Indoleamine 2,3-dioxygenase inhibitors, methods of making the same, and pharmaceutical compositions comprising the same

Abstract

The present application provides a compound having a cyclohexyl-(alkyl or cycloalkyl-substituted)ethylene-amino-heteroaryl moiety or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition comprising the same, and a use thereof. The compound or the pharmaceutically acceptable salt thereof not only has excellent inhibitory activity against indoleamine 2,3-dioxygenase (IDO), but also exhibits significantly high in vivo exposure after oral administration. Accordingly, the compound or the pharmaceutically acceptable salt thereof can be effectively applied to the prevention or treatment of various diseases associated with IDO.

Description

TECHNICAL FIELD

[0001] The present invention relates to a compound having inhibitory activity against indoleamine 2,3-dioxygenase (IDO), i.e., a derivative having a cyclohexyl-(alkyl or cycloalkyl substituted)ethylidene-amino-heteroaryl moiety or a pharmaceutically acceptable salt thereof, a method of preparing the same, a pharmaceutical composition comprising the same, and a use thereof. BACKGROUND

[0002] The rapid proliferation of cancer is derived from the evasion of immune system attack. It has been reported that tryptophan plays an important role in cancer immune evasion (Opitz, C. A. et al. Nature 478, 197-203 (2011)). In particular, the complex interaction between cancer cells and immune cells is one of the key factors that determine the survival and death of early cancer cells. The approach used by cancer cells to escape the attack of immune cells is related to the immunosuppressive pathway. Recently, the role of indoleamine 2,3-dioxygenase (IDO) in the degradation process of tryptophan and the resulting kynurenine has attracted attention.

[0003] Tryptophan is an amino acid essential for cell proliferation and survival. Indoleamine 2,3-dioxygenase (commonly referred to as "IDO-1") is a heme-containing enzyme that catalyzes the first step, i.e., the rate-limiting step, of tryptophan degradation to N-formyl-kynurenine. IDO acts on the metabolism of L-tryptophan to degrade it to N-formyl-kynurenine, and then metabolize it through various steps to produce nicotinamide adenine dinucleotide (NAD+). It is known that tryptophan catabolites, such as kynurenine, produced from N-formyl-kynurenine are cytotoxic to T cells. Thus, IDO depletes tryptophan and produces kynurenine, thereby inhibiting the activity of immune cells including T cells through various mechanisms (Mellor, A. L. & Munn, D. H. 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 (as well as cancer cells) and acts on these cells to inhibit the ability of the immune system to recognize and attack cancer cells. Thus, overexpression of IDO can lead to increased resistance in the tumor microenvironment, resulting in continuous growth of cancer tissue.

[0004] It has been reported that upregulation of IDO leads to poor prognosis in cancer patients (Uyttenhove, C. et al. Nature Med. 9, 1269-1274 (2003)). It has been confirmed that IDO plays a key role in immune tolerance and inflammatory carcinogenesis through tests using IDO gene knockout mice (Muller, A.J., Mandik-Nayak, L. & Prendergast, G.C. Immunotherapy 2, 293-297 (2010) Muller, A.J. et al. Proc. Natl Acad. Sci. USA 105, 17073-17078 (2008)). In particular, it has been reported that the use of IDO inhibitors as an adjuvant therapy improves the effects of immunotherapy, radiotherapy, and anticancer vaccines (Muller, A.J., DuHadaway, J.B., Donover, P.S., Sutanto-Ward, E. & Prendergast, G.C. Nature Med. 11, 312-319 (2005)). In addition, it has been reported that the strong effect of the anticancer drug imatinib (Gleevec) on solid gastrointestinal stromal tumors is derived from the inhibition of IDO (Balachandran, V.P. et al. Nature Med. 17, 1094-1100 (2011)).

[0005] Accordingly, IDO inhibitors can be effective in inhibiting cancer metastasis and cancer proliferation. Also, IDO inhibitors can be effectively used for 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, malignancy, or virus-induced T cell suppression. Although the mechanism of action is not yet clear, it is expected that IDO inhibitors can also be used to treat patients suffering from neuropsychiatric diseases or symptoms such as depression. For example, WO 2016 / 073770, WO 2018 / 039512, and the like have disclosed compounds having inhibitory activity against indoleamine 2,3-dioxygenase and pharmaceutical compositions comprising the same. SUMMARY

[0006] TECHNICAL PROBLEM

[0007] The present inventors have found that a derivative having a cyclohexyl-(alkyl or cycloalkyl-substituted)ethylidene-amino-heteroaryl moiety or a pharmaceutically acceptable salt thereof not only has excellent inhibitory activity against indoleamine 2,3-dioxygenase, but also exhibits extremely high in vivo exposure after oral administration. Accordingly, the derivative or the pharmaceutically acceptable salt thereof can be effectively used for the prevention or treatment of various diseases associated with IDO, for example, proliferative diseases such as cancer, viral infections, and / or autoimmune diseases, and the like.

[0008] Accordingly, the present application provides the derivatives having a cyclohexyl-(alkyl or cycloalkyl substituted)ethylidene-amino-heteroaryl moiety or a pharmaceutically acceptable salt thereof, a method for preparing the same, a pharmaceutical composition comprising the same, and uses thereof.

[0009] Solution to the problem

[0010] According to one aspect of the present application, there are provided derivatives having a cyclohexyl-(alkyl or cycloalkyl substituted)ethylidene-amino-heteroaryl moiety or a pharmaceutically acceptable salt thereof.

[0011] According to another aspect of the present application, there is provided a method for preparing the derivatives having a cyclohexyl-(alkyl or cycloalkyl substituted)ethylidene-amino-heteroaryl moiety or a pharmaceutically acceptable salt thereof.

[0012] According to still another aspect of the present application, there is provided a pharmaceutical composition comprising the derivatives having a cyclohexyl-(alkyl or cycloalkyl substituted)ethylidene-amino-heteroaryl moiety or a pharmaceutically acceptable salt thereof as an active ingredient.

[0013] According to still another aspect of the present application, there is provided a method for treatment, comprising administering the derivatives having a cyclohexyl-(alkyl or cycloalkyl substituted)ethylidene-amino-heteroaryl moiety or a pharmaceutically acceptable salt thereof.

[0014] According to still another aspect of the present application, there is provided use of the derivatives having a cyclohexyl-(alkyl or cycloalkyl substituted)ethylidene-amino-heteroaryl moiety or a pharmaceutically acceptable salt thereof for the preparation of a medicament for inhibiting indoleamine 2,3-dioxygenase.

[0015] Advantageous effects

[0016] It has been found that the derivatives having a cyclohexyl-(alkyl or cycloalkyl substituted)ethylidene-amino-heteroaryl moiety or a pharmaceutically acceptable salt thereof not only have excellent inhibitory activity against indoleamine 2,3-dioxygenase, but also exhibit a very high in vivo exposure amount upon oral administration. Accordingly, the compounds according to the present application or a pharmaceutically acceptable salt thereof can be effectively used for preventing or treating various diseases associated with indoleamine 2,3-dioxygenase, such as proliferative diseases such as cancer, viral infections, and / or autoimmune diseases, etc. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 Blood concentration profiles obtained from rats orally administered with the compounds of the present application and a control (BMS-986205) are shown. DETAILED DESCRIPTION

[0018] The present application provides a compound or a salt thereof having excellent inhibitory activity against indoleamine 2,3-dioxygenase, i.e., a compound of Formula 1 or a pharmaceutically acceptable salt thereof:

[0019] <Formula 1>

[0020]

[0021] wherein,

[0022] R is C1-C6 alkyl or C3-C6 cycloalkyl, 10 cycloalkyl,

[0023] A is a heteroaryl selected from quinazolinyl, 2H-chromen-2-on-yl, benzothiazolyl, benzoxazolyl, thiazolopyridinyl, oxazolopyridinyl, isoquinolinyl, and phthalazinyl, wherein the heteroaryl is optionally substituted with one or two substituents selected from halogen, C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, trifluoromethoxy, and cyano.

[0024] In one embodiment of the present application, R can be methyl, ethyl, or cyclopropyl.

[0025] In another embodiment of the present application, A can be substituted or unsubstituted quinazolinyl, preferably quinazolinyl substituted with one or two substituents selected from halogen, C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, trifluoromethoxy, and cyano. For example, A can have the following structure of Formula 1a.

[0026] <Formula 1a>

[0027]

[0028] wherein R 11 and R 12 are each independently selected from hydrogen, halogen, C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, trifluoromethoxy, and cyano; and R 13 may be hydrogen or halogen. In one embodiment, R 13 may be hydrogen, Cl, or F.

[0029] In still another embodiment of the present application, A can be substituted or unsubstituted 2H-chromen-2-on-yl, preferably 2H-chromen-2-on-yl substituted with one or two halogens. For example, A can have the following structure of Formula 1b.

[0030] <Formula 1b>

[0031]

[0032] wherein R 21 and R 22 are each independently selected from the group consisting of hydrogen, halogen, Ci-C6alkyl, trifluoromethyl, Ci-C6alkoxy, halo-Ci-C6alkoxy, trifluoromethoxy, and cyano.

[0033] In still another embodiment of the application, A can be a substituted or unsubstituted benzothiazolyl, preferably a benzothiazolyl substituted with one or two substituents selected from the group consisting of halogen and Ci-C6alkoxy. For example, A can have the following structure of Formula 1c.

[0034] <Formula 1c>

[0035]

[0036] wherein R 31 and R 32 are each independently selected from the group consisting of hydrogen, halogen, Ci-C6alkyl, trifluoromethyl, Ci-C6alkoxy, halo-Ci-C6alkoxy, trifluoromethoxy, and cyano.

[0037] In still another embodiment of the application, A can be a substituted or unsubstituted benzothiazolyl, preferably a benzothiazolyl substituted with one or two substituents selected from the group consisting of halogen and Ci-C6alkoxy. For example, A can have the following structure of Formula 1c.

[0038] <Formula 1c>

[0039]

[0040] <Formula 1c>

[0041]

[0042] wherein R 41 and R 42 are each independently selected from the group consisting of hydrogen, halogen, Ci-C6alkyl, trifluoromethyl, Ci-C6alkoxy, halo-Ci-C6alkoxy, trifluoromethoxy, and cyano.

[0043] In still another embodiment of the application, A can be a substituted or unsubstituted benzothiazolyl, preferably a benzothiazolyl substituted with one or two substituents selected from the group consisting of halogen and Ci-C6alkoxy. For example, A can have the following structure of Formula 1c.

[0044] <Formula 1c>

[0045]

[0046] wherein R 51and R 52 independently of one another, are selected from the group consisting of hydrogen, halogen, Ci-C6-alkyl, trifluoromethyl, Ci-C6-alkoxy, halogen-Ci-C6-alkoxy, trifluoromethoxy and cyano.

[0047] In yet another embodiment of the present application, A can be a substituted or unsubstituted isoquinolinyl, preferably an isoquinolinyl substituted with halogen. For example, A can have the following structure of Formula Ig.

[0048] <Formula Ig>

[0049]

[0050] <Formula Ig>

[0051]

[0052] in which R 61 and R 62 independently of one another, are selected from the group consisting of hydrogen, halogen, Ci-C6-alkyl, trifluoromethyl, Ci-C6-alkoxy, halogen-Ci-C6-alkoxy, trifluoromethoxy and cyano.

[0053] In yet another embodiment of the present application, A can be a substituted or unsubstituted isoquinolinyl, preferably an isoquinolinyl substituted with halogen. For example, A can have the following structure of Formula Ig.

[0054] <Formula Ig>

[0055]

[0056] in which R 71 and R 72 independently of one another, are selected from the group consisting of hydrogen, halogen, Ci-C6-alkyl, trifluoromethyl, Ci-C6-alkoxy, halogen-Ci-C6-alkoxy, trifluoromethoxy and cyano.

[0057] In yet another embodiment of the present application, A can be a substituted or unsubstituted isoquinolinyl, preferably an isoquinolinyl substituted with halogen. For example, A can have the following structure of Formula Ig.

[0058] <Formula Ig>

[0059]

[0060] in which R 81 and R 82 independently of one another, are selected from the group consisting of hydrogen, halogen, Ci-C6-alkyl, trifluoromethyl, Ci-C6-alkoxy, halogen-Ci-C6-alkoxy, trifluoromethoxy and cyano.

[0061] In the present specification, when a heteroaryl group is substituted with two halogens, the halogens can be the same or different. When a heteroaryl group is substituted with two C1-C6 alkyl groups, the C1-C6 alkyl groups can be the same or different. When a heteroaryl group is substituted with two C1-C6 alkoxy groups, the C1-C6 alkoxy groups can be the same or different. When a heteroaryl group is substituted with two halo-C1-C6 alkoxy groups, the halo-C1-C6 alkoxy groups can be the same or different.

