Novel azabicyclo derivative and pharmaceutical composition for inhibiting autotaxin comprising same

Abstract

The present invention provides: a novel azabicyclo derivative compound, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition for preventing or treating autotaxin-related diseases, comprising the same as an active ingredient. The azabicyclo derivative compound according to the present invention exhibits excellent inhibitory activity against autotaxin, and thus can be used for treating and preventing diseases associated with autotaxin inhibition. The compounds can be used for treating diseases such as fibrotic diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, metabolic diseases, cancers and cancer metastases, ocular diseases, cholestatic and other forms of chronic pruritus, and acute or chronic organ transplant rejection.

Description

TECHNICAL FIELD

[0001] This application claims priority to Korean Patent Application No. 10-2023-0043184, filed on March 31, 2023. The entire disclosure of its specification is incorporated herein by reference. The present invention relates to novel azabicyclic derivatives, and more particularly, to novel azabicyclic derivatives having autotaxin inhibitory activity. BACKGROUND

[0002] Autotaxin (ATX), also known as ectonucleotide pyrophosphatase / phosphodiesterase family member 2 (ENPP2), is a secreted enzyme that is critical for the production of the lipid signaling molecule lysophosphatidic acid (LPA). Autotaxin exhibits lysophospholipase D activity, which converts lysophosphatidylcholine (LPC) to LPA. Thus, LPA levels in plasma and ascites fluid are correlated with ATX activity.

[0003] Plasma LPA is a bioactive lipid that influences migration, proliferation, and survival of multiple cell types. In addition, the ATX-LPA signaling process is involved in physiological and pathophysiological functions of multiple diseases, including nervous system function, vascular development, cardiovascular physiology, tissue regeneration, immune system function, chronic inflammation, tumor metastasis and progression, organ fibrosis, and obesity and / or other metabolic diseases (e.g., diabetes).

[0004] Accordingly, increased ATX activity and increased LPA levels, altered LPA receptor expression and altered responses to LPA can be associated with initiation, progression, and / or outcome of multiple pathophysiological diseases involving the ATX / LPA signaling pathway. In particular, it is known to be associated with cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases (e.g., idiopathic pulmonary fibrosis (IPF)), and thrombosis. Therefore, it is necessary to reduce the level of LPA and / or induce the level of autotaxin (ATX) of LPA for the treatment of these diseases. SUMMARY

[0005] OBJECTIVES OF THE INVENTION

[0006] The problem to be solved by the present invention is to provide a novel structural autotaxin inhibitory compound exhibiting excellent inhibitory activity against autotaxin.

[0007] Further, the present application aims to solve the problem of providing a pharmaceutical composition for preventing or treating autocrine motility factor-related diseases, the pharmaceutical composition comprising an autocrine motility factor inhibitory compound having a novel structure.

[0008] Further, the present application aims to solve the problem of providing a method for preventing or treating autocrine motility factor-related diseases, the method comprising administering to a subject in need thereof a therapeutically effective amount of an autocrine motility factor inhibitory compound having a novel structure.

[0009] Further, the present application aims to solve the problem of providing a use of a novel structural autocrine motility factor inhibitory compound as an active ingredient in the manufacture of a medicament for preventing or treating autocrine motility factor-related diseases.

[0010] The problems to be solved by the present application are not limited to the above-mentioned problems, and other technical problems not mentioned can be clearly understood by those skilled in the art to which the present application pertains from the following description.

[0011] Technical Solution

[0012] To solve the above problems, according to one aspect of the present application, there is provided an azabicyclo derivative compound represented by the following Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:

[0013] <Formula 1>

[0014]

[0015] wherein,

[0016] X is C 5-7 aryl; 5- or 6-membered heteroaryl having 1 to 3 N; or a fused bicyclic ring, wherein C 5-7 the aryl ring is fused with a 5- or 6-membered cycloalkyl ring having 0 to 3 O, wherein X is optionally substituted with one or more independent R x ,

[0017] wherein R x is C 1-4 alkyl, C 1-4 alkoxy, cyano, halogen, or C 1-4 haloalkyl,

[0018] p is an integer of 0 to 3,

[0019] R N is hydrogen or C 1-4 alkyl,

[0020] A is 5- or 6-membered heteroaryl having 1 to 3 heteroatoms selected from N and S, wherein A is optionally substituted with one or more independent R Asubstituted,

[0021] wherein R A is C 1-4 alkyl,

[0022] L is -(CH2) m C(O)-, -CHCHC(O)- or a 5- or 6-membered aromatic or non-aromatic heterocycle having 1 to 4 heteroatoms selected from N and O, wherein m is an integer of 1 to 5, and

[0023] B is -(CH2) n C(O)OH, or a 5- or 6-membered heteroaryl having 1 to 4 N, wherein n is an integer of 1 to 3, wherein B is optionally substituted with one or more independent R B substituted,

[0024] wherein R B is C 1-4 alkyl.

[0025] According to another aspect of the present application, there is provided a pharmaceutical composition for preventing or treating autocrine motility factor-related diseases, the pharmaceutical composition comprising an azabicyclic derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0026] According to another aspect of the present application, there is provided a method for preventing or treating autocrine motility factor-related diseases, the method comprising administering to a subject in need thereof a therapeutically effective amount of an azabicyclic derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0027] According to another aspect of the present application, there is provided use of an azabicyclic derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient for the preparation of a medicament for preventing or treating autocrine motility factor-related diseases.

[0028] According to another aspect of the present application, there is provided a pharmaceutical composition comprising an azabicyclic derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

[0029] Advantages

[0030] It was confirmed that the novel azabicyclic derivative compounds of the present application exhibit excellent autocrine motility factor inhibitory activity, and thus found that they are useful for preventing or treating autocrine motility factor-related diseases.

[0031] Accordingly, the novel structure of the azabicyclic derivative compound of the present application can be used in the medical and pharmaceutical fields for treating and preventing autocrine motility factor-related diseases such as fibrotic diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, metabolic diseases, cancer and cancer metastasis, ocular diseases, cholestatic and other forms of chronic pruritus, and acute or chronic organ transplant rejection.

[0032] Effects of the present application are not limited to the above-mentioned effects, and should be understood to include all effects that can be inferred from the composition of the present application described in the specification or claims of the present application. DETAILED DESCRIPTION

[0033] In the present specification, autotaxin (ATX) is a secreted enzyme that plays an important role in the production of lysophosphatidic acid (LPA), also known as ectonucleotide pyrophosphatase / phosphodiesterase family member 2 (ENPP2). Autotaxin exhibits lysophospholipase D activity, which converts lysophosphatidylcholine (LPC) to LPA. Therefore, LPA levels in plasma and ascites are correlated with ATX activity.

[0034] The present application provides an azabicyclic derivative compound represented by the following formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:

[0035] <Formula 1>

[0036]

[0037] wherein,

[0038] X is C 5-7 aryl; 5- or 6-membered heteroaryl having 1 to 3 N; or a fused bicyclic ring, wherein C 5-7 the aryl ring is fused with a 5- or 6-membered cycloalkyl ring having 0 to 3 O, wherein X is optionally substituted with one or more independent R x substituted,

[0039] wherein R x is C 1-4 alkyl, C 1-4 alkoxy, cyano, halogen, or C 1-4 haloalkyl,

[0040] p is an integer of 0 to 3,

[0041] R N is hydrogen or C 1-4 alkyl,

[0042] A is a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms selected from N and S, wherein A is optionally substituted with one or more independent R A substituted,

[0043] wherein R A is C 1-4 alkyl,

[0044] L is -(CH2) m C(O)-, -CHCHC(O)- or a 5- or 6-membered aromatic or non-aromatic heterocycle having 1 to 4 heteroatoms selected from N and O, wherein m is an integer from 1 to 5, and

[0045] B is -(CH2) n C(O)OH, or a 5- or 6-membered heteroaryl having 1 to 4 N, wherein n is an integer from 1 to 3, wherein B is optionally substituted with one or more independent R B substituents,

[0046] wherein R B is C 1-4 alkyl.

[0047] In one embodiment, X can be phenyl, pyridyl, indenyl or benzodioxolyl.

[0048] In one embodiment, R x may be methyl, methoxy, cyano, fluoro, chloro, bromo, difluoromethyl and trifluoromethyl.

[0049] In one embodiment, p can be 0, 1 or 2.

[0050] In one embodiment, R N may be hydrogen or methyl.

[0051] In one embodiment, A can be pyridyl, pyrimidinyl, pyrazinyl and thiadiazolyl.

[0052] In one embodiment, R A may be methyl.

[0053] In one embodiment, L can be -(CH2)2C(O)-, -(CH2)3C(O)-, -CHCHC(O)-, dihydroiso xazolyl or xazolyl.

[0054] In one embodiment, B can be -CH2C(O)OH or triazolyl.

[0055] In one embodiment, R B may be methyl.

[0056] Some representative examples of azabicyclic derivative compounds according to the present application are as follows:

[0057] [1] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (2-diazolyl)-N-benzylpyrimidine-2-amine

[0058] [2] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- diazol-2-yl)-N-(3-chlorobenzyl)pyrimidin-2-amine,

[0059] [3] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- diazol-2-yl)-N-(4-chlorobenzyl)pyrimidin-2-amine

[0060] [4] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- diazol-2-yl)-N-(3,4-difluorobenzyl)pyrimidin-2-amine

[0061] [5] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- diazol-2-yl)-N-(3,5-difluorobenzyl)pyrimidin-2-amine

[0062] [6] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- diazol-2-yl)-N-(3,4-dichlorobenzyl)pyrimidin-2-amine

[0063] [7] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- diazol-2-yl)-N-(3,5-dichlorobenzyl)pyrimidin-2-amine

[0064] [8] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-dimethylbenzyl)pyrimidin-2-amine,

[0065] [9] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-dimethylbenzyl)pyrimidin-2-amine, 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-dimethylbenzyl)pyrimidin-2-amine,

[0066]

[10] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-dimethylbenzyl)pyrimidin-2-amine, 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-dimethylbenzyl)pyrimidin-2-amine,

[0067]

[11] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-dimethylbenzyl)pyrimidin-2-amine, 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-dimethylbenzyl)pyrimidin-2-amine,

[0068]

[12] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-dimethylbenzyl)pyrimidin-2-amine, 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-dimethylbenzyl)pyrimidin-2-amine,

[0069]

[13] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-dimethylbenzyl)pyrimidin-2-amine, 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-dimethylbenzyl)pyrimidin-2-amine,

[0070]

[14] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-dimethylbenzyl)pyrimidin-2-amine, 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-dimethylbenzyl)pyrimidin-2-amine,

[0071]

[15] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-dimethylbenzyl)pyrimidin-2-amine, 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-dimethylbenzyl)pyrimidin-2-amine,

[0072]

[16] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[0073]

[17] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[0074]

[18] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[0075]

[19] 1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-(2-((2,3- dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propan-1-one,

[0076]

[20] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-(trifluoromethyl)benzyl)pyrimidin-2-amine,

[0077]

[21] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3-(trifluoromethyl)benzyl)pyrimidin-2-amine,

[0078]

[22] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(2-(trifluoromethyl)benzyl)pyrimidin-2-amine,

[0079]

[23] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-(difluoromethyl)benzyl)pyrimidin-2-amine,

[24] 4-(((5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-yl)amino)methyl)benzonitrile,

[0080]

[25] 3-(((5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-yl)amino)methyl)benzonitrile,

[26] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-(trifluoromethyl)phenethyl)pyrimidin-2-amine,

[0081]

[27] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-bromophenethyl)pyrimidin-2-amine,

[0082]

[28] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(2-chlorophenethyl)pyrimidin-2-amine,

[29] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine,

[0083]

[30] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-(trifluoromethoxy)phenethyl)pyrimidin-2-amine,

[0084]

[31] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-(trifluoromethoxy)benzyl)pyrimidin-2-amine,

[32] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-(trifluoromethoxy)phenethyl)pyrimidin-2-amine,

[0085]

[33] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-(trifluoromethoxy)benzyl)pyrimidin-2-amine,

[0086] ​​​

[30] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-methoxyphenethyl)pyrimidin-2-amine,

[31] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-methylphenethyl)pyrimidin-2-amine,

[0087]

[32] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(2-(pyridin-2-yl)ethyl)pyrimidin-2-amine,

[33] 4-(2-((5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)benzonitrile,

[0088]

[34] 5-(5-((1R,5S,6R)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-((R)-2,3-dihydro-1H-inden-1-yl)pyrimidin-2-amine,

[35] 5-(5-((1R,5S,6S)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-((S)-2,3-dihydro-1H-inden-1-yl)pyrimidin-2-amine,

[0089]

[36] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-phenylpyrimidin-2-amine,

[37] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(2-(pyridin-3-yl)ethyl)pyrimidin-2-amine,

[0090]

[38] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(2-(pyridin-4-yl)ethyl)pyrimidin-2-amine,

[39] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(2-(1H-indol-5-yl)ethyl)pyrimidin-2-amine,

[0091]

[40] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(2-(1H-indol-6-yl)ethyl)pyrimidin-2-amine,

[41] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(2-(1H-indol-7-yl)ethyl)pyrimidin-2-amine,

[0092]

[42] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(2-(1H-indol-2-yl)ethyl)pyrimidin-2-amine,

[43] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(2-(1H-indol-3-yl)ethyl)pyrimidin-2-amine,

[44] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(2-(1H-indol-4-yl)ethyl)pyrimidin-2-amine,

[0093]

[37] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-chlorophenethyl)-N-methylpyrimidin-2-amine,

[38] 1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-(5-((2,3- dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)butan-1-one,

[0094]

[39] 1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-(5-((2,3- dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)propan-1-one,

[0095]

[40] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-chlorophenethyl)-4-methylpyrimidin-2-amine,

[0096]

[41] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-chlorophenethyl)pyridin-2-amine,

[42] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-chlorophenethyl)pyrazin-2-amine,

[0097]

[43] 1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-(2-((4- chlorophenethyl)amino)pyrimidin-5-yl)propan-1-one,

[0098]

[44] 1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-(2-((4- chlorophenethyl)amino)pyrimidin-5-yl)propan-1-one,

[45] 1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-(2-((4- chlorophenethyl)amino)pyrimidin-5-yl)propan-1-one,

[0099]

[46] 1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-(2-((4- chlorophenethyl)amino)pyrimidin-5-yl)propan-1-one,

[0100] ​

[44] 1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-4-(2-((3,5-dichlorobenzyl)amino)pyrimidin-5-yl)butane-1-one,

[0101]

[45] (E)-1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-3-(2-((4-chlorophenylethyl)amino)pyrimidin-5-yl)prop-2-en-1-one,

[0102]

[46] (E)-1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)prop-2-en-1-one,

[0103]

[47] N-(4-chlorophenylethyl)-5-(5-((1R,5S,6r)-6-(1-methyl-1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (diazol-2-yl)pyrimidin-2-amine,

[0104]

[48] ​​N-(4-chlorophenylethyl)-5-(5-((1R,5S,6r)-6-(4-methyl-1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (diazol-2-yl)pyrimidin-2-amine,

[0105]

[49] 5-(3-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-4,5-dihydroisocyanate (-5-yl)-N-(4-chlorophenylethyl)pyrimidin-2-amine

[0106]

[50] 5-(3-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-4,5-dihydroisocyanate (azol-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, and

[0107]

[51] 2-((1R,5S,6S)-3-(5-(2-((4-chlorophenylethyl)amino)pyrimidin-5-yl)-1,3,4- Oxazol-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid.

