RU2817736C1 - Novel compounds as histone deacetylase 6 inhibitor and pharmaceutical composition containing thereof - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention relates to a novel compound of Formula I having histone deacetylase 6 (HDAC6) inhibitory activity, stereoisomers thereof, pharmaceutically acceptable salts, a pharmaceutical composition, an inhibition method and use in preparing a medicinal agent.

where each X₁ - X₄ is independently CA or N; A is H or halogen; L is C1-C2 alkylene; R₁ is CF₂H or CF₃; B is (in this document Y₁ is CR₂ or each N, Y₂ and Y₃ is independently CR' or N and R' is H or C1-C5 alkyl) or (in this document Y₁ is O or NR₂); R₂ is H or C1-C5 alkyl, where in C1-C5 alkyl at least one H can be substituted with OH or N(C1-C5 alkyl)₂; R₃ is halogen; C1-C5 alkyl; (in this document, a, b and c independently represent 0, 1, 2 or 3, where a and b cannot be 0 at the same time, and Z₁ is CH₂, NH or O); C4-C6 cycloalkenyl; C6-C12 aryl; 5–9 membered heteroaryl including at least one heteroatom selected from N, O and S; (in this document, each a or b independently represents integer 1 or 2); ; (in this document, each a independently represents integer 0, 1 or 2); or pyridinone; at least one H of R₃ can each be independently substituted with halogen or -(CH₂)_n-Q1-Q2-Ra (in this document n equals 0 or 1); Q1 is a single bond, -SO₂-, -NH-, -N(C1-C5 alkyl)-, -NHC(=O)-, -N(C1-C5 alkyl)C(=O)- or -C(=O)-; Q2 is a single bond, C1-C5 alkylene, -NH- or -N(C1-C5 alkyl)-; Ra is OH; C1-C5 alkyl; C1-C5 haloalkyl; -NR₄R₅ (in this document, each R₄ and R₅ independently represents H or C1-C5 alkyl); C1-C5 alkoxy; (in this document, each a and b is independently 1 or 2, M₁ is CH₂, O, NH or SO₂ and M₂ is CH or N); (in this document, M₃ represents CH or N); diazabicycloheptane; or 5- or 6-membered heteroaryl, including 1–3 of N; and at least one H of Ra can each be independently substituted with OH; halogen; C1-C5 alkyl; (in this document, each a and b independently represents 0 or 1, but cannot be 0 at the same time, c equals 0 or 1, M₄ is CH₂, NH or O and at least one H of M₄ can be substituted with halogen, C1-C5 alkyl, C3-C6 cycloalkyl or -C(=O)-O(C1-C5 alkyl)); -NR₆R₇ (in this document, each R₆ and R₇ is independently H or C1-C5 alkyl); -C(=O)-(C1-C5 alkyl); C(=O)-O(C1-C5alkyl); or -NH-C(=O)-O(C1-C5 alkyl).

EFFECT: novel compounds having selective inhibitory activity on HDAC6 are obtained.

12 cl, 189 tbl, 591 ex

Description

Field of technology

The present invention relates to a new compound having histone deacetylase 6 (HDAC6) inhibitory activity, its stereoisomers, its pharmaceutically acceptable salts, its use in the preparation of a medicament, a pharmaceutical composition comprising it, a prophylactic or therapeutic method thereof, and a method for its preparation.

State of the art

In cells, post-translational modification such as acetylation serves as a very important regulatory module at the center of biological processes and is also tightly controlled by a number of enzymes. As the core protein that makes up chromatin, histone acts as an axis around which DNA is wound and thus promotes DNA condensation. In addition, the balance between histone acetylation and deacetylation plays a very important role in gene expression.

As an enzyme for removing the acetyl group from the lysine residue of histone protein that constitutes chromatin, histone deacetylase (HDAC) is known to be associated with gene silencing and causes cell cycle arrest, inhibition of angiogenesis, immunoregulation, apoptosis, etc. (Hassig et al. , Curr. Chem. 1997, 1, 300-308). In addition, inhibition of HDAC enzyme functions has been reported to induce cancer cells to commit self-apoptosis by reducing the activity of factors associated with cancer cell survival and activating factors associated with cancer cell death in the body (Warrell et al., J. Natl. Cancer Inst. 1998, 90, 1621-1625).

In humans, 18 HDACs are known, which are divided into four classes according to homology with yeast HDACs. In this case, the eleven HDACs using zinc as a cofactor can be divided into three groups: class I (HDAC1, 2, 3, 8), class II (IIa: HDAC4, 5, 7, 9; IIb: HDAC6, 10) and class IV (HDAC11). In addition, seven class III HDACs (SIRT 1-7) use NAD+ as a cofactor instead of zinc (Bolden et al., Nat. Rev. Drug Discov. 2006, 5(9), 769-784).

Various HDAC inhibitors are currently in preclinical or clinical development, but until now only non-selective HDAC inhibitors have been known as anticancer agents. Vorinostat (SAHA) and romidepsin (FK228) have received approval as therapeutic agents for cutaneous T-cell lymphoma, while panobinostat (LBH-589) has received approval as a therapeutic agent for the treatment of multiple myeloma. However, it is known that non-selective HDAC inhibitors usually cause side effects such as fatigue, nausea and the like at high doses (Piekarz et al., Pharmaceuticals 2010, 3, 2751-2767). Side effects are reported to be caused by class I HDAC inhibition. Due to side effects, etc., non-selective HDAC inhibitors have been subject to drug development restrictions in areas other than anti-cancer agents (Witt et al., Cancer Letters 277, (2009), 8-21).

Meanwhile, it is reported that selective inhibition of class II HDACs will not exhibit the toxicity that occurs with inhibition of class I HDACs. If selective HDAC inhibitors are developed, the side effects such as toxicity etc. caused by non-selective HDAC inhibition are likely to be eliminated. Accordingly, there is a possibility that selective HDAC inhibitors could be developed as effective therapeutic agents for the treatment of various diseases (Matthias et al., Mol. Cell. Biol. 2008, 28, 1688-1701).

It is known that HDAC6, one of the class IIb HDACs, is mainly present in the cytoplasm and contains the protein tubulin, thus involved in the deacetylation of a number of non-histone substrates (HSP90, cortactin, etc.) (Yao et al., Mol Cell 2005, 18 , 601-607). HDAC6 has two catalytic domains in which a zinc finger domain at the C-terminus can bind to the ubiquitinated protein. HDAC6 is known to have a number of non-histone proteins as substrates and thus plays an important role in various diseases such as cancer, inflammatory diseases, autoimmune diseases, neurological diseases, neurodegenerative disorders and the like (Santo et al., Blood 2012 119, 2579-2589; Vishwakarma et al., International Immunopharmacology 2013, 16, 72-78; Hu et al., J. Neurol. Sci. 2011, 304, 1-8).

A structural feature that is common to various HDAC inhibitors consists of a cap group, a linker group, and a zinc binding group (ZBG), as shown in the following structure of vorinostat. Many researchers have conducted research on the inhibitory activity and selectivity towards enzymes due to the structural modification of the cap group and linker group. From these groups, the zinc-binding group is known to play a more important role in the inhibitory activity and selectivity of the enzyme (Wiest et al., J. Org. Chem. 2013 78: 5051-5055; Methot et al., Bioorg, Med. Chem. Lett. 2008, 18, 973-978).

Most of this zinc-binding group consists of hydroxamic acid or benzamide, of which hydroxamic acid derivatives exhibit strong HDAC inhibitory effect but have problems of low bioavailability and serious off-target activity hazard. Benzamide contains aniline and thus has the problem that it can produce toxic metabolites in vivo (Woster et al., Med. Chem. Commun. 2015, online publication).

Accordingly, there is a need to develop a selective HDAC6 inhibitor for the treatment of cancer, inflammatory diseases, autoimmune diseases, neurological diseases, neurodegenerative disorders and the like, which has a zinc-binding group with improved bioavailability without causing side effects, unlike non-selective inhibitors. having side effects.

<Related Prior Art Links>

<Patent Documents>

International Patent Publication No. WO 2011/091213 (Published July 28, 2011): ACY-1215.

International Patent Publication No. WO 2011/011186 (published January 27, 2011): Tubastatin.

International Patent Publication No. WO 2013/052110 (Published April 11, 2013): Sloan-K

International Patent Publication No. WO 2013/041407 (published March 28, 2013): Cellzome

International Patent Publication No. WO 2013/134467 (published September 12, 2013): Kozi

International Patent Publication No. WO 2013/008162 (Published January 17, 2013): Novartis

International Patent Publication No. WO 2013/080120 (Published June 06, 2013): Novartis

International Patent Publication No. WO 2013/066835 (published May 10, 2013): Tempero

International Patent Publication No. WO 2013/066838 (published May 10, 2013): Tempero

International Patent Publication No. WO 2013/066833 (published May 10, 2013): Tempero

International Patent Publication No. WO 2013/066839 (published May 10, 2013): Tempero

Detailed Description of the Invention

Technical problem

An object of the present invention is to provide a compound having selective inhibitory activity against HDAC6, its stereoisomers or pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a pharmaceutical composition comprising a compound having selective HDAC6 inhibitory activity, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a method for its preparation.

Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of diseases associated with HDAC6 activity.

Another object of the present invention is to provide its use in the preparation of a medicament for the prevention or treatment of diseases associated with HDAC6 activity.

It is yet another object of the present invention to provide a method for preventing or treating diseases associated with HDAC6 activity, including administering a therapeutically effective amount of a compound.

Another object of the present invention is to provide its use for the prevention or treatment of diseases associated with HDAC6 activity.

Technical solution

The present inventors have discovered an oxadiazole derivative having histone deacetylase 6 (HDAC6) inhibitory activity and used it to inhibit or treat diseases associated with HDAC6 activity, thereby completing the present invention.

Hereinafter, the present invention will be described in more detail. In other words, all combinations of the various elements described in the present invention are included within the scope of the present invention. Moreover, the scope of the present invention is not intended to be limited to the specific description given below.

The compound represented by formula I

The present invention may provide the compound represented by Formula I below, stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[Formula I]

Where

each X ₁ - X ₄ independently represents CA or N;

A represents H or halogen;

L represents C1-C2 alkylene;

R ₁ represents CF ₂ H or CF ₃ ;

B represents (as used herein, Y ₁ is CR ₂ or N, Y ₂ and Y ₃ are each independently CR' or N, and R' is H or C1-C5 alkyl), or (herein, Y ₁ represents O or NR ₂ );

R ₂ represents H or C1-C5 alkyl, in which at least one H of the C1-C5 alkyl may be replaced by OH or N(C1-C5 alkyl) ₂ ;

R ₃ represents halogen; C1-C5 alkyl; C1-C5 haloalkyl; (herein, a, b and c independently represent 0, 1, 2 or 3, where a and b cannot be 0 at the same time, and Z ₁ represents CH ₂ , NH or O); C4-C6 cycloalkenyl; C6-C12 aryl; 5-9 membered heteroaryl, including at least one heteroatom selected from N, O and S; (herein, each a and b are independently an integer 1 or 2); ; (as used herein, a is an integer 0, 1 or 2); or pyridinone;

at least one H of R ₃ may each be independently substituted with halogen or -(CH ₂ ) _n -Q1-Q2-Ra (herein, n is 0 or 1);

Q1 is a single bond, -SO ₂ -, -NH-, -N(C1-C5 alkyl)-, -NHC(=O)-, -N(C1-C5 alkyl)C(=O)- or -C (=O)-;

Q2 represents a single bond, C1-C5 alkylene, -NH-, -(C1-C5 alkylene)-NH-C(=O)- or -N(C1-C5 alkyl)-;

Ra represents OH; C1-C5 alkyl; C1-C5 haloalkyl; -NR ₄ R ₅ (herein, each R ₄ and R ₅ independently represents H or C1-C5 alkyl); C1-C5 alkoxy; (herein, each a and b independently represents 1 or 2, M ₁ represents CH ₂ , O, NH or SO ₂ , and M ₂ represents CH or N); (herein, M ₃ represents CH or N); diazabicycloheptane; or 5- or 6-membered heteroaryl, including 1-3 of N; And

at least one H of Ra may each be independently substituted with OH; halogen; C1-C5 alkyl; (as used herein, a and b are each independently 0 or 1 but cannot be 0 at the same time, c is 0 or 1, M ₄ is CH ₂ , NH, or O, and at least one H of M ₄ may be substituted with halogen, C1-C5 alkyl, C3-C6 cycloalkyl or -C(=O)-O(C1-C5 alkyl)); C1-C6 haloalkyl; -NR ₆ R ₇ (herein, each R ₆ and R ₇ independently represents H or C1-C5 alkyl); -C(=O)-(C1-C5 alkyl); C(=O)-O(C1-C5 alkyl); or -NH-C(=O)-O(C1-C5 alkyl).

In one embodiment, the compound represented by Formula I above may include the compound represented by Formula II below:

[Formula II]

where X ₁ - X ₄ , L, R ₁ , R ₃ , and Y ₁ - Y ₃ from Formula I are as defined in Formula I.

In one embodiment, in the above Formula II,

each X ₁ - X ₄ independently represents CA or N;

A represents H or halogen;

L represents C1-C2 alkylene;

R ₁ represents CF ₂ H or CF ₃ ;

Y ₁ represents CH or N;

R ₃ represents phenyl; 6- or 9-membered heteroaryl including at least one heteroatom selected from N and O; or pyridinone;

at least one H of R ₃ may each be independently substituted with halogen or -(CH ₂ ) _n -Q1-Q2-Ra (herein, n is 0 or 1);

Q1 is a single bond, -NH-, -NHC(=O)- or -C(=O)-;

Q2 represents a single bond or -N(C1-C5 alkyl)-;

Ra represents C1-C5 alkyl; C1-C5 haloalkyl; -NR ₄ R ₅ (herein, each R ₄ and R ₅ independently represents H or C1-C5 alkyl); C1-C5 alkoxy; (herein, each a and b independently represents 1 or 2, M ₁ represents CH ₂ , O, NH or SO ₂ , and M ₂ represents CH or N); or (herein, M ₃ represents CH or N); And

at least one H of Ra may each be independently substituted with C1-C5 alkyl; (as used herein, a and b are each independently 0 or 1 but cannot be 0 at the same time, c is 0 or 1, M ₄ is CH ₂ , NH, or O, and at least one H of M ₄ may be substituted with halogen or C1-C5 alkyl); -NR ₆ R ₇ (herein, each R ₆ and R ₇ independently represents H or C1-C5 alkyl); or -NH-C(=O)-O(C1-C5 alkyl).

In one embodiment, in the above formula II,

each X ₁ - X ₄ independently represents CA or N;

A represents H or halogen;

L represents C1-C2 alkylene;

R ₁ represents CF ₂ H;

Y ₁ represents CH;

R ₃ represents phenyl; or 9-membered heteroaryl including at least one N;

at least one H of R ₃ may each be independently substituted with -(CH ₂ ) _n -Q1-Ra (herein, n is 0 or 1);

Q1 represents a single bond, NH or -NHC(=O)-;

Ra represents (herein, a and b are each independently 1 or 2, M ₁ is CH ₂ , O, or NH, and M ₂ is N) or C1-C5 haloalkyl; And

at least one H of Ra may each be independently substituted with C1-C5 alkyl.

In the present invention, "Cx-Cy" (herein, x and y are an integer equal to 1 or more) refers to the number of carbon atoms. For example, C1-C5 alkyl refers to alkyl having 1 or more and 5 or less carbon atoms, and C6-C12 aryl refers to aryl having 6 or more and 12 or less carbon atoms.

In the present invention, "halogen" refers to F, Cl, Br or I.

In the present invention, "alkyl" means a linear or branched saturated hydrocarbon group and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl etc.

In the present invention, "alkylene" means a divalent functional group derived from alkyl (including linear and branched) as defined above.

As used herein, “haloalkyl” means a functional group in which at least one alkyl H as defined above (including both straight and branched) is replaced with halogen. For example, haloalkyl may include -CF ₃ , -CF ₂ H or -CFH ₂ .

In the present invention, "cycloalkyl" may be a monocyclic cycloalkyl or a polycyclic cycloalkyl. The number of carbon atoms of the cycloalkyl may be 3 or more and 9 or less.

In the present invention, "heterocycloalkyl" may be a monocyclic heterocycloalkyl or a polycyclic heterocycloalkyl, and the heterocycloalkyl may be a 3-9 membered ring.

In the present invention, cycloalkyl or heterocycloalkyl may be represented by the general formula , or . An example of cycloalkyl may include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. An example of heterocycloalkyl may include, but is not limited to, oxidized propylene, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, piperidine, pyrrolidine, etc.

In the present invention, "aryl" refers to a monocyclic aromatic or polycyclic aromatic functional group consisting of only carbon and hydrogen, and the number of carbon atoms of the aryl may be 6 or more and 12 or less. An example of aryl may include, but is not limited to, phenyl, naphthyl, etc.

In the present invention, “heteroaryl” refers to a monocyclic or polycyclic heteroring in which at least one carbon of the monocyclic or polycyclic aromatic functional group is replaced by a heteroatom, and may be monocyclic or polycyclic. An example of a heteroatom may include nitrogen (N), oxygen (O), sulfur (S), etc. Heteroaryl may be a 5-10 membered ring or a 5-9 membered ring. When heteroaryl contains at least two heteroatoms, the two or more heteroatoms may be the same or different from each other. An example of a heteroaryl may include thiophene, benzothiophene, indazole, furan, benzofuran, indole, pyrazole, pyridine, imidazopyridine, pyrimidine, pyrrolopyridine, imidazole, benzoimidazole, thiazole, oxazole, oxadiazole, triazole, pyrizine, bipyridine, triazine, pyridazine, pyrazine, quinoline, quinazoline or isoquinoline, but is not limited to them.

In the present invention " " represents the connected part.

In the present invention, pharmaceutically acceptable salts may refer to salts commonly used in the pharmaceutical industry, for example, inorganic ion salts derived from calcium, potassium, sodium, magnesium or the like; salts of inorganic acids obtained from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, periodic acid, perchloric acid, sulfuric acid or the like; salts of organic acids obtained from acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid , glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc.; sulfonic acid salts derived from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene sulfonic acid or the like; amino acid salts obtained from glycine, arginine, lysine, etc.; amine salts obtained from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc.; and the like, but the types of salts contemplated in the present invention are not limited to the listed salts.

In the present invention, preferred salts may include hydrochloric acid, trifluoroacetic acid, citric acid, bromic acid, maleic acid, phosphoric acid, sulfuric acid, tartaric acid, etc.

As one example, a pharmaceutically acceptable salt of the present invention may be a salt of compound 3867 as described herein.

The compound represented by Formula I of the present invention may contain at least one asymmetric carbon and thus may be present as a racemate, a racemic mixture, a single enantiomer, a mixture of diastereomers and their respective diastereomers. Such isomers of the compound represented by formula I can themselves be separated by resolution in accordance with the prior art, for example, using column chromatography, HPLC or the like. Alternatively, the corresponding stereoisomers of the compound represented by Formula I can be stereospecifically synthesized with a known range of optically pure starting materials and/or reagents.

In the present invention, "stereoisomer" includes a diastereomer and an optical isomer (enantiomer), wherein the optical isomer includes not only an enantiomer, but also a mixture of an enantiomer and even a racemate.

The compound represented by Formula I of the present invention may be any one selected from the compounds shown in Table 1 below.

Table 1

Herein, the compound represented by the above formula I, its stereoisomers or pharmaceutically acceptable salts thereof may be selected from the group consisting of compounds 3825, 3826, 3838, 3839, 3840, 3841, 3843, 3845, 3944, 3962, 3986, 3987, 3988, 4072, 4075, 4108, 4109, 4110, 4111, 4112, 4134, 4186, 4187, 4233, 4340, 4343, 4344, 4345, 4346, 4347, 4348, 49, 4453, 4466, 4484, 4489, 4492, 4493, 4496, 4497, 4502, 4503, 4504, 4521, 4523, 4524, 4525, 4526, 4527, 4548, 4551, 4558, 4560, 4565, 4569, 4591, 92, 4609, 4610 and 17255.

Herein, the compound represented by the above formula I, its stereoisomers, or its pharmaceutically acceptable salts may be selected from the group consisting of compounds 3838, 3839, 3840, 3841, 3843, 3944, 3986, 3987, 4108, 4187, 4340, 4343, 4346, 4347, 4348, 4466, 4493, 4524, 4525, 4558, 4565 and 17255.

Method for preparing a compound of formula I

The preferred method for preparing the compound represented by the above formula I, its stereoisomers or pharmaceutically acceptable salts thereof is the same as shown in reaction formulas 1-19, and even the production method modified to a level obvious to those skilled in the art is also included into it.

Hereinafter, in the reaction formulas, symbols the same as in formula (I) but not specifically described are the same as those defined in formula (I), and the corresponding description is omitted. Additionally, in the reaction formulas, PG may represent an amine protecting group and may be, for example, tert-butyloxycarbonyl (Boc).

Moreover, in the reaction formulas, each Xa-Xc independently represents H, halogen, a C1-C5 alkyl group, or a C1-C5 haloalkyl group.

[Reaction formula 1]

According to the above reaction formula 1, compound 1-2 can be synthesized by replacing the halide portion of compound 1-1 with azide.

Compound 1-2 can be used in the synthesis of all compounds having a triazole backbone.

[Reaction formula 1-1]

According to the above reaction formula 1-1, compound 1-4 can be obtained by replacing the halide portion of compound 1-3 with azide. Compound 1-4 can be used in the synthesis of all compounds having a triazole backbone. In the above reaction formula 1-1, alkyl may be C1-C5 alkyl.

[Reaction formula 2]

The above reaction formula 2 can be the synthesis reaction of compound 2-3 having a triple bond, a precursor of a compound having a triazole structure, and can synthesize compound 2-3 having a triple bond by reacting the aldehyde of compound 2-1 with compound 2-2 in as a phosphonate reagent.

Compound 2-3 can be used in the synthesis of all compounds having a triazole backbone.

[Reaction formula 2-1]

Like reaction formula 2, the above reaction formula 2-1 may be the synthesis reaction of compound 2-3 including a triple bond, which is a precursor of a compound having a triazole structure. According to the above reaction formula 2-1, compound 2-3 having a triple bond can be synthesized using the aldehyde of compound 2-1 through the Corey-Fuchs reaction. Compound 2-3 can be used in the synthesis of all compounds having a triazole backbone.

[Reaction formula 3]

The above reaction formula 3 may be a method for synthesizing a compound having a triazole structure. According to the above reaction formula 3, compound 3-2 can be obtained by click reaction between formula 3-1 and compound 1-2.

The compound obtained according to the above reaction formula 3 may be compounds 3657, 3658, 3661, 3662, 3695, 3696, 3697, 3698, 3733, 3734, 3735, 3736, 3737, 3738, 3820, 3832, , 3832, 3833 , 3834, 3835, 3837, 3838, 3839, 3840, 3841, 3842, 3843, 3844, 3845, 3846, 3853, 3854, 3855, 3856, 3860, 3861, 3879, 3880, 3881, 3882, 3883, 3884, 3902 , 3925, 3960, 3985, 4071, 4072, 4073, 4074, 4075, 4076, 4077, 4078, 4079, 4080, 4081, 4082, 4135, 4178, 4179, 4180, 4181, 4182, 4183, 4184, 4185, 4284 , 4285, 4286, 4289, 4340, 4341, 4342, 4343, 4344, 4345, 4346, 4347, 4348, 4487, 4488, 4489, 4524, 4525, 4526, 4527, 16781, 16928, 16930, 17261, 17263, 17347 , 17983, 17984, 18256, 18258, 18305, 18470, 18736, 17198, 17201, 17848, 17851, 17854, 17857, 18918, 18919, 18920, 18921, 9058, etc.

[Reaction formula 3-1]

The above reaction formula 3-1 may be a reaction to prepare compound 3-1-3 through an amine substitution reaction between compound 3-1-1 and compound 3-1-2 prepared by substantially the same method as described in the above reaction formula Formula 3. At this time, in the above reaction formula 3-1, X may be F, Cl, etc., as a leaving group, and Ry may be OH; halogen; C1-C5 alkyl; ; C1-C6 haloalkyl; -NR ₆ R ₇ ; -C(=O)-(C1-C5 alkyl); C(=O)-O(C1-C5 alkyl); or -NH-C(=O)-O(C1-C5 alkyl). may mean heteroaryl including N, for example pyridinyl.

The compound obtained according to the above reaction formula 3-1 may be 4582, 4591, 4592, 4593, 4594, 4633, 4634, 4635, 4636, 16789, etc.

[Reaction formula 3-2]

In the above reaction formula 3-3, compound 3-1-5 can be prepared by an amine substitution reaction between compound 3-1-1 and compound 3-1-4 prepared by substantially the same method as described in the above reaction formula 3. After removal of the amine protecting group, compound 3-1-3 subjected to a reductive amination reaction is obtained using the compound Ry-H. In this case, in the above reaction formula 3-2, X, Ry and may be the same as defined in the above reaction formula 3-1.

As the compound 3-2-1 obtained according to the above reaction formula 3-2, compounds 4640, 17362, 17363, 17364, 17635, etc. can be represented.

[Reaction formula 3-3]

According to the above reaction formula 3-3, compound 3-1-6 can be obtained by a Suzuki reaction between compound 3-1-1 and boronic compound 3-2-1. In the above reaction formula 3-3, the A ring may be (herein, each a and b independently represents 1 or 2, M ₁ represents CH ₂ , O, NH or SO ₂ , and M ₂ represents CH or N); (herein, M ₃ represents CH or N); diazabicycloheptane; or 5- or 6-membered heteroaryl, including 1-3 of N.

The compound obtained according to the above reaction formula 3-2 may be compound 17058, etc.

[Reaction formula 4]

According to the above reaction formula 4, compound 4-2 can be prepared by a click reaction between compound 4-1 having a triple bond and compound 1-2. In the above reaction formula 4, W ₁ represents N-(C1-C5 alkyl) or O.

The compound obtained according to the above reaction formula 4 may be compounds 3866, 3867, 4104, 4105, 4106, 4107, 4336, 4337, 4338, 4339, etc.

[Reaction formula 5]

In the above reaction formula 5, a and b may each independently represent 1 or 2, Y may represent N or CH, and PG may represent C(=O)-O(C1-C5 alkyl), such as Boc. Rz may be OH; halogen; C1-C5 alkyl; (as used herein, a and b are each independently 0 or 1 but cannot be 0 at the same time, c is 0 or 1, M ₄ is CH ₂ , NH, or O, and at least one H of M ₄ may be substituted with halogen or C1-C5 alkyl); C1-C6 haloalkyl; -NR ₆ R ₇ (herein, each R ₄ and R ₅ independently represents H or C1-C5 alkyl); -C(=O)-(C1-C5 alkyl); C(=O)-O(C1-C5 alkyl); or -NH-C(=O)-O(C1-C5 alkyl). Rw may be C1-C5 alkyl.

According to the above reaction formula 5, compound 18868 can be obtained as compound 5-2 having a triazole structure through a click reaction between compound 5-1 including a triple bond obtained from reaction formula 2 or reaction formula 2-1, and connection 1-2.

Thereafter, the amine protecting group can be removed from compound 5-2 and subjected to a reductive amination reaction (to give compound 5-3), so as to obtain compounds 3988, 3989, 3990, 3991, 4070, 4368, 4369, 4370, 4371, 4373, 4374, 4375, 4376, 4460, 4461, 4462, 4502, 4503, 4504, 4505, 4506, 4507, 4508, 4509, 4510, 4511, 4528, 17698, 17699, 17700, 18869, 18870, 18871, 18924, 18926, etc. as a 5-4 compound.

Alternatively, according to the above reaction formula 5, compounds 4372 and 4377 can be obtained as compound 5-5 through the acylation reaction of compound 5-3.

[Reaction formula 5-1]

In the above reaction formula 5-1, a and b can each independently represent 1 or 2, Y can represent N or CH, and PG can represent C(=O)-O(C1-C5 alkyl), for example, Boc. In the above reaction formula 5-1, Rz may be halogen, C1-C5 alkyl, or C3-C6 cycloalkyl.

According to the above reaction formula 5-1, compound 18872 can be produced as compound 5-3-1 by a reductive amination reaction between compound 5-3 obtained according to reaction formula 5 and compound 8-2-1 having an amine protecting group.

Thereafter, the amine protecting group can be removed from compound 5-3-1 to obtain compound 5-3-2 and obtain compounds 18877 and 18878 as compound 5-3-3 by a reductive amination reaction.

[Reaction formula 6]

In the above reaction formula 6, a and b may each independently represent 1 or 2, and Rz may be the same as described in reaction formula 5 or reaction formula 5-1.

According to the above reaction formula 6, compound 6-2 wherein the aldehyde group of compound 6-1 is protected by an acetal group can be obtained, and compound 6-4 can be obtained by C-N coupling (Buchwald reaction) with compound 6-3. Thereafter, compound 6-5 having an aldehyde structure can be obtained by removing the acetal protecting group, and compound 6-7 having a triple bond can be obtained by carrying out a Corey-Fuchs reaction, and then compound 6-8 having a triazole structure can be obtained. can be prepared by a click reaction with compound 1-2. The amine protecting group (PG) of compound 6-8 can be removed to synthesize compounds 4316, 4317, 4396, 4397, 4398, 4399, 4439, 4440, 4450, 16797 and 18893, corresponding to compound 6-9. A reductive amination reaction can be carried out on compound 6-9 to produce compound 6-10.

Compounds 6-10 prepared according to the above reaction formula 6 may be compounds 4318, 4319, 4320, 4321, 4322, 4419, 4420, 4421, 4422, 4424, 4425, 4426, 4427, 4429, 4441, 4442 , 4443, 4444, 4451, 4452, 4453, 4454, 4455, 4483, 4484, 4485, 4486, 4569, 4570, 4571, 4572, 4573, 4576, 4577, 4578, 4579, 4580, 4600, 4601, 4602, 4603 , 18327, 18961, etc.

[Reaction formula 7]

In the above reaction formula 7, a and b may each independently be 1 or 2, n may be an integer of 0-5, and Rz and Rw may be the same as described in reaction formula 5.

According to the above reaction formula 7, compounds 3805, 3926, 3961, 3999, 4000, etc., can be obtained as compound 7-2 having a triazole structure through a click reaction between compound 7-1 having a triple bond, and connection 1-2. In addition, the amine protecting group can be removed from compound 7-2 to obtain compound 7-3 and subsequently obtain compound 7-4 by a reductive amination reaction.

Compounds 7-4 prepared according to the above reaction formula 7 may be compounds 3806, 3807, 3808, 3809, 3810, 3951, 3952, 3953, 3954, 3955, 4002, 4003, 4005, 4006, 4007, 4008, 4014 , 4026, 4027, etc.

In addition, compound 7-3 can be subjected to an acylation reaction or amidation reaction to obtain amide compound 7-5, for example, compounds 3811, 3812, 3813, 3891, 3892, 3893, 3894, 3956, 3957, 3958, 3959, 4004, 4009, 4015, 4028, 4029, etc.

[Reaction Formula 7-1]

In the above reaction formula 7-1, a and b can each independently represent 1 or 2, n can each represent an integer of 0-5, alkyl can represent C1-C5 alkyl, and R ₅ and R ₆ can each independently represent is an H, halogen or C1-C5 alkyl group.

According to the above reaction formula 7-1, compound 7-1-1 having a triazole structure can be prepared by click reaction between compound 7-1 and compound 1-4, after which the amine protecting group can be removed with acid to obtain compound 7 -1-2. After this, compound 7-1-4 can be prepared by reaction with compound 7-1-3, which is an oxirane compound, and compound 7-1-5 can be prepared by replacing the hydroxy group with fluoride, and then compound 7-1-6 can be obtained using hydrazine. Thereafter, compound 7-1-7 can be prepared by reaction with trifluoroacetic anhydride or difluoroacetic anhydride. The compound obtained by reaction formula 7-1 may be compounds 3895, 3896, etc.

[Reaction formula 8]

In the above reaction formula 8, a and b may each independently be 1 or 2, alkyl may be C1-C5 alkyl, and Rz may be the same as described in reaction formula 5.

According to the above reaction formula 8, compound 8-2 having a triazole structure can be obtained by click reaction between compound 8-1 having a triple bond and compound 1-4, after which compound 8-4 can be obtained by C-C coupling (reaction Suzuki) with compound 8-3 having a protecting group. Thereafter, compound 8-5 can be obtained by a reduction reaction, and compound 8-6 can be prepared using hydrazine and then reacted with trifluoroacetic anhydride or difluoroacetic anhydride to obtain compound 4001 as compound 8-7. After preparing compound 8-8 by removing the amine protecting group of compound 8-7, compound 8-9 can be prepared by a reductive amination reaction, and compounds 4010, 4011, 4012, 4013, 4290, 4291, 4292, 4293, 19087, etc. .d., as connection 8-9.

[Reaction Formula 8-1]

In the above reaction formula 8-1, alkyl may be a C1-C5 alkyl, and R ₈ and R ₉ may each independently be H, halogen or a C1-C5 alkyl group.

According to the above reaction formula 8-1, compound 8-1-1 can be obtained by removing the amine protecting group of compound 8-5 obtained according to reaction formula 8 with an acid, followed by reaction with compound 7-1-3, which is connecting the oxirane to give compound 8-1-2. After preparing compound 8-1-3 by replacing the hydroxyl group of compound 8-1-2 with fluoride, compound 8-1-4 can be prepared by using hydrazine, and then reacting with trifluoroacetic anhydride or difluoroacetic anhydride to obtain compound 8-1-5.

The compound obtained according to reaction formula 8-1 may be compounds 4349, 4350, etc.

[Reaction formula 8-2]

In the above reaction formula 8-2, R ₁₀ may be H, halogen or C1-C5 alkyl.

According to the above reaction formula 8-2, compound 8-2-2 can be produced by a reductive amination reaction between compound 8-8 obtained according to reaction formula 8 and compound 8-2-1 having an amine protecting group, and the amine protecting group can be removed to obtain compound 8-2-3 and subsequently obtain compound 8-2-4 by a reductive amination reaction.

The compound obtained by reaction formula 8-2 may be compounds 4294, 4295, 4296, etc.

[Reaction formula 9]

In the above reaction formula 9, R ₁₁ may be or , where H is a functional group, each may be independently substituted with OH; halogen; C1-C5 alkyl; C1-C6 haloalkyl, etc.

According to the above reaction formula 9, compound 9-2 having a triazole structure can be obtained by a click reaction between compound 9-1 and compound 1-2, after which compound 9-3 can be obtained by a reductive amination reaction.

The compound obtained according to the above reaction formula 9 may be compounds 3915, 3916, 3917, 3918, 3919, 3963, 3964, 3965, 3966, 4400, 4401, 4402, 4403, 4404, 4405, 4406, 7, 4408, 4409, 4410, 4411, 4412, 4413, 4414, 4415, 4416, 4417, 4418, 4466, 4467, 4468, 4469, 4470, 4471, 4472, 4473, 4474, 4475, 76, 4477, 4494, 4521, 4522, 4523, 4548, 4549, 4550, 4551, 4552, 4553, 4554, 4555, 4556, 4557, 4558, 4559, 4560, 4561, 4562, 4563, 4564, 4565, 4566, 67, 4583, 4585, 4586, 4587, 4588, 4589, 4590, 18058, 18306, 18307, 18308, 18457, 18459, 18822, 18823, 18882, 4604, 4605, 4606, 4607, 4608, 4609, 4611, etc.

[Reaction formula 9-1]

In the above reaction formula 9-1, the A ring may be C4-C6 cycloalkenyl; C6-C12 aryl; 5-9 membered heteroaryl including at least one heteroatom selected from N, O and S; (herein, each a or b is independently an integer 1 or 2); ; (as used herein, a is an integer 0, 1 or 2); or pyridinone. In this case, R ₁₁ may be halogen or -Q1-Q2-Ra. In addition, the X associated with the A ring may be F, Cl or Br.

According to the above reaction formula 9-1, compound 9-1-3 having a trimethylsilane protecting group can be obtained by C-C (Sonogashira) coupling between the halide of compound 9-1-1 and compound 9-1-2 having a triple bond, after whereby compound 9-1-4 having an aldehyde structure can be obtained by removing the trimethylsilane protecting group.

Compound 9-1-5 having a triazole structure can be prepared by a click reaction between compound 9-1-4 and compound 1-2, after which compound 9-1-6 can be prepared by a reductive amination reaction.

The compound obtained according to the above reaction formula 9-1 may be compounds 18059, 18309, 18310, 18311, 18483, 18554, 18622, 18711, 18712, 18713, 19088, 19089, 19090, 19091, 19092, 19093, 19094, 19096 , 19098, 19099, 19100, 17532, 17533, 17534, 17535, 17545, 17773, 17774, 17775, 17777, 17778, 17912, 17913, 17914, 17915, 7916, 17917, 17922, 18174, 18175, 18176, 18177, 18178 , 18180, 18185, 18187, 18188, 18260, 18947, 18948, 18949 and 18950.

[Reaction formula 10]

In the above reaction formula 10, a and b may each independently be 1 or 2, and W ₂ may be O, CH ₂ , CH(C1-C5 alkyl), NH or N-(C1-C5)alkyl.

In the above reaction formula 10, R ₄ and R ₅ can each independently represent H or C1-C5 alkyl, and at least one H can each independently represent (as used herein, a and b are each independently 0 or 1 but cannot be 0 at the same time, c is 0 or 1, M ₄ is CH ₂ , NH, or O, and at least one H of M ₄ may be substituted with halogen, C1-C5 alkyl, C3-C6 cycloalkyl or -C(=O)-O(C1-C5 alkyl), or -NR ₆ R ₇ (herein, each R ₆ and R ₇ independently represents H or C1-C5 alkyl).

According to the above reaction formula 10, compounds 3659, 3660, 3731, 3732 and 3739 can be obtained as compound 10-2 having a triazole structure by click reaction between compound 10-1 and compound 1-2.

Through the amide bond with compound 10-2, compounds 3829, 3885, 3886, 3887, 4448, 4482, etc. can be obtained as amide compound 10-3, and compounds 4449 and 4480 can be obtained as compound 10 -4.

[Reaction formula 11]

In the above reaction formula 11, each R ₄ and R ₅ independently may be H or C1-C5 alkyl, and at least one H each independently may be substituted with OH; halogen; etc.

According to the above reaction formula 11, compound 11-2 having a triazole structure can be prepared by click reaction between compound 11-1 and compound 1-2, followed by compounds 3774, 3824, 3827, 3828, 3830, 4323, 4324, 4325, 4326, 4330, 4331, 4332, 4431, 4432, 4433, 4434, 4435, 4436, 4437 and 4438 can be prepared as compound 11-3 by a reductive amination reaction.

Compound 11-2 can be subjected to an acylation reaction and an amidation reaction to give compounds 3775, 3776, 3777, 3825, 3826, 3987, 4229, 4230, 4231, 4327, 4328, 4329, 4333, 4334, 4351, , 4352, 4353 etc., as connection 11-4.

[Reaction formula 11-1]

In the above reaction formula 11-1, R ₁₂ may represent OH; halogen; C1-C5 alkyl; ; C1-C6 haloalkyl; -NR ₆ R ₇ (herein, each R ₆ and R ₇ independently can be H or C1-C5 alkyl); -C(=O)-(C1-C5 alkyl); C(=O)-O(C1-C5 alkyl); or -NH-C(=O)-O(C1-C5 alkyl).

According to reaction formula 11-1, after preparing compound 11-4 which forms an amide bond between compound 11-2 obtained according to reaction formula 11 and compound 11-3 having an amine protecting group, compound 4463 can be obtained as compound 11 -5 by removing the amine protecting group.

Compound 11-5 can be subjected to a reductive amination reaction to produce compounds 4464 and 4465 as compound 11-6.

[Reaction formula 11-2]

In the above reaction formula 11-2, n may be 1 or 2.

According to the above reaction formula 11-2, compounds 4495 and 4496 can be obtained as compound 11-2-2, which forms an amide bond between compound 11-2 obtained according to reaction formula 11 and compound 11-2-1 having amine protecting group. Thereafter, the amine protecting group can be removed to provide compounds 4497 and 4498 as compound 11-2-3.

[Reaction formula 11-3]

According to the above reaction formula 11-3, compound 3741 having the structure of compound 11-3-2 having a triazole structure can be produced by a click reaction between compound 11-3-1 having an amine protecting group and compound 1-2. Thereafter, the amine protecting group can be removed to obtain compound 11-2, and then compound 11-3-3 is obtained by a reductive amination reaction.

[Reaction formula 11-4]

In the above reaction formula 11-4, Rx may be C1-C5 alkyl or C1-C5 alkoxy.

According to the above reaction formula 11-4, compound 11-1 having a triple bond can be subjected to a reductive amination reaction to obtain compound 11-4-1, and to obtain compound 11-4-2 having a triazole structure by click reaction with connection 1-2. Thereafter, compounds 3889 and 3890 can be prepared as compound 11-4-3 by acylation reaction.

[Reaction formula 12]

In the above reaction formula 12, R ₁₃ may be -Q1-Q2-Ra.

According to the above reaction formula 12, compound 12-1 having an aldehyde structure can be subjected to Mannich reaction to obtain compound 12-2, after which compound 12-3 having a triple bond structure can be synthesized with compound 2-2 which is a phosphonate reagent. Thereafter, compounds 3944, 3962, 3986, 4108, 4109, 4110, 4111, 4112, 4134, 4492, 4493 and 17255 can be prepared as compound 12-4 having a triazole structure by click reaction with compound 1-2.

[Reaction formula 12-1]

In the above reaction formula 12-1, R ₁₃ may be -(CH ₂ ) _n -Q1-Q2-Ra (herein, n is 0 or 1).

According to the above reaction formula 12-1, compound 12-1 having an aldehyde structure can be subjected to a reductive amination reaction to obtain compound 12-1-1, after which compound 12-1-2 having a triple bond structure can be synthesized with compound 2-2, which is a phosphonate reagent. Thereafter, compounds 3914 and 4136 can be prepared as compound 12-1-3 having a triazole structure by click reaction with compound 1-2.

[Reaction formula 12-2]

According to the above reaction formula 12-2, compound 12-2-2 having a triazole structure can be obtained by click reaction between compound 12-2-1 obtained according to reaction formula 2 and compound 1-2, then compounds 4023, 4186 and 4187 can be prepared as compound 12-2-4 by the Mannich reaction with compound 12-2-3.

[Reaction formula 12-3]

According to the above reaction formula 12-3, compound 12-3-1 can be subjected to Pd(II)-catalyzed indole synthesis to produce compound 12-3-2, and compound 12-3-3 having an alcohol structure is produced by a reduction reaction . Then, compound 12-3-4 having an aldehyde structure can be produced by an oxidation reaction, and compound 12-3-5 having a triple bond structure can be produced with compound 2-2, which is a phosphonate reagent. Thereafter, compounds 4287 and 4288 can be prepared as compound 12-3-6, having a triazole structure, by click reaction with compounds 1-2, which are 1,3,4-oxadiazole.

[Reaction formula 13]

In the above reaction formula 13, n may be 1 or 2, alkyl may be C1-C5 alkyl, and _R13 may be -( _CH2 ) _n -Q1-Q2-Ra (herein, n is 0 or 1).

According to the above reaction formula 13, compound 13-2 having a triazole structure can be obtained by a click reaction between compound 13-1 obtained according to reaction formula 2 and compound 1-4, after which compound 13-3 can be prepared using hydrazine and then reacted with trifluoroacetic anhydride or difluoroacetic anhydride to obtain compound 13-4. Thereafter, the amine protecting group can be removed to obtain compound 4539 as compound 13-5, and then compound 13-6 is obtained by a reductive amination reaction.

The compound obtained according to the above reaction formula 13 may be compounds 4051, 4052, 4053, 4054, 4055, 4209, 4210, 4211, 4212, 4213, 4358, 4359, 4360, 4361, 4362, 4363, 4, 4365, 4366 , 4367, 4513, 4515, 4516, 4517, 4518, 4519, 4529, 4530, 4531, 4532, 4533, 4534, 4535, 4536, 4537, 4538, 4540, 4541, 4542, 4543, 4595, 4596, 4597, 4598 , 4599, 17458, 17460, 19002, 19004, etc.

[Reaction formula 13-1]

In the above reaction formula 13-1, R ₁₄ may represent OH; halogen; C1-C5 alkyl; ; C1-C6 haloalkyl; -NR ₆ R ₇ ; -C(=O)-(C1-C5 alkyl); C(=O)-O(C1-C5 alkyl); or -NH-C(=O)-O(C1-C5 alkyl).

According to the above reaction formula 13-1, compound 13-4 having a triazole structure can be prepared by a click reaction between compound 13-1 obtained according to reaction formula 2 and compound 1-2, after which the amine protecting group can be removed to obtain compound 13-5. Thereafter, compound 13-1-1 can be produced by a reductive amination reaction with compound 8-2-1 having an amine protecting group, and the amine protecting group can be removed to obtain compound 13-1-2, and then compound 13-1 is obtained -3 reductive amination reaction.

The compound obtained according to the above reaction formula 13-1 may be compounds 4392, 4393, 4394, 4395, etc.

[Reaction formula 14]

In the above reaction formula 14, R ₁₃ may be -(CH ₂ ) _n -Q1-Q2-Ra (herein, n is 0 or 1).

According to the above reaction formula 14, compound 14-2 having a triazole structure can be obtained by a click reaction between compound 14-1 having an amine protecting group obtained according to reaction formula 2-1 and compound 1-2, after whereby the amine protecting group can be removed to obtain compound 4499 as compound 14-3. Thereafter, compounds 4500, 4501, etc., can be prepared as compound 14-4 by a reductive amination reaction.

[Reaction formula 15]

According to the above reaction formula 15, compound 15-2 having a triazole structure can be prepared by a click reaction between compound 15-1 having a triple bond and compound 1-2. The compounds prepared according to the above reaction formula may be 4276, 4277, 4278 and 4279. Thereafter, the hydroxyl group of compound 15-2 can be replaced with fluoride to give compounds 4280, 4281, 4282 and 4283 having the structure of compound 15-3 .

[Reaction formula 16]

In the above reaction formula 16, R ₂ ' may represent H, C1-C5 alkyl, OH or N(C1-C5 alkyl) ₂ .

According to the above reaction formula 16, compound 16-2 having a triazole structure can be prepared by a click reaction between the aldehyde compound 16-1 having a triple bond and compound 1-2, after which compound 16-3 can be prepared by a reduction reaction and the reductive amination reaction.

The compound obtained according to the above reaction formula 16 may be compounds 4478, 4479, 4490 and 4491.

[Reaction formula 17]

According to the above reaction formula 17, compound 3949 can be obtained as compound 17-2 by a substitution reaction between compound 17-1 and compound 1-1. After this, compound 17-4 can be prepared by C-C coupling (Suzuki reaction) with compound 17-3.

The compound obtained according to the above reaction formula 17 may be compounds 3945, 3950, 4133, 4208, etc.

[Reaction formula 18]

In the above reaction formula 18, alkyl may be C1-C5 alkyl.

According to the above reaction formula 18, compound 18-1 can be used to obtain compound 18-2 as a tetrazole, and compound 18-3 can be obtained by a substitution reaction with compound 1-3 under basic conditions. Thereafter, compound 18-4 can be prepared using hydrazine, and then reacted with trifluoroacetic anhydride or difluoroacetic anhydride to obtain compound 18-5.

The compound obtained according to the above reaction formula 18 may be compounds 4232, 4233, 4234, 4235, etc.

[Reaction formula 19]

In the above reaction formula 19, alkyl may be C1-C5 alkyl.

According to the above reaction formula 19, compound 19-3 can be prepared by reacting the amide bond between compound 19-1 and compound 19-2, and then reacting with 1-methoxy-N-triethylammoniosulfonylmethanimidate (Burgess reagent) to obtain compound 19-4, having an oxadiazole structure. Thereafter, compound 19-5 can be prepared using hydrazine, followed by reaction with trifluoroacetic anhydride or difluoroacetic anhydride to obtain compound 3980 as compound 19-6.

Additionally, compound 19-4 can be reacted with methylamine (2.0 M in THF) to give compound 19-7, after which compound 19-8 can be prepared using hydrazine and then reacted with trifluoroacetic anhydride or difluoroacetic anhydride to obtain compound 3981 as compound 19-9.

Composition comprising a compound represented by Formula I, its use and a therapeutic method using it

The present invention can provide a pharmaceutical composition comprising the compound represented by the above formula I, stereoisomers thereof, or pharmaceutically acceptable salts thereof, as an effective ingredient.

In addition, the present invention can provide a pharmaceutical composition for the prevention or treatment of diseases associated with the activity of histone deacetylase 6, including the compound represented by the above formula I, stereoisomers thereof or pharmaceutically acceptable salts thereof as an effective ingredient.

The pharmaceutical composition of the present invention can selectively inhibit histone deacetylase 6, thereby showing a remarkable effect in the prevention or treatment of diseases associated with histone deacetylase 6 activity.

Diseases associated with histone deacetylase 6 activity may include cancer, inflammatory disease, autoimmune disease, neurological or degenerative neurological disease, particularly lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, brain cancer, cancer ovarian, stomach cancer, skin cancer, pancreatic cancer, glioma, glioblastoma carcinoma, leukemia, lymphoma, multiple myeloma, solid cancer, Wilson's disease, spinocerebellar ataxia, prion disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, amyloidosis, Alzheimer's disease, alcoholic liver disease, spinal muscular atrophy, rheumatoid arthritis or osteoarthritis, in addition to symptoms or diseases associated with abnormal histone deacetylase functions.

Examples of diseases mediated by histone deacetylase include infectious diseases, neoplasms, endocrinopathies, nutritional and metabolic disorders, mental and behavioral disorders, neurological diseases, diseases of the eyes and ocular appendages, diseases of the circulatory system, respiratory diseases, digestive problems, diseases of the skin and subcutaneous tissue. fiber, diseases of the musculoskeletal system and connective tissue or teratosis, deformations and chromosomal aberrations.

The endocrinopathy, nutritional and metabolic disease may be Wilson's disease, amyloidosis or diabetes, the mental and behavioral disorder may be depression or Rett syndrome, and the neurological disease may be central nervous system atrophy, neurodegenerative disease, movement disorder, neuropathy, motor neuron disease or demyelinating disease of the central nervous system, disease of the eyes and ocular appendages may be uveitis, disease of the skin and subcutaneous tissue may be psoriasis, musculoskeletal and connective tissue disease may be rheumatoid arthritis, osteoarthritis or systemic lupus erythematosus, teratosis, deformities and the chromosomal aberration may be autosomal dominant polycystic kidney disease, the infectious disease may be a prion disease, the neoplasm may be a benign tumor or a malignant tumor, the circulatory disease may be atrial fibrillation or stroke, the respiratory disease may be asthma, and the disease digestive problems may be alcoholic liver disease, inflammatory bowel disease, Crohn's disease, or peptic ulcer disease.

Said pharmaceutically acceptable salts are the same as those described for the pharmaceutically acceptable salts of the compound represented by Formula I of the present invention.

For administration, the pharmaceutical composition of the present invention may further contain at least one type of pharmaceutically acceptable carrier in addition to the compound represented by the above formula I, stereoisomers thereof, or pharmaceutically acceptable salts thereof. In this case, the pharmaceutically acceptable carrier used may include saline, sterilized water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerin, ethanol and a mixture of at least one ingredient, and with the addition of other conventional additives such as antioxidants , buffer solutions, bacteriostatic agents, etc., if necessary. In addition, diluents, dispersants, surfactants, binders and lubricants may be added to formulate injectable dosage forms such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules or tablets. Thus, the composition of the present invention can be in the form of patches, liquid drugs, pills, capsules, granules, tablets, suppositories, etc. The preparations can be prepared in accordance with a conventional method used for formulation in the art, or a method described in Remington's Pharmaceutical Science (latest edition), Merck Publishing Company, Easton PA, and the composition may be formulated into different preparations depending on each disease or component.

The composition of the present invention can be administered orally or parenterally (for example, administered intravenously, subcutaneously, intraperitoneally or topically) in accordance with a targeted method in which its dose varies within a certain range depending on the body weight, age, gender of the patient, health status and diet , time of administration, route of administration, rate of elimination, severity of the disease and the like. The daily dose of the compound represented by Formula I of the present invention may be from about 1 to 1000 mg/kg, preferably from 5 to 100 mg/kg, and can be administered once a day or several times a day in divided daily doses of the compound .

Said pharmaceutical composition of the present invention may further contain at least one effective component that exhibits the same or similar medical effect, in addition to the compound represented by the above formula I, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

The present invention may provide a method for preventing or treating diseases associated with the activity of histone deacetylase 6, comprising the step of administering a therapeutically effective amount of a compound represented by the above formula I, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

As used herein, the term “therapeutically effective amount” may refer to an amount of a compound represented by Formula I above that is effective for the prevention or treatment of diseases associated with histone deacetylase 6 activity.

In addition, the present invention may provide a method for selectively inhibiting HDAC6 by administering a compound represented by Formula I above, stereoisomers thereof, or pharmaceutically acceptable salts thereof to mammals, including humans.

The method of preventing or treating diseases associated with the activity of histone deacetylase 6 according to the present invention may include not only combating the diseases themselves before symptoms appear, but also inhibiting or avoiding such symptoms by administering a compound represented by the above formula I. In treating the disease, prophylactic or the therapeutic dose of a particular active ingredient may vary depending on the nature and severity of the disease or condition and the route of administration of the active ingredient. The dose and frequency of administration may vary depending on the age, body weight and response of the individual patient. Those skilled in the art can readily select the appropriate dosage and use, taking into account such factors, of course. In addition, the method of preventing or treating diseases associated with histone deacetylase 6 activity of the present invention may further comprise administering a therapeutically effective amount of an additional active agent useful in treating the diseases together with a compound represented by the above Formula I, wherein the additional active agent may exhibit a synergistic effect or adjuvant effect together with a compound of the above formula I.

The present invention may also be directed to the use of a compound represented by the above formula I, its stereoisomers or pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment of diseases associated with the activity of histone deacetylase 6. The compound represented by the above formula I for the preparation of a medicament may be combined with a suitable adjuvant, diluent, carrier, etc., and may be formulated as a complex agent together with other active agents, thereby having a synergistic effect of the active components.

The matters mentioned in the use, composition and therapeutic method of the present invention apply equally if not inconsistent with each other.

Beneficial Effects

According to the present invention, the compound represented by the above formula I, stereoisomers thereof or pharmaceutically acceptable salts thereof can selectively inhibit HDAC6, thereby having an extremely excellent effect in preventing or treating diseases associated with histone deacetylase 6 activity.

Method for carrying out the invention

Hereinafter, the present invention will be described in detail with the help of preferred examples for a better understanding of the present invention. However, the following examples are presented for the purpose of illustrating the present invention only, and thus the present invention is not limited to them.

The following reagents and solvents were purchased from Sigma-Aldrich, TCI unless otherwise noted, and Waters e2695 was used for HPLC, and Merck (230-400 mesh) was used for silica gel column chromatography. ¹ H NMR data were measured using a Bruker 400 MHz and the mass spectrum was measured on an Agilent 1100 series.

Example 1: Synthesis of Compound 3657, 2-(difluoromethyl)-5-(4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole

2-(4-(Bromomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (1.500 g, 5.189 mmol) and sodium azide (0.405 g, 6.227 mmol) were dissolved in N,N-dimethylformamide (15 ml) at room temperature, after which the resulting solution was stirred at 40°C for 18 hours, and then the reaction was completed by lowering the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.950 g, 72.9%) in the form of a colorless oil.

[Stage 2] Synthesis of compound 3657

2-(4-(Azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.080 g, 0.318 mmol) obtained in step 1 was dissolved in tert-butanol (1 ml)/water (1 ml) at room temperature, after which ethynylbenzene (0.035 ml, 0.318 mmol) was added to the resulting solution and stirred at the same temperature. Sodium ascorbate (1.00 M solution, 0.032 mL, 0.032 mmol) and copper(II) sulfate pentahydrate (0.001 g, 0.003 mmol) were added to the reaction mixture and then stirred at the same temperature for 18 hours. Water is poured into the reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=10-50%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-phenyl-1H-1,2,3 -triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.070 g, 62.2%) as a white solid.

¹ H NMR(700 MHz, CD₃OD) δ 8.44 (s, 1H), 8.19-8.15 (m, 2H), 7.86-7.82 (m, 2H), 7.64-7.60 (m, 2H) , 7.48-7.42 (m, 2H), 7.39-7.34 (m, 1H), 7.23 (t,J=51.6 Hz, 1H), 5.80 (s, 2H);MCNR(ER) m/z 354.2 (M⁺+1).

Example 2: Synthesis of Compound 3658, 2-(difluoromethyl)-5-(3-fluoro-4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3 ,4-oxadiazole

[Step 1] Synthesis of 2-(4-(azidomethyl)fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole

2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (1.500 g, 4.885 mmol) and sodium azide (0.381 g, 5.862 mmol) are dissolved in N, N- dimethylformamide (15 ml) at room temperature, after which the resulting solution was stirred at 40°C for 18 hours, and then the reaction was completed by lowering the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3. 4-oxadiazole (0.930 g, 70.7%) in the form of a colorless oil.

[Stage 2] Synthesis of compound 3658

2-(4-(Azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.080 g, 0.297 mmol) obtained in step 1 was dissolved in tert-butanol (1 ml)/ water (1 ml) at room temperature, after which ethynylbenzene (0.033 ml, 0.297 mmol) was added to the resulting solution and stirred at the same temperature. Sodium ascorbate (1.00 M solution, 0.030 ml, 0.030 mmol) and copper(II) sulfate pentahydrate (0.001 g, 0.003 mmol) were added to the reaction mixture and then stirred at the same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=10-50%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-phenyl-1H-1 ,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.065 g, 58.9%) as a white solid.

¹ H NMR(700 MHz, CD₃OD) δ 8.45 (s, 1H), 8.00 (dd,J=8.0, 1.7 Hz, 1H), 7.97 (dd,J=10.1, 1.7 Hz, 1H), 7.88-7.82 (m, 2H), 7.61 (t,J=7.7 Hz, 1H), 7.48-7.43 (m, 2H), 7.37 (ddt,J=7.9, 6.9, 1.3 Hz, 2H), 7.24 (t,J=51.6 Hz, 1H), 5.86 (s, 2H);MCNR(ER) m/z 372.3 (M⁺+1).

Example 16: Synthesis of Compound 3736, 2-(difluoromethyl)-5-(6-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3 ,4-oxadiazole

[Step 1] Synthesis of 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (1.000 g, 3.447 mmol) was dissolved in N,N-dimethylformamide (10 ml) at room temperature, after which sodium azide (0.224 g, 3.447 mmol) was added to the resulting solution and stirred at 40°C for 2 hours, and then the reaction was completed by lowering the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3 ,4-oxadiazole (0.800 g, 92.0%) as a yellow solid.

[Step 2] Synthesis of compound 3736

2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.198 mmol) obtained in step 1, dissolved in tert-butanol (1 ml) /water (1 ml) at room temperature, after which ethynylbenzene (0.022 ml, 0.198 mmol) was added to the resulting solution and stirred at the same temperature. Sodium ascorbate (1.00 M solution, 0.020 mL, 0.020 mmol) and copper(II) sulfate pentahydrate (0.50 M solution, 0.004 mL, 0.002 mmol) were added to the reaction mixture and then stirred at the same temperature for 18 hours . Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-phenyl-1H-1,2,3 -triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.035 g, 49.8%) as a white solid.

¹ H NMR(400 MHz, CDCl₃) δ 9.31 (d,J=1.8 Hz, 1H), 8.41 (dt,J=8.1, 1.8 Hz, 1H), 8.03 (d,J=1.4 Hz, 1H), 7.81 (dt,J=8.1, 1.3 Hz, 2H), 7.48-7.35 (m, 4H), 7.33 (d,J=8.2 Hz, 1H), 6.95 (t,J=51.6, 1.4 Hz, 1H), 5.81 (d,J=1.5 Hz, 2H);MCNR(ER) m/z 356.1 (M⁺+1).

Example 21: Synthesis of compound 3774 , 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol- 4-yl)-N,N-dimethylaniline

[Step 1] Synthesis of 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4- yl)aniline

2-(4-(Azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.200 g, 0.743 mmol) obtained in step 1 of example 2 was dissolved in tert-butanol (1 ml )/water (1 ml) at room temperature, after which 3-ethynylaniline (0.087 g, 0.743 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution is poured into the reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=0-40%) and concentrated to give 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2 -yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)aniline (0.198 g, 69.0%) in the form of a beige solid.

[Step 2] Synthesis of compound 3774

3-(1-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)aniline (0.030 g, 0.078 mmol) obtained in step 1, and formaldehyde (37.00%, 0.063 g, 0.777 mmol) was dissolved in acetonitrile (1 ml)/acetic acid (0.01 ml), after which the resulting solution was stirred at room temperature for 0.5 hour, and then sodium cyanoborohydride (0.015 g, 0.233 mmol) was added thereto and then stirred at the same temperature for 1 hour. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazole-2 -yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylaniline (0.020 g, 62.2%) in the form of a light yellow oil.

¹ H NMR(400 MHz, CD₃OD) δ 8.40 (s, 1H), 8.02-7.92 (m, 2H), 7.59 (t,J=7.7 Hz, 1H), 7.30-7.24 (m, 2H), 7.24 (t,J=51.6 Hz, 1H), 7.13 (dt,J=7.6, 1.2 Hz, 1H), 6.79 (ddd,J=8.4, 2.7, 0.9 Hz, 1H), 5.84 (s, 2H), 3.00 (s, 6H);MCNR(ER) m/z 415.3 (M⁺+1).

The compounds of Table 3 were synthesized according to substantially the same method as described above for the synthesis of compound 3774 except for the use of 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl )-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)aniline and the reagent from Table 2.

table 2 Example Connection no. Reagent Exit (%) 232 4330 Cyclohexanone 69 233 4331 Tetrahydro-4H-pyran-4-one 67 234 4332 Oxetan-3-one 52

Table 3 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 232 4330 N-cyclohexyl-3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl )aniline
¹ H NMR (400 MHz, CD ₃ OD) δ 8.34 (s, 1H), 8.02-7.92 (m, 2H), 7.58 (t, J=7.7 Hz, 1H), 7.38-7.09 (m, 3H), 7.03 (dt, J=7.7, 1.2 Hz, 1H), 6.64 (ddd, J=8.2, 2.5, 1 .0 Hz, 1H), 5.83 (s, 2H), 2.07 (d, J=12.6 Hz, 2H), 1.81 (dt, J=13.3, 3.7 Hz, 2H ), 1.74-1.64 (m, 1H), 1.51-1.36 (m, 2H), 1.34-1.14 (m, 4H); MSNR (IER) m/z 469.5 (M ⁺ + H). 233 4331 N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) phenyl)tetrahydro-2H-pyran-4-amine
¹ H NMR (400 MHz, CD ₃ OD) δ 8.36 (s, 1H), 8.02-7.92 (m, 2H), 7.58 (t, J=7.7 Hz, 1H), 7.24 (t, J=51.6 Hz, 1H), 7.20-7.14 (m, 2H), 7.05 (dt, J=7.8, 1.1 Hz, 1H), 6 .68 (ddd, J=8.3, 2.4, 1.0 Hz, 1H), 5.84 (s, 2H), 3.99 (dt, J=11.9, 3.5 Hz, 2H ), 3.64-3.52 (m, 3H), 2.07-1.99 (m, 2H), 1.58-1.43 (m, 2H); MSNR (IER) m/z 471.5 (M ⁺ + H). 234 4332 N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) phenyl)oxetan-3-amine
¹ H NMR (400 MHz, CD ₃ OD) δ 8.37 (s, 1H), 8.02-7.92 (m, 2H), 7.59 (t, J=7.6 Hz, 1H), 7.37-7.10 (m, 3H), 7.01 (t, J=2.0 Hz, 1H), 6.56 (ddd, J=8.1, 2.4, 1.0 Hz, 1H), 5.84 (s, 2H), 5.03 (t, J=6.6 Hz, 2H), 4.70 (p, J=6.5 Hz, 1H), 4.58 (t, J=6.1 Hz, 2H); MSNR (IER) m/z 443.5 (M ⁺ + H).

Example 22: Synthesis of compound 3775 , N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3 -triazol-4-yl)phenyl)acetamide

3-(1-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)aniline (0.030 g, 0.078 mmol) obtained in step 1 of Example 21, and triethylamine (0.013 ml, 0.093 mmol) was dissolved in dichloromethane (1 ml) at room temperature, after which acetyl chloride (0.006 ml, 0.078 mmol) was added to the resulting solution and stirred at the same temperature for 1 hour. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give N-(3-(1-(4-(5-(difluoromethyl)-1,3,4- Oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)acetamide (0.022 g, 66.1%) as a white solid.

¹ H NMR(400 MHz, CD₃OD) δ 8.42 (s, 1H), 8.05 (s, 1H), 8.02-7.93 (m, 2H), 7.58 (dt,J=17.6, 8.6 Hz, 3H), 7.40 (t,J=7.9 Hz, 1H), 7.24 (t,J=51.6 Hz, 1H), 5.88-5.84 (m, 2H), 2.16 (s, 3H);MCNR(ER) m/z 429.2 (M⁺+1).

The compounds of Table 5 were synthesized according to substantially the same method as described above for the synthesis of compound 3775 except for the use of 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl )-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)aniline and the reagent from Table 4.

Table 4 Example Connection no. Reagent Exit (%) 23 3776 Methyl chloroformate 66 24 3777 Trifluoroacetic anhydride 72 235 4333 Trimethylacetyl chloride 82

Table 5 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 23 3776 Methyl (3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl )carbamate
^1H NMR (400 MHz, CD ₃ OD) δ 8.41 (s, 1H), 7.98 (ddd, J =11.7, 9.0, 1.7 Hz, 2H), 7.91 (d , J =2.0 Hz, 1H), 7.60 (t, J =7.7 Hz, 1H), 7.51 (dt, J =7.6, 1.4 Hz, 1H), 7.45 (d, J =8.3 Hz, 1H), 7.39-7.36 (m, 1H), 7.36-7.09 (m, 1H), 5.86 (s, 2H), 3, 77 (s, 3H); MSNR (ER) m/z 445.2 (M ⁺ +1). 24 3777 N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) phenyl)-2,2,2-trifluoroacetamide
^1H NMR (400 MHz, CD ₃ OD) δ 8.47 (s, 1H), 8.14 (t, J =1.9 Hz, 1H), 8.03-7.93 (m, 2H), 7.74-7.63 (m, 2H), 7.61 (t, J =7.6 Hz, 1H), 7.49 (t, J =7.9 Hz, 1H), 7.24 (t , J =51.6 Hz, 1H), 5.87 (s, 2H); MSNR (ER) m/z 483.2 (M ⁺ +1). 235 4333 N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) phenyl)pivalamide
^1H NMR (400 MHz, CD ₃ OD) δ 8.37 (s, 1H), 8.41 (s, 1H), 8.04-7.92 (m, 3H), 7.65-7.58 (m, 2H), 7.54 (ddd, J=8.1, 2.1, 1.1 Hz, 1H), 7.44-7.11 (m, 2H), 5.85 (s, 2H ), 1.33 (s, 9H); MSNR (IER) m/z 471.5 (M ⁺ + H).

Example 25: Synthesis of compound 3805 , tert-butyl 4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1 ,2,3-triazol-4-yl)piperidine-1-carboxylate

2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.800 g, 3.172 mmol) prepared in Step 1 of Example 16, tert-butyl 4-ethynylpiperidin- 1-carboxylate (0.730 g, 3.490 mmol), sodium ascorbate (1.00 M solution in H ₂ O, 0.317 ml, 0.317 mmol) and copper(II) sulfate pentahydrate (0.50 M solution in H ₂ O, 0.063 ml , 0.032 mmol) was dissolved in tert-butanol (10 ml)/water (10 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane=0-70%) and concentrated to give tert-butyl 4-(1-((5-(5-(difluoromethyl)-1,3,4 -oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)piperidin-1-carboxylate (1.100 g, 75.1%) as a white solid.

¹ H NMR(400 MHz, CDCl₃) δ 9.33 (dd,J=2.2, 0.8 Hz, 1H), 8.41 (dd,J=8.2, 2.2 Hz, 1H), 7.49 (d,J=0.4 Hz, 1H), 7.37 (dd,J=8.2, 0.6 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H), 5.75 ( s, 2H), 4.16 (s, 2H), 3.09-2.75 (m, 3H), 2.05 (dd,J=12.9, 2.3 Hz, 2H), 1.73-1.54 (m, 2H), 1.48 (s, 9H);MCNR(ER) m/z 462.22 (M⁺+1).

Example 26: Synthesis of Compound 3806, 2-(difluoromethyl)-5-(6-((4-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin- 3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of 2-(difluoromethyl)-5-(6-((4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl) -1,3,4-oxadiazole

Tert-butyl 4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)piperidin-1-carboxylate (1.100 g, 2.384 mmol) prepared in Example 25 and trifluoroacetic acid (0.548 ml, 7.151 mmol) were dissolved in dichloromethane (80 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 3 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without further purification process, (2-(difluoromethyl)-5-(6-((4-(piperidin-4-yl)-1H-1,2,3 -triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.700 g, 81.3%, yellow oil).

[Step 2] Synthesis of compound 3806

2-(Difluoromethyl)-5-(6-((4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3, 4-oxadiazole (0.050 g, 0.138 mmol) obtained in step 1, N,N-diisopropylethylamine (0.048 ml, 0.277 mmol) and formaldehyde (0.008 g, 0.277 mmol) are dissolved in dichloromethane (20 ml), after which the resulting solution is stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (0.059 g, 0.277 mmol) was added thereto, and then stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(1-methylpiperidin-4-yl) -1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.029 g, 55.8%) as a white solid.

¹ H NMR (400 MHz, CDCl₃) δ 9.33 (d,J=1.5 Hz, 1H), 8.40 (dd,J=8.2, 2.2 Hz, 1H), 7.50 (s, 1H), 7.35 (d,J=8.2 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H), 5.75 (s, 2H) , 3.02 (d,J=11.6 Hz, 2H), 2.85 (t,J=11.5 Hz, 1H), 2.39 (s, 3H), 2.29-2.01 (m, 4H), 1.95-1.65 (m, 2H);MCNR(ER) m/z 376.2 (M⁺+1).

The compounds of Table 7 were synthesized according to substantially the same method as described above for the synthesis of compound 3806 except for the use of 2-(difluoromethyl)-5-(6-((4-(piperidin-4-yl)-1H-1 ,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reagent from Table 6.

Table 6 Example Connection no. Reagent Exit (%) 27 3807 Acetaldehyde 55 28 3808 Propan-2-one 66 29 3809 Oxetan-3-one 58 thirty 3810 2-oxaspiro[3,3]heptan-6-one 61

Table 7 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 27 3807 2-(difluoromethyl)-5-(6-((4-(1-ethylpiperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.33 (d, J = 1.5 Hz, 1H), 8.40 (dd, J = 8.2, 2.2 Hz, 1H), 7.60 -7.45 (m, 1H), 7.35 (d, J =8.1 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6, 83 (s, 0.3H), 5.75 (s, 2H), 3.14 (d, J =11.4 Hz, 2H), 2.91 (s, 1H), 2.57 (s, 2H ), 2.16 (d, J =12.4 Hz, 4H), 1.87 (d, J =11.7 Hz, 2H), 1.20 (t, J =7.1 Hz, 3H); MSNR (ER) m/z 390.4 (M ⁺ +1). 8 3808 2-(difluoromethyl)-5-(6-((4-(1-isopropylpiperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.33 (d, J = 1.5 Hz, 1H), 8.40 (dd, J = 8.2, 2.2 Hz, 1H), 7.51 (s, 1H), 7.34 (d, J =8.1 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H), 5.75 (s, 2H), 3.09 (s, 2H), 2.90 (s, 2H), 2.42 (s, 2H), 2.15 (s, 2H), 1.90 (s, 2H), 1.17 (s, 6H); MSNR (ER) m/z 404.4 (M ⁺ +1). 29 3809 2-(difluoromethyl)-5-(6-((4-(1-(oxetan-3-yl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin- 3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.31 (d, J = 1.7 Hz, 1H), 8.39 (dd, J = 8.2, 2.2 Hz, 1H), 7.49 (s, 1H), 7.34 (d, J =8.2 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H), 5.74 (s, 2H), 4.77-4.52 (m, 4H), 3.54 (dd, J =12.9, 6.5 Hz, 1H), 2.86 (dd, J =11.2, 8.5 Hz, 3H), 2.22-1.88 (m, 4H), 1.78 (kvd, J =12.4, 3.3 Hz, 2H); MSNR (ER) m/z 418.0 (M ⁺ +1). thirty 3810 2-(6-((4-(1-(2-oxaspiro[3,3]heptan-6-yl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl) pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 9.35-9.21 (m, 1H), 8.37 (dd, J = 8.2, 2.2 Hz, 1H), 7.47 (s, 1H), 7.32 (d, J =8.2 Hz, 1H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.3H ), 5.72 (s, 2H), 4.70 (s, 2H), 4.58 (s, 2H), 2.98 (d, J =9.6 Hz, 2H), 2.84 (s , 1H), 2.61 (s, 1H), 2.50-2.32 (m, 2H), 2.08 (t, J = 15.7 Hz, 4H), 1.97 (d, J = 10.4 Hz, 2H), 1.73 (d, J =11.2 Hz, 2H); MSNR (ER) m/z 458.3 (M ⁺ +1).

Example 31: Synthesis of compound 3811 , 1-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1 ,2,3-triazol-4-yl)piperidin-1-yl)ethan-1-one

2-(Difluoromethyl)-5-(6-((4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3, 4-oxadiazole (0.050 g, 0.138 mmol) prepared in step 1 of Example 26, triethylamine (0.023 ml, 0.166 mmol) and acetic anhydride (0.026 ml, 0.277 mmol) were dissolved in dichloromethane (10 ml) at room temperature, after which the resulting the solution is stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 1-(4-(1-((5-(5-(difluoromethyl)-1,3,4 -oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)ethan-1-one (0.041 g, 73.5%) in the form of a white solid.

¹ H NMR (400 MHz, CDCl₃) δ 9.31 (d,J=1.8 Hz, 1H), 8.40 (dd,J=8.2, 2.2 Hz, 1H), 7.51 (s, 1H), 7.38 (d,J=8.2 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H), 5.74 (s, 2H) , 4.64 (d,J=13.0 Hz, 1H), 3.89 (d,J=13.0 Hz, 1H), 3.22 (t,J=12.3 Hz, 1H), 3.05 (tt,J=11.4, 3.8 Hz, 1H), 2.76 (t,J=11.9 Hz, 1H), 2.27-1.97 (m, 5H), 1.66 (dd,J=25.7, 12.8 Hz, 2H);MCNR(ER) m/z 403.9 (M⁺+1).

The compounds of Table 9 were synthesized according to substantially the same method as described above for the synthesis of compound 3811 except for the use of 2-(difluoromethyl)-5-(6-((4-(piperidin-4-yl)-1H-1 ,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reagent from Table 8.

Table 8 Example Connection no. Reagent Exit (%) 32 3812 Methanesulfonyl chloride 34 77 3891 Methyl chloroformate 56 78 3892 Ethyl carbonochloridate 46 79 3893 Trimethylacetyl chloride 45

Table 9 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 32 3812 2-(difluoromethyl)-5-(6-((4-(1-(methylsulfonyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl) -1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.34 (d, J = 1.9 Hz, 1H), 8.43 (dd, J = 8.2, 2.2 Hz, 1H), 7.55 (s, 1H), 7.42 (d, J =8.4 Hz, 1H), 7.09 (s, 0.2H), 6.99 (s, 0.5H), 6.84 (s, 0.3H), 5.76 (s, 2H), 3.89 (d, J =12.4 Hz, 2H), 3.03-2.93 (m, 1H), 2.88 (td, J =12.0, 2.6 Hz, 2H), 2.83 (s, 3H), 2.21 (d, J =10.7 Hz, 2H), 1.84 (ddd, J =25.0, 11.7, 3.9 Hz, 2H); MSNR (ER) m/z 440.1 (M ⁺ +1). 77 3891 Methyl4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl )piperidine-1-carboxylate
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.32 (d, J = 1.6 Hz, 1H), 8.41 (dd, J = 8.2, 2.2 Hz, 1H), 7.49 (s, 1H), 7.38 (d, J =8.2 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H), 5.74 (s, 2H), 4.20 (s, 2H), 3.71 (s, 3H), 3.02-2.92 (m, 3H), 2.08-2 .04 (m, 2H), 1.68-1.58 (m, 2H); MSNR (ER) m/z 420.2 (M ⁺ +1). 78 3892 Ethyl4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl )piperidine-1-carboxylate
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.33 (dd, J = 2.2, 0.7 Hz, 1H), 8.41 (dd, J = 8.2, 2.2 Hz, 1H) , 7.52-7.48 (m, 1H), 7.41-7.34 (m, 1H), 7.10 (s, 0.2H), 6.97 (s, 0.5H), 6 .83 (s, 0.3H), 5.75 (s, 2H), 4.30-4.06 (m, 4H), 2.98 (ddt, J = 27.3, 19.7, 5, 4 Hz, 3H), 2.14-1.99 (m, 2H), 1.64 (ddd, J = 25.1, 12.2, 4.2 Hz, 2H), 1.27 (kv, J =6.8 Hz, 3H); MSNR (ER) m/z 434.3 (M ⁺ +1). 79 3893 1-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)piperidin-1-yl)-2,2-dimethylpropan-1-one
¹ H NMR (400 MHz, CD ₃ OD) δ 9.25 (s, 1H), 8.50 (dd, J =8.2, 2.1 Hz, 1H), 7.97 (s, 1H), 7.52 (d, J =8.2 Hz, 1H), 7.38 (s, 0.2H), 7.25 (s, 0.5H), 7.12 (s, 0.3H), 5 .83 (s, 2H), 4.49 (d, J =13.2 Hz, 2H), 3.10-3.03 (m, 3H), 2.09 (d, J =13.2 Hz, 2H), 1.70-1.61 (m, 2H), 1.31 (s, 9H); MSNR (ER) m/z 446.4 (M ⁺ +1).

