KR102502940B1 - Novel compounds as autotaxin inhibitors and use thereof - Google Patents

Abstract

The present invention relates to a compound that is an inhibitor of autotaxin (ATX). More specifically, the present invention relates to a novel compound having an autotaxin activity inhibitory effect, a pharmaceutical composition comprising such compounds as active ingredients, and uses thereof. The novel compound and a pharmaceutically acceptable salt thereof as the autotaxin inhibitor of the present invention provide excellent inhibitory activity on autotaxin and consequently inhibit the production of lysophosphatidic acid, thereby treating or preventing diseases related to autotaxin activation.

Description

Novel compounds as autotaxin inhibitors and their uses {NOVEL COMPOUNDS AS AUTOTAXIN INHIBITORS AND USE THEREOF}

The present invention relates to compounds that are inhibitors of autotaxin (ATX). More specifically, the present invention relates to novel compounds having an autotaxin activity inhibitory effect, pharmaceutical compositions comprising such compounds as active ingredients, and uses thereof.

Pulmonary fibrosis is a respiratory disease in which the lung tissue hardens, causing serious breathing difficulties. Hardening of the lungs means excessive accumulation of fibrous connective tissue, and this process is called 　fibrosis. As fibrosis progresses, the lung wall thickens, reducing the amount of oxygen supplied to the blood. As a result, the patient has a constant terrible feeling of shortness of breath.

Although there are patients who can diagnose a clear cause of fibrosis, there are cases where the cause cannot be identified, and this case is called idiopathic pulmonary fibrosis. Due to pulmonary fibrosis, there is no way to restore fibrotic lung tissue. However, because it can be slowed down by drug treatment, the demand for drugs that can slow down such fibrosis is gradually increasing.

Autotaxin (ATX) is an enzyme that causes an increase in lysophosphatidic acid (LPA) in ascites and plasma. ) is an important secreted enzyme for conversion to Autotaxin is also referred to as ectonucleotide pyrophosphatase/phosphodiesterase 2 or lysophospholipase D.

It was confirmed that these autotaxin and lysophosphatidic acid were expressed at very high levels in lung tissue of patients with pulmonary fibrosis. Therefore, the inventors of the present invention developed a compound capable of selectively inhibiting autotaxin with the view that if it inhibits autotaxin to reduce the level of lysophosphatidic acid in vivo, it can provide therapeutic uses for these fibrotic diseases. I did.

In addition, the ATX-LPA signaling axis includes, for example, nervous system action, vascular development, cardiovascular physiology, regeneration, immune system action, chronic inflammation, tumor metastasis and progression, organ fibrosis and obesity and/or other metabolic diseases such as diabetes mellitus. It is involved in a wide range of physiological and pathophysiological actions. Thus, increased activity of ATX and/or increased levels of LPA, altered LPA receptor expression, and altered response to LPA may contribute to the initiation, progression and/or outcome of a variety of different pathophysiological diseases associated with the ATX/LPA axis. there is.

An object of the present invention is to provide novel compounds, optical isomers thereof and pharmaceutically acceptable salts thereof as autotaxin inhibitors.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating diseases related to autotaxin activity, containing a novel compound as an autotaxin inhibitor, an optical isomer thereof, and a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is a novel compound as an autotaxin (ATX) inhibitor, an optical isomer thereof, and a pharmaceutically acceptable salt thereof containing as an active ingredient the activity of ATX and/or the biological activity of lysophosphatidic acid (LPA). treatment or prevention of disorders or diseases related to, in particular, kidney disease, liver disease, inflammatory disease, nervous system disease, respiratory system disease, vascular and cardiovascular disease, fibrotic disease, cancer, ocular disease, metabolic disease, cholestatic form and other forms To provide a pharmaceutical composition for preventing or treating chronic pruritus and acute and chronic organ transplant rejection.

In order to achieve the above object, the present invention provides a compound represented by Formula 1 below, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

here,

또는

이고;Y is

or

ego;

R ¹ and R ² are each independently selected from the group consisting of halogen, C _1-5 alkyl, C _1-5 alkyloxy, and C _1-5 alkyl substituted with one or more halogens;

로 이루어진 군으로부터 선택되고;X is O, -CH ₂ -, NH and

It is selected from the group consisting of;

A is a 5- to 6-membered divalent heteroalicyclic radical containing at least one heteroatom selected from the group consisting of N, O and S;

,

,

,

,

,

,

,

,

,

, 및

로 이루어진 군으로부터 선택되고;L ¹ and L ² do not exist independently of each other;

,

,

,

,

,

,

,

,

,

, and

It is selected from the group consisting of;

B is absent or selected from the group consisting of a 6-membered ring divalent aromatic radical and a 5- to 6-membered ring divalent heteroaromatic radical containing two or more heteroatoms selected from the group consisting of N, O and S;

C is a 5- to 6-membered saturated or unsaturated heterocyclyl containing two or more heteroatoms selected from the group consisting of N, O and S;

The heterocyclyl is further substituted or unsubstituted with substituents selected from the group consisting of one or more amines, oxo, C _1-5 alkyl, C _1-5 alkyloxy and C _1-5 alkyl substituted with one or more halogens. no;

l, m and n are each independently an integer of 1 to 3.

According to another aspect of the present invention, the novel compound as an autotaxin inhibitor, its optical isomer, and its pharmaceutically acceptable salt containing as an active ingredient the activity of ATX and / or the biological activity of lysophosphatidic acid (LPA) Treatment or prevention of related disorders or diseases, in particular renal disease, liver disease, inflammatory disease, nervous system disease, respiratory system disease, vascular and cardiovascular disease, fibrotic disease, cancer, ocular disease, metabolic disease, cholestatic form and other forms Provided is a pharmaceutical composition for preventing or treating chronic pruritus and acute and chronic organ transplant rejection.

The novel compounds and pharmaceutically acceptable salts thereof as autotaxin inhibitors of the present invention provide excellent inhibitory activity against autotaxin and consequently inhibit the production of lysophosphatidic acid, thereby treating or preventing diseases related to autotaxin activation. can be useful for

Specifically, the pharmaceutical composition containing the compound according to the present invention as an active ingredient is used for the treatment or prevention of disorders or diseases related to the activity of ATX and/or the biological activity of lysophosphatidic acid (LPA), particularly kidney disease and liver disease. , for the prevention or treatment of inflammatory diseases, diseases of the nervous system, diseases of the respiratory system, vascular and cardiovascular diseases, fibrotic diseases, cancer, ocular diseases, metabolic diseases, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection can be usefully used.

The definitions listed below are definitions of various terms used to describe the present invention. These definitions apply throughout this specification, either individually or as part of a term comprising them, unless otherwise limited.

As used herein, the term 'halogen' means any one of fluorine, chlorine, bromine or iodine, or both, unless otherwise specified.

As used herein, unless otherwise specified, the term 'alkyl' refers to a saturated, straight-chain or branched hydrocarbon radical represented by C _n H _2n+1 , specifically between 1 to 6, 1 to 6, respectively. Refers to a saturated, straight-chain or branched hydrocarbon radical containing between 8, between 1 and 10, or between 1 and 20 carbon atoms. Examples of these radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, and octyl radicals.

As used herein, the term 'cycloalkyl', unless otherwise specified, denotes a monovalent group derived from a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring compound. For example, examples of C ₃ -C ₆ cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; Examples of C ₃ -C ₁₂ -cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl. do.

As used herein, unless otherwise indicated, the term 'aryl' refers to, but is not limited to, a mono- or poly-cyclic carbocyclic ring system having one or more aromatic rings, fused or non-fused; phenyl, naphthyl, tetrahydronaphthyl, indenyl, idenyl, and the like.

As used herein, the term 'heteroalicyclic' includes a heterocycloalkyl group and a heterocycloalkenyl group unless otherwise specified.

As used herein, the term 'heterocyclyl' or 'heterocycloalkyl', unless otherwise specified, is a saturated or partially saturated or partially containing at least one heteroatom selected from N, O and S, for example from 1 to 4 heteroatoms. It means an unsaturated 3- to 10-membered monocyclic or polycyclic substituent. Monocyclic heterocycloalkyls include, but are not limited to, piperidinyl, morpholinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperazinyl, and similar groups. it is not going to be

As used herein, unless otherwise specified, the term 'heteroaryl' is a 5 to 12 membered monocyclic or bicyclic containing at least one selected from O, N and S, for example, 1 to 4 heteroatoms. Refers to an aromatic group above a click. Examples of monocyclic heteroaryls include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridine yl, pyridazinyl, pyrimidinyl, pyrazinyl, and similar groups, but are not limited thereto. Examples of bicyclic heteroaryls include indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, purinyl, puropyridinyl and similar groups, but is not limited thereto.

Hereinafter, the present invention will be described in more detail.

The present invention provides a compound represented by Formula 1 below, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

here,

또는

이고;Y is

or

ego;

R ¹ and R ² are each independently halogen, C _1-5 alkyl, C _3-6 cycloalkyl, C _1-5 alkyloxy, C _6-10 aryl and C _1-5 substituted with one or more halogens. is selected from the group consisting of alkyl;

로 이루어진 군으로부터 선택되고;X is O, -CH ₂ -, NH and

It is selected from the group consisting of;

A is a 5- to 6-membered divalent heteroalicyclic radical containing at least one heteroatom selected from the group consisting of N, O and S;

,

,

,

,

,

,

,

,

,

, 및

로 이루어진 군으로부터 선택되고;L ¹ and L ² do not exist independently of each other;

,

,

,

,

,

,

,

,

,

, and

It is selected from the group consisting of;

B is absent or selected from the group consisting of a 6-membered ring divalent aromatic radical and a 5- to 6-membered ring divalent heteroaromatic radical containing two or more heteroatoms selected from the group consisting of N, O and S;

C is a 5- to 6-membered saturated or unsaturated heterocyclyl containing at least two heteroatoms selected from the group consisting of N, O and S or a 5 to 6-membered heteroaryl;

wherein said heterocyclyl or heteroaryl is further substituted with a substituent selected from the group consisting of one or more amines, oxo, C _1-5 alkyl, C _1-5 alkyloxy and C _1-5 alkyl substituted with one or more halogens; is not substituted or substituted;

l, m and n are each independently an integer of 1 to 3.

이고; R¹ 및 R²는 각각 독립적으로, H, 할로젠, C_1-5 알킬, C_1-5 알콕시 및 하나 이상의 할로젠으로 치환된 C_1-5 알킬로 이루어진 군으로부터 선택될 수 있다.In one specific embodiment of the present invention, Y of Formula 1 is

ego; R ¹ and R ² may each independently be selected from the group consisting of H, halogen, C _1-5 alkyl, C _1-5 alkoxy, and C _1-5 alkyl substituted with one or more halogens.

이고; R¹ 및 R²는 각각 독립적으로, H, 할로젠, C_1-5 알킬, C_1-5 알콕시 및 하나 이상의 할로젠으로 치환된 C_1-5 알킬로 이루어진 군으로부터 선택될 수 있다.In one specific embodiment of the present invention, Y of Formula 1 is

ego; R ¹ and R ² may each independently be selected from the group consisting of H, halogen, C _1-5 alkyl, C _1-5 alkoxy, and C _1-5 alkyl substituted with one or more halogens.

또는

이다. In one specific embodiment of the present invention, A of Formula 1 is

or

am.

,

,

및

로 이루어진 군으로부터 선택된다.In one specific embodiment of the present invention, B in Formula 1 does not exist,

,

,

and

is selected from the group consisting of

In a specific embodiment of the present invention, C in Formula 1 is a 5-membered saturated or unsaturated heterocyclyl containing two or more hetero atoms selected from the group consisting of N, O and S, or a 5- to 6-membered heterocyclyl. aryl, wherein the heterocyclyl or heteroaryl may be unsubstituted or further substituted with a C _1-5 alkyl or amine group.

,

,

,

및

로 이루어진 군으로부터 선택된 작용기(functional group)이고, 상기 작용기는 아미노 또는 C_1-5 알킬로 추가로 치환되거나 치환되지 않을 수 있다.In one specific embodiment of the present invention, C of Formula 1 is

,

,

,

and

A functional group selected from the group consisting of, and the functional group may be further substituted or unsubstituted with amino or C _1-5 alkyl.

또는

이며, L²는

및

로 이루어진 군으로부터 선택되고, l 및 m은 각각 독립적으로 1 또는 2일 수 있다.In one specific embodiment of the present invention, L ¹ of Formula 1 is not present, and B is

or

, and L ² is

and

It is selected from the group consisting of, and l and m may each independently be 1 or 2.

이고; R¹ 및 R²는 각각 독립적으로 할로젠 및 C_1-5 알킬로 이루어진 군으로부터 선택되고;In one specific embodiment of the present invention, Y of Formula 1 is

ego; R ¹ and R ² are each independently selected from the group consisting of halogen and C _1-5 alkyl;

n is 1;

X is O;

또는

이며;A is

or

is;

L ¹ does not exist,

이며,B is

is,

및

로 이루어진 군으로부터 선택되고, ^L2 is

and

It is selected from the group consisting of

l and m are each independently 1 or 2;

In a specific embodiment of the present invention, the compound of Formula 1 may be selected from the group consisting of the following compounds, but is not limited thereto:

# compound # compound 18a 3,5-Dichlorobenzyl 4-((4-(2-aminothiazol-5-yl)phenyl)amino)piperidine-1-carboxylate
18b 3,5-dichlorobenzyl 4-((3-(2-aminothiazol-5-yl)phenyl)amino)piperidine-1-carboxylate 18c 3,5-Dichlorobenzyl 4-((4-(1-methyl-1 H -imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate 18d 3,5-Dichlorobenzyl 4-((3-(1-methyl-1H-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate 18e 3,5-dichlorobenzyl 4-((4-(1 H -imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate
18f 3,5-dichlorobenzyl 4-((3-(1 H -imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate 18g 3,5-Dichlorobenzyl 4-((4-(2-methyl-1 H -imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate 18h 3,5-dichlorobenzyl 4-((3-(2-methyl-1 H -imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate 18i 3,5-Dichlorobenzyl 4-((4-(4-methyl-1 H -imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate 18j 3,5-dichlorobenzyl 4-((3-(4-methyl-1H-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate 18k 3,5-Dichlorobenzyl 4-((4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)amino)piperidine-1-carboxylate 18l 3,5-Dichlorobenzyl 4-((3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)amino)piperidine-1-carboxylate 18m 3,5-dichlorobenzyl 4-((3-(2-methyloxazol-5-yl)phenyl)amino)piperidine-1-carboxylate 18n 3,5-dichlorobenzyl 4-((3-(1 H -1,2,3-triazol-5-yl)phenyl)amino)piperidine-1-carboxylate 27a 3,5-dichlorobenzyl 4-((4-(2-aminothiazol-5-yl)phenyl)carbamoyl)piperidine-1-carboxylate 27b 3,5-dichlorobenzyl 4-((3-(2-aminothiazol-5-yl)phenyl)carbamoyl)piperidine-1-carboxylate 27c 3,5-dichlorobenzyl 4-((4-(1 H -imidazol-5-yl)phenyl)carbamoyl)piperidine-1-carboxylate 27d 3,5-dichlorobenzyl 4-((3-(1 H -imidazol-5-yl)phenyl)carbamoyl)piperidine-1-carboxylate 27e 3,5-Dichlorobenzyl 4-(4-(1H-imidazol-5-yl)piperidine-1-carbonyl)piperidine-1-carboxylate 27f 3,5-dichlorobenzyl 4-(4-(1 H -1,2,3-triazol-5-yl)piperidine-1-carbonyl)piperidine-1-carboxylate 27g 3,5-dichlorobenzyl 4-(4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidine-1-carbonyl)piperidine- 1-carboxylate 27h 3,5-dichlorobenzyl 4-((4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)carbamoyl)piperidine-1-carboxyl rate 27i 3,5-dichlorobenzyl 4-((3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)carbamoyl)piperidine-1-carboxyl rate 33a 3,5-Dichlorobenzyl 4-((4-( 1H -imidazol-5-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate 33b 3,5-dichlorobenzyl 4-(2-(4-(1 H -imidazol-5-yl)piperidin-1-yl)ethyl)piperidine-1-carboxylate 33c 3,5-dichlorobenzyl 4-((4-( 1H -1,2,3-triazol-5-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate 33d 3,5-Dichlorobenzyl 4-(2-(4-(1 H -imidazol-5-yl)phenoxy)ethyl)piperidine-1-carboxylate 33e 3,5-Dichlorobenzyl 4-((4-(1 H -imidazol-5-yl)phenoxy)methyl)piperidine-1-carboxylate 33f 3,5-dichlorobenzyl 4-(4-(1 H -imidazol-5-yl)phenoxy)piperidine-1-carboxylate 33g 3,5-Dichlorobenzyl 4-((3-(1 H -imidazol-5-yl)phenoxy)methyl)piperidine-1-carboxylate 33h 3,5-dichlorobenzyl 4-(3-(1H-imidazol-5-yl)phenoxy)piperidine-1-carboxylate 33i 3,5-Dichlorobenzyl 4-((3-(2-methyl-1 H -imidazol-5-yl)phenoxy)methyl)piperidine-1-carboxylate 33j 3,5-dichlorobenzyl 4-((4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidin-1-yl)methyl)piperi Dean-1-carboxylate 33k 3,5-dichlorobenzyl 4-(((4-(2-aminothiazol-5-yl)phenyl)amino)methyl)piperidine-1-carboxylate 33l 3,5-dichlorobenzyl 4-(((3-(2-aminothiazol-5-yl)phenyl)amino)methyl)piperidine-1-carboxylate 33m 3,5-dichlorobenzyl 4-(((4-(1 H -imidazol-5-yl)phenyl)amino)methyl)piperidine-1-carboxylate 33n 3,5-dichlorobenzyl 4-(((3-(1 H -imidazol-5-yl)phenyl)amino)methyl)piperidine-1-carboxylate 33o 3,5-Dichlorobenzyl 4-(((4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)amino)methyl)piperidin-1 -Carboxylate 33p 3,5-dichlorobenzyl 4-(((3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)amino)methyl)piperidin-1 -Carboxylate 38a 3,5-dichlorobenzyl 4-(2-(4-(1 H -imidazol-5-yl)piperidin-1-yl)acetyl)piperazine-1-carboxylate 38b
3,5-dichlorobenzyl 4-(2-(4-(1 H -imidazol-5-yl)piperidin-1-yl)ethyl)piperazine-1-carboxylate 38c 3,5-Dichlorobenzyl 4-(3-(4-(1 H -imidazol-5-yl)piperidin-1-yl)propyl)piperazine-1-carboxylate 38d 4-(2-(4-(1H-imidazol-5-yl)piperidin-1-yl)acetyl)-N-(3-chlorophenethyl)piperazine-1-carboxamide 44a 3,5-dichlorobenzyl 4-(5-((( 1H- 1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)p Peridine-1-carboxylate 44b 3,5-dibromobenzyl 4-(5-((( 1H -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl )piperidine-1-carboxylate 44c 3,5-bis(trifluoromethyl)benzyl 4-(5-((( 1H -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazole -2-yl)piperidine-1-carboxylate 44d 3,5-dimethylbenzyl 4-(5-((( 1H- 1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)p Peridine-1-carboxylate 44e 3,5-dimethoxybenzyl 4-(5-((( 1H- 1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl) Piperidine-1-carboxylate 44f 3,5-difluorobenzyl 4-(5-((( 1H- 1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl )piperidine-1-carboxylate 44g 3-Bromo-5-methylbenzyl 4-(5-(((1H - 1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazole-2- 1) piperidine-1-carboxylate 44h 3-Bromo-5-chlorobenzyl 4-(5-((( 1H- 1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazole-2- 1) piperidine-1-carboxylate 44i 3-chloro-5-fluorobenzyl 4-(5-((( 1H- 1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazole-2- 1) piperidine-1-carboxylate 44j 2,5-dichlorobenzyl 4-(5-((( 1H- 1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)p Peridine-1-carboxylate 44k 3,4-dichlorobenzyl 4-(5-((( 1H- 1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)p Peridine-1-carboxylate 44l Benzo[ d ][1,3]dioxol-5-ylmethyl 4-(5-((( 1H- 1,2,3-triazol-5-yl)methyl)amino)-1,3,4 -Oxadiazol-2-yl)piperidine-1-carboxylate 44m 1-(4-(5-((( 1H -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidin- 1-yl)-3-(3,5-dichlorophenyl)propan-1-one 44n 4-(5-((( 1H- 1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl) -N- (3,5 -Dichlorobenzyl)piperidine-1-carboxamide 47a 3,5-dichlorobenzyl 4-(5-(((1 H -tetrazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxyl rate 47b 3,5-dichlorobenzyl 4-(5-(((1-methyl- 1H -1,2,3-triazol-4-yl)methyl)amino)-1,3,4-oxadiazole-2 -yl)piperidine-1-carboxylate 47c 3,5-dichlorobenzyl 4-(5-(((4-methyl- 1H -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazole-2 -yl)piperidine-1-carboxylate 50a 3,5-dichlorobenzyl 4-(5-(2-(1 H -1,2,3-triazol-5-yl)ethyl)-1,3,4-thiadiazol-2-yl)piperazine -1-carboxylate 50b 3,5-dichlorobenzyl 4-(5-(2-(1 H -1,2,3-triazol-5-yl)ethyl)-1,3,4-oxadiazol-2-yl)piperazine -1-carboxylate 50c 3,5-dichlorobenzyl 4-(5-(2-(1 H -1,2,3-triazol-5-yl)ethyl)-1,3,4-oxadiazol-2-yl)piperi Dean-1-carboxylate 53a 3,5-dichlorobenzyl 4-(2-(((1 H -1,2,3-triazol-5-yl)methyl)amino)thiazol-5-yl)piperazine-1-carboxylate 53b 3,5-dichlorobenzyl 4-(5-((( 1H- 1,2,3-triazol-5-yl)methyl)amino)-1,3,4-thiadiazol-2-yl)pipe Razine-1-carboxylate 58 3,5-dichlorobenzyl 4-((4-((1H-1,2,3-triazol-4-yl)methoxy)phenyl)amino)piperidine-1-carboxylate 61 3,5-dichlorobenzyl 4-(4-(((1H-1,2,3-triazol-4-yl)methyl)amino)phenyl)-[1,4′-bipiperidine]-1′ -Carboxylate 64 3,5-dichlorobenzyl 4-(3-((1H-1,2,3-triazol-5-yl)methoxy)phenyl)-[1,4'-bipiperidine]-1'-carboxyl rate 65 1-(4-( 1H -imidazol-5-yl)piperidin-1-yl)-2-(4-(3,5-dichlorobenzyl)piperazin-1-yl)ethan-1-one

In one specific embodiment of the present invention, the novel compound as an autotaxin inhibitor, its optical isomer and its pharmaceutically acceptable salt containing as an active ingredient the activity of ATX and / or the biological activity of lysophosphatidic acid (LPA) Treatment or prevention of related disorders or diseases, in particular renal disease, liver disease, inflammatory disease, nervous system disease, respiratory system disease, vascular and cardiovascular disease, fibrotic disease, cancer, ocular disease, metabolic disease, cholestatic form and other forms A pharmaceutical composition for preventing or treating chronic pruritus and acute and chronic organ transplant rejection is provided.

In addition, in one specific embodiment of the present invention, the activity of autotaxin (ATX) and / or a disorder or disease related to the biological activity of lysophosphatidic acid (LPA).

Renal disease includes, but is not limited to, acute renal failure, and chronic kidney disease with or without proteinuria (including end-stage renal disease (ESRD)). More specifically, renal disease is characterized by glomerulosclerosis (particularly diabetic nephropathy and diabetic nephropathy and amyloidosis), focal thrombosis of the glomerular capillaries (particularly thrombotic microangiopathy), global fibrotic necrosis, ischemic lesions, malignant renal sclerosis (e.g., ischemic contracture, reduced renal blood flow, and renal arterial disease), intracapillary (endothelial and edema and proliferation of intervascular) and/or extracapillary cells (hemis) including, but not limited to, glomerulonephritis entities, focal segmental glomerulosclerosis, IgA nephropathy, vasculitis/systemic diseases as well as acute and chronic kidney transplant rejection. it is not going to be

Liver disease includes, but is not limited to, liver cirrhosis, hepatic hemorrhage, cholestatic liver disease such as pruritus, non-alcoholic steatohepatitis, and acute and chronic liver transplant rejection.

Inflammatory diseases include, but are not limited to, arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, abnormal excretory disorders, and the like, as well as inflammatory airway diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) or chronic bronchial tuberculosis. including but not limited to asthma.

In addition, diseases of the respiratory system include, but are not limited to, other diffuse interstitial lung diseases of different etiologies, such as iatrogenic drug-induced fibrosis, occupationally and/or environmentally induced fibrosis, systemic diseases and vasculitis, granulomatous diseases (sarcomatosis, hypersensitivity pneumonitis), Collagen Vascular Disease, Alveolar Proteinosis, Langerhans Cell Granulomatosis, Lymphangioleiomyomatosis, Hereditary Diseases (Hermansky-Pudlak Syndrome, Crystalline Crystallosis, Neurofibromatosis, Metabolic Storage Disease, Familial Interstitial Lung Disease) , radiation-induced fibrosis, silicosis, asbestos-induced pulmonary fibrosis, or acute respiratory distress syndrome (ARDS).

Nervous system disorders include, but are not limited to, neurogenic pain, schizophrenia, neuroinflammation (eg, astrocytosis), peripheral and/or autonomic (diabetic) neuropathy, and the like.

Vascular diseases include, but are not limited to, atherosclerosis, vascular thrombotic diseases as well as thrombotic microangiopathy, proliferative arteriopathy (e.g., dilated endomyosclerosis and nodular densification surrounding mucous extracellular matrix), atherosclerosis, reduced vascular elasticity (eg, stiffness, reduced ventricular elasticity and reduced vascular elasticity), endothelial dysfunction, and the like.

Cardiovascular disease includes, but is not limited to, acute coronary syndrome, coronary heart disease, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmias such as atrial fibrillation, stroke and other vascular damage.

Fibrotic diseases include, but are not limited to, myocardial and vascular fibrosis, renal fibrosis, liver fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma, and cystic peritonitis. Specifically, pulmonary fibrosis can be idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).

The compound of formula 1 according to the present invention can be prepared in the form of a pharmaceutically acceptable salt to which an inorganic acid or an organic acid is added, and preferred salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, and lactic acid. , pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid , salts derived from salicylic acid, methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid and the like.