[0108] Unless explicitly defined, the following definitions are used in the specification in defining the compounds of Formula 1.

[0109] The term "alkyl" means straight-chain or branched-chain saturated hydrocarbon, preferably C 1-10 alkyl. Some examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.

[0110] The term "cycloalkyl" means partially or fully saturated monocyclic or fused ring hydrocarbon, preferably C 3-10 monocyclic, bicyclic, or tricyclic functional group. Some examples of monocyclic functional groups in cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexynyl, and the like. Bicyclic functional groups in cycloalkyl include bicycloalkyl and spiro functional groups, and some specific examples include bicyclo[l. l. l]pentyl, bicyclo[3. l.0]hexyl, bicyclo[2. l. l]hexyl, bicyclo[2.2. l]heptyl, spiro[2.3]hexyl, spiro[3.3]heptyl, and the like.

[0111] The term "hydroxy" or "hydroxyl" is defined as -OH, and unless otherwise defined, the term "alkoxy" means an alkyl group in which a hydrogen atom in the hydroxyl group is replaced by a C 1-10 alkyl group.

[0112] The term "halogen" or "halo" means fluorine (F), chlorine (CI), bromine (Br), or iodine (I).

[0113] The terms "haloalkyl" and "haloalkoxy" mean an alkyl or alkoxy group substituted with one or more halogen atoms.

[0114] The term "heteroatom" means N, O, or S.

[0115] The term "aryl" means an aromatic hydrocarbon, including polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused with one or more other rings. Preferably it is a C 5-12 aryl, more preferably a C 5-10 aryl. For example, aryl includes, but is not limited to, phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0116] The term "heteroaryl" or "aromatic heterocycle" means a 3- to 12-membered, more preferably 5- to 10-membered, aromatic hydrocarbon forming a monocyclic or fused ring, which contains one or more heteroatoms selected from N, O, and S as ring atoms, and can be benzo- or C3-8 Cycloalkyl fused. For example, heteroaryl includes, but is not limited to, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, oxazolyl, isoxazolyl, indolyl, indazolyl, isoxazolyl, oxazolyl, isoxazolyl, indolyl, indazolyl, isoxazolyl, oxazolyl, isoxazolyl, indolyl, indazolyl, isoxazolyl, oxazolyl, isoxazolyl, indolyl, indazolyl, isoxazolyl, oxazolyl, isoxazolyl, indolyl, indazolyl, isoxazolyl,

[0117] In addition, heteroaryl includes groups in which a heteroaryl ring is fused with a cycloalkyl or non-aromatic heterocyclic ring, such as dihydrocyclopentapyrazinyl and the like.

[0118] The term "heterocycle" or "heterocycloalkyl" refers to a non-aromatic carbocyclic ring containing one or more heteroatoms (e.g., N, O, or S) within the ring. The ring can be 5-, 6-, 7-, or 8-membered and / or can be fused with another ring (e.g., a cycloalkyl ring or an aromatic ring). Some examples of such compounds include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, indolinyl, phthalazinyl, oxazolidinyl, isoxazolidinyl, indolinyl, phthalazinyl,

[0119] The compound represented by Formula 1 according to the present application can be prepared and used in the form of a prodrug, a hydrate, a solvate, and a pharmaceutically acceptable salt to facilitate in vivo absorption or to increase solubility, and thus the prodrug, the hydrate, the solvate, and the pharmaceutically acceptable salt also fall within the scope of the present application. In addition, the compound represented by Formula 1 has a chiral carbon, and thus stereoisomers thereof exist, and such stereoisomers are also included in the scope of the present application.

[0120] The term "prodrug" refers to a substance that is converted into a parent drug in vivo. Prodrugs are often used because, in some situations, they are easier to administer than the parent drug. For example, they can be bioavailable by oral administration whereas the parent drug can not be. Prodrugs can have improved solubility in pharmaceutical compositions compared to the parent drug. For example, a prodrug can be an in vivo hydrolysable ester of a compound according to the present application and pharmaceutically acceptable salts thereof. Another example of a prodrug can be a short peptide (a polyamino acid) that is linked to an acidic group which is metabolized to reveal the active site of the peptide.

[0121] The term "hydrate" means a compound of the present application or a salt thereof having a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0122] The term "solvate" means a compound of the present application or a salt thereof having a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Preferred solvents thus include solvents that are volatile, non-toxic, and / or suitable for administration to humans.

[0123] The term "isomer" means a compound of the present application or a salt thereof having the same formula or molecular formula but different structures or spatial arrangements. Such isomers include structural isomers (e.g., tautomers) and stereoisomers (e.g., R or S isomers having asymmetric carbon centers) as well as geometric isomers (trans, cis). All such isomers and mixtures thereof are included within the scope of the present application. In particular, when a compound of Formula 1 has optical isomers, stereoisomers, regioisomers, or rotamers, these are also included in the compound of Formula 1 and can be obtained as single products according to synthetic and isolation methods known in the art. For example, when a compound of Formula 1 includes optical isomers, the optical isomers resolved from the compound are also included in the compound of Formula 1. The optical isomers can be prepared by methods known per se.

[0124] The term "pharmaceutically acceptable salt" means a salt form of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and physical properties of the compound. Pharmaceutically acceptable salts include acid addition salts formed with acids that include a nontoxic acid, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and the like, organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, and the like, sulfonic acids, for example, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. For example, pharmaceutically acceptable carboxylic acid salts include metal or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, magnesium, and the like; salts with amino acids such as lysine, arginine, guanidine, and the like; organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine. The compound of Formula 1 according to the present application can be converted into a salt thereof by a conventional method.

[0125] In addition, the present application provides a method for preparing a compound of Formula 1. The synthesis methods of Examples 1 to 51 are exemplified as a method for preparing a compound of Formula 1 of the present application, and these synthesis methods of Examples 1 to 51 do not limit the method for preparing a compound of Formula 1 according to the present application. The synthesis methods of Examples 1 to 51 are only examples, and it is obvious that they can be easily modified by those skilled in the art according to the specific substituents.

[0126] The present application also provides a pharmaceutical composition for preventing or treating autocrine motility factor-related diseases, the pharmaceutical composition comprising the azabicyclic derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0127] The present application also provides a method for preventing or treating autocrine motility factor-related diseases, the method comprising administering to a subject in need thereof a therapeutically effective amount of the azabicyclic derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0128] The present application also provides the use of the azabicyclic derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient for the manufacture of a medicament for preventing or treating autocrine motility factor-related diseases.

[0129] As a result of measuring the autocrine motility factor protein inhibitory activity of the azabicyclic derivative compound of the present application, it was determined that even at a very low compound concentration (nM level), it exhibits superior autocrine motility factor inhibitory activity, and thus it is useful for the treatment and prevention of autocrine motility factor-related diseases.

[0130] In one embodiment, the autocrine motility factor-related diseases can be selected from the group consisting of fibrotic diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, metabolic diseases, cancer and cancer metastasis, ocular diseases, cholestatic and other forms of chronic pruritus, and acute or chronic organ transplant rejection.

[0131] The above fibrotic diseases include, but are not limited to, idiopathic pulmonary fibrosis (IPF), interstitial lung disease, liver fibrosis, cirrhosis, nonalcoholic steatohepatitis, radiation-induced fibrosis, kidney fibrosis, skin fibrosis, glomerulosclerosis, myocardial fibrosis, and vascular fibrosis.

[0132] The above inflammatory diseases include, but are not limited to, rheumatoid arthritis, osteoarthritis, atopic dermatitis, inflammatory bowel disease, inflammatory airway disease, chronic obstructive pulmonary disease (COPD), and asthma.

[0133] The above autoimmune diseases include, but are not limited to, multiple sclerosis and scleroderma.

[0134] The above respiratory diseases include, but are not limited to, asbestos-induced pulmonary fibrosis and acute respiratory distress syndrome (ARDS).

[0135] The above cardiovascular diseases include, but are not limited to, arteriosclerosis, myocardial infarction, arterial and pulmonary hypertension, arrhythmia, stroke, and other vascular injuries.

[0136] The above metabolic diseases include, but are not limited to, obesity and diabetes.

[0137] The above cancers and cancer metastasis include, but are not limited to, breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, liver cancer, gastrointestinal cancer, pancreatic cancer, and progression and metastasis thereof.

[0138] The above eye diseases include, but are not limited to, proliferative and non-proliferative retinopathy, diabetic retinopathy, dry and wet age-related macular degeneration (AMD), macular edema, central artery / vein occlusion, traumatic injury, and glaucoma.

[0139] The present application also provides a pharmaceutical composition or preparation comprising the azabicyclic derivative compound represented by Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

[0140] The above additive can include a pharmaceutically acceptable carrier such as a commonly used excipient, disintegrant, sweetener, lubricant, or flavoring agent, and can be formulated into an oral preparation such as a tablet, capsule, powder, granule, and suspension, emulsion, or syrup; or a parenteral preparation such as an external solution, external suspension, external emulsion, gel (ointment, etc.), inhalant, spray, and injection, according to a conventional method. The preparation can be formulated into various forms such as a single dose or multiple dose dosage form.

[0141] The subject to which the pharmaceutical composition of the present application is administered can be, for example, a human, monkey, cow, horse, sheep, pig, chicken, turkey, cat, dog, mouse, rat, rabbit, or guinea pig, and can be, for example, a mammal such as a human, but is not limited thereto.

[0142] In addition, the pharmaceutical composition of the present application can be administered orally or parenterally, and in the case of parenteral administration, it can be administered by, for example, the following routes: cutaneous, transdermal, ocular, intraperitoneal, transrectal or intravenous, intramuscular, subcutaneous, intrauterine epidural, intracerebroventricular injection, or surface administration. Surface ocular administration includes, for example, direct administration into the eye, or administration around the eye, behind the eye, under the retina, in the center of the retina, extrafoveally, subconjunctivally, intravitreally, intracameral, or suprachoroidally. The pharmaceutical composition can be administered through an insertion device.

[0143] The dosage of the active ingredient contained in the pharmaceutical composition of the present application varies depending on the condition and body weight of the patient, the degree of the disease, the form of the active ingredient, the route of administration, and the period of administration, and can be appropriately adjusted depending on the patient. For example, the active ingredient can be administered at a dosage of 0.0001 to 1000 mg / kg, preferably 0.001 to 100 mg / kg per day, and the dosage can be administered once a day or divided into several times. In addition, the pharmaceutical composition of the present application can contain 0.001 to 90% by weight of the active ingredient based on the total weight of the composition.

[0144] Hereinafter, the present application will be described in more detail by synthetic examples, examples, and test examples. However, the following synthetic examples, examples, and test examples are intended to illustrate the present application, and the scope of the present application is not limited thereto.

[0145] Synthesis method

[0146] <Scheme 1>

[0147]

[0148] Reagents and conditions: (a) Bestmann-Ohira reagent, K2CO3, MeOH, rt; (b) Me3SiN3, CuI, DMF, 100 °C, 12 h; (c) 4 N HC1 in dioxane, rt, 2 h.

[0149] <Scheme 2>

[0150]

[0151] Reagents and conditions: (a) 2-chloropyrimidine-5-carboxylic acid ethyl ester, DIEA, DMF, 100 °C, 3 h or 2-chloropyrimidine-5-carboxylic acid ethyl ester, DIEA, 1,4-dioxane, 100 °C, 2 h; (b) N2H4-H2O, EtOH, reflux, 8-15 h; (c) triphosgene, TEA, THF, DMF, rt, 2 h or 1,1'-carbonyldiimidazole (CDI), THF, 0 °C (15 min) -> rt, 20 h; (d) (1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, BOP reagent, DIEA, DMF, rt, 8-22 h.

[0152] <Scheme 3>

[0153]

[0154] Reagents and conditions: (a) 2-chloropyrimidine-5-carboxylic acid ethyl ester, DIEA, DMF, 100 °C, 3 h or 2-chloropyrimidine-5-carboxylic acid ethyl ester, DIEA, 1,4-dioxane, 100 °C, 2 h; (b) N2H4.H2O, EtOH, reflux, 8-15 h; (c) triphosgene, TEA, THF, DMF, rt, 2 h or 1,1'- carbonyldiimidazole (CDI), THF, 0 °C (15 min) -> rt, 20 h; (d) (1R,5S,6r)-6-(1H- 1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, BOP reagent, DIEA, DMF, rt, 8-22 h.

[0155] <SCHEME 4>

[0156]

[0157] Reagents and conditions: (a) 2-chloropyrimidine-5-carboxylic acid ethyl ester, DIEA, DMF, 100 °C, 3 h; (b) N2H4.H2O, EtOH, reflux, 8 h; (c) triphosgene, TEA, THF, DMF, rt, 2 h; (d) (1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, BOP reagent, DIEA, DMF, rt, 8 h.

[0158] <SCHEME 5>

[0159]

[0160] Reagents and conditions: (a) ethyl acrylate, Pd(OAc)2, tris(o-tolyl)phosphine, DIEA, DMF, reflux, 4 h; (b) 2-aminoindane, Et3N, dioxane, 100 °C, 6 h; (c) H2, Pd / C, EA, MeOH, EtOH, DCM, rt, 6 h; (d) LiOH, THF, MeOH, H2O, rt, 1 h; (e) (1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, HATU, DIEA, DMF, rt, 2 h.

[0161] <SCHEME 6>

[0162]

[0163] Reagents and conditions: (a) 2-chloropyrimidine-5-carboxylic acid ethyl ester, DIEA, 1,4-dioxane, 100 °C, 2 h; (b) N2H4.H2O, EtOH, reflux, 15 h; (c) 1,1'- carbonyldiimidazole, TEA, THF, 0 °C (15 min) -> rt, 20 h; (d) (1R,5S,6r)-6-(1H-1,2,3- triazol-5-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, BOP reagent, DIEA, DMF, 0 °C -> rt, 22 h.

[0164] <SCHEME 7>

[0165]

[0166] Reagents and conditions: (a) 2-chloropyrimidine-5-carboxylic acid ethyl ester, DIEA, 1,4-dioxane, 100 °C, 2 h; (b) N2H4.H2O, EtOH, reflux, 15 h; (c) 1,1'- carbonyldiimidazole, TEA, THF, 0 °C (15 min) -> rt, 20 h; (d) (1R,5S,6r)-6-(1H-1,2,3- triazol-5-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, BOP reagent, DIEA, DMF, 0 °C -> rt, 22 h.

[0167] <SCHEME 8>

[0168]

[0169] Reagents and conditions: (a) iodomethane, NaH, DMF, 0 °C -> rt, 6.5 h; (b) N2H4.H2O, EtOH, reflux, 15 h; (c) 1,1'-carbonyldiimidazole, TEA, THF, 0 °C (15 min) -> rt, 20 h; (d) (1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, BOP reagent, DIEA, DMF, 0 °C -> rt, 22 h.