[0062] In the compounds of Formula 1 or pharmaceutically acceptable salts, preferred compounds include a compound selected from the group consisting of:

[0063] 4-(((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)amino)quinazoline-7- carbonitrile;

[0064] 7-bromo-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4- amine;

[0065] 7-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4- amine;

[0066] 7-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4- amine;

[0067] 7-bromo-4-(((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)amino)-2H- chromen-2-one;

[0068] 7-chloro-4-(((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)amino)-2H- chromen-2-one;

[0069] 6-bromo-4-(((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)amino)-2H- chromen-2-one;

[0070] 7-chloro-4-(((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)amino)-2H- chromen-2-one;

[0071] 7-bromo-4-(((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)amino)-2H- chromen-2-one;

[0072] 7-bromo-3-fluoro-4-(((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)amino)-2H-chromen-2-one;

[0073] 7-bromo-3-fluoro-4-(((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)amino)-2H-chromen-2-one;

[0074] 7-bromo-3-fluoro-4-(((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)amino)-2H-chromen-2-one;

[0075] 6-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazol- 2-amine;

[0076] N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-6-methoxybenzo[d]thiazol- 2-amine;

[0077] N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)butan-2-yl)-6-methoxybenzo[d]thiazol- 2-amine;

[0078] N-((S)-1-cyclopropyl-2-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-6-methoxybenzo[d]thiazol- 2-amine;

[0079] 4,6-difluoro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazol- 2-amine;

[0080] 7-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazol- 2-amine;

[0081] 6-ethoxy-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazol- 2-amine;

[0082] 6-ethoxy-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)butan-2-yl)benzo[d]thiazol- 2-amine;

[0083] N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)thiazolo[4,5-b]pyridin-2- amine;

[0084] N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-5- methoxythiazolo[5,4-b]pyridin-2-amine;

[0085] 6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)thiazolo[4,5- b]pyridin-2-amine;

[0086] N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol-2- amine;

[0087] 6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol- 2-amine;

[0088] N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-6-methoxybenzo[d]oxazol- 2-amine;

[0089] 6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)butan-2-yl)benzo[d]oxazol-2- amine;

[0090] 4-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol-2- amine;

[0091] 6-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol-2- amine;

[0092] N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)oxazolo[5,4-b]pyridin-2- amine;

[0093] 6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)oxazolo[4,5- b]pyridin-2-amine;

[0094] N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)oxazolo[4,5-b]pyridin-2- amine;

[0095] 6-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)isoquinolin-1- amine;

[0096] 6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)isoquinolin- 1 -amine;

[0097] 4-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazol- 2-amine;

[0098] 5-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol- 2-amine;

[0099] 7-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol- 2-amine;

[0100] 2-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4- amine;

[0101] 6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)phthalazin-1- amine;

[0102] 2,7-dichloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4- amine;

[0103] 2,7-dichloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin- 4-amine;

[0104] 7-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-6-methoxybenzo[d] oxazol-2-amine;

[0105] 6-chloro-5-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d] oxazol-2-amine;

[0106] 6-ethoxy-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol-2- amine;

[0107] 6-(2-fluoroethoxy)-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d] oxazol-2-amine;

[0108] 6,7-dichloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)benzo[d]oxazol-2-amine;

[0109] 6,7-dichloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)benzo[d]oxazol-2-amine;

[0110] 2-chloro-6-fluoro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)quinazolin-4-amine;

[0111] 2,6-dichloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl) quinazolin-4-amine;

[0112] 2-chloro-8-fluoro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)quinazolin-4-amine;

[0113] 2,8-dichloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl) quinazolin-4-amine;

[0114] 2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-8- methoxyquinazolin-4-amine;

[0115] 2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-8- (trifluoromethoxy)quinazolin-4-amine;

[0116] 2-chloro-7-fluoro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)quinazolin-4-amine;

[0117] 2-chloro-4-(((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)amino) quinazoline-7-carbonitrile;

[0118] 7-bromo-2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)quinazolin-4-amine;

[0119] 2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7- methylquinazolin-4-amine;

[0120] 2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7- methoxyquinazolin-4-amine;

[0121] 2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7- methoxyquinazolin-4-amine;

[0122] 2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7- methoxyquinazolin-4-amine;

[0123] 2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7- methoxyquinazolin-4-amine;

[0124] 2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7- methoxyquinazolin-4-amine;

[0125] 2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7- methoxyquinazolin-4-amine;

[0126] carbonitrile;

[0127] 2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7- methoxyquinazolin-4-amine;

[0128] 2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7- methoxyquinazolin-4-amine;

[0129] 2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7- methoxyquinazolin-4-amine;

[0130] 2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7- methoxyquinazolin-4-amine;

[0131] 2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7- methoxyquinazolin-4-amine;

[0132] 2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7- methoxyquinazolin-4-amine;

[0133] 2-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-8- methoxyquinazolin-4-amine; and

[0134] 2-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-8- methoxyquinazolin-4-amine; and

[0135] In the compounds of Formula 1 or pharmaceutically acceptable salts, more preferred compounds include a compound selected from the group consisting of:

[0136] 7-bromo-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin- 4-amine;

[0137] 7-bromo-4-(((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)amino)- 2H-chromen-2-one;

[0138] 6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol- 2-amine;

[0139] 6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol- 2-amine;

[0140] 4-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol- 2-amine;

[0141] 6-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol- 2-amine; and

[0142] 6,7-difluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol- 2-amine.

[0143] In the compounds of Formula 1 or pharmaceutically acceptable salts thereof, particularly preferred compounds include 6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4- yl)cyclohexyl)propan-2-yl)benzo[d]oxazol-2-amine or a pharmaceutically acceptable salt thereof.

[0144] The compound of Formula 1 or a pharmaceutically acceptable salt thereof can have a substituent including an asymmetric atom, and can have geometric isomers by the cyclohexyl group. That is, the compound of Formula 1 or a pharmaceutically acceptable salt thereof can be in the form of a cis-geometric isomer or a trans-geometric isomer; in the form of an (R)-optical isomer or an (S)-optical isomer; or in the form of a racemic mixture (RS). Thus, unless otherwise specified, the compound of Formula 1 or a pharmaceutically acceptable salt thereof includes the cis-geometric isomer or the trans-geometric isomer, the (R)-optical isomer or the (S)-optical isomer, and the racemic mixture (RS).

[0145] The compound of Formula 1 of the present application can be in the form of a pharmaceutically acceptable salt. The salt can be in the form of a conventional acid addition salt, which includes, 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. In addition, the salt includes a conventional metal salt form, for example, a salt derived from a metal such as lithium, sodium, potassium, magnesium, or calcium. The acid addition salt or metal salt can be prepared according to a conventional method.

[0146] The present application includes, within its scope, a method for preparing the compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[0147] For example, the compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present application can be prepared by a method including the step of reacting a compound of Formula 2 or a salt thereof with a compound of Formula 3 to obtain a compound of Formula 1; and optionally converting the compound of Formula 1 into a pharmaceutically acceptable salt thereof:

[0148] <Formula 2>

[0149]

[0150] <Formula 3>

[0151] X-A

[0152] wherein R and A are the same as defined above; and X is halogen.

[0153] The compound of Formula 3 is commercially available. The coupling reaction between the compound of Formula 2 or a salt thereof (e.g., a hydrochloride salt) and the compound of Formula 3 can be performed in the presence of a base and a solvent. The base can be cesium carbonate, potassium carbonate, sodium carbonate, triethylamine, or the like, and the solvent can be an organic solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, ethanol, or isopropanol. In addition, the reaction can be performed at room temperature to 100°C.

[0154] The compound of Formula 2, or a salt thereof, can be effectively used as an intermediate for preparing a derivative according to the present application having a cyclohexyl-(alkyl or cycloalkyl substituted)ethylidene-amino-heteroaryl moiety, or a pharmaceutically acceptable salt thereof (i.e., a compound of Formula 1, or a pharmaceutically acceptable salt thereof). Thus, the present application includes within its scope the compound of Formula 2, or a salt thereof. The salt of the compound of Formula 2 includes an acid addition salt, such as a hydrochloride salt.

[0155] For example, the compound of Formula 2, a (R = methyl), can be prepared according to the following Reaction Scheme 1.

[0156] <Reaction Scheme 1>

[0157]

[0158] The compound of formula 5 can be prepared by Suzuki reaction between a compound of formula 4, which is commercially available, and 4-chloro-6-fluoroquinoline. The reaction can be carried out using a palladium catalyst such as palladium(II) acetate (Pd(OAc)2), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (Pd(dppf)Cl2), and the like. In addition, the reaction can also be carried out in the presence of a ligand and a base in addition to the palladium catalyst. The ligand includes (S)-2,2’-bis(diphenylphosphino)-1,1’-binaphthyl (BINAP), 1,1’-bis(diphenylphosphino)ferrocene (dppf), tri(o-tolyl)phosphine (P(o-Tol)3), and the like. The base includes 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), potassium tert-butoxide (tert-BuOK), and the like. The reaction can be carried out in a non-polar 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 the reaction time can be determined according to the known method of Suzuki reaction (Barbara Czako and Laszlo Kurti, STRATEGIC APPLICATIONS of NAMED REACTIONS in ORGANIC SYNTHESIS, 2005).

[0159] The reduction of the compound of formula 5 can be carried out using palladium on carbon in an organic solvent such as ethyl acetate or methanol. The reduction can be typically carried out using hydrogen gas at room temperature.

[0160] The reduction of the compound of formula 6 can be carried out using lithium aluminum hydride in an organic solvent such as tetrahydrofuran or dichloromethane. The reduction can be typically carried out at -78 °C to room temperature.

[0161] The oxidation of the compound of formula 7 can be carried out using an oxidizing agent in an organic solvent such as ethyl acetate or dichloromethane. The oxidation can be generally carried out at 0 °C to room temperature.

[0162] The compound of formula 9 can be prepared by condensing the compound of formula 8 with (S)-(-)-2-methyl-2-propanesulfonamide. The condensation can 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 tetraethyl titanate(IV). The reaction can be carried out at -78 °C to room temperature.

[0163] The compound of formula 10 can be prepared by reacting the compound of formula 9 with an alkyl Grignard reagent. In addition, deprotection of the compound of formula 10 can give the compound of formula 2a or a salt thereof (e.g., hydrochloride). The deprotection can be carried out according to known methods (Theodora W. Greene and Peter G. M. Wuts, Protective groups in organic synthesis, 3rd Ed., 1999). For example, the deprotection can be carried out using a solution of trifluoroacetic acid or hydrochloric acid in an organic solvent such as dichloromethane, 1,4-dioxane or ethyl acetate at room temperature.

[0164] The derivative having a cyclohexyl-(alkyl or cycloalkyl-substituted)ethylidene-amino-heteroaryl moiety according to the present application or a pharmaceutically acceptable salt thereof (i.e., the compound of formula 1 or a pharmaceutically acceptable salt thereof) has excellent inhibitory activity against indoleamine 2,3-dioxygenase (IDO). Also, the compound of formula 1 or a pharmaceutically acceptable salt thereof shows extremely high in vivo exposure after oral administration. The present inventors conducted a study on biomarker changes and pharmacokinetics in a subcutaneous MC38 colorectal model of C57BL / 6 mice. Compared with the excipient group and the positive control group (BMS-986205, Epacadostat), the group administered with the compound of the present application showed a significant decrease in the level of kynurenine in the plasma and tumor tissue at 1 day after oral administration. The group administered with the compound of the present application showed a significant decrease in the level of kynurenine in the plasma and tumor tissue at 3 days after oral administration. In particular, in the group administered with a certain compound of the present application for 3 days, the level of kynurenine in the plasma and tumor tissue was almost completely decreased. Thus, the compound of formula 1 or a pharmaceutically acceptable salt thereof can be effectively used for the prevention or treatment of various diseases associated with IDO.

[0165] Accordingly, the present application includes within its scope pharmaceutical compositions for inhibiting indoleamine 2,3-dioxygenase, comprising a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. In one embodiment, the present application provides a pharmaceutical composition for preventing or treating an IDO-related disease, such as a viral infection; an autoimmune disease (e.g., rheumatoid arthritis); a cancer (e.g., melanoma, pancreatic cancer, prostate cancer, brain cancer); or a neuropsychiatric disease (e.g., depression), comprising a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0166] The pharmaceutical composition of the present application can comprise a pharmaceutically acceptable carrier, such as a diluent, a disintegrant, a sweetening agent, a lubricant, or a flavoring agent commonly used in the art. The pharmaceutical composition can be formulated into an oral dosage form, such as a tablet, a capsule, a powder, a granule, a suspension, an emulsion, or a syrup; or a parenteral dosage form, such as a topical solution, a topical suspension, a topical emulsion, a gel (e.g., an ointment), an inhalant, a spray, an injection, according to a conventional method. The dosage form can be in various forms, such as a dosage form for single administration or multiple administration.

[0167] The pharmaceutical composition of the present application can comprise, for example, a diluent (e.g., lactose, corn starch, etc.); a lubricant (e.g., magnesium stearate); an emulsifying agent; a suspending agent; a stabilizer; and / or an isotonic agent. If necessary, the composition further comprises a sweetening agent and / or a flavoring agent.