Specifically, the pharmaceutically acceptable salt according to the present invention is prepared by dissolving the compound of Formula 1 in an organic solvent, such as acetone, methanol, ethanol, or acetonitrile, and filtering the precipitated crystals by adding an organic or inorganic acid. do. Alternatively, it may be prepared by reducing the solvent or excess acid in the reaction mixture to which acid is added and drying the residue, or by filtering a precipitated salt by adding another organic solvent.

The compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention may be in the form of a hydrate or solvate, and such compounds are also included in the present invention.

In addition, the present invention provides a pharmaceutical composition containing a pharmaceutically acceptable carrier and a pharmaceutically effective amount of the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. In a specific embodiment of the present invention, at least one pharmaceutically acceptable pharmaceutical composition containing a pharmaceutically effective amount of the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient A pharmaceutical composition is provided which further comprises possible surfactants, additional carriers, diluents, excipients, smoothing agents, suspending agents, film forming substances, coating assistants and the like.

As used herein, the term “pharmaceutically acceptable carrier” refers to any standard pharmaceutical carrier such as phosphate buffered saline solutions, water, emulsions (eg, oil/water or water/oil emulsions) and wetting agents of various types. say The composition may also contain stabilizers and preservatives. Examples of carriers, stabilizers and adjuvants are described in Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA, 1975.

When the pharmaceutical composition according to the present invention is prepared in the form of an oral dosage form, examples of carriers used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, and stearic acid. Calcium acid, gelatin, talc, surfactant, suspending agent, emulsifying agent, diluent, etc. are mentioned. When the pharmaceutical composition according to the present invention is prepared in the form of an injection, the carrier includes water, saline, glucose aqueous solution, analog sugar aqueous solution, alcohol, glycol, ether (eg polyethylene glycol 400), oil, fatty acid, fatty acid ester , glycerides, surfactants, suspending agents, emulsifying agents and the like can be used.

The term "diluent" means a compound diluted in water that will dissolve the desired composition and stabilize the biologically active form of the compound. A salt dissolved in a buffer solution is used as a diluent in the art. A commonly used buffer solution is phosphate buffered saline because it simulates the salt conditions of human blood. Because buffer salts can adjust the pH of a solution at low concentrations, buffered diluents hardly change the biological activity of the compound.

As used herein, "excipient" provides properties to a composition, including but not limited to bulk, consistency, stability, binding ability, lubrication, disintegration ability, and the like. means an inactive substance added to the composition for A "dilunet" is a type of excipient.

In addition, preservatives, stabilizers, dyes, sweeteners, fragrances, flavoring agents and the like may be provided in the pharmaceutical composition of the present invention. For example, sodium benzoate, ascorbic acid and esters of p-hydroxybenzoic acid may be added as preservatives. In addition, antioxidants and suspending agents may be used. In various embodiments, alcohols, esters, sulfated aliphatic alcohols, and the like may be used as surfactants; Sucrose, glucose, lactose, starch, microcrystalline cellulose, crystallized cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium metasilicate aluminate, synthetic aluminum silicate, calcium carbonate, sodium acid carbonate , calcium hydrogen phosphate, calcium carboxymethyl cellulose, etc. may be used as excipients; Magnesium stearate, talc, hardened oil and the like can be used as leveling agents; Coconut oil, olive oil, sesame oil, peanut oil, soya oil may be used as a suspending agent or lubricant; As a derivative of carbohydrates such as cellulose or sugar, cellulose acetate phthalate, or as a polyvinyl derivative, methyl acetate-methacrylate copolymer can be used as a suspending agent; Plasticizers such as ester phthalates and the like can be used as suspending agents.

As used herein, a “pharmaceutically effective amount” or “therapeutically effective amount” of a compound according to the present invention refers to an amount of the compound sufficient to reduce a symptom or disorder in a subject. As is well understood in the medical arts, a pharmaceutically or therapeutically effective amount of a compound according to the present invention will be at a reasonable benefit/risk ratio applicable to any medical treatment.

The dosage of the compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention may vary depending on the subject to be treated, the severity of the disease or condition, the speed of administration, and the judgment of the prescribing physician, but is usually Oral or parenteral route of the compound as an active ingredient for humans in an amount of 0.1 to 2,000 mg, preferably 1 to 1,000 mg per day based on body weight of 70 kg, 1 to 4 times a day or on an on / off schedule can be administered through In some cases, doses lower than the above-mentioned ranges may be more suitable, and larger doses may be used without adverse side effects, with larger doses divided into several smaller doses throughout the day. do.

The pharmaceutical composition according to the present invention can be formulated according to a conventional method, and can be administered in various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions, or intramuscular, intravenous or subcutaneous administration. The same parenteral dosage form can be prepared.

Hereinafter, the present invention will be described in detail by examples. However, the following examples are only to illustrate the present invention, and the content of the present invention is not limited by the following examples.

Preparation 1. Synthesis of Building Blocks A-E.

Reagents and conditions : (a) thiourea, EtOH, reflux, 2 h; (b) (Boc) ₂ O, DMAP, THF, 90 °C, 2 h; (c) H ₂ , Pd/C 10%, MeOH, THF, 8 h; (d) Formamide, 150 °C, 24 h; (e) NaH, CH ₃ I, DMF, 6 h; (f) Acetamide, 180 °C, 18 h; (g) HNO ₃ (conc .), H ₂ SO ₄ (conc.), 0 ℃ to rt to 60 ℃, 4 h; (h) Br ₂ , AcOH, 30 ℃, 18 h; (i) Triphosgene, Et ₃ N, THF, 12 h; (j) Me ₃ SiN ₃ , CuI, DMF, MeOH, 100° C., 12 h.

NO ₂ - General process for reduction A.

To a mixture of the nitro-aryl derivative (2.00 mmol) in MeOH/THF (10 mL/10 mL) in a round bottom flask was added palladium on carbon (10% wt) (84 mg) at room temperature. The reaction mixture was vigorously stirred at room temperature under a hydrogen gas atmosphere. The mixture was filtered through celite® and the filtrate was concentrated. The residue was purified by column chromatography (ethyl acetate/hexane) to give aniline.

General process for imidazole ring formation B.

A mixture of 2-bromo-acetophenone (5.00 mmol) and formamide (10 mL) was heated at 150 °C for 24 h. After cooling, the mixture was poured into saturated NaHCO ₃ solution. The organics were extracted with ethyl acetate, dried over anhydrous Na ₂ SO ₄ and concentrated. The product was purified by column chromatography (CH ₂ Cl ₂ /MeOH) to obtain the desired imidazole.

5-(4-nitrophenyl)-1,3,4-thiadiazol-2-amine (1a).

A mixture of 2-bromo-4' nitroacetophenone (2.44 g, 10.00 mmol) and thiourea (0.91 g, 12.00 mmol) in ethanol (10 mL) was refluxed for 2 hours. After cooling, the solvent was concentrated and the crude product was purified by column chromatography (CH ₂ Cl ₂ /MeOH) to give 1a (1.81 g, 81.8%) as a yellow solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.19 (d, J = 8.9 Hz, 2H), 8.00 (d, J = 9.0 Hz, 2H), 7.36 (s, 1H), 7.19 (s, 2H) .

t -Butyl(tert-butoxycarbonyl)(5-(4-nitrophenyl)thiazol-2-yl)carbamate (2a).

To a round bottom flask was placed 1a (1.11 g, 5.00 mmol), 4-(dimethylamino)pyridine (61.09 mg, 0.50 mmol) in tetrahydrofuran (20 mL) and di- tert-Butyl dicarbonate 30% was added to the mixture at room temperature. The reaction mixture was heated at 40 °C for 2 h and then refluxed for 2 h. The solution was concentrated and the residue was purified by column chromatography (ethyl acetate/hexane) to give 2a as a light yellow solid (quantitative).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.25 (d, J = 9.0 Hz, 2H), 7.98 (d, J = 9.0 Hz, 2H), 7.45 (s, 1H), 1.59 (s, 18H).

t -Butyl(tert-butoxycarbonyl)(5-(3-nitrophenyl)thiazol-2-yl)carbamate (2b).

Following the process for 1a , Compound (1b ) was prepared as a yellow solid (1.81 g, 82.0%) using 2-bromo-3' nitroacetophenone (2.44 g, 10.00 mmol) and obtained by the following procedure for 2a to obtain 1b ( 1.11 g). , 5.00 mmol) and introducing a Boc-protecting group to obtain 2b Obtained as a light yellow solid (quantitative).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.72 (dd, J = 2.2, 1.7 Hz, 1H), 8.17 - 8.10 (m, 2H), 7.58 - 7.52 (m, 1H), 7.39 (s, 1H), 1.60 (s, 18H).

t -Butyl(5-(4-aminophenyl)thiazol-2-yl)(tert-butoxycarbonyl)carbamate (3a).

Following General Procedure A, 2a (2.00 mmol) was used to obtain 3a as a white solid (0.71 g, 90.4%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.6 Hz, 2H), 7.06 (s, 1H), 6.70 (d, J = 8.6 Hz, 2H), 3.74 (s, 2H), 1.54 (s, 18H).

t -Butyl(5-(3-aminophenyl)thiazol-2-yl)(tert-butoxycarbonyl)carbamate (3b).

Following General Procedure A, 2b ( 0.84 g, 2.00 mmol) was used to obtain 3b as a white solid (0.53 g, 67.2%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.28 - 7.14 (m, 4H), 6.69 - 6.61 (m, 1H), 3.70 (s, 2H), 1.54 (s, 18H).

5-(4-nitrophenyl)-1 H -imidazole (4a).

Following General Procedure B, 4a was obtained as a brown solid (0.50 g, 52.9%) using 2-bromo-4' nitroacetophenone (1.22 g, 5.00 mmol).

^1H NMR (400 MHz, DMSO- d6 ) δ 12.47 (s, 1H) _, 8.23 (d, J = 8.7 Hz, 2H), 8.04 (d, J = 8.5 Hz, 2H), 7.95 (s, 1H) , 7.83(s, 1H).

5-(3-nitrophenyl)-1 H -imidazole (4b).

4b was prepared according to General Procedure B using 2-bromo-3' nitroacetophenone (1.22 g, 5.00 mmol). Obtained as a brown solid (0.52 g, 55.1%).

^1H NMR (400 MHz, MeOD) δ 8.59 (t, J = 2.0 Hz, 1H), 8.12 - 8.05 (m, 2H), 7.79 (d, J = 1.2 Hz, 1H), 7.65 (s, 1H), 7.60 (t, J = 8.0 Hz, 1H).

1-methyl-5-(4-nitrophenyl)-1 H -imidazole (5a).

To a stirred mixture of 4a ( 94.58 mg, 0.50 mmol) in DMF (4 mL) was added sodium hydride 60% (24 mg, 0.60 mmol) at room temperature. The reaction mixture was continuously stirred at room temperature for 1 h until bubbling ceased. Methyl iodide (62.25 μL, 1.00 mmol) was added to the mixture and the reaction mixture was continuously stirred at room temperature for 6 h. The mixture was extracted with diethyl ether and washed with water. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (ethyl acetate/hexane) to obtain 5a. Obtained as a light yellow solid (59.23 mg, 58.3%).

^1H NMR (400 MHz, CDCl- ₃ ) δ 8.21 (d, J = 8.9 Hz, 2H), 7.88 (d, J = 9.0 Hz, 2H), 7.52 (s, 1H), 7.34 (d, J = 1.3 Hz, 1 H), 3.77 (s, 3 H).

1-methyl-5-(3-nitrophenyl)-1H-imidazole (5b).

Following procedure for 5a , 5b was prepared using 4b (94.58 mg, 0.50 mmol) Obtained as a light yellow solid (88.90 mg, 87.5%).

^1H NMR (400 MHz, CDCl ₃ ) δ 8.55 (t, J = 2.0 Hz, 1H), 8.11 (ddd, J = 7.8, 1.7, 1.0 Hz, 1H), 8.06 (ddd, J = 8.2, 2.3, 1.0 Hz, 1H), 7.55 - 7.49 (m, 2H), 7.31 (d, J = 1.3 Hz, 1H), 3.77 (s, 3H).

4-(1-methyl-1 H -imidazol-5-yl)aniline (6a).

6a was prepared using 5a (59.23 mg, 0.29 mmol) according to General Procedure A. Obtained as a white solid (quantitative).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56 (d, J = 8.5 Hz, 2H), 7.41 (s, 1H), 7.02 (d, J = 1.4 Hz, 1H), 6.70 (d, J = 8.5 Hz) , 2H), 3.69(s, 3H), 3.65(s, 2H).

3-(1-methyl-1 H -imidazol-5-yl)aniline (6b) :

Following General Procedure A, 5b ( 88.90 mg, 0.44 mmol) was used to obtain 6b as a white solid (quantitatively).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.45 - 7.44 (m, 1H), 7.19 (ddd, J = 2.2, 1.5, 0.5 Hz, 1H), 7.17 - 7.09 (m, 3H), 6.58 (ddd, J = 7.6, 2.4, 1.3 Hz, 1H), 3.71(s, 3H), 3.67(s, 2H).

4-(1 H -imidazol-5-yl)aniline (7a).

Following General Procedure A, 4a (0.38 g, 2.00 mmol) was used to obtain 7a as a white solid (0.29 g, 91.1%).

^1H NMR (400 MHz, MeOD) δ 7.64 (d, J = 1.2 Hz, 1H), 7.44 (d, J = 8.7 Hz, 2H), 7.19 (d, J = 1.2 Hz, 1H), 6.75 (d, J = 8.6 Hz, 2H).

3-(1 H -imidazol-5-yl)aniline (7b).

Following General Procedure A, 4b ( 0.38 g, 2.00 mmol) was used to obtain 7b as a white solid (0.29 g, 91.3%).

¹ H NMR (400 MHz, MeOD- d ₄ ) δ 7.68 (d, J = 1.1 Hz, 1H), 7.32 (d, J = 1.1 Hz, 1H), 7.14 - 7.01 (m, 3H), 6.62 (ddd, J = 7.9, 2.3, 1.1 Hz, 1H).

2-methyl-5-(4-nitrophenyl)-1 H -imidazole (8a).

A mixture of 2-bromo-4' nitroacetophenone (1.22 g, 5.00 mmol) and acetamide (10 mL) was heated at 180 °C for 1 day. After cooling, the mixture was poured into a saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (CH ₂ Cl ₂ /MeOH) to give 8a as a brown solid (0.73 g, 72.1%).

¹ H NMR (400 MHz, MeOD) δ 8.20 (d, J = 9.0 Hz, 2H), 7.87 (d, J = 9.0 Hz, 2H), 7.54 (s, 1H), 2.43 (s, 3H).

2-methyl-5-(3-nitrophenyl)-1 H -imidazole (8b).

Following the process for 8a , 8b was obtained as a light yellow solid (0.30 g, 30.0%) using 2-bromo-3' nitroacetophenone (1.22 g, 5.00 mmol).

^1H NMR (400 MHz, MeOD) δ 8.53 (t, J = 2.0 Hz, 1H), 8.06 - 8.02 (m, 2H), 7.57 (t, J = 8.0 Hz, 1H), 7.48 (s, 1H), 2.42(s, 3H).

4-(2-methyl-1 H -imidazol-5-yl)aniline (9a).

Following General Procedure A, 8a (0.20 g, 1.00 mmol) was used to obtain 9a as a white solid (0.14 g, 82.1%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.33 (d, J = 8.5 Hz, 2H), 7.03 (s, 1H), 6.53 (d, J = 8.5 Hz, 2H), 5.00 (br s, 2H) ), 2.27(s, 3H).

3-(2-methyl-1 H -imidazol-5-yl)aniline (9b).

Following General Procedure A, 8b (0.20 g, 1.00 mmol) was used to obtain 9b as a white solid (0.16 g, 93.0%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.18 (s, 1H), 6.99 - 6.90 (m, 2H), 6.82 (dt, J = 7.6, 1.2 Hz, 1H), 6.38 (ddd, J = 7.9 , 2.3, 1.1 Hz, 1H), 4.97 (s, 2H), 2.28 (s, 3H).

4-methyl-5-phenyl-1 H -imidazole (10).

Following General Procedure B, using 2-bromopropiophenone (2.13 g, 10.00 mmol), 10 was obtained as a white solid (1.34 g, 84.9%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.21 (br s, 1H), 7.61 - 7.56 (m, 2H), 7.50 (s, 1H), 7.44 - 7.34 (m, 2H), 7.28 - 7.21 (m, 1H), 2.42(s, 3H).

4-methyl-5-(4-nitrophenyl)-1 H -imidazole (11a).

0 ℃ In a round bottom flask containing concentrated nitric acid and sulfuric acid (1:1, 10 mL), 10 (1.34 g, 8.49 mmol) was suspended in the above solution. The reaction mixture was stirred at room temperature for 2 h and then heated at 60 °C for 4 h. The mixture was cooled to 0 °C and quenched with saturated NaHCO ₃ solution. The mixture was extracted with ethyl acetate and washed with brine. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (ethyl acetate/hexane) to give 11a as a yellow solid (1.16 g, 67.0%).

^1H NMR (400 MHz, DMSO- d6 ) δ 12.27 (s, 1H) _, 8.24 (d, J = 8.5 Hz, 2H), 7.93 (d, J = 8.5 Hz, 2H), 7.68 (s, 1H) , 2.48(s, 3H).

4-(4-methyl- 1H -imidazol-5-yl)aniline (12a).

12a was obtained as a white solid (quantitatively) using 11a (1.16 g, 5.71 mmol) according to General Procedure A.

¹ H NMR (400 MHz, MeOD) δ 7.73 (s, 1H), 7.27 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 2.33 (s, 3H).

2-Bromo-1-(3-nitrophenyl)propan-1-one (13).

To a mixture of 3'-nitropropiophenone (1.79 g, 10.00 mmol) in acetic acid (20 mL) was added dropwise bromine (0.28 mL, 11.00 mmol). The reaction mixture was stirred overnight at 30 °C. The mixture was quenched with cold saturated sodium hydrogencarbonate and extracted with CH ₂ Cl ₂ . The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (hexane/ethyl acetate) to obtain 13 as a white solid (2.35 g, 91.0%).

^1H NMR (400 MHz, CDCl ₃ ) δ 8.85 (t, J = 1.9 Hz, 1H), 8.45 (ddd, J = 8.2, 2.3, 1.1 Hz, 1H), 8.36 (ddd, J = 7.8, 1.7, 1.1 Hz, 1H), 7.72 (t, J = 7.9 Hz, 1H), 5.29 (q, J = 6.6 Hz, 1H), 1.95 (d, J = 6.6 Hz, 3H).

4-methyl-5-(3-nitrophenyl)-1 H -imidazole (11b).

Following General Procedure B, 13 (1.29 g, 5.00 mmol) was used to obtain 11b as a light yellow solid (0.80 g, 78.7%).

^1H NMR (400 MHz, MeOD) δ 8.45 (t, J = 2.0 Hz, 1H), 8.10 (ddd, J = 8.2, 2.4, 1.0 Hz, 1H), 7.98 (ddd, J = 7.8, 1.7, 1.0 Hz , 1H), 7.67 - 7.61 (m, 2H), 2.47 (s, 3H).

3-(4-methyl-1H-imidazol-5-yl)aniline (12b).

Following general procedure A, 11b (0.20 g, 1.00 mmol) was used to obtain 12b as a white solid (0.15 g, 89.3%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.70 (br s, 1H), 7.51 (s, 1H), 7.01 (t, J = 7.8 Hz, 1H), 6.84 (t, J = 1.9 Hz, 1H) ), 6.72 (dt, J = 7.7, 1.3 Hz, 1H), 6.42 (ddd, J = 7.9, 2.3, 1.0 Hz, 1H), 5.04 (br s, 2H), 2.32 (s, 3H).

5-(4-nitrophenyl)-1,3,4-oxadiazole-2(3 H )-ron (13a).

Triphosgene (0.59 g, 2.00 mmol) in tetrahydrofuran was added to a mixture of 4-nitrobenzohydrazide ( 0.90 g, 5.00 mmol) and triethylamine (1.02 g, 10.00 mmol) in tetrahydrofuran (2 mL). ) was added dropwise at 0 °C. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated to dryness. The product was extracted with ethyl acetate and washed with brine. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate/hexane) to give 13a as a yellow solid (0.93 g, 90.1%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.87 (br s, 1H), 8.36 (d, J = 9.0 Hz, 2H), 8.04 (d, J = 9.0 Hz, 2H).

5-(3-nitrophenyl)-1,3,4-oxadiazole-2(3 H )-ron (13b).

Following the procedure for 13a , 3-nitrobenzohydrazide ( 0.90 g, 5.00 mmol) was used to obtain 13b as a yellow solid (0.96 g, 92.6%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.84 (br s, 1H), 8.46 - 8.43 (m, 1H), 8.40 (ddd, J = 8.2, 2.4, 1.0 Hz, 1H), 8.21 (ddd, J = 7.8, 1.7, 1.0 Hz, 1H), 7.89 - 7.82 (m, 1H).

5-(4-aminophenyl)-1,3,4-oxadiazole-2(3 H )-ron (14a).

13a (0.83 g, 4.00 mmol) was used according to General Procedure A to obtain 14a as a white solid (0.57 g, 80.3%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.39 (d, J = 8.6 Hz, 2H), 6.58 (d, J = 8.7 Hz, 2H), 5.77 (s, 2H).

5-(3-aminophenyl)-1,3,4-oxadiazole-2(3 H )-ron (14b).

Following General Procedure A, 13b (0.83 g, 4.00 mmol) was used to obtain 14b as a white solid (0.60 g, 80.3%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.10 (t, J = 7.8 Hz, 1H), 6.95 (t, J = 2.0 Hz, 1H), 6.86 (dt, J = 7.6, 1.3 Hz, 1H) , 6.67 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 5.39 (s, 2H).

3-(2-methyloxazol-5-yl)aniline (15).

According to General Procedure A, 15 was obtained as a white solid (quantitatively) using 2-methyl-5-(3-nitrophenyl)oxazole (0.20 g, 1.00 mmol).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.74 (s, 1H), 7.15 (t, J = 7.7 Hz, 1H), 7.08 - 7.03 (m, 2H), 6.60 (ddd, J = 7.8, 2.4, 1.1 Hz, 1H), 3.74 (s, 2H), 2.48 (s, 3H).

3-(1 H -1,2,3-triazol-5-yl)aniline (16).

3-ethynylaniline (0.12 g, 1.00 mmol), trimethylsilyl azide (0.13 g, 1.10 mmol) and kappa(I) iodide (9.52 mg, 0.05 mmol) were added to DMF/MeOH (9/1, 2 mL). ) was added under nitrogen gas to the mixture. The reaction mixture was heated at 100 °C for 12 h under nitrogen gas. The solvent was evaporated to dryness, extracted with ethyl acetate and washed with brine. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (CH ₂ Cl ₂ /MeOH) to give 16 as a white solid (19.54 mg, 12.2%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94 (s, 1H), 7.23 (t, J = 7.9 Hz, 1H), 7.21 - 7.17 (m, 2H), 6.71 (ddd, J = 7.7, 2.4, 1.3 Hz, 1H).

Preparation 2. Synthesis of compounds 18a-n.

^a Reagents and conditions: (a) i: CDI, DMF, 6 h, ii: 4-Piperidone, 15 h; (b) 3a-b , 6a-b , 7a-b , 9a-b , 12a-b , 14a -b , 15 , or 16 , NaBH(OAc) ₃ , AcOH, CH ₂ Cl ₂ , 15 h; (c) 25% TFA, CH ₂ Cl ₂ , 3 h for Boc deprotection.

General process for carbamate formation C.

To a stirred solution of alcohol (10.00 mmol) in DMF (20 mL) was added 1,1'-carbonyldiimidazole (1.94 g, 12.00 mmol) at room temperature and stirred for 6 h. After adding the amine (12 mmol), the mixture was stirred at room temperature overnight. The organics were extracted with diethyl ether and washed twice with water. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (ethyl acetate/hexane) to obtain the desired carbamate.

General process for reductive amination D.

To a 10 ml-vial containing ketone (0.10 mmol), amine (0.10 mmol), and acetic acid (2 drops) was added sodium triacetoxyborohydride (25.43 mg, 0.12 mmol). The reaction mixture was stirred at room temperature overnight before quenching with saturated NaHCO ₃ solution. The organics were extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The product was purified by column chromatography (ethyl acetate/hexane) to obtain the desired substituted amine.

3,5-dichlorobenzyl 4-oxopiperidine-1-carboxylate (17) :

According to General Procedure C, using 3,5-dichlorobenzyl alcohol (1.77 g, 10.00 mmol) and 4-piperidone monohydrate (3.07 g, 20 mmol), 17 was obtained as a white solid (2.76 g, 91.3%). .

^1H NMR (400 MHz, CDCl ₃ ) δ 7.33 (t, J = 1.9 Hz, 1H), 7.26 - 7.23 (m, 2H), 5.12 (s, 2H), 3.81 (t, J = 6.3 Hz, 4H) , 2.49 (t, J = 6.2 Hz, 4H).

3,5-dichlorobenzyl 4-((4-(2-aminothiazol-5-yl)phenyl)amino)piperidine-1-carboxylate (18a).

3,5-Dichlorobenzyl 4-((4-(2-(bis(tert-butoxycarbonyl) using 17 (30.21 mg, 0.10 mmol) and 3a (39.15 mg, 0.10 mmol) according to General Procedure D Obtained )amino)thiazol-5-yl)phenyl)amino)piperidine-1-carboxylate as a white solid (35.78 mg, 52.8%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66 (d, J = 8.6 Hz, 2H), 7.31 (t, J = 1.9 Hz, 1H), 7.23 (d, J = 1.8 Hz, 2H), 7.04 (s , 1H), 6.61 (d, J = 8.7 Hz, 2H), 5.07 (s, 2H), 4.20 - 4.05 (m, 2H), 3.66 (s, 1H), 3.56 - 3.44 (m, 1H), 3.13 - 2.96 (m, 2H), 2.19 - 2.03 (m, 2H), 1.54 (s, 18H), 1.45 - 1.33 (m, 2H).

