide (4 mg), prepared in Preparation Example 1, were dissolved in dimethyl sulfoxide (1.0 ml), and then potassium carbonate (48 mg) was added. The reaction mixture was stirred in a microwave reactor (100 °C, 600 W) for 3 hours and then cooled to room temperature. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with aqueous ammonia and brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 2, v / v) to obtain 2.3 mg of the title compound. (Yield: 7.1%) 1 H-NMR (CDCl3) δ 8.79 (d, 1H), 8.13-8.10(m, 1H), 7.65(d, 1H), 7.47 (t, 1H), 7.43(d, 1H), 7.31(d, 1H), 7.13(s, 1H), 6.88(d, 1H), 5.00(m, 1H), 4.03(q, 2H) , 3.83(m, 1H), 3.21(m, 1H), 2.04(br, 1H), 1.81-1.63(m, 9H), 1.41(t, 3H), 1.36(d, 3H)

[0084] Example 20: 6-Ethoxy-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)butan-2-yl)benzo[d]thiazole-2-amine (R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)butan-2-amine hydrochloride (30 mg), 2-chloro-6-ethoxy-1,3-benzothiazole (18 mg), and copper(I) iodide (6 mg), prepared in Preparation Example 2, were dissolved in dimethyl sulfoxide (1.0 ml), and then potassium carbonate (60 mg) was added. The reaction mixture was stirred in a microwave reactor (120 °C, 600 W) for 2 hours and then cooled to room temperature. Water was added to the reaction mixture to stop the reaction, and then the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous ammonia and brine, dried over anhydrous magnesium sulfate, and then filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 2, v / v) to obtain 7.8 mg of the title compound as a white solid. (Yield: 18.7%) 1 H-NMR (CDCl3) δ 8.78 (d, 1H), 8.12-8.09 (m, 1H), 7.65 (d, 1H), 7.46-7.38 (m, 2H), 7.28 (d, 1H), 7.12 (s, 1H), 6.88 (d, 1H), 5.18 (m, 1H), 4.03 (d, 2H), 3.59 (s, 1H), 3.20 (s, 1H), 2.04 (s, 1H), 1.81-1.56 (m, 12H), 1.41 (t, 3H), 1.02 (t, 3H)

[0085] Example 21: N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)thiazolo[4,5-b]pyridine-2-amine Using 2-chlorothiazolo[4,5-b]pyridine (18 mg) instead of 2-chloro-6-ethoxy-1,3-benzothiazole, 19.2 mg of the title compound was prepared following the same procedure as in Example 19. (Yield: 43.6%) 1H-NMR (CDCl3) δ 8.77 (d, 1H), 8.55 (s, 1H), 8.12-8.08 (m, 1H), 7.84 (d, 1H), 7.63 (d, 1H), 7.47-7.43 (m, 1H), 7.23 (d, 1H), 6.95 (t, 1H), 6.65 (s, 1H), 3.95 (s, 1H), 3.22 (s, 1H), 2.04-1.94 (m, 2H), 1.78-1.41 (m, 9H), 1.41 (d, 3H)

[0086] Example 22: N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-5-methoxythiazolo[5,4-b]pyridine-2-amine Using 2-chloro-5-methoxy-thiazolo[5,4-b]pyridine (21.1 mg) instead of 2-chloro-6-ethoxy-1,3-benzothiazole, 11.6 mg of the title compound was prepared following the same procedure as in Example 19. (Yield: 18.4%) 1 H-NMR (CDCl3) δ 8.80 (d, 1H), 8.13-8.10 (m, 1H), 7.66-7.64 (m, 2H), 7.46-7.44 (m, 1H), 7.31 (d, 1H), 6.68 (d, 1H), 5.08 (m, 1H), 3.93(s, 3H), 3.89 (m, 1H), 3.22 (m, 1H), 2.04-2.00 (m, 1H), 1.88-1.64 (m, 10H), 1.36 (d, 3H)

[0087] Example 23: 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)thiazolo[4,5-b]pyridine-2-amine Using 2,6-dichlorothiazolo[4,5-b]pyridine (18 mg) instead of 2-chloro-6-ethoxy-1,3-benzothiazole, 2 mg of the title compound was prepared following the same procedure as in Example 19. (Yield: 6.0%) 1H-NMR (CDCl3) δ 8.80 (d, 1H), 8.41-8.30 (bs, 1H), 8.12-8.09 (m, 1H), 7.83 (s, 1H), 7.65 (d, 1H), 7.49-7.60 (m, 1H), 7.29 (d, 1H), 6.32 (bs, 1H), 3.97 (m, 1H), 3.76 (m, 1H), 3.20-3.15 (m, 1H), 2.05-1.26 (m, 13H)

[0088] Example 24: N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine (R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride (100 mg) and 2-chlorobenzo[d]oxazole (71 mg), prepared in Preparation Example 1, were dissolved in N,N-dimethylformamide (1.0 ml), and then 1,8-diazabicyclo[5,4,0]undeca-7-ene (71 mg) was gradually added. The reaction mixture was stirred in a microwave reactor (180°C, 1200 W) for 2 hours and then cooled to room temperature. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 2, v / v) to obtain 12.1 mg of the title compound. (Yield: 8.2%) 1 H-NMR (CDCl3) δ 8.77 (d, 1H), 8.12-8.08 (m, 1H), 7.66-7.63 (m, 1H), 7.47 (t, 1H), 7.43 (d, 1H), 7.37 (d, 1H), 7.26-7.23 (m, 2H), 7.16 (t, 1H), 7.03 (t, 1H), 5.00 (d, 1H), 4.14-4.09 (m, 1H), 3.12 (t, 1H), 2.13-1.95 (m, 4H), 1.81 (s, 1H), 1.66-1.50 (m, 4H), 1.38-1.24 (m, 5H)

[0089] Example 25: 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine (R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride (22 mg) and 2,6-dichlorobenzoxazole (15 mg), prepared in Preparation Example 1, were dissolved in 1,4-dioxane (1.0 ml), and then N,N-diisopropylethylamine (40 μL) was gradually added. The reaction mixture was stirred at 80°C for 12 hours and then cooled to room temperature. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 2, v / v) to obtain 14.7 mg of the title compound. (Yield: 43.7%) 1 H-NMR (CDCl3) δ 8.79 (d, 1H), 8.13-8.10 (m, 1H), 7.67-7.64 (d, 1H), 7.49-7.44 (m, 1H), 7.31 (d, 1H), 7.26-7.24 (m, 1H), 7.15 (d, 1H), 4.92 (d, 1H), 4.06-4.02 (m, 1H), 3.21-3.19 (m, 1H), 2.04-2.00 (m, 1H), 1.88-1.64 (m, 11H), 1.36 (d, 3H)