[0170] <SCHEME 9>

[0171]

[0172] Reagents and conditions: (a) O,O'-di-2-pyridylthiocarbonate, DIEA, DCM, rt, 12 h; (b) N2H4.H2O, EtOH, rt, 12 h; (c) ethyl 3-cyano propanoate or ethyl 4-cyano butanoate, TFA, 80 °C, 12 h; (d) LiOH, THF, MeOH, H2O, rt, 3 h; (e) (1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, HATU, DIEA, DCM, rt, 12 h.

[0173] <SCHEME 10>

[0174]

[0175] Reagents and conditions: (a) ethyl acrylate or ethyl but-3-enoate, Pd(OAc)2, tri(o-tolyl)phosphine, DIEA, DMF, reflux, 4 h; (b) H2, Pd / C, EtOAc, rt, 12 h; (c) 2-(4-chlorophenyl)ethan-1-amine or (3,5-dichlorophenyl)methanamine, DIEA, n-butanol, microwave, 150 °C, 2 h; (d) LiOH, THF, MeOH, H2O, rt, 3 h; (e) (1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, HATU, DIEA, DCM, rt, 12 h.

[0176] <SCHEME 11>

[0177]

[0178] Reagents and conditions: (a) 2-(4-chlorophenyl)ethan-1-amine or (3,5-dichlorophenyl)methanamine, DIEA, n-butanol, microwave, 150 °C, 2 h; (d) LiOH, THF, MeOH, H2O, rt, 3 h; (e) (1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, HATU, DIEA, DCM, rt, 12 h.

[0179] <SCHEME 12>

[0180]

[0181] Reagents and conditions: (a) i) n-BuLi (2.5 M in hexanes), THF, -78 °C, 30 min, ii) iodomethane, rt, 12 h; (b) Me3SiN3, microwave, 200 °C, 7 h; (c) 4 N HC1 in dioxane, 1,4-dioxane, rt, 3 h; (d) 2-(4-chlorophenyl)ethan-1-amine, BOP reagent, DIEA, DMF, rt, 5 h.

[0182] <SCHEME 13>

[0183]

[0184] Reagents and conditions: (a) i) n-BuLi (2.5 M in hexanes), THF, -78 °C, 30 min, ii) iodomethane, rt, 12 h; (b) Me3SiN3, microwave, 200 °C, 7 h; (c) 4 N HC1 in dioxane, 1,4-dioxane, rt, 3 h; (d) 2-(4-chlorophenyl)ethan-1-amine, BOP reagent, DIEA, DMF, rt, 5 h.

[0185] <SCHEME 14>

[0186]

[0187] Reagents and conditions: (a) 2-(4-chlorophenyl)ethan-1-amine or 2,3-dihydro-1H- inden-2-amine, DIEA, n-butan-1-ol, microwave, 150 °C, 2 h; (b) i) 1,1-dibromoformoxime, -10 °C, DMF, ii) KHCO3, H2O, rt, 1 h; (c) (1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3- azabicyclo[3.1.0]hexane hydrochloride, DIEA, tert-butan-1-ol, microwave, 200 °C, 3 h.

[0188] <SCHEME 15>

[0189]

[0190] Reagents and conditions: (a) iodomethane, K2CO3, DMF, rt, 15 h; (b) 4 N HC1 in dioxane, 1,4-dioxane, rt, 5 h; (c) 2-(4-chlorophenyl)ethan-1-amine, DIEA, DMF, 0 °C (30 min) -> BOP reagent, rt, 15 h; (d) 1 N NaOH, THF, rt, 1.5 h.

[0191] Synthesis Example 1. (1R,5S,6s)-6-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (2)

[0192]

[0193] (1R,5S,6r)-6-Formyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1 mmol) and K2CO3 (2 mmol) in MeOH were stirred. Then a mixture of dimethyl (1-diazo-2-oxopropyl)phosphonate (1.2 mmol) dissolved in ACN was added slowly dropwise. The solvent was evaporated under reduced pressure and extracted with CH2Cl2. The combined organic solution was dried over Na2SO4 and concentrated. The solvent was removed under reduced pressure and the residue was purified by column chromatography (SiO2, hexane: ethyl acetate) to give compound (2) (400 mg, yield: 64.3%);

[0194]

[0195] Synthesis Example 2. (1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3- carboxylic acid tert-butyl ester (3)

[0196]

[0197] (1R,5S,6s)-6-Ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1) (1.03 mmol), trimethylsilyl azide (1.15 mmol) and copper(I) iodide (0.05 mmol) were dissolved in DMF. The mixture was stirred at 100 °C under argon atmosphere for 12 hours. Then the mixture was filtered through a pad of celite, rinsed with ethyl acetate and washed with water. The combined organic solution was dried over Na2SO4 and concentrated. The solvent was removed under reduced pressure and the residue was purified by column chromatography (SiO2, hexane: ethyl acetate) to give compound (3) (181 mg, yield 70%);

[0198]

[0199] Synthesis Example 3. (1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane HCl (4)

[0200]

[0201] 4.0 M HC1 in dioxane was added to (1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (3, 0.68 mmol) in dioxane. The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated to dryness to give compound (4) (quantitative);

[0202]

[0203] For C7H 11 N4[M+H] + MS calculated 151.15, found 151.15.

[0204] General procedure (I) for the synthesis of 6a to j, 11a to e and 16a to c

[0205] A mixture of 2-chloropyrimidine-5-carboxylic acid ethyl ester (1.4 mmol), various substituted amines (1.68 mmol) and DIEA (3 mmol) in DMF (5 mL) was stirred at 100 °C for 3 hours. After cooling, the solvent was evaporated and the crude product was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was obtained by column chromatography (hexane / ethyl acetate) to obtain 6a to j, 11a to e and 16a to c.

[0206] Synthesis example 4. 2-(benzylamino)pyrimidine-5-carboxylic acid ethyl ester (6a)

[0207]

[0208] Yield: 78%;

[0209]

[0210] For C 14 H 15 N3O2 [M+H] + MS calculated 258.12, found 258.10.

[0211] Synthesis example 5. 2-((3-chlorobenzyl)amino)pyrimidine-5-carboxylic acid ethyl ester (6b)

[0212]

[0213] Yield: 95%;

[0214]

[0215] For C 14 H 15 ClN3O2 [M+H] + MS calculated 292.08, found 292.00.

[0216] Synthesis example 6. 2-((4-chlorobenzyl)amino)pyrimidine-5-carboxylic acid ethyl ester (6c)

[0217]

[0218] Yield: 74%;

[0219]

[0220] For C 14 H 16 ClN3O2 [M+H] + MS calculated 292.08, found 292.05.

[0221] Synthesis Example 7. 2-((3,4-difluorobenzyl)amino)pyrimidine-5-carboxylic acid ethyl ester (6d)

[0222]

[0223] Yield: 74%;

[0224]

[0225] For C 14 H 14 F2N3O2 [M+H] + MS calculated 294.10, found 294.15.

[0226] Synthesis Example 8. 2-((3,5-difluorobenzyl)amino)pyrimidine-5-carboxylic acid ethyl ester (6e)

[0227]

[0228] Yield: 51%;

[0229]

[0230] For C 14 H 14 F2N3O2 [M+H] + MS calculated 294.10, found 294.15.

[0231] Synthesis Example 9. 2-((3,4-dichlorobenzyl)amino)pyrimidine-5-carboxylic acid ethyl ester (6f)

[0232]

[0233] Yield: 94%;

[0234]

[0235] For C 14 H 14 Cl2N3O2 [M+H] +MS calculated 326.05, found 326.05.

[0236] Synthesis Example 10. 2-((3,5-dichlorobenzyl)amino)pyrimidine-5-carboxylic acid ethyl ester (6g)

[0237]

[0238] Yield: 96%;

[0239]

[0240] For C 14 H 14 Cl2N3O2 [M+H] + MS calculated 326.05, found 326.05.

[0241] Synthesis Example 11. 2-((3,5-dibromobenzyl)amino)pyrimidine-5-carboxylic acid ethyl ester (6h)

[0242]

[0243] Yield: 82%;

[0244]

[0245] For C 14 H 14 C l2 N5O2 [M+H] + MS calculated 413.94, found 415.95.

[0246] Synthesis Example 12. 2-((benzo[d][l,3]dioxol-5-ylmethyl)amino)pyrimidine-5-carboxylic acid ethyl ester (6i)

[0247]

[0248] Yield: 87%;

[0249]

[0250] For C 14 H 16 N3O4 [M+H] + MS calculated 302.11, found 302.10.

[0251] Synthesis Example 13. 2-((3,5-bis(trifluoromethyl)benzyl)amino)pyrimidine-5-carboxylic acid ethyl ester (6j)

[0252]

[0253] Yield: 93%;

[0254]

[0255] For C 16 H 13 F6N3O2 [M+H] + MS calculated 394.10, found 394.05.

[0256] Synthesis Example 14. 2-(phenethylamino)pyrimidine-5-carboxylic acid ethyl ester (11a)

[0257]

[0258] Yield: 80%;

[0259]

[0260] For C 15 H 18 N3O2 [M+H] + MS calculated 272.14, found 272.05.

[0261] Synthesis Example 15. 2-((3-fluorophenethyl)amino)pyrimidine-5-carboxylic acid ethyl ester (11b)

[0262]

[0263] Yield: 82%;

[0264]

[0265] For C 15 H 16 FN3O2 [M+H] + MS calculated 290.13, found 290.00.

[0266] Synthesis Example 16. 2-((4-fluorophenethyl)amino)pyrimidine-5-carboxylic acid ethyl ester (11c)

[0267]

[0268] Yield: 75%;

[0269]

[0270] For C 15 H 16 FN3O2 [M+H] + MS calculated 290.13, found 290.00.

[0271] Synthesis Example 17. 2-((3-chlorophenethyl)amino)pyrimidine-5-carboxylic acid ethyl ester (11d)

[0272]

[0273] Yield: 83%;

[0274]

[0275] For C 15 H 16 ClN3O2 [M+H] + MS calculated 306.10, found 306.00.

[0276] Synthesis Example 18. 2-((4-chlorophenethyl)amino)pyrimidine-5-carboxylic acid ethyl ester (11e)

[0277]

[0278] Yield: 82%;

[0279]

[0280] For C 15 H 16 ClN3O2 [M+H] + MS calculated 306.10, found 305.95.

[0281] Synthesis Example 19. 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid ethyl ester (16a)

[0282]

[0283] Yield: 64%;

[0284]

[0285] For C 16 H 18 N3O2 [M+H]+, MS calculated 284.14, found 284.10.

[0286] Synthesis Example 20. 2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid ethyl ester (16b)

[0287]

[0288] Yield: 86%;

[0289]

[0290] For C 16 H 16 F2N3O2 [M+H] + MS calculated 320.12, found 320.10.

[0291] Synthesis Example 21. 2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5- carboxylic acid ethyl ester (16c)

[0292]

[0293] Yield: 63%;

[0294]

[0295] For C 16 H 17 BrN3O2 [M+H] + MS calculated 362.05, found 364.00.

[0296] General procedure (II) for the synthesis of 7a to j, 12a to e and 17a to c

[0297] Compound 6a to j, 11a to e and 16a to c (5 mmol) and hydrazine monohydrate (50 mmol) were dissolved in EtOH and refluxed for 3 hours. After completion of the reaction, the reaction mixture was evaporated under vacuum to obtain 7a to j, 12a to e and 17a to c.

[0298] Synthesis Example 22. 2-(benzylamino)pyrimidine-5-carbohydrazide (7a)

[0299]

[0300] Yield: quantitative;

[0301]

[0302] For C 12 H 14 N5O2 [M+H] + MS calculated 244.12, found 244.15.

[0303] Synthesis Example 23. 2-((3-chlorobenzyl)amino)pyrimidine-5-carbohydrazide (7b)

[0304]

[0305] Yield: quantitative;

[0306]

[0307] For C 12 H 13 ClN5O2 [M+H] + MS calculated 278.08, found 278.10.

[0308] Synthesis Example 24. 2-((4-chlorobenzyl)amino)pyrimidine-5-carbohydrazide (7c)

[0309]

[0310] Yield: quantitative;

[0311]

[0312] For C 12 H 13 ClN5O2 [M+H] + MS calculated 278.08, found 278.10.

[0313] Synthesis Example 25. 2-((3,4-difluorobenzyl)amino)pyrimidine-5-carbohydrazide (7d)

[0314]

[0315] Yield: quantitative;

[0316]

[0317] For C 12 H 12 F2N5O2 [M+H] + MS calculated 280.10, found 280.15.

[0318] Synthesis Example 26. 2-((3,5-difluorobenzyl)amino)pyrimidine-5-carbohydrazide (7e)

[0319]

[0320] Yield: quantitative;

[0321]

[0322] For C 12 H 12 F2N5O2 [M+H] + MS calculated 280.10, found 280.10.

[0323] Synthesis Example 27. 2-((3,4-dichlorobenzyl)amino)pyrimidine-5-carbohydrazide (7f)

[0324]

[0325] Yield: quantitative;

[0326]

[0327] For C 12 H 12 Cl2N5O2 [M+H]+, MS calculated 312.04, found 312.10.

[0328] Synthesis Example 28. 2-((3,5-dichlorobenzyl)amino)pyrimidine-5-carbohydrazide (7g)

[0329]

[0330] Yield: quantitative;

[0331]

[0332] For C 12 H 12 Cl2N5O2 [M+H] + , MS calculated 312.04, found 312.05.

[0333] Synthesis Example 29. 2-((3,5-dibromobenzyl)amino)pyrimidine-5-carbohydrazide (7h)

[0334]

[0335] Yield: quantitative;

[0336]

[0337] For C 12 H 12 Br2N5O2 [M+H] + , MS calculated 399.94, found 401.95.

[0338] Synthesis Example 30. 2-((benzo[d][l,3]dioxol-5-ylmethyl)amino)pyrimidine-5-carbohydrazide (7i)

[0339]

[0340] Yield: quantitative;

[0341]

[0342] For C 13 H 14 N5O3 [M+H] + MS calculated 288.11, found 288.15.

[0343] Synthesis Example 31. 2-((3,5-bis(trifluoromethyl)benzyl)amino)pyrimidine-5- carbohydrazide (7j)

[0344]

[0345] Yield: quantitative;

[0346]

[0347] For C 14 H 12 F6N6O [M+H] + MS calculated 380.09, found 380.10.

[0348] Synthesis Example 32. 2-(phenethylamino)pyrimidine-5-carbohydrazide (12a)

[0349]

[0350] Yield: quantitative;

[0351]

[0352] For C 13 H 16 N5O [M+H] + MS calculated 258.30, found 258.10.

[0353] Synthesis Example 33. 2-((3-fluorophenethyl)amino)pyrimidine-5-carbohydrazide (12b)

[0354]

[0355] Yield: quantitative;

[0356]

[0357] For C 13 H 15 FN5O [M+H] + MS calculated 276.29, found 276.05.

[0358] Synthesis Example 34. 2-((4-fluorophenethyl)amino)pyrimidine-5-carbohydrazide (12c)

[0359]

[0360] Yield: quantitative;

[0361]

[0362] For C 13 H 15 FN5O [M+H] + MS calculated for C12H10CIN5O, 276.29, found 276.05.