It was dissolved in a 25% TFA solution in CH ₂ Cl ₂ and stirred at room temperature for 3 h. The mixture was concentrated and purified by column chromatography (ethyl acetate/hexane) to give the title compound 18a as a white solid (15.91 mg, 63.1%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59 (d, J = 8.7 Hz, 2H), 7.32 - 7.29 (m, 1H), 7.23 - 7.22 (m, 2H), 6.60 (d, J = 8.7 Hz, 2H), 6.49(s, 1H), 5.07(s, 2H), 5.04(s, 2H), 4.20 - 4.05(m, 2H), 3.61(d, J = 7.8 Hz, 1H), 3.55 - 3.44(m) , 1H), 3.13 - 2.99 (m, 2H), 2.13 - 2.07 (m, 2H), 1.45 - 1.33 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 166.97, 154.72, 151.59, 146.27, 140.22, 135.11, 128.16, 127.32, 126.09, 124.82, 113.22, 99.73, 65.295, 3.4.84, 49 HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₂ H ₂₃ Cl ₂ N ₄ O ₂ S = 477.09; found 477.0915.

3,5-dichlorobenzyl 4-((3-(2-aminothiazol-5-yl)phenyl)amino)piperidine-1-carboxylate (18b).

Boc - protected intermediate 3,5-dichlorobenzyl 4-( ( 3-(2-(bis(tert Obtained -butoxycarbonyl)amino)thiazol-5-yl)phenyl)amino)piperidine-1-carboxylate as a white solid (63.83 mg, 94.2%);

¹ H NMR (400 MHz, CDCl ₃ δ 7.31 (t, J = 2.0 Hz, 1H), 7.25 - 7.22 (m, 3H), 7.21 - 7.13 (m, 3H), 6.59 - 6.54 (m, 1H), 5.08 (s, 2H), 4.18 - 4.07 (m, 2H), 3.59 (s, 1H), 3.57 - 3.50 (m, 1H), 3.10 - 2.99 (m, 2H), 2.13 - 2.06 (m, 2H), 1.55 (s, 18H), 1.43 - 1.33 (m, 2H) This was deprotected to obtain 18b as a white solid (35.64 mg, 79.1%) ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.31 - 7.29 (m, 1H), 7.24 - 7.21(m, 2H), 7.17(t, J = 8.0 Hz, 1H), 7.10 - 7.06(m, 2H), 6.68(s, 1H), 6.56 - 6.52(m, 1H), 5.09 (s, 2H), 5.07(s, 2H), 4.18 - 4.03(m, 2H), 3.63 - 3.50(m, 2H), 3.04(s, 2H), 2.12 - 2.05(m, 2H), 1.43 - 1.31 (m, 2h). ¹³ C NMR (100 MHz, CDCL ₃ ) Δ 167.02, 154.72, 151.60, 146.97, 140.25, 135.80, 135.11, 129.59, 128.14, 126.07, 115.49, 112.73, 111.40, 102.93, 65.52, 49.98 HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₂ H ₂₃ Cl ₂ N ₄ O ₂ S = 477.09;

3,5-dichlorobenzyl 4-((4-(1-methyl-1 H -imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate (18c).

Using 17 (30.21 mg, 0.10 mmol) and 6a (17.32 mg, 0.10 mmol) according to General Procedure D, 18c was obtained as a white solid (31.74 mg, 69.1%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.58 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 1.4 Hz, 1H), 7.30 (t, J = 1.9 Hz, 1H), 7.23 (d , J = 1.9 Hz, 2H), 7.01 (d, J = 1.4 Hz, 1H), 6.62 (d, J = 8.7 Hz, 2H), 5.07 (s, 2H), 4.19 - 4.06 (m, 2H), 3.69 (s, 3H), 3.58 - 3.47 (m, 2H), 3.12 - 2.94 (m, 2H), 2.17 - 2.04 (m, 2H), 1.45 - 1.32 (m, 2H). ¹³ C NMR (100 MHz, CDCL ₃ ) δ 154.72, 145.55, 142.79, 140.25, 137.63, 135.10, 128.14, 126.08, 126.05, 124.36, 114.19, 113.53, 65.51, 50.00, 43.00, 33.44, 32.31. HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₃ H ₂₅ Cl ₂ N ₄ O ₂ = 459.14; found 459.1350

3,5-dichlorobenzyl 4-((3-(1-methyl-1H-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate (18d).

According to General Procedure D, using 17 (30.21 mg, 0.10 mmol) and 6b (17.32 mg, 0.10 mmol), 18d was obtained as a white solid (40.42 mg, 88.0%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.44 (d, J = 1.4 Hz, 1H), 7.30 (t, J = 1.9 Hz, 1H), 7.24 - 7.22 (m, 2H), 7.18 - 7.12 (m, 3H), 7.02 (dt, J = 7.9, 1.1 Hz, 1H), 6.49 (ddd, J = 7.8, 2.5, 1.0 Hz, 1H), 5.07 (s, 2H), 4.22 - 3.99 (m, 2H), 3.70 (s, 3H), 3.61 - 3.50 (m, 2H), 3.13 - 2.99 (m, 2H), 2.16 - 2.06 (m, 2H), 1.45 - 1.30 (m, 2H). ¹³ C NMR (100 MHz, CDCL ₃ ) δ 154.72, 147.06, 142.61, 140.28, 137.84, 135.34, 135.09, 129.52, 128.12, 126.07, 116.04, 114.44, 112.11, 109.75, 65.49, 49.82, 32.43. HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₃ H ₂₅ Cl ₂ N ₄ O ₂ = 459.14; found 459.1351

3,5-Dichlorobenzyl 4-((4-(1 H -imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate (18e).

Using 17 (30.21 mg, 0.10 mmol) and 7a (15.92 mg, 0.10 mmol) according to General Procedure D, 18e was obtained as a white solid (36.61 mg, 82.2%).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.38 (br s, 1H), 7.62 (d, J = 1.1 Hz, 1H), 7.51 (d, J = 8.6 Hz, 2H), 7.31 - 7.29 (m, 1H) ), 7.23 - 7.21 (m, 2H), 7.18 (d, J = 1.1 Hz, 1H), 6.61 (d, J = 8.6 Hz, 2H), 5.07 (s, 2H), 4.17 - 4.07 (m, 2H) , 3.66 (br s, 1H), 3.52 - 3.44 (m, 1H), 3.09 - 2.97 (m, 2H), 2.11 - 2.05 (m, 2H), 1.42 - 1.32 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 154.91, 145.96, 140.37, 138.45, 135.28, 135.23, 128.33, 126.44, 126.24, 122.69, 114.64, 113.75, 6, 43.72, 65.2.18, 5 HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₂ H ₂₃ Cl ₂ N ₄ O ₂ = 445.12; found 445.1194.

3,5-Dichlorobenzyl 4-((3-(1 H -imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate (18f).

According to General Procedure D, 17 (30.21 mg, 0.10 mmol), 7b (15.92 mg, 0.10 mmol) was used to obtain 18f as a white solid (31.22 mg, 70.1%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.68 (d, J = 1.1 Hz, 1H), 7.32 - 7.29 (m, 2H), 7.22 (d, J = 1.9 Hz, 2H), 7.17 (t, J = 7.8 Hz, 1H), 7.06 (t, J = 2.0 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.50 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 5.06 (s, 2H), 4.18 - 3.94(m, 2H), 3.49(tt, J = 10.1, 3.9 Hz, 1H), 3.06 - 2.91(m, 2H), 2.09 - 2.00(m, 2H), 1.40 - 1.28(m, 2H). ¹³ C NMR (100 MHz, CDCL ₃ ) δ 154.89, 147.33, 140.40, 138.95, 135.62, 135.28, 134.00, 129.98, 128.32, 126.22, 115.94, 114.62, 112.52, 109.93 HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₂ H ₂₃ Cl ₂ N ₄ O ₂ = 445.12; found 445.1203.

3,5-dichlorobenzyl 4-((4-(2-methyl-1 H -imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate (18 g).

According to general process D, 17 (30.21 mg, 0.10 mmol) and 9a (17.32 mg, 0.10 mmol) to give 18g as a white solid (38.63 mg, 84.1%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48 (d, J = 8.6 Hz, 2H), 7.30 (t, J = 1.9 Hz, 1H), 7.24 - 7.21 (m, 2H), 7.03 (s, 1H) , 6.60 (d, J = 8.7 Hz, 2H), 5.07 (s, 2H), 4.18 - 4.05 (m, 2H), 3.50 - 3.42 (m, 1H), 3.12 - 2.97 (m, 2H), 2.42 (s , 3H), 2.13 - 2.05 (m, 2H), 1.42 - 1.31 (m, 2H). ¹³ C NMR (100 MHz, CDCL ₃ ) δ 154.72, 145.52, 144.37, 144.07, 140.20, 138.32, 135.10, 128.15, 126.06, 125.99, 122.90, 113.56, 65.53, 49.95, 42.97, 32.36, 14.4. HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₃ H ₂₅ Cl ₂ N ₄ O ₂ = 459.14; found 459.1351.

3,5-Dichlorobenzyl 4-((3-(2-methyl-1 H -imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate (18h).

According to general procedure D, using 17 (30.21 mg, 0.10 mmol) and 9b (17.32 mg, 0.10 mmol), 18h was obtained as a white solid (40.38 mg, 87.9%).

^1H NMR (400 MHz, , CDCl ₃ ) δ 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 7.18 - 7.16 (m, 1H), 7.13 (t, J = 7.8 Hz, 1H), 7.02 - 6.99 (m, 1H), 6.97 (dt, J = 7.8, 1.2 Hz, 1H), 6.47 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 5.06 (s, 2H), 4.14 - 3.96(m, 2H), 3.52 - 3.39(m, 1H), 3.05 - 2.86(m, 2H), 2.41(s, 3H), 2.07 - 1.99(m, 2H), 1.38 - 1.25( m, 2H). ¹³ C NMR (100 MHz, CDCL ₃ ) δ 154.70, 147.10, 144.86, 140.23, 135.09, 134.11, 129.70, 128.13, 126.04, 114.23, 111.95, 109.63, 65.49, 49.76, 42.91, 32.37, 14.21. HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₃ H ₂₅ Cl ₂ N ₄ O ₂ = 459.14; found 459.1351

3,5-Dichlorobenzyl 4-((4-(4-methyl-1 H -imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate (18i).

According to General Procedure D, using 17 (30.21 mg, 0.10 mmol) and 12a (17.32 mg, 0.10 mmol), 18i was obtained as a white solid (23.11 mg, 50.3%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.02 (s, 1H), 7.47 (s, 1H), 7.38 (d, J = 8.6 Hz, 2H), 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 2.0 Hz, 2H), 6.63 (d, J = 8.7 Hz, 2H), 5.06 (s, 2H), 4.18 - 4.04 (m, 2H), 3.70 - 3.54 (m, 1H), 3.52 - 3.43 (m, 1H), 3.15 - 2.96 (m, 2H), 2.38 (s, 3H), 2.13 - 2.03 (m, 2H), 1.45 - 1.31 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 154.72, 145.26, 140.18, 135.09, 133.01, 128.14, 127.96, 126.05, 113.40, 65.53, 49.90, 42.96, 32.31, 12.35 HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₃ H ₂₅ Cl ₂ N ₄ O ₂ = 459.14; found 459.1349

3,5-dichlorobenzyl 4-((3-(4-methyl-1H-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate (18j).

According to General Procedure D, using 17 (30.21 mg, 0.10 mmol) and 12b (17.32 mg, 0.10 mmol), 18j was obtained as a white solid (33.58 mg, 73.1%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.14 (s, 1H), 7.51 (s, 1H), 7.29 (t, J = 2.0 Hz, 1H), 7.21 (d, J = 1.9 Hz, 2H), 7.17 (t, J = 8.0 Hz, 1H), 6.91 - 6.85 (m, 2H), 6.49 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 5.05 (s, 2H), 4.14 - 3.97 (m, 2H) ), 3.46 - 3.38 (m, 1H), 3.01 - 2.84 (m, 2H), 2.41 (s, 3H), 2.06 - 1.98 (m, 2H), 1.36 - 1.25 (m, 2H). ¹³ C NMR (100 MHz, CDCL ₃ ) δ 154.70, 146.96, 140.19, 135.08, 134.58, 133.36, 132.64, 129.54, 128.12, 126.61, 126.03, 116.11, 111.74 HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₃ H ₂₅ Cl ₂ N ₄ O ₂ = 459.14; found 459.1350

3,5-Dichlorobenzyl 4-((4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)amino)piperidine-1-carboxylate (18k).

According to General Procedure D, using 17 (30.21 mg, 0.10 mmol) and 14a (17.72 mg, 0.10 mmol), 18k was obtained as a white solid (16.63 mg, 35.9%).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.04 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.31 (t, J = 2.0 Hz, 1H), 7.24 (d, J = 1.9 Hz , 2H), 6.62 (d, J = 8.8 Hz, 2H), 5.08 (s, 2H), 4.22 - 4.09 (m, 2H), 4.00 (d, J = 7.8 Hz, 1H), 3.59 - 3.49 (m, 1H), 3.15 - 2.99 (m, 2H), 2.13 - 2.06 (m, 2H), 1.49 - 1.37 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 155.91, 154.71, 149.33, 140.06, 135.12, 128.21, 127.60, 126.11, 112.64, 112.30, 65.64, 49.54, 42.86, 32.06. HRMS (ESI) m/z(M+H) ⁺ calcd for C ₂₁ H ₂₁ Cl ₂ N ₄ O ₄ = 463.09; found 463.0936

3,5-Dichlorobenzyl 4-((3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)amino)piperidine-1-carboxylate (18l).

According to general procedure D, using 17 (30.21 mg, 0.10 mmol) and 14b (17.72 mg, 0.10 mmol), 18l was obtained as a white solid (29.93 mg, 64.6%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.82 (s, 1H), 7.30 (t, J = 1.9 Hz, 1H), 7.27 - 7.25 (m, 1H), 7.23 (d, J = 2.2 Hz, 2H) , 7.18 (dt, J = 7.7, 1.3 Hz, 1H), 7.04 (t, J = 2.0 Hz, 1H), 6.72 (ddd, J = 8.1, 2.5, 1.1 Hz, 1H), 5.09 (s, 2H), 4.23 - 4.05(m, 2H), 3.84 - 3.72(m, 1H), 3.59 - 3.47(m, 1H), 3.16 - 2.99(m, 2H), 2.16 - 2.04(m, 2H), 1.46 - 1.32(m , 2H). ¹³ C NMR (100 MHz, CDCL ₃ ) Δ 155.62, 155.02, 154.82, 147.00, 140.06, 135.12, 130.07, 128.20, 126.10, 124.75, 116.77, 114.99, 109.40, 65.69, 49.69, 42.93, 32.05 HRMS (ESI) m/z(M+H) ⁺ calcd for C ₂₁ H ₂₁ Cl ₂ N ₄ O ₄ = 463.09; found 463.0935

3,5-Dichlorobenzyl 4-((3-(2-methyloxazol-5-yl)phenyl)amino)piperidine-1-carboxylate (18m):

Using 17 (30.21 mg, 0.10 mmol) and 15 (17.42 mg, 0.10 mmol) according to General Procedure D, 18m was obtained as a white solid (33.33 mg, 74.2%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.76 (s, 1H), 7.30 (t, J = 2.0 Hz, 1H), 7.23 (d, J = 1.9 Hz, 2H), 7.18 (t, J = 7.8 Hz , 1H), 7.03 - 6.97 (m, 2H), 6.55 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 5.07 (s, 2H), 4.18 - 4.04 (m, 2H), 3.65 - 3.50 (m , 2H), 3.13 - 2.99 (m, 2H), 2.50 (s, 3H), 2.14 - 2.05 (m, 2H), 1.37 (m, 2H). ¹³ C NMR (100 MHz, CDCL ₃ ) δ 161.67, 154.71, 147.08, 140.83, 140.23, 135.10, 133.28, 132.25, 129.74, 128.15, 126.08, 114.84, 112.81 HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₃ H ₂₄ Cl ₂ N ₃ O ₃ = 460.12; found 460.1191

3,5-Dichlorobenzyl 4-((3-(1 H -1,2,3-triazol-5-yl)phenyl)amino)piperidine-1-carboxylate (18n).

According to General Procedure D, using 17 (30.21 mg, 0.10 mmol) and 16 (16.02 mg, 0.10 mmol), 18n was obtained as a white solid (9.06 mg, 50.3%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93 (s, 1H), 7.30 (t, J = 1.9 Hz, 1H), 7.26 - 7.21 (m, 3H), 7.14 - 7.09 (m, 2H), 6.62 ( ddd, J = 8.1, 2.4, 1.1 Hz, 1H), 5.08 (s, 2H), 4.21 - 4.04 (m, 2H), 3.60 - 3.52 (m, 1H), 3.14 - 2.94 (m, 2H), 2.18 - 2.03 (m, 2H), 1.47 - 1.32 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 154.81, 147.19, 140.12, 135.11, 130.81, 130.02, 128.17, 126.08, 115.62, 113.77, 110.70, 65.62, 49.26, 42.96, 42.98 HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₁ H ₂₂ Cl ₂ N ₅ O ₂ = 446.12; found 446.1160.

Preparation method 3. Synthesis of building blocks F and G

Reagents and conditions: (a) Me ₃ SiN ₃ , CuI, DMF, MeOH, 100 °C, 12 h; (b) 4M HCl in dioxane, 18 h; (c) (Boc) ₂ O, Et ₃ N, CH _2- Cl ₂ , 15 h; (d) N ₂ H ₄ .H ₂ O, MeOH, reflux, 6 h; (e) CDI, DMF, 80 °C, 15 h.

t -Butyl 4-(1 H -1,2,3-triazol-5-yl)piperidine-1-carboxylate (19).

t -Butyl 4-ethynylpiperidine-1-carboxylate (1.05 g, 5.00 mmol), trimethylsilyl azide (5.5 mmol) and kappa(I) iodide (0.25 mmol) were dissolved in DMF (9 mL) under argon. ) and MeOH (1 mL). The reaction mixture was stirred at 100 °C for 8 h. The solvent was evaporated to dryness, extracted with ethyl acetate and washed with brine. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (CH ₂ Cl ₂ /MeOH) to give 19 as a white solid (1.03 g, 81.3%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 12.73 (br s, 1H), 7.52 (s, 1H), 4.32 - 4.01 (m, 2H), 3.00 - 2.86 (m, 3H), 2.04 - 1.97 (m, 2H), 1.73 - 1.60 (m, 2H), 1.48 (s, 9H).

4-(1 H -1,2,3-triazol-5-yl)piperidine hydrochloride (20).

To a solution of 19 (1.01 g, 4.00 mmol) in dioxane (10 mL) was added a 4.0 M hydrogen chloride solution in dioxane (2 mL). The reaction mixture was stirred overnight at room temperature. The solvent was evaporated to dryness and 20 was obtained as a white solid (quantitative).

¹ H NMR (400 MHz, MeOD) δ 8.37 (s, 1H), 3.56 - 3.47 (m, 2H), 3.44 - 3.35 (m, 1H), 3.27 - 3.18 (m, 2H), 2.37 - 2.30 (m, 2H), 2.12 - 1.98 (m, 2H).

One- t -Butyl 4-methylpiperidine-1,4-dicarboxylate (21).

To a round bottom flask containing methyl piperidine-4-carboxylate (1.43 g, 10.00 mmol), triethylamine (2.02 g, 20.00 mmol) in CH ₂ Cl ₂ (20 mL) in tetrahydrofuran at 0 °C. Di-tert-butyl dicarbonate 30% (10.91 g, 15.00 mmol) was added. The reaction mixture was stirred overnight at room temperature. The solution was concentrated and the residue was purified by column chromatography (ethyl acetate/hexane) to give 21 as a white solid (2.08 g, 85.5%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 4.09 - 3.94 (m, 2H), 3.69 (s, 3H), 2.88 - 2.77 (m, 2H), 2.50 - 2.41 (m, 1H), 1.91 - 1.83 (m , 2H), 1.69 - 1.57 (m, 2H), 1.46 (s, 9H).

t -Butyl 4-(hydrazinecarbonyl)piperidine-1-carboxylate (22).

A mixture of 21 (1.21 g, 5.00 mmol) and hydrazine monohydrate (0.5 mL) in MeOH (10 mL) was refluxed for 1 h. The solvent was removed by rotary evaporator and the residue (crude 22; white solid; quantitative) was used in the next step without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.12 (s, 1H), 4.25 - 4.07 (m, 2H), 4.03 - 3.64 (m, 2H), 2.82 - 2.66 (m, 2H), 2.34 - 2.15 (m , 1H), 1.86 - 1.75 (m, 2H), 1.71 - 1.58 (m, 2H), 1.46 (s, 9H).

t -Butyl 4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (23).

To a mixture of 22 (1.22 g, 5.0 mmol) in DMF (25 mL) was added 1,1'-carbonyldiimidazole (0.973 g, 6.0 mmol). The reaction mixture was stirred overnight at 80 °C. The solvent was evaporated to dryness. The product was extracted with ethyl acetate and washed with water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate/hexane) to obtain 23 as a white solid (0.97 g, 72.2%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.87 (br s, 1H), 4.21 - 3.91 (m, 2H), 2.99 - 2.85 (m, 2H), 2.81 - 2.70 (m, 1H), 2.00 - 1.93 ( m, 2H), 1.77 - 1.61 (m, 2H), 1.47 (s, 9H).

5-(piperidin-4-yl)-1,3,4-oxadiazole-2(3 H )-rone hydrochloride (24).

To a solution of 23 (0.97 g, 3.60 mmol) in dioxane (10 mL) was added a 4.0 M hydrogen chloride solution in dioxane (2 mL). The reaction mixture was stirred overnight at room temperature. The solvent was evaporated to dryness to give 24 as a white solid (quantitatively).

¹ H NMR (400 MHz, D ₂ O ) δ 3.50 - 3.38 (m, 2H), 3.19 - 3.04 (m, 3H), 2.28 - 2.17 (m, 2H), 1.98 - 1.83 (m, 2H).

Preparation 4. Synthesis of compounds 27a-g

^f Reagents and conditions: (a) i: CDI, DMF, 6 h, ii: methyl 4-piperidinecarboxylate, 15 h; (b); i: LiOH, THF, MeOH, H ₂ O, 6 h, ii: 1M HCl; (c) i: HBTU, DIEA, DMF, ii: 3a-b , 7a-b , 4-( 1H -imidazole- 5-day) piperidine, 20 , or 24 , 15 h; (d) TFA, CH ₂ Cl ₂ , 3 h.

1-(3,5-dichlorobenzyl) 4-methylpiperidine-1,4-dicarboxylate (25).

According to General Procedure C, using 3,5-dichlorobenzyl alcohol (1.77 g, 10.00 mmol) and methyl 4-piperidinecarboxylate (2.86 g, 20.00 mmol), 25 was prepared as a colorless oil (2.55 g, 73.6%) got it with

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.32 - 7.29 (m, 1H), 7.24 - 7.20 (m, 2H), 5.06 (d, J = 5.2 Hz, 2H), 4.17 - 3.99 (m, 2H), 3.70 (d, J = 0.8 Hz, 3H), 3.06 - 2.88 (m, 2H), 2.55 - 2.45 (m, 1H), 1.99 - 1.87 (m, 2H), 1.73 - 1.61 (m, 2H).

1-(((3,5-dichlorobenzyl)oxy)carbonyl)piperidine-4-carboxylic acid (26).

A solution of lithium hydroxide (0.600 g, 25 mmol) in water (10 mL) was added to a solution of a mixture of 25 (2.18 g, 5.00 mmol) in THF/MeOH (18 ml / 2 ml). The reaction mixture was stirred at room temperature for 6 h. Then the solvent was evaporated, re-dissolved in water and acidified with 1M HCl solution. The mixture was extracted with ethyl acetate and washed with water. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (ethyl acetate/hexane) to obtain 26 as a white solid (quantitatively).

^1H NMR (400 MHz, CDCl ₃ ) δ 10.84 (s, 1H), 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.8 Hz, 2H), 5.07 (d, J = 5.1 Hz , 2H), 4.16 - 4.02 (m, 2H), 3.07 - 2.90 (m, 2H), 2.62 - 2.45 (m, 1H), 2.02 - 1.92 (m, 2H), 1.77 - 1.61 (m, 2H).

General process for amide coupling E.

Carboxylic acid (0.10 mmol) and HBTU (45.51 mg, 0.12 mmol) were added to a 10-mL vial containing 2 ml DMF and stirred for 10 minutes. Amine (0.10 mmol) and triethylamine (20.24 mg, 0.20 mmol) were added to the stirring mixture. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated to dryness and the crude product was separated by column chromatography (CH ₂ Cl ₂ /MeOH) to obtain the desired amide.

3,5-dichlorobenzyl 4-((4-(2-aminothiazol-5-yl)phenyl)carbamoyl)piperidine-1-carboxylate (27a).

According to general procedure E, using 26 (33.21 mg, 0.10 mmol) and 3a (39.15 mg, 0.10 mmol), the Boc-protected product was obtained as a white solid (61.74 mg, 87.5%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.78 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.33 (s, 1H), 7.32 - 7.30 (m, 1H) , 7.25 - 7.22(m, 2H), 7.20(s, 1H), 5.08(d, J = 18.5 Hz, 2H), 4.32 - 4.17(m, 2H), 3.00 - 2.85(m, 2H), 2.49 - 2.38 (m, 1H), 1.99 - 1.91 (m, 2H), 1.86 - 1.75 (m, 2H), 1.56 (s, 18H).

This was dissolved in a solution of 25% TFA in CH ₂ Cl ₂ (20 mL) and stirred at room temperature for 3 h. The mixture was concentrated and purified by column chromatography (ethyl acetate/hexane) to give 27a as a white solid (35.08 mg, 79.3%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.96 (s, 1H), 7.71 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H), 7.57 - 7.55 (m, 1H), 7.45 - 7.40(m, 2H), 7.00(s, 2H), 6.87(s, 1H), 5.09(s, 2H), 4.12 - 4.02(m, 2H), 2.90(s, 2H), 2.58 - 2.51 (m, 1H), 1.86 - 1.77 (m, 2H), 1.54 (qd, J = 12.5, 4.2 Hz, 2H). ¹³ C NMR (100 MHz, DMSO) Δ 173.28, 168.55, 154.54, 150.12, 141.84, 138.77, 134.55, 130.47, 127.90, 126.64, 126.35, 119.49, 100.64, 65.16, 43.57, 42.87, 28.51. HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₃ H ₂₃ Cl ₂ N ₄ O ₃ S = 505.09; found 505.0865.

3,5-dichlorobenzyl 4-((3-(2-aminothiazol-5-yl)phenyl)carbamoyl)piperidine-1-carboxylate (27b).