[0090] Example 26: N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-6-methoxybenzo[d]oxazole-2-amine (R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride (50 mg), 2-chloro-6-methoxy-1,3-benzoxazole hydrochloride (50 mg), and potassium carbonate (43 mg), prepared in Preparation Example 1, were dissolved in N,N-dimethylformamide (1.0 ml), and triethylamine (40 μL) was gradually added. The reaction mixture was stirred at 80°C for 12 hours and then cooled to room temperature. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 2, v / v) to obtain 8.3 mg of the title compound. (Yield: 12.4%) 1 H-NMR (CDCl3) δ 8.79 (d, 1H), 8.13-8.09 (m, 1H), 7.65 (d, 1H), 7.46 (t, 1H), 7.31 (d, 1H), 7.25 (d, 1H), 6.86 (s, 1H) 6.76 (d, 1H), 4.74 (bs, 1H), 4.11 (t, 1H), 3.81 (s, 3H), 3.21 (s, 1H), 2.04 (s, 1H), 1.81-1.70 (m, 10H), 1.36 (d, 3H)

[0091] Example 27: 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)butan-2-yl)benzo[d]oxazole-2-amine (R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)butan-2-amine hydrochloride (70 mg), 2,6-dichlorobenzoxazole (32 mg), and potassium carbonate (57 mg), prepared in Preparation Example 2, were dissolved in N,N-dimethylformamide (1.0 ml), and triethylamine (30 μL) was gradually added. The reaction mixture was stirred at 80°C for 12 hours and then cooled to room temperature. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 2, v / v) to obtain 42 mg of the title compound. (Yield: 44.7%) 1 H-NMR (CDCl3) δ 8.79 (d, 1H), 8.13-8.09 (m, 1H), 7.64 (d, 1H), 7.45 (t, 1H), 7.26-7.21 (m, 3H), 7.14 (d, 1H), 5.60 (s, 1H), 3.88 (s, 1H), 3.19 (s, 1H), 2.04 (s, 1H), 1.82-1.61 (m, 12H), 1.01 (t, 3H)

[0092] Example 28: 4-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine (R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride (30 mg) and 2-chloro-4-fluoro-1,3-benzoxazole (16 mg), prepared in Preparation Example 1, were dissolved in 1,4-dioxane (1.0 ml), and then N,N-diisopropylethylamine (50 μL) was gradually added. The reaction mixture was stirred at 100°C for 12 hours and then cooled to room temperature. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 2, v / v) to obtain 9.7 mg of the title compound. (Yield: 23.8%) 1 H-NMR (CDCl3) δ 8.80 (d, 1H), 8.13-8.09 (m, 1H), 7.64 (d, 1H), 7.49-7.44 (m, 1H), 7.31 (d, 1H), 7.26-7.24 (m, 1H), 7.06 (d, 1H), 6.99-6.91 (m, 2H), 5.42-5.30 (bs, 1H), 4.13-4.08 (m, 1H), 3.21-3.19 (m, 1H), 2.04-2.00 (m, 1H), 1.88-1.64 (m, 11H), 1.36 (d, 3H)

[0093] Example 29: 6-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine Using 2-chloro-6-fluoro-1,3-benzoxazole (16 mg) instead of 2-chloro-4-fluoro-1,3-benzoxazole, 3.9 mg of the title compound was prepared following the same procedure as in Example 28. (Yield: 9.5%) 1H-NMR (CDCl3) δ 8.80 (d, 1H), 8.13-8.10 (m, 1H), 7.64 (d, 1H), 7.49-7.47 (m, 1H), 7.31 (d, 1H), 7.26-7.24 (m, 1H), 7.01 (d, 1H), 6.93-6.88 (m, 1H), 4.74 (m, 1H), 4.05-4.01 (m, 1H), 3.21-3.19 (m, 1H), 2.04-2.00 (m, 1H), 1.88-1.64 (m, 11H), 1.36 (d, 3H)

[0094] Example 30: N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)oxazolo[5,4-b]pyridine-2-amine (R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride (50 mg), 2-chlorooxazolo[5,4-b]pyridine (24 mg), and potassium carbonate (43 mg), prepared in Preparation Example 1, were dissolved in N,N-dimethylformamide (1.0 ml), and triethylamine (40 μL) was gradually added. The reaction mixture was stirred at 80°C for 12 hours and then cooled to room temperature. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 2, v / v) to obtain 40.1 mg of the title compound. (Yield: 64.0%) 1 H-NMR (CDCl3) δ 8.80 (d, 1H), 8.12-8.10 (m, 1H), 7.94 (d, 1H), 7.65 (d, 1H), 7.57 (d, 1H), 7.46 (t, 1H), 7.29 (d, 1H), 7.13 (t, 1H), 5.80 (d, 1H), 4.15-4.07 (m, 1H), 3.21-3.19 (m, 1H), 2.05 (s, 1H), 1.82-1.70 (m, 10H), 1.40 (d, 3H)

[0095] Example 31: 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)oxazolo[4,5-b]pyridine-2-amine (R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride (50 mg), 2,6-dichlorooxazolo[4,5-b]pyridine (30 mg), and potassium carbonate (42 mg), prepared in Preparation Example 1, were dissolved in N,N-dimethylformamide (1.0 ml), and triethylamine (21 μL) was gradually added. The reaction mixture was stirred at 80°C for 12 hours and then cooled to room temperature. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 2, v / v) to obtain 16 mg of the title compound. (Yield: 23.5%) 1 H-NMR (CDCl3) δ 8.80 (d, 1H), 8.20 (s, 1H), 8.14-8.10 (m, 1H), 7.64 (d, 1H), 7.48-7.46 (m, 1H), 7.31 (d, 1H), 7.26 (s, 1H), 6.15 (m, 1H), 4.12 (m, 1H), 3.21 (m, 1H), 2.04-2.00 (m, 1H), 1.88-1.64 (m, 11H), 1.41 (d, 3H)

[0096] Example 32: N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)oxazolo[4,5-b]pyridine-2-amine Using 2-chlorooxazolo[4,5-b]pyridine (24 mg) instead of 2,6-dichlorooxazolo[4,5-b]pyridine, 9.2 mg of the title compound was prepared following the same procedure as in Example 31. (Yield: 14.7%) 1H-NMR (CDCl3) δ 8.80 (d, 1H), 8.23 ​​(d, 1H), 8.16-8.12 (m, 1H), 7.65 (d, 1H), 7.49-7.42 (m, 2H), 7.34 (d, 1H), 6.94-6.91 (m, 1H), 5,72 (m, 1H), 4.13 (m, 1H), 3.24-3.21 (m, 1H), 2.04-2.00 (m, 1H), 1.98-1.75 (m, 11H), 1.40 (d, 3H)

[0097] Example 33: 6-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)isoquinoline-1-amine (R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride (20 mg) prepared in Preparation Example 1 was dissolved in 1-chloro-6-fluoroisoquinoline (13 mg) 1,4-dioxane (1.0 ml), and then N,N-diisopropylethylamine (35 μL) was gradually added. The reaction mixture was stirred at 80°C for 12 hours and then cooled to room temperature. After stopping the reaction by adding water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 2, v / v) to obtain 1.5 mg of the title compound. (Yield: 5.6%) 1 H-NMR (CDCl3) δ 8.82(d, 1H), 8.20(dd, 1H), 8.03(dd, 1H), 7.87(d, 1H), 7.66(dd, 1H), 7.52(td, 1H), 7.41(d, 1H), 7.32(m , 2H), 6.92(d, 1H), 4.51(m, 1H), 3.23(m, 1H), 2.07(br, 1H), 1.95-1.76(m, 8H), 1.38(d, 3H), 1.26(m, 2H)