[0363] Synthesis Example 35. 2-((3-chlorophenethyl)amino)pyrimidine-5-carbohydrazide (12d)

[0364]

[0365] Yield: quantitative;

[0366]

[0367] For C 13 H 15 ClN5O [M+H] + MS calculated for C12H10CIN5O, 276.29, found 276.05.

[0368] Synthesis Example 36. 2-((4-chlorophenethyl)amino)pyrimidine-5-carbohydrazide (12e)

[0369]

[0370] Yield: quantitative;

[0371]

[0372] For C 13 H 15 ClN5O [M+H] + MS calculated for C12H10CIN5O, 276.29, found 276.05.

[0373] Synthesis Example 37. 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbohydrazide (17a)

[0374]

[0375] Yield: quantitative;

[0376]

[0377] For C 14 H16 N5O [M+H] + MS calculated for 270.13, found 270.15.

[0378] Synthesis Example 38. 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5- carbohydrazide (17b)

[0379]

[0380] Yield: quantitative;

[0381]

[0382] For C 14 H 14 F2N5O [M+H] + MS calculated for 306.12, found 306.10.

[0383] Synthesis Example 39. 2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine- 5-carbohydrazide (17c)

[0384]

[0385] Yield: quantitative;

[0386]

[0387] For C 14 H 12 F6N6O [M+H] + MS calculated for 380.09, found 380.10.

[0388] General procedure (III) for the synthesis of 8a to j, 13a to e and 18a to c

[0389] Compound 7a to j, 12a to e and 17a to c (0.1 mmol) dissolved in DMF (5 mL) and TEA (0.5 mmol) was slowly added to a solution of triphosgene (0.04 mmol) in THF (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated to dryness. The product was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (EA / Hex) to give 8a to j, 13a to e and 18a to c.

[0390] Synthesis Example 40. 5-(2-(benzylamino)pyrimidin-5-yl)-1,3,4- oxadiazol-2(3H)-one (8a) oxadiazol-2(3H)-one (8a)

[0391]

[0392] Yield: 10%;

[0393]

[0394] For C 13 H 12 N5O2[M+H] + MS calculated 270.10, found 270.05.

[0395] Synthesis Example 41. 5-(2-((3-chlorobenzyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazol-2(3H)-one (8b)

[0396]

[0397] Yield: 36.9%;

[0398]

[0399] For C 13 H 11 ClN5O2[M+H] + MS calculated 304.06, found 304.05.

[0400] Synthesis Example 42. 5-(2-((4-chlorobenzyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazol-2(3H)-one (8c)

[0401]

[0402] Yield: 10%;

[0403]

[0404] For C 13 H 11 ClN5O2[M+H] + MS calculated 304.06, found 304.05.

[0405] Synthesis Example 43. 5-(2-((3,4-difluorobenzyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazol-2(3H)-one (8d)

[0406]

[0407] Yield: 41%;

[0408]

[0409] For C 13 H 10 F2N5O2[M+H] + MS calculated 306.08, found 306.05.

[0410] Synthesis Example 44. 5-(2-((3,5-difluorobenzyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazol-2(3H)-one (8e)

[0411]

[0412] Yield: 47%;

[0413]

[0414] For C 13 H 10 F2N5O2[M+H] + MS calculated 306.08, found 306.10.

[0415] Synthesis Example 45. 5-(2-((3,4-dichlorobenzyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazol-2(3H)-one (8f)

[0416]

[0417] Yield: 20%;

[0418]

[0419] For C 13 H 10 Cl2N5O2 [M+H] + MS calculated 338.02, found 339.05.

[0420] Synthesis Example 46. 5-(2-((3,5-dichlorobenzyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazol-2(3H)-one (8g)

[0421]

[0422] Yield: 15%;

[0423]

[0424] For C13 H 10 Cl2N5O2 [M+H] + , MS calculated 338.02, found 338.00.

[0425] Synthesis Example 47. 5-(2-((3,5-dibromobenzyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazol-2(3H)-one (8h)

[0426]

[0427] Yield: 65%;

[0428]

[0429] For C 13 H 10 Br2N5O2 [M+H] + , MS calculated 425.92, found 427.95.

[0430] Synthesis Example 48. 5-(2-((benzo[d][1,3]dioxol-5-ylmethyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazol-2(3H)-one (8i)

[0431]

[0432] Yield: 33%;

[0433]

[0434] For C 14 H 12 N5O4 [M+H] + , MS calculated 314.09, found 314.15.

[0435] Synthesis Example 49. 5-(2-((3,5-bis(trifluoromethyl)benzyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazol-2(3H)-one (8j)

[0436]

[0437] Yield: 10%;

[0438]

[0439] For C 15 H 10 F6N6O2 [M+H] +MS calculated 406.07, found 405.95.

[0440] Synthesis Example 50. 5-(2-(phenethylamino)pyrimidin-5-yl)-1,3,4- oxadiazol-2(3H)-one (13a)

[0441]

[0442] Yield: 7%;

[0443]

[0444] For C 14 H 14 N5O2 [M+H] + MS calculated 284.11, found 284.05.

[0445] Synthesis Example 51. 5-(2-((3-fluorophenethyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazol-2(3H)-one (13b)

[0446]

[0447] Yield: 10%;

[0448]

[0449] For C 14 H 13 FN5O2 [M+H] + MS calculated 302.10, found 302.05.

[0450] Synthesis Example 52. 5-(2-((4-fluorophenethyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazol-2(3H)-one (13c)

[0451]

[0452] Yield: 11%;

[0453]

[0454] For C 14 H 13 FN5O2 [M+H] + MS calculated 302.10, found 302.05.

[0455] Synthesis Example 53. 5-(2-((3-chlorophenethyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazol-2(3H)-one (13d)

[0456]

[0457] Yield: 18%;

[0458]

[0459] For C 14 H 13 ClN5O2 [M+H] + , MS calculated 318.08, found 318.00.

[0460] Synthesis Example 54. 5-(2-((4-chlorophenethyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazol-2(3H)-one (13e)

[0461]

[0462] Yield: 27%;

[0463]

[0464] For C 14 H 13 ClN5O2 [M+H] + , MS calculated 318.08, found 318.05.

[0465] Synthesis Example 55. 5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazol-2(3H)-one (18a)

[0466]

[0467] Yield: 30%;

[0468]

[0469] For C 15 H 14 N5O2 [M+H] + , MS calculated 296.11, found 296.10.

[0470] Synthesis Example 56. 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- Oxazol-2(3H)-one (18b)

[0471]

[0472] Yield: 42%;

[0473]

[0474] For C 15 H 12 F2N5O2 [M+H] + MS calculated 332.09, found 332.01.

[0475] Synthesis Example 57. 5-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- Oxazol-2(3H)-one (18c)

[0476]

[0477] Yield: 42%;

[0478]

[0479] For C 15 H 13 BrN5O2 [M+H] + MS calculated 374.02, found 374.00.

[0480] General procedure (IV) for the synthesis of 9a to j, 14a to e and 19a to c

[0481] Compound 8a to j, 13a to e and 18a to c (1 mmol), (1R,5S,6r)-6-(1H-1,2,3- triazol-5-yl)-3-azabicyclo[3.1.0]hexane (3, 1.2 mmol), DIEA (3.5 mmol) and BOP reagent (1.2 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred at room temperature for 8 hours. After completion of the reaction, the solvent was evaporated to dryness. The crude product was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was isolated by column chromatography (DCM / MeOH) to give 9a to j, 14a to e and 19a to c.

[0482] Example 1. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- Oxazol-2-yl)-N-(4-chlorobenzyl)pyrimidin-2-amine (9c)

[0483]

[0484] Yield: 36%;

[0485]

[0486] For C 20 H 20 N9O + [M+H] + HRMS (ESI, m / z) calculated for 402.1785, found 402.1785.

[0487] Example 2. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- Oxazol-2-yl)-N-(4-chlorobenzyl)pyrimidin-2-amine (9c)

[0488]

[0489] Yield: 21%;

[0490]

[0491] For C 20 H 19 ClN9O + [M+H] + HRMS (ESI, m / z) calculated for 436.1396, found 436.1395.

[0492] Example 3. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- Oxazol-2-yl)-N-(4-chlorobenzyl)pyrimidin-2-amine (9c)

[0493]

[0494] Yield: 24.4%;

[0495]

[0496] For C 20 H 19 ClN9O + [M+H] +, HRMS (ESI, m / z) calculated for C26H26FN9O 518.2086, found 518.2088.

[0497] Example 4. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,4-difluorobenzyl)pyrimidin-2-amine (9d)

[0498]

[0499] Yield: 31%;

[0500]

[0501] For C 20 H 18 F2N9O + [M+H] + , HRMS (ESI, m / z) calculated for C26H26FN9O 518.2086, found 518.2088.

[0502] Example 5. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-difluorobenzyl)pyrimidin-2-amine (9e)

[0503]

[0504] Yield: 35%;

[0505]

[0506] For C 20 H 18 F2N9O + [M+H] + , HRMS (ESI, m / z) calculated for C26H26FN9O 518.2086, found 518.2088.

[0507] Example 6. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,4-dichlorobenzyl)pyrimidin-2-amine (9f)

[0508]

[0509] Yield: 25%;

[0510]

[0511] For C 20 H 18 Cl2N9O + [M+H] + The calculated value of HRMS (ESI, m / z) is 470.1006, and the measured value is 470.1007.

[0512] Example 7. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (diazol-2-yl)-N-(3,5-dichlorobenzyl)pyrimidin-2-amine (9g)

[0513]

[0514] Yield: 15%;

[0515]

[0516] For C 20 H 18 Cl2N9O + [M+H] + The calculated value of HRMS (ESI, m / z) is 470.1006, and the measured value is also 470.1006.

[0517] Example 8. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (diazol-2-yl)-N-(3,5-dibromobenzyl)pyrimidin-2-amine (9h)

[0518]

[0519] Yield: 22%;

[0520]

[0521] For C 20 H 18 Br2N9O + [M+H] + The calculated HRMS (ESI, m / z) value is 557.9996, and the measured value is 559.9979.

[0522] Example 9. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (diazol-2-yl)-N-(benzo[d][1,3]m-dioxacyclopenten-5-ylmethyl)pyrimidin-2-amine (9i)

[0523]

[0524] Yield: 35%;

[0525]

[0526]

[0527] For C 21 H 20 N9O3 [M+H] + The calculated value of HRMS (ESI, m / z) is 446.1684, and the measured value is 446.1685.

[0528] Example 10. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (diazol-2-yl)-N-(3,5-bis(trifluoromethyl)benzyl)pyrimidin-2-amine (9j)

[0529]

[0530] Yield: 43%;

[0531]

[0532] For C 22 H 18 F6N9O + [M+H] + The calculated value of HRMS (ESI, m / z) is 538.1533, and the measured value is 538.1531.

[0533] Example 11. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (14a)-N-phenylethylpyrimidin-2-amine (2-diazolyl)-N-phenylethylpyrimidin-2-amine

[0534]

[0535] Yield: 36%;

[0536]

[0537] For C 21 H 22 N9O + [M+H] + HRMS (ESI, m / z) calculated for 416.1942, found 416.1942.

[0538] Example 12. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3-fluorophenethyl)pyrimidin-2-amine (14b)

[0539]

[0540] Yield: 41%;

[0541]

[0542] For C 21 H 21 FN9O + [M+H] + HRMS (ESI, m / z) calculated for 434.1848, found 434.1847.

[0543] Example 13. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-fluorophenethyl)pyrimidin-2-amine (14c)

[0544]

[0545] Yield: 33%;

[0546]

[0547] For C 21 H 21 FN9O + [M+H] + HRMS (ESI, m / z) calculated for 434.1848, found 434.1847.

[0548] Example 14. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)- 1,3,4-oxadiazol-2-yl)-N-(3-chlorophenethyl)pyrimidin-2-amine (14d) Example 14. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)- 1,3,4-oxadiazol-2-yl)-N-(3-chlorophenethyl)pyrimidin-2-amine (14d)

[0549]

[0550] Yield: 28%;

[0551]

[0552] For C 21 H 21 ClN9O + [M+H] + HRMS (ESI, m / z) calculated for 450.1552, found 450.1554.

[0553] Example 15. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)- 1,3,4-oxadiazol-2-yl)-N-(4-chlorophenethyl)pyrimidin-2-amine (14e) Example 15. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)- 1,3,4-oxadiazol-2-yl)-N-(4-chlorophenethyl)pyrimidin-2-amine (14e)

[0554]

[0555] Yield: 56%;

[0556]

[0557] For C 21 H 21 ClN9O + [M+H] + HRMS (ESI, m / z) calculated for 450.1552, found 450.1552.

[0558] Example 16. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)- 1,3,4-oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (19a) Example 16. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)- 1,3,4-oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (19a)

[0559]

[0560] Yield: 48%;

[0561]

[0562]

[0563] For C 22 H 22 N9O + [M+H] + The calculated value of HRMS (ESI, m / z) is 428.1942, and the measured value is 428.1943.

[0564] Example 17. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (19b)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0565]

[0566] Yield: 76%;

[0567]

[0568] For C 22 H 20 F2N9O + [M+H] + The calculated HRMS (ESI, m / z) value is 464.1753, and the measured value is 464.1755.

[0569] Example 18. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (diazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (19c)

[0570]

[0571] Yield: 30%;

[0572]

[0573]

[0574] For C 22 H 21 BrN9O + [M+H] +The calculated value of HRMS (ESI, m / z) is 506.1047, and the measured value is also 506.1047.

[0575] Synthetic Example 58. Ethyl (E)-3-(2-chloropyrimidin-5-yl)acrylate (21)

[0576]

[0577] A mixture of 5-bromo-2-chloropyrimidine (0.19 g, 1.00 mmol), ethyl acrylate (0.42 mL, 4.00 mmol), palladium(II) diacetate (8.98 mg, 0.04 mmol), and tris(o-tolyl)phosphine (30.43 mg, 0.10 mmol) in dimethylformamide (2 mL) and diisopropylethylamine (1 mL) was heated to reflux for 4 hours, then cooled to room temperature. The solvent was evaporated to dryness and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (ethyl acetate / hexane) to give the title product; yield: 74%.

[0578]

[0579] Synthetic Example 59. Ethyl (E)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylate (22)

[0580]

[0581] Compound 22 was synthesized using compound 21 and 2-aminoindene according to general step I; yield: 82%;

[0582]

[0583] Synthetic Example 60. Ethyl 3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propionate (23)

[0584]

[0585] Compound 23 (1 mmol) was dissolved in EtOH (5 mL) / DCM (5 mL), and palladium on carbon was added to the mixture at room temperature. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound; yield: 61%.

[0586]

[0587] Synthesis Example 61. 3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propanoic acid (24)

[0588]

[0589] A solution of lithium hydroxide (0.12 g, 5.00 mmol) in water (2 mL) was added to a solution of compound 23 in methanol. The reaction mixture was stirred for 1 hour. After evaporation of the solvent, the mixture was dissolved again in water and acidified (pH 4-5) with 1 M hydrochloric acid and a white solid was precipitated. The precipitate was filtered to obtain the title product; yield: 89%;

[0590]

[0591] Example 19. 1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-(2-((2,3- dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propan-1-one (25)

[0592]

[0593] Compound 24 (1 mmol), 4 (1.2 mmol), DIEA (3.5 mmol) and HATU (1.2 mmol) were dissolved in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated to dryness. The crude product was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was separated by column chromatography (DCM / MeOH) to obtain the title compound; yield: 50%;

[0594]

[0595]

[0596] For C 23 H 26 N7O + [M+H] + , HRMS (ESI, m / z) calculated 416.2193, found 416.2193.