Following the procedure for 27a , using 26 ( 58.43 mg, 0.083 mmol) and 3b (39.15 mg, 0.10 mmol) gave the boc-protected intermediate (58.43 mg, 0.083 mmol);

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.57 - 7.51 (m, 1H), 7.39 - 7.32 (m, 4H), 7.26 - 7.25 (m, 2H), 5.10 (d, J = 16.7 Hz, 2H), 4.34 - 4.19 (m, 2H), 3.04 - 2.88 (m, 2H), 2.49 - 2.40 (m, 1H), 2.01 - 1.93 ( m, 2H), 1.89 - 1.78 (m, 2H), 1.57 (s, 18H) and 27b was obtained as a white solid (30.14 mg, 72.0%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.95 (br s, 1H), 8.09 (t, J = 1.9 Hz, 1H), 7.58 - 7.56 (m, 1H), 7.49 - 7.44 (m, 2H) , 7.44 - 7.41(m, 2H), 7.26(t, J = 7.9 Hz, 1H), 7.03(s, 2H), 6.90(s, 1H), 5.10(s, 2H), 4.14 - 4.04(m, 2H) ), 3.02 - 2.78 (m, 2H), 2.61 - 2.53 (m, 1H), 1.87 - 1.79 (m, 2H), 1.61 - 1.48 (m, 2H). ¹³ C NMR (100 MHz, DMSO- D ₆ ) δ 172.83, 168.07, 154.05, 149.80, 141.35, 139.39, 135.33, 134.06, 128.64, 127.40, 126.14, 120.31, 118.09, 116.83, 101.51, 64.66, 43. . HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₃ H ₂₃ Cl ₂ N ₄ O ₃ S = 505.09; found 505.0865.

3,5-Dichlorobenzyl 4-((4-(1 H -imidazol-5-yl)phenyl)carbamoyl)piperidine-1-carboxylate (27c).

According to General Procedure E, 26 (33.21 mg, 0.10 mmol) and 7a (15.92 mg, 0.10 mmol) were used to obtain 27c as a white solid (24.33 mg, 51.4%).

^1H NMR (400 MHz, CD ₃ OD) δ 7.70 (d, J = 1.2 Hz, 1H), 7.65 (d, J = 8.7 Hz, 2H), 7.57 (d, J = 8.7 Hz, 2H), 7.39 - 7.38(m, 1H), 7.37(d, J = 1.2 Hz, 1H), 7.34 - 7.32(m, 2H), 5.10(s, 2H), 4.22(m, 2H), 3.00 - 2.86(m, 2H) , 2.63 - 2.56 (m, 1H), 1.88 (m, 2H), 1.76 - 1.66 (m, 2H). ¹³ C NMR (100 MHz, CD ₃ OD) δ 174.16, 154.96, 140.87, 137.20, 135.54, 134.79, 127.50, 125.88, 124.78, 120.04, 65.23, 43.20, 43.16, 28.19. HRMS (ESI) m/z(M+H) ⁺ calcd for C ₂₃ H ₂₃ Cl ₂ N ₄ O ₃ = 473.11; found 473.1147.

3,5-Dichlorobenzyl 4-((3-(1 H -imidazol-5-yl)phenyl)carbamoyl)piperidine-1-carboxylate (27d).

Following General Procedure E, 26 (33.21 mg, 0.10 mmol) and 7b (15.92 mg, 0.10 mmol) were used to obtain 27d as a white solid (35.41 mg, 74.8%).

^1H NMR (400 MHz, CD ₃ OD) δ 7.85 (t, J = 1.9 Hz, 1H), 7.76 (d, J = 1.1 Hz, 1H), 7.48 - 7.43 (m, 2H), 7.42 (d, J = 1.2 Hz, 1H), 7.39 (t, J = 1.9 Hz, 1H), 7.35 - 7.33 (m, 2H), 7.31 (t, J = 7.8 Hz, 1H), 5.11 (s, 2H), 4.26 - 4.19 (m, 2H), 3.04 - 2.88 (m, 2H), 2.64 - 2.56 (m, 1H), 1.93 - 1.86 (m, 2H), 1.78 - 1.66 (m, 2H). ¹³ C NMR (100 MHz, CD ₃ OD) Δ 174.32, 155.00, 140.92, 138.83, 138.05, 135.73, 134.83, 133.55, 128.82, 127.54, 125.92, 120.40, 118.53, 116.34, 115.16, 65.27, 43.24 HRMS (ESI) m/z(M+H) ⁺ calcd for C ₂₃ H ₂₃ Cl ₂ N ₄ O ₃ = 473.11; found 473.1160.

3,5-dichlorobenzyl 4-(4-(1H-imidazol-5-yl)piperidine-1-carbonyl)piperidine-1-carboxylate (27e).

27e was obtained as a white solid ( 26.57 mg, 57.1%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.65 (br s, 1H), 7.75 (s, 1H), 7.29 (t, J = 2.0 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 6.81(s, 1H), 5.16 - 5.02(m, 2H), 4.67 - 4.59(m, 1H), 4.24 - 4.10(m, 2H), 4.04 - 3.92(m, 1H), 3.26 - 3.11(m, 1H) ), 2.98 - 2.81 (m, 3H), 2.79 - 2.66 (m, 2H), 2.16 - 1.99 (m, 2H), 1.80 - 1.68 (m, 4H), 1.65 - 1.51 (m, 2H). ¹³ C NMR (100 MHz, CDCL ₃ ) δ 172.75, 154.72, 141.19, 140.19, 135.07, 134.54, 128.12, 126.05, 113.91, 65.52, 45.55, 43.49, 42.02, 38.10, 34.53, 32.62 . HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₂ H ₂₇ Cl ₂ N ₄ O ₃ = 465.15; found 465.1455.

3,5-Dichlorobenzyl 4-(4-(1 H -1,2,3-triazol-5-yl) piperidine-1-carbonyl) piperidine-1-carboxylate (27f).

According to General Procedure E, using 26 (33.21 mg, 0.10 mmol) and 20 (22.64 mg, 0.12 mmol), 27f was obtained as a white solid (32.55 mg, 69.8%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.98 (s, 1H), 7.49 (s, 1H), 7.29 (t, J = 1.9 Hz, 1H), 7.23 (d, J = 1.9 Hz, 2H), 5.20 - 4.96(m, 2H), 4.71 - 4.60(m, 1H), 4.30 - 4.14(m, 2H), 4.05 - 3.92(m, 1H), 3.33 - 3.17(m, 1H), 3.12 - 3.02(m, 1H), 2.99 - 2.68 (m, 4H), 2.20 - 2.01 (m, 2H), 1.86 - 1.61 (m, 6H). ¹³ C NMR (100 MHz, CDCL ₃ ) δ 172.85, 154.78, 149.66, 140.11, 135.07, 128.78, 128.14, 126.10, 65.61, 45.48, 43.52, 41.98, 38.22, 33.17, 32.55, 31.39, 28.25. HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₁ H ₂₆ Cl ₂ N ₅ O ₃ = 466.14; found 466.1412.

3,5-dichlorobenzyl 4-(4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidine-1-carbonyl)piperidine- 1-Carboxylate (27 g).

Following General Procedure E, using 26 (33.21 mg, 0.10 mmol) and 24 (20.56 mg, 0.10 mmol), 27 g was obtained as a white solid (27.11 mg, 56.1%).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.67 (s, 1H), 7.30 (t, J = 1.9 Hz, 1H), 7.23 (d, J = 1.9 Hz, 2H), 5.17 - 5.00 (m, 3H) ( m, 1H), 2.12 - 1.98 (m, 2H), 1.80 - 1.68 (m, 6H). ¹³ C NMR (100 MHz, CDCL ₃ ) δ 172.79, 158.89, 154.91, 154.73, 140.10, 135.08, 128.15, 126.10, 65.62, 44.47, 43.45, 40.93, 38.15, 33.90, 28.77, 28.34, 28.21, 28.21 HRMS(ESI) m/z(M+Na) ⁺ calcd for C ₂₁ H ₂₄ Cl ₂ N ₄ O ₅ Na = 505.10; found 505.1017.

Preparation 5. Synthesis of compound 27h-i.

ⁿ Reagents and conditions: (a) methyl 4-aminobenzoate, EDC, DMAP, CH ₂ Cl ₂ , 18 h; (b) N ₂ H ₄ .H ₂ O, 110 °C, 1 day; (c) CDI, DMF, 90° C., 15 h; (d) 14b , EDC, DMAP, CH ₂ Cl ₂ , 18 h; (e) i: LiOH, THF, MeOH, H ₂ O, 6 h, ii: 1M HCl.

3,5-dichlorobenzyl 4-((4-(methoxycarbonyl)phenyl)carbamoyl)piperidine-1-carboxylate (28).

Using 26 (33.22 mg, 0.10 mmol) and methyl 4-aminobenzoate (18.14 mg, 0.12 mmol) according to General Procedure E, 28 was obtained as a white solid (37.23 mg, 80.0%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.99 (d, J = 8.7 Hz, 2H), 7.84 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.30 (t, J = 1.9 Hz) , 1H), 7.22 (d, J = 2.0 Hz, 2H), 5.18 - 4.98 (m, 2H), 4.37 - 4.15 (m, 2H), 3.90 (s, 3H), 3.03 - 2.78 (m, 2H), 2.54 - 2.41 (m, 1H), 1.97 - 1.89 (m, 2H), 1.85 - 1.70 (m, 2H).

3,5-dichlorobenzyl 4-((4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)carbamoyl)piperidine-1-carboxyl Rate (27h).

A mixture of 28 (38.25 mg, 0.086 mmol) and hydrazine monohydrate (1 mL) was refluxed for 24 h and dried under vacuum. The product residue (44.33 mg, 0.1 mmol) was dissolved in DMF (2 mL) and 1,1'-carbonyldiimidazole (19.45 mg, 0.12 mmol) was mixed. The reaction mixture was heated at 80 °C overnight. The solvent was evaporated to dryness. The product was extracted with ethyl acetate and washed with water. The organic layer was dehydrated with anhydrous sodium sulfate, concentrated and purified by column chromatography (ethyl acetate/hexane) to give 27h as a white solid (17.92 mg, 45.6%).

^1H NMR (400 MHz, DMSO- d6 ) δ 7.57 (t, J = 2.0 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 2.0 Hz _, 2H), 6.66 (d, J = 8.7 Hz, 2H), 6.08 (s, 2H), 5.09 (s, 2H), 4.09 - 4.01 (m, 2H), 3.48 - 3.39 (m, 1H), 3.07 - 2.90 (m, 2H) ), 1.98 - 1.89 (m, 2H), 1.60 - 1.46 (m, 2H). ¹³ C NMR (100 MHz, DMSO- d6 ) δ 173.85, 155.03 _, 154.54, 154.20, 142.45, 141.83, 134.54, 127.90, 126.64, 126.57, 119.66, 118.82, 4.2.81, 45.17, 4.2.81 HRMS(ESI) m/z(M+Na)+ calcd for C ₂₂ H ₂₁ Cl ₂ N ₄ O ₅ Na = 513.07; found 513.0708.

1-(3,5-dichlorobenzyl) 4-(5-(3-(1-(((3,5-dichlorobenzyl)oxy)carbonyl)piperidine-4-carboxamido)phenyl)-1 ,3,4-oxadiazol-2-yl) piperidine-1,4-dicarboxylate (29).

To a mixture containing 26 (83.04 mg, 0.25 mmol), 14b (17.72 mg, 0.10 mmol) and DMAP (0.61 mg, 0.005 mmol) in CH ₂ Cl ₂ (2 mL) was added EDCI (23.00 mg, 0.12 mmol). did The reaction mixture was stirred overnight at room temperature. The mixture was extracted with CH ₂ Cl ₂ and washed with water. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The crude product was separated by column chromatography (ethyl acetate/hexane) to obtain 29 as a white solid (45.19 mg, 56.1%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 - 8.07 (m, 1H), 8.01 - 7.79 (m, 2H), 7.65 - 7.50 (m, 1H), 7.48 - 7.36 (m, 1H), 7.30 - 7.25 (m, 2H), 7.23 - 7.17 (m, 4H), 5.14 - 5.01 (m, 4H), 4.31 - 4.15 (m, 4H), 3.58 - 3.49 (m, 1H), 3.13 - 2.84 (m, 4H) , 2.61 - 2.49 (m, 1H), 2.05 - 1.92 (m, 4H), 1.89 - 1.74 (m, 4H).

3,5-dichlorobenzyl 4-((3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)carbamoyl)piperidine-1-carboxyl Rate (27i).

A solution of lithium hydroxide (0.12 g, 5 mmol) in water (2 mL) was added to a solution of 29 (45.19 mg, 0.056 mmol) in a mixture of THF (18 mL) and MeOH (2 ml). The reaction mixture was stirred at room temperature for 6 h. The solvent was then evaporated, redissolved in water and acidified with 1M HCl. The mixture was extracted with ethyl acetate and washed with water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (ethyl acetate/hexane) to give 27i as a white solid (11.36 mg, 41.2%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.57 (br s, 1H), 10.18 (s, 1H), 8.18 (q, J = 1.4 Hz, 1H), 7.75 - 7.67 (m, 1H), 7.57 (t, J = 2.0 Hz, 1H), 7.47 - 7.45 (m, 2H), 7.43 (d, J = 1.9 Hz, 2H), 5.10 (s, 2H), 4.12 - 4.04 (m, 2H), 3.04 - 2.84 (m, 2H), 2.63 - 2.54 (m, 1H), 1.87 - 1.79 (m, 2H), 1.61 - 1.50 (m, 2H). ¹³ C NMR (100 MHz, DMSO) Δ 173.75, 154.99, 154.54, 154.16, 141.83, 140.43, 134.55, 130.20, 127.89, 126.64, 124.85, 122.15, 120.26, 115.93, 65.17, 43.52, 42.52, 42.52 HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₂ H ₂₁ Cl ₂ N ₄ O ₅ = 491.09; found 491.0886.

Preparation 6. Synthesis of building blocks 30a-c and 32a-d.

Reagents and conditions: (a) formamide, 150 °C, 1 day; (b) acetamide, 180 °C, 18 h; (c) i: CDI, DMF, 6 h; ii: amine, 15 h; (d) CBr ₄ , PPh ₃ , CH ₂ Cl ₂ , 0 °C to rt, 6 h; (e) PCC, CH ₂ Cl ₂ , 15 h.

4-(1 H -imidazol-5-yl)phenol (30a).

Following General Procedure B, using 2-bromo-4'hydroxyacetophenone (1.07 g, 5.00 mmol), 30a was obtained as a white solid (0.65 g, 80.6%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.09 (br s, 1H), 9.33 (s, 1H), 7.63 (s, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.33 (s , 1H), 6.75 (d, J = 8.6 Hz, 2H).

3-(1 H -imidazol-5-yl)phenol (30b).

Following General Procedure B, using 2-bromo-3'-hydroxyacetophenone (1.07 g, 5.00 mmol), 30b was obtained as a white solid (0.77 g, 96.7%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.18 (br s, 1H), 9.35 (s, 1H), 7.68 (d, J = 1.1 Hz, 1H), 7.47 (s, 1H), 7.21 - 7.15 (m, 2H), 7.13 (t, J = 7.6 Hz, 1H), 6.60 (ddd, J = 7.5, 2.5, 1.5 Hz, 1H).

3-(2-methyl-1 H -imidazol-5-yl)phenol (30c).

A mixture of 2-bromo-3'hydroxyacetophenone (1.07 g, 5.00 mmol) and acetamide (10 mL) was heated at 180 °C for 18 h. After cooling, the mixture was poured into saturated NaHCO ₃ solution and extracted with ethyl acetate. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (CH ₂ Cl ₂ /MeOH) to give 30c as a light yellow solid (0.43 g, 49.4%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.35 (s, 1H), 7.32 (s, 1H), 7.16 - 7.08 (m, 3H), 6.62 - 6.54 (m, 1H), 2.31 (s, 3H) ).

3,5-dichlorobenzyl 4-hydroxypiperidine-1-carboxylate (31a).

31a was prepared by General Procedure C using 3,5-dichlorobenzyl alcohol (0.18 g, 1.00 mmol) and 4-hydroxypiperidine (0.20 g, 2.00 mmol) as a colorless oil (0.26 g, 85.4%). got it

^1H NMR (400 MHz, CDCl ₃ ) δ 7.30 (t, J = 1.9 Hz, 1H), 7.23 (d, J = 1.9 Hz, 2H), 5.06 (s, 2H), 4.00 - 3.81 (m, 3H) , 3.27 - 3.11 (m, 2H), 1.95 - 1.83 (m, 2H), 1.57 (d, J = 4.1 Hz, 1H), 1.55 - 1.46 (m, 2H).

3,5-dichlorobenzyl 4-(hydroxymethyl)piperidine-1-carboxylate (31b).

31b was obtained as a colorless oil (2.92 g, 91.8%) by General Procedure C using 3,5-dichlorobenzyl alcohol (1.77 g, 10.00 mmol) and 4-piperidinemethanol (2.30 g, 20.00 mmol). .

^1H NMR (400 MHz, CDCl ₃ ) δ 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 5.06 (s, 2H), 4.28 - 4.13 (m, 2H) , 3.51 (t, J = 5.6 Hz, 2H), 2.91 - 2.73 (m, 2H), 1.81 - 1.74 (m, 2H), 1.73 - 1.65 (m, 1H), 1.47 (t, J = 5.3 Hz, 1H) ), 1.25 - 1.13 (m, 2H).

3,5-dichlorobenzyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (31c).

According to the general process C, 31c was obtained as a colorless oil (1.55 g, 93.3%) using 3,5-dichlorobenzyl alcohol (0.88 g, 5.00 mmol) and 4-piperidineethanol (1.29 g, 10.00 mmol).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 5.06 (s, 2H), 4.26 - 4.03 (m, 2H) , 3.76 - 3.67 (m, 2H), 2.89 - 2.71 (m, 2H), 1.76 - 1.70 (m, 2H), 1.68 - 1.60 (m, 1H), 1.53 (q, J = 6.6 Hz, 2H), 1.34 (t, J = 4.3 Hz, 1H), 1.22 - 1.11 (m, 2H).

3,5-dichlorobenzyl 4-bromopiperidine-1-carboxylate (32a).

To a mixture of 31a (0.26 g, 0.85 mmol) and triphenylphosphine (0.27 g, 1.02 mmol) in CH ₂ Cl ₂ (2 mL) at 0 °C, tetrabromomethane (0.34 g, 0.34 mmol) in CH ₂ Cl ₂ (2 mL) g, 1.02 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the crude mixture was extracted with ethyl acetate and washed with water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (CH ₂ Cl ₂ /MeOH) to give 32a as a colorless oil (0.22 g, 70.4%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 2.0 Hz, 2H), 5.07 (s, 2H), 4.42 - 4.35 (m, 1H) , 3.77 - 3.68 (m, 2H), 3.53 - 3.35 (m, 2H), 2.18 - 2.07 (m, 2H), 2.04 - 1.92 (m, 2H).

3,5-dichlorobenzyl 4-(bromomethyl)piperidine-1-carboxylate (32b).

Following the procedure for 32a , using 31b (0.32 g, 1.00 mmol), triphenylphosphine (0.31 g, 1.20 mmol), tetrabromomethane (0.40 g, 1.20 mmol), 32b was prepared as a colorless oil (quantitatively). got it

^1H NMR (400 MHz, CDCl ₃ ) δ 7.30 (t, J = 2.0 Hz, 1H), 7.22 (d, J = 1.8 Hz, 2H), 5.07 (s, 2H), 4.39 - 4.09 (m, 2H) , 3.30 (d, J = 6.1 Hz, 2H), 2.97 - 2.62 (m, 2H), 1.92 - 1.77 (m, 3H), 1.33 - 1.14 (m, 2H).

3,5-dichlorobenzyl 4-(2-bromoethyl)piperidine-1-carboxylate (32c).

Following the procedure for 32a , 32c was prepared as a colorless oil (0.25 g, 63.3%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.29 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 5.06 (s, 2H), 4.24 - 4.06 (m, 2H) , 3.45 (t, J = 6.8 Hz, 2H), 2.95 - 2.72 (m, 2H), 1.82 (q, J = 6.7 Hz, 2H), 1.76 - 1.68 (m, 3H), 1.22 - 1.06 (m, 2H) ).

3,5-dichlorobenzyl 4-formylpiperidine-1-carboxylate (32d) :

To a solution of 31b (1.59 g, 5.00 mmol) in CH ₂ Cl ₂ (10 mL) was added pyridinium chlorochromate (1.29 g, 6.00 mmol) in portions. The reaction mixture was stirred overnight at room temperature. The crude mixture was filtered through celite®. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (hexane/ethyl acetate) to give 32d as a colorless oil (1.33 g, 84.0%).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.63 (s, 1H), 7.26 (t, J = 1.9 Hz, 1H), 7.18 (d, J = 1.9 Hz, 2H), 5.01 (s, 2H), 4.04 - 3.94 (m, 2H), 3.09 - 2.92 (m, 2H), 2.47 - 2.35 (m, 1H), 1.96 - 1.82 (m, 2H), 1.63 - 1.50 (m, 2H).

Preparation 7. Synthesis of compounds 33a-p.

Reagents and conditions: (a) amine or alcohol, K ₂ CO ₃ , DMF, 80 °C, overnight; (b) i: N ₂ H ₄ .H ₂ O, MeOH, reflux, 24 h; ii: CDI, DMF, 80 °C, 15 h; (c) 3a-b , 7a-b , or 14a-b , NaBH(OAc) ₃ , AcOH, CH ₂ Cl ₂ , 15 h; (d) TFA; CH ₂ Cl ₂ , 3 h.

General process for amine or ether formation F.

Alkyl bromide ( 32b-c ; in DMF (1 mL); 0.10 mmol), amine or alcohol (0.15 mmol), and K ₂ CO ₃ (27.6 mg, 0.20 mmol) were stirred at 80 °C for 15 h. After removing the solvent under vacuum, the organics were extracted with ethyl acetate, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The product was purified by column chromatography (CH ₂ Cl ₂ /MeOH) to give the desired amine or ether.

3,5-Dichlorobenzyl 4-((4-(1 H -imidazol-5-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (33a).

33a was prepared as a white solid ( 32.50 mg, 72.0%).

^1H NMR (400 MHz, CDCl ₃ ) δ 10.31 (br s, 1H), 7.63 - 7.52 (m, 1H), 7.29 (t, J = 2.0 Hz, 1H), 7.22 (d, J = 2.0 Hz, 2H) ), 6.77(s, 1H), 5.06(s, 2H), 4.22 - 4.09(m, 2H), 2.94 - 2.87(m, 2H), 2.84 - 2.71(m, 2H), 2.60(tt, J = 11.8 , 3.8 Hz, 1H), 2.18 (d, J = 7.0 Hz, 2H), 2.07 - 1.93 (m, 4H), 1.81 - 1.65 (m, 5H), 1.17 - 1.04 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 154.81, 142.01, 140.43, 135.05, 134.40, 128.03, 125.95, 115.12, 65.33, 64.78, 54.41, 44.26, 34.69, 33.69, 33.69 . HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₂ H ₂₉ Cl ₂ N ₄ O ₂ = 451.17; found 451.1669.

3,5-Dichlorobenzyl 4-(2-(4-(1) H -imidazol-5-yl)piperidin-1-yl)ethyl)piperidine-1-carboxylate (33b).

According to General Procedure C, 32c (39.51 mg, 0.10 mmol), 4-(1 H -imidazol-4(5)-yl)piperidine (22.68 mg, 0.15 mmol), and sodium hydrogencarbonate (16.8 mg , 0.20 mmol) was used to obtain 33b as a white solid (37.56 mg, 80.7%).

^1H NMR (400 MHz, CDCl ₃ ) δ 10.09 (br s, 1H), 7.55 (d, J = 1.1 Hz, 1H), 7.29 (t, J = 2.0 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 6.76(s, 1H), 5.06(s, 2H), 4.22 - 4.04(m, 2H), 3.04 - 2.94(m, 2H), 2.91 - 2.69(m, 2H), 2.61(tt, J = 11.8, 3.7 Hz, 1H), 2.42 - 2.33 (m, 2H), 2.08 - 1.98 (m, 4H), 1.77 - 1.63 (m, 4H), 1.55 - 1.43 (m, 3H), 1.24 - 1.09 ( m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 154.76, 140.43, 135.06, 134.31, 128.04, 125.98, 65.34, 56.44, 53.95, 44.32, 34.49, 33.67, 32.12. HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₃ H ₃₁ Cl ₂ N ₄ O ₂ = 465.18; found 465.1823.

3,5-Dichlorobenzyl 4-((4-(1 H -1,2,3-triazol-5-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (33c).

According to General Procedure C, using 32b (38.11 mg, 0.10 mmol) and 20 (22.64 mg, 0.12 mmol), 33c was obtained as a white solid (17.60 mg, 38.9%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.73 (br s, 1H), 7.51 (s, 1H), 7.29 (s, 1H), 7.22 (d, J = 1.9 Hz, 2H), 5.07 (s, 2H) ), 4.24 - 4.07 (m, 2H), 3.01 - 2.91 (m, 2H), 2.88 - 2.72 (m, 3H), 2.23 (d, J = 6.8 Hz, 2H), 2.14 - 2.05 (m, 2H), 2.02 - 1.92 (m, 2H), 1.87 - 1.70 (m, 5H), 1.22 - 1.07 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 154.84, 150.80, 140.39, 135.05, 129.78, 128.05, 125.99, 65.39, 64.77, 54.16, 44.22, 33.66, 33.03, 30.87, 31.85. HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₁ H ₂₈ Cl ₂ N ₅ O ₂ = 452.16; found 452.1615.

3,5-Dichlorobenzyl 4-(2-(4-(1) H -imidazol-5-yl)phenoxy)ethyl)piperidine-1-carboxylate (33d).

According to General Procedure C, using 32c (39.51 mg, 0.10 mmol) and 30a (32.03 mg, 0.20 mmol), 33d was obtained as a white solid (13.28 mg, 28.0%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.98 (s, 1H), 7.66 (d, J = 1.1 Hz, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.29 (t, J = 1.9 Hz , 1H), 7.24 (d, J = 1.1 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 5.06 (s, 2H), 4.23 - 4.11 (m, 2H), 4.02 (t, J = 5.8 Hz, 2H), 2.95 - 2.72 (m, 2H), 1.83 - 1.68 (m, 5H), 1.28 - 1.14 (m, 2H). ¹³ C NMR (100 MHz, CDCL ₃ ) δ 158.08, 154.77, 140.37, 138.65, 135.28, 135.06, 128.05, 126.20, 125.98, 125.88, 114.72, 114.18, 65.37, 65.29, 44.27, 35.68, 32.82 HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₄ H ₂₆ Cl ₂ N ₃ O ₃ = 474.14; found 474.1348.