[0098] Example 34: 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)isoquinoline-1-amine Using 1,6-dichloroisoquinoline (14 mg) instead of 1-chloro-6-fluoroisoquinoline, 1.4 mg of the title compound was prepared following the same procedure as in Example 33. (Yield: 5.1%) 1 H-NMR (CDCl3) δ 8.84(d, 1H), 8.19(dd, 1H), 7.98(dd, 1H), 7.74(d, 1H), 7.68(m, 2H), 7.52(td, 1H), 7.48(dd, 1H), 7.41(d , 1H), 6.87(d, 1H), 4.51(m, 1H), 3.22(m, 1H), 2.07(br, 1H), 1.95-1.76(m, 8H), 1.38(d, 3H), 1.26(m, 2H)

[0099] Example 35: 4-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazole-2-amine (R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride (50 mg) and 2,4-dichlorobenzothiazole (32 mg), prepared in Preparation Example 1, were dissolved in tetrahydrofuran (1.0 ml). The resulting solution was placed in a sealed tube, and triethylamine (110 μL) was gradually added. After sealing the tube, the reaction mixture was stirred at 120°C for 12 hours, and then cooled to room temperature. Water was added to the reaction mixture to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 2, v / v) to obtain 15 mg of the title compound. (Yield: 21.3%) 1H-NMR (CDCl3) δ 8.80(d, 1H), 8.13(dd, 1H), 7.66(dd, 1H), 7.50-7.46(m, 2H), 7.34-7.30(m, 2H), 7.03-6.99(m, 1H), 5.4 7(br, 1H), 3.71(br, 1H), 3.26-3.20(m, 1H), 2.05(br, 1H), 1.84-1.61(m, 8H), 1.38(d, 3H), 1.26(d, 2H)

[0100] Example 36: 5-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine Using 2-chloro-5-fluorobenzoxazole (29 mg) instead of 2,4-dichlorobenzothiazole, 31 mg of the title compound was prepared as a yellow liquid following the same procedure as in Example 35. (Yield: 47.5%) 1 H-NMR (CDCl3) δ 8.81(d, 1H), 8.11(dd, 1H), 7.66(dd, 1H), 7.47(td, 1H), 7.33(dd, 1H), 7.14(dd, 1H), 7.06(d, 1H), 6.74(td, 1 H), 4.84(br, 1H), 4.06(m, 1H), 3.25-3.19(m, 1H), 2.07(br, 1H), 1.89-1.61(m, 8H), 1.38(d, 3H), 1.26(d, 2H)

[0101] Example 37: 7-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine Using 2-chloro-7-fluorobenzoxazole (29 mg) instead of 2,4-dichlorobenzothiazole, 26 mg of the title compound was prepared as a yellow liquid following the same procedure as in Example 35. (Yield: 39.8%) 1H-NMR (CDCl3) δ 8.81(d, 1H), 8.12(dd, 1H), 7.66(dd, 1H), 7.47(td, 1H), 7.33(dd, 1H), 7.16-7.07(m, 2H), 6.83(m, 1H), 5 .02(br, 1H), 4.06(m, 1H), 3.23-3.20(m, 1H), 2.07(br, 1H), 1.89-1.61(m, 8H), 1.38(d, 3H), 1.26(d, 2H)

[0102] Example 38: 2-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine Using 2,4-dichloroquinazoline (34 mg) instead of 2,4-dichlorobenzothiazole, 43 mg of the title compound was prepared following the same procedure as in Example 35. (Yield: 62.4%) 1 H-NMR (CDCl3) δ 8.81(d, 1H), 8.12(dd, 1H), 7.80-7.65(m, 4H), 7.47(td, 1H), 7.38(dd, 1H), 5.73(m , 1H), 4.60(m, 1H), 3.25-3.19(m, 1H), 1.98-1.61(m, 9H), 1.38(d, 3H), 1.26(d, 2H)

[0103] Example 39: 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)phthalazine-1-amine (R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride (50 mg), 1,6-dichlorophthalazine (34 mg), and copper(I) iodide (9 mg), prepared in Preparation Example 1, were dissolved in dimethyl sulfoxide (1.0 ml). The resulting solution was placed in a sealed tube, and potassium carbonate (43 mg) was added. After sealing the tube, the reaction mixture was stirred at 140°C for 3 hours and then cooled to room temperature. Water was added to the reaction mixture to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 2, v / v) to obtain 5.1 mg of the title compound as a yellow liquid. (Yield: 7.3%) 1 H-NMR (CDCl3) δ 8.85(br, 1H), 8.81(d, 1H), 8.12(br, 1H), 7.89(d, 1H), 7.73(br, 2H), 7.66(d, 1H), 7.47(td, 1H), 7.36(br, 1H) ), 4.87(br, 1H), 4.73(br, 1H), 3.23-3.19(br, 1H), 2.07(br, 1H), 1.98-1.61(m, 8H), 1.38(d, 3H), 1.26(d, 2H)

[0104] Example 40: 2,7-Dichloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine Using 2,4-dichlorobenzothiazole instead of 2,4-trichloroquinazoline (40 mg), 37 mg of the title compound was prepared following the same procedure as in Example 35. (Yield: 49.3%) 1 H-NMR (CDCl3) δ 8.81(d, 1H), 8.12(dd, 1H), 7.77(d, 1H), 7.68-7.62(m, 2H), 7.47(td, 1H), 7.42-7.36(m, 2H) , 5.71((br, 1H), 4.58(m, 1H), 3.23-3.19(m, 1H), 1.98-1.61(m, 9H), 1.38(d, 3H), 1.26(d, 2H)

[0105] Example 41: 2,7-Dichloro-N-((R)-1-((Trans)-4-(6-Fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)Quinazoline-4-amine (R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride (50 mg) and 2,4,7-trichloroquinazoline (40 mg), prepared in Preparation Example 4, were dissolved in tetrahydrofuran (1.0 ml). The resulting solution was placed in a sealed tube, and triethylamine (110 μL) was added. After sealing the tube, the reaction mixture was stirred at 80°C for 12 hours, and then cooled to room temperature. Water was added to the reaction mixture to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 2, v / v) to obtain 40 mg of the title compound as a white solid. (Yield: 54.1%) 1 H-NMR (CDCl3) δ 8.79(d, 1H), 8.12(dd, 1H), 7.77(d, 1H), 7.68-7.62(m, 2H), 7.47(td, 1H), 7.42-7.36(m, 2H), 5.58(br, 1H), 4 .72(m, 1H), 3.23-3.19(m, 1H), 2.20(br, 1H), 2.06-1.98(m, 2H), 1.68-1.52(m, 6H), 1.38(d, 3H), 1.26(d, 2H)