[0597] Example 20. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- Oxazol-2-yl)-N-(4-(trifluoromethyl)benzyl)pyrimidin-2-amine (9k)

[0598]

[0599] Step 1: Ethyl 2-((4-(trifluoromethyl)benzyl)amino)pyrimidine-5-carboxylate (6k)

[0600] After dissolving (4-(trifluoromethyl)benzyl)methanamine (110 mg, 0.63 mmol) in anhydrous 1,4-dioxane (2.1 mL), DIPEA (214 uL, 1.26 mmol) and ethyl 2-chloropyrimidine-5-carboxylate (106 mg, 0.57 mmol) were added sequentially and the mixture was stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature, DW (6 mL) was added and the mixture was stirred for 30 minutes. The resulting solid was filtered, washed with DW and dried under vacuum to give compound 6k as a yellow solid (144 mg, yield: 78%).

[0601] .

[0602] Step 2: 2-((4-(trifluoromethyl)benzyl)amino)pyrimidine-5-carbohydrazide (7k)

[0603] A reaction mixture of compound 6k (142 mg, 0.44 mmol), hydrazine monohydrate (0.49 mL, 6.55 mmol) and EtOH (4.9 mL) was stirred at 100 °C for 15 hours. After cooling to room temperature, DW was added and the mixture was stirred for 30 minutes. The resulting solid was filtered and dried under vacuum to give compound 7k as an off-white solid (107 mg, yield: 79%).

[0604] .

[0605] Step 3: 5-(2-((4-(trifluoromethyl)benzyl)amino)pyrimidin-5-yl)-1,3,4- oxazol-2(3H)-one (8k)

[0606] Compound 7k (105 mg, 0.34 mmol) was dissolved in THF (1.8 mL) and cooled to 0 °C. TEA (47 uL, 0.34 mmol) and CDI (65.6 mg, 0.41 mmol) were added slowly and the mixture was stirred at 0 °C for 15 minutes. After stirring at room temperature for 20 hours, DW was added and stirred for 30 minutes. The resulting solid was filtered and dried under vacuum to obtain compound 8k as a white solid (107 mg, yield: 79%).

[0607] .

[0608] Step 4: 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-(trifluoromethyl)benzyl)pyrimidin-2-amine (9k)

[0609] Compound 8k (30.1 mg, 0.09 mmol) and (1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (20 mg, 0.11 mmol) were dissolved in DMF (1.8 mL) and cooled to 0 °C. DIPEA (76 uL, 0.45 mmol) was added and stirred for 10 min. After that, BOP reagent (47.6 mg, 0.11 mmol) was added and stirred at room temperature for 22 h. To the reaction mixture was added DW, extracted with EtOAc, and the organic layer was washed with brine. The organic layer was dried over MgSO4, filtered and concentrated, and the residue was purified by silica gel column chromatography (0 to 1% MeOH / DCM). The resulting residue was developed on preparative TLC (5% MeOH / DCM -> 7% MeOH / DCM) to give compound 9k (6.5 mg, yield: 15%) as a white solid.

[0610] .

[0611] Example 21. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3-(trifluoromethyl)benzyl)pyrimidin-2-amine (9l)

[0612] The synthesis was carried out in the same manner as Example 20, except that (3- (trifluoromethyl)phenyl)methanamine was used instead of (4-(trifluoromethyl)phenyl)methanamine.

[0613] Step 1: 2-((3-(trifluoromethyl)benzyl)amino)pyrimidine-5-carboxylic acid ethyl ester (6l)

[0614] off-white solid (150 mg, yield: 81%);

[0615] .

[0616] ​​Step 2: 2-((3-(trifluoromethyl)benzyl)amino)pyrimidine-5-carbohydrazide (7l)

[0617] White solid (93 mg, yield: 65%); .

[0618] Step 3: 5-(2-((3-(trifluoromethyl)benzyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazol-2(3H)-one (8l)

[0619] White solid (90 mg, yield: 89%); .

[0620] Step 4: 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3-(trifluoromethyl)benzyl)pyrimidin-2-amine (9l)

[0621] Yellow solid (20 mg, yield: 38%);

[0622] .

[0623] Example 22. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(2-(trifluoromethyl)benzyl)pyrimidin-2-amine (9m)

[0624]

[0625] The synthesis was performed in the same manner as in Example 20, except that (2- (trifluoromethyl)phenyl)methanamine was used instead of (4-(trifluoromethyl)phenyl)methanamine.

[0626] Step 1: 2-((2-(trifluoromethyl)benzyl)amino)pyrimidine-5-carboxylate (6m)

[0627] Off-white solid (250 mg, yield: 71%); .

[0628] Step 2: 2-((2-(trifluoromethyl)benzyl)amino)pyrimidine-5-carbohydrazide (7m)

[0629] White solid (194 mg, yield: 81%);

[0630] .

[0631] Step 3: 5-(2-((2-(trifluoromethyl)benzyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazol-2(3H)-one (8m)

[0632] Off-white solid (141 mg, quantitative); .

[0633] Step 4: 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(2-(trifluoromethyl)benzyl)pyrimidin-2-amine (9m)

[0634] Off-white solid (21 mg, yield: 51%);

[0635] .

[0636] Example 23. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-(difluoromethyl)benzyl)pyrimidin-2-amine (9n)

[0637]

[0638] The synthesis was performed in the same manner as in Example 20, except that (4- (difluoromethyl)phenyl)methanamine was used instead of (4-(trifluoromethyl)phenyl)methanamine.

[0639] Step 1: 2-((4-(difluoromethyl)benzyl)amino)pyrimidine-5-carboxylic acid ethyl ester (6n)

[0640] Off-white solid (165 mg, yield: 95%);

[0641] .

[0642] Step 2: 2-((4-(difluoromethyl)benzyl)amino)pyrimidine-5-carbohydrazide (7n)

[0643] Off-white solid (124 mg, yield: 80%);

[0644] .

[0645] Step 3: 5-(2-((4-(difluoromethyl)benzyl)amino)pyrimidin-5-yl)-1,3,4- Diazole-2(3H)-one(8n)

[0646] Grayish-white solid (106 mg, yield: 80%) .

[0647] Step 4: 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (diazol-2-yl)-N-(4-(difluoromethyl)benzyl)pyrimidin-2-amine (9n)

[0648] Grayish-white solid (16.5 mg, yield: 41%).

[0649] .

[0650] Example 24. 4-(((5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (diazol-2-yl)pyrimidin-2-yl)amino)methyl)benzylnitrile (9o)

[0651]

[0652] The synthesis was carried out in the same manner as in Example 20, except that 4-(aminomethyl)benzylnitrile was used instead of (4-(trifluoromethyl)phenyl)methylamine.

[0653] Step 1: Ethyl 2-((4-cyanobenzyl)amino)pyrimidine-5-carboxylate (6o)

[0654] Grayish-white solid (136 mg, yield: 81%) .

[0655] Step 2: 2-((4-cyanobenzyl)amino)pyrimidine-5-carbonylhydrazine (7o)

[0656] Pink solid (92 mg, yield: 71%) .

[0657] Step 3: 4-(((5-(5-oxo-4,5-dihydro-1,3,4- (diazol-2-yl)pyrimidin-2-yl)amino)methyl)benzylnitrile (8o)

[0658] Pink solid (85 mg, yield: 84%) .

[0659] Step 4: 4-(((5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (diazol-2-yl)pyrimidin-2-yl)amino)methyl)benzylnitrile (9o)

[0660] Pink solid (23 mg, yield: 49%)

[0661] .

[0662] Example 25. 3-(((5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (diazol-2-yl)pyrimidin-2-yl)amino)methyl)benzylnitrile (9p)

[0663]

[0664] The synthesis was carried out in the same manner as in Example 20, except that 3-(aminomethyl)benzylnitrile was used instead of (4-(trifluoromethyl)phenyl)methylamine.

[0665] Step 1: 2-((3-cyanobenzyl)amino)pyrimidine-5-carboxylic acid ethyl ester (6p)

[0666] Yellow solid (175 mg, yield: 82%) .

[0667] Step 2: 2-((3-cyanobenzyl)amino)pyrimidine-5-carbonylhydrazide (7p)

[0668] White solid (139 mg, yield: 84%) .

[0669] Step 3: 3-(((5-(5-oxo-4,5-dihydro-1,3,4- (diazol-2-yl)pyrimidin-2-yl)amino)methyl)benzylnitrile (8p)

[0670] Grayish-white solid (136 mg, yield: 89%) .

[0671] Step 4: 3-(((5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (diazol-2-yl)pyrimidin-2-yl)amino)methyl)benzylnitrile (9p)

[0672] Yellow solid (28 mg, yield: 59%);

[0673] .

[0674] Example 26. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-(trifluoromethyl)phenethyl)pyrimidin-2-amine (14f)

[0675]

[0676] The synthesis was performed in the same manner as in Example 20, except that 2-(4- (trifluoromethyl)phenyl)ethan-1 -amine was used instead of (4-(trifluoromethyl)phenyl)methanamine.

[0677] Step 1: Ethyl 2-((4-(trifluoromethyl)phenethyl)amino)pyrimidine-5-carboxylate (11f)

[0678] Light brown solid (245 mg, yield: 77%); .

[0679] Step 2: 2-((4-(trifluoromethyl)phenethyl)amino)hydrazinecarbonylpyrimidine-5- carboxylate (12f)

[0680] White solid (177 mg, yield: 83%); .

[0681] Step 3: 5-(2-((4-(trifluoromethyl)phenethyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazol-2(3H)-one (13f)

[0682] Yellow solid (123 mg, yield: 65%);

[0683] .

[0684] Step 4: 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-(trifluoromethyl)phenethyl)pyrimidin-2-amine (14f)

[0685] White solid (7.5 mg, yield: 18%);

[0686]

[0687] .

[0688] Example 27. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-bromophenethyl)pyrimidin-2-amine (14g)

[0689]

[0690] The synthesis was performed in the same manner as in Example 20, except that 2-(4- bromophenyl)ethan-1 -amine was used instead of (4-(trifluoromethyl)phenyl)methanamine.

[0691] Step 1: Ethyl 2-((4-bromophenethyl)amino)pyrimidine-5-carboxylate (11g)

[0692] off-white solid (150 mg, yield: 86%); .

[0693] Step 2: 2-((4-bromophenethyl)amino)pyrimidine-5-carbohydrazide (12g)

[0694] white solid (97 mg, yield: 67%); .

[0695] Step 3: 5-(2-((4-bromophenethyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazol-2(3H)-one (13g)

[0696] off-white solid (66 mg, yield: 63%); .

[0697] Step 4: 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-bromophenethyl)pyrimidin-2-amine (14g)

[0698] off-white solid (19 mg, yield: 35%);

[0699] .

[0700] Example 28. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)- 1,3,4-oxadiazol-2-yl)-N-(2-chlorophenethyl)pyrimidin-2-amine (14h) Example 28. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)- 1,3,4-oxadiazol-2-yl)-N-(2-chlorophenethyl)pyrimidin-2-amine (14h)

[0701]

[0702] The synthesis was performed in the same manner as in Example 20, except that 2-(2- chlorophenyl)ethan-1 -amine was used instead of (4-(trifluoromethyl)phenyl)methanamine.

[0703] Step 1: 2-((2-chlorophenethyl)amino)pyrimidine-5-carboxylic acid ethyl ester (11h)

[0704] Off-white solid (167 mg, yield: 85%); .

[0705] Step 2: 2-((2-chlorophenethyl)amino)pyrimidine-5-carbohydrazide (12h)

[0706] White solid (126 mg, yield: 79%); .

[0707] Step 3: 5-(2-((2-chlorophenethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (13h) Step 3: 5-(2-((2-chlorophenethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (13h)

[0708] Off-white solid (95 mg, yield: 69%); .

[0709] Step 4: 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(2-chlorophenethyl)pyrimidin-2-amine (14h) Step 4: 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(2-chlorophenethyl)pyrimidin-2-amine (14h)

[0710] Off-white solid (28 mg, yield: 56%);

[0711] .

[0712] Example 29. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine (14i) Example 29. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine (14i)

[0713]

[0714] The synthesis was performed in the same manner as in Example 20, except that 2-(3,5-dichlorophenyl)ethan-1-amine was used instead of (4-(trifluoromethyl)phenyl)methanamine.

[0715] Step 1: Ethyl 2-((3,5-dichlorophenethyl)amino)pyrimidine-5-carboxylate (11i)

[0716] Light brown solid (144 mg, yield: 44%);

[0717] .

[0718] Step 2: 2-((3,5-dichlorophenethyl)amino)hydrazinecarboxamide (12i)

[0719] White solid (120 mg, yield: 86%); .

[0720] Step 3: 5-(2-((3,5-dichlorophenethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (13i)

[0721] White solid (108 mg, yield: 84%);

[0722] .

[0723] Step 4: 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine (14i)

[0724] White solid (7 mg, yield: 17%);

[0725] .

[0726] Example 30. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4-oxadiazol-2-yl)-N-(4-methoxyphenethyl)pyrimidin-2-amine (14j)

[0727]

[0728] ​​​The synthesis was performed in the same manner as in Example 20, except that 2-(4- methoxyphenyl)ethan-1 -amine was used instead of (4-(trifluoromethyl)phenyl)methanamine.

[0729] Step 1 : 2-((4-methoxyphenethyl)amino)pyrimidine-5-carboxylic acid ethyl ester (11j)

[0730] Brown solid (122 mg, yield: 72%);

[0731] .

[0732] Step 2: 2-((4-methoxyphenethyl)amino)pyrimidine-5-carbohydrazide (12j)

[0733] Brown solid (44 mg, yield: 38%);

[0734] .

[0735] Step 3: 5-(2-((4-methoxyphenethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)- one (13j)

[0736] Off-white solid (44 mg, yield: 38%); .

[0737] Step 4: 5-(5-((1 R,5S,6r)-6-(1 H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxazol-2-yl)-N-(4-methoxyphenethyl)pyrimidin-2-amine (14j)

[0738] Off-white solid (13.7 mg, yield: 34%);

[0739] .

[0740] Example 31. 5-(5-((1 R,5S,6r)-6-(1 H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxazol-2-yl)-N-(4-methoxyphenethyl)pyrimidin-2-amine (14j)

[0741] The synthesis was performed in the same manner as in Example 20, except that 2-(4- methoxyphenyl)ethan-1 -amine was used instead of (4-(trifluoromethyl)phenyl)methanamine.

[0742] ​​​

[0743] Step 1: Ethyl 2-((4-methylphenethyl)amino)pyrimidine-5-carboxylate (11k)

[0744] Light brown solid (167 mg, yield: 84%) .

[0745] Step 2: 2-((4-methylphenethyl)amino)pyrimidine-5-carbazide (12kJ)

[0746] White solid (128 mg, yield: 81%) .

[0747] Step 3: 5-(2-((4-methylphenylethyl)amino)pyrimidin-5-yl)-1,3,4- Diazole-2(3H)-one(13k)

[0748] White solid (72 mg, yield: 51%)

[0749] .

