Novel azabicycle derivatives and pharmaceutical compositions for autotaxin inhibition containing the same

Abstract

The present invention provides novel azabicycle derivative compounds, their hydrates, their solvates, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions for the prevention or treatment of autotaxin-related diseases containing them as active ingredients. The azabicycle derivative compounds according to the present invention exhibit excellent inhibitory activity against autotaxin and can be usefully used for the treatment and prevention of autotaxin inhibition-related diseases, including fibrous 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.

Description

[Technical Field]

[0001] This application claims priority under Korean Patent Application No. 10-2023-0043184, filed on March 31, 2023, and all disclosures in the specification and drawings of said application are incorporated herein by reference. The present invention relates to novel azabicycle derivatives, and more particularly to novel azabicycle derivatives having autotaxin inhibitory activity. [Background technology]

[0002] Autotaxin (ATX) is a secretory enzyme crucial for the production of lysophosphatidic acid (LPA), a lipid signaling molecule, and is 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 fluid are associated with ATX activity.

[0003] Plasma LPAs are bioactive lipids that influence the migration, proliferation, and survival of various cell types. Furthermore, the ATX-LPA signaling process is associated with the physiological and pathophysiological effects of a variety of diseases, including nervous system activity, vascular development, cardiovascular physiology, tissue regeneration, immune system activity, chronic inflammation, tumor metastasis and progression, organofibrosis and obesity, and / or other metabolic disorders (e.g., diabetes mellitus).

[0004] Therefore, increased ATX activity and LPA levels, altered LPA receptor expression, and altered responses to LPA may be associated with the onset, progression, and / or outcomes of a variety of pathophysiological diseases related to the ATX / LPA signaling process. In particular, these are known to be associated with cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrous diseases (e.g., idiopathic pulmonary fibrosis, IPF), and thrombosis. For this reason, it is necessary to lower the levels of LPA and / or autotaxin (ATX) that induces it in order to treat such diseases. [Overview of the project] [Problems that the invention aims to solve]

[0005] The problem that this invention aims to solve is to provide an autotaxin inhibitor compound with a novel structure that exhibits excellent inhibitory activity against autotaxin.

[0006] Furthermore, the problem that the present invention aims to solve is to provide a pharmaceutical composition for the prevention or treatment of autotaxin-related diseases, comprising the autotaxin inhibitor compound of the novel structure described above.

[0007] Furthermore, the problem that the present invention aims to solve is to provide a method for preventing or treating autotaxin-related diseases, which includes administering a therapeutically effective amount of the novel autotaxin inhibitor compound to an individual in need of it.

[0008] Furthermore, the problem that the present invention aims to solve is to provide an active ingredient for the novel structure of the autotaxin inhibitor compound in the manufacture of pharmaceuticals for the prevention or treatment of autotaxin-related diseases.

[0009] The problems that this invention aims to solve are not limited to those described above, and other technical problems can be clearly understood by a person with ordinary skill in the art to which this invention belongs from the description of the invention below. [Means for solving the problem]

[0010] To solve the above problems, one aspect of the present invention provides an azabicycle derivative compound represented by the following Chemical Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

Chemical formula

[0011] Another aspect of the present invention provides a pharmaceutical composition for the prevention or treatment of autotaxin-related diseases, comprising as an active ingredient an azabicycle derivative compound represented by chemical formula 1, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof.

[0012] A further aspect of the present invention provides a method for preventing or treating autotaxin-related diseases, comprising administering a therapeutically effective amount of an azabicycle derivative compound represented by chemical formula 1, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof to an individual in need.

[0013] Yet another aspect of the present invention provides the use of an azabicycle derivative compound represented by chemical formula 1, its hydrate, its solvate, or its pharmaceutically acceptable salt as an active ingredient in the manufacture of a pharmaceutical product for the prevention or treatment of autotaxin-related diseases.

[0014] A further aspect of the present invention provides a pharmaceutical composition comprising an azabicycle derivative compound represented by chemical formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. [Effects of the Invention]

[0015] A novel azabicycle derivative compound according to one aspect of the present invention has been confirmed to exhibit excellent autotaxin inhibitory activity, and it has become clear that it can be used for the prevention or treatment of autotaxin-related diseases.

[0016] Therefore, a novel azabicycle derivative compound with a novel structure according to one aspect of the present invention can be usefully used in the pharmaceutical and pharmacy fields for the treatment and prevention of autotaxin-related diseases such as fibrous 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.

[0017] It should be understood that the effects of the present invention are not limited to those described above, but include all effects that can be inferred from the configuration of the invention as described in the description or claims. [Modes for carrying out the invention]

[0018] In this specification, autotaxin (ATX) is a secretory enzyme that plays a crucial role in the production of lysophosphatidic acid (LPA), and is also referred to as ectonucleotide pyrophosphatase / phosphodiesterase 2 (ENPP2). Autotaxin exhibits lysophospholipase D activity, which converts lysophosphatidylcholine (LPC) to LPA. Therefore, LPA levels in plasma and ascites are related to ATX activity.

[0019] The present invention provides azabicycle derivative compounds represented by the following chemical formula 1, their hydrates, their solvates, or pharmaceutically acceptable salts thereof. [ka] In chemical formula 1, X is C 5-7 Aryl; a 5- or 6-membered heteroaryl containing 1 to 3 nitrogen atoms; C 5-7 A bicyclic fusion ring formed by the fusion of an aryl ring and a 5-membered or 6-membered cycloalkyl ring containing 0 to 3 oxygen atoms, wherein X is one or more independent R x It is either replaced by or not replaced by The aforementioned R x C 1-4 Alkyl, C 1-4 Alkyl, cyano, halogen, or C 1-4 It is a haloalkyl, p is an integer between 0 and 3. R N is hydrogen, or C 1-4 It is alkyl, A is a 5-membered or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N and S, and A is one or more independent R A It is either replaced by or not replaced by The aforementioned R A C 1-4 It is alkyl, L is -(CH2) m A 5-membered or 6-membered aromatic or non-aromatic heteroring containing 1 to 4 heteroatoms selected from C(O)-, -CHCHC(O)-, or N and O, wherein m is an integer from 1 to 5. B is -(CH2) n C(O)OH, or a 5-membered or 6-membered heteroaryl containing 1 to 4 N atoms, where n is an integer from 1 to 3, and B is one or more independent R atoms. B It is either replaced by or not replaced by The aforementioned R B C 1-4 It is alkyl.

[0020] In one embodiment, X may be phenyl, pyridinyl, dihydroindenyl, or benzodioxolyl.

[0021] In one example, the R x This can be methyl, methoxy, cyano, fluoro, chloro, bromo, difluoromethyl, or trifluoromethyl.

[0022] In one embodiment, p may be 0, 1, or 2.

[0023] In one example, the R N This can be hydrogen or methyl.

[0024] In one embodiment, A may be pyridinyl, pyrimidinyl, pyrazinyl, or thiadiazolyl.

[0025] In one example, the R A It can be methyl.

[0026] In one embodiment, L may be -(CH2)2C(O)-, -(CH2)3C(O)-, -CHCHC(O)-, dihydroisoxazolyl, or oxadiazolyl.

[0027] In one embodiment, B may be -CH2C(O)OH or triazolyl.

[0028] In one example, the R B It can be methyl.

[0029] Specific examples of azabicycle derivative compounds according to the present invention are as follows:

[0030] [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-oxadiazole-2-yl)-N-benzylpyrimidine-2-amine, [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-oxadiazole-2-yl)-N-(3-chlorobenzyl)pyrimidine-2-amine, [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-oxadiazole-2-yl)-N-(4-chlorobenzyl)pyrimidine-2-amine, [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-oxadiazole-2-yl)-N-(3,4-difluorobenzyl)pyrimidine-2-amine, [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-oxadiazole-2-yl)-N-(3,5-difluorobenzyl)pyrimidine-2-amine, [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-oxadiazole-2-yl)-N-(3,4-dichlorobenzyl)pyrimidine-2-amine, [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-oxadiazole-2-yl)-N-(3,5-dichlorobenzyl)pyrimidine-2-amine, [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-oxadiazole-2-yl)-N-(3,5-dibromobenzyl)pyrimidine-2-amine, [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-oxadiazole-2-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidine-2-amine,

[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-oxadiazole-2-yl)-N-(3,5-bis(trifluoromethyl)benzyl)pyrimidine-2-amine,

[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-oxadiazole-2-yl)-N-phenethylpyrimidine-2-amine,

[12] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(3-fluorophenethyl)pyrimidine-2-amine,

[13] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-fluorophenethyl)pyrimidine-2-amine,

[14] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(3-chlorophenethyl)pyrimidine-2-amine,

[15] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-chlorophenethyl)pyrimidine-2-amine,

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

[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-oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidine-2-amine,

[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-oxadiazole-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrimidine-2-amine,

[19] 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)pyrimidine-5-yl)propan-1-one,

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

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

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

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

[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-oxadiazole-2-yl)pyrimidine-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]hexane-3-yl)-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl)amino)methyl)benzonitrile,

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

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

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

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

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

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

[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-oxadiazole-2-yl)-N-(2-(pyridine-2-yl)ethyl)pyrimidine-2-amine,

[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-oxadiazole-2-yl)pyrimidine-2-yl)amino)ethyl)benzonitrile,

[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-oxadiazole-2-yl)-N-((R)-2,3-dihydro-1H-inden-1-yl)pyrimidine-2-amine,

[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-oxadiazole-2-yl)-N-((S)-2,3-dihydro-1H-inden-1-yl)pyrimidine-2-amine,

[36] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-phenylpyrimidine-2-amine,

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

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

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

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

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

[42] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-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]hexane-3-yl)-3-(2-((4-chlorophenethyl)amino)pyrimidine-5-yl)propan-1-one,

[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)pyrimidine-5-yl)butan-1-one,

[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-chlorophenethyl)amino)pyrimidine-5-yl)prop-2-en-1-one,

[46] (E)-1-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-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]hexane-3-yl)-1,3,4-oxadiazole-2-yl)pyrimidine-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]hexane-3-yl)-1,3,4-oxadiazole-2-yl)pyrimidine-2-amine,

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

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

[51] 2-((1R, 5S, 6s)-3-(5-(2-((4-chlorophenethyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl)acetic acid.

[0031] In this specification, unless otherwise specified, the following definitions apply when defining compounds of chemical formula 1.

[0032] The term "alkyl" refers to a linear or branched saturated hydrocarbon, where C 1-10 Alkyl is preferred. For example, the alkyl includes, but is not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0033] The term "cycloalkyl" refers to a single or fused cyclic hydrocarbon that is partially or completely saturated, C 3-10This refers to monocyclic, bicyclic, or tricyclic functional groups. Among cycloalkyls, monocyclic functional groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexynyl. Among cycloalkyls, bicyclic functional groups include bicycloalkyl and spiro functional groups, with specific examples including bicyclo[1.1.1]fentanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, spiro[2.3]hexanyl, and spiro[3.3]heptanyl.

[0034] The term "hydroxy" or "hydroxyl" is defined as -OH, and the term "alkoxy" means alkyloxy, which is a radical in which one to ten alkyl atoms of a hydroxyl group are substituted, unless otherwise defined.

[0035] The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0036] The terms "haloalkyl" and "haloalkoxy" refer to alkyl or alkoxy molecules substituted with one or more halogen atoms.

[0037] The term "heteroatom" refers to N, O, or S.

[0038] The term "aryl" means aromatic hydrocarbon and includes polycyclic aromatic ring systems in which a carbocyclic aromatic ring or a heteroaryl ring is fused with one or more other rings. Preferably, C 5-12 Aryl, more preferably C 5-10 It is an aryl compound. For example, the aryl compound includes, but is not limited to, phenyl, naphthyl, and tetrahydronaphthyl.

[0039] The term "heteroaryl" or "aromatic heterocycle" refers to a ring containing one or more heteroatoms selected from N, O, and S, and containing benzo or C 3-8The heteroaryl group includes, but is not limited to, three- to twelve-membered, more preferably five- to ten-membered aromatic hydrocarbons that form a single or fusion ring fused with a cycloalkyl group. For example, the heteroaryl group includes, but is not limited to, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridadinyl, triazinyl, oxadiazolyl, isoxadiazolyl, tetrazolyl, indolyl, indazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, furanyl, benzofuranyl, thiophenyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, and the like.

[0040] Furthermore, heteroaryl groups include groups in which a heteroaryl ring is fused to a cycloalkyl or non-aromatic heterocycle, such as dihydrocyclopentapyrazinyl.

[0041] The term “heterocyclic” or “heterocycloalkyl” refers to a non-aromatic alkyl ring that contains one or more heteroatoms such as N, O, or S within the ring. The ring is 5-membered, 6-membered, 7-membered, or 8-membered, or may be fused to other rings such as cycloalkyl or aromatic rings. Examples of such compounds include pyrrolidinyl, tetrahydrofuranil, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanil, oxathiolanil, dithiolanil, piperidinyl, tetrahydropyranil, thianyl, piperazinyl, morpholino, and dioxanil.

[0042] The compound represented by Chemical Formula 1 according to the present invention can be produced and used in the form of a prodrug, hydrate, solvate, and pharmaceutically acceptable salt to enhance bioavailability or increase solubility; therefore, the prodrug, hydrate, solvate, and pharmaceutically acceptable salt also fall within the scope of the present invention. Furthermore, the compound represented by Chemical Formula 1 has a chiral carbon, and stereoisomers exist, and such stereoisomers are also included within the scope of the present invention.

[0043] The term "prodrug" refers to a substance that transforms into a parent drug in the body. Prodrugs are sometimes used because, in some cases, they are easier to administer than parent drugs. For example, they may be bioavailable when administered orally, whereas the parent drug may not be. Also, prodrugs may have improved solubility in pharmaceutical compositions compared to parent drugs. For example, a prodrug may be a biohydrolyzable ester of a compound according to the present invention and a pharmaceutically acceptable salt thereof. Another example of a prodrug may be a short peptide (polyamino acid) to which an acid group is bound, and the peptide is converted by metabolism to reveal an active site.

[0044] The term "hydrate" refers to the compound or salt thereof of the present invention that contains a stoichiometric or non-stoichiometric amount of water bonded by non-covalent intermolecular forces.

[0045] The term "solvate" refers to a compound or salt thereof of the present invention that contains a stoichiometric or non-stoichiometric amount of solvent bonded by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and / or suitable for administration to humans.

[0046] The term "isomer" refers to a compound or salt thereof of the present invention that has the same chemical or molecular formula but is structurally or stereochemically different. Such isomers include structural isomers such as tautomers, and stereoisomers such as R or S isomers with asymmetric carbon centers, geometric isomers (trans, cis), and diastereomers. All of these isomers and mixtures thereof are also within the scope of the present invention. In particular, if the compound of chemical formula 1 has optical isomers, stereoisomers, regioisomers, or rotamers, these are also included in the compound of chemical formula 1 and can be obtained as single products by known synthesis and separation methods. For example, if the compound of chemical formula 1 contains optical isomers, the optical isomers separated from this compound are also included in the compound of chemical formula 1. Optical isomers can be produced by known methods.

[0047] The term "pharmaceutically acceptable salt" refers to a salt form of a compound that does not induce serious irritation in the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. Such pharmaceutically acceptable salts include acid addition salts formed by acids that form nontoxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids like hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and hydroiodic acid; organic carbonates like tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, malic acid, and salicylic acid; and sulfonic acids like methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. For example, pharmaceutically acceptable carboxylate salts include metal salts or alkaline earth metal salts formed from lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, and guanidine, and organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine. The compound of chemical formula 1 according to the present invention can be converted to its salt by conventional methods.

[0048] Furthermore, the present invention provides a method for producing the compound of chemical formula 1. Examples 1 to 51 illustrate the synthesis methods for producing the compound of chemical formula 1 according to the present invention, but the synthesis methods in Examples 1 to 51 do not limit the method for producing the compound of chemical formula 1 according to the present invention. The synthesis methods in Examples 1 to 51 are merely illustrative, and it is obvious to an ordinary person that they can be easily modified by specific substituted compounds.

[0049] The present invention also provides a pharmaceutical composition for the prevention or treatment of autotaxin-related diseases, comprising as an active ingredient an azabicycle derivative compound represented by the chemical formula 1, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof.

[0050] The present invention also provides a method for preventing or treating autotaxin-related diseases, comprising administering a therapeutically effective amount of an azabicycle derivative compound represented by chemical formula 1, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof to an individual in need.

[0051] The present invention also provides the use of an azabicycle derivative compound represented by chemical formula 1, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof as an active ingredient in the manufacture of pharmaceuticals for the prevention or treatment of autotaxin-related diseases.

[0052] The autotaxin protein inhibitory activity of the azabicycle derivative compound of the present invention was measured, and it was found that it exhibited excellent autotaxin inhibitory activity even at very low compound concentrations (nM level), confirming its applicability for the treatment and prevention of autotaxin-related diseases.

[0053] In one embodiment, the autotaxin activity-related disease may be selected from the group consisting of fibrous 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.

[0054] The aforementioned fibrotic diseases include, without limitation, idiopathic pulmonary fibrosis (IPF), interstitial lung disease, hepatic fibrosis, hepatosclerosis, non-alcoholic steatohepatitis, radiation-induced fibrosis, renal fibrosis, cutaneous fibrosis, glomerulosclerosis, myocardial and vascular fibrosis.

[0055] The aforementioned inflammatory diseases include, without limitation, rheumatoid arthritis, osteoarthritis, atopic dermatitis, inflammatory bowel disease, inflammatory airway disease, chronic obstructive pulmonary disease (COPD), and asthma.

[0056] The aforementioned autoimmune diseases include, without limitation, multiple sclerosis and scleroderma.

[0057] The aforementioned respiratory diseases include, without limitation, asbestos-induced pulmonary fibrosis and acute respiratory distress syndrome (ARDS).

[0058] The aforementioned cardiovascular diseases include, without limitation, arteriosclerosis, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmias, stroke, and other vascular injuries.

[0059] The aforementioned metabolic disorders include, without limitation, obesity and diabetes.

[0060] The aforementioned cancers and cancer metastases include, without limitation, breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, hepatoma, gastrointestinal cancer, pancreatic cancer, and their progression and metastatic invasion.

[0061] The aforementioned eye diseases include, without limitation, proliferative and non-proliferative retinopathy, diabetic retinopathy, dry and wet age-related macular degeneration (AMD), macular edema, central arterial / venous occlusion, traumatic injury, and glaucoma.

[0062] The present invention also provides a pharmaceutical composition or dosage form comprising an azabicycle derivative compound represented by chemical formula 1, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

[0063] The additive may include pharmaceutically acceptable carriers such as commonly used excipients, disintegrants, sweeteners, lubricants, or flavorings, and may be formulated by conventional methods into oral formulations such as tablets, capsules, powders, granules, suspensions, emulsions, or syrups; or into parenteral formulations such as topical solutions, topical suspensions, topical emulsions, gels (such as ointments), inhalants, sprays, or injections. The formulation may be formulated in various forms, such as single-dose or multi-dose dosage forms.

[0064] The organism to which the pharmaceutical composition of the present invention is administered may be, for example, a human, monkey, cattle, horse, sheep, pig, chicken, turkey, cat, dog, mouse, rat, rabbit, or guinea pig, and may be, for example, a mammal, such as a human.

[0065] Furthermore, the pharmaceutical composition of the present invention can be administered orally or parenterally. In the case of parenteral administration, it can be administered via routes such as skin, transdermal, ocular, abdominal, rectal or venous, intramuscular, subcutaneous, intracervical, intracerebral, intravascular (intracerebroventricular) injection, or local administration. Local administration of the ocular body includes, for example, direct intraocular administration, or administration around the eyeball, at the back of the eyeball, subretinal, central retinal, outside the fovea, subconjunctival, intravitreous, intracameral, or suprachoroidal. The pharmaceutical composition can be administered through an insertion device.