[0106] Example 42: 7-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-6-methoxybenzo[d]oxazole-2-amine Using 2-chloro-7-fluoro-6-methoxy-1,3-benzoxazole (34 mg) instead of 2,4-dichlorobenzothiazole, 39 mg of the title compound was prepared as a white solid following the same procedure as in Example 35. (Yield: 56.0%) 1H-NMR (CDCl3) δ 8.78(d, 1H), 8.11(dd, 1H), 7.66(dd, 1H), 7.47(td, 1H), 7.30(d, 1H), 7.02(d, 1H), 6.80(t, 1H), 5 .26(br, 1H), 4.02(m, 1H), 3.89(s, 3H), 3.20(m, 1H), 1.81-1.74(m, 8H), 1.36(d, 3H), 1.26(d, 2H)

[0107] Example 43: 6-Chloro-5-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine Using 2,6-dichloro-5-fluoro-1,3-benzoxazole (35 mg) instead of 2,4-dichlorobenzothiazole, 35 mg of the title compound was prepared as a white solid following the same procedure as in Example 35. (Yield: 51.0%) 1 H-NMR (CDCl3) δ 8.79(d, 1H), 8.12(dd, 1H), 7.65(dd, 1H), 7.48(td, 1H), 7.30-7.26(m, 2H), 7.11(d, 1H) ), 5.43(br, 1H), 4.03(m, 1H), 3.21(m, 1H), 1.81-1.74(m, 9H), 1.36(d, 3H), 1.26(d, 2H)

[0108] Example 44: 6-Ethoxy-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine Using 2-chloro-6-ethoxy-1,3-benzoxazole (34 mg) instead of 2,4-dichlorobenzothiazole, 4.6 mg of the title compound was prepared following the same procedure as in Example 35. (Yield: 6.6%) 1H-NMR (CDCl3) δ 8.81(d, 1H), 8.12(dd, 1H), 7.65(dd, 1H), 7.47(td, 1H), 7.32(d, 1H), 7.27-7.22(m, 1H), 6.87(s, 1H), 6 .77(dd, 1H), 4.05-4.00(m, 3H), 3.22(m, 1H), 2.08(br, 1H), 1.83-1.65(m, 8H), 1.42(t, 3H), 1.38(d, 3H)

[0109] Example 45: 6-(2-fluoroethoxy)-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine Using 2-chloro-6-(2-fluoroethoxy)-1,3-benzoxazole (37 mg) instead of 2,4-dichlorobenzothiazole, 36.6 mg of the title compound was prepared following the same procedure as in Example 35. (Yield: 50.7%) 1 H-NMR (CDCl3) δ 8.79(d, 1H), 8.12(dd, 1H), 7.64(dd, 1H), 7.47(td, 1H), 7.32(d, 1H), 7.27-7.23(m, 1H), 6.91(s, 1H), 6.77(d, 1H), 5.06(br, 1H), 4 .81(d, 1H), 4.69(d, 1H), 4.24(d, 1H), 4.17(d, 1H), 4.05-4.00(m, 1H), 3.21(m, 1H), 2.08(br, 1H), 1.83-1.65(m, 10H), 1.37(d, 3H)

[0110] Example 46: 6,7-Dichloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine Using 2,6,7-trichloro-1,3-benzoxazole (38 mg) instead of 2,4-dichlorobenzothiazole, 5.1 mg of the title compound was prepared following the same procedure as in Example 35. (Yield: 7.0%) 1H-NMR (CDCl3) δ 8.80(d, 1H), 8.13(dd, 1H), 7.64(dd, 1H), 7.48(td, 1H), 7.32(d, 1H), 7.27-7.23(m, 1H), 7.17( d, 1H), 4.95(br, 1H), 4.06(m, 1H), 3.24(m, 1H), 2.08(br, 1H), 1.83-1.65(m, 10H), 1.37(d, 3H)

[0111] Example 47: 6,7-Difluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine Using 2-chloro-6,7-difluoro-1,3-benzoxazole (33 mg) instead of 2,4-dichlorobenzothiazole, 51.5 mg of the title compound was prepared following the same procedure as in Example 35. (Yield: 75.6%) 1 H-NMR (CDCl3) δ 8.79(d, 1H), 8.12(dd, 1H), 7.64(dd, 1H), 7.48(td, 1H), 7.32(d, 1H), 7.02-6.94(m, 2H) , 5.38(d, 1H), 4.04(m, 1H), 3.21(m, 1H), 2.08(br, 1H), 1.81-1.71(m, 10H), 1.38(d, 3H)

[0112] Example 48: 2-Chloro-6-fluoro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine (R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-amine hydrochloride (30 mg) and 2,4-dichloro-6-fluoroquinazoline (30 mg), prepared in Preparation Example 4, were dissolved in 1,4-dioxane (2.0 ml). The resulting solution was placed in a sealed tube, and triethylamine (45 μL) was added. After sealing the tube, the reaction mixture was stirred at 100°C for 4 hours, and then cooled to room temperature. Water was added to the reaction mixture to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 2, v / v) to obtain 12 mg of the title compound. (Yield: 27.7%) 1 H-NMR (CDCl3) δ 8.78(d, 1H), 8.12(dd, 1H), 7.78(dd, 1H), 7.66(dd, 1H), 7.51-7.46(m, 2H), 7.36(d, 1H), 7.25(m, 1H), 5.62(d, 1H), 4.70(m, 1H), 3.18(m, 1H), 2.22(br, 1H), 2.06-1.97(m, 4H), 1.68(br, 2H), 1.58-1.52(m, 4H), 1.38(d, 3H)

[0113] Example 49: 2,6-Dichloro-N-((R)-1-((Trans)-4-(6-Fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)Quinazoline-4-amine Using 2,4-trichloroquinazoline (33 mg) instead of 2,4-dichloro-6-fluoroquinazoline, 12 mg of the title compound was prepared following the same procedure as in Example 48. (Yield: 25.8%) 1H-NMR (CDCl3) δ 8.78(d, 1H), 8.12(dd, 1H), 7.73-7.65(m, 4H), 7.48(td, 1H), 7.25(m, 1H), 5.69(d, 1H), 4.70(m, 1H), 3.18(m, 1H), 2.19(br, 1H), 2.06-1.97(m, 4H), 1.68(br, 2H), 1.58-1.52(m, 4H), 1.38(d, 3H)

[0114] Example 50: 2-Chloro-8-fluoro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine Using 2,4-dichloro-8-fluoroquinazoline (30 mg) instead of 2,4-dichloro-6-fluoroquinazoline, 10.3 mg of the title compound was prepared following the same procedure as in Example 48. (Yield: 23.7%) 1 H-NMR (CDCl3) δ 8.79(d, 1H), 8.13(dd, 1H), 7.67(dd, 1H), 7.51-7.39(m, 4H), 7.25(m, 1H), 5.75(d, 1H), 4.75(m , 1H), 3.15(m, 1H), 2.19(d, 1H), 2.06-1.97(m, 4H), 1.68(m, 2H), 1.58-1.52(m, 4H), 1.38(d, 3H)