Example 33: Synthesis of compound 3813 , 1-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1 ,2,3-triazol-4-yl)piperidin-1-yl)-2-hydroxyethan-1-one

2-(Difluoromethyl)-5-(6-((4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3, 4-oxadiazole (0.050 g, 0.138 mmol) prepared in step 1 of Example 26, 2-hydroxyacetic acid (0.013 g, 0.166 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.043 g, 0.277 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (0.037 g, 0.277 mmol) was dissolved in dichloromethane (10 ml) at room temperature, followed by N,N-diisopropylethylamine (0.048 ml, 0.277 mmol) added to the resulting solution and stirred at the same temperature for 30 minutes. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 1-(4-(1-((5-(5-(difluoromethyl)-1,3,4 -oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)-2-hydroxyethan-1-one (0.021 g, 36, 2%) in the form of a white solid.

¹ H NMR (400 MHz, CDCl₃) δ 9.32 (d,J=1.7 Hz, 1H), 8.41 (dd,J=8.2, 2.2 Hz, 1H), 7.60-7.47 (m, 2H), 7.41 (d,J=8.1 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H), 5.75 (s, 2H) , 4.61 (d,J=13.6 Hz, 1H), 4.19 (s, 2H), 3.59 (d,J=13.9 Hz, 1H), 3.24-2.99 (m, 2H), 2.99-2.81 (m, 1H), 2.24-2.07 (m, 2H), 1, 77-1.54 (m, 2H);MCNR(ER) m/z 420.3 (M⁺+1).

The compound of Table 11 was synthesized in accordance with substantially the same method as described above for the synthesis of compound 3813 except for the use of 2-(difluoromethyl)-5-(6-((4-(piperidin-4-yl)-1H-1 ,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reagent from Table 10.

Table 10 Example Connection no. Reagent Exit (%) 80 3894 2-fluoro-2-methylpropanoic acid 47

Table 11 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 80 3894 1-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)piperidin-1-yl)-2-fluoro-2-methylpropan-1-one
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.34 (d, J = 1.7 Hz, 1H), 8.44 (dd, J = 8.2, 2.2 Hz, 1H), 7.59 (s, 1H), 7.44 (d, J =8.0 Hz, 1H), 7.10 (s, 0.2H), 6.97 (s, 0.5H), 6.84 (s, 0.3H), 5.78 (s, 2H), 4.58 (d, J =26.7 Hz, 2H), 3.30-3.06 (m, 2H), 2.83 (s, 1H ), 2.16 (s, 2H), 1.68 (s, 2H), 1.67 (s, 3H), 1.61 (s, 3H); MSNR (ER) m/z 450.2 (M ⁺ +1).

Example 36: Synthesis of compound 3824 , 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2, 3-triazol-4-yl)-N,N-dimethylaniline

[Step 1] Synthesis of 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3- triazol-4-yl)aniline

2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.500 g, 1.983 mmol) obtained in step 1 of Example 16 was dissolved in tert-butanol (4 ml)/water (4 ml) at room temperature, after which 3-ethynylaniline (0.223 ml, 1.983 mmol) was added to the resulting solution and stirred at the same temperature. Sodium ascorbate (1.00 M solution, 0.198 mL, 0.198 mmol) and copper(II) sulfate pentahydrate (0.50 M solution, 0.040 mL, 0.020 mmol) were added to the reaction mixture and then stirred at the same temperature for 18 hours . A saturated aqueous solution of ammonium chloride is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=0-40%) and concentrated to give 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol- 2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)aniline (0.650 g, 88.8%) in the form of a beige solid.

[Step 2] Synthesis of compound 3824

3-(1-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl )aniline (0.030 g, 0.078 mmol) obtained in step 1 and formaldehyde (37.00%, 0.063 g, 0.777 mmol) are dissolved in acetonitrile (1 ml)/acetic acid (0.01 ml), and the resulting solution stirred at room temperature for 0.5 hours, and then sodium cyanoborohydride (0.015 g, 0.233 mmol) was added thereto, and then stirred at the same temperature for 1 hour. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol- 2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylaniline (0.012 g, 37.3%) in the form of a light yellow oil.

¹ H NMR(400 MHz, DMSO-d₆) δ 9.20 (d,J=2.2 Hz, 1H), 8.69 (s, 1H), 8.49 (dd,J=8.2, 2.3 Hz, 1H), 7.73-7.44 (m, 3H), 7.28-7.20 (m, 2H), 6.75-6.68 (m, 1H ), 5.92 (s, 2H), 2.95 (s, 6H);MCNR(ER) m/z 398.2 (M⁺+1).

The compounds of Table 13 were synthesized in accordance with substantially the same method as described above for the synthesis of compound 3824 except for the use of 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2- yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)aniline and the reagent from Table 12.

Table 12 Example Connection no. Reagent Exit (%) 39 3827 Tetrahydro-4H-pyran-4-one 45 40 3828 Cyclohexanone 52 42 3830 1-methylpiperidin-4-one 33

Table 13 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 39 3827 N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)phenyl)tetrahydro-2H-pyran-4-amine
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.23-9.17 (m, 1H), 8.60 (s, 1H), 8.49 (dd, J = 8.2, 2.3 Hz, 1H), 7.58 (t, J =51.3 Hz, 1H), 7.54 (d, J =8.2 Hz, 1H), 7.17-7.09 (m, 2H), 7.00 (dd, J =7.6, 1.4 Hz, 1H), 6.62-6.55 (m, 1H), 5.91 (s, 2H), 3.93-3.84 ( m, 2H), 3.58-3.48 (m, 1H), 3.44 (td, J =11.5, 2.2 Hz, 2H), 1.90 (d, J =12.9 Hz , 2H), 1.47-1.32 (m, 2H); MSNR (ER) m/z 454.2 (M ⁺ +1). 40 3828 N-cyclohexyl-3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazole -4-yl)aniline
^1H NMR (400 MHz, DMSO- _d6 ) δ 9.20 (dd, J = 2.2, 0.8 Hz, 1H), 8.58 (s, 1H), 8.49 (dd, J = 8.2, 2.3 Hz, 1H), 7.58 (t, J =51.3 Hz, 1H), 7.54 (d, J =8.2 Hz, 1H), 7.15-7, 07 (m, 2H), 6.96 (d, J =7.6 Hz, 1H), 6.58-6.51 (m, 1H), 5.91 (s, 2H), 3.24 (s , 1H), 2.02-1.91 (m, 2H), 1.73 (d, J =13.1 Hz, 2H), 1.61 (d, J =12.7 Hz, 1H), 1 .34 (t, J =12.5 Hz, 2H), 1.23-1.13 (m, 3H); MSNR (ER) m/z 451.9 (M ⁺ +1). 42 3830 N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)phenyl)-1-methylpiperidin-4-amine
^1H NMR (400 MHz, DMSO) δ 9.23-9.17 (m, 1H), 8.59 (s, 1H), 8.49 (dd, J =8.2, 2.3 Hz, 1H ), 7.58 (t, J =51.3 Hz, 1H), 7.54 (d, J =8.1 Hz, 1H), 7.16-7.08 (m, 2H), 6.98 (d, J =7.7 Hz, 1H), 6.56 (d, J =7.1 Hz, 1H), 5.91 (s, 2H), 3.23 (s, 1H), 2.73 (d, J =11.7 Hz, 2H), 2.17 (s, 3H), 2.07-1.97 (m, 2H), 1.90 (d, J =12.6 Hz, 2H) , 1.41 (kV, J =9.9 Hz, 2H); MSNR (ER) m/z 467.3 (M ⁺ +1).

Example 37: Synthesis of compound 3825 , N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1 ,2,3-triazol-4-yl)phenyl)pivalamide

3-(1-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl )aniline (0.050 g, 0.135 mmol) obtained in step 1 of Example 36 and triethylamine (0.028 ml, 0.203 mmol) were dissolved in dichloromethane (1 ml) at room temperature, after which trimethylacetyl chloride (0.020 ml, 0.162 mmol) was added to the resulting solution and stir at the same temperature for 1 hour. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give N-(3-(1-((5-(5-(difluoromethyl)-1,3,4 -oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)pivalamide (0.023 g, 37.5%) as a white solid.

¹ H NMR(400 MHz, DMSO-d₆) δ 9.32 (s, 1H), 9.21 (dd,J=2.3, 0.9 Hz, 1H), 8.67 (s, 1H), 8.50 (dd,J=8.2, 2.3 Hz, 1H), 8.21 (t,J=1.9 Hz, 1H), 7.65 (ddd,J=8.1, 2.1, 1.0 Hz, 1H), 7.72-7.45 (m, 2H), 7.52 (dt,J=7.7, 1.3 Hz, 1H), 7.37 (t,J=7.9 Hz, 1H), 5.93 (s, 2H), 1.25 (s, 9H);MCNR(ER) m/z 454.3 (M⁺+1).

The compound of Table 15 was synthesized in accordance with substantially the same method as described above for the synthesis of compound 3825 except for the use of 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2- yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)aniline and the reagent from Table 14.

Table 14 Example Connection no. Reagent Exit (%) 38 3826 Ethyl chloroformate 50

Table 15 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 38 3826 Ethyl (3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4 -yl)phenyl)carbamate
^1H NMR (400 MHz, DMSO- _d6 ) δ 9.72 (s, 1H), 9.20 (dd, J =2.3, 0.8 Hz, 1H), 8.65 (s, 1H) , 8.49 (dd, J =8.3, 2.3 Hz, 1H), 8.07 (s, 1H), 7.72-7.53 (m, 1H), 7.49-7.40 (m, 2H), 7.38-7.32 (m, 1H), 5.93 (s, 2H), 4.15 (kV, J =7.1 Hz, 2H), 1.26 (t, J =7.1 Hz, 3H); MSNR (ER) m/z 442.2 (M ⁺ +1).

Example 41: Synthesis of compound 3829 , (3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2 ,3-triazol-4-yl)phenyl)(pyrrolidin-1-yl)methanone

3-(1-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl )benzoic acid (0.050 g, 0.126 mmol) obtained in example 19, pyrrolidine (0.012 g, 0.163 mmol) and hexafluorophosphate 3-oxide 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4 ,5-b]pyridinium (0.095 g, 0.251 mmol) was dissolved in dichloromethane (5 ml) at room temperature, after which diisopropylethylamine (0.032 g, 0.251 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-70%) and concentrated to give (3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazole -2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)(pyrrolidin-1-yl)methanone (0.032 g, 56.5%) in the form of light - yellow gum.

¹ H NMR (400 MHz, CD₃OD) δ 9.28 (dd,J=2.3, 0.9 Hz, 1H), 8.58 (s, 1H), 8.53 (dd,J=8.2, 2.2 Hz, 1H), 8.02 (t,J=1.6 Hz, 1H), 7.98 (dt,J=7.5, 1.6 Hz, 1H), 7.61 (dd,J=8.2, 0.8 Hz, 1H), 7.59-7.54 (m, 1H), 7.52 (dt,J=7.7, 1.5 Hz, 1H), 7.26 (t,J=51.6 Hz, 1H), 5.93 (s, 2H), 3.64 (t,J=7.0 Hz, 2H), 3.52 (t,J=6.6 Hz, 2H), 2.02 (dt,J=7.7, 5.8 Hz, 2H), 1.99-1.89 (m, 2H);MCNR(ER) m/z 452.2 (M⁺+1).

The compounds of Table 17 were synthesized in accordance with substantially the same method as described above for the synthesis of compound 3829 except for the use of 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2- yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzoic acid and the reagent from Table 16.

Table 16 Example Connection no. Reagent Exit (%) 72 3885 Morpholine 42 73 3886 Azetidine 56 74 3887 1-methylpiperazine 47 327 4448 1-isopropylpiperazine 51 328 4449 N1,N1,N2-trimethylethane-1,2-diamine 49 355 4480 1-methylazetidine-3-amine 54 356 4482 1-ethylpiperazine 46

Table 17 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 72 3885 (3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4- yl)phenyl)(morpholino)methanone
^1H NMR (400 MHz, DMSO- _d6 ) δ 9.20 (dd, J = 2.3, 0.9 Hz, 1H), 8.81 (s, 1H), 8.50 (dd, J = 8.2, 2.3 Hz, 1H), 7.98 (dt, J =7.8, 1.4 Hz, 1H), 7.90 (t, J =1.7 Hz, 1H), 7, 72-7.44 (m, 4H), 7.38 (dt, J =7.6, 1.4 Hz, 1H), 5.94 (s, 2H), 3.63 (dd, J =10, 5, 6.3 Hz, 4H), 3.21-3.10 (m, 4H); MSNR (ER) m/z 468.3 (M ⁺ +1). 73 3886 Azetidin-1-yl(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3 -triazol-4-yl)phenyl)methanone
^1H NMR (400 MHz, DMSO- _d6 ) δ 9.20 (dd, J = 2.3, 0.8 Hz, 1H), 8.84 (s, 1H), 8.50 (dd, J = 8.2, 2.3 Hz, 1H), 8.10 (s, 1H), 8.01 (dt, J =7.1, 1.8 Hz, 1H), 7.73-7.44 (m , 4H), 5.94 (s, 2H), 4.33 (t, J = 7.6 Hz, 2H), 4.11-4.05 (m, 2H), 2.28 (p, J = 7.7 Hz, 2H); MSNR (ER) m/z 438.3 (M ⁺ +1). 74 3887 (3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4- yl)phenyl)(4-methylpiperazin-1-yl)methanone
^1H NMR (400 MHz, CD ₃ OD) δ 9.27 (dd, J =2.2, 0.9 Hz, 1H), 8.59 (s, 1H), 8.53 (dd, J =8 ,2, 2.2 Hz, 1H), 7.98 (dt, J =7.9, 1.5 Hz, 1H), 7.93 (t, J =1.8 Hz, 1H), 7.65 -7.53 (m, 2H), 7.42 (dt, J =7.7, 1.4 Hz, 1H), 7.26 (t, J =51.6 Hz, 1H), 5.93 ( s, 2H), 3.83 (brs, 2H), 3.53 (brs, 2H), 2.58 (brs, 2H), 2.48 (brs, 2H), 2.36 (s, 3H); MSNR (ER) m/z 481.3 (M ⁺ +1). 327 4448 (3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4- yl)phenyl)(4-isopropylpiperazin-1-yl)methanone
¹ H NMR (400 MHz, CD ₃ OD) δ 9.27-8.29 (m, 1H), 8.57 (d, J =8.48 Hz, 1H), 8.53 (dd, J =8 ,20, 2.20 Hz, 1H), 8.36 (t, J = 1.71 Hz, 1H), 8.08-7.86 (m, 2H), 7.62 (dd, J = 8, 20, 1.28 Hz, 1H), 7.57 (t, J =7.71 Hz, 1H), 7.26 (t, J =51.6 Hz, 1H), 5.94 (s, 2H) , 3.82-3.50 (m, 4H), 2.80-2.59 (m, 5H), 1.12 (d, J =6.56 Hz, 6H); MSNR (ER) m/z 509.5 (M ⁺ +1). 328 4449 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl )-N-(2-(dimethylamino)ethyl)-N-methylbenzamide
^1H NMR (400 MHz, CD ₃ OD) δ 9.29 (dd, J =2.3, 0.9 Hz, 1H), 8.57 (s, 1H), 8.54 (dd, J =8 ,2, 2.2 Hz, 1H), 8.37 (t, J =1.7 Hz, 1H), 8.07 (dt, J =7.8, 1.3 Hz, 1H), 7.91 -7.84 (m, 1H), 7.62 (d, J =8.3 Hz, 1H), 7.58 (t, J =7.7 Hz, 1H), 7.26 (t, J = 51.6 Hz, 1H), 5.95 (s, 2H), 3.11-2.93 (m, 10H), 2.22 (s, 3H); MSNR (ER) m/z 483.5 (M ⁺ +1). 355 4480 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl )-N-(1-methylazetidin-3-yl)benzamide
^1H NMR (400 MHz, CD ₃ OD) δ 9.28 (dd, J =2.3, 0.9 Hz, 1H), 8.61 (s, 1H), 8.53 (dd, J =8 ,2, 2.2 Hz, 1H), 8.43 (t, J =1.8 Hz, 1H), 8.10-8.03 (m, 1H), 7.89 (ddd, J =7, 8, 1.9, 1.1 Hz, 1H), 7.67-7.56 (m, 2H), 7.26 (t, J =51.6 Hz, 1H), 5.95 (s, 2H ), 4.84-4.76 (m, 1H), 4.65-4.35 (m, 4H), 3.06 (s, 3H); MSNR (ER) m/z 467.5 (M ⁺ +1). 356 4482 (3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4- yl)phenyl)(4-ethylpiperazin-1-yl)methanone
^1H NMR (400 MHz, CD ₃ OD) δ 9.26 (dd, J =2.2, 0.9 Hz, 1H), 8.58 (s, 1H), 8.52 (dd, J =8 ,2, 2.2 Hz, 1H), 8.02-7.95 (m, 1H), 7.94 (d, J =1.7 Hz, 1H), 7.65-7.54 (m, 2H), 7.44 (dt, J =7.7, 1.3 Hz, 1H), 7.26 (t, J =51.6 Hz, 1H), 5.93 (s, 2H), 3, 95-3.54 (m, 4H), 2.91-2.60 (m, 6H), 1.20 (t, J =7.3 Hz, 3H); MSNR (ER) m/z 495.5 (M ⁺ +1).

Example 47: Synthesis of Compound 3835, 2-(difluoromethyl)-5-(6-((4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3- yl)-1,3,4-oxadiazole

[Step 1] Synthesis of 3-ethynylpyridine

Dimethyl (1-diazo-2-oxopropyl)phosphonate (0.771 ml, 5.135 mmol) and potassium carbonate (1.290 g, 9.336 mmol) are dissolved in methanol (20 ml) at room temperature, after which nicotinaldehyde (0.439 ml, 4.668 mmol) is added to the resulting solution and stir at the same temperature for 4 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 3-ethynylpyridine (0.204 g, 42.4%) as a white solid.

[Step 2] Synthesis of compound 3835

3-Ethynylpyridine (0.100 g, 0.970 mmol) obtained in step 1, 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.245 g, 0.970 mmol ) obtained in step 1 of example 16, sodium ascorbate (0.019 g, 0.097 mmol) and copper(II) sulfate pentahydrate (0.002 g, 0.010 mmol) were dissolved in tert-butanol (2 ml)/water (2 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Hexane (20 ml) and dichloromethane (10 ml) were added to the resulting concentrate and stirred to filter the precipitated solid, washed with hexane and dried to give 2-(difluoromethyl)-5-(6-((4-(pyridine-3 -yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.270 g, 78.4%) as a white solid.

¹ H NMR(400 MHz, CD₃OD) δ 9.27 (dd,J=2.2, 0.9 Hz, 1H), 9.08 (s, 1H), 8.67 (s, 1H), 8.54 (d,J=2.2 Hz, 1H), 8.52 (d,J=2.2 Hz, 1H), 8.36-8.29 (m, 1H), 7.63 (dd,J=8.2, 0.9 Hz, 1H), 7.56 (t,J=6.5 Hz, 1H), 7.26 (t,J=51.6 Hz, 1H), 5.96 (s, 2H);MCNR(ER) m/z 356.2 (M⁺+1).

Example 75: Synthesis of compound 3889 , (N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H- 1,2,3-triazol-4-yl)phenyl)-N-methylpivalamide

[Step 1] Synthesis of 3-ethynyl-N-methylaniline

3-ethynylaniline (0.800 g, 6.829 mmol), potassium carbonate (3.775 g, 27.315 mmol) and iodomethane (1.063 ml, 17.072 mmol) were dissolved in dimethyl sulfoxide (8 ml) at room temperature, after which the resulting solution was stirred at the same temperature in within 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 3-ethynyl-N-methylaniline (0.100 g, 11.2%) as a colorless oil.

[Step 2] Synthesis of 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3- triazol-4-yl)-N-methylaniline

2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.198 mmol) prepared in Step 1 of Example 16 and 3-ethynyl-N- Methylaniline (0.026 g, 0.198 mmol) obtained in step 1 is dissolved in tert-butanol (0.5 ml)/water (0.5 ml) at room temperature, followed by sodium ascorbate (1.00 M solution, 0.020 ml , 0.020 mmol) and copper(II) sulfate pentahydrate (0.50 M solution, 0.004 ml, 0.002 mmol) were added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution is poured into the reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-40%) and concentrated to give 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol- 2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N-methylaniline (0.040 g, 52.6%) as a light yellow solid.

[Step 3] Synthesis of compound 3889

3-(1-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl )-N-Methylaniline (0.010 g, 0.026 mmol) obtained in step 2, triethylamine (0.005 ml, 0.039 mmol) and pivaloyl chloride (0.004 ml, 0.031 mmol) are dissolved in dichloromethane (0.5 ml) at room temperature, then the resulting solution is stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution is poured into the reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-40%) and concentrated to give N-(3-(1-((5-(5-(difluoromethyl)-1,3,4 -oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-N-methylpivalamide (0.005 g, 41.0%) as a white solid .

¹ H NMR(400 MHz, CDCl₃) δ 9.37 (s, 1H), 8.54-8.45 (m, 1H), 8.08 (s, 1H), 7.87-7.76 (m, 2H), 7.58- 7.44 (m, 2H), 7.25-7.20 (m, 1H), 6.97 (t,J=51.6 Hz, 1H), 5.88 (s, 2H), 3.28 (d,J=1.6 Hz, 3H), 1.10 (s, 9H);MCNR(ER) m/z 468.3 (M⁺+1).

The compound of Table 19 was synthesized in accordance with essentially the same method as for the synthesis of compound 3889 described above, except for the use of 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol- 2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N-methylaniline and the reagent from Table 18.

Table 18 Example Connection no. Reagent Exit (%) 76 3890 Ethyl chloroformate 50

Table 19 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 76 3890 Ethyl (3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4 -yl)phenyl)(methyl)carbamate (0.006 g, 50.5%) is obtained as a white solid.
^1H NMR (400 MHz, CDCl ₃ ) δ 9.37 (s, 1H), 8.50-8.43 (m, 1H), 8.06 (s, 1H), 7.81 (s, 1H) , 7.70 (d, J =7.8 Hz, 1H), 7.50 (d, J =8.2 Hz, 1H), 7.44 (t, J =7.9 Hz, 2H), 6 .97 (t, J =51.6 Hz, 1H), 5.87 (s, 2H), 4.21 (kv, J =7.1 Hz, 2H), 3.37 (s, 3H), 1 .27 (t, J =7.2 Hz, 3H); MSNR (ER) m/z 456.3 (M ⁺ +1).

Example 81: Synthesis of Compound 3895, 2-(difluoromethyl)-5-(6-((4-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-1H-1,2,3-triazole -1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of methyl 6-(azidomethyl)nicotinate

Methyl 6-(bromomethyl)nicotinate (5.000 g, 21.733 mmol) and sodium azide (1.695 g, 26.080 mmol) were dissolved in N,N-dimethylformamide (120 ml) at 50°C, after which the resulting solution was stirred at the same temperature in for 12 hours, and then the reaction is completed by lowering the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give methyl 6-(azidomethyl)nicotinate (4,000 g, 95.8%) as a yellow solid.

[Step 2] Synthesis of methyl 6-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate

Methyl 6-(azidomethyl)nicotinate (1.500 g, 7.805 mmol) obtained in step 1, tert-butyl 4-ethynylpiperidine-1-carboxylate (1.797 g, 8.586 mmol), sodium ascorbate (1.00 M solution in H ₂ O , 0.781 ml, 0.781 mmol) and copper(II) sulfate pentahydrate (0.50 M solution in H ₂ O, 0.156 ml, 0.078 mmol) are dissolved in tert-butanol (10 ml)/water (10 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane=0-70%) and concentrated to give methyl 6-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H- 1,2,3-triazol-1-yl)methyl)nicotinate (1.800 g, 57.4%) as a yellow solid.

[Step 3] Synthesis of methyl 6-((4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate hydrochloride

Methyl 6-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate (1.000 g, 2.491 mmol) obtained from step 1 and hydrogen chloride (4.00 M solution in 1,4-dioxane, 1.868 ml, 7.473 mmol) were dissolved in dichloromethane (30 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. The solvent was removed from the reaction mixture under reduced pressure, after which the precipitated solid was filtered off, washed with dichloromethane and dried to obtain methyl 6-((4-(piperidin-4-yl)-1H-1,2,3-triazol-hydrochloride 1-yl)methyl)nicotinate (0.800 g, 95.1%) in the form of a yellow solid.

[Step 4] Synthesis of methyl 6-((4-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate

Methyl 6-((4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate hydrochloride (0.200 g, 0.592 mmol) obtained in step 2, potassium carbonate (0.164 g, 1.184 mmol) and 2,2-dimethyloxylane (0.213 g, 2.960 mmol) are mixed in ethanol (12 ml)/water (3 ml), heated at 110°C for 15 minutes by microwave irradiation, and the reaction is completed by reducing the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Then, the resulting product is used without additional purification process (methyl 6-((4-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl) methyl)nicotinate, 0.160 g, 72.4%, yellow oil).

[Step 5] Synthesis of methyl 6-((4-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate

Methyl 6-((4-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate (0.100 g, 0.268 mmol) , obtained in step 3, and diethylaminosulfur trifluoride (0.042 ml, 0.321 mmol) are dissolved in dichloromethane (10 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 3 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Then, the resulting product is used without additional purification process (methyl 6-((4-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl) methyl)nicotinate, 0.076 g, 75.6%, yellow solid).

[Step 6] Synthesis of 6-((4-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinohydrazide

Methyl 6-((4-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate (0.076 g, 0.202 mmol) , obtained in step 4, and hydrazine monohydrate (0.098 ml, 2.024 mmol) are dissolved in ethanol (30 ml) at 90°C, after which the resulting solution is stirred at the same temperature for 12 hours, and then the reaction is completed by reducing the temperature to room temperature temperature. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without additional purification process (6-((4-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-1H-1,2, 3-triazol-1-yl)methyl)nicotine hydrazide, 0.070 g, 92.1%, white solid).

[Step 7] Synthesis of compound 3895

6-((4-(1-(2-Fluoro-2-methylpropyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinohydrazide (0.070 g, 0.186 mmol), obtained in step 5, imidazole (0.038 g, 0.559 mmol) and 2,2-difluoroacetic anhydride (0.070 ml, 0.559 mmol) are mixed in dichloromethane (30 ml) at room temperature, after which the resulting mixture is heated to reflux for 12 hours and cool to room temperature. Then, water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-3%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(1-(2-fluoro-2 -methylpropyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.039 g, 48.0%) in form of a white solid.

¹ H NMR (400 MHz, CDCl₃) δ 9.33 (d,J=1.5 Hz, 1H), 8.40 (dd,J=8.2, 2.2 Hz, 1H), 7.49 (s, 1H), 7.34 (d,J=8.2 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.84 (s, 0.3H), 5.75 (s, 2H) , 3.05 (s, 2H), 2.80 (s, 1H), 2.51 (d,J=23.0 Hz, 2H), 2.32 (s, 2H), 2.02 (s, 2H), 1.80 (s, 2H), 1.42 (t,J=21.6 Hz, 6H);MCNR(ER) m/z 436.3 (M⁺+1).

Example 82: Synthesis of Compound 3896, 2-(difluoromethyl)-5-(6-((4-(1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)-1H-1,2,3-triazole -1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of methyl 6-((4-(1-(2-ethyl-2-hydroxybutyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate

Methyl 6-((4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate hydrochloride (0.200 g, 0.592 mmol) prepared in step 2 of Example 81, potassium carbonate ( 0.164 g, 1.184 mmol) and 2,2-dimethyloxylane (0.296 g, 2.960 mmol) are mixed in ethanol (12 ml)/water (3 ml), heated at 110°C for 15 minutes by microwave irradiation, and the reaction is completed by reducing the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Then, the resulting product is used without additional purification process (methyl 6-((4-(1-(2-ethyl-2-hydroxybutyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl) methyl)nicotinate, 0.140 g, 58.9%, yellow oil).

[Step 2] Synthesis of methyl 6-((4-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate

Methyl 6-((4-(1-(2-ethyl-2-hydroxybutyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate (0.100 g, 0.249 mmol) , obtained in step 1, and diethylaminosulfur trifluoride (0.039 ml, 0.299 mmol) are dissolved in dichloromethane (10 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 3 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Then, the resulting product is used without additional purification process (methyl 6-((4-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl) methyl)nicotinate, 0.066 g, 70.6%, yellow solid).

[Step 3] Synthesis of 6-((4-(1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinohydrazide

Methyl 6-((4-(1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate (0.066 g, 0.164 mmol) , obtained in step 2, and hydrazine monohydrate (0.079 ml, 1.636 mmol) are dissolved in ethanol (30 ml) at 90°C, after which the resulting solution is stirred at the same temperature for 12 hours, and then the reaction is completed by reducing the temperature to room temperature temperature. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without additional purification process (6-((4-(1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)-1H-1,2, 3-triazol-1-yl)methyl)nicotine hydrazide, 0.060 g, 90.9%, white solid).

[Step 4] Synthesis of compound 3896

6-((4-(1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinohydrazide (0.060 g, 0.149 mmol), obtained in step 3, imidazole (0.030 g, 0.446 mmol) and 2,2-difluoroacetic anhydride (0.055 ml, 0.446 mmol) are mixed in dichloromethane (30 ml) at room temperature, after which the resulting mixture is heated to reflux for 12 hours and cool to room temperature. Then, water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-3%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(1-(2-ethyl-2 -fluorobutyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.039 g, 56.6%) in form of a white solid.

¹ H NMR (400 MHz, CDCl₃) δ 9.32 (d,J=1.4 Hz, 1H), 8.39 (dd,J=8.2, 2.2 Hz, 1H), 7.47 (d,J=13.7 Hz, 1H), 7.33 (d,J=8.2 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H), 5.74 (s, 2H) , 3.06 (d,J=11.3 Hz, 2H), 2.79 (t,J=11.6 Hz, 1H), 2.56 (dd,J=25.7, 15.4 Hz, 2H), 2.30 (t,J=11.2 Hz, 2H), 2.01 (s, 2H), 1.74 (tt,J=15.0, 9.6 Hz, 6H), 0.89 (t,J=7.5 Hz, 6H);MCNR(ER) m/z 464.10 (M⁺+1).

Example 84: Synthesis of Compound 3914, 2-(difluoromethyl)-5-(6-((4-(1-methyl-1H-indol-6-yl)-1H-1,2,3-triazol-1-yl) methyl)pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of 1-methyl-1H-indole-6-carbaldehyde

1H-indole-6-carbaldehyde (0.500 g, 3.444 mmol) and cesium carbonate (1.329 g, 6.889 mmol) are dissolved in acetonitrile (7 ml) at room temperature, after which the resulting solution is heated at reflux for 2 hours, and iodomethane (0.236 ml, 3.789 mmol) are added and heated again at reflux for 1 hour, and then the reaction is terminated by reducing the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 1-methyl-1H-indole-6-carbaldehyde (0.200 g, 36.5%) as a colorless oil. .

[Step 2] Synthesis of 6-ethynyl-1-methyl-1H-indole

1-Methyl-1H-indole-6-carbaldehyde (0.095 g, 0.597 mmol) obtained in step 1 and dimethyl (1-diazo-2-oxopropyl)phosphonate (0.134 ml, 0.895 mmol) are dissolved in methanol (2 ml) at room temperature, after which potassium carbonate (0.165 g, 1.194 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting concentrate is poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-20%) and concentrated to give 6-ethynyl-1-methyl-1H-indole (0.080 g, 86.4%) as light yellow solid.

[Step 3] Synthesis of compound 3914

2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.198 mmol) prepared in Step 1 of Example 16 and 6-ethynyl-1- methyl 1H-indole (0.031 g, 0.198 mmol) is dissolved in tert-butanol (1 ml)/water (1 ml) at room temperature, followed by sodium ascorbate (1.00 M solution, 0.020 ml, 0.020 mmol) and pentahydrate Copper(II) sulfate (0.50 M solution, 0.004 ml, 0.002 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution is poured into the reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=5-40%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(1-methyl-1H-indol- 6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.050 g, 61.9%) as a white solid.

^1H NMR (400 MHz, CD ₃ OD) δ 9.30 (s, 1H), 8.71 (s, 1H), 8.57-8.50 (m, 2H), 7.79-7.71 (m, 2H), 7.67 (d, J =8.2 Hz, 1H), 7.61 (d, J =8.4 Hz, 1H), 7.26 (t, J =51.6 Hz , 1H), 6.71 (d, J =3.7 Hz, 1H), 5.94 (s, 2H), 4.10 (s, 3H); MSNR (ER) m/z 408.3 (M ⁺ +1).

Example 85: Synthesis of compound 3915 , 1-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1 ,2,3-triazol-4-yl)phenyl)-N,N-dimethylmethanamine

[Step 1] Synthesis of 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3- triazol-4-yl)benzaldehyde

2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.250 g, 0.991 mmol) prepared in Step 1 of Example 16 and 3-ethynylbenzaldehyde (0.129 g , 0.991 mmol) dissolved in tert-butanol (1 ml)/water (1 ml) at room temperature, followed by sodium ascorbate (1.00 M solution, 0.099 ml, 0.099 mmol) and copper(II) sulfate pentahydrate (0. 50 M solution, 0.020 ml, 0.010 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous ammonia solution is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=10-50%) and concentrated to give 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol- 2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzaldehyde (0.300 g, 79.2%) as a light yellow solid.

[Step 2] Synthesis of compound 3915

3-(1-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl )benzaldehyde (0.030 g, 0.078 mmol) obtained in step 1 and dimethylamine (2.00 M solution, 0.039 ml, 0.078 mmol) are dissolved in dichloromethane (0.7 ml) at room temperature, followed by sodium triacetoxyborohydride (0.050 ml , 0.235 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-70%) and concentrated to give 1-(3-(1-((5-(5-(difluoromethyl)-1,3,4 -oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-N,N-dimethylmethanamine (0.015 g, 46.5%) in the form of colorless oils

¹ H NMR(400 MHz, CD₃OD) δ 9.31-9.26 (m, 1H), 8.53 (dd,J=8.2, 2.3 Hz, 1H), 8.50 (s, 1H), 7.85-7.78 (m, 2H), 7.60 (d,J=8.2 Hz, 1H), 7.46 (t,J=7.6 Hz, 1H), 7.38-7.33 (m, 1H), 7.26 (t,J=51.6 Hz, 1H), 5.93 (s, 2H), 3.59 (s, 2H), 2.31 (s, 6H);MCNR(ER) m/z 412.3 (M⁺+1).

The compounds of Table 21 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 3915 except for the use of 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2- yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzaldehyde and the reagent from Table 20.

Table 20 Example Connection no. Reagent Exit (%) 86 3916 Morpholine 61 87 3917 1-methylpiperazine 51 88 3918 N1,N1,N2-trimethylethane-1,2-diamine 49 89 3919 Methylamine 48 108 3963 Azetidine hydrochloride 60 109 3964 3-fluoroazetidine hydrochloride 60 110 3965 2-oxa-6-azaspiro[3,3]heptane-oxalic acid 49 111 3966 Pyrrolidine 64 284 4400 3,3-difluoroazetidine 49 285 4401 4,4-difluoropiperidine 55

Table 21 Example Connection no. Name of compound, 1H-NMR, MS (ESI) 86 3916 4-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)benzyl)morpholine
^1H NMR (400 MHz, CD ₃ OD) δ 8.00 (dd, J =2.2, 0.9 Hz, 1H), 7.25 (dd, J =8.2, 2.3 Hz, 1H ), 7.23 (s, 1H), 6.58 (t, J =1.8 Hz, 1H), 6.50 (dt, J =7.7, 1.5 Hz, 1H), 6.32 (dd, J =8.3, 0.9 Hz, 1H), 6.16 (t, J =7.6 Hz, 1H), 6.12-5.84 (m, 2H), 4.65 ( s, 2H), 2.47-2.40 (m, 4H), 2.32 (s, 2H), 1.23 (t, J =4.7 Hz, 4H); MSNR (ER) m/z 454.3 (M ⁺ +1). 87 3917 2-(difluoromethyl)-5-(6-((4-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridine -3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 7.60 (d, J = 2.2 Hz, 1H), 6.85 (dd, J = 8.2, 2.3 Hz, 1H), 6, 82 (s, 1H), 6.17 (d, J =1.8 Hz, 1H), 6.10 (dt, J =7.6, 1.6 Hz, 1H), 5.92 (d, J =8.2 Hz, 1H), 5.76 (t, J =7.6 Hz, 1H), 5.70-5.66 (m, 1H), 5.58 (t, J =51.6 Hz , 1H), 4.25 (s, 2H), 1.95 (s, 2H), 0.90 (s, 8H), 0.66 (s, 3H); MSNR (ER) m/z 467.3 (M ⁺ +1). 88 3918 N1-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)benzyl)-N1,N2,N2-trimethylethane-1,2-diamine
¹ H NMR (400 MHz, CD ₃ OD) δ 9.28 (d, J = 2.2 Hz, 1H), 8.53 (dd, J = 8.2, 2.2 Hz, 1H), 8, 50 (s, 1H), 7.86 (s, 1H), 7.78 (d, J =8.0 Hz, 1H), 7.61 (d, J =8.3 Hz, 1H), 7, 44 (t, J =7.7 Hz, 1H), 7.37 (d, J =7.8 Hz, 1H), 7.26 (t, J =51.6 Hz, 1H), 5.93 ( s, 2H), 3.63 (s, 2H), 3.37 (s, 4H), 2.60 (s, 3H), 2.29 (s, 6H); MSNR (ER) m/z 369.3 (M ⁺ +1). 89 3919 1-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)phenyl)-N-methylmethanamine
¹ H NMR (400 MHz, CD ₃ OD) δ 9.28 (d, J = 2.2 Hz, 1H), 8.53 (dd, J = 8.2, 2.3 Hz, 1H), 8, 50 (s, 1H), 7.85 (s, 1H), 7.80 (d, J =7.7 Hz, 1H), 7.61 (d, J =8.1 Hz, 1H), 7, 46 (t, J =7.7 Hz, 1H), 7.40-7.12 (m, 2H), 5.93 (s, 2H), 3.83 (s, 2H), 2.45 (s , 3H); MSNR (ER) m/z 398.3 (M ⁺ +1). 108 3963 2-(6-((4-(3-(azetidin-1-ylmethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl) -1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.31-9.25 (m, 1H), 8.53 (dd, J =8.2, 2.2 Hz, 1H), 8.51 (s , 1H), 7.84-7.77 (m, 2H), 7.61 (d, J =8.2 Hz, 1H), 7.45 (t, J =7.6 Hz, 1H), 7 .34 (d, J =8.0 Hz, 1H), 7.26 (t, J =51.6 Hz, 1H), 5.93 (s, 2H), 3.80 (s, 2H), 3 .48 (t, J =7.3 Hz, 4H), 2.21 (p, J =7.3 Hz, 2H); MSNR (ER) m/z 424.3 (M ⁺ +1). 109 3964 2-(difluoromethyl)-5-(6-((4-(3-((3-fluoroazetidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridine -3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.28 (d, J = 2.2 Hz, 1H), 8.53 (dd, J = 8.2, 2.3 Hz, 1H), 8, 50 (d, J =1.8 Hz, 1H), 7.88-7.75 (m, 2H), 7.60 (d, J =8.2 Hz, 1H), 7.44 (td, J =7.6, 2.8 Hz, 1H), 7.33 (d, J =7.7 Hz, 1H), 7.26 (t, J =51.6 Hz, 1H), 5.93 (s , 2H), 5.26-5.04 (m, 1H), 3.77 (s, 2H), 3.74-3.61 (m, 2H), 3.41-3.33 (m, 7H ); MSNR (ER) m/z 442.3 (M ⁺ +1). 110 3965 6-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)benzyl)-2-oxa-6-azaspiro[3,3]heptane
¹ H NMR (400 MHz, CD ₃ OD) δ 7.78-7.73 (m, 1H), 7.00 (dd, J =8.2, 2.3 Hz, 1H), 6.97 (s , 1H), 6.25 (dd, J =7.4, 1.4 Hz, 2H), 6.08 (d, J =8.2 Hz, 1H), 5.90 (td, J =7, 4, 1.0 Hz, 1H), 5.77 (dt, J =7.6, 1.5 Hz, 1H), 5.73 (t, J =51.6 Hz, 1H), 4.40 ( s, 2H), 3.22 (s, 4H), 2.13 (s, 2H), 1.96 (s, 4H); MSNR (ER) m/z 466.4 (M ⁺ +1). 111 3966 2-(difluoromethyl)-5-(6-((4-(3-(pyrrolidin-1-ylmethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl) -1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.31-9.25 (m, 1H), 8.53 (dd, J =8.2, 2.2 Hz, 1H), 8.50 (s , 1H), 7.86 (d, J =1.8 Hz, 1H), 7.80 (dt, J =7.7, 1.5 Hz, 1H), 7.60 (d, J =8, 2 Hz, 1H), 7.45 (t, J =7.7 Hz, 1H), 7.40-7.36 (m, 1H), 7.26 (d, J =51.6 Hz, 1H) , 5.93 (s, 2H), 3.77 (s, 2H), 2.71-2.63 (m, 4H), 1.86 (p, J =3.2 Hz, 4H); MSNR (ER) m/z 438.3 (M ⁺ +1). 284 4400 2-(6-((4-(3-((3,3-difluoroazetidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl )-5-(difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.28 (dd, J = 2.3, 0.8 Hz, 1H), 8.56-8.48 (m, 2H), 7.83 (d , J =1.9 Hz, 1H), 7.79 (dt, J =7.7, 1.5 Hz, 1H), 7.60 (dd, J =8.2, 0.9 Hz, 1H) , 7.44 (t, J =7.6 Hz, 1H), 7.35 (dt, J =7.9, 1.4 Hz, 1H), 7.26 (t, J =51.6 Hz, 1H), 5.93 (s, 2H), 3.84 (d, J =1.9 Hz, 2H), 3.68 (t, J =12.1 Hz, 4H); MSNR (ER) m/z 460.3 (M ⁺ +1). 285 4401 2-(difluoromethyl)-5-(6-((4-(3-((4,4-difluoropiperidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl )pyridin-3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.28 (d, J = 2.3 Hz, 1H), 8.52 (d, J = 11.6 Hz, 2H), 7.86 (d, J =2.1 Hz, 1H), 7.77 (d, J =7.7 Hz, 1H), 7.60 (d, J =8.2 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.37 (d, J =7.6 Hz, 1H), 7.26 (t, J =51.6 Hz, 1H), 5.93 (s, 2H), 3 .65 (s, 2H), 2.62 (t, J =5.8 Hz, 4H), 2.01 (ddt, J =19.4, 12.6, 5.6 Hz, 4H); MSNR (ER) m/z 488.5 (M ⁺ +1).

Example 92: Synthesis of compound 3944 , 4-((6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H- 1,2,3-triazol-4-yl)-1H-indol-3-yl)methyl)morpholine

[Step 1] Synthesis of 3-(morpholinomethyl)-1H-indole-6-carbaldehyde

Morpholine (0.238 ml, 2.755 mmol) and formaldehyde (37.00%, 0.224 g, 2.755 mmol) are dissolved in acetic acid (3 ml), after which the resulting solution is stirred at 0°C for 0.4 hour, and then 1H α-indole-6-carbaldehyde (0.260 g, 1.791 mmol) was added and then stirred at room temperature for 18 hours. an aqueous solution of 1N-sodium hydroxide is poured into the resulting reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=0-60%) and concentrated to give 3-(morpholinomethyl)-1H-indole-6-carbaldehyde (0.180 g, 26.7%) as light yellow oil.

[Step 2] Synthesis of 4-((6-ethynyl-1H-indol-3-yl)methyl)morpholine

3-(Morpholinomethyl)-1H-indole-6-carbaldehyde (0.100 g, 0.409 mmol) obtained in step 1, dimethyl (1-diazo-2-oxopropyl)phosphonate (0.094 g, 0.491 mmol) and potassium carbonate (0.113 g , 0.819 mmol) was dissolved in methanol (3 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting concentrate is poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=90-40%) and concentrated to give 4-((6-ethynyl-1H-indol-3-yl)methyl)morpholine (0.050 g, 50 .8%) in the form of a white solid.

[Step 3] Synthesis of compound 3944

2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.030 g, 0.119 mmol) prepared in Step 1 of Example 16, and 4-((6- Ethynyl-1H-indol-3-yl)methyl)morpholine (0.026 g, 0.107 mmol) obtained in step 2 is dissolved in tert-butanol (1 ml)/water (1 ml) at room temperature, followed by sodium ascorbate ( 1.00 M solution, 0.012 ml, 0.012 mmol) and copper(II) sulfate pentahydrate (0.50 M solution, 0.002 ml, 0.001 mmol) were added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution is poured into the reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-70%) and concentrated to give 4-((6-(1-((5-(5-(difluoromethyl)-1,3, 4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indol-3-yl)methyl)morpholine (0.025 g, 42.7 %) in the form of a white solid.

¹ H NMR(400 MHz, CD₃OD) δ 9.30 (dd,J=2.2, 0.9 Hz, 1H), 8.54 (dd,J=8.2, 2.3 Hz, 1H), 8.44 (s, 1H), 7.90 (dd,J=1.5, 0.7 Hz, 1H), 7.75 (dd,J=8.3, 0.8 Hz, 1H), 7.60 (d,J=8.0 Hz, 1H), 7.53 (dd,J=8.3, 1.5 Hz, 1H), 7.30 (s, 1H), 7.26 (t,J=51.6 Hz, 1H), 5.93 (s, 2H), 3.77 (s, 2H), 3.71 (t,J=4.7 Hz, 4H), 2.58 (s, 4H);MCNR(ER) m/z 393.3 (M⁺+1).

The compounds of Table 23 were synthesized in accordance with substantially the same method as described above for the synthesis of compound 3944, except for the use of 4-((6-ethynyl-1H-indol-3-yl)methyl)morpholine and the reagent from Table 22.

Table 22 Example Connection no. Reagent Exit (%) 169 4112 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 36 174 4134 2-(4-(azidomethyl)pyridyl)-5-(difluoromethyl)-1,3,4-oxadiazole 42

Table 23 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 169 4112 4-((6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazole -4-yl)-1H-indol-3-yl)methyl)morpholine
¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 8.03-7.93 (m, 2H), 7.89 (dd, J = 1.5, 0.7 Hz , 1H), 7.74 (dd, J =8.3, 0.7 Hz, 1H), 7.61 (t, J =7.6 Hz, 1H), 7.51 (dd, J =8, 3, 1.5 Hz, 1H), 7.30 (s, 1H), 7.24 (t, J =51.6 Hz, 1H), 5.86 (s, 2H), 3.77 (s, 2H), 3.71 (t, J =4.7 Hz, 4H), 2.61-2.53 (m, 4H); MSNR (ER) m/z 510.1 (M ⁺ +1). 171 4134 4-((6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-1H -indol-3-yl)methyl)morpholine
^1H NMR (400 MHz, CDCl ₃ ) δ 8.04 (d, J =8.0 Hz, 2H), 7.98 (s, 1H), 7.88 (s, 1H), 7.59 (d , J =12.5 Hz, 2H), 7.43 (t, J =7.5 Hz, 3H), 6.80 (d, J =51.8 Hz, 1H), 5.63 (s, 2H ), 4.34 (s, 2H), 3.98-3.82 (m, 4H), 3.32-3.26 (m, 2H), 2.96-2.87 (m, 2H); MSNR (ER) m/z 492.5 (M ⁺ +1).

Example 93: Synthesis of Compound 3945, 2-(difluoromethyl)-5-(6-((2-methyl-4-phenyl-1H-imidazol-1-yl)methyl)pyridin-3-yl)-1,3,4 -oxadiazole

[Step 1] Synthesis of 2-(6-((4-bromo-2-methyl-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

4-bromo-2-methyl-1H-imidazole (0.200 g, 1.242 mmol), 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.360 g , 1.242 mmol) and potassium carbonate (0.343 g, 2.484 mmol) were dissolved in N,N-dimethylformamide (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 3 hours. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give 2-(6-((4-bromo-2-methyl-1H-imidazol-1-yl)methyl )pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.308 g, 67.0%) as a yellow solid.

[Step 2] Synthesis of compound 3945

2-(6-((4-Bromo-2-methyl-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.100 g, 0.270 mmol) obtained in step 1, phenylboronic acid (0.033 g, 0.270 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) (Pd(dtbpf)Cl ₂ , 0.018 g, 0.027 mmol) and cesium carbonate (0.156 g, 0.810 mmol) are mixed in 1,4-dioxane (3 ml)/water (1 ml) at room temperature, after which the resulting mixture is irradiated with microwaves, then heated at 100 ° C for 20 minutes, and then the reaction is completed by lowering the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give 2-(difluoromethyl)-5-(6-((2-methyl-4-phenyl-1H-imidazole -1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.032 g, 32.2%) in the form of a brown solid.

¹ H NMR(400 MHz, CD₃OD) δ 9.28 (d,J=2.2 Hz, 1H), 8.50 (dd,J=8.2, 2.3 Hz, 1H), 7.75-7.68 (m, 2H), 7.51 (s, 1H), 7.44 (dd,J=8.3, 3.0 Hz, 1H), 7.40-7.33 (m, 2H), 7.27-7.11 (m, 2H), 5.43 (d,J=23.7 Hz, 2H), 2.41 (d,J=29.3 Hz, 3H);MCNR(ER) m/z 368.2 (M⁺+1).

Example 94: Synthesis of Compound 3949, 2-(6-((4-bromo-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

4-bromo-1H-imidazole (0.200 g, 1.361 mmol), 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.395 g, 1.361 mmol) and potassium carbonate (0.376 g, 2.721 mmol) were dissolved in N,N-dimethylformamide (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 3 hours. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give 2-(6-((4-bromo-1H-imidazol-1-yl)methyl)pyridin-3 -yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.344 g, 71.0%) as a yellow solid.

¹ H NMR(400 MHz, CD₃OD) δ 9.26 (dd,J=2.3, 0.9 Hz, 1H), 8.51 (dd,J=8.2, 2.2 Hz, 1H), 7.81 (d,J=1.5 Hz, 1H), 7.51 (dd,J=8.2, 0.9 Hz, 1H), 7.30 (d,J=1.5 Hz, 1H), 7.26 (t,J=51.6 Hz, 1H), 5.47 (s, 2H);MCNR(ER) m/z 358.1 (M⁺+1).

Example 95: Synthesis of Compound 3950, 2-(difluoromethyl)-5-(6-((4-phenyl-1H-imidazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

2-(6-((4-Bromo-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.100 g, 0.281 mmol), which is compound 3949 from Example 94, phenylboronic acid (0.034 g, 0.281 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) (Pd(dtbpf)Cl ₂ , 0.018 g, 0.028 mmol) and cesium carbonate (0.163 g, 0.842 mmol) are mixed in 1,4-dioxane (3 ml)/water (1 ml) at room temperature, after which the resulting mixture is irradiated with microwaves, then heated at 100 ° C for 20 minutes, and then the reaction is completed by lowering the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-phenyl-1H-imidazol-1-yl )methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.007 g, 7.1%) in the form of a brown oil.

¹ H NMR(400 MHz, CD₃OD) δ 9.27 (ddd,J=7.2, 2.2, 0.8 Hz, 1H), 8.50 (dt,J=8.2, 1.9 Hz, 1H), 7.86 (dd,J=44.8, 1.4 Hz, 1H), 7.76-7.69 (m, 1H), 7.60 (d,J=1.4 Hz, 1H), 7.51 (dd,J=8.2, 3.8 Hz, 1H), 7.44-7.32 (m, 2H), 7.31-7.11 (m, 2H), 5.49 (d,J=22.3 Hz, 2H);MCNR(ER) m/z 353.3 (M⁺+1).

Example 96: Synthesis of compound 3951, 2-(difluoromethyl)-5-(6-((4-(1-ethylazetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin- 3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of 2-(6-((4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl) -1,3,4-oxadiazole

Tert-butyl 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)azetidine-1-carboxylate (0.625 g, 1.442 mmol) obtained in Example 91 and trifluoroacetic acid (1.104 ml, 14.420 mmol) were dissolved in dichloromethane (10 ml) at room temperature, after which the resulting solution was stirred at same temperature for 4 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without further purification process (2-(6-((4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl) methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole, 0.480 g, 99.9%, yellow oil).

[Step 2] Synthesis of compound 3951

2-(6-((4-(Azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3, 4-oxadiazole (0.040 g, 0.120 mmol) obtained in step 1 and acetaldehyde (0.013 ml, 0.240 mmol) are dissolved in dichloromethane (1 ml), after which the resulting solution is stirred at room temperature for 15 minutes, and then triacetoxyborohydride is added sodium (0.076 g, 0.360 mmol) and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(1-ethylpiperidin-3-yl) -1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.013 g, 30.0%) as a white solid.

¹ H NMR(400 MHz, CD₃OD) δ 9.25 (dd,J=2.2, 0.9 Hz, 1H), 8.51 (dd,J=8.2, 2.2 Hz, 1H), 8.08 (s, 1H), 7.56 (dd,J=8.2, 0.9 Hz, 1H), 7.26 (t,J=51.6 Hz, 1H), 5.86 (s, 2H), 4.03-3.91 (m, 3H), 3.60 (s, 2H), 2.82 (sq,J=7.3 Hz, 2H), 1.09 (t,J=7.2 Hz, 3H);MCNR(ER) m/z 362.3 (M⁺+1).

The compounds of Table 25 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 3951, except for the use of 2-(6-((4-(azetidin-3-yl)-1H-1,2,3- triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole and the reagent from Table 24.

Table 24 Example Connection no. Reagent Exit (%) 97 3952 Acetone 76 98 3953 Butyraldehyde 77 99 3954 Cyclobutanone 60 100 3955 Oxetanone 62

Table 25 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 97 3952 2-(difluoromethyl)-5-(6-((4-(1-isopropylazetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.25 (dd, J=2.3, 0.9 Hz, 1H), 8.51 (dd, J=8.2, 2.2 Hz, 1H ), 8.09 (s, 1H), 7.57 (dd, J=8.2, 0.8 Hz, 1H), 7.26 (t, J=51.6 Hz, 1H), 5.86 (s, 2H), 4.07-3.99 (m, 2H), 3.99-3.87 (m, 1H), 3.67 (t, J=7.8 Hz, 2H), 2, 90 (p, J=6.3 Hz, 1H), 1.10 (d, J=6.3 Hz, 6H); MSNR (IER) m/z 376.3 (M ⁺ + H). 98 3953 2-(6-((4-(1-butylazetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.19 (dd, J=2.3, 0.9 Hz, 1H), 8.48 (dd, J=8.2, 2.3 Hz, 1H), 8.19 (s, 1H), 7.59 (t, J=51.3 Hz, 1H), 7.52 (dd, J=8.2, 0.9 Hz, 1H), 5, 85 (s, 2H), 3.87 (s, 3H), 3.47 (s, 2H), 2.69 (s, 2H), 1.32 (kW, J=5.7, 3.4 Hz , 4H), 0.92-0.84 (m, 3H); MSNR (IER) m/z 390.3 (M ⁺ + H). 99 3954 2-(6-((4-(1-cyclobutylazetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.19 (dd, J=2.3, 0.8 Hz, 1H), 8.48 (dd, J=8.2, 2.3 Hz, 1H), 8.19 (s, 1H), 7.58 (t, J=51.2 Hz, 1H), 7.52 (dd, J=8.2, 0.9 Hz, 1H), 5, 85 (s, 2H), 3.82 (s, 3H), 3.51 (s, 3H), 2.00 (dd, J=10.7, 5.9 Hz, 2H), 1.95-1 .83 (m, 2H), 1.80-1.61 (m, 2H); MSNR (IER) m/z 388.3 (M ⁺ + H). 100 3955 2-(difluoromethyl)-5-(6-((4-(1-(oxetan-3-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin- 3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.26 (dd, J=2.3, 0.9 Hz, 1H), 8.51 (dd, J=8.2, 2.3 Hz, 1H ), 8.09 (d, J=0.5 Hz, 1H), 7.55 (dd, J=8.2, 0.8 Hz, 1H), 7.26 (t, J=51.6 Hz , 1H), 5.85 (s, 2H), 4.77 (td, J=6.7, 0.6 Hz, 2H), 4.56 (ddd, J=6.8, 5.0, 0 .6 Hz, 2H), 3.98-3.85 (m, 2H), 3.85-3.76 (m, 2H), 3.51-3.42 (m, 2H); MSNR (IER) m/z 390.3 (M ⁺ + H).

Example 101: Synthesis of compound 3956 , 1-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1 ,2,3-triazol-4-yl)azetidin-1-yl)ethan-1-one

2-(6-((4-(Azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3, 4-oxadiazole (0.040 g, 0.120 mmol) prepared in step 1 of Example 96 and N,N-diisopropylethylamine (0.042 ml, 0.240 mmol) were dissolved in dichloromethane (1 ml) at room temperature, followed by acetyl chloride (0.010 ml, 0.144 mmol) is added to the resulting solution and stirred at the same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 1-(3-(1-((5-(5-(difluoromethyl)-1,3,4 -oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)azetidin-1-yl)ethan-1-one (0.028 g, 62.2%) in the form of a white solid.

¹ H NMR(400 MHz, CD₃OD) δ 9.28-9.23 (m, 1H), 8.51 (dd,J=8.2, 2.2 Hz, 1H), 8.13 (s, 1H), 7.56 (d,J=8.0 Hz, 1H), 7.26 (t,J=51.6 Hz, 1H), 5.87 (s, 2H), 4.63 (t,J=8.5 Hz, 1H), 4.45-4.33 (m, 2H), 4.15-4.00 (m, 2H), 1.92 (s, 3H);MCNR(ER) m/z 376.2 (M⁺+1).

The compounds of Table 27 were synthesized in accordance with substantially the same method as described above for the synthesis of compound 3956, except for the use of 2-(6-((4-(azetidin-3-yl)-1H-1,2,3- triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole and the reagent from Table 26.

Table 26 Example Connection no. Reagent Exit (%) 102 3957 Propionyl chloride 36 103 3958 Isobuturyl chloride 45 104 3959 Methyl carbonochloridate 60

Table 27 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 102 3957 1-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)azetidin-1-yl)propan-1-one
¹ H NMR (400 MHz, CD ₃ OD) δ 9.26 (dd, J=2.3, 0.9 Hz, 1H), 8.51 (dd, J=8.2, 2.2 Hz, 1H ), 8.12 (s, 1H), 7.56 (dd, J=8.2, 0.8 Hz, 1H), 7.26 (t, J=51.6 Hz, 1H), 5.87 (s, 2H), 4.62 (t, J=8.4 Hz, 1H), 4.45-4.31 (m, 2H), 4.15 &#8211; 4.01 (m, 2H), 2.21 (kv, J=7.6 Hz, 2H), 1.13 (t, J=7.6 Hz, 3H); MSNR (IER) m/z 390.2 (M ⁺ + H). 103 3958 1-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)azetidin-1-yl)-2-methylpropan-1-one
¹ H NMR (400 MHz, CD ₃ OD) δ 9.26 (dd, J=2.3, 0.9 Hz, 1H), 8.51 (dd, J=8.2, 2.3 Hz, 1H ), 8.12 (s, 1H), 7.56 (dd, J=8.2, 0.9 Hz, 1H), 7.26 (t, J=51.6 Hz, 1H), 5.87 (s, 2H), 4.71-4.62 (m, 1H), 4.45-4.35 (m, 2H), 4.15-4.03 (m, 2H), 2.60 (g , J=6.8 Hz, 1H), 1.12 (dd, J=6.8, 3.0 Hz, 6H); MSNR (IER) m/z 404.2 (M ⁺ + H). 104 3959 Methyl 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4- yl)azetidine-1-carboxylate
¹ H NMR (400 MHz, CD ₃ OD) δ 9.25 (dd, J=2.2, 0.9 Hz, 1H), 8.51 (dd, J=8.2, 2.2 Hz, 1H ), 8.11 (d, J=0.5 Hz, 1H), 7.55 (dkv, J=8.2, 0.6 Hz, 1H), 7.26 (t, J=51.6 Hz , 1H), 5.86 (s, 2H), 4.40 (t, J=8.5 Hz, 2H), 4.14 (t, J=7.2 Hz, 2H), 4.03 (dddd , J=9.0, 8.4, 6.3, 5.7 Hz, 1H), 3.69 (s, 3H); MSNR (IER) m/z 392.2 (M ⁺ + H).

Example 107: Synthesis of compound 3962 , 1-(6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1 ,2,3-triazol-4-yl)-1H-indol-3-yl)-N,N-dimethylmethanamine

[Step 1] Synthesis of 3-((dimethylamino)methyl)-1H-indole-6-carbaldehyde

Dimethylamine (2.00 M solution in THF, 1.331 ml, 2.661 mmol) and formaldehyde (37.00%, 0.216 g, 2.661 mmol) were dissolved in acetic acid (3 ml), after which the resulting solution was stirred at 0°C for 0.4 hours, and then 1H-indole-6-carbaldehyde (0.251 g, 1.730 mmol) was added and then stirred at room temperature for 18 hours. An aqueous solution of 1N-sodium hydroxide is poured into the resulting reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=0-60%) and concentrated to give 3-((dimethylamino)methyl)-1H-indole-6-carbaldehyde (0.070 g, 13.0% ) in the form of a light yellow oil.

[Step 2] Synthesis of 1-(6-ethynyl-1H-indol-3-yl)-N,N-dimethylmethanamine

3-((Dimethylamino)methyl)-1H-indole-6-carbaldehyde (0.100 g, 0.494 mmol) obtained in step 1, dimethyl (1-diazo-2-oxopropyl)phosphonate (0.114 g, 0.593 mmol) and potassium carbonate (0.137 g, 0.989 mmol) was dissolved in methanol (3 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting concentrate is poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=90-40%) and concentrated to give 1-(6-ethynyl-1H-indol-3-yl)-N,N-dimethylmethanamine (0.020 g , 20.4%) in the form of a colorless oil.

[Step 3] Synthesis of compound 3962

2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.198 mmol) prepared in Step 1 of Example 16, and 1-(6-ethynyl- 1H-indol-3-yl)-N,N-dimethylmethanamine (0.035 g, 0.178 mmol) obtained in step 2 is dissolved in tert-butanol (1 ml)/water (1 ml) at room temperature, followed by sodium ascorbate (1.00 M solution, 0.020 ml, 0.020 mmol) and copper(II) sulfate pentahydrate (0.50 M solution, 0.004 ml, 0.002 mmol) were added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution is poured into the reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate is purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-70%) and concentrated, after which the resulting product is purified again by column chromatography (SiO ₂ plate, 20x20x1 mm; dichloromethane/methanol=80%) and concentrate to give 1-(6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2, 3-triazol-4-yl)-1H-indol-3-yl)-N,N-dimethylmethanamine (0.010 g, 11.2%)) in the form of a light yellow gum.

¹ H NMR(400 MHz, CD₃OD) δ 9.29 (s, 1H), 8.54 (dd,J=8.2, 2.3 Hz, 1H), 8.50 (s, 1H), 8.00 (s, 1H), 7.82 (d,J=8.3 Hz, 1H), 7.70-7.65 (m, 1H), 7.65-7.59 (m, 2H), 7.26 (t,J=51.6 Hz, 1H), 5.94 (s, 2H), 3.59 (d,J=10.8 Hz, 2H), 2.90 (s, 6H);MCNR(ER) m/z 451.2 (M⁺+1).

Example 112: Synthesis of Compound 3980, 2-(difluoromethyl)-5-(4-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of methyl 4-(2-(2-benzoylhydrazinyl)-2-oxoethyl)benzoate

Benzohydrazide (0.500 g, 3.672 mmol), 2-(4-(methoxycarbonyl)phenyl)acetic acid (0.927 g, 4.774 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3 3-oxide hexafluorophosphate -triazolo[4,5-b]pyridinium (1.815 g, 4.774 mmol) was dissolved in N,N-dimethylformamide (50 ml), after which the resulting solution was stirred at room temperature for 30 hours, and then N, N- was added thereto diisopropylethylamine (1.663 ml, 9.548 mmol) and then stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was used without further purification process (methyl 4-(2-(2-benzoylhydrazinyl)-2-oxoethyl)benzoate, 1,000 g, 87.2%, white solid).

[Step 2] Synthesis of methyl 4-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)benzoate

Methyl 4-(2-(2-benzoylhydrazinyl)-2-oxoethyl)benzoate (1.000 g, 3.202 mmol) prepared in step 1, and 1-methoxy-N-triethylammoniosulfonyl methanimidate (Burgess Reagent, 2.289 g, 9.605 mmol) mixed in tetrahydrofuran (20 ml) at room temperature, after which the resulting mixture was heated at reflux for 12 hours and cooled to room temperature. Then, water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-40%) and concentrated to give methyl 4-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl) benzoate (0.600 g, 63.7%) in the form of a white solid.

[Step 3] Synthesis of methyl 4-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)benzoate

Methyl 4-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)benzoate (0.600 g, 2.039 mmol) obtained in step 2 and hydrazine monohydrate (0.991 ml, 20.387 mmol) are dissolved in ethanol (50 ml) at 90°C, after which the resulting solution was stirred at the same temperature for 12 hours, and then the reaction was completed by lowering the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was then used without further purification process (4-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)benzohydrazide, 0.380 g, 63.3%, white solid).

[Step 4] Synthesis of compound 3980

4-((5-Phenyl-1,3,4-oxadiazol-2-yl)methyl)benzohydrazide (0.380 g, 1.291 mmol) obtained in step 3, imidazole (0.264 g, 3.873 mmol) and 2,2-difluoroacetic the anhydride (0.482 ml, 3.873 mmol) is mixed in dichloromethane (20 ml) at room temperature, after which the resulting mixture is refluxed for 12 hours and cooled to room temperature. Water is then poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-60%) and concentrated to give 2-(difluoromethyl)-5-(4-((5-phenyl-1,3,4-oxadiazole -2-yl)methyl)phenyl)-1,3,4-oxadiazole (0.120 g, 26.2%) as a white solid.

¹ H NMR (400 MHz, CDCl₃) δ 8.15 (d,J=8.3 Hz, 2H), 8.08-7.99 (m, 2H), 7.63-7.45 (m, 5H), 7.06 (s, 0.2H), 6.93 ( s, 0.5H), 6.80 (s, 0.3H), 4.41 (s, 2H).

Example 113: Synthesis of Compound 3981, 2-(difluoromethyl)-5-(4-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-1,3 ,4-oxadiazole

[Step 1] Synthesis of methyl 4-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)methyl)benzoate

Methyl 4-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)benzoate (0.210 g, 0.714 mmol) prepared in step 2 of Example 112, acetic acid (0.163 ml, 2.854 mmol) and methanamine (2.00 M solution in THF, 8.919 ml, 17.838 mmol) was mixed at 150° C., after which the reaction mixture was stirred at the same temperature for 12 hours, and then the reaction was terminated by reducing the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-70%) and concentrated to give methyl 4-((4-methyl-5-phenyl-4H-1,2,4-triazol- 3-yl)methyl)benzoate (0.100 g, 45.6%) in the form of a white solid.

[Step 2] Synthesis of 4-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)methyl)benzohydrazide

Methyl 4-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)methyl)benzoate (0.100 g, 0.325 mmol) obtained in step 1 and hydrazine monohydrate (0.158 ml, 3.254 mmol) was dissolved in ethanol (15 ml) at 90°C, after which the resulting solution was stirred at the same temperature for 12 hours, and then the reaction was completed by lowering the temperature to room temperature. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without further purification process (4-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)methyl)benzohydrazide, 0.081 g, 81.0%, white solid).

[Step 3] Synthesis of compound 3981

4-((4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)methyl)benzohydrazide (0.080 g, 0.260 mmol) obtained in step 2, imidazole (0.053 g, 0.781 mmol) and 2,2-difluoroacetic anhydride (0.097 ml, 0.781 mmol) were mixed in dichloromethane (30 ml) at room temperature, after which the resulting mixture was refluxed for 12 hours and cooled to room temperature. Water is then poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-methyl-5-phenyl-4H-1 ,2,4-triazol-3-yl)methyl)phenyl)-1,3,4-oxadiazole (0.061 g, 63.8%) as a white solid.

¹ H NMR (400 MHz, CDCl₃) δ 8.12 (d,J=8.3 Hz, 2H), 7.69-7.58 (m, 2H), 7.52 (dd,J=7.6, 4.7 Hz, 5H), 7.06 (s, 0.2H), 6.93 (s, 0.5H), 6.80 (s, 0.3H), 4.39 ( s, 2H), 3.51 (s, 3H);MCNR(ER) m/z 368.4 (M⁺+1).

Example 115: Synthesis of Compound 3986, 2-(difluoromethyl)-5-(6-((4-(3-((4-methylpiperazin-1-yl)methyl)-1H-indol-6-yl)-1H-1 ,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of 3-((4-methylpiperazin-1-yl)methyl)-1H-indole-6-carbaldehyde

1-Methylpiperazine (0.278 ml, 2.496 mmol) and formaldehyde (37.00%, 0.203 g, 2.496 mmol) were dissolved in acetic acid (3 ml), after which the resulting solution was stirred at 0°C for 0.4 hours, and then 1H-indole-6-carbaldehyde (0.235 g, 1.622 mmol) was added and then stirred at room temperature for 18 hours. An aqueous solution of 1N-sodium hydroxide is poured into the resulting reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=0-60%) and concentrated to give 3-((4-methylpiperazin-1-yl)methyl)-1H-indole-6-carbaldehyde (0.100 g, 15.6%) in the form of a light yellow oil.

[Step 2] Synthesis of 6-ethynyl-3-((4-methylpiperazin-1-yl)methyl)-1H-indole

3-((4-Methylpiperazin-1-yl)methyl)-1H-indole-6-carbaldehyde (0.100 g, 0.389 mmol) obtained in step 1, dimethyl(1-diazo-2-oxopropyl)phosphonate (0.090 g, 0.466 mmol) and potassium carbonate (0.107 g, 0.777 mmol) were dissolved in methanol (3 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting concentrate is poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=90-40%) and concentrated to give 6-ethynyl-3-((4-methylpiperazin-1-yl)methyl)-1H-indole (0.030 g, 30.5%) in the form of a white solid.

[Step 3] Synthesis of compound 3986

2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.020 g, 0.079 mmol) prepared in Step 1 of Example 16 and 6-ethynyl-3- ((4-methylpiperazin-1-yl)methyl)-1H-indole (0.018 g, 0.071 mmol) obtained in step 2 is dissolved in tert-butanol (1 ml)/water (1 ml) at room temperature, then Sodium ascorbate (1.00 M solution, 0.008 ml, 0.008 mmol) and copper(II) sulfate pentahydrate (0.50 M solution, 0.002 ml, 0.001 mmol) were added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous solution of ammonium chloride is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-70%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(3-((4-methylpiperazine- 1-yl)methyl)-1H-indol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.007 g, 17.5%) in the form of light yellow gum.

¹ H NMR(400 MHz, CD₃OD) δ 9.29 (d,J=2.4 Hz, 1H), 8.54 (dd,J=8.2, 2.3 Hz, 1H), 8.47 (s, 1H), 7.94 (d,J=1.3 Hz, 1H), 7.79 (d,J=8.3 Hz, 1H), 7.61 (t,J=9.6 Hz, 2H), 7.44 (s, 1H), 7.26 (t,J=51.6 Hz, 1H), 5.93 (s, 2H), 4.17 (s, 2H), 3.27-2.78 (m, 8H), 2.62 (s, 3H);MCNR(ER) m/z 506.4 (M⁺+1).

Example 116: Synthesis of compound 3987 , N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1 ,2,3-triazol-4-yl)phenyl)-2-fluoro-2-methylpropanamide

3-(1-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl )aniline (0.050 g, 0.135 mmol) obtained in step 1 of Example 36 and 2-fluoro-2-methylpropanoic acid (0.017 g, 0.162 mmol) were dissolved in dichloromethane (2 ml) at room temperature, after which 3-oxide hexafluorophosphate 1 -[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium (0.103 g, 0.271 mmol) and N,N-diisopropylethylamine (0.047 ml, 0.271 mmol) were added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous sodium chloride solution is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate is purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 0-30%) and concentrated, after which the resulting product is purified again by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane = 0-20%) and concentrated to give N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2, 3-triazol-4-yl)phenyl)-2-fluoro-2-methylpropanamide (0.025 g, 40.4%) as a white solid.

¹ H NMR(400 MHz, CDCl₃) δ 9.37 (s, 1H), 8.45 (dd,J=8.4, 2.3 Hz, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 7.72 (d,J=7.7 Hz, 1H), 7.59 (d,J=8.6 Hz, 1H), 7.45 (t,J=8.0 Hz, 2H), 6.97 (t,J=51.7 Hz, 1H), 5.85 (s, 2H), 1.67 (s, 6H);MCNR(ER) m/z 358.3 (M⁺+1).

The compounds of Table 29 were synthesized in accordance with substantially the same method as described above for the synthesis of compound 3987 except for the use of 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2- yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)aniline and the reagent from Table 28.

Table 28 Example Connection no. Reagent Exit (%) 190 4229 3-(dimethylamino)propanoic acid 39 191 4230 Dimethylglycine 46 192 4231 2-(dimethylamino)-2-methylpropanoic acid thirty 369 4495 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid 58 370 4496 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid 58

Table 29 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 190 4229 N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)phenyl)-3-(dimethylamino)propanamide
^1H NMR (400 MHz, CD ₃ OD) δ 9.26 (dd, J =2.2, 0.8 Hz, 1H), 8.51 (dd, J =8.2, 2.2 Hz, 1H ), 8.49 (s, 1H), 8.14 (t, J =1.9 Hz, 1H), 7.61 (dd, J =8.2, 0.8 Hz, 1H), 7.57 (ddd, J =8.3, 2.8, 1.2 Hz, 2H), 7.43-7.12 (m, 2H), 5.93 (s, 2H), 3.51 (t, J =6.4 Hz, 2H), 2.98 (d, J =6.4 Hz, 2H), 2.96 (s, 6H); MSNR (ER) m/z 469.3 (M ⁺ +1). 191 4230 N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)phenyl)-2-(dimethylamino)acetamide
^1H NMR (400 MHz, CD ₃ OD) δ 9.26 (dd, J =2.2, 0.9 Hz, 1H), 8.51 (dd, J =8.2, 2.2 Hz, 1H ), 8.48 (s, 1H), 8.10 (t, J =1.9 Hz, 1H), 7.60 (dddd, J =8.2, 5.5, 3.0, 1.2 Hz, 3H), 7.42 (t, J =7.9 Hz, 1H), 7.25 (t, J =51.6 Hz, 1H), 5.92 (s, 2H), 3.32 ( s, 2H), 2.50 (s, 6H); MSNR (ER) m/z 455.4 (M ⁺ +1). 192 4231 N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)phenyl)-2-(dimethylamino)-2-methylpropanamide
^1H NMR (400 MHz, CD ₃ OD) δ 9.27 (dd, J =2.2, 0.9 Hz, 1H), 8.58 (s, 1H), 8.54 (dd, J =8 ,2, 2.2 Hz, 1H), 8.35 (d, J =8.4 Hz, 1H), 7.70 (dt, J =7.8, 1.2 Hz, 1H), 7.64 (dd, J =8.2, 0.9 Hz, 1H), 7.61 (t, J =1.9 Hz, 1H), 7.54 (t, J =7.9 Hz, 1H), 7 .46 (dd, J =8.3, 4.3 Hz, 1H), 7.26 (t, J =51.6 Hz, 1H), 7.07 (ddd, J =8.0, 2.3 , 1.0 Hz, 1H), 5.94 (s, 2H), 3.04 (s, 12H); MSNR (ER) m/z 483.3 (M ⁺ +1). 369 4495 tert-butyl (1-((3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2 ,3-triazol-4-yl)phenyl)carbamoyl)cyclobutyl)carbamate
^1H NMR (400 MHz, CD ₃ OD) δ 9.28 (dd, J =2.3, 0.9 Hz, 1H), 8.53 (dd, J =8.2, 2.3 Hz, 1H ), 8.47 (s, 1H), 8.05 (s, 1H), 7.65-7.57 (m, 2H), 7.55 (s, 1H), 7.46-7.10 ( m, 2H), 5.93 (s, 2H), 1.52 (s, 6H), 1.44 (s, 9H); MSNR (ER) m/z 555.5 (M ⁺ +1). 370 4496 tert-butyl (1-((3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2 ,3-triazol-4-yl)phenyl)carbamoyl)cyclobutyl)carbamate
¹ H NMR (400 MHz, CD ₃ OD) δ 9.31-9.26 (m, 1H), 8.52 (dd, J =8.2, 2.2 Hz, 1H), 8.45 (s , 1H), 8.06 (s, 1H), 7.84 (s, 1H), 7.65-7.56 (m, 2H), 7.41 (t, J =7.9 Hz, 1H) , 7.23 (t, J =51.6 Hz, 1H), 5.92 (s, 2H), 3.73 (p, J =6.7 Hz, 1H), 3.23 (sq, J = 7.4 Hz, 1H), 2.79-2.67 (m, 2H), 2.19 (kv, J =9.0 Hz, 2H), 1.99 (dd, J =16.3, 8 .7 Hz, 2H), 1.43-1.35 (m, 10H); MSNR (ER) m/z 567.6 (M ⁺ +1).