3,5-Dichlorobenzyl 4-((4-(1 H -imidazol-5-yl)phenoxy)methyl)piperidine-1-carboxylate (33e).

According to General Procedure C, using 32b (38.11 mg, 0.10 mmol) and 30a (32.03 mg, 0.20 mmol), 33e was obtained as a white solid (12.93 mg, 28.1%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.38 (s, 1H), 7.70 - 7.55 (m, 3H), 7.32 - 7.27 (m, 1H), 7.27 - 7.18 (m, 3H), 6.89 (d, J = 8.7 Hz, 2H), 5.11 - 5.02 (m, 2H), 4.30 - 4.15 (m, 2H), 3.82 (d, J = 6.3 Hz, 2H), 2.96 - 2.77 (m, 2H), 2.08 - 1.95 ( m, 1H), 1.91 - 1.83 (m, 2H), 1.39 - 1.27 (m, 2H). ¹³ C NMR (100 MHz, CDCL ₃ ) Δ 158.12, 154.78, 140.32, 137.18, 135.27, 135.08, 128.09, 126.21, 126.02, 125.54, 114.74, 113.75, 77.35, 77.03 . HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₃ H ₂₄ Cl ₂ N ₃ O ₃ = 460.12; found 460.1190.

3,5-Dichlorobenzyl 4-(4-(1 H -imidazol-5-yl)phenoxy)piperidine-1-carboxylate (33f).

According to General Procedure C, using 32a ( 0.18 g, 0.50 mmol) and 30a ( 0.16 g, 1.00 mmol), 33f was obtained as a white solid (8.26 mg, 3.7%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.68 (d, J = 1.1 Hz, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.31 (t, J = 1.9 Hz, 1H), 7.25 (d , J = 1.1 Hz, 1H), 7.24 (d, J = 1.9 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 5.08 (s, 2H), 4.57 - 4.50 (m, 1H), 3.80 - 3.69 (m, 2H), 3.57 - 3.47 (m, 2H), 1.98 - 1.90 (m, 2H), 1.88 - 1.80 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 156.25, 154.78, 140.24, 135.16, 135.10, 128.14, 126.31, 126.07, 116.46, 71.62, 65.51, 40.76, 30.23. HRMS(ESI) m/z(M+Na)+ calcd for C ₂₂ H ₂₁ Cl ₂ N ₃ O ₃ Na = 468.09; found 468.0860.

3,5-Dichlorobenzyl 4-((3-(1 H -imidazol-5-yl)phenoxy)methyl)piperidine-1-carboxylate (33 g).

Following General Procedure C, using 32b (38.11 mg, 0.10 mmol) and 30b (32.03 mg, 0.20 mmol), 33 g was obtained as a white solid (9.71 mg, 21.1%).

^1H NMR (400 MHz, CDCl ₃ ) δ 10.18 (s, 1H), 7.70 (d, J = 1.1 Hz, 1H), 7.35 (d, J = 1.1 Hz, 1H), 7.34 - 7.31 (m, 1H) , 7.30 (t, J = 1.9 Hz, 1H), 7.29 - 7.26 (m, 2H), 7.23 (d, J = 1.9 Hz, 2H), 6.81 - 6.76 (m, 1H), 5.07 (d, J = 10.4 Hz, 2H), 4.31 - 4.12(m, 2H), 3.84(d, J = 6.3 Hz, 2H), 2.96 - 2.74(m, 2H), 2.06 - 1.92(m, 1H), 1.90 - 1.80(m, 2H), 1.37 - 1.23 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 159.38, 154.78, 140.32, 135.44, 135.07, 129.77, 128.08, 126.02, 117.39, 113.49, 110.63, 72.04, 65.46, 0.26.42, 43.84 HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₃ H ₂₄ Cl ₂ N ₃ O ₃ = 460.12; found 460.1192.

3,5-dichlorobenzyl 4-(3-(1H-imidazol-5-yl)phenoxy)piperidine-1-carboxylate (33h).

According to General Procedure C, using 32a ( 0.18 g, 0.50 mmol) and 30b ( 0.16 g, 1.00 mmol), 33h was obtained as a white solid (10.49 mg, 4.7%).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.56 (br s, 1H), 7.70 (d, J = 1.1 Hz, 1H), 7.52 - 7.31 (m, 3H), 7.30 (t, J = 1.9 Hz, 1H) ), 7.28 (d, J = 7.6 Hz, 1H), 7.23 (dt, J = 1.9, 0.7 Hz, 2H), 6.85 - 6.78 (m, 1H), 5.08 (s, 2H), 4.64 - 4.56 (m, 1H), 3.78 - 3.67 (m, 2H), 3.54 - 3.43 (m, 2H), 2.00 - 1.88 (m, 2H), 1.87 - 1.77 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 157.55, 154.78, 140.26, 135.37, 135.10, 129.86, 128.13, 126.25, 126.05, 117.88, 115.06, 112.60, 71.49, 0, 0.49, 65.48 HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₂ H ₂₂ Cl ₂ N ₃ O ₃ = 446.10; found 446.1037.

3,5-Dichlorobenzyl 4-((3-(2-methyl-1 H -imidazol-5-yl)phenoxy)methyl)piperidine-1-carboxylate (33i).

According to General Procedure C, using 32b (38.11 mg, 0.10 mmol) and 30c (34.84 mg, 0.20 mmol), 33i was obtained as a white solid (9.15 mg, 19.3%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.30 (t, J = 1.9 Hz, 1H), 7.27 - 7.24 (m, 3H), 7.23 (d, J = 1.8 Hz, 2H), 7.20 (s, 1H) , 6.80 - 6.71 (m, 1H), 5.07 (d, J = 10.4 Hz, 2H), 4.30 - 4.12 (m, 2H), 3.84 (d, J = 6.3 Hz, 2H), 2.98 - 2.75 (m, 2H) ), 2.47 (s, 3H), 2.06 - 1.92 (m, 1H), 1.91 - 1.81 (m, 2H), 1.38 - 1.26 (m, 2H). ¹³ C NMR (100 MHz, CDCL ₃ ) δ 159.36, 154.77, 144.88, 140.34, 135.07, 134.70, 129.68, 128.08, 126.03, 117.19, 113.15, 110.43, 72.04, 65.41, 43.95, 36.11, 28.33. HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₄ H ₂₆ Cl ₂ N ₃ O ₃ = 474.14; found 474.1353.

3,5-Dichlorobenzyl 4-((4-(methoxycarbonyl)piperidin-1-yl)methyl)piperidine-1-carboxylate (34).

A mixture of 32b ( 0.38 g, 1.00 mmol) and methyl piperidine-4-carboxylate (0.29 g, 2.00 mmol) in DMF (10 mL) was heated at 80 °C overnight. The organic matter was extracted with ethyl acetate and washed with water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. Purification by column chromatography (ethyl acetate/hexane) gave 34 as a white solid (0.36 g, 81.4%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.29 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 5.06 (s, 2H), 4.23 - 4.08 (m, 2H) , 3.67(s, 3H), 2.89 - 2.68(m, 4H), 2.33 - 2.23(m, 1H), 2.14(d, J = 7.1 Hz, 2H), 2.00 - 1.92(m, 2H), 1.90 - 1.83 (m, 2H), 1.79 - 1.70 (m, 4H), 1.69 - 1.60 (m, 1H), 1.15 - 1.02 (m, 2H).

3,5-dichlorobenzyl 4-((4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidin-1-yl)methyl)piperi din-1-carboxylate (33j).

Compound 34 (0.22 g, 0.50 mmol) was refluxed with hydrazine monohydrate (200 μL) in MeOH for 1 h. Solvent was removed under vacuum. The residue was dissolved in DMF (10 mL) and mixed with 1,1'-carbonyldiimidazole (97.25 mg, 0.60 mmol). After stirring at 80 °C for 12 h, the solvent was evaporated to dryness. The organics were extracted with ethyl acetate, washed with water, dehydrated with anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate/hexane) to give 33j as a white solid (103.7 mg, 44.2%).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.59 (br s, 1H), 7.29 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 5.09 - 5.03 (m, 2H) ), 4.24 - 4.06(m, 2H), 2.92 - 2.73(m, 4H), 2.62 - 2.52(m, 1H), 2.20(d, J = 7.0 Hz, 2H), 2.11 - 2.02(m, 2H), 1.99 - 1.91 (m, 2H), 1.86 - 1.74 (m, 4H), 1.73 - 1.62 (m, 1H), 1.18 - 1.04 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 160.14, 155.50, 154.83, 140.34, 135.03, 128.04, 125.99, 65.41, 64.44, 53.07, 44.18, 34.01, 33.56, 20.71, 38.71. HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₁ H ₂₇ Cl ₂ N ₄ O ₄ = 469.14; found 469.1405.

3,5-Dichlorobenzyl 4-(((4-(2-aminothiazol-5-yl)phenyl)amino)methyl)piperidine-1-carboxylate (33k).

According to general procedure C, 32d (31.62 mg, 0.10 mmol) and 3a (39.15 mg, 0.10 mmol) were used to obtain the Boc-protected intermediate as a white solid (63.22 mg, 91.4%);

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (d, J = 8.7 Hz, 2H), 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 7.03 (s , 1H), 6.60 (d, J = 8.7 Hz, 2H), 5.06 (s, 2H), 4.28 - 4.11 (m, 2H), 3.92 - 3.85 (m, 1H), 3.07 (d, J = 6.3 Hz, 2H), 2.90 - 2.72(m, 2H), 1.85 - 1.78(m, 3H), 1.54(s, 18H), 1.25 - 1.16(m, 2H).

This was subjected to Boc deprotection to obtain 33k as a white solid (27.31 mg, 60.8%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59 (d, J = 8.6 Hz, 2H), 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 6.58 (d , J = 8.6 Hz, 2H), 6.48(s, 1H), 5.15 - 4.97(m, 4H), 4.27 - 4.13(m, 2H), 3.94 - 3.75(m, 1H), 3.10 - 3.03(m, 2H) ), 2.88 - 2.72 (m, 2H), 1.86 - 1.72 (m, 3H), 1.28 - 1.16 (m, 2H). ¹³ C NMR (100 MHz, CDCL ₃ ) δ 167.03, 154.73, 151.63, 147.79, 140.36, 135.08, 128.09, 127.24, 126.05, 124.50, 112.60, 99.52, 65.42, 49.52, 44.07, 35.92, 30.04. HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₃ H ₂₅ Cl ₂ N ₄ O ₂ S = 491.11; found 491.1078.

3,5-dichlorobenzyl 4-(((3-(2-aminothiazol-5-yl)phenyl)amino)methyl)piperidine-1-carboxylate (33l).

According to general procedure D, using 32d (31.62 mg, 0.10 mmol) and 3b ( 39.15 mg, 0.10 mmol), the Boc-protected intermediate was obtained as a white solid (56.92 mg, 82.3%);

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.30 (t, J = 1.9 Hz, 1H), 7.24 - 7.22 (m, 3H), 7.21 - 7.13 (m, 3H), 6.60 - 6.51 (m, 1H), 5.07(s, 2H), 4.32 - 4.10(m, 2H), 3.87 - 3.77(m, 1H), 3.08(d, J = 6.3 Hz, 2H), 2.91 - 2.72(m, 2H), 1.89 - 1.74( m, 3H), 1.55 (s, 18H), 1.28 - 1.16 (m, 2H).

This was Boc deprotected to give 33l as a white solid (30.21 mg, 74.7%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 7.17 (t, J = 8.1 Hz, 1H), 7.07 (dt , J = 7.1, 1.5 Hz, 2H), 6.67(s, 1H), 6.56 - 6.49(m, 1H), 5.16(s, 2H), 5.06(s, 2H), 4.26 - 4.12(m, 2H), 3.93 - 3.74 (m, 1H), 3.11 - 3.03 (m, 2H), 2.90 - 2.68 (m, 2H), 1.85 - 1.72 (m, 3H), 1.26 - 1.11 (m, 2H). ¹³ C NMR (100 MHz, CDCL ₃ ) δ 167.15, 154.74, 151.66, 148.46, 140.38, 135.69, 135.07, 129.50, 128.08, 126.05, 115.18, 112.04, 110.72 HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₃ H ₂₅ Cl ₂ N ₄ O ₂ S = 491.11; found 491.1076.

3,5-Dichlorobenzyl 4-(((4-(1 H -imidazol-5-yl)phenyl)amino)methyl)piperidine-1-carboxylate (33m).

According to General Procedure D, using 32d (31.62 mg, 0.10 mmol) and 7a (15.92 mg, 0.10 mmol), 33m was obtained as a white solid (41.71 mg, 90.8%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.86 (s, 1H), 7.63 (s, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 7.18 (s, 1H), 6.62 (d, J = 8.7 Hz, 2H), 5.06 (s, 2H), 4.27 - 4.13 (m, 2H), 3.93 - 3.67 ( m, 1H), 3.06 (d, J = 6.2 Hz, 2H), 2.89 - 2.72 (m, 2H), 1.87 - 1.75 (m, 3H), 1.27 - 1.15 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 154.74, 147.30, 140.32, 135.07, 134.91, 128.09, 126.16, 126.03, 112.90, 65.42, 49.60, 44.06, 35.91, 30.07. HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₃ H ₂₅ Cl ₂ N ₄ O ₂ = 459.14; found 459.1354.

3,5-Dichlorobenzyl 4-(((3-(1 H -imidazol-5-yl)phenyl)amino)methyl)piperidine-1-carboxylate (33n).

According to General Procedure D, using 32d (31.62 mg, 0.10 mmol) and 7b (15.92 mg, 0.10 mmol), 33n was obtained as a white solid (25.31 mg, 55.1%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.67 (s, 1H), 7.30 - 7.28 (m, 2H), 7.21 (d, J = 1.9 Hz, 2H), 7.15 (t, J = 7.8 Hz, 1H) , 7.04 - 6.96(m, 2H), 6.50 - 6.45(m, 1H), 5.05(s, 2H), 4.27 - 4.02(m, 2H), 3.07 - 2.92(m, 2H), 2.86 - 2.66(m, 2H), 1.83 - 1.64 (m, 3H), 1.21 - 1.06 (m, 2H). ¹³ C NMR (100 MHz, CDCL ₃ ) δ 154.74, 148.64, 140.31, 138.43, 135.42, 135.06, 133.47, 129.69, 128.07, 126.00, 115.90, 114.10, 111.61, 109.16, 65.50, 65.41, 49.43, 44. , 30.09. HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₃ H ₂₅ Cl ₂ N ₄ O ₂ = 459.14; found 459.1360.

3,5-dichlorobenzyl 4-(((4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)amino)methyl)piperidin-1 -Carboxylate (33o).

According to General Procedure D, using 32d (31.62 mg, 0.10 mmol) and 14a (17.72 mg, 0.10 mmol), 33o was obtained as a white solid (15.80 mg, 33.1%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.14 (s, 1H), 7.56 (t, J = 2.0 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 1.9 Hz, 2H), 6.66 (d, J = 8.9 Hz, 2H), 6.49 (t, J = 5.8 Hz, 1H), 5.07 (s, 2H), 4.08 - 3.98 (m, 2H), 3.02 - 2.94 ( m, 2H), 2.90 - 2.70 (m, 2H), 1.83 - 1.71 (m, 3H), 1.18 - 1.03 (m, 2H). ¹³ C NMR (100 MHz, DMSO) δ 155.24, 155.19, 154.52, 151.99, 141.91, 134.54, 127.86, 127.13, 126.59, 112.08, 110.60, 65.05, 48.29, 34.00, 44.00 HRMS (ESI) m/z(M+H) ⁺ calcd for C ₂₂ H ₂₃ Cl ₂ N ₄ O ₄ = 477.11; found 477.1094.

3,5-dichlorobenzyl 4-(((3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)amino)methyl)piperidin-1 -Carboxylate (33p).

According to General Procedure D, using 32d (31.62 mg, 0.10 mmol) and 14b (17.72 mg, 0.10 mmol), 33p was obtained as a white solid (34.13 mg, 71.5%).

^1H NMR (400 MHz, CDCl ₃ ) δ 8.79 (s, 1H), 7.29 (t, J = 2.0 Hz, 1H), 7.27 - 7.21 (m, 3H), 7.17 (d, J = 7.7 Hz, 1H) , 7.03 (t, J = 2.0 Hz, 1H), 6.75 - 6.67 (m, 1H), 5.08 (d, J = 4.5 Hz, 2H), 4.31 - 4.14 (m, 2H), 4.06 - 3.95 (m, 1H) ), 3.12 - 3.02 (m, 2H), 2.93 - 2.74 (m, 2H), 1.88 - 1.73 (m, 3H), 1.24 (tt, J = 15.3, 7.8 Hz, 2H). ¹³ C NMR (100 MHz, CDCL ₃ ) Δ 155.66, 155.20, 154.88, 148.49, 140.19, 135.08, 129.92, 128.13, 126.06, 124.70, 116.11, 114.70, 108.92, 65.59, 49.31, 44.06, 35.81 HRMS (ESI) m/z(M+H) ⁺ calcd for C ₂₂ H ₂₃ Cl ₂ N ₄ O ₄ = 477.11; found 477.1096.

Preparation 8. Synthesis of compounds 38a-c.

Reagents and conditions: (a) i: CDI, DMF, 6 h, ii: Boc-piperazine, 15 h; (b) TFA, CH ₂ Cl ₂ , 3 h; (c) bromoethanol, K ₂ CO ₃ , THF, reflux, 15 h; (d) CBr ₄ , PPh ₃ , CH ₂ Cl ₂ , 0 °C to rt, 6 h; (e) 1,3-dibromopropane, TEA, CH ₂ Cl ₂ , 15 h; (f) i: chloroacetyl chloride, TEA, CH ₂ Cl ₂ , 1 h; ii: 4-(1 H -imidazol-5-yl)piperidine, TEA, DMF, 75° C., 2 h; (g) 4-(1 H -imidazol-5-yl)piperidine, NaHCO ₃ , DMF, 60° C., 12 h; (h) Boc-piperazine, CH ₂ Cl ₂ , 1 h.

One- t -Butyl 4-(3,5-dichlorobenzyl)piperazine-1,4-dicarboxylate (34).

To a stirred mixture of 3,5-dichlorobenzyl alcohol (1.77 g, 10.0 mmol) in DMF (20 mL) at room temperature was added 1,1'-carbonyldiimidazole (1.94 g, 12.0 mmol) and stirred at room temperature for 6 h. while stirring. t -Butylpiperazine-1-carboxylate (3.72 g, 20.0 mmol) was added to the mixture and further stirred at room temperature overnight. The material was extracted with diethyl ether and washed twice with water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (ethyl acetate/hexane) to give 34 as a colorless oil (2.48 g, 63.7%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.31 (t, J = 1.9 Hz, 1H), 7.23 (dt, J = 2.0, 0.7 Hz, 2H), 5.08 (s, 2H), 3.51 - 3.41 (m, 8H), 1.47(s, 9H).

3,5-dichlorobenzyl piperazine-1-carboxylate (35).

To a solution of 34 ( 1.95 g, 5.00 mmol) in CH ₂ Cl ₂ (10 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated to dryness. The product was neutralized with 1M K ₂ CO ₃ solution and extracted with ethyl acetate. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The product was purified by amino column chromatography (hexane/ethyl acetate) to give 35 as a colorless oil (1.44 g, 93.2%).

^1H NMR (400 MHz, MeOD) δ 7.40 (t, J = 1.9 Hz, 1H), 7.37 (d, J = 1.9 Hz, 2H), 5.13 (s, 2H), 3.82 - 3.69 (m, 4H), 3.28 - 3.21 (m, 4H).

3,5-dichlorobenzyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (36).

A mixture of 35 ( 0.29 g, 1.00 mmol), 2-bromoethanol (0.19 g, 1.50 mmol) and potassium carbonate (0.28 g, 2.00 mmol) in THF (5 mL) was refluxed overnight. The solvent was evaporated to dryness and the mixture was extracted with diethyl ether and washed with water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (CH ₂ Cl ₂ /MeOH) to give 36 as a colorless oil (0.32 g, 96.1%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.31 (t, J = 1.9 Hz, 1H), 7.23 (d, J = 1.9 Hz, 2H), 5.07 (s, 2H), 3.64 (t, 2H), 3.56 - 3.53 (m, 4H), 2.58 (t, J = 5.5 Hz, 2H), 2.54 - 2.48 (m, 4H), 2.47 - 2.25 (m, 1H).

3,5-dichlorobenzyl 4-(2-bromoethyl)piperazine-1-carboxylate (37a).

To a mixture of 36 (0.17 g, 0.50 mmol) and triphenylphosphine (0.16 g, 0.60 mmol) in CH ₂ Cl ₂ (2 mL) was added CBr ₄ (0.20 g, 0.60 mmol) in CH ₂ Cl ₂ at 0 °C. The solution was added dropwise. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the crude mixture was extracted with ethyl acetate and washed with water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (CH ₂ Cl ₂ /MeOH) to give 37a as a colorless oil (70.70 mg, 35.7%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 5.07 (s, 2H), 3.57 - 3.49 (m, 4H) , 3.42 (t, J = 7.2 Hz, 2H), 2.81 (t, J = 7.2 Hz, 2H), 2.54 - 2.46 (m, 4H).

3,5-dichlorobenzyl 4-(3-bromopropyl)piperazine-1-carboxylate (37b).

To a mixture of 35 (57.83 mg, 0.20 mmol) and TEA (40.48 mg, 0.40 mmol) in CH ₂ Cl ₂ (2 mL) at 0 °C was added 1,3-dibromopropane (40.38 mg, 0.40 mmol). . The reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the crude mixture was extracted with ethyl acetate and washed with water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (ethyl acetate/hexanes) to give 37b as a colorless oil (36.25 mg, 44.2%);

^1H NMR (400 MHz, CDCl ₃ ) δ 7.30 (t, J = 2.0 Hz, 1H), 7.22 (dd, J = 1.9, 0.8 Hz, 2H), 5.07 (s, 2H), 3.54 - 3.50 (m, 4H), 3.47 (t, J = 6.6 Hz, 2H), 2.50 (t, J = 6.9 Hz, 2H), 2.46 - 2.38 (m, 4H), 2.02 (p, J = 6.7 Hz, 2H).

3,5-dichlorobenzyl 4-(2-(4-(1 H -imidazol-5-yl)piperidin-1-yl)acetyl)piperazine-1-carboxylate (38a). Compound 35 (1 mmol) and TEA (1 mmol) were dissolved in CH ₂ Cl ₂ (10 mL). Chloroacetyl chloride (3 mmol) was added to the reaction mixture. The resulting solution was stirred for 1 h. After completion of the reaction, the solvent was removed under vacuum. The residue was dissolved in DMF and TEA (2 mmol) and 4-(1 H -imidazol-5-yl)piperidine (1.2 mmol) in DMF were added. The reaction mixture was stirred at 75 °C for 2 h. The solvent was removed under vacuum and the crude mixture was extracted with ethyl acetate and washed with brine. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (CH ₂ Cl ₂ /MeOH) to give 38a ( 43.5%);

^1H NMR (400 MHz, MeOD- d ₄ ) δ 7.59 (s, 1H), 7.37 - 7.31 (m, 3H), 6.80 (s, 1H), 3.65 (t, J = 5.1 Hz, 2H), 3.61 ( t, J = 5.2 Hz, 2H), 3.56 - 3.52 (m, 2H), 3.34 (s, 2H), 3.07 - 2.97 (m, 2H), 2.61 (ddd, J = 11.8, 8.0, 4.1 Hz, 1H) , 2.49 (t, J = 5.1 Hz, 2H), 2.44 (t, J = 5.1 Hz, 2H), 2.29 (t, J = 11.6 Hz, 2H), 1.97 (d, J = 12.8 Hz, 2H), 1.73 (qd, J = 12.3, 3.7 Hz, 2H); MS (ESI, m/z) calcd for C ₂₂ H ₂₈ Cl ₂ N ₅ O ₃ [M+H] ⁺ 480.15; found 480.10.

3,5-Dichlorobenzyl 4-(2-(4-(1) H -imidazol-5-yl)piperidin-1-yl)ethyl)piperazine-1-carboxylate (38b).

37a (39.61 mg, 0.10 mmol), 4-(1H-imidazol-4(5)-yl)piperidine (22.68 mg, 0.15 mmol), and sodium hydrogencarbonate (16.8 mg, 0.20 mmol) was stirred at 60 °C for 12 h. The solvent was evaporated to dryness and the mixture was dissolved in CH ₂ Cl ₂ . The crude mixture was purified by amino column chromatography (CH ₂ Cl ₂ /MeOH) to give 38b as a white solid (26.77 mg, 57.4%);

^1H NMR (400 MHz, CDCl ₃ ) δ 9.76 (br s, 1H), 7.56 (d, J = 1.2 Hz, 1H), 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 6.75 (d, J = 1.0 Hz, 1H), 5.06 (s, 2H), 3.56 - 3.48 (m, 4H), 3.03 - 2.97 (m, 2H), 2.65 - 2.58 (m, 1H) , 2.57 - 2.51 (m, 4H), 2.50 - 2.45 (m, 4H), 2.16 - 2.08 (m, 2H), 2.04 - 1.97 (m, 2H), 1.75 - 1.63 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 160.87, 154.70, 140.14, 135.09, 134.36, 128.14, 126.05, 65.50, 56.21, 56.08, 54.30, 53.28, 43.88, 34.64, HRMS(ESI) m/z(M+H) ⁺ calcd for C ₂₂ H ₃₀ Cl ₂ N ₅ O ₂ = 466.18; found 466.1773.

3,5-Dichlorobenzyl 4-(3-(4-(1) H -imidazol-5-yl)piperidin-1-yl)propyl)piperazine-1-carboxylate (38c):

37b (36.25 mg, 0.09 mmol), 4-(1 H -imidazol-4(5)-yl)piperidine (21.17 mg, 0.14 mmol) and sodium hydrogencarbonate (15.12 mg, 0.18 mmol) was stirred at 60 °C for 12 h. The solvent was evaporated to dryness and the mixture was dissolved in CH ₂ Cl ₂ . The crude mixture was purified by column chromatography (CH ₂ Cl ₂ /MeOH) to give 38c as a white solid (33.21 mg, 76.8%).