[0115] Example 51: 2,8-Dichloro-N-((R)-1-((Trans)-4-(6-Fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)Quinazoline-4-amine Using 2,4-trichloroquinazoline (33 mg) instead of 2,4-dichloro-6-fluoroquinazoline, 12.1 mg of the title compound was prepared following the same procedure as in Example 48. (Yield: 26.9%) 1H-NMR (CDCl3) δ 8.79(d, 1H), 8.13(dd, 1H), 7.84(d, 1H), 7.67-7.63(m, 2H), 7.45(m, 1H), 7.37(td, 1H), 7.25(m, 1H), 5.77(d , 1H), 4.75(m, 1H), 3.15(m, 1H), 2.19(d, 1H), 2.06-1.97(m, 4H), 1.68(m, 2H), 1.58-1.52(m, 4H), 1.38(d, 3H)

[0116] Example 52: 2-Chloro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-8-methoxyquinazoline-4-amine Using 2,4-dichloro-8-methoxyquinazoline (32 mg) instead of 2,4-dichloro-6-fluoroquinazoline, 9.6 mg of the title compound was prepared following the same procedure as in Example 48. (Yield: 21.6%) 1 H-NMR (CDCl3) δ 8.79(d, 1H), 8.11(dd, 1H), 7.67(dd, 1H), 7.47(td, 1H), 7.39(td, 1H), 7.25(m, 2H), 7.13(d, 1H), 5.63(d, 1H), 4. 72(m, 1H), 4.02(s, 3H), 3.15(m, 1H), 2.19(d, 1H), 2.06-1.97(m, 4H), 1.68(m, 2H), 1.58-1.52(m, 4H), 1.38(d, 3H)

[0117] Example 53: 2-Chloro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-8-(trifluoromethoxy)quinazoline-4-amine Using 2,4-dichloro-8-(trifluoromethoxy)quinazoline (40 mg) instead of 2,4-dichloro-6-fluoroquinazoline, 10.8 mg of the title compound was prepared following the same procedure as in Example 48. (Yield: 21.8%) 1H-NMR (CDCl3) δ 8.79(d, 1H), 8.11(dd, 1H), 7.69-7.65(m, 3H), 7.49-7.43(m, 2H), 7.25(m, 1H), 5.74(d, 1H), 4.70 (m, 1H), 3.18(m, 1H), 2.19(d, 1H), 2.06-1.97(m, 4H), 1.68(m, 2H), 1.58-1.52(m, 4H), 1.38(d, 3H)

[0118] Example 54: 2-Chloro-7-fluoro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine Using 2,4-dichloro-7-fluoroquinazoline (30 mg) instead of 2,4-dichloro-6-fluoroquinazoline, 6.9 mg of the title compound was prepared following the same procedure as in Example 48. (Yield: 15.9%) 1 H-NMR (CDCl3) δ 8.79(d, 1H), 8.12(dd, 1H), 7.73-7.64(m, 2H), 7.47-7.40(m, 2H), 7.25(m, 1H), 7.23(t, 1H), 5.61(d, 1H) , 4.72(m, 1H), 3.18(td, 1H), 2.19(d, 1H), 2.06-1.97(m, 4H), 1.68(m, 2H), 1.58-1.52(m, 4H), 1.38(d, 3H)

[0119] Example 55: 2-Chloro-4-(((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)quinazoline-7-carbonitrile Using 2,4-dichloroquinazoline-7-carbonitrile (32 mg) instead of 2,4-dichloro-6-fluoroquinazoline, 4.6 mg of the title compound was prepared following the same procedure as in Example 48. (Yield: 10.4%) 1H-NMR (CDCl3) δ 8.79(d, 1H), 8.12(d, 1H), 8.09(s, 1H), 7.81(d, 1H), 7.67-7.62(m, 2H), 7.46(m, 1H), 7.25(m, 1H), 5.81(d, 1H), 4. 72(m, 1H), 3.17(td, 1H), 2.19(d, 1H), 2.06-1.97(m, 4H), 1.68(m, 1H), 1.58-1.52(m, 4H), 1.38(d, 3H), 1.35(m, 1H)

[0120] Example 56: 7-Bromo-2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine Using 7-bromo-2,4-dichloroquinazoline (39 mg) instead of 2,4-dichloro-6-fluoroquinazoline, 8.0 mg of the title compound was prepared following the same procedure as in Example 48. (Yield: 16.3%) 1 H-NMR (CDCl3) δ 8.79(d, 1H), 8.12(t, 1H), 7.95(s, 1H), 7.66(d, 1H), 7.55(m, 2H), 7.46(t, 1H), 7.25(m, 1H), 5.68(d, 1H) , 4.72(m, 1H), 3.16(td, 1H), 2.19(d, 1H), 2.06-1.97(m, 4H), 1.68(m, 2H), 1.58-1.52(m, 4H), 1.38(d, 3H)

[0121] Example 57: 2-Chloro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-7-methylquinazoline-4-amine Using 2,4-dichloro-7-methylquinazoline (30 mg) instead of 2,4-dichloro-6-fluoroquinazoline, 7.1 mg of the title compound was prepared following the same procedure as in Example 48. (Yield: 16.5%) 1H-NMR (CDCl3) δ 8.79(d, 1H), 8.12(t, 1H), 7.67(d, 1H), 7.58(m, 2H), 7.46(t, 1H), 7.30-7.24(m, 2H), 5.56(d, 1H), 4.73(m, 1) H), 3.16(td, 1H), 2.51(s, 3H), 2.22(d, 1H), 2.06-1.97(m, 4H), 1.68(m, 2H), 1.58-1.52(m, 4H), 1.36(d, 3H)

[0122] Example 58: 2-Chloro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-7-(trifluoromethyl)quinazoline-4-amine Using 2,4-dichloro-7-(trifluoromethyl)quinazoline (38 mg) instead of 2,4-dichloro-6-fluoroquinazoline, 7.7 mg of the title compound was prepared following the same procedure as in Example 48. (Yield: 16.0%) 1 H-NMR (CDCl3) δ 8.79(d, 1H), 8.12(t, 1H), 8.07(s, 1H), 7.84(d, 1H), 7.65(t, 2H), 7.46(t, 1H), 7.27-7.24(m, 1H), 5.82(d, 1) H), 4.73(m, 1H), 3.16(td, 1H), 2.22(d, 1H), 2.06-1.97(m, 4H), 1.68(m, 2H), 1.58-1.52(m, 4H), 1.36(d, 3H)

[0123] Example 59: 2-Chloro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-7-methoxyquinazoline-4-amine Using 2,4-dichloro-7-methoxyquinazoline (32 mg) instead of 2,4-dichloro-6-fluoroquinazoline, 9.7 mg of the title compound was prepared following the same procedure as in Example 48. (Yield: 21.8%) 11H-NMR (CDCl3) δ 8.78 (d, 1H), 8.11 (t, 1H), 7.68 (d, 1H), 7.65 (d, 1H), 7.46 (td, 1H), 7.27 - 7.24 (m, 1H), 7.13 (s, 1H), 7.05 (d, 1H), 5.48 (d, 1H), 4.70 (m, 1H), 3.92 (s, 3H), 3.16 (td, 1H), 2.22 (d, 1H), 2.06 - 1.97 (m, 4H), 1.68 (m, 2H), 1.58 - 1.52 (m, 4H), 1.36 (d, 3H)