Example 117: Synthesis of Compound 3988, 2-(difluoromethyl)-5-(6-((4-(3-(4-ethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 4-(3-ethynylphenyl)piperazine-1-carboxylate

Tert-butyl 4-(3-formylphenyl)piperazine-1-carboxylate (0.500 g, 1.722 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (0.397 g, 2.066 mmol) were dissolved in methanol (7 ml) at room temperature temperature, after which potassium carbonate (0.476 g, 3.444 mmol) is added to the resulting solution and stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, after which a saturated aqueous ammonium chloride solution was poured into the resulting concentrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=100-20%) and concentrated to give tert-butyl 4-(3-ethynylphenyl)piperazine-1-carboxylate (0.450 g, 91.3% ) in the form of a white solid.

[Step 2] Synthesis of tert-butyl 4-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H- 1,2,3-triazol-4-yl)phenyl)piperazine-1-carboxylate

2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.190 g, 0.753 mmol) prepared in Step 1 of Example 16 and tert-butyl 4-( 3-ethynylphenyl)piperazine-1-carboxylate (0.216 g, 0.753 mmol) obtained in step 1 is dissolved in tert-butanol (1 ml)/water (1 ml) at room temperature, followed by sodium ascorbate (1.00 M solution, 0.075 ml, 0.075 mmol) and copper(II) sulfate pentahydrate (0.50 M solution, 0.015 ml, 0.008 mmol) were added to the resulting solution and stirred at the same temperature for 18 hours. The saturated aqueous solution was poured into the reaction mixture, and extraction was carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=10-50%) and concentrated to give tert-butyl 4-(3-(1-((5-(5-(difluoromethyl)-1, 3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)piperazine-1-carboxylate (0.300 g, 74.0%) in form of a white solid.

[Step 3] Synthesis of 2-(difluoromethyl)-5-(6-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridine -3-yl)-1,3,4-oxadiazole

Tert-butyl 4-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3 -triazol-4-yl)phenyl)piperazine-1-carboxylate (0.200 g, 0.371 mmol) obtained in step 2 and trifluoroacetic acid (0.853 ml, 11.141 mmol) are dissolved in dichloromethane (3 ml) at room temperature, then the resulting solution is stirred at the same temperature for 18 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without additional purification process (2-(difluoromethyl)-5-(6-((4-(3-(piperazin-1-yl)phenyl)-1H-1 ,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole, 0.190 g, 116.7%, light yellow oil).

[Step 4] Synthesis of compound 3988

2-(Difluoromethyl)-5-(6-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl) -1,3,4-oxadiazole (0.020 g, 0.046 mmol) obtained in step 3 and acetaldehyde (0.006 g, 0.137 mmol) are dissolved in dichloromethane (1 ml) at room temperature, followed by sodium triacetoxyborohydride (0.048 g, 0.228 mmol) is added to the resulting solution and stirred at the same temperature for 18 hours. The saturated aqueous solution is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(3-(4-ethylpiperazine-1 -yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.010 g, 47.0%) in the form of a colorless oil.

¹ H NMR(400 MHz, CD₃OD) δ 9.28 (dd,J=2.3, 0.9 Hz, 1H), 8.53 (dd,J=8.2, 2.3 Hz, 1H), 8.49 (s, 1H), 7.60 (dd,J=8.2, 0.9 Hz, 1H), 7.54-7.49 (m, 1H), 7.37-7.31 (m, 2H), 7.26 (t,J=51.6 Hz, 1H), 7.01 (dt,J=6.7, 2.6 Hz, 1H), 5.92 (s, 2H), 3.34 (t, 7H), 2.83 (t,J=5.1 Hz, 4H), 2.67 (kv,J=7.3 Hz, 2H), 1.22 (t,J=7.3 Hz, 3H);MCNR(ER) m/z 367.3 (M⁺+1).

The compounds of Table 31 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 3988 except for the use of 2-(difluoromethyl)-5-(6-((4-(3-(piperazin-1-yl)phenyl )-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reagent from Table 30.

Table 30 Example Connection no. Reagent Exit (%) 118 3989 Oxetan-3-one 31 148 4070 N,N-diisopropylethylamine 32

Table 31 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 118 3989 2-(difluoromethyl)-5-(6-((4-(3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)pyridin-3-yl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 9.28 (dd, J =2.3, 0.8 Hz, 1H), 8.53 (dd, J =8.2, 2.2 Hz, 1H ), 8.48 (s, 1H), 7.60 (d, J =8.2 Hz, 1H), 7.50 (d, J =2.8 Hz, 1H), 7.37-7.29 (m, 2H), 7.26 (t, J =51.6 Hz, 1H), 7.00 (dt, J =7.0, 2.5 Hz, 1H), 5.92 (s, 2H) , 4.75 (t, J =6.7 Hz, 2H), 4.67 (t, J =6.2 Hz, 2H), 3.58 (kv, J =6.4 Hz, 2H), 3 .32-3.27 (m, 4H), 2.60-2.53 (m, 4H); MSNR (ER) m/z 495.3 (M ⁺ +1). 148 4070 2-(difluoromethyl)-5-(6-((4-(3-(4-isopropylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3- yl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 9.28 (dd, J =2.3, 0.9 Hz, 1H), 8.53 (dd, J =8.2, 2.2 Hz, 1H ), 8.49 (s, 1H), 7.63-7.56 (m, 1H), 7.50 (s, 1H), 7.37-7.31 (m, 2H), 7.26 ( t, J =51.6 Hz, 1H), 7.01 (dt, J =7.0, 2.6 Hz, 1H), 5.92 (s, 2H), 3.33-3.17 (m , 4H), 2.87-2.78 (m, 5H), 1.18 (d, J =6.5 Hz, 6H); MSNR (ER) m/z 481.4 (M ⁺ +1).

Example 119: Synthesis of compound 3990 , 1-(4-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)- 1H-1,2,3-triazol-4-yl)phenyl)piperazin-1-yl)ethan-1-one

2-(Difluoromethyl)-5-(6-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl) -1,3,4-oxadiazole (0.025 g, 0.057 mmol) obtained in step 3 of Example 117 and triethylamine (0.040 ml, 0.285 mmol) were dissolved in dichloromethane (1 ml) at room temperature, followed by acetyl chloride (0.013 g, 0.171 mmol) is added to the resulting solution and stirred at the same temperature for 18 hours. The saturated aqueous solution is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give 1-(4-(3-(1-((5-(5-(difluoromethyl)-1, 3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)piperazin-1-yl)ethan-1-one (0.011 g, 40.2%) in the form of a colorless oil.

¹ H NMR(400 MHz, CD₃OD) δ 9.28 (dd,J=2.3, 0.9 Hz, 1H), 8.53 (dd,J=8.2, 2.3 Hz, 1H), 8.49 (s, 1H), 7.60 (d,J=8.2 Hz, 1H), 7.52 (t,J=1.7 Hz, 1H), 7.37-7.31 (m, 2H), 7.26 (t,J=51.6 Hz, 1H), 7.06-6.99 (m, 1H), 5.92 (s, 2H), 3.76 (dt,J=16.1, 5.3 Hz, 4H), 3.33-3.21 (m, 4H), 2.17 (s, 3H);MCNR(ER) m/z 481.3 (M⁺+1).

The compound of Table 33 was synthesized in accordance with substantially the same method as described above in the synthesis of compound 3990 except for the use of 2-(difluoromethyl)-5-(6-((4-(3-(piperazin-1-yl)phenyl )-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reagent from Table 32.

Table 32 Example Connection no. Reagent Exit (%) 120 3991 Propionyl chloride 35

Table 33 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 120 3991 1-(4-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3 -triazol-4-yl)phenyl)piperazin-1-yl)propan-1-one
^1H NMR (400 MHz, CD ₃ OD) δ 9.28 (dd, J =2.3, 0.9 Hz, 1H), 8.53 (dd, J =8.2, 2.3 Hz, 1H ), 8.49 (s, 1H), 7.60 (d, J =8.3 Hz, 1H), 7.54-7.49 (m, 1H), 7.36-7.33 (m, 2H), 7.26 (t, J =51.6 Hz, 1H), 7.06-6.98 (m, 1H), 5.92 (s, 2H), 3.76 (dt, J =17 ,3, 5.3 Hz, 4H), 3.27 (dt, J =18.9, 5.2 Hz, 4H), 2.49 (kv, J =7.5 Hz, 2H), 1.17 (t, J =7.5 Hz, 3H); MSNR (ER) m/z 495.4 (M ⁺ +1).

Example 123: Synthesis of compound 4001 , tert-butyl 4-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)- 1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate

[Step 1] Synthesis of methyl 6-((4-(3-bromophenyl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate

Methyl 6-(azidomethyl)nicotinate (1.000 g, 5.203 mmol) prepared in step 1 of Example 81, 1-bromo-3-ethynylbenzene (1.130 g, 6.244 mmol), sodium ascorbate (1.00 M solution, 0.520 ml, 0.520 mmol) and copper(II) sulfate pentahydrate (0.50 M solution, 0.104 ml, 0.052 mmol) are dissolved in tert-butanol (20 ml)/water (20 ml) at room temperature, after which the resulting solution is stirred at the same temperature within 12 hours. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane=0-70%) and concentrated to give methyl 6-((4-(3-bromophenyl)-1H-1,2,3-triazole-1 -yl)methyl)nicotinate (1.500 g, 77.2%) in the form of a white solid.

[Step 2] Synthesis of methyl 6-((4-(3-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)nicotinate

Methyl 6-((4-(3-bromophenyl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate (1.000 g, 2.679 mmol) obtained in step 1, tert-butyl 4-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.911 g, 2.947 mmol), [1,1'-bis] dichloride (di-tert-butylphosphino)ferrocene]palladium(II) (0.175 g, 0.268 mmol) and cesium carbonate (1.746 g, 5.359 mmol) are mixed in 1,4-dioxane (20 ml)/water (5 ml) at room temperature , after which the resulting mixture is heated at reflux for 12 hours and cooled to room temperature. Then, water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-60%) and concentrated to give methyl 6-((4-(3-(1-(tert-butoxycarbonyl)-1,2,3 ,6-tetrahydropyridin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate (0.450 g, 35.3%) as a white solid.

[Step 3] Synthesis of methyl 6-((4-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate

Methyl 6-((4-(3-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl) Methyl)nicotinate (0.450 g, 0.946 mmol) obtained in step 2 is dissolved in methanol (20 ml) at room temperature, after which 10%-Pd/C (90 mg) is slowly added and stirred for 12 hours in the presence of hydrogen cylinder attached to it at the same temperature. The reaction mixture was filtered through a pad of celite to remove solid matter, after which the solvent was removed from the resulting filtrate under reduced pressure, and then the resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-70%) and concentrated to give methyl 6-((4-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate (0.420 g, 92.9%) in the form of a yellow oil.

[Step 4] Synthesis of tert-butyl 4-(3-(1-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidin- 1-carboxylate

Methyl 6-((4-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate (0.420 g, 0.879 mmol ) obtained in step 3 and hydrazine monohydrate (0.427 ml, 8.795 mmol) are dissolved in ethanol (30 ml) at 90°C, after which the resulting solution is stirred at the same temperature for 12 hours, and then the reaction is completed by reducing the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Then, the resulting product is used without additional purification process (tert-butyl 4-(3-(1-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl )phenyl)piperidine-1-carboxylate, 0.350 g, 83.3%, white solid).

[Step 5] Synthesis of compound 4001

Tert-butyl 4-(3-(1-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate (0.350 g, 0.733 mmol) obtained in step 4, imidazole (0.150 g, 2.199 mmol) and 2,2-difluoroacetic anhydride (0.273 ml, 2.199 mmol) are mixed in dichloromethane (50 ml) at room temperature, after which the resulting mixture is heated at reflux for 12 hours and cool to room temperature. Then, water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-60%) and concentrated to give tert-butyl 4-(3-(1-((5-(5-(difluoromethyl)-1, 3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidin-1-carboxylate (0.320 g, 81.2%) in form of a white solid.

¹ H NMR (400 MHz, CDCl₃) δ 9.35 (d,J=1.6 Hz, 1H), 8.42 (dd,J=8.2, 2.2 Hz, 1H), 8.00 (s, 1H), 7.76 (d,J=1.6 Hz, 1H), 7.70-7.61 (m, 1H), 7.47-7.35 (m, 2H), 7.21 (d,J=7.7 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H), 5.84 (s, 2H) , 4.27 (s, 2H), 2.83 (t,J=12.3 Hz, 2H), 2.72 (ddd,J=12.2, 7.9, 3.5 Hz, 1H), 1.87 (d,J=13.6 Hz, 2H), 1.69 (kvd,J=12.7, 4.4 Hz, 2H), 1.51 (d,J=4.3 Hz, 9H);MCNR(ER) m/z 538.42 (M⁺+1).

Example 124: Synthesis of Compound 4002, 2-(difluoromethyl)-5-(6-((4-(1-ethylpiperidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin- 3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of 2-(difluoromethyl)-5-(6-((4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl) -1,3,4-oxadiazole

Tert-butyl 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)piperidin-1-carboxylate (0.446 g, 0.966 mmol) prepared in Example 106 and trifluoroacetic acid (0.740 ml, 9.665 mmol) were dissolved in dichloromethane (5 ml) at room temperature, after which the resulting solution was stirred at same temperature for 18 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without additional purification process (2-(difluoromethyl)-5-(6-((4-(piperidin-3-yl)-1H-1,2,3- triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.350 g, 100.2%, orange oil).

[Step 2] Synthesis of compound 4002

2-(Difluoromethyl)-5-(6-((4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3, 4-oxadiazole (0.070 g, 0.194 mmol) obtained in step 1 and acetaldehyde (0.022 ml, 0.387 mmol) are dissolved in dichloromethane (1 ml), after which the resulting solution is stirred at room temperature for 15 minutes, and then added sodium triacetoxyborohydride (0.123 g, 0.581 mmol) and then stirred at the same temperature for 18 hours. An aqueous solution of sodium 1N-bicarbonate is poured into the resulting reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(1-ethylpiperidin-3-yl) -1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.039 g, 51.7%) in the form of a light yellow oil.

¹ H NMR(400 MHz, CD₃OD) δ 9.25 (dd,J=2.3, 0.9 Hz, 1H), 8.51 (dd,J=8.2, 2.3 Hz, 1H), 8.03 (d,J=0.6 Hz, 1H), 7.55 (dd,J=8.2, 0.9 Hz, 1H), 7.26 (t,J=51.6 Hz, 1H), 5.85 (s, 2H), 3.44 (d,J=12.0 Hz, 1H), 3.28-3.12 (m, 2H), 2.81 (kv,J=7.3 Hz, 2H), 2.49 (dt,J=36.9, 11.4 Hz, 2H), 2.15 (dd,J=13.4, 3.5 Hz, 1H), 1.97-1.91 (m, 1H), 1.89-1.77 (m, 1H), 1.64 (kvd,J=12.2, 4.1 Hz, 1H), 1.25 (t,J=7.3 Hz, 3H);MCNR(ER) m/z 390.1 (M⁺+1).

The compound of Table 35 was synthesized in accordance with substantially the same method as described above in the synthesis of compound 4002 except for the use of 2-(difluoromethyl)-5-(6-((4-(piperidin-3-yl)-1H-1 ,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reagent from Table 34.

Table 34 Example Connection no. Reagent Exit (%) 125 4003 Oxetanone 87

Table 35 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 125 4003 2-(difluoromethyl)-5-(6-((4-(1-(oxetan-3-yl)piperidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin- 3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.26 (dd, J=2.3, 0.9 Hz, 1H), 8.50 (dd, J=8.2, 2.2 Hz, 1H ), 7.99 (d, J=0.6 Hz, 1H), 7.51 (dd, J=8.3, 0.8 Hz, 1H), 7.26 (t, J=51.6 Hz , 1H), 5.83 (s, 2H), 4.67 (dtd, J=24.0, 6.4, 4.6 Hz, 4H), 3.60-3.49 (m, 1H), 3.09 (tt, J=10.9, 3.8 Hz, 1H), 2.99 (d, J=11.4 Hz, 1H), 2.77 (d, J=11.2 Hz, 1H ), 2.14-1.91 (m, 3H), 1.89-1.67 (m, 2H), 1.62-1.48 (m, 1H); MSNR (IER) m/z 345.2 (M ⁺ + H).

Example 126: Synthesis of Compound 4004 , 1-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1 ,2,3-triazol-4-yl)piperidin-1-yl)ethan-1-one

2-(Difluoromethyl)-5-(6-((4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3, 4-oxadiazole (0.070 g, 0.194 mmol) prepared in step 1 of Example 124 and N,N-diisopropylethylamine (0.067 ml, 0.387 mmol) were dissolved in dichloromethane (1 ml) at room temperature, followed by acetyl chloride (0.017 ml, 0.232 mmol) is added to the resulting solution and stirred at the same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 1-(3-(1-((5-(5-(difluoromethyl)-1,3,4 -oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)ethan-1-one (0.064 g, 81.9%) in the form of a light yellow oil.

¹ H NMR(400 MHz, CD₃OD) δ 9.26 (dd,J=2.0, 1.0 Hz, 1H), 8.51 (dt,J=8.2, 2.2 Hz, 1H), 8.05-7.98 (m, 1H), 7.58-7.48 (m, 1H), 7.26 (td,J=51.6, 0.7 Hz, 1H), 5.85 (d,J=4.3 Hz, 2H), 4.55-3.83 (m, 2H), 3.27 (ddd,J=14.0, 10.7, 2.9 Hz, 1H), 3.10-2.86 (m, 2H), 2.23-2.14 (m, 1H), 2.14 (s, 3H ), 1.93-1.76 (m, 2H), 1.75-1.54 (m, 1H);MCNR(ER) m/z 404.2 (M⁺+1).

Example 127: Synthesis of Compound 4005, 2-(difluoromethyl)-5-(6-((4-(4-fluoro-1-methylpiperidin-4-yl)-1H-1,2,3-triazol-1-yl) methyl)pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of 2-(difluoromethyl)-5-(6-((4-(4-fluoropiperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3- yl)-1,3,4-oxadiazole

Tert-butyl 4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)-4-fluoropiperidine-1-carboxylate (0.650 g, 1.356 mmol) prepared in Example 121 and trifluoroacetic acid (0.311 ml, 4.067 mmol) were dissolved in dichloromethane (20 ml) at room temperature, and the resulting solution stir at the same temperature for 3 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without additional purification process (2-(difluoromethyl)-5-(6-((4-(4-fluoropiperidin-4-yl)-1H-1,2, 3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole, 0.500 g, 97.2%, yellow oil)

[Step 2] Synthesis of compound 4005

2-(Difluoromethyl)-5-(6-((4-(4-fluoropiperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1, 3,4-oxadiazole (0.080 g, 0.211 mmol) obtained in step 1, N,N-diisopropylethylamine (0.073 ml, 0.422 mmol), formaldehyde (37.00%, 0.034 g, 0.422 mmol) and sodium triacetoxyborohydride (0.089 g , 0.422 mmol) was dissolved in dichloromethane (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(4-fluoro-1-methylpiperidin- 4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.021 g, 25.3%) as a white solid.

¹ H NMR (400 MHz, CDCl₃) δ 9.33 (d,J=1.6 Hz, 1H), 8.47-8.37 (m, 1H), 7.78 (d,J=0.6 Hz, 1H), 7.40 (t,J=11.6 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H), 5.77 (s, 2H) , 2.78 (d,J=11.5 Hz, 2H), 2.50 (t,J=10.9 Hz, 2H), 2.45-2.32 (m, 4H), 2.31-2.19 (m, 3H);MCNR(ER) m/z 494.26 (M⁺+1).

The compounds of Table 37 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4005 except for the use of 2-(difluoromethyl)-5-(6-((4-(4-fluoropiperidin-4-yl)-1H -1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reagent from Table 36.

Table 36 Example Connection no. Reagent Exit (%) 128 4006 Acetaldehyde 14 129 4007 Propan-2-one 24 130 4008 Oxetan-3-one 33

Table 37 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 128 4006 2-(difluoromethyl)-5-(6-((4-(1-ethyl-4-fluoropiperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl )-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.34 (d, J = 1.6 Hz, 1H), 8.42 (dd, J = 8.2, 2.2 Hz, 1H), 7.78 (s, 1H), 7.42 (d, J =8.2 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H), 5.78 (s, 2H), 2.94 (d, J =10.7 Hz, 2H), 2.59 (dt, J =18.8, 9.4 Hz, 4H), 2.42 (ddd, J =13.1, 11.4, 4.5 Hz, 1H), 2.30 (t, J =12.7 Hz, 3H), 1.19 (t, J =7, 2 Hz, 3H); MSNR (ER) m/z 408.29 (M ⁺ +1). 129 4007 2-(difluoromethyl)-5-(6-((4-(4-fluoro-1-isopropylpiperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl )-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.34 (d, J = 1.7 Hz, 1H), 8.44 (dd, J = 8.2, 2.2 Hz, 1H), 7.82 (s, 1H), 7.45 (d, J =8.1 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H), 5.78 (s, 2H), 3.27-3.20 (m, 3H), 3.02 (s, 2H), 2.61-2.50 (m, 4H), 1 .30 (d, J =6.6 Hz, 6H); MSNR (ER) m/z 422.03 (M ⁺ +1). 130 4008 2-(difluoromethyl)-5-(6-((4-(4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl) methyl)pyridin-3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.34 (d, J = 1.6 Hz, 1H), 8.42 (dd, J = 8.2, 2.2 Hz, 1H), 7.79 (s, 1H), 7.41 (d, J =10.1 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H), 5.78 (s, 2H), 4.76-4.59 (m, 4H), 3.59 (p, J =6.5 Hz, 1H), 2.72-2.59 (m, 2H), 2.44-2.17 (m, 6H); MSNR (ER) m/z 436.27 (M ⁺ +1).

Example 131: Synthesis of compound 4009 , 1-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1 ,2,3-triazol-4-yl)-4-fluoropiperidin-1-yl)ethan-1-one

2-(Difluoromethyl)-5-(6-((4-(4-fluoropiperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1, 3,4-oxadiazole (0.080 g, 0.211 mmol) obtained in step 1 of Example 127, triethylamine (0.059 ml, 0.422 mmol) and acetic anhydride (0.060 ml, 0.633 mmol) were dissolved in dichloromethane (5 ml) at room temperature, after whereupon the resulting solution is stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 1-(4-(1-((5-(5-(difluoromethyl)-1,3,4 -oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-4-fluoropiperidin-1-yl)ethan-1-one (0.021 g, 23, 6%) in the form of a white solid.

¹ H NMR (400 MHz, CDCl₃) δ 9.34 (d,J=1.7 Hz, 1H), 8.43 (dd,J=8.2, 2.2 Hz, 1H), 7.82 (s, 1H), 7.45 (d,J=8.2 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H), 5.78 (s, 2H) , 4.48 (d,J=13.2 Hz, 1H), 3.79 (d,J=13.6 Hz, 1H), 3.63-3.51 (m, 1H), 3.24-3.10 (m, 1H), 2.38-2.11 (m, 7H);MCNR(ER) m/z 422.24 (M⁺+1).

Example 132: Synthesis of Compound 4010, 2-(difluoromethyl)-5-(6-((4-(3-(1-methylpiperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of 2-(difluoromethyl)-5-(6-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridine -3-yl)-1,3,4-oxadiazole

Tert-butyl 4-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3 -triazol-4-yl)phenyl)piperidine-1-carboxylate (0.320 g, 0.595 mmol) obtained in step 5 of Example 123 and trifluoroacetic acid (0.137 ml, 1.786 mmol) were dissolved in dichloromethane (20 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 3 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without additional purification process (2-(difluoromethyl)-5-(6-((4-(3-(piperidin-4-yl)phenyl)-1H-1 ,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole, 0.250 g, 96.0%, yellow oil).

[Step 2] Synthesis of compound 4010

2-(Difluoromethyl)-5-(6-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl) -1,3,4-oxadiazole (0.080 g, 0.183 mmol) obtained in step 1, N,N-diisopropylethylamine (0.064 ml, 0.366 mmol) and formaldehyde (37.00%, 0.030 g, 0.366 mmol) are dissolved in dichloromethane (5 ml), after which the resulting solution was stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (0.078 g, 0.366 mmol) was added thereto, and then stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(3-(1-methylpiperidine-4 -yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.032 g, 38.8%) as a white solid .

¹ H NMR (400 MHz, CDCl₃) δ 9.35 (d,J=1.7 Hz, 1H), 8.41 (dd,J=8.2, 2.2 Hz, 1H), 7.97 (s, 1H), 7.75 (s, 1H), 7.68 (d,J=7.7 Hz, 1H), 7.44-7.33 (m, 2H), 7.24 (d,J=7.7 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H), 5.83 (s, 2H) , 3.04 (d,J=11.7 Hz, 2H), 2.62-2.48 (m, 1H), 2.37 (s, 3H), 2.18-2.07 (m, 2H), 1.94-1, 85 (m, 4H);MCNR(ER) m/z 452.13 (M⁺+1).

The compounds of Table 39 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4010 except for the use of 2-(difluoromethyl)-5-(6-((4-(3-(piperidin-4-yl)phenyl )-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reagent from Table 38.

Table 38 Example Connection no. Reagent Exit (%) 133 4011 Acetaldehyde 24 134 4012 Propan-2-one 12 135 4013 Oxetan-3-one 16

Table 39 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 133 4011 2-(difluoromethyl)-5-(6-((4-(3-(1-ethylpiperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3- yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.36 (dd, J = 2.2, 0.8 Hz, 1H), 8.42 (dd, J = 8.2, 2.2 Hz, 1H) , 7.98 (s, 1H), 7.76 (d, J =1.8 Hz, 1H), 7.73-7.66 (m, 1H), 7.40 (dd, J =17.6 , 7.9 Hz, 2H), 7.25 (d, J =7.7 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H), 5.84 (s, 2H), 3.22 (d, J =11.3 Hz, 2H), 2.63-2.55 (m, 3H), 2.18 ( dd, J =14.8, 8.4 Hz, 2H), 2.02-1.87 (m, 4H), 1.20 (t, J =7.3 Hz, 3H); MSNR (ER) m/z 466.04 (M ⁺ +1). 134 4012 2-(difluoromethyl)-5-(6-((4-(3-(1-isopropylpiperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3- yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.36 (dd, J = 2.2, 0.8 Hz, 1H), 8.42 (dd, J = 8.2, 2.2 Hz, 1H) , 7.96 (s, 1H), 7.76 (t, J =1.7 Hz, 1H), 7.73-7.65 (m, 1H), 7.44-7.33 (m, 2H ), 7.25 (d, J =7.7 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H) , 5.83 (s, 2H), 3.06 (d, J =11.4 Hz, 2H), 2.83 (dt, J =13.2, 6.5 Hz, 1H), 2.57 ( ddd, J =16.0, 10.8, 5.3 Hz, 1H), 2.30 (tt, J =15.9, 7.8 Hz, 2H), 1.97-1.88 (m, 4H), 1.12 (d, J =6.6 Hz, 6H); MSNR (ER) m/z 480.08 (M ⁺ +1). 135 4013 2-(difluoromethyl)-5-(6-((4-(3-(1-(oxetan-3-yl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)pyridin-3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.36 (dd, J = 2.2, 0.8 Hz, 1H), 8.42 (dd, J = 8.2, 2.2 Hz, 1H) , 7.97 (s, 1H), 7.78 (t, J =1.7 Hz, 1H), 7.71-7.65 (m, 1H), 7.47-7.34 (m, 2H ), 7.24 (d, J =7.7 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H) , 5.83 (s, 2H), 4.73-4.64 (m, 4H), 3.60-3.48 (m, 1H), 2.91 (d, J =9.8 Hz, 2H ), 2.66-2.54 (m, 1H), 2.03-1.83 (m, 6H); MSNR (ER) m/z 494.31 (M ⁺ +1).

Example 136: Synthesis of Compound 4014, 2-(difluoromethyl)-5-(6-((4-((1-methylpiperidin-4-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl )pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of 2-(difluoromethyl)-5-(6-((4-(piperidin-4-ylmethyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl) -1,3,4-oxadiazole

Tert-butyl 4-((1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazole -4-yl)methyl)piperidin-1-carboxylate (0.700 g, 1.472 mmol) prepared in Example 122 and trifluoroacetic acid (0.338 ml, 4.416 mmol) were dissolved in dichloromethane (20 ml) at room temperature, and the resulting solution stir at the same temperature for 3 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without additional purification process (2-(difluoromethyl)-5-(6-((4-(piperidin-4-ylmethyl)-1H-1,2,3- triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.550 g, 99.5%, yellow oil)

[Step 2] Synthesis of compound 4014

2-(Difluoromethyl)-5-(6-((4-(piperidin-4-ylmethyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3, 4-oxadiazole (0.080 g, 0.213 mmol) obtained in step 1, N,N-diisopropylethylamine (0.074 ml, 0.426 mmol) and formaldehyde (37.00%, 0.035 g, 0.426 mmol) are dissolved in dichloromethane (5 ml), after which the resulting solution was stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (0.090 g, 0.426 mmol) was added thereto, and then stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-((1-methylpiperidin-4-yl )methyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.021 g, 25.3%) as a white solid.

¹ H NMR (400 MHz, CDCl₃) δ 9.33 (d,J=1.6 Hz, 1H), 8.40 (dd,J=8.2, 2.2 Hz, 1H), 7.48 (d,J=12.2 Hz, 1H), 7.34 (d,J=8.2 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H), 5.74 (s, 2H) , 2.87 (d,J=11.5 Hz, 2H), 2.69 (d,J=6.4 Hz, 2H), 2.29 (s, 3H), 1.94 (t,J=11.0 Hz, 2H), 1.69 (t,J=10.1 Hz, 3H), 1.35 (dt,J=32.6, 18.4 Hz, 2H);MCNR(ER) m/z 390.5 (M⁺+1).

Example 137: Synthesis of compound 4015 , 1-(4-((1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H- 1,2,3-triazol-4-yl)methyl)piperidin-1-yl)ethan-1-one

2-(Difluoromethyl)-5-(6-((4-(piperidin-4-ylmethyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3, 4-oxadiazole (0.080 g, 0.213 mmol) obtained in step 1 of Example 136, triethylamine (0.036 ml, 0.256 mmol) and acetic anhydride (0.022 ml, 0.234 mmol) were dissolved in dichloromethane (5 ml) at room temperature, after which the resulting the solution is stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 1-(4-((1-((5-(5-(difluoromethyl)-1,3, 4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)piperidin-1-yl)ethan-1-one (0.023 g, 25, 9%) in the form of a white solid.

¹ H NMR (400 MHz, CDCl₃) δ 9.30 (d,J=1.7 Hz, 1H), 8.39 (dd,J=8.2, 2.2 Hz, 1H), 7.51 (s, 1H), 7.36 (d,J=8.2 Hz, 1H), 7.08 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H), 5.73 (s, 2H) , 4.58 (d,J=13.3 Hz, 1H), 3.79 (d,J=13.6 Hz, 1H), 3.09-2.92 (m, 1H), 2.68 (d,J=6.9 Hz, 2H), 2.50 (dd,J=18.2, 7.5 Hz, 1H), 2.06 (s, 3H), 2.00-1.88 (m, 1H), 1.74 (dd,J=29.3, 13.0 Hz, 2H), 1.30-1.05 (m, 2H);MCNR(ER) m/z 418.2 (M⁺+1).

Example 138: Synthesis of compound 4023 , 4-((4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H- 1,2,3-triazol-4-yl)-1H-indol-3-yl)methyl)morpholine

[Step 1] Synthesis of 4-ethynyl-1H-indole

1H-indole-4-carbaldehyde (0.500 g, 3.444 mmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (0.794 g, 4.133 mmol) and potassium carbonate (0.952 g, 6.889 mmol) are dissolved in methanol (5 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 12 hours. Water is poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove solid residue and a layer of aqueous solution, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 4-ethynyl-1H-indole (0.300 g, 61.7%) as a yellow solid.

[Step 2] 2-(6-((4-(1H-indol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl )-1,3,4-oxadiazole

4-Ethynyl-1H-indole (0.280 g, 1.983 mmol) obtained in step 1, 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.500 g, 1.983 mmol) obtained in step 1 of Example 16, copper(II) sulfate pentahydrate (0.005 g, 0.020 mmol) and sodium ascorbate (0.039 g, 0.198 mmol) were dissolved in tert-butanol (5 ml)/water (5 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-60%) and concentrated to give 2-(6-((4-(1H-indol-4-yl)-1H-1,2 ,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.400 g, 51.3%) as a white solid.

[Step 3] Synthesis of compound 4023

Morpholine (10.00 M solution in water, 0.023 ml, 0.230 mmol), formaldehyde (37.00%, 0.020 g, 0.253 mmol) and acetic acid (0.013 ml, 0.230 mmol) are dissolved in methanol (5 ml) at room temperature , after which 2-(6-((4-(1H-indol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl) -1,3,4-oxadiazole (1.00 M In MeOH solution, 0.230 ml, 0.230 mmol) obtained in step 3 was added to the resulting solution and stirred at the same temperature for 12 hours. An aqueous solution of sodium 1N-bicarbonate is poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove solid residue and a layer of aqueous solution, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 4-((4-(1-((5-(5-(difluoromethyl)-1,3, 4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indol-3-yl)methyl)morpholine (0.020 g, 17.7 %) in the form of a white solid.

¹ H NMR(400 MHz, CDCl₃) δ 9.29 (d,J=2.3 Hz, 1H), 9.08 (s, 1H), 8.42 (s, 1H), 8.37 (dd,J=8.1, 2.3 Hz, 1H), 7.46 (d,J=8.2 Hz, 1H), 7.37 (d,J=8.0 Hz, 1H), 7.28-7.20 (m, 1H), 7.20-7.10 (m, 1H), 7.09-6.78 (m, 2H), 5, 79 (s, 2H), 3.47 (d,J=4.1 Hz, 6H), 2.21 (t,J=4.7 Hz, 4H);MCNR(ER) m/z 493.4 (M⁺+1).

Example 139: Synthesis of Compound 4026, (S)-2-(difluoromethyl)-5-(6-((4-(1-(oxetan-3-yl)pyrrolidin-2-yl)-1H-1,2,3 -triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl( S )-2-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H -1,2,3-triazol-4-yl)pyrrolidin-1-carboxylate

Tert-butyl ( S )-2-ethynylpyrrolidine-1-carboxylate (0.400 g, 2.049 mmol), 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.517 g, 2.049 mmol) obtained in step 1 of Example 16, sodium ascorbate (0.036 g, 0.205 mmol) and copper(II) sulfate pentahydrate (0.005 g, 0.020 mmol) were dissolved in water (3 ml)/tert-butanol (3 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Then, the resulting product is used without additional purification process (tert-butyl ( S )-2-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl )methyl)-1H-1,2,3-triazol-4-yl)pyrrolidine-1-carboxylate, 0.850 g, 92.7%, as a brown solid).

[Step 2] Synthesis of ( S )-2-(difluoromethyl)-5-(6-((4-(pyrrolidin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin- 3-yl)-1,3,4-oxadiazole

Tert-butyl ( S )-2-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2, 3-triazol-4-yl)pyrrolidin-1-carboxylate (0.850 g, 1.900 mmol) obtained in step 1 and trifluoroacetic acid (2.909 ml, 37.993 mmol) were dissolved in dichloromethane (10 ml) at room temperature, after which the resulting the solution is stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, after which the resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; methanol/dichloromethane=10%) and concentrated to give ( S )-2-(difluoromethyl)-5-(6- ((4-(pyrrolidin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.775 g, 117.5% ) in the form of a colorless gel.

[Step 3] Synthesis of compound 4026

( S )-2-(difluoromethyl)-5-(6-((4-(pyrrolidin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)- 1,3,4-oxadiazole (0.070 g, 0.202 mmol) obtained in step 2, oxetan-3-one (0.029 g, 0.403 mmol) and sodium triacetoxyborohydride (0.128 g, 0.605 mmol) are dissolved in dichloromethane (1 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate is purified by chromatography (SiO ₂ plate, 20x20x1 mm; methanol/dichloromethane=10%) and concentrated to give ( S )-2-(difluoromethyl)-5-(6-((4-(1-(oxetane- 3-yl)pyrrolidin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.012 g, 14.8%) in the form of a light yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.32 (dd, J = 2.2, 0.9 Hz, 1H), 8.40 (dd, J = 8.2, 2.2 Hz, 1H) , 7.59 (s, 1H), 7.37 (d, J =8.2 Hz, 1H), 6.94 (t, J =51.6 Hz, 1H), 5.73 (s, 2H) , 4.71 (dd, J =12.7, 6.8 Hz, 4H), 3.84 (s, 1H), 3.71-3.60 (m, 1H), 3.16 (s, 1H ), 2.88 (s, 1H), 2.76 (s, 2H), 2.07 (dt, J = 13.2, 6.9 Hz, 1H); MSNR (ER) m/z 404.3 (M ⁺ +1).

The compound of Table 41 was synthesized in accordance with substantially the same method as described above in the synthesis of compound 4026 except for the use of ( S )-2-(difluoromethyl)-5-(6-((4-(pyrrolidin-2-yl) -1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reagent from Table 40.

Table 40 Example Connection no. Reagent Exit (%) 140 4027 2-oxaspiro[3,3]heptan-6-one 29

Table 41 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 140 4027 ( S )-2-(6-((4-(1-(2-oxaspiro[3,3]heptan-6-yl)pyrrolidin-2-yl)-1H-1,2,3-triazol-1- yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole
¹ H NMR ((400 MHz, CDCl ₃ ) δ 9.30 (d, J =2.1 Hz, 1H), 8.38 (dd, J =8.2, 2.3 Hz, 1H), 7, 66 (s, 1H), 7.35 (d, J =8.2 Hz, 1H), 6.94 (t, J =51.6 Hz, 1H), 5.73 (s, 2H), 4, 61 (kv, J =5.9 Hz, 2H), 4.51 (d, J =6.4 Hz, 1H), 4.43 (d, J =6.5 Hz, 1H), 3.73 ( s, 1H), 3.04 (s, 1H), 2.87 (kv, J =8.0 Hz, 1H), 2.45-2.17 (m, 3H), 2.17-2.01 (m, 2H), 1.99-1.86 (m, 2H), 1.83 (t, J =8.4 Hz, 1H), 1.72 (t, J =10.2 Hz, 1H) ; MSNR (ER) m/z 444.3 (M ⁺ +1).

Example 141: Synthesis of compound 4028 , methyl ( S )-2-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H -1,2,3-triazol-4-yl)pyrrolidin-1-carboxylate

( S )-2-(difluoromethyl)-5-(6-((4-(pyrrolidin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)- 1,3,4-oxadiazole (0.070 g, 0.202 mmol) obtained in step 2 of Example 139, (chlorocarbonyl)oxy)methyl (0.023 g, 0.242 mmol) and triethylamine (0.034 ml, 0.242 mmol) were dissolved in dichloromethane (1 ml ) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate is purified by chromatography (SiO ₂ plate, 20x20x1 mm; methanol/dichloromethane=10%) and concentrated to give methyl ( S )-2-(1-((5-(5-(difluoromethyl)-1,3, 4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrrolidin-1-carboxylate (0.035 g, 42.8%) as a white solid .

¹ H NMR (400 MHz, CDCl₃; two rotamers in a ratio of 6:4) δ 9.31 (d,J=2.2 Hz, 1H), 8.38 (d,J=8.0 Hz, 1H), 7.71 (s, 0.6H), 7.52 (s, 0.4H), 7.31 (d,J=8.8 Hz, 1H), 6.94 (t,J=51.6 Hz, 1H), 5.72 (d,J=6.7 Hz, 2H), 5.09 (dd,J=7.5, 2.7 Hz, 1H), 3.68 (s, 2H), 3.63 (s, 1H), 3.59-3.40 (m, 2H), 2.48 (s, 0.5H), 2.38-2.08 (m, 2H), 1.98 (s, 1.5H);MCNR(ER) m/z 406.3 (M⁺+1).

The compound of Table 43 was synthesized in accordance with substantially the same method as described above in the synthesis of compound 4028 except for the use of ( S )-2-(difluoromethyl)-5-(6-((4-(pyrrolidin-2-yl) -1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reagent from Table 42.

Table 42 Example Connection no. Reagent Exit (%) 142 4029 Acetic anhydride 53

Table 43 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 142 4029 (S)-1-(2-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2, 3-triazol-4-yl)pyrrolidin-1-yl)ethan-1-one
¹ H NMR (400 MHz, CDCl₃; two rotamers in a ratio of 7:3) δ 9.30 (s, 1H), 8.42 (dd,J=8.2, 2.2 Hz, 0.3H), 8.37 (dd,J=8.2, 2.2 Hz, 0.7H), 7.74 (s, 0.7H), 7.55 (s, 0.3H), 7.41 (d,J=8.2 Hz, 0.3H), 7.30 (dd,J=8.2, 0.8 Hz, 0.7H), 6.94 (td,J=51.6, 1.6 Hz, 1H), 5.78-5.71 (m, 1H), 5.67 (d,J=15.8 Hz, 1H), 5.28 (d,J=7.8 Hz, 1H), 5.16 (d,J=7.4 Hz, 0H), 3.73-3.61 (m, 1H), 3.61-3.46 (m, 1H), 2.57 (d,J=10.5 Hz, 1H), 2.43-2.29 (m, 1H), 2.19 (td,J=11.4, 5.5 Hz, 1H), 2.06 (s, 3H), 1.97 (s, 1H);MCNR(ER) m/z 390.3 (M⁺+1).

Example 143: Synthesis of Compound 4051, 2-(difluoromethyl)-5-(6-((4-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3- triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 6-ethynyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

Tert-butyl 6-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.500 g, 1.913 mmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (0.345 ml, 2.296 mmol) and potassium carbonate (0.529 g, 3.827 mmol) was dissolved in methanol (10 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was then used without further purification process (tert-butyl 6-ethynyl-3,4-dihydroisoquinoline-2(1H)-carboxylate, 0.490 g, 99.5%, yellow solid).

[Step 2] Synthesis of tert-butyl 6-(1-((5-(methoxycarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline- 2(1H)-carboxylate

Tert-butyl 6-ethynyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.500 g, 1.943 mmol) obtained in step 1, methyl 6-(azidomethyl)nicotinate (0.373 g, 1.943 mmol) obtained in step 1 of Example 81, sodium ascorbate (0.038 g, 0.194 mmol) and copper(II) sulfate pentahydrate (0.005 g, 0.019 mmol) were dissolved in ethanol (150 ml) at room temperature, after which the resulting solution was stirred at 80 ° C for 18 hours, and then the reaction is completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, after which the resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-80%) and concentrated to give tert-butyl 6-(1-((5-( methoxycarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.853 g, 97.7%) as yellow solid matter.

[Step 3] Synthesis of tert-butyl 6-(1-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline- 2(1H)-carboxylate

Tert-butyl 6-(1-((5-(methoxycarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)- The carboxylate (1.100 g, 2.447 mmol) obtained in step 2 and hydrazine monohydrate (1.287 ml, 36.707 mmol) are mixed in ethanol (50 ml) at room temperature, after which the resulting mixture is refluxed and cooled to room temperature . The solvent is then removed from the reaction mixture under reduced pressure, after which the resulting product is used without further purification process (tert-butyl 6-(1-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-1H-1,2 ,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate, 1.100 g, 100.0%, yellow solid).

[Step 4] Synthesis of tert-butyl 6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2 ,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

Tert-butyl 6-(1-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)- The carboxylate (0.490 g, 1.090 mmol) obtained in step 3 and triethylamine (0.456 ml, 3.270 mmol) are dissolved in tetrahydrofuran (15 ml) at room temperature, after which difluoroacetic anhydride (0.678 ml, 5.450 mmol) is added to the resulting solution and stir at the same temperature for 5 hours. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane=0-80%) and concentrated to give tert-butyl 6-(1-((5-(5-(difluoromethyl)-1,3,4 -oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.471 g, 84.8 %) in the form of a white solid.

[Step 5] Synthesis of 2-(difluoromethyl)-5-(6-((4-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl) methyl)pyridin-3-yl)-1,3,4-oxadiazole trifluoroacetic acid

TFC

Tert-butyl 6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.471 g, 0.924 mmol) obtained in step 4 was dissolved in dichloromethane (15 ml) at room temperature, followed by trifluoroacetic acid (TFA, 0.212 ml , 2.773 mmol) was added to the resulting solution and stirred at the same temperature for 5 hours. The solvent was removed from the reaction mixture under reduced pressure, after which the precipitated solid was filtered off, washed with dichloromethane and dried to give 2-(difluoromethyl)-5-(6-((4-(1,2,3,4-tetrahydroisoquinoline- 6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazoletrifluoroacetic acid (0.450 g, 96.1%) as a white solid .

[Step 6] Synthesis of compound 4051

2-(Difluoromethyl)-5-(6-((4-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3 -yl)-1,3,4-oxadiazoletrifluoroacetic acid (0.050 g, 0.099 mmol) obtained in step 5, formaldehyde (37.00% solution in H ₂ O, 0.020 ml, 0.197 mmol) and N,N-diisopropylethylamine ( 0.034 ml, 0.197 mmol) was dissolved in dichloromethane (5 ml) at room temperature, after which sodium triacetoxyborohydride (0.052 g, 0.246 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-15%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(2-methyl-1,2, 3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.007 g, 16.8%) in the form of a yellow solid.

¹ H NMR(400 MHz, CDCl₃) δ 9.32 (dd,J=2.3, 0.9 Hz, 1H), 8.38 (dd,J=8.2, 2.3 Hz, 1H), 7.93 (s, 1H), 7.63 (d,J=1.8 Hz, 1H), 7.56 (dd,J=7.9, 1.8 Hz, 1H), 7.39 (dd,J=8.2, 0.9 Hz, 1H), 7.08 (d,J=8.2 Hz, 1H), 7.06-6.94 (m, 1H), 5.80 (s, 2H), 3.62 (s, 2H), 2.98 (t,J=6.0 Hz, 2H), 2.73 (t,J=6.0 Hz, 2H), 2.48 (s, 3H);MCNR(ER) m/z 424.1 (M⁺+1).

The compounds of Table 45 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4051, except for the use of 2-(difluoromethyl)-5-(6-((4-(1,2,3,4-tetrahydroisoquinoline -6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reagent from Table 44.

Table 44 Example Connection no. Reagent Exit (%) 144 4052 Acetaldehyde 16 145 4053 Propan-2-one eleven 146 4054 Cyclobutanone 24 147 4055 Oxetan-3-one 21

Table 45 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 144 4052 2-(difluoromethyl)-5-(6-((4-(2-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl )pyridin-3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.33 (dd, J = 2.2, 0.9 Hz, 1H), 8.39 (dd, J = 8.2, 2.2 Hz, 1H) , 7.93 (s, 1H), 7.65-7.53 (m, 2H), 7.39 (dt, J =8.3, 1.5 Hz, 1H), 7.12-7.04 (m, 1H), 7.07-6.94 (m, 1H), 5.80 (s, 2H), 3.70 (s, 2H), 3.03-2.90 (m, 2H), 2.81 (t, J =6.0 Hz, 2H), 2.65 (kv, J =7.2 Hz, 2H), 1.22 (t, J =7.2 Hz, 3H); MSNR (ER) m/z 438.3 (M ⁺ +1). 145 4053 2-(difluoromethyl)-5-(6-((4-(2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl )pyridin-3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.33 (dd, J = 2.2, 0.9 Hz, 1H), 8.39 (dd, J = 8.2, 2.2 Hz, 1H) , 7.92 (s, 1H), 7.62 (d, J =1.7 Hz, 1H), 7.56 (dd, J =7.9, 1.8 Hz, 1H), 7.40 ( dd, J =8.2, 0.9 Hz, 1H), 7.09 (d, J =7.9 Hz, 1H), 7.07-6.94 (m, 1H), 5.80 (s , 2H), 3.79 (s, 2H), 2.97 (s, 3H), 2.84 (t, J =5.9 Hz, 2H), 1.17 (d, J =6.5 Hz , 6H); MSNR (ER) m/z 452.4 (M ⁺ +1). 146 4054 2-(6-((4-(2-cyclobutyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl )-5-(difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.32 (dd, J = 2.2, 0.8 Hz, 1H), 8.38 (dd, J = 8.2, 2.2 Hz, 1H) , 7.92 (s, 1H), 7.62 (d, J =1.8 Hz, 1H), 7.55 (dd, J =7.9, 1.8 Hz, 1H), 7.39 ( dd, J =8.2, 0.9 Hz, 1H), 7.08 (d, J =8.2 Hz, 1H), 7.06-6.94 (m, 1H), 5.79 (s , 2H), 3.54 (s, 2H), 2.94 (kv, J =9.0, 7.6 Hz, 3H), 2.64 (t, J =6.0 Hz, 2H), 2 .20-2.08 (m, 2H), 2.05-1.97 (m, 2H), 1.75 (kW, J =10.2, 8.3 Hz, 2H); MSNR (ER) m/z 464.5 (M ⁺ +1). 147 4055 2-(difluoromethyl)-5-(6-((4-(2-(oxetan-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazole -1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.32 (dd, J = 2.2, 0.9 Hz, 1H), 8.39 (dd, J = 8.2, 2.2 Hz, 1H) , 7.93 (s, 1H), 7.64 (d, J =1.7 Hz, 1H), 7.56 (dd, J =7.9, 1.8 Hz, 1H), 7.40 ( dd, J =8.2, 0.9 Hz, 1H), 7.10-7.03 (m, 1H), 7.07-6.94 (m, 1H), 5.80 (s, 2H) , 4.74 (dd, J =6.5, 2.9 Hz, 4H), 3.70 (p, J =6.5 Hz, 1H), 3.53 (s, 2H), 2.97 ( t, J =6.0 Hz, 2H), 2.63 (t, J =5.9 Hz, 2H); MSNR (ER) m/z 466.4 (M ⁺ +1).

Example 165: Synthesis of Compound 4108, 2-(difluoromethyl)-5-(4-((4-(3-(pyrrolidin-1-ylmethyl)-1H-indol-6-yl)-1H-1,2,3- triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 3-(pyrrolidin-1-ylmethyl)-1H-indole-6-carbaldehyde

Pyrrolidine (0.300 g, 4.218 mmol) and formaldehyde (37.00%, 0.377 g, 4.640 mmol) are dissolved in acetic acid (3 ml), after which the resulting solution is stirred at 0°C for 0.4 hours, and then added 1H-indole-6-carbaldehyde (0.490 g, 3.375 mmol) and then stirred at room temperature for 18 hours. An aqueous solution of 2N-sodium hydroxide is poured into the resulting reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 3-(pyrrolidin-1-ylmethyl)-1H-indole-6-carbaldehyde (0.300 g, 31.2 %) in the form of yellow gum.

[Step 2] Synthesis of 6-ethynyl-3-(pyrrolidin-1-ylmethyl)-1H-indole

3-(Pyrrolidin-1-ylmethyl)-1H-indole-6-carbaldehyde (0.100 g, 0.438 mmol) obtained in step 1 and dimethyl (1-diazo-2-oxopropyl)phosphonate (0.101 g, 0.526 mmol) are dissolved in methanol (2 ml) at room temperature, after which potassium carbonate (0.121 g, 0.876 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting concentrate is poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 6-ethynyl-3-(pyrrolidin-1-ylmethyl)-1H-indole (0.065 g, 66.2 %) in the form of a yellow oil.

[Step 3] Synthesis of compound 4108

2-(4-(Azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.030 g, 0.104 mmol) prepared in Step 1 of Example 1 and 6-ethynyl-3-(pyrrolidine-1 -ylmethyl)-1H-indole (0.023 g, 0.104 mmol) obtained in step 2 is dissolved in tert-butanol (1 ml)/water (1 ml) at room temperature, followed by sodium ascorbate (1.00 M solution, 0.010 ml, 0.010 mmol) and copper(II) sulfate pentahydrate (0.50 M solution, 0.002 ml, 0.001 mmol) were added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution is poured into the reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(3-(pyrrolidin-1-ylmethyl) )-1H-indol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.012 g, 24.3%) in the form of light yellow oil.

¹ H NMR(400 MHz, CD₃OD) δ 8.43 (s, 1H), 8.21-8.14 (m, 2H), 7.97 (d,J=1.6 Hz, 1H), 7.82 (d,J=8.4 Hz, 1H), 7.67-7.61 (m, 3H), 7.59 (s, 1H), 7.23 (t,J=51.6 Hz, 1H), 5.81 (s, 2H), 4.59 (d,J=7.9 Hz, 2H), 3.38 (d,J=7.1 Hz, 4H), 2.09 (s, 4H);MCNR(ER) m/z 476.3 (M⁺+1).

The compounds of Table 47 are synthesized in accordance with substantially the same method as described above for the synthesis of compound 4108, except for the use of 6-ethynyl-3-(pyrrolidin-1-ylmethyl)-1H-indole and the reagent from Table 46.

Table 46 Example Connection no. Reagent Exit (%) 166 4109 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 27 367 4493 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 20

Table 47 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 166 4109 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(pyrrolidin-1-ylmethyl)-1H-indol-6-yl)-1H-1,2,3-triazol-1 -yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.43 (s, 1H), 8.04-7.94 (m, 3H), 7.82 (d, J = 8.4 Hz, 1H), 7.69-7.58 (m, 3H), 7.24 (t, J =51.6 Hz, 2H), 5.87 (s, 2H), 4.59 (s, 2H), 3.48 -3.35 (m, 4H), 2.16-2.01 (m, 4H); MSNR (ER) m/z 494.5 (M ⁺ +1). 367 4493 2-(difluoromethyl)-5-(6-((4-(3-(pyrrolidin-1-ylmethyl)-1H-indol-6-yl)-1H-1,2,3-triazol-1-yl)methyl )pyridin-3-yl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 9.28 (dd, J =2.3, 0.9 Hz, 1H), 8.53 (dd, J =8.2, 2.2 Hz, 1H ), 8.50 (s, 1H), 7.98 (d, J =1.4 Hz, 1H), 7.86-7.81 (m, 1H), 7.69-7.59 (m, 3H), 7.26 (t, J =51.6 Hz, 1H), 5.94 (s, 2H), 4.60 (s, 2H), 3.45-3.35 (m, 4H), 2.10 (p, J =3.7 Hz, 4H); MSNR (ER) m/z 477.2 (M ⁺ +1).

Example 167: Synthesis of Compound 4110, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-((4-methylpiperidin-1-yl)methyl)-1H-indol-6-yl) -1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 3-((4-methylpiperidin-1-yl)methyl)-1H-indole-6-carbaldehyde

4-methylpiperidine (0.300 g, 3.025 mmol) and formaldehyde (37.00%, 0.270 g, 3.327 mmol) are dissolved in acetic acid (3 ml), after which the resulting solution is stirred at 0°C for 0.4 hours, and then 1H-indole-6-carbaldehyde (0.351 g, 2.420 mmol) was added and then stirred at room temperature for 18 hours. An aqueous solution of 2N-sodium hydroxide is poured into the resulting reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 3-((4-methylpiperidin-1-yl)methyl)-1H-indole-6-carbaldehyde (0.150 g, 19.3%) in the form of yellow gum.

[Step 2] Synthesis of 6-ethynyl-3-((4-methylpiperidin-1-yl)methyl)-1H-indole

3-((4-Methylpiperidin-1-yl)methyl)-1H-indole-6-carbaldehyde (0.100 g, 0.390 mmol) obtained in step 1 and dimethyl (1-diazo-2-oxopropyl)phosphonate (0.090 g , 0.468 mmol) was dissolved in methanol (2 ml) at room temperature, after which potassium carbonate (0.108 g, 0.780 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting concentrate is poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 6-ethynyl-3-((4-methylpiperidin-1-yl)methyl)-1H-indole (0.055 g, 55.9%) in the form of a yellow oil.

[Step 3] Synthesis of compound 4110

2-(4-(Azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.030 g, 0.111 mmol) prepared in Step 1 of Example 2 and 6-ethynyl-3-( (4-methylpiperidin-1-yl)methyl)-1H-indole (0.028 g, 0.111 mmol) obtained in step 2 is dissolved in tert-butanol (1 ml)/water (1 ml) at room temperature, followed by ascorbate sodium (1.00 M solution, 0.011 ml, 0.011 mmol) and copper(II) sulfate pentahydrate (0.50 M solution, 0.002 ml, 0.001 mmol) were added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution is poured into the reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-50%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(( 4-methylpiperidin-1-yl)methyl)-1H-indol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.011 g, 18.9%) in the form of a light yellow oil.

¹ H NMR(400 MHz, CD₃OD) δ 8.43 (s, 1H), 8.02-7.93 (m, 3H), 7.80 (d,J=8.5 Hz, 1H), 7.68-7.60 (m, 2H), 7.59 (s, 1H), 7.24 (t,J=51.6 Hz, 1H), 5.87 (s, 2H), 4.49 (s, 2H), 3.57-3.46 (m, 2H), 3.10-2.96 (m, 2H), 1.93 (d,J=14.3 Hz, 2H), 1.75-1.64 (m, 1H), 1.51-1.34 (2, 3H), 1.02 (d,J=6.5 Hz, 3H);MCNR(ER) m/z 522.5 (M⁺+1).

The compounds of Table 49 are synthesized in accordance with substantially the same method as described above in the synthesis of compound 4110 except for the use of 6-ethynyl-3-((4-methylpiperidin-1-yl)methyl)-1H-indole and the reagent from the table 48.

Table 48 Example Connection no. Reagent Exit (%) 168 4111 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 17 366 4492 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 15

Table 49 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 168 4111 2-(difluoromethyl)-5-(6-((4-(3-((4-methylpiperidin-1-yl)methyl)-1H-indol-6-yl)-1H-1,2,3-triazol- 1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.29 (d, J = 1.8 Hz, 1H), 8.54 (dd, J = 8.2, 2.2 Hz, 1H), 8, 49 (s, 1H), 7.98 (d, J =1.1 Hz, 1H), 7.80 (d, J =8.3 Hz, 1H), 7.69-7.60 (m, 2H ), 7.57 (s, 1H), 7.26 (t, J =51.6 Hz, 1H), 5.94 (s, 2H), 4.44 (s, 2H), 3.57-3 .46 (m, 2H), 2.97 (s, 2H), 1.91 (d, J =14.4 Hz, 2H), 1.73-1.59 (m, 1H), 1.56- 1.25 (m, 2H), 1.01 (d, J =6.5 Hz, 3H); MSNR (ER) m/z 505.5 (M ⁺ +1). 366 4492 2-(difluoromethyl)-5-(4-((4-(3-((4-methylpiperidin-1-yl)methyl)-1H-indol-6-yl)-1H-1,2,3-triazol- 1-yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.42 (s, 1H), 8.20-8.14 (m, 2H), 7.96 (d, J = 1.3 Hz, 1H), 7.82-7.75 (m, 1H), 7.63 (dd, J = 8.2, 1.3 Hz, 3H), 7.56 (s, 1H), 7.23 (t, J = 51.6 Hz, 2H), 5.81 (s, 2H), 4.42 (s, 2H), 3.48 (d, J =12.4 Hz, 2H), 2.96 (t, J = 12.3 Hz, 2H), 1.96-1.86 (m, 2H), 1.67 (s, 1H), 1.41 (kv, J = 17.2, 14.8 Hz, 2H), 1.01 (d, J =6.5 Hz, 3H); MSNR (ER) m/z 504.3 (M ⁺ +1).

Example 170: Synthesis of 4133, 2-(difluoromethyl)-5-(6-((4-phenyl-1H-pyrazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of 2-(6-((4-bromo-1H-pyrazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

4-Bromo-1H-pyrazole (0.200 g, 1.361 mmol), 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.395 g, 1.361 mmol) and potassium carbonate (0.376 g, 2.721 mmol) were dissolved in N,N-dimethylformamide (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give 2-(6-((4-bromo-1H-pyrazol-1-yl)methyl)pyridin-3 -yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.395 g, 81.5%) in the form of a yellow oil.

[Step 2] Synthesis of compound 4133

Phenylboronic acid (0.040 g, 0.328 mmol), 2-(6-((4-bromo-1H-pyrazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4- oxadiazole (0.117 g, 0.328 mmol) obtained in step 1, [1,1'-bis(di-tert-butylphosphino)ferrocene] palladium(II) dichloride (Pd(dtbpf)Cl ₂ , 0.021 g, 0.033 mmol) and Cesium carbonate (0.190 g, 0.984 mmol) is mixed in 1,4-dioxane (3 ml)/water (1 ml) at room temperature, after which the resulting mixture is irradiated with microwaves, and heated at 100 ° C for 20 minutes, and then the reaction is completed by lowering the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate is purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0-10%) and concentrated, after which the resulting product is purified again by chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0-5%) and concentrate to give 2-(difluoromethyl)-5-(6-((4-phenyl-1H-pyrazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.014 g, 12. 1%) in the form of a brown solid.

¹ H NMR(400 MHz, CDCl₃) δ 9.33 (dd,J=2.3, 0.9 Hz, 1H), 8.38 (dd,J=8.2, 2.2 Hz, 1H), 7.92 (d,J=0.8 Hz, 1H), 7.85 (d,J=0.8 Hz, 1H), 7.56-7.48 (m, 2H), 7.45-7.37 (m, 2H), 7.28-7.23 (m, 2H), 6, 96 (t,J=51.6 Hz, 1H), 5.61 (s, 2H);MCNR(ER) m/z 354.2 (M⁺+1).

The compound of Table 51 was synthesized in accordance with substantially the same method as described above for the synthesis of compound 4133 except for the use of 2-(6-((4-bromo-1H-pyrazol-1-yl)methyl)pyridin-3-yl )-5-(difluoromethyl)-1,3,4-oxadiazole and the reagent from Table 50.

Table 50 Example Connection no. Reagent Exit (%) 184 4208 (1H-indol-6-yl)boronic acid 15

Table 51 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 184 4208 2-(6-((4-(1H-indol-6-yl)-1H-pyrazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.05 (s, 1H), 9.21 (dd, J=2.3, 0.8 Hz, 1H), 8.45 (dd, J= 8.2, 2.3 Hz, 1H), 8.33 (d, J=0.8 Hz, 1H), 7.96 (d, J=0.9 Hz, 1H), 7.72-7, 43 (m, 3H), 7.34-7.29 (m, 2H), 7.26 (dd, J=8.2, 1.5 Hz, 1H), 6.40 (dt, J=2, 7, 1.6 Hz, 1H), 5.61 (s, 2H); MSNR (IER) m/z 393.3 (M ⁺ + H).

Example 173: Synthesis of Compound 4136, 2-(difluoromethyl)-5-(6-((4-(1-ethyl-1H-indol-6-yl)-1H-1,2,3-triazol-1-yl) methyl)pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of 1-ethyl-1H-indole-6-carbaldehyde

1H-indole-6-carbaldehyde (0.500 g, 3.444 mmol) and cesium carbonate (1.329 g, 6.889 mmol) are dissolved in acetonitrile (7 ml) at room temperature, after which the resulting solution is heated at reflux for 2 hours and add iodoethane (0.305 ml, 3.789 mmol) and heat again at reflux for 1 hour, and then the reaction is terminated by reducing the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 1-ethyl-1H-indole-6-carbaldehyde (0.180 g, 30.2%) as a colorless oil. .

[Step 2] Synthesis of 6-ethynyl-1-methyl-1H-indole

1-Methyl-1H-indole-6-carbaldehyde (0.095 g, 0.597 mmol) obtained in step 1 and dimethyl (1-diazo-2-oxopropyl)phosphonate (0.134 ml, 0.895 mmol) are dissolved in methanol (2 ml) at room temperature, after which potassium carbonate (0.165 g, 1.194 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting concentrate is poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-20%) and concentrated to give 6-ethynyl-1-methyl-1H-indole (0.080 g, 86.4%) as light yellow solid.

[Step 3] Synthesis of compound 4136

2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.040 g, 0.159 mmol) prepared in Step 1 of Example 16 and 1-ethyl-6- ethynyl-1H-indole (0.027 g, 0.159 mmol) obtained in step 2 is dissolved in tert-butanol (1 ml)/water (1 ml) at room temperature, followed by sodium ascorbate (1.00 M solution, 0.016 ml , 0.016 mmol) and copper(II) sulfate pentahydrate (0.50 M solution, 0.003 ml, 0.002 mmol) were added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution is poured into the reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=5-40%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(1-ethyl-1H-indol- 6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.050 g, 74.8%) as a light yellow solid substances.

¹ H NMR(400 MHz, CDCl₃) δ 9.40-9.35 (m, 1H), 8.47 (dd,J=8.2, 2.2 Hz, 1H), 8.29 (d,J=32.0 Hz, 1H), 8.14 (d,J=7.3 Hz, 1H), 7.70-7.66 (m, 1H), 7.55 (d,J=8.0 Hz, 1H), 7.43 (dd,J=8.2, 1.5 Hz, 1H), 7.23 (d,J=3.1 Hz, 1H), 6.97 (t,J=51.6 Hz, 1H), 6.53 (dd,J=3.2, 0.9 Hz, 1H), 5.89 (s, 2H), 4.30 (kv,J=7.3 Hz, 2H), 1.58-1.51 (m, 3H);MCNR(ER) m/z 422.3 (M⁺+1).

Example 182: Synthesis of Compound 4186 , 4-((5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazole -4-yl)-1H-indol-3-yl)methyl)morpholine

Morpholine (0.010 ml, 0.115 mmol) and formaldehyde (37.00%, 0.010 g, 0.126 mmol) are dissolved in acetic acid (0.5 ml)/methanol (0.5 ml), after which the resulting solution is stirred at 0°C for 0.4 hours, and then 2-(4-((4-(1H-indol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5 is added thereto -(difluoromethyl)-1,3,4-oxadiazole (0.027 g, 0.069 mmol) obtained in Example 158 and then stirred at room temperature for 18 hours. An aqueous solution of 2N-sodium hydroxide is poured into the resulting reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 4-((5-(1-(4-(5-(difluoromethyl)-1,3,4 -oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-1H-indol-3-yl)methyl)morpholine (0.003 g, 5.3%) in the form of yellow gum.

¹ H NMR(400 MHz, CD₃OD) δ 8.41 (s, 1H), 8.27-8.20 (m, 1H), 8.21-8.15 (m, 3H), 7.70-7.61 (m, 4H) , 7.54 (dd,J=8.6, 0.7 Hz, 1H), 7.24 (t,J=51.6 Hz, 1H), 5.81 (d,J=8.1 Hz, 2H), 4.61 (s, 2H), 4.12-3.97 (m, 2H), 3.80-3.60 (m, 4H), 3.54-3, 40 (m, 2H);MCNR(ER) m/z 492.2 (M⁺+1).

Example 183: Synthesis of compound 4187 , 4-((5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H- 1,2,3-triazol-4-yl)-1H-indol-3-yl)methyl)morpholine

Morpholine (0.010 ml, 0.115 mmol) and formaldehyde (37.00%, 0.010 g, 0.126 mmol) are dissolved in acetic acid (0.5 ml)/methanol (0.5 ml), after which the resulting solution is stirred at 0°C for 0.4 hours, and then 2-(6-((4-(1H-indol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3- yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.027 g, 0.069 mmol) obtained in step 2 of Example 150 and then stirred at room temperature for 18 hours. An aqueous solution of 2N-sodium hydroxide is poured into the resulting reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 4-((5-(1-((5-(5-(difluoromethyl)-1,3, 4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indol-3-yl)methyl)morpholine (0.005 g, 8.8 %) in the form of a colorless oil.

¹ H NMR (400 MHz, CD₃OD) δ 9.30 (d,J=1.7 Hz, 1H), 8.54 (dd,J=8.2, 2.2 Hz, 1H), 8.46 (d,J=8.5 Hz, 1H), 8.23 (d,J=10.5 Hz, 1H), 7.73-7.63 (m, 1H), 7.62 (d,J=7.7 Hz, 1H), 7.56-7.49 (m, 1H), 7.45 (d,J=25.6 Hz, 1H), 7.26 (t,J=51.6 Hz, 1H), 5.93 (s, 2H), 4.14-4.07 (m, 2H), 3.84-3.76 (m, 3H), 3.67-3, 54 (m, 2H), 3.08 (d,J=12.0 Hz, 1H), 2.89 (s, 2H);MCNR(ER) m/z 493.5 (M⁺+1).

Example 185: Synthesis of Compound 4209, 2-(difluoromethyl)-5-(6-((4-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3- triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 7-ethynyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

Tert-butyl 7-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.000 g, 3.827 mmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (0.882 g, 4.592 mmol) and potassium carbonate (1.058 g, 7.653 mmol) was dissolved in methanol (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting concentrate is poured into water, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-20%) and concentrated to give tert-butyl 7-ethynyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.200 g, 87 .8%) in the form of a yellow oil.

[Step 2] Synthesis of tert-butyl 7-(1-((5-(methoxycarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline- 2(1H)-carboxylate

Tert-butyl 7-ethynyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.170 g, 4.547 mmol) obtained in step 1, methyl 6-(azidomethyl)nicotinate (0.874 g, 4.547 mmol) obtained in step 1 of Example 81, copper(II) sulfate pentahydrate (0.114 g, 0.455 mmol) and sodium ascorbate (0.009 g, 0.045 mmol) were dissolved in tert-butanol (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature in within 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-80%) and concentrated to give tert-butyl 7-(1-((5-(methoxycarbonyl)pyridin-2-yl)methyl)- 1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.100 g, 102.8%) as a yellow solid.

[Step 3] Synthesis of tert-butyl 7-(1-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline- 2(1H)-carboxylate

Tert-butyl 7-(1-((5-(methoxycarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)- The carboxylate (2.100 g, 4.672 mmol) obtained in step 2 and hydrazine monohydrate (2.271 ml, 46.718 mmol) are dissolved in ethanol (50 ml) at room temperature, after which the resulting solution is heated at reflux for 12 hours, and then the reaction is completed by lowering the temperature to room temperature. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without further purification process (tert-butyl 7-(1-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-1H-1,2,3 -triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate, 2.000 g, 95.2%, yellow solid).

[Step 4] Synthesis of tert-butyl 7-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2 ,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

Tert-butyl 7-(1-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)- The carboxylate (2.000 g, 4.449 mmol) obtained in step 3, difluoroacetic anhydride (2.323 g, 13.348 mmol) and triethylamine (1.850 ml, 13.348 mmol) are dissolved in dichloromethane (100 ml) at room temperature, after which the resulting solution is heated to boiling under reflux for 12 hours, and then the reaction is completed by reducing the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-100%) and concentrated to give tert-butyl 7-(1-((5-(5-(difluoromethyl)-1,3,4 -oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.000 g, 44.1 %) in the form of a white solid.

[Step 5] Synthesis of 2-(difluoromethyl)-5-(6-((4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl) methyl)pyridin-3-yl)-1,3,4-oxadiazole

Tert-butyl 7-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.000 g, 1.963 mmol) obtained in step 4 and trifluoroacetic acid (1.503 ml, 19.626 mmol) were dissolved in dichloromethane (50 ml) at room temperature , after which the resulting solution is stirred at the same temperature for 3 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(1,2,3,4- tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.600 g, 74.7%) as a white solid substances.

[Step 6] Synthesis of compound 4209

2-(Difluoromethyl)-5-(6-((4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3 -yl)-1,3,4-oxadiazole (0.060 g, 0.147 mmol) obtained in step 5, formaldehyde (0.009 g, 0.293 mmol) and acetic acid (0.009 ml, 0.161 mmol) are dissolved in methanol (5 ml) at room temperature, after which sodium triacetoxyborohydride (0.062 g, 0.293 mmol) was added to the resulting solution and stirred at the same temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution is poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove solid residue and a layer of aqueous solution, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(2-methyl-1,2, 3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.025 g, 40.3%) in the form of a yellow solid.

¹ H NMR(400 MHz, CDCl₃) δ 9.32-9.26 (m, 1H), 8.36 (dd,J=8.2, 2.3 Hz, 1H), 7.93 (s, 1H), 7.60-7.50 (m, 2H), 7.38 (d,J=8.2 Hz, 1H), 7.14 (d,J=7.9 Hz, 1H), 6.93 (t,J=51.6 Hz, 1H), 5.78 (s, 2H), 3.73 (s, 2H), 2.97 (t,J=6.0 Hz, 2H), 2.84 (t,J=6.0 Hz, 2H), 2.51 (s, 3H);MCNR(ER) m/z 493.4 (M⁺+1).

The compounds of Table 53 were synthesized in accordance with substantially the same method as described above for the synthesis of compound 4209 except for the use of 2-(difluoromethyl)-5-(6-((4-(1,2,3,4-tetrahydroisoquinoline- 7-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reagent from Table 52.

Table 52 Example Connection no. Reagent Exit (%) 186 4210 Propan-2-one 45 187 4211 Acetaldehyde 15 188 4212 Cyclobutanone 51 189 4213 Oxetan-3-one 51

Table 53 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 186 4210 2-(difluoromethyl)-5-(6-((4-(2-isopropyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl )pyridin-3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.32 (d, J=2.3 Hz, 1H), 8.39 (dt, J=8.2, 1.7 Hz, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.65-7.53 (m, 2H), 7.40 (dd, J=8.3, 3.3 Hz, 1H), 7.16 ( d, J=8.0 Hz, 1H), 6.94 (s, 1H), 5.79 (s, 2H), 3.02 (d, J=5.8 Hz, 1H), 2.96 ( d, J=6.0 Hz, 2H), 2.77 (t, J=6.0 Hz, 2H), 2.51 (s, 2H), 1.28-1.22 (m, 6H); MSNR (ER) m/z 452.5 (M ⁺ +1). 187 4211 2-(difluoromethyl)-5-(6-((4-(2-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl )pyridin-3-yl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 9.32 (s, 1H), 8.39 (d, J=8.0 Hz, 1H), 7.93 (d, J=9.7 Hz, 1H ), 7.63-7.53 (m, 2H), 7.41 (d, J=8.3 Hz, 1H), 7.18 (d, J=8.1 Hz, 1H), 6.93 (t, J=51.6 Hz, 1H), 5.79 (s, 2H), 3.93 (s, 2H), 3.05 (s, 2H), 2.67 (d, J=28, 8 Hz, 2H), 1.77 (s, 2H), 0.98 (t, J=7.3 Hz, 3H); MSNR (ER) m/z 438.5 (M ⁺ +1). 188 4212 2-(6-((4-(2-cyclobutyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl )-5-(difluoromethyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 9.28 (s, 1H), 8.35 (dd, J=8.2, 2.3 Hz, 1H), 7.92 (s, 1H), 7 .57-7.50 (m, 2H), 7.37 (d, J=8.2 Hz, 1H), 7.12 (d, J=7.9 Hz, 1H), 6.93 (t, J=51.6 Hz, 1H), 5.77 (s, 2H), 3.60 (s, 2H), 2.97 (t, J=8.0 Hz, 1H), 2.91 (t, J=6.4 Hz, 2H), 2.69 (t, J=6.0 Hz, 2H), 2.08 (dt, J=20.0, 9.2 Hz, 4H), 1.73 ( tt, J=19.3, 8.7 Hz, 2H); MSNR (ER) m/z 464.50 (M ⁺ +1). 189 4213 2-(difluoromethyl)-5-(6-((4-(2-(oxetan-3-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazole -1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.30 (d, J=2.2 Hz, 1H), 8.37 (dd, J=8.2, 2.3 Hz, 1H), 7.92 (s, 1H), 7.55 (d, J=9.1 Hz, 2H), 7.39 (d, J=8.2 Hz, 1H), 7.15 (d, J=7.8 Hz , 1H), 6.93 (t, J=51.6 Hz, 1H), 5.78 (s, 2H), 4.78-4.68 (m, 4H), 3.71 (p, J= 6.5 Hz, 1H), 3.56 (s, 2H), 2.94 (t, J=6.0 Hz, 2H), 2.64 (t, J=6.0 Hz, 2H); MSNR (ER) m/z 466.5 (M ⁺ +1).

Example 193: Synthesis of Compound 4232, 2-(difluoromethyl)-5-(6-((5-(thiophen-2-yl)-2H-tetrazol-2-yl)methyl)pyridin-3-yl)-1,3 ,4-oxadiazole

[Step 1] Synthesis of 5-(thiophen-2-yl)-2H-tetrazole

Thiophene-2-carbonitrile (0.500 g, 4.581 mmol), sodium azide (0.655 g, 10.078 mmol) and ammonium chloride (0.539 g, 10.078 mmol) were dissolved in N,N-dimethylformamide (10 ml) at room temperature, after which the resulting the solution is stirred at 120°C for 18 hours, and then the reaction is completed by lowering the temperature to room temperature. After adding 10 ml of water, 1N hydrogen chloride was added to filter the precipitated solid, which was then washed with hexane and dried to give 5-(thiophen-2-yl)-2H-tetrazole (0.620 g, 88.9%) as white solid matter.