[0168] The composition of the present application can be administered orally or parenterally, including inhalation, intravenous, intraperitoneal, subcutaneous, rectal and topical routes of administration. Thus, the composition of the present application can be formulated in various forms, for example, tablets, capsules, aqueous solutions or suspensions. In the case of tablets for oral administration, carriers such as lactose, corn starch and lubricants such as magnesium stearate are generally used. In the case of capsules for oral administration, lactose and / or dry corn starch can be used as diluents. When an aqueous suspension is required for oral administration, the active ingredient can be combined with an emulsifying agent and / or a suspending agent. If necessary, certain sweetening agents and / or flavoring agents can be used. For intramuscular, intraperitoneal, subcutaneous and intravenous administration, a sterile solution of the active ingredient is generally prepared, and the pH of the solution should be appropriately adjusted and buffered. For intravenous administration, the total concentration of solutes should be controlled in order to make the preparation isotonic. The composition of the present application can be in the form of an aqueous solution containing a pharmaceutically acceptable carrier, for example, saline having a pH of 7.4. The solution can be introduced into the muscle blood stream of a patient by local bolus injection.

[0169] The compound of Formula 1 or a pharmaceutically acceptable salt thereof can be administered to a subject patient in a therapeutically effective amount of about 5 mg / kg to about 50 mg / kg per day, preferably about 10 mg / kg to about 20 mg / kg per day, in a single or multiple doses. Of course, the dose can vary depending on the age, body weight, susceptibility, symptoms of the patient or the activity of the compound.

[0170] The present application includes, within its scope, a method for inhibiting indoleamine 2,3-dioxygenase in a mammal, the method comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof. In one embodiment, the present application provides a method for treating a disease associated with indoleamine 2,3-dioxygenase, such as a viral infection; an autoimmune disease (e.g., rheumatoid arthritis); a cancer (e.g., melanoma, pancreatic cancer, prostate cancer, brain cancer); or a neuropsychiatric disease (e.g., depression), comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[0171] The present application also provides the use of a compound of Formula 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting indoleamine 2,3-dioxygenase in a mammal. In one embodiment, the present application provides the use of a compound of Formula 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing or treating a disease associated with indoleamine 2,3-dioxygenase, such as a viral infection; an autoimmune disease (e.g., rheumatoid arthritis); a cancer (e.g., melanoma, pancreatic cancer, prostate cancer, brain cancer); or a neuropsychiatric disease (e.g., depression).

[0172] The following examples and experimental examples are for illustrative purposes only and are not intended to limit the scope of the present application.

[0173] The following compounds prepared in the examples below were analyzed by nuclear magnetic resonance (NMR) spectroscopy using a Bruker 400 MHz spectrometer and their chemical shifts were analyzed in ppm. Column chromatography was performed on silica gel (Merck, 70-230 mesh) (W. C. Still, J. Org. Chem., 43, 2923, 1978). Each starting material was a known compound, synthesized according to the literature or purchased commercially, for example, from Sigma-Aldrich.

[0174] Preparation 1. (R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride

[0175]

[0176] Step 1: 2-(4-(6-fluoroquinolin-4-yl)cyclohex-3-en-1-yl)acetic acid ethyl ester

[0177]

[0178] Ethyl 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l-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). To the solution was added [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (Pd(dppf)Cl2) (675 mg), and then stirred at 95°C overnight. The reaction mixture was concentrated, and then ethyl acetate was added thereto. The mixture was washed with distilled water, dried over anhydrous magnesium sulfate, and then 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%)

[0179] 1 H-NMR (CDC13) δ 8.79 (d, IH), 8.10 (t, IH), 7.61 (d, IH), 7.51 (t, IH), 7.18 (d, IH), 5.81 (s, IH), 4.18 (q, 2H), 2.51-2.28 (m, 7H), 2.02 (m, 2H), 1.58 (m, IH), 1.28 (t, 3H)

[0180] Step 2: Ethyl 2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)acetate

[0181]

[0182] A solution of ethyl 2-(4-(6-fluoroquinolin-4-yl)cyclohex-3-en-l-yl)acetate (4.40 g) prepared in Step 1, 10% Pd / C (440 mg) and acetic acid (0.16 ml) in methanol (30 ml) was stirred under a hydrogen atmosphere for 12 hours. The reaction mixture was dried, and then 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%)

[0183] 1H-NMR (CDC13) δ 8.80 (s, IH), 8.11 (t, IH), 7.65 (d, IH), 7.46 (t, IH), 7.30 (d, IH), 4.16 (q, 2H), 3.21-3.06 (m, IH), 2.49 (s, IH), 2.30 (d, IH), 2.04-1.72 (m, 7H), 1.62 (q, IH), 1.37-1.24 (m, 4H)

[0184] Step 3: 2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)-l-ethanol

[0185]

[0186] A solution of ethyl 2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)acetate (2.27 g) prepared in Step 2 in tetrahydrofuran (24 ml) was stirred at 0 °C for 10 minutes, and then lithium aluminum hydride (355 mg) was slowly added thereto. The reaction mixture was stirred at room temperature for 6 hours. The reaction was quenched by adding water to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then filtered. The resulting filtrate was concentrated under reduced pressure. Two stereoisomers were collected, which were confirmed by TLC, and then purified by silica gel column chromatography (n-hexane / ethyl acetate = 1 / 2, v / v) to give 1.53 g of the title compound as a white solid. (Yield: 73.2 %)

[0187] 1 H-NMR (DMSO-d6) δ 8.77 (d, IH), 8.06 (t, IH), 7.89 (d, IH), 7.62 (t,

[0188] 1H), 7.35 (d, IH), 4.63 (t, 1 / 2H), 4.39 (t, 1 / 2H), 3.47 (q, 2H), 3.20 (t, 1 / 2H), 3.12 (t, 1 / 2H), 1.87-1.72 (m, 4H), 1.50-1.36 (m, 4H), 1.21-1.14 (q, 2H)

[0189] Step 4: 2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)acetaldehyde

[0190]

[0191] A solution of 2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)ethan-1-ol (15.14 g) prepared in Step 3 in dichloromethane (185 ml) was stirred at 0 °C for 30 minutes, and then Dess-Martin oxidizing reagent (35.2 g) was slowly added thereto. The reaction mixture was stirred at room temperature for 5 hours. The reaction was quenched by adding water to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then filtered. The resulting filtrate was concentrated under reduced pressure. The lower material of two stereoisomers confirmed by TLC was purified from the resulting residue by silica gel column chromatography (n-hexane / ethyl acetate / = 3 / 1, v / v) to produce 8.72 g of the title compound as a white solid. (Yield: 57.9 %)

[0192] 1 H-NMR (CDC13) 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)

[0193] Step 5: (S)-N-(2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethylidene)-2- methylpropane-2-sulfmamide

[0194]

[0195] A solution of 2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethanal (4.50 g) and (S)-(-)-2-methyl-2-propanesulfinamide (4.02 g) prepared in Step 4 in dichloromethane (55 ml) was stirred at 0 °C for 10 minutes, and then titanium (IV) isopropoxide (9.82 ml) was slowly added thereto. The reaction mixture was stirred at room temperature for 8 hours. The reaction was quenched by adding water to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with 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 / 1, v / v) to produce 5.22 g of the title compound as a white solid. (Yield: 84.0 %)

[0196] 1H-NMR (CDC13) δ 8.82 (IH, d), 8.14-8.10 (m, 2H), 7.64 (d, IH), 7.46 (t, IH), 7.33 (d, IH), 3.22 (t, IH), 2.72 (t, 2H), 2.04 (s, IH), 1.95-1.68 (m, 8H), 1.21 (s, 9H)

[0197] Step 6: (R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride

[0198]

[0199] The title compound was prepared as a white solid (276 mg) following the same procedure as in Preparation 1, substituting ethylmagnesium bromide in tetrahydrofuran (2.0 M, 1.3 mL) for the methylmagnesium bromide in ether. (Yield: 86.0 %)

[0200] A solution of methylpropane-2-sulfonamide (2.54 g) in dichloromethane (23 mL) was stirred at 0 °C for 10 minutes, and then a solution of methylmagnesium bromide in ether (3.0 M, 4.6 mL) was slowly added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of saturated ammonium chloride solution to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The resulting material was dissolved in ethyl acetate (25 mL), and a solution of hydrochloric acid in 1,4-dioxane (4 N, 2 mL) was slowly 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 give 1.67 g of the title compound as a white solid. (Yield: 86.0 %)

[0201] 1 H-NMR (CDC13) δ 8.82 (IH, d), 8.14-8.10 (m, 2H), 7.64 (d, IH), 7.46 (t, IH), 7.33 (d, IH), 3.22 (t, IH), 2.72 (t, 2H), 2.04 (s, IH), 1.95-1.68 (m, 8H), 1.21 (s, 9H)

[0202] Preparation 2. (R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)butan-2-amine hydrochloride

[0203]

[0204] The title compound was prepared as a white solid (276 mg) following the same procedure as in Preparation 1, substituting ethylmagnesium bromide in tetrahydrofuran (2.0 M, 1.3 mL) for the methylmagnesium bromide in ether. (Yield: 86.0 %)

[0205] 1 H-NMR (DMSO-d6) δ 9.22 (d, IH), 8.58 (q, IH), 8.43 (d, IH), 8.30 (s, 2H), 8.09 (t, 2H), 3.64 (s, IH), 2.43 (s, IH), 2.17 (s, 2H), 1.99-1.68 (m, 9H), 0.94 (s, IH), 0.63-0.37 (m, 4H)

[0206] Preparation 3. (S)-1-Cyclopropyl-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethan-1- amine hydrochloride

[0207]

[0208] Following the same procedure as in Preparation 1, the title compound was prepared as a white solid (298 mg) using a solution of cyclopropylmagnesium bromide in tetrahydrofuran (1.0 M, 1.3 ml) instead of methylmagnesium bromide in diethyl ether.

[0209] 1.3 ml) instead of methylmagnesium bromide in diethyl ether. (Yield: 71.4 %)

[0210] 1 H-NMR (DMSO-d6) δ 9.22 (d, IH), 8.58 (q, IH), 8.43 (d, IH), 8.30 (s, 2H), 8.09 (t, 2H), 3.64 (s, IH), 2.43 (s, IH), 2.17 (s, 2H), 1.99-1.68 (m, 9H), 0.94 (s, IH), 0.63-0.37 (m, 4H)

[0211] Preparation 4. (R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride

[0212] Step 1: 2-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)acetaldehyde

[0213]

[0214] A solution of 2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)ethan-1-ol (15.14 g) prepared in step 3 of Preparation 1 in dichloromethane (185 ml) was stirred at 0 °C for 30 minutes, and then Dess-Martin oxidizing reagent (35.2 g) was slowly added thereto. The reaction mixture was stirred at room temperature for 5 hours. The reaction was quenched by adding water to the reaction mixture, and then 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 upper material of two stereoisomers confirmed by TLC was purified from the obtained residue by silica gel column chromatography (n-hexane / ethyl acetate / = 3 / 1, v / v) to prepare 5.48 g of the title compound as a white solid. (Yield: 36.5%)

[0215] 1 H-NMR (CDC13) δ 9.84 (s, 1H), 8.83 (d, 1H), 8.12 (dd, 1H), 7.67 (dd,

[0216] 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)

[0217] Step 2: (S)-N-(2-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-2-methylpropane-2- sulfonamide

[0218]

[0219] A solution of 2-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethanal (3.00 g) prepared in step 1 and (S)-2-methyl-2-propanesulfonamide (1.61 g) in tetrahydrofuran (40 ml) was stirred at 0 °C for 10 minutes, and then titanium (IV) isopropoxide (6.55 ml) was slowly added thereto. The reaction mixture was stirred at room temperature for 8 hours. The reaction was quenched by adding water to the reaction mixture, and then 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 / 1, v / v) to obtain 4.1 g of the title compound as a white solid. (Yield: 99.0%)

[0220] 1H-NMR (CDC13) δ 8.82 (d, IH), 8.13 (dd, IH), 7.65 (dd, IH), 7.48 (dd, IH),

[0221] 1H), 7.30 (d, IH), 3.20-3.14 (dt, IH), 2.56 (dd, 2H), 2.08-2.02 (m, 4H),

[0222] 1.96-1.91 (m, IH), 1.67-1.58 (m, 2H), 1.43-1.33 (m, 2H), 1.22 (s, 9H)

[0223] Step 3: (R)-l-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride

[0224]

[0225] The title compound was prepared as a white solid (1.9 g) according to the same procedure as in Step 6 of Preparation 1, using (S)-N-(2-((trans)-4-(6-fluoroquinolin-4- yl)cyclohexyl)ethylidene)-2-methylpropane-2-sulfmamide (3.2 g) prepared in Step 2 instead of (S)-N-(2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethylidene)-2- methylpropane-2-sulfmamide. (Yield: 68.9%)

[0226] 1 H-NMR (CDC13) δ 8.82 (d, IH), 8.13 (dd, IH), 7.65 (dd, IH), 7.48 (dd, IH),