[0750] Step 4: 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (diazol-2-yl)-N-(4-methylphenylethyl)pyrimidin-2-amine (14k)

[0751] White solid (12 mg, yield: 32%)

[0752] .

[0753] Example 32. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (30a)-N-(2-(pyridin-2-yl)ethyl)pyrimidin-2-amine

[0754]

[0755] The synthesis was carried out in the same manner as in Example 20, except that 2-(pyridin-2-yl)ethane-1-amine was used instead of (4-(trifluoromethyl)phenyl)methylamine.

[0756] Step 1: Ethyl 2-((2-(pyridin-2-yl)ethyl)amino)pyrimidine-5-carboxylate (27a)

[0757] Light brown solid (160 mg, yield: 73%) .

[0758] Step 2: 2-((2-(pyridin-2-yl)ethyl)amino)pyrimidine-5-carbazide (28a)

[0759] Yellow solid (144 mg, yield: 95%) .

[0760] Step 3: 5-(2-((2-(pyridin-2-yl)ethyl)amino)pyrimidin-5-yl)-1,3,4- Diazole-2(3H)-one (29a)

[0761] White solid (145 mg, yield: 92%)

[0762] .

[0763] Step 4: 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (30a)-N-(2-(pyridin-2-yl)ethyl)pyrimidin-2-amine

[0764] Yellow solid (8.9 mg, yield: 25%).

[0765] .

[0766] Example 33. 4-(2-((5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (Diazol-2-yl)pyrimidin-2-yl)amino)ethyl)benzyl nitrile (14l)

[0767]

[0768] The synthesis was carried out in the same manner as in Example 20, except that 4-(2-aminoethyl)benzylnitrile was used instead of (4-(trifluoromethyl)phenyl)methylamine.

[0769] Step 1: Ethyl 2-((4-cyanophenethyl)amino)pyrimidine-5-carboxylate (11l)

[0770] Brown solid (138 mg, yield: 83%)

[0771] .

[0772] Step 2: 2-((4-cyanophenylethyl)amino)pyrimidine-5-carbazide (12l)

[0773] Grayish-white solid (70 mg, yield: 54%)

[0774] .

[0775] Step 3: 4-(2-((5-(5-oxo-4,5-dihydro-1,3,4- (Diazol-2-yl)pyrimidin-2-yl)amino)ethyl)benzyl nitrile (13l)

[0776] Grayish-white solid (61 mg, yield: 82%) .

[0777] Step 4: 4-(2-((5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (Diazol-2-yl)pyrimidin-2-yl)amino)ethyl)benzyl nitrile (14l)

[0778] White solid (5.6 mg, yield: 14%).

[0779] .

[0780] Example 34. 5-(5-((1R,5S,6R)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (35a)-N-((R)-2,3-dihydro-1H-inden-1-yl)pyrimidin-2-amine

[0781]

[0782] The synthesis was carried out in the same manner as in Example 20, except that (R)-2,3-dihydro-1H-indene-1-amine was used instead of (4-(trifluoromethyl)phenyl)methylamine.

[0783] Step 1: (R)-2-((2,3-dihydro-1H-inden-1-yl)amino)pyrimidine-5-carboxylic acid ethyl ester (32a)

[0784] Brown solid (175 mg, yield: 82%) .

[0785] Step 2: (R)-2-((2,3-dihydro-1H-inden-1-yl)amino)pyrimidine-5-carbazide (33a)

[0786] Grayish-white solid (105 mg, yield: 63%) .

[0787] Step 3: (R)-5-(2-((2,3-dihydro-1H-inden-1-yl)amino)pyrimidin-5-yl)-1,3,4- Diazole-2(3H)-one (34a)

[0788] Grayish-white solid (40 mg, yield: 35%); .

[0789] Step 4: 5-(5-((1R,5S,6R)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (35a)-N-((R)-2,3-dihydro-1H-inden-1-yl)pyrimidin-2-amine

[0790] Yellow solid (26 mg, yield: 55%)

[0791]

[0792] .

[0793] Example 35. 5-(5-((1R,5S,6S)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (35b)-N-((S)-2,3-dihydro-1H-inden-1-yl)pyrimidin-2-amine

[0794]

[0795] The synthesis was carried out in the same manner as in Example 20, except that (S)-2,3-dihydro-1H-indene-1-amine was used instead of (4-(trifluoromethyl)phenyl)methylamine.

[0796] Step 1: (S)-2-((2,3-dihydro-1H-inden-1-yl)amino)pyrimidine-5-carboxylic acid ethyl ester (32b)

[0797] Brown solid (151 mg, yield: 71%) .

[0798] Step 2: (S)-2-((2,3-dihydro-1H-inden-1-yl)amino)pyrimidine-5-carbazide (33b)

[0799] White solid (122 mg, yield: 85%); .

[0800] Step 3: (S)-5-(2-((2,3-dihydro-lH-inden-l-yl)amino)pyrimidin-5-yl)-l,3,4- oxadiazol-2(3H)-one (34b)

[0801] Off-white solid (104 mg, yield: 78%); .

[0802] Step 4: 5-(5-((lR,5S,6S)-6-(lH-l,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-l,3,4- oxadiazol-2-yl)-N-((S)-2,3-dihydro-lH-inden-l-yl)pyrimidin-2-amine (35b)

[0803] Yellow solid (30 mg, yield: 63%);

[0804] .

[0805] Example 36. 5-(5-((lR,5S,6r)-6-(lH-l,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-l,3,4- oxadiazol-2-yl)-N-phenylpyrimidin-2-amine (30b)

[0806]

[0807] The synthesis was performed in the same manner as in Example 20, except that aniline was used instead of (4-(trifluoromethyl)phenyl)methanamine.

[0808] Step 1: 2-(phenylamino)pyrimidine-5-carboxylic acid ethyl ester (27b)

[0809] Yellow solid (79 mg, yield: 61%); .

[0810] Step 2: 2-(phenylamino)pyrimidine-5-carbohydrazide (28b)

[0811] White solid (112 mg, yield: 77%); .

[0812] Step 3: 5-(2-(phenylamino)pyrimidin-5-yl)-l,3,4- oxadiazol-2(3H)-one (29b)

[0813] Yellow solid (56 mg, yield: 56%); .

[0814] Step 4: 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-phenylpyrimidin-2-amine (30b) Step 4: 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-phenylpyrimidin-2-amine (30b)

[0815] Yellow solid (56 mg, yield: 56%);

[0816] .

[0817] Example 37. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-chlorophenethyl)-N-methylpyrimidin-2-amine (39) Example 37. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-chlorophenethyl)-N-methylpyrimidin-2-amine (39)

[0818]

[0819] Step 1: 2-((4-chlorophenethyl)(methyl)amino)pyrimidine-5-carboxylic acid ethyl ester (36)

[0820] Compound 11e (0.3 g, 0.981 mmol) was dissolved in DMF (9.8 mL) and NaH (60% dispersion in mineral oil) (59 mg, 1.47 mmol) was added at 0 °C and stirred for 30 min. After that, iodomethane (92 μL, 1.47 mmol) was added at the same temperature and stirred for 6 h at room temperature. Distilled water was added to the reaction mixture, extracted with EtOAc, dried over Na2S04, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (10% to 15% EtOAc in Hex) to obtain compound 36 as a white solid (0.275 g, yield: 87.6%).

[0821] .

[0822] Synthesis of steps 2 to 4 of example 37 was carried out in the same way as steps 2 to 4 of example 20.

[0823] Step 2: 2-((4-chlorophenethyl)(methyl)amino)pyrimidine-5-carboxylic acid hydrazide (37)

[0824] White solid (241 mg, yield: 92.3%); ​

[0825] .

[0826] Step 3: 5-(2-((4-chlorophenethyl)(methyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazol-2(3H)-one (38)

[0827] White solid (250 mg, yield: 95.6%);

[0828] .

[0829] Step 4: 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-chlorophenethyl)-N-methylpyrimidin-2-amine (39)

[0830] White solid (10 mg, yield: 23.8%);

[0831] .

[0832] Example 38. 1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-(5-((2,3- dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)butan-1-one (44b)

[0833]

[0834] Step 1: 2-isothiocyanato-2,3-dihydro-1H-indene (40)

[0835] To DCM (20 mL) was added 2,3-dihydro-1H-inden-2-amine (478 mg, 3.58 mmol) and DIEA (1.83 mL, 10.7 mmol) and maintained at 0 °C under nitrogen atmosphere. O,O'-Di-2-pyridyl thiocarbonate (1.0 g, 4.3 mmol) dissolved in DCM (5 mL) was added dropwise for 5 min and the reaction temperature was raised to room temperature and reacted for 12 h. Distilled water was added to the reaction solution, extracted with DCM and the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (100% n-hexane) to obtain compound 40 as a white solid (560 mg, yield: 89%).

[0836] . ​​

[0837] Step 2: N-(2,3-dihydro-lH-inden-2-yl)hydrazinecarbothioamide (41)

[0838] Compound 40 (560 mg, 3.19 mmol) was dissolved in EtOH (20 mL) and hydrazine monohydrate (776 uL, 16 mmol) was added and stirred at room temperature for 12 hours. After removing all solvents, distilled water was added and the mixture was extracted with EtOAc. The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. The resulting residue was recrystallized from (EtOAc / n-hexane) to obtain compound 41 (580 mg, yield: 87%) as a white solid.

[0839] .

[0840] Step 3: Ethyl 4-(5-((2,3-dihydro-lH-inden-2-yl)amino)-l,3,4-thiadiazol-2-yl)butanoate (42b)

[0841] Compound 41 (150 mg, 0.75 mmol) and ethyl 4-cyanobutanoate (106 mg, 0.75 mmol) were added to TFA (4.5 mL) and stirred at 80 °C for 12 hours. After removing all solvents from the reaction mixture, saturated aqueous sodium bicarbonate solution was added to neutralize and extracted with DCM. The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0 to 2% MeOH in DCM) to obtain compound 42b (120 mg, yield: 50%) as a white solid.

[0842] .

[0843] Step 4: 4-(5-((2,3-dihydro-lH-inden-2-yl)amino)-l,3,4-thiadiazol-2-yl)butanoic acid (43b)

[0844] A solution of LiOH (21.7 mg, 0.91 mmol) dissolved in H20 (390 uL) was added to a mixture of compound 42b (60 mg, 0.19 mmol) dissolved in THF / MeOH (3.5 mL / 390 uL) and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, all solvents were removed and pH was adjusted to 3 at 0 °C using 1 N HC1. The resulting solid was filtered to obtain compound 43b (30 mg, yield: 55%) as a yellow solid.

[0845] .

[0846] Step 5: l-((lR,5S,6r)-6-(lH-l,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-(5-((2,3- dihydro-lH-inden-2-yl)amino)-l,3,4-thiadiazol-2-yl)butan-l-one (44b)

[0847] A reaction mixture of compound 43b (30 mg, 0.10 mmol), compound 4 (27.7 mg, 0.15 mmol), HATU (47 mg, 0.12 mmol), DIEA (60 uL, 0.35 mmol) and DCM (1.5 mL) was stirred at room temperature for 12 h. Distilled water was added to the reaction solution and the mixture was extracted with DCM. The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0 to 25% MeOH in CH2CI2) to afford compound 44b (24 mg, yield: 56%) as a white solid.

[0848] .

[0849] Example 39. l-((lR,5S,6r)-6-(lH-l,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-(5-((2,3- dihydro-lH-inden-2-yl)amino)-l,3,4-thiadiazol-2-yl)propan-l-one (44a)

[0850]

[0851] The synthesis was carried out in the same manner as steps 3 to 5 of Example 38, except that 3-cyanopropionic acid ethyl ester was used instead of 4-cyanobutyric acid ethyl ester.

[0852] Step 1: 3-(5-((2,3-dihydro-lH-inden-2-yl)amino)-l,3,4-thiadiazol-2-yl)propanoic acid ethyl ester (42a)

[0853] White solid (110 mg, yield: 46%);

[0854] .

[0855] Step 2: 3-(5-((2,3-dihydro-lH-inden-2-yl)amino)-l,3,4-thiadiazol-2-yl)propanoic acid (43a)

[0856] White solid (38 mg, yield: 69%);

[0857] .

[0858] Step 3: 1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)propan-1-one (44a)

[0859] White solid (30 mg, yield: 59%);

[0860] .

[0861] Example 40. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- thiadiazol-2-yl)-N-(4-chlorophenethyl)-4-methylpyrimidin-2-amine (30c)

[0862]

[0863] The synthesis was carried out in the same manner as in Example 20, except that 2-(4-chlorophenyl)ethan-1-amine was used instead of (4-(trifluoromethyl)phenyl)methanamine and 2-fluoro-4-methylpyrimidine-5-carboxylic acid ethyl ester was used instead of 2-chloropyrimidine-5-carboxylic acid ethyl ester.

[0864] Step 1: 2-((4-chlorophenethyl)amino)-4-methylpyrimidine-5-carboxylic acid ethyl ester (27c)

[0865] Yellow solid (268 mg, yield: 86.9%);

[0866] .

[0867] Step 2: 2-((4-chlorophenethyl)amino)-4-methylpyrimidine-5-carbohydrazide (28c)

[0868] White solid (214 mg, yield: 83%);

[0869] .

[0870] Step 3: 5-(2-((4-chlorophenethyl)amino)-4-methylpyrimidin-5-yl)-1,3,4- thiadiazol-2(3H)-one (29c)

[0871] Off-white solid (41.4 mg, yield: 38%); .

[0872] Step 4: 5-(5-((lR,5S,6r)-6-(lH-l,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-l,3,4- oxadiazol-2-yl)-N-(4-chlorophenethyl)-4-methylpyrimidin-2-amine (30c)

[0873] Off-white solid (20.1 mg, yield: 48.5%);

[0874]

[0875] .

[0876] Example 41. 5-(5-((lR,5S,6r)-6-(lH-l,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-l,3,4- oxadiazol-2-yl)-N-(4-chlorophenethyl)pyridin-2-amine (30d)

[0877]

[0878] The synthesis was performed in the same manner as in Example 20, except that 2-(4- chlorophenyl)ethan-l -amine was used instead of (4-(trifluoromethyl)phenyl)methanamine and 6-chloronicotinic acid ethyl ester was used instead of 2-chloropyrimidine-5-carboxylic acid ethyl ester.

[0879] Step 1: 6-((4-chlorophenethyl)amino)nicotinic acid ethyl ester (27d)

[0880] Off-white solid (130 mg, yield: 27.6%); .

[0881] Step 2: 6-((4-chlorophenethyl)amino)nicotinohydrazide (28d)

[0882] Yellow solid (60.5 mg, yield: 49%); .

[0883] Step 3: 5-(6-((4-chlorophenethyl)amino)pyridin-3-yl)-l,3,4- oxadiazol-2(3H)-one (29d)

[0884] Yellow solid (80.5 mg, quantitative); .

[0885] Step 4: 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)- 1,3,4-oxadiazol-2-yl)-N-(4-chlorophenethyl)pyridin-2-amine (30d) Step 4: 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)- 1,3,4-oxadiazol-2-yl)-N-(4-chlorophenethyl)pyridin-2-amine (30d)

[0886] Off-white solid (24.5 mg, yield: 61%);

[0887] .