[Step 2] Synthesis of methyl 6-((5-(thiophen-2-yl)-2H-tetrazol-2-yl)methyl)nicotinate

5-(Thiophen-2-yl)-2H-tetrazole (0.200 g, 1.314 mmol) obtained in step 1 and potassium carbonate (0.182 g, 1.314 mmol) were dissolved in acetonitrile (5 ml) at room temperature, then methyl 6-(bromomethyl)nicotinate (0.333 g, 1.446 mmol) was added to the resulting solution and stirred at 100° C. for 18 hours, and then the reaction was terminated by lowering the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give methyl 6-((5-(thiophen-2-yl)-2H-tetrazol-2-yl) methyl)nicotinate (0.320 g, 80.8%) in the form of a white solid.

[Step 3] 6-((5-(thiophen-2-yl)-2H-tetrazol-2-yl)methyl)nicotine hydrazide

Methyl 6-((5-(thiophen-2-yl)-2H-tetrazol-2-yl)methyl)nicotinate (0.150 g, 0.499 mmol) obtained in step 2 and hydrazine monohydrate (0.485 ml, 9.989 mmol) are dissolved in ethanol (3 ml), after which the resulting solution was stirred at 80°C for 18 hours, and then stirred at room temperature for 18 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without further purification process (6-((5-(thiophen-2-yl)-2H-tetrazol-2-yl)methyl)nicotinohydrazide, 0.150 g, 100, 0%, white solid).

[Step 4] Synthesis of compound 4232

6-((5-(Thiophen-2-yl)-2H-tetrazol-2-yl)methyl)nicotinohydrazide (0.070 g, 0.233 mmol) obtained in step 3, triethylamine (0.195 ml, 1.398 mmol) and anhydride 2, 2-difluoroacetic acid (0.116 ml, 0.932 mmol) was dissolved in tetrahydrofuran (3 ml) at room temperature, after which the resulting solution was heated with stirring at 80°C for 4 hours, and then the reaction was terminated by reducing the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 2-(difluoromethyl)-5-(6-((5-(thiophen-2-yl)-2H -tetrazol-2-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.055 g, 65.3%) as a white solid.

¹ H NMR(400 MHz, CDCl₃) δ 9.36 (dd,J=2.3, 0.8 Hz, 1H), 8.45 (dd,J=8.2, 2.2 Hz, 1H), 7.86 (dd,J=3.7, 1.2 Hz, 1H), 7.50 (dd,J=5.0, 1.2 Hz, 1H), 7.39 (d,J=8.2 Hz, 1H), 7.19 (dd,J=5.0, 3.7 Hz, 1H), 6.96 (t,J=51.6 Hz, 1H), 6.10 (s, 2H);MCNR(ER) m/z 362.1 (M⁺+1).

The compound of Table 55 was synthesized in accordance with substantially the same method as described above for the synthesis of compound 4232 except for the use of 6-((5-(thiophen-2-yl)-2H-tetrazol-2-yl)methyl)nicotinohydrazide and reagent from table 54.

Table 54 Example Connection no. Reagent Exit (%) 194 4233 Trifluoroacetic anhydride 69

Table 55 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 194 4233 2-(6-((5-(thiophen-2-yl)-2H-tetrazol-2-yl)methyl)pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.35 (dd, J = 2.2, 0.9 Hz, 1H), 8.45 (dd, J = 8.2, 2.2 Hz, 1H) , 7.86 (dd, J =3.7, 1.2 Hz, 1H), 7.50 (dd, J =5.0, 1.2 Hz, 1H), 7.44-7.37 (m , 1H), 7.19 (dd, J =5.0, 3.7 Hz, 1H), 6.10 (s, 2H); MSNR (ER) m/z 380.3 (M ⁺ +1).

Example 195: Synthesis of Compound 4234, 2-(difluoromethyl)-5-(6-((5-phenyl-2H-tetrazol-2-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of 5-phenyl-2H-tetrazole

Benzonitrile (0.500 g, 4.128 mmol), sodium azide (0.590 g, 9.083 mmol) and ammonium chloride (0.486 g, 9.083 mmol) were dissolved in N,N-dimethylformamide (10 ml) at room temperature, after which the resulting solution was stirred at 120 °C for 18 hours, and then the reaction is completed by lowering the temperature to room temperature. After adding 10 ml of water, 1N hydrogen chloride was added to filter the precipitated solid, which was then washed with hexane and dried to give 5-phenyl-2H-tetrazole (0.600 g, 99.4%) as a white solid.

[Step 2] Synthesis of methyl 6-((5-phenyl-2H-tetrazol-2-yl)methyl)nicotinate

5-phenyl-2H-tetrazole (0.200 g, 1.368 mmol) obtained in step 1 and potassium carbonate (0.189 g, 1.368 mmol) were dissolved in acetonitrile (5 ml) at room temperature, followed by methyl 6-(bromomethyl)nicotinate (0.346 g, 1.505 mmol) was added to the resulting solution and stirred at 100°C for 18 hours, and then the reaction was terminated by lowering the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give methyl 6-((5-phenyl-2H-tetrazol-2-yl)methyl)nicotinate (0.300 g , 74.2%) in the form of a white solid.

[Step 3] Synthesis of (6-((5-phenyl-2H-tetrazol-2-yl)methyl)nicotine hydrazide

Methyl 6-((5-phenyl-2H-tetrazol-2-yl)methyl)nicotinate (0.150 g, 0.508 mmol) obtained in step 2 and hydrazine monohydrate (0.494 ml, 10.159 mmol) are dissolved in ethanol (3 ml) , after which the resulting solution was stirred at 80°C for 18 hours and then stirred at room temperature for 18 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without further purification process (6-((5-phenyl-2H-tetrazol-2-yl)methyl)nicotine hydrazide, 0.150 g, 100.3%, white solid ).

[Step 4] Synthesis of compound 4234

6-((5-Phenyl-2H-tetrazol-2-yl)methyl)nicotinohydrazide (0.070 g, 0.237 mmol) obtained in step 3, triethylamine (0.198 ml, 1.422 mmol) and 2,2-difluoroacetic anhydride (0.118 ml, 0.948 mmol) was dissolved in tetrahydrofuran (3 ml) at room temperature, after which the resulting solution was stirred at 80°C for 4 hours, and then the reaction was completed by lowering the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 2-(difluoromethyl)-5-(6-((5-phenyl-2H-tetrazol-2-yl )methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.056 g, 66.5%) in the form of a white solid.

¹ H NMR(400 MHz, CDCl₃) δ 9.36 (dd,J=2.1, 0.9 Hz, 1H), 8.44 (dd,J=8.2, 2.2 Hz, 1H), 8.23-8.16 (m, 2H), 7.52 (dd,J=5.1, 2.0 Hz, 3H), 7.39 (d,J=8.2 Hz, 1H), 6.96 (t,J=51.6 Hz, 1H), 6.12 (s, 2H);MCNR(ER) m/z 356.3 (M⁺+1).

The compound of Table 57 was synthesized in accordance with substantially the same method as described above for the synthesis of compound 4234 except for the use of 6-((5-phenyl-2H-tetrazol-2-yl)methyl)nicotine hydrazide and the reagent from Table 56.

Table 56 Example Connection no. Reagent Exit (%) 196 4235 Trifluoroacetic anhydride 64

Table 57 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 196 4235 2-(6-((5-phenyl-2H-tetrazol-2-yl)methyl)pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.36 (dd, J = 2.3, 0.9 Hz, 1H), 8.45 (dd, J = 8.2, 2.2 Hz, 1H) , 8.22-8.17 (m, 2H), 7.56-7.48 (m, 3H), 7.43-7.37 (m, 1H), 6.13 (s, 2H); MSNR (ER) m/z 374.3 (M ⁺ +1).

Example 201: Synthesis of Compound 4280, 2-(difluoromethyl)-5-(6-((4-(3-fluoroxetan-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin- 3-yl)-1,3,4-oxadiazole

3-(1-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl )oxetan-3-ol (0.020 g, 0.057 mmol) prepared in Example 197 and diethylaminosulfur trifluoride (0.009 ml, 0.069 mmol) were dissolved in dichloromethane (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature in within 1 hour. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(3-fluoroxetan-3-yl) -1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.011 g, 54.7%) as a white solid.

¹ H NMR (400 MHz, CDCl₃) δ 9.34 (s, 1H), 8.44 (dd,J=8.2, 2.2 Hz, 1H), 7.86 (s, 1H), 7.47 (d,J=8.2 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.84 (s, 0.3H), 5.80 (s, 2H) , 5.19 (dd,J=7.9, 1.1 Hz, 1H), 5.11 (ddd,J=17.2, 8.0, 1.1 Hz, 2H), 5.04 (dd,J=7.9, 1.1 Hz, 1H);MCNR(ER) m/z 353.25 (M⁺+1).

Example 202: Synthesis of Compound 4281, 2-(difluoromethyl)-5-(6-((4-(3-fluorotetrahydrofuran-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin- 3-yl)-1,3,4-oxadiazole

3-(1-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl )tetrahydrofuran-3-ol (0.020 g, 0.057 mmol) obtained in Example 198 and diethylaminosulfur trifluoride (DAST, 0.009 ml, 0.069 mmol) were dissolved in dichloromethane (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 1 hour. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(3-fluorotetrahydrofuran-3-yl) -1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.008 g, 39.8%) as a white solid.

¹ H NMR (400 MHz, CDCl₃) δ 9.35 (d,J=1.5 Hz, 1H), 8.44 (dd,J=8.2, 2.2 Hz, 1H), 7.86 (s, 1H), 7.45 (d,J=8.2 Hz, 1H), 7.09 (s, 0.2H), 6.97 (s, 0.5H), 6.84 (s, 0.3H), 5.79 (s, 2H) , 4.35-4.06 (m, 4H), 2.81-2.46 (m, 2H).

Example 203: Synthesis of Compound 4282, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-fluorooxetan-3-yl)-1H-1,2,3-triazol-1-yl) methyl)phenyl)-1,3,4-oxadiazole

3-(1-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)oxetan-3 -ol (0.020 g, 0.054 mmol) obtained in Example 199 and diethylaminosulfur trifluoride (0.009 ml, 0.065 mmol) were dissolved in dichloromethane (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 1 hour. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-fluoroxetane- 3-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.013 g, 64.6%) as a white solid.

¹ H NMR (400 MHz, CDCl₃) δ 7.99-7.90 (m, 2H), 7.70 (s, 1H), 7.50 (t,J=7.6 Hz, 1H), 7.07 (s, 0.2H), 6.94 (s, 0.51H), 6.82 (s, 0.3H), 5.72 (s, 2H) , 5.18 (dd,J=8.0, 1.2 Hz, 1H), 5.10 (ddd,J=17.9, 8.0, 1.2 Hz, 2H), 5.02 (dd,J=8.0, 1.1 Hz, 1H);MCNR(ER) m/z 370.29 (M⁺+1).

Example 204: Synthesis of Compound 4283, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-fluorotetrahydrofuran-3-yl)-1H-1,2,3-triazol-1-yl) methyl)phenyl)-1,3,4-oxadiazole

3-(1-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)tetrahydrofuran-3 -ol (0.020 g, 0.052 mmol) obtained in Example 200 and diethylaminosulfur trifluoride (DAST, 0.008 ml, 0.063 mmol) were dissolved in dichloromethane (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 1 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-fluorotetrahydrofuran- 3-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.016 g, 79.6%) as a white solid.

¹ H NMR (400 MHz, CDCl₃) δ 7.99-7.89 (m, 2H), 7.71 (s, 1H), 7.50 (t,J=7.6 Hz, 1H), 7.07 (s, 0.2H), 6.94 (s, 0.5H), 6.82 (s, 0.3H), 5.70 (s, 2H) , 4.32-4.03 (m, 4H), 2.83-2.43 (m, 2H);MCNR(ER) m/z 384.33 (M⁺+1).

Example 208: Synthesis of Compound 4287, 2-(difluoromethyl)-5-(6-((4-(2-methyl-1H-indol-6-yl)-1H-1,2,3-triazol-1-yl) methyl)pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of methyl 2-methyl-1H-indole-6-carboxylate

Methyl 3-aminobenzoate (3.000 g, 19.845 mmol), copper acetate monohydrate (11.886 g, 59.536 mmol), acetone (34.578 g, 595.356 mmol) and acetic acid with palladium (II, 0.089 g, 0.397 mmol) are dissolved in dimethyl sulfoxide (15 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 48 hours. The reaction mixture is filtered through a pad of celite to remove solid matter, after which the solvent is removed from the resulting filtrate without solid matter under reduced pressure. The resulting concentrate was then purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give methyl 2-methyl-1H-indole-6-carboxylate (0.150 g, 4.0%) in the form of a light yellow solid.

[Step 2] Synthesis of (2-methyl-1H-indol-6-yl)methanol

Methyl 2-methyl-1H-indole-6-carboxylate (0.130 g, 0.687 mmol) obtained in step 1 is dissolved in tetrahydrofuran (2 ml), after which the resulting solution is stirred at 0°C for 0.1 hour, and then lithium aluminum hydride (1.00 M solution, 1.718 mL, 1.718 mmol) was added to the resulting solution, and then stirred at room temperature for 2 hours. The reaction mixture is filtered through a pad of celite to remove solid matter from it, after which the solid-free solvent is removed from the resulting filtrate under reduced pressure, and then the resulting product is used without further purification process ((2-methyl-1H-indol-6-yl) methanol, 0.113 g, 102.0%, colorless oil).

[Step 3] Synthesis of 2-methyl-1H-indole-6-carbaldehyde

(2-Methyl-1H-indol-6-yl)methanol (0.130 g, 0.806 mmol) obtained in step 2 and MANGAS(ip) oxide (0.491 g, 5.645 mmol) are dissolved in dichloromethane (3 ml) at room temperature , after which the resulting solution is stirred at the same temperature for 18 hours. The reaction mixture is filtered through a pad of celite to remove solid matter from it, after which the solid-free solvent is removed from the resulting filtrate under reduced pressure, and then the resulting product is used without further purification process (2-methyl-1H-indole-6-carbaldehyde, 0.110 g, 85.7%, yellow solid).

[Step 4] Synthesis of 6-ethynyl-2-methyl-1H-indole

2-Methyl-1H-indole-6-carbaldehyde (0.100 g, 0.628 mmol) obtained in step 3 and dimethyl (1-diazo-2-oxopropyl)phosphonate (0.189 ml, 1.256 mmol) are dissolved in methanol (2 ml) at room temperature, after which potassium carbonate (0.243 g, 1.759 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting concentrate is poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-40%) and concentrated to give 6-ethynyl-2-methyl-1H-indole (0.040 g, 41.0%) as light yellow solid.

[Step 5] Synthesis of compound 4287

2-(4-(Azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.028 g, 0.111 mmol) prepared in Step 1 of Example 18 and 6-ethynyl-2-methyl-1H- indole (0.017 g, 0.111 mmol) obtained in step 4 is dissolved in tert-butanol (1 ml)/water (1 ml) at room temperature, followed by sodium ascorbate (1.00 M solution, 0.011 ml, 0.011 mmol) and copper(II) sulfate pentahydrate (0.50 M solution, 0.002 ml, 0.001 mmol) were added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution is poured into the reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-80%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(2-methyl-1H-indol- 6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.032 g, 70.8%) as a light yellow solid substances.

¹ H NMR(400 MHz, DMSO-d₆) δ 11.02 (s, 1H), 9.21 (dd,J=2.3, 0.9 Hz, 1H), 8.61 (s, 1H), 8.49 (dd,J=8.2, 2.3 Hz, 1H), 7.79 (kv,J=1.0 Hz, 1H), 7.58 (t,J=51.2 Hz, 1H), 7.55 (d,J=8.1 Hz, 1H), 7.43 (d,J=1.5 Hz, 1H), 6.16-6.11 (m, 1H), 5.91 (s, 2H), 2.40 (d,J=1.0 Hz, 3H);MCNR(ER) m/z 408.1 (M⁺+1).

The compound of Table 59 was synthesized in accordance with substantially the same method as described above for the synthesis of compound 4287 except for the use of 6-ethynyl-2-methyl-1H-indole and the reagent from Table 58.

Table 58 Example Connection no. Reagent Exit (%) 209 4288 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 77

Table 59 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 209 4288 2-(difluoromethyl)-5-(4-((4-(2-methyl-1H-indol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.01 (s, 1H), 8.61 (s, 1H), 8.10 (d, J =7.9 Hz, 2H), 7.78 (s, 1H), 7.69-7.53 (m, 3H), 7.47-7.37 (m, 2H), 6.13 (s, 1H), 5.78 (s, 2H), 2.40 (s, 3H); MSNR (ER) m/z 407.2 (M ⁺ +1).

Example 211: Synthesis of Compound 4290, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(1-methylpiperidin-4-yl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of methyl 4-(azidomethyl)-3-fluorobenzoate

Methyl 4-(bromomethyl)-3-fluorobenzoate (2.000 g, 8.095 mmol) and sodium azide (0.632 g, 9.714 mmol) were dissolved in N,N-dimethylformamide (50 ml) at 50°C, after which the resulting solution was stirred at same temperature for 5 hours, and then the reaction is completed by lowering the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane=0-20%) and concentrated to give methyl 4-(azidomethyl)-3-fluorobenzoate (1,500 g, 88.6%) as a yellow oil .

[Step 2] Synthesis of methyl 4-((4-(3-bromophenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorobenzoate

Methyl 4-(azidomethyl)-3-fluorobenzoate (0.900 g, 4.303 mmol) obtained in step 1, 1-bromo-4-ethynylbenzene (0.935 g, 5.163 mmol), sodium ascorbate (1.00 M solution in H ₂ O , 0.430 ml, 0.430 mmol), and copper(II) sulfate pentahydrate (0.50 M solution in H ₂ O, 0.086 ml, 0.043 mmol) dissolved in tert-butanol (15 ml)/water (15 ml) at room temperature , after which the resulting solution is stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give methyl 4-((4-(3-bromophenyl)-1H-1,2,3-triazol- 1-yl)methyl)-3-fluorobenzoate (1,300 g, 77.4%) as a white solid.

[Step 3] Synthesis of methyl 4-((4-(3-bromophenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorobenzoate

Methyl 4-((4-(3-bromophenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorobenzoate (1.300 g, 3.332 mmol) obtained in step 2, tert-butyl 4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.236 g, 3.998 mmol), bis(triphenylphosphine) dichloride palladium(I) (0.117 g, 0.167 mmol) and sodium carbonate (1.059 g, 9.995 mmol) are mixed in N,N-dimethylformamide (20 ml)/water (10 ml) at 60°C, after which the resulting mixture is stirred at that same temperature for 5 hours, and then the reaction is completed by lowering the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane=0-40%) and concentrated to give tert-butyl 4-(3-(1-(2-fluoro-4-(methoxycarbonyl)benzyl)- 1H-1,2,3-triazol-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1,400 g, 85.3%) as a white solid.

[Step 4] Synthesis of tert-butyl 4-(3-(1-(2-fluoro-4-(methoxycarbonyl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate

Tert-butyl 4-(3-(1-(2-fluoro-4-(methoxycarbonyl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)-3,6-dihydropyridine-1(2H )-carboxylate (1.000 g, 2.030 mmol) obtained in step 3 is dissolved in methanol (50 ml) at room temperature, after which 10%-Pd/C (150 mg) is slowly added and stirred for 12 hours in the presence of hydrogen cylinder connected to it at the same temperature. The reaction mixture was filtered through a pad of celite to remove solid matter, after which the solvent was removed from the resulting filtrate under reduced pressure, and then the resulting concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl 4-(3-(1-(2-fluoro-4-(methoxycarbonyl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate (0.900 g , 89.6%) in the form of yellow oil

[Step 5] Synthesis of tert-butyl 4-(3-(1-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate

Tert-butyl 4-(3-(1-(2-fluoro-4-(methoxycarbonyl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate (0.900 g, 1.820 mmol) obtained in step 4 and hydrazine monohydrate (0.884 ml, 18.198 mmol) are dissolved in ethanol (50 ml) at 90°C, after which the resulting solution is stirred at the same temperature for 12 hours, and then the reaction is terminated by reducing the temperature to room temperature. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting concentrate is poured into water, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Then, the resulting product is used without additional purification process (tert-butyl 4-(3-(1-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl) piperidine-1-carboxylate, 0.820 g, 91.1%, white solid).

[Step 6] Synthesis of tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2, 3-triazol-4-yl)phenyl)piperidine-1-carboxylate

Tert-butyl 4-(3-(1-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate (0.820 g, 1.658 mmol) obtained in step 5, imidazole (0.339 g, 4.974 mmol) and 2,2-difluoroacetic anhydride (0.618 ml, 4.974 mmol) are mixed in dichloromethane (50 ml) at room temperature, after which the resulting mixture is heated to reflux refrigerator for 12 hours and cool to room temperature. Then, water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3 ,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate (0.770 g, 83.7%) as a white solid .

[Step 7] Synthesis of 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)phenyl)-1,3,4-oxadiazole

Tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4 -yl)phenyl)piperidine-1-carboxylate (0.770 g, 1.388 mmol) obtained in step 6 and trifluoroacetic acid (0.319 ml, 4.165 mmol) were dissolved in dichloromethane (20 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 3 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without further purification process (2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(piperidin-4-yl)phenyl) -1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole, 0.510 g, 80.8%, yellow oil).

[Step 8] Synthesis of compound 4290

2-(Difluoromethyl)-5-(3-fluoro-4-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl) -1,3,4-oxadiazole (0.070 g, 0.154 mmol) obtained in step 7, formaldehyde (36.00%, 0.026 g, 0.308 mmol), acetic acid (0.011 ml, 0.185 mmol) and sodium triacetoxyborohydride (0.065 g , 0.308 mmol) was dissolved in dichloromethane (5 ml), after which the resulting solution was stirred at room temperature for 30 minutes, and then stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(1 -methylpiperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.029 g, 40.2%) as a white solid .

¹ H NMR (400 MHz, CDCl₃) δ 7.97-7.91 (m, 2H), 7.89 (s, 1H), 7.73 (d,J=9.0 Hz, 2H), 7.47 (t,J=7.7 Hz, 1H), 7.40 (t,J=7.6 Hz, 1H), 7.26 (d,J=7.5 Hz, 1H), 7.07 (s, 0.2H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 5.75 (s, 2H) , 3.37 (s, 2H), 2.77-2.47 (m, 5H), 2.30-2.28 (m, 3H), 2.01 (d,J=12.0 Hz, 2H);MCNR(ER) m/z 469.5 (M⁺+1).

The compounds of Table 61 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4290 except for the use of 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(piperidine-4 -yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole and the reagent from Table 60.

Table 60 Example Connection no. Reagent Exit (%) 212 4291 Acetaldehyde 40 213 4292 Propan-2-one 40 214 4293 Oxetan-3-one 36

Table 61 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 212 4291 2-(difluoromethyl)-5-(4-((4-(3-(1-ethylpiperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl )-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 7.96-7.89 (m, 2H), 7.86 (s, 1H), 7.76-7.67 (m, 2H), 7.47 ( t, J =7.7 Hz, 1H), 7.37 (t, J =7.7 Hz, 1H), 7.23 (d, J =7.7 Hz, 1H), 7.07 (s, 0.2H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 5.74 (s, 2H), 3.29 (d, J =11.6 Hz, 2H ), 2.73-2.56 (m, 3H), 2.27 (dd, J =12.2, 10.2 Hz, 2H), 2.12-1.85 (m, 4H), 1, 22 (t, J =7.2 Hz, 3H); MSNR (ER) m/z 483.5 (M ⁺ +1). 213 4292 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(1-isopropylpiperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl) phenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 7.93 (dd, J =8.8, 6.5 Hz, 3H), 7.76 (d, J =6.4 Hz, 2H), 7.46 (t, J =7.7 Hz, 1H), 7.39 (t, J =7.9 Hz, 1H), 7.26 (d, J =7.5 Hz, 1H), 7.07 (s , 0.2H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 5.75 (s, 2H), 3.33 (s, 2H), 2.69- 2.61 (m, 3H), 2.00 (d, J =12.7 Hz, 2H), 1.69-1.58 (m, 3H), 1.30 (d, J =12.9 Hz , 6H); MSNR (ER) m/z 497.5 (M ⁺ +1). 214 4293 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(1-(oxetan-3-yl)piperidin-4-yl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)phenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 7.94 (d, J =8.6 Hz, 2H), 7.83 (s, 1H), 7.75 (s, 1H), 7.67 (d , J =7.7 Hz, 1H), 7.48 (t, J =7.6 Hz, 1H), 7.38 (t, J =7.7 Hz, 1H), 7.24 (d, J =7.7 Hz, 1H), 7.07 (s, 0.2H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 5.75 (s, 2H) , 4.71 (t, J =8.4 Hz, 4H), 3.61-3.48 (m, 1H), 2.92 (d, J =9.7 Hz, 2H), 2.70- 2.50 (m, 1H), 1.95 (dd, J =22.2, 7.6 Hz, 6H); MSNR (ER) m/z 511.6 (M ⁺ +1).

Example 215: Synthesis of Compound 4294, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(1-(1-methylazetidin-3-yl)piperidin-4-yl)phenyl)- 1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 3-(4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1 ,2,3-triazol-4-yl)phenyl)piperidin-1-yl)azetidine-1-carboxylate

2-(Difluoromethyl)-5-(3-fluoro-4-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl) -1,3,4-oxadiazole (0.400 g, 0.880 mmol) obtained from step 7 of Example 211, tert-butyl 3-oxoazetidine-1-carboxylate (0.301 g, 1.760 mmol), acetic acid (0.060 ml, 1.056 mmol) and sodium triacetoxyborohydride (0.373 g, 1.760 mmol) were dissolved in dichloromethane (5 ml), after which the resulting solution was stirred at room temperature for 30 minutes, and then stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give tert-butyl 3-(4-(3-(1-(4-(5-(difluoromethyl)- 1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidin-1-yl)azetidine-1-carboxylate (0.300 g, 55 .9%) in the form of a white solid.

[Step 2] Synthesis of 2-(4-((4-(3-(1-(azetidin-3-yl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl) methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole

Tert-butyl 3-(4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3- triazol-4-yl)phenyl)piperidin-1-yl)azetidine-1-carboxylate (0.300 g, 0.492 mmol) obtained in step 1 and trifluoroacetic acid (0.113 ml, 1.476 mmol) were dissolved in dichloromethane (20 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 3 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Then, the resulting product is used without additional purification process (2-(4-((4-(3-(1-(azetidin-3-yl)piperidin-4-yl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole, 0.200 g, 79.8%, yellow oil).

[Step 3] Synthesis of compound 4294

2-(4-((4-(3-(1-(Azetidin-3-yl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3- fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.070 g, 0.137 mmol) obtained in step 2, formaldehyde (0.008 g, 0.275 mmol) and acetic acid (0.009 ml, 0.165 mmol) are dissolved in dichloromethane (5 ml), after which the resulting solution was stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (0.058 g, 0.275 mmol) was added thereto and then stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(1 -(1-methylazetidin-3-yl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.036 g, 50 .1%) in the form of a white solid.

¹ H NMR (400 MHz, CDCl₃) δ 7.94 (d,J=8.8 Hz, 2H), 7.81 (s, 1H), 7.76 (d,J=9.6 Hz, 1H), 7.66 (d,J=7.6 Hz, 1H), 7.48 (t,J=7.6 Hz, 1H), 7.37 (t,J=7.7 Hz, 1H), 7.22 (d,J=7.7 Hz, 1H), 7.07 (s, 0.2H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 5.74 (s, 2H) , 3.71 (s, 2H), 3.05 (s, 3H), 2.89 (d,J=11.0 Hz, 2H), 2.64-2.52 (m, 1H), 2.47 (s, 3H), 2.02-1.73 (m, 6H);MCNR(ER) m/z 524.2 (M⁺+1).

The compounds of Table 63 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4294 except for the use of 2-(4-((4-(3-(1-(azetidin-3-yl)piperidin-4- yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole and the reagent from Table 62.

Table 62 Example Connection no. Reagent Exit (%) 216 4295 Acetaldehyde 39 217 4296 Propan-2-one 40

Table 63 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 216 4295 2-(difluoromethyl)-5-(4-((4-(3-(1-(1-ethylazetidin-3-yl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1 -yl)methyl)-3-fluorophenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 7.94 (d, J =9.1 Hz, 2H), 7.82 (s, 1H), 7.75 (s, 1H), 7.65 (d , J =7.7 Hz, 1H), 7.47 (t, J =7.7 Hz, 1H), 7.37 (t, J =7.7 Hz, 1H), 7.22 (d, J =7.7 Hz, 1H), 7.07 (s, 0.2H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 5.74 (s, 2H) , 3.86 (s, 2H), 3.16 (dd, J =16.0, 6.3 Hz, 3H), 2.89 (d, J =11.1 Hz, 2H), 2.76 ( dd, J =14.2, 7.1 Hz, 2H), 2.64-2.49 (m, 1H), 2.01-1.73 (m, 6H), 1.11 (t, J = 7.2 Hz, 3H); MSNR (ER) m/z 538.6 (M ⁺ +1). 217 4296 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(1-(1-isopropylazetidin-3-yl)piperidin-4-yl)phenyl)-1H-1,2,3 -triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, _CDCl3 ) δ 7.95-7.89 (m, 2H), 7.82 (s, 1H), 7.73 (s, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.46 (t, J =7.7 Hz, 1H), 7.35 (t, J =7.7 Hz, 1H), 7.21 (d, J =7, 8 Hz, 1H), 7.07 (s, 0.2H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 5.73 (s, 2H), 3, 70 (d, J =30.7 Hz, 2H), 3.11-2.98 (m, 3H), 2.89 (d, J =11.2 Hz, 2H), 2.65-2.48 (m, 2H), 1.99-1.73 (m, 6H), 1.04 (d, J =6.3 Hz, 6H); MSNR (ER) m/z 552.6 (M ⁺ +1).

Example 218: Synthesis of Compound 4316, 2-(4-((4-(3-((1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl)phenyl)-1H-1 ,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 2-(3-bromophenyl)-1,3-dioxolane

3-bromobenzaldehyde (3.145 ml, 27.024 mmol), para-toulenesulfonic acid monohydrate (0.051 g, 0.270 mmol) and ethylene glycol (1.813 ml, 32.429 mmol) were dissolved in toluene (20 ml) at room temperature, after which the resulting solution was stirred at same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was used without further purification process (2-(3-bromophenyl)-1,3-dioxolane, 5.500 g, 88.8%, brown oil).

[Step 2] Synthesis of tert-butyl (1S,4S)-5-(3-(1,3-dioxolan-2-yl)phenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate

Tert-butyl (1S,4S)-5-(3-(1,3-dioxolan-2-yl)phenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate (0.900 g, 2.598 mmol) obtained in step 1, and hydrochloric acid (1.00 M solution, 12.990 ml, 12.990 mmol) was dissolved in water (50 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 6 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl (1S,4S)-5-(3-(1,3-dioxolane-2- yl)phenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate (0.550 g, 70.0%) as a yellow solid.

[Step 3] Synthesis of tert-butyl (1S,4S)-5-(3-formylphenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate

Tert-butyl (1S,4S)-5-(3-(1,3-dioxolan-2-yl)phenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate (0.900 g, 2.598 mmol) obtained in step 2, and hydrochloric acid (1.00 M solution, 12.990 ml, 12.990 mmol) was dissolved in water (50 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 6 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl (1S,4S)-5-(3-formylphenyl)-2,5-diazabicyclo[ 2,2,1]heptane-2-carboxylate (0.550 g, 70.0%) as a yellow solid.

[Step 4] Synthesis of tert-butyl (1S,4S)-5-(3-(2,2-dibromovinyl)phenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate

Tert-butyl (1S,4S)-5-(3-formylphenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate (2.300 g, 7.607 mmol) obtained in step 3, carbon tetrabromide ( 5.045 g, 15.213 mmol) and triphenylphosphine (5.985 g, 22.820 mmol) were dissolved in dichloromethane (50 ml) at room temperature, after which the resulting solution was stirred at the same temperature for two hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl (1S,4S)-5-(3-(2,2-dibromovinyl)phenyl)- 2,5-diazabicyclo[2,2,1]heptane-2-carboxylate (3.450 g, 99.0%) as a yellow oil.

[Step 5] Synthesis of tert-butyl (1S,4S)-5-(3-ethynylphenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate

Tert-butyl (1S,4S)-5-(3-(2,2-dibromovinyl)phenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate (3.450 g, 7.530 mmol), prepared in step 4, 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (4.504 ml, 30.119 mmol) was dissolved in acetonitrile (50 ml) at room temperature, after which the resulting the solution is stirred at the same temperature for 16 hours. A saturated aqueous solution of ammonium chloride is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl (1S,4S)-5-(3-ethynylphenyl)-2,5-diazabicyclo[ 2,2,1]heptane-2-carboxylate (1.100 g, 49.0%) as a white solid.

[Step 6] Synthesis of tert-butyl (1S,4S)-5-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)- 1H-1,2,3-triazol-4-yl)phenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate

Tert-butyl (1S,4S)-5-(3-ethynylphenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate (0.500 g, 1.676 mmol) obtained in step 5, 2-( 4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.451 g, 1.676 mmol) prepared in step 1 of example 2, copper(II) sulfate pentahydrate (0.004 g, 0.017 mmol) and sodium ascorbate (0.033 g, 0.168 mmol) were dissolved in tert-butanol (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl (1S,4S)-5-(3-(1-(4-(5-( difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-2,5-diazabicyclo[2,2,1] heptane-2-carboxylate (0.400 g, 42.1%) in the form of a yellow solid.

[Step 7] Synthesis of compound 4316

Tert-butyl (1S,4S)-5-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2 ,3-triazol-4-yl)phenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate (0.420 g, 0.740 mmol) obtained in step 6, and trifluoroacetic acid (0.567 ml, 7.400 mmol) was dissolved in dichloromethane (50 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(4-((4-(3-((1S,4S)-2,5-diazabicyclo [2,2,1]heptan-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4- oxadiazole (0.200 g, 57.8%) in the form of a white solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.94-7.85 (m, 2H), 7.82 (s, 1H), 7.42 (t,J=7.6 Hz, 1H), 7.22 (kv,J=6.8, 5.7 Hz, 1H), 7.12 (t,J=1.9 Hz, 1H), 7.05-6.76 (m, 2H), 6.55-6.48 (m, 1H), 5.70 (s, 2H), 4.41 (s, 1H), 3.95 (s, 1H), 3.65 (dd,J=9.4, 2.2 Hz, 1H), 3.22-3.07 (m, 3H), 2.67 (s, 1H), 2.00 (d,J=10.0 Hz, 1H), 1.92 (d,J=9.9 Hz, 1H);MCNR(ER) m/z 468.2 (M⁺+1).

Example 219: Synthesis of Compound 4317, 2-(4-((4-(3-((1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl)phenyl)-1H-1 ,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl (1S,4S)-5-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1 ,2,3-triazol-4-yl)phenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate

Tert-butyl (1S,4S)-5-(3-ethynylphenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate (0.400 g, 1.341 mmol) obtained from step 5 of example 218, 2 -(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.337 g, 1.341 mmol) prepared in Step 1 of Example 2, copper(II) sulfate pentahydrate (0.003 g, 0.013 mmol ) and sodium ascorbate (0.027 g, 0.134 mmol) are dissolved in tert-butanol (5 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl (1S,4S)-5-(3-(1-(4-(5-( difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)-2,5-diazabicyclo[2,2,1]heptane-2 -carboxylate (0.560 g, 76.0%) in the form of a yellow solid.

[Step 2] Synthesis of compound 4317

Tert-butyl (1S,4S)-5-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3- triazol-4-yl)phenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate (0.560 g, 1.019 mmol) obtained in step 1 and trifluoroacetic acid (0.780 ml, 10.190 mmol) are dissolved in dichloromethane (50 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(4-((4-(3-((1S,4S)-2,5-diazabicyclo [2,2,1]heptan-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.360 g, 78.6%) in the form of a brown solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.92 (d,J=8.0 Hz, 2H), 7.86 (s, 1H), 7.32 (d,J=8.1 Hz, 2H), 7.10 (t,J=8.0 Hz, 1H), 7.03-6.73 (m, 3H), 6.51 (s, 1H), 6.37 (d,J=8.2 Hz, 1H), 5.52 (s, 2H), 4.27 (s, 1H), 3.92 (s, 1H), 3.48 (d,J=9.0 Hz, 1H), 3.08 (dd,J=15.5, 10.0 Hz, 2H), 3.00 (d,J=10.1 Hz, 1H), 1.88 (d,J=9.6 Hz, 1H);MCNR(ER) m/z 450.9 (M⁺+1).

Example 220: Synthesis of compound 4318, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-((1S,4S)-5-methyl-2,5-diazabicyclo[2,2, 1]heptan-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

2-(4-((4-(3-((1S,4S)-2,5-Diazabicyclo[2,2,1]heptan-2-yl)phenyl)-1H-1,2,3-triazol- 1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.060 g, 0.128 mmol) prepared in step 8 of Example 218, paraformaldehyde (0.008 g, 0.257 mmol) and acetic acid the acid (0.008 ml, 0.141 mmol) was dissolved in dichloromethane (5 ml) at room temperature, after which sodium triacetoxyborohydride (0.054 g, 0.257 mmol) was added to the resulting solution and stirred at the same temperature for 12 hours. Water is poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove solid residue and a layer of aqueous solution, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(( 1S,4S)-5-methyl-2,5-diazabicyclo[2,2,1]heptan-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1 ,3,4-oxadiazole (0.025 g, 40.5%) as a white solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.88 (dt,J=9.8, 1.7 Hz, 2H), 7.81 (s, 1H), 7.46-7.37 (m, 1H), 7.22 (t,J=7.9 Hz, 1H), 7.18-7.12 (m, 1H), 7.05-6.77 (m, 2H), 6.52 (dd,J=8.0, 2.5 Hz, 1H), 5.70 (s, 2H), 4.33 (s, 1H), 3.69 (s, 1H), 3.46 (d,J=1.5 Hz, 2H), 3.10 (dd,J=10.0, 2.0 Hz, 1H), 2.77 (dd,J=10.0, 1.6 Hz, 1H), 2.45 (s, 3H), 2.13-2.06 (m, 1H), 1.98 (d,J=9.2 Hz, 1H);MCNR(ER) m/z 482.1 (M⁺+1).

The compound of Table 65 was synthesized in accordance with substantially the same method as described above for the synthesis of compound 4318 except for the use of 2-(4-((4-(3-((1S,4S)-2,5-diazabicyclo[2 ,2,1]heptan-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole and reagent from table 64.

Table 64 Example Connection no. Reagent Exit (%) 221 4319 Cyclobutanone 52

Table 65 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 221 4319 2-(4-((4-(3-((1S,4S)-5-cyclobutyl-2,5-diazabicyclo[2,2,1]heptan-2-yl)phenyl)-1H-1,2, 3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93-7.82 (m, 3H), 7.42 (t, J=7.7 Hz, 1H), 7.23 (t, J=7, 9 Hz, 1H), 7.15 (dd, J=2.6, 1.5 Hz, 1H), 7.06-6.76 (m, 2H), 6.55-6.48 (m, 1H ), 5.70 (s, 2H), 4.33 (s, 1H), 4.08 (d, J=3.7 Hz, 1H), 3.50 (dd, J=10.1, 2, 2 Hz, 1H), 3.47-3.38 (m, 2H), 2.79-2.62 (m, 2H), 2.25 (d, J=10.8 Hz, 1H), 2, 03 (d, J=10.9 Hz, 1H), 1.17 (dd, J=17.3, 6.2 Hz, 6H); MSNR (ER) m/z 522.5 (M ⁺ +1).

Example 222: Synthesis of compound 4320, 2-(difluoromethyl)-5-(4-((4-(3-((1S,4S)-5-methyl-2,5-diazabicyclo[2,2,1]heptane- 2-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

2-(4-((4-(3-((1S,4S)-2,5-Diazabicyclo[2,2,1]heptan-2-yl)phenyl)-1H-1,2,3-triazol- 1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.060 g, 0.128 mmol) prepared in step 2 of Example 219, cyclobutanone (0.018 g, 0.257 mmol) and acetic acid (0.008 ml, 0.141 mmol) was dissolved in dichloromethane (5 ml) at room temperature, after which sodium triacetoxyborohydride (0.054 g, 0.257 mmol) was added to the resulting solution and stirred at the same temperature for 12 hours. Water is poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove solid residue and a layer of aqueous solution, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(3-((1S,4S) -5-methyl-2,5-diazabicyclo[2,2,1]heptan-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4 -oxadiazole (0.036 g, 53.8%) in the form of a white solid.

¹ H NMR(400 MHz, CDCl₃) δ 8.15-8.07 (m, 2H), 7.73 (s, 1H), 7.44 (d,J=8.3 Hz, 2H), 7.23 (dd,J=16.6, 8.7 Hz, 1H), 7.17-7.12 (m, 1H), 7.06-6.76 (m, 2H), 6.52 (dd,J=8.1, 2.5 Hz, 1H), 5.65 (s, 2H), 4.32 (s, 1H), 3.69 (s, 1H), 3.45 (s, 2H), 3 .10 (dd,J=9.9, 2.0 Hz, 1H), 2.75 (dd,J=9.9, 1.6 Hz, 1H), 2.44 (s, 3H), 2.08 (dt,J=10.0, 1.6 Hz, 1H), 1.96 (s, 1H);MCNR(ER) m/z 464.1 (M⁺+1).

The compounds of Table 67 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4320 except for the use of 2-(4-((4-(3-((1S,4S)-2,5-diazabicyclo[2 ,2,1]heptan-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole and the reagent from the table 66.

Table 66 Example Connection no. Reagent Exit (%) 223 4321 Propan-2-one 54 224 4322 Cyclobutanone 51

Table 67 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 223 4321 2-(difluoromethyl)-5-(4-((4-(3-((1S,4S)-5-isopropyl-2,5-diazabicyclo[2,2,1]heptan-2-yl)phenyl)- 1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 8.11-8.03 (m, 2H), 7.82 (s, 1H), 7.46-7.37 (m, 2H), 7.21 ( t, J=7.9 Hz, 1H), 7.17-7.11 (m, 1H), 7.02 (dd, J=2.4, 1.3 Hz, 1H), 6.83 (d , J=51.7 Hz, 1H), 6.53-6.46 (m, 1H), 5.64 (s, 2H), 4.33 (s, 1H), 4.14 (s, 1H) , 3.55-3.40 (m, 3H), 2.82-2.68 (m, 2H), 2.32-2.25 (m, 1H), 2.09-2.00 (m, 1H), 1.20 (dd, J=15.9, 6.3 Hz, 6H); MSNR (ER) m/z 492.1 (M ⁺ +1). 224 4322 2-(4-((4-(3-((1S,4S)-5-cyclobutyl-2,5-diazabicyclo[2,2,1]heptan-2-yl)phenyl)-1H-1,2, 3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 8.12-8.04 (m, 2H), 7.80 (s, 1H), 7.46-7.39 (m, 2H), 7.20 ( t, J=7.9 Hz, 1H), 7.11 (dd, J=2.5, 1.5 Hz, 1H), 7.05-6.75 (m, 2H), 6.48 (dd , J=8.3, 2.6, 1.0 Hz, 1H), 5.63 (s, 2H), 4.33 (s, 1H), 3.89 (d, J=2.1 Hz, 1H), 3.44 (d, J=1.4 Hz, 2H), 3.24 (p, J=7.9 Hz, 1H), 3.15 (dd, J=10.2, 2.0 Hz, 1H), 2.77 (dd, J=10.4, 1.8 Hz, 1H), 2.19-1.97 (m, 6H), 1.77 (tdt, J=11.9, 9.5, 2.5 Hz, 1H), 1.64 (tt, J=10.6, 8.3 Hz, 1H); MSNR (ER) m/z 504.4 (M ⁺ +1).

Example 225: Synthesis of Compound 4323 , 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl )-N,N-dimethylaniline

[Step 1] Synthesis of 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)aniline

3-ethynylaniline (0.289 ml, 2.089 mmol), 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.525 g, 2.089 mmol) prepared in step 1 of example 1, Sodium ascorbate (0.50 M solution in water, 0.418 ml, 0.209 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.042 ml, 0.042 mmol) are dissolved in tert-butanol (5 ml)/water (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The precipitated solid is filtered, washed with hexane and dried to give 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3 -triazol-4-yl)aniline (0.193 g, 25.1%) in the form of a brown solid.

[Step 2] Synthesis of compound 4323

3-(1-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)aniline (0.040 g, 0.109 mmol) obtained in step 1, and formaldehyde (37.00% solution in water, 0.016 ml, 0.217 mmol) was dissolved in dichloromethane (1 ml), after which the resulting solution was stirred at room temperature for 15 minutes, and then added sodium triacetoxyborohydride (0.069 g, 0.326 mmol) and then stirred at the same temperature for 18 hours. An aqueous solution of 1N-sodium hydrogencarbonate is poured into the resulting reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2 -yl)benzyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylaniline (0.004 g, 9.3%) as a yellow solid.

¹ H NMR(400 MHz, CD₃OD) δ 8.40 (s, 1H), 8.18-8.14 (m, 2H), 7.61 (d,J=8.4 Hz, 2H), 7.36-7.10 (m, 4H), 6.83-6.75 (m, 1H), 5.79 (d,J=4.3 Hz, 2H), 3.00 (s, 6H);MCNR(ER) m/z 397.4 (M⁺+1).

The compounds of Table 69 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4323 except for the use of 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl )benzyl)-1H-1,2,3-triazol-4-yl)aniline and the reagent from table 68.

Table 68 Example Connection no. Reagent Exit (%) 226 4324 Cyclohexanone 35 227 4325 Tetrahydro-4H-pyran-4-one 55 228 4326 Oxetan-3-one 61

Table 69 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 226 4324 N-cyclohexyl-3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)aniline
^1H NMR (400 MHz, DMSO- _d6 ) δ 8.57 (s, 1H), 8.13-8.06 (m, 2H), 7.69-7.41 (m, 3H), 7. 14-7.06 (m, 2H), 6.94 (dd, J=7.7, 1.4 Hz, 1H), 6.58-6.50 (m, 1H), 5.78 (s, 2H), 5.51 (d, J=8.2 Hz, 1H), 1.94 (d, J=12.1 Hz, 2H), 1.73 (d, J=13.4 Hz, 2H) , 1.61 (d, J=12.7 Hz, 1H), 1.33 (t, J=12.5 Hz, 2H), 1.24-1.10 (m, 3H); MSNR (IER) m/z 451.5 (M ⁺ + H). 227 4325 N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)tetrahydro -2H-pyran-4-amine
^1H NMR (400 MHz, CD ₃ OD) δ 8.35 (s, 1H), 8.20-8.12 (m, 2H), 7.63-7.56 (m, 2H), 7.23 (t, J=51.7 Hz, 1H), 7.21-7.15 (m, 2H), 7.05 (dt, J=7.8, 1.2 Hz, 1H), 6.68 ( ddd, J=8.2, 2.4, 1.0 Hz, 1H), 5.78 (s, 2H), 3.99 (dt, J=11.8, 3.6 Hz, 2H), 3 .64-3.52 (m, 3H), 2.07-1.99 (m, 2H), 1.58-1.43 (m, 2H); MSNR (IER) m/z 453.5 (M ⁺ + H). 228 4326 N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)oxetane -3-amine
^1H NMR (400 MHz, CD ₃ OD) δ 8.36 (s, 1H), 8.20-8.13 (m, 2H), 7.64-7.57 (m, 2H), 7.36 -7.09 (m, 3H), 7.01 (t, J=2.0 Hz, 1H), 6.56 (ddd, J=8.0, 2.4, 1.0 Hz, 1H), 5.79 (s, 2H), 5.03 (t, J=6.6 Hz, 2H), 4.70 (p, J=6.6 Hz, 1H), 4.58 (t, J=6 ,1 Hz, 2H); MSNR (IER) m/z 425.4 (M ⁺ + H).

Example 229: Synthesis of compound 4327 , N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol- 4-yl)phenyl)pivalamide

3-(1-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)aniline (0.040 g, 0.109 mmol) obtained in step 1 of Example 225, and N,N-diisopropylethylamine (0.038 ml, 0.217 mmol) was dissolved in dichloromethane (1 ml) at room temperature, after which trimethylacetyl chloride (0.016 ml, 0.130 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give N-(3-(1-(4-(5-(difluoromethyl)-1,3,4- Oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)pivalamide (0.031 g, 63.1%) in the form of a brown solid.

¹ H NMR(400 MHz, CD₃OD) δ 8.40 (s, 1H), 8.20-8.12 (m, 2H), 8.02 (t,J=1.9 Hz, 1H), 7.65-7.58 (m, 3H), 7.54 (ddd,J=8.1, 2.2, 1.1 Hz, 1H), 7.40 (t,J=7.9 Hz, 1H), 7.23 (t,J=51.7 Hz, 1H), 5.80 (s, 2H), 1.33 (s, 9H);MCNR(ER) m/z 453.5 (M⁺+1).

Example 230: Synthesis of compound 4328 , N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol- 4-yl)phenyl)-2-fluoro-2-methylpropanamide

3-(1-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)aniline (0.040 g, 0.109 mmol) obtained in step 1 of example 225, 2-fluoro-2-methylpropanoic acid (0.014 g, 0.130 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[3-oxide hexafluorophosphate 4,5-b]pyridinium (0.124 g, 0.326 mmol) and N,N-diisopropylethylamine (0.038 ml, 0.217 mmol) were dissolved in N,N-dimethylformamide (1 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give N-(3-(1-(4-(5-(difluoromethyl)-1,3,4- Oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-fluoro-2-methylpropanamide (0.022 g, 44.4%) in the form of a brown solid.

¹ H NMR(400 MHz, CD₃OD) δ 8.42 (s, 1H), 8.20-8.13 (m, 2H), 8.08 (t,J=1.9 Hz, 1H), 7.63 (dddd,J=7.9, 6.5, 2.4, 1.2 Hz, 4H), 7.43 (t,J=8.0 Hz, 1H), 7.23 (t,J=51.7 Hz, 1H), 5.80 (s, 2H), 1.65 (d,J=21.7 Hz, 6H);MCNR(ER) m/z 457.4 (M⁺+1).

The compounds of Table 71 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4328 except for the use of 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl )benzyl)-1H-1,2,3-triazol-4-yl)aniline and the reagent from Table 70.

Table 70 Example Connection no. Reagent Exit (%) 231 4329 Dimethylglycine 24 253 4351 2-(dimethylamino)-2-methylpropanoic acid 4

Table 71 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 231 4329 N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)- 2-(dimethylamino)acetamide
¹ H NMR (400 MHz, CD ₃ OD) δ 8.42 (s, 1H), 8.20-8.12 (m, 2H), 8.09 (t, J=1.9 Hz, 1H), 7.65-7.56 (m, 4H), 7.42 (t, J=7.9 Hz, 1H), 7.23 (t, J=51.6 Hz, 1H), 5.80 (s , 2H), 3.20 (s, 2H), 2.42 (s, 6H); MSNR (IER) m/z 454.4 (M ⁺ + H). 253 4351 N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)- 2-(dimethylamino)-2-methylpropanamide
¹ H NMR (400 MHz, CD ₃ OD) δ 8.42 (s, 1H), 8.20-8.13 (m, 2H), 8.05 (t, J=1.9 Hz, 1H), 7.65-7.55 (m, 4H), 7.41 (t, J=7.9 Hz, 1H), 7.23 (t, J=51.7 Hz, 1H), 5.80 (s , 2H), 2.32 (s, 6H), 1.29 (s, 6H); MSNR (IER) m/z 482.5 (M ⁺ + H).

Example 236: Synthesis of compound 4334 , N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3 -triazol-4-yl)phenyl)-2-fluoro-2-methylpropanamide

3-(1-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)aniline (0.080 g, 0.207 mmol) obtained from step 1 of Example 232, 2-fluoro-2-methylpropanoic acid (0.026 g, 0.248 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3 3-oxide hexafluorophosphate -triazolo[4,5-b]pyridinium (0.236 g, 0.621 mmol) and N,N-diisopropylethylamine (0.072 ml, 0.414 mmol) were dissolved in N,N-dimethylformamide (1 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give N-(4-(1-(4-(5-(difluoromethyl)-1,3,4- Oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-fluoro-2-methylpropanamide (0.038 g, 38.7%) as a white solid .

¹ H NMR(400 MHz, CD₃OD) δ 8.43 (s, 1H), 8.09 (t,J=1.9 Hz, 1H), 8.03-7.92 (m, 2H), 7.68-7.57 (m, 3H), 7.43 (t,J=7.9 Hz, 1H), 7.24 (t,J=51.6 Hz, 1H), 5.86 (s, 2H), 1.68 (s, 3H), 1.63 (s, 3H);MCNR(ER) m/z 475.4 (M⁺+1).

The compound of Table 73 was synthesized in accordance with substantially the same method as described above for the synthesis of compound 4334 except for the use of 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl )-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)aniline and the reagent from Table 72.

Table 72 Example Connection no. Reagent Exit (%) 237 4335 3-(dimethylamino)propanoic acid 49

Table 73 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 237 4335 N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) phenyl)-3-(dimethylamino)propanamide
¹ H NMR (400 MHz, CD ₃ OD) δ 8.40 (d, J=15.5 Hz, 1H), 8.16 (t, J=1.9 Hz, 1H), 8.03-7, 92 (m, 2H), 7.65-7.51 (m, 3H), 7.44-7.11 (m, 2H), 5.85 (d, J=7.7 Hz, 2H), 3 .51 (t, J=6.2 Hz, 2H), 3.04-2.86 (m, 8H); MSNR (IER) m/z 486.5 (M ⁺ + H).

Example 251: Synthesis of Compound 4349, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)phenyl)- 1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of methyl 3-fluoro-4-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)benzoate hydrochloride

Tert-butyl 4-(3-(1-(2-fluoro-4-(methoxycarbonyl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate (0.500 g, 0.841 mmol) obtained in step 4 of Example 211, and hydrogen chloride (4.00 M solution in 1,4-dioxane, 0.841 ml, 3.364 mmol) was dissolved in dichloromethane (50 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without additional purification process (methyl 3-fluoro-4-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2 hydrochloride, 3-triazol-1-yl)methyl)benzoate, 0.420 g, 94.1%, white solid).

[Step 2] Synthesis of methyl 3-fluoro-4-((4-(3-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol- 1-yl)methyl)benzoate

Methyl 3-fluoro-4-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)benzoate hydrochloride (0.200 g, 0.464 mmol), The 2,2-dimethyloxylane obtained in step 1 (0.335 g, 4.641 mmol) and potassium carbonate (0.128 g, 0.928 mmol) are mixed in ethanol (10 ml), heated at 110°C for 20 hours by microwave irradiation, and the reaction is completed lowering the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Then, the resulting product is used without additional purification process (methyl 3-fluoro-4-((4-(3-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)phenyl)-1H-1,2 ,3-triazol-1-yl)methyl)benzoate, 0.100 g, 46.2%, yellow oil).

[Step 3] Synthesis of methyl 3-fluoro-4-((4-(3-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol- 1-yl)methyl)benzoate

Methyl 3-fluoro-4-((4-(3-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl )benzoate (0.100 g, 0.214 mmol) obtained in step 2 and diethylaminosulfur trifluoride (0.031 ml, 0.236 mmol) were dissolved in dichloromethane (20 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 1 hour. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give methyl 3-fluoro-4-((4-(3-(1-(2-fluoro-2- methylpropyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)benzoate (0.090 g, 89.6%) as a white solid.

[Step 4] Synthesis of 3-fluoro-4-((4-(3-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1 -yl)methyl)benzohydrazide

Methyl 3-fluoro-4-((4-(3-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl )benzoate (0.090 g, 0.192 mmol) obtained in step 3 and hydrazine monohydrate (0.093 ml, 1.921 mmol) are dissolved in ethanol (10 ml) at 90°C, after which the resulting solution is stirred at the same temperature for 12 hours , and then the reaction is completed by lowering the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Then, the resulting product is used without an additional purification process (3-fluoro-4-((4-(3-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)phenyl)-1H-1,2, 3-triazol-1-yl)methyl)benzohydrazide, 0.081 g, 90.0%, white solid).

[Step 5] Synthesis of compound 4349

3-Fluoro-4-((4-(3-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl) The benzohydrazide (0.081 g, 0.173 mmol) obtained in step 4, imidazole (0.035 g, 0.519 mmol) and 2,2-difluoroacetic anhydride (0.064 ml, 0.519 mmol) are mixed in dichloromethane (20 ml) at room temperature, then the resulting the mixture is heated at reflux for 12 hours and cooled to room temperature. Then, water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-70%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(1 -(2-fluoro-2-methylpropyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.055 g, 60 .2%) in the form of a white solid.

¹ H NMR (400 MHz, CDCl₃) δ 7.94 (d,J=8.7 Hz, 2H), 7.85 (s, 1H), 7.76 (s, 1H), 7.66 (dd,J=4.8, 2.7 Hz, 1H), 7.47 (ddd,J=17.0, 8.1, 2.0 Hz, 1H), 7.37 (t,J=7.7 Hz, 1H), 7.24 (d,J=7.8 Hz, 1H), 7.07 (s, 0.2H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 5.75 (s, 2H) , 3.11 (s, 2H), 2.56 (s, 3H), 2.33-2.30 (m, 2H), 1.84 (d,J=10.3 Hz, 4H), 1.69 (s, 3H), 1.64 (s, 3H);MCNR(ER) m/z 529.6 (M⁺+1).

Example 252: Synthesis of Compound 4350, 2-(difluoromethyl)-5-(4-((4-(3-(1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)phenyl)-1H-1, 2,3-triazol-1-yl)methyl)-3-fluorophenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of methyl 4-((4-(3-(1-(2-ethyl-2-hydroxybutyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl) methyl)-3-fluorobenzoate

Methyl 3-fluoro-4-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)benzoate hydrochloride (0.200 g, 0.464 mmol), from step 1 of Example 251, 2,2-diethyloxylane (0.465 g, 4.641 mmol) and potassium carbonate (0.128 g, 0.928 mmol) are mixed in ethanol (10 ml), heated at 110°C for 20 hours by microwave irradiation, and the reaction is completed by lowering the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Then, the resulting product is used without additional purification process (methyl 4-((4-(3-(1-(2-ethyl-2-hydroxybutyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)-3-fluorobenzoate, 0.110 g, 47.9%, yellow oil).

[Step 2] Synthesis of methyl 4-((4-(3-(1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl) methyl)-3-fluorobenzoate

Methyl 4-((4-(3-(1-(2-ethyl-2-hydroxybutyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3- The fluorobenzoate (0.110 g, 0.222 mmol) obtained in step 1 and diethylaminosulfur trifluoride (0.032 ml, 0.245 mmol) are dissolved in dichloromethane (20 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 1 hour. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give methyl 4-((4-(3-(1-(2-ethyl-2-fluorobutyl)piperidine- 4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorobenzoate (0.080 g, 72.4%) as a white solid.

[Step 3] Synthesis of 4-((4-(3-(1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl )-3-fluorobenzohydrazide

Methyl 4-((4-(3-(1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3- fluorobenzoate (0.080 g, 0.161 mmol) obtained in step 2 and hydrazine monohydrate (0.078 ml, 1.611 mmol) are dissolved in ethanol (10 ml) at 90°C, after which the resulting solution is stirred at the same temperature for 12 hours, and then the reaction is completed by lowering the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Then, the resulting product is used without an additional purification process (4-((4-(3-(1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol- 1-yl)methyl)-3-fluorobenzohydrazide, 0.070 g, 87.5%, white solid).

[Step 4] Synthesis of compound 4350

4-((4-(3-(1-(2-Ethyl-2-fluorobutyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorobenzohydrazide (0.081 g, 0.163 mmol) obtained in step 3, imidazole (0.033 g, 0.489 mmol) and 2,2-difluoroacetic anhydride (0.061 ml, 0.489 mmol) are mixed in dichloromethane (20 ml) at room temperature, then the resulting mixture Heat at reflux for 12 hours and cool to room temperature. Then, water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-70%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(3-(1-(2- ethyl 2-fluorobutyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-1,3,4-oxadiazole (0.060 g, 66, 1%) in the form of a white solid.

¹ H NMR (400 MHz, CDCl₃) δ 7.94 (d,J=8.6 Hz, 2H), 7.85 (s, 1H), 7.76 (s, 1H), 7.66 (d,J=6.8 Hz, 1H), 7.46 (t,J=7.6 Hz, 1H), 7.37 (t,J=7.7 Hz, 1H), 7.24 (d,J=7.7 Hz, 1H), 7.07 (s, 0.2H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 5.75 (s, 2H) , 3.08 (s, 1H), 2.50 (d,J=24.2 Hz, 2H), 2.23 (s, 1H), 1.80 (d,J=32.7 Hz, 6H), 1.60 (s, 3H), 1.28 (t,J=7.1 Hz, 2H), 0.94 (t,J=7.3 Hz, 6H);MCNR(ER) m/z 557.6 (M⁺+1).

Example 254: Synthesis of compound 4352 , N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3 -triazol-4-yl)phenyl)-2-(dimethylamino)acetamide

3-(1-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)aniline (0.080 g, 0.207 mmol) obtained from step 1 of Example 232, dimethylglycine (0.026 g, 0.248 mmol), hexafluorophosphate 3-oxide 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium (0.236 g, 0.621 mmol) and N,N-diisopropylethylamine (0.072 ml, 0.414 mmol) were dissolved in N,N-dimethylformamide (1 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give N-(3-(1-(4-(5-(difluoromethyl)-1,3,4- Oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(dimethylamino)acetamide (0.015 g, 15.4%) as a yellow solid.

¹ H NMR(400 MHz, CD₃OD) δ 8.43 (s, 1H), 8.09 (t,J=1.9 Hz, 1H), 8.02-7.92 (m, 2H), 7.61 (dddd,J=8.3, 4.5, 2.4, 1.1 Hz, 3H), 7.42 (t,J=7.9 Hz, 1H), 7.24 (t,J=51.6 Hz, 1H), 5.86 (s, 2H), 3.25 (s, 2H), 2.45 (s, 6H);MCNR(ER) m/z 472.5 (M⁺+1).

The compound of Table 75 was synthesized in accordance with substantially the same method as described above for the synthesis of compound 4352 except for the use of 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl )-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)aniline and the reagent from Table 74.

Table 74 Example Connection no. Reagent Exit (%) 255 4353 2-(dimethylamino)-2-methylpropanoic acid 5

Table 75 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 255 4353 N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) phenyl)-2-(dimethylamino)-2-methylpropanamide
^1H NMR (400 MHz, CD ₃ OD) δ 8.42 (s, 1H), 8.05 (t, J=1.9 Hz, 1H), 8.02 &#8211; 7.92 (m, 2H), 7.65 &#8211; 7.55 (m, 3H), 7.41 (t, J=7.9 Hz, 1H), 7.24 (t, J=51.6 Hz, 1H), 5.85 (s, 2H), 2.32 (s, 6H), 1.29 (s, 6H); MSNR (IER) m/z 500.5 (M ⁺ + H).

Example 256: Synthesis of compound 4358, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1, 2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazole -4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

2-(4-(Azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.300 g, 1.114 mmol) prepared in Step 1 of Example 2, tert-butyl 6-ethynyl-3 ,4-dihydroisoquinoline-2(1H)-carboxylate (0.344 g, 1.337 mmol) prepared in step 1 of Example 150, sodium ascorbate (1.00 M solution in H ₂ O, 0.111 ml, 0.111 mmol), and copper sulfate pentahydrate (II) (0.50 M solution in H ₂ O, 0.022 ml, 0.011 mmol) was dissolved in tert-butanol (10 ml)/water (10 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-70%) and concentrated to give tert-butyl 6-(1-(4-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.450 g, 76.7%) as white solid.

[Step 2] Synthesis of 2-(difluoromethyl)-5-(3-fluoro-4-((4-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol- 1-yl)methyl)phenyl)-1,3,4-oxadiazole

Tert-butyl 6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) -3,4-dihydroisoquinoline-2(1H)-carboxylate (0.450 g, 0.855 mmol) obtained in step 1 and trifluoroacetic acid (0.196 ml, 2.564 mmol) were dissolved in dichloromethane (50 ml) at room temperature, after which the resulting the solution is stirred at the same temperature for 3 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without additional purification process (2-(difluoromethyl)-5-(3-fluoro-4-((4-(1,2,3,4-tetrahydroisoquinoline-6 -yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole, 0.350 g, 96.0%, yellow oil).

[Step 3] Synthesis of compound 4358

2-(Difluoromethyl)-5-(3-fluoro-4-((4-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl )phenyl)-1,3,4-oxadiazole (0.070 g, 0.164 mmol) obtained in step 2, formaldehyde (0.010 g, 0.328 mmol), acetic acid (0.010 ml, 0.181 mmol) and sodium triacetoxyborohydride (0.070 g, 0.328 mmol) was dissolved in dichloromethane (5 ml), after which the resulting solution was stirred at room temperature for 30 minutes, and then stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-methyl- 1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.033 g, 45.6%) in the form of a white solid.

¹ H NMR (400 MHz, CDCl₃) δ 7.92 (dd,J=6.2, 4.7 Hz, 2H), 7.81 (s, 1H), 7.63 (s, 1H), 7.56 (dd,J=7.9, 1.7 Hz, 1H), 7.46 (t,J=7.7 Hz, 1H), 7.09 (d,J=8.0 Hz, 1H), 7.07 (s, 0.2H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 5.73 (s, 2H) , 3.65 (s, 2H), 3.00 (t,J=5.9 Hz, 2H), 2.76 (t,J=6.0 Hz, 2H), 2.51 (s, 3H);MCNR(ER) m/z 441.5 (M⁺+1).

The compounds of Table 77 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4358 except for the use of 2-(difluoromethyl)-5-(3-fluoro-4-((4-(1,2,3, 4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole and the reagent from Table 76.

Table 76 Example Connection no. Reagent Exit (%) 257 4359 Acetaldehyde 38 258 4360 Propan-2-one 50 259 4361 Cyclobutanone 49 260 4362 Oxetan-3-one 51

Table 77 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 257 4359 2-(difluoromethyl)-5-(4-((4-(2-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl )-3-fluorophenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 7.93 (dd, J =6.4, 4.6 Hz, 2H), 7.81 (s, 1H), 7.63 (s, 1H), 7 .57 (dt, J =9.4, 4.7 Hz, 1H), 7.47 (t, J =7.7 Hz, 1H), 7.11 (d, J =8.0 Hz, 1H) , 7.07 (s, 0.2H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 5.73 (s, 2H), 3.74 (s, 2H ), 3.07-2.94 (m, 2H), 2.85 (t, J =5.9 Hz, 2H), 2.69 (kv, J =7.2 Hz, 2H), 1.30 -1.22 (m, 3H); MSNR (ER) m/z 455.5 (M ⁺ +1). 258 4360 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1 -yl)methyl)phenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 7.93 (dd, J =6.3, 4.7 Hz, 2H), 7.81 (s, 1H), 7.62 (s, 1H), 7 .57 (dd, J =7.9, 1.6 Hz, 1H), 7.47 (t, J =7.7 Hz, 1H), 7.11 (d, J =8.0 Hz, 1H) , 7.07 (s, 0.2H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 5.73 (s, 2H), 3.80 (s, 2H ), 3.00 (dd, J =12.6, 6.4 Hz, 3H), 2.91-2.79 (m, 2H), 1.20 (d, J =6.5 Hz, 6H) ; MSNR (ER) m/z 469.3 (M ⁺ +1). 259 4361 2-(4-((4-(2-cyclobutyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl) -5-(difluoromethyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 7.92 (dd, J =6.5, 4.6 Hz, 2H), 7.80 (s, 1H), 7.62 (s, 1H), 7 .56 (dd, J =7.9, 1.7 Hz, 1H), 7.47 (t, J =7.7 Hz, 1H), 7.09 (d, J =8.0 Hz, 1H) , 7.07 (s, 0.2H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 5.73 (s, 2H), 3.56 (s, 2H ), 3.01-2.88 (m, 3H), 2.66 (t, J =6.0 Hz, 2H), 2.23-2.11 (m, 2H), 2.10-1, 97 (m, 2H), 1.87-1.66 (m, 2H); MSNR (ER) m/z 481.6 (M ⁺ +1). 260 4362 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-(oxetan-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2 ,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, _CDCl3 ) δ 7.98-7.90 (m, 2H), 7.82 (s, 1H), 7.65 (s, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.51-7.45 (m, 1H), 7.09 (d, J =8.0 Hz, 1H), 7.07 (s, 0.2H), 6, 94 (s, 0.5H), 6.81 (s, 0.3H), 5.75 (s, 2H), 4.78 (d, J =6.5 Hz, 4H), 3.80-3 .70 (m, 1H), 3.59 (s, 2H), 3.01 (t, J =5.6 Hz, 2H), 2.69 (s, 2H); MSNR (ER) m/z 483.15 (M ⁺ +1).

Example 261: Synthesis of compound 4363, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1, 2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 7-ethynyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

Tert-butyl 7-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.500 g, 1.913 mmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (0.441 g, 2.296 mmol) and potassium carbonate (0.529 g, 3.827 mmol) was dissolved in methanol (20 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was then used without further purification process (tert-butyl 7-ethynyl-3,4-dihydroisoquinoline-2(1H)-carboxylate, 0.450 g, 91.4%, white solid).

[Step 2] Synthesis of tert-butyl 7-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazole -4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

2-(4-(Azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.500 g, 1.857 mmol) prepared in step 1 of example 2, tert-butyl 7-ethynyl-3 ,4-dihydroisoquinoline-2(1H)-carboxylate (0.574 g, 2.229 mmol) obtained in step 1, sodium ascorbate (1.00 M solution in H ₂ O, 0.186 ml, 0.186 mmol), and copper(II) sulfate pentahydrate ) (0.50 M solution in H ₂ O, 0.037 ml, 0.019 mmol) dissolved in tert-butanol (10 ml)/water (10 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours . Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-60%) and concentrated to give tert-butyl 7-(1-(4-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.580 g, 59.3%) as white solid.

[Step 3] Synthesis of 2-(difluoromethyl)-5-(3-fluoro-4-((4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol- 1-yl)methyl)phenyl)-1,3,4-oxadiazole

Tert-butyl 7-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) -3,4-dihydroisoquinoline-2(1H)-carboxylate (0.400 g, 0.760 mmol) obtained in step 2 and trifluoroacetic acid (0.175 ml, 2.279 mmol) were dissolved in dichloromethane (30 ml) at room temperature, after which the resulting the solution is stirred at the same temperature for 3 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without additional purification process (2-(difluoromethyl)-5-(3-fluoro-4-((4-(1,2,3,4-tetrahydroisoquinoline-7 -yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole, 0.320 g, 98.8%, yellow oil).

[Step 4] Synthesis of compound 4363

2-(Difluoromethyl)-5-(3-fluoro-4-((4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl )phenyl)-1,3,4-oxadiazole (0.070 g, 0.164 mmol) obtained in step 3, formaldehyde (0.006 g, 0.197 mmol), acetic acid (0.010 ml, 0.181 mmol) and sodium triacetoxyborohydride (0.070 g, 0.328 mmol) was dissolved in dichloromethane (5 ml), after which the resulting solution was stirred at room temperature for 30 minutes, and then stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.026 g, 36.0%) in the form of a white solid.

¹ H NMR (400 MHz, CDCl₃) δ 7.91 (dd,J=6.6, 4.6 Hz, 2H), 7.81 (d,J=2.4 Hz, 1H), 7.55 (d,J=6.4 Hz, 2H), 7.45 (t,J=7.7 Hz, 1H), 7.17 (d,J=8.5 Hz, 1H), 7.07 (s, 0.2H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 5.72 (s, 2H) , 3.63 (d,J=6.2 Hz, 2H), 2.96 (t,J=5.8 Hz, 2H), 2.74 (t,J=6.0 Hz, 2H), 2.49 (s, 3H);MCNR(ER) m/z 441.5 (M⁺+1).

The compounds of Table 79 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4363 except for the use of 2-(difluoromethyl)-5-(3-fluoro-4-((4-(1,2,3, 4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole and the reagent from Table 78.

Table 78 Example Connection no. Reagent Exit (%) 262 4364 Acetaldehyde 50 263 4365 Propan-2-one 50 264 4366 Cyclobutanone 52 265 4367 Oxetan-3-one 61

Table 79 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 262 4364 2-(difluoromethyl)-5-(4-((4-(2-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl )-3-fluorophenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.95-7.88 (m, 2H), 7.81 (d, J =2.9 Hz, 1H), 7.56 (d, J =6, 8 Hz, 2H), 7.47 (dd, J =13.8, 6.0 Hz, 1H), 7.16 (d, J =8.5 Hz, 1H), 7.07 (s, 0, 2H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 5.72 (s, 2H), 3.79-3.64 (m, 2H), 2.98 (dd, J =13.8, 7.9 Hz, 2H), 2.84 (t, J =6.0 Hz, 2H), 2.68 (kv, J =7.2 Hz, 2H), 1 .23 (t, J =7.2 Hz, 3H); MSNR (ER) m/z 455.3 (M ⁺ +1). 263 4365 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-isopropyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1 -yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94-7.88 (m, 2H), 7.80 (s, 1H), 7.54 (dd, J = 10.8, 3.0 Hz, 2H), 7.46 (t, J =7.8 Hz, 1H), 7.15 (d, J =7.9 Hz, 1H), 7.07 (s, 0.2H), 6.94 ( s, 0.5H), 6.81 (s, 0.3H), 5.72 (s, 2H), 3.77 (d, J =7.1 Hz, 2H), 3.00-2.89 (m, 3H), 2.80 (dd, J =14.4, 8.4 Hz, 2H), 1.16 (d, J =6.5 Hz, 6H); MSNR (ER) m/z 469.5 (M ⁺ +1). 264 4366 2-(4-((4-(2-cyclobutyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl) -5-(difluoromethyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 7.91 (dt, J =3.8, 1.6 Hz, 2H), 7.80 (d, J =4.4 Hz, 1H), 7.55 (d, J =6.4 Hz, 2H), 7.46 (t, J =7.7 Hz, 1H), 7.15 (d, J =8.5 Hz, 1H), 7.07 (s , 0.2H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 5.72 (s, 2H), 3.55 (d, J =7.5 Hz, 2H), 2.98-2.85 (m, 3H), 2.65 (t, J =6.0 Hz, 2H), 2.22-2.10 (m, 2H), 2.08-1 .94 (m, 2H), 1.87-1.67 (m, 2H); MSNR (ER) m/z 481.6 (M ⁺ +1). 265 4367 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-(oxetan-3-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2 ,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 7.95-7.88 (m, 2H), 7.80 (s, 1H), 7.60-7.53 (m, 2H), 7.50- 7.43 (m, 1H), 7.18 (d, J =8.3 Hz, 1H), 7.07 (s, 0.2H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 5.72 (s, 2H), 4.82-4.71 (m, 4H), 3.73 (p, J =6.5 Hz, 1H), 3.58 ( s, 2H), 2.97 (dd, J =13.7, 7.8 Hz, 2H), 2.66 (t, J =5.9 Hz, 2H); MSNR (ER) m/z 483.4 (M ⁺ +1).

Example 266: Synthesis of Compound 4368, 2-(difluoromethyl)-5-(4-((4-(3-(4-ethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazole -4-yl)phenyl)piperazine-1-carboxylate

2-(4-(Azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.300 g, 1.194 mmol) prepared in Step 1 of Example 1 and tert-butyl 4-(3-ethynylphenyl) piperazine-1-carboxylate (0.342 g, 1.194 mmol) obtained in step 1 of Example 117 was dissolved in tert-butanol (1 ml)/water (1 ml) at room temperature, followed by sodium ascorbate (1.00 M solution, 0.119 ml, 0.119 mmol) and copper(II) sulfate pentahydrate (0.50 M solution, 0.024 ml, 0.012 mmol) were added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution is poured into the reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=100-70%) and concentrated to give tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3 ,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperazine-1-carboxylate (0.430 g, 67.0%) as a white solid.

[Step 2] Synthesis of (2-(difluoromethyl)-5-(4-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl) phenyl)-1,3,4-oxadiazole

Tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl) Phenyl)piperazine-1-carboxylate (0.300 g, 0.558 mmol) obtained in step 1 and trifluoroacetic acid (1.282 ml, 16.742 mmol) were dissolved in dichloromethane (3.5 ml) at room temperature, after which the resulting solution was stirred at same temperature for 3 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without additional purification process (2-(difluoromethyl)-5-(4-((4-(3-(piperazin-1-yl)phenyl)-1H-1 ,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole, 0.310 g, 100.7%, light yellow oil).

[Step 3] Synthesis of compound 4368

2-(Difluoromethyl)-5-(4-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3 ,4-oxadiazole (0.050 g, 0.114 mmol) obtained in step 2 and acetaldehyde (0.015 g, 0.342 mmol) are dissolved in dichloromethane (1 ml) at room temperature, after which sodium triacetoxyborohydride (0.121 g, 0.570 mmol) is added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-70%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(3-(4-ethylpiperazine-1 -yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.035 g, 65.9%) in the form of a light yellow oil.