[0066] The dosage of the active ingredient contained in the pharmaceutical composition of the present invention varies depending on the patient's condition and weight, the severity of the disease, the form of the active ingredient, the route of administration, and the duration, and can be appropriately adjusted for each patient. For example, the active ingredient may be administered at a dose of 0.0001 mg / kg to 1000 mg / kg per day, preferably 0.001 mg / kg to 100 mg / kg, and the administration may be once a day or divided into several doses. Furthermore, the pharmaceutical composition of the present invention may contain the active ingredient in an amount of 0.001% to 90% by weight relative to the total weight of the composition.

[0067] The present invention will be described in more detail below through synthesis examples, embodiments, and test examples. However, the following synthesis examples, embodiments, and test examples are for illustrative purposes only, and the scope of the present invention is not limited thereto.

[0068] Synthesis method <Reaction Equation 1> [ka] Reagents and conditions: (a) Bestmann-Ohira reagent, K2CO3, MeOH, rt; (b) Me3SiN3, CuI, DMF, 100℃, 12h; (c) 4N HCl-containing dioxane, rt, 2h

[0069] <Reaction Equation 2> [ka] Reagents and conditions: (a) Ethyl 2-chloropyrimidine-5-carboxylate, DIEA, DMF, 100 °C, 3 h, or Ethyl 2-chloropyrimidine-5-carboxylate, DIEA, 1,4-dioxane, 100 °C, 2 h; (b) N2H4·H2O, EtOH, reflux, 8 h to 15 h; (c) Triphosgene, TEA, THF, DMF, r.t., 2 h, or 1,1'-Carbonyl diimidazole (CDI), THF, 0 °C (15 min) → r.t., 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, r.t., 8 h to 22 h

[0070] <Reaction Scheme 3>

Chem.

[0071] <Reaction Scheme 4>

Chem.

[0072] <Reaction Equation 5> [ka] Reagents and conditions: (a) Ethyl acrylate, Pd(OAc)2, tri(o-tolyl)phosphine, DIEA, DMF, reflux, 4h; (b) 2-aminoindan, Et3N, dioxane, 100°C, 6h; (c) H2, Pd / C, EA, MeOH, EtOH, DCM, rt, 6h; (d) LiOH, THF, MeOH, H2O, rt, 1h; (e) (1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, HATU, DIEA, DMF, rt, 2h

[0073] <Reaction Equation 6> [ka] Reagents and conditions: (a) Ethyl 2-chloropyrimidine-5-carboxylate, DIEA, 1,4-dioxane, 100°C, 2h; (b) N2H4·H2O, EtOH, reflux, 15h; (c) 1,1'-carbonyldiimidazole, TEA, THF, 0°C (15 min) → rt, 20h; (d) (1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, BOP reagent, DIEA, DMF, 0°C → rt, 22h

[0074] <Reaction Equation 7> [ka] Reagents and conditions: (a) Ethyl 2-chloropyrimidine-5-carboxylate, DIEA, 1,4-dioxane, 100°C, 2h; (b) N2H4·H2O, EtOH, reflux, 115h; (c) 1,1'-carbonyldiimidazole, TEA, THF, 0°C (15 min) → rt, 20h; (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, 22h

[0075] <Reaction Equation 8> [ka] Reagents and conditions: (a) Iodomethane, NaH, DMF, 0°C → rt, 6.5h; (b) N2H4·H2O, EtOH, reflux, 15h; (c) 1,1'-Carbonyldiimidazole, TEA, THF, 0°C (15 min) → rt, 20h; (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, 22h

[0076] <Reaction Equation 9> [ka] Reagents and conditions: (a) O,O'-Di-2-pyridylthiocarbonate, DIEA, DCM, rt, 12h; (b) N2H4·H2O, EtOH, rt, 12h; (c) Ethyl 3-cyanopropanoate or ethyl 4-cyanobutanoate, TFA, 80℃, 12h; (d) LiOH, THF, MeOH, H2O, rt, 3h; (e) (1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, HATU, DIEA, DCM, rt, 12h

[0077] <Reaction Equation 10> [Chemistry] 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, r.t., 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, r.t., 3 h; (e) (1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, HATU, DIEA, DCM, r.t., 12 h

[0078] <Reaction Scheme 11> [Chemistry] 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, r.t., 3 h; (e) (1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, HATU, DIEA, DCM, r.t., 12 h

[0079] <Reaction Scheme 12> [Chemistry] Reagents and conditions: (a) iodomethane, NaH, DMF, 0 °C → r.t., 15 h; (b) dioxane containing 4N HCl, 1,4-dioxane, r.t., 3 h; (c) 2-(4-chlorophenyl)ethan-1-amine, DIEA, DMF, 0 °C (30 min) → BOP reagent, r.t., 15 h

[0080] <Reaction Scheme 13> [ka] Reagents and conditions: (a) i) n-BuLi (2.5 M in hexane), THF, -78°C, 30 min, ii) iodomethane, rt, 12 h; (b) Me3SiN3, microwave, 200°C, 7 h; (c) 4N HCl-containing dioxane, 1,4-dioxane, rt, 3 h; (d) 2-(4-chlorophenyl)ethane-1-amine, BOP reagent, DIEA, DMF, rt, 5 h

[0081] <Reaction Equation 14> [ka] Reagents and conditions: (a) 2-(4-chlorophenyl)ethane-1-amine or 2,3-dihydro-1H-inden-2-amine, DIEA, n-butanol, microwave, 150°C, 2h; (b) i) 1,1-dibromoformaldehyde, -10°C, DMF, ii) KHCO3, H2O, rt, 1h; (c) (1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, DIEA, tert-butanol, microwave, 200°C, 3h

[0082] <Reaction Equation 15> [ka] Reagents and conditions: (a) Iodomethane, K2CO3, DMF, rt, 15h; (b) 4N HCl-containing dioxane, 1,4-dioxane, rt, 5h; (c) 2-(4-chlorophenyl)ethane-1-amine, DIEA, DMF, 0°C (30 min) → BOP reagent, rt, 15h; (d) 1N NaOH, THF, rt, 1.5h

[0083] Synthesis Example 1. tert-butyl(1R,5S,6s)-6-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylate(2) [ka] A mixture of tert-butyl(1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (1 mmol) and K2CO3 (2 mmol) was stirred in MeOH. Then, a mixture of dimethyl(1-diazo-2-oxopropyl)phosphonate (1.2 mmol) dissolved in ACN was slowly added 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 obtain compound (2) (400 mg, yield: 64.3%). 1 H NMR (400 MHz, CD3OD) δ 3.59 - 3.52 (m, 2H), 3.39 - 3.32 (m, 2H), 2.18 (d, J = 2.1 Hz, 1H), 1.87 - 1.80 (m, 2H), 1.43 (s, 9H), 1.06 - 1.02 (m, 1H).

[0084] Synthesis Example 2. tert-butyl(1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(3) [ka] tert-butyl(1R,5S,6s)-6-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylate(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 for 12 hours under an argon stream. The mixture was then filtered through a Celite pad, 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 obtain compound (3) (181 mg, yield: 70%). 1 H NMR (400 MHz, CDCl3) δ 13.41 (s, 1H), 7.45 (s, 1H), 3.82 - 3.68 (m, 2H), 3.52 - 3.44 (m, 2H), 1.98 - 1.93 (m, 2H), 1.86 - 1.83 (m, 1H), 1.47 (s, 9H).

[0085] Synthesis Example 3. (1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane·HCl(4) [ka] A solution of tert-butyl 6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (3,0.68 mmol) in dioxane was mixed with 4.0 M HCl in dioxane. The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated to obtain compound (4) (quantitatively). 1 H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 3.73 - 3.59 (m, 4H), 2.57 - 2.43 (m, 3H).; MS calculated for C7H 11 N4[M+H] + 151.15, found 151.15.

[0086] General process (I) for the synthesis of 6a-6j, 11a-11e, and 16a-16c A mixture of ethyl 2-chloropyrimidine-5-carboxylate (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 then concentrated. The product was obtained by column chromatography (hexane / ethyl acetate) to acquire 6a-6j, 11a-11e, and 16a-16c.

[0087] Synthesis Example 4. Ethyl 2-(benzylamino)pyrimidine-5-carboxylate (6a) [ka] Yield: 78% 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 1.6 Hz, 2H), 8.63 (t, J = 6.4 Hz, 1H), 7.34 - 7.19 (m, 5H), 4.58 (d, J = 6.4 Hz, 2H), 4.25 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H); MS calculated for C 14 H 15 N3O2[M+H] + 258.12, found 258.10.

[0088] Synthesis Example 5. Ethyl 2-((3-chlorobenzyl)amino)pyrimidine-5-carboxylate (6b) [ka] Yield: 95%; 1H NMR (400 MHz, CDCl3) δ 9.00 - 8.72 (m, 2H), 7.35 - 7.32 (m, 1H), 7.30 - 7.26 (m, 1H), 7.26 - 7.20 (m, 2H), 6.00 (s, 1H), 4.70 (dd, J = MS calculated for C 14 H 15 ClN3O2[M+H] + 292.08, found 292.00.

[0089] Synthesis Example 6. Ethyl 2-((4-chlorobenzyl)amino)pyrimidine-5-carboxylate(6c) [ka] Yield: 74%; 1 H NMR (400 MHz, CDCl3) δ 8.95 - 8.68 (m, 2H), 7.33 - 7.26 (m, 4H), 6.11 (s, 1H), 4.67 (d, J = 6.1 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H); MS calculated for C 14 H 16 ClN3O2[M+H] + 292.08, found 292.05.

[0090] Synthesis Example 7. Ethyl 2-((3,4-difluorobenzyl)amino)pyrimidine-5-carboxylate(6d) [ka] Yield: 74%; 1H NMR (400 MHz, CDCl3) δ 8.86 (s, 2H), 7.22 - 7.03 (m, 3H), 5.88 (s, 1H), 4.67 (dq, J = 6.3, 0.8 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H); MS calculated for C 14 H 14 F2N3O2[M+H] + 294.10, found 294.15.

[0091] Synthesis Example 8. Ethyl 2-((3,5-difluorobenzyl)amino)pyrimidine-5-carboxylate(6e) [ka] Yield: 51% 1 H NMR (400 MHz, CDCl3) δ 8.86 (s, 2H), 6.89 - 6.82 (m, 2H), 6.71 (tt, J = 8.9, 2.3 Hz, 1H), 6.02 (s, 1H), 4.71 (dd, J = 6.4, 0.7 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H); MS calculated for C 14 H 14 F2N3O2[M+H] + 294.10, found 294.15.

[0092] Synthesis Example 9. Ethyl 2-((3,4-dichlorobenzyl)amino)pyrimidine-5-carboxylate(6f) [ka] Yield: 94%; 1H NMR (400 MHz, CDCl3) δ 8.86 (s, 2H), 7.46 - 7.37 (m, 2H), 7.17 (ddt, J = 8.2, 2.1, 0.7 Hz, 1H), 5.92 (s, 1H), 4.67 (dt, J = 6.3, 0.8 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H); 14 H 14 Cl2N3O2[M+H] + 326.05, found 326.05.

[0093] Synthesis Example 10. Ethyl 2-((3,5-dichlorobenzyl)amino)pyrimidine-5-carboxylate (6g) [ka] Yield: 96%; 1 H NMR (400 MHz, CDCl3) δ 8.90 (s, 2H), 7.32 - 7.30 (m, 2H), 7.27 - 7.26 (m, 1H), 6.09 (d, J = 6.4 Hz, 1H), 4.72 (d, J = 6.3 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H); MS calculated for C 14 H 14 Cl2N3O2[M+H] + 326.05, found 326.05.

[0094] Synthesis Example 11. Ethyl 2-((3,5-dibromobenzyl)amino)pyrimidine-5-carboxylate (6h) [ka] Yield: 82% 1H NMR (400 MHz, CDCl3) δ 8.92 - 8.71 (m, 2H), 7.57 (t, J = 1.8 Hz, 1H), 7.44 - 7.40 (m, 2H), 6.33 - 6.22 (m, 1H), 4.69 - 4.65 (m, 2H), 4.36 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H).; MS calculated for C 14 H 14 C l2 N5O2[M+H] + 413.94, found 415.95.

[0095] Synthesis Example 12. Ethyl 2-((benzo[d][1,3]dioxol-5-ylmethyl)aminopyrimidine-5-carboxylate(6i) [ka] Yield: 87%; 1 H NMR (400 MHz, CDCl3) δ 8.99 - 8.64 (m, 2H), 6.86 - 6.74 (m, 3H), 5.98 (s, 1H), 5.95 (s, 2H), 4.60 (dd, J = 6.0, 0.6 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H);MS calculated for C 14 H 16 N3O4[M+H] + 302.11, found 302.10.

[0096] Synthesis Example 13. Ethyl 2-((3,5-bis(trifluoromethyl)benzyl)aminopyrimidine-5-carboxylate(6j) [ka] Yield: 93%; 11H NMR (400 MHz, CDCl3) δ 8.88 (s, 2H), 7.80 (s, 3H), 6.02 (t, J = 4.7 Hz, 1H), 4.84 (d, J = 6.4 Hz, 2H), 4.36 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H); MS calculated for C 16 H 13 F6N3O2[M+H] + 394.10, found 394.05.

[0097] Synthesis Example 14. Ethyl 2-(phenethylamino)pyrimidine-5-carboxylate (11a)

Chemical Structure

[0098] Synthesis Example 15. Ethyl 2-((3-fluorophenethyl)amino)pyrimidine-5-carboxylate (11b)

Chemical Structure

[0099] Synthesis Example 16. Ethyl 2-((4-fluorophenethyl)amino)pyrimidine-5-carboxylate (11c)

Chemical Structure

[0100] Synthesis Example 17. Ethyl 2-((3-chlorophenethyl)amino)pyrimidine-5-carboxylate (11d)

Chemical Structure

[0101] Synthesis Example 18. Ethyl 2-((4-chlorophenethyl)amino)pyrimidine-5-carboxylate (11e) [ka] Yield: 82% 1 H NMR (400 MHz, CDCl3) δ 8.96 - 8.68 (m, 2H), 7.27 (d, J = 6.3 Hz, 1H), 7.25 (s, 1H), 7.17 - 7.13 (m, 2H), 5.66 (s, 1H), 4.35 (q, J = 7.1 MS calculated for C 15 H 16 ClN3O2[M+H] + 306.10, found 305.95.

[0102] Synthesis Example 19. Ethyl 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate (16a) [ka] Yield: 64%; 1 H NMR (400 MHz, CD3OD) δ 8.92 - 8.64 (m, 2H), 7.24 - 7.09 (m, 4H), 4.83 - 4.77 (m, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.37 - 3.31 (m, 2H), 2.93 (dd, J = 15.7, 6.4 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H); MS calculated for C 16 H 18 N3O2[M+H]+ 284.14, found 284.10.

[0103] Synthesis Example 20. Ethyl 2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate (16b) [ka] Yield: 86% 1 H NMR (400 MHz, CDCl3) δ 8.85 (d, J = 35.7 Hz, 2H), 7.02 (t, J = 8.8 Hz, 2H), 5.82 (s, 1H), 4.90 (qt, J = 7.2, 5.2 Hz, 1H), 4.36 (q, J = 7.1 MS calculated for C 16 H 16 F2N3O2[M+H] + 320.12, found 320.10.

[0104] Synthesis Example 21. Ethyl 2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate(16c) [ka] Yield: 63% 1 H NMR (400 MHz, CDCl3) δ 9.00 - 8.75 (m, 2H), 7.40 (d, J = 1.8 Hz, 1H), 7.37 - 7.31 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H), 5.76 (d, J = 8.0 Hz, MS calculated for C 16 H 17 BrN3O2[M+H] + 362.05, found 364.00.

[0105] General process (II) for 7a-7j, 12a-12e, and 17a-17c Compounds 6a-6j, 11a-11e, and 16a-16c (5 mmol each), along with hydrazine monohydrate (50 mmol), were dissolved in EtOH and refluxed for 3 hours. After the reaction was complete, the reaction mixture was evaporated under vacuum to obtain compounds 7a-7j, 12a-12e, and 17a-17c.

[0106] Synthesis Example 22.2-(benzylamino)pyrimidine-5-carbohydrazide (7a) [ka] Yield: Quantitative; 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.66 (s, 2H), 8.27 (t, J = 6.4 Hz, 1H), 7.30 - 7.20 (m, 5H), 4.54 (d, J = 6.3 Hz, 2H), 4.40 (s, 2H); MS calculated for C12 H 14 N5O2[M+H] + 244.12, found 244.15.

[0107] Synthesis Example 23.2-((3-chlorobenzyl)amino)pyrimidine-5-carbohydrazide(7b) [ka] Yield: Quantitative; 1 H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.68 (s, 2H), 8.32 (t, J = 6.4 Hz, 1H), 7.37 - 7.33 (m, 2H), 7.31 - 7.26 (m, 2H), 4.56 (d, J = 6.3 Hz, 2H), 4.49 (d, J = 6.0 Hz, 1H); MS calculated for C 12 H 13 ClN5O2[M+H] + 278.08, found 278.10.

[0108] Synthesis Example 24.2-((4-chlorobenzyl)amino)pyrimidine-5-carbohydrazide(7c) [ka] Yield: Quantitative; 1 H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.66 (s, 2H), 8.30 (t, J = 6.4 Hz, 1H), 7.38 - 7.30 (m, 4H), 4.52 (d, J = 6.3 Hz, 2H), 4.47 - 4.32 (m, 2H); MS calculated for C 12 H 13 ClN5O2[M+H] + 278.08, found 278.10.

[0109] Synthesis Example 25.2-((3,4-difluorobenzyl)amino)pyrimidine-5-carbohydrazide(7d) [ka] Yield: Quantitative; 1 H NMR (400 MHz, CD3OD) δ 8.67 (s, 2H), 7.26 - 7.16 (m, 2H), 7.15 - 7.11 (m, 1H), 4.60 (s, 2H); MS calculated for C 12 H 12 F2N5O2[M+H] + 280.10, found 280.15.

[0110] Synthesis Example 26.2-((3,5-difluorobenzyl)amino)pyrimidine-5-carbohydrazide(7e) [ka] Yield: Quantitative; 1 H NMR (400 MHz, MeOD) δ 8.67 (s, 2H), 6.95 - 6.89 (m, 2H), 6.78 (tt, J = 9.1, 2.4 Hz, 1H), 4.63 (s, 2H); MS calculated for C 12 H 12 F2N5O2[M+H] + 280.10, found 280.10.

[0111] Synthesis Example 27.2-((3,4-dichlorobenzyl)amino)pyrimidine-5-carbohydrazide(7f) [ka] Yield: Quantitative; 1H NMR (400 MHz, CD3OD) δ 8.67 (s, 2H), 7.49 - 7.43 (m, 2H), 7.28 - 7.24 (m, 1H), 4.60 (s, 2H); MS calculated for C 12 H 12 Cl2N5O2[M+H]+ 312.04, found 312.10.

[0112] Synthesis Example 28.2-((3,5-dichlorobenzyl)amino)pyrimidine-5-carbohydrazide (7g) [ka] Yield: Quantitative; 1 H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.68 (s, 2H), 8.32 (t, J = 6.4 Hz, 1H), 7.46 (t, J = 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 2H), 4.54 (d, J = 6.3 Hz, 2H), 3.99 (s, 2H); MS calculated for C 12 H 12 Cl2N5O2[M+H] + 312.04, found 312.05.

[0113] Synthesis Example 29.2-((3,5-dibromobenzyl)amino)pyrimidine-5-carbohydrazide(7h) [ka] Yield: Quantitative; 1 H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.71 (s, 2H), 8.37 (s, 1H), 7.70 (t, J = 1.8 Hz, 1H), 7.54 - 7.51 (m, 2H), 4.58 - 4.53 (m, 2H); MS calculated for C 12 H 12Br2N5O2[M+H] + 399.94, found 401.95.