[0888] Example 42. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)- 1,3,4-oxadiazol-2-yl)-N-(4-chlorophenethyl)pyridin-2-amine (30d) Step 4: 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)- 1,3,4-oxadiazol-2-yl)-N-(4-chlorophenethyl)pyridin-2-amine (30d)

[0889]

[0890] The synthesis was performed in the same manner as in Example 20, except that 2-(4- chlorophenyl)ethan-1 -amine was used instead of (4-(trifluoromethyl)phenyl)methanamine and 5-chloropyrazine-2-carboxylic acid ethyl ester was used instead of 2-chloropyrimidine-5- carboxylic acid ethyl ester.

[0891] Step 1 : 5-((4-chlorophenethyl)amino)pyrazine-2-carboxylic acid ethyl ester (27e)

[0892] Brown solid (321 mg, yield: 68%); .

[0893] Step 2: 5-((4-chlorophenethyl)amino)pyrazine-2-carbohydrazide (28e)

[0894] White solid (224 mg, yield: 73%); .

[0895] Step 3: 5-(5-((4-chlorophenethyl)amino)pyrazin-2-yl)-1,3,4- oxadiazol-2(3H)-one (29e)

[0896] Off-white solid (151 mg, yield: 62%);

[0897] .

[0898] Step 4: 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)- 1,3,4-oxadiazol-2-yl)-N-(4-chlorophenethyl)pyridin-2-amine (30d) Oxazol-2-yl)-N-(4-chlorophenethyl)pyrazine-2-amine (30e)

[0899] Off-white solid (24.6 mg, yield: 61%);

[0900] .

[0901] Example 43. 1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-(2-((4- chlorophenethyl)amino)pyrimidin-5-yl)propan-1-one (49a)

[0902]

[0903] Step 1: 3-(2-chloropyrimidin-5-yl)propanoic acid ethyl ester (46a)

[0904] Compound 21 (45a) (424 mg, 2.0 mmol) was dissolved in EtOAc (20 mL), Pd / C (300 mg) was added, and the mixture was reacted under a hydrogen gas atmosphere for 12 hours. After the completion of the reaction, the mixture was filtered through a celite pad, and the filtrate was concentrated to obtain compound 46a (412 mg, yield: 96%) as a white liquid.

[0905] .

[0906] Step 2: 3-(2-((4-chlorophenethyl)amino)pyrimidin-5-yl)propanoic acid ethyl ester (47a)

[0907] A mixture of 2-(4-chlorophenyl)ethan-1-amine (348 mg, 2.23 mmol), compound 46a (400 mg, 1.86 mmol), DIEA (1.58 mL, 9.9 mmol), and n-butanol (2.5 mL) was reacted at 150°C for 2 hours using a microwave reactor. After the completion of the reaction, all the solvent was removed, distilled water was added, and extraction was performed with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0 to 5% MeOH in CH2Cl2) to obtain compound 47a (68 mg, yield: 9%) as a white solid.

[0908] .

[0909] Step 3: 3-(2-((4-chlorophenethyl)amino)pyrimidin-5-yl)propanoic acid (48a)

[0910] A solution of LiOH (23.3 mg, 0.97 mmol) dissolved in H2O (387 uL) was added to a mixture of compound 47a (65 mg, 0.19 mmol) dissolved in THF / MeOH (3.4 mL / 387 uL) and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, all the solvents were removed and pH was adjusted to 3 using 1 N HCI at 0 °C. The resulting solid was filtered to obtain compound 48a (33 mg, 59%) as a white solid.

[0911] .

[0912] Step 4: l-((lR,5S,6r)-6-(lH-l,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-(2-((4- chlorobenzyl)amino)pyrimidin-5-yl)propan-l-one (49a)

[0913] A reaction mixture of compound 48a (30 mg, 0.10 mmol), compound 4 (27.5 mg, 0.15 mmol), HATU (47 mg, 0.12 mmol), DIEA (60 uL, 0.35 mmol) and DCM (1.0 mL) was stirred at room temperature for 12 hours. Distilled water was added to the reaction solution and extracted with DCM. The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0 to 5% MeOH in CH2CI2) to obtain compound 49a (40 mg, yield: 93%) as a white solid.

[0914] .

[0915] Example 44. l-((lR,5S,6r)-6-(lH-l,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-(2-((3,5- dichlorobenzyl)amino)pyrimidin-5-yl)butan-l-one (49b)

[0916]

[0917] Step 1: (E)-4-(2-chloropyrimidin-5-yl)but-3-enoic acid ethyl ester (45b)

[0918] A reaction mixture of 5-bromo-2-chloropyrimidine (400 mg, 2.1 mmol), ethyl but-3-enoate (958 mg, 8.4 mmol), Pd(OAc)2(19 mg, 0.084 mmol), tri(o- tolyl)phosphine (64 mg, 0.21 mmol), DIEA (2 mL) and DMF (5 mL) was reacted at 150 °C for 4 h. After all the solvent was removed, distilled water was added and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (20% to 30% EtOAc in n-hexane) to obtain compound 45b (40 mg, 8%) as a yellow solid.

[0919] .

[0920] Step 2: Ethyl 4-(2-chloropyrimidin-5-yl)butanoate (46b)

[0921] Synthesized in the same manner as Step 1 of Example 43.

[0922] Yellow liquid (30 mg, yield: 74%);

[0923] .

[0924] Step 3: Ethyl 4-(2-((3,5-dichlorobenzyl)amino)pyrimidin-5-yl)butanoate (47b)

[0925] Synthesized in the same manner as Step 2 of Example 43, except that (3,5- dichlorophenyl)methanamine was used instead of 2-(4-chlorophenyl)ethan-1-amine.

[0926] Yellow liquid (15 mg, yield: 31%);

[0927] .

[0928] Step 4: 4-(2-((3,5-dichlorobenzyl)amino)pyrimidin-5-yl)butanoic acid (48b)

[0929] Synthesized in the same manner as Step 3 of Example 43.

[0930] White solid (7 mg, yield: 51%);

[0931] .

[0932] Step 5: 1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-(2-((3,5-dichlorobenzyl)amino)pyrimidin-5-yl)butan-1-one (49b)

[0933] The synthesis was carried out in the same manner as in Step 4 of Example 43.

[0934] White solid (6 mg, yield: 63%);

[0935] .

[0936] Example 45. (E)-1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-(2-((4-chlorophenethyl)amino)pyrimidin-5-yl)prop-2-en-1-one (52a)

[0937]

[0938] Step 1: (E)-ethyl 3-(2-((4-chlorophenethyl)amino)pyrimidin-5-yl)acrylate (50a)

[0939] A reaction mixture of 2-(4-chlorophenyl)ethan-1-amine (439 mg, 2.82 mmol), compound 21 (500 mg, 2.35 mmol), DIEA (2.0 mL, 12.5 mmol) and n-butanol (2.5 mL) was reacted in a microwave reactor at 150°C for 2 hours. After completion of the reaction, the solvent was completely removed, distilled water was added, and the resulting solid was filtered to obtain compound 50a as a brown solid (500 mg, yield: 53%).

[0940] .

[0941] Step 2: (E)-3-(2-((4-chlorophenethyl)amino)pyrimidin-5-yl)acrylic acid (51a)

[0942] The synthesis was carried out in the same manner as in Step 3 of Example 43.

[0943] White solid (120 mg, yield: 88%);

[0944] .

[0945] Step 3: (E)-1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-(2-((4- chlorophenethyl)amino)pyrimidin-5-yl)prop-2-en-1-one (52a)

[0946] The synthesis was carried out in the same manner as in Step 4 of Example 43.

[0947] White solid (17 mg, yield: 32%);

[0948] .

[0949] Example 46. (E)-1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-(2-((2,3- dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)prop-2-en-1-one (52b)

[0950]

[0951] Step 1: (E)-ethyl 3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylate (50b)

[0952] The synthesis was carried out in the same manner as in Step 1 of Example 45, except that 2,3-dihydro-1H-inden-2-amine was used instead of 2-(4-chlorophenyl)ethan-1-amine.

[0953] Brown solid (260 mg, yield: 84%);

[0954] .

[0955] Step 2: (E)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylic acid (51b)

[0956] The synthesis was carried out in the same manner as in Step 3 of Example 43.

[0957] White solid (120 mg, yield: 89%);

[0958] .

[0959] Step 3: (E)-1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)prop-2-en-1-one (52b)

[0960] The synthesis was carried out in the same manner as step 4 of Example 43.

[0961] Yellow solid (18 mg, yield: 36%)

[0962] .

[0963] Example 47. N-(4-chlorophenylethyl)-5-(5-((1R,5S,6r)-6-(1-methyl-1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (diazol-2-yl)pyrimidin-2-amine (55)

[0964]

[0965] Step 1: (1R,5S,6r)-6-(1-methyl-1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (53)

[0966] Compound 3 (0.150 g, 0.599 mmol) was dissolved in DMF (6.0 mL), and NaH (60%, dispersed in mineral oil) (28.8 mg, 0.719 mmol) was added at 0 °C and stirred for 30 min. Then, methyl iodide (CH3I) (37 μL, 0.599 mmol) was added at the same temperature, and the mixture was stirred at room temperature for 15 h. Distilled water was added to the reaction mixture, which was extracted with EtOAc and washed several times with brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (0–1% MeOH in DCM) to obtain compound 53 (52 mg, 32.8%) as a yellow oil.

[0967] .

[0968] Step 2: (1R,5S,6r)-6-(1-methyl-1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (54)

[0969] A mixture of compound 53 (50 mg, 0.189 mmol) dissolved in 1,4-dioxane (0.7 mL) was slowly added with 4 M HCl (0.47 mL, 1.89 mmol in dioxane) and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain compound 54 (30 mg, 79.0%) as a white solid, which was used in the next reaction without further purification.

[0970] .

[0971] Step 3: N-(4-chlorophenylethyl)-5-(5-((1R,5S,6r)-6-(1-methyl-1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (diazol-2-yl)pyrimidin-2-amine (55)

[0972] A mixture of compound 13e (38 mg, 0.120 mmol) and compound 54 (28.8 mg, 0.144 mmol) dissolved in DMF (0.6 mL) was cooled to 0 °C, DIEA (61 μL, 0.359 mmol) was added, and the mixture was stirred for 30 min. BOP reagent (63.9 mg, 0.144 mmol) was added at the same temperature, and the mixture was stirred at room temperature for 15 h. Distilled water was added to the reaction mixture, which was extracted with EtOAc and washed several times with brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (0–1% MeOH in DCM) to obtain compound 55 (26 mg, 46.9%) as a white solid.

[0973] .

[0974] Example 48. N-(4-chlorophenylethyl)-5-(5-((1R,5S,6r)-6-(4-methyl-1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4- (diazol-2-yl)pyrimidin-2-amine (59)

[0975]

[0976] Step 1: (1R,5S,6s)-6-(prop-1-yn-1-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (56)

[0977] Compound 2 (400 mg, 1.93 mmol) was dissolved in THF (6 mL) and the mixture was maintained at -78°C under nitrogen atmosphere. 2.5 M n-BuLi (0.77 mL, 1.93 mmol) was added dropwise over 10 minutes and then stirred for 30 minutes. The reaction temperature was raised to room temperature and CH3I (181 uL, 2.9 mmol) was added and the reaction was allowed to proceed for 12 hours. Distilled water was added to the reaction mixture and then extracted with EtOAc. The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (10% EtOAc in n-hexane) to obtain compound 56 (390 mg, yield: 91%) as a white solid.

[0978] .

[0979] Step 2: (1R,5S,6r)-6-(4-methyl-1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3- carboxylic acid tert-butyl ester (57)

[0980] A mixture of compound 56 (200 mg, 0.9 mmol) and TMSN3 (180 uL, 1.39 mmol) was reacted in a microwave reactor at 200 °C for 7 hours. After concentration of the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (0 to 5% MeOH in DCM) to obtain compound 57 (32 mg, 13%) as a yellow solid.

[0981] .

[0982] Step 3: (1R,5S,6r)-6-(4-methyl-1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (58)

[0983] To a reaction mixture of compound 57 (30 mg, 0.11 mmol) dissolved in 1,4- dioxane (1 mL) was added 4 M HC1 in dioxane (282 uL, 1.1 mmol). After 3 hours of reaction at room temperature, the solvent was concentrated to obtain compound 58 (20 mg, yield: 91%) as a brown solid which was used in the next reaction without further purification.

[0984] .

[0985] Step 4: N-(4-chlorophenethyl)-5-(5-((1R,5S,6r)-6-(4-methyl-1H-1,2,3-triazol-5-yl)-3- azabicyclo[3.1.0]hexan-3-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (59) Step 4: N-(4-chlorophenethyl)-5-(5-((1R,5S,6r)-6-(4-methyl-1H-1,2,3-triazol-5-yl)-3- azabicyclo[3.1.0]hexan-3-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (59)

[0986] Compound 58 (20 mg, 0.1 mmol) was added to a reaction mixture in which compound 13e (25 mg, 0.08 mmol) was dissolved in DMF (1.5 mL) and cooled to 0 °C. BOP reagent (44 mg, 0.1 mmol) and DIPEA (87 μL, 0.5 mmol) were added and the mixture was stirred at room temperature for 5 hours. Distilled water was added to the reaction mixture, extracted with EtOAc and the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0 to 5% MeOH in DCM) to obtain compound 59 (13 mg, yield: 35%) as a yellow solid.

[0987] .

[0988] Example 49. 5-(3-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-4,5- dihydroisoxazol-5-yl)-N-(4-chlorophenethyl)pyrimidin-2-amine (63a) Step 4: N-(4-chlorophenethyl)-5-(5-((1R,5S,6r)-6-(4-methyl-1H-1,2,3-triazol-5-yl)-3- azabicyclo[3.1.0]hexan-3-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (59)

[0989]

[0990] Step 1: N-(4-chlorophenethyl)-5-vinylpyrimidin-2-amine (61a)

[0991] A reaction mixture of 2-(4-chlorophenyl)ethan-1 -amine (0.3 g, 1.93 mmol), 2-chloro-5-vinylpyrimidine (0.542 g, 3.86 mmol), DIPEA (6.6 mL, 38.6 mmol) and n-butanol (3.9 mL) was reacted in a microwave reactor at 150 °C for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (10% to 30% EA in Hex) to obtain compound 61a (0.315 g, 62.9%) as a white solid.

[0992] .

[0993] Step 2: 5-(3-bromo-4,5-dihydroisoxazol-5-yl)-N-(4-chlorophenethyl)pyrimidin-2-amine (62a) 5-(3-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-4,5- dihydroisoxazol-5-yl)-N-(4-chlorophenethyl)pyrimidin-2-amine (63a)

[0994] Compound 61a (0.31 g, 1.18 mmol) was dissolved in DMF (3.0 mL), cooled to -10 °C, and 1,1-dibromoformoxime (0.484 g, 2.39 mmol) was added. A solution of KHCO3(0.299 g, 2.98 mmol) in H2O (3.0 mL) was slowly added to the reaction mixture and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, distilled water was added, extracted with EtOAc, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (0 to 1% MeOH in DCM) to give compound 62a (0.41 g, 90.0%) as a yellow solid.