¹ H NMR(400 MHz, CD₃OD) δ 8.42 (s, 1H), 8.20-8.13 (m, 2H), 7.62 (d,J=8.4 Hz, 2H), 7.48 (d,J=2.1 Hz, 1H), 7.35-7.28 (m, 2H), 7.23 (t,J=51.6 Hz, 1H), 6.99 (dt,J=7.5, 2.2 Hz, 1H), 5.79 (s, 2H), 3.30 (d,J=5.4 Hz, 4H), 2.73-2.66 (m, 4H), 2.54 (kv,J=7.3 Hz, 2H), 1.18 (t,J=7.2 Hz, 3H) ;MCNR(ER) m/z 466.3 (M⁺+1).

The compounds of Table 81 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4368 except for the use of 2-(difluoromethyl)-5-(4-((4-(3-(piperazin-1-yl)phenyl )-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole and the reagent from Table 80.

Table 80 Example Connection no. Reagent Exit (%) 267 4369 Propionaldehyde 67 268 4370 Oxetan-3-one 67 269 4371 Cyclobutanone 69

Table 81 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 267 4369 2-(difluoromethyl)-5-(4-((4-(3-(4-propylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1 ,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 8.42 (s, 1H), 8.20-8.13 (m, 2H), 7.65-7.58 (m, 2H), 7.51 -7.45 (m, 1H), 7.35-7.26 (m, 2H), 7.23 (t, J =51.7 Hz, 1H), 6.99 (dt, J =7.5 , 2.1 Hz, 1H), 5.79 (s, 2H), 3.32-3.27 (m, 4H), 2.75-2.68 (m, 4H), 2.49-2, 41 (m, 2H), 1.69-1.55 (m, 2H), 0.98 (t, J =7.4 Hz, 3H); MSNR (ER) m/z 480.3 (M ⁺ +1). 268 4370 2-(difluoromethyl)-5-(4-((4-(3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.42 (s, 1H), 8.20-8.13 (m, 2H), 7.61 (d, J =8.3 Hz, 2H), 7.48 (t, J =2.0 Hz, 1H), 7.35-7.26 (m, 2H), 7.23 (t, J =51.7 Hz, 1H), 6.99 (dt , J =7.5, 2.0 Hz, 1H), 5.79 (s, 2H), 4.75 (t, J =6.7 Hz, 2H), 4.67 (t, J =6, 2 Hz, 2H), 3.58 (p, J =6.3 Hz, 1H), 3.30 (d, J =4.9 Hz, 4H), 2.59-2.52 (m, 4H) ; MSNR (ER) m/z 494.3 (M ⁺ +1). 269 4371 2-(4-((4-(3-(4-cyclobutylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1 ,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.42 (s, 1H), 8.17 (d, J =8.4 Hz, 2H), 7.61 (d, J =8.3 Hz, 2H), 7.47 (s, 1H), 7.31 (kv, J =7.9 Hz, 2H), 7.23 (t, J =51.7 Hz, 1H), 7.02-6, 96 (m, 1H), 5.79 (s, 2H), 3.29 (t, J =5.1 Hz, 5H), 2.87 (t, J =8.1 Hz, 1H), 2, 60-2.53 (m, 4H), 2.12 (s, 2H), 1.98 (t, J =10.5 Hz, 2H), 1.80 (dd, J =9.6, 5, 3 Hz, 2H); MSNR (ER) m/z 492.2 (M ⁺ +1).

Example 270: Synthesis of compound 4372 , 1-(4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3 -triazol-4-yl)phenyl)piperazin-1-yl)propan-1-one

2-(Difluoromethyl)-5-(4-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3 ,4-oxadiazole (0.050 g, 0.114 mmol) obtained in step 2 of Example 266 and propionyl chloride (0.032 g, 0.342 mmol) were dissolved in dichloromethane (1 ml) at room temperature, after which triethylamine (0.079 ml, 0.570 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-70%) and concentrated to give 1-(4-(3-(1-(4-(5-(difluoromethyl)-1,3 ,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperazin-1-yl)propan-1-one (0.034 g, 60.4%) as light yellow oil.

¹ H NMR (400 MHz, CD₃OD) δ 8.43 (s, 1H), 8.20-8.13 (m, 2H), 7.65-7.58 (m, 2H), 7.52-7.47 (m, 1H) , 7.35-7.29 (m, 2H), 7.23 (t,J=51.6 Hz, 1H), 7.01 (dt,J=6.9, 2.6 Hz, 1H), 5.80 (s, 2H), 3.75 (dt,J=17.5, 5.3 Hz, 4H), 3.30-3.20 (m, 4H), 2.49 (sq,J=7.5 Hz, 2H), 1.16 (t,J=7.5 Hz, 3H);MCNR(ER) m/z 494.3 (M⁺+1).

Example 271: Synthesis of Compound 4373, 2-(difluoromethyl)-5-(4-((4-(3-(4-ethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)-3-fluorophenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2, 3-triazol-4-yl)phenyl)piperazine-1-carboxylate

2-(4-(Azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.300 g, 1.114 mmol) prepared in Step 1 of Example 2 and tert-butyl 4-(3 -ethynylphenyl)piperazine-1-carboxylate (0.319 g, 1.114 mmol) obtained in step 1 of Example 117 was dissolved in tert-butanol (1 ml)/water (1 ml) at room temperature, followed by sodium ascorbate (1.00 M solution, 0.111 ml, 0.111 mmol) and copper(II) sulfate pentahydrate (0.50 M solution, 0.022 ml, 0.011 mmol) were added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution is poured into the reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=100-70%) and concentrated to give tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3 ,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperazine-1-carboxylate (0.470 g, 75.9%) as a white solid .

[Step 2] Synthesis of (2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1- yl)methyl)phenyl)-1,3,4-oxadiazole

Tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4 -yl)phenyl)piperazine-1-carboxylate (0.300 g, 0.540 mmol) obtained in step 1 and trifluoroacetic acid (1.241 ml, 16.200 mmol) were dissolved in dichloromethane (3.5 ml) at room temperature, and then the resulting solution stir at the same temperature for 3 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without further purification process (2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(piperazin-1-yl)phenyl) -1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole, 0.310 g, 100.8%, light yellow oil).

[Step 3] Synthesis of compound 4373

2-(Difluoromethyl)-5-(3-fluoro-4-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl) -1,3,4-oxadiazole (0.050 g, 0.110 mmol) obtained in step 2 and acetaldehyde (0.015 g, 0.329 mmol) are dissolved in dichloromethane (1 ml) at room temperature, followed by sodium triacetoxyborohydride (0.116 g, 0.549 mmol) is added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-70%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(3-(4-ethylpiperazine-1 -yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-1,3,4-oxadiazole (0.036 g, 67.8%) as a light yellow oil .

¹ H NMR(400 MHz, CD₃OD) δ 8.43 (s, 1H), 8.03-7.93 (m, 2H), 7.61 (t,J=7.7 Hz, 1H), 7.50 (d,J=2.8 Hz, 1H), 7.37-7.28 (m, 2H), 7.24 (t,J=51.6 Hz, 1H), 7.00 (dt,J=7.3, 2.4 Hz, 1H), 5.85 (s, 2H), 3.35 (d,J=3.8 Hz, 4H), 2.81 (t,J=5.1 Hz, 4H), 2.66 (kv,J=7.3 Hz, 2H), 1.22 (t,J=7.3 Hz, 3H);MCNR(ER) m/z 484.3 (M⁺+1).

The compounds of Table 83 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4373 except for the use of 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(piperazine-1 -yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole and the reagent from Table 82.

Table 82 Example Connection no. Reagent Exit (%) 272 4374 Propionaldehyde 75 273 4375 Oxetan-3-one 76 274 4376 Cyclobutanone 66

Table 83 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 272 4374 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(4-propylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl) phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.43 (s, 1H), 8.03-7.92 (m, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.51-7.46 (m, 1H), 7.36-7.27 (m, 2H), 7.24 (t, J =51.6 Hz, 1H), 6.99 (dt, J = 7.3, 2.3 Hz, 1H), 5.85 (s, 2H), 3.30 (d, J =4.8 Hz, 4H), 2.78-2.71 (m, 4H), 2.52-2.44 (m, 2H), 1.63 (dkv, J =15.0, 7.4 Hz, 2H), 0.98 (t, J =7.4 Hz, 3H); MSNR (ER) m/z 498.3 (M ⁺ +1). 273 4375 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.43 (s, 1H), 8.03-7.92 (m, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.48 (s, 1H), 7.36-7.27 (m, 2H), 7.24 (t, J =51.6 Hz, 1H), 6.99 (dt, J =7.5, 2.2 Hz, 1H), 5.85 (s, 2H), 4.75 (t, J =6.7 Hz, 2H), 4.71-4.63 (m, 2H), 3.59 ( p, J =6.3 Hz, 1H), 3.30 (s, 4H), 2.60-2.53 (m, 4H); MSNR (ER) m/z 512.1 (M ⁺ +1). 274 4376 2-(4-((4-(3-(4-cyclobutylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl )-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.43 (s, 1H), 8.03-7.92 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.47 (s, 1H), 7.36-7.26 (m, 2H), 7.24 (t, J =51.6 Hz, 1H), 6.99 (dt, J =7.3, 2.2 Hz, 1H), 5.85 (s, 2H), 3.31-3.25 (m, 4H), 2.87 (p, J =7.9 Hz, 1H), 2.60- 2.53 (m, 4H), 2.13 (dt, J = 8.5, 5.4 Hz, 2H), 2.01-1.89 (m, 2H), 1.84-1.71 ( m, 2H); MSNR (ER) m/z 510.3 (M ⁺ +1).

Example 275: Synthesis of compound 4377 , 1-(4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1, 2,3-triazol-4-yl)phenyl)piperazin-1-yl)propan-1-one

2-(Difluoromethyl)-5-(3-fluoro-4-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl) -1,3,4-oxadiazole (0.050 g, 0.110 mmol) obtained in step 2 of Example 271 and propionyl chloride (0.030 g, 0.329 mmol) were dissolved in dichloromethane (1 ml) at room temperature, followed by triethylamine (0.077 ml, 0.549 mmol) is added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-70%) and concentrated to give 1-(4-(3-(1-(4-(5-(difluoromethyl)-1,3 ,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperazin-1-yl)propan-1-one (0.032 g, 57.0% ) in the form of a light yellow oil.

¹ H NMR(400 MHz, CD₃OD) δ 8.43 (s, 1H), 8.03-7.93 (m, 2H), 7.61 (t,J=7.7 Hz, 1H), 7.52-7.47 (m, 1H), 7.37-7.29 (m, 2H), 7.24 (t,J=51.6 Hz, 1H), 7.05-6.98 (m, 1H), 5.85 (s, 2H), 3.75 (dt,J=17.5, 5.3 Hz, 4H), 3.26 (dt,J=18.6, 5.4 Hz, 4H), 2.49 (kv,J=7.5 Hz, 2H), 1.16 (t,J=7.5 Hz, 3H);MCNR(ER) m/z 512.3 (M⁺+1).

Example 276: Synthesis of Compound 4392, 2-(difluoromethyl)-5-(4-((4-(2-(1-ethylazetidin-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)- 1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 3-(6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2, 3-triazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)azetidin-1-carboxylate

2-(Difluoromethyl)-5-(3-fluoro-4-((4-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl )phenyl)-1,3,4-oxadiazole (0.200 g, 0.469 mmol) obtained from step 2 of Example 256, tert-butyl 3-oxoazetidine-1-carboxylate (0.096 g, 0.563 mmol), acetic acid (0.030 ml, 0.516 mmol) and sodium triacetoxyborohydride (0.199 g, 0.938 mmol) were dissolved in dichloromethane (5 ml), after which the resulting solution was stirred at room temperature for 30 minutes, and then stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give tert-butyl 3-(6-(1-(4-(5-(difluoromethyl)-1,3 ,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)azetidin-1-carboxylate (0.150 g, 55.0%) in the form of a white solid.

[Step 2] Synthesis of 2-(4-((4-(2-(azetidin-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol- 1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole

Tert-butyl 3-(6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4 -yl)-3,4-dihydroisoquinolin-2(1H)-yl)azetidin-1-carboxylate (0.150 g, 0.258 mmol) obtained in step 1 and trifluoroacetic acid (0.059 ml, 0.774 mmol) are dissolved in dichloromethane (30 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 3 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Then, the resulting product is used without an additional purification process (2-(4-((4-(2-(azetidin-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2 ,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole, 0.120 g, 96.6%, yellow oil).

[Step 3] Synthesis of compound 4392

2-(4-((4-(2-(Azetidin-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl )-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.104 mmol) obtained in step 2, acetaldehyde (0.006 g, 0.208 mmol) and acetic acid (0.007 ml, 0.114 mmol ) was dissolved in dichloromethane (5 ml), after which the resulting solution was stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (0.044 g, 0.208 mmol) was added thereto and then stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(2-(1-ethyl azetidin-3 -yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-1,3,4-oxadiazole (0.031 g, 58.6%) in the form of a white solid.

¹ H NMR (400 MHz, CDCl₃) δ 7.92 (dd,J=7.8, 2.5 Hz, 2H), 7.81 (s, 1H), 7.63 (s, 1H), 7.59-7.52 (m, 1H), 7.48 (t,J=7.7 Hz, 1H), 7.10-7.04 (m, 1.2H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 5.74 ( d,J=10.4 Hz, 2H), 4.00 (t,J=7.1 Hz, 2H), 3.53 (s, 2H), 3.38 (dt,J=13.2, 6.5 Hz, 1H), 3.27 (t,J=7.5 Hz, 2H), 2.96 (t,J=5.9 Hz, 2H), 2.82 (kv,J=7.2 Hz, 2H), 2.63 (t,J=5.9 Hz, 2H), 1.19-1.06 (m, 3H);MCNR(ER) m/z 510.6 (M⁺+1).

The compounds of Table 85 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4392 except for the use of 2-(4-((4-(2-(azetidin-3-yl)-1,2,3. 4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole and the reagent from Table 84.

Table 84 Example Connection no. Reagent Exit (%) 277 4393 Propan-2-one 53 278 4394 Cyclobutanone 37 279 4395 Oxetan-3-one 55

Table 85 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 277 4393 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-(1-isopropylazetidin-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1 ,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.92 (dt, J = 3.8, 1.5 Hz, 2H), 7.81 (s, 1H), 7.62 (s, 1H), 7 .55 (dd, J =7.9, 1.6 Hz, 1H), 7.47 (t, J =7.7 Hz, 1H), 7.10-7.04 (m, 1.2H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 5.73 (s, 2H), 3.74 (t, J =6.8 Hz, 2H), 3.52 (s, 2H), 3.25-3.13 (m, 1H), 3.05 (t, J =7.3 Hz, 2H), 3.00-2.88 (m, 2H), 2, 62 (t, J =6.0 Hz, 2H), 2.50 (dt, J =12.3, 6.1 Hz, 1H), 1.03 (d, J =6.2 Hz, 6H); MSNR (ER) m/z 524.6 (M ⁺ +1). 278 4394 2-(4-((4-(2-(1-cyclobutylazetidin-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl )methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 7.95-7.88 (m, 2H), 7.81 (s, 1H), 7.62 (s, 1H), 7.58-7.53 ( m, 1H), 7.47 (t, J =7.7 Hz, 1H), 7.09-7.04 (m, 1.2H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 5.74 (s, 2H), 3.71 (t, J =6.8 Hz, 2H), 3.51 (s, 2H), 3.36-3.22 ( m, 2H), 3.16 (t, J =7.3 Hz, 2H), 3.00-2.87 (m, 2H), 2.61 (t, J =5.9 Hz, 2H), 2.10-1.90 (m, 4H), 1.87-1.62 (m, 2H); MSNR (ER) m/z 536.5 (M ⁺ +1). 279 4395 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-(1-(oxetan-3-yl)azetidin-3-yl)-1,2,3,4-tetrahydroisoquinoline-6 -yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, _CDCl3 ) δ 7.95-7.89 (m, 2H), 7.81 (s, 1H), 7.63 (s, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.47 (t, J =7.7 Hz, 1H), 7.08 (d, J =7.8 Hz, 1.2H), 6.94 (s, 0. 5H), 6.81 (s, 0.3H), 5.73 (s, 2H), 4.71 (t, J =6.7 Hz, 2H), 4.62-4.53 (m, 2H ), 3.90-3.79 (m, 1H), 3.65 (t, J =6.4 Hz, 2H), 3.54 (s, 2H), 3.29-3.22 (m, 1H), 3.18 (t, J =6.8 Hz, 2H), 2.96 (t, J =5.8 Hz, 2H), 2.64 (t, J =5.9 Hz, 2H) ; MSNR (ER) m/z 538.4 (M ⁺ +1).

Example 280: Synthesis of Compound 4396, 2-(difluoromethyl)-5-(4-((4-(4-fluoro-3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1 -yl)methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 2-(3-bromo-4-fluorophenyl)-1,3-dioxolane

3-bromo-4-fluorobenzaldehyde (10.500 g, 51.722 mmol), PTSA (0.098 g, 0.517 mmol) and ethylene glycol (3.471 ml, 62.066 mmol) were dissolved in toluene (50 ml) at room temperature, after which the resulting solution was stirred at same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane=0-20%) and concentrated to give 2-(3-bromo-4-fluorophenyl)-1,3-dioxolane (10.420 g, 81.5 %) in the form of a yellow oil.

[Step 2] Synthesis of tert-butyl 4-(5-(1,3-dioxolan-2-yl)-2-fluorophenyl)piperazine-1-carboxylate

2-(3-Bromo-4-fluorophenyl)-1,3-dioxolane (5.000 g, 20.238 mmol) obtained in step 1, tert-butyl piperazine-1-carboxylate (4.146 g, 22.262 mmol), tris(dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ , 0.185 g, 0.202 mmol), rac-BINAP (0.252 g, 0.405 mmol) and NaOBut (3.890 g, 40.476 mmol) are dissolved in toluene (50 ml) at room temperature, after which the resulting solution heated at reflux for 18 hours, and then the reaction is completed by reducing the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl 4-(5-(1,3-dioxolan-2-yl)-2-fluorophenyl) piperazine-1-carboxylate (3.450 g, 48.4%) as a yellow oil.

[Step 3] Synthesis of tert-butyl 4-(2-fluoro-5-formylphenyl)piperazine-1-carboxylate

Tert-butyl 4-(5-(1,3-dioxolan-2-yl)-2-fluorophenyl)piperazine-1-carboxylate (3.450 g, 9.790 mmol) obtained in step 2 and hydrochloric acid (1.00 M solution, 29.369 ml, 29.369 mmol) was dissolved in methanol (10 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 4 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl 4-(2-fluoro-5-formylphenyl)piperazine-1-carboxylate (2.600 g, 86 .1%) in the form of a yellow oil.

[Step 4] Synthesis of tert-butyl 4-(5-(2,2-dibromovinyl)-2-fluorophenyl)piperazine-1-carboxylate

Tert-butyl 4-(2-fluoro-5-formylphenyl)piperazine-1-carboxylate (2.600 g, 8.432 mmol) obtained in step 3, carbon tetrabromide (5.593 g, 16.864 mmol) and triphenylphosphine triphenylphosphine (8.846 g, 33.728 mmol ) is dissolved in dichloromethane (100 ml) at room temperature, after which the resulting solution is stirred at the same temperature for two hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl 4-(5-(2,2-dibromovinyl)-2-fluorophenyl)piperazine-1- carboxylate (3.300 g, 84.3%) in the form of a yellow oil.

[Step 5] Synthesis of tert-butyl 4-(5-ethynyl-2-fluorophenyl)piperazine-1-carboxylate

Tert-butyl 4-(5-(2,2-dibromovinyl)-2-fluorophenyl)piperazine-1-carboxylate (3.300 g, 7.109 mmol) obtained in step 4, and 2,3,4,6,7,8 ,9,10-octahydropyrimido[1,2-a]azepine (4.253 ml, 28.438 mmol) was dissolved in acetonitrile (50 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 16 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl 4-(5-ethynyl-2-fluorophenyl)piperazine-1-carboxylate (0.550 g, 25 .4%) in the form of a colorless oil.

[Step 6] Synthesis of tert-butyl 4-(5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazole -4-yl)-2-fluorophenyl)piperazine-1-carboxylate

Tert-butyl 4-(5-ethynyl-2-fluorophenyl)piperazine-1-carboxylate (0.275 g, 0.904 mmol) prepared in step 5, 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1 ,3,4-oxadiazole (0.272 g, 1.084 mmol) obtained in step 1 of Example 1, copper(II) sulfate pentahydrate (0.002 g, 0.009 mmol) and sodium ascorbate (0.018 g, 0.090 mmol) were dissolved in tert-butanol ( 10 ml)/water (10 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl 4-(5-(1-(4-(5-(difluoromethyl)-1,3 ,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-2-fluorophenyl)piperazine-1-carboxylate (0.480 g, 95.6%) as a white solid .

[Step 7] Synthesis of compound 4396

Tert-butyl 4-(5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl) -2-fluorophenyl)piperazine-1-carboxylate (0.480 g, 0.864 mmol) obtained in step 6 and trifluoroacetic acid (0.662 ml, 8.640 mmol) were dissolved in dichloromethane (25 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(4-fluoro-3-(piperazine -1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.330 g, 83.9%) as a yellow solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.90 (p,J=9.4 Hz, 4H), 7.34 (d,J=8.1 Hz, 2H), 7.27-7.22 (m, 1H), 7.05-6.70 (m, 2H), 5.56 (s, 2H), 3.17 (s, 8H);MCNR(ER) m/z 456.3 (M⁺+1).

Example 281: Synthesis of Compound 4397, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(4-fluoro-3-(piperazin-1-yl)phenyl)-1H-1,2,3 -triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 4-(5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2, 3-triazol-4-yl)-2-fluorophenyl)piperazine-1-carboxylate

Tert-butyl 4-(5-ethynyl-2-fluorophenyl)piperazine-1-carboxylate (0.275 g, 0.904 mmol) prepared in step 5 of Example 280, 2-(4-(azidomethyl)-3-fluorophenyl)-5- (difluoromethyl)-1,3,4-oxadiazole (0.292 g, 1.084 mmol) prepared in step 1 of Example 2, copper(II) sulfate pentahydrate (0.002 g, 0.009 mmol) and sodium ascorbate (0.018 g, 0.090 mmol) were dissolved in tert-butanol (5 ml)/water (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl 4-(5-(1-(4-(5-(difluoromethyl)-1,3 ,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-2-fluorophenyl)piperazine-1-carboxylate (0.480 g, 92.6%) as white solid.

[Step 2] Synthesis of compound 4397

Tert-butyl 4-(5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4 -yl)-2-fluorophenyl)piperazine-1-carboxylate (0.480 g, 0.837 mmol) obtained in step 1 and trifluoroacetic acid (0.641 ml, 8.369 mmol) were dissolved in dichloromethane (25 ml) at room temperature, after which the resulting the solution is stirred at the same temperature for 12 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(4-fluoro- 3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.350 g, 88.3%) as yellow solid matter.

¹ H NMR(400 MHz, CDCl₃) δ 7.86-7.73 (m, 3H), 7.47-7.34 (m, 2H), 7.22 (ddd,J=8.6, 4.1, 2.0 Hz, 1H), 7.07-6.68 (m, 2H), 5.64 (s, 2H), 3.17-2.90 (m, 8H );MCNR(ER) m/z 474.4 (M⁺+1).

Example 282: Synthesis of Compound 4398, 2-(4-((4-(3-((1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl)-4-fluorophenyl)- 1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl (1S,4S)-5-(5-(1,3-dioxolan-2-yl)-2-fluorophenyl)-2,5-diazabicyclo[2,2,1]heptane- 2-carboxylate

2-(3-Bromo-4-fluorophenyl)-1,3-dioxolane (5.000 g, 20.238 mmol) prepared in step 1 of Example 280, tert-butyl (1S,4S)-2,5-diazabicyclo[2,2 ,1]heptane-2-carboxylate (4.414 g, 22.262 mmol), tris(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ , 0.185 g, 0.202 mmol), rac-BINAP (0.252 g, 0.405 mmol) and NaOBut (3.890 g, 40.476 mmol) was dissolved in toluene (50 ml) at room temperature, after which the resulting solution was heated at reflux for 18 hours, and then the reaction was completed by reducing the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl (1S,4S)-5-(5-(1,3-dioxolan-2-yl )-2-fluorophenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate (3.740 g, 50.7%) as a yellow oil.

[Step 2] Synthesis of tert-butyl (1S,4S)-5-(2-fluoro-5-formylphenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate

Tert-butyl (1S,4S)-5-(5-(1,3-dioxolan-2-yl)-2-fluorophenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate (5.450 g, 14.955 mmol) obtained in step 1, and hydrochloric acid (1.00 M solution, 44.866 ml, 44.866 mmol) was dissolved in methanol (10 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 4 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl (1S,4S)-5-(2-fluoro-5-formylphenyl)-2. 5-diazabicyclo[2,2,1]heptane-2-carboxylate (4.200 g, 87.7%) as a yellow oil.

[Step 3] Synthesis of tert-butyl (1S,4S)-5-(5-(2,2-dibromovinyl)-2-fluorophenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate

Tert-butyl (1S,4S)-5-(2-fluoro-5-formylphenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate (4.300 g, 13.422 mmol) obtained in step 2 , carbon tetrabromide (8.903 g, 26.845 mmol) and triphenylphosphine triphenylphosphine (14.082 g, 53.690 mmol) were dissolved in dichloromethane (100 ml) at room temperature, after which the resulting solution was stirred at the same temperature for two hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl (1S,4S)-5-(5-(2,2-dibromovinyl)-2- fluorophenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate (2,500 g, 39.1%) as a white solid.

[Step 4] Synthesis of tert-butyl (1S,4S)-5-(5-ethynyl-2-fluorophenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate

Tert-butyl (1S,4S)-5-(5-(2,2-dibromovinyl)-2-fluorophenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate (2,500 g, 5,250 mmol ) obtained in step 3, and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (3.141 ml, 21,000 mmol) was dissolved in acetonitrile (50 ml) at room temperature , after which the resulting solution is stirred at the same temperature for 16 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl (1S,4S)-5-(5-ethynyl-2-fluorophenyl)-2.5 -diazabicyclo[2,2,1]heptane-2-carboxylate (0.450 g, 27.1%) as a white solid.

[Step 5] Synthesis of tert-butyl (1S,4S)-5-(5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1 ,2,3-triazol-4-yl)-2-fluorophenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate

Tert-butyl (1S,4S)-5-(5-ethynyl-2-fluorophenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate (0.220 g, 0.695 mmol) obtained in step 4 , 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.210 g, 0.834 mmol) prepared in step 1 of Example 1, copper(II) sulfate pentahydrate (0.002 g, 0.007 mmol) and sodium ascorbate (0.014 g, 0.070 mmol) were dissolved in tert-butanol (5 ml)/water (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl (1S,4S)-5-(5-(1-(4-(5-( difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-2-fluorophenyl)-2,5-diazabicyclo[2,2,1] heptane-2-carboxylate (0.200 g, 50.7%) in the form of a white solid.

[Step 6] Synthesis of compound 4398

Tert-butyl (1S,4S)-5-(5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3- triazol-4-yl)-2-fluorophenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate (0.200 g, 0.352 mmol) obtained in step 5, and trifluoroacetic acid (0.270 ml, 3.524 mmol) was dissolved in dichloromethane (25 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol = 0-10%) and concentrated to give 2-(4-((4-(3-((1S,4S)-2,5-diazabicyclo [2,2,1]heptan-2-yl)-4-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4- oxadiazole (0.055 g, 33.4%) in the form of a yellow solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.88-7.77 (m, 3H), 7.38 (t, J=7.7 Hz, 1H), 7.13-7.07 (m, 1H), 7.07-6, 75 (m, 3H), 5.64 (s, 2H), 4.49 (s, 1H), 4.08 (s, 1H), 3.68 (d, J=10.2 Hz, 1H), 3.51-3.23 (m, 2H), 3.16 (d, J=10.5 Hz, 1H), 2.08-1.83 (m, 2H);MCNR(ER) m/z 468.5 (M⁺+1).

Example 283: Synthesis of Compound 4399, 2-(4-((4-(3-((1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl)-4-fluorophenyl)- 1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl (1S,4S)-5-(5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)- 1H-1,2,3-triazol-4-yl)-2-fluorophenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate

Tert-butyl (1S,4S)-5-(5-ethynyl-2-fluorophenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate (0.220 g, 0.695 mmol) obtained in step 4 example 281, 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.225 g, 0.834 mmol) prepared in step 1 of example 2, copper(II) sulfate pentahydrate ) (0.002 g, 0.007 mmol) and sodium ascorbate (0.014 g, 0.070 mmol) are dissolved in tert-butanol (5 ml)/water (5 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 2 hours . Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl (1S,4S)-5-(5-(1-(4-(5-( difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-2-fluorophenyl)-2,5-diazabicyclo[2,2 ,1]heptane-2-carboxylate (0.200 g, 49.1%) as a white solid.

[Step 2] Synthesis of compound 4399

Tert-butyl (1S,4S)-5-(5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2 ,3-triazol-4-yl)-2-fluorophenyl)-2,5-diazabicyclo[2,2,1]heptane-2-carboxylate (0.200 g, 0.342 mmol) obtained in step 1, and trifluoroacetic acid (0.262 ml , 3.416 mmol) was dissolved in dichloromethane (25 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol = 0-10%) and concentrated to give 2-(4-((4-(3-((1S,4S)-2,5-diazabicyclo [2,2,1]heptan-2-yl)-4-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3 ,4-oxadiazole (0.060 g, 36.2%) as a yellow solid.

¹ H NMR(400 MHz, CDCl₃) δ 8.09-8.03 (m, 2H), 7.79 (s, 1H), 7.44-7.39 (m, 2H), 7.04-6.76 (m, 3H), 5.60 (s, 2H), 4.56 (s, 1H), 4.25 (s, 1H), 3.69 (d,J=10.9 Hz, 1H), 3.52 (d,J=10.8 Hz, 1H), 3.41 (d,J=11.0 Hz, 1H), 3.26 (d,J=10.8 Hz, 1H), 2.15-2.01 (m, 2H);MCNR(ER) m/z 486.5 (M⁺+1).

Example 286: Synthesis of Compound 4402, 2-(4-((4-(3-(azetidin-1-ylmethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl) -5-(difluoromethyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4- yl)benzaldehyde

2-(4-(Azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.500 g, 1.857 mmol) prepared in step 1 of Example 2, and 3-ethynylbenzaldehyde (0.242 g, 1.857 mmol) dissolved in tert-butanol (3 ml)/water (3 ml) at room temperature, followed by sodium ascorbate (1.00 M solution, 0.186 ml, 0.186 mmol) and copper(II) sulfate pentahydrate (0.50 M solution, 0.037 ml, 0.019 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution is poured into the reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2 -yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)benzaldehyde (0.620 g, 83.6%) as a white solid.

[Step 2] Synthesis of compound 4402

3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)benzaldehyde (0.040 g, 0.100 mmol) obtained in step 1, and azetidine (0.028 g, 0.301 mmol) was dissolved in dichloromethane (1 ml) at room temperature, after which sodium triacetoxyborohydride (0.106 g, 0.501 mmol) was added to the resulting solution and stirred at that same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-70%) and concentrated to give 2-(4-((4-(3-(azetidin-1-ylmethyl)phenyl)-1H- 1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.034 g, 77.1%) as a white solid.

¹ H NMR(400 MHz, CD₃OD) δ 8.44 (s, 1H), 8.03-7.93 (m, 2H), 7.80-7.74 (m, 2H), 7.61 (t,J=7.7 Hz, 1H), 7.43 (t,J=8.0 Hz, 1H), 7.31 (d,J=7.7 Hz, 1H), 7.24 (t,J=51.6 Hz, 1H), 5.86 (s, 2H), 3.71 (s, 2H), 3.41-3.35 (m, 4H), 2.16 (p,J=7.2 Hz, 2H);MCNR(ER) m/z 441.5 (M⁺+1).

The compounds of Table 87 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4402 except for the use of 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl )-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)benzaldehyde and the reagent from Table 86.

Table 86 Example Connection no. Reagent Exit (%) 287 4403 3-fluoroazetidine 58 288 4404 Morpholine 83 289 4405 4,4-difluoropiperidine 61 290 4406 1-methylpiperazine 70 291 4407 1-ethylpiperazine 64 292 4408 1-isopropylpiperazine 56 302 4418 3,3-difluoroazetidine 60

Table 87 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 287 4403 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-((3-fluoroazetidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.45 (d, J = 1.1 Hz, 1H), 8.03-7.93 (m, 2H), 7.81-7.72 (m , 2H), 7.61 (t, J =7.7 Hz, 1H), 7.46-7.38 (m, 1H), 7.35-7.29 (m, 1H), 7.24 ( t, J =51.6 Hz, 1H), 5.86 (s, 2H), 5.26-5.19 (m, 0.5H), 5.08 (s, 0.5H), 3.76 (s, 2H), 3.73-3.60 (m, 2H), 3.37 (s, 2H), 3.33-3.26 (m, 2H); MSNR (ER) m/z 459.5 (M ⁺ +1). 288 4404 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) benzyl)morpholine
^1H NMR (400 MHz, CD ₃ OD) δ 8.45 (s, 1H), 8.03-7.93 (m, 2H), 7.87-7.82 (m, 1H), 7.76 (dt, J =7.6, 1.5 Hz, 1H), 7.61 (t, J =7.7 Hz, 1H), 7.43 (t, J =7.6 Hz, 1H), 7 .39-7.10 (m, 2H), 5.86 (s, 2H), 3.74-3.68 (m, 4H), 3.59 (s, 2H), 2.50 (t, J =4.7 Hz, 4H); MSNR (ER) m/z 471.5 (M ⁺ +1). 289 4405 2-(difluoromethyl)-5-(4-((4-(3-((4,4-difluoropiperidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl )-3-fluorophenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.45 (s, 1H), 8.03-7.93 (m, 2H), 7.85 (d, J = 1.9 Hz, 1H), 7.76 (dt, J =7.7, 1.6 Hz, 1H), 7.61 (t, J =7.7 Hz, 1H), 7.43 (t, J =7.6 Hz, 1H ), 7.38-7.10 (m, 2H), 5.86 (s, 2H), 3.64 (s, 2H), 2.61 (t, J =5.6 Hz, 4H), 2 .01 (ddd, J =19.5, 12.9, 5.7 Hz, 4H); MSNR (ER) m/z 505.5 (M ⁺ +1). 290 4406 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.03-7.92 (m, 2H), 7.83 (t, J = 1.8 Hz, 1H), 7.76 (dt, J =7.8, 1.5 Hz, 1H), 7.61 (t, J =7.6 Hz, 1H), 7.43 (t, J =7.6 Hz, 1H ), 7.35 (dt, J =7.8, 1.4 Hz, 1H), 7.24 (t, J =51.6 Hz, 1H), 5.86 (s, 2H), 3.61 (s, 2H), 2.55 (s, 8H), 2.31 (s, 3H); MSNR (ER) m/z 484.6 (M ⁺ +1). 291 4407 2-(difluoromethyl)-5-(4-((4-(3-((4-ethylpiperazin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)- 3-fluorophenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.03-7.93 (m, 2H), 7.83 (d, J = 1.8 Hz, 1H), 7.77 (dt, J =7.7, 1.5 Hz, 1H), 7.61 (t, J =7.7 Hz, 1H), 7.43 (t, J =7.7 Hz, 1H ), 7.37-7.34 (m, 1H), 7.24 (t, J =51.6 Hz, 1H), 5.86 (s, 2H), 3.61 (s, 2H), 2 .82-2.36 (m, 10H), 1.11 (t, J =7.3 Hz, 3H); MSNR (ER) m/z 498.5 (M ⁺ +1). 292 4408 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-((4-isopropylpiperazin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)phenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.03-7.93 (m, 2H), 7.83 (s, 1H), 7.80-7.73 (m, 1H), 7.61 (t, J =7.7 Hz, 1H), 7.43 (t, J =7.7 Hz, 1H), 7.38-7.11 (m, 2H) , 5.86 (s, 2H), 3.61 (s, 2H), 2.63 (s, 9H), 1.10 (d, J =6.6 Hz, 6H); MSNR (ER) m/z 512.6 (M ⁺ +1). 302 4418 2-(4-((4-(3-((3,3-difluoroazetidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl) -5-(difluoromethyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 8.46 (s, 1H), 8.03-7.93 (m, 2H), 7.82 (s, 1H), 7.78 (d, J =7.9 Hz, 1H), 7.61 (t, J =7.7 Hz, 1H), 7.44 (t, J =7.6 Hz, 1H), 7.35 (d, J =7 .7 Hz, 1H), 7.24 (t, J =51.6 Hz, 1H), 5.86 (s, 2H), 3.83 (s, 2H), 3.67 (t, J =12 ,1 Hz, 4H); MSNR (ER) m/z 477.4 (M ⁺ +1).

Example 293: Synthesis of Compound 4409, 2-(4-((4-(3-(azetidin-1-ylmethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5- (difluoromethyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)benzaldehyde

2-(4-(Azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.500 g, 1.990 mmol) prepared in step 1 of Example 1, and 3-ethynylbenzaldehyde (0.259 g, 1.990 mmol) dissolve in tert-butanol (3 ml)/water (3 ml) at room temperature, followed by sodium ascorbate (1.00 M solution, 0.199 ml, 0.199 mmol) and copper(II) sulfate pentahydrate (0.50 M solution, 0.040 ml, 0.020 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution is poured into the reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2 -yl)benzyl)-1H-1,2,3-triazol-4-yl)benzaldehyde (0.640 g, 84.3%) as a white solid.

[Step 2] Synthesis of compound 4409

3-(1-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)benzaldehyde (0.050 g, 0.131 mmol) obtained in step 1 and azetidine (0.037 g, 0.393 mmol) are dissolved in dichloromethane (1 ml) at room temperature, after which sodium triacetoxyborohydride (0.139 g, 0.656 mmol) is added to the resulting solution and stirred at the same temperature in within 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-70%) and concentrated to give 2-(4-((4-(3-(azetidin-1-ylmethyl)phenyl)-1H- 1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.037 g, 66.8%) as a white solid.

¹ H NMR(400 MHz, CD₃OD) δ 8.43 (s, 1H), 8.21-8.13 (m, 2H), 7.76 (dd,J=6.4, 1.4 Hz, 2H), 7.65-7.58 (m, 2H), 7.46-7.39 (m, 1H), 7.31 (dt,J=7.7, 1.5 Hz, 1H), 7.23 (t,J=51.6 Hz, 1H), 5.81 (s, 2H), 3.69 (s, 2H), 3.36 (d,J=7.2 Hz, 4H), 2.15 (p,J=7.2 Hz, 2H);MCNR(ER) m/z 423.4 (M⁺+1).

The compounds of Table 89 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4409 except for the use of 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl )benzyl)-1H-1,2,3-triazol-4-yl)benzaldehyde and the reagent from Table 88.

Table 88 Example Connection no. Reagent Exit (%) 294 4410 3-fluoroazetidine 60 295 4411 Morpholine 64 296 4412 Thiomorpholine 1,1-dioxide 38 297 4413 4,4-difluoropiperidine 54 298 4414 1-methylpiperazine 70 299 4415 1-ethylpiperazine 50 300 4416 1-isopropylpiperazine 44 301 4417 3,3-difluoroazetidine 53

Table 89 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 294 4410 2-(difluoromethyl)-5-(4-((4-(3-((3-fluoroazetidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl )-1,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.21-8.13 (m, 2H), 7.81-7.74 (m, 2H), 7.65 -7.58 (m, 2H), 7.46-7.39 (m, 1H), 7.34-7.30 (m, 1H), 7.23 (t, J =51.7 Hz, 1H ), 5.81 (s, 2H), 5.25-5.18 (m, 0.5H), 5.11-5.04 (m, 0.5H), 3.76 (s, 2H), 3.73-3.60 (m, 2H), 3.37 (d, J =4.3 Hz, 1H), 3.31-3.26 (m, 1H); MSNR (ER) m/z 441.5 (M ⁺ +1). 295 4411 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)benzyl)morpholine
^1H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.21-8.13 (m, 2H), 7.84 (s, 1H), 7.76 (dt, J =7.6, 1.6 Hz, 1H), 7.65-7.59 (m, 2H), 7.43 (t, J =7.6 Hz, 1H), 7.39-7.35 ( m, 1H), 7.25-7.10 (m, 1H), 5.80 (s, 2H), 3.74-3.67 (m, 4H), 3.59 (s, 2H), 2 .50 (t, J =4.7 Hz, 4H); MSNR (ER) m/z 453.5 (M ⁺ +1). 296 4412 1,1-dioxide 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4- yl)benzyl)thiomorpholine
^1H NMR (400 MHz, CD ₃ OD) δ 8.46 (s, 1H), 8.19-8.14 (m, 2H), 7.88 (s, 1H), 7.75 (d, J =7.7 Hz, 1H), 7.62 (d, J =8.3 Hz, 2H), 7.44 (t, J =7.6 Hz, 1H), 7.41-7.09 (m , 2H), 5.81 (s, 2H), 3.76 (s, 2H), 3.17-3.11 (m, 4H), 3.02 (dd, J =7.1, 3.5 Hz, 4H); MSNR (ER) m/z 501.3 (M ⁺ +1). 297 4413 2-(difluoromethyl)-5-(4-((4-(3-((4,4-difluoropiperidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl )phenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.21-8.14 (m, 2H), 7.84 (s, 1H), 7.76 (d, J =7.6 Hz, 1H), 7.62 (d, J =8.3 Hz, 2H), 7.43 (t, J =7.6 Hz, 1H), 7.39-7.33 (m , 1H), 7.25-7.08 (m, 1H), 5.80 (s, 2H), 3.64 (s, 2H), 2.65-2.56 (m, 4H), 2, 00 (tt, J =13.1, 5.8 Hz, 4H); MSNR (ER) m/z 487.3 (M ⁺ +1). 298 4414 2-(difluoromethyl)-5-(4-((4-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl )-1,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.21-8.13 (m, 2H), 7.83 (s, 1H), 7.76 (dt, J =7.8, 1.5 Hz, 1H), 7.62 (d, J =8.4 Hz, 2H), 7.43 (t, J =7.7 Hz, 1H), 7.37-7 .33 (m, 1H), 7.25-7.09 (m, 1H), 5.80 (s, 2H), 3.61 (s, 2H), 2.57 (shs, 8H), 2, 32 (s, 3H); MSNR (ER) m/z 466.3 (M ⁺ +1). 299 4415 2-(difluoromethyl)-5-(4-((4-(3-((4-ethylpiperazin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl )-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.17 (d, J =8.4 Hz, 2H), 7.83 (s, 1H), 7.80- 7.73 (m, 1H), 7.62 (d, J =8.3 Hz, 2H), 7.43 (t, J =7.6 Hz, 1H), 7.38-7.33 (m , 1H), 7.25-7.09 (m, 1H), 5.80 (s, 2H), 3.61 (s, 2H), 2.71-2.38 (m, 10H), 1, 11 (t, J =7.2 Hz, 3H); MSNR (ER) m/z 480.5 (M ⁺ +1). 300 4416 2-(difluoromethyl)-5-(4-((4-(3-((4-isopropylpiperazin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl )-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.21-8.14 (m, 2H), 7.83 (d, J = 1.8 Hz, 1H), 7.80-7.73 (m, 1H), 7.62 (d, J =8.4 Hz, 2H), 7.43 (t, J =7.6 Hz, 1H), 7.39-7 .32 (m, 1H), 7.25-7.09 (m, 1H), 5.80 (s, 2H), 3.61 (s, 2H), 2.73-2.48 (m, 9H ), 1.09 (d, J =6.6 Hz, 6H); MSNR (ER) m/z 494.6 (M ⁺ +1). 301 4417 2-(4-((4-(3-((3,3-difluoroazetidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5- (difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.45 (s, 1H), 8.21-8.13 (m, 2H), 7.81 (d, J = 1.9 Hz, 1H), 7.77 (dt, J =7.7, 1.5 Hz, 1H), 7.62 (d, J =8.4 Hz, 2H), 7.44 (t, J =7.7 Hz, 1H ), 7.36-7.32 (m, 1H), 7.23 (t, J =51.6 Hz, 1H), 5.81 (s, 2H), 3.83 (s, 2H), 3 .67 (t, J =12.1 Hz, 4H); MSNR (ER) m/z 459.4(M ⁺ +1).

Example 303: Synthesis of Compound 4419, 2-(difluoromethyl)-5-(4-((4-(4-fluoro-3-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)phenyl)-1,3,4-oxadiazole

2-(Difluoromethyl)-5-(4-((4-(4-fluoro-3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl) -1,3,4-oxadiazole (0.060 g, 0.132 mmol) obtained in step 7 of Example 280, formaldehyde (0.008 g, 0.263 mmol) and acetic acid (0.008 ml, 0.145 mmol) were dissolved in dichloromethane (5 ml) at room temperature temperature, after which sodium triacetoxyborohydride (0.056 g, 0.263 mmol) is added to the resulting solution and stirred at the same temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution is poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove solid residue and a layer of aqueous solution, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(4-fluoro-3-(4 -methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.035 g, 56.6%) as a white solid .

¹ H NMR(400 MHz, CDCl₃) δ 8.10 (d,J=7.9 Hz, 2H), 7.70 (s, 1H), 7.45 (t,J=9.3 Hz, 3H), 7.30-7.22 (m, 1H), 7.02 (dd,J=9.3, 3.1 Hz, 1H), 7.00-6.75 (m, 1H), 5.65 (s, 2H), 3.16 (t,J=4.8 Hz, 4H), 2.60 (t,J=4.8 Hz, 4H), 2.34 (s, 3H);MCNR(ER) m/z 470.0 (M⁺+1).

The compounds of Table 91 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4419 except for the use of 2-(difluoromethyl)-5-(4-((4-(4-fluoro-3-(piperazine-1 -yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole and the reagent from Table 90.

Table 90 Example Connection no. Reagent Exit (%) 304 4420 Acetaldehyde 53 305 4421 Propan-2-one 55 306 4422 Cyclobutanone 55

Table 91 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 304 4420 2-(difluoromethyl)-5-(4-((4-(3-(4-ethylpiperazin-1-yl)-4-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl )-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08 (d, J=7.9 Hz, 2H), 7.71 (s, 1H), 7.42 (d, J=7.9 Hz, 3H ), 7.25 (dd, J=8.0, 3.9 Hz, 1H), 7.01 (dd, J=11.3, 3.2 Hz, 1H), 6.98-6.75 ( m, 1H), 5.63 (s, 2H), 3.15 (t, J=5.9 Hz, 4H), 2.67-2.60 (m, 4H), 2.48 (sq, J =7.1 Hz, 2H), 1.17-1.06 (m, 3H); MSNR (ER) m/z 484.6 (M ⁺ +1). 305 4421 2-(difluoromethyl)-5-(4-((4-(4-fluoro-3-(4-isopropylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl) phenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 8.17-8.10 (m, 2H), 7.68 (s, 1H), 7.51-7.42 (m, 3H), 7.31 ( ddd, J =8.3, 4.3, 2.1 Hz, 1H), 7.09-7.03 (m, 1H), 7.03-6.76 (m, 1H), 5.67 ( s, 2H), 3.23 (t, J =4.9 Hz, 4H), 2.82 (dt, J =17.7, 5.7 Hz, 5H), 1.14 (d, J =6 .5 Hz, 6H); MSNR (ER) m/z 498.55 (M ⁺ +1). 306 4422 2-(4-((4-(3-(4-cyclobutylpiperazin-1-yl)-4-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl )-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (d, J = 8.0 Hz, 2H), 7.69 (s, 1H), 7.45 (td, J = 5.6, 2, 6 Hz, 3H), 7.30-7.22 (m, 1H), 7.03 (dd, J =9.0, 3.3 Hz, 1H), 7.00-6.76 (m, 1H ), 5.65 (s, 2H), 3.17 (t, J =4.9 Hz, 4H), 2.82 (p, J =8.1 Hz, 1H), 2.53 (t, J =4.9 Hz, 4H), 2.05 (kvd, J =9.6, 8.5, 2.7 Hz, 2H), 2.00-1.86 (m, 2H), 1.79- 1.62 (m, 2H); MSNR (ER) m/z 510.2 (M ⁺ +1).

Example 307: Synthesis of Compound 4424, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(4-fluoro-3-(4-methylpiperazin-1-yl)phenyl)-1H-1,2 ,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

2-(Difluoromethyl)-5-(3-fluoro-4-((4-(4-fluoro-3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl) Methyl)phenyl)-1,3,4-oxadiazole (0.060 g, 0.127 mmol) obtained in step 2 of Example 281, formaldehyde (0.008 g, 0.253 mmol) and acetic acid (0.008 ml, 0.139 mmol) were dissolved in dichloromethane (5 ml) at room temperature, after which sodium triacetoxyborohydride (0.054 g, 0.253 mmol) was added to the resulting solution and stirred at the same temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution is poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove solid residue and a layer of aqueous solution, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(4-fluoro- 3-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.043 g, 69.6%) in form of a white solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.86 (dd,J=8.6, 4.9 Hz, 2H), 7.78 (s, 1H), 7.43 (kv,J=8.2, 7.5 Hz, 2H), 7.25 (d,J=5.6 Hz, 1H), 7.06-7.00 (m, 1H), 6.99-6.75 (m, 1H), 5.68 (s, 2H), 3.16 (t,J=4.9 Hz, 4H), 2.61 (t,J=4.9 Hz, 4H), 2.34 (s, 3H);MCNR(ER) m/z 488.3 (M⁺+1).

The compounds of Table 93 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4424 except for the use of 2-(difluoromethyl)-5-(3-fluoro-4-((4-(4-fluoro-3- (piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole and the reagent from Table 92.

Table 92 Example Connection no. Reagent Exit (%) 308 4425 Propan-2-one 69 309 4426 Cyclobutanone 67 310 4427 Oxetan-3-one 66

Table 93 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 308 4425 2-(difluoromethyl)-5-(3-fluoro-4-((4-(4-fluoro-3-(4-isopropylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1- yl)methyl)phenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 7.93-7.84 (m, 2H), 7.77 (s, 1H), 7.49-7.39 (m, 2H), 7.28 ( dkv, J =6.4, 2.2 Hz, 1H), 7.04 (dd, J =7.7, 4.6 Hz, 1H), 7.01-6.77 (m, 1H), 5 .69 (s, 2H), 3.18 (t, J =4.8 Hz, 4H), 2.74 (dt, J =9.7, 5.6 Hz, 5H), 1.09 (d, J =6.5 Hz, 6H); MSNR (ER) m/z 516.1 (M ⁺ +1). 309 4426 2-(4-((4-(3-(4-cyclobutylpiperazin-1-yl)-4-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5 -(difluoromethyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 7.90-7.82 (m, 2H), 7.77 (s, 1H), 7.47-7.37 (m, 2H), 7.30- 7.22 (m, 1H), 7.02 (dd, J =11.3, 3.0 Hz, 1H), 6.99-6.76 (m, 1H), 5.68 (s, 2H) , 3.16 (t, J =4.8 Hz, 4H), 2.81 (p, J =7.9, 7.2 Hz, 1H), 2.52 (t, J =4.8 Hz, 4H), 2.10-2.00 (m, 2H), 1.98-1.85 (m, 2H), 1.78-1.55 (m, 2H); MSNR (ER) m/z 528.1 (M ⁺ +1). 310 4427 2-(difluoromethyl)-5-(3-fluoro-4-((4-(4-fluoro-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1H-1,2 ,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 7.91-7.83 (m, 2H), 7.78 (s, 1H), 7.50-7.38 (m, 2H), 7.30- 7.22 (m, 1H), 7.07-7.01 (m, 1H), 7.00-6.77 (m, 1H), 5.69 (s, 2H), 4.65 (dt, J =14.7, 6.4 Hz, 4H), 3.56 (p, J =6.4 Hz, 1H), 3.18 (t, J =4.8 Hz, 4H), 2.51 ( t, J =4.8 Hz, 4H); MSNR (ER) m/z 530.4 (M ⁺ +1).

Example 311: Synthesis of compound 4429, 2-(difluoromethyl)-5-(4-((4-(4-fluoro-3-((1S,4S)-5-methyl-2,5-diazabicyclo[2,2, 1]heptan-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

2-(4-((4-(3-((1S,4S)-2,5-Diazabicyclo[2,2,1]heptan-2-yl)-4-fluorophenyl)-1H-1,2,3 -triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.107 mmol) prepared in step 6 of Example 282, formaldehyde (0.006 g, 0.214 mmol) and acetic acid the acid (0.007 ml, 0.118 mmol) was dissolved in dichloromethane (5 ml) at room temperature, after which sodium triacetoxyborohydride (0.045 g, 0.214 mmol) was added to the resulting solution and stirred at the same temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution is poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove solid residue and a layer of aqueous solution, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(4-fluoro-3-(( 1S,4S)-5-methyl-2,5-diazabicyclo[2,2,1]heptan-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1 ,3,4-oxadiazole (0.033 g, 64.1%) as a white solid.

¹ H NMR(400 MHz, CDCl₃) δ 8.16-8.05 (m, 2H), 7.73 (s, 1H), 7.49-7.41 (m, 2H), 7.26-7.18 (m, 1H), 7.06-6.76 (m, 3H), 5.65 (s, 2H), 4.45 (s, 1H), 3.73 (s, 1H), 3.61 (dd,J=3.0, 1.6 Hz, 2H), 3.11 (dd,J=10.4, 2.2 Hz, 1H), 2.98 (dd,J=10.5, 1.7 Hz, 1H), 2.52 (s, 3H), 2.10 (dt,J=10.2, 1.7 Hz, 1H), 2.06-1.97 (m, 1H);MCNR(ER) m/z 482.1 (M⁺+1).

Example 312: Synthesis of Compound 4430, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(4-fluoro-3-((1S,4S)-5-methyl-2,5-diazabicyclo[ 2,2,1]heptan-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

2-(4-((4-(3-((1S,4S)-2,5-Diazabicyclo[2,2,1]heptan-2-yl)phenyl)-1H-1,2,3-triazol- 1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.060 g, 0.128 mmol) prepared in step 2 of Example 283, paraformaldehyde (0.008 g, 0.257 mmol) and acetic acid the acid (0.008 ml, 0.141 mmol) was dissolved in dichloromethane (5 ml) at room temperature, after which sodium triacetoxyborohydride (0.054 g, 0.257 mmol) was added to the resulting solution and stirred at the same temperature for 12 hours. Water is poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove solid residue and a layer of aqueous solution, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(( 1S,4S)-5-methyl-2,5-diazabicyclo[2,2,1]heptan-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1 ,3,4-oxadiazole (0.025 g, 40.5%) as a white solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.89-7.78 (m, 3H), 7.40 (dd,J=8.2, 7.2 Hz, 1H), 7.20-7.13 (m, 1H), 7.05-6.76 (m, 3H), 5.67 (s, 2H), 4, 40 (s, 1H), 3.65 (d,J=2.3 Hz, 1H), 3.62-3.49 (m, 2H), 3.05 (dd,J=10.3, 2.2 Hz, 1H), 2.92 (dd,J=10.3, 1.6 Hz, 1H), 2.47 (s, 3H), 2.08-2.00 (m, 1H), 1.96 (sq,J=1.9, 1.5 Hz, 1H);MCNR(ER) m/z 500.4 (M⁺+1).

Example 313: Synthesis of compound 4431 , N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3 -triazol-4-yl)-2-fluorophenyl)-1-methylpiperidin-4-amine

[Step 1] Synthesis of 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4- yl)-2-fluoroaniline

2-(4-(Azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.300 g, 1.114 mmol) prepared in Step 1 of Example 2, 3-ethynyl-2-fluoroaniline ( 0.181 g, 1.337 mmol), sodium ascorbate (1.00 M solution, 0.111 mL, 0.111 mmol), and copper(II) sulfate pentahydrate (0.50 M solution, 0.022 mL, 0.011 mmol) are dissolved in tert-butanol (10 ml)/water (10 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-40%) and concentrated to give 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2 -yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-2-fluoroaniline (0.410 g, 91.0%) as a white solid.

[Step 2] Synthesis of compound 4431

3-(1-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-2- fluoroaniline (0.070 g, 0.173 mmol) obtained in step 1, 1-methylpiperidin-4-one (0.039 g, 0.346 mmol) and sodium triacetoxyborohydride (0.073 g, 0.346 mmol) were dissolved in dichloromethane (5 ml), and the resulting solution stir at room temperature for 30 minutes, and then stir at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give N-(3-(1-(4-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-2-fluorophenyl)-1-methylpiperidin-4-amine (0.039 g, 44.9%) as white solid.

¹ H NMR (400 MHz, CDCl₃) δ 7.99 (d,J=3.6 Hz, 1H), 7.92 (d,J=9.0 Hz, 2H), 7.57 (t,J=6.7 Hz, 1H), 7.44 (t,J=7.7 Hz, 1H), 7.09 (dd,J=14.2, 6.2 Hz, 1.2H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 6.70 (t,J=7.8 Hz, 1H), 5.76 (s, 2H), 3.86 (s, 1H), 3.39 (s, 1H), 2.94 (t,J=12.6 Hz, 2H), 2.41 (s, 3H), 2.31 (t,J=10.5 Hz, 2H), 2.14 (d,J=11.5 Hz, 2H), 1.68 (dd,J=20.5, 10.0 Hz, 2H);MCNR(ER) m/z 502.6 (M⁺+1).

The compounds of Table 95 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4431 except for the use of 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl )-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-2-fluoroaniline and the reagent from Table 94.

Table 94 Example Connection no. Reagent Exit (%) 314 4432 1-isopropylpiperidin-4-one 28 315 4433 1-acetylpiperidin-4-one 33 316 4434 1-propylpiperidin-4-one 39

Table 95 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 314 4432 N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) -2-fluorophenyl)-1-isopropylpiperidin-4-amine
^1H NMR (400 MHz, CDCl ₃ ) δ 8.00 (d, J =3.5 Hz, 1H), 7.93 (d, J =9.0 Hz, 2H), 7.60 (t, J =6.8 Hz, 1H), 7.44 (t, J =7.7 Hz, 1H), 7.09 (dd, J =14.6, 6.6 Hz, 1.2H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 6.70 (t, J =8.0 Hz, 1H), 5.77 (s, 2H), 3.92 (s, 1H), 3.46 (s, 1H), 3.13 (s, 3H), 2.61 (s, 2H), 2.25 (s, 2H), 1.91 (s, 2H), 1. 27 (d, J =6.4 Hz, 6H); MSNR (ER) m/z 530.46 (M ⁺ +1). 315 4433 1-(4-((3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol- 4-yl)-2-fluorophenyl)amino)piperidin-1-yl)ethan-1-one
^1H NMR (400 MHz, CDCl ₃ ) δ 7.99 (d, J =3.6 Hz, 1H), 7.95-7.88 (m, 2H), 7.62 (t, J =6, 9 Hz, 1H), 7.44 (t, J =7.7 Hz, 1H), 7.12 (t, J =7.9 Hz, 1H), 7.07 (s, 0.2H), 6 .94 (s, 0.5H), 6.81 (s, 0.3H), 6.76 (t, J =7.7 Hz, 1H), 5.76 (s, 2H), 4.51 ( d, J =13.4 Hz, 1H), 3.84 (ddd, J =26.6, 12.6, 6.3 Hz, 3H), 3.64-3.47 (m, 1H), 3 .22 (dd, J =18.2, 6.9 Hz, 1H), 2.88 (dd, J =14.9, 7.8 Hz, 1H), 2.50 (dt, J =9.8 , 6.4 Hz, 1H), 2.11 (d, J =11.0 Hz, 3H), 1.51-1.35 (m, 2H); MSNR (ER) m/z 530.34 (M ⁺ +1). 316 4434 N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) -2-fluorophenyl)-1-propylpiperidin-4-amine
^1H NMR (400 MHz, CDCl ₃ ) δ 8.00 (d, J =3.6 Hz, 1H), 7.93 (d, J =9.0 Hz, 2H), 7.59 (t, J =6.7 Hz, 1H), 7.44 (t, J =7.7 Hz, 1H), 7.10 (dd, J =15.2, 7.3 Hz, 1.2H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 6.70 (t, J =7.6 Hz, 1H), 5.77 (s, 2H), 3.90 (s, 1H), 3.46 (s, 1H), 3.14 (s, 2H), 2.49 (d, J =52.9 Hz, 4H), 2.19 (s, 2H), 1.76 ( d, J =54.1 Hz, 4H), 0.97 (t, J =7.3 Hz, 3H); MSNR (ER) m/z 530.6 (M ⁺ +1).

Example 317: Synthesis of compound 4435 , N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3 -triazol-4-yl)-4-fluorophenyl)-1-methylpiperidin-4-amine

[Step 1] Synthesis of 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4- yl)-4-fluoroaniline

2-(4-(Azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.300 g, 1.114 mmol) prepared in Step 1 of Example 2, 3-ethynyl-4-fluoroaniline ( 0.181 g, 1.337 mmol), sodium ascorbate (1.00 M solution, 0.111 ml, 0.111 mmol) and copper(II) sulfate pentahydrate (0.50 M solution, 0.022 ml, 0.011 mmol) are dissolved in tert-butanol (10 ml )/water (10 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-40%) and concentrated to give 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2 -yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-4-fluoroaniline (0.410 g, 91.0%) as a white solid.

[Step 2] Synthesis of compound 4435

3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-4- fluoroaniline (0.050 g, 0.124 mmol) obtained in step 1 is dissolved in dichloromethane (5 ml), after which the resulting solution is stirred at room temperature for 30 minutes, and then 1-methylpiperidin-4-one (0.017 g, 0.148 mmol) and then stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give N-(3-(1-(4-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-4-fluorophenyl)-1-methylpiperidin-4-amine (0.029 g, 46.8%) as white solid.

¹ H NMR (400 MHz, CDCl₃) δ 8.00 (d,J=3.5 Hz, 1H), 7.92 (dt,J=4.3, 1.7 Hz, 2H), 7.53 (dd,J=6.0, 3.0 Hz, 1H), 7.43 (t,J=7.7 Hz, 1H), 7.07 (s, 0.2H), 7.00-6.95 (m, 1H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 6.54 (ddd,J=8.8, 4.0, 3.1 Hz, 1H), 5.75 (s, 2H), 3.41 (s, 1H), 2.93 (d,J=11.5 Hz, 2H), 2.38 (d,J=11.5 Hz, 3H), 2.28 (t,J=11.0 Hz, 2H), 2.15 (t,J=13.9 Hz, 2H), 1.61 (dd,J=20.4, 10.3 Hz, 2H);MCNR(ER) m/z 502.45 (M⁺+1).

The compounds of Table 97 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4435 except for the use of 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl )-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-4-fluoroaniline and the reagent from Table 96.

Table 96 Example Connection no. Reagent Exit (%) 318 4436 1-isopropylpiperidin-4-one 59 319 4437 1-acetylpiperidin-4-one 47 320 4438 1-propylpiperidin-4-one 58

Table 97 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 318 4436 N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) -4-fluorophenyl)-1-isopropylpiperidin-4-amine
^1H NMR (400 MHz, CDCl ₃ ) δ 8.00 (d, J =3.5 Hz, 1H), 7.92 (dt, J =4.4, 1.7 Hz, 2H), 7.52 (dd, J =6.0, 3.0 Hz, 1H), 7.43 (t, J =7.7 Hz, 1H), 7.07 (s, 0.2H), 6.99-6, 91 (m, 1.5H), 6.81 (s, 0.3H), 6.54 (ddd, J =8.8, 4.0, 3.1 Hz, 1H), 5.75 (s, 2H), 3.41 (td, J =10.2, 5.2 Hz, 1H), 3.04-2.85 (m, 3H), 2.44 (t, J =10.5 Hz, 2H ), 2.14 (t, J =14.4 Hz, 3H), 1.63 (dd, J =20.7, 10.0 Hz, 2H), 1.14 (d, J =6.6 Hz , 6H); MSNR (ER) m/z 530.40 (M ⁺ +1). 319 4437 1-(4-((3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol- 4-yl)-4-fluorophenyl)amino)piperidin-1-yl)ethan-1-one
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (d, J = 3.5 Hz, 1H), 7.96-7.89 (m, 2H), 7.60 (dd, J = 5, 8, 2.9 Hz, 1H), 7.45 (dd, J =10.1, 5.3 Hz, 1H), 7.07 (s, 0.2H), 7.03-6.95 (m , 1H), 6.94 (s, 0.5H), 6.81 (s, 0.3H), 6.66-6.57 (m, 1H), 5.76 (s, 2H), 4, 52 (dd, J =13.6, 1.7 Hz, 1H), 3.94-3.73 (m, 2H), 3.66-3.50 (m, 1H), 3.23 (ddd, J =14.0, 11.6, 2.8 Hz, 1H), 2.92-2.79 (m, 1H), 2.51 (dt, J =9.6, 6.4 Hz, 1H) , 2.18 (d, J =6.4 Hz, 1H), 2.13 (d, J =3.9 Hz, 4H); MSNR (ER) m/z 530.09 (M ⁺ +1). 320 4438 N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) -4-fluorophenyl)-1-propylpiperidin-4-amine
^1H NMR (400 MHz, CDCl ₃ ) δ 8.00 (d, J =3.5 Hz, 1H), 7.96-7.88 (m, 2H), 7.53 (dd, J =6, 0, 3.0 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.07 (s, 0.2H), 7.00-6.90 (m, 1.5H ), 6.81 (s, 0.3H), 6.58-6.51 (m, 1H), 5.75 (s, 2H), 3.42 (d, J =10.0 Hz, 1H) , 2.98 (d, J =10.3 Hz, 2H), 2.47-2.33 (m, 2H), 2.23 (d, J =11.2 Hz, 2H), 2.13 ( d, J =12.1 Hz, 2H), 1.59 (td, J =14.9, 7.4 Hz, 4H), 0.98-0.90 (m, 3H); MSNR (ER) m/z 530.40 (M ⁺ +1).

Example 321: Synthesis of Compound 4439, 2-(difluoromethyl)-5-(4-((4-(3-((3R,5S)-3,5-dimethylpiperazin-1-yl)phenyl)-1H-1,2 ,3-triazol-1-yl)methyl)-3-fluorophenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of (3R,5S)-1-(3-(1,3-dioxolan-2-yl)phenyl)-3,5-dimethylpiperazine

2-(3-bromophenyl)-1,3-dioxolane (1.500 g, 6.548 mmol) prepared in step 2 of Example 218, (2R,6S)-2,6-dimethylpiperazine (0.748 g, 6.548 mmol), tris(dibenzylideneacetone )dipalladium (Pd ₂ (dba) ₃ , 0.060 g, 0.065 mmol), rac-BINAP (0.082 g, 0.131 mmol) and NaOBut (1.259 g, 13.096 mmol) were dissolved in toluene (25 ml) at room temperature, after which the resulting the solution is heated at reflux for 18 hours, and then the reaction is completed by reducing the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give (3R,5S)-1-(3-(1,3-dioxolan-2-yl)phenyl) -3,5-dimethylpiperazine (1.260 g, 73.3%) in the form of a yellow oil.

[Step 2] Synthesis of tert-butyl (2R,6S)-4-(3-(1,3-dioxolan-2-yl)phenyl)-2,6-dimethylpiperazine-1-carboxylate

(3R,5S)-1-(3-(1,3-dioxolan-2-yl)phenyl)-3,5-dimethylpiperazine (2.440 g, 9.301 mmol) obtained in step 1, di-tert-butyl dicarbonate ( 2.564 ml, 11.161 mmol) and N,N-diisopropylethylamine (1.944 ml, 11.161 mmol) were dissolved in dichloromethane (50 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl (2R,6S)-4-(3-(1,3-dioxolan-2-yl )phenyl)-2,6-dimethylpiperazine-1-carboxylate (3.550 g, 105.3%) in the form of a brown oil.

[Step 3] Synthesis of tert-butyl (2R,6S)-4-(3-(1,3-dioxolan-2-yl)phenyl)-2,6-dimethylpiperazine-1-carboxylate

Tert-butyl (2R,6S)-4-(3-(1,3-dioxolan-2-yl)phenyl)-2,6-dimethylpiperazine-1-carboxylate (3.550 g, 9.794 mmol) obtained in step 2, and hydrochloric acid (1.00 M solution, 29.382 ml, 29.382 mmol) were dissolved in methanol (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 4 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl (2R,6S)-4-(3-formylphenyl)-2,6-dimethylpiperazine-1 -carboxylate (2.160 g, 69.3%) in the form of a yellow oil.

[Step 4] Synthesis of tert-butyl (2R,6S)-4-(3-(2,2-dibromovinyl)phenyl)-2,6-dimethylpiperazine-1-carboxylate

Tert-butyl (2R,6S)-4-(3-formylphenyl)-2,6-dimethylpiperazine-1-carboxylate (2.160 g, 6.783 mmol) obtained in step 3, carbon tetrabromide (4.499 g, 13.567 mmol) and triphenylphosphine triphenylphosphine (7.117 g, 27.134 mmol) was dissolved in dichloromethane (50 ml) at room temperature, after which the resulting solution was stirred at the same temperature for two hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-20%) and concentrated to give tert-butyl (2R,6S)-4-(3-(2,2-dibromovinyl)phenyl)- 2,6-Dimethylpiperazine-1-carboxylate (2.541 g, 79.0%) as a yellow oil.

[Step 5] Synthesis of tert-butyl (2R,6S)-4-(3-ethynylphenyl)-2,6-dimethylpiperazine-1-carboxylate

Tert-butyl (2R,6S)-4-(3-(2,2-dibromovinyl)phenyl)-2,6-dimethylpiperazine-1-carboxylate (2.541 g, 5.358 mmol) obtained in step 4, and 2,3 ,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (3.205 ml, 21.432 mmol) was dissolved in acetonitrile (50 ml) at room temperature, after which the resulting solution was stirred at the same temperature in within 16 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-10%) and concentrated to give tert-butyl (2R,6S)-4-(3-ethynylphenyl)-2,6-dimethylpiperazine-1 -carboxylate (0.475 g, 28.2%) in the form of a yellow oil.

[Step 6] Synthesis of tert-butyl (2R,6S)-4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)- 1H-1,2,3-triazol-4-yl)phenyl)-2,6-dimethylpiperazine-1-carboxylate

Tert-butyl (2R,6S)-4-(3-ethynylphenyl)-2,6-dimethylpiperazine-1-carboxylate (0.250 g, 0.795 mmol) prepared in step 5, 2-(4-(azidomethyl)-3- fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.257 g, 0.954 mmol) prepared in step 1 of Example 2, copper(II) sulfate pentahydrate (0.002 g, 0.008 mmol) and sodium ascorbate (0.016 g , 0.080 mmol) was dissolved in tert-butanol (10 ml)/water (10 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl (2R,6S)-4-(3-(1-(4-(5-( difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-2,6-dimethylpiperazine-1-carboxylate (0.300 g , 64.7%) in the form of a colorless oil.

[Step 7] Synthesis of compound 4439

Tert-butyl (2R,6S)-4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2 ,3-triazol-4-yl)phenyl)-2,6-dimethylpiperazine-1-carboxylate (0.300 g, 0.514 mmol) obtained in step 5 and trifluoroacetic acid (0.394 ml, 5.140 mmol) are dissolved in dichloromethane (50 ml ) at room temperature, after which the resulting solution is stirred at the same temperature for 12 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(3-((3R,5S) -3,5-dimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-1,3,4-oxadiazole (0.180 g, 72.4 %) in the form of a white solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.87-7.78 (m, 3H), 7.38 (t,J=7.7 Hz, 1H), 7.24 (t,J=7.6 Hz, 1H), 7.17 (d,J=7.6 Hz, 1H), 7.06-6.74 (m, 3H), 5.66 (s, 2H), 4.92 (s, 1H), 3.64-3.56 (m, 2H), 3.26-3.14 (m, 2H), 2.61 (t,J=11.6 Hz, 2H), 1.22 (d,J=6.4 Hz, 7H);MCNR(ER) m/z 484.5 (M⁺+1).

Example 322: Synthesis of Compound 4440, 2-(difluoromethyl)-5-(4-((4-(3-((3R,5S)-3,5-dimethylpiperazin-1-yl)phenyl)-1H-1,2 ,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl (2R,6S)-4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1 ,2,3-triazol-4-yl)phenyl)-2,6-dimethylpiperazine-1-carboxylate

Tert-butyl (2R,6S)-4-(3-ethynylphenyl)-2,6-dimethylpiperazine-1-carboxylate (0.250 g, 0.795 mmol) prepared in Step 5 of Example 321, 2-(4-(azidomethyl)phenyl )-5-(difluoromethyl)-1,3,4-oxadiazole (0.240 g, 0.954 mmol) obtained in synthesis step 1 of compound 1, copper(II) sulfate pentahydrate (0.002 g, 0.008 mmol) and sodium ascorbate (0.016 g , 0.080 mmol) was dissolved in tert-butanol (10 ml)/water (10 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl (2R,6S)-4-(3-(1-(4-(5-( difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)-2,6-dimethylpiperazine-1-carboxylate (0.290 g, 64, 5%) in the form of a white solid.

[Step 2] Synthesis of compound 4440

Tert-butyl (2R,6S)-4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3- triazol-4-yl)phenyl)-2,6-dimethylpiperazine-1-carboxylate (0.300 g, 0.530 mmol) obtained in step 1 and trifluoroacetic acid (0.406 ml, 5.304 mmol) were dissolved in dichloromethane (50 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 12 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(3-((3R,5S) -3,5-dimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.165 g, 66.8%) in form of a white solid.

¹ H NMR(400 MHz, CDCl₃) δ 8.02 (s, 3H), 7.78 (s, 1H), 7.38 (s, 3H), 7.13-6.76 (m, 3H), 5.59 (s, 2H) , 3.54 (d,J=11.6 Hz, 2H), 3.17 (s, 2H), 3.04 (s, 2H), 1.12 (s, 6H);MCNR(ER) m/z 466.6 (M⁺+1).

Example 323: Synthesis of Compound 4441, 2-(difluoromethyl)-5-(4-((4-(3-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1 ,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

2-(Difluoromethyl)-5-(4-((4-(3-((3R,5S)-3,5-dimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1- yl)methyl)phenyl)-1,3,4-oxadiazole (0.080 g, 0.172 mmol) obtained in step 2 of Example 322, formaldehyde (0.010 g, 0.344 mmol) and acetic acid (0.011 ml, 0.189 mmol) were dissolved in dichloromethane (5 ml) at room temperature, after which sodium triacetoxyborohydride (0.073 g, 0.344 mmol) was added to the resulting solution and stirred at the same temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution is poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove solid residue and a layer of aqueous solution, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(3-((3R,5S) -3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.043 g, 52.2% ) in the form of a white solid.

¹ H NMR(400 MHz, CDCl₃) δ 8.12-8.06 (m, 2H), 7.75 (s, 1H), 7.51-7.41 (m, 3H), 7.29-7.21 (m, 1H), 7.14 (d,J=7.5 Hz, 1H), 7.05-6.75 (m, 2H), 5.64 (s, 2H), 3.57-3.48 (m, 2H), 2.67 (t,J=11.3 Hz, 2H), 2.51-2.39 (m, 2H), 2.34 (s, 3H), 1.19 (d,J=6.2 Hz, 6H);MCNR(ER) m/z 480.6 (M⁺+1).

The compound of Table 99 was synthesized in accordance with substantially the same method as described above for the synthesis of compound 4441 except for the use of 2-(difluoromethyl)-5-(4-((4-(3-((3R,5S)-3 ,5-dimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole and the reagent from Table 98.

Table 98 Example Connection no. Reagent Exit (%) 324 4442 Acetaldehyde 48

Table 99 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 324 4442 2-(difluoromethyl)-5-(4-((4-(3-((3R,5S)-4-ethyl-3,5-dimethylpiperazin-1-yl)phenyl)-1H-1,2,3- triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 8.14-8.06 (m, 2H), 7.74 (s, 1H), 7.50-7.42 (m, 3H), 7.29- 7.21 (m, 1H), 7.14 (d, J =7.5 Hz, 1H), 7.05-6.76 (m, 2H), 5.65 (s, 2H), 3.58 -3.49 (m, 2H), 3.02 (kvd, J =7.2 Hz, 2H), 2.85 (kvd, J =6.5, 3.5 Hz, 2H), 2.66 ( t, J =11.2 Hz, 2H), 1.18 (d, J =6.2 Hz, 6H), 0.95 (t, J =7.1 Hz, 3H); MSNR (ER) m/z 494.1 (M ⁺ +1).

Example 325: Synthesis of Compound 4443, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)phenyl) -1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

2-(Difluoromethyl)-5-(4-((4-(3-((3R,5S)-3,5-dimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1- yl)methyl)-3-fluorophenyl)-1,3,4-oxadiazole (0.080 g, 0.165 mmol) prepared in step 7 of Example 321, formaldehyde (0.010 g, 0.331 mmol) and acetic acid (0.010 ml, 0.182 mmol) dissolved in dichloromethane (5 ml) at room temperature, after which sodium triacetoxyborohydride (0.070 g, 0.331 mmol) was added to the resulting solution and stirred at the same temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution is poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove solid residue and a layer of aqueous solution, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(( 3R,5S)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.025 g, 30.4%) in the form of a yellow solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.93-7.85 (m, 2H), 7.82 (s, 1H), 7.52-7.38 (m, 2H), 7.32-7.23 (m, 1H), 7.16 (s, 1H), 7.07-6.75 (m, 2H), 5.71 (s, 2H), 3.59-3.51 (m, 2H), 2.73 (t,J=11.4 Hz, 2H), 2.59-2.46 (m, 2H), 2.38 (s, 3H), 1.23 (d,J=6.2 Hz, 6H);MCNR(ER) m/z 498.1 (M⁺+1).