[0114] Synthesis Example 30.2-((benzo[d][1,3]dioxol-5-ylmethyl)amino)pyrimidine-5-carbohydrazide(7i) [ka] Yield: Quantitative; 1 H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.66 (s, 2H), 8.20 (t, J = 6.3 Hz, 1H), 6.87 - 6.81 (m, 2H), 6.79 - 6.76 (m, 1H), 5.96 (s, 2H), 4.44 (d, J = 6.4 Hz, 2H), 4.39 (s, 2H) ;MS calculated for C 13 H 14 N5O3[M+H] + 288.11, found 288.15.

[0115] Synthesis Example 31.2-((3,5-bis(trifluoromethyl)benzyl)amino)pyrimidine-5-carbohydrazide(7j) [ka] Yield: Quantitative; 1 H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.68 (s, 2H), 8.40 (t, J = 6.4 Hz, 1H), 7.99 (dd, J = 10.3, 2.0 Hz, 3H), 4.72 (d, J = 6.3 Hz, 2H), 4.41 (s, 2H); MS calculated for C 14 H 12 F6N6O [M+H] + 380.09, found 380.10.

[0116] Synthesis Example 32. 2-(phenethylamino)pyrimidine-5-carbohydrazide (12a) [ka] Yield: Quantitative; 1 H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.72 - 8.56 (m, 2H), 7.79 (t, J = 5.8 Hz, 1H), 7.32 - 7.15 (m, 5H), 4.39 (s, 2H), 3.53 (ddd, J = 8.6, 7.5, 6.0 Hz, 2H), 2.84 (dd, J = 8.3, 6.6 Hz, 2H); MS calculated for C 13 H 16 N5O [M+H] + 258.30, found 258.10.

[0117] Synthesis Example 33.2-((3-fluorophenethyl)amino)pyrimidine-5-carbohydrazide(12b) [ka] Yield: Quantitative; 1 H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.66 (d, J = 16.1 Hz, 2H), 7.80 (t, J = 5.8 Hz, 1H), 7.32 (td, J = 8.1, 6.4 Hz, 1H), 7.11 - 6.97 (m, 3H), 4.40 (s, 2H), 3.55 (dt, J = 7.6, 6.3 Hz, 2H), 2.87 (t, J = 7.2 Hz, 2H); MS calculated for C 13 H 15 FN5O [M+H] + 276.29, found 276.05.

[0118] Synthesis Example 34.2-((4-fluorophenethyl)amino)pyrimidine-5-carbohydrazide(12c) [ka] Yield: Quantitative; 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.66 (d, J = 15.9 Hz, 2H), 7.79 (t, J = 5.8 Hz, 1H), 7.30 - 7.23 (m, 2H), 7.14 - 7.06 (m, 2H), 4.39 (s, 2H), 3.52 (dt, J = 7.9, 6.3 Hz, 2H), 2.83 (t, J = 7.3 Hz, 2H); MS calculated for C 13 H 15 FN5O [M+H] + 276.29, found 276.05.

[0119] Synthesis Example 35.2-((3-chlorophenethyl)amino)pyrimidine-5-carbohydrazide(12d) [ka] Yield: Quantitative; 1 H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.66 (d, J = 16.0 Hz, 2H), 7.80 (t, J = 5.8 Hz, 1H), 7.33 - 7.23 (m, 3H), 7.19 (dt, J = 7.5, 1.5 MS calculated for C 13 H 15 ClN5O [M+H] + 292.75, found 292.00.

[0120] Synthesis Example 36.2-((4-chlorophenethyl)amino)pyrimidine-5-carbohydrazide(12e) [ka] Yield: Quantitative; 1 H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.66 (d, J = 16.6 Hz, 2H), 7.79 (t, J = 5.8 Hz, 1H), 7.35 - 7.30 (m, 2H), 7.28 - 7.22 (m, 2H), 4.40 (s, 2H), 3.52 (dt, J = 7.7, 6.2 Hz, 2H), 2.83 (t, J = 7.2 Hz, 2H); MS calculated for C 13 H 15 ClN5O [M+H] + 292.75, found 292.00.

[0121] Synthesis Example 37.2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbohydrazide (17a) [ka] Yield: Quantitative; 1 H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.69 (s, 2H), 8.06 (d, J = 6.9 Hz, 1H), 7.26 - 7.09 (m, 4H), 4.72 - 4.61 (m, 1H), 4.41 (s, 2H), 3.28 - 3.22 (m, 2H), 2.95 - 2.86 (m, 2H); MS calculated for C 14 H 16 N5O [M+H] + 270.13, found 270.15.

[0122] Synthesis Example 38.2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbohydrazide(17b) [ka] Yield: Quantitative; 1 H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.69 (d, J = 14.2 Hz, 2H), 8.12 (d, J = 6.9 Hz, 1H), 7.28 (t, J = 9.3 Hz, 2H), 4.73 - 4.61 (m, MS calculated for C 14 H 14 F2N5O [M+H] + 306.12, found 306.10.

[0123] Synthesis Example 39.2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbohydrazide(17c) [ka] Yield: Quantitative; 1 H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.69 (s, 2H), 8.08 (dd, J = 6.9, 2.9 Hz, 1H), 7.42 (d, J = 1.9 Hz, 1H), 7.32 (dd, J = 8.0, 2.0 Hz, MS calculated for C 14 H 12 F6N6O [M+H] +380.09, found 380.10.

[0124] General process (III) for 8a-8j, 13a-13e, and 18a-18c Compounds 7a-7j, 12a-12e, and 17a-17c (0.1 mmol each), dissolved in DMF (5 mL), were each mixed with TEA (0.5 mmol) and slowly added at 0°C to a solution of triphosgene (0.04 mmol) in THF (5 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was evaporated. The product was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by column chromatography (EA / Hex) to obtain compounds 8a-8j, 13a-13e, and 18a-18c.

[0125] Synthesis example 40.5-(2-(benzylamino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(8a) [ka] Yield: 10%; 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.63 (s, 2H), 8.50 (t, J = 6.3 Hz, 1H), 7.31 (d, J = 4.8 Hz, 4H), 7.26 - 7.20 (m, 1H), 4.57 (d, J = 6.3 Hz, 2H); MS calculated for C 13 H 12 N5O2[M+H] + 270.10, found 270.05.

[0126] Synthesis Example 41. 5-(2-((3-chlorobenzyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(8b) [ka] Yield: 36.9% 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.64 (d, J = 4.0 Hz, 2H), 8.52 (t, J = 6.4 Hz, 1H), 7.37 - 7.26 (m, 4H), 4.57 (d, J = 6.4 Hz, 2H); MS calculated for C 13 H 11 ClN5O2[M+H] + 304.06, found 304.05.

[0127] Synthesis Example 42.5-(2-((4-chlorobenzyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(8c) [ka] Yield: 10%; 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.63 (s, 2H), 8.51 (t, J = 6.3 Hz, 1H), 7.39 - 7.36 (m, 2H), 7.32 (d, J = 8.6 Hz, 2H), 4.55 (d, J = 6.3 Hz, 2H); MS calculated for C 13 H 11 ClN5O2[M+H] + 304.06, found 304.05.

[0128] Synthesis Example 43. 5-(2-((3,4-difluorobenzyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(8d) [ka] Yield: 41% 1H NMR (400 MHz, MeOD) δ 8.67 (s, 2H), 7.28 - 7.13 (m, 3H), 4.60 (s, 2H); MS calculated for C 13 H 10 F2N5O2[M+H] + 306.08, found 306.05.

[0129] Synthesis Example 44.5-(2-((3,5-difluorobenzyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(8e) [ka] Yield: 47% 1 H NMR (400 MHz, CD3OD) δ 8.68 (s, 2H), 6.97 - 6.90 (m, 2H), 6.79 (tt, J = 9.2, 2.4 Hz, 1H), 4.64 (s, 2H); MS calculated for C 13 H 10 F2N5O2[M+H] + 306.08, found 306.10.

[0130] Synthesis example 45.5-(2-((3,4-dichlorobenzyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(8f) [ka] Yield: 20%; 1 H NMR (400 MHz, CD3OD) δ 8.68 (s, 2H), 7.49 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.30 - 7.25 (m, 1H), 4.61 (s, 2H); MS calculated for C 13 H 10 Cl2N5O2[M+H] + 338.02, found 339.05.

[0131] Synthesis Example 46. 5-(2-((3,5-dichlorobenzyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one (8g) [ka] Yield: 15%; 1 H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.66 (s, 2H), 8.53 (t, J = 6.4 Hz, 1H), 7.49 (t, J = 2.0 Hz, 1H), 7.36 (d, J = 1.9 Hz, 2H), 4.58 (d, J = 6.3 Hz, 2H); MS calculated for C 13 H 10 Cl2N5O2[M+H] + 338.02, found 338.00.

[0132] Synthesis Example 47. 5-(2-((3,5-dibromobenzyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(8h) [ka] Yield: 65%; 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.69 - 8.63 (m, 2H), 8.52 (t, J = 6.4 Hz, 1H), 7.71 (t, J = 1.8 Hz, 1H), 7.53 (d, J = 1.8 Hz, 2H), 4.57 (d, J = 6.2 Hz, 2H); MS calculated for C 13 H 10 Br2N5O2[M+H] + 425.92, found 427.95.

[0133] Synthesis Example 48.5-(2-((benzo[d][1,3]dioxol-5-ylmethyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(8i) [ka] Yield: 33%; 1 H NMR (400 MHz, MeOD) δ 8.66 (s, 2H), 6.85 - 6.80 (m, 2H), 6.76 - 6.72 (m, 1H), 5.90 (s, 2H), 4.53 (s, 2H); MS calculated for C 14 H 12 N5O4[M+H] + 314.09, found 314.15.

[0134] Synthesis Example 49. 5-(2-((3,5-bis(trifluoromethyl)benzyl)aminopyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(8j) [ka] Yield: 10%; 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.71 - 8.51 (m, 3H), 8.02 - 7.95 (m, 3H), 4.78 - 4.70 (m, 2H); MS calculated for C 15 H 10 F6N6O2[M+H] + 406.07, found 405.95.

[0135] Synthesis example 50.5-(2-(phenethylamino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(13a) [ka] Yield: 7% 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.74 - 8.43 (m, 2H), 8.15 - 8.02 (m, 1H), 7.31 - 7.17 (m, 5H), 3.59 - 3.51 (m, 2H), 2.88 - 2.80 (m, 2H); MS calculated for C 14 H 14 N5O2[M+H] + 284.11, found 284.05.

[0136] Synthesis example 51. 5-(2-((3-fluorophenethyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(13b) [ka] Yield: 10%; 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.62 (d, J = 14.7 Hz, 2H), 8.05 (t, J = 5.8 Hz, 1H), 7.32 (td, J = 8.1, 6.3 Hz, 1H), 7.10 - 6.99 (m, 3H), 3.58 (dt, J = 7.7, 6.3 Hz, 2H), 2.88 (t, J = 7.2 Hz, 2H);MS calculated for C 14 H 13 FN5O2[M+H] + 302.10, found 302.05.

[0137] Synthesis example 52.5-(2-((4-fluorophenethyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(13c) [ka] Yield: 11%; 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.62 (d, J = 15.0 Hz, 2H), 8.04 (t, J = 5.8 Hz, 1H), 7.30 - 7.23 (m, 2H), 7.13 - 7.07 (m, 2H), 3.55 (dt, J = 7.8, 6.3 Hz, 2H), 2.85 (t, J = 7.3 Hz, 2H); MS calculated for C 14 H 13 FN5O2[M+H] + 302.10, found 302.05.

[0138] Synthesis example 53.5-(2-((3-chlorophenethyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(13d) [ka] Yield: 18%; 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.62 (d, J = 14.2 Hz, 2H), 8.05 (t, J = 5.8 Hz, 1H), 7.33 - 7.29 (m, 2H), 7.27 - 7.24 (m, 1H), 7.20 (dt, J = 7.4, 1.5 Hz, 1H), 3.57 (dt, J = 7.5, 6.4 Hz, 2H), 2.87 (t, J = 7.2 Hz, 2H); MS calculated for C 14 H 13 ClN5O2[M+H] + 318.08, found 318.00.

[0139] Synthesis example 54.5-(2-((4-chlorophenethyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(13e) [ka] Yield: 27%; 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.62 (d, J = 15.7 Hz, 2H), 8.04 (t, J = 5.8 Hz, 1H), 7.36 - 7.31 (m, 2H), 7.27 - 7.23 (m, 2H), 3.55 (dt, J = 7.7, 6.3 Hz, 2H), 2.85 (t, J = 7.2 Hz, 2H); MS calculated for C 14 H 13 ClN5O2[M+H] + 318.08, found 318.05.

[0140] Synthesis example 55.5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(18a) [ka] Yield: 30%; 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.76 - 8.55 (m, 2H), 8.32 (d, J = 6.9 Hz, 1H), 7.28 - 7.09 (m, 4H), 4.74 - 4.63 (m, 1H), 3.30 - 3.24 (m, 2H), 2.97 - 2.87 (m, 2H); MS calculated for C 15 H 14 N5O2[M+H] + 296.11, found 296.10.

[0141] Synthesis example 56. 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(18b) [ka] Yield: 42%; 1 H NMR (400 MHz, CD3OD) δ 8.67 (s, 2H), 7.11 (t, J = 9.1 Hz, 2H), 4.82 - 4.78 (m, 2H), 3.36 - 3.33 (m, 1H), 2.92 (dd, J = 15.9, 6.2 Hz, 2H); MS (ESI, m / z) calculated for C 15 H 12 F2N5O2[M+H] + 332.09, found 332.01.

[0142] Synthesis example 57. 5-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(18c) [ka] Yield: 15%; 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.66 (d, J = 14.5 Hz, 2H), 8.32 (d, J = 6.8 Hz, 1H), 7.43 (d, J = 1.9 Hz, 1H), 7.33 (dd, J = 8.0, MS calculated for C 15 H 13 BrN5O2[M+H] + 374.02, found 374.00.

[0143] General process (IV) for 9a-9j, 14a-14e, and 19a-19c Compounds 8a-8j, 13a-13e, and 18a-18c (1 mmol each) were dissolved in DMF (5 mL) with (1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane (3,1.2 mmol), DIEA (3.5 mmol), and BOP reagent (1.2 mmol). The reaction mixture was stirred at room temperature for 8 hours. After the reaction was complete, the solvent was evaporated. The crude product was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated. The product was separated by column chromatography (DCM / MeOH) to obtain compounds 9a-9j, 14a-14e, and 19a-19c.

[0144] Example 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-oxadiazole-2-yl)-N-benzylpyrimidine-2-amine(9a) [ka] Yield: 36%; 1 H NMR (400 MHz, Acetone-d6) δ 13.84 (s, 1H), 8.73 (s, 2H), 7.59 (s, 1H), 7.47 - 7.38 (m, 3H), 7.33 - 7.29 (m, 2H), 7.24 (td, J = 5.5, 2.5 Hz, 1H), 4.72 - 4.70 (m, 2H), 3.92 (d, J = 10.2 Hz, 2H), 3.74 - 3.71 (m, 2H), 2.81 (s, 1H), 2.16 (ddd, J = 3.7, 2.5, 1.3 Hz, 2H); 13C NMR (100 MHz, Acetone-d6) δ 162.83, 162.50, 155.73, 155.03, 147.04, 139.77, 130.67, 128.29, 127.37, 126.84, 109.30, 50.01, 44.59, 25.75 (d, J = 5.7 Hz), 17.77; HRMS (ESI, m / z) calculated for C 20 H 20 N9O + [M+H] + 402.1785, found 402.1785.

[0145] Example 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-oxadiazole-2-yl)-N-(3-chlorobenzyl)pyrimidine-2-amine(9b) [ka] Yield: 21% 1 H NMR (400 MHz, acetone-d6) δ 8.75 (s, 2H), 7.59 (s, 1H), 7.52 (t, J = 6.5 Hz, 1H), 7.44 - 7.41 (m, 1H), 7.36 - 7.32 (m, 2H), 7.30 - 7.25 (m, 1H), 4.72 (dd, J = 6.5, 0.7 Hz, 2H), 3.93 - 3.90 (m, 2H), 3.74 - 3.71 (m, 2H), 2.18 - 2.14 (m, 2H), 2.02 (t, J = 3.5 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 163.72, 163.53, 156.65, 156.00, 148.02, 143.45, 134.66, 131.67, 130.99, 128.28, 127.84, 126.88, 110.57, 51.01, 45.07, 26.71, 18.78; HRMS (ESI, m / z) calculated for C 20 H 19 ClN9O + [M+H] + 436.1396, found 436.1395.

[0146] Example 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-oxadiazole-2-yl)-N-(4-chlorobenzyl)pyrimidine-2-amine(9c) [ka] Yield: 24.4% 1 H NMR (400 MHz, Acetone-d6) δ 13.84 (s, 1H), 8.74 (s, 2H), 7.59 (s, 1H), 7.49 (dd, J = 11.8, 5.4 Hz, 1H), 7.43 - 7.40 (m, 2H), 7.36 - 7.32 (m, 2H), 4.70 (d, J = 6.4 Hz, 2H), 3.92 (d, J = 10.2 Hz, 2H), 3.74 - 3.70 (m, 2H), 2.16 (ddd, J = 3.7, 2.6, 1.3 Hz, 2H), 2.02 (t, J = 3.6Hz, 1H); 13C NMR (100 MHz, Acetone-d6) δ 163.71, 163.50, 156.65, 156.01, 148.01, 139.81, 133.05, 131.65, 130.13, 129.27, 110.45, 51.00, 44.93, 26.70, 18.79.; HRMS (ESI, m / z) calculated for C 20 H 19 ClN9O + [M+H] + 436.1396, found 436.1390.

[0147] Example 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-oxadiazole-2-yl)-N-(3,4-difluorobenzyl)pyrimidine-2-amine(9d) [ka] Yield: 31% 1 H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 8.76 (s, 2H), 8.47 (t, J = 6.4 Hz, 1H), 7.61 (s, 1H), 7.39 (tt, J = 7.9, 2.8 Hz, 2H), 7.21 - 7.18 (m, 1H), 4.58 (d, J = 6.2 Hz, 2H), 3.86 - 3.82 (m, 2H), 3.72 - 3.67 (m, 2H), 2.14 - 2.10 (m, 2H), 1.97 (t, J = 3.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 162.15, 162.07, 155.62, 155.27, 155.11, 150.00 (dd, J = 91.9, 12.6 Hz), 147.56 (dd, J = 90.3, 12.6 Hz), 146.46, 137.50 (dd, J = 5.3, 3.6 Hz), 130.88, 129.64, 123.74 (dd, J = 6.5, 3.4 Hz), 116.66 (dt, J = 105.5, 17.3 Hz), 108.54, 49.96, 43.15, 25.39, 17.60.; HRMS (ESI, m / z) calculated for C 20 H 18 F2N9O + [M+H] + 438.1597, found 438.1599.

[0148] Example 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-oxadiazole-2-yl)-N-(3,5-difluorobenzyl)pyrimidine-2-amine(9e) [ka] Yield: 35%; 1 H NMR (400 MHz, CDCl3) δ 12.91 (s, 1H), 8.80 (s, 2H), 7.49 (s, 1H), 6.90 - 6.84 (m, 2H), 6.71 (tt, J = 8.9, 2.4 Hz, 1H), 6.21 (t, J = 6.3 Hz, 1H), 4.70 (d, J = 6.4 Hz, 2H), 3.97 (d, J = 10.3 Hz, 2H), 3.79 - 3.74 (m, 2H), 2.17 (td, J = 3.1, 1.3 Hz, 2H), 1.98 (t, J = 3.6 Hz, 1H); 13C NMR (100 MHz, Acetone-d6) δ 163.99 (dd, J = 246.6, 12.8 Hz), 163.62, 163.48, 156.56, 156.01, 147.97, 145.88 (t, J = 8.6 Hz), 131.61, HRMS (ESI, m / z) calculated for C 20 H 18 F2N9O + [M+H] + 438.1597, found 438.1596.