[0124] Example 60: 2-Chloro-6-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4-amine (R)-1-((cis)-4-(6-Fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride (50 mg) and 2,4-dichloro-6-fluoroquinazoline (34 mg) prepared in Production Example 1 were dissolved in tetrahydrofuran (1.0 ml). After putting the obtained solution into a sealed tube, triethylamine (110 μL) was added. After sealing the sealed tube, the reaction mixture was stirred at 80°C for 12 hours and then cooled to room temperature. After adding water to the reaction mixture to stop the reaction, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then filtered. The obtained filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 2, v / v) to obtain 38 mg of the title compound as a white solid. (Yield: 52.4%) 1 1H-NMR (CDCl3) δ 8.81 (d, 1H), 8.12 (t, 1H), 7.80 (d, 1H), 7.67 (d, 1H), 7.52 - 7.46 (m, 2H), 7.38 - 7.35 (m, 2H), 5.68 (d, 1H), 4.60 (m, 1H), 3.23 (td, 1H), 1.99 - 1.62 (m, 11H), 1.39 (d, 3H)

[0125] Example 61: 2,6-Dichloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine Using 2,4,6-trichloroquinazoline (37 mg) instead of 2,4-dichloro-6-fluoroquinazoline, 45.2 mg of the title compound was prepared as a white solid following the same procedure as in Example 60. (Yield: 60.3%) 1 H-NMR (CDCl3) δ 8.81(d, 1H), 8.12(t, 1H), 7.73-7.65(m, 4H), 7.46(t, 1H), 7.37(s, 1H), 5.79(d, 1H), 4.59(m, 1H), 3.22(td, 1H), 1.99-1.62(m, 11H), 1.39(d, 3H)

[0126] Example 62: 2-Chloro-7-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine Using 2,4-dichloro-7-fluoroquinazoline (37 mg) instead of 2,4-dichloro-6-fluoroquinazoline, 40.7 mg of the title compound was prepared as a pale yellow liquid following the same procedure as in Example 60. (Yield: 56.3%) 1 H-NMR (CDCl3) δ 8.81(d, 1H), 8.12(t, 1H), 7.73(dd, 1H), 7.65(dd, 1H), 7.46(td, 1H), 7.41(dd, 1H), 7.37(d, 1H), 7.22(td, 1H), 5.71(d, 1H), 4.59(m, 1H), 3.22(td, 1H), 1.99-1.62(m, 11H), 1.39(d, 3H)

[0127] Example 63: 2-Chloro-4-(((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)quinazoline-7-carbonitrile Using 2,4-dichloroquinazoline-7-carbonitride (39 mg) instead of 2,4-dichloro-6-fluoroquinazoline, 33 mg of the title compound was prepared as a pale yellow liquid following the same procedure as in Example 60. (Yield: 45.0%) 1 H-NMR (CDCl3) δ 8.81(d, 1H), 8.12(t, 1H), 8.09(s, 1H), 7.81(d, 1H), 7.68-7.62(m, 2H), 7.46(td, 1H) , 7.36(d, 1H), 5.89(d, 1H), 4.61(m, 1H), 3.23(m, 1H), 1.99-1.62(m, 11H), 1.39(d, 3H)

[0128] Example 64: 7-Bromo-2-chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine Using 7-bromo-2,4-dichloroquinazoline (48 mg) instead of 2,4-dichloro-6-fluoroquinazoline, 53.4 mg of the title compound was prepared as a pale yellow liquid following the same procedure as in Example 60. (Yield: 65.3%) 1 H-NMR (CDCl3) δ 8.81(d, 1H), 8.12(t, 1H), 7.94(s, 1H), 7.67(d, 1H), 7.59-7.55(m, 2H), 7.46(td, 1H) , 7.36(d, 1H), 5.89(d, 1H), 4.58(m, 1H), 3.22(m, 1H), 1.99-1.62(m, 11H), 1.39(d, 3H)

[0129] Example 65: 2-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-7-methylquinazoline-4-amine Using 2,4-dichloro-7-methylquinazoline (37 mg) instead of 2,4-dichloro-6-fluoroquinazoline, 49.5 mg of the title compound was prepared as a pale yellow liquid following the same procedure as in Example 60. (Yield: 69.3%) 11H-NMR (CDCl3) δ 8.81 (d, 1H), 8.12 (t, 1H), 7.67 (dd, 1H), 7.59 - 7.56 (m, 2H), 7.47 (td, 1H), 7.36 (d, 1H), 7.28 (m, 1H), 5.67 (d, 1H), 4.58 (m, 1H), 3.21 (m, 1H), 2.51 (s, 3H), 1.99 - 1.62 (m, 11H), 1.39 (d, 3H)

[0130] Example 66: 2-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7-(trifluoromethyl)quinazolin-4-amine Using 2,4-dichloro-7-(trifluoromethyl)quinazoline (46 mg) instead of 2,4-dichloro-6-fluoroquinazoline, following the same procedure as in Example 60, 44.8 mg of the title compound was produced as a pale yellow liquid. (Yield: 56.0%) 1 1H-NMR (CDCl3) δ 8.81 (d, 1H), 8.12 (t, 1H), 8.10 (s, 1H), 7.86 (d, 1H), 7.68 - 7.63 (m, 2H), 7.47 (td, 1H), 7.36 (d, 1H), 5.91 (d, 1H), 4.62 (m, 1H), 3.23 (m, 1H), 1.99 - 1.62 (m, 11H), 1.39 (d, 3H)

[0131] Example 67: 2-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7-methoxyquinazolin-4-amine Using 2,4-dichloro-7-methoxyquinazoline (39 mg) instead of 2,4-dichloro-6-fluoroquinazoline, following the same procedure as in Example 60, 52.1 mg of the title compound was produced as a pale yellow liquid. (Yield: 70.2%) 1H-NMR (CDCl3) δ 8.81(d, 1H), 8.12(t, 1H), 7.67(dd, 1H), 7.58(d, 1H), 7.46(td, 1H), 7.37(d, 1H), 7.13(d, 1H), 7. 04(dd, 1H), 5.58(d, 1H), 4.60(m, 1H), 3.92(s, 3H), 3.22(m, 1H), 1.99-1.62(m, 11H), 1.39(d, 3H)

[0132] Example 68: 2,8-Dichloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine Using 2,4-trichloroquinazoline (40 mg) instead of 2,4-dichloro-6-fluoroquinazoline, 49.5 mg of the title compound was prepared as a pale yellow liquid following the same procedure as in Example 60. (Yield: 66.1%) 1 H-NMR (CDCl3) δ 8.81(d, 1H), 8.12(t, 1H), 7.83(d, 1H), 7.68-7.73(m, 2H), 7.46(td, 1H), 7.39-7. 35(m, 2H), 5.82(d, 1H), 4.60(m, 1H), 3.22(m, 1H), 1.99-1.62(m, 11H), 1.39(d, 3H)

[0133] Example 69: 2-Chloro-8-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine Using 2,4-dichloro-8-fluoroquinazoline (37 mg) instead of 2,4-dichloro-6-fluoroquinazoline, 44.7 mg of the title compound was prepared as a pale yellow liquid following the same procedure as in Example 60. (Yield: 61.8%) 1 H-NMR (CDCl3) δ 8.81(d, 1H), 8.12(t, 1H), 7.67(dd, 1H), 7.49-7.44(m, 3H), 7.40-7.37(m, 2 H), 5.82(d, 1H), 4.60(m, 1H), 3.22(m, 1H), 1.99-1.62(m, 11H), 1.39(d, 3H)