[0227] Example

[0228] Example 1.4-(((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)amino)quinazoline-7-carbonitrile

[0229] A solution of (R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- amine hydrochloride (30 mg) prepared in Preparation 1, 4-chloroquinazoline-7- carbonitrile (19 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. The reaction was quenched by adding water to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with 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 / 1, v / v) to give 12.2 mg of the title compound as a white solid. (Yield: 33.2 %)

[0230] 1 H-NMR (CDC13) δ 8.80 (d, IH), 8.71 (s, IH), 8.17 (s, IH), 8.12 (t, IH), 7.86 (d, IH), 7.67-7.60 (m, 2H), 7.47 (t, IH), 7.31 (d, IH), 5.82 (d, IH), 4.67-4.64 (m, IH), 3.22 (s, IH), 2.03 (s, IH), 1.92-1.73 (m, 10H), 1.39 (d, 3H)

[0231] Example 7 -N-((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)quinazolin-4-amine

[0232] A solution of (R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- amine hydrochloride (120 mg) prepared in Preparation 1, 7-bromo-4-chloroquinazoline (117.6 mg), and triethylamine (155.4 μl) in ethanol (1.0 ml) was refluxed at 90 °C for 4 hours. The reaction mixture was concentrated under reduced pressure. The reaction was quenched by adding water to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with 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 / 1, v / v) to give 113.0 mg of the title compound as a white solid. (Yield: 61.6 %)

[0233] 1H-NMR (CDC13) δ 8.80 (d, IH), 8.63 (s, IH), 8.11 (t, IH), 8.01 (s, IH), 7.65 (d, IH), 7.57 (dd, 2H), 7.46 (t, IH), 7.31 (s, IH), 5.60 (d, IH), 4.66-4.61 (m, IH), 3.20 (s, IH), 2.03 (s, IH), 1.89-1.71 (m, 10H), 1.37 (d, 3H)

[0234] Example 3. 7-Chloro-N-((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)quinazolin-4-amine

[0235] A solution of (R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride (57.5 mg) prepared in Preparation 1, 4,7-dichloroquinazoline (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. The reaction was quenched by adding water to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with 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 / 1, v / v) to give 52.2 mg of the title compound as a white solid. (Yield: 46.3 %)

[0236] 1 H-NMR (CDC13) δ 8.80 (d, IH), 8.63 (s, IH), 8.11 (t, IH), 8.01 (s, IH), 7.65 (d, IH), 7.57 (dd, 2H), 7.46 (t, IH), 7.31 (s, IH), 5.60 (d, IH), 4.66-4.61 (m, IH), 3.20 (s, IH), 2.03 (s, IH), 1.89-1.71 (m, 10H), 1.37 (d, 3H)

[0237] Example 4. 7-Chloro-N-((R)-l-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)quinazolin-4-amine

[0238] A solution of (R)-l-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- amine hydrochloride (130 mg) prepared in Preparation 4, 4,7-dichloroquinazoline (180.7 mg), and triethylamine (190 μl) in ethanol (1.0 ml) was refluxed at 90 °C for 4 hours. The reaction mixture was concentrated under reduced pressure. The reaction was quenched by adding water to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with 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 / 1, v / v) to give 45.2 mg of the title compound as a white solid. (Yield: 34.8 %)

[0239] 1 H-NMR (CDC13) δ 8.78 (d, IH), 8.65 (s, IH), 8.12-8.08 (m, IH), 7.84 (s, IH), 7.66-7.63 (m, 2H), 7.48-7.42 (m, 2H), 7.24 (d, IH), 5.44 (m, IH), 4.72 (m, IH), 3.18-3.12 (m, IH), 2.11 (d, IH), 2.05-2.00 (m, 3H), 1.70-1.53 (m, 7H), 1.38 (d, 3H)

[0240] Example 5. 7-Bromo-4-(((R)-l-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan- 2-yl)amino)-2H-chromen-2-one

[0241] A solution of (R)-l-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- amine hydrochloride (30 mg) prepared in Preparation 4, 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. The reaction was quenched by adding water to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with 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 / 1, v / v) to give 23.2 mg of the title compound as a white solid. (Yield: 43.8 %)

[0242] 1H-NMR (CDC13) δ 8.78 (d, IH), 8.12-8.10 (m, IH), 7.65 (dd, IH), 7.50-7.41 (m, 4H), 7.27 (s, IH), 5.35 (s, IH), 5.15 (d, IH), 3.78-3.72 (m, IH), 3.18-3.10 (m, IH), 2.10-1.89 (m, H), 1.86-1.44 (m, 5H), 1.40-1.18 (m, 9H)

[0243] Example 6. 7-Chloro-4-(((R)-l-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)amino)-2H-chromen-2-one

[0244] A solution of (R)-l-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride (30 mg) prepared in Preparation 4, 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. The reaction was quenched by adding water to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with 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 / 1, v / v) to give 11.0 mg of the title compound as a white solid. (Yield: 22.6 %)

[0245] 1 H-NMR (CDC13) δ 8.78 (d, IH), 8.12-8.10 (m, IH), 7.65 (dd, IH), 7.50-7.41 (m, 4H), 7.27 (s, IH), 5.35 (s, IH), 5.15 (d, IH), 3.78-3.72 (m, IH), 3.18-3.10 (m, IH), 2.10-1.89 (m, H), 1.86-1.44 (m, 5H), 1.40-1.18 (m, 9H)

[0246] Example 7. 6-Bromo-4-(((R)-l-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)amino)-2H-chromen-2-one

[0247] A solution of (R)-l-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- amine hydrochloride (80.8 mg) prepared in Preparation 4, 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. The reaction was quenched by adding water to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with 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 / 1, v / v) to give 54.3 mg of the title compound as a white solid. (Yield: 55.3%)

[0248] 1 H-NMR (CDC13) δ 8.81 (d, IH), 8.26 (t, IH), 7.71-7.60 (m, 3H), 7.52 (t, IH), 7.34 (d, IH), 7.23 (t, IH), 5.38 (s, IH), 5.04 (d, IH), 3.83-3.78 (m, IH), 3.19 (t, IH), 2.12-1.98 (m, 4H), 1.77 (t, IH), 1.64-1.55 (m, 4H), 1.38-1.22 (m, 5H)

[0249] Example 8. 7-Chloro-4-(((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)amino)-2H-chromen-2-one

[0250] A solution of (R)-l-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- amine hydrochloride (30 mg) prepared in Preparation 1, 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. The reaction was quenched by adding water to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with 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 / 1, v / v) to give 5.5 mg of the title compound as a white solid. (Yield: 11.3%)

[0251] 1H-NMR (CDC13) δ 8.80 (d, IH), 8.13-8.10 (m, IH), 7.66-7.63 (d, IH), 7.50-7.45 (m, IH), 7.39-7.31 (m, 3H), 7.26-7.24 (m, IH), 5.35 (s, IH), 4.88 (d, IH), 3.74-3.70 (m, IH), 3.23-3.20 (m, IH), 2.04-2.00 (m, IH), 1.88-1.64 (m, 10H), 1.36 (d, 3H)

[0252] Example 9. 7-Bromo-4-(((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)amino)-2H-chromen-2-one

[0253] A solution of (R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride (30 mg) prepared in Preparation 1, 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. The reaction was quenched by adding water to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with 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 / 1, v / v) to give 19.5 mg of the title compound as a white solid. (Yield: 36.0 %)

[0254] 1 H-NMR (CDC13) δ 8.80 (d, IH), 8.13-8.10 (m, IH), 7.66-7.63 (d, IH), 7.50-7.45 (m, IH), 7.39-7.31 (m, 3H), 7.26-7.24 (m, IH), 5.35 (s, IH), 4.88 (d, IH), 3.74-3.70 (m, IH), 3.23-3.20 (m, IH), 2.04-2.00 (m, IH), 1.88-1.64 (m, 10H), 1.36 (d, 3H)

[0255] Example 10. 7-Chloro-3-fluoro-4-(((R)-l-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan- 2-yl)amino)-2H-chromen-2-one

[0256] The 7-chloro-4-(((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)amino)-2H-chromen-2-one hydrochloride (100 mg) 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 fluorinating reagent Selectfluor (83.4 mg) was slowly added thereto. The reaction mixture was stirred at -10°C for 10 minutes, and then at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The reaction was quenched by adding water to the reaction mixture, and then 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 / 1, v / v) to obtain 5.2 mg of the title compound as a white solid. (Yield: 84.0%)

[0257] 1 H-NMR (CDCI3) 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)

[0258] Example 11. 7-Bromo-3-fluoro-4-(((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)amino)-2H-chromen-2-one

[0259] The 7-bromo-4-(((R)-1-((cis)-4-(6-fluoroquinolin-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 fluorinating reagent Selectfluor (77.7 mg) was slowly added thereto. The reaction mixture was stirred at -10°C for 10 minutes, and then at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The reaction was quenched by adding water to the reaction mixture, and then 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 / 1, v / v) to obtain 61.0 mg of the title compound as a white solid. (Yield: 86.4%)

[0260] 1 H-NMR (CDC13) 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)

[0261] Example 12. 7-Bromo-3-fluoro-4-(((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)prop-2-yl)amino)-2H-chromen-2-one

[0262] Example 12. 7-Bromo-3-fluoro-4-(((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)prop-2-yl)amino)-2H-chromen-2-one

[0263] 1 H-NMR (CDC13) 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)

[0264] Example 13. 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)prop-2-yl)benzo[d]thiazol-2-amine

[0265] (R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride (150 mg) prepared in Preparation 1 and 2,6-dichloro-l,3-benzothiazole (22 mg) were dissolved in N-methyl-2-pyrrolidone (1.0 ml), and then N,N-diisopropylethylamine (55 μl) was slowly added thereto. The reaction mixture was stirred in a microwave reactor (180°C, 1200W) for 2 hours, and then cooled to room temperature. The reaction was quenched by adding water to the reaction mixture, and then 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 / 1, v / v) to obtain 10.7 mg of the title compound as a white solid. (Yield: 22.5%)

[0266] 1 H-NMR (CDC13) δ 8.78 (d, IH), 8.13-8.10 (m, IH), 7.64 (d, IH), 7.54 (s, IH), 7.48-7.39 (m, 2H), 7.28-7.23 (m, 2H), 5.48 (m, IH), 3.84 (m, IH), 3.12 (m, IH), 2.04 (s, 2H), 1.80-1.49 (m, 8H), 1.36 (d, 3H)

[0267] Example 14. N-((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-6- methoxybenzo[d]thiazol-2-amine

[0268] The title compound (5.2 mg) was prepared according to the same procedure as in Example 13, using 2-chloro-6-methoxy-l,3-benzothiazole (21 mg) instead of 2,6-dichloro-l,3-benzothiazole. (Yield: 11.0%)

[0269] 1 H-NMR (CDC13) δ 8.78 (d, IH), 8.13-8.09 (m, IH), 7.65 (d, IH), 7.48-7.41 (m, 2H), 7.30 (d, IH), 7.13 (s, IH), 6.88 (d, IH), 5.04 (m, IH), 3.82-3.78 (m, 4H), 3.21-3.19 (m, IH), 2.08-2.04 (m, IH), 1.81-1.51 (m, 10H), 1.38 (d, 3H)

[0270] Example 15. N-((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)butan-2-yl)-6- methoxybenzo[d]thiazol-2-amine

[0271] (R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)butan-2-amine hydrochloride (35.5 mg) prepared in Preparation 2 and 2-chloro-6-methoxy-l,3-benzothiazole (30 mg) were dissolved in N-methyl-2-pyrrolidone (1.0 ml), and then N,N-diisopropylethylamine (78.5 μl) was slowly added thereto. The reaction mixture was stirred in a microwave reactor (180 °C, 1200 W) for 2 hours, and then cooled to room temperature. The reaction was quenched by adding water to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with 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 / 1, v / v) to obtain 22 mg of the title compound as a white solid. (Yield: 31.6 %)

[0272] 1 H-NMR (CDC13) 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)

[0273] Example 16. N-((S)-l-cyclopropyl-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-6- methoxybenzo[d]thiazol-2-amine

[0274] methoxybenzo[d]thiazol-2-amine

[0275] (S)-1-cyclopropyl-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethan-1-amine hydrochloride (36.7 mg) prepared in Preparation 3 and 2-chloro-6-methoxy-1,3-benzothiazole (30 mg) were dissolved in N-methyl-2-pyrrolidone (1.0 ml), and then N,N-diisopropylethylamine (78.5 μl) was slowly added thereto. The reaction mixture was stirred in a microwave reactor (180°C, 1200 W) for 2 hours, and then cooled to room temperature. The reaction was quenched by adding water to the reaction mixture, and then 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 / 1, v / v) to obtain 27.3 mg of the title compound as a white solid. (Yield: 38.2%)

[0276] 1 H-NMR (CDC13) 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)

[0277] Example 17. 4,6-difluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)benzo[d]thiazol-2-amine