[0149] Example 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-oxadiazole-2-yl)-N-(3,4-dichlorobenzyl)pyrimidine-2-amine(9f) [ka] Yield: 25%; 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 5.7 Hz, 2H), 8.46 (q, J = 7.8 Hz, 1H), 7.64 - 7.53 (m, 3H), 7.31 (dd, J = 8.3, 2.1 Hz, 1H), 4.58 - 4.51 (m, 2H), 3.81 (d, J = 10.2 Hz, 2H), 3.66 (dt, J = 10.2, 1.9 Hz, 2H), 2.11 - 2.06 (m, 2H), 1.94 (t, J = 3.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 162.11, 162.07, 155.63, 155.24, 155.10, 144.90, 141.00, 130.84, 130.49, 129.23, 129.07, 127.48, 108.62, 49.95, 43.07, 25.36, 17.29; HRMS (ESI, m / z) calculated for C 20 H 18 Cl2N9O + [M+H] + 470.1006, found 470.1007.

[0150] 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-oxadiazole-2-yl)-N-(3,5-dichlorobenzyl)pyrimidine-2-amine (9g) [ka] Yield: 15%; 1 H NMR (400 MHz, DMSO-d6) δ 14.66 (s, 1H), 8.73 (s, 2H), 8.45 (t, J = 6.4 Hz, 1H), 7.62 (s, 1H), 7.48 (t, J = 2.0 Hz, 1H), 7.36 (d, J = 1.9 Hz, 2H), 4.57 (d, J = 6.3 Hz, 2H), 3.84 - 3.79 (m, 2H), 3.68 - 3.64 (m, 2H), 2.11 - 2.07 (m, 2H), 1.94 (t, J = 3.6 Hz, 1H).; 13 C NMR (100 MHz, DMSO-d6) δ 162.08, 155.74, 155.22, 144.23, 133.93, 129.64, 126.51 - 126.32 (m), 125.84, 108.75, 54.91, 49.96, 43.23, 25.36.; HRMS (ESI, m / z) calculated for C20 H 18 Cl2N9O + [M+H] + 470.1006, found 470.1006.

[0151] 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-oxadiazole-2-yl)-N-(3,5-dibromobenzyl)pyrimidine-2-amine(9h) [ka] Yield: 22%; 1 H NMR (400 MHz, CDCl3) δ 12.06 (s, 1H), 8.83 (s, 2H), 7.60 (t, J = 1.8 Hz, 1H), 7.52 (s, 1H), 7.46 (dd, J = 1.6, 0.8 Hz, 2H), 6.03 (t, J = 6.3 Hz, 1H), 4.70 - 4.67 (m, 2H), 4.00 (d, J = 10.3 Hz, 2H), 3.79 (dt, J = 10.2, 1.9 Hz, 2H), 2.19 (ddd, J = 3.7, 2.5, 1.2 Hz, 2H), 2.01 (t, J = 3.5 Hz, 1H 13 C NMR (100 MHz, DMSO-d6) δ 162.07, 162.04, 155.66, 155.20, 155.10, 144.69, 131.69, 131.69, 129.07, 129.03, 122.36, 108.74, 49.95, 43.08, 25.34, 17.28. HRMS (ESI, m / z) calculated for C 20 H 18 Br2N9O + [M+H] + 557.9996, found 559.9979.

[0152] 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-oxadiazole-2-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidine-2-amine(9i) [ka] Yield: 35%; 1 H NMR (400 MHz, DMSO-d6) δ 14.66 (s, 1H), 8.71 (s, 2H), 8.34 (t, J = 6.4 Hz, 1H), 7.62 (s, 1H), 6.88 (d, J = 1.6 Hz, 1H), 6.85 - 6.82 (m, 1H), 6.80 - 6.77 (m, 1H), 5.96 (s, 2H), 4.46 (d, J = 6.4 Hz, 2H), 3.83 - 3.78 (m, 2H), 3.69 - 3.64 (m, 2H), 2.11 - 2.07 (m, 2H), 1.94 (t, J = 3.5 Hz, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 162.16, 162.02, 155.51, 155.33, 155.08, 147.19, 146.02, 144.43, 133.44, 129.62, 120.32, 108.20, 108.00, 107.80, 100.76, 49.95, 43.81, 25.35, 17.40; HRMS (ESI, m / z) calculated for C 21 H 20 N9O3[M+H] + 446.1684, found 446.1685.

[0153] 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-oxadiazole-2-yl)-N-(3,5-bis(trifluoromethyl)benzyl)pyrimidine-2-amine(9j) [ka] Yield: 43%; 1 H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J = 7.7 Hz, 2H), 8.54 (t, J = 6.3 Hz, 1H), 8.03 - 7.97 (m, 3H), 7.62 (s, 1H), 4.75 (d, J = 6.3 Hz, 2H), 3.81 (d, J = 10.2 Hz, 2H), 3.66 (dt, J = 10.2, 2.0 Hz, 2H), 2.08 (td, J = 3.1, 1.3 Hz, 2H), 1.93 (t, J = 3.5 Hz, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 162.58, 162.56, 156.22, 155.65, 145.35, 143.84, 130.62 (q, J = 32.5 Hz), 128.43 (d, J = 4.0 Hz), 123.85 (q, J = 272.8 Hz), 121.26 - 120.97 (m), 109.36, 50.43, 43.90, 25.83, 17.77; HRMS (ESI, m / z) calculated for C 22 H 18 F6N9O + [M+H] + 538.1533, found 538.1531.

[0154] 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-oxadiazole-2-yl)-N-phenethylpyrimidine-2-amine(14a) [ka] Yield: 36%; 1H NMR (400 MHz, DMSO-d6) δ 14.69 (s, 1H), 8.71 (d, J = 17.3 Hz, 2H), 7.96 (t, J = 5.8 Hz, 1H), 7.64 (s, 1H), 7.32 - 7.27 (m, 2H), 7.26 - 7.23 (m, 2H), 7.22 - 7.18 (m, 1H), 3.82 (d, J = 10.2 Hz, 2H), 3.67 (dt, J = 10.1, 1.9 Hz, 2H), 3.56 (ddd, J = 8.6, 7.5, 6.0 Hz, 2H), 2.87 (dd, J = 8.3, 6.5 Hz, 2H), 2.12 - 2.07 (m, 2H), 1.95 (t, J = 3.5 Hz, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 162.17, 162.01, 155.41, 155.11, 145.80, 139.44, 131.04, 128.68, 128.31, 126.07, 107.85, 49.96, 42.38, 34.77, 25.38, 17.39; HRMS (ESI, m / z) calculated for C 21 H 22 N9O + [M+H] + 416.1942, found 416.1942.

[0155] Example 12. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(3-fluorophenethyl)pyrimidine-2-amine(14b) [ka] Yield: 41% 1H NMR (400 MHz, DMSO-d6) δ 14.66 - 14.62 (m, 1H), 8.70 (d, J = 13.6 Hz, 2H), 7.97 (t, J = 5.8 Hz, 1H), 7.64 (s, 1H), 7.32 (td, J = 8.1, 6.4 Hz, 1H), 7.11 - 7.07 (m, 2H), 7.04 - 6.99 (m, 1H), 3.82 (d, J = 10.2 Hz, 2H), 3.67 (dt, J = 10.1, 1.9 Hz, 2H), 3.58 (dt, J = 7.7, 6.2 Hz, 2H), 2.89 (t, J = 7.2 Hz, 2H), 2.11 - 2.07 (m, 2H), 1.95 (t, J = 3.6 Hz, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 162.66 (d, J = 242.8 Hz), 162.65, 162.50, 155.87, 155.56, 145.41, 142.94 (d, J = 7.5 Hz), 130.59 (d, J = 8.3 Hz), 128.82, 125.36 (d, J = 2.5 Hz), 115.87 (d, J = 20.7 Hz), 113.32 (d, J = 20.7 Hz), 108.39, 50.44, 42.45, 34.80 (d, J = 1.7 Hz), 25.85, 17.77.; HRMS (ESI, m / z) calculated for C 21 H 21 FN9O + [M+H] + 434.1848, found 434.1847.

[0156] Example 13. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-fluorophenethyl)pyrimidine-2-amine(14c) [ka] Yield: 33%; 1 H NMR (400 MHz, DMSO-d6) δ 14.70 (s, 1H), 8.70 (d, J = 13.3 Hz, 2H), 7.96 (t, J = 5.8 Hz, 1H), 7.64 (s, 1H), 7.30 - 7.25 (m, 2H), 7.13 - 7.08 (m, 2H), 3.82 (d, J = 10.2 Hz, 2H), 3.67 (dt, J = 10.1, 1.9 Hz, 2H), 3.55 (dt, J = 7.9, 6.2 Hz, 2H), 2.86 (t, J = 7.3 Hz, 2H), 2.11 - 2.08 (m, 2H), 1.95 (t, J = 3.6 Hz, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 162.17, 161.21 (d, J = 240.1 Hz), 155.40, 155.08, 145.24, 135.59 (d, J = 3.0 Hz), 130.50, 130.43, 129.26, 115.06, 114.85, 107.87, 49.96, 42.36, 33.85, 25.38, 17.30; HRMS (ESI, m / z) calculated for C 21 H 21 FN9O + [M+H] + 434.1848, found 434.1847.

[0157] Example 14. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(3-chlorophenethyl)pyrimidine-2-amine(14d) [ka] Yield: 28% 1H NMR (400 MHz, DMSO-d6) δ 14.68 (s, 1H), 8.70 (d, J = 11.7 Hz, 2H), 7.96 (t, J = 5.8 Hz, 1H), 7.63 (s, 1H), 7.33 - 7.19 (m, 4H), 3.81 (d, J = 10.1 Hz, 2H), 3.66 (dt, J = 10.1, 1.9 Hz, 2H), 3.60 - 3.54 (m, 2H), 2.87 (t, J = 7.1 Hz, 2H), 2.09 (t, J = 2.6 Hz, 2H), 1.94 (t, J = 3.5 Hz, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 162.61, 162.45, 155.82, 155.51, 145.81, 142.55, 133.31, 130.53, 130.07, 129.03, 127.95, 126.50, 108.36, 50.40, 42.42, 34.66, 25.81, 17.77; HRMS (ESI, m / z) calculated for C 21 H 21 ClN9O + [M+H] + 450.1552, found 450.1554.

[0158] Example 15. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-chlorophenethyl)pyrimidine-2-amine(14e) [ka] Yield: 56% 1H NMR (400 MHz, DMSO-d6) δ 14.66 (s, 1H), 8.66 (d, J = 13.0 Hz, 2H), 7.91 (t, J = 5.8 Hz, 1H), 7.60 (s, 1H), 7.32 - 7.28 (m, 2H), 7.24 - 7.20 (m, 2H), 3.78 (d, J = 10.2 Hz, 2H), 3.63 (dt, J = 10.1, 1.9 Hz, 2H), 3.52 (dt, J = 7.7, 6.3 Hz, 2H), 2.82 (t, J = 7.2 Hz, 2H), 2.07 - 2.04 (m, 2H), 1.91 (t, J = 3.5 Hz, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 162.60, 162.45, 155.83, 155.51, 145.55, 138.94, 131.15, 131.04, 128.69 - 128.58 (m), 108.35, 50.40, 42.56, 34.40, 25.81, 17.74; HRMS (ESI, m / z) calculated for C 21 H 21 ClN9O + [M+H] + 450.1552, found 450.1552.

[0159] Example 16. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidine-2-amine (19a) [ka] Yield: 48%; 1H NMR (400 MHz, CDCl3+CD3OD) δ 8.76 (s, 2H), 7.50 (s, 1H), 7.28 - 7.15 (m, 4H), 4.84 (tt, J = 7.1, 5.5 Hz, 1H), 3.96 (d, J = 10.2 Hz, 2H), 3.82 - 3.77 (m, 2H), 3.41 (dd, J = 15.9, 7.2 Hz, 2H), 2.96 (dd, J = 15.9, 5.6 Hz, 2H), 2.22 - 2.18 (m, 2H), 2.00 - 1.97 (m, 1H); 13 C NMR (100 MHz, CD3OD) δ 162.48, 162.26, 156.46, 156.06, 146.06, 141.25, 130.70, 127.03, 125.02, 108.72, 52.96, 50.63, 40.01, 29.95, 25.96; HRMS (ESI, m / z) calculated for C 22 H 22 N9O + [M+H] + 428.1942, found 428.1943.

[0160] 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-oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidine-2-amine (19b) [ka] Yield: 76% 1H NMR (400 MHz, CDCl3+CD3OD) δ 8.77 (s, 2H), 7.50 (s, 1H), 7.05 (t, J = 8.9 Hz, 2H), 4.89 - 4.83 (m, 1H), 4.04 (s, 1H), 3.97 - 3.94 (m, 2H), 3.82 - 3.78 (m, 2H), 3.39 (d, J = 7.2 Hz, 1H), 3.34 (s, 1H), 2.92 (dd, J = 16.0, 5.8 Hz, 2H), 2.22 - 2.19 (m, 2H), 1.99 (t, J = 3.6Hz, 1H); 13 C NMR (100 MHz, CD3OD) δ 162.57, 162.30, 156.50, 156.13, 150.01 (dd, J = 246.8, 14.9 Hz), 137.69 - 137.19 (m), 130.07, 113.65 (dd, J = HRMS (ESI, m / z) calculated for C 22 H 20 F2N9O + [M+H] + 464.1753, found 464.1755.

[0161] 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-oxadiazole-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrimidine-2-amine(19c) [ka] Yield: 30%; 1H NMR (400 MHz, DMSO-d6) δ 14.71 (s, 1H), 8.74 (s, 2H), 8.23 ​​(d, J = 6.8 Hz, 1H), 7.63 (s, 1H), 7.42 (d, J = 1.9 Hz, 1H), 7.36 - 7.31 (m, 1H), 7.19 (d, J = 8.0 Hz, 1H), 4.68 (h, J = 6.9 Hz, 1H), 3.82 (d, J = 10.2 Hz, 2H), 3.67 (dt, J = 10.1, 1.9 Hz, 2H), 3.28 - 3.21 (m, 2H), 2.97 - 2.85 (m, 2H), 2.11 - 2.07 (m, 2H), 1.95 (t, J = 3.5 Hz, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 162.05, 161.90, 155.39, 155.12, 144.36, 140.80, 139.77, 129.16, 127.43, 126.61 - 126.49 (m), 119.26, 108.15, 66.36, 54.92, 52.23, 49.98, 38.72, 38.30, 25.39, 17.32; HRMS (ESI, m / z) calculated for C 22 H 21 BrN9O + [M+H] + 506.1047 was found.

[0162] Synthesis Example 58. Ethyl(E)-3-(2-クロロピリミジン-5-イル)アクリレート(21)

change

[0163] Synthesis Example 59. Ethyl(E)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-yl)acrylate(22) [ka] Compound 22 was synthesized using Compound 21 and 2-aminoindan according to general procedure (I); yield: 82%; 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 2H), 8.09 (d, J = 6.9 Hz, 1H), 7.50 (d, J = 16.1 Hz, 1H), 7.25 - 7.12 (m, 4H), 6.53 (d, J = 16.1 Hz, 1H), 4.66 (h, J = 7.1 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.26 (dd, J = 15.8, 7.6 Hz, 2H), 2.91 (dd, J = 15.8, 6.8 Hz, 2H), 1.25 (t, J = 7.1Hz, 3H).

[0164] Synthesis Example 60. Ethyl 3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-yl)propanoate (23) [ka] Compound 23 (1 mmol) was dissolved in EtOH (5 mL) / DCM (5 mL), and then palladium on carbon was added to the mixture at room temperature. The reaction mixture was stirred at room temperature under a hydrogen stream for 6 hours. The mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by column chromatography (ethyl acetate / hexane) to obtain the title compound; yield: 61%. 1 H NMR (400 MHz, CDCl3) δ 8.01 (s, 2H), 7.22 - 7.15 (m, 4H), 6.12 (t, J = 6.9 Hz, 1H), 4.78 (dqd, J = 7.2, 5.0, 2.4 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 3.37 (dd, J = 16.0, 7.1 Hz, 2H), 2.86 (dd, J = 16.0, 4.9 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 2.54 - 2.49 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H).

[0165] Synthesis Example 61. 3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-yl)propanoic acid (24) [ka] 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. The solvent was then evaporated, the mixture was dissolved again in water, and acidified with 1 M hydrochloric acid (pH 4-5) to obtain a white solid precipitate. The precipitate was filtered to obtain the title product; yield: 89%. 1 H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 8.19 (s, 2H), 7.29 (d, J = 6.8 Hz, 1H), 7.20 (dd, J = 5.4, 3.4 Hz, 2H), 7.16 - 7.10 (m, 2H), 4.57 (h, J = 7.1 Hz, 1H), 3.22 (dd, J = 15.7, 7.5 Hz, 2H), 2.86 (dd, J = 15.7, 7.0 Hz, 2H), 2.62 (t, J = 7.3 Hz, 2H).

[0166] Example 19.1-((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)pyrimidine-5-yl)propan-1-one(25) [ka] Compounds 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 the reaction was complete, the solvent was evaporated. The crude product was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated. The product was separated by column chromatography (DCM / MeOH) to obtain the title compound; yield: 50%. 1 H NMR (400 MHz, CDCl3) δ 8.18 (s, 2H), 7.42 (s, 1H), 7.23 - 7.13 (m, 4H), 5.77 (d, J = 7.7 Hz, 1H), 4.83 - 4.68 (m, 1H), 3.98 (d, J = 12.2 Hz, 1H), 3.67 - 3.58 (m, 2H), 3.54 - 3.48 (m, 1H), 3.37 (dd, J = 15.9, 7.1 Hz, 2H), 2.90 - 2.78 (m, 4H), 2.57 - 2.42 (m, 2H), 2.05 - 1.96 (m, 2H), 1.71 (t, J = 3.5 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 171.21, 160.90, 158.02, 146.17, 141.26, 129.70, 126.61, 124.78, 122.55, 52.54, 49.16, 48.33, 40.21, 36.23, 25.98, 24.88, 24.67, 18.47; HRMS (ESI, m / z) calculated for C 23 H 26 N7O + [M+H] + 416.2193, found 416.2193.

[0167] Example 20. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-(trifluoromethyl)benzyl)pyrimidine-2-amine(9k) [ka]

[0168] Step 1: Ethyl 2-((4-(trifluoromethyl)benzyl)aminopyrimidine-5-carboxylate (6k) (4-(trifluoromethyl)phenyl)methanamine (110 mg, 0.63 mmol) was dissolved in anhydrous 1,4-dioxane (2.1 mL), and then DIPEA (214 μL, 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. After 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 then vacuum-dried to obtain compound 6k (144 mg, yield: 78%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.85 (s, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 7.9 Hz, 2H), 6.05 (s, 1H), 4.78 (d, J = 6.2 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H); LCMS m / z 326[M+H] +

[0169] Stage 2: 2-((4-(trifluoromethyl)benzyl)aminopyrimidine-5-carbohydrazide (7k) The 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 then vacuum-dried to obtain compound 7k (107 mg, yield: 79%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 2H), 7.60 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.08 (s, 1H), 5.86 (s, 1H), 4.77 (d, J = 6.2 Hz, 2H), 4.06 (s, 2H); LCMS m / z 312[M+H] +

[0170] Stage 3: 5-(2-((4-(trifluoromethyl)benzyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(8k) Compound 7k (105 mg, 0.34 mmol) was dissolved in THF (1.8 mL) and cooled to 0°C. Then, TEA (47 μL, 0.34 mmol) and CDI (65.6 mg, 0.41 mmol) were slowly added, and the mixture was stirred at 0°C for 15 minutes. After stirring at room temperature for 20 hours, DW was added and the mixture was stirred for 30 minutes. The resulting solid was filtered and vacuum-dried to obtain compound 8k (107 mg, yield: 79%) as a white solid. LCMS m / z 338[M+H] +

[0171] Stage 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-oxadiazole-2-yl)-N-(4-(trifluoromethyl)benzyl)pyrimidine-2-amine(9k) 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. Then, DIPEA (76 μL, 0.45 mmol) was added and the mixture was stirred for 10 minutes. Next, BOP reagent (47.6 mg, 0.11 mmol) was added and the mixture was stirred at room temperature for 22 hours. After adding DW to the reaction mixture, it was extracted with ethyl acetate, and the organic layer was washed with brine. The organic layer was dried over MgSO4, filtered, concentrated, and the resulting residue was purified by silica gel column chromatography (0-1% MeOH / DCM). The collected residue was developed on prep-TLC (5% MeOH / DCM → 7% MeOH / DCM) to obtain compound 9k (6.5 mg, yield: 15%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 14.66 (s, 1H), 8.72 (s, 2H), 8.48 (t, J = 6.3 Hz, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.62 (s, 1H), 7.53 (d, J = 8.0 LCMS m / z 470[M+H] +

[0172] Example 21. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(3-(trifluoromethyl)benzyl)pyrimidine-2-amine (9l) [ka] The synthesis was carried out in the same manner as in Example 20, except that (3-(trifluoromethyl)phenyl)methaneamine was used instead of (4-(trifluoromethyl)phenyl)methaneamine.