[0134] Example 70: 2-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-8-methoxyquinazoline-4-amine Using 2,4-dichloro-8-methoxyquinazoline (39 mg) instead of 2,4-dichloro-6-fluoroquinazoline, 36.1 mg of the title compound was prepared as a pale yellow liquid following the same procedure as in Example 60. (Yield: 48.6%) 1 H-NMR (CDCl3) δ 8.81(d, 1H), 8.12(t, 1H), 7.67(dd, 1H), 7.48(td, 1H), 7.44-7.37(m, 2H), 7.22(d, 1H), 7.13 (d, 1H), 5.65(d, 1H), 4.58(m, 1H), 4.01(s, 3H), 3.22(m, 1H), 1.99-1.62(m, 11H), 1.39(d, 3H)

[0135] Example 71: 2-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-8-(trifluoromethoxy)quinazoline-4-amine Using 2,4-dichloro-8-(trifluoromethoxy)quinazoline (49 mg) instead of 2,4-dichloro-6-fluoroquinazoline, 58.4 mg of the title compound was prepared as a pale yellow liquid following the same procedure as in Example 60. (Yield: 70.7%) 1 H-NMR (CDCl3) δ 8.81(d, 1H), 8.12(t, 1H), 7.68-7.64(m, 3H), 7.49-7.41(m, 2H), 7.37(d, 1 H), 5.86(d, 1H), 4.59(m, 1H), 3.22(m, 1H), 1.99-1.62(m, 11H), 1.39(d, 3H)

[0136] Test Example 1: Analysis of IDO1 cell activity using HeLa cells Hela cells were seeded at a density of 20,000 cells / well in 100 μl of medium (EMEM supplemented with 10% FBS, 100 U / ml penicillin, and 100 μg / ml streptomycin) in a tissue culture-treated 96-well plate. The cells were cultured in a 5% CO2 incubator for 24 hours, treated with recombinant human interferon-gamma at a concentration of 50 ng / ml, and then cultured in a 5% CO2 incubator for 48 hours to induce IDO expression.

[0137] IDO1 cell activity was measured using the IDO1 cell activity measurement substrate (IDO1 cell activity quickDetect supplement, catalog number 62000-2, BPS Bioscience). Specifically, assay media was prepared by diluting IDO1 assay medium substrate 1 and IDO1 assay medium supplement 2 in a 1:100 ratio in culture medium. Each test compound was diluted to the specified concentration in fresh assay medium. After removing the medium using a multipipette, 200 μl of assay medium containing each test substance was added to each well and incubated in a 5% CO2 incubator for 24 hours. The following day, 140 μl of medium from each well was transferred to a new 96-well plate. 10 μl of 6.1N trichloroacetic acid was added to each well and cultured in a 50°C incubator for 30 minutes. The plate was centrifuged at 2500 rpm for 10 minutes to allow the precipitate to settle. The detection reagent solution was prepared by diluting the detection reagent (Component D kit, catalog number 62000-2, BPS Bioscience) 50-fold with acetic acid. 100 μl of supernatant collected from a centrifuged plate was transferred to a new clear 96-well plate, and 100 μl of detection reagent solution was added. After reacting at room temperature for 10 minutes, the absorbance at a wavelength of 480 nm was measured. For the analysis of the results, the absorbance (At) of the well containing HeLa cells in which IDO protein expression was induced without inhibitor treatment was set to 100%, and the absorbance (Ab) of the well containing HeLa cells in which IDO protein expression was not induced was set to 0. The % absorbance was calculated according to the following formula: % absorbance = (A - Ab) / (At - Ab), where A = absorbance of the well treated with the test compound.

[0138] From the absorbance values obtained as described above, the 50% inhibitory concentration (IC 50 ) of each compound was calculated, and the results are shown in Table 1 below.

Table 1

[0139] From the results in Table 1, it can be seen that the compounds of the present invention exhibit excellent inhibitory activity against indoleamine-2,3-dioxygenase.

[0140] Test Example 2: Analysis of IDO1 cell activity using HEK293 cells HEK293 cells were seeded at a density of 30,000 cells / well in 100 μl of medium (DMEM supplemented with 10% FBS, 100 U / ml penicillin, and 100 μg / ml streptomycin) in a 96-well plate treated with tissue culture. The cells were cultured in a 5% CO2 incubator for 24 hours, transfected with an IDO1 expression vector (Component A of the IDO1 cell-based assay kit, catalog number 72031, BPS Bioscience) using Lipofectamine 2000 (Life Technologies, #11668027), and then cultured in a 5% CO2 incubator for 24 hours to express the IDO protein.

[0141] Activity was measured using the IDO1 cell-based assay kit (catalog number 72031, BPS Bioscience). Specifically, assay media was prepared by diluting IDO1 assay medium substrate 1 and IDO1 assay medium supplement 2 in a 1:100 ratio in culture medium. Each test compound was diluted to the specified concentration in fresh assay medium. After removing the medium using a multipipette, 200 μl of assay medium containing each test substance was added to each well and incubated in a 5% CO2 incubator for 24 hours. The following day, 140 μl of medium from each well was transferred to a new 96-well plate. 10 μl of 6.1N trichloroacetic acid was added to each well and cultured in a 50°C incubator for 30 minutes. The plate was centrifuged at 2500 rpm for 10 minutes to allow the precipitate to settle. The detection reagent solution was prepared by diluting the detection reagent (component D of the IDO1 cell-based assay kit, catalog number 72031, BPS Bioscience) 50-fold with acetic acid. 100 μl of supernatant collected from a centrifuged plate was transferred to a new clear 96-well plate, and 100 μl of detection reagent solution was added. After reacting at room temperature for 10 minutes, the absorbance at a wavelength of 480 nm was measured. For the analysis of the results, the absorbance (At) of the well containing HEK293 cells expressing IDO protein without inhibitor treatment was set to 100%, and the absorbance (Ab) of the well containing HEK293 cells in which IDO protein expression was not induced was set to 0. The % absorbance was calculated according to the following formula: % absorbance = (A - Ab) / (At - Ab), where A = absorbance of the well treated with the test compound.

[0142] From the absorbance values ​​obtained as described above, the 50% inhibitory concentration (IC) of each compound can be calculated. 50 The results of the calculation are shown in Table 2 below. [Table 2]

[0143] The results in Table 2 show that the compounds of the present invention exhibit excellent inhibitory activity against indoleamine-2,3-dioxygenase.