[0278] (R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride (34 mg) prepared in Preparation 1, 2-chloro-4,6-difluorobenzothiazole (21.3 mg), and copper (I) iodide (6 mg) were dissolved in dimethyl sulfoxide (1.0 ml), and then potassium carbonate (43 mg) was added thereto. The reaction mixture was stirred in a microwave reactor (100°C, 600 W) for 3 hours, and then cooled to room temperature. The reaction was quenched by adding water to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with an ammonia solution and 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 25 mg of the title compound as a white solid. (Yield: 52.4%)

[0279] 1H-NMR (CDC13) 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)

[0280] Example 18. 7-Chloro-N-((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)benzo[d]thiazol-2-amine

[0281] The title compound (18.4 mg) was prepared according to the same procedure as in Example 17, using 2,7-dichlorobenzo[d]thiazole (21.3 mg) instead of 2-chloro-4,6- difluorobenzothiazole. (Yield: 38.7%)

[0282] 1 H-NMR (CDC13) 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)

[0283] Example 19. 6-Ethoxy-N-((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)benzo[d]thiazol-2-amine

[0284] (R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride (20 mg) prepared in Preparation 1, 2-chloro-6-ethoxy-l,3-benzothiazole (23 mg), and copper (I) iodide (4 mg) were dissolved in dimethyl sulfoxide (1.0 ml), and then potassium carbonate (48 mg) was added thereto. The reaction mixture was stirred in a microwave reactor (100 °C, 600 W) for 3 hours, and then cooled to room temperature. The reaction was quenched by adding water to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with an ammonia solution and 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 2.3 mg of the title compound. (Yield: 7.1%)

[0285] 1 H-NMR (CDC13) δ 8.79 (d, IH), 8.13-8.10 (m, IH), 7.65 (d, IH), 7.47 (t, IH), 7.43 (d, IH), 7.31 (d, IH), 7.13 (s, IH), 6.88 (d, IH), 5.00 (m, IH), 4.03 (q, 2H), 3.83 (m, IH), 3.21 (m, IH), 2.04 (br, IH), 1.81-1.63 (m, 9H), 1.41 (t, 3H), 1.36 (d, 3H)

[0286] Example 20. 6-Ethoxy-N-((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)butan-2- yl)benzo[d]thiazol-2-amine

[0287] (R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)butan-2-amine hydrochloride prepared in Preparation 2 (30 mg), 2-chloro-6-ethoxy-l,3-benzothiazole (18 mg), copper (I) iodide (6 mg) were dissolved in dimethyl sulfoxide (1.0 ml), and then potassium carbonate (60 mg) was added thereto. The reaction mixture was stirred in a microwave reactor (120 °C, 600 W) for 2 hours, and then cooled to room temperature. The reaction was quenched by adding water to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with an ammonia solution and 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 7.8 mg of the title compound as a white solid. (Yield: 18.7 %)

[0288] 1 H-NMR (CDC13) δ 8.78 (d, IH), 8.12-8.09 (m, IH), 7.65 (d, IH), 7.46-7.38 (m, 2H), 7.28 (d, IH), 7.12 (s, IH), 6.88 (d, IH), 5.18 (m, IH), 4.03 (d, 2H), 3.59 (s, IH), 3.20 (s, IH), 2.04 (s, IH), 1.81-1.56 (m, 12H), 1.41 (t, 3H), 1.02 (t, 3H)

[0289] Example 21. N-((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)thiazolo[4,5- b]pyridin-2-amine

[0290] The title compound (19.2 mg) was prepared according to the same method as in Example 19, using 2-chlorothiazole[4,5-b]pyridine (18 mg) instead of 2-chloro-6-ethoxy-l,3-benzothiazole. (Yield: 43.6%)

[0291] 1 H-NMR (CDC13) δ 8.77 (d, IH), 8.55 (s, IH), 8.12-8.08 (m, IH), 7.84 (d, IH), 7.63 (d, IH), 7.47-7.43 (m, IH), 7.23 (d, IH), 6.95 (t, IH), 6.65 (s,

[0292] 1H), 3.95 (s, IH), 3.22 (s, IH), 2.04-1.94 (m, 2H), 1.78-1.41 (m, 9H), 1.41 (d, 3H)

[0293] Example 22. N-((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-5- methoxythiazolo[5,4-b]pyridin-2-amine

[0294] The title compound (11.6 mg) was prepared according to the same method as in Example 19, using 2-chloro-5-methoxy-thiazolo[5,4-b]pyridine (21.1 mg) instead of 2-chloro-6-ethoxy-l,3-benzothiazole. (Yield: 18.4%)

[0295] 1 H-NMR (CDC13) δ 8.77 (d, IH), 8.55 (s, IH), 8.12-8.08 (m, IH), 7.84 (d, IH), 7.63 (d, IH), 7.47-7.43 (m, IH), 7.23 (d, IH), 6.95 (t, IH), 6.65 (s,

[0296] Example 23. 6-Chloro-N-((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)thiazolo[4,5-b]pyridin-2-amine

[0297] The title compound (2 mg) was prepared according to the same method as in Example 19, using 2,6-dichlorothiazolo[4,5-b]pyridine (18 mg) instead of 2-chloro-6-ethoxy-l,3-benzothiazole. (Yield: 6.0%)

[0298] 1H-NMR (CDC13) δ 8.80 (d, IH), 8.41-8.30 (bs, IH), 8.12-8.09 (m, IH), 7.83 (s, IH), 7.65 (d, IH), 7.49-7.60 (m, IH), 7.29 (d, IH), 6.32 (bs, IH), 3.97 (m, IH), 3.76 (m, IH), 3.20-3.15 (m, IH), 2.05-1.26 (m, 13H)

[0299] Example 24. N-((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2- amine

[0300] (R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride (100 mg) prepared in Preparation 1 and 2-chlorobenzo[d]oxazole (71 mg) were dissolved in N,N-dimethylformamide (1.0 ml), and then 1,8-diazabicyclo[5,4,0]undec-7-ene (71 mg) was slowly added thereto. The reaction mixture was stirred in a microwave reactor (180 °C, 1200 W) for 2 hours, and then cooled to room temperature. The reaction was quenched by adding water to the reaction mixture, and then 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 12.1 mg of the title compound. (Yield: 8.2 %)

[0301] 1 H-NMR (CDC13) δ 8.77 (d, IH), 8.12-8.08 (m, IH), 7.66-7.63 (m, IH), 7.47 (t, IH), 7.43 (d, IH), 7.37 (d, IH), 7.26-7.23 (m, 2H), 7.16 (t, IH), 7.03 (t, IH), 5.00 (d, IH), 4.14-4.09 (m, IH), 3.12 (t, IH), 2.13-1.95 (m, 4H), 1.81 (s, IH), 1.66-1.50 (m, 4H), 1.38-1.24 (m, 5H)

[0302] Example 25. 6-chloro-N-((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2- amine

[0303] (R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride (22 mg) prepared in Preparation 1 and 2,6-dichlorobenzoxazole (15 mg) were dissolved in 1,4-dioxane (1.0 ml), and then N,N-diisopropylethylamine (40 μL) was slowly added thereto. The reaction mixture was stirred at 80°C for 12 hours, and then cooled to room temperature. The reaction was quenched by adding water to the reaction mixture, and then 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 with a silica gel column chromatography (n-hexane / ethyl acetate = 1 / 2, v / v) to obtain 14.7 mg of the title compound. (Yield: 43.7%)

[0304] ethyl acetate / = 1 / 2, v / v) to obtain 14.7 mg of the title compound. (Yield: 43.7%)

[0305] 1 H-NMR (CDC13) 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)

[0306] Example 26. N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-6- methoxybenzo[d]oxazol-2-amine

[0307] (R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride (50 mg) prepared in Preparation 1, 2-chloro-6-methoxy-1,3-benzoxazole hydrochloride (50 mg), and potassium carbonate (43 mg) were dissolved in N,N-dimethylformamide (1.0 ml), and then triethylamine (40 μl) was slowly added thereto. The reaction mixture was stirred at 80°C for 12 hours, and then cooled to room temperature. The reaction was quenched by adding water to the reaction mixture, and then 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 with a silica gel column chromatography (n-hexane / ethyl acetate = 1 / 2, v / v) to obtain 8.3 mg of the title compound. (Yield: 12.4%)

[0308] 1H-NMR (CDC13) 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)

[0309] Example 27. 6-Chloro-N-((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)butan-2- yl)benzo[d]oxazol-2-amine

[0310] (R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)butan-2-amine hydrochloride prepared in Preparation 2 (70 mg), 2,6-dichlorobenzoxazole (32 mg) and potassium carbonate (57 mg) were dissolved in N,N-dimethylformamide (1.0 ml), and then triethylamine (30 μL) was slowly added thereto. The reaction mixture was stirred at 80°C for 12 hours, and then cooled to room temperature. The reaction was quenched by adding water to the reaction mixture, and then 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 with a silica gel column chromatography (n-hexane / ethyl acetate = 1 / 2, v / v) to obtain 42 mg of the title compound. (Yield: 44.7%)

[0311] 1 H-NMR (CDC13) 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)

[0312] Example 28. 4-Fluoro-N-((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)benzo[d]oxazol-2-amine

[0313] The (R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propane-2-amine hydrochloride (30 mg) and 2-chloro-4-fluoro-1,3-benzoxazole (16 mg) prepared in Preparation 1 were dissolved in 1,4-dioxane (1.0 mL), and then N,N-diisopropylethylamine (50 μL) was slowly added. The reaction mixture was stirred at 100 °C for 12 h, and then cooled to room temperature. The reaction was quenched by adding water to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with 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 give 9.7 mg of the title compound.

[0314] (Yield: 23.8%)

[0315] 1 H-NMR(CDCl3)δ8.80(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)

[0316] Example 29. 6-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propyl-2-yl)benzo[d]oxazol-2-amine

[0317] The title compound (3.9 mg) was prepared by replacing 2-chloro-4-fluoro-1,3-benzoxazole with 2-chloro-6-fluoro-1,3-benzoxazole (16 mg) according to the same method as in Example 28. (Yield: 9.5%)

[0318] 1 H-NMR(CDCl3)δ8.80(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)

[0319] Example 30. N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)oxazolo[5,4- b]pyridin-2-amine

[0320] (R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride (50 mg) prepared in Preparation 1, 2-chloro-oxazolo[5,4-b]pyridine (24 mg), and potassium carbonate (43 mg) were dissolved in N,N-dimethylformamide (1.0 ml), and then triethylamine (40 μL) was slowly added thereto. The reaction mixture was stirred at 80°C for 12 hours, and then cooled to room temperature. The reaction was quenched by adding water to the reaction mixture, and then 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 40.1 mg of the title compound.

[0321] (yield: 64.0%)

[0322] 1 H-NMR (CDCI3) 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)

[0323] Example 31. 6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)oxazolo[4,5- b]pyridin-2-amine

[0324] (R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride (50 mg) prepared in Preparation 1, 2,6-dichlorooxazolo[4,5-b]pyridine (30 mg), and potassium carbonate (42 mg) were dissolved in N,N-dimethylformamide (1.0 mL), and then triethylamine (21 μL) was slowly added thereto. The reaction mixture was stirred at 80°C for 12 hours, and then cooled to room temperature. The reaction was quenched by adding water to the reaction mixture, and then 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 16 mg of the title compound. (Yield: 23.5%)

[0325] 1 H-NMR (CDCI3) 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)

[0326] Example 32. N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)oxazolo[4,5-b]pyridin-2-amine

[0327] The title compound (9.2 mg) was prepared according to the same procedure as in Example 31, using 2-chlorooxazolo[4,5-b]pyridine (24 mg) instead of 2,6-dichlorooxazolo[4,5-b]pyridine. (Yield: 14.7%).