The compound of Table 101 was synthesized in accordance with substantially the same method as described above in the synthesis of compound 4443 except for the use of 2-(difluoromethyl)-5-(4-((4-(3-((3R,5S)-3 ,5-dimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-1,3,4-oxadiazole and the reagent from Table 100.

Table 100 Example Connection no. Reagent Exit (%) 326 4444 Acetaldehyde thirty

Table 101 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 326 4444 2-(difluoromethyl)-5-(4-((4-(3-((3R,5S)-4-ethyl-3,5-dimethylpiperazin-1-yl)phenyl)-1H-1,2,3- triazol-1-yl)methyl)-3-fluorophenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 7.90 (d, J =8.8 Hz, 2H), 7.82 (s, 1H), 7.49 (t, J =2.1 Hz, 1H ), 7.42 (t, J =7.6 Hz, 1H), 7.32-7.24 (m, 1H), 7.18 (s, 1H), 7.06-6.78 (m, 2H), 5.72 (s, 2H), 3.57 (d, J =11.5 Hz, 2H), 3.02 (kv, J =7.2 Hz, 2H), 2.85 (ddd, J =15.6, 7.3, 4.1 Hz, 2H), 2.65 (t, J =11.1 Hz, 2H), 1.20 (d, J =6.2 Hz, 6H), 0.96 (t, J =7.1 Hz, 3H); MSNR (ER) m/z 512.2 (M ⁺ +1).

Example 329: Synthesis of Compound 4450, 2-(difluoromethyl)-5-(4-((4-(2-fluoro-5-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1 -yl)methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 2-(5-bromo-2-fluorophenyl)-1,3-dioxolane

5-Bromo-2-fluorobenzaldehyde (5.000 g, 24.629 mmol), p-toluenesulfonic acid (0.047 g, 0.246 mmol) and ethylene glycol (7.302 g, 29.555 mmol) were dissolved in toluene (50 ml) at room temperature, and the resulting solution heated at reflux for 18 hours, and then the reaction is completed by reducing the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane=0-10%) and concentrated to give 2-(5-bromo-2-fluorophenyl)-1,3-dioxolane (6,000 g, 98.6 %) in the form of a yellow oil.

[Step 2] Synthesis of tert-butyl 4-(3-(1,3-dioxolan-2-yl)-4-fluorophenyl)piperazine-1-carboxylate

2-(5-Bromo-2-fluorophenyl)-1,3-dioxolane (5.000 g, 20.238 mmol) obtained in step 1, tert-butyl piperazine-1-carboxylate (3.770 g, 20.238 mmol), tris(dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ , 0.185 g, 0.202 mmol), rac-BINAP (0.252 g, 0.405 mmol) and NaOBut (3.890 g, 40.476 mmol) are dissolved in toluene (50 ml) at room temperature, after which the resulting solution heated at reflux for 18 hours, and then the reaction is completed by reducing the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl 4-(3-(1,3-dioxolan-2-yl)-4-fluorophenyl) piperazine-1-carboxylate (6.950 g, 97.4%) as a brown oil.

[Step 3] Synthesis of tert-butyl 4-(4-fluoro-3-formylphenyl)piperazine-1-carboxylate

Tert-butyl 4-(3-(1,3-dioxolan-2-yl)-4-fluorophenyl)piperazine-1-carboxylate (6.950 g, 19.721 mmol) obtained in step 2 and hydrochloric acid (1.00 M solution, 59.164 ml, 59.164 mmol) was dissolved in methanol (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 3 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl 4-(4-fluoro-3-formylphenyl)piperazine-1-carboxylate (2.400 g, 39 .5%) in the form of brown oil.

[Step 4] Synthesis of tert-butyl 4-(3-(2,2-dibromovinyl)-4-fluorophenyl)piperazine-1-carboxylate

Tert-butyl 4-(4-fluoro-3-formylphenyl)piperazine-1-carboxylate (2.400 g, 7.783 mmol) obtained in step 3, carbon tetrabromide (5.162 g, 15.567 mmol) and triphenylphosphine triphenylphosphine (8.166 g, 31.133 mmol ) is dissolved in dichloromethane (50 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl 4-(3-(2,2-dibromovinyl)-4-fluorophenyl)piperazine-1- carboxylate (3.340 g, 92.4%) in the form of a brown oil.

[Step 5] Synthesis of tert-butyl 4-(3-ethynyl-4-fluorophenyl)piperazine-1-carboxylate

Tert-butyl 4-(3-(2,2-dibromovinyl)-4-fluorophenyl)piperazine-1-carboxylate (3.340 g, 7.196 mmol) obtained in step 4, and 2,3,4,6,7,8 ,9,10-octahydropyrimido[1,2-a]azepine (4.304 ml, 28.783 mmol) was dissolved in acetonitrile (50 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 16 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl 4-(3-ethynyl-4-fluorophenyl)piperazine-1-carboxylate (0.500 g, 22 .8%) in the form of a brown solid.

[Step 6] Synthesis of tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2, 3-triazol-4-yl)-4-fluorophenyl)piperazine-1-carboxylate

Tert-butyl 4-(3-ethynyl-4-fluorophenyl)piperazine-1-carboxylate (0.500 g, 1.643 mmol) prepared in step 5, 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1 ,3,4-oxadiazole (0.495 g, 1.971 mmol) obtained in step 1 of Example 2, copper(II) sulfate pentahydrate (0.004 g, 0.016 mmol) and sodium ascorbate (0.033 g, 0.164 mmol) were dissolved in tert-butanol ( 10 ml)/water (10 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3 ,4-oxadiazol-2-yl)-2-benzyl)-1H-1,2,3-triazol-4-yl)-4-fluorophenyl)piperazine-1-carboxylate (0.650 g, 69.0%) as white solid.

[Step 7] Synthesis of compound 4450

Tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-benzyl)-1H-1,2,3-triazol-4 -yl)-4-fluorophenyl)piperazine-1-carboxylate (0.650 g, 1.133 mmol) obtained in step 6 and trifluoroacetic acid (0.868 ml, 11.333 mmol) were dissolved in dichloromethane (25 ml) at room temperature, after which the resulting the solution is stirred at the same temperature for 12 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(2-fluoro-5-(piperazine -1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.530 g, 98.8%) as a yellow solid.

¹ H NMR(400 MHz, CDCl₃) δ 8.12 (d,J=8.0 Hz, 2H), 7.92 (d,J=3.6 Hz, 1H), 7.86 (dd,J=6.2, 3.1 Hz, 1H), 7.45 (d,J=8.0 Hz, 2H), 7.07-6.76 (m, 3H), 5.69 (s, 2H), 3.21 (t,J=4.9 Hz, 4H), 3.09 (dd,J=6.6, 3.5 Hz, 4H);MCNR(ER) m/z 456.5 (M⁺+1).

Example 330: Synthesis of Compound 4451, 2-(difluoromethyl)-5-(4-((4-(2-fluoro-5-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)phenyl)-1,3,4-oxadiazole

2-(Difluoromethyl)-5-(4-((4-(2-fluoro-5-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl) -1,3,4-oxadiazole (0.060 g, 0.132 mmol) obtained in step 7 of Example 329, formaldehyde (0.008 g, 0.263 mmol) and acetic acid (0.008 ml, 0.145 mmol) were dissolved in dichloromethane (5 ml) at room temperature temperature, after which sodium triacetoxyborohydride (0.056 g, 0.263 mmol) is added to the resulting solution and stirred at the same temperature for 12 hours. Water is poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove solid residue and a layer of aqueous solution, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol = 0-10%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(2-fluoro-5-(4 -methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.030 g, 48.5%) as a yellow solid .

¹ H NMR(400 MHz, CDCl₃) δ 8.10 (d,J=8.0 Hz, 2H), 7.91 (d,J=3.6 Hz, 1H), 7.84 (dd,J=6.2, 3.1 Hz, 1H), 7.43 (d,J=7.9 Hz, 2H), 7.05-6.74 (m, 3H), 5.67 (s, 2H), 3.23 (t,J=5.1 Hz, 4H), 2.61 (t,J=4.9 Hz, 4H), 2.36 (s, 3H);MCNR(ER) m/z 470.5 (M⁺+1).

The compounds of Table 103 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4451 except for the use of 2-(difluoromethyl)-5-(4-((4-(2-fluoro-5-(piperazine-1 -yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole and the reagent from Table 102.

Table 102 Example Connection no. Reagent Exit (%) 331 4452 Acetaldehyde 47 332 4453 Propan-2-one 49 333 4454 Cyclobutanone 52 334 4455 Oxetan-3-one 45

Table 103 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 331 4452 2-(difluoromethyl)-5-(4-((4-(5-(4-ethylpiperazin-1-yl)-2-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl )-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.12-8.05 (m, 2H), 7.91 (d, J =3.5 Hz, 1H), 7.83 (dd, J =6, 2, 3.1 Hz, 1H), 7.46-7.39 (m, 2H), 7.05-6.74 (m, 3H), 5.66 (s, 2H), 3.30-3 .23 (m, 4H), 2.71 (t, J =5.0 Hz, 4H), 2.55 (kv, J =7.2 Hz, 2H), 1.14 (t, J =7, 2 Hz, 3H); MSNR (ER) m/z 484.6 (M ⁺ +1). 332 4453 2-(difluoromethyl)-5-(4-((4-(2-fluoro-5-(4-isopropylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl) phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.12-8.05 (m, 2H), 7.91 (d, J =3.5 Hz, 1H), 7.83 (dd, J =6, 2, 3.1 Hz, 1H), 7.46-7.39 (m, 2H), 7.05-6.74 (m, 3H), 5.66 (s, 2H), 3.32-3 .23 (m, 4H), 2.90 (p, J =6.5 Hz, 1H), 2.81 (t, J =5.0 Hz, 4H), 1.14 (d, J =6, 5 Hz, 6H); MSNR (ER) m/z 498.6 (M ⁺ +1). 333 4454 2-(4-((4-(5-(4-cyclobutylpiperazin-1-yl)-2-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl )-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 8.08 (d, J =8.0 Hz, 2H), 7.91 (d, J =3.5 Hz, 1H), 7.83 (dd, J =6.2, 3.1 Hz, 1H), 7.42 (d, J =8.0 Hz, 2H), 7.05-6.73 (m, 3H), 5.66 (s, 2H) , 3.23 (t, J =5.0 Hz, 4H), 2.81 (p, J =8.0 Hz, 1H), 2.52 (t, J =5.0 Hz, 4H), 2 .08-1.92 (m, 4H), 1.80-1.61 (m, 2H); MSNR (ER) m/z 510.6 (M ⁺ +1). 334 4455 2-(difluoromethyl)-5-(4-((4-(2-fluoro-5-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)phenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 8.09 (d, J =8.1 Hz, 2H), 7.92 (d, J =3.6 Hz, 1H), 7.84 (dd, J =6.2, 3.1 Hz, 1H), 7.43 (d, J =8.0 Hz, 2H), 7.05-6.75 (m, 3H), 5.67 (s, 2H) , 4.66 (dt, J =14.7, 6.3 Hz, 4H), 3.54 (p, J =6.4 Hz, 1H), 3.24 (t, J =4.9 Hz, 4H), 2.50 (t, J =4.9 Hz, 4H); MSNR (ER) m/z 512.6 (M ⁺ +1).

Example 335: Synthesis of Compound 4460, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(1-methylazetidin-3-yl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 3-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2, 3-triazol-4-yl)phenyl)azetidine-1-carboxylate

Tert-butyl 3-(3-ethynylphenyl)azetidine-1-carboxylate (0.130 g, 0.505 mmol), 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.136 g, 0.505 mmol) obtained in step 1 of Example 2, sodium ascorbate (0.50 M solution in water, 0.101 ml, 0.051 mmol) and copper sulfate pentahydrate (1.00 M solution in water, 0.010 ml, 0.010 mmol ) was dissolved in tert-butanol (1.5 ml)/water (1.5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give tert-butyl 3-(3-(1-(4-(5-(difluoromethyl)-1,3 ,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)azetidine-1-carboxylate (0.221 g, 83.1%) as a white solid .

[Step 2] Synthesis of 2-(4-((4-(3-(azetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5 -(difluoromethyl)-1,3,4-oxadiazole

Tert-butyl 3-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4 -yl)phenyl)azetidine-1-carboxylate (0.221 g, 0.420 mmol) obtained in step 1 and trifluoroacetic acid (0.321 ml, 4.197 mmol) were dissolved in dichloromethane (2 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. An aqueous solution of 1N-sodium chloride is poured into the resulting reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Then, the resulting product is used without an additional purification process (2-(4-((4-(3-(azetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3 -fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole, 0.180 g, 100.6%, yellow oil).

[Step 3] Synthesis of compound 4460

2-(4-((4-(3-(Azetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)- 1,3,4-oxadiazole (0.060 g, 0.141 mmol) obtained in step 2 and formaldehyde (37.00% solution in water, 0.021 ml, 0.281 mmol) are dissolved in dichloromethane (1 ml), after which the resulting solution is stirred at room temperature for 15 minutes, and then sodium triacetoxyborohydride (0.089 g, 0.422 mmol) was added thereto, and then stirred at the same temperature for 18 hours. A saturated aqueous sodium chloride solution is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate is purified by column chromatography ( _SiO2 , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated, after which the resulting product is purified again by column chromatography (SiO2, 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(1-methylazetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)phenyl)-1,3,4-oxadiazole (0.009 g, 14.5%) in the form of a colorless oil.

¹ H NMR(400 MHz, CD₃OD) δ 8.48 (s, 1H), 8.03-7.92 (m, 2H), 7.84 (d,J=1.9 Hz, 1H), 7.73 (dt,J=7.8, 1.4 Hz, 1H), 7.62 (t,J=7.7 Hz, 1H), 7.44 (t,J=7.7 Hz, 1H), 7.36-7.30 (m, 1H), 7.24 (t,J=51.6 Hz, 1H), 5.86 (s, 2H), 4.05 (td,J=7.8, 7.4, 1.9 Hz, 2H), 3.94 (p,J=7.9 Hz, 1H), 3.63 (t,J=8.2 Hz, 2H), 2.61 (s, 3H);MCNR(ER) m/z 441.5 (M⁺+1).

The compounds of Table 105 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4460 except for the use of 2-(4-((4-(3-(azetidin-3-yl)phenyl)-1H-1, 2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole and the reagent from Table 104.

Table 104 Example Connection no. Reagent Exit (%) 336 4461 Acetone 73 337 4462 Oxetanone 66

Table 105 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 336 4461 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(1-isopropylazetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl) phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.48 (s, 1H), 8.01-7.89 (m, 2H), 7.83 (t, J=1.9 Hz, 1H), 7.72 (dt, J=7.7, 1.4 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.43 (t, J=7.7 Hz, 1H ), 7.34-7.28 (m, 1H), 7.24 (t, J=51.6 Hz, 1H), 5.85 (s, 2H), 4.02 (ddd, J=8, 8, 7.2, 1.9 Hz, 2H), 3.87 (p, J=8.3 Hz, 1H), 3.54 (td, J=7.7, 6.8, 1.8 Hz , 2H), 2.81 (dkv, J=12.7, 6.4 Hz, 1H), 1.09 (d, J=6.4 Hz, 6H); MSNR (IER) m/z 469.5 (M ⁺ + H). 337 4462 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(1-(oxetan-3-yl)azetidin-3-yl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.47 (s, 1H), 8.00-7.90 (m, 2H), 7.82 (t, J=1.8 Hz, 1H), 7.70 (dt, J=7.7, 1.4 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.41 (t, J=7.7 Hz, 1H ), 7.32 (dt, J=7.7, 1.5 Hz, 1H), 7.24 (t, J=51.6 Hz, 1H), 5.84 (s, 2H), 4.77 (t, J=6.7 Hz, 2H), 4.55 (dd, J=6.8, 5.0 Hz, 2H), 3.94-3.77 (m, 4H), 3.44- 3.34 (m, 2H); MSNR (IER) m/z 483.5 (M ⁺ + H).

Example 338: Synthesis of compound 4463 , N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1 ,2,3-triazol-4-yl)phenyl)azetidine-3-carboxamide

[Step 1] Synthesis of tert-butyl 3-((3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H -1,2,3-triazol-4-yl)phenyl)carbamoyl)azetidine-1-carboxylate

3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl )aniline (0.245 g, 0.663 mmol) prepared in step 1 of Example 36, 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (0.147 g, 0.730 mmol), 1-[bis(dimethylamino)methylene 3-oxide hexafluorophosphate ]-1H-1,2,3-triazolo[4,5-b]pyridinium (0.504 g, 1.327 mmol) and N,N-diisopropylethylamine (0.231 ml, 1.327 mmol) are dissolved in dichloromethane (5 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=100-80%) and concentrated to give tert-butyl 3-((3-(1-((5-(5-(difluoromethyl)-1 ,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)carbamoyl)azetidine-1-carboxylate (0.270 g, 73.7 %) in the form of a light yellow solid.

[Step 2] Synthesis of compound 4463

Tert-butyl 3-((3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2, 3-triazol-4-yl)phenyl)carbamoyl)azetidine-1-carboxylate (0.150 g, 0.271 mmol) obtained in step 1 is dissolved in dichloromethane (2 ml) at room temperature, followed by trifluoroacetic acid (0.624 ml, 8.144 mmol) is added to the resulting solution and stirred at the same temperature for 3 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting concentrate is purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol = 100-70%) and concentrated to give N-(3-(1-((5-( 5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)azetidin-3-carboxamide (0.115 g, 93.6%) in the form of a yellow oil.

¹ H NMR (400 MHz, CD₃OD) δ 9.28 (dd,J=2.2, 0.9 Hz, 1H), 8.54 (dd,J=8.2, 2.2 Hz, 1H), 8.50 (d,J=0.9 Hz, 1H), 8.16 (t,J=1.9 Hz, 1H), 7.66-7.57 (m, 3H), 7.43 (t,J=7.9 Hz, 1H), 7.26 (t,J=51.6 Hz, 1H), 5.93 (s, 2H), 4.39-4.25 (m, 4H), 3.86 (td,J=8.8, 7.1 Hz, 1H);MCNR(ER) m/z 453.5 (M⁺+1).

Example 339: Synthesis of compound 4464 , N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1 ,2,3-triazol-4-yl)phenyl)-1-ethyl azetidin-3-carboxamide

N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)phenyl)azetidine-3-carboxamide (0.050 g, 0.111 mmol) obtained in step 2 of Example 338 and acetaldehyde (0.010 g, 0.221 mmol) were dissolved in dichloromethane (1.5 ml) at room temperature, then Sodium triacetoxyborohydride (0.117 g, 0.553 mmol) was added to the resulting solution and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-70%) and concentrated to give N-(3-(1-((5-(5-(difluoromethyl)-1,3,4 -oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-1-ethyl azetidin-3-carboxamide (0.020 g, 37.7%) in form of a colorless oil.

¹ H NMR(400 MHz, CD₃OD) δ 9.28 (dd,J=2.2, 0.9 Hz, 1H), 8.52 (dd,J=8.2, 2.3 Hz, 1H), 8.48 (s, 1H), 8.11 (t,J=1.9 Hz, 1H), 7.65-7.56 (m, 3H), 7.41 (t,J=7.9 Hz, 1H), 7.26 (t,J=51.6 Hz, 1H), 5.93 (s, 2H), 3.92-3.85 (m, 2H), 3.72 (dd,J=8.8, 7.1 Hz, 2H), 3.66-3.55 (m, 1H), 2.84 (sq,J=7.2 Hz, 2H), 1.09 (t,J=7.2 Hz, 3H);MCNR(ER) m/z 481.6 (M⁺+1).

The compound of Table 107 was synthesized in accordance with substantially the same method as described above in the synthesis of compound 4464 except for the use of 2-(4-((4-(3-(azetidin-3-yl)phenyl)-1H-1, 2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole and the reagent from Table 106.

Table 106 Example Connection no. Reagent Exit (%) 340 4465 Oxetan-3-one 40

Table 107 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 340 4465 N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)phenyl)-1-(oxetan-3-yl)azetidine-3-carboxamide
^1H NMR (400 MHz, CD ₃ OD) δ 9.28 (dd, J =2.3, 0.8 Hz, 1H), 8.53 (dd, J =8.2, 2.2 Hz, 1H ), 8.48 (s, 1H), 8.10 (t, J =1.9 Hz, 1H), 7.63-7.55 (m, 3H), 7.41 (t, J =7, 9 Hz, 1H), 7.26 (t, J =51.6 Hz, 1H), 5.93 (s, 2H), 4.77 (t, J =6.8 Hz, 2H), 4.57 (dd, J =6.9, 5.0 Hz, 2H), 3.88 (tt, J =6.7, 5.0 Hz, 1H), 3.73-3.65 (m, 2H), 3.61-3.53 (m, 3H); MSNR (ER) m/z 509.5 (M ⁺ +1).

Example 341: Synthesis of Compound 4466, 2-(4-((4-(4-(azetidin-1-ylmethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl) -5-(difluoromethyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4- yl)benzaldehyde

2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (1.000 g, 3.715 mmol) prepared in step 1 of Example 2, and 4-ethynylbenzaldehyde (0.484 g, 3.715 mmol) dissolved in tert-butanol (5 ml)/water (5 ml) at room temperature, followed by sodium ascorbate (1.00 M solution, 0.371 ml, 0.371 mmol) and copper(II) sulfate pentahydrate (0.50 M solution, 0.074 ml, 0.037 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution is poured into the reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; dichloromethane/methanol=100-90%) and concentrated to give 4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2 -yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)benzaldehyde (1.200 g, 80.9%) as a white solid.

[Step 2] Synthesis of compound 4466

4-(1-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)benzaldehyde (0.040 g, 0.100 mmol) obtained in step 1, and azetidine hydrochloride (0.019 g, 0.200 mmol) was dissolved in dichloromethane (1.5 ml) at room temperature, after which sodium triacetoxyborohydride (0.106 g, 0.501 mmol) was added to the resulting solution and stir at the same temperature. Sodium triacetoxyborohydride (0.106 g, 0.501 mmol) was poured into the reaction mixture, and then stirred at room temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-70%) and concentrated to give 2-(4-((4-(4-(azetidin-1-ylmethyl)phenyl)-1H- 1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.030 g, 68.0%) as a white solid.

¹ H NMR(400 MHz, CD₃OD) δ 8.44 (s, 1H), 8.02-7.93 (m, 2H), 7.82 (d,J=8.1 Hz, 2H), 7.60 (t,J=7.7 Hz, 1H), 7.39 (d,J=7.9 Hz, 2H), 7.24 (t,J=51.6 Hz, 1H), 5.85 (s, 2H), 3.69 (s, 2H), 3.41-3.34 (m, 4H), 2.17 (sq,J=7.3 Hz, 2H);MCNR(ER) m/z 441.2 (M⁺+1).

The compounds of Table 109 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4466 except for the use of 4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl )-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)benzaldehyde and the reagent from Table 108.

Table 108 Example Connection no. Reagent Exit (%) 342 4467 3-fluoroazetidine 47 343 4468 3-fluoroazetidine hydrogen chloride 46 344 4469 Oxetan-3-amine 41 345 4470 1-methylazetidine-3-amine 42 346 4471 Morpholine 48 347 4472 3-fluoroazetidine hydrogen chloride 41 348 4473 1-methylpiperazine 51 349 4474 1-ethylpiperazine 52 350 4475 1-isopropylpiperazine 41 351 4476 - 39 352 4477 4,4-difluorocyclohexane-1-amine 28 368 4494 N,N-dimethylpiperidin-4-amine 48 392 4521 Pyrrolidine 50 393 4522 Dimethylamine 55 394 4523 2-oxa-6-azaspiro[3,3]heptane 64 466 4604 (S)-N,N-dimethylpyrrolidin-3-amine 56 467 4605 (R)N,N-dimethylpyrrolidin-3-amine 72 468 4606 (S)-3-fluoropyrrolidine 65 469 4607 (R)-3-fluoropyrrolidine 71 470 4608 -diethylamine 56 471 4609 Cyclopentanamine 66 472 4610 Piperidine 69 473 4611 4-methylpiperidine 65

Table 109 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 342 4467 2-(difluoromethyl)-5-(3-fluoro-4-((4-(4-((3-fluoroazetidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (d, J = 2.5 Hz, 1H), 8.03-7.92 (m, 2H), 7.86-7.79 (m , 2H), 7.60 (t, J =7.7 Hz, 1H), 7.43 (dd, J =20.4, 8.1 Hz, 2H), 7.24 (t, J =51, 6 Hz, 1H), 5.85 (s, 2H), 5.23 (t, J =4.6 Hz, 0.5H), 5.09 (s, 0.5H), 3.74 (s, 2H), 3.71-3.59 (m, 2H), 3.38-3.25 (m, 2H); MSNR (ER) m/z 459.2 (M ⁺ +1). 343 4468 N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) benzyl)cyclobutanamine
¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.02-7.93 (m, 2H), 7.82 (d, J = 8.2 Hz, 2H), 7.60 (t, J =7.6 Hz, 1H), 7.44 (d, J =8.2 Hz, 2H), 7.24 (t, J =51.6 Hz, 1H), 5, 86 (s, 2H), 3.74 (s, 2H), 3.32-3.27 (m, 1H), 2.25-2.15 (m, 2H), 1.94-1.64 ( m, 4H); MSNR (ER) m/z 455.2 (M ⁺ +1). 344 4469 N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) benzyl)oxetane-3-amine
¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.02-7.93 (m, 2H), 7.82 (d, J = 8.2 Hz, 2H), 7.60 (t, J =7.7 Hz, 1H), 7.43 (d, J =8.1 Hz, 2H), 7.24 (t, J =51.6 Hz, 1H), 5, 86 (s, 2H), 4.72 (t, J =6.8 Hz, 2H), 4.45 (t, J =6.4 Hz, 2H), 4.03 (p, J =6.7 Hz, 1H), 3.74 (s, 2H); MSNR (ER) m/z 457.3 (M ⁺ +1). 345 4470 N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) benzyl)-1-methylazetidine-3-amine
^1H NMR (400 MHz, CD ₃ OD) δ 8.45 (s, 1H), 8.03-7.93 (m, 2H), 7.87-7.81 (m, 2H), 7.61 (t, J =7.7 Hz, 1H), 7.45 (d, J =8.2 Hz, 2H), 7.38-7.09 (m, 1H), 5.86 (s, 2H) , 4.19 (s, 2H), 3.87-3.66 (m, 5H), 2.88 (s, 3H); MSNR (ER) m/z 470.5 (M ⁺ +1). 346 4471 4-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) benzyl)morpholine
¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.02-7.93 (m, 2H), 7.82 (d, J = 8.2 Hz, 2H), 7.60 (t, J =7.7 Hz, 1H), 7.44 (d, J =8.1 Hz, 2H), 7.24 (t, J =51.6 Hz, 1H), 5, 85 (s, 2H), 3.75-3.68 (m, 4H), 3.57 (s, 2H), 2.49 (t, J =4.7 Hz, 4H); MSNR (ER) m/z 471.2 (M ⁺ +1). 347 4472 2-(difluoromethyl)-5-(4-((4-(4-((4,4-difluoropiperidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl )-3-fluorophenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.02-7.93 (m, 2H), 7.82 (d, J = 8.2 Hz, 2H), 7.61 (t, J =7.6 Hz, 1H), 7.44 (d, J =8.1 Hz, 2H), 7.24 (t, J =51.6 Hz, 1H), 5, 86 (s, 2H), 3.62 (s, 2H), 2.60 (d, J =5.9 Hz, 4H), 2.05-1.93 (m, 4H); MSNR (ER) m/z 505.2 (M ⁺ +1). 348 4473 2-(difluoromethyl)-5-(3-fluoro-4-((4-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.02-7.93 (m, 2H), 7.82 (d, J = 8.3 Hz, 2H), 7.60 (t, J =7.6 Hz, 1H), 7.43 (d, J =8.2 Hz, 2H), 7.24 (t, J =51.6 Hz, 1H), 5, 85 (s, 2H), 3.59 (s, 2H), 2.61 (d, J =53.9 Hz, 8H), 2.31 (s, 3H); MSNR (ER) m/z 484.1 (M ⁺ +1). 349 4474 2-(difluoromethyl)-5-(4-((4-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)- 3-fluorophenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.03-7.93 (m, 2H), 7.82 (d, J = 8.2 Hz, 2H), 7.60 (t, J =7.6 Hz, 1H), 7.44 (d, J =8.1 Hz, 2H), 7.24 (t, J =51.6 Hz, 1H), 5, 86 (s, 2H), 3.59 (s, 2H), 2.75-2.37 (m, 10H), 1.12 (t, J =7.2 Hz, 3H); MSNR (ER) m/z 498.3 (M ⁺ +1). 350 4475 2-(difluoromethyl)-5-(3-fluoro-4-((4-(4-((4-isopropylpiperazin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)phenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.03-7.92 (m, 2H), 7.85-7.79 (m, 2H), 7.61 (t, J =7.6 Hz, 1H), 7.44 (d, J =8.2 Hz, 2H), 7.24 (t, J =51.6 Hz, 1H), 5.85 (s , 2H), 3.59 (s, 2H), 2.78-2.47 (m, 9H), 1.12 (d, J =6.5 Hz, 6H); MSNR (ER) m/z 512.1 (M ⁺ +1). 351 4476 (4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl) methanol
^1H NMR (400 MHz, CD ₃ OD) δ 8.43 (s, 1H), 8.03-7.93 (m, 2H), 7.86-7.80 (m, 2H), 7.60 (t, J =7.6 Hz, 1H), 7.45 (d, J =8.1 Hz, 2H), 7.24 (t, J =51.6 Hz, 1H), 5.86 (s , 2H), 4.65 (s, 2H); MSNR (ER) m/z 402.4 (M ⁺ +1). 352 4477 N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) benzyl)-4,4-difluorocyclohexane-1-amine
¹ H NMR (400 MHz, CD ₃ OD) δ 8.43 (s, 1H), 8.00-7.94 (m, 2H), 7.82 (d,=8.32 Hz, 2H), 7 .60 (t, J =7.48 Hz, 1H), 7.46 (d, J =8.28 Hz, 2H), 7.24 (t, J =51.6 Hz, 1H), 5.85 (s, 2H), 3.84 (s, 2H), 2.65-2.69 (m, 1H), 2.17-1.99 (m, 4H), 1.95-1.95 (m , 2H), 1.61-1.52 (m, 2H); MSNR (ER) m/z 519.5 (M ⁺ +1). 368 4494 1-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) benzyl)-N,N-dimethylpiperidin-4-amine
^1H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.03-7.92 (m, 2H), 7.85-7.78 (m, 2H), 7.60 (t, J =7.7 Hz, 1H), 7.46-7.39 (m, 2H), 7.24 (t, J =51.6 Hz, 1H), 5.85 (s, 2H) , 3.56 (s, 2H), 3.00 (d, J =11.7 Hz, 2H), 2.31 (s, 6H), 2.28-2.19 (m, 1H), 2, 06 (t, J =11.3 Hz, 2H), 1.93-1.84 (m, 2H), 1.56 (kvd, J =12.3, 3.8 Hz, 2H); MSNR (ER) m/z 512.3 (M ⁺ +1). 392 4521 2-(difluoromethyl)-5-(3-fluoro-4-((4-(4-(pyrrolidin-1-ylmethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl) -1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.03-7.93 (m, 2H), 7.83 (d, J = 8.0 Hz, 2H), 7.60 (t, J =7.7 Hz, 1H), 7.45 (d, J =8.0 Hz, 2H), 7.24 (t, J =51.6 Hz, 1H), 5, 86 (s, 2H), 3.71 (s, 2H), 2.67-2.56 (m, 4H), 1.90-1.79 (m, 4H); MSNR (ER) m/z 455.3 (M ⁺ +1). 393 4522 1-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) phenyl)-N,N-dimethylmethanamine
¹ H NMR (400 MHz, CD ₃ OD) δ 8.45 (s, 1H), 8.02-7.93 (m, 2H), 7.84 (d, J =7.9 Hz, 2H), 7.60 (t, J =7.6 Hz, 1H), 7.42 (d, J =8.0 Hz, 2H), 7.24 (t, J =51.6 Hz, 2H), 5, 86 (s, 2H), 3.55 (s, 2H), 2.29 (s, 6H); MSNR (ER) m/z 429.4 (M ⁺ +1). 394 4523 6-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) benzyl)-2-oxa-6-azaspiro[3,3]heptane
¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.03-7.93 (m, 2H), 7.81 (d, J = 8.0 Hz, 2H), 7.60 (t, J =7.6 Hz, 1H), 7.41-7.09 (m, 3H), 5.85 (s, 2H), 4.75 (s, 4H), 3.62 (s, 2H), 3.47 (s, 4H); MSNR (ER) m/z 483.5 (M ⁺ +1). 466 4604 (S)-1-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol- 4-yl)benzyl)-N,N-dimethylpyrrolidin-3-amine
¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 3H), 8.02-7.93 (m, 6H), 7.82 (d, J=8.2 Hz, 6H), 7.60 (t, J=7.7 Hz, 3H), 7.44 (d, J=8.2 Hz, 6H), 7.24 (t, J=51.6 Hz, 1H), 5, 85 (s, 6H), 3.68 (dd, J=32.5, 12.9 Hz, 7H), 3.33 (dt, J=3.3, 1.6 Hz, 75H), 2.96 -2.83 (m, 1H), 2.82-2.72 (m, 1H), 2.58 (dd, J=15.7, 9.0 Hz, 1H), 2.44-2.29 (m, 1H), 2.25 (s, 2H), 2.13-1.96 (m, 1H), 2.10-1.77 (m, 7H), 1.85-1.69 (m , 1H); MSNR (ER) m/z 498.34 (M ⁺ +1). 467 4605 (R)-1-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol- 4-yl)benzyl)-N,N-dimethylpyrrolidin-3-amine
¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 7.98 (dd, J=10.7, 9.0 Hz, 1H), 7.82 (d, J=8 .2 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.24 (t, J=51.6 Hz, 1H), 5.85 (s, 1H), 4.87 (s, 74H), 4.60 (s, 1H), 3, 77-3.48 (m, 2H), 2.96-2.83 (m, 1H), 2.78 (dd, J=14.0, 8.7 Hz, 1H), 2.58 (dd, J=16.0, 9.1 Hz, 1H), 2.34 (d, J=23.4 Hz, 1H), 2.25 (s, 3H), 2.03 (d, J=6.7 Hz, 1H), 1.76 (s, 1H); MSNR (ER) m/z 498.34 (M ⁺ +1). 468 4606 (S)-2-(difluoromethyl)-5-(3-fluoro-4-((4-(4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, J=3.4 Hz, 1H), 8.03-7.92 (m, 2H), 7.82 (d, J=8 .2 Hz, 2H), 7.60 (t, J=7.7 Hz, 1H), 7.45 (d, J=8.1 Hz, 2H), 7.24 (t, J=51.6 Hz, 1H), 5.86 (s, 2H), 5.31-5.08 (m, J=55.7 Hz, 1H), 3.71 (dd, J=29.6, 12.8 Hz , 2H), 2.99-2.82 (m, 2H), 2.72 (ddd, J=30.7, 11.8, 5.1 Hz, 1H), 2.48 (dd, J=15 ,1, 8.2 Hz, 1H), 2.34-2.13 (m, 1H), 2.01 (dd, J=26.1, 20.1 Hz, 1H); MSNR (ER) m/z 473.32 (M ⁺ +1). 469 4607 (R)-2-(difluoromethyl)-5-(3-fluoro-4-((4-(4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, J=3.4 Hz, 1H), 8.03-7.92 (m, 2H), 7.82 (d, J=8 .2 Hz, 2H), 7.60 (t, J=7.6 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H), 7.24 (t, J=51.6 Hz, 1H), 5.86 (s, 2H), 5.29-5.08 (m, J=55.7 Hz, 1H), 3.71 (dd, J=29.6, 12.8 Hz , 2H), 2.99-2.82 (m, 2H), 2.72 (ddd, J=30.4, 11.6, 4.9 Hz, 1H), 2.48 (dd, J=16 ,0, 8.1 Hz, 1H), 2.31-2.14 (m, 1H), 2.10-1.96 (m, 1H); MSNR (ER) m/z 473.32 (M ⁺ +1). 470 4608 N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) benzyl)-N-ethylethaneamine
¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 7.98 (dd, J=10.7, 9.1 Hz, 2H), 7.82 (d, J=8 .2 Hz, 2H), 7.60 (t, J=7.7 Hz, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.24 (t, J=51.6 Hz, 1H), 5.86 (s, 2H), 3.68 (s, 2H), 2.61 (dd, J=14.6, 7.5 Hz, 4H), 1.12 (t, J =7.2 Hz, 6H); MSNR (ER) m/z 457.30 (M ⁺ +1). 471 4609 N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) benzyl)cyclopentanamine
¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.02-7.92 (m, 2H), 7.83 (d, J=8.2 Hz, 2H), 7.60 (t, J=7.7 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 7.24 (t, J=51.6 Hz, 1H), 5, 85 (s, 2H), 3.82 (s, 2H), 3.20-3.08 (m, 1H), 1.95 (dt, J=10.6, 6.3 Hz, 2H), 1 .82-1.67 (m, 2H), 1.65-1.51 (m, 2H), 1.50-1.37 (m, 2H); MSNR (ER) m/z 469.35 (M ⁺ +1). 472 4610 2-(difluoromethyl)-5-(3-fluoro-4-((4-(4-(piperidin-1-ylmethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl) -1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 2H), 8.02-7.92 (m, 2H), 7.82 (d, J=8.2 Hz, 2H), 7.60 (t, J=7.7 Hz, 1H), 7.43 (d, J=8.2 Hz, 2H), 7.24 (t, J=51.6 Hz, 1H), 5, 86 (s, 2H), 3.57 (s, J=29.2 Hz, 2H), 2.59-2.40 (m, 3H), 1.70-1.56 (m, 5H), 1 .49 (s, 2H); MSNR (ER) m/z 469.35 (M ⁺ +1). 473 4611 2-(difluoromethyl)-5-(3-fluoro-4-((4-(4-((4-methylpiperidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 7.98 (dd, J=10.8, 9.1 Hz, 2H), 7.82 (d, J=8 .2 Hz, 2H), 7.60 (t, J=7.6 Hz, 1H), 7.43 (d, J=8.2 Hz, 2H), 7.24 (t, J=51.6 Hz, 1H), 5.86 (s, 2H), 3.59 (s, 2H), 2.94 (d, J=12.2 Hz, 2H), 2.20-2.01 (m, 2H ), 1.67 (d, J=13.0 Hz, 2H), 1.49-1.36 (m, 1H), 1.36-1.20 (m, 2H), 0.95 (d, J=6.4 Hz, 3H); MSNR (ER) m/z 483.38 (M ⁺ +1).

Examples 353 and 364: Synthesis of compounds 4478 and 4490, (1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-phenyl- 1H-1,2,3-triazol-5-yl)methanol ( 4478 ), 1-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2 -yl)methyl)-4-phenyl-1H-1,2,3-triazol-5-yl)-N,N-dimethylmethanamine ( 4490 )

[Step 1] Synthesis of 1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-phenyl-1H-1,2,3 -triazole-5-carbaldehyde

3-phenylpropiolaldehyde (0.050 g, 0.384 mmol) and 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.097 g, 0.384 mmol) obtained in step 1 of Example 16 was dissolved in toluene (2 ml) at room temperature, after which the resulting solution was stirred at 80°C for 18 hours, and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, after which the resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give 1-((5-(5-(difluoromethyl)- 1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-phenyl-1H-1,2,3-triazole-5-carbaldehyde (0.035 g, 23.8%) as brown oils

[Step 2] Synthesis of compounds 4478 and 4490

1-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-phenyl-1H-1,2,3-triazol-5- carbaldehyde (0.090 g, 0.235 mmol) obtained in step 1 and dimethylamine (2.00 M solution, 0.235 ml, 0.471 mmol) are dissolved in dichloromethane (2 ml) at room temperature, followed by sodium triacetoxyborohydride (0.249 g, 1.177 mmol ) is added to the resulting solution and stirred at the same temperature. Sodium triacetoxyborohydride (0.249 g, 1.177 mmol) was poured into the reaction mixture, and then stirred at room temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-70%) and concentrated to give (1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2- yl)pyridin-2-yl)methyl)-4-phenyl-1H-1,2,3-triazol-5-yl)methanol (0.010 g, 11.1%) and 1-(1-((5-( 5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-phenyl-1H-1,2,3-triazol-5-yl)-N, N- dimethylmethanamine (0.012 g, 12.4%) in the form of a colorless oil.

4478: ^1H NMR (400 MHz, CD ₃ OD) δ 9.16 (dd, J =2.3, 0.9 Hz, 1H), 8.42 (dd, J =8.2, 2.3 Hz , 1H), 7.50 (s, 5H), 7.40-7.36 (m, 1H), 7.36-7.11 (m, 1H), 5.81 (s, 2H), 4, 63 (s, 2H); MSNR (ER) m/z 435.3 (M ⁺ +1).

4490: ^1H NMR (400 MHz, CD ₃ OD) δ 9.15 (dd, J =2.2, 0.9 Hz, 1H), 8.41 (dd, J =8.2, 2.3 Hz , 1H), 7.53-7.42 (m, 5H), 7.34 (dd, J =8.2, 0.9 Hz, 1H), 7.25 (t, J =51.6 Hz, 1H), 5.79 (s, 2H), 3.61 (s, 2H), 2.24 (s, 6H); MSNR (ER) m/z 412.5 (M ⁺ +1).

Examples 354 and 365: Synthesis of compounds 4479 and 4491, (1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-phenyl-1H-1, 2,3-triazol-5-yl)methanol ( 4479 ), 1-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4- phenyl-1H-1,2,3-triazol-5-yl)-N,N-dimethylmethanamine ( 4491 )

[Step 1] Synthesis of 1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-phenyl-1H-1,2,3-triazol-5 -carbaldehyde

3-phenylpropiolaldehyde (0.050 g, 0.384 mmol) and 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.103 g, 0.384 mmol) obtained in step 1 Example 2 was dissolved in toluene (2 ml) at room temperature, after which the resulting solution was stirred at 80°C for 18 hours, and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, after which the resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give 1-(4-(5-(difluoromethyl)-1 ,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-phenyl-1H-1,2,3-triazole-5-carbaldehyde (0.040 g, 26.1%) as a light yellow solid .

[Step 2] Synthesis of compounds 4479 and 4491

4-(1-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)benzaldehyde (0.030 g, 0.075 mmol) obtained in step 1, and dimethylamine (2.00 M solution, 0.075 ml, 0.150 mmol) was dissolved in dichloromethane (1 ml) at room temperature, after which sodium triacetoxyborohydride (0.080 g, 0.376 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-70%) and concentrated to give (1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl )-2-fluorobenzyl)-4-phenyl-1H-1,2,3-triazol-5-yl)methanol (0.008 g, 26.5%) and 1-(1-(4-(5-(difluoromethyl) -1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-phenyl-1H-1,2,3-triazol-5-yl)-N,N-dimethylmethanamine (0.009 g, 28.0 %) in the form of a white solid.

4479: ^1H NMR (400 MHz, CD ₃ OD) δ 7.85 (dd, J =8.0, 1.7 Hz, 1H), 7.80 (dd, J =10.2, 1.7 Hz , 1H), 7.53 (dd, J =5.0, 2.0 Hz, 3H), 7.47-7.41 (m, 2H), 7.36-7.08 (m, 2H), 5.75 (s, 2H), 4.60 (s, 2H); MSNR (ER) m/z 402.4 (M ⁺ +1).

4491: ^1H NMR (400 MHz, CD ₃ OD) δ 7.84 (dd, J =8.0, 1.7 Hz, 1H), 7.79 (dd, J =10.2, 1.7 Hz , 1H), 7.58-7.47 (m, 3H), 7.44-7.37 (m, 2H), 7.37-7.08 (m, 2H), 5.72 (s, 2H ), 3.57 (s, 2H), 2.22 (s, 6H); MSNR (ER) m/z 429.4 (M ⁺ +1).

Example 357: Synthesis of Compound 4483, 2-(difluoromethyl)-5-(4-((4-(2-fluoro-3-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 2-(3-bromo-2-fluorophenyl)-1,3-dioxolane

3-Bromo-2-fluorobenzaldehyde (5.000 g, 24.629 mmol), p-toluenesulfonic acid (0.047 g, 0.246 mmol) and ethylene glycol (7.302 g, 29.555 mmol) were dissolved in toluene (50 ml) at room temperature, and the resulting solution heated at reflux for 18 hours, and then the reaction is completed by reducing the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane=0-10%) and concentrated to give 2-(3-bromo-2-fluorophenyl)-1,3-dioxolane (6,000 g, 98.6 %) in the form of a yellow oil.

[Step 2] Synthesis of tert-butyl 4-(3-(1,3-dioxolan-2-yl)-2-fluorophenyl)piperazine-1-carboxylate

2-(3-bromo-2-fluorophenyl)-1,3-dioxolane (5.000 g, 20.238 mmol) obtained in step 1, tert-butyl piperazine-1-carboxylate (3.769 g, 20.238 mmol), tris(dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ , 0.185 g, 0.202 mmol), rac-BINAP (0.252 g, 0.405 mmol) and sodium tert-butoxide (3.890 g, 40.476 mmol) are dissolved in toluene (50 ml) at room temperature, after whereupon the resulting solution is heated at reflux for 18 hours, and then the reaction is completed by lowering the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl 4-(3-(1,3-dioxolan-2-yl)-2-fluorophenyl) piperazine-1-carboxylate (3.950 g, 53.6%) as a brown oil.

[Step 3] Synthesis of tert-butyl 4-(2-fluoro-3-formylphenyl)piperazine-1-carboxylate

Tert-butyl 4-(3-(1,3-dioxolan-2-yl)-2-fluorophenyl)piperazine-1-carboxylate (3.950 g, 11.209 mmol) obtained in step 2 and hydrochloric acid (1.00 M solution, 33.626 ml, 33.626 mmol) was dissolved in methanol (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 3 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl 4-(2-fluoro-3-formylphenyl)piperazine-1-carboxylate (2.900 g, 83 .9%) in the form of brown oil.

[Step 4] Synthesis of tert-butyl 4-(3-(2,2-dibromovinyl)-2-fluorophenyl)piperazine-1-carboxylate

Tert-butyl 4-(2-fluoro-3-formylphenyl)piperazine-1-carboxylate (2.900 g, 9.405 mmol) obtained in step 3, carbon tetrabromide (6.238 g, 18.810 mmol) and triphenylphosphine triphenylphosphine (9.867 g, 37.620 mmol ) is dissolved in dichloromethane (50 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl 4-(3-(2,2-dibromovinyl)-2-fluorophenyl)piperazine-1- carboxylate (2.100 g, 48.1%) in the form of a brown oil.

[Step 5] Synthesis of tert-butyl 4-(3-ethynyl-2-fluorophenyl)piperazine-1-carboxylate

Tert-butyl 4-(3-(2,2-dibromovinyl)-2-fluorophenyl)piperazine-1-carboxylate (2.100 g, 4.524 mmol) obtained in step 4, and 2,3,4,6,7,8 ,9,10-Octahydropyrimido[1,2-a]azepine (2.706 ml, 18.097 mmol) was dissolved in acetonitrile (50 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 16 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl 4-(3-ethynyl-2-fluorophenyl)piperazine-1-carboxylate (0.570 g, 41 .4%) in the form of a yellow oil.

[Step 6] Synthesis of tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazole -4-yl)-2-fluorophenyl)piperazine-1-carboxylate

Tert-butyl 4-(3-ethynyl-2-fluorophenyl)piperazine-1-carboxylate (0.570 g, 1.873 mmol) prepared in step 5, 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1 ,3,4-oxadiazole (0.565 g, 2.247 mmol) obtained in step 1 of Example 16, copper(II) sulfate pentahydrate (0.005 g, 0.019 mmol) and sodium ascorbate (0.037 g, 0.187 mmol) were dissolved in tert-butanol ( 10 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3 ,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-2-fluorophenyl)piperazine-1-carboxylate (0.450 g, 43.3%) in the form of a yellow oil.

[Step 7] Synthesis of 2-(difluoromethyl)-5-(4-((4-(2-fluoro-3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)phenyl)-1,3,4-oxadiazole

Tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl) -2-fluorophenyl)piperazine-1-carboxylate (0.450 g, 0.810 mmol) obtained in step 6 and trifluoroacetic acid (0.924 g, 8.100 mmol) were dissolved in dichloromethane (25 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. A saturated aqueous sodium chloride solution is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous solution, then dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(2-fluoro-3-(piperazine -1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.260 g, 70.5%) as a white solid.

[Step 8] Synthesis of compound 4483

2-(Difluoromethyl)-5-(4-((4-(2-fluoro-3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl) -1,3,4-oxadiazole (0.060 g, 0.132 mmol) obtained in step 7, formaldehyde (0.008 g, 0.263 mmol) and acetic acid (0.008 ml, 0.145 mmol) are dissolved in dichloromethane (5 ml) at room temperature, after which sodium triacetoxyborohydride (0.056 g, 0.263 mmol) is added to the resulting solution and stirred at the same temperature for 12 hours. Water is poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove solid residue and a layer of aqueous solution, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(2-fluoro-3-(4 -methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.030 g, 48.5%) as a yellow solid .

¹ H NMR(400 MHz, CDCl₃) δ 8.13 (d,J=7.9 Hz, 2H), 7.92 (kv,J=5.5, 3.7 Hz, 2H), 7.46 (d,J=7.9 Hz, 2H), 7.17 (t,J=7.9 Hz, 1H), 7.06-6.77 (m, 2H), 5.69 (s, 2H), 3.17 (t,J=4.7 Hz, 4H), 2.70 (s, 4H), 2.41 (s, 3H);MCNR(ER) m/z 470.5 (M⁺+1).

The compounds of Table 111 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4483 except for the use of 2-(difluoromethyl)-5-(4-((4-(2-fluoro-3-(piperazine-1 -yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole and the reagent from Table 110.

Table 110 Example Connection no. Reagent Exit (%) 358 4484 Acetaldehyde 47 359 4485 Cyclobutanone 52 360 4486 Oxetan-3-one 45

Table 111 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 358 4484 2-(difluoromethyl)-5-(4-((4-(5-(4-ethylpiperazin-1-yl)-2-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl )-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (d, J =7.9 Hz, 2H), 7.90 (t, J =5.8 Hz, 2H), 7.44 (d, J =7.9 Hz, 2H), 7.15 (t, J =7.9 Hz, 1H), 7.05-6.76 (m, 2H), 5.68 (s, 2H), 3.14 (t, J =5.0 Hz, 4H), 2.65 (s, 4H), 2.50 (kv, J =8.1, 7.3 Hz, 2H), 1.12 (t, J = 7.2 Hz, 3H); MSNR (ER) m/z 484.5 (M ⁺ +1). 359 4485 2-(4-((4-(5-(4-cyclobutylpiperazin-1-yl)-2-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl )-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (d, J = 7.9 Hz, 2H), 7.91 (q, J = 5.7, 4.4 Hz, 2H), 7.45 (d, J =7.9 Hz, 2H), 7.16 (t, J =7.9 Hz, 1H), 7.04-6.77 (m, 2H), 5.68 (s, 2H) , 3.13 (t, J = 4.9 Hz, 4H), 2.82 (p, J = 7.6 Hz, 1H), 2.53 (s, 4H), 2.06 (sq, J = 8.4 Hz, 2H), 1.93 (kv, J =10.0 Hz, 2H), 1.70 (dt, J =19.3, 9.5 Hz, 2H); MSNR (ER) m/z 510.6 (M ⁺ +1). 360 4486 2-(difluoromethyl)-5-(4-((4-(2-fluoro-5-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, J = 8.0 Hz, 2H), 7.98-7.88 (m, 2H), 7.46 (d, J = 8, 0 Hz, 2H), 7.18 (t, J = 7.9 Hz, 1H), 7.05-6.77 (m, 2H), 5.69 (s, 2H), 4.73-4, 66 (m, 4H), 3.64-3.56 (m, 1H), 3.17 (t, J = 4.9 Hz, 4H), 2.55 (s, 4H), 1.25 (s , 1H); MSNR (ER) m/z 512.5 (M ⁺ +1).

Example 361: Synthesis of Compound 4487, 2-(difluoromethyl)-5-(4-((4-(3-(difluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)- 1,3,4-oxadiazole

[Step 1] Synthesis of 1-(difluoromethyl)-3-ethynylbenzene

3-(difluoromethyl)benzaldehyde (0.500 g, 3.202 mmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (0.577 ml, 3.843 mmol) and potassium carbonate (0.885 g, 6.405 mmol) are dissolved in methanol (25 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 12 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting concentrate is poured into water, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 1-(difluoromethyl)-3-ethynylbenzene (0.300 g, 61.6%) as a yellow oil.

[Step 2] Synthesis of compound 4487

1-(Difluoromethyl)-3-ethynylbenzene (0.100 g, 0.657 mmol) obtained in step 1, 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.165 g, 0.657 mmol) obtained in step 1 of example 1, copper(II) sulfate pentahydrate (0.002 g, 0.007 mmol) and sodium ascorbate (0.013 g, 0.066 mmol) were dissolved in tert-butanol (10 ml)/water (10 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(3-(difluoromethyl)phenyl)- 1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.260 g, 98.1%) as a white solid.

¹ H NMR(400 MHz, CDCl₃) δ 8.10 (d,J=7.9 Hz, 2H), 7.92 (d,J=7.7 Hz, 2H), 7.84 (s, 1H), 7.46 (t,J=7.0 Hz, 4H), 7.07-6.47 (m, 2H), 5.67 (s, 2H);MCNR(ER) m/z (M⁺+1).

Example 362: Synthesis of Compound 4488, 2-(difluoromethyl)-5-(4-((4-(3-(difluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3- fluorophenyl)-1,3,4-oxadiazole

1-(Difluoromethyl)-3-ethynylbenzene (0.100 g, 0.657 mmol) prepared in Step 1 of Example 361, 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4- Oxadiazole (0.177 g, 0.657 mmol) obtained in step 1 of Example 2, copper(II) sulfate pentahydrate (0.002 g, 0.007 mmol) and sodium ascorbate (0.013 g, 0.066 mmol) are dissolved in tert-butanol (10 ml)/water (10 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(3-(difluoromethyl)phenyl)- 1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-1,3,4-oxadiazole (0.250 g, 90.3%) as a white solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.98-7.83 (m, 5H), 7.54-7.41 (m, 3H), 7.08-6.79 (m, 1H), 6.79-6.49 (m , 1H), 5.73 (d,J=1.1 Hz, 2H);MCNR(ER) m/z (M⁺+1).

Example 371: Synthesis of compound 4497 , 2-amino-N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl) -1H-1,2,3-triazol-4-yl)phenyl)-2-methylpropanamide

Tert-butyl (1-((3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2 ,3-triazol-4-yl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate (0.030 g, 0.054 mmol) obtained in Example 369 was dissolved in dichloromethane (0.5 ml) at room temperature, after which trifluoroacetic acid (0.124 ml, 1.623 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. The solvent is removed from the reaction mixture under reduced pressure, after which a saturated aqueous solution of sodium hydrogen carbonate is poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-70%) and concentrated to give 2-amino-N-(3-(1-((5-(5-(difluoromethyl)-1 ,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-methylpropanamide (0.017 g, 69.2%) in form of a colorless oil.

¹ H NMR(400 MHz, CD₃OD) δ 9.28 (dd,J=2.2, 0.9 Hz, 1H), 8.53 (dd,J=8.2, 2.2 Hz, 1H), 8.49 (s, 1H), 8.10 (t,J=1.9 Hz, 1H), 7.66-7.55 (m, 3H), 7.43 (t,J=7.9 Hz, 1H), 7.26 (t,J=51.6 Hz, 1H), 5.93 (s, 2H), 1.45 (s, 6H);MCNR(ER) m/z 455.3 (M⁺+1).

Example 372: Synthesis of compound 4498 , 1-amino-N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl) -1H-1,2,3-triazol-4-yl)phenyl)cyclobutane-1-carboxamide

Tert-butyl (1-((3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2 ,3-triazol-4-yl)phenyl)carbamoyl)cyclobutyl)carbamate (0.030 g, 0.053 mmol) obtained in Example 370 was dissolved in dichloromethane (0.5 ml) at room temperature, followed by trifluoroacetic acid (0.122 ml, 1.589 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, after which a saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-70%) and concentrated to give 1-amino-N-(3-(1-((5-(5-(difluoromethyl)-1 ,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)cyclobutan-1-carboxamide (0.018 g, 72.9%) in the form of a colorless oil.

¹ H NMR (400 MHz, CD₃OD) δ 9.28 (dt,J=2.8, 1.4 Hz, 1H), 8.53 (dd,J=8.2, 2.2 Hz, 1H), 8.49 (s, 1H), 8.11 (t,J=1.9 Hz, 1H), 7.66-7.54 (m, 3H), 7.47-7.12 (m, 2H), 5.93 (s, 2H), 2.76-2, 64 (m, 2H), 2.59 (ddd,J=13.2, 9.1, 4.7 Hz, 1H), 2.33 (ddd,J=12.6, 10.1, 8.1 Hz, 1H), 2.12-1.91 (m, 2H);MCNR(ER) m/z 467.3 (M⁺+1).

Example 373: Synthesis of Compound 4499, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)- 1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 2-(2,2-dibromovinyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate

Tert-butyl 2-formyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (1.000 g, 3.741 mmol), carbon tetrabromide (2.481 g, 7.481 mmol) and triphenylphosphine triphenylphosphine (3.924 g , 14.962 mmol) was dissolved in dichloromethane (100 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl 2-(2,2-dibromovinyl)-4,7-dihydrothieno[2,3-c ]pyridine-6(5H)-carboxylate (1.100 g, 69.5%) as a yellow solid.

[Step 2] Synthesis of tert-butyl 2-ethynyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate

Tert-butyl 2-(2,2-dibromovinyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (1.100 g, 2.599 mmol) obtained from step 1 and 2,3 ,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (1.555 ml, 10.398 mmol) was dissolved in acetonitrile (25 ml) at room temperature, after which the resulting solution was stirred at the same temperature in within 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl 2-ethynyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H )-carboxylate (0.180 g, 26.3%) in the form of a colorless oil.

[Step 3] Synthesis of tert-butyl 2-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazole -4-yl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-carboxylate

Tert-butyl 2-ethynyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (0.180 g, 0.684 mmol) prepared in step 2, 2-(4-(azidomethyl)-3 -fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.184 g, 0.684 mmol) obtained in step 1 of example 2, copper(II) sulfate pentahydrate (0.002 g, 0.007 mmol) and sodium ascorbate (0.014 g, 0.068 mmol) was dissolved in tert-butanol (10 ml)/water (10 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl 2-(1-(4-(5-(difluoromethyl)-1,3,4- Oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (0.310 g , 85.2%) in the form of a yellow solid.

[Step 4] Synthesis of compound 4499

Tert-butyl 2-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) -4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (0.310 g, 0.582 mmol) obtained in step 3 and trifluoroacetic acid (0.446 ml, 5.821 mmol) are dissolved in dichloromethane (50 ml ) at room temperature, after which the resulting solution is stirred at the same temperature for 6 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(4.5, 6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.070 g, 27 .8%) in the form of a white solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.86 (dd,J=8.6, 5.7 Hz, 2H), 7.68 (s, 1H), 7.41 (t,J=7.7 Hz, 1H), 7.07-6.76 (m, 2H), 5.66 (s, 2H), 3.99 (s, 2H), 3.09 (t,J=5.8 Hz, 2H), 2.61 (t,J=6.0 Hz, 2H), 2.07 (s, 1H);MCNR(ER) m/z (M⁺+1).

Example 374: Synthesis of Compound 4500, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2 -yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

2-(difluoromethyl)-5-(3-fluoro-4-((4-(4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-1H-1,2,3 -triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.040 g, 0.093 mmol) prepared in step 4 of Example 373, formaldehyde (0.006 g, 0.185 mmol) and acetic acid (0.006 ml, 0.102 mmol) was dissolved in dichloromethane (5 ml) at room temperature, after which sodium triacetoxyborohydride (0.039 g, 0.185 mmol) was added to the resulting solution and stirred at the same temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution is poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove solid residue and a layer of aqueous solution, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(6-methyl- 4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole ( 0.010 g, 24.2%) as a white solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.93-7.84 (m, 2H), 7.67 (s, 1H), 7.44 (t,J=7.7 Hz, 1H), 7.07 (s, 1H), 6.92 (t,J=51.7 Hz, 1H), 5.68 (s, 2H), 3.68 (s, 2H), 2.78 (s, 4H), 2.52 (s, 3H);MCNR(ER) m/z 447.4 (M⁺+1).

The compound of Table 113 was synthesized in accordance with substantially the same method as described above in the synthesis of compound 4500 except for the use of 2-(difluoromethyl)-5-(3-fluoro-4-((4-(4,5,6, 7-tetrahydrothieno[2,3-c]pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole and the reagent from Table 112.

Table 112 Example Connection no. Reagent Exit (%) 375 4501 Propan-2-one 23

Table 113 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 375 4501 2-(difluoromethyl)-5-(3-fluoro-4-((4-(6-isopropyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-1H-1 ,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94-7.88 (m, 2H), 7.67 (s, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7 .07-6.78 (m, 2H), 5.68 (s, 2H), 3.96 (s, 2H), 3.19 (s, 1H), 2.95 (d, J =47.4 Hz, 4H), 1.30-1.25 (m, 6H); MSNR (ER) m/z 475.4 (M ⁺ +1).

Example 376: Synthesis of Compound 4502, 2-(difluoromethyl)-5-(6-((4-(3-(1-ethylazetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 3-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H- 1,2,3-triazol-4-yl)phenyl)azetidine-1-carboxylate

Tert-butyl 3-(3-ethynylphenyl)azetidine-1-carboxylate (0.300 g, 1.166 mmol), 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4- oxadiazole (0.294 g, 1.166 mmol) obtained in step 1 of Example 16, sodium ascorbate (0.50 M solution in water, 0.233 ml, 0.117 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.023 ml, 0.023 mmol) was dissolved in tert-butanol (2 ml)/water (2 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give tert-butyl 3-(3-(1-((5-(5-(difluoromethyl)-1, 3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)azetidine-1-carboxylate (0.500 g, 84.2%) in form of a yellow solid.

[Step 2] Synthesis of 2-(6-((4-(3-(azetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)- 5-(difluoromethyl)-1,3,4-oxadiazole

Tert-butyl 3-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3 -triazol-4-yl)phenyl)azetidine-1-carboxylate (0.500 g, 0.981 mmol) obtained in step 1 and trifluoroacetic acid (0.751 ml, 9.813 mmol) were dissolved in dichloromethane (2 ml) at room temperature, then the resulting solution is stirred at the same temperature for 18 hours. A saturated aqueous sodium chloride solution is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Then, the resulting product is used without an additional purification process (2-(6-((4-(3-(azetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin- 3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole, 0.400 g, 99.6%, yellow oil).

[Step 3] Synthesis of compound 4502

2-(6-((4-(3-(azetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl) -1,3,4-oxadiazole (0.080 g, 0.195 mmol) obtained in step 2 and acetaldehyde (0.022 ml, 0.391 mmol) are dissolved in dichloromethane (1 ml), after which the resulting solution is stirred at room temperature for 15 minutes , and then sodium triacetoxyborohydride (0.124 g, 0.586 mmol) was added thereto, and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate is purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0-10%) and concentrated, after which the resulting product is purified again by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0-10%) and concentrate to give 2-(difluoromethyl)-5-(6-((4-(3-(1-ethylazetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl) pyridin-3-yl)-1,3,4-oxadiazole (0.051 g, 59.7%) as an orange solid.

¹ H NMR(400 MHz, CD₃OD) δ 9.28 (dd,J=2.3, 0.9 Hz, 1H), 8.54 (d,J=5.7 Hz, 2H), 7.88 (d,J=1.8 Hz, 1H), 7.79-7.73 (m, 1H), 7.63 (d,J=8.1 Hz, 1H), 7.47 (t,J=7.7 Hz, 1H), 7.35 (d,J=7.8 Hz, 1H), 7.26 (t,J=51.6 Hz, 1H), 5.93 (s, 2H), 4.16 (t,J=8.5 Hz, 2H), 4.04 (p,J=8.2 Hz, 1H), 3.75 (d,J=8.7 Hz, 2H), 2.96 (kv,J=7.2 Hz, 2H), 1.15 (t,J=7.2 Hz, 3H);MCNR(ER) m/z 438.0 (M⁺+1).

The compounds of Table 115 are synthesized in accordance with substantially the same method as described above in the synthesis of compound 4502 except for the use of 2-(6-((4-(3-(azetidin-3-yl)phenyl)-1H-1, 2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole and the reagent from Table 114.

Table 114 Example Connection no. Reagent Exit (%) 377 4503 Acetone 19 378 4504 Cyclobutanone 36 379 4505 Oxetanone 25

Table 115 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 377 4503 2-(difluoromethyl)-5-(6-((4-(3-(1-isopropylazetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3- yl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 9.28 (dd, J=2.3, 0.9 Hz, 1H), 8.57-8.48 (m, 2H), 7.84 (t , J=1.8 Hz, 1H), 7.74 (dt, J=7.6, 1.4 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.44 (t, J=7.7 Hz, 1H), 7.33 (d, J=7.7 Hz, 1H), 7.26 (t, J=51.6 Hz, 1H), 5.93 (s , 2H), 3.97 (t, J=8.0 Hz, 2H), 3.85 (p, J=8.2 Hz, 1H), 3.47 (t, J=8.1 Hz, 2H ), 2.78-2.71 (m, 1H), 1.08 (d, J=6.3 Hz, 6H); MSNR (IER) m/z 452.1 (M ⁺ + H). 378 4504 2-(6-((4-(3-(1-cyclobutylazetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-( difluoromethyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 9.28 (dd, J=2.2, 0.9 Hz, 1H), 8.57-8.50 (m, 2H), 7.85 (t , J=1.8 Hz, 1H), 7.75 (dt, J=7.7, 1.4 Hz, 1H), 7.65-7.59 (m, 1H), 7.46 (t, J=7.7 Hz, 1H), 7.33 (dt, J=7.7, 1.4 Hz, 1H), 7.26 (t, J=51.6 Hz, 1H), 5.93 ( s, 2H), 3.95 (d, J=5.5 Hz, 3H), 3.60 (s, 2H), 3.53 (d, J=7.6 Hz, 1H), 2.23- 2.11 (m, 2H), 2.08-1.94 (m, 2H), 1.91-1.77 (m, 2H); MSNR (IER) m/z 464.2 (M ⁺ + H). 379 4505 2-(difluoromethyl)-5-(6-((4-(3-(1-(oxetan-3-yl)azetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)pyridin-3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.31-9.26 (m, 1H), 8.57-8.50 (m, 2H), 7.85 (d, J=1.8 Hz , 1H), 7.73 (dt, J=7.8, 1.4 Hz, 1H), 7.61 (d, J=8.6 Hz, 1H), 7.44 (t, J=7, 7 Hz, 1H), 7.37-7.31 (m, 1H), 7.26 (t, J=51.6 Hz, 1H), 5.93 (s, 2H), 4.79 (t, J=6.8 Hz, 2H), 4.56 (dd, J=6.8, 5.0 Hz, 2H), 3.94-3.82 (m, 4H), 3.41 (td, J =5.7, 2.4 Hz, 2H); MSNR (IER) m/z 466.0 (M ⁺ + H).

Example 380: Synthesis of Compound 4506, 2-(difluoromethyl)-5-(4-((4-(3-(1-ethylazetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)-3-fluorophenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 3-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2, 3-triazol-4-yl)phenyl)azetidine-1-carboxylate

Tert-butyl 3-(3-ethynylphenyl)azetidine-1-carboxylate (0.150 g, 0.583 mmol), 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.157 g, 0.583 mmol) obtained in step 1 of Example 2, sodium ascorbate (0.50 M solution in water, 0.117 ml, 0.058 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.012 ml , 0.012 mmol) was dissolved in tert-butanol (2 ml)/water (2 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl 3-(3-(1-(4-(5-(difluoromethyl)-1,3 ,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)azetidine-1-carboxylate (0.287 g, 93.5%) as a white solid .

[Step 2] Synthesis of 2-(4-((4-(3-(azetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5 -(difluoromethyl)-1,3,4-oxadiazole

Tert-butyl 3-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4 -yl)phenyl)azetidine-1-carboxylate (0.287 g, 0.545 mmol) obtained in step 1 and trifluoroacetic acid (0.417 ml, 5.451 mmol) were dissolved in dichloromethane (2 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 3 hours. A saturated aqueous sodium chloride solution is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Then, the resulting product is used without an additional purification process (2-(4-((4-(3-(azetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3 -fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole, 0.230 g, 99.0%, yellow oil).

[Step 3] Synthesis of compound 4506

2-(4-((4-(3-(Azetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)- 1,3,4-oxadiazole (0.075 g, 0.176 mmol) obtained in step 2, acetaldehyde (0.020 ml, 0.352 mmol) and acetic acid (0.010 ml, 0.176 mmol) are dissolved in dichloromethane (1 ml), and the resulting solution stirred at room temperature for 15 minutes, and then sodium triacetoxyborohydride (0.112 g, 0.528 mmol) was added thereto, and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate is purified by column chromatography ( _SiO2 , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated, after which the resulting product is purified again by column chromatography (SiO2, 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(3-(1-ethylazetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)- 3-fluorophenyl)-1,3,4-oxadiazole (0.056 g, 70.1%) in the form of a yellow oil.

¹ H NMR(400 MHz, CD₃OD) δ 8.47 (s, 1H), 8.02-7.92 (m, 2H), 7.81 (t,J=1.7 Hz, 1H), 7.71 (dt,J=7.8, 1.4 Hz, 1H), 7.61 (t,J=7.7 Hz, 1H), 7.42 (t,J=7.7 Hz, 1H), 7.31 (dt,J=7.6, 1.5 Hz, 1H), 7.24 (t,J=51.6 Hz, 1H), 5.86 (s, 2H), 3.90-3.78 (m, 3H), 3.30 (sq,J=3.3 Hz, 2H), 2.64 (kv,J=7.2 Hz, 2H), 1.05 (t,J=7.2 Hz, 3H);MCNR(ER) m/z 455.5 (M⁺+1).

The compound of Table 117 was synthesized in accordance with substantially the same method as described above in the synthesis of compound 4506 except for the use of 2-(4-((4-(3-(azetidin-3-yl)phenyl)-1H-1, 2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole and the reagent from Table 116.

Table 116 Example Connection no. Reagent Exit (%) 381 4507 Cyclobutanone 65

Table 117 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 381 4507 2-(4-((4-(3-(1-cyclobutylazetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl )-1,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 8.47 (s, 1H), 8.02-7.92 (m, 2H), 7.82-7.77 (m, 1H), 7.71 (dt, J=7.7, 1.4 Hz, 1H), 7.61 (t, J=7.7 Hz, 1H), 7.41 (t, J=7.7 Hz, 1H), 7 .30 (dt, J=7.6, 1.7 Hz, 1H), 7.24 (t, J=51.6 Hz, 1H), 5.86 (s, 2H), 3.88-3, 71 (m, 3H), 3.34 (s, 1H), 3.32-3.23 (m, 2H), 2.14-2.01 (m, 2H), 2.00-1.88 ( m, 2H), 1.88-1.67 (m, 2H); MSNR (IER) m/z 481.6 (M ⁺ + H).

Example 382: Synthesis of Compound 4508, 2-(difluoromethyl)-5-(4-((4-(3-(1-ethylazetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 3-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazole -4-yl)phenyl)azetidine-1-carboxylate

Tert-butyl 3-(3-ethynylphenyl)azetidine-1-carboxylate (0.300 g, 1.166 mmol), 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.293 g , 1.166 mmol) obtained in step 1 of Example 1, sodium ascorbate (0.50 M solution in water, 0.233 ml, 0.117 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.023 ml, 0.023 mmol ) was dissolved in tert-butanol (2 ml)/water (2 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl 3-(3-(1-(4-(5-(difluoromethyl)-1,3 ,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)azetidine-1-carboxylate (0.583 g, 98.3%) as a white solid.

[Step 2] Synthesis of 2-(4-((4-(3-(azetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl )-1,3,4-oxadiazole

Tert-butyl 3-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl) Phenyl)azetidine-1-carboxylate (0.583 g, 1.146 mmol) obtained in step 1 and trifluoroacetic acid (0.878 ml, 11.464 mmol) are dissolved in dichloromethane (4 ml) at room temperature, after which the resulting solution is stirred at the same temperature within 3 hours. A saturated aqueous sodium chloride solution is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Then, the resulting product is used without additional purification process (2-(4-((4-(3-(azetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl) -5-(difluoromethyl)-1,3,4-oxadiazole, 0.460 g, 98.2%, yellow oil).

[Step 3] Synthesis of compound 4508

2-(4-((4-(3-(Azetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3 ,4-oxadiazole (0.090 g, 0.220 mmol) obtained in step 2, acetaldehyde (0.025 ml, 0.441 mmol) and acetic acid (0.013 ml, 0.220 mmol) are dissolved in dichloromethane (1 ml), after which the resulting solution is stirred at room temperature for 15 minutes, and then sodium triacetoxyborohydride (0.140 g, 0.661 mmol) was added thereto, and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate is purified by column chromatography ( _SiO2 , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated, after which the resulting product is purified again by column chromatography (SiO2, 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(3-(1-ethylazetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl )-1,3,4-oxadiazole (0.038 g, 39.5%) in the form of a yellow oil.

¹ H NMR(400 MHz, CD₃OD) δ 8.46 (s, 1H), 8.20-8.12 (m, 2H), 7.80 (d,J=1.8 Hz, 1H), 7.70 (dt,J=7.7, 1.4 Hz, 1H), 7.65-7.58 (m, 2H), 7.41 (t,J=7.7 Hz, 1H), 7.30 (dt,J=7.7, 1.5 Hz, 1H), 7.23 (t,J=51.6 Hz, 1H), 5.80 (s, 2H), 3.87-3.75 (m, 3H), 3.31-3.20 (m, 2H), 2.61 (sq,J=7.2 Hz, 2H), 1.04 (t,J=7.2 Hz, 3H);MCNR(ER) m/z 437.5 (M⁺+1).

The compounds of Table 119 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4508 except for the use of 2-(4-((4-(3-(azetidin-3-yl)phenyl)-1H-1, 2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole and the reagent from Table 118.

Table 118 Example Connection no. Reagent Exit (%) 383 4509 Acetone 36 384 4510 Cyclobutanone 17 385 4511 Oxetanone 19 399 4528 Formaldehyde 5

Table 119 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 383 4509 2-(difluoromethyl)-5-(4-((4-(3-(1-isopropylazetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1 ,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.47 (s, 1H), 8.20-8.10 (m, 2H), 7.80 (t, J=1.8 Hz, 1H), 7.70 (dt, J=7.8, 1.4 Hz, 1H), 7.65-7.58 (m, 2H), 7.47-7.37 (m, 1H), 7.33- 7.26 (m, 1H), 7.23 (t, J=51.7 Hz, 1H), 5.80 (s, 2H), 3.88-3.71 (m, 3H), 3.31 -3.24 (m, 2H), 2.56 (hept, J=6.1 Hz, 1H), 1.02 (d, J=6.3 Hz, 6H); MSNR (IER) m/z 451.5 (M ⁺ + H). 384 4510 2-(4-((4-(3-(1-cyclobutylazetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1 ,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.46 (s, 1H), 8.20-8.12 (m, 2H), 7.79 (t, J=1.8 Hz, 1H), 7.70 (dt, J=7.7, 1.4 Hz, 1H), 7.65-7.58 (m, 2H), 7.41 (t, J=7.7 Hz, 1H), 7 ,33-7.26 (m, 1H), 7.23 (t, J=51.7 Hz, 1H), 5.80 (s, 2H), 3.88-3.72 (m, 3H), 3.35 (d, J=1.3 Hz, 1H), 3.32-3.23 (m, 2H), 2.14-2.01 (m, 2H), 2.01-1.87 ( m, 2H), 1.87-1.70 (m, 2H); MSNR (IER) m/z 463.6 (M ⁺ + H). 385 4511 2-(difluoromethyl)-5-(4-((4-(3-(1-(oxetan-3-yl)azetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)phenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 8.46 (s, 1H), 8.20-8.10 (m, 2H), 7.86-7.80 (m, 1H), 7.71 (dt, J=7.7, 1.4 Hz, 1H), 7.65-7.58 (m, 2H), 7.42 (t, J=7.7 Hz, 1H), 7.33 ( dt, J=7.7, 1.5 Hz, 1H), 7.23 (t, J=51.6 Hz, 1H), 5.80 (s, 2H), 4.78 (t, J=6 .7 Hz, 2H), 4.55 (dd, J=6.8, 5.0 Hz, 2H), 3.95-3.80 (m, 4H), 3.46-3.36 (m, 2H); MSNR (IER) m/z 465.5 (M ⁺ + H). 399 4528 2-(difluoromethyl)-5-(4-((4-(3-(1-methylazetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1 ,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.48 (s, 1H), 8.20-8.11 (m, 2H), 7.86 (t, J=1.8 Hz, 1H), 7.74 (dt, J=7.8, 1.5 Hz, 1H), 7.62 (d, J=8.3 Hz, 2H), 7.45 (t, J=7.7 Hz, 1H ), 7.34 (d, J=7.8 Hz, 1H), 7.23 (t, J=51.7 Hz, 1H), 5.81 (s, 2H), 4.17-4.08 (m, 2H), 4.06-3.94 (m, 1H), 3.75 (t, J=8.5 Hz, 2H), 2.68 (s, 3H); MSNR (IER) m/z 423.4 (M ⁺ + H).