^1H NMR (400 MHz, CDCl- ₃ ) δ 10.47 (br s, 1H), 7.55 (d, J = 1.1 Hz, 1H), 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 6.76(s, 1H), 5.06(s, 2H), 3.54 - 3.50(m, 4H), 3.01 - 2.96(m, 2H), 2.66 - 2.57(m, 1H), 2.45 - 2.37 (m, 8H), 2.07 - 1.99 (m, 4H), 1.75 - 1.66 (m, 4H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 154.70, 140.16, 135.09, 134.35, 128.13, 126.05, 65.48, 56.90, 56.71, 53.88, 52.87, 43.92, 34.69, 34.43, 24.08. HRMS(ESI) m/z(M+H)+ calcd for C ₂₃ H ₃₂ Cl ₂ N ₅ O ₂ = 480.19; found 480.1941.

t -Butyl 4-((3-chlorophenethyl)carbamoyl)piperazine-1-carboxylate (39).

To a solution of Boc-piperazine (0.5 mmol) in CH ₂ CL ₂ (5 ml) was added 1-chloro-3-(2-isocyanatoethyl)benzene (0.5 mmol) and stirred at room temperature for 1 h. After evaporation of the solvent, the residue was purified by column chromatography to obtain the target compound (quantitatively);

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.26 - 6.98 (m, 4H), 4.65 (t, J = 5.7 Hz, 1H), 3.47 (td, J = 6.9, 5.7 Hz, 2H), 3.44 - 3.36 ( m, 4H), 3.30 (dd, J = 6.9, 3.8 Hz, 4H), 2.81 (t, J = 6.9 Hz, 2H), 1.47 (s, 9H).

4-(2-(4-(1H-imidazol-5-yl)piperidin-1-yl)acetyl)-N-(3-chlorophenethyl)piperazine-1-carboxamide (38d).

To a solution of 39 (0.5 mmol) in CH ₂ Cl ₂ (10 mL) was added trifluoroacetic acid (5 mL) and stirred at room temperature for 3 h. The solvent was evaporated to dryness and the remaining organic residue (0.5 mmol) was dissolved in CH ₂ Cl ₂ (10 mL) with TEA (0.5 mmol). After adding chloroacetyl chloride (3 mmol) to the reaction mixture, the resulting solution was stirred for 1 h and then the solvent was removed under vacuum. The residue was dissolved in DMF (5 ml) and mixed with TEA (1 mmol) and 4-(1 H -imidazol-5-yl)piperidine (0.6 mmol). The reaction mixture was stirred at 75 °C for 2 h. The solvent was removed in vacuo and the crude mixture was extracted with ethyl acetate and washed with brine. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (CH ₂ Cl ₂ /MeOH) to give 38d ;

^1H NMR (400 MHz, MeOD) δ 7.65 (d, J = 1.2 Hz, 1H), 7.30 - 7.20 (m, 2H), 7.20 (dd, J = 2.2, 1.3 Hz, 1H), 7.18 - 7.11 (m , 1H), 6.84(s, 1H), 3.63 - 3.53(m, 4H), 3.48(s, 2H), 3.48 - 3.41(m, 2H), 3.38(td, J = 6.5, 2.1 Hz, 4H), 3.11 (dt, J = 12.1, 3.7 Hz, 2H), 2.80 (dd, J = 7.9, 6.6 Hz, 2H), 2.66 (ddt, J = 11.7, 7.7, 3.8 Hz, 1H), 2.42 (td, J = 11.8, 2.5 Hz, 2H), 2.07 - 1.95 (m, 2H), 1.86 - 1.70 (m, 2H); 13C NMR (100 MHz, MEOD) Δ 169.5, 159.8, 143.3, 142.3, 135.9, 135.1, 130.9, 130.0, 128.4, 127.3, 115.9, 61.0, 54.8, 46.2, 45.0, 44.5, 43.1, 42.8, 36.9, 34.9 . MS(ESI) m/z(M+H) ⁺ calcd for C ₂₃ H ₃₂ ClN ₆ O ₂ = 459.23; found 459.31.

Preparation 9. Synthesis of building blocks 41a-d.

(a) Me ₃ SiN ₃ , CuI, DMF, MeOH, 100° C., 8 h; (b) 4M HCl in dioxane, 1 h; (c) (azidomethyl)trimethylsilane, CuI, DMF, MeOH; 60 °C, 12 h; (d) TBAF, THF, H2O, 12 h; (e) NaN ₃ , NH ₄ Cl, DMF, 125 °C, 8 h; (f) NaN ₃ , NH ₄ Cl, dioxane, H ₂₀ , 75 °C, 2 d; (g) i: PPh ₃ , diethyl ether, 24 h; ii: H ₂ O, THF, reflux, 1.5 h.

t -butyl((1 H -1,2,3-triazol-5-yl)methyl)carbamate ( 40a).

t -Butyl pro-2-pin-1-ylcarbamate (5.00 mmol), trimethylsilyl azide (5.5 mmol), and kappa(I) iodide (0.25 mmol) were mixed in DMF/MeOH (9 mmol) under argon gas. /1, 10 mL) was added to the mixture. The reaction mixture was heated at 100 °C for 8 h. The solvent was evaporated to dryness, extracted with ethyl acetate and washed with brine. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (CH ₂ Cl ₂ /MeOH) to give 40a (42.5%);

¹ H NMR (400 MHz, CDCl ₃ ) δ 12.97 (s, 1H), 7.66 (s, 1H), 4.44 (d, J = 6.0 Hz, 2H), 1.46 (s, 9H).

(One H -1,2,3-triazol-5-yl)methanamine·HCl (41a).

To compound 40a (1.7 mmol) in dioxane (1 mL) was added 4.0 M HCl and stirred at room temperature for 1 h. The solvent was evaporated to dryness to give 41a as a white solid (quantitatively).

¹ H NMR (400 MHz, D ₂ O) δ 7.91 (s, 1H), 4.25 (s, 2H).

t -Butyl((1-((trimethylsilyl)methyl)-1 H -1,2,3-triazol-4-yl)methyl)carbamate (40b).

To a solution of t -butyl prop-2-pin-1-ylcarbamate (0.64 mmol) in DMF and MeOH was added CuI (0.03 mmol) and (azidomethyl)trimethylsilane (0.71 mmol). The mixture was stirred at 60 °C overnight. After the reaction was completed, the solvent was evaporated to dryness. The residue was extracted with ethyl acetate and filtered through a pad of celite. Thereafter, the filtrate was washed with brine. The organic layer was dehydrated with anhydrous magnesium sulfate, concentrated, and purified by column chromatography (ethyl acetate/hexane) to give 40b (32.1%);

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39 (s, 1H), 5.16 (s, 1H), 4.37 (d, J = 6.0 Hz, 2H), 3.89 (s, 2H), 1.44 (s, 9H) , 0.13(s, 9H).

(1-methyl- 1H -1,2,3-triazol-4-yl)methanamine hydrochloride salt (41b) :

To a solution of 40b (2.2 mmol) in THF (10 mL) was added TBAF 1M solution (2.6 mmol) and H ₂ O (4.4 mmol) and stirred for 12 hr at room temperature. After evaporation of the solvent, the organics were extracted with diethylether, washed with brine, dehydrated with anhydrous magnesium sulfate and concentrated. It was diluted with CH ₂ Cl ₂ and 4N HCl in dioxane (2 mL) was added. The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated to dryness to give 41b . The purity of the product was about 80% on the NMR spectrum (yield: 16.4%);

¹ H NMR (400 MHz, D ₂ O) δ 8.05 (s, 1H), 4.33 (s, 2H), 4.13 (s, 3H).

t -butyl((1 H -tetrazol-5-yl)methyl)carbamate (40c).

t -Butyl(cyanomethyl)carbamate (6.5 mmol), ammonium chloride (7.2 mmol) and sodium azide (6.8 mmol) were dissolved in DMF (10 mL). The reaction mixture was stirred at 125 °C for 8 h. After the reaction was complete, 10% HCl solution (15 mL) was added to the mixture. The precipitate obtained was filtered and dried under vacuum to obtain 40c ( 43.8%);

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.55 (t, J = 6.0 Hz, 1H), 4.41 (d, J = 5.9 Hz, 2H), 1.39 (s, 9H).

(One H -tetrazol-5-yl)methanamine HCl (41c):

Compound 40c (2.27 mmol) was dissolved in 4M HCl in dioxane (3 mL) and stirred at room temperature for 3 h. The solvent was evaporated under vacuum to give 41c (quantitative);

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.15 - 8.63 (m, 2H), 4.41 (s, 2H).

5-(azidomethyl)-4-methyl-1H - 1,2,3-triazole (40d) :

1-Bromobut-2-yne (17 mmol), sodium azide (68 mmol) and ammonium chloride (34 mmol) were dissolved in dioxane (24 mL) and H ₂ O (6 mL). The reaction mixture was stirred at 75 °C for 2 days. After the reaction was completed, the solvent was evaporated to dryness. The product was extracted with ethyl acetate and washed with brine. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (EA/Hex) to give 40d (56%);

¹ H NMR (400 MHz, CDCl ₃ ) δ 13.36(s, 1H), 4.48(s, 2H), 2.41(s, 3H).

(4-methyl- 1H -1,2,3-triazol-5-yl)methanamine (41d) :

Compound 40d (2.1 mmol) and triphenylphosphine (2.38 mmol) were dissolved in dry diethyl ether (5 mL) and stirred for 24 h. The solvent was removed under vacuum and the crude mixture was dissolved in THF (10 mL). Water (3 mL) was added to the reaction mixture and refluxed for 1.5 h. After the reaction was complete, the solvent was evaporated. Water was added and washed with diethyl ether. Removal of the solvent gave 41d as a white solid (67.2%);

¹ H NMR (400 MHz, CDCl ₃ ) δ 4.70 (s, 2H), 2.16 (s, 2H).

Preparation 10. Synthesis of compounds 44a-n.

^a Reagents and conditions: (a) 41a , BOP reagent, DIEA, DMF, 8 h; (b) 4M HCl in dioxane, 1 h; (c) CDI, TEA, DMF, benzyl alcohol, 5 h; (d) 3-(3,5-dichlorophenyl)propanoyl chloride, TEA, DMF, rt, 8 h; (e) i: triphosgene, TEA, CH ₂ Cl ₂ , 3 h; ii: 3,5-dichlorobenzylamine, DMF, 5 h.

t -Butyl 4-(5-(((1 H -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (42).

23 (1 mmol), 41a (1.2 mmol), DIEA (3.5 mmol), and BOP reagent (1.2 mmol) were dissolved in DMF (5 mL) and stirred at room temperature for 8 h. After the reaction was completed, the solvent was evaporated and dried. The product was extracted with ethyl acetate and washed with brine. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (CH ₂ Cl ₂ /MeOH) to give 41 (57.8%);

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 14.78 (s, 1H), 7.96 (dt, J = 6.6, 4.4 Hz, 1H), 7.87 - 7.52 (m, 1H), 4.43 (d, J = 5.8 Hz, 2H), 3.98 - 3.79 (m, 2H), 2.97 (dtd, J = 15.0, 11.0, 5.6 Hz, 3H), 1.90 (dt, J = 13.3, 3.6 Hz, 2H), 1.49 (dtd, J = 13.2, 11.2, 4.2 Hz, 2H), 1.40(s, 9H).

N -((One H -1,2,3-triazol-5-yl)methyl)-5-(piperidin-4-yl)-1,3,4-oxadiazol-2-amine HCl (43).

To a solution of 42 (1.7 mmol) in dioxane (1 mL) was added 4 M HCl in dioxane (3 mL) and stirred at room temperature for 1 hr. The solvent was removed in vacuo to give 43 as a white solid (quantitative);

^1H NMR (400 MHz, DMSO- d ₆ ) δ 8.91 (s, 1H), 8.73 (s, 1H), 8.19 (s, 1H), 7.78 (s, 1H), 4.44 (d, J = 5.1 Hz, 2H), 3.28 (m, 2H), 3.14 (m, 1H), 3.00 (m, 2H), 2.14 - 2.01 (m, 2H), 1.90 - 1.76 (m, 2H).

3,5-Dichlorobenzyl 4-(5-(((1 H -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (44a).

Following General Procedure C, 44a was obtained as a white solid (53.1%) using 3,5-dichlorobenzylamine;

^1H NMR (400 MHz, CDCl ₃ ) δ 7.68 (s, 1H), 7.29 (t, J = 1.9 Hz, 1H), 7.21 (d, J = 1.9 Hz, 2H), 7.02 - 6.66 (m, 1H) , 5.06 (d, J = 13.9 Hz, 2H), 4.63 (s, 2H), 4.15 - 4.05 (m, 2H), 3.11 - 2.90 (m, 3H), 2.06 - 1.96 (m, 2H), 1.79 - 1.66 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 163.35, 162.46, 154.73, 142.59, 139.97, 135.09, 129.27, 128.19, 126.12, 65.68, 43.14, 38.12, 33.01, 28.65. HRMS (ESI, m/z) calculated for C ₁₈ H ₂₀ Cl ₂ N ₇ O ₃ [M+H] ⁺ 452.0999, found 452.1004.

3,5-Dibromobenzyl 4-(5-(((1 H -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (44b).

Following General Procedure C, 44b was obtained as a white solid (37.3%) using 3,5-dibromobenzylamine;

^1H NMR (400 MHz, CDCl ₃ - d ) δ 7.69 (s, 1H), 7.60 (t, J = 1.8 Hz, 1H), 7.42 (d, J = 1.8 Hz, 2H), 6.54 (s, 1H) , 5.06 (d, J = 11.1 Hz, 2H), 4.64 (s, 2H), 4.10 (d, J = 13.3 Hz, 2H), 3.18 - 2.86 (m, 3H), 2.01 (dd, J = 13.5, 3.9 Hz, 2H), 1.90 - 1.68 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 163.3, 162.5, 154.7, 142.7, 140.5, 133.7, 129.9, 129.5, 123.0, 65.5, 43.2, 38.3, 33.1, 28.7; HRMS (ESI, m/z) calculated for C ₁₈ H ₂₀ Br ₂ N ₇ O ₃ [M+H] ⁺ 539.9899, found 539.9987.

3,5-bis(trifluoromethyl)benzyl 4-(5-(((1 H -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (44c).

Following General Procedure C, using 3,5-bis(trifluoromethyl)benzyl amine, 44c was obtained as a white solid (36.5%);

¹ H NMR (400 MHz, CDCl ₃ - d ) δ 7.84 (s, 1H), 7.80 (d, J = 1.6 Hz, 2H), 7.72 (s, 1H), 5.77 (s, 1H), 5.32 - 5.18 ( m, 2H), 4.66(s, 2H), 4.13(d, J = 8.7 Hz, 2H), 3.23 - 2.93(m, 3H), 2.05(dd, J = 13.5, 3.8 Hz, 2H), 1.79(dtd) , J = 14.8, 10.9, 4.2 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ - d ) δ 163.25, 162.50, 154.56, 142.73, 139.32, 131.94 (q, J = 33.6 Hz), 130.29-130.11 (m), 127.95 - 127.74 (m), 123.18 , J = 272.8 Hz), 122.07 (dt, J = 7.7, 3.8 Hz), 65.58, 43.20, 38.32, 33.03, 28.70; HRMS (ESI, m/z) calculated for C ₂₀ H ₂₀ F ₆ N ₇ O ₃ [M+H] ⁺ 520.1526, found 520.1533.

3,5-dimethylbenzyl 4-(5-(((1 H -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (44d).

Following General Procedure C, 44d was obtained as a white solid (48.7%) using 3,5-dimethylbenzylamine;

¹ H NMR (400 MHz, CDCl ₃ - d ) δ 7.66 (s, 1H), 6.94 (d, J = 3.8 Hz, 3H), 5.13 - 4.97 (m, 2H), 4.61 (s, 2H), 4.11 ( d, J = 13.6 Hz, 2H), 3.04 - 2.83 (m, 3H), 2.30 (d, J = 0.7 Hz, 6H), 2.01 - 1.92 (m, 2H), 1.71 (dtd, J = 13.4, 11.0, 4.1 Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 163.3, 162.6, 155.4, 142.7, 138.1, 136.3, 129.8, 129.2, 125.8, 67.5, 43.1, 38.1, 33.1, 28.7, 21.3; HRMS (ESI, m/z) calculated for C ₂₀ H ₂₆ N ₇ O ₃ [M+H] ⁺ 412.2092, found 412.2096.

3,5-Dimethoxybenzyl 4-(5-(((1 H -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (44e).

Following General Procedure C, 44e was obtained as a white solid (55.8%) using 3,5-dimethoxybenzylamine;

^1H NMR (400 MHz, CDCl ₃ - d ) δ 7.68 (s, 1H), 6.64 (d, J = 36.1 Hz, 1H), 6.49 (d, J = 2.3 Hz, 2H), 6.40 (t, J = 2.3 Hz, 1H), 5.06(s, 2H), 4.63(s, 2H), 4.12(d, J = 13.6 Hz, 2H), 3.78(s, 6H), 3.10 - 2.86(m, 4H), 1.99( dd, J = 13.6, 3.7 Hz, 2H), 1.73 (dtd, J = 13.3, 11.0, 4.1 Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 163.3, 162.6, 160.9, 155.2, 142.6, 138.9, 129.7, 105.7, 99.8, 67.2, 55.4, 43.1, 38.2, 33.1, 28.7; HRMS (ESI, m/z) calculated for C ₂₀ H ₂₆ N ₇ O ₅ [M+H] ⁺ 444.1990, found 444.1990.

3,5-difluorobenzyl 4-(5-(((1 H -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (44f).

Following General Procedure C, 44f was obtained as a white solid (49.5%) using 3,5-difluorobenzylamine;

¹ H NMR (400 MHz, CDCl ₃ - d ) δ 13.90 (s, 1H), 7.70 (s, 1H), 6.90 - 6.80 (m, 2H), 6.74 (tt, J = 8.9, 2.4 Hz, 1H), 6.39(s, 1H), 5.10(d, J = 4.5 Hz, 2H), 4.66(s, 2H), 4.13(d, J = 12.4 Hz, 2H), 3.05(s, 2H), 2.97(tt, J = 10.7, 3.7 Hz, 1H), 2.10 - 1.95 (m, 2H), 1.86 - 1.69 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ - d ) δ 163.31, 163.05 (dd, J = 249.0, 12.7 Hz), 162.53, 154.74, 142.64, 140.58 (t, J = 9.1 Hz), 129.98, 112.38 - 108.44 (m ), 103.37 (t, J = 25.3 Hz), 65.82 (t, J = 2.2 Hz), 43.15, 38.24, 33.06, 28.71; HRMS (ESI, m/z) calculated for C ₁₈ H ₂₀ F ₂ N ₇ O ₃ [M+H] ⁺ 420.1590, found 420.1593.

3-Bromo-5-methylbenzyl 4-(5-(((1 H -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (44 g).

Following general procedure C, using 3-bromo-5-methylbenzylamine, 44 g was obtained as a white solid (57.6%);

¹ H NMR (400 MHz, CDCl ₃ - d ) δ 7.68 (s, 1H), 7.31 - 7.25 (m, 2H), 7.09 - 7.03 (m, 1H), 6.59 (s, 1H), 5.05 (d, J = 6.4 Hz, 2H), 4.64(s, 2H), 4.11(d, J = 13.4 Hz, 2H), 3.13 - 2.85(m, 3H), 2.41 - 2.23(m, 3H), 2.00(dt, J = 13.7, 3.6 Hz, 2H), 1.74 (dtd, J = 13.2, 11.0, 4.1 Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 163.3, 162.6, 155.0, 142.6, 140.4, 138.6, 131.8, 129.7, 127.9, 127.3, 122.3, 66.4, 43.1, 38.2, 33.1, 21.1; HRMS (ESI, m/z) calculated for C ₁₉ H ₂₃ BrN ₇ O ₃ [M+H] ⁺ 476.1040, found 476.1041.

3-Bromo-5-chlorobenzyl 4-(5-(((1 H -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (44h).

Following general procedure C, using 3-bromo-5-chlorobenzylamine, 44h was obtained as a white solid (48.2%);

¹ H NMR (400 MHz, CDCl ₃ - d ) δ 7.69 (s, 1H), 7.45 (t, J = 1.9 Hz, 1H), 7.37 (t, J = 1.6 Hz, 1H), 6.50 (s, 1H) , 5.06 (d, J = 10.2 Hz, 2H), 4.65 (s, 2H), 4.11 (d, J = 13.4 Hz, 2H), 3.04 (s, 2H), 2.96 (ddt, J = 10.7, 6.9, 3.9 Hz, 1H), 2.02 (dd, J = 13.6, 3.8 Hz, 2H), 1.83 - 1.69 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 163.3, 162.5, 154.7, 142.7, 140.3, 135.2, 131.0, 129.9, 129.0, 126.6, 122.8, 65.6, 43.2, 38.2, 33.0, 28.7; HRMS (ESI, m/z) calculated for C ₁₈ H ₂₀ BrClN ₇ O ₃ [M+H] ⁺ 496.0494, found 496.0495.

3-chloro-5-fluorobenzyl 4-(5-(((1 H -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (44i).

Following general procedure C, using 3-chloro-5-fluorobenzylamine, 44i was obtained as a white solid (49.8%);

¹ H NMR (400 MHz, CDCl ₃ - d ) δ 7.69 (s, 1H), 7.12 (d, J = 1.8 Hz, 1H), 7.03 (dt, J = 8.5, 2.2 Hz, 1H), 6.96 (ddd, J = 8.9, 2.4, 1.4 Hz, 1H), 6.48 (s, 1H), 5.09 (d, J = 6.9 Hz, 2H), 4.65 (s, 2H), 4.12 (d, J = 13.4 Hz, 2H), 3.04 (s, 3H), 2.96 (ddt, J = 10.7, 7.7, 3.9 Hz, 1H), 2.10 - 1.97 (m, 2H), 1.88 - 1.67 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ - d ) δ 163.31, 162.69 (d, J = 249.9 Hz), 162.53, 154.74, 142.71, 140.41 (d, J = 8.3 Hz), 135.18 (d, J = 10.6 Hz) , 129.97, 123.52 (d, J = 3.1 Hz), 115.81 (d, J = 24.7 Hz), 113.04 (d, J = 21.9 Hz), 65.73 (d, J = 2.1 Hz), 43.16, 38.27, 33.07, 28.72 ; ; HRMS (ESI, m/z) calculated for C ₁₈ H ₂₀ ClFN ₇ O ₃ [M+H] ⁺ 436.1295, found 436.1299.

2,5-Dichlorobenzyl 4-(5-(((1 H -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (44j).

Following General Procedure C, using 2,5-dichlorobenzylamine, 44j was obtained as a white solid (58.1%);

¹ H NMR (400 MHz, CDCl ₃ - d ) δ 7.69 (s, 1H), 7.46 - 7.37 (m, 2H), 7.19 (dd, J = 8.2, 2.0 Hz, 1H), 6.47 (s, 1H), 5.10 - 5.04(m, 2H), 4.64(s, 2H), 4.11(d, J = 13.4 Hz, 2H), 3.02(s, 1H), 2.95(tt, J = 10.7, 3.9 Hz, 2H), 2.01 (dd, J = 13.6, 3.9 Hz, 2H), 1.75 (dtd, J = 13.3, 10.9, 4.2 Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 163.3, 162.5, 154.8, 142.6, 136.9, 132.6, 132.2, 130.6, 129.9, 127.2, 65.8, 43.1, 38.2, 33.1, 28.7; HRMS (ESI, m/z) calculated for C ₁₈ H ₂₀ Cl ₂ N ₇ O ₃ [M+H] ⁺ 452.0999, found 436.129952.1001.

3,4-dichlorobenzyl 4-(5-(((1 H -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (44k).

Following General Procedure C, 44k was obtained as a white solid (52.8%) using 3,4-dichlorobenzylamine;

^1H NMR (400 MHz, CDCl ₃ - d ) δ 7.69 (s, 1H), 7.36 (d, J = 2.5 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.22 (dd, J = 8.5, 2.5 Hz, 1H), 6.69 (s, 1H), 5.19 (d, J = 3.8 Hz, 2H), 4.13 (dt, J = 14.2, 4.1 Hz, 2H), 3.20 - 2.88 (m, 3H), 2.12 - 1.96 (m, 2H), 1.89 - 1.69 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 163.35, 162.51, 154.71, 136.02, 132.74, 131.54, 130.66, 129.33, 129.27, 129.25, 64.08, 43.18, 38.18, 328.08, 33.18; HRMS (ESI, m/z) calculated for C ₁₈ H ₂₀ Cl ₂ N ₇ O ₃ [M+H] ⁺ 452.0999, found 452.1002.

benzo[ d ][1,3]dioxol-5-ylmethyl 4-(5-(((1 H -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (44l).

Following general procedure C, using benzo[ d ][1,3]dioxol-5-ylmethanamine, 44l was obtained as a white solid (48.6%);

^1H NMR (400 MHz, CDCl ₃ - d ) δ 7.68 (s, 1H), 6.84 (d, J = 1.6 Hz, 1H), 6.81 (d, J = 1.6 Hz, 1H), 6.76 (dd, J = 7.8, 0.5 Hz, 1H), 5.94(s, 2H), 5.02(s, 2H), 4.62(s, 2H), 4.18 - 4.00(m, 2H), 3.05 - 2.90(m, 2H), 2.94 - 2.85 (m, 1H), 2.04 - 1.88 (m, 2H), 1.78 - 1.61 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 163.3, 162.6, 155.3, 147.8, 147.5, 142.6, 130.3, 129.5, 121.9, 108.8, 108.2, 101.1, 67.3, 43.1, 38.1, 28.1, 33.1; ; HRMS (ESI, m/z) calculated for C ₁₉ H ₂₂ N ₇ O ₅ [M+H] ⁺ 428.1677, found 428.1681.

1-(4-(5-(((1 H -1,2,3-triazol-5-yl) methyl) amino) -1,3,4-oxadiazol-2-yl) piperidin-1-yl) -3- (3,5-dichloro phenyl)propan-1-one (44 m).