[0173] Stage 1: Ethyl 2-((3-(trifluoromethyl)benzyl)aminopyrimidine-5-carboxylate (6L) Off-white solid (150 mg, yield: 81%); LCMS m / z 326[M+H] + Stage 2: 2-((3-(trifluoromethyl)benzyl)aminopyrimidine-5-carbohydrazide (7L) White solid (93 mg, yield: 65%); LC-MS m / z 312[M+H] + Stage 3: 5-(2-((3-(trifluoromethyl)benzyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(8l) White solid (90 mg, yield: 89%); LCMS m / z 338[M+H] + Stage 4: 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(3-(trifluoromethyl)benzyl)pyrimidine-2-amine(9l) Yellow solid (20 mg, yield: 38%); 1 H NMR (400 MHz, DMSO-d6) δ 14.73 (d, J = 168.1 Hz, 1H), 8.72 (s, 2H), 8.47 (t, J = 6.3 Hz, 1H), 7.68 - 7.53 (m, 5H), 4.66 (d, J = 6.3 Hz, LCMS m / z 470[M+H] +

[0174] Example 22. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(2-(trifluoromethyl)benzyl)pyrimidine-2-amine(9m) [ka] The synthesis was carried out in the same manner as in Example 20, except that (2-(trifluoromethyl)phenyl)methaneamine was used instead of (4-(trifluoromethyl)phenyl)methaneamine.

[0175] Step 1: Ethyl 2-((2-(trifluoromethyl)benzyl)aminopyrimidine-5-carboxylate (6m) Off-white solid (250 mg, yield: 71%); LC-MS m / z 326 [M+H] + Stage 2: 2-((2-(trifluoromethyl)benzyl)amino)pyrimidine-5-carbohydrazide (7m) White solid (194 mg, yield: 81%); 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.68 (s, 2H), 8.27 (t, J = 6.2 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.51 - 7.41 (m, 2H), 4.75 (d, J = 6.1 Hz, 2H), 4.41 (s, 2H); LCMS m / z 312[M+H] + Stage 3: 5-(2-((2-(trifluoromethyl)benzyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(8m) Off-white solid (141 mg, quantitative); LCMS m / z 338 [M+H] + Stage 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-oxadiazole-2-yl)-N-(2-(trifluoromethyl)benzyl)pyrimidine-2-amine(9m) Off-white solid (21 mg, yield: 51%); 1 H NMR (400 MHz, DMSO-d6) δ 14.65 (broad s, 1H), 8.72 (broad s, 2H), 8.42 (t, J = 6.1 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 7.6 Hz, 2H), 7.51 (d, J = 7.7 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 4.77 (d, J = 6.0 Hz, 2H), 3.81 (d, J = 10.2 Hz, 2H), 3.66 (d, J = 9.6 Hz, 2H), 2.09 (s, 2H), 1.94 (t, J = 3.4 Hz, 1H); LCMS m / z 470[M+H] +

[0176] Example 23. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-(difluoromethyl)benzyl)pyrimidine-2-amine(9n) [ka] The synthesis was carried out in the same manner as in Example 20, except that (4-(difluoromethyl)phenyl)methaneamine was used instead of (4-(trifluoromethyl)phenyl)methaneamine.

[0177] Step 1: Ethyl 2-((4-(difluoromethyl)benzyl)aminopyrimidine-5-carboxylate(6n) Off-white solid (165 mg, yield: 95%); 1H NMR (400 MHz, CDCl3) δ 8.85 (s, 2H), 7.49 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 6.63 (t, J = 56.5 Hz, 1H), 5.97 (s, 1H), 4.76 (d, LCMS m / z 308[M+H] + Stage 2: 2-((4-(difluoromethyl)benzyl)amino)pyrimidine-5-carbohydrazide(7n) Off-white solid (124 mg, yield: 80%); 1 LCMS m / z 294[M+H] + Stage 3: 5-(2-((4-(difluoromethyl)benzyl)aminopyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(8n) Off-white solid (106 mg, yield: 80%); LCMS m / z 320 [M+H] + Stage 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-oxadiazole-2-yl)-N-(4-(difluoromethyl)benzyl)pyrimidine-2-amine(9n) Off-white solid (16.5 mg, yield: 41%); 1H NMR (400 MHz, DMSO-d6) δ 14.52 (s, 1H), 8.71 (s, 2H), 8.45 (t, J = 6.3 Hz, 1H), 7.57 (s, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 6.99 (t, J = 56.0 Hz, 1H), 4.62 (d, J = 6.1 Hz, 2H), 3.81 (d, J = 10.2 Hz, 2H), 3.66 (d, J = 9.9 Hz, 2H), 2.08 (s, 2H), 1.94 (t, J = 3.3 Hz, 1H); LCMS m / z 452[M+H] +

[0178] 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-oxadiazole-2-yl)pyrimidine-2-yl)amino)methyl)benzonitrile(9o) [ka] It was synthesized in the same manner as in Example 20, except that 4-(aminomethyl)benzonitrile was used instead of (4-(trifluoromethyl)phenyl)methaneamine.

[0179] Step 1: Ethyl 2-((4-cyanobenzyl)amino)pyrimidine-5-carboxylate (60) Off-white solid (136 mg, yield: 81%); LCMS m / z 283 [M+H] + Stage 2: 2-((4-cyanobenzyl)amino)pyrimidine-5-carbohydrazide(70) Pale pink solid (92 mg, yield: 71%); LCMS m / z 269 [M+H] + Stage 3: 4-(((5-(5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl)amino)methyl)benzonitrile(80) Pale pink solid (85 mg, yield: 84%); LCMS m / z 295 [M+H] + Stage 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-oxadiazole-2-yl)pyrimidine-2-yl)amino)methyl)benzonitrile(9o) Pale pink solid (23 mg, yield: 49%); 1 H NMR (400 MHz, DMSO-d6) δ 14.67 (s, 1H), 8.72 (s, 2H), 8.48 (t, J = 6.3 Hz, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.62 (s, 1H), 7.50 (d, J = 8.2 LCMS m / z 427[M+H] +

[0180] 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-oxadiazole-2-yl)pyrimidine-2-yl)amino)methyl)benzonitrile(9p) [ka] The synthesis was carried out in the same manner as in Example 20, except that 3-(aminomethyl)benzonitrile was used instead of (4-(trifluoromethyl)phenyl)methaneamine.

[0181] Stage 1: Ethyl 2-((3-cyanobenzyl)amino)pyrimidine-5-carboxylate (6p) Yellow solid (175 mg, yield: 82%); LCMS m / z 283 [M+H] + Stage 2: 2-((3-cyanobenzyl)amino)pyrimidine-5-carbohydrazide (7p) White solid (139 mg, yield: 84%); LC-MS m / z 269 [M+H] + Stage 3: 3-(((5-(5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl)amino)methyl)benzonitrile(8p) Off-white solid (136 mg, yield: 89%); LCMS m / z 295 [M+H] + Stage 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-oxadiazole-2-yl)pyrimidine-2-yl)amino)methyl)benzonitrile(9p) Yellow solid (28 mg, yield: 59%); 1 H NMR (400 MHz, DMSO-d6) δ 14.64 (s, 1H), 8.73 (s, 2H), 8.44 (t, J = 6.3 Hz, 1H), 7.75 (s, 1H), 7.73 - 7.58 (m, 3H), 7.54 (t, J = 7.7 Hz, LCMS m / z 427[M+H] +

[0182] Example 26. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-(trifluoromethyl)phenethyl)pyrimidine-2-amine(14f) [ka] The synthesis was carried out in the same manner as in Example 20, except that 2-(4-(trifluoromethyl)phenyl)ethane-1-amine was used instead of (4-(trifluoromethyl)phenyl)methaneamine.

[0183] Step 1: Ethyl 2-((4-(trifluoromethyl)phenethyl)aminopyrimidine-5-carboxylate (11f) Light brown solid (245 mg, yield: 77%); LCMS m / z 340 [M+H] + Stage 2: 2-((4-(trifluoromethyl)phenethyl)amino)pyrimidine-5-carbohydrazide(12f) White solid (177 mg, yield: 83%); LCMS m / z 326 [M+H] + Stage 3: 5-(2-((4-(trifluoromethyl)phenethyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(13f) Yellow solid (123 mg, yield: 65%); 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.61 (d, J = 5.9 Hz, 2H), 8.03 (t, J = 5.8 Hz, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 3.61 (dd, J = 13.4, 6.7 Hz, 2H), 2.96 (t, J = 7.1 Hz, 2H); LCMS m / z 352 [M+H] + Stage 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-oxadiazole-2-yl)-N-(4-(trifluoromethyl)phenethyl)pyrimidine-2-amine(14f) White solid (7.5 mg, yield: 18%); 1 H NMR (400 MHz, DMSO-d6) δ 15.06 -14.42 (m, 1H), 8.70 (s, 2H), 7.95 (t, J = 5.8 Hz, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.58 (s, 1H), 7.47 (d, J = 8.0 Hz, 2H), 3.82 (d, J = 10.2 Hz, 2H), 3.67 (d, J = 10.3 Hz, 2H), 3.61 (dd, J = 13.5, 6.7 Hz, 2H), 2.98 (dd, J = 12.5, 5.3 Hz, 2H), 2.08 (s, 2H), 1.94 (s, 1H); LCMS m / z 484 [M+H] +

[0184] Example 27. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-bromophenethyl)pyrimidine-2-amine (14g) [ka] The synthesis was carried out in the same manner as in Example 20, except that 2-(4-bromophenyl)ethane-1-amine was used instead of (4-(trifluoromethyl)phenyl)methaneamine.

[0185] Stage 1: Ethyl 2-((4-bromophenethyl)amino)pyrimidine-5-carboxylate (11g) Off-white solid (150 mg, yield: 86%); LCMS m / z 350 [M+H] + Stage 2: 2-((4-bromophenethyl)amino)pyrimidine-5-carbohydrazide (12g) White solid (97 mg, yield: 67%); LCMS m / z 336 [M+H] + Stage 3: 5-(2-((4-bromophenethyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one (13g) Off-white solid (66 mg, yield: 63%); LCMS m / z 362 [M+H] + Stage 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-oxadiazole-2-yl)-N-(4-bromophenethyl)pyrimidine-2-amine (14g) Off-white solid (19 mg, yield: 35%); 1 H NMR (400 MHz, DMSO-d6) δ 15.08 - 14.43 (m, 1H), 8.69 (s, 2H), 7.91 (t, J = 5.8 Hz, 1H), 7.87 - 7.55 (m, 1H), 7.50 - 7.44 (m, 2H), 7.21 (d, J = 8.4 Hz, 2H), 3.82 (d, J = 10.2 Hz, 2H), 3.67 (d, J = 9.8 Hz, 2H), 3.61 - 3.52 (m, 2H), 2.84 (t, J = 7.2 Hz, 2H), 2.09 (s, 2H), 1.95 (t, J = 3.4 Hz, 1H); LCMS m / z 494 [M+H] +

[0186] Example 28. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(2-chlorophenethyl)pyrimidine-2-amine(14h) [ka] The synthesis was carried out in the same manner as in Example 20, except that 2-(2-chlorophenyl)ethane-1-amine was used instead of (4-(trifluoromethyl)phenyl)methaneamine.

[0187] Stage 1: Ethyl 2-((2-chlorophenethyl)amino)pyrimidine-5-carboxylate (11h) Off-white solid (167 mg, yield: 85%); LCMS m / z 306 [M+H] + Stage 2: 2-((2-chlorophenethyl)amino)pyrimidine-5-carbohydrazide (12h) White solid (126 mg, yield: 79%); LCMS m / z 292 [M+H] + Stage 3: 5-(2-((2-chlorophenethyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(13h) Off-white solid (95 mg, yield: 69%); LCMS m / z 318 [M+H] + Stage 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-oxadiazole-2-yl)-N-(2-chlorophenethyl)pyrimidine-2-amine(14h) Off-white solid (28 mg, yield: 56%); 1H NMR (400 MHz, DMSO-d6) δ 15.21 - 14.31 (m, 1H), 8.70 (s, 2H), 7.96 (t, J = 5.8 Hz, 1H), 7.88 - 7.47 (m, 1H), 7.41 (dd, J = 7.4, 1.8 Hz, 1H), 7.35 (dd, J = 7.2, 2.1 Hz, 1H), 7.29 - 7.21 (m, 2H), 3.82 (d, J = 10.2 Hz, 2H), 3.67 (d, J = 9.9 Hz, 2H), 3.63 - 3.56 (m, 2H), 3.00 (t, J = 7.2 Hz, 2H), 2.09 (s, 2H), 1.95 (t, J = 3.4 Hz, 1H); LCMS m / z 450 [M+H] +

[0188] Example 29. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(3,5-dichlorophenethyl)pyrimidine-2-amine(14i) [ka] The synthesis was carried out in the same manner as in Example 20, except that 2-(3,5-dichlorophenyl)ethane-1-amine was used instead of (4-(trifluoromethyl)phenyl)methaneamine.

[0189] Step 1: Ethyl 2-((3,5-dichlorophenethyl)amino)pyrimidine-5-carboxylate (11i) Light brown solid (144 mg, yield: 44%); 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 2H), 7.24 (t, J = 1.9 Hz, 1H), 7.12 (d, J = 1.9 Hz, 2H), 5.59 (t, J = 5.9 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.75 (dd, J = 13.5, 6.9 Hz, 2H), 2.90 (t, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H); LCMS m / z 340 [M+H] + Stage 2: 2-((3,5-dichlorophenethyl)amino)pyrimidine-5-carbohydrazide(12i) White solid (120 mg, yield: 86%); LCMS m / z 326 [M+H] + Stage 3: 5-(2-((3,5-dichlorophenethyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(13i) White solid (108 mg, yield: 84%); 1 H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 8.61 (s, 2H), 8.02 (t, J = 5.7 Hz, 1H), 7.41 (t, J = 1.8 Hz, 1H), 7.31 (d, J = 1.9 Hz, 2H), 3.59 (q, J = 6.7 Hz, 2H), 2.88 (t, J = 6.9 Hz, 2H); LCMS m / z 352[M+H] + Stage 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-oxadiazole-2-yl)-N-(3,5-dichlorophenethyl)pyrimidine-2-amine(14i) White solid (7 mg, yield: 17%); 1H NMR (400 MHz, DMSO-d6) δ 14.6 (s, 1H), 8.70 (s, 2H), 7.93 (t, J = 5.8 Hz, 1H), 7.61 (s, 1H), 7.41 (t, J = 1.8 Hz, 1H), 7.32 (d, J = 1.8 Hz, 2H), 3.82 (d, J = 10.2 Hz, 2H), 3.67 (d, J = 10.1 Hz, 2H), 3.59 (dd, J = 12.8, 6.6 Hz, 2H), 2.89 (t, J = 6.8 Hz, 2H), 2.09 (s, 2H), 1.94 (t, J = 3.5 Hz, 1H); LCMS m / z 483[M+H] +

[0190] Example 30. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-methoxyphenethyl)pyrimidine-2-amine(14j) [ka] The synthesis was carried out in the same manner as in Example 20, except that 2-(4-methoxyphenyl)ethane-1-amine was used instead of (4-(trifluoromethyl)phenyl)methaneamine.

[0191] Stage 1: Ethyl 2-((4-methoxyphenethyl)amino)pyrimidine-5-carboxylate (11j) Brown solid (122 mg, yield: 72%); 1H NMR (400 MHz, CDCl3) δ 8.83 (d, J = 31.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 5.56 (s, 1H), 4.35 (q, J = 7.1 Hz, LCMS m / z 302[M+H] + Stage 2: 2-((4-methoxyphenethyl)amino)pyrimidine-5-carbohydrazide(12j) Brown solid (44 mg, yield: 38%); 1 H NMR (400 MHz, CD3OD) δ 8.65 (s, 2H), 7.14 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 3.75 (s, 3H), 3.66 - 3.57 (m, 2H), 2.84 (t, J = 7.3 Hz, 2H); LCMS m / z 288[M+H] + Stage 3: 5-(2-((4-methoxyphenethyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(13j) Off-white solid (44 mg, yield: 38%); LCMS m / z 314[M+H] + Stage 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-oxadiazole-2-yl)-N-(4-methoxyphenethyl)pyrimidine-2-amine(14j) Off-white solid (13.7 mg, yield: 34%); 1H NMR (400 MHz, DMSO-d6) δ 14.52 (s, 1H), 8.70 (d, J = 9.6 Hz, 2H), 7.89 (t, J = 5.8 Hz, 1H), 7.58 (s, 1H), 7.15 (d, J = 8.6 Hz, 2H), 6.91 - 6.73 (m, 2H), 3.82 (d, J = 10.2 Hz, 2H), 3.71 (s, 3H), 3.67 (d, J = 9.9 Hz, 2H), 3.52 (dd, J = 14.5, 6.2 Hz, 2H), 2.79 (t, J = 7.4 Hz, 2H), 2.09 - 2.08 (m, 2H), 1.95 (t, J = 3.2 Hz, 1H); LCMS m / z 446 [M+H] +

[0192] Example 31. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-methylphenethyl)pyrimidine-2-amine(14k) [ka] The synthesis was carried out in the same manner as in Example 20, except that 2-(p-tolyl)ethane-1-amine was used instead of (4-(trifluoromethyl)phenyl)methaneamine.

[0193] Step 1: Ethyl 2-((4-methylphenethyl)amino)pyrimidine-5-carboxylate (11k) Light brown solid (167 mg, yield: 84%); LCMS m / z 286 [M+H] + Stage 2: 2-((4-methylphenethyl)amino)pyrimidine-5-carbohydrazide (12k) White solid (128 mg, yield: 81%); LCMS m / z 272[M+H] + Stage 3: 5-(2-((4-methylphenethyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(13k) White solid (72 mg, yield: 51%); 1 H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.62 (d, J = 17.7 Hz, 2H), 7.98 (t, J = 5.8 Hz, 1H), 7.15 - 7.00 (m, 4H), 3.58 - 3.49 (m, 2H), 2.81 (t, J = 7.4 Hz, 2H), 2.26 (s, 3H); LCMS m / z 298 [M+H] + Stage 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-oxadiazole-2-yl)-N-(4-methylphenethyl)pyrimidine-2-amine(14k) White solid (12 mg, yield: 32%); 1 H NMR (400 MHz, DMSO-d6) δ 15.14 - 14.35 (m, 1H), 8.69 (s, 2H), 7.89 (t, J = 5.8 Hz, 1H), 7.58 (s, 1H), 7.11 (q, J = 8.2 Hz, 4H), 3.82 (d, J = 10.2 Hz, 2H), 3.67 (d, J = 10.2 Hz, 2H), 3.53 (dd, J = 14.6, 6.2 Hz, 2H), 2.81 (t, J = 7.1 Hz, 2H), 2.26 (s, 3H), 2.09 (s, 2H), 1.94 (t, J = 3.5Hz, 1H); LCMS m / z 430 [M+H] +

[0194] 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-oxadiazole-2-yl)-N-(2-(pyridine-2-yl)ethyl)pyrimidine-2-amine (30a) [ka] The synthesis was carried out in the same manner as in Example 20, except that 2-(pyridine-2-yl)ethane-1-amine was used instead of (4-(trifluoromethyl)phenyl)methaneamine.