[0995] .

[0996] Step 3: 5-(3-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-4,5- dihydroisoxazol-5-yl)-N-(4-chlorophenethyl)pyrimidin-2-amine (63a) 5-(3-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-4,5- dihydroisoxazol-5-yl)-N-(4-chlorophenethyl)pyrimidin-2-amine (63a)

[0997] A reaction mixture of compound 62a (80 mg, 0.210 mmol), compound 4 (47.0 mg, 0.252 mmol), DIEA (356 μL, 2.10 mmol), and tert-butanol (4.2 mL) was reacted in a microwave reactor at 200 °C for 3 hours. The reaction mixture was filtered and concentrated, and the resulting residue was purified by silica gel column chromatography (0 to 1% MeOH in DCM) to obtain compound 63a (9.9 mg, 10.5%) as a yellow solid.

[0998] .

[0999] Example 50. 5-(3-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-4,5- dihydroisoxazol-5-yl)-N-(4-chlorophenethyl)pyrimidin-2-amine (63a) 5-(3-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-4,5- dihydroisoxazol-5-yl)-N-(4-chlorophenethyl)pyrimidin-2-amine (63a)

[1000]

[1001] The synthesis was carried out in the same manner as in Example 49, except that 2,3-dihydro-1H-indene-2-amine was used instead of 2-(4-chlorophenyl)ethane-1-amine.

[1002] Step 1: N-(2,3-dihydro-1H-inden-2-yl)-5-vinylpyrimidin-2-amine (61b)

[1003] Yellow solid (281 mg, yield: 78.9%).

[1004] .

[1005] Step 2: 5-(3-bromo-4,5-dihydroisocyanate) (62b)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[1006] White solid (249 mg, yield: 59%)

[1007] .

[1008] Step 3: 5-(3-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-4,5-dihydroisocyanuric acid (63b)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[1009] Yellow solid (4.3 mg, yield: 24%).

[1010] .

[1011] Example 51. 2-((1R,5S,6S)-3-(5-(2-((4-chlorophenylethyl)amino)pyrimidin-5-yl)-1,3,4- (diazol-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl)acetic acid (68)

[1012]

[1013] Step 1: (1R,5S,6s)-6-(2-methoxy-2-oxoethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (65)

[1014] Step 1: 2-((1R,5S,6s)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid (63)

[1015] .

[1016] Step 2: Methyl 2-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)acetate hydrochloride (64)

[1017] Compound 65 (95 mg, 0.372 mmol) was dissolved in 1,4-dioxane (1.4 mL), 4 M HC1 (in dioxane, 0.93 mL, 37.2 mmol) was added slowly, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain compound 66 (71 mg, quantitative) as a yellow solid, which was used in the next reaction without further purification.

[1018] .

[1019] Step 3: Methyl 2-((1R,5S,6s)-3-(5-(2-((4-chlorophenethyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazol-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (67)

[1020] Compound 13e (80 mg, 0.252 mmol) and compound 66 (57.9 mg, 0.302 mmol) were dissolved in DMF (1.3 mL). The reaction mixture was cooled to 0 °C, DIEA (128 μL, 0.756 mmol) was added and stirred for 30 minutes. BOP reagent (134 mg, 0.302 mmol) was added at the same temperature, and the mixture was stirred at room temperature for 15 hours. Distilled water was added to the reaction mixture, extracted with EtOAc, and washed with brine several times. The organic layer was dried over Na2S04, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (0 to 1% MeOH in DCM) to obtain compound 67 (80 mg, yield: 69.8%) as a yellow solid.​

[1021] .

[1022] Step 4: 2-((lR,5S,6s)-3-(5-(2-((4-chlorophenethyl)amino)pyrimidin-5-yl)-l,3,4- oxadiazol-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid (68)

[1023] Compound 67 (40 mg, 0.088 mmol) was dissolved in THF (0.44 mL), 1 N NaOH (220 μL, 0.220 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated, EtOAc was added, and the mixture was stirred for 1 hour. The resulting solid was filtered to obtain compound 68 (30 mg, 77.4%) as a yellow solid.

[1024] .

[1025] Test Example 1. Evaluation of inhibitory activity against human autotaxin protein

[1026] (1) Experimental method

[1027] A solution of each synthesized compound (80 uM, 100% dimethyl sulfoxide) was sequentially diluted 5-fold with dimethyl sulfoxide to make 6 concentrations. Each concentration of compound was diluted 2-fold with 1 x assay buffer (50 mM Tris-Cl (pH 8.0), 5 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 140 mM NaCl, deionized water, 1 mg / mL BSA), and 1 uL (1.25% dimethyl sulfoxide) of the diluted mixture was dispensed into each well of a 96-well clear-bottomed plate. 9 uL of 1 x assay buffer was added, and 20 uL of 240 nM human autotaxin protein (buffer: 50 mM Tris-HCl, pH 8.0, with 150 mM sodium chloride and 20% glycerol) was added. 10 uL of sonicated 360 uM 18: 1 LysoPC (diluted with 1 x assay buffer) was added. The reaction was performed at 37°C in a shaking incubator for 2 hours, and a secondary reaction mixture (Choline Assay Kit, KA1662) (65 uL of 1 x assay buffer: 1 uL choline oxidase: 1 uL dye probe) was prepared. 60 uL of the secondary reaction mixture was added to the reaction-performed plate, and incubated on a shaker for 30 minutes. The absorbance value was measured at a wavelength of 570 nm using a SpectraMax iD3 microplate reader. The inhibitory activity was evaluated by the formula: (1 - absorbance value of each well) x 100 测试组Absorbance values 对照组 The percent inhibition activity value (%) was calculated as follows: (1 - absorbance value of the test compound) x 100.

[1028] (2) Results

[1029] The activity inhibition rates as measured above are shown in Table 1 below.

[1030] [Table 1]

[1031]

[1032]

[1033]

[1034] All of the synthesized compounds of Examples 1 to 51 exhibited excellent inhibitory activity against human autocrine motility factor protein.

[1035] The foregoing description of the application is merely meant to be illustrative of the present application and various changes or modifications can be made to the application disclosed herein without departing from the spirit or essential characteristics of the present application. It will be apparent to those skilled in the art that various changes or modifications can be made to the application disclosed herein without departing from the spirit or essential characteristics thereof. Therefore, it is to be understood that the foregoing embodiments are merely meant to be illustrative of the present application and are not intended to limit the scope of the present application in any way. For example, components described in a single form can also be implemented in a distributed manner, and similarly, components described as distributed can also be implemented in a combined form.

[1036] The scope of the present application is indicated by the appended patent claims. The meaning and scope of the patent claims along with all modifications or variations derived therefrom are considered to fall within the scope of the present application.

Claims

1. An azabicyclic derivative compound represented by the following Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof: wherein: <Formula 1> X is C 5-7 aryl; 5- or 6-membered heteroaryl having 1 to 3 N; or a fused bicyclic ring, wherein C 5-7 aryl ring is fused with a 5- or 6-membered cycloalkyl ring having 0 to 3 O, wherein X is optionally substituted with one or more independent R x substituted, wherein R x is C 1-4 alkyl, C 1-4 alkoxy, cyano, halogen or C 1-4 haloalkyl, p is an integer of 0 to 3, R N is hydrogen or C 1-4 alkyl, A is a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms selected from N and S, wherein A is optionally substituted with one or more independent R A substituted, wherein R A is C 1-4 alkyl, L is -(CH2) m C(O)-, -CHCHC(O)-, or a 5- or 6-membered aromatic or nonaromatic heterocycle having 1 to 4 heteroatoms selected from N and O, wherein m is an integer from 1 to 5, and B is -(CH2) n C(O)OH, or 5- or 6-membered heteroaryl having 1 to 4 N, wherein n is an integer from 1 to 3, wherein B is optionally substituted with one or more independent R B substituted, wherein R B is C 1-4 alkyl.

2. The compound of claim 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein X is phenyl, pyridyl, dihydroindenyl, or benzodioxolyl.

3. The compound of claim 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R x is methyl, methoxy, cyano, fluoro, chloro, bromo, difluoromethyl, and trifluoromethyl.

4. The compound of claim 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

5. The compound of claim 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R N is hydrogen or methyl.

6. The compound of claim 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein A is pyridyl, pyrimidyl, pyrazinyl, and thiadiazolyl.

7. The compound of claim 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R A is methyl.

8. The compound of claim 1, its hydrate, its solvate, or its pharmaceutically acceptable salt, wherein L is -(CH2)2C(O)-, -(CH2)3C(O)-, -CHCHC(O)-, or dihydroisocyanate. azole or Diazole group.

9. The compound of claim 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein B is -CH2C(O)OH or triazolyl.

10. The compound of claim 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R B is methyl.

11. The compound of claim 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by Formula 1 is any one selected from the following: [1] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-benzylpyrimidin-2-amine, [2] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3-chlorobenzyl)pyrimidin-2-amine, [3] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-chlorobenzyl)pyrimidin-2-amine, [4] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,4-difluorobenzyl)pyrimidin-2-amine, [5] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-difluorobenzyl)pyrimidin-2-amine, [6] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,4-dichlorobenzyl)pyrimidin-2-amine, [7] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-dichlorobenzyl)pyrimidin-2-amine, [8] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-dibromobenzyl)pyrimidin-2-amine, [9] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidin-2-amine, [10] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-bis(trifluoromethyl)benzyl)pyrimidin-2-amine, [11] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-phenethylpyrimidin-2-amine, [12] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3-fluorophenethyl)pyrimidin-2-amine, [13] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-fluorophenethyl)pyrimidin-2-amine, [14] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3-chlorophenethyl)pyrimidin-2-amine, [15] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-chlorophenethyl)pyrimidin-2-amine, [16] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [17] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [18] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [19] 1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propan-1-one, [20] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-(trifluoromethyl)benzyl)pyrimidin-2-amine, [21] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3-(trifluoromethyl)benzyl)pyrimidin-2-amine, [22] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(2-(trifluoromethyl)benzyl)pyrimidin-2-amine, [23] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-(difluoromethyl)benzyl)pyrimidin-2-amine, [24] 4-(((5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-yl)amino)methyl)benzonitrile, [25] 3-(((5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-yl)amino)methyl)benzonitrile, [26] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-(trifluoromethyl)phenethyl)pyrimidin-2-amine, [27] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-bromophenethyl)pyrimidin-2-amine, [28] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(2-chlorophenethyl)pyrimidin-2-amine, [29] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine, [30] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-methoxyphenethyl)pyrimidin-2-amine, [31] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-methoxyphenethyl)pyrimidin-2-amine, [32] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(2-(pyridin-2-yl)ethyl)pyrimidin-2-amine, [33] 4-(2-((5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-yl)amino)ethyl)benzonitrile, [34] 5-(5-((1R,5S,6R)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxazol-2-yl)-N-((R)-2,3-dihydro-1H-inden-1-yl)pyrimidin-2-amine, [35] 5-(5-((1R,5S,6S)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-((S)-2,3-dihydro-1H-inden-1-yl)pyrimidin-2-amine, [36] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-phenylpyrimidin-2-amine, [37] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-chlorophenethyl)-N-methylpyrimidin-2-amine, [38] 1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)butan-1-one, [39] 1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)propan-1-one, [40] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-chlorophenethyl)-4-methylpyrimidin-2-amine, [41] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-chlorophenethyl)pyridin-2-amine, [42] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4- oxadiazol-2-yl)-N-(4-chlorophenethyl)pyrazine-2-amine, [43] 1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-(2-((4-chlorophenethyl)amino)pyrimidin-5-yl)propan-1-one, [44] 1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-(2-((3,5-dichlorobenzyl)amino)pyrimidin-5-yl)butan-1-one, [45] (E)-1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-(2-((4-chlorophenethyl)amino)pyrimidin-5-yl)prop-2-en-1-one, [46] (E)-1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)prop-2-en-1-one, [47] N-(4-chlorophenethyl)-5-(5-((1R,5S,6r)-6-(1-methyl-1H-1,2,3-triazol-5-yl)-3- azabicyclo[3.1.0]hexan-3-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine, N-(4-chlorophenethyl)-5-(5-((1R,5S,6r)-6-(1-methyl-1H-1,2,3-triazol-5-yl)-3- azabicyclo[3.1.0]hexan-3-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine, [48] N-(4-chlorophenethyl)-5-(5-((1R,5S,6r)-6-(4-methyl-1H-1,2,3-triazol-5-yl)-3- azabicyclo[3.1.0]hexan-3-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine, N-(4-chlorophenethyl)-5-(5-((1R,5S,6r)-6-(4-methyl-1H-1,2,3-triazol-5-yl)-3- azabicyclo[3.1.0]hexan-3-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine, [49] 5-(3-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-4,5- dihydroisoxazol-5-yl)-N-(4-chlorophenethyl)pyrimidin-2-amine, 5-(3-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-4,5- dihydroisoxazol-5-yl)-N-(4-chlorophenethyl)pyrimidin-2-amine, [50] 5-(3-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-4,5- dihydroisoxazol-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, and 5-(3-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-4,5- dihydroisoxazol-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, and [51] 2-((1R,5S,6s)-3-(5-(2-((4-chlorophenethyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazol-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid.

12. A pharmaceutical composition for use in the prevention or treatment of an autocrine motility factor-related disease, comprising the azabicyclic derivative compound, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 as an active ingredient.

13. The pharmaceutical composition according to claim 12, wherein the autocrine motility factor-related disease is selected from the group consisting of fibrotic diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, metabolic diseases, cancers and cancer metastasis, ocular diseases, cholestatic and other forms of chronic pruritus, and acute or chronic organ transplant rejection.

14. A pharmaceutical composition comprising the azabicyclic derivative compound, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 as an active ingredient, for use in the prevention or treatment of one or more diseases selected from the group consisting of fibrotic diseases selected from idiopathic pulmonary fibrosis (IPF), interstitial lung disease, liver fibrosis, cirrhosis, nonalcoholic steatohepatitis, radiation-induced fibrosis, kidney fibrosis, skin fibrosis, glomerulosclerosis, myocardial fibrosis, and vascular fibrosis; inflammatory diseases selected from rheumatoid arthritis, osteoarthritis, atopic dermatitis, inflammatory bowel disease, inflammatory airway disease, chronic obstructive pulmonary disease (COPD), and asthma; autoimmune diseases selected from multiple sclerosis and scleroderma; respiratory diseases selected from asbestos-induced pulmonary fibrosis and acute respiratory distress syndrome (ARDS); cardiovascular diseases selected from atherosclerosis, myocardial infarction, arterial and pulmonary arterial hypertension, arrhythmia, stroke, and other vascular damage; metabolic diseases selected from obesity and diabetes; cancers and cancer metastasis selected from breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, liver cancer, gastrointestinal cancer, pancreatic cancer, and progression and metastatic invasion thereof; ocular diseases selected from proliferative and non-proliferative retinopathies, diabetic retinopathy, dry and wet age-related macular degeneration (AMD), macular edema, central artery / vein occlusion, traumatic injury, and glaucoma; cholestatic and other forms of chronic pruritus; and acute or chronic organ transplant rejection.

15. A pharmaceutical composition comprising the azabicyclic derivative compound, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, and a pharmaceutically acceptable additive.

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