Example 386: Synthesis of Compound 4513, 2-(difluoromethyl)-5-(4-((4-(2-methylisoindolin-5-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl) -1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 5-ethynylisoindoline-2-carboxylate

Tert-butyl 5-formylisoindoline-2-carboxylate (2.500 g, 10.110 mmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (1.821 ml, 12.132 mmol) and potassium carbonate (2.794 g, 20.219 mmol) are dissolved in methanol ( 10 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting concentrate is poured into water, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl 5-ethynylisoindoline-2-carboxylate (1.460 g, 59.4%) as a yellow oil.

[Step 2] Synthesis of tert-butyl 5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4- yl)isoindoline-2-carboxylate

Tert-butyl 5-ethynylisoindoline-2-carboxylate (0.550 g, 2.260 mmol) obtained in step 1, 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.625 g , 2.487 mmol) obtained in step 1 of Example 1, copper(II) sulfate pentahydrate (0.006 g, 0.023 mmol) and sodium ascorbate (0.045 g, 0.226 mmol) were dissolved in tert-butanol (5 ml)/water (5 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-80%) and concentrated to give tert-butyl 5-(1-(4-(5-(difluoromethyl)-1,3,4- Oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)isoindoline-2-carboxylate (0.370 g, 33.1%) as a white solid.

[Step 3] Synthesis of 2-(difluoromethyl)-5-(4-((4-(isoindolin-5-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3 ,4-oxadiazole

Tert-butyl 5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)isoindolin-2 The β-carboxylate (0.370 g, 0.748 mmol) obtained in step 2 and trifluoroacetic acid (0.573 ml, 7.482 mmol) were dissolved in dichloromethane (50 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(isoindolin-5-yl)-1H -1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.070 g, 23.7%) as a white solid.

[Step 4] Synthesis of compound 4513

2-(Difluoromethyl)-5-(4-((4-(isoindolin-5-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole ( 0.070 g, 0.177 mmol) obtained in step 3, formaldehyde (0.011 g, 0.355 mmol) and acetic acid (0.011 ml, 0.195 mmol) are dissolved in dichloromethane (5 ml) at room temperature, after which sodium triacetoxyborohydride (0.075 g, 0.355 mmol) is added to the resulting solution and stirred at the same temperature for 12 hours. An aqueous solution of sodium 1N-bicarbonate is poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove solid residue and a layer of aqueous solution, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(2-methylisoindolin-5-yl) -1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.025 g, 34.5%) as a brown solid.

¹ H NMR(400 MHz, CDCl₃) δ 8.10 (d,J=8.1 Hz, 2H), 7.73 (s, 1H), 7.66 (s, 1H), 7.64-7.57 (m, 1H), 7.44 (d,J=8.0 Hz, 2H), 7.21 (d,J=7.8 Hz, 1H), 6.91 (t,J=51.7 Hz, 1H), 5.64 (s, 2H), 3.97 (s, 3H), 2.61 (s, 3H);MCNR(ER) m/z 409.1 (M⁺+1).

Example 387: Synthesis of Compound 4515, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-methylisoindolin-5-yl)-1H-1,2,3-triazol-1-yl) methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazole -4-yl)isoindoline-2-carboxylate

Tert-butyl 5-ethynylisoindoline-2-carboxylate (0.550 g, 2.260 mmol) prepared in Step 1 of Example 386, 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4 -oxadiazole (0.669 g, 2.487 mmol) obtained in step 1 of example 2, copper(II) sulfate pentahydrate (0.006 g, 0.023 mmol) and sodium ascorbate (0.045 g, 0.226 mmol) are dissolved in tert-butanol (5 ml)/ water (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-80%) and concentrated to give tert-butyl 5-(1-(4-(5-(difluoromethyl)-1,3,4- Oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)isoindoline-2-carboxylate (0.960 g, 82.9%) as a white solid.

[Step 2] Synthesis of 2-(difluoromethyl)-5-(3-fluoro-4-((4-(isoindolin-5-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl) -1,3,4-oxadiazole

Tert-butyl 5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) Isoindoline-2-carboxylate (0.960 g, 1.873 mmol) obtained in step 1 and trifluoroacetic acid (1.434 ml, 18.732 mmol) were dissolved in dichloromethane (50 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(isoindoline-5- yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.590 g, 76.4%) as a white solid.

[Step 3] Synthesis of compound 4515

2-(Difluoromethyl)-5-(3-fluoro-4-((4-(isoindolin-5-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3, 4-oxadiazole (0.080 g, 0.194 mmol) obtained in step 2, formaldehyde (0.012 g, 0.388 mmol) and acetic acid (0.012 ml, 0.213 mmol) are dissolved in dichloromethane (5 ml) at room temperature, after which sodium triacetoxyborohydride ( 0.082 g, 0.388 mmol) was added to the resulting solution and stirred at the same temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution is poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove solid residue and a layer of aqueous solution, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol = 0-10%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-methylisoindolin- 5-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.030 g, 36.3%) as a brown solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.87 (dd,J=8.3, 4.2 Hz, 2H), 7.81 (s, 1H), 7.67 (s, 1H), 7.63 (d,J=7.8 Hz, 1H), 7.42 (t,J=7.7 Hz, 1H), 7.22 (d,J=7.8 Hz, 1H), 6.91 (t,J=51.7 Hz, 1H), 5.69 (s, 2H), 4.01 (s, 4H), 2.63 (s, 3H);MCNR(ER) m/z 427.1 (M⁺+1).

The compounds of Table 121 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4515 except for the use of 2-(difluoromethyl)-5-(3-fluoro-4-((4-(isoindolin-5-yl) -1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole and the reagent from Table 120.

Table 120 Example Connection no. Reagent Exit (%) 388 4516 Acetaldehyde 35 389 4517 Propan-2-one 37 390 4518 Cyclobutanone 39 391 4519 Oxetan-3-one 44 495 17458 Tetrahydro-4H-pyran-4-one 47 496 17460 1-fluorocyclopropane-1-carbaldehyde 43

Table 121 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 388 4516 2-(difluoromethyl)-5-(4-((4-(2-ethylisoindolin-5-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-1,3 ,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 7.94-7.86 (m, 2H), 7.84 (s, 1H), 7.75-7.61 (m, 2H), 7.46 ( t, J =7.7 Hz, 1H), 7.28 (s, 1H), 6.92 (t, J =51.7 Hz, 1H), 5.71 (s, 2H), 4.24 ( s, 4H), 3.03 (kv, J =7.2 Hz, 2H), 1.42-1.21 (m, 3H); MSNR (ER) m/z 441.5 (M ⁺ +1). 389 4517 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-isopropylisoindolin-5-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86-7.79 (m, 3H), 7.64 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7 .39 (t, J =7.7 Hz, 1H), 7.19 (d, J =7.8 Hz, 1H), 6.90 (t, J =51.7 Hz, 1H), 5.65 (s, 2H), 4.07 (s, 4H), 2.91 (hept, J =6.3 Hz, 1H), 1.20 (d, J =6.3 Hz, 6H); MSNR (ER) m/z 455.1 (M ⁺ +1). 390 4518 2-(4-((4-(2-cyclobutylisoindolin-5-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3 ,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 7.88-7.80 (m, 3H), 7.66 (s, 1H), 7.64-7.58 (m, 1H), 7.41 ( t, J =7.7 Hz, 1H), 7.21 (d, J =7.8 Hz, 1H), 6.91 (t, J =51.7 Hz, 1H), 5.67 (s, 2H), 4.03 (s, 4H), 3.38 (p, J =7.8 Hz, 1H), 2.22-2.04 (m, 4H), 1.87-1.70 (m , 2H); MSNR (ER) m/z 467.2 (M ⁺ +1). 391 4519 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-(oxetan-3-yl)isoindolin-5-yl)-1H-1,2,3-triazol-1-yl) methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90-7.84 (m, 2H), 7.82 (s, 1H), 7.70 (d, J = 1.6 Hz, 1H), 7 .63 (dd, J =7.8, 1.6 Hz, 1H), 7.43 (t, J =7.7 Hz, 1H), 7.23 (d, J =7.8 Hz, 1H) , 6.91 (t, J =51.6 Hz, 1H), 5.69 (s, 2H), 4.75 (dt, J =16.4, 6.4 Hz, 4H), 4.05 ( p, J =6.3 Hz, 1H), 3.98 (s, 4H); MSNR (ER) m/z 469.5 (M ⁺ +1). 495 17458 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-(tetrahydro-2H-pyran-4-yl)isoindolin-5-yl)-1H-1,2,3-triazol- 1-yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ d 7.84-7.81 (m, 3H), 7.65 (s, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.39 (t, J=7.7 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 6.90 (t, J=51.7 Hz, 1H), 1, 65-1.61 (m, 2H); MSNR (ER) m/z 497.2 (M ⁺ +1). 496 17460 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-((1-fluorocyclopropyl)methyl)isoindolin-5-yl)-1H-1,2,3-triazol-1-yl )methyl)phenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ d 7.86-7.83 (m, 2H), 7.80 (s, 1H), 7.66 (s, 1H), 7.60 (d, J =7.7 Hz, 1H), 7.48 (t, J=40.4 Hz, 1H), 7.21 (d, J=7.8 Hz, 1H), 6.91 (t, J=51 .7 Hz, 1H), 5.67 (s, 2H), 4.07 (s, 4H), 3.07 (d, J=22.0 Hz, 2H), 1.13-1.08 (m , 2H), 0.69-0.67 (m, 2H); MSNR (ER) m/z 485.3(M ⁺ +1).

Example 400: Synthesis of Compound 4529, 2-(difluoromethyl)-5-(4-((4-(2-methylisoindolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl) -1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 4-ethynylisoindoline-2-carboxylate

Tert-butyl 4-formylisoindoline-2-carboxylate (0.500 g, 2.022 mmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (0.334 ml, 2.224 mmol) and potassium carbonate (0.559 g, 4.044 mmol) are dissolved in methanol ( 10 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 4 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl 4-ethynylisoindoline-2-carboxylate (0.429 g, 87.2%) as a white solid. .

[Step 2] Synthesis of tert-butyl 4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4- yl)isoindoline-2-carboxylate

Tert-butyl 4-ethynylisoindoline-2-carboxylate (0.210 g, 0.863 mmol) obtained in step 1, 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.217 g , 0.863 mmol) obtained in step 1 of Example 1, sodium ascorbate (0.50 M solution in water, 0.173 ml, 0.086 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.017 ml, 0.017 mmol ) was dissolved in tert-butanol (2 ml)/water (2 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl 4-(1-(4-(5-(difluoromethyl)-1,3,4- Oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)isoindoline-2-carboxylate (0.415 g, 97.2%) as a white solid.

[Step 3] Synthesis of 2-(difluoromethyl)-5-(4-((4-(isoindolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3 ,4-oxadiazole

Tert-butyl 4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)isoindolin-2 The β-carboxylate (0.415 g, 0.839 mmol) obtained in step 2 and trifluoroacetic acid (0.643 ml, 8.392 mmol) were dissolved in dichloromethane (4 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 3 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without additional purification process (2-(difluoromethyl)-5-(4-((4-(isoindolin-4-yl)-1H-1,2,3- triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole, 0.330 g, 99.7%, brown oil).

[Step 4] Synthesis of compound 4529

2-(Difluoromethyl)-5-(4-((4-(isoindolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole ( 0.065 g, 0.165 mmol) obtained in step 3, and formaldehyde (37.00% solution in water, 0.025 ml, 0.330 mmol) was dissolved in dichloromethane (1 ml), after which the resulting solution was stirred at room temperature for 15 minutes, and then sodium triacetoxyborohydride (0.105 g, 0.494 mmol) was added thereto, and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate is purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0-10%) and concentrated, after which the resulting product is purified again by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0-10%) and concentrate to give 2-(difluoromethyl)-5-(4-((4-(2-methylisoindolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1, 3,4-oxadiazole (0.055 g, 81.7%) as a brown solid.

¹ H NMR(400 MHz, CD₃OD) δ 8.48 (s, 1H), 8.20-8.13 (m, 2H), 7.77-7.70 (m, 1H), 7.65-7.54 (m, 2H) , 7.42 (t,J=7.6 Hz, 1H), 7.34 (d,J=7.5 Hz, 1H), 7.23 (t,J=51.6 Hz, 1H), 5.82 (s, 2H), 4.66 (s, 2H), 4.37 (s, 2H), 2.91 (s, 3H);MCNR(ER) m/z 409.4 (M⁺+1).

The compounds of Table 123 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4529 except for the use of 2-(difluoromethyl)-5-(4-((4-(isoindolin-4-yl)-1H-1 ,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole and the reagent from Table 122.

Table 122 Example Connection no. Reagent Exit (%) 401 4530 Acetaldehyde 78 402 4531 Acetone 74 403 4532 Cyclobutanone 81 404 4533 Oxetanone 81

Table 123 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 401 4530 2-(difluoromethyl)-5-(4-((4-(2-ethylisoindolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4- oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.47 (s, 1H), 8.20-8.12 (m, 2H), 7.73 (d, J=7.7 Hz, 1H), 7.67-7.59 (m, 2H), 7.41 (t, J=7.6 Hz, 1H), 7.34 (d, J=7.6 Hz, 1H), 7.23 (t , J=51.6 Hz, 1H), 5.82 (s, 2H), 4.60 (s, 2H), 4.33 (s, 2H), 3.16 (kV, J=7.3 Hz , 2H), 1.35 (t, J=7.3 Hz, 3H); MSNR (IER) m/z 423.4 (M ⁺ + H). 402 4531 2-(difluoromethyl)-5-(4-((4-(2-isopropylisoindolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4- oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.51 (d, J=7.9 Hz, 1H), 8.20-8.13 (m, 2H), 7.75 (dd, J=7 ,7, 1.1 Hz, 1H), 7.66-7.59 (m, 2H), 7.45 (t, J=7.7 Hz, 1H), 7.39-7.10 (m, 2H), 5.83 (s, 2H), 4.76 (d, J=16.0 Hz, 2H), 4.49 (s, 2H), 3.44 (s, 1H), 1.41 ( d, J=6.5 Hz, 6H); MSNR (IER) m/z 437.4 (M ⁺ + H). 403 4532 2-(4-((4-(2-cyclobutylisoindolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4- oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 8.50 (s, 1H), 8.20-8.13 (m, 2H), 7.77-7.71 (m, 1H), 7.65 -7.59 (m, 2H), 7.44 (t, J=7.6 Hz, 1H), 7.39-7.10 (m, 2H), 5.82 (s, 2H), 4, 63 (s, 2H), 4.35 (s, 2H), 3.82-3.73 (m, 1H), 2.35 (kv, J=9.0, 7.8 Hz, 2H), 2 .21 (dd, J=20.0, 10.0 Hz, 2H), 1.91 (dt, J=18.5, 8.8 Hz, 2H); MSNR (IER) m/z 449.5 (M ⁺ + H). 404 4533 2-(difluoromethyl)-5-(4-((4-(2-(oxetan-3-yl)isoindolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl) -1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.40 (s, 1H), 8.20-8.13 (m, 2H), 7.71 (d, J=7.6 Hz, 1H), 7.61 (d, J=8.2 Hz, 2H), 7.38-7.32 (m, 1H), 7.31-7.09 (m, 2H), 5.81 (s, 2H) , 4.84 (d, J=6.7 Hz, 2H), 4.79-4.71 (m, 2H), 4.26 (s, 2H), 4.12 (p, J=6.3 Hz, 1H), 4.04 (s, 2H); MSNR (IER) m/z 451.4 (M ⁺ + H).

Example 405: Synthesis of Compound 4534, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-methylisoindolin-4-yl)-1H-1,2,3-triazol-1-yl) methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazole -4-yl)isoindoline-2-carboxylate

Tert-butyl 4-ethynylisoindoline-2-carboxylate (0.210 g, 0.863 mmol) prepared in Step 1 of Example 400, 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4 -oxadiazole (0.232 g, 0.863 mmol) obtained in step 1 of Example 2, sodium ascorbate (0.50 M solution in water, 0.173 ml, 0.086 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.017 ml, 0.017 mmol) was dissolved in tert-butanol (2 ml)/water (2 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl 4-(1-(4-(5-(difluoromethyl)-1,3,4- Oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)isoindoline-2-carboxylate (0.380 g, 85.9%) as a white solid.

[Step 2] Synthesis of 2-(difluoromethyl)-5-(3-fluoro-4-((4-(isoindolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl) -1,3,4-oxadiazole

Tert-butyl 4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) Isoindoline-2-carboxylate (0.380 g, 0.741 mmol) obtained in step 1 and trifluoroacetic acid (0.568 ml, 7.415 mmol) were dissolved in dichloromethane (3 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 3 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without additional purification process (2-(difluoromethyl)-5-(3-fluoro-4-((4-(isoindolin-4-yl)-1H-1, 2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole, 0.300 g, 98.1%, brown oil).

[Step 3] Synthesis of compound 4534

2-(Difluoromethyl)-5-(3-fluoro-4-((4-(isoindolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3, 4-oxadiazole (0.060 g, 0.145 mmol) obtained in step 2 and formaldehyde (37.00% solution in water, 0.022 ml, 0.291 mmol) were dissolved in dichloromethane (1 ml), after which the resulting solution was stirred at room temperature in for 15 minutes, and then sodium triacetoxyborohydride (0.093 g, 0.436 mmol) was added thereto, and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate is purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0-10%) and concentrated, after which the resulting product is purified again by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0-10%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-methylisoindolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl )-1,3,4-oxadiazole (0.044 g, 70.9%) in the form of a brown solid.

¹ H NMR(400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.97 (ddd,J=11.7, 9.0, 1.7 Hz, 2H), 7.69 (d,J=7.7 Hz, 1H), 7.59 (t,J=7.7 Hz, 1H), 7.39-7.31 (m, 1H), 7.29-7.11 (m, 2H), 5.87 (s, 2H), 4.27 (s, 2H), 4.04 (s, 2H), 2.68 (s, 3H);MCNR(ER) m/z 427.4 (M⁺+1).

The compounds of Table 125 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4534 except for the use of 2-(difluoromethyl)-5-(3-fluoro-4-((4-(isoindolin-4-yl) -1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole and the reagent from Table 124.

Table 124 Example Connection no. Reagent Exit (%) 406 4535 Acetaldehyde 72 407 4536 Acetone 45 408 4537 Cyclobutanone 87 409 4538 Oxetanone 78

Table 125 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 406 4535 2-(difluoromethyl)-5-(4-((4-(2-ethylisoindolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-1,3 ,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 8.48 (s, 1H), 8.03-7.92 (m, 2H), 7.76-7.70 (m, 1H), 7.61 (t, J=7.7 Hz, 1H), 7.41 (t, J=7.6 Hz, 1H), 7.38-7.11 (m, 2H), 5.88 (s, 2H) , 4.59 (s, 2H), 4.31 (s, 2H), 3.15 (kv, J=7.3 Hz, 2H), 1.35 (t, J=7.3 Hz, 3H) ; MSNR (IER) m/z 441.4 (M ⁺ + H). 407 4536 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-isopropylisoindolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.51 (d, J=8.0 Hz, 1H), 8.03-7.92 (m, 2H), 7.74 (d, J=7 .7 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 7.44 (t, J=7.6 Hz, 1H), 7.40-7.11 (m, 2H ), 5.88 (s, 2H), 4.69 (d, J=16.7 Hz, 2H), 4.44 (s, 2H), 3.38 (kv, J=6.4 Hz, 1H ), 1.39 (d, J=6.4 Hz, 6H); MSNR (IER) m/z 455.5 (M ⁺ + H). 408 4537 2-(4-((4-(2-cyclobutylisoindolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3 ,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.45 (s, 1H), 8.02-7.90 (m, 2H), 7.71 (d, J=7.7 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.43-7.11 (m, 3H), 5.87 (s, 2H), 4.40 (s, 2H), 4.15 (s, 2H), 3.65-3.49 (m, 1H), 2.26 (kvd, J=8.4, 7.2, 3.5 Hz, 2H), 2.21-2.09 (m, 2H), 1.96-1.80 (m, 2H); MSNR (IER) m/z 467.5 (M ⁺ + H). 409 4538 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-(oxetan-3-yl)isoindolin-4-yl)-1H-1,2,3-triazol-1-yl) methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.45 (s, 1H), 8.02-7.90 (m, 2H), 7.71 (d, J=7.7 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.43-7.11 (m, 3H), 5.87 (s, 2H), 4.40 (s, 2H), 4.15 (s, 2H), 3.65-3.49 (m, 1H), 2.26 (kvd, J=8.4, 7.2, 3.5 Hz, 2H), 2.21-2.09 (m, 2H), 1.96-1.80 (m, 2H); MSNR (IER) m/z 469.4 (M ⁺ + H).

Example 410: Synthesis of Compound 4539, 2-(difluoromethyl)-5-(6-((4-(isoindolin-5-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3- yl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2 ,3-triazol-4-yl)isoindoline-2-carboxylate

Tert-butyl 5-ethynylisoindolin-2-carboxylate (0.750 g, 3.082 mmol) prepared in Step 1 of Example 387, 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3, 4-oxadiazole (0.855 g, 3.391 mmol) prepared in step 1 of Example 16, copper(II) sulfate pentahydrate (0.008 g, 0.031 mmol) and sodium ascorbate (0.061 g, 0.308 mmol) were dissolved in tert-butanol (5 ml) /water (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl 5-(1-((5-(5-(difluoromethyl)-1,3,4 -oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)isoindoline-2-carboxylate (1.300 g, 85.1%) in the form of a brown solid.

[Step 2] Synthesis of compound 4539

Tert-butyl 5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)isoindoline-2-carboxylate (1.300 g, 2.624 mmol) obtained in step 1 and trifluoroacetic acid (2.009 ml, 26.237 mmol) were dissolved in dichloromethane (50 ml) at room temperature, after which the resulting solution was stirred at same temperature for 12 hours. An aqueous solution of sodium 1N-bicarbonate is poured into the resulting reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(isoindolin-5-yl)-1H -1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.460 g, 44.3%) in the form of a brown solid.

¹ H NMR(400 MHz, CDCl₃) δ 9.14 (dd,J=2.2, 0.9 Hz, 1H), 8.48 (s, 1H), 8.40 (dd,J=8.2, 2.3 Hz, 1H), 7.85-7.76 (m, 2H), 7.52 (dd,J=8.2, 0.9 Hz, 1H), 7.42 (d,J=8.0 Hz, 1H), 7.20 (t,J=51.6 Hz, 1H), 5.85 (s, 2H), 4.64 (d,J=7.7 Hz, 4H);MCNR(ER) m/z 396.3 (M⁺+1).

Example 411: Synthesis of Compound 4540, 2-(difluoromethyl)-5-(6-((4-(2-methylisoindolin-5-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin- 3-yl)-1,3,4-oxadiazole

2-(Difluoromethyl)-5-(6-((4-(isoindolin-5-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3, 4-oxadiazole (0.070 g, 0.177 mmol) obtained in step 2 of Example 410, formaldehyde (0.011 g, 0.354 mmol) and acetic acid (0.011 ml, 0.195 mmol) were dissolved in dichloromethane (5 ml) at room temperature, after which the triacetoxyborohydride sodium (0.075 g, 0.354 mmol) was added to the resulting solution and stirred at the same temperature for 12 hours. Water is poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove solid residue and a layer of aqueous solution, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(2-methylisoindolin-5-yl) -1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.010 g, 13.8%) as a brown solid.

¹ H NMR(400 MHz, CDCl₃) δ 9.32 (d,J=2.3 Hz, 1H), 8.40 (dd,J=8.1, 2.2 Hz, 1H), 7.97 (s, 1H), 7.77-7.68 (m, 2H), 7.43 (d,J=8.1 Hz, 1H), 7.28 (d,J=7.8 Hz, 1H), 6.94 (t,J=51.6 Hz, 1H), 5.80 (s, 2H), 4.24 (d,J=4.9 Hz, 4H), 2.01 (s, 3H);MCNR(ER) m/z 410.4 (M⁺+1).

The compounds of Table 127 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4540 except for the use of 2-(difluoromethyl)-5-(6-((4-(isoindolin-5-yl)-1H-1 ,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reagent from Table 126.

Table 126 Example Connection no. Reagent Exit (%) 412 4541 Propan-2-one 32 413 4542 Cyclobutanone 38 414 4543 Oxetan-3-one 44

Table 127 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 412 4541 2-(difluoromethyl)-5-(6-((4-(2-isopropylisoindolin-5-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.27 (d, J = 2.1 Hz, 1H), 8.34 (dd, J = 8.2, 2.3 Hz, 1H), 7.94 (s, 1H), 7.67 (s, 1H), 7.62 (dd, J =7.8, 1.6 Hz, 1H), 7.37 (d, J =8.2 Hz, 1H) , 7.21 (d, J =7.8 Hz, 1H), 6.93 (s, 1H), 5.76 (s, 2H), 4.07 (s, 4H), 2.90 (hept, J =6.3 Hz, 1H), 1.21 (d, J =6.3 Hz, 6H); MSNR (ER) m/z 438.5 (M ⁺ +1). 413 4542 2-(6-((4-(2-cyclobutylisoindolin-5-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.28 (d, J = 2.2 Hz, 1H), 8.35 (dd, J = 8.2, 2.2 Hz, 1H), 7.94 (s, 1H), 7.68 (s, 1H), 7.62 (dd, J =7.7, 1.5 Hz, 1H), 7.37 (d, J =8.2 Hz, 1H) , 7.21 (d, J =7.8 Hz, 1H), 6.93 (t, J =51.6 Hz, 1H), 5.77 (s, 2H), 3.96 (s, 4H) , 3.33 (p, J = 7.8 Hz, 1H), 2.09 (kv, J = 7.7, 7.1 Hz, 4H), 1.85-1.64 (m, 2H); MSNR (ER) m/z 450.5 (M ⁺ +1). 414 4543 2-(difluoromethyl)-5-(6-((4-(2-(oxetan-3-yl)isoindolin-5-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin- 3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.31 (d, J = 2.2 Hz, 1H), 8.39 (dd, J = 8.2, 2.3 Hz, 1H), 7.96 (s, 1H), 7.73 (s, 1H), 7.66 (dd, J =7.8, 1.6 Hz, 1H), 7.41 (d, J =8.2 Hz, 1H) , 7.26 (d, J =7.8 Hz, 1H), 6.94 (t, J =51.6 Hz, 1H), 5.80 (s, 2H), 4.85-4.67 ( m, 4H), 4.08 (p, J =6.3 Hz, 1H), 4.01 (s, 4H); MSNR (ER) m/z 452.5 (M ⁺ +1).

Example 415: Synthesis of Compound 4548, 2-(4-((4-(4-(azetidin-1-ylmethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5- (difluoromethyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)benzaldehyde

2-(4-(Azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.800 g, 3.185 mmol) prepared in step 1 of Example 1, and 4-ethynylbenzaldehyde (0.414 g, 3.185 mmol) dissolve in tert-butanol (2 ml)/water (2 ml) at room temperature, followed by sodium ascorbate (1.00 M solution, 0.318 ml, 0.318 mmol) and copper(II) sulfate pentahydrate (0.50 M solution, 0.064 ml, 0.032 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution is poured into the reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; hexane/ethyl acetate = 100-40%) and concentrated to give 4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazole-2 -yl)benzyl)-1H-1,2,3-triazol-4-yl)benzaldehyde (0.850 g, 70.0%) in the form of a beige solid.

[Step 2] Synthesis of compound 4548

4-(1-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)benzaldehyde (0.050 g, 0.131 mmol) obtained in step 1 and azetidine hydrogen chloride (0.025 g, 0.262 mmol) are dissolved in dichloromethane (1 ml) at room temperature, after which sodium triacetoxyborohydride (0.139 g, 0.656 mmol) is added to the resulting solution and stirred at the same temperature within 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-60%) and concentrated to give 2-(4-((4-(4-(azetidin-1-ylmethyl)phenyl)-1H- 1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.032 g, 57.8%) as a white solid.

¹ H NMR(400 MHz, CD₃OD) δ 8.43 (s, 1H), 8.20-8.13 (m, 2H), 7.85-7.78 (m, 2H), 7.61 (d,J=8.3 Hz, 2H), 7.39 (d,J=8.1 Hz, 2H), 7.23 (t,J=51.6 Hz, 1H), 5.80 (s, 2H), 3.68 (s, 2H), 3.40-3.34 (m, 4H), 2.16 (p,J=7.2 Hz, 2H);MCNR(ER) m/z 423.4 (M⁺+1).

The compounds of Table 129 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4548 except for the use of 4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl )benzyl)-1H-1,2,3-triazol-4-yl)benzaldehyde and the reagent from Table 128.

Table 128 Example Connection no. Reagent Exit (%) 416 4549 3-fluoroazetidine hydrogen chloride 43 417 4550 Pyrrolidine 41 418 4551 2-oxa-6-azaspiro[3,3]heptane 50 419 4552 1-methylpiperazine 44 420 4553 1-ethylpiperazine 47 421 4554 N,N-dimethylpiperidin-4-amine 17 422 4555 Cyclobutanamine 57 423 4556 Oxetan-3-amine 45 424 4557 1-methylazetidine-3-amine thirty

Table 129 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 416 4549 2-(difluoromethyl)-5-(4-((4-(4-((3-fluoroazetidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl )-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.43 (d, J = 2.3 Hz, 1H), 8.20-8.13 (m, 2H), 7.85-7.78 (m , 2H), 7.61 (d, J =8.2 Hz, 2H), 7.40 (d, J =8.1 Hz, 2H), 7.23 (t, J =51.7 Hz, 1H ), 5.80 (s, 2H), 5.23 (p, J =5.2 Hz, 1H), 5.08 (t, J =5.2 Hz, 1H), 3.73 (s, 2H ), 3.70-3.58 (m, 2H), 3.38-3.25 (m, 2H); MSNR (ER) m/z 441.4 (M ⁺ +1). 417 4550 2-(difluoromethyl)-5-(4-((4-(4-(pyrrolidin-1-ylmethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3 ,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.20-8.13 (m, 2H), 7.86-7.79 (m, 2H), 7.61 (d, J =8.3 Hz, 2H), 7.45 (d, J =8.2 Hz, 2H), 7.23 (t, J =51.6 Hz, 1H), 5.80 (s , 2H), 3.71 (s, 2H), 2.62 (s, 4H), 1.85 (p, J =3.2 Hz, 4H); MSNR (ER) m/z 437.3 (M ⁺ +1). 418 4551 6-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)benzyl)- 2-oxa-6-azaspiro[3,3]heptane
^1H NMR (400 MHz, CD ₃ OD) δ 8.43 (s, 1H), 8.20-8.12 (m, 2H), 7.85-7.77 (m, 2H), 7.64 -7.58 (m, 2H), 7.39-7.09 (m, 3H), 5.80 (s, 2H), 4.75 (s, 4H), 3.62 (s, 2H), 3.46 (s, 4H); MSNR (ER) m/z 465.5 (M ⁺ +1). 419 4552 2-(difluoromethyl)-5-(4-((4-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl )-1,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 8.43 (s, 1H), 8.20-8.13 (m, 2H), 7.87-7.78 (m, 2H), 7.62 (d, J =8.4 Hz, 2H), 7.43 (d, J =8.1 Hz, 2H), 7.23 (t, J =51.7 Hz, 2H), 5.80 (s , 2H), 3.58 (s, 2H), 2.53 (s, 8H), 2.30 (s, 3H); MSNR (ER) m/z 466.5 (M ⁺ +1). 420 4553 2-(difluoromethyl)-5-(4-((4-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl )-1,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 8.43 (s, 1H), 8.20-8.13 (m, 2H), 7.85-7.78 (m, 2H), 7.62 (d, J =8.4 Hz, 2H), 7.43 (d, J =8.2 Hz, 2H), 7.23 (t, J =51.6 Hz, 2H), 5.80 (s , 2H), 3.59 (s, 2H), 2.75-2.38 (m, 10H), 1.11 (t, J =7.2 Hz, 3H); MSNR (ER) m/z 480.5 (M ⁺ +1). 421 4554 1-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)benzyl)- N,N-dimethylpiperidin-4-amine
¹ H NMR (400 MHz, CD ₃ OD) δ 8.43 (s, 1H), 8.20-8.13 (m, 2H), 7.81 (d, J = 8.2 Hz, 2H), 7.62 (d, J =8.3 Hz, 2H), 7.43 (d, J =8.1 Hz, 2H), 7.23 (t, J =51.7 Hz, 1H), 5, 80 (s, 2H), 3.56 (s, 2H), 3.00 (d, J =11.8 Hz, 2H), 2.32 (s, 6H), 2.29-2.20 (m , 1H), 2.06 (t, J =11.5 Hz, 2H), 1.94-1.85 (m, 2H), 1.64-1.50 (m, 2H); MSNR (ER) m/z 494.5 (M ⁺ +1). 422 4555 N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)benzyl)cyclobutanamine
^1H NMR (400 MHz, CD ₃ OD) δ 8.42 (s, 1H), 8.20-8.13 (m, 2H), 7.84-7.77 (m, 2H), 7.61 (d, J =8.4 Hz, 2H), 7.47-7.40 (m, 2H), 7.23 (t, J =51.6 Hz, 1H), 5.80 (s, 2H) , 3.71 (s, 2H), 3.33-3.25 (m, 1H), 2.26-2.15 (m, 2H), 1.89-1.63 (m, 4H); MSNR (ER) m/z 437.4 (M ⁺ +1). 423 4556 N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)benzyl)oxetane -3-amine
^1H NMR (400 MHz, CD ₃ OD) δ 8.43 (s, 1H), 8.20-8.12 (m, 2H), 7.85-7.78 (m, 2H), 7.61 (d, J =8.3 Hz, 2H), 7.43 (d, J =8.2 Hz, 2H), 7.23 (t, J =51.7 Hz, 1H), 5.80 (s , 2H), 4.72 (t, J =6.8 Hz, 2H), 4.45 (t, J =6.4 Hz, 2H), 4.03 (p, J =6.7 Hz, 1H ), 3.74 (s, 2H); MSNR (ER) m/z 439.4 (M ⁺ +1). 424 4557 N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)benzyl)- 1-methylazetidine-3-amine
¹ H NMR (400 MHz, CD ₃ OD) δ 8.45 (s, 1H), 8.20-8.13 (m, 2H), 7.86 (d, J =8.3 Hz, 2H), 7.62 (d, J =8.3 Hz, 2H), 7.45 (d, J =8.1 Hz, 2H), 7.23 (t, J =51.7 Hz, 2H), 5, 80 (s, 2H), 4.67 (d, J =15.5 Hz, 1H), 4.47-4.33 (m, 2H), 4.24 (dd, J =8.8, 6, 2 Hz, 1H), 3.90-3.79 (m, 1H), 2.80-2.66 (m, 2H), 2.32 (s, 3H); MSNR (ER) m/z 452.4 (M ⁺ +1).

Example 425: Synthesis of Compound 4558, 2-(6-((4-(4-(azetidin-1-ylmethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl )-5-(difluoromethyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3- triazol-4-yl)benzaldehyde

2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.400 g, 1.586 mmol) prepared in Step 1 of Example 16 and 4-ethynylbenzaldehyde (0.206 g , 1.586 mmol) dissolved in tert-butanol (2 ml)/water (2 ml) at room temperature, followed by sodium ascorbate (1.00 M solution, 0.159 ml, 0.159 mmol) and copper(II) sulfate pentahydrate (0. 50 M solution, 0.032 ml, 0.016 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution is poured into the reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; hexane/ethyl acetate = 100-40%) and concentrated to give 4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol- 2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzaldehyde (0.530 g, 87.4%) as a beige solid.

[Step 2] Synthesis of compound 4558

4-(1-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl )benzaldehyde (0.050 g, 0.131 mmol) obtained in step 1 and azetidine hydrogen chloride (0.024 g, 0.262 mmol) are dissolved in dichloromethane (1 ml) at room temperature, after which sodium triacetoxyborohydride (0.139 g, 0.654 mmol) is added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-60%) and concentrated to give 2-(6-((4-(4-(azetidin-1-ylmethyl)phenyl)-1H- 1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.032 g, 57.8%) as a white solid.

¹ H NMR(400 MHz, CD₃OD) δ 9.28 (d,J=2.2 Hz, 1H), 8.57-8.48 (m, 2H), 7.84 (d,J=8.1 Hz, 2H), 7.60 (d,J=8.2 Hz, 1H), 7.41 (d,J=8.1 Hz, 2H), 7.26 (t,J=51.6 Hz, 1H), 5.92 (s, 2H), 3.73 (s, 2H), 3.48-3.38 (m, 4H), 2.22-2.14 (m, 2H);MCNR(ER) m/z 424.4 (M⁺+1).

The compounds of Table 131 were synthesized in accordance with substantially the same method as described above for the synthesis of compound 4558 except for the use of 4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2- yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzaldehyde and the reagent from Table 130.

Table 130 Example Connection no. Reagent Exit (%) 426 4559 3-fluoroazetidine hydrogen chloride 43 427 4560 Pyrrolidine 54 428 4561 2-oxa-6-azaspiro[3,3]heptane 27 429 4562 1-methylpiperazine 34 430 4563 1-ethylpiperazine 43 431 4564 N,N-dimethylpiperidin-4-amine 29 432 4565 Cyclobutanamine 36 433 4566 Oxetan-3-amine 43 434 4567 1-methylazetidine-3-amine 32

Table 131 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 426 4559 2-(difluoromethyl)-5-(6-((4-(4-((3-fluoroazetidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridine -3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.28 (d, J = 2.1 Hz, 1H), 8.53 (dd, J = 8.2, 2.3 Hz, 1H), 8, 49 (d, J =2.2 Hz, 1H), 7.84 (d, J =8.2 Hz, 2H), 7.60 (d, J =8.3 Hz, 1H), 7.41 ( d, J =8.1 Hz, 2H), 7.26 (t, J =51.6 Hz, 1H), 5.92 (s, 2H), 5.23 (t, J =5.3 Hz, 0.5H), 5.10 (d, J =4.9 Hz, 0.5H), 3.74 (s, 2H), 3.72-3.60 (m, 2H), 3.33 (dd , J =33.2, 4.6 Hz, 2H); MSNR (ER) m/z 442.4 (M ⁺ +1). 427 4560 2-(difluoromethyl)-5-(6-((4-(4-(pyrrolidin-1-ylmethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl) -1,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 9.28 (dd, J =2.2, 0.9 Hz, 1H), 8.53 (dd, J =8.2, 2.2 Hz, 1H ), 8.50 (s, 1H), 7.88-7.81 (m, 2H), 7.60 (d, J =8.1 Hz, 1H), 7.46 (d, J =8, 2 Hz, 2H), 7.26 (t, J =51.6 Hz, 2H), 5.93 (s, 2H), 3.73 (s, 2H), 2.63 (s, 4H), 1 .86 (p, J =3.2 Hz, 4H); MSNR (ER) m/z 438.5 (M ⁺ +1). 428 4561 6-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)benzyl)-2-oxa-6-azaspiro[3,3]heptane
¹ H NMR (400 MHz, CD ₃ OD) δ 9.28 (d, J = 2.1 Hz, 1H), 8.53 (dd, J = 8.2, 2.3 Hz, 1H), 8, 50 (s, 1H), 7.87-7.80 (m, 2H), 7.60 (d, J =8.2 Hz, 1H), 7.42-7.11 (m, 3H), 5 .92 (s, 2H), 4.75 (s, 4H), 3.64 (s, 2H), 3.49 (s, 4H); MSNR (ER) m/z 466.5 (M ⁺ +1). 429 4562 2-(difluoromethyl)-5-(6-((4-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridine -3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.28 (d, J = 2.1 Hz, 1H), 8.53 (dd, J = 8.2, 2.2 Hz, 1H), 8, 49 (s, 1H), 7.83 (d, J =8.2 Hz, 2H), 7.60 (d, J =8.2 Hz, 1H), 7.44 (d, J =8.1 Hz, 2H), 7.26 (t, J =51.6 Hz, 1H), 5.92 (s, 2H), 3.59 (s, 2H), 2.69-2.36 (m, 8H ), 2.30 (s, 3H); MSNR (ER) m/z 467.5 (M ⁺ +1). 430 4563 2-(difluoromethyl)-5-(6-((4-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridine -3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.30-9.26 (m, 1H), 8.53 (dd, J =8.2, 2.2 Hz, 1H), 8.49 (s , 1H), 7.84 (d, J =8.3 Hz, 2H), 7.60 (d, J =8.4 Hz, 1H), 7.45 (d, J =8.1 Hz, 2H ), 7.26 (t, J =51.6 Hz, 1H), 5.92 (s, 2H), 3.60 (s, 2H), 2.79-2.42 (m, 10H), 1 .12 (t, J =7.2 Hz, 3H); MSNR (ER) m/z 481.5 (M ⁺ +1). 431 4564 1-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)benzyl)-N,N-dimethylpiperidin-4-amine
¹ H NMR (400 MHz, CD ₃ OD) δ 9.31-9.26 (m, 1H), 8.53 (dd, J =8.2, 2.2 Hz, 1H), 8.50 (s , 1H), 7.83 (d, J =8.2 Hz, 2H), 7.60 (d, J =8.1 Hz, 1H), 7.44 (d, J =8.2 Hz, 2H ), 7.26 (t, J =51.6 Hz, 2H), 5.92 (s, 2H), 3.57 (s, 2H), 3.01 (d, J =11.6 Hz, 2H ), 2.32 (s, 6H), 2.24 (d, J =9.1 Hz, 1H), 2.07 (t, J =11.7 Hz, 2H), 1.89 (d, J =14.9 Hz, 2H), 1.63-1.50 (m, 2H); MSNR (ER) m/z 495.6 (M ⁺ +1). 432 4565 N-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)benzyl)cyclobutanamine
^1H NMR (400 MHz, CD ₃ OD) δ 9.28 (dd, J =2.2, 0.9 Hz, 1H), 8.53 (dd, J =8.2, 2.2 Hz, 1H ), 8.49 (s, 1H), 7.87-7.80 (m, 2H), 7.60 (d, J =8.2 Hz, 1H), 7.44 (d, J =8, 2 Hz, 2H), 7.26 (t, J =51.6 Hz, 1H), 5.92 (s, 2H), 3.72 (s, 2H), 3.30 (s, 1H), 2 .27-2.15 (m, 2H), 1.91-1.79 (m, 2H), 1.79-1.64 (m, 2H); MSNR (ER) m/z 438.5 (M ⁺ +1). 433 4566 N-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)benzyl)oxetan-3-amine
^1H NMR (400 MHz, CD ₃ OD) δ 9.28 (dd, J =2.3, 0.9 Hz, 1H), 8.53 (dd, J =8.2, 2.3 Hz, 1H ), 8.49 (s, 1H), 7.87-7.80 (m, 2H), 7.59 (d, J =8.2 Hz, 1H), 7.44 (d, J =8, 2 Hz, 2H), 7.26 (t, J =51.6 Hz, 1H), 5.92 (s, 2H), 4.72 (t, J =6.8 Hz, 2H), 4.45 (t, J =6.4 Hz, 2H), 4.03 (p, J =6.6 Hz, 1H), 3.75 (s, 2H); MSNR (ER) m/z 440.5 (M ⁺ +1). 434 4567 N-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)benzyl)-1-methylazetidin-3-amine
¹ H NMR (400 MHz, CD ₃ OD) δ 9.30-9.26 (m, 1H), 8.57-8.50 (m, 2H), 7.89 (d, J = 8.2 Hz , 2H), 7.61 (d, J =8.1 Hz, 1H), 7.46 (d, J =8.2 Hz, 2H), 7.40-7.11 (m, 1H), 5 .93 (s, 2H), 4.68 (d, J =15.5 Hz, 1H), 4.48-4.35 (m, 2H), 4.25 (dd, J =8.9, 6 .1 Hz, 1H), 3.90-3.82 (m, 1H), 2.82-2.71 (m, 2H), 2.35 (s, 3H); MSNR (ER) m/z 453.5 (M ⁺ +1).

Example 435: Synthesis of Compound 4569, 2-(difluoromethyl)-5-(6-((4-(2-fluoro-3-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 4-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H- 1,2,3-triazol-4-yl)-2-fluorophenyl)piperazine-1-carboxylate

Tert-butyl 4-(3-ethynyl-2-fluorophenyl)piperazine-1-carboxylate (0.860 g, 2.826 mmol) prepared in step 5 of Example 357, 2-(6-(azidomethyl)pyridin-3-yl)-5 -(difluoromethyl)-1,3,4-oxadiazole (0.784 g, 3.108 mmol) prepared in step 1 of Example 16, copper(II) sulfate pentahydrate (0.007 g, 0.028 mmol) and sodium ascorbate (0.056 g, 0.283 mmol) dissolved in tert-butanol (5 ml)/water (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 4 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl 4-(3-(1-((5-(5-(difluoromethyl)-1, 3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-fluorophenyl)piperazine-1-carboxylate (0.610 g, 38.8 %) in the form of a white solid.

[Step 2] Synthesis of 2-(difluoromethyl)-5-(6-((4-(2-fluoro-3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)pyridin-3-yl)-1,3,4-oxadiazole

Tert-butyl 4-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3 -triazol-4-yl)-2-fluorophenyl)piperazine-1-carboxylate (0.610 g, 1.096 mmol) obtained in step 1 and trifluoroacetic acid (0.839 ml, 10.960 mmol) are dissolved in dichloromethane (25 ml) at room temperature , after which the resulting solution is stirred at the same temperature for 12 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(2-fluoro-3-(piperazine -1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.440 g, 88.0%) as yellow oils

[Step 3] Synthesis of compound 4569

2-(Difluoromethyl)-5-(6-((4-(2-fluoro-3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin- 3-yl)-1,3,4-oxadiazole (0.060 g, 0.131 mmol) obtained in step 2, formaldehyde (0.008 g, 0.263 mmol) and acetic acid (0.008 ml, 0.145 mmol) are dissolved in dichloromethane (5 ml) at room temperature, after which sodium triacetoxyborohydride (0.056 g, 0.263 mmol) was added to the resulting solution and stirred at the same temperature for 12 hours. Water is poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove solid residue and a layer of aqueous solution, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(2-fluoro-3-(4 -methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.020 g, 32.3%) in form of a white solid.

¹ H NMR(400 MHz, CDCl₃) δ 9.31 (d,J=2.2 Hz, 1H), 8.37 (dd,J=8.2, 2.2 Hz, 1H), 8.11 (d,J=3.9 Hz, 1H), 7.91 (ddd,J=8.0, 6.4, 1.6 Hz, 1H), 7.36 (d,J=8.2 Hz, 1H), 7.16 (t,J=7.9 Hz, 1H), 7.09-6.73 (m, 2H), 5.82 (s, 2H), 3.16 (t,J=4.9 Hz, 4H), 2.72 (t,J=4.8 Hz, 4H), 2.40 (s, 3H);MCNR(ER) m/z 471.5 (M⁺+1).

The compounds of Table 133 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4569 except for the use of 2-(difluoromethyl)-5-(6-((4-(2-fluoro-3-(piperazine-1 -yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reagent from Table 132.

Table 132 Example Connection no. Reagent Exit (%) 436 4570 Acetaldehyde 31 437 4571 Propan-2-one 38 438 4572 Cyclobutanone 45 439 4573 Oxetan-3-one 45 462 4600 1-fluorocyclopropane-1-carbaldehyde 29 463 4601 3,3-difluorocyclobutane-1-carbaldehyde 27

Table 133 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 436 4570 2-(difluoromethyl)-5-(6-((4-(3-(4-ethylpiperazin-1-yl)-2-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridine -3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.30 (d, J = 2.2 Hz, 1H), 8.37 (dd, J = 8.2, 2.3 Hz, 1H), 8.11 (d, J =3.8 Hz, 1H), 7.95-7.87 (m, 1H), 7.36 (d, J =8.2 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 7.09-6.74 (m, 2H), 5.82 (s, 2H), 3.20 (t, J = 4.9 Hz, 4H), 2.81 ( t, J =4.8 Hz, 4H), 2.64 (kv, J =7.3 Hz, 2H), 1.17 (t, J =7.2 Hz, 3H); MSNR (ER) m/z 485.6 (M ⁺ +1). 437 4571 2-(difluoromethyl)-5-(6-((4-(2-fluoro-3-(4-isopropylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl) pyridin-3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.30 (d, J = 2.2 Hz, 1H), 8.37 (dd, J = 8.2, 2.3 Hz, 1H), 8.10 (d, J =3.8 Hz, 1H), 7.91 (td, J =7.2, 6.4, 1.6 Hz, 1H), 7.37 (d, J =8.2 Hz, 1H), 7.15 (t, J =7.9 Hz, 1H), 7.09-6.74 (m, 2H), 5.82 (s, 2H), 3.24 (t, J =4 .9 Hz, 4H), 3.06 (p, J =6.6 Hz, 1H), 2.94 (t, J =4.8 Hz, 4H), 1.19 (d, J =6.6 Hz, 6H); MSNR (ER) m/z 499.6 (M ⁺ +1). 438 4572 2-(6-((4-(3-(4-cyclobutylpiperazin-1-yl)-2-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)- 5-(difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.30 (d, J = 2.2 Hz, 1H), 8.37 (dd, J = 8.2, 2.3 Hz, 1H), 8.11 (d, J =3.8 Hz, 1H), 7.90 (ddd, J =8.0, 6.4, 1.6 Hz, 1H), 7.36 (d, J =8.2 Hz, 1H), 7.15 (t, J =7.9 Hz, 1H), 7.08-6.78 (m, 2H), 5.81 (s, 2H), 3.17 (t, J =4 .9 Hz, 4H), 2.91 (p, J =8.2 Hz, 1H), 2.64 (t, J =4.8 Hz, 4H), 2.06 (td, J =8.4 , 5.6 Hz, 4H), 1.80-1.62 (m, 2H); MSNR (ER) m/z 511.1 (M ⁺ +1). 439 4573 2-(difluoromethyl)-5-(6-((4-(2-fluoro-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.31 (d, J = 2.2 Hz, 1H), 8.37 (dd, J = 8.2, 2.2 Hz, 1H), 8.12 (d, J =3.9 Hz, 1H), 7.92 (ddd, J =8.0, 6.4, 1.7 Hz, 1H), 7.36 (d, J =8.2 Hz, 1H), 7.17 (t, J =7.9 Hz, 1H), 7.10-6.78 (m, 2H), 5.82 (s, 2H), 4.68 (p, J =6 .4 Hz, 4H), 3.59 (p, J =6.5 Hz, 1H), 3.16 (t, J =4.8 Hz, 4H), 2.54 (t, J =4.7 Hz, 4H); MSNR (ER) m/z 513.5 (M ⁺ +1). 462 4600 2-(difluoromethyl)-5-(6-((4-(2-fluoro-3-(4-((1-fluorocyclopropyl)methyl)piperazin-1-yl)phenyl)-1H-1,2,3- triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.32 (d, J = 2.2 Hz, 1H), 8.38 (dd, J = 8.2, 2.3 Hz, 1H), 8.12 (d, J =3.9 Hz, 1H), 7.92 (ddd, J =7.9, 6.4, 1.6 Hz, 1H), 7.36 (d, J =8.2 Hz, 1H), 7.17 (t, J =7.9 Hz, 1H), 7.09-6.78 (m, 2H), 5.83 (s, 2H), 3.19 (t, J =4 .9 Hz, 4H), 2.84 (td, J =11.8, 11.2, 6.4 Hz, 6H), 1.09 (dd, J =18.9, 6.8 Hz, 2H) , 0.65 (t, J =8.0 Hz, 2H); MSNR (ER) m/z 529.4 (M ⁺ +1). 463 4601 2-(6-((4-(3-(4-((3,3-difluorocyclobutyl)methyl)piperazin-1-yl)-2-fluorophenyl)-1H-1,2,3-triazol-1-yl )methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.30 (d, J = 2.2 Hz, 1H), 8.37 (dd, J = 8.2, 2.3 Hz, 1H), 8.11 (d, J =3.9 Hz, 1H), 7.91 (ddd, J =8.0, 6.4, 1.6 Hz, 1H), 7.36 (d, J =8.2 Hz, 1H), 7.15 (t, J =7.9 Hz, 1H), 7.07-6.78 (m, 2H), 5.82 (s, 2H), 3.11 (t, J =4 .9 Hz, 4H), 2.94 (s, 2H), 2.86 (s, 2H), 2.74-2.67 (m, 1H), 2.67-2.61 (m, 4H) , 2.55 (d, J =7.3 Hz, 2H); MSNR (ER) m/z 561.4 (M ⁺ +1).

Example 440: Synthesis of Compound 4576, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-fluoro-3-(4-methylpiperazin-1-yl)phenyl)-1H-1,2 ,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2, 3-triazol-4-yl)-2-fluorophenyl)piperazine-1-carboxylate

Tert-butyl 4-(3-ethynyl-2-fluorophenyl)piperazine-1-carboxylate (0.860 g, 2.826 mmol) prepared in Step 5 of Example 357, 2-(4-(azidomethyl)-3-fluorophenyl)-5- (difluoromethyl)-1,3,4-oxadiazole (0.837 g, 3.108 mmol) obtained in synthesis step 1 of example 2, copper(II) sulfate pentahydrate (0.007 g, 0.028 mmol) and sodium ascorbate (0.056 g, 0.283 mmol) are dissolved in tert-butanol (5 ml)/water (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 4 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3 ,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-2-fluorophenyl)piperazine-1-carboxylate (0.700 g, 43.2%) as white solid.

[Step 2] Synthesis of 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-fluoro-3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)phenyl)-1,3,4-oxadiazole

Tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4 -yl)-2-fluorophenyl)piperazine-1-carboxylate (0.700 g, 1.220 mmol) obtained in step 1 and trifluoroacetic acid (0.935 ml, 12.205 mmol) were dissolved in dichloromethane (25 ml) at room temperature, after which the resulting the solution is stirred at the same temperature for 12 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-fluoro- 3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.630 g, 109.0%) as yellow oils

[Step 3] Synthesis of compound 4576

2-(Difluoromethyl)-5-(3-fluoro-4-((4-(2-fluoro-3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl) Methyl)phenyl)-1,3,4-oxadiazole (0.060 g, 0.127 mmol) obtained in step 2, formaldehyde (0.008 g, 0.253 mmol) and acetic acid (0.008 ml, 0.139 mmol) are dissolved in dichloromethane (5 ml) at room temperature, after which sodium triacetoxyborohydride (0.054 g, 0.253 mmol) was added to the resulting solution and stirred at the same temperature for 12 hours. Water is poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove solid residue and a layer of aqueous solution, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-fluoro- 3-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.015 g, 24.3%) in form of a colorless oil.

¹ H NMR(400 MHz, CDCl₃) δ 7.98 (d,J=3.8 Hz, 1H), 7.93-7.82 (m, 3H), 7.41 (t,J=7.7 Hz, 1H), 7.15 (t,J=7.9 Hz, 1H), 7.07-6.75 (m, 2H), 5.72 (s, 2H), 3.15 (t,J=4.9 Hz, 4H), 2.71 (d,J=4.9 Hz, 4H), 2.39 (s, 3H);MCNR(ER) m/z 488.5 (M⁺+1).

The compounds of Table 135 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4576 except for the use of 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-fluoro-3- (piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole and the reagent from Table 134.

Table 134 Example Connection no. Reagent Exit (%) 441 4577 Acetaldehyde 32 442 4578 Propan-2-one 46 443 4579 Cyclobutanone 45 444 4580 Oxetan-3-one 45 464 4602 1-fluorocyclopropane-1-carbaldehyde 33 465 4603 3,3-difluorocyclobutane-1-carbaldehyde 34

Table 135 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 441 4577 2-(difluoromethyl)-5-(4-((4-(3-(4-ethylpiperazin-1-yl)-2-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)- 3-fluorophenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (d, J = 3.9 Hz, 1H), 7.92-7.84 (m, 3H), 7.41 (t, J = 7, 7 Hz, 1H), 7.14 (t, J = 7.9 Hz, 1H), 7.06-6.74 (m, 2H), 5.72 (s, 2H), 3.17 (t, J =4.9 Hz, 4H), 2.73 (t, J =4.8 Hz, 4H), 2.57 (kv, J =7.2 Hz, 2H), 1.14 (t, J = 7.2 Hz, 3H); MSNR (ER) m/z 502.5 (M ⁺ +1). 442 4578 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-fluoro-3-(4-isopropylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1- yl)methyl)phenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 7.97 (d, J =3.8 Hz, 1H), 7.94-7.81 (m, 3H), 7.42 (t, J =7, 7 Hz, 1H), 7.14 (t, J = 7.9 Hz, 1H), 7.07-6.76 (m, 2H), 5.72 (s, 2H), 3.30 (t, J =4.9 Hz, 4H), 3.10 (hept, J =6.5 Hz, 1H), 2.98 (t, J =4.9 Hz, 4H), 1.24 (d, J = 6.6 Hz, 6H); MSNR (ER) m/z 516.5 (M ⁺ +1). 443 4579 2-(4-((4-(3-(4-cyclobutylpiperazin-1-yl)-2-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5 -(difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (d, J = 3.9 Hz, 1H), 7.93-7.84 (m, 3H), 7.41 (t, J = 7, 7 Hz, 1H), 7.14 (t, J = 7.9 Hz, 1H), 7.06-6.73 (m, 2H), 5.72 (s, 2H), 3.14 (t, J =4.9 Hz, 4H), 2.85 (p, J =7.9 Hz, 1H), 2.63-2.49 (m, 4H), 2.01 (ddd, J =27.5 , 14.8, 5.3 Hz, 4H), 1.80-1.62 (m, 2H); MSNR (ER) m/z 528.4 (M ⁺ +1). 444 4580 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-fluoro-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1H-1,2 ,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (d, J = 3.8 Hz, 1H), 7.93-7.82 (m, 3H), 7.41 (t, J = 7, 7 Hz, 1H), 7.15 (t, J = 7.9 Hz, 1H), 7.06-6.77 (m, 2H), 5.72 (s, 2H), 4.67 (dt, J =14.3, 6.3 Hz, 4H), 3.57 (p, J =6.4 Hz, 1H), 3.14 (t, J =4.7 Hz, 4H), 2.52 ( t, J =4.7 Hz, 4H); MSNR (ER) m/z 530.4 (M ⁺ +1). 464 4602 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-fluoro-3-(4-((1-fluorocyclopropyl)methyl)piperazin-1-yl)phenyl)-1H-1, 2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 7.99 (d, J =3.9 Hz, 1H), 7.93-7.85 (m, 3H), 7.42 (t, J =7, 7 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 7.04-6.79 (m, 2H), 5.73 (s, 2H), 3.16 (sq, J =5.7, 5.2 Hz, 4H), 2.85-2.76 (m, 6H), 1.08 (dd, J =18.9, 6.8 Hz, 2H), 0.70 -0.58 (m, 2H); MSNR (ER) m/z 546.3 (M ⁺ +1). 465 4603 2-(4-((4-(3-(4-((3,3-difluorocyclobutyl)methyl)piperazin-1-yl)-2-fluorophenyl)-1H-1,2,3-triazol-1-yl )methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.99 (d, J = 4.0 Hz, 1H), 7.92-7.83 (m, 3H), 7.42 (t, J = 7, 8 Hz, 1H), 7.15 (t, J = 7.9 Hz, 1H), 7.03-6.78 (m, 2H), 5.72 (s, 2H), 3.10 (sq, J =8.2, 6.4 Hz, 4H), 2.68-2.54 (m, 9H), 2.23 (ddd, J =21.2, 10.3, 4.7 Hz, 2H) ; MSNR (ER) m/z 578.4 (M ⁺ +1).

Example 445: Synthesis of Compound 4582, 2-(difluoromethyl)-5-(6-((4-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-1,2,3-triazole -1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

2-(Difluoromethyl)-5-(6-((4-(2-fluoropyridin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1, 3,4-oxadiazole (0.050 g, 0.134 mmol) prepared in Example 181, 1-methylpiperazine (0.018 ml, 0.161 mmol) and N,N-diisopropylethylamine (0.028 ml, 0.161 mmol) were dissolved in dimethyl sulfoxide (1 ml), after whereby the resulting solution is stirred at 100°C for 18 hours and then stirred at 130°C for 18 hours, and then the reaction is completed by lowering the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(2-(4-methylpiperazine-1 -yl)pyridin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.019 g, 31.3%) in form of a brown solid.

¹ H NMR(400 MHz, CD₃OD) δ 9.27 (d,J=2.2 Hz, 1H), 8.67 (s, 1H), 8.53 (dd,J=8.2, 2.2 Hz, 1H), 8.17 (d,J=5.3 Hz, 1H), 7.62 (d,J=8.2 Hz, 1H), 7.39-7.13 (m, 3H), 5.94 (s, 2H), 3.64 (t,J=5.1 Hz, 4H), 2.61 (t,J=5.1 Hz, 4H), 2.38 (s, 3H);MCNR(ER) m/z 454.4 (M⁺+1).

The compounds of Table 137 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4582 except for the use of 2-(difluoromethyl)-5-(6-((4-(2-fluoropyridin-4-yl)-1H -1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reagent from Table 136.

Table 136 Example Connection no. Reagent Exit (%) 453 4591 1-ethylpiperazine 59 454 4592 1-isopropylpiperazine 50 455 4593 1-cyclopropylpiperazine 39 456 4594 1-(oxetan-3-yl)piperazine 48

Table 137 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 453 4591 2-(difluoromethyl)-5-(6-((4-(2-(4-ethylpiperazin-1-yl)pyridin-4-yl)-1H-1,2,3-triazol-1-yl)methyl) pyridin-3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.27 (dd, J=2.3, 0.9 Hz, 1H), 8.68 (s, 1H), 8.53 (dd, J=8 ,2, 2.2 Hz, 1H), 8.17 (d, J=5.3 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.40-7.13 (m, 3H), 5.94 (s, 2H), 3.67-3.60 (m, 4H), 2.64 (t, J=5.2 Hz, 4H), 2.53 (sq, J=7.3 Hz, 2H), 1.18 (t, J=7.2 Hz, 3H); MSNR (IER) m/z 468.4 (M ⁺ + H). 454 4592 2-(difluoromethyl)-5-(6-((4-(2-(4-isopropylpiperazin-1-yl)pyridin-4-yl)-1H-1,2,3-triazol-1-yl)methyl) pyridin-3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.27 (d, J=2.2 Hz, 1H), 8.68 (s, 1H), 8.53 (dd, J=8.2, 2 .2 Hz, 1H), 8.16 (d, J=5.3 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.40-7.13 (m, 3H ), 5.94 (s, 2H), 3.66-3.59 (m, 4H), 2.78-2.69 (m, 5H), 1.15 (d, J=6.5 Hz, 6H); MSNR (IER) m/z 482.4 (M ⁺ + H). 455 4593 2-(6-((4-(2-(4-cyclopropylpiperazin-1-yl)pyridin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl) -5-(difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.30-9.25 (m, 1H), 8.68 (s, 1H), 8.53 (dd, J=8.2, 2.2 Hz , 1H), 8.16 (d, J=5.3 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.40-7.13 (m, 3H), 5 .94 (s, 2H), 3.59 (t, J=5.1 Hz, 4H), 2.79 (t, J=5.2 Hz, 4H), 1.75 (tt, J=6, 7, 3.8 Hz, 1H), 0.61-0.46 (m, 4H); MSNR (IER) m/z 480.4 (M ⁺ + H). 456 4594 2-(difluoromethyl)-5-(6-((4-(2-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-4-yl)-1H-1,2,3-triazole -1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.30-9.25 (m, 1H), 8.68 (s, 1H), 8.54 (dd, J=8.2, 2.2 Hz , 1H), 8.17 (d, J=5.3 Hz, 1H), 7.63 (d, J=8.1 Hz, 1H), 7.34 (s, 1H), 7.26 (t , J=51.6 Hz, 1H), 7.15 (dd, J=5.3, 1.3 Hz, 1H), 5.94 (s, 2H), 4.76-4.66 (m, 4H), 3.69-3.62 (m, 4H), 3.57 (t, J=6.3 Hz, 1H), 2.51 (t, J=5.1 Hz, 4H); MSNR (IER) m/z 496.4 (M ⁺ + H).

Example 446: Synthesis of Compound 4583, 2-(4-((4-(2-(azetidin-1-ylmethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl) -5-(difluoromethyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 2-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4- yl)benzaldehyde

2-(4-(Azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.700 g, 2.776 mmol) prepared in step 1 of Example 2, and 2-ethynylbenzaldehyde (0.361 g, 2.776 mmol) dissolved in tert-butanol (5 ml)/water (5 ml) at room temperature, followed by sodium ascorbate (1.00 M solution, 0.278 ml, 0.278 mmol) and copper(II) sulfate pentahydrate (0.50 M solution, 0.056 ml, 0.028 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution is poured into the reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; hexane/ethyl acetate = 100-70%) and concentrated to give 2-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazole-2 -yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)benzaldehyde (0.850 g, 76.7%) in the form of a beige solid.

[Step 2] Synthesis of compound 4583

2-(1-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)benzaldehyde (0.050 g, 0.125 mmol) obtained in step 1, azetidine hydrogen chloride (0.023 g, 0.250 mmol) and sodium triacetoxyborohydride (0.133 g, 0.626 mmol) are dissolved in dichloromethane (1 ml) at room temperature, after which the resulting solution is stirred at the same temperature within 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-60%) and concentrated to give 2-(4-((4-(2-(azetidin-1-ylmethyl)phenyl)-1H- 1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.032 g, 58.0%) in the form of a light yellow oil.

¹ H NMR(400 MHz, CD₃OD) δ 8.44 (s, 1H), 8.05-7.94 (m, 2H), 7.68 (sq,J=7.7, 7.2 Hz, 2H), 7.50 (d,J=7.3 Hz, 1H), 7.46-7.40 (m, 2H), 7.25 (t,J=51.6 Hz, 1H), 5.90 (s, 2H), 3.97 (s, 2H), 3.71-3.36 (m, 4H), 2.20 (d,J=14.5 Hz, 2H);MCNR(ER) m/z 441.1 (M⁺+1).

The compounds of Table 139 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4583 except for the use of 2-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl )-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)benzaldehyde and the reagent from Table 138.

Table 138 example Connection no. Reagent Exit (%) 447 4585 Pyrrolidine 56 448 4586 2-oxa-6-azaspiro[3,3]heptane 43 449 4587 1-methylpiperazine 64 450 4588 1-ethylpiperazine 57 451 4589 Cyclobutanamine 38 452 4590 Oxetan-3-amine 56

Table 139 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 447 4585 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-(pyrrolidin-1-ylmethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl) -1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.57 (s, 1H), 8.05-7.94 (m, 2H), 7.78 (d, J =7.6 Hz, 1H), 7.70 (t, J =7.7 Hz, 1H), 7.60 (d, J =7.6 Hz, 1H), 7.55 (t, J =7.5 Hz, 1H), 7. 48 (t, J =7.4 Hz, 1H), 7.26 (t, J =51.6 Hz, 1H), 5.91 (s, 2H), 4.28 (s, 2H), 3, 15 (s, 4H), 2.09-1.95 (m, 4H); MSNR (ER) m/z 455.4 (M ⁺ +1). 448 4586 6-(2-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) benzyl)-2-oxa-6-azaspiro[3,3]heptane
^1H NMR (400 MHz, CD ₃ OD) δ 8.37 (s, 1H), 8.06-7.95 (m, 2H), 7.71-7.63 (m, 2H), 7.45 -7.11 (m, 4H), 5.89 (s, 2H), 4.70 (s, 4H), 3.71 (s, 2H), 3.39 (s, 4H); MSNR (ER) m/z 483.4 (M ⁺ +1). 449 4587 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.42 (s, 1H), 8.02 (dd, J =15.1, 8.9 Hz, 2H), 7.73 (t, J =7 .9 Hz, 2H), 7.45-7.38 (m, 2H), 7.37-7.12 (m, 2H), 5.89 (s, 2H), 3.49 (s, 2H) , 2.68-2.26 (m, 8H), 2.22 (s, 3H); MSNR (ER) m/z 484.5 (M ⁺ +1). 450 4588 2-(difluoromethyl)-5-(4-((4-(2-((4-ethylpiperazin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)- 3-fluorophenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.41 (s, 1H), 8.07-7.96 (m, 2H), 7.74 (t, J = 7.3 Hz, 2H), 7.44-7.13 (m, 4H), 5.89 (s, 2H), 3.49 (s, 2H), 2.65-2.24 (m, 10H), 1.05 (t, J =7.2 Hz, 3H); MSNR (ER) m/z 498.5 (M ⁺ +1). 451 4589 N-(2-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) benzyl)cyclobutanamine
¹ H NMR (400 MHz, CD ₃ OD) δ 8.39 (s, 1H), 8.05-7.94 (m, 2H), 7.66 (t, J = 7.7 Hz, 1H), 7.62-7.55 (m, 1H), 7.51 (dd, J =5.6, 3.5 Hz, 1H), 7.42 (dd, J =5.7, 3.4 Hz, 2H), 7.25 (t, J =51.6 Hz, 1H), 5.90 (s, 2H), 3.84 (s, 2H), 3.39-3.35 (m, 1H), 2.14 (d, J =9.1 Hz, 2H), 1.93-1.79 (m, 2H), 1.75-1.63 (m, 2H); MSNR (ER) m/z 455.4 (M ⁺ +1). 452 4590 N-(2-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) benzyl)oxetane-3-amine
¹ H NMR (400 MHz, CD ₃ OD) δ 8.40 (s, 1H), 8.05-7.94 (m, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.62-7.54 (m, 1H), 7.51-7.44 (m, 1H), 7.43-7.38 (m, 2H), 7.25 (t, J =51.6 Hz, 1H), 5.90 (s, 2H), 4.64 (t, J =6.8 Hz, 2H), 4.36 (t, J =6.4 Hz, 2H), 4.01 ( p, J =6.7 Hz, 1H), 3.82 (s, 2H); MSNR (ER) m/z 457.5 (M ⁺ +1).

Example 457: Synthesis of Compound 4595, 2-(difluoromethyl)-5-(6-((4-(2-methylisoindolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin- 3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2 ,3-triazol-4-yl)isoindoline-2-carboxylate

Tert-butyl 4-ethynylisoindolin-2-carboxylate (0.210 g, 0.863 mmol) prepared in Step 1 of Example 400, 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3, 4-oxadiazole (0.218 g, 0.863 mmol) prepared in step 1 of Example 16, sodium ascorbate (0.50 M solution in water, 0.173 ml, 0.086 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water , 0.017 ml, 0.017 mmol) was dissolved in tert-butanol (2 ml)/water (2 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give tert-butyl 4-(1-((5-(5-(difluoromethyl)-1,3,4 -oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)isoindoline-2-carboxylate (0.351 g, 82.1%) as a white solid.

[Step 2] Synthesis of 2-(difluoromethyl)-5-(6-((4-(isoindolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl) -1,3,4-oxadiazole

Tert-butyl 4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)isoindoline-2-carboxylate (0.351 g, 0.708 mmol) obtained in step 1 and trifluoroacetic acid (0.542 ml, 7.084 mmol) were dissolved in dichloromethane (3 ml) at room temperature, after which the resulting solution was stirred at same temperature for 3 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without additional purification process (2-(difluoromethyl)-5-(6-((4-(isoindolin-4-yl)-1H-1,2,3- triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole, 0.280 g, 100.0%, brown oil).

[Step 3] Synthesis of compound 4595

2-(Difluoromethyl)-5-(6-((4-(isoindolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3, 4-oxadiazole (0.056 g, 0.142 mmol) obtained in step 2 and formaldehyde (37.00% solution in water, 0.021 ml, 0.283 mmol) were dissolved in dichloromethane (1 ml), after which the resulting solution was stirred at room temperature in for 15 minutes, and then sodium triacetoxyborohydride (0.090 g, 0.425 mmol) was added thereto, and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate is purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0-10%) and concentrated, after which the resulting product is purified again by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0-10%) and concentrate to give 2-(difluoromethyl)-5-(6-((4-(2-methylisoindolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl )-1,3,4-oxadiazole (0.011 g, 19.0%) as a yellow solid.

¹ H NMR(400 MHz, CD₃OD) δ 9.28 (d,J=2.2 Hz, 1H), 8.53 (dd,J=8.2, 2.2 Hz, 1H), 8.45 (s, 1H), 7.72 (d,J=7.6 Hz, 1H), 7.60 (d,J=8.2 Hz, 1H), 7.36 (dd,J=14.2, 6.7 Hz, 1H), 7.30-7.12 (m, 2H), 5.94 (s, 2H), 4.28 (s, 2H), 4.04 (s, 2H), 2.68 (s, 3H);MCNR(ER) m/z 410.3 (M⁺+1).

The compounds of Table 141 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4595 except for the use of 2-(difluoromethyl)-5-(6-((4-(isoindolin-4-yl)-1H-1 ,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reagent from Table 140.

Table 140 Example Connection no. Reagent Exit (%) 458 4596 Acetaldehyde 65 459 4597 Acetone 86 460 4598 Cyclobutanone 49 461 4599 Oxetanone 72

Table 141 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 458 4596 2-(difluoromethyl)-5-(6-((4-(2-ethylisoindolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.27 (d, J=2.2 Hz, 1H), 8.60-8.48 (m, 2H), 7.74 (d, J=7 .7 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.46-7.36 (m, 1H), 7.35-7.11 (m, 2H), 5 .94 (s, 2H), 4.48 (s, 2H), 4.22 (s, 2H), 3.06 (kv, J=7.2 Hz, 2H), 1.32 (t, J= 7.2 Hz, 3H); MSNR (IER) m/z 424.3 (M ⁺ + H). 459 4597 2-(difluoromethyl)-5-(6-((4-(2-isopropylisoindolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.27 (d, J=2.2 Hz, 1H), 8.53 (dd, J=8.2, 2.3 Hz, 1H), 8, 47 (s, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.40-7.11 (m, 3H ), 5.94 (s, 2H), 4.32 (s, 2H), 4.09 (s, 2H), 2.92 (p, J=6.4 Hz, 1H), 1.28 (d , J=6.3 Hz, 6H); MSNR (IER) m/z 438.3 (M ⁺ + H). 460 4598 2-(6-((4-(2-cyclobutylisoindolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.30-9.25 (m, 1H), 8.53 (dd, J=8.2, 2.3 Hz, 1H), 8.45 (s , 1H), 7.72 (d, J=7.6 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.40-7.12 (m, 3H), 5 .94 (s, 2H), 4.22 (s, 2H), 3.99 (s, 2H), 3.44 (p, J=7.8 Hz, 1H), 2.20 (dkv, J= 7.6, 4.0 Hz, 2H), 2.15-2.01 (m, 2H), 1.94-1.78 (m, 2H); MSNR (IER) m/z 450.4 (M ⁺ + H). 461 4599 2-(difluoromethyl)-5-(6-((4-(2-(oxetan-3-yl)isoindolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin- 3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.27 (d, J=2.2 Hz, 1H), 8.52 (dd, J=8.2, 2.3 Hz, 1H), 8, 45 (s, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.41-7.11 (m, 3H ), 5.93 (s, 2H), 4.84 (d, J=6.7 Hz, 2H), 4.79-4.72 (m, 2H), 4.28 (d, J=1, 9 Hz, 2H), 4.12 (ddd, J=12.3, 6.7, 5.5 Hz, 1H), 4.05 (s, 2H); MSNR (IER) m/z 452.3 (M ⁺ + H).

Example 474: Synthesis of Compound 4633, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-1,2 ,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-fluoropyridin-4-yl)-1H-1,2,3-triazol-1-yl)methyl) phenyl)-1,3,4-oxadiazole

4-Ethynyl-2-fluoropyridine (0.490 g, 4.046 mmol) prepared in Step 1 of Example 181, 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole ( 1.089 g, 4.046 mmol) obtained in step 1 of Example 2, sodium ascorbate (0.50 M solution in water, 0.809 ml, 0.405 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.040 ml, 0.040 mmol) was dissolved in tert-butanol (7 ml)/water (7 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of ammonium chloride is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Dichloromethane (20 ml) and hexane (500 ml) were added to the resulting concentrate and stirred to filter the precipitated solid, washed with hexane and dried to give 2-(difluoromethyl)-5-(3-fluoro-4-((4- (2-fluoropyridin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (1.100 g, 69.7%) as light yellow solid matter.