[0328] 1 H-NMR (CDCI3) 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)

[0329] Example 33. 6-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)isoquinolin-1-amine

[0330] (R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride (20 mg) prepared in Preparation 1 and 1-chloro-6-fluoro-isoquinoline (13 mg) were dissolved in 1,4-dioxane (1.0 ml), and then N,N-diisopropylethylamine (35 μL) was slowly added thereto. The reaction mixture was stirred at 80°C for 12 hours, and then cooled to room temperature. The reaction was quenched by adding water to the reaction mixture, and then 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 1.5 mg of the title compound. (Yield: 5.6%)

[0331] 1 H-NMR (CDC13) 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)

[0332] Example 34. 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)isoquinlin-1-amine

[0333] The title compound (1.4 mg) was prepared in the same manner as in Example 33, using 1,6-dichloroisoquinoline (14 mg) instead of 1-chloro-6-fluoro-isoquinoline. (Yield: 5.1%)

[0334] 1 H-NMR (CDC13) 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)

[0335] Example 35. 4-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)benzo[d]thiazol-2-amine

[0336] (R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride (50 mg) prepared in Preparation 1 and 2,4-dichlorobenzothiazole (32 mg) were dissolved in tetrahydrofuran (1.0 ml). The resulting solution was placed in a sealed tube, and then triethylamine (110 μL) was slowly added thereto. After the sealed tube was sealed, the reaction mixture was stirred at 120°C for 12 hours, and then cooled to room temperature. The reaction was quenched by adding water to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with 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 15 mg of the title compound. (Yield: 21.3%)

[0337] 1 H-NMR (CDC13) 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), 5.47 (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)

[0338] Example 36. 5-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)benzo[d]oxazole-2-amine

[0339] The title compound (31 mg) was prepared as a yellow liquid according to the same method as in Example 35, using 2-chloro-5-fluorobenzoxazole (29 mg) instead of 2,4-dichlorobenzothiazole. (Yield: 47.5%)

[0340] 1 H-NMR (CDC13) 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), 5.47 (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)

[0341] Example 37. 7-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)benzo[d]oxazol-2-amine

[0342] The title compound was prepared as a yellow liquid (26 mg) according to the same method as in Example 35, using 2-chloro-7-fluorobenzoxazole (29 mg) instead of 2,4- dichlorobenzothiazole. (Yield: 39.8%)

[0343] 1 H-NMR (CDC13) 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)

[0344] Example 38. 2-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)quinazolin-4-amine

[0345] The title compound was prepared (43 mg) according to the same method as in Example 35, using 2,4-dichloroquinazoline (34 mg) instead of 2,4-dichlorobenzothiazole. (Yield: 62.4%)

[0346] 1 H-NMR (CDC13) 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)

[0347] Example 39. 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)phthalazin-1-amine

[0348] (R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride (50 mg) prepared in Preparation 1, 1,6-dichlorophthalazine (34 mg), and copper (I) iodide (9 mg) were dissolved in dimethyl sulfoxide (1.0 ml). The resulting solution was placed in a sealed tube, and then potassium carbonate (43 mg) was added thereto. After the sealed tube was sealed, the reaction mixture was stirred at 140°C for 3 hours, and then cooled to room temperature. The reaction was quenched by adding water to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with 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 5.1 mg of the title compound as a yellow liquid. (Yield: 7.3%)

[0349] 1 H-NMR (CDCI3) 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)

[0350] Example 40. 2,7-Dichloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4-amine

[0351] The title compound (37 mg) was prepared in the same manner as in Example 35, using 2,4,7-trichloroquinazoline (40 mg) instead of 2,4-dichlorobenzothiazole. (Yield: 49.3%)

[0352] 1 H-NMR (CDCI3) 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)

[0353] Example 41. 2,7-Dichloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4-amine

[0354] (R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride (50 mg) prepared in Preparation 4 and 2,4,7-trichloroquinazoline (40 mg) were dissolved in tetrahydrofuran (1.0 ml). The resulting solution was placed in a sealed tube, and then triethylamine (110 μL) was added thereto. After the sealed tube was sealed, the reaction mixture was stirred at 80°C for 12 hours, and then cooled to room temperature. The reaction was quenched by adding water to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with 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 40 mg of the title compound as a white solid. (Yield: 54.1%)

[0355] 1 H-NMR (CDC13) 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)

[0356] Example 42. 7-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-6-

[0357] methoxybenzo[d]oxazol-2-amine

[0358] The title compound (39 mg) was prepared as a white solid according to the same method as in Example 35, using 2-chloro-7-fluoro-6-methoxy-1,3-benzoxazole (34 mg) instead of 2,4-dichlorobenzothiazole.

[0359] (yield: 56.0%)

[0360] 1H-NMR (CDC13) δ 8.78 (d, IH), 8.11 (dd, IH), 7.66 (dd, IH), 7.47 (td, IH), 7.30 (d, IH), 7.02 (d, IH), 6.80 (t, IH), 5.26 (br, IH), 4.02 (m, IH), 3.89 (s, 3H), 3.20 (m, IH), 1.81-1.74 (m, 8H), 1.36 (d, 3H), 1.26 (d, 2H)

[0361] Example 43. 6-Chloro-5-fluoro-N-((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol-2-amine

[0362] The title compound was prepared as a white solid (35 mg) according to the same procedure as in Example 35, using 2,6-dichloro-5-fluoro-l,3-benzoxazole (35 mg) instead of 2,4-dichlorobenzothiazole. (Yield: 51.0%)

[0363] 1 H-NMR (CDC13) δ 8.78 (d, IH), 8.11 (dd, IH), 7.66 (dd, IH), 7.47 (td, IH), 7.30 (d, IH), 7.02 (d, IH), 6.80 (t, IH), 5.26 (br, IH), 4.02 (m, IH), 3.89 (s, 3H), 3.20 (m, IH), 1.81-1.74 (m, 8H), 1.36 (d, 3H), 1.26 (d, 2H)

[0364] 1H), 7.30-7.26 (m, 2H), 7.11 (d, IH), 5.43 (br, IH), 4.03 (m, IH), 3.21 (m, IH),

[0365] 1.81-1.74 (m, 9H), 1.36 (d, 3H), 1.26 (d, 2H)

[0366] Example 44. 6-Ethoxy-N-((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol-2-amine

[0367] The title compound was prepared according to the same procedure as in Example 35, using 2-chloro-6-ethoxy-l,3-benzoxazole (34 mg) instead of 2,4-dichlorobenzothiazole. (Yield: 6.6%)

[0368] 1 H-NMR (CDC13) δ 8.78 (d, IH), 8.11 (dd, IH), 7.66 (dd, IH), 7.47 (td, IH), 7.30 (d, IH), 7.02 (d, IH), 6.80 (t, IH), 5.26 (br, IH), 4.02 (m, IH), 3.89 (s, 3H), 3.20 (m, IH), 1.81-1.74 (m, 8H), 1.36 (d, 3H), 1.26 (d, 2H)

[0369] 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)

[0370] Example 45. 6-(2-Fluoroethoxy)-N-((R)-1-((cis)-4-(6-fluoroquinolin-4- yl)cyclohexyl)propan-2-yl)benzo[d]oxazol-2-amine

[0371] The title compound (36.6 mg) was prepared according to the same method as in Example 35, using 2-chloro-6-(2-fluoroethoxy)-1,3-benzoxazole (37 mg) instead of 2,4- dichlorobenzothiazole. (Yield: 50.7%)

[0372] 1 H-NMR (CDC13) δ 8.79 (d, 1H), 8.12 (dd, 1H), 7.64 (dd, 1H), 7.47 (td,

[0373] 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,

[0374] 1H), 2.08 (br, 1H), 1.83-1.65 (m, 10H), 1.37 (d, 3H)

[0375] Example 46. 6,7-Dichloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4- yl)cyclohexyl)propan-2-yl)benzo[d]oxazol-2-amine

[0376] The title compound (5.1 mg) was prepared according to the same method as in Example 35, using 2,6,7-trichloro-1,3-benzoxazole (38 mg) instead of 2,4-dichlorobenzothiazole. (Yield: 7.0%)

[0377] 1H-NMR (CDC13) δ 8.80 (d, IH), 8.13 (dd, IH), 7.64 (dd, IH), 7.48 (td, IH), 7.32 (d, IH), 7.27-7.23 (m, IH), 7.17 (d, IH), 4.95 (br, IH), 4.06 (m, IH), 3.24 (m, IH), 2.08 (br, IH), 1.83-1.65 (m, 10H), 1.37 (d, 3H)

[0378] Example 47. 6,7-Difluoro-N-((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)benzo[d]oxazole-2-amine

[0379] The title compound (51.5 mg) was prepared according to the same method as in Example 35, using 2-chloro-6,7-difluoro-l,3-benzoxazole (33 mg) instead of 2,4- dichlorobenzothiazole. (Yield: 75.6%)

[0380] 1 H-NMR (CDC13) δ 8.80 (d, IH), 8.13 (dd, IH), 7.64 (dd, IH), 7.48 (td, IH), 7.32 (d, IH), 7.27-7.23 (m, IH), 7.17 (d, IH), 4.95 (br, IH), 4.06 (m, IH), 3.24 (m, IH), 2.08 (br, IH), 1.83-1.65 (m, 10H), 1.37 (d, 3H)

[0381] Example 48. 2-Chloro-6-fluoro-N-((R)-l-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan- 2-yl)quinazolin-4-amine

[0382] (R)-l-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride (30 mg) prepared in Preparation 4 and 2,4-dichloro-6-fluoroquinazoline (30 mg) were dissolved in 1,4-dioxane (2.0 ml). The resulting solution was placed in a sealed tube, and then triethylamine (45 μL) was added thereto. After the sealed tube was sealed, the reaction mixture was stirred at 100°C for 4 hours, and then cooled to room temperature. The reaction was quenched by adding water to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with 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 12 mg of the title compound. (Yield: 27.7%)

[0383] 1H-NMR (CDC13) δ 8.78 (d, IH), 8.12 (dd, IH), 7.78 (dd, IH), 7.66 (dd, IH), 7.51-7.46 (m, 2H), 7.36 (d, IH), 7.25 (m, IH), 5.62 (d, IH), 4.70 (m, IH), 3.18 (m, IH), 2.22 (br, IH), 2.06-1.97 (m, 4H), 1.68 (br, 2H), 1.58-1.52 (m, 4H), 1.38 (d, 3H)

[0384] Example 49. 2,6-Dichloro-N-((R)-l-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4-amine

[0385] The title compound (12 mg) was prepared according to the same method as in Example 48, using 2,4,6-trichloroquinazoline (33 mg) instead of 2,4-dichloro-6-fluoroquinazoline. (Yield: 25.8%)

[0386] 1 H-NMR (CDC13) δ 8.78 (d, IH), 8.12 (dd, IH), 7.78 (dd, IH), 7.66 (dd, IH), 7.51-7.46 (m, 2H), 7.36 (d, IH), 7.25 (m, IH), 5.62 (d, IH), 4.70 (m, IH), 3.18 (m, IH), 2.22 (br, IH), 2.06-1.97 (m, 4H), 1.68 (br, 2H), 1.58-1.52 (m, 4H), 1.38 (d, 3H)

[0387] Example 50. 2-Chloro-8-fluoro-N-((R)-l-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4-amine

[0388] The title compound (10.3 mg) was prepared according to the same method as in Example 48, using 2,4-dichloro-8-fluoroquinazoline (30 mg) instead of 2,4-dichloro-6-fluoroquinazoline. (Yield: 23.7%)

[0389] 1 H-NMR (CDC13) δ 8.78 (d, IH), 8.12 (dd, IH), 7.78 (dd, IH), 7.66 (dd, IH), 7.51-7.46 (m, 2H), 7.36 (d, IH), 7.25 (m, IH), 5.62 (d, IH), 4.70 (m, IH), 3.18 (m, IH), 2.22 (br, IH), 2.06-1.97 (m, 4H), 1.68 (br, 2H), 1.58-1.52 (m, 4H), 1.38 (d, 3H)

[0390] Example 51. 2,8-Dichloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4-amine

[0391] The title compound (12.1 mg) was prepared according to the same method as in Example 48, using 2,4,8-trichloroquinazoline (33 mg) instead of 2,4-dichloro-6-fluoroquinazoline. (Yield: 26.9%)

[0392] 1 H-NMR (CDC13) 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),

[0393] 1.38 (d, 3H)

[0394] Example 52. 2-Chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-8-

[0395] methoxyquinazolin-4-amine

[0396] The title compound (9.6 mg) was prepared according to the same method as in Example 48, using 2,4-dichloro-8-methoxyquinazoline (32 mg) instead of 2,4-dichloro-6-fluoroquinazoline. (Yield: 21.6%)

[0397] 1 H-NMR (CDC13) 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),

[0398] Example 53. 2-Chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-8- (trifluoromethoxy)quinazolin-4-amine

[0399] The title compound (10.8 mg) was prepared according to the same method as in Example 48, by replacing 2,4-dichloro-6-fluoroquinazoline with 2,4-dichloro-8- (trifluoromethoxy)quinazoline (40 mg).