Oxalyl chloride (1 mL) and 1 drop of DMF were added to a stirred solution of 3,5-dichlorophenyl propionic acid (0.1 mmol) in CH ₂ Cl ₂ (10 mL) in an ice bath. After stirring at room temperature for 3 h, the solvent was removed under vacuum. The product, crude 3-(3,5-dichlorophenyl)propanoyl chloride, was dissolved in DMF and added to a mixture of TEA (0.3 mmol) and 43 (0.1 mmol) in DMF at 0 °C. The reaction mixture was stirred at room temperature for 8 h. After the reaction was completed, the solvent was evaporated and dried. The product was extracted with ethyl acetate and washed with brine. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (CH ₂ Cl ₂ /MeOH) to give 44m (52.3%);

¹ H NMR (400 MHz, MeOD- d ₄ ) δ 7.78 (s, 1H), 7.28 - 7.20 (m, 3H), 4.55 (s, 2H), 4.45 - 4.33 (m, 1H), 3.98 - 3.89 (m , 1H), 3.21 (ddd, J = 14.2, 11.4, 2.9 Hz, 1H), 3.12 - 3.02 (m, 1H), 2.96 - 2.85 (m, 3H), 2.82 - 2.65 (m, 2H), 2.07 - 1.96 (m, 2H), 1.68 - 1.51 (m, 2H); ¹³ C NMR (100 MHz, MeOD- d ₄ ) δ 172.4, 165.1, 163.9, 146.6, 136.0, 128.5, 127.3, 46.0, 42.1, 38.8, 34.8, 34.2, 31.9, 30.4, 29.9; HRMS (ESI, m/z) calculated for C ₁₉ H ₂₂ Cl ₂ N ₇ O ₂ [M+H] ⁺ 450.1207, found 450.1208.

4-(5-(((1 H -1,2,3-triazol-5-yl) methyl) amino) -1,3,4-oxadiazol-2-yl) - N -(3,5-dichlorobenzyl)piperidine-1-carboxamide (44n).

3,5-dichlorobenzyl amine (0.1 mmol) and TEA (2.5 mmol) were dissolved in CH ₂ Cl ₂ (5 mL). Triphosgene (0.1 mmol) in CH ₂ Cl ₂ was slowly added dropwise to the reaction mixture and stirred for 3h. The solvent was removed under vacuum and the crude mixture was dissolved in DMF (3 mL). Compound 43 (0.1 mmol) was added to the reaction mixture and stirred at room temperature for additional 5 h. After evaporation of the solvent, the organics were extracted with ethyl acetate, washed with brine, dehydrated with anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (CH ₂ Cl ₂ /MeOH) to give 44n ( 32.0%);

^1H NMR (400 MHz, MeOD- d ₄ ) δ 7.78 (s, 1H), 7.28 (t, J = 1.9 Hz, 1H), 7.24 (d, J = 1.9 Hz, 2H), 4.55 (s, 2H) , 4.31(s, 2H), 4.07 - 3.98(m, 2H), 3.10 - 2.98(m, 3H), 2.07 - 1.98(m, 2H), 1.70(dtd, J = 13.4, 11.2, 4.0 Hz, 2H) ; ¹³ C NMR (100 MHz, MeOD- d ₄ ) δ 165.1, 164.2, 159.7, 146.0, 136.0, 127.8, 126.9, 44.5, 44.3, 38.8, 34.4, 30.0; HRMS (ESI, m/z) calculated for C ₁₈ H ₂₁ Cl ₂ N ₈ O ₂ [M+H] ⁺ 451.1159, found 451.1162.

Preparation 11. Synthesis of compounds 47a-c.

^a Reagents and conditions: (a) i: Boc-NHNH ₂ , EDC, DMAP, CH ₂ Cl ₂ , 15 h; ii: 4M HCl in dioxane, 3h; (b) Triphosgene, TEA, THF, 3h; (c) 41b-d , BOP reagent, DIEA, DMF, 8h.

3,5-dichlorobenzyl 4-(hydrazinecarbonyl)piperidine-1-carboxylate (45).

N- ( ₃ -dimethylaminopropyl) to a mixture of 26 (0.60 mmol), tert -butyl hydrazinecarboxylate (0.90 mmol), and 4-(dimethylamino)pyridine (0.03 mmol) in CH ₂ Cl 2 (2 mL) - Added N' -ethylcarbodiimide hydrochloride (0.90 mmol) and stirred overnight at room temperature. The organics were extracted with CH ₂ Cl ₂ , washed with water, dehydrated over anhydrous sodium sulfate and dried under vacuum. Column chromatography (ethyl acetate/hexane) yielded 3,5-dichlorobenzyl 4-(2-(tert-butoxycarbonyl)hydrazinecarbonyl)piperidine-1-carboxylate as a white solid (0.25 g, 92.3%). ) was obtained;

^1H NMR (400 MHz, CDCl ₃ ) δ 8.01 (br s, 1H), 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.9 Hz, 2H), 6.78 (br s, 1H) ( m, 2H), 1.46 (s, 9H).

To this Boc-protected intermediate (0.2 mmol) in dioxane (0.5 mL) was added 4 M HCl in dioxane (1.5 mL). After stirring at room temperature for 1 hr, the solvent was evaporated and the residue was dried under vacuum to give crude 45 (quantitative);

^1H NMR (400 MHz, CDCl ₃ ) δ 7.31 (t, J = 1.9 Hz, 1H), 7.22 (dd, J = 1.9, 0.6 Hz, 2H), 6.78 (bs, 1H), 5.06 (d, J = 13.5 Hz, 2H), 4.21 (bs, 2H), 3.92 (m, 2H), 2.87 (m, 2H), 2.34 - 2.15 (m, 1H), 1.87 - 1.78 (m, 2H), 1.77 - 1.65 (m , 2H).

3,5-dichlorobenzyl 4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (46).

After dissolving TEA (8.96 mmol) in THF (20 mL), the mixture was added at 0 °C to a solution of triphosgene (1.69 mmol) in THF (5 mL) and stirred at room temperature for an additional 3 h. After the reaction was completed, the solvent was evaporated and dried. The product was extracted with ethyl acetate and washed with brine. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate/hexanes) to give 18 as a white solid (69.23 mg, 93.0%);

¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.56 (bs, 1H), 7.31 (t, J = 1.9 Hz, 1H), 7.23 (d, J = 1.9 Hz, 2H), 5.08 (d, J = 6.4 Hz, 2H), 4.13 (d, J = 16.1 Hz, 2H), 3.04 (m, 2H), 2.87 - 2.73 (m, 1H), 2.02 (m, 2H), 1.82 - 1.63 (m, 2H).

General process G.

To a solution of oxadiazol-2-one (0.1 mmol) in anhydrous DMF (2 mL) was added DIEA (0.3 mmol), amine (0.1 mmol), and BOP reagent (0.1 mmol). After stirring at room temperature for 8 h, the solvent was evaporated to dryness. The organics were extracted with ethyl acetate, washed with brine, dehydrated with anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (MeOD/CH ₂ Cl ₂ ) to give the desired product.

3,5-Dichlorobenzyl 4-(5-(((1 H -tetrazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (47a).

According to General Procedure G, 46 and 41c were used to obtain 47a as a white solid (35.1%);

¹ H NMR (400 MHz, MeOD- d ₄ ) δ 7.39 (t, J = 1.9 Hz, 1H), 7.34 (dd, J = 1.7, 0.9 Hz, 2H), 5.10 (s, 2H), 4.71 (s, 2H), 4.11 (d, J = 13.5 Hz, 2H), 3.06 (tt, J = 10.8, 3.8 Hz, 3H), 2.05 (dd, J = 13.5, 3.7 Hz, 2H), 1.79 - 1.64 (m, 2H) ); ¹³ C NMR (100 MHz, DMSO- d6 ) δ 163.2, 161.7, 156.6, 154.1, 141.4, _134.1 , 127.5, 126.2, 64.8, 42.7, 37.6, 32.0, 29.1; HRMS (ESI, m/z) calculated for C ₁₈ H ₁₉ Cl ₂ N ₈ O ₃ [M+H] ⁺ 453.0952, found 453.0952.

3,5-dichlorobenzyl 4-(5-(((1-methyl-1H - 1,2,3-triazol-4-yl)methyl)amino)-1,3,4-oxadiazole-2 -yl)piperidine-1-carboxylate (47b) .

According to General Procedure G, 46 and 41b were used to obtain 47b as a white solid (23.9%);

^1H NMR (400 MHz, CDCl ₃ ) δ 7.71 (s, 1H), 7.30 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 1.8 Hz, 2H), 6.23 (d, J = 6.1 Hz , 1H), 5.16-4.96(m, 2H), 4.59(d, J = 5.2 Hz, 2H), 4.15-4.08(m, 2H), 4.07(s, 3H), 3.05(s, 2H), 3.00- 2.88 (m, 1H), 2.07-1.94 (m, 2H), 1.85-1.68 (m, 2H); ¹³ C NMR (100 MHz, CDCL ₃ ) δ 163.13, 162.51, 154.64, 144.27, 140.11, 135.10, 128.17, 126.11, 123.76, 65.58 _, 43.14, 38.37, 36.72, 33.01, _28.73 . ₂ N ₇ O ₃ [M+H] ⁺ 466.1156, found 466.1162.

3,5-dichlorobenzyl 4-(5-(((4-methyl-1 H -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (47c).

46 and 41d were used according to General Procedure G to obtain 47c as a white solid (48.5%);

^1H NMR (400 MHz, CDCl ₃ ) δ 7.29 (t, J = 2.0 Hz, 1H), 7.22 (d, J = 2.0 Hz, 2H), 6.63 (s, 1H), 5.07 (d, J = 9.7 Hz , 2H), 4.55(s, 2H), 4.11(d, J = 13.5 Hz, 2H), 3.15 - 2.86(m, 3H), 2.32(s, 3H), 2.02(dq, J = 12.0, 3.5 Hz, 2H), 1.85 - 1.68 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 163.4, 162.4, 154.7, 140.0, 135.1, 128.2, 126.1, 65.7, 43.2, 37.6, 33.0, 28.7, 9.1; HRMS (ESI, m/z) calculated for C ₁₉ H ₂₂ Cl ₂ N ₇ O ₃ [M+H] ⁺ 466.1156, found 466.1155.

Preparation 12. Synthesis of compounds 50a-c

Reagents and conditions: (a) Triphosgene, Et ₃ N, THF, 12 h; (b) i: TCDI, EtOH, 1 h; ii: N ₂ H ₄ .H ₂ O, 18 h; (c) 4-pentynnitrile, TFA, 50 °C, 24 h; (d) Me ₃ SiN ₃ , CuI, DMF, MeOH, 80 °C, 24 h (e) 48 , BOP reagent, DIEA, DMF, 15 h; (f) 4-pentinoic acid, EDC, DMAP, CH ₂ Cl ₂ , 15 h; (g) Burgess reagent, dioxane, reflux, 5 h ;

5-(but-3-yn-1-yl)-1,3,4-oxadiazole-2(3 H )-lone (48) :

Following the procedure for 13a , phen-4-tin hydrazide (0.27 g, 1.82 mmol) was used to obtain 48 as a colorless oil (53.79 mg, 21.4%);

^1H NMR (400 MHz, CDCl ₃ ) δ 9.84 (br s, 1H), 2.82 (t, J = 7.2 Hz, 2H), 2.61 (td, J = 7.0, 2.6 Hz, 3H), 2.06 (d, J = 2.6 Hz, 1H).

3,5-dichlorobenzyl 4-(5-(but-3-yn-1-yl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (49a).

To a mixture of 35 (0.29 g, 1.00 mmol) in ethanol (5 mL) stirred at room temperature was added 1,1'-thiocarbonyldiimidazole (0.21 g, 1.20 mmol). After stirring at room temperature for 1 h, hydrazine monohydrate (200 μL) was added to the mixture. The reaction mixture was stirred at room temperature overnight and dried under vacuum. The organics were extracted with ethyl acetate, washed with brine, dehydrated with anhydrous sodium sulfate and concentrated. Column chromatography (ethyl acetate/hexane) gave 3,5-dichlorobenzyl 4-(hydrazinecarbothionyl)piperazine-1-carboxylate as a white solid (0.27 g, 74.6%). This (0.55 mmol) was dissolved in trifluoroacetic acid (3 mL) along with 4-pentynnitrile (43.50 mg, 0.55 mmol) and heated at 50 °C overnight. The mixture was cooled to 0 °C, quenched with saturated NaHCO ₃ solution, and extracted with ethyl acetate. The organic layer was concentrated by dehydration with anhydrous Na ₂ SO ₄ and purified by column chromatography (CH ₂ Cl ₂ /MeOH) to give 49a as a white solid (99.89 mg, 42.7%);

^1H NMR (400 MHz, CDCl ₃ ) δ 7.32 (t, J = 1.9 Hz, 1H), 7.24 (d, J = 1.9 Hz, 2H), 5.10 (s, 2H), 3.71 - 3.62 (m, 4H) , 3.58 - 3.47 (m, 4H), 3.15 (t, J = 7.2 Hz, 2H), 2.63 (td, J = 7.2, 2.7 Hz, 2H), 2.06 (t, J = 2.6 Hz, 1H).

3,5-dichlorobenzyl 4-(5-(but-3-yn-1-yl)-1,3,4-oxadiazol-2-yl)piperazine-1-carboxylate (49b).

Using 48 (27.62 mg, 0.20 mmol) and 35 (69.40 mg, 0.24 mmol) according to General Procedure G, 49b was obtained as a white solid (38.88 mg, 47.5%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.32 (t, J = 1.9 Hz, 1H), 7.24 (d, J = 1.9 Hz, 2H), 5.10 (s, 2H), 3.67 - 3.61 (m, 4H) , 3.55 - 3.48 (m, 4H), 2.97 (t, J = 7.5 Hz, 2H), 2.64 (dt, J = 7.4, 2.7 Hz, 2H), 2.03 (t, J = 2.7 Hz, 1H).

3,5-dichlorobenzyl 4-(5-(but-3-yn-1-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (49c).

To a mixture of 45 (86.55 mg, 0.25 mmol), 4-pentinoic acid (29.43 mg, 0.30 mmol), and DMAP (0.03 mmol) in CH ₂ Cl ₂ (2 mL) was added EDCI (0.24 mmol). After stirring at room temperature for 12 h, the organics were extracted with CH ₂ Cl ₂ , washed with water, dehydrated over anhydrous sodium sulfate and concentrated. Purification by column chromatography (ethyl acetate/hexane) yielded the intermediate 3,5-dichlorobenzyl 4-(2-(phen-4-tinnoyl)hydrazinecarbonyl)piperidine-1-carboxylate as a white solid (63.94 mg, 0.15 mmol). It was mixed with Burgess reagent (0.14 g, 0.60 mmol) in anhydrous dioxane (5 mL) and refluxed under nitrogen gas for 5 h. The reaction mixture was diluted with saturated NaHCO ₃ solution. The organics were extracted with ethyl acetate, dehydrated with sodium sulfate and concentrated. The product was purified by column chromatography (ethyl acetate/hexane) to give 49c as a white solid (32.15 mg, 52.7%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.31 (t, J = 1.9 Hz, 1H), 7.23 (d, J = 1.8 Hz, 2H), 5.15 - 5.01 (m, 2H), 4.20 - 4.10 (m, 2H), 3.19 - 3.01 (m, 5H), 2.70 (td, J = 7.4, 2.6 Hz, 2H), 2.13 - 2.04 (m, 2H), 2.02 (t, J = 2.6 Hz, 1H), 1.90 - 1.79 (m, 2H).

3,5-Dichlorobenzyl 4-(5-(2-(1) H -1,2,3-triazol-5-yl)ethyl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (50a).

Compound 49a (97.82 mg, 0.23 mmol), trimethylsilyl azide (0.25 mmol), and kappa(I) iodide (0.025 mmol) were dissolved in a solution of DMF (0.9 mL) and MeOH (0.1 mL) under argon gas. added. The reaction mixture was stirred at 80 °C for 24 h. The solvent was evaporated to dryness, extracted with ethyl acetate and washed with brine. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (CH ₂ Cl ₂ /MeOH) to give 50a as a white solid (7.54 mg, 29.0%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.54 (s, 1H), 7.32 (t, J = 1.9 Hz, 1H), 7.24 (d, J = 1.9 Hz, 2H), 5.10 (s, 2H), 3.70 - 3.62 (m, 4H), 3.56 - 3.46 (m, 4H), 3.33 (t, J = 6.9 Hz, 2H), 3.23 (t, J = 7.0 Hz, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.08, 159.20, 154.60, 139.64, 135.19, 128.40, 126.28, 65.93, 49.28, 43.01, 29.62, 24.15. HRMS (ESI) m/z (M+H) ⁺ calculated for C ₁₈ H ₂₀ Cl ₂ N ₇ O ₂ S = 468.08; found 468.0779.

3,5-Dichlorobenzyl 4-(5-(2-(1) H -1,2,3-triazol-5-yl)ethyl)-1,3,4-oxadiazol-2-yl)piperazine-1-carboxylate (50b).

Following the procedure for 50a , 49b ( 40.93 mg, 0.10 mmol) was used to obtain 50b as a white solid (13.12 mg, 29.0%).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.55 (s, 1H), 7.32 (t, J = 1.9 Hz, 1H), 7.24 (d, J = 1.9 Hz, 2H), 5.10 (s, 2H), 3.69 - 3.59 (m, 4H), 3.54 - 3.44 (m, 4H), 3.25 - 3.19 (m, 2H), 3.18 - 3.09 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 164.12, 160.46, 154.64, 139.61, 135.19, 128.40, 126.30, 65.96, 45.86, 42.98, 25.21, 21.79. HRMS (ESI) m/z (M+H) ⁺ calculated for C ₁₈ H ₂₀ Cl ₂ N ₇ O ₃ = 452.10; found 452.1003.

3,5-dichlorobenzyl 4-(5-(2-(1 H -1,2,3-triazol-5-yl)ethyl)-1,3,4-oxadiazol-2-yl)piperi Dean-1-carboxylate (50c) :

Following the procedure for 50a , 49c ( 32.15 mg, 0.079 mmol) was used to obtain 50c as a white solid (21.64 mg, 60.7%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 12.16 (s, 1H), 7.55 (s, 1H), 7.31 (t, J = 1.9 Hz, 1H), 7.23 (d, J = 1.9 Hz, 2H), 5.08 (d, J = 9.2 Hz, 2H), 4.21 - 4.07 (m, 2H), 3.31 - 3.21 (m, 4H), 3.15 - 3.01 (m, 3H), 2.11 - 2.03 (m, 2H), 1.89 - 1.77 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.41, 165.93, 154.69, 140.00, 135.13, 128.23, 126.16, 65.68, 43.15, 33.06, 28.78, 25.04, 21.88. HRMS (ESI) m/z (M+Na) ⁺ calculated for C ₁₉ H ₂₀ Cl ₂ N _6- NaO ₃ = 473.09; found 473.0868.

Preparation 13. Synthesis of compound 53a-b.

Reagents and conditions: (a) propargyl bromide, K ₂ CO ₃ , DMF, 12 h; (b) 51 , K ₂ CO ₃ , DMF, 12 h; (c) TFA, CH ₂ Cl ₂ , 2 h; d) CuSO ₄ , TMSN ₃ , sodium ascorbate, THF, H ₂ O, 80 °C, 12 h; (e) 5-bromo-1,3,4-thiadiazol-2-amine, K ₂ CO ₃ , DMF, 12 h; (f) CuI, TMSN ₃ , sodium ascorbate, DMF, H ₂ O, 80 °C, 15 h; (g) 4M HCl in dioxane, 1 h; (h) 3,5-dichloro Benzyl alcohol, CDI, DMF, 18 h.

t -Butyl(5-bromotiazol-2-yl)(pro-2-pin-1-yl)carbamate (51).

To a solution of NaH (60% in mineral oil) (2.1 mmol) in DMF was added t-butyl(5-bromotiazol-2-yl)carbamate (2.1 mmol) and propargyl bromide (2.1 mmol). After stirring at room temperature for 2 h, the solvent was evaporated to dryness. The organics were extracted with ethyl acetate, washed with brine, dehydrated with anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate/hexane) to give 49 (yield: 95.8%);

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.33 (m, 1H), 4.81 (t, J = 2.2 Hz, 2H), 2.23 (t, J = 2.4 Hz, 1H), 1.60 (s, 9H) .

3,5-dichlorobenzyl 4-(2-(pro-2-pin-1-ylamino)thiazol-5-yl)piperazine-1-carboxylate (52).

To a solution of 51 (0.3 mmol) in CH ₂ Cl ₂ was added trifluoroacetic acid (1 mL). After stirring at room temperature for 2 h, the mixture was dried in vacuo to obtain 5-bromo- N- (pro-2-pin-1-yl)thiazol-2-amine trifluoroacetate salt. This salt was added to anhydrous DMF (2 mL) and stirred with K ₂ CO ₃ (1.0 mmol) and 35 (0.3 mmol) at room temperature for 12 h. After the reaction was completed, the solvent was evaporated and dried. The residue was extracted with ethyl acetate and washed with brine. The organic layer was dehydrated with anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate/hexane) to give 52 (53.2%);

^1H NMR (400 MHz, CDCl ₃ ) δ 7.31 (t, J = 1.9 Hz, 1H), 7.23 (d, J = 1.9 Hz, 2H), 6.61 (s, 1H), 5.08 (s, 2H), 4.07 (d, J = 2.5 Hz, 2H), 3.68–3.54 (m, 4H), 2.91 (t, J = 5.1 Hz, 4H), 2.28 (t, J = 2.5 Hz, 1H).

3,5-dichlorobenzyl 4-(2-(((1H - 1,2,3-triazol-5-yl)methyl)amino)thiazol-5-yl)piperazine-1-carboxylate (53a ). CuSO _{4 H 2 O} (0.01 mmol), sodium ascorbate (0.02 mmol), and azidotrimethylsilane (0.71 mmol) were added to a solution of 52 (0.24 mmol) in THF and H 2 O (2:1). was added and vigorously stirred at 80 °C for 12 h. After the reaction was completed, the solvent was evaporated and dried. The residue was extracted with ethyl acetate and filtered through a pad of celite. Thereafter, the filtrate was washed with brine. The organic layer was dehydrated over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate/hexane) to give 53a (5.3%);

¹ H NMR (400 MHz, CDCl ₃ ) δ 12.76 (s, 1H), 10.53 (s, 1H), 7.97 (s, 1H), 7.32 (t, J = 1.9 Hz, 1H), 7.26-7.20 (m, 2H), 6.39(s, 1H), 5.33(s, 2H), 5.09(s, 2H), 3.63(t, J = 4.9 Hz, 4H), 2.84(s, 4H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 159.22, 154.73, 140.58, 139.74, 135.17, 131.16, 128.34, 126.32, 126.22, 103.80, 65.87, 52.50, 43.97, 38.01; HRMS calculated for C ₁₈ H ₂₀ Cl ₂ N ₇ O ₂ S [M+H] ⁺ 468.0771, found 468.0778.

t -Butyl 4-(5-amino-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (54).

N -Boc-piperazine (1.0 mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (1.0 mmol) were mixed in DMF with K- ₂ CO ₃ (2 eq) at room temperature. did After stirring for 12 h, the solvent was removed under vacuum. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 54 (86%);

¹ H NMR (400 MHz, CDCl ₃ ) δ 4.78 (s, 2H), 3.54 (m, 4H), 3.35 (m, 4H), 1.47 (s, 9H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.82, 160.25, 154.55, 80.35, 49.67, 42.83, 28.38. LRMS (ESI, m/z) calculated for C ₁₁ H ₁₉ N ₅ O ₂ S [M+H] ⁺ 286.1259, found 186.10.

t -Butyl 4-(5-(pro-2-pin-1-ylamino)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (55).

Compound 54 (1 mmol), propargyl bromide (1.2 mmol), and K ₂ CO ₃ (1.2 mmol) were mixed in DMF. After stirring at 50 °C for 18 h, the mixture was dried under vacuum. The residue was purified by silica gel column chromatography (EA/Hexanes) to give 55 (32%);

¹ H NMR (400 MHz, CDCl ₃ ) δ 4.56 (m, 1H), 4.10 (m, 2H), 3.54 (m, 5H), 3.36 (m, 4H), 3.27 - 3.16 (m, 2H), 2.33 - 2.27(m, 1H), 1.47(s, 9H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 151.30, 150.01, 149.29, 80.54, 80.39, 71.99, 49.14, 48.00, 31.44, 28.38. MS(ESI, m/z) calculated for C ₁₄ H ₂₁ N ₅ O ₂ S [M+H] ⁺ 324.1416, found 324.10.

t -Butyl 4-(5-(((1H - 1,2,3-triazol-5-yl)methyl)amino)-1,3,4-thiadiazol-2-yl)piperazine-1 -carboxylates (56). Compound 55 (0.1 mmol) was dissolved in DMF (2 ml) and H ₂ O (0.5 mL) with TMS azide (0.2 mmol), sodium ascorbate (0.05 mmol) and CuI (30 mol%) and 80 ^°C C for 15 h. After cooling to room temperature, the solvent was removed under vacuum. The residue was purified by silica gel column chromatography (EA/Hexanes) to give 56 (26%);

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.69 (s, 1H), 4.61 (s, 2H), 3.52 (m, 5H), 3.33 (m, 5H), 1.48 (s, 1H), 1.47 (s, 9H), 1.44(s, 1H), 1.30(s, 1H), 1.25(s, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 164.86, 162.20, 154.59, 142.18, 129.96, 80.48, 49.63, 42.81, 39.87, 28.39. LRMS (ESI, m/z) calculated for C ₁₄ H ₂₂ N ₈ O ₂ S [M+H] ⁺ 367.1586, found 367.15.

3,5-Dichlorobenzyl 4-(5-(((1 H -1,2,3-triazol-5-yl)methyl)amino)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (53b).

3,5-Dichlorobenzyl alcohol (0.1 mmol) was dissolved in DMF (2 mL) along with CDI (0.12 mmol) at room temperature. After stirring for 5 h, 53 (0.1 mmol) was added to the solution and stirred for an additional 12 h. Solvent was removed under vacuum. The residue was purified by silica gel column chromatography (EA/Hexanes) to give 53b (96%);

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.67 (s, 1H), 7.31 (m, 1H), 7.22 (m, 2H), 5.08 (s, 2H), 4.61 (s, 2H), 3.61 (m, 4H), 3.49 (s, 1H), 3.37 (m, 4H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 164.61, 162.30, 154.63, 142.31, 139.69, 135.18, 130.07, 128.36, 126.25, 65.90, 43.03, 39.92, 29.70. HRMS (ESI, m/z) calculated for C ₁₇ H ₁₈ Cl ₂ N ₈ O ₂ S [M+H] ⁺ 469.0650, found 469.0727.

Preparation 14. Synthesis of Compound 58.

Reagents and conditions: (a) 4-(pro-2-pin-1-yloxy)aniline, AcOH, NaBH(OAc)- ₃ , CH ₂ Cl ₂ , 18 h; (b) CuI, TMS azide, DMF :H ₂ O (9:1), 100 °C, 5 h.