[0144] Study Example 3: Comparative study of pharmacokinetics after oral administration to normal rats The pharmacokinetics of the compounds from Examples 2, 5, and 25, and BMS-986205 (control substance), were measured in rats. The compounds from Examples 2, 5, and 25, and BMS-986205 (control substance), were each suspended in 0.5% methylcellulose containing 0.2% Tween 80, and then orally administered to rats at a dose of 10 mg / 5 mL / kg. Blood samples were collected from the rats at predetermined intervals. The concentrations of the compounds in each sample were analyzed to obtain blood concentration profiles (Figure 1). The resulting pharmacokinetic parameters are shown in Table 3 below. [Table 3]

[0145] As can be seen from the results in Table 3, the compounds of the present invention exhibit a Cmax 3.3 to 27.5 times higher and an AUC 4.0 to 27.3 times higher in normal rats compared to the control (BMS-986205). These results indicate that the compounds of the present invention exhibit significantly higher in vivo exposure levels. Therefore, it is expected that the compounds of the present invention will exhibit superior efficacy by showing significantly higher in vivo exposure levels than BMS-986205 even at the same dose. Furthermore, since the compounds of the present invention can achieve similar in vivo exposure levels to BMS-986205 even when administered at low doses, they are expected to exhibit superior safety.

Claims

1. Compounds of chemical formula 1 or their pharmaceutically acceptable salts: 【Chemistry 1】 During the ceremony, R is C １ ~C ６ Alkyl or C ３ ~C １０ It is a cycloalkyl group, A is a heteroaryl group selected from the group consisting of quinazolinyl, 2H-chromen-2-one-yl, benzothiazolyl, benzoxazolyl, thiazolopyridinyl, oxazolopyridinyl, isoquinolinyl, and phthalazinyl, and the heteroaryl group is halogen, C １ ~C ６ alkyl, trifluoromethyl, C １ ~C ６ alkoxy, halogeno-C １ ~C ６ alkoxy, trifluoromethoxy, and cyano, and may be substituted with one or two substituents selected from the group consisting of.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is methyl, ethyl, or cyclopropyl.

3. A is halogen, C １ ~C ６ Alkyl, trifluoromethyl, C １ ~C ６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the quinazolinyl group is substituted with one or two substituents selected from the group consisting of alkoxy, trifluoromethoxy, and cyano.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is a 2H-chromen-2-on-yl group substituted with one or two halogens.

5. A is halogen and C １ ~C ６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the benzothiazolyl group is substituted with one or two substituents selected from the group consisting of alkoxys.

6. A is halogen or C １ ~C ６ The compound according to claim 1, wherein the thiazolopyridinyl group may be substituted with an alkoxy, or a pharmaceutically acceptable salt thereof.

7. A is halogen, C １ ~C ６ Alkoxy and halogen-C １ ~C ６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the benzoxazolyl group is substituted with one or two substituents selected from the group consisting of alkoxys.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is an oxazolopyridinyl group which may be substituted with a halogen.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is an isoquinolinyl group substituted with a halogen.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is a halogen-substituted phthalazinyl group.

11. 4-(((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)quinazoline-7-carbonitrile; 7-Bromo-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 7-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 7-Chloro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 7-Bromo-4-(((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one; 7-Chloro-4-(((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one; 6-Bromo-4-(((R)-1-((Trans)-4-(6-Fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-Cromen-2-one; 7-Chloro-4-(((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one; 7-Bromo-4-(((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one; 7-Chloro-3-fluoro-4-(((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one; 7-Bromo-3-fluoro-4-(((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one; 7-Bromo-3-fluoro-4-(((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one; 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazole-2-amine; N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-6-methoxybenzo[d]thiazole-2-amine; N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)butan-2-yl)-6-methoxybenzo[d]thiazole-2-amine; N-((S)-1-cyclopropyl-2-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)ethyl)-6-methoxybenzo[d]thiazole-2-amine; 4,6-Difluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazole-2-amine; 7-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazole-2-amine; 6-Ethoxy-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazole-2-amine; 6-Ethoxy-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)butan-2-yl)benzo[d]thiazole-2-amine; N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)thiazolo[4,5-b]pyridine-2-amine; N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-5-methoxythiazolo[5,4-b]pyridine-2-amine; 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)thiazolo[4,5-b]pyridine-2-amine; N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-6-methoxybenzo[d]oxazole-2-amine; 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)butan-2-yl)benzo[d]oxazole-2-amine; 4-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; 6-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)oxazolo[5,4-b]pyridine-2-amine; 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)oxazolo[4,5-b]pyridine-2-amine; N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)oxazolo[4,5-b]pyridine-2-amine; 6-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)isoquinoline-1-amine; 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)isoquinoline-1-amine; 4-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazole-2-amine; 5-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; 7-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; 2-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)phthalazine-1-amine; 2,7-Dichloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 2,7-Dichloro-N-((R)-1-((Trans)-4-(6-Fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 7-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-6-methoxybenzo[d]oxazole-2-amine; 6-Chloro-5-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; 6-Ethoxy-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; 6-(2-fluoroethoxy)-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; 6,7-Dichloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; 6,7-Difluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; 2-Chloro-6-fluoro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 2,6-Dichloro-N-((R)-1-((Trans)-4-(6-Fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 2-Chloro-8-fluoro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 2,8-Dichloro-N-((R)-1-((Trans)-4-(6-Fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 2-Chloro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-8-methoxyquinazoline-4-amine; 2-Chloro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-8-(trifluoromethoxy)quinazoline-4-amine; 2-Chloro-7-fluoro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 2-Chloro-4-(((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)quinazoline-7-carbonitrile; 7-Bromo-2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 2-Chloro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-7-methylquinazoline-4-amine; 2-Chloro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-7-(trifluoromethyl)quinazoline-4-amine; 2-Chloro-N-((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-7-methoxyquinazoline-4-amine; 2-Chloro-6-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 2,6-Dichloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 2-Chloro-7-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 2-Chloro-4-(((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)quinazoline-7-carbonitrile; 7-Bromo-2-chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 2-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-7-methylquinazoline-4-amine; 2-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-7-(trifluoromethyl)quinazoline-4-amine; 2-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-7-methoxyquinazoline-4-amine; 2,8-Dichloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 2-Chloro-8-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 2-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-8-methoxyquinazoline-4-amine; and 2-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)-8-(trifluoromethoxy)quinazoline-4-amine A compound according to claim 1, selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

12. 7-Bromo-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)quinazoline-4-amine; 7-Bromo-4-(((R)-1-((trans)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one; 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)butan-2-yl)benzo[d]oxazole-2-amine; 4-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; 6-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine; and 6,7-Difluoro-N-((R)-1-((cis)-4-(6-fluoroquinoline-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2-amine A compound according to claim 1, selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

13. A method for producing a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof, comprising the steps of: reacting a compound of chemical formula 2 or a salt thereof with a compound of chemical formula 3 to obtain a compound of chemical formula 1; and optionally converting the compound of chemical formula 1 into a pharmaceutically acceptable salt thereof: 【Chemistry 2】 【Transformation 3】 <Chemical formula 3> X-A In the formula, R and A are the same as defined in claim 1, and X is a halogen.

14. A pharmaceutical composition for inhibiting indoleamine-2,3-dioxygenase, comprising a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof as an active ingredient.

15. The pharmaceutical composition according to claim 14 for preventing or treating a viral infection; rheumatoid arthritis; a cancer selected from the group consisting of melanoma, pancreatic cancer, prostate cancer, and brain cancer; or depression.

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