[0400] 1 H-NMR (CDC13) δ 8.79 (d, IH), 8.11 (dd, IH), 7.69-7.65 (m, 3H), 7.49-7.43 (m, 2H), 7.25 (m, IH), 5.74 (d, IH), 4.70 (m, IH), 3.18 (m, IH), 2.19 (d, IH), 2.06-1.97 (m, 4H), 1.68 (m, 2H), 1.58-1.52 (m, 4H), 1.38 (d, 3H)

[0401] Example 54. 2-Chloro-7-fluoro-N-((R)-l-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan- 2-yl)quinazolin-4-amine

[0402] The title compound (6.9 mg) was prepared according to the same method as in Example 48, by replacing 2,4-dichloro-6-fluoroquinazoline with 2,4-dichloro-7-fluoroquinazoline (30 mg). (Yield: 15.9 %)

[0403] 1 H-NMR (CDC13) δ 8.79 (d, IH), 8.11 (dd, IH), 7.69-7.65 (m, 3H), 7.49-7.43 (m, 2H), 7.25 (m, IH), 5.74 (d, IH), 4.70 (m, IH), 3.18 (m, IH), 2.19 (d, IH), 2.06-1.97 (m, 4H), 1.68 (m, 2H), 1.58-1.52 (m, 4H), 1.38 (d, 3H)

[0404] Example 55. 2-Chloro-4-(((R)-l-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)amino)quinazoline-7-carbonitrile

[0405] The title compound (4.6 mg) was prepared according to the same method as in Example 48, by replacing 2,4-dichloro-6-fluoroquinazoline with 2,4-dichloroquinazoline-7- carbonitrile (32 mg). (Yield: 10.4 %)

[0406] 1H-NMR (CDC13) δ 8.79 (d, IH), 8.12 (d, IH), 8.09 (s, IH), 7.81 (d, IH), 7.67-7.62 (m, 2H), 7.46 (m, IH), 7.25 (m, IH), 5.81 (d, IH), 4.72 (m, IH), 3.17 (td, IH), 2.19 (d, IH), 2.06-1.97 (m, 4H), 1.68 (m, IH), 1.58-1.52 (m, 4H), 1.38 (d, 3H), 1.35 (m, IH)

[0407] Example 56. 7-Bromo-2-chloro-N-((R)-l-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4-amine

[0408] The title compound (8.0 mg) was prepared according to the same procedure as in Example 48, using 7-bromo-2,4-dichloroquinazoline (39 mg) instead of 2,4-dichloro-6-fluoroquinazoline. (Yield: 16.3%)

[0409] 1 H-NMR (CDC13) δ 8.79 (d, IH), 8.12 (d, IH), 8.09 (s, IH), 7.81 (d, IH), 7.67-7.62 (m, 2H), 7.46 (m, IH), 7.25 (m, IH), 5.81 (d, IH), 4.72 (m, IH), 3.17 (td, IH), 2.19 (d, IH), 2.06-1.97 (m, 4H), 1.68 (m, IH), 1.58-1.52 (m, 4H), 1.38 (d, 3H), 1.35 (m, IH)

[0410] Example 57. 2-Chloro-N-((R)-l-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7-methylquinazolin-4-amine

[0411] The title compound (7.1 mg) was prepared according to the same procedure as in Example 48, using 2,4-dichloro-7-methylquinazoline (30 mg) instead of 2,4-dichloro-6-fluoroquinazoline. (Yield: 16.5%)

[0412] 1H-NMR (CDC13) δ 8.79 (d, IH), 8.12 (t, IH), 8.07 (s, IH), 7.84 (d, IH), 7.65 (t, 2H), 7.46 (t, IH), 7.27-7.24 (m, IH), 5.82 (d, IH), 4.73 (m, IH), 3.16 (td, IH), 2.22 (d, IH), 2.06-1.97 (m, 4H), 1.68 (m, 2H), 1.58-1.52 (m, 4H), 1.36 (d, 3H)

[0413] Example 58. 2-Chloro-N-((R)-l-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan- 2-yl)-7-(trifluoromethyl)quinazolin-4-amine

[0414] The title compound (9.7 mg) was prepared according to the same method as in Example 48, by using 2,4-dichloro-7-methoxyquinazoline (32 mg) instead of 2,4-dichloro-6-fluoroquinazoline. (Yield: 21.8 %)

[0415] 1 H-NMR (CDC13) δ 8.79 (d, IH), 8.12 (t, IH), 8.07 (s, IH), 7.84 (d, IH), 7.65 (t, 2H), 7.46 (t, IH), 7.27-7.24 (m, IH), 5.82 (d, IH), 4.73 (m, IH), 3.16 (td, IH), 2.22 (d, IH), 2.06-1.97 (m, 4H), 1.68 (m, 2H), 1.58-1.52 (m, 4H), 1.36 (d, 3H)

[0416] Example 59. 2-Chloro-N-((R)-l-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan- 2-yl)-7-

[0417] methoxyquinazolin-4-amine

[0418] The title compound (9.7 mg) was prepared according to the same method as in Example 48, by using 2,4-dichloro-7-methoxyquinazoline (32 mg) instead of 2,4-dichloro-6-fluoroquinazoline. (Yield: 21.8 %)

[0419] 1H-NMR (CDC13) δ 8.78 (d, IH), 8.11 (t, IH), 7.68 (d, IH), 7.65 (d, IH), 7.46 (td, IH), 7.27-7.24 (m, IH), 7.13 (s, IH), 7.05 (d, IH), 5.48 (d, IH), 4.70 (m, IH), 3.92 (s, 3H), 3.16 (td, IH), 2.22 (d, IH), 2.06-1.97 (m, 4H), 1.68 (m, 2H), 1.58-1.52 (m, 4H), 1.36 (d, 3H)

[0420] Example 60. 2-Chloro-6-fluoro-N-((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4-amine

[0421] (R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride (50 mg) prepared in Preparation 1 and 2,4-dichloro-6-fluoroquinazoline (34 mg) were dissolved in tetrahydrofuran (1.0 ml). The resulting solution was placed in a sealed tube, and then triethylamine (110 μL) was added thereto. After the sealed tube was sealed, the reaction mixture was stirred at 80°C for 12 hours, and then cooled to room temperature. The reaction was quenched by adding water to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with 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 38 mg of the title compound as a white solid. (Yield: 52.4%)

[0422] 1 H-NMR (CDC13) δ 8.81 (d, IH), 8.12 (t, IH), 7.80 (d, IH), 7.67 (d, IH), 7.52-7.46 (m, 2H), 7.38-7.35 (m, 2H), 5.68 (d, IH), 4.60 (m, IH), 3.23 (td, IH), 1.99-1.62 (m, 11H), 1.39 (d, 3H)

[0423] Example 61. 2,6-Dichloro-N-((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4-amine

[0424] The title compound (45.2 mg) was prepared as a white solid according to the same procedure as in Example 60, using 2,4,6-trichloroquinazoline (37 mg) instead of 2,4-dichloro-6-fluoroquinazoline. (Yield: 60.3%)

[0425] 1 H-NMR (CDC13) δ 8.81 (d, 1H), 8.12 (t, 1H), 7.73-7.65 (m, 4H), 7.46 (t,

[0426] 1H), 7.37 (s, 1H), 5.79 (d, 1H), 4.59 (m, 1H), 3.22 (td, 1H), 1.99-1.62 (m, 11H),

[0427] 1.39 (d, 3H)

[0428] Example 62. 2-Chloro-7-fluoro-N-((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4-amine

[0429] The title compound was prepared as a light yellow liquid (40.7 mg) according to the same procedure as in Example 60, using 2,4-dichloro-7-fluoroquinazoline (37 mg) instead of 2,4-dichloro-6-fluoroquinazoline. (Yield: 56.3%)

[0430] 1 H-NMR (CDC13) δ 8.81 (d, 1H), 8.12 (t, 1H), 7.73-7.65 (m, 4H), 7.46 (t,

[0431] 1H), 7.37 (s, 1H), 5.79 (d, 1H), 4.59 (m, 1H), 3.22 (td, 1H), 1.99-1.62 (m, 11H),

[0432] Example 63. 2-Chloro-4-(((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)amino)quinazoline-7-carbonitrile

[0433] The title compound was prepared as a light yellow liquid (33 mg) according to the same procedure as in Example 60, using 2,4-dichloroquinazoline-7-carbonitrile (39 mg) instead of 2,4-dichloro-6-fluoroquinazoline. (Yield: 45.0%)

[0434] 1H-NMR (CDC13) 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)

[0435] Example 64. 7-Bromo-2-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4-amine

[0436] The title compound was prepared as a light yellow liquid (49.5 mg) according to the same procedure as in Example 60, by replacing 2,4-dichloro-6-fluoroquinazoline with 2,4-dichloro-7-methylquinazoline (37 mg). (Yield: 69.3%)

[0437] 1 H-NMR (CDC13) 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)

[0438] Example 65. 2-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7-

[0439] methylquinazolin-4-amine

[0440] The title compound was prepared as a light yellow liquid (49.5 mg) according to the same procedure as in Example 60, by replacing 2,4-dichloro-6-fluoroquinazoline with 2,4-dichloro-7-methylquinazoline (37 mg). (Yield: 69.3%)

[0441] 1 H-NMR (CDC13) 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)

[0442] Example 66. 2-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7- (trifluoromethyl)quinazolin-4-amine

[0443] The title compound was prepared as a yellow liquid (52.1 mg) according to the same procedure as in Example 60, by replacing 2,4-dichloro-6-fluoroquinazoline with 2,4-dichloro-7- methoxyquinazoline (39 mg). (Yield: 70.2 %)

[0444] 1 H-NMR (CDC13) 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)

[0445] Example 67. 2-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7-

[0446] methoxyquinazolin-4-amine

[0447] The title compound was prepared as a yellow liquid (52.1 mg) according to the same procedure as in Example 60, by replacing 2,4-dichloro-6-fluoroquinazoline with 2,4-dichloro-7- methoxyquinazoline (39 mg). (Yield: 70.2 %)

[0448] 1 H-NMR (CDC13) 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)

[0449] 1H), 3.92 (s, 3H), 3.22 (m, 1H), 1.99-1.62 (m, 11H), 1.39 (d, 3H)

[0450] Example 68. 2,8-Dichloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4-amine

[0451] The title compound was obtained as a yellow liquid (49.5 mg) by the same procedure as in Example 60, using 2,4,8-trichloroquinazoline (40 mg) instead of 2,4-dichloro-6-fluoroquinazoline. (Yield: 66.1 %)

[0452] 1 H-NMR (CDC13) δ 8.81 (d, IH), 8.12 (t, IH), 7.83 (d, IH), 7.68-7.73 (m, 2H), 7.46 (td, IH), 7.39-7.35 (m, 2H), 5.82 (d, IH), 4.60 (m, IH), 3.22 (m, IH),

[0453] 1.99-1.62 (m, 11H), 1.39 (d, 3H)

[0454] Example 69. 2-Chloro-8-fluoro-N-((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4-amine

[0455] The title compound was obtained as a yellow liquid (49.5 mg) by the same procedure as in Example 60, using 2,4,8-trichloroquinazoline (40 mg) instead of 2,4-dichloro-6-fluoroquinazoline. (Yield: 66.1 %)

[0456] 1 H-NMR (CDC13) δ 8.81 (d, IH), 8.12 (t, IH), 7.83 (d, IH), 7.68-7.73 (m, 2H), 7.46 (td, IH), 7.39-7.35 (m, 2H), 5.82 (d, IH), 4.60 (m, IH), 3.22 (m, IH),

[0457] 11H), 1.39 (d, 3H)

[0458] Example 70. 2-Chloro-N-((R)-l-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-8-

[0459] methoxyquinazolin-4-amine

[0460] The title compound was obtained as a yellow liquid (49.5 mg) by the same procedure as in Example 60, using 2,4,8-trichloroquinazoline (40 mg) instead of 2,4-dichloro-6-fluoroquinazoline. (Yield: 66.1 %)

[0461] 1H-NMR (CDC13) 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)

[0462] Example 71.2-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-8- (trifluoromethoxy)quinazolin-4-amine

[0463] Following the same procedure as in Example 60, substituting 2,4-dichloro-8- (trifluoromethoxy)quinazoline (49 mg) for 2,4-dichloro-6-fluoroquinazoline, the title compound was prepared as a light yellow liquid (58.4 mg). (Yield: 70.7%)

[0464] 1 H-NMR (CDC13) 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)

[0465] Experimental Example 1: Analysis of IDOl cellular activity using Hela cells

[0466] Hela cells were seeded at a density of 20000 cells / well in 100 μl of culture medium (EMEM supplemented with 10% FBS, 100 U / ml penicillin and 100 μg / ml streptomycin) in tissue culture treated 96 well plates. Cells were incubated in a 5% carbon dioxide incubator for 24 hours, treated with recombinant human interferon gamma at a concentration of 50 ng / ml and then incubated in a 5% carbon dioxide incubator for 48 hours to induce IDO expression.

[0467] Activity was measured using the IDOl cellular activity measurement substrate (IDO1 cellular activity quickDetect supplements, catalog number: #62000-2, BPS Bioscience). Specifically, assay media was prepared by diluting the IDOl assay media substrate 1 and IDOl assay media supplement 2 in media at a ratio of 1:100, respectively. Test compounds were diluted in fresh assay media to predetermined concentrations. After removing the media using a multichannel pipette, 200 μΐ of each test media containing the test material was added to the corresponding well, which was then incubated in a 5% carbon dioxide incubator for 24 hours. The next day, 140 μΐ of media from each well was transferred to a new 96-well plate. To each well, 10 μΐ of 6.1 N trichloroacetic acid was added, which was then incubated in an incubator at 50°C for 30 minutes. The plate was centrifuged at 2500 rpm for 10 minutes to precipitate any precipitates. A detection reagent solution was prepared by diluting the detection reagent (component D kit, catalog number: #62000-2, BPS Bioscience) 50-fold in acetic acid. 100 μΐ of supernatant from the centrifuged plate was transferred to a new clear 96-well plate, to which 100 μΐ of the detection reagent solution was added. After allowing it to react for 10 minutes at room temperature, the absorbance was measured at a wavelength of 480 nm. In analyzing the results, the absorbance of the well containing HeLa cells that had been induced to express IDO protein without treatment with an inhibitor (At) was 100%; while the absorbance of the well containing HeLa cells that had not been induced to express IDO protein (Ab) was 0. The percent absorbance was calculated according to the following equation: % absorbance = (A - Ab) / (At - Ab), A = absorbance of the well treated with the test compound.