3,5-dichlorobenzyl 4-((4-(pro-2-pin-1-yloxy)phenyl)amino)piperidine-1-carboxylate (57).

Compound 17 (1.0 mmol) and 4-(2-propyn-1-yloxy)benzenamine (1.0 mmol) were dissolved in CH ₂ with acetic acid (1.0 eq) and sodium acetoxyborohydride (1.5 eq) at room temperature. Cl ₂ (10 mL). After stirring for 18 h, the organics were extracted with CH ₂ Cl ₂ , washed with brine, dehydrated over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH) to give 57 (98%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.30 (m, 1H), 7.23 (m, 2H), 6.90 - 6.81 (m, 2H), 6.62 - 6.53 (m, 2H), 5.07 (s, 2H), 4.61(m, 2H), 4.12(m, 3H), 3.38(m 1H), 3.27(s, 1H), 2.49(m, 1H), 2.04(s, 1H), 1.35(s, 1H), 1.34 1.22 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 154.83, 150.36, 141.70, 140.35, 135.21, 128.26, 126.19, 116.72, 114.88, 79.27, 75.28, 65.62, 60.53, 551.93; MS(ESI, m/z) calculated for C ₂₂ H ₂₂ Cl ₂ N ₂ O ₃ [M+H] ⁺ 433.1080, found 433.05.

3,5-dichlorobenzyl 4-((4-((1H-1,2,3-triazol-4-yl)methoxy)phenyl)amino)piperidine-1-carboxylate (58).

To a stirred solution of 57 (0.5 mmol) in DMF (4.5 mL) and H ₂ O (0.5 mL) at room temperature was added TMS azide (0.75 mmol) and CuI (0.1 mmol). After stirring at 100 °C for 5 h, the solvent was removed in vacuo. The organics were extracted with CH ₂ Cl ₂ , washed with brine, dehydrated over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH) to give 58 (yield: 39%);

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.75 (s, 1H), 7.34 - 7.24 (m, 1H), 7.22 (m, 2H), 6.89 - 6.80 (m, 2H), 6.62 - 6.53 (m, 2H) ), 5.14(s, 2H), 5.10 - 5.05(m, 2H), 4.12(m, 1H), 3.38(m, 1H), 3.01(s, 2H), 2.05(m, 3H), 1.42(s, 1H), 1.40 - 1.22 (m, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 154.95, 151.02, 143.93, 141.38, 140.23, 135.20, 131.44, 128.27, 126.18, 116.52, 115.25, 65.72, 63.14, 84.04, 51.72 HRMS (ESI, m/z) calculated for C ₂₂ H ₂₄ Cl ₂ N ₅ O ₃ [M+H] ⁺ 476.1251, found 476.1258.

Preparation 15. Synthesis of compounds 61 and 64.

Reagents and conditions: (a) i: propargyl bromide, K ₂ CO ₃ , DMF, 1 h; ii: 4M HCl in dioxane; (b) NaBH(OAc) ₃ , acetic acid, THF, 18 h; (c) CuI, TMS azide, DMF:H ₂ O(9:1), 100° C., 5 h; (d) i: 3-(piperidin-4-yl)phenol, toluene, reflux, 1 h; ii: NaBH- ₄ , EtOH.

4-(piperidin-4-yl)-N-(pro-2-pin-1-yl)aniline (59).

4-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester (1.0 mmol) and propargyl bromide (1.2 mmol) were dissolved in DMF with K ₂ CO ₃ (3 eq). After stirring at room temperature for 1 h, the solvent was removed under vacuum. The organics were extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The main material was isolated by silica gel column chromatography (ethyl acetate/hexane) and dried under vacuum. The residue was dissolved in 4M HCl in dioxane (5 mL) and stirred at room temperature for 1 h. The solvent was removed in vacuo to give 59 (45%);

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.09 - 7.01 (m, 2H), 6.69 - 6.61 (m, 2H), 3.92 (d, J = 2.4 Hz, 2H), 3.82 (s, 1H), 2.78 m , 2H), 2.54 (m, 1H), 2.21 (m, 1H), 1.82 - 1.73 (m, 2H), 1.65 - 1.52 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 145.40, 136.18, 127.63, 113.75, 79.47, 71.38, 41.93, 33.92, 28.63. LRMS(ESI, m/z) calculated for C ₁₄ H ₁₈ N ₂ [M+H] ⁺ 215.1543, found 214.05

3,5-dichlorobenzyl 4-(4-(pro-2-pin-1-ylamino)phenyl)-[1,4′-bipiperidine]-1′-carboxylate (60).

Compounds 17 (1.0 mmol) and 59 (1.0 mmol) were dissolved in THF (10 mL) at room temperature along with acetic acid (1.0 eq) and sodium triacetoxyborohydride (1.5 mmol). After stirring for 18 h, the solvent was removed under vacuum. The organics were extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 60 (44%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.30 (m, 1H), 7.22 (m, 2H), 7.11 - 7.03 (m, 2H), 6.68 - 6.60 (m, 2H), 5.09 - 5.03 (m, 2H) ), 4.23(s, 2H), 3.91 m, 2H), 3.80(s, 1H), 3.01(m, 2H), 2.82(s, 2H), 2.44(m, 2H), 2.33 - 2.18(m, 3H) ), 1.85 (m, 4H), 1.71 (m, 2H), 1.50 (m, 1H). ¹³ C NMR (100 MHz, CDCL ₃ ) δ 154.76, 145.33, 140.41, 136.35, 135.21, 128.24, 127.68, 126.18, 113.74, 81.29, 71.36, 65.58, 62.14, 43.88, 41.97, 33.94, 33.67. LRMS (ESI, m/z) calculated for C ₂₇ H ₃₁ Cl ₂ N ₃ O ₂ [M+H] ⁺ 500.1866, found 500.25.

3,5-dichlorobenzyl 4-(4-(((1H-1,2,3-triazol-4-yl)methyl)amino)phenyl)-[1,4′-bipiperidine]-1′ -carboxylates (61).

To compound 60 (0.25 mmol) in DMF (2.25 mL) and H ₂ O (0.25 mL) at room temperature was added TMS azide (0.38 mmol) and CuI (0.05 mmol). After stirring at 100 °C for 5 h, the solvent was removed under vacuum. The organics were extracted with CH ₂ Cl ₂ , washed with brine, dehydrated over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH) to give 61 (13%);

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.12 - 7.47 (m, 2H), 7.36 - 7.26 (m, 1H), 7.22 (m, 2H), 7.01 (m, 2H), 6.62 (t, J = 8.0 Hz, 2H), 5.11 (s, 0H), 5.06 - 5.02 (m, 2H), 4.43 (s, 2H), 3.61 (m, 4H), 3.08 (m, 2H), 2.73 - 1.89 (m, 4H) , 1.82 - 0.66 (m, 8H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 154.81, 140.42, 135.21, 128.24, 127.73, 127.57, 126.18, 113.40, 65.59, 63.84, 62.25, 43.96, 42.09, 43.53. HRMS (ESI, m/z) calculated for C ₂₇ H ₃₂ Cl ₂ N ₆ O ₂ [M+H] ⁺ 543.2037, found 543.2038.

3,5-dichlorobenzyl 4-(3-hydroxyphenyl)-[1,4′-bipiperidine]-1′-carboxylate (62).

3-(piperidin-4-yl)phenol (1.0 mmol) and 17 (1.0 mmol) were dissolved in toluene (20 ml) and refluxed for 1 h. The solvent was removed in vacuo and the residue was dissolved in EtOH (5 mL) with sodium borohydride (1.2 mmol) at room temperature and stirred overnight. After removing the solvent in vacuo, the organics were extracted with ethyl acetate, washed with brine, dehydrated with anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA/Hexanes) to give 62 (62%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.30 (m, 1H), 7.22 (m, 2H), 7.13 (m, 1H), 6.71 m, 1H), 6.64 (m, 1H), 6.59 (m, 1H) ), 5.05(m, 2H), 4.23(s, 2H), 3.07 - 2.98(m, 2H), 2.79(s, 2H), 2.50(m, 1H), 2.37 m, 1H), 2.34 - 2.23(m) , 2H), 1.88 (m, 2H), 1.70 (m, 4H), 1.53 (m, 1H), 1.47 (m, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 156.46, 154.78, 148.02, 140.33, 135.21, 129.69, 128.26, 126.19, 119.27, 113.74, 113.71, 65.65, 62.39, 5.4.39, 5.4.39, 43.39 LRMS(ESI, m/z) calculated for C ₂₄ H ₂₈ C _l2 N ₂ O ₃ [M+H] ⁺ 463.1550, found 463.25.

3,5-dichlorobenzyl 4-(3-(pro-2-pin-1-yloxy)phenyl)-[1,4′-bipiperidine]-1′-carboxylate (63).

Compound 62 (0.5 mmol), propargyl bromide (0.6 mmol), and K ₂ CO ₃ (0.6 mmol) were added to DMF and stirred for 12 h. After removing the solvent in vacuo, the organics were extracted with ethyl acetate, washed with brine, dehydrated with anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 63 (58%);

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.30 (m, 1H), 7.26 - 7.18 (m, 3H), 6.90 - 6.78 (m, 3H), 5.06 (m, 2H), 4.67 (m, 2H), 4.23(s, 1H), 4.12(m, 1H), 3.02(m 2H), 2.82(m, 0H), 2.50 - 2.41(m, 2H), 2.30(m, 2H), 2.04(s, 1H), 1.91 - 1.67 (m, 8H), 1.50 (m, 2H); ¹³ C NMR (100 MHz, CDCL ₃ ) δ 157.68, 154.66, 148.12, 140.34, 135.09, 129.37, 128.10, 126.05, 120.21, 113.69, 112.28, 78.71, 77.44, 75.44 , 33.75; MS(ESI, m/z) calculated for C ₂₇ H ₃₀ Cl ₂ N ₂ O ₃ [M+H] ⁺ 501.1706, found 501.30.

3,5-dichlorobenzyl 4-(3-((1H-1,2,3-triazol-5-yl)methoxy)phenyl)-[1,4'-bipiperidine]-1'-carboxyl Rate (64).

To compound 63 (0.25 mmol) in DMF (2.25 mL) and H ₂ O (0.25 mL) at room temperature was added TMS azide (0.38 mmol) and CuI (0.05 mmol). After stirring at 100 °C for 5 h, the solvent was removed under vacuum. The organics were extracted with CH ₂ Cl ₂ , washed with brine, dehydrated over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH) to give 64 (32%);

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77 (s, 1H), 7.30 (m, 2H), 7.21 - 7.08 (m, 1H), 6.93 (m, 1H), 6.82 (m, 3H), 5.18 ( s, 2H), 5.07(s, 3H), 4.28(s, 3H), 3.13(m, 2H), 2.96(s, 1H), 2.89(m, 1H), 2.77 - 2.65(m, 1H), 2.60 - 2.49(m, 1H), 2.00(m, 5H), 1.59(m, 3H). ¹³ C NMR (100 MHz, CDCL ₃ ) Δ 158.73, 154.77, 147.73, 143.71, 140.30, 135.22, 132.08, 129.56, 128.27, 126.20, 120.49, 113.53, 112.26 , 33.02. HRMS (ESI, m/z) calculated for C ₂₇ H ₃₁ Cl ₂ N ₅ O ₃ [M+H] ⁺ 544.1877, found 544.1881.

Preparation 16. Synthesis of compound 65.

Reagents and conditions: i: chloroacetyl chloride, TEA, 1 drop of DMF, CH ₂ Cl ₂ , cool, 1h; ii: 1-(3,5-dichloro-benzyl) piperazine, TEA, DMF, 120° C., 3 h.

1-(4-(1 H -imidazol-5-yl)piperidin-1-yl)-2-(4-(3,5-dichlorobenzyl)piperazin-1-yl)ethan-1-one (65).

4-(1 H -imidazol-5-yl)piperidine (1 mmol) and TEA (1 mmol) were dissolved in CH ₂ Cl ₂ (10 mL). Chloroacetyl chloride (3 mmol) was added to the reaction mixture. The resulting solution was stirred for 1 h. After completion of the reaction, the solvent was removed under vacuum. The residue was dissolved in DMF and TEA (2 mmol) and 1-(3,5-dichloro-benzyl) piperazine (1.1 mmol) in DMF were added. The reaction mixture was stirred at 75 °C for 2 h. The solvent was removed in vacuo and the crude mixture was extracted with ethyl acetate and washed with brine. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (CH ₂ Cl ₂ /MeOH) to obtain the desired compound as a white solid (65%);

^1H NMR (400 MHz, MeOD- d ₄ ) δ 7.59 (s, 1H), 7.37 - 7.31 (m, 3H), 6.80 (s, 1H), 3.65 (t, J = 5.1 Hz, 2H), 3.61 ( t, J = 5.2 Hz, 2H), 3.56 - 3.52 (m, 2H), 3.34 (s, 2H), 3.07 - 2.97 (m, 2H), 2.61 (ddd, J = 11.8, 8.0, 4.1 Hz, 1H) , 2.49 (t, J = 5.1 Hz, 2H), 2.44 (t, J = 5.1 Hz, 2H), 2.29 (t, J = 11.6 Hz, 2H), 1.97 (d, J = 12.8 Hz, 2H), 1.73 (qd, J = 12.3, 3.7 Hz, 2H); MS(ESI, m/z) calculated for C ₂₁ H ₂₈ Cl ₂ N ₅ O [M+H] ⁺ 436.38, found 436.10.

[Experimental Example 1] Evaluation of human autotaxin inhibitory activity

(1) Experiment method

Each compound solution (80 uM, 100% dimethyl sulfoxide) was serially diluted 5-fold with dimethyl sulfoxide to make 6 concentrations. Compounds at each concentration were diluted in duplicate with 1x test buffer (50 mM Tris-Cl (pH 8.0), 5 mM KCl, 1 mM CaCl ₂ , 1 mM MgCl ₂ , 140 mM NaCl, 3-distilled water, 1 mg/mL BSA). After dilution, 1 uL (1.25% dimethyl sulfoxide) was dispensed into a 96 well clear round bottom plate. 9 uL of 1x test buffer was added, and 20 uL of 240 nM human autotaxin protein (buffer: 50 mM Tris-HCl, pH 8.0, with 150 mM sodium chloride and 20% glycerol) was added. Add 10 uL of sonicated 360 uM 18:1 LysoPC (diluted in 1x test buffer). The reaction was performed in a 37° C. shaking incubator for 2 hours, and a secondary reaction mixture (choline assay kit, KA1662) (1x test buffer 65 uL: choline oxidase 1 uL: dye probe 1 uL) was prepared. 60 uL of the secondary reaction mixture was added to the reaction plate and reacted for 30 minutes on a shaker. Absorbance values were measured at a wavelength of 570 nm using a SpectraMax iD3 microplate reader. The percent inhibition (% inhibition) was calculated using the formula of (1 - absorbance value _{test group} /absorbance value _{control group} ) X 100.

(2) Results

The percentage value (% inhibition) of autotaxin inhibitory activity measured at a concentration of 500 nM for the Example compounds is shown in Table 2 below.

Example number Inhibition rate (%) at 500 nM Example number Inhibition rate (%) at 500 nM 18n 66.2 27e 42.9 27f 63.5 44a 94.1 44b 87.8 44c 88.6 44d 80.9 44e 52.4 44f 40.7 44g 85.2 44h 87.1 44i 78.9 44j 76.7 44k 69.1 47c 94.1 50a 71.6 50b 88.0 50c 96.5 53b 45.7

Claims (18)

A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

here,
Y is

or

ego;
R ¹ and R ² are each independently halogen, C _1-5 alkyl, C _3-6 cycloalkyl, C _1-5 alkyloxy, C _6-10 aryl and C _1-5 substituted with one or more halogens. is selected from the group consisting of alkyl;
X is O, -CH ₂ -, NH and

It is selected from the group consisting of;
A is

or

is;
L ¹ and L ² do not exist independently of each other;

,

,

,

,

,

,

,

,

, and

It is selected from the group consisting of;
B does not exist, or

,

,

and

It is selected from the group consisting of;
C is a 5- to 6-membered saturated or unsaturated heterocyclyl containing at least two heteroatoms selected from the group consisting of N, O and S or a 5- to 6-membered heteroaryl;
wherein said heterocyclyl or heteroaryl is further substituted with a substituent selected from the group consisting of one or more amines, oxo, C _1-5 alkyl, C _1-5 alkyloxy and C _1-5 alkyl substituted with one or more halogens; is not substituted or substituted;
l, m and n are each independently an integer from 1 to 3;
However, if B does not exist, L ¹ is

and L ² is

am. delete delete According to claim 1,
Y is

ego;
R ¹ and R ² are each independently a compound selected from the group consisting of H, halogen, C _1-5 alkyl, C _1-5 alkoxy and C _1-5 alkyl substituted with one or more halogens, optical isomers thereof or a pharmaceutically acceptable salt thereof. According to claim 4,
Y is

ego;
R ¹ and R ² are each independently a compound selected from the group consisting of H, halogen, C _1-5 alkyl, C _1-5 alkoxy, and C _1-5 alkyl substituted with one or more halogens, optical isomers thereof or a pharmaceutically acceptable salt thereof. According to claim 1,
C is a 5-membered saturated or unsaturated heterocyclyl or 5-membered heteroaryl containing at least two heteroatoms selected from the group consisting of N, O and S;
The heterocyclyl or heteroaryl may or may not be further substituted with a C _1-5 alkyl or amine group, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. According to claim 6,
C is

,

,

,

and

A functional group selected from the group consisting of
The functional group may or may not be further substituted with amino or C _1-5 alkyl, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. According to claim 1,
L ¹ does not exist,
B is

or

is,
^L2 is

and

It is selected from the group consisting of
1 and m are each independently 1 or 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. According to claim 1,
Y is

ego;
R ¹ and R ² are each independently selected from the group consisting of halogen and C _1-5 alkyl;
n is 1;
X is O;
A is

or

is;
L ¹ does not exist,
B is

is,
^L2 is

and

It is selected from the group consisting of
1 and m are each independently 1 or 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein the compound represented by Formula 1 is any one compound selected from the group consisting of the following compounds, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
18a: 3,5-dichlorobenzyl 4-((4-(2-aminothiazol-5-yl)phenyl)amino)piperidine-1-carboxylate
18b: 3,5-dichlorobenzyl 4-((3-(2-aminothiazol-5-yl)phenyl)amino)piperidine-1-carboxylate
18c: 3,5-dichlorobenzyl 4-((4-(1-methyl-1H-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate
18d: 3,5-Dichlorobenzyl 4-((3-(1-methyl-1H-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate
18e: 3,5-dichlorobenzyl 4-((4-(1H-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate
18f: 3,5-dichlorobenzyl 4-((3-(1H-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate
18g: 3,5-dichlorobenzyl 4-((4-(2-methyl-1H-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate
18h: 3,5-dichlorobenzyl 4-((3-(2-methyl-1H-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate
18i: 3,5-dichlorobenzyl 4-((4-(4-methyl-1H-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate
18j: 3,5-dichlorobenzyl 4-((3-(4-methyl-1H-imidazol-5-yl)phenyl)amino)piperidine-1-carboxylate
18k: 3,5-dichlorobenzyl 4-((4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)amino)piperidin-1- carboxylate
18l: 3,5-dichlorobenzyl 4-((3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)amino)piperidin-1- carboxylate
18m: 3,5-dichlorobenzyl 4-((3-(2-methyloxazol-5-yl)phenyl)amino)piperidine-1-carboxylate
18n: 3,5-dichlorobenzyl 4-((3-(1H-1,2,3-triazol-5-yl)phenyl)amino)piperidine-1-carboxylate
27a: 3,5-dichlorobenzyl 4-((4-(2-aminothiazol-5-yl)phenyl)carbamoyl)piperidine-1-carboxylate
27b: 3,5-dichlorobenzyl 4-((3-(2-aminothiazol-5-yl)phenyl)carbamoyl)piperidine-1-carboxylate
27c: 3,5-dichlorobenzyl 4-((4-(1H-imidazol-5-yl)phenyl)carbamoyl)piperidine-1-carboxylate
27d: 3,5-dichlorobenzyl 4-((3-(1H-imidazol-5-yl)phenyl)carbamoyl)piperidine-1-carboxylate
27e: 3,5-dichlorobenzyl 4-(4-(1H-imidazol-5-yl)piperidine-1-carbonyl)piperidine-1-carboxylate
27f: 3,5-dichlorobenzyl 4-(4-(1H-1,2,3-triazol-5-yl)piperidine-1-carbonyl)piperidine-1-carboxylate
27g: 3,5-dichlorobenzyl 4-(4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidine-1-carbonyl)piperi Dean-1-carboxylate
27h: 3,5-dichlorobenzyl 4-((4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)carbamoyl)piperidin-1 -Carboxylate
27i: 3,5-dichlorobenzyl 4-((3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)carbamoyl)piperidine-1 -Carboxylate
33d: 3,5-dichlorobenzyl 4-(2-(4-(1H-imidazol-5-yl)phenoxy)ethyl)piperidine-1-carboxylate
33e: 3,5-dichlorobenzyl 4-((4-(1H-imidazol-5-yl)phenoxy)methyl)piperidine-1-carboxylate
33f: 3,5-dichlorobenzyl 4-(4-(1H-imidazol-5-yl)phenoxy)piperidine-1-carboxylate
33g: 3,5-dichlorobenzyl 4-((3-(1H-imidazol-5-yl)phenoxy)methyl)piperidine-1-carboxylate
33h: 3,5-dichlorobenzyl 4-(3-(1H-imidazol-5-yl)phenoxy)piperidine-1-carboxylate
33i: 3,5-dichlorobenzyl 4-((3-(2-methyl-1H-imidazol-5-yl)phenoxy)methyl)piperidine-1-carboxylate
33k: 3,5-dichlorobenzyl 4-(((4-(2-aminothiazol-5-yl)phenyl)amino)methyl)piperidine-1-carboxylate
33l: 3,5-dichlorobenzyl 4-(((3-(2-aminothiazol-5-yl)phenyl)amino)methyl)piperidine-1-carboxylate
33m: 3,5-Dichlorobenzyl 4-(((4-(1H-imidazol-5-yl)phenyl)amino)methyl)piperidine-1-carboxylate
33n: 3,5-dichlorobenzyl 4-(((3-(1H-imidazol-5-yl)phenyl)amino)methyl)piperidine-1-carboxylate
33o: 3,5-dichlorobenzyl 4-(((4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)amino)methyl)piperidine -1-carboxylate
33p: 3,5-dichlorobenzyl 4-(((3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl)amino)methyl)piperidine -1-carboxylate
44a: 3,5-dichlorobenzyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl) Piperidine-1-carboxylate
44b: 3,5-dibromobenzyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazole-2- 1) piperidine-1-carboxylate
44c: 3,5-bis(trifluoromethyl)benzyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadia zol-2-yl)piperidine-1-carboxylate
44d: 3,5-dimethylbenzyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl) Piperidine-1-carboxylate
44e: 3,5-dimethoxybenzyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl )piperidine-1-carboxylate
44f: 3,5-difluorobenzyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazole-2- 1) piperidine-1-carboxylate
44g: 3-bromo-5-methylbenzyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazole-2 -yl)piperidine-1-carboxylate
44h: 3-Bromo-5-chlorobenzyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazole-2 -yl)piperidine-1-carboxylate
44i: 3-chloro-5-fluorobenzyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazole-2 -yl)piperidine-1-carboxylate
44j: 2,5-dichlorobenzyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl) Piperidine-1-carboxylate
44k: 3,4-dichlorobenzyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl) Piperidine-1-carboxylate
44l: Benzo[d][1,3]dioxol-5-ylmethyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3, 4-oxadiazol-2-yl)piperidine-1-carboxylate
44m: 1-(4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidine -1-yl)-3-(3,5-dichlorophenyl)propan-1-one
44n: 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)-N-(3, 5-dichlorobenzyl)piperidine-1-carboxamide
47a: 3,5-dichlorobenzyl 4-(5-(((1H-tetrazol-5-yl)methyl)amino)-1,3,4-oxadiazol-2-yl)piperidin-1- carboxylate
47b: 3,5-dichlorobenzyl 4-(5-(((1-methyl-1H-1,2,3-triazol-4-yl)methyl)amino)-1,3,4-oxadiazole- 2-yl)piperidine-1-carboxylate
47c: 3,5-dichlorobenzyl 4-(5-(((4-methyl-1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-oxadiazole- 2-yl)piperidine-1-carboxylate
50a: 3,5-dichlorobenzyl 4-(5-(2-(1H-1,2,3-triazol-5-yl)ethyl)-1,3,4-thiadiazol-2-yl)pipette Razine-1-carboxylate
50b: 3,5-dichlorobenzyl 4-(5-(2-(1H-1,2,3-triazol-5-yl)ethyl)-1,3,4-oxadiazol-2-yl)pipette Razine-1-carboxylate
50c: 3,5-dichlorobenzyl 4-(5-(2-(1H-1,2,3-triazol-5-yl)ethyl)-1,3,4-oxadiazol-2-yl)p Peridine-1-carboxylate
53a: 3,5-dichlorobenzyl 4-(2-(((1H-1,2,3-triazol-5-yl)methyl)amino)thiazol-5-yl)piperazine-1-carboxylate
53b: 3,5-dichlorobenzyl 4-(5-(((1H-1,2,3-triazol-5-yl)methyl)amino)-1,3,4-thiadiazol-2-yl) Piperazine-1-carboxylate
58: 3,5-dichlorobenzyl 4-((4-((1H-1,2,3-triazol-4-yl)methoxy)phenyl)amino)piperidine-1-carboxylate
61: 3,5-dichlorobenzyl 4-(4-(((1H-1,2,3-triazol-4-yl)methyl)amino)phenyl)-[1,4′-bipiperidine]- 1'-carboxylates and
64: 3,5-dichlorobenzyl 4-(3-((1H-1,2,3-triazol-5-yl)methoxy)phenyl)-[1,4'-bipiperidine]-1' -carboxylates. delete delete A pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound according to claim 1 selected from the group consisting of myocardial and vascular fibrosis, renal fibrosis, liver fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma and cystic peritonitis A pharmaceutical composition for use in the treatment or prevention of a disease. 14. The pharmaceutical composition according to claim 13, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). 14. The pharmaceutical composition according to claim 13, wherein the pulmonary fibrosis is radiation-induced fibrosis.
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