[0195] Step 1: Ethyl 2-((2-(pyridine-2-yl)ethyl)amino)pyrimidine-5-carboxylate (27a) Light brown solid (160 mg, yield: 73%); LCMS m / z 273[M+H] + Stage 2: 2-((2-(pyridine-2-yl)ethyl)amino)pyrimidine-5-carbohydrazide (28a) Yellow solid (144 mg, yield: 95%); LCMS m / z 259[M+H] + Stage 3: 5-(2-((2-(pyridine-2-yl)ethyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(29a) White solid (145 mg, yield: 92%); 1 H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 8.62 (d, J = 13.9 Hz, 2H), 8.52 - 8.47 (m, 1H), 8.00 (t, J = 5.8 Hz, 1H), 7.69 (td, J = 7.6, 1.9 LCMS m / z 285 [M+H] + Stage 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-oxadiazole-2-yl)-N-(2-(pyridine-2-yl)ethyl)pyrimidine-2-amine(30a) Yellow solid (8.9 mg, yield: 25%); 1 H NMR (400 MHz, DMSO-d6) δ 15.04 - 14.46 (m, 1H), 8.69 (s, 2H), 8.53 - 8.48 (m, 1H), 7.91 (t, J = 5.9 Hz, 1H), 7.69 (td, J = 7.6, 1.9 Hz, 1H), 7.58 (s, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.24 - 7.19 (m, 1H), 3.82 (d, J = 10.1 Hz, 2H), 3.76 - 3.65 (m, 4H), 3.02 (t, J = 7.3 Hz, 1H), 2.09 (s, 2H), 1.94 (t, J = 3.1 Hz, 1H); LCMS m / z 417[M+H] +

[0196] 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-oxadiazole-2-yl)pyrimidine-2-yl)amino)ethyl)benzonitrile (14l) [ka] The synthesis was carried out in the same manner as in Example 20, except that 4-(2-aminoethyl)benzonitrile was used instead of (4-(trifluoromethyl)phenyl)methaneamine.

[0197] Stage 1: Ethyl 2-((4-cyanophenethyl)amino)pyrimidine-5-carboxylate (11L) Brown solid (138 mg, yield: 83%); 1H NMR (400 MHz, CDCl3) δ 8.83 (s, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 5.61 (s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.78 (q, J LCMS m / z 297[M+H] + Stage 2: 2-((4-cyanophenethyl)amino)pyrimidine-5-carbohydrazide (12L) Off-white solid (70 mg, yield: 54%); 1 H NMR (400 MHz, CD3OD) δ 8.65 (s, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 3.70 (t, J = 7.2 Hz, 2H), 3.00 (t, J = 7.1 Hz, 2H); LCMS m / z 283[M+H] + Stage 3: 4-(2-((5-(5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl)amino)ethyl)benzonitrile (13L) Off-white solid (61 mg, yield: 82%); LCMS m / z 309 [M+H] + Stage 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-oxadiazole-2-yl)pyrimidine-2-yl)amino)ethyl)benzonitrile (14l) White solid (5.6 mg, yield: 14%); 1H NMR (400 MHz, DMSO-d6) δ 14.52 (s, 1H), 8.69 (s, 2H), 7.94 (t, J = 5.7 Hz, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 1.5 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 3.82 (d, J = 10.2 Hz, 2H), 3.67 (d, J = 9.7 Hz, 2H), 3.61 (dd, J = 13.2, 6.8 Hz, 2H), 2.96 (t, J = 7.1 Hz, 2H), 2.09 (s, 2H), 1.95 (t, J = 3.4 Hz, 1H); LCMS m / z 441[M+H] +

[0198] 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-oxadiazole-2-yl)-N-((R)-2,3-dihydro-1H-inden-1-yl)pyrimidine-2-amine (35a) [ka] The synthesis was carried out in the same manner as in Example 20, except that (R)-2,3-dihydro-1H-inden-1-amine was used instead of (4-(trifluoromethyl)phenyl)methaneamine.

[0199] Step 1: Ethyl(R)-2-((2,3-dihydro-1H-inden-1-yl)amino)pyrimidine-5-carboxylate(32a) Brown solid (175 mg, yield: 82%); LCMS m / z 284[M+H] + Stage 2: (R)-2-((2,3-dihydro-1H-inden-1-yl)amino)pyrimidine-5-carbohydrazide(33a) Off-white solid (105 mg, yield: 63%); LCMS m / z 270 [M+H] + Stage 3: (R)-5-(2-((2,3-dihydro-1H-inden-1-yl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(34a) Off-white solid (40 mg, yield: 35%); LCMS m / z 296 [M+H] + Stage 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-oxadiazole-2-yl)-N-((R)-2,3-dihydro-1H-inden-1-yl)pyrimidine-2-amine(35a) Yellow solid (26 mg, yield: 55%); 1 H NMR (400 MHz, DMSO-d6) δ 14.66 (s, 1H), 8.75 (s, 2H), 8.23 ​​(d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.27 - 7.13 (m, 4H), 5.61 (q, J = 8.0 Hz, 1H), 3.83 (d, J = 10.2 Hz, 2H), 3.68 (d, J = 10.0 Hz, 2H), 2.99 (ddd, J = 15.7, 8.7, 3.2 Hz, 1H), 2.89 - 2.78 (m, 1H), 2.49 - 2.43 (m, 1H), 2.10 (s, 2H), 2.03 - 1.92 (m, 2H); LCMS m / z 428[M+H] +

[0200] 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-oxadiazole-2-yl)-N-((S)-2,3-dihydro-1H-inden-1-yl)pyrimidine-2-amine (35b) [ka] The synthesis was carried out in the same manner as in Example 20, except that (S)-2,3-dihydro-1H-idden-1-amine was used instead of (4-(trifluoromethyl)phenyl)methaneamine.

[0201] Stage 1: Ethyl(S)-2-((2,3-dihydro-1H-inden-1-yl)amino)pyrimidine-5-carboxylate(32b) Brown solid (151 mg, yield: 71%); LCMS m / z 284[M+H] + Stage 2: (S)-2-((2,3-dihydro-1H-inden-1-yl)amino)pyrimidine-5-carbohydrazide(33b) White solid (122 mg, yield: 85%); LCMS m / z 270 [M+H] + Stage 3: (S)-5-(2-((2,3-dihydro-1H-inden-1-yl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(34b) Off-white solid (104 mg, yield: 78%); LCMS m / z 296 [M+H] + Stage 4: 5-(5-((1R,5S,6S)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-((S)-2,3-dihydro-1H-inden-1-yl)pyrimidine-2-amine(35b) Yellow solid (30 mg, yield: 63%); 1H NMR (400 MHz, DMSO-d6) δ 15.13 - 14.36 (m, 1H), 8.75 (s, 2H), 8.23 ​​(d, J = 8.5 Hz, 1H), 7.97 - 7.40 (m, 1H), 7.29 - 7.11 (m, 4H), 5.61 (q, J = 8.0 Hz, 1H), 3.83 (d, J = 10.2 Hz, 2H), 3.68 (d, J = 9.9 Hz, 2H), 2.99 (ddd, J = 15.7, 8.7, 3.2 Hz, 1H), 2.90 - 2.77 (m, 1H), 2.48 - 2.41 (m, 1H), 2.16 - 2.06 (m, 2H), 2.01 - 1.91 (m, 2H); LCMS m / z 428[M+H] +

[0202] Example 36. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-phenylpyrimidine-2-amine (30b) [ka] The synthesis was carried out in the same manner as in Example 20, except that aniline was used instead of (4-(trifluoromethyl)phenyl)methaneamine.

[0203] Stage 1: Ethyl 2-(phenylamino)pyrimidine-5-carboxylate (27b) Yellow solid (79 mg, yield: 61%); LCMS m / z 244[M+H] + Stage 2: 2-(phenylamino)pyrimidine-5-carbohydrazide (28b) White solid (112 mg, yield: 77%); LCMS m / z 230[M+H] + Stage 3: 5-(2-(phenylamino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(29b) Yellow solid (56 mg, yield: 56%); LCMS m / z 256 [M+H] + Stage 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-oxadiazole-2-yl)-N-phenylpyrimidine-2-amine(30b) Yellow solid (15 mg, yield: 35%); 1 H NMR (400 MHz, DMSO-d6) δ 15.17 - 14.30 (m, 1H), 10.14 (s, 1H), 8.89 (s, 2H), 7.77 (d, J = 7.7 Hz, 2H), 7.58 (d, J = 1.2 Hz, 1H), 7.36 - 7.29 (m, 2H), 7.02 (t, J = 7.4 Hz, 1H), 3.85 (d, J = 10.2 Hz, 2H), 3.69 (d, J = 9.9 Hz, 2H), 2.10 (s, 2H), 1.99 - 1.93 (m, 1H); LCMS m / z 388[M+H] +

[0204] Example 37. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-chlorophenethyl)-N-methylpyrimidine-2-amine (39) [ka]

[0205] Step 1: Ethyl 2-((4-chlorophenethyl)(methyl)amino)pyrimidine-5-carboxylate (36) Compound 11e (0.3 g, 0.981 mmol) was dissolved in DMF (9.8 mL), and then NaH (60%, dispersed in mineral oil) (59 mg, 1.47 mmol) was added at 0°C and the mixture was stirred for 30 minutes. Next, iodomethane (92 μL, 1.47 mmol) was added at the same temperature and the mixture was stirred at room temperature for 6 hours. Distilled water was added to the reaction mixture and extracted with siRNA, then dried over Na₂SO₄, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (10-15% siRNA in Hex) to obtain compound 36 (0.275 g, yield: 87.6%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 2H), 7.34 - 7.31 (m, 2H), 7.27 - 7.24 (m, 2H), 4.26 (q, J = 7.1 Hz, 2H), 3.92 - 3.86 (m, 2H), 3.11 (s, 3H), 2.91 - 2.85 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H); LCMS m / z 320[M+H] +

[0206] Steps 2-4 of Example 37 were synthesized in the same manner as steps 2-4 of Example 20. Stage 2: 2-((4-chlorophenethyl)(methyl)amino)pyrimidine-5-carbohydrazide(37) White solid (241 mg, yield: 92.3%); 1 H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.71 (s, 2H), 7.34 - 7.31 (m, 2H), 7.27 - 7.24 (m, 2H), 4.40 (s, 2H), 3.90 - 3.80 (m, 2H), 3.08 (s, 3H), 2.90 - 2.83 (m, 2H); LCMS m / z 306 [M+H] + Stage 3: 5-(2-((4-chlorophenethyl)(methyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(38) White solid (250 mg, yield: 95.6%); 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 2H), 7.35 - 7.31 (m, 2H), 7.28 - 7.25 (m, 2H), 3.91 - 3.84 (m, 2H), 3.10 (s, 3H), 2.92 - 2.85 (m, 2H). LCMS m / z 332 [M+H] + Stage 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-oxadiazole-2-yl)-N-(4-chlorophenethyl)-N-methylpyrimidine-2-amine(39) White solid (10 mg, yield: 23.8%); 1 H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 2H), 7.35 - 7.32 (m, 2H), 7.27 (d, J = 8.5 Hz, 2H), 3.91 - 3.85 (m, 2H), 3.82 (d, J = 10.2 Hz, 2H), 3.67 (d, J = 9.8 Hz, 2H), 3.11 (s, 3H), 2.91 - 2.87 (m, 2H), 2.09 (s, 2H), 1.95 (s, 1H), 1.24 (s, 1H); LCMS m / z 464[M+H] +

[0207] Example 38.1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazole-2-yl)butan-1-one(44b) [ka]

[0208] Stage 1: 2-Isothiocyanate-2,3-dihydro-1H-indene(40) 2,3-Dihydro-1H-inden-2-amine (478 mg, 3.58 mmol) and DIEA (1.83 mL, 10.7 mmol) were placed in a 20 mL dihydrochloride cell (DCM) and maintained at 0°C under nitrogen atmosphere. O,O'-Di-2-pyridylthiocarbonate (1.0 g, 4.3 mmol) was dissolved in a 5 mL DCM and added dropwise for 5 minutes. The reaction temperature was then raised to room temperature and the reaction was allowed to proceed for 12 hours. Distilled water was added to the reaction mixture 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 (100% n-hexane) to obtain compound 40 (560 mg, yield: 89%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.25 - 7.19 (m, 4H), 4.54 - 4.50 (m, 1H), 3.34 (dd, J = 20, 4.0 Hz, 2H), 3.18 (dd, J = 20, 4.0 Hz, 2H)

[0209] Stage 2: N-(2,3-dihydro-1H-inden-2-yl)hydrazinecarbothioamide (41) Compound 40 (560 mg, 3.19 mmol) was dissolved in EtOH (20 mL), then hydrazine monohydrate (776 μL, 16 mmol) was added, and the mixture was stirred at room temperature for 12 hours. After removing all the solvent, distilled water was added and the mixture was extracted with SiO2. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized with (SiO2 / n-hexane) to obtain compound 41 (580 mg, yield: 87%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.27 - 7.16 (m, 4H), 5.21 - 5.13 (m, 1H), 3.68 (s, 2H), 3.46 (dd, J = 20, 4.0 Hz, 2H), 2.96 (dd, J = 20, 4.0 Hz, 2H), 1.56 (s, 1H); LCMS m / z 208 [M+H] +

[0210] Step 3: Ethyl 4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazole-2-yl)butanoate (42b) Compound 41 (150 mg, 0.75 mmol) and ethyl 4-cyanobutanoate (106 mg, 0.75 mmol) were placed in TFA (4.5 mL) and stirred at 80°C for 12 hours. After removing all the solvent from the reaction mixture, the mixture was neutralized with saturated sodium bicarbonate aqueous solution 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 (0-2% MeOH in DCM) to obtain compound 42b (120 mg, yield: 50%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J = 8.0 Hz, 1H), 7.25 - 7.22 (m, 2H), 7.17 -7.13 (m, 2H), 4.43 (m, 1H), 4.07 (q, J = 8.0 Hz, 2H), 3.31 (dd, J = 24, 8.0 Hz, 2H), 2.91 - 2.81 (m, 4H), 2.37 (t, J = 8.0 Hz, 2H), 1.87 (t, J = 8.0 Hz, 2H), 1.18 (t, J = 8.0 Hz, 3H); LCMS m / z 332 [M+H] +

[0211] Stage 4: 4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazole-2-yl)butanoic acid (43b) Compound 42b (60 mg, 0.19 mmol) was dissolved in THF / MeOH (3.5 mL / 390 μL). To this mixture, a solution of LiOH (21.7 mg, 0.91 mmol) dissolved in H2O (390 μL) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, all solvent was removed, and the pH was adjusted to 3 using 1N HCl at 0°C. The resulting solid was filtered to obtain compound 43b (30 mg, yield: 55%) as a yellow solid. 1H NMR(400 MHz, DMSO-d6) δ 7.93 (d, J = 8.0 Hz, 1H), 7.25 - 7.22 (m, 2H), 7.17 -7.14 (m, 2H), 4.43 (m, 1H), 3.31 (dd, J = 24, 8.0 Hz, 2H), 2.91 - 2.81 (m, 4H), 2.30 (t, J = 8.0 Hz, 2H), 1.84 (t, J = 8.0 Hz, 2H); LCMS m / z 304[M+H] +

[0212] Stage 5: 1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazole-2-yl)butan-1-one(44b) The 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 μL, 0.35 mmol), and DCM (1.5 mL) was stirred at room temperature for 12 hours. Distilled water was added to the reaction mixture and extracted with DCM. The organic layer was then dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-25% MeOH in CH2Cl2) to obtain compound 44b (24 mg, yield: 56%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 14.5(s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.24 - 7.21 (m, 2H), 7.17 -7.14 (m, 2H), 4.43 (m, 1H), 3.76 (dd, J = 16, 4.0 Hz, 2H), 3.61 (dd, J = 12, 4.0 Hz, 1H), 3.38 (dd, J = 16, 4.0 Hz, 1H), 3.31 (dd, J = 24, 8.0 Hz, 2H), 2.91 - 2.81 (m, 4H), 2.39 - 2,22 (m, LCMS m / z 436 [M+H] +

[0213] Example 39.1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-3-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazole-2-yl)propan-1-one(44a) [ka] The synthesis was carried out in the same manner as in steps 3-5 of Example 38, except that ethyl 3-cyanopropanoate was used instead of ethyl 4-cyanobutanoate.

[0214] Step 1: Ethyl 3-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazole-2-yl)propanoate (42a) White solid (110 mg, yield: 46%); 1H NMR (400 MHz, CDCl3) δ 7.25 - 7.17 (m, 4H), 5.23 (s, 1H), 4.47 (s, 1H), 4.18 (q, J = 8.0 Hz, 2H), 3.42 (dd, J = 24, 8.0 Hz, 2H), 3.21 (t, LCMS m / z 318 [M+H] + Stage 2: 3-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazole-2-yl)propanoic acid (43a) White solid (38 mg, yield: 69%); 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 8.0 Hz, 1H), 7.25 - 7.14 (m, 4H), 4.42 (m, 1H), 3.30 (dd, J = 24, 8.0 Hz, 2H), 3.02 (t, J = 8.0 Hz, 2H), 2.90 (dd, J = 20, 4.0 Hz, 2H), 2.63 (t, J = 8.0 Hz, 2H); LCMS m / z 290 [M+H] + Stage 3: 1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-3-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazole-2-yl)propan-1-one(44a) White solid (30 mg, yield: 59%); 1H NMR (400 MHz, DMSO-d6) δ 14.6(s, 1H), 7.81 (d, J = 4.0 Hz, 1H), 7.24 - 7.14 (m, 4H), 4.42 (m, 1H), 3.77 - 3.74 (m, 2H), 3.64 (dd, J = 16, 4.0 Hz, 2H), 3.39 (dd, J = 16, 4.0 Hz, 2H), 3.30 (dd, J = 24, 8.0 Hz, 2H), 3.03 (t, J = 8.0 Hz, 2H), 2.90 (dd, J = 20, 4.0 Hz, 2H), 2.74 - 2.55 (m, 2H), 2.00(m, 1H), 1.92 (m, 1H), 1.75 (m, 1H). LCMS m / z 422[M+H] +

[0215] Example 40. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-chlorophenethyl)-4-methylpyrimidine-2-amine(30c) [ka] The synthesis was carried out in the same manner as in Example 20, except that 2-(4-chlorophenyl)ethane-1-amine was used instead of (4-(trifluoromethyl)phenyl)methaneamine, and ethyl 2-chloro-4-methylpyrimidine-5-carboxylate was used instead of ethyl 2-chloropyrimidine-5-carboxylate.