[0468] The 50% inhibition concentration (IC50) of each compound was calculated from the absorbance values obtained as described above. 50 The results obtained are shown in Table 1 below.

[0469] Table 1

[0470] Inhibitory activity (IC 50 , nM)]]> Inhibitory activity (IC 50 , nM)]]> Example 1 16 Example 17 19 Example 2 8.8 Example 18 7.5 Example 3 14 Example 19 14 Example 4 11 Example 20 24 Example 5 16 Example 21 18 Example 6 17 Example 22 16 Example 7 19 Example 23 27 Example 8 5.9 Example 24 17 Example 9 18 Example 25 4.4 Example 10 10.2 Example 26 15 Example 11 18.7 Example 27 23 Example 12 7.2 Example 28 12 Example 13 30 Example 29 10 Example 14 1 Example 30 23.5 Example 15 5.1 Example 31 17.5 Example 16 4 Example 32 11.4

[0471] As can be seen from the results of Table 1, the compounds of the present application exhibit excellent inhibitory activity against indoleamine 2,3-dioxygenase.

[0472] Experimental Example 2: IDOl cellular activity assay using HEK293 cells

[0473] HEK293 cells were seeded at a density of 30000 cells / well in 100 μΐ of culture medium (EMEM supplemented with 10% FBS, 100 U / ml penicillin and 100 μg / ml streptomycin) in tissue culture treated 96-well plates. Cells were incubated in a 5% carbon dioxide incubator for 24 hours, transfected with IDOl expression vector (component A in IDOl cell-based assay kit, cat. #72031, BPS Bioscience) using Lipofectamine 2000 (Life Technologies, #11668027) and then incubated in a 5% carbon dioxide incubator for 24 hours to express IDO protein.

[0474] Activity was measured using IDOl cell-based assay kit (cat. #72031, BPS Bioscience). Specifically, assay medium was prepared by diluting IDOl assay medium substrate 1 and IDOl assay medium supplement 2 in culture medium at a ratio of 1 : 100 respectively. Test compounds were diluted to predetermined concentrations in fresh assay medium. After removing the culture medium using a multichannel pipette, 200 μΐ of each assay medium containing test material was added to the respective wells and then incubated in a 5% carbon dioxide incubator for 24 hours. The next day, 140 μΐ of culture medium from each well was transferred to a new 96-well plate. 10 μΐ of 6.1 N trichloroacetic acid was added to each well and then incubated in a 50 °C incubator for 30 minutes. The plate was centrifuged at 2500 rpm for 10 minutes to precipitate any precipitates. Test reagent solution was prepared by diluting test reagent (component D in IDOl cell-based assay kit, cat. #72031, BPS Bioscience) 50-fold in acetic acid. 100 μΐ of supernatant from the centrifuged plate was transferred to a new clear 96-well plate and then 100 μΐ of test reagent solution was added thereto. After reacting for 10 minutes at room temperature, absorbance was measured at a wavelength of 480 nm. When analyzing the results, the absorbance of the well containing HEK293 cells expressing IDO protein without treatment with inhibitor (At) was 100%; while the absorbance of the well containing HEK293 cells in which IDO protein was not expressed (Ab) was 0. The percentage of absorbance was calculated according to the following equation: % absorbance = (A - Ab) / (At - Ab), A = absorbance of the well treated with test compound.

[0475] The 50% inhibition concentration (IC 50 ) of each compound was calculated from the absorbance values obtained as described above, and the results obtained are shown in Table 2 below.

[0476] Table 2

[0477] Inhibitory activity (IC 50 , nM)]]> Inhibitory activity (IC 50 , nM)]]> Example 10 9.5 Example 44 4.4 Example 11 18.3 Example 45 5.5 Example 12 11.2 Example 46 17.2 Example 13 32.6 Example 47 5.5 Example 17 20.6 Example 48 45.4 Example 18 4 Example 49 72.0 Example 19 8 Example 50 62.3 Example 20 14.3 Example 51 123.8 Example 22 10.9 Example 52 260.1 Example 23 7.6 Example 53 57.4 Example 25 5.2 Example 54 43.6 Example 26 6.5 Example 55 28.2 Example 27 7.4 Example 56 19.3 Example 28 8.6 Example 57 25.2 Example 29 9.9 Example 58 16.8 Example 30 19.1 Example 59 19.4 Example 31 9.1 Example 60 61.1 Example 32 8.7 Example 61 406.4 Example 33 116.5 Example 62 56.6 Example 34 68.6 Example 63 27.5 Example 35 104.7 Example 64 38.8 Example 36 5.7 Example 65 16.1 Example 37 7.6 Example 66 30.8 Example 38 23.7 Example 67 47.5 Example 39 9.7 Example 68 50.5 Example 40 21.9 Example 69 18.8 Example 41 7.6 Example 70 114.5 Example 42 6.6 Example 71 275.8 Example 43 6.3

[0478] As can be seen from the results of Table 2, the compounds of the present application exhibit excellent inhibitory activity against indoleamine 2,3-dioxygenase.

[0479] Experimental Example 3: Pharmacokinetic comparative study of oral administration to normal rats

[0480] The pharmacokinetics of the compounds of Example 2, Example 5 and Example 25 and BMS-986205 (control) were measured in rats, respectively. The compounds of Example 2, Example 5 and Example 25 and BMS-986205 (control) 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 over a predetermined period of time. The concentration of the compound in each sample was analyzed to obtain the blood concentration profile (AUC). Figure 1 The pharmacokinetic parameters thus obtained are shown in Table 3 below.

[0481] Table 3

[0482]

[0483] As can be seen from the results of Table 3, the compounds of the present application exhibit 3.3-27.5 times higher Cmax and 4.0-27.3 times higher AUC in normal rats compared to the control group (BMS-986205). These results indicate that the compounds of the present application show significantly higher in vivo exposure. Therefore, it is expected that the compounds of the present application exhibit excellent efficacy by showing significantly higher in vivo exposure than BMS-986205 at the same dose. Furthermore, since the compounds of the present application can achieve similar in vivo exposure to BMS-986205 even at a low dose, they are also expected to exhibit excellent safety.

Claims

1. A compound of Formula 1 : ###0001### Formula 1 or a pharmaceutically acceptable salt thereof, wherein: R is methyl, ethyl, or cyclopropyl; A is a heteroaryl selected from quinazolinyl, 2H-chromen-2-onyl, benzothiazolyl, benzoxazolyl, thiazolopyridinyl, oxazolopyridinyl, isoquinolinyl, and phthalazinyl, wherein the heteroaryl is optionally substituted with one or two substituents selected from halo, Ci-C6 alkyl, trifluoromethyl, Ci-C6 alkoxy, halo-Ci-C6 alkoxy, trifluoromethoxy, and cyano.

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

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is quinazolinyl substituted with one or two substituents selected from halo, Ci-C6 alkyl, trifluoromethyl, Ci-C6 alkoxy, trifluoromethoxy, and cyano. R is C1to C6alkyl or C3to C6cycloalkyl, 10 cycloalkyl, 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is 2H-chromen-2-onyl substituted with one or two halo.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is benzothiazolyl substituted with one or two substituents selected from halo and Ci-C6 alkoxy.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is thiazolopyridinyl optionally substituted with halo or Ci-C6 alkoxy.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is benzoxazolyl optionally substituted with one or two substituents selected from halo, Ci-C6 alkoxy, and halo-Ci-C6 alkoxy.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, 8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is oxazolopyridinyl optionally substituted with halo.

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

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

11. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the following: 4-(((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)amino)quinazoline-7- carbonitrile; 7-bromo-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4- amine; 7-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4- amine; 7-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4- amine; 7-bromo-4-(((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)amino)-2H- chromen-2-one; 7-chloro-4-(((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)amino)-2H- chromen-2-one; ​ ​ ​ ​ ​ ​ ​ ​ ​ 6-bromo-4-(((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)amino)- 2H-chromen-2-one; 7-chloro-4-(((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)amino)- 2H-chromen-2-one; 7-bromo-4-(((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)amino)- 2H-chromen-2-one; 7-chloro-3-fluoro-4-(((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)amino)-2H-chromen-2-one; 7-bromo-3-fluoro-4-(((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)amino)-2H-chromen-2-one; 7-bromo-3-fluoro-4-(((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)amino)-2H-chromen-2-one; 6-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazol- 2-amine; N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-6-methoxybenzo[d]thiazol- 2-amine; N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)butan-2-yl)-6-methoxybenzo[d]thiazol- 2-amine; N-((S)-1-cyclopropyl-2-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-6-methoxybenzo[d]thiazol- 2-amine; 4,6-difluoro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazol- 2-amine; 7-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazol- 2-amine; 6-ethoxy-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazol- 2-amine; 6-ethoxy-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)butan-2-yl)benzo[d]thiazol- 2-amine; N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)thiazolo[4,5-b]pyridin-2- amine; N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-5-methoxythiazolo[5,4- b]pyridin-2-amine; 6-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)thiazolo[4,5- b]pyridin-2-amine; N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole-2- amine; 6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol- 2-amine; N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-6-methoxybenzo[d]oxazol- 2-amine; 6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)butan-2-yl)benzo[d]oxazol-2- amine; 4-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol-2- amine; 6-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol-2- amine; N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)oxazolo[5,4-b]pyridin-2- amine; 6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)oxazolo[4,5- b]pyridin-2-amine; N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)oxazolo[4,5-b]pyridin-2- amine; 6-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)isoquinolin-1- amine; 6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)isoquinolin-1- amine; 4-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]thiazol-2- amine; 5-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol-2- amine; 7-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol-2- amine; 2-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4- amine; 6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-phthalazin-1- amine; 2,7-dichloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4- amine; 2,7-dichloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4- amine; 7-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-6-methoxybenzo[d] oxazol-2-amine; 6-chloro-5-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)benzo[d]oxazol-2-amine; 6-ethoxy-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol- 2-amine; 6-(2-fluoroethoxy)-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d] oxazol-2-amine; 6,7-dichloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol- 2-amine; 6,7-difluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol- 2-amine; 2-chloro-6-fluoro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin- 4-amine; 2,6-dichloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4- amine; 2-chloro-8-fluoro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin- 4-amine; 2,8-dichloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin-4- amine; 2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-8-methoxyquinazolin- 4-amine; 2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-8- (trifluoromethoxy)quinazolin-4-amine; 2-chloro-7-fluoro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin- 4-amine; 2-chloro-4-(((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)amino)quinazoline- 7-carbonitrile; 7-bromo-2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin- 4-amine; 2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7-methylquinazolin- 4-amine; 2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7- (trifluoromethyl)quinazolin-4-amine; 2-chloro-N-((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7-methoxyquinazolin- 4-amine; 2-chloro-6-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin- 4-amine; 2,6-dichloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)quinazolin-4-amine; 2-chloro-7-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)quinazolin-4-amine; 2-chloro-4-(((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)amino)quinazoline-7-carbonitrile; 7-bromo-2-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)quinazolin-4-amine; 2-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7- methylquinazolin-4-amine; 2-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7- (trifluoromethyl)quinazolin-4-amine; 2-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7- methoxyquinazolin-4-amine; 2,8-dichloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)quinazolin-4-amine; 2-chloro-8-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)quinazolin-4-amine; 2-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-8- methoxyquinazolin-4-amine; and 2-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-8- (trifluoromethoxy)quinazolin-4-amine.

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from the following compounds: 7-bromo-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)quinazolin- 4-amine; 7-bromo-4-(((R)-1-((trans)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2- yl)amino)-2H-chromen-2-one; 6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d] oxazol-2-amine; 6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)butan-2-yl)benzo[d] oxazol-2-amine; 4-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d] oxazol-2-amine; 6-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d] oxazol-2-amine; and 6,7-difluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol-2-amine. 13.A method for preparing a compound or a pharmaceutically acceptable salt thereof, the method comprising reacting a compound of Formula 2 or a salt thereof with a compound of Formula 3 to obtain a compound of Formula 1; and optionally converting the compound of Formula 1 into a pharmaceutically acceptable salt thereof: <Formula 1> <Formula 2> <Formula 3> X-A wherein, R and A are the same as defined in claim 1; and X is halogen. 14.A compound of Formula 2 or a salt thereof: <Formula 2> wherein, R is the same as defined in claim 1. 15.A pharmaceutical composition for inhibiting indoleamine 2,3-dioxygenase, comprising a compound or a pharmaceutically acceptable salt thereof as recited in any one of claims 1 to 12 as an active ingredient. 16.Use of the pharmaceutical composition according to claim 15 for the manufacture of a medicament 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. 17.Use of the pharmaceutical composition according to claim 15 for the manufacture of a medicament for inhibiting indoleamine 2,3-dioxygenase in a mammal.

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