[0216] Step 1: Ethyl 2-((4-chlorophenethyl)amino)-4-methylpyrimidine-5-carboxylate(27c) Yellow solid (268 mg, yield: 86.9%); 1H NMR (400 MHz, CDCl3) δ 8.80 (broad s, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 5.41 (s, 1H), 4.32 (q, J = 7.1 Hz, 2H), 3.73 (dd, J = 13.3, 6.8 Hz, 2H), 2.89 (t, J = 7.0 Hz, 2H), 2.64 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H); LCMS m / z 320[M+H] + Stage 2: 2-((4-chlorophenethyl)amino)-4-methylpyrimidine-5-carbohydrazide(28c) White solid (214 mg, yield: 83%); 1 H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.24 (s, 1H), 7.47 (s, 1H), 7.33 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 4.37 (s, 2H), 3.50 (q, J = 6.8 Hz, 2H), 2.83 (t, J = 7.2 Hz, 2H), 2.38 (s, 3H); LCMS m / z 306[M+H] + Stage 3: 5-(2-((4-chlorophenethyl)amino)-4-methylpyrimidine-5-yl)-1,3,4-oxadiazole-2(3H)-one(29c) Off-white solid (41.4 mg, yield: 38%); LCMS m / z 332[M+H] + Stage 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-oxadiazole-2-yl)-N-(4-chlorophenethyl)-4-methylpyrimidine-2-amine(30c) Off-white solid (20.1 mg, yield: 48.5%); 1H NMR (400 MHz, DMSO-d6) δ 15.10- 14.35 (m, 1H), 8.57 (broad s, 1H), 7.87 - 7.69 (m, 1H), 7.60 - 7.46 (m, 1H), 7.33 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 3.81 (d, J = 10.1 Hz, 2H), 3.66 (d, J = 9.7 Hz, 2H), 3.61 - 3.47 (m, 2H), 2.93 - 2.78 (m, 2H), 2.55 (s, 3H), 2.08 (s, 2H), 1.95 (s, 1H); LCMS m / z 464[M+H] +

[0217] Example 41. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-chlorophenethyl)pyridine-2-amine(30d) [ka] The synthesis was carried out in the same manner as in Example 20, except that 2-(4-chlorophenyl)ethane-1-amine was used instead of (4-(trifluoromethyl)phenyl)methaneamine, and ethyl 6-chloronicotinate was used instead of ethyl 2-chloropyrimidine-5-carboxylate.

[0218] Stage 1: Ethyl 6-((4-chlorophenethyl)amino)nicotinate (27d) Off-white solid (130 mg, yield: 27.6%); LCMS m / z 305[M+H] + Stage 2: 6-((4-chlorophenethyl)amino)nicotinohydrazide (28d) Yellow solid (60.5 mg, yield: 49%); LC-MS m / z 291[M+H] + Stage 3: 5-(6-((4-chlorophenethyl)amino)pyridine-3-yl)-1,3,4-oxadiazole-2(3H)-one(29d) Yellow solid (80.5 mg, quantitative); LCMS m / z 317[M+H] + Stage 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-oxadiazole-2-yl)-N-(4-chlorophenethyl)pyridine-2-amine(30d) Off-white solid (24.5 mg, yield: 61%); 1 H NMR (400 MHz, DMSO-d6) δ 15.17 - 14.33 (m, 1H), 8.46 (d, J = 1.8 Hz, 1H), 7.77 (dd, J = 8.9, 2.0 Hz, 1H), 7.59 (broad s, 1H), 7.34 (d, J = 8.3 Hz, 2H), 7.31 - 7.21 (m, 3H), 6.58 (d, J = 8.8 Hz, 1H), 3.80 (d, J = 10.1 Hz, 2H), 3.66 (d, J = 9.7 Hz, 2H), 3.53 (q, J = 6.4 Hz, 2H), 2.85 (t, J = 7.1 Hz, 2H), 2.09 (s, 2H), 1.99 - 1.93 (m, 1H); LCMS m / z 449[M+H] +

[0219] Example 42. 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-chlorophenethyl)pyrazine-2-amine(30e) [ka] The synthesis was carried out in the same manner as in Example 20, except that 2-(4-chlorophenyl)ethane-1-amine was used instead of (4-(trifluoromethyl)phenyl)methaneamine, and ethyl 5-chloropyrazine-2-carboxylate was used instead of ethyl 2-chloropyrimidine-5-carboxylate.

[0220] Step 1: Ethyl 5-((4-chlorophenethyl)amino)pyrazine-2-carboxylate (27e) Brown solid (321 mg, yield: 68%); LCMS m / z 306[M+H] + Stage 2: 5-((4-chlorophenethyl)amino)pyrazine-2-carbohydrazide(28e) White solid (224 mg, yield: 73%); LC-MS m / z 292[M+H] + Stage 3: 5-(5-((4-chlorophenethyl)amino)pyrazine-2-yl)-1,3,4-oxadiazole-2(3H)-one(29e) Off-white solid (151 mg, yield: 62%); 1 H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 8.41 (s, 1H), 7.98 (s, 1H), 7.87 (t, J = 5.2 Hz, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 3.57 (dd, J = 13.0, 6.6 Hz, 2H), 2.86 (t, J = 7.1 Hz, 2H); LCMS m / z 318[M+H] + Stage 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-oxadiazole-2-yl)-N-(4-chlorophenethyl)pyrazine-2-amine(30e) Off-white solid (24.6 mg, yield: 61%); 1H NMR (400 MHz, DMSO-d6) δ 14.71 (broad s, 1H), 8.53 (d, J = 1.1 Hz, 1H), 7.98 (d, J = 1.2 Hz, 1H), 7.76 (t, J = 5.4 Hz, 1H), 7.58 (broad s, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 3.80 (d, J = 10.1 Hz, 2H), 3.68 (d, J = 9.7 Hz, 2H), 3.56 (q, J = 6.8 Hz, 2H), 2.87 (t, J = 7.1 Hz, 2H), 2.09 (s, 2H), 2.02 - 1.92 (m, 1H); LCMS m / z 450[M+H] +

[0221] Example 43.1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-3-(2-((4-chlorophenethyl)amino)pyrimidine-5-yl)propan-1-one(49a) [ka] Step 1: Ethyl 3-(2-chloropyrimidine-5-yl)propanoate (46a) Compound 21(45a) (424 mg, 2.0 mmol) was dissolved in SiO (20 mL), and then Pd / C (300 mg) was added and the mixture was reacted under a hydrogen atmosphere for 12 hours. After the reaction was complete, 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. 1 H NMR (400 MHz, CDCl3) δ 8.51 (s, 2H), 4.14 (q, J = 8.0 Hz, 2H), 2.94 (t, J = 8.0 Hz, 2H), 2.65 (t, J = 8.0 Hz, 2H),1.24 (t, J = 8.0 Hz, 3H); LCMS m / z 215 [M+H] +

[0222] Step 2: Ethyl 3-(2-((4-chlorophenethyl)amino)pyrimidine-5-yl)propanoate (47a) A mixture of 2-(4-chlorophenyl)ethane-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 in a microwave reactor at 150°C for 2 hours. After the reaction was complete, all solvent was removed, and the mixture was extracted with distilled water using DCM. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-5% MeOH in CH2Cl2) to obtain compound 47a (68 mg, yield: 9%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.98 (t, J = 8.0 Hz, 1H), 4.05 (q, J = 8.0 Hz, LCMS m / z 334 [M+H] +

[0223] Stage 3: 3-(2-((4-chlorophenethyl)amino)pyrimidine-5-yl)propanoic acid (48a) Compound 47a (65 mg, 0.19 mmol) was dissolved in THF / MeOH (3.4 mL / 387 μL). A solution of LiOH (23.3 mg, 0.97 mmol) dissolved in H2O (387 μL) was added to this mixture and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, all solvent was removed and the pH was adjusted to 3 using 1N HCl at 0°C. The resulting solid was filtered to obtain compound 48a (33 mg, 59%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.96 (t, J = 8.0 Hz, 1H), 3.46 (q, J = 8.0 Hz, LCMS m / z 306 [M+H] +

[0224] Stage 4: 1-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-3-(2-((4-chlorophenethyl)amino)pyrimidine-5-yl)propan-1-one(49a) The 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 μL, 0.35 mmol), and DCM (1.0 mL) was stirred at room temperature for 12 hours. Distilled water was added to the reaction mixture and extracted with DCM. The organic layer was then dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-5% MeOH in CH2Cl2) to obtain compound 49a (40 mg, yield: 93%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 14.6(s, 1H), 8.16 (s, 2H), 7.56 (s, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.95 (t, J = 8.0 Hz, 1H), 3.72 (t, J = 8.0 Hz, 2H), 3.58 (dd, J = 16, 4.0 Hz, 1H), 3.46 (q, J = 8.0 Hz, 2H), 3.36 (dd, J = 16, 4.0 Hz, 1H),2.81 (t, J = 8.0 Hz, 2H), 2.60 (q, J = 8.0 Hz, 2H), 2.53 -2.39 (m, 2H), 2.05(m, 1H), 1.96 (m, 1H), 1.79 (m, 1H); LCMS m / z 438 [M+H] +

[0225] Example 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)pyrimidine-5-yl)butan-1-one(49b) [ka]

[0226] Stage 1: Ethyl(E)-4-(2-chloropyrimidine-5-yl)buto-3-enoate(45b) A reaction mixture of 5-bromo-2-chloropyrimidine (400 mg, 2.1 mmol), ethyl buto-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 hours. After removing all solvent, distilled water was added and the mixture was 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 (20-30% siRNA in n-hexane) to obtain compound 45b (40 mg, 8%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 2H), 6.64 (m, 1H), 6.56 (d, J = 16 Hz, 1H), 4.12 (q, J = 8.0 Hz, 2H), 3.35 (d, J = 8.0 Hz, 2H), 1.21 (t, J = 8.0 Hz, 3H); LCMS m / z 227 [M+H] +

[0227] Stage 2: Ethyl 4-(2-chloropyrimidine-5-yl)butanoate (46b) It was synthesized in the same manner as in Step 1 of Example 43. Yellow liquid (30 mg, yield: 74%); 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 2H), 4.04 (q, J = 8.0 Hz, 2H), 2.63 (t, J = 8.0 Hz, 2H), 2.32 (t, J = 8.0 Hz, 2H), 1.86 (m, 2H), 1.17 (t, J = 8.0 Hz, 3H); LCMS m / z 229 [M+H] +

[0228] Stage 3: Ethyl 4-(2-((3,5-dichlorobenzyl)amino)pyrimidine-5-yl)butanoate (47b) The synthesis was carried out in the same manner as in Step 2 of Example 43, except that (3,5-dichlorophenyl)methaneamine was used instead of 2-(4-chlorophenyl)ethane-1-amine. Yellow liquid (15 mg, yield: 31%); 1 H NMR (400 MHz, DMSO-d6)δ8.14 (s, 2H), 7.58 (m, 1H), 7.43 (m, 1H), 7.33 (d, J = 4.0 Hz, 2H), 4.48 (d, J = 8.0 Hz, 2H), 4.02 (q, J = 8.0 Hz, LCMS m / z 368[M+H] +

[0229] Stage 4: 4-(2-((3,5-dichlorobenzyl)amino)pyrimidine-5-yl)butanoic acid (48b) It was synthesized in the same manner as in step 3 of Example 43. White solid (7 mg, yield: 51%); 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 2H), 7.57 (m, 1H), 7.42 (m, 1H), 7.33 (d, J = 4.0 Hz, 2H), 4.48 (d, J = 8.0 Hz, 2H), 2.39 (t, J = 8.0 Hz, 2H), 2.19 (t, J = 8.0 Hz, 2H), 1.72 (m, 2H); LCMS m / z 368[M+H] +

[0230] Stage 5: 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)pyrimidine-5-yl)butan-1-one(49b) It was synthesized in the same manner as in step 4 of Example 43. White solid (6 mg, yield: 63%);1 H NMR (400 MHz, DMSO-d6) δ 14.6(s, 1H), 8.15 (s, 2H), 7.56 (m, 2H), 7.42 (m, 1H), 7.33 (d, J = 4.0 Hz, 2H), 4.48 (d, J = 8.0 Hz, 2H), 3.70 (t, J = 8.0 Hz, 2H), 3.59 (dd, J = 12, 4.0 Hz, 1H), 3.35 (dd, J = 16, 4.0 Hz, 1H), 2.40 (t, J = 8.0 Hz, 2H), 2.27 - 2.15 (m, 2H), 1.97 (m, 1H), 1.89 (m, 1H), 1.77 - 1.68 (m, 3H); LCMS m / z 472[M+H] +

[0231] Example 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-chlorophenethyl)amino)pyrimidine-5-yl)prop-2-en-1-one(52a) [ka]

[0232] Step 1: Ethyl (E)-3-(2-((4-chlorophenethyl)amino)pyrimidine-5-yl)acrylate (50a) A mixture of 2-(4-chlorophenyl)ethane-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 the reaction was complete, all solvent was removed, distilled water was added, and the resulting solid was filtered to obtain compound 50a (500 mg, yield 53%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 2H), 7.78 (t, J = 8.0 Hz, 1H), 7.49 (d, J = 16 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, LCMS m / z 332[M+H] +

[0233] Stage 2: (E)-3-(2-((4-chlorophenethyl)amino)pyrimidine-5-yl)acrylic acid (51a) It was synthesized in the same manner as in step 3 of Example 43. White solid (120 mg, yield: 88%); 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 2H), 7.73 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 16 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, LCMS m / z 304[M+H] +

[0234] Stage 3: (E)-1-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-3-(2-((4-chlorophenethyl)amino)pyrimidine-5-yl)prop-2-en-1-one(52a) It was synthesized in the same manner as in step 4 of Example 43. White solid (17 mg, yield: 32%); 1H NMR (400 MHz, DMSO-d6) δ 14.6(s, 1H), 8.64 (s, 2H), 7.67 (t, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.34 - 7.24 (m, 5H), 6.87 (d, J = 16 Hz, 1H), 4.09 (d, J = 12 Hz, 1H), 3.88 (d, J = 12 Hz, 1H), 3.73 (m, 1H), 3.56 - 3.45 (m, 3H), 2.84 (t, J = 8.0 Hz, 2H), 2.05(m, 1H), 1.96 (m, 1H), 1.78 (m, 1H); LCMS m / z 436[M+H] +

[0235] Example 46. (E)-1-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-yl)prop-2-en-1-one(52b) [ka]

[0236] Step 1: Ethyl(E)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-yl)acrylate(50b) It was synthesized 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)ethane-1-amine. Brown solid (260 mg, yield: 84%); 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 2H), 8.06 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 16 Hz, 1H), 7.22 - 7.19 (m, 2H), 7.16 - 7.13 (m, 2H), 6.54 (d, J = 16 Hz, 1H), 4.69 - 4.64 (m, 1H), 4.18 (q, J = 8.0 Hz, 2H), 3.27 (dd, J = 16, 4.0 Hz, 2H), 2.90 (dd, J = 16, 4.0 Hz, 2H), 1.25 (t, J = 8.0 Hz, 3H); LCMS m / z 310 [M+H] +

[0237] Stage 2: (E)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-yl)acrylic acid (51b) It was synthesized in the same manner as in step 3 of Example 43. White solid (120 mg, yield: 89%); 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 2H), 8.01 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 16 Hz, 1H), 7.22 - 7.19 (m, 2H), 7.16 - 7.13 (m, 2H), 6.44 (d, J = 16 Hz, 1H), 4.69 - 4.64 (m, 1H), 3.29 (dd, J = 16, 4.0 Hz, 2H), 2.94 (dd, J = 16, 4.0 Hz, 2H); LCMS m / z 282[M+H] +

[0238] Stage 3: (E)-1-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-yl)prop-2-en-1-one(52b) It was synthesized in the same manner as in step 4 of Example 43. Yellow solid (18 mg, yield: 36%); 1 H NMR (400 MHz, DMSO-d6) δ 14.5(s, 1H), 8.66 (s, 2H), 7.94 (d, J = 8.0 Hz, 1H), 7.59 (s, 1H), 7.36 (d, J = 16 Hz, 1H), 7.22 - 7.19 (m, 2H), 7.16 - 7.13 (m, 2H), 6.89 (d, J = 16 Hz, 1H), 4.71 -4.62 (m, 1H), 4.09 (d, J = 12 Hz, 1H), 3.89 (d, J = 12 Hz, 1H), 3.75 (dd, J = 16, 4.0 Hz, 1H), 3.49 (dd, J = LCMS m / z 414[M+H] +

[0239] Example 47. N-(4-chlorophenethyl)-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-oxadiazole-2-yl)pyrimidine-2-amine(55) [ka]

[0240] Step 1: tert-butyl(1R,5S,6r)-6-(1-methyl-1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(53) Compound 3 (0.150 g, 0.599 mmol) was dissolved in DMF (6.0 mL), and then NaH (60%, dispersed in mineral oil) (28.8 mg, 0.719 mmol) was added at 0°C and the mixture was stirred for 30 minutes. Next, iodomethane (CH3I) (37 μL, 0.599 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 and extracted with RINKAN, followed by several washes 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. 1 H NMR (400 MHz, DMSO-d6) δ 7.51 (s, 1H), 4.03 (s, 3H), 3.56 (d, J = 11.0 Hz, 2H), 1.87 (t, J = 2.7 Hz, 2H), 1.68 (t, J = 3.5 Hz, 1H), 1.39 (s, 9H)

[0241] Stage 2: (1R,5S,6r)-6-(1-methyl-1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (54) Compound 53 (50 mg, 0.189 mmol) was dissolved in 1,4-dioxane (0.7 mL). 4M HCl (0.47 mL, 1.89 mmol in the dioxane) was slowly added to this mixture, and the mixture was 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. 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 7.54 (s, 1H), 4.05 (s, 3H), 3.42 (d, J = 11.7 Hz, 2H), 3.33 (d, J = 13.0 Hz, 2H), 2.18 (t, J = 3.7 Hz, 1H), 2.06 (d, J = 2.5 Hz, 2H)

[0242] Stage 3: N-(4-chlorophenethyl)-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-oxadiazole-2-yl)pyrimidine-2-amine(55) Compound 13e (38 mg, 0.120 mmol) and compound 54 (28.8 mg, 0.144 mmol) were dissolved in DMF (0.6 mL) and the mixture was cooled to 0°C. DIEA (61 μL, 0.359 mmol) was added, and the mixture was stirred for 30 minutes. At the same temperature, BOP reagent (63.9 mg, 0.144 mmol) was added, and the mixture was stirred at room temperature for 15 hours. Distilled water was added to the reaction mixture, and it was extracted with SiO2, followed by several washes 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. 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 2H), 7.92 (t, J = 5.7 Hz, 1H), 7.54 (s, 1H), 7.35 - 7.32 (m, 2H), 7.26 (d, J = 8.5 Hz, 2H), 4.05 (s, 3H), 3.81 (d, J = 10.2 Hz, 2H), 3.66 (d, J = 10.3 Hz, 2H), 3.56 (dd, J = 13.7, 6.5 Hz, 2H), 2.86 (t, J = 7.2 Hz, 2H), 2.07 (s, 2H), 1.91 (d, J = 2.0 Hz, 1H); LCMS m / z 464 [M+H] +

[0243] Example 48. N-(4-chlorophenethyl)-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-oxadiazole-2-yl)pyrimidine-2-amine (59) [ka]

[0244] Step 1: tert-butyl(1R,5S,6s)-6-(prop-1-in-1-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(56) Compound 2 (400 mg, 1.93 mmol) was dissolved in THF (6 mL), and the mixture was maintained at -78°C under nitrogen atmosphere. Then, 2.5 M n-BuLi (0.77 mL, 1.93 mmol) was added dropwise for 10 minutes, followed by stirring for 30 minutes. The reaction temperature was raised to room temperature, CH3I (181 μL, 2.9 mmol) was added, and the mixture was reacted for 12 hours. Distilled water was added to the reaction mixture, and it was extracted with siRNA. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (10% siRNA in n-hexane) to obtain compound 56 (390 mg, yield: 91%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 3,63 - 3.52 (m, 2H), 3.35 - 3.33 (m, 2H), 1.83 - 1.81 (m, 2H), 1.76 (s, 3H), 1.43 (s, 9H), 1.12 - 1.09 (m, 1H)

[0245] Step 2: tert-butyl(1R,5S,6r)-6-(4-methyl-1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(57) Compound 56 (200 mg, 0.9 mmol) and TMSN3 (180 μL, 1.39 mmol) were reacted in a microwave reactor at 200°C for 7 hours. After concentrating the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to obtain compound 57 (32 mg, 13%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.99 (s, 1H), 3.79 - 3.67 (m, 2H), 3.48 - 3.46 (m, 2H), 2.32 (s, 3H), 2.03 - 1.95 (m, 2H), 1.63 -1.61 (m, 1H), 1.47 (s, 9H)

[0246] Stage 3: (1R,5S,6r)-6-(4-methyl-1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (58) Compound 57 (30 mg, 0.11 mmol) was dissolved in 1,4-dioxane (1 mL) to prepare a reaction mixture to which 4 M HCl (282 μL, 1.1 mmol) from the dioxane was added. After reacting at room temperature for 3 hours, 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. 1 H NMR (400 MHz, CD3OD)δ 3.66 - 3.57 (m, 4H), 2.40 (s, 3H), 2.35 (m, 2H), 2.15 (m, 1H)

[0247] Stage 4: N-(4-chlorophenethyl)-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-oxadiazole-2-yl)pyrimidine-2-amine(59) Compound 58 (20 mg, 0.1 mmol) was added to a reaction mixture prepared by dissolving compound 13e (25 mg, 0.08 mmol) 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 and extracted with SiO, after which the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to obtain compound 59 (13 mg, yield: 35%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 14.1(s, 1H), 8.69 (s, 2H), 7.91 (m, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 3.83 (d, J = 8.0 Hz, 2H), 3.68 (d, J = 8.0 Hz, 2H), 3.58 (q, J = 8.0 Hz, 2H), 2.86 (t, J = 8.0 Hz, 2H), 2.23 (s, 3H), 2.08(m, 2H), 1.84 (m, 1H); LCMS m / z 464 [M+H] +

[0248] Example 49. 5-(3-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-4,5-dihydroisoxazole-5-yl)-N-(4-chlorophenethyl)pyrimidine-2-amine(63a) [ka]

[0249] Stage 1: N-(4-chlorophenethyl)-5-vinylpyrimidine-2-amine (61a) A reaction mixture of 2-(4-chlorophenyl)ethane-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 (10-30% EA in Hex) to obtain compound 61a (0.315 g, 62.9%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 2H), 7.35 - 7.31 (m, 3H), 7.27 - 7.23 (m, 2H), 6.56 - 6.46 (m, 1H), 5.69 (dd, J = 17.8, 0.9 Hz, 1H), 5.08 (dd, J = 11.2, 0.9 Hz, 1H), 3.54 - 3.43 (m, 2H), 2.83 (t, J = 7.3 Hz, 2H); LCMS m / z 260[M+H] +

[0250] Stage 2: 5-(3-bromo-4,5-dihydroisoxazole-5-yl)-N-(4-chlorophenethyl)pyrimidine-2-amine (62a) 1,1-Dibromoformaldehyde (0.484 g, 2.39 mmol) was dissolved in DMF (3.0 mL), cooled to -10°C, and compound 61a (0.31 g, 1.18 mmol) was added. To this reaction mixture, a solution of KHCO3 (0.299 g, 2.98 mmol) dissolved in H2O (3.0 mL) was slowly added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, distilled water was added, and the mixture was extracted with SiO2, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (0-1% MeOH in DCM) to obtain compound 62a (0.41 g, 90.0%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 2H), 7.43 (t, J = 5.7 Hz, 1H), 7.34 - 7.31 (m, 2H), 7.25 (d, J = 8.4 Hz, 2H), 5.55 (t, J = 10.4 Hz, LCMS m / z 381[M+H] +

[0251] Stage 3: 5-(3-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-4,5-dihydroisoxazole-5-yl)-N-(4-chlorophenethyl)pyrimidine-2-amine(63a) The 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 t-butanol (4.2 mL) was reacted in a microwave reactor at 200°C for 3 hours. After filtering the reaction mixture, the concentrated residue was purified by silica gel column chromatography (0-1% MeOH in DCM) to obtain compound 63a (9.9 mg, 10.5%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 5.25 - 5.19 (m, 1H), 4.04 (tdd, J = 7.1, 4.8, 2.7 Hz, 1H), 3.49 (s, 2H), 3.40 (t, J = 9.2 Hz, 2H), 3.36 - 3.31 (m, 1H), 3.17 (d, J = 5.3 Hz, 2H), 2.86 - 2.81 (m, 2H), 1.98 (d, J = 5.5Hz, 2H), 1.92 - 1.87 (m, 2H); LCMS m / z 451[M+H] +

[0252] Example 50. 5-(3-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-4,5-dihydroisoxazole-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidine-2-amine(63b) [ka] The compound was synthesized in the same manner as in Example 49, except that 2,3-dihydro-1H-inden-2-amine was used instead of 2-(4-chlorophenyl)ethane-1-amine.

[0253] Stage 1: N-(2,3-dihydro-1H-inden-2-yl)-5-vinylpyrimidine-2-amine(61b) Yellow solid (281 mg, yield: 78.9%); 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 2H), 7.59 (d, J = 6.8 Hz, 1H), 7.20 (dt, J = 7.2, 3.5 Hz, 2H), 7.16 - 7.12 (m, 2H), 6.54 (dd, J = 17.8, 11.2 Hz, 1H), 5.71 (dd, J = 17.8, 0.8 Hz, 1H), 5.10 (dd, J = 11.2, 0.8 Hz, 1H), 4.67 - 4.57 (m, 1H), 3.24 (dd, J = 15.8, 7.6 Hz, 2H), 2.89 (dd, J = 15.7, 6.9 Hz, 2H); LCMS m / z 238[M+H] + Stage 2: 5-(3-bromo-4,5-dihydroisoxazole-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidine-2-amine(62b) White solid (249 mg, yield: 59%); 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 2H), 7.70 (d, J = 6.9 Hz, 1H), 7.20 (dt, J = 7.1, 3.5 Hz, 2H), 7.15 - 7.12 (m, 2H), 5.56 (t, J = 10.4 Hz, 1H), 4.61 (dt, J = 14.2, 7.1 Hz, 1H), 3.62 (dd, J = 17.5, 10.6 Hz, 1H), 3.51 - 3.44 (m, 1H), 3.26 - 3.21 (m, 2H), 2.91 (d, J = 6.9 Hz, 2H); LCMS m / z 359[M+H] + Stage 3: 5-(3-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-4,5-dihydroisoxazole-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidine-2-amine(63b) Yellow solid (4.3 mg, yield: 24%); 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 2H), 7.54 (d, J = 6.9 Hz, 1H), 7.21 (dd, J = 5.3, 3.3 Hz, 2H), 7.15 - 7.12 (m, 2H), 5.24 (t, J = 9.3 Hz, 1H), 4.61 (dd, J = 14.4, 7.2 Hz, 1H), 3.51 (d, J = 10.2 Hz, 2H), 3.40 (t, J = 9.4 Hz, 2H), 3.34 (dd, J = 15.8, 9.2 Hz, 1H), 3.27 - 3.25 (m, 2H), 3.23 - 3.20 (m, LCMS m / z 429[M+H] +

[0254] Example 51.2-((1R,5S,6s)-3-(5-(2-((4-chlorophenethyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl)acetic acid (68) [ka]

[0255] Step 1: tert-butyl(1R,5S,6s)-6-(2-methoxy-2-oxoethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(65) 2-((1R,5S,6s)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-yl)acetic acid (0.1 g, 0.414 mmol) was dissolved in DMF (2.1 mL), and then K2CO3 (57.3 mg, 0.414 mmol) and CH3I (31 μL, 0.497 mmol) were added sequentially, and the mixture was stirred at room temperature for 15 hours. Distilled water was added to the reaction mixture, and it was extracted with ELISA, followed by several washes with brine. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain compound 65 (96 mg, yield: 96.7%) in a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 3.60 (s, 3H), 3.43 - 3.38 (m, 2H), 3.22 (d, J = 13.6 Hz, 2H), 2.31 - 2.28 (m, 2H), 1.41 - 1.38 (m, 2H), 1.38 - 1.36 (m, 9H), 0.69 - 0.64 (m, 1H)

[0256] Stage 2: Methyl 2-((1R,5S,6s)-3-azabicyclo[3.1.0]hexane-6-yl)acetate hydrochloride (66) Compound 65 (95 mg, 0.372 mmol) was dissolved in 1,4-dioxane (1.4 mL), and then 4 M HCl (0.93 mL, 37.2 mmol in the dioxane) was slowly added, 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, quantified) as a yellow solid, which was used in the next reaction without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 3.60 (s, 3H), 3.24 (d, J = 3.0 Hz, 4H), 2.32 (d, J = 7.0 Hz, 2H), 1.62 (s, 2H), 1.20 - 1.15 (m, 1H)

[0257] Step 3: Methyl 2-((1R,5S,6s)-3-(5-(2-((4-chlorophenethyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl)acetate(67) 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, and DIEA (128 μL, 0.756 mmol) was added and the mixture was stirred for 30 minutes. At the same temperature, BOP reagent (134 mg, 0.302 mmol) was added, and the mixture was stirred at room temperature for 15 hours. Distilled water was added to the reaction mixture, and it was extracted with RINKAN, followed by several washes 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 67 (80 mg, yield: 69.8%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.73 - 8.62 (m, 2H), 7.93 - 7.86 (m, 1H), 7.35 - 7.31 (m, 2H), 7.27 - 7.24 (m, 2H), 3.64 (d, J = 10.0 Hz, 2H), 3.61 (s, 3H), 3.54 (t, J = 5.9 Hz, 4H), 2.85 (t, J = 7.2 Hz, 2H), 2.36 (d, J = 7.1 Hz, 2H), 1.61 (s, 2H), 0.91 - 0.83 (m, 1H); LCMS m / z 455[M+H] +

[0258] Stage 4: 2-((1R,5S,6s)-3-(5-(2-((4-chlorophenethyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl)acetic acid (68) Compound 67 (40 mg, 0.088 mmol) was dissolved in THF (0.44 mL), then 1N NaOH (220 μL, 0.220 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. After concentrating the reaction mixture, SiO 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. 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 2H), 7.89 (t, J = 5.8 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 3.63 - 3.47 (m, 6H), 2.89 - 2.81 (m, 2H), 1.87 (d, J = 6.7 Hz, 2H), 1.44 (s, 2H), 0.81 (tt, J = 7.3, 3.8 Hz, 1H); LCMS m / z 441[M+H] +

[0259] Test Example 1. Evaluation of inhibitory activity against human autotaxin protein. (1) Experimental method Solutions of each synthesized compound (80 μM, 100% dimethyl sulfoxide) were sequentially diluted fivefold using dimethyl sulfoxide to produce six different concentrations. Each concentration of the compound was diluted twofold with 1× test buffer (50 mM Tris-Cl (pH 8.0), 5 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 140 mM NaCl, tertiary distilled water, 1 mg / mL BSA), and 1 μL (1.25% dimethyl sulfoxide) was dispensed into a 96-well clear round-bottom plate. 9 μL of 1× test buffer was added, followed by 20 μL of 240 nM human autotaxin protein (buffer: 50 mM Tris-HCl, pH 8.0, 150 mM sodium chloride, 20% glycerol). 10 μL of sonicated 360 μM 18:1 LysoPC (diluted with 1× test buffer) was added. The mixture was reacted in a 37°C shaking incubator for 2 hours to prepare the secondary reaction mixture (choline assay kit, KA1662) (65 μL of 1× test buffer: 1 μL of choline oxidase: 1 μL of dye probe). 60 μL of the secondary reaction mixture was added to the plate in which the reaction had taken place, and the mixture was stirred for 30 minutes. Absorbance was measured at a wavelength of 570 nm using a SpectraMax® iD3 microplate reader. (1 - absorbance) 試験群 / absorbance 対照群 The inhibitory activity percentage (inhibition%) was calculated using the formula ) × 100.

[0260] (2) Results The activity inhibition rates measured as described above are shown in Table 1 below. [Table 1] JPEG2026511574000131.jpg128169

[0261] All of the compounds synthesized in Examples 1 to 51 showed excellent inhibitory activity against human autotaxin protein.

[0262] The above description of the present invention is illustrative, and a person with ordinary skill in the art to which the invention pertains will understand that it can be easily modified into other specific forms without altering the technical idea or essential features of the invention. Therefore, it should be understood that the above-described embodiments are illustrative in all respects and not limiting. For example, each component described as a single type can be implemented separately, and similarly, the separated components can be implemented in a combined form.

[0263] The scope of this invention is defined by the claims described below, and any modifications or alterations derived from the meaning and scope of the claims and the concept of equivalents thereof are to be interpreted as being included within the scope of this invention.

Claims

1. Azabicycle derivative compound represented by the following chemical formula 1, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 In chemical formula 1, X is C ５－７ Aryl; a 5-membered or 6-membered heteroaryl containing 1 to 3 nitrogen atoms; C ５－７ A bicyclic fusion ring formed by the fusion of an aryl ring and a 5-membered or 6-membered cycloalkyl ring containing 0 to 3 oxygen atoms, wherein X is one or more independent R ｘ It is either replaced by or not replaced by The aforementioned R ｘ C １－４ Alkyl, C １－４ Alkoxy, cyano, halogen, or C １－４ It is a haloalkyl, p is an integer between 0 and 3. R Ｎ is hydrogen or C １－４ alkyl, A is a 5-membered or 6-membered heteroaryl compound containing one to three heteroatoms selected from N and S, and A is one or more independent R Ａ It is either replaced by or not replaced by The aforementioned R Ａ C １－４ It is alkyl, L is - (CH ２ ) ｍ A five-membered or six-membered aromatic or non-aromatic heteroring containing one to four heteroatoms selected from C(O)-, -CHCHC(O)-, or N and O, wherein m is an integer from 1 to 5. B is - (CH ２ ) ｎ C(O)OH, or a 5-membered or 6-membered heteroaryl containing 1 to 4 N atoms, where n is an integer from 1 to 3, and B is one or more independent R atoms. Ｂ It is either replaced by or not replaced by The aforementioned R Ｂ C １－４ It is alkyl.

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

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

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

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

6. The compound according to claim 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein A is pyridinyl, pyrimidinyl, pyrazinyl, or thiadiazolyl.

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

8. The aforementioned L is -(CH ２ ) ２ C(O)-,-(CH ２ ) ３ A compound according to claim 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is C(O)-, -CHCHC(O)-, dihydroisoxazolyl, or oxadiazolyl.

9. The aforementioned B is -CH ２ The compound according to claim 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is C(O)OH or triazolyl.

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

11. The compound according to claim 1, its hydrate, its solvate, or its pharmaceutically acceptable salt, wherein the compound represented by chemical formula 1 is selected from the group consisting of the following compounds. [1] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-benzylpyrimidine-2-amine, [2] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(3-chlorobenzyl)pyrimidine-2-amine, [3] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-chlorobenzyl)pyrimidine-2-amine, [4] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(3,4-difluorobenzyl)pyrimidine-2-amine, [5] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(3,5-difluorobenzyl)pyrimidine-2-amine, [6] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(3,4-dichlorobenzyl)pyrimidine-2-amine, [7] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(3,5-dichlorobenzyl)pyrimidine-2-amine, [8] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(3,5-dibromobenzyl)pyrimidine-2-amine, [9] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidine-2-amine, [10] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(3,5-bis(trifluoromethyl)benzyl)pyrimidine-2-amine, [11] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-phenethylpyrimidine-2-amine, [12] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(3-fluorophenethyl)pyrimidine-2-amine, [13] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-fluorophenethyl)pyrimidine-2-amine, [14] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(3-chlorophenethyl)pyrimidine-2-amine, [15] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-chlorophenethyl)pyrimidine-2-amine, [16] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidine-2-amine, [17] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidine-2-amine, [18] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrimidine-2-amine, [19] 1-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-yl)propan-1-one, [20] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-(trifluoromethyl)benzyl)pyrimidine-2-amine, [21] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(3-(trifluoromethyl)benzyl)pyrimidine-2-amine, [22] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(2-(trifluoromethyl)benzyl)pyrimidine-2-amine, [23] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-(difluoromethyl)benzyl)pyrimidine-2-amine, [24] 4-(((5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl)amino)methyl)benzonitrile, [25] 3-(((5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl)amino)methyl)benzonitrile, [26] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-(trifluoromethyl)phenethyl)pyrimidine-2-amine, [27] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-bromophenethyl)pyrimidine-2-amine, [28] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(2-chlorophenethyl)pyrimidine-2-amine, [29] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(3,5-dichlorophenethyl)pyrimidine-2-amine, [30] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-methoxyphenethyl)pyrimidine-2-amine, [31] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-methylphenethyl)pyrimidine-2-amine, [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-oxadiazole-2-yl)-N-(2-(pyridine-2-yl)ethyl)pyrimidine-2-amine, [33] 4-(2-((5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)pyrimidine-2-yl)amino)ethyl)benzonitrile, [34] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-((R)-2,3-dihydro-1H-inden-1-yl)pyrimidine-2-amine, [35] 5-(5-((1R,5S,6S)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-((S)-2,3-dihydro-1H-inden-1-yl)pyrimidine-2-amine, [36] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-phenylpyrimidine-2-amine, [37] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-chlorophenethyl)-N-methylpyrimidine-2-amine, [38] 1-((1R,5S,6r)-6-(1H-1,2,3-triazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazole-2-yl)butan-1-one, [39] 1-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-3-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazole-2-yl)propan-1-one, [40] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-chlorophenethyl)-4-methylpyrimidine-2-amine, [41] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-chlorophenethyl)pyridine-2-amine, [42] 5-(5-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)-N-(4-chlorophenethyl)pyrazine-2-amine, [43] 1-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-3-(2-((4-chlorophenethyl)amino)pyrimidine-5-yl)propan-1-one, [44] 1-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-4-(2-((3,5-dichlorobenzyl)amino)pyrimidine-5-yl)butan-1-one, [45] (E)-1-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-3-(2-((4-chlorophenethyl)amino)pyrimidine-5-yl)prop-2-en-1-one, [46] (E)-1-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-yl)prop-2-en-1-one, [47] N-(4-chlorophenethyl)-5-(5-((1R,5S,6r)-6-(1-methyl-1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)pyrimidine-2-amine, [48] ​​N-(4-chlorophenethyl)-5-(5-((1R,5S,6r)-6-(4-methyl-1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-1,3,4-oxadiazole-2-yl)pyrimidine-2-amine, [49] 5-(3-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-4,5-dihydroisoxazole-5-yl)-N-(4-chlorophenethyl)pyrimidine-2-amine, [50] 5-(3-((1R,5S,6r)-6-(1H-1,2,3-triazole-5-yl)-3-azabicyclo[3.1.0]hexane-3-yl)-4,5-dihydroisoxazole-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidine-2-amine, and [51] 2-((1R,5S,6s)-3-(5-(2-((4-chlorophenethyl)amino)pyrimidine-5-yl)-1,3,4-oxadiazole-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl)acetic acid.

12. A pharmaceutical composition for the prevention or treatment of autotaxin-related diseases, comprising as an active ingredient an azabicycle derivative compound according to any one of claims 1 to 11, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

13. The pharmaceutical composition according to claim 12, wherein the autotaxin-related disease is selected from the group consisting of fibrous 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.

14. A fibrous disease selected from idiopathic pulmonary fibrosis (IPF), interstitial lung disease, hepatic fibrosis, hepatosclerosis, non-alcoholic steatohepatitis, radiation-induced fibrosis, renal fibrosis, dermatofibrosis, glomerulosclerosis, myocardial and vascular fibrosis; an inflammatory disease selected from rheumatoid arthritis, osteoarthritis, atopic dermatitis, inflammatory bowel disease, inflammatory airway disease, chronic obstructive pulmonary disease (COPD) and asthma; an autoimmune disease selected from multiple sclerosis and scleroderma; and an asbestos-induced pulmonary fibrosis and acute respiratory distress syndrome (ARDS). Pharmaceutical compositions for the prevention or treatment of one or more diseases selected from the group consisting of respiratory diseases; cardiovascular diseases selected from arteriosclerosis, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmias, stroke and other vascular injuries; metabolic diseases selected from obesity and diabetes; cancers and cancer metastases selected from breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, hepatocarcinoma, gastrointestinal cancer, pancreatic cancer and their progression and metastatic invasion; ophthalmic diseases selected from proliferative and non-proliferative retinopathy, diabetic retinopathy, dry and wet age-related macular degeneration (AMD), macular edema, central arterial / venous occlusion, traumatic injury and glaucoma; chronic pruritus of the cholestatic form and other forms; and acute or chronic organ transplant rejection.

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

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