[Step 2] Synthesis of compound 4633

2-(Difluoromethyl)-5-(3-fluoro-4-((4-(2-fluoropyridin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1, 3,4-oxadiazole (0.060 g, 0.154 mmol) obtained in step 1, 1-methylpiperazine (0.026 ml, 0.231 mmol) and N,N-diisopropylethylamine (0.040 ml, 0.231 mmol) are dissolved in dimethyl sulfoxide (1 ml) at 130 °C, after which the resulting solution is stirred at the same temperature for 18 hours, and then the reaction is completed by lowering the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-(4 -methylpiperazin-1-yl)pyridin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.041 g, 56.7%) in form of a brown solid.

¹ H NMR (400 MHz, CD₃OD) δ 8.61 (s, 1H), 8.16 (d,J=5.3 Hz, 1H), 8.00-7.94 (m, 2H), 7.62 (t,J=7.7 Hz, 1H), 7.37-7.11 (m, 3H), 5.87 (s, 2H), 3.63 (t,J=5.0 Hz, 4H), 2.59 (t,J=5.1 Hz, 4H), 2.37 (s, 3H);MCNR (ER) m/z 471.3 (M⁺+1).

The compounds of Table 143 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 4633 except for the use of 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-fluoropyridine-4- yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole and the reagent from Table 142.

Table 142 Example Connection no. Reagent Exit (%) 475 4634 1-ethylpiperazine 59 476 4635 1-isopropylpiperazine 74 477 4636 1-(oxetan-3-yl)piperazine 46

Table 143 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 475 4634 2-(difluoromethyl)-5-(4-((4-(2-(4-ethylpiperazin-1-yl)pyridin-4-yl)-1H-1,2,3-triazol-1-yl)methyl) -3-fluorophenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD₃OD) δ 8.61 (s, 1H), 8.15 (d,J=5.3 Hz, 1H), 8.00-7.94 (m, 2H), 7.62 (t,J=7.7 Hz, 1H), 7.37-7.11 (m, 3H), 5.86 (s, 2H), 3.63 (t,J=5.1 Hz, 4H), 2.63 (t,J=5.1 Hz, 4H), 2.52 (kv,J=7.2 Hz, 2H), 1.18 (t,J=7.2 Hz, 3H);MCNR (IER) m/z 485.2 (M⁺ + H). 476 4635 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-(4-isopropylpiperazin-1-yl)pyridin-4-yl)-1H-1,2,3-triazol-1- yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD₃OD) δ 8.61 (s, 1H), 8.15 (d,J=5.3 Hz, 1H), 8.00-7.94 (m, 2H), 7.62 (t,J=7.7 Hz, 1H), 7.37-7.11 (m, 3H), 5.87 (s, 2H), 3.62 (t,J=5.1 Hz, 4H), 2.79-2.70 (m, 5H), 1.15 (d,J=6.5 Hz, 6H);MCNR (IER) m/z 499.3 (M⁺ + H). 477 4636 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-4-yl)-1H-1,2 ,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD₃OD) δ 8.61 (s, 1H), 8.16 (d,J=5.3 Hz, 1H), 8.01-7.95 (m, 2H), 7.62 (t,J=7.7 Hz, 1H), 7.37-7.11 (m, 3H), 5.87 (s, 2H), 4.71 (dt,J=28.6, 6.4 Hz, 4H), 3.65 (t,J=5.1 Hz, 4H), 3.59-3.53 (m, 1H), 2.50 (t,J=5.0 Hz, 4H);MCNR (IER) m/z 513.3 (M⁺ + H).

Example 478: Synthesis of Compound 4640, 2-(4-((4-(2-(4-cyclobutylpiperazin-1-yl)pyridin-4-yl)-1H-1,2,3-triazol-1-yl)methyl )-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 4-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2, 3-triazol-4-yl)pyridin-2-yl)piperazine-1-carboxylate

2-(Difluoromethyl)-5-(3-fluoro-4-((4-(2-fluoropyridin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1, 3,4-oxadiazole (0.200 g, 0.512 mmol) prepared in step 1 of Example 474, tert-butyl piperazine-1-carboxylate (0.143 g, 0.769 mmol) and N,N-diisopropylethylamine (0.134 mL, 0.769 mmol) were dissolved in dimethyl sulfoxide (2 ml) at 130°C, after which the resulting solution was stirred at the same temperature for 18 hours, and then the reaction was completed by lowering the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give tert-butyl 4-(4-(1-(4-(5-(difluoromethyl)-1,3 ,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)piperazin-1-carboxylate (0.220 g, 77.1%) in form of a yellow solid.

[Step 2] Synthesis of 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-(piperazin-1-yl)pyridin-4-yl)-1H-1,2,3-triazole -1-yl)methyl)phenyl)-1,3,4-oxadiazole

Tert-butyl 4-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4 -yl)pyridin-2-yl)piperazin-1-carboxylate (0.178 g, 0.320 mmol) obtained in step 1 and trifluoroacetic acid (0.245 ml, 3.198 mmol) were dissolved in dichloromethane (2 ml) at room temperature, then the resulting solution is stirred at the same temperature for 18 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without additional purification process (2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-(piperazin-1-yl)pyridin- 4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole, 0.140 g, 95.9%, brown oil).

[Step 3] Synthesis of compound 4640

2-(Difluoromethyl)-5-(3-fluoro-4-((4-(2-(piperazin-1-yl)pyridin-4-yl)-1H-1,2,3-triazol-1-yl) Methyl)phenyl)-1,3,4-oxadiazole (0.070 g, 0.153 mmol) obtained in step 2 and cyclobutanone (0.023 ml, 0.307 mmol) were dissolved in dichloromethane (1 ml), after which the resulting solution was stirred at room temperature for 15 minutes, and then sodium triacetoxyborohydride (0.098 g, 0.460 mmol) was added thereto, and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give 2-(4-((4-(2-(4-cyclobutylpiperazin-1-yl)pyridin-4 -yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.046 g, 58.8%) as white solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.61 (s, 1H), 8.15 (d, J= 5.3 Hz, 1H), 8.01-7.94 (m, 2H), 7.62 (t, J= 7.7 Hz, 1H), 7.37-7.11 (m, 3H), 5.87 (s, 2H), 3.62 (t, J= 5.1 Hz , 4H), 2.90-2.82 (m, 1H), 2.52 (t, J= 5.1 Hz, 4H), 2.16-2.09 (m, 2H), 2.01- 1.93 (m, 2H), 1.82-1.75 (m, 2H); MSNR (ER) m/z 511.4 (M ⁺ +1).

Example 480: Synthesis of Compound 16789, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-1,2 ,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

2-(4-((4-(6-Chloropyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3 ,4-oxadiazole (0.100 g, 0.246 mmol) of compound 479, 1-methylpiperazine (0.041 ml, 0.369 mmol) and N,N-diisopropylethylamine (0.064 ml, 0.369 mmol) were dissolved in dimethyl sulfoxide (1 ml) at 130 °C, after whereupon the resulting solution is stirred at the same temperature for 18 hours, and then the reaction is completed by lowering the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(6-(4 -methylpiperazin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.016 g, 13.8%) in form of a brown solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.57 (d, J= 2.0 Hz, 1H), 8.36 (s, 1H), 8.03-7.95 (m, 3H), 7.60 (t, J= 7.7 Hz, 1H), 7.24 (t, J= 51.6 Hz, 1H), 6.92 (d, J= 9.0 Hz, 1H), 5, 84 (s, 2H), 3.63 (t, J= 5.0 Hz, 4H), 2.58 (t, J= 5.0 Hz, 4H), 2.37 (s, 3H); MSNR (ER) m/z 471.3 (M ⁺ +1).

Example 481: Synthesis of Compound 16797, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-fluoro-4-(piperazin-1-yl)phenyl)-1H-1,2,3 -triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 2-(4-bromo-2-fluorophenyl)-1,3-dioxolane

4-bromo-2-fluorobenzaldehyde (10.000 g, 49.259 mmol), p-toluenesulfonic acid (0.094 g, 0.493 mmol) and ethylene glycol (3.305 ml, 59.110 mmol) were dissolved in toluene (50 ml) at room temperature, and the resulting solution heated at reflux for 18 hours, and then the reaction is completed by reducing the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-20%) and concentrated to give 2-(4-bromo-2-fluorophenyl)-1,3-dioxolane (11.600 g, 95.3 %) in the form of a colorless oil.

[Step 2] Synthesis of tert-butyl 4-(4-(1,3-dioxolan-2-yl)-3-fluorophenyl)piperazine-1-carboxylate

2-(4-Bromo-2-fluorophenyl)-1,3-dioxolane (6.000 g, 24.286 mmol) obtained in step 1, tert-butyl piperazine-1-carboxylate (4.523 g, 24.286 mmol), tris(dibenzylideneacetone) dipalladium (Pd2(dba)3, 0.222 g, 0.243 mmol), rac-BINAP (0.302 g, 0.486 mmol) and sodium tert-butoxide (4.668 g, 48.571 mmol) are dissolved in toluene (50 ml) at room temperature, then the resulting solution is heated at reflux for 18 hours, and then the reaction is completed by reducing the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl 4-(4-(1,3-dioxolan-2-yl)-3-fluorophenyl) piperazine-1-carboxylate (6.400 g, 74.8%) as a brown solid.

[Step 3] Synthesis of tert-butyl 4-(3-fluoro-4-formylphenyl)piperazine-1-carboxylate

Tert-butyl 4-(4-(1,3-dioxolan-2-yl)-3-fluorophenyl)piperazine-1-carboxylate (6.400 g, 18.161 mmol) obtained in step 2 and hydrochloric acid (1.00 M solution, 54.482 ml, 54.482 mmol) was dissolved in methanol (25 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 6 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without further purification (tert-butyl 4-(3-fluoro-4-formylphenyl)piperazine-1-carboxylate, 4.200 g, 75.0%, brown solid ).

[Step 4] Synthesis of tert-butyl 4-(4-(2,2-dibromovinyl)-3-fluorophenyl)piperazine-1-carboxylate

Tert-butyl 4-(3-fluoro-4-formylphenyl)piperazine-1-carboxylate (4.300 g, 13.945 mmol) obtained in step 3, carbon tetrabromide (9.249 g, 27.890 mmol) and triphenylphosphine triphenylphosphine (10.973 g, 41.836 mmol ) is dissolved in dichloromethane (100 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0-20%) and concentrated to give tert-butyl 4-(4-(2,2-dibromovinyl)-3-fluorophenyl)piperazine-1- carboxylate (4.300 g, 66.4%) in the form of a yellow solid.

[Step 5] Synthesis of tert-butyl 4-(4-ethynyl-3-fluorophenyl)piperazine-1-carboxylate

Tert-butyl 4-(4-(2,2-dibromovinyl)-3-fluorophenyl)piperazine-1-carboxylate (4.200 g, 9.048 mmol) obtained in step 4, and 2,3,4,6,7,8 ,9,10-Octahydropyrimido[1,2-a]azepine (DBU, 4.060 ml, 27.145 mmol) was dissolved in acetonitrile (100 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. The solvent is removed from the reaction mixture under reduced pressure, after which a saturated aqueous ammonium chloride solution is poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane=0-20%) and concentrated to give tert-butyl 4-(4-ethynyl-3-fluorophenyl)piperazine-1-carboxylate (1,400 g, 50 .8%) in the form of a yellow solid.

[Step 6] Synthesis of tert-butyl 4-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2, 3-triazol-4-yl)-3-fluorophenyl)piperazine-1-carboxylate

Tert-butyl 4-(4-ethynyl-3-fluorophenyl)piperazine-1-carboxylate (0.710 g, 2.333 mmol) prepared in step 5, 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1 ,3,4-oxadiazole (0.645 g, 2.566 mmol) obtained in step 1 of Example 2, copper(II) sulfate pentahydrate (0.006 g, 0.023 mmol) and sodium ascorbate (0.046 g, 0.233 mmol) were dissolved in tert-butanol ( 10 ml)/water (10 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl 4-(4-(1-(4-(5-(difluoromethyl)-1,3 ,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-3-fluorophenyl)piperazine-1-carboxylate (0.300 g, 23.1%) as yellow solid.

[Step 7] Synthesis of compound 16797

Tert-butyl 4-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4 -yl)-3-fluorophenyl)piperazine-1-carboxylate (1.000 g, 1.744 mmol) obtained in step 6 and trifluoroacetic acid (1.335 ml, 17.435 mmol) were dissolved in dichloromethane (100 ml) at room temperature, after which the resulting the solution is stirred at the same temperature for 12 hours. A saturated aqueous solution of ammonium chloride is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Then, the resulting product is used without an additional purification process (2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-fluoro-4-(piperazin-1-yl)phenyl)-1H-1, 2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole, 0.660 g, 80.0%, yellow solid).

¹ H NMR(400 MHz, CDCl₃) δ 8.10 (t, J=8.8 Hz, 1H), 7.88-7.86 (m, 3H), 7.38 (t, J=7.7 Hz, 1H), 7.04 -6.75 (m, 2H), 6.60 (d, J=16.4 Hz, 1H), 5.70 (s, 2H), 3.25 (t, J=4.9 Hz, 4H) , 2.57 (t, J=4.8 Hz, 4H);MCNR(ER) m/z 473.4 (M⁺+1).

Example 484: Synthesis of Compound 17058, 2-(4-((4-(5-(1H-pyrazol-4-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl )-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole

2-(4-((4-(5-(1H-pyrazol-4-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)- 5-(difluoromethyl)-1,3,4-oxadiazole (0.080 g, 0.177 mmol) of compound 183, (1H-pyrazol-4-yl)boronic acid (0.040 g, 0.355 mmol), [1,1'-bis( di-tert-butylphosphino)ferrocene]palladium(II) dichloride (Pd(dtbpf)Cl ₂ , 0.012 g, 0.018 mmol) and cesium carbonate (0.103 g, 0.532 mmol) are mixed in 1,4-dioxane (3 ml)/water (1 ml) at room temperature, after which the resulting mixture is irradiated with microwaves, then heated at 100°C for 10 minutes, and then the reaction is completed by reducing the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give 2-(4-((4-(5-(1H-pyrazol-4-yl)pyridin-3 -yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.009 g, 11.6%) as brown solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.88 (d, J = 2.0 Hz, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.66 (s, 1H), 8.50 (t, J= 2.0 Hz, 1H), 8.22-8.13 (m, 2H), 8.02-7.96 (m, 2H), 7.65 (t , J= 7.7 Hz, 1H), 7.24 (t, J= 51.6 Hz, 1H), 5.90 (s, 2H); MSNR (ER) m/z 439.1 (M ⁺ +1).

Example 487: Synthesis of compound 17255 , 4-((5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazole -4-yl)-1H-indol-3-yl)methyl)morpholine

Pyrrolidine (0.020 g, 0.281 mmol) and formaldehyde (37.00%, 0.025 g, 0.309 mmol) are dissolved in acetic acid (0.5 ml)/methanol (0.5 ml), and the resulting solution is stirred at 0°C for 0.4 hours, and then 2-(4-((4-(1H-indol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl is added thereto )-5-(difluoromethyl)-1,3,4-oxadiazole (0.069 g, 0.169 mmol) obtained in Example 172, and then stirred at room temperature for 18 hours. An aqueous solution of potassium 2N-hydroxide is poured into the resulting reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-50%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(pyrrolidine -1-ylmethyl)-1H-indol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.035 g, 25.2%) in the form of a light brown solid.

¹ H NMR(400 MHz, CD₃OD) δ 8.41 (s, 1H), 8.27-8.20 (m, 1H), 8.21-8.15 (m, 3H), 7.70-7.61 (m, 4H) , 7.54 (dd,J=8.6, 0.7 Hz, 1H), 7.24 (t,J=51.6 Hz, 1H), 5.81 (d,J=8.1 Hz, 2H), 4.61 (s, 2H), 4.12-3.97 (m, 2H), 3.80-3.60 (m, 4H), 3.54-3, 40 (m, 2H);MCNR(ER) m/z 492.2 (M⁺+1).

Example 490: Synthesis of 17347, 2-(difluoromethyl)-5-(5-fluoro-6-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl) -1,3,4-oxadiazole

[Step 1] Synthesis of 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

2-(6-(bromomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.200 g, 0.649 mmol) dissolved in acetone (4 ml)/water (2 ml ) at 0°C, after which sodium azide (0.042 g, 0.649 mmol) was added to the resulting solution and stirred at room temperature for 3 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)- 1,3,4-oxadiazole (0.040 g, 22.8%) as a white solid.

[Step 2] Synthesis of compound 17347

Ethynylbenzene (0.016 ml, 0.147 mmol), 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.040 g, 0.147 mmol), obtained from step 1, sodium ascorbate (0.50 M solution in water, 0.029 ml, 0.015 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.001 ml, 0.001 mmol) are dissolved in tert-butanol (0. 5 ml)/water (0.5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. An aqueous solution of ammonium chloride N-carbonate is poured into the resulting reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Dichloromethane (3 ml) and hexane (50 ml) were added to the resulting concentrate and stirred to filter the precipitated solid, washed with hexane and dried to give 2-(difluoromethyl)-5-(5-fluoro-6-((4- phenyl-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.012 g, 21.9%) as a yellow oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (s, 1H), 8.69 (s, 1H), 8.50 (dd, J= 9.8, 1.6 Hz, 1H) , 7.87 (d, J= 7.3 Hz, 2H), 7.72-7.44 (m, 3H), 7.35 (t, J= 7.4 Hz, 1H), 6.00 ( d, J= 1.4 Hz, 2H); MSNR (ER) m/z 373.2 (M ⁺ +1).

The compounds of Table 145 are synthesized in accordance with substantially the same method as described in the synthesis of compounds 3657, 3658, 3736 and 17347 using azide compound 1-2 and acetylene compound 2-3 in Table 144 as reagents, and using click -reactions.

Table 144 Example Connection no. Reagent (acetylene) Reagent (azide) Exit (%) 3 3659 3-ethynylbenzoic acid 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 47 4 3660 3-ethynylbenzoic acid 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 56 5 3661 4-ethynyl-1,2-difluorobenzene 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 56 6 3662 4-ethynyl-1,2-difluorobenzene 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 62 7 3695 1-ethynyl-3,5-bis(trifluoromethyl)benzene 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 51 8 3696 1-ethynyl-3,5-bis(trifluoromethyl)benzene 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 53 9 3697 Tert-butyl(3-ethynylphenyl)carbamate 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 38 10 3698 Tert-butyl(3-ethynylphenyl)carbamate 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 50 eleven 3731 4-ethynylbenzoic acid 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 56 12 3732 4-ethynylbenzoic acid 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 68 13 3733 1-ethynyl-4-methylbenzene 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 58 14 3734 Tert-butyl-3-ethynylpyrrolidine-1-carboxylate 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 53 15 3735 Tert-butyl-4-ethynylpiperidine-1-carboxylate 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 61 17 3737 4-ethynyl-1,2-difluorobenzene 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 54 18 3738 1-ethynyl-4-methylbenzene 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 58 19 3739 3-ethynylbenzoic acid 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 71 20 3741 Tert-butyl (3-ethynylphenyl)carbamate 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 80 34 3820 Tert-butyl 3-ethynylpyrrolidine-1-carboxylate 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 52 35 3822 2-(but-3-yn-1-yl)imidazo[1,2-a]pyridine 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 66 43 3831 Pent-1-in 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 56 44 3832 Hex-1-in 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 62 45 3833 Pent-1-in-1-ol 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 73 46 3834 Hex-5-in-1-ol 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 56 57 3846 Ethynylcyclopentane 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 47 58 3853 1-ethynyl-2-fluorobenzene 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 27 59 3854 1-ethynyl-3-fluorobenzene 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 50 60 3855 1-ethynyl-4-fluorobenzene 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 73 61 3856 1-ethynyl-3-methylbenzene 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 22 62 3860 1-ethynyl-2-methylbenzene 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 69 63 3861 2-ethynylfuran 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 70 66 3879 1-ethynylcyclohex-1-ene 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 63 67 3880 Ethynylcyclohexane 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 68 83 3902 2-ethynylthiophene 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 39 91 3926 Tert-butyl 3-ethynyl azetidin-1-carboxylate 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 85 105 3960 5-ethynylpyrimidine 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 84 106 3961 Tert-butyl 3-ethynylpiperidine-1-carboxylate 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 60 114 3985 4-ethynyl-1H-pyrazole 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 8 121 3999 Tert-butyl 4-ethynyl-4-fluoropiperidine-1-carboxylate 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 85 122 4000 Tert-butyl 4-(prop-2-yn-1-yl)piperidine-1-carboxylate 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 92 197 4276 3-ethynoxetan-3-ol 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 87 198 4277 3-ethynyltetrahydrofuran-3-ol 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 81 199 4278 3-ethynoxetan-3-ol 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 89 200 4279 3-ethynyltetrahydrofuran-3-ol 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 90 238 4336 1-(3-ethynylphenyl)-4-methylpiperazine 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 55 239 4337 1-(3-ethynylphenyl)-4-methylpiperazine 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 55 240 4338 4-(3-ethynylphenyl)morpholine 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 51 241 4339 4-(3-ethynylphenyl)morpholine 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 61 242 4340 6-ethynyl-1H-indazole 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 58 243 4341 6-ethynyl-1H-indazole 2-(6-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 60 244 4342 6-ethynyl-1H-indazole 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 55 245 4343 5-ethynyl-1H-indazole 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 55 246 4344 5-ethynyl-1H-indazole 2-(6-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 56 247 4345 5-ethynyl-1H-indazole 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 59 248 4346 4-ethynyl-1H-indazole 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 60 249 4347 4-ethynyl-1H-indazole 2-(6-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 54 250 4348 4-ethynyl-1H-indazole 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 59 395 4524 5-ethynyl-1H-pyrrolo[2,3-b]pyridine 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 49 396 4525 5-ethynyl-1H-pyrrolo[2,3-b]pyridine 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 43 397 4526 4-ethynyl-1H-pyrrolo[2,3-b]pyridine 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 51 398 4527 4-ethynyl-1H-pyrrolo[2,3-b]pyridine 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 54 479 16781 2-chloro-5-ethynylpyridine 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 79 482 16928 5-bromo-2-ethynylpyridine 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 56 483 16930 3-bromo-5-ethynylpyridine 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 89 488 17261 4-ethynyl-1H-pyrazole 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 3 521 17983 2-ethynylpyridine 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 57 522 17984 2-ethynylthiophene 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 50 534 18256 2-ethynylpyridine 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 71 535 18258 2-ethynylthiophene 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 41 547 18470 4-ethynyl-2,2-difluorobenzo[d][1,3]dioxole 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 56 557 18868 Tert-butyl 4-(3-ethynylphenyl)piperidine-1-carboxylate 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 82 566 18918 6-ethynyl-1H-indole 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole thirty 567 18919 6-ethynyl-1H-indazole 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 31 568 18920 5-ethynyl-1H-indazole 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5 -(difluoromethyl)-1,3,4-oxadiazole 32 569 18921 4-ethynyl-1H-indole 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 33 579 19058 4-ethynyl-1H-indazole 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 31

Table 145 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 3 3659 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)benzoic acid
^1H NMR (400 MHz, CD ₃ OD) δ 8.54 (s, 1H), 8.51 (t, J =1.8 Hz, 1H), 8.20-8.14 (m, 2H), 8.12-8.06 (m, 1H), 8.03 (dt, J =7.9, 1.3 Hz, 1H), 7.63 (d, J =8.3 Hz, 2H), 7 .58 (t, J =7.7 Hz, 1H), 7.23 (t, J =51.6 Hz, 1H), 5.82 (s, 2H); MSNR (ER) m/z 398.3 (M ⁺ +1). 4 3660 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)benzoic acid
^1H NMR (400 MHz, CD ₃ OD) δ 8.55 (s, 1H), 8.52 (t, J =1.7 Hz, 1H), 8.09 (ddd, J =7.8, 1 .9, 1.2 Hz, 1H), 8.03 (dt, J =7.8, 1.4 Hz, 1H), 8.00 (dd, J =7.9, 1.7 Hz, 1H) , 7.96 (dd, J =10.1, 1.6 Hz, 1H), 7.60 (dt, J =15.7, 7.6 Hz, 2H), 7.24 (t, J =51 .6 Hz, 1H), 5.87 (s, 2H); MSNR (ER) m/z 416.2 (M ⁺ +1). 5 3661 2-(difluoromethyl)-5-(4-((4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (700 MHz, CD ₃ OD) δ 8.47 (s, 1H), 8.19-8.15 (m, 2H), 7.78 (ddd, J = 11.7, 7.6, 2.1 Hz, 1H), 7.66 (dddd, J =8.6, 3.8, 2.2, 1.4 Hz, 1H), 7.64-7.59 (m, 2H), 7 .36 (dt, J =10.5, 8.5 Hz, 2H), 7.24 (t, J =51.6 Hz, 1H), 5.80 (s, 2H); MSNR (ER) m/z 390.3 (M ⁺ +1). 6 3662 2-(difluoromethyl)-5-(4-((4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-1,3,4 -oxadiazole
¹ H NMR (700 MHz, CD ₃ OD) δ 8.48 (s, 1H), 8.00 (dd, J =8.0, 1.7 Hz, 1H), 7.96 (dd, J =10 ,1, 1.6 Hz, 1H), 7.78 (dddd, J =11.6, 7.6, 2.1 Hz, 1H), 7.67 (dddd, J =8.6, 4.2 , 2.2, 1.4 Hz, 1H), 7.61 (t, J =7.7 Hz, 1H), 7.36 (dt, J =10.5, 8.5 Hz, 1H), 7 .25 (t, J =51.6 Hz, 1H), 5.85 (s, 2H); MSNR (ER) m/z 408.2 (M ⁺ +1). 7 3695 2-(4-((4-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3, 4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 8.30 (s, 2H), 8.20 (d, J =8.2 Hz, 2H), 7.92 (s, 1H), 7.86 (s , 1H), 7.53 (d, J =8.2 Hz, 2H), 6.94 (s, 1H), 5.75 (s, 2H); MSNR (ER) m/z 489.9 (M ⁺ +1). 8 3696 2-(4-((4-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1 ,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 8.33-8.28 (m, 2H), 8.03-7.93 (m, 4H), 7.86 (s, 1H), 7.55 ( t, J =7.7 Hz, 1H), 6.95 (t, J =51.7 Hz, 1H), 5.79 (s, 2H); MSNR (ER) m/z 508.2 (M ⁺ +1). 9 3697 Tert-butyl (3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl )phenyl)carbamate
^1H NMR (400 MHz, CDCl ₃ ) δ 8.23 (s, 1H), 8.18 (d, J =8.0 Hz, 2H), 8.06 (s, 1H), 7.50 (d , J =8.1 Hz, 2H), 7.38 (d, J =8.7 Hz, 1H), 6.94 (t, J =51.7 Hz, 1H), 6.61 (s, 1H ), 5.73 (s, 2H), 1.55 (s, 9H); MSNR (ER) m/z 487.0 (M ⁺ +1). 10 3698 Tert-butyl (3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl) carbamate
^1H NMR (400 MHz, CDCl ₃ ) δ 8.31 (s, 1H), 8.05 (d, J =2.5 Hz, 1H), 7.98-7.90 (m, 5H), 7 .51-7.43 (m, 2H), 7.39 (d, J =8.7 Hz, 1H), 6.94 (t, J =51.7 Hz, 1H), 6.60 (s, 1H), 5.77 (s, 2H), 1.55 (s, 9H); MSNR (ER) m/z 467.2 (M ⁺ +1). eleven 3731 4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)benzoic acid
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.15-8.04 (m, 4H), 7.90 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7 .48 (d, J =8.2 Hz, 2H), 6.92 (t, J =51.7 Hz, 1H), 5.68 (s, 2H); MSNR (ER) m/z 398.3 (M ⁺ +1). 12 3732 4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)benzoic acid
¹ H NMR (400 MHz, CD ₃ OD) δ 8.57 (s, 1H), 8.14-8.07 (m, 2H), 7.98 (tt, J =9.8, 2.2 Hz , 4H), 7.62 (t, J =7.7 Hz, 1H), 7.24 (t, J =51.6 Hz, 1H), 5.88 (s, 2H); MSNR (ER) m/z 416.0 (M ⁺ +1). 13 3733 2-(difluoromethyl)-5-(3-fluoro-4-((4-(p-tolyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4- oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93-7.85 (m, 2H), 7.83 (d, J =1.8 Hz, 1H), 7.66 (dd, J =8, 0, 1.8 Hz, 2H), 7.45 (t, J =7.7 Hz, 1H), 7.21 (d, J =7.6 Hz, 2H), 6.92 (t, J = 51.9, 1.9 Hz, 1H), 5.70 (s, 2H), 2.96 (d, J =1.9 Hz, 3H); MSNR (ER) m/z 386.3 (M ⁺ +1). 14 3734 Tert-butyl 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) pyrrolidine-1-carboxylate
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90 (t, J =9.1 Hz, 2H), 7.48-7.39 (m, 2H), 6.93 (t, J =51, 6, 1.0 Hz, 1H), 5.64 (s, 2H), 3.78 (dd, J =10.4, 7.4 Hz, 1H), 3.56-3.48 (m, 2H ), 3.42-3.33 (m, 3H), 2.30 (s, 1H), 1.44 (d, J =1.0 Hz, 9H); MSNR (ER) m/z 465.3 (M ⁺ +1). 15 3735 Tert-butyl 4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) piperidine-1-carboxylate
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.92-7.82 (m, 2H), 7.45-7.36 (m, 2H), 6.92 (t, J =51.6 Hz, 1H), 5.62 (s, 2H), 4.10 (d, J =13.4 Hz, 2H), 2.95-2.78 (m, 3H), 1.97 (d, J =13 ,2 Hz, 2H), 1.60-1.54 (m, 1H), 1.51 (dd, J =12.3, 4.3 Hz, 1H), 1.41 (d, J =1, 0 Hz, 9H); MSNR (ER) m/z 479.4 (M ⁺ +1). 17 3737 2-(difluoromethyl)-5-(6-((4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3, 4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 9.33-9.28 (m, 1H), 8.42 (dd, J =8.2, 2.2 Hz, 1H), 8.02 (s, 1H), 7.70-7.63 (m, 1H), 7.52 (s, 1H), 7.48 (d, J =8.2 Hz, 1H), 7.26-7.16 (m , 2H), 6.95 (t, J =51.6 Hz, 1H), 5.80 (s, 2H); MSNR (ER) m/z 391.1 (M ⁺ +1). 18 3738 2-(difluoromethyl)-5-(6-((4-(p-tolyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4- oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.30 (d, J = 2.2 Hz, 1H), 8.41 (dd, J = 8.2, 2.2 Hz, 1H), 7.99 (s, 1H), 7.69 (d, J =7.9 Hz, 2H), 7.44 (d, J =8.2 Hz, 1H), 7.23 (d, J =7.9 Hz , 2H), 6.95 (t, J =51.6 Hz, 1H), 5.80 (s, 2H), 2.65 (t, J =2.5 Hz, 3H); MSNR (ER) m/z 369.2 (M ⁺ +1). 19 3739 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2yl)methyl-1H-1,2,3-triazol-4-yl)benzoic acid
^1H NMR (400 MHz, CD ₃ OD) δ 9.29 (dd, J =2.2, 0.9 Hz, 1H), 8.59 (s, 1H), 8.53 (dd, J =8 ,2, 2.2 Hz, 2H), 8.13-8.06 (m, 1H), 8.06-8.00 (m, 1H), 7.64-7.55 (m, 2H), 7.26 (t, J =51.6 Hz, 1H), 5.94 (s, 2H); MSNR (ER) m/z 399.2 (M ⁺ +1). 20 3741 Tert-butyl (3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazole -4-yl)phenyl)carbamate
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.30 (dd, J = 2.3, 0.9 Hz, 1H), 8.41 (dd, J = 8.2, 2.2 Hz, 1H) , 8.10 (s, 1H), 7.75 (t, J =2.0 Hz, 1H), 7.47 (d, J =8.1 Hz, 1H), 7.45-7.41 ( m, 2H), 7.32 (t, J =7.9 Hz, 1H), 6.95 (t, J =51.6 Hz, 1H), 5.80 (s, 2H), 1.51 ( s, 9H); MSNR (ER) m/z 470.1 (M ⁺ +1). 34 3820 Tert-butyl 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)pyrrolidine-1-carboxylate
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.19 (d, J = 2.2 Hz, 1H), 8.47 (dd, J = 8.2, 2.3 Hz, 1H), 8 .12 (s, 1H), 7.58 (t, J =51.3 Hz, 1H), 7.49 (d, J =8.2 Hz, 1H), 5.83 (s, 2H), 4 .10 (kv, J =5.3 Hz, 1H), 3.67 (kv, J =8.1 Hz, 1H), 3.54-3.45 (m, 1H), 3.41 (ddd, J =10.8, 8.0, 4.2 Hz, 1H), 3.31 (s, 2H), 2.22 (d, J =7.8 Hz, 1H), 2.01 (s, 1H ), 1.41 (s, 9H); MSNR (ER) m/z 448.4 (M ⁺ +1). 35 3822 2-(difluoromethyl)-5-(6-((4-(2-(imidazo[1,2-a]pyridin-2-yl)ethyl)-1H-1,2,3-triazol-1-yl) methyl)pyridin-3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.19 (d, J = 2.2 Hz, 1H), 8.47 (dd, J = 8.2, 2.3 Hz, 1H), 8 .12 (s, 1H), 7.58 (t, J =51.3 Hz, 1H), 7.49 (d, J =8.2 Hz, 1H), 5.83 (s, 2H), 4 .10 (kv, J =5.3 Hz, 1H), 3.67 (kv, J =8.1 Hz, 1H), 3.54-3.45 (m, 1H), 3.41 (ddd, J =10.8, 8.0, 4.2 Hz, 1H), 3.31 (s, 2H), 2.22 (d, J =7.8 Hz, 1H), 2.01 (s, 1H ), 1.41 (s, 9H); MSNR (ER) m/z 423.2 (M ⁺ +1). 43 3831 2-(difluoromethyl)-5-(6-((4-propyl-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.33 (d, J = 1.6 Hz, 1H), 8.40 (dd, J = 8.2, 2.2 Hz, 1H), 7.49 (s, 1H), 7.33 (d, J =8.2 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H), 5.75 (s, 2H), 2.75 (t, J =7.6 Hz, 2H), 1.83-1.63 (m, 2H), 1.00 (t, J =7.4 Hz, 3H); MSNR (ER) m/z 321.0 (M ⁺ +1). 44 3832 2-(6-((4-butyl-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.33 (dd, J = 2.2, 0.7 Hz, 1H), 8.40 (dd, J = 8.2, 2.2 Hz, 1H) , 7.48 (s, 1H), 7.33 (d, J =8.2 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6, 83 (s, 0.3H), 5.75 (s, 2H), 2.84-2.68 (m, 2H), 1.69 (ddd, J = 13.0, 8.5, 6.5 Hz, 2H), 1.41 (dkv, J =14.6, 7.4 Hz, 2H), 0.96 (t, J =7.4 Hz, 3H); MSNR (ER) m/z 335.3 (M ⁺ +1). 45 3833 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl )propan-1-ol
^1H NMR (400 MHz, CDCl ₃ ) δ 9.41-9.25 (m, 1H), 8.41 (dd, J =8.2, 2.2 Hz, 1H), 7.57 (s, 1H), 7.38 (d, J =8.2 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H ), 5.76 (s, 2H), 3.74 (t, J =6.1 Hz, 2H), 2.90 (t, J =7.3 Hz, 2H), 2.71 (s, 1H ), 2.09-1.87 (m, 2H); MSNR (ER) m/z 337.2 (M ⁺ +1). 46 3834 4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl )butan-1-ol
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.32 (d, J = 1.5 Hz, 1H), 8.40 (dd, J = 8.2, 2.2 Hz, 1H), 7.54 (s, 1H), 7.36 (d, J =8.2 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H), 5.75 (s, 2H), 3.70 (t, J =6.4 Hz, 2H), 2.81 (t, J =7.5 Hz, 2H), 2.31 ( s, 1H), 1.89-1.73 (m, 2H), 1.73-1.60 (m, 2H); MSNR (ER) m/z 351.2 (M ⁺ +1). 57 3846 2-(6-((4-cyclopentyl-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.34 (d, J = 1.6 Hz, 1H), 8.40 (dd, J = 8.2, 2.2 Hz, 1H), 7.47 (s, 1H), 7.35 (d, J =8.2 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H), 5.75 (s, 2H), 3.24 (dd, J =16.0, 8.2 Hz, 1H), 2.13 (dd, J =10.6, 6.4 Hz , 2H), 1.91-1.55 (m, 6H); MSNR (ER) m/z 347.3 (M ⁺ +1). 58 3853 2-(difluoromethyl)-5-(6-((4-(2-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4- oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.19 (dd, J=2.3, 0.9 Hz, 1H), 8.62 (d, J=3.8 Hz, 1H), 8 .48 (dd, J=8.2, 2.3 Hz, 1H), 8.16 (td, J=7.6, 1.7 Hz, 1H), 7.57 (t, J=51.3 Hz, 1H), 7.55 (dd, J=8.2, 0.8 Hz, 1H), 7.44-7.39 (m, 1H), 7.39-7.31 (m, 2H) , 5.98 (s, 2H); MSNR (IER) m/z 373.2 (M ⁺ + H). 59 3854 2-(difluoromethyl)-5-(6-((4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4- oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.19 (dd, J=2.2, 0.8 Hz, 1H), 8.79 (s, 1H), 8.49 (dd, J= 8.2, 2.3 Hz, 1H), 7.77-7.65 (m, 2H), 7.62-7.42 (m, 3H), 7.18 (dddd, J=9.2, 8.3, 2.7, 1.0 Hz, 1H), 5.94 (s, 2H); MSNR (IER) m/z 373.2 (M ⁺ + H). 60 3855 2-(difluoromethyl)-5-(6-((4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4- oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.19 (dd, J=2.3, 0.8 Hz, 1H), 8.71 (s, 1H), 8.48 (dd, J= 8.2, 2.3 Hz, 1H), 7.96-7.87 (m, 2H), 7.71-7.44 (m, 2H), 7.35-7.24 (m, 2H) , 5.93 (s, 2H); MSNR (IER) m/z 373.2 (M ⁺ + H). 61 3856 2-(difluoromethyl)-5-(6-((4-(m-tolyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4- oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.19 (dd, J=2.3, 0.9 Hz, 1H), 8.68 (s, 1H), 8.48 (dd, J= 8.2, 2.3 Hz, 1H), 7.73-7.68 (m, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.60-7.44 (m , 2H), 7.33 (t, J=7.6 Hz, 1H), 7.16 (ddt, J=7.5, 1.9, 0.9 Hz, 1H), 5.92 (s, 2H), 2.36 (s, 3H); MSNR (IER) m/z 369.2 (M ⁺ + H). 62 3860 2-(difluoromethyl)-5-(6-((4-(o-tolyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4- oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.21 (dd, J=2.2, 0.8 Hz, 1H), 8.57 (s, 1H), 8.49 (dd, J= 8.2, 2.3 Hz, 1H), 7.81-7.77 (m, 1H), 7.58 (t, J=51.3 Hz, 1H), 7.55 (dd, J=8 ,3, 0.9 Hz, 1H), 7.34-7.25 (m, 3H), 5.95 (s, 2H), 2.46 (d, J=0.6 Hz, 3H); MSNR (IER) m/z 369.2 (M ⁺ + H). 63 3861 2-(difluoromethyl)-5-(6-((4-(furan-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3, 4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.19 (dd, J=2.3, 0.8 Hz, 1H), 8.56 (s, 1H), 8.49 (dd, J= 8.2, 2.3 Hz, 1H), 7.77 (dd, J=1.8, 0.8 Hz, 1H), 7.72-7.44 (m, 2H), 6.83 (dd , J=3.3, 0.8 Hz, 1H), 6.62 (dd, J=3.3, 1.8 Hz, 1H), 5.94 (s, 2H); MSNR (IER) m/z 345.1 (M ⁺ + H). 66 3879 2-(6-((4-(cyclohex-1-en-1-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)- 1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.32 (d, J = 1.6 Hz, 1H), 8.38 (dd, J = 8.2, 2.2 Hz, 1H), 7.59 (s, 1H), 7.33 (d, J =8.2 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H), 6.60-6.52 (m, 1H), 5.76 (s, 2H), 2.45-2.33 (m, 2H), 2.27-2.15 (m, 2H), 1.83-1.73 (m, 2H), 1.72-1.62 (m, 2H); MSNR (ER) m/z 359.26 (M ⁺ +1). 67 3880 2-(6-((4-cyclohexyl-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 9.41-9.27 (m, 1H), 8.40 (dd, J =8.2, 2.2 Hz, 1H), 7.45 (s, 1H), 7.34 (d, J =8.2 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H ), 5.75 (s, 2H), 2.81 (dd, J =9.1, 5.4 Hz, 1H), 2.09 (d, J =8.1 Hz, 2H), 1.82 (dd, J =8.4, 3.7 Hz, 2H), 1.75 (d, J =12.6 Hz, 1H), 1.51-1.34 (m, 4H), 1.34- 1.19 (m, 1H); MSNR (ER) m/z 361.33 (M ⁺ +1). 83 3902 2-(difluoromethyl)-5-(6-((4-(thiophen-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3, 4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.28 (dd, J=2.2, 0.9 Hz, 1H), 8.53 (dd, J=8.2, 2.2 Hz, 1H ), 8.40 (s, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.48-7.42 (m, 2H), 7.39-7.09 (m, 2H), 5.90 (s, 2H); MSNR (IER) m/z 361.2 (M ⁺ + H). 91 3926 Tert-butyl 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)azetidine-1-carboxylate
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.19 (dd, J=2.3, 0.8 Hz, 1H), 8.47 (dd, J=8.2, 2.3 Hz, 1H), 8.23 (s, 1H), 7.58 (t, J=51.3 Hz, 1H), 7.50 (dd, J=8.2, 0.9 Hz, 1H), 5, 85 (s, 2H), 4.22 (s, 2H), 3.91 (dq, J=11.5, 5.8 Hz, 3H), 1.40 (s, 9H); MSNR (IER) m/z 432.2 (M ⁺ + H). 105 3960 2-(difluoromethyl)-5-(6-((4-(pyrimidin-5-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3, 4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 9.30-9.24 (m, 3H), 9.15 (s, 1H), 8.76 (s, 1H), 8.54 (dd, J =8.2, 2.3 Hz, 1H), 7.65 (dd, J=8.2, 0.8 Hz, 1H), 7.26 (t, J=51.6 Hz, 1H), 5 .97 (s, 2H); MSNR (IER) m/z 357.2 (M ⁺ + H). 106 3961 Tert-butyl 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)piperidine-1-carboxylate
¹ H NMR (400 MHz, CD ₃ OD) δ 9.26 (dd, J=2.2, 0.9 Hz, 1H), 8.51 (dd, J=8.2, 2.3 Hz, 1H ), 7.99 (s, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.26 (t, J=51.6 Hz, 1H), 5.84 (s, 2H ), 4.22-4.13 (m, 1H), 3.96 (d, J=13.2 Hz, 1H), 3.12-2.88 (m, 3H), 2.18-2, 10 (m, 1H), 1.78 (kv, J=10.2, 9.4 Hz, 2H), 1.59 (t, J=12.2 Hz, 1H), 1.47 (s, 9H ); MSNR (IER) m/z 462.3 (M ⁺ + H). 114 3985 2-(6-((4-(1H-pyrazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.28 (dd, J=2.2, 0.9 Hz, 1H), 8.53 (dd, J=8.2, 2.2 Hz, 1H ), 8.29 (s, 1H), 7.96 (s, 2H), 7.58 (d, J=8.2 Hz, 1H), 7.26 (t, J=51.6 Hz, 1H ), 5.90 (s, 2H); MSNR (IER) m/z 345.2 (M ⁺ + H). 121 3999 Tert-butyl 4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)-4-fluoropiperidine-1-carboxylate
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.34 (dd, J = 2.2, 0.8 Hz, 1H), 8.43 (dd, J = 8.2, 2.2 Hz, 1H) , 7.80 (d, J =0.6 Hz, 1H), 7.43 (dd, J =8.2, 0.8 Hz, 1H), 7.09 (s, 0.2H), 6, 96 (s, 0.5H), 6.83 (s, 0.3H), 5.78 (s, 2H), 4.01 (d, J =11.8 Hz, 2H), 3.27 (d , J =10.7 Hz, 2H), 2.32-2.20 (m, 1H), 2.21-2.10 (m, 3H), 1.49 (s, 9H); MSNR (ER) m/z 478.2 (M ⁺ -1). 122 4000 Tert-butyl 4-((1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazole -4-yl)methyl)piperidine-1-carboxylate
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.33 (dd, J = 2.2, 0.8 Hz, 1H), 8.41 (dd, J = 8.2, 2.2 Hz, 1H) , 7.50 (s, 1H), 7.36 (d, J =8.2 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6, 83 (s, 0.3H), 5.75 (s, 2H), 4.09 (s, 2H), 2.76-2.60 (m, 4H), 1.87 (ddt, J =15, 3, 7.7, 3.8 Hz, 1H), 1.68 (d, J =13.0 Hz, 2H), 1.46 (s, 9H), 1.18 (ddd, J =25.0 , 12.7, 4.4 Hz, 2H); MSNR (ER) m/z 476.4 (M ⁺ -1). 197 4276 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl )oxetan-3-ol
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.34 (d, J = 1.7 Hz, 1H), 8.44 (dd, J = 8.2, 2.2 Hz, 1H), 7.93 (s, 1H), 7.46 (d, J =8.2 Hz, 1H), 7.10 (s, 0.2H), 6.97 (s, 0.5H), 6.84 (s, 0.3H), 5.81 (s, 2H), 5.02-4.84 (m, 4H); MSNR (ER) m/z 351.31 (M ⁺ +1). 198 4277 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl )tetrahydrofuran-3-ol
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.34 (d, J = 1.6 Hz, 1H), 8.43 (dd, J = 8.2, 2.2 Hz, 1H), 7.80 (s, 1H), 7.43 (d, J =8.2 Hz, 1H), 7.09 (s, 0.2H), 6.97 (s, 0.5H), 6.84 (s, 0.3H), 5.77 (s, 2H), 4.21 (td, J =8.5, 7.4 Hz, 1H), 4.12 (td, J =8.9, 4.1 Hz , 1H), 3.96 (s, 2H), 2.61 (dt, J =13.1, 8.8 Hz, 1H), 2.44-2.18 (m, 2H); MSNR (ER) m/z 365.22 (M ⁺ +1). 199 4278 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)oxetan-3 -ol
^1H NMR (400 MHz, CDCl ₃ ) δ 8.01-7.88 (m, 2H), 7.77 (s, 1H), 7.55-7.44 (m, 1H), 7.08 ( s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.3H), 5.72 (s, 2H), 4.92 (kV, J =7.0 Hz , 4H); MSNR (ER) m/z 368.23 (M ⁺ +1). 200 4279 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)tetrahydrofuran-3 -ol
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97-7.89 (m, 2H), 7.66 (s, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7 .06 (s, 0.2H), 6.94 (s, 0.5H), 6.78 (s, 0.3H), 5.68 (s, 2H), 4.25-4.16 (m , 1H), 4.12 (ddd, J =17.7, 7.9, 4.5 Hz, 1H), 4.02-3.96 (m, 2H), 2.61 (dt, J =13 ,2, 8.8 Hz, 1H), 2.36-2.25 (m, 1H); MSNR (ER) m/z 382.26 (M ⁺ +1). 238 4336 2-(difluoromethyl)-5-(4-((4-(3-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1 ,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 8.42 (s, 1H), 8.20-8.13 (m, 2H), 7.65-7.57 (m, 2H), 7.50 -7.45 (m, 1H), 7.35-7.26 (m, 2H), 7.23 (t, J =51.7 Hz, 1H), 6.99 (dt, J =7.3 , 2.3 Hz, 1H), 5.79 (s, 2H), 3.31-3.26 (m, 4H), 2.69-2.62 (m, 4H), 2.37 (s, 3H); MSNR (ER) m/z 452.6 (M ⁺ +1). 239 4337 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl) phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.43 (s, 1H), 8.03-7.93 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.47 (s, 1H), 7.35-7.27 (m, 2H), 7.24 (t, J =51.6 Hz, 1H), 6.99 (dt, J =7.1, 2.4 Hz, 1H), 5.85 (s, 2H), 3.29 (t, J =5.1 Hz, 4H), 2.69-2.62 (m, 4H), 2.38 ( s, 3H); MSNR (ER) m/z 470.5 (M ⁺ +1). 240 4338 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)morpholine
¹ H NMR (400 MHz, CD ₃ OD) δ 8.42 (s, 1H), 8.20-8.13 (m, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.47 (t, J =2.0 Hz, 1H), 7.36-7.27 (m, 2H), 7.23 (t, J =51.7 Hz, 1H), 6.99 (dt , J =7.4, 2.2 Hz, 1H), 5.79 (s, 2H), 3.90-3.83 (m, 4H), 3.25-3.18 (m, 4H); MSNR (ER) m/z 439.3 (M ⁺ +1). 241 4339 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) phenyl)morpholine
¹ H NMR (400 MHz, CD ₃ OD) δ 8.43 (s, 1H), 8.03-7.92 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.50-7.44 (m, 1H), 7.36-7.28 (m, 2H), 7.24 (t, J =51.6 Hz, 1H), 6.99 (dt, J = 7.2, 2.3 Hz, 1H), 5.85 (s, 2H), 3.90-3.83 (m, 4H), 3.25-3.19 (m, 4H); MSNR (ER) m/z 457.1 (M ⁺ +1). 242 4340 2-(6-((4-(1H-indazol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1, 3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 9.29 (dd, J =2.2, 0.9 Hz, 1H), 8.59 (s, 1H), 8.54 (dd, J =8 ,2, 2.2 Hz, 1H), 8.08 (d, J =1.7 Hz, 2H), 7.87 (dd, J =8.4, 0.7 Hz, 1H), 7.63 (td, J =8.5, 1.1 Hz, 2H), 7.26 (t, J =51.6 Hz, 1H), 5.95 (s, 2H); MSNR (ER) m/z 395.2 (M ⁺ +1). 243 4341 2-(4-((4-(1H-indazol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4- oxadiazole
^1H NMR (400 MHz, CDD ₃ OD) δ 8.53 (s, 1H), 8.21-8.14 (m, 2H), 8.07 (s, 2H), 7.85 (dd, J =8.5, 0.8 Hz, 1H), 7.67-7.59 (m, 2H), 7.23 (t, J =51.6 Hz, 1H), 5.83 (s, 2H) ; MSNR (ER) m/z 394.2 (M ⁺ +1). 244 4342 2-(4-((4-(1H-indazol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3 ,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 8.53 (s, 1H), 8.07 (d, J =2.0 Hz, 2H), 8.04-7.93 (m, 2H), 7.86 (dd, J =8.5, 0.8 Hz, 1H), 7.67-7.59 (m, 2H), 7.24 (t, J =51.6 Hz, 1H), 5 .88 (s, 2H); MSNR (ER) m/z 412.2 (M ⁺ +1). 245 4343 2-(6-((4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.29 (d, J = 2.0 Hz, 1H), 8.54 (dd, J = 8.2, 2.2 Hz, 1H), 8, 51 (s, 1H), 8.28 (t, J =1.2 Hz, 1H), 8.12 (s, 1H), 7.92 (dd, J =8.8, 1.6 Hz, 1H ), 7.63 (dd, J =11.8, 8.4 Hz, 2H), 7.26 (t, J =51.6 Hz, 1H), 5.94 (s, 2H); MSNR (ER) m/z 395.8 (M ⁺ +1). 246 4344 2-(4-((4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4- oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.26 (s, 1H), 8.18 (d, J =8.8 Hz, 2H), 8.11 ( s, 1H), 7.90 (d, J =8.9 Hz, 1H), 7.63 (d, J =8.7 Hz, 3H), 7.23 (t, J =51.4 Hz, 1H), 5.82 (s, 2H); MSNR (ER) m/z 394.2 (M ⁺ +1). 247 4345 2-(4-((4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3 ,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.45 (s, 1H), 8.26 (s, 1H), 8.12 (s, 1H), 7.99 (t, J =10.9 Hz, 2H), 7.90 (d, J =9.1 Hz, 1H), 7.62 (t, J =8.1 Hz, 2H), 7.24 (t, J =51.4 Hz, 1H), 5.87 (s, 2H), 1.25 (d, J =7.8 Hz, 1H); MSNR (ER) m/z 412.2 (M ⁺ +1). 248 4346 2-(6-((4-(1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1, 3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 9.29 (dd, J =2.3, 0.9 Hz, 1H), 8.73 (s, 1H), 8.59 (d, J =1 ,1 Hz, 1H), 8.54 (dd, J =8.2, 2.2 Hz, 1H), 7.69-7.62 (m, 2H), 7.58 (d, J =8, 4 Hz, 1H), 7.49 (dd, J =8.4, 7.1 Hz, 1H), 7.26 (t, J =51.6 Hz, 1H), 5.99 (s, 2H) ; MSNR (ER) m/z 395.2 (M ⁺ +1). 249 4347 2-(4-((4-(1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4- oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 8.67 (s, 1H), 8.58 (s, 1H), 8.21-8.14 (m, 2H), 7.69-7.61 (m, 3H), 7.57 (d, J =8.4 Hz, 1H), 7.48 (dd, J =8.4, 7.1 Hz, 1H), 7.23 (t, J = 51.6 Hz, 1H), 5.86 (s, 2H); MSNR (ER) m/z 394.2 (M ⁺ +1). 250 4348 2-(4-((4-(1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3 ,4-oxadiazole (0.091 g, 59.6%) is obtained as a beige solid.
^1H NMR (400 MHz, CD ₃ OD) δ 8.67 (s, 1H), 8.60-8.55 (m, 1H), 8.04-7.94 (m, 2H), 7.67 -7.60 (m, 2H), 7.58 (d, J =8.3 Hz, 1H), 7.48 (dd, J =8.4, 7.1 Hz, 1H), 7.24 ( t, J =51.6 Hz, 1H), 5.92 (s, 2H); MSNR (ER) m/z 12.2 (M ⁺ +1). 395 4524 2-(4-((4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5 -(difluoromethyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 8.69 (s, 1H), 8.50 (s, 1H), 8.44 (s, 1H), 8.04-7.94 (m, 2H ), 7.63 (t, J =7.6 Hz, 1H), 7.45 (d, J =3.5 Hz, 1H), 7.24 (t, J =51.6 Hz, 1H), 6.57 (d, J =3.5 Hz, 1H), 5.88 (s, 2H); MSNR (ER) m/z 412.3 (M ⁺ +1). 396 4525 2-(4-((4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl )-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.68 (s, 1H), 8.49 (s, 1H), 8.44 (d, J =2.1 Hz, 1H), 8.18 ( d, J =8.2 Hz, 2H), 7.64 (d, J =8.1 Hz, 2H), 7.45 (d, J =3.5 Hz, 1H), 7.23 (t, J =51.6 Hz, 1H), 6.57 (d, J =3.4 Hz, 1H), 5.83 (s, 2H); MSNR (ER) m/z 394.4 (M ⁺ +1). 397 4526 2-(4-((4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5 -(difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.78 (s, 1H), 8.27 (d, J =5.2 Hz, 1H), 7.99 (t, J =10.2 Hz, 2H), 7.68-7.60 (m, 2H), 7.51 (d, J =3.5 Hz, 1H), 7.24 (t, J =51.6 Hz, 3H), 7, 01 (d, J =3.6 Hz, 1H), 5.94 (s, 2H); MSNR (ER) m/z 412.3 (M ⁺ +1). 398 4527 2-(4-((4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl )-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.78 (s, 1H), 8.27 (d, J =5.2 Hz, 1H), 8.18 (d, J =8.2 Hz, 2H), 7.64 (dd, J =10.5, 6.7 Hz, 3H), 7.50 (d, J =3.6 Hz, 1H), 7.23 (t, J =51.6 Hz, 1H), 7.01 (d, J =3.5 Hz, 1H), 5.88 (s, 2H); MSNR (ER) m/z 394.4 (M ⁺ +1). 479 16781 2-(4-((4-(6-chloropyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3 ,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.86-8.85 (m, 1H), 8.60 (s, 1H), 8.27 (dd, J= 8.4, 2.4 Hz , 1H), 8.00-7.94 (m, 2H), 7.63 (t, J= 7.7 Hz, 1H), 7.56 (dd, J= 8.4, 0.6 Hz, 1H), 7.24 (t, J= 51.6 Hz, 1H), 5.88 (s, 2H); MSNR (IER) m/z 407.1 (M ⁺ + H). 482 16928 2-(4-((4-(5-bromopyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3 ,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.78 (s, 1H), 8.74 (s, 1H), 8.16 (dd, J= 8.5, 2.2 Hz, 1H), 8.01 (d, J= 8.5 Hz, 1H), 7.94 (d, J= 9.2 Hz, 2H), 7.60 (t, J= 7.6 Hz, 1H), 7, 55 (t, J= 51.3 Hz, 1H), 5.88 (s, 2H); MSNR (IER) m/z 451.2 (M ⁺ + H). 483 16930 2-(4-((4-(5-bromopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3 ,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.01 (s, 1H), 8.65 (d, J= 4.3 Hz, 2H), 8.50 (t, J= 1.9 Hz, 1H), 8.00-7.95 (m, 2H), 7.63 (t, J= 7.7 Hz, 1H), 7.24 (t, J= 51.6 Hz, 1H), 5, 88 (s, 2H); MSNR (IER) m/z 451.0 (M ⁺ + H). 488 17261 2-(4-((4-(1H-pyrazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3 ,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 8.23 (s, 1H), 8.00-7.97 (m, 3H), 7.95-7.95 (m, 1H), 7.75 (s, 1H), 7.60 (t, J= 7.6 Hz, 1H), 7.24 (t, J= 51.6 Hz, 1H), 5.83 (s, 2H); MSNR (IER) m/z 451.2 (M ⁺ + H). 521 17983 2-(difluoromethyl)-5-(5-fluoro-6-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)- 1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.61-8.59 (m, 2H), 8.39 (dd, J=9.6, 1.6 Hz , 1H), 8.11 (d, J=8.0 Hz, 1H), 7.94 (td, J=7.8, 1.6 Hz, 1H), 7.41-7.14 (m, 2H), 6.05 (d, J=1.7 Hz, 1H); MSNR (IER) m/z 374.2 (M ⁺ + H). 522 17984 2-(difluoromethyl)-5-(5-fluoro-6-((4-(thiophen-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)- 1,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 9.11 (s, 1H), 8.40-8.38 (m, 2H), 7.46-7.44 (m, 2H), 7.40 -7.11 (m, 2H), 5.99 (d, J=1.8 Hz, 2H); MSNR (IER) m/z 379.2 (M ⁺ + H). 534 18256 2-(difluoromethyl)-5-(3-fluoro-4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3, 4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.74 (s, 1H), 8.61 (s, 1H), 8.05 (d, J=7.6 Hz, 1H), 7.96 -7.89 (m, 3H), 7.69-7.43 (m, 2H), 7.36 (s, 1H), 5.89 (s, 2H); MSNR (IER) m/z 373.3 (M ⁺ + H). 535 18258 2-(difluoromethyl)-5-(3-fluoro-4-((4-(thiophen-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3, 4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.35 (s, 1H), 8.00-7.94 (m, 2H), 7.60 (t, J=7.7 Hz, 1H), 7.44 (d, J=4.3 Hz, 2H), 7.37-7.10 (m, 2H), 5.84 (s, 2H); MSNR (IER) m/z 378.2 (M ⁺ + H). 547 18470 2-(4-((4-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl )-5-(difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 (s, 1H), 7.99-7.93 (m, 3H), 7.47 (t, J = 7.7 Hz, 1H), 7 .21 (t, J =8.1 Hz, 1H), 7.05 (s, 1H), 7.05 (s, 0.2H), 6.94 (s, 0.5H), 6.81 ( s, 0.2H), 5.79 (s, 2H); MSNR (ER) m/z 453.55 (M ⁺ +1). 557 18868 Tert-butyl 4-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1, 2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate
^1H NMR (400 MHz, CDCl ₃ ) δ 9.08 (s, 1H), 8.18 (d, J =7.5 Hz, 1H), 7.52 (s, 0.5H), 7.34 -7.22 (m, 5H), 7.14 (s, 0.5H), 5.48 (s, 2H), 4.62-4.54 (m, 4H), 3.93 (s, 3H ), 3.44 (s, 2H), 1.39-1.24 (m, 9H); MSNR (ER) m/z (M ⁺ +1). 566 18918 2-(6-((4-(1H-indol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl) -1,3,4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.21 (s, 1H), 9.06 (d, J=1.0 Hz, 1H), 8.62 (s, 1H), 8.51 (dd, J=9.8, 1.7 Hz, 1H), 7.92 (s, 1H), 7.73-7.46 (m, 3H), 7.40-7.37 (m, 1H ), 6.44 (dd, J=2.5, 1.5 Hz, 1H), 5.98 (d, J=1.5 Hz, 2H); MSNR (ER) m/z 412.53 (M ⁺ +1). 567 18919 2-(6-((4-(1H-indazol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl) -1,3,4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.17 (s, 1H), 9.06 (d, J=1.0 Hz, 1H), 8.79 (s, 1H), 8.51 (dd, J=9.8, 1.7 Hz, 1H), 8.09 (s, 1H), 8.04 (d, J=0.9 Hz, 1H), 7.83 (dd, J= 8.4, 0.7 Hz, 1H), 7.63 (dd, J=8.4, 1.3 Hz, 1H), 7.59 (t, J=51.2 Hz, 1H), 6, 01 (d, J=1.4 Hz, 2H); MSNR (ER) m/z 413.29 (M ⁺ +1). 568 18920 2-(6-((4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl) -1,3,4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.17 (s, 1H), 9.06 (d, J=1.0 Hz, 1H), 8.67 (s, 1H), 8.51 (dd, J=9.8, 1.7 Hz, 1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.88 (dd, J=8.7, 1.5 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.59 (t, J=51.2 Hz, 1H), 6.00 (d, J=1.4 Hz, 2H); MSNR (ER) m/z 413.29 (M ⁺ +1). 569 18921 2-(6-((4-(1H-indol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl) -1,3,4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.29 (s, 1H), 9.05 (s, 1H), 8.77 (s, 1H), 8.51 (dd, J=9, 8, 1.7 Hz, 1H), 7.74-7.38 (m, 4H), 7.21-7.13 (m, 1H), 6.98-6.91 (m, 1H), 6 .03 (d, J=1.3 Hz, 2H); MSNR (ER) m/z 412.53 (M ⁺ +1). 579 19058 2-(6-((4-(1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl) -1,3,4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (s, 1H), 8.93 (s, 1H), 8.57 (s, 1H), 8.51 (dd, J=9, 8, 1.7 Hz, 1H), 7.74-7.37 (m, 4H), 6.05 (d, J=1.3 Hz, 2H); MSNR (ER) m/z 413.29 (M ⁺ +1).

Example 491: Synthesis of Compound 17362, 2-(difluoromethyl)-5-(4-((4-(6-(4-ethylpiperazin-1-yl)pyridin-2-yl)-1H-1,2,3-triazole -1-yl)methyl)-3-fluorophenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 4-(6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2, 3-triazol-4-yl)pyridin-2-yl)piperazine-1-carboxylate

2-(4-((4-(6-Bromopyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3 ,4-oxadiazole (0.800 g, 1.773 mmol) prepared in step 2 of Example 489, tert-butyl piperazine-1-carboxylate (0.660 g, 3.546 mmol) and N,N-diisopropylethylamine (0.463 ml, 2.660 mmol) were dissolved in dimethyl sulfoxide (10 ml) at 130°C, after which the resulting solution was stirred at the same temperature for 18 hours, and then the reaction was completed by lowering the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl 4-(6-(1-(4-(5-(difluoromethyl)-1,3, 4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)piperazin-1-carboxylate (0.407 g, 41.2%) as yellow oil.

[Step 2] Synthesis of 2-(difluoromethyl)-5-(3-fluoro-4-((4-(6-(piperazin-1-yl)pyridin-2-yl)-1H-1,2,3-triazole -1-yl)methyl)phenyl)-1,3,4-oxadiazole

Tert-butyl 4-(6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4 -yl)pyridin-2-yl)piperazin-1-carboxylate (0.407 g, 0.731 mmol) obtained in step 1 and trifluoroacetic acid (0.560 ml, 7.313 mmol) were dissolved in dichloromethane (5 ml) at room temperature, then the resulting solution is stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting product is used without an additional purification process (2-(difluoromethyl)-5-(3-fluoro-4-((4-(6-(piperazin-1-yl)pyridin-2-yl)-1H-1,2, 3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole, 0.325 g, 97.4%, brown oil).

[Step 3] Synthesis of compound 17362

2-(difluoromethyl)-5-(3-fluoro-4-((4-(6-(piperazin-1-yl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl) Methyl)phenyl)-1,3,4-oxadiazole (0.065 g, 0.142 mmol) obtained in step 2 and acetaldehyde (0.016 ml, 0.285 mmol) are dissolved in dichloromethane (1 ml), after which the resulting solution is stirred at room temperature for 15 minutes, and then sodium triacetoxyborohydride (0.091 g, 0.427 mmol) was added thereto, and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(6-(4-ethylpiperazine-1 -yl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-1,3,4-oxadiazole (0.020 g, 29.0%) as yellow solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.50 (s, 1H), 7.98 (t, J= 10.0 Hz, 2H), 7.67 (t, J= 7.9 Hz, 1H), 7.60 (t, J= 7.7 Hz, 1H), 7.39 (d, J= 7.4 Hz, 1H), 7.24 (t, J= 51.6 Hz, 1H) , 6.83 (d, J= 8.6 Hz, 1H), 5.87 (s, 2H), 3.76 (s, 4H), 2.90 (s, 4H), 2.82-2, 76 (m, 2H), 1.26 (t, J= 7.2 Hz, 3H); MSNR (ER) m/z 485.4 (M ⁺ +1).

The compounds of Table 147 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 17362 except for the use of 2-(difluoromethyl)-5-(3-fluoro-4-((4-(6-(piperazine-1 -yl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole and the reagent from Table 146.

Table 146 Example Connection no. Reagent Exit (%) 492 17363 Acetone 79 493 17364 Cyclobutanone 37 494 17365 Oxetanone 75

Table 147 Example Connection no. Name of compound, 1H-NMR, MS (ESI) 492 17363 2-(difluoromethyl)-5-(3-fluoro-4-((4-(6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)-1H-1,2,3-triazol-1- yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD₃OD) δ 8.48 (s, 1H), 7.99-7.94 (m, 2H), 7.65-7.57 (m, 2H), 7.37-7.11 (m, 2H), 6. 78 (d,J=8.6 Hz, 1H), 5.86 (s, 2H), 3.64 (t,J=5.0 Hz, 4H), 2.79-2.69 (m, 5H), 1.15 (d,J=6.5 Hz, 6H);MCNR (IER) m/z 499.2 (M⁺ + H). 493 17364 2-(4-((4-(6-(4-cyclobutylpiperazin-1-yl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)- 5-(difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD₃OD) δ 8.48 (s, 1H), 7.97 (t,J=11.7 Hz, 2H), 7.65-7.56 (m, 2H), 7.36-7.11 (m, 2H), 6.78 (d,J=8.5 Hz, 1H), 5.86 (s, 2H), 3.64 (t,J=5.0 Hz, 4H), 2.89-2.81 (m, 1H), 2.50 (t,J=5.0 Hz, 4H), 2.13-2.10 (m, 2H), 2.03-1.93 (m, 2H), 1.82-1.75 (m, 2H);MCNR (IER) m/z 511.4 (M⁺ +H). 494 17365 2-(difluoromethyl)-5-(3-fluoro-4-((4-(6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)-1H-1,2 ,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 7.96 (t,J=10.0 Hz, 2H), 7.65-7.55 (m, 2H), 7.34-7.11 (m, 2H), 6.77 (d,J=8.5 Hz, 1H), 5.85 (s, 2H), 4.70 (dt,J=28.9, 6.4 Hz, 4H), 3.66 (t,J=4.9 Hz, 4H), 3.58-3.50 (m, 1H), 2.48 (t,J=4.9 Hz, 4H);MCNR (IER) m/z 513.2 (M⁺ +H).

Example 497: Synthesis of Compound 17532, 2-(4-((4-(5-(azetidin-1-yl-methyl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl )-3-fluorophenyl)5-(difluoromethyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 6-((trimethylsilyl)ethynyl)nicotinaldehyde

6-Bromonicotinaldehyde (1.000 g, 5.376 mmol), bis(triphenylphosphine) palladium dichloride (0.151 g, 0.215 mmol), copper iodide (I/II, 0.102 g, 0.538 mmol) and 4,5-bis(diphenylphosphino)-9, 9-diphenylxanthene (Xantphos, 0.124 g, 0.215 mmol) was dissolved in triethylamine (15 ml), after which trimethylsilylacetylene (0.836 ml, 5.914 mmol) was added to the resulting solution at room temperature and stirred at the same temperature for 18 hours. The reaction mixture is filtered through a pad of celite to remove solid matter, after which the solvent is removed from the resulting filtrate without solid matter under reduced pressure. The resulting concentrate was then purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give 6-((trimethylsilyl)ethynyl)nicotinaldehyde (0.400 g, 36.6%) as light -brown solid.

[Step 2] Synthesis of 6-ethynylnicotinaldehyde

6-((Trimethylsilyl)ethynyl)nicotinaldehyde (0.370 g, 1.820 mmol) obtained in step 1 and potassium carbonate (0.755 g, 5.459 mmol) are dissolved in methanol (5 ml) at room temperature, after which the resulting solution is stirred at same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-40%) and concentrated to give 6-ethynylnicotinaldehyde (0.200 g, 83.8%) as a beige solid.

[Step 3] Synthesis of 6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4- yl)nicotinaldehyde

6-Ethynylnicotinaldehyde (0.100 g, 0.763 mmol) obtained in step 2, and 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.205 g, 0.763 mmol ) obtained in step 1 of example 2 is dissolved in tert-butanol (2 ml)/water (2 ml) at room temperature, followed by sodium ascorbate (1.00 M solution, 0.076 ml, 0.076 mmol) and copper sulfate (I /II, 1.00 M solution, 0.038 ml, 0.038 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution is poured into the reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give 6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2 -yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)nicotinaldehyde (0.190 g, 62.2%) in the form of a light yellow solid.

[Step 4] Synthesis of compound 17532

6-(1-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)nicotinaldehyde (0.040 g, 0.104 mmol) obtained in step 3, and azetidine (0.020 g, 0.209 mmol) was dissolved in dichloromethane (1 ml) at room temperature, after which sodium triacetoxyborohydride (0.111 g, 0.522 mmol) was added to the resulting solution and stirred at that same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-80%) and concentrated to give 2-(4-((4-(5-(azetidin-1-yl-methyl)pyridin-2 -yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)5-(difluoromethyl)-1,3,4-oxadiazole (0.021 g, 47.4%) as white solid matter.

¹ H NMR (400 MHz, CD₃OD) δ 8.53 (s, 1H), 8.07 (d, J=8.2 Hz, 1H), 7.98 (dd, J=11.6, 9.1 Hz, 1H), 7, 87 (dd, J=8.0, 2.0 Hz, 1H), 7.63 (t, J=7.7 Hz, 1H), 7.24 (t, J=51.6 Hz, 1H), 5.89 (s, 2H), 4.60 (s, 2H), 3.75 (s, 2H), 3.41 (t, J=7.2 Hz, 4H), 2.19 (p, J =7.3 Hz, 2H). ^; MCNR(ER) m/z 442.89 (M⁺+1).

The compounds of Table 149 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 17532 except for the use of 6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl )-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)nicotinaldehyde and the reagent from Table 148.

Table 148 Example Connection no. Reagent Exit (%) 498 17533 Pyrrolidine 58 499 17534 Dimethylamine 65 500 17535 4-methylpiperidine 63 501 17545 - 12 531 18185 (S)-(+)-3-fluoropyrrolidine 44 536 18260 (R)-(-)-3-fluoropyrrolidine 46

Table 149 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 498 17533 2-(difluoromethyl)-5-(3-fluoro-4-((4-(5-(pyrrolidin-1-ylmethyl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl) methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.57 (s, 1H), 8.54 (s, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.98 ( dd, J=11.3, 9.1 Hz, 2H), 7.93 (d, J=6.1 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7, 24 (t, J=51.6 Hz, 1H), 5.89 (s, 2H), 3.75 (s, 2H), 2.69-2.54 (m, 4H), 1.90-1 .78 (m, 4H); MSNR (IER) m/z 455.92 (M ⁺ + 1). 499 17534 1-(6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) pyridin-3-yl)-N,N-dimethylmethanamine
^1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.21 (s, J=49.6 Hz, 1H), 8.18 (d, J=8.1 Hz, 1H) , 7.98-7.87 (m, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 6.94 ( t, J=51.7 Hz, 1H), 5.76 (s, 2H), 3.50 (s, 2H), 2.30 (s, 6H); MSNR (IER) m/z 429.92 (M ⁺ + 1). 500 17535 2-(difluoromethyl)-5-(3-fluoro-4-((4-(5-((4-methylpiperidin-1-yl)methyl)pyridin-2-yl)-1H-1,2,3-triazole -1-yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.53 (d, J=2.6 Hz, 1H), 8.07 (d, J=7.8 Hz, 1H), 8.02-7, 93 (m, 2H), 7.91 (dd, J=8.1, 2.2 Hz, 1H), 7.63 (t, J=7.7 Hz, 1H), 7.24 (t, J =51.6 Hz, 1H), 5.89 (s, 2H), 3.60 (s, 2H), 2.90 (d, J=11.6 Hz, 2H), 2.09 (t, J =10.8 Hz, 2H), 1.67 (d, J=12.8 Hz, 2H), 1.41 (s, 1H), 1.35-1.19 (m, 2H), 0.95 (d, J=6.5 Hz, 3H); MSNR (IER) m/z 484.99 (M ⁺ + 1). 501 17545 (6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)pyridin- 3-yl)methanol
¹ H NMR (400 MHz, CD ₃ OD) δ 8.60 (s, 1H), 8.04-7.88 (m, 4H), 7.64 (t, J=7.7 Hz, 1H), 7.60-7.42 (m, 1H), 7.24 (t, J=51.6 Hz, 1H), 5.89 (s, 2H), 4.72 (s, 2H); MSNR (IER) m/z 403.30 (M ⁺ + 1). 531 18185 (S)-2-(difluoromethyl)-5-(3-fluoro-4-((4-(5-((3-fluoropyrrolidin-1-yl)methyl)pyridin-2-yl)-1H-1,2 ,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.57 (s, 1H), 8.53 (s, 1H), 8.08 (d, J=8.2 Hz, 1H), 8.03- 7.97 (m, 1H), 7.97-7.91 (m, 2H), 7.64 (t, J=7.7 Hz, 1H), 7.24 (t, J=51.6 Hz , 1H), 5.90 (s, 2H), 5.31-5.08 (m, J=56.8 Hz, 1H), 3.83-3.68 (m, 2H), 3.44- 3.34 (m, 1H), 3.01-2.85 (m, 2H), 2.74 (ddd, J=16.8, 11.5, 4.9 Hz, 1H), 2.49 ( dd, J=15.3, 8.7 Hz, 1H), 2.24 (ddd, J=22.0, 14.4, 8.2 Hz, 1H), 2.14-1.94 (m, 1H); MSNR (IER) m/z 474.72 (M ⁺ + 1). 536 18260 (R)-2-(difluoromethyl)-5-(3-fluoro-4-((4-(5-((3-fluoropyrrolidin-1-yl)methyl)pyridin-2-yl)-1H-1,2 ,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.57 (s, 1H), 8.53 (s, 1H), 8.08 (d, J=8.2 Hz, 1H), 8.02- 7.91 (m, 3H), 7.64 (t, J=7.6 Hz, 1H), 7.24 (t, J=51.6 Hz, 1H), 5.90 (s, 2H), 5.29-5.09 (m, J=53.8 Hz, 1H), 3.76 (kv, J=13.1 Hz, 2H), 3.49-3.36 (m, 1H), 3 .00-2.86 (m, 2H), 2.81-2.65 (m, 1H), 2.49 (dd, J=16.2, 8.5 Hz, 1H), 2.32-2 .15 (m, 1H), 2.13-1.96 (m, 1H); MSNR (IER) m/z 474.72 (M ⁺ + 1).

Example 502: Synthesis of compound 17698 , 2-(4-((4-(4-(1-cyclobutylazetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3- fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 3-(4-ethynylphenyl)azetidine-1-carboxylate

Dimethyl (1-diazo-2-oxopropyl)phosphonate (0.316 ml, 2.105 mmol) and potassium carbonate (0.529 g, 3.827 mmol) were dissolved in methanol (10 ml) at room temperature, after which tert-butyl 3-(4-formylphenyl) )azetidine-1-carboxylate (0.500 g, 1.913 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give tert-butyl 3-(4-ethynylphenyl)azetidine-1-carboxylate (0.287 g, 58.3%) in the form of a yellow oil.

[Step 2] Synthesis of tert-butyl 3-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2, 3-triazol-4-yl)phenyl)azetidine-1-carboxylate

Tert-butyl 3-(4-ethynylphenyl)azetidine-1-carboxylate (0.095 g, 0.369 mmol) obtained in step 1, 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1, 3,4-oxadiazole (0.099 g, 0.369 mmol) prepared in step 1 of Example 2, sodium ascorbate (0.50 M solution in water, 0.074 ml, 0.037 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.007 ml, 0.007 mmol) dissolved in tert-butanol (1 ml)/water (1 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl 3-(4-(1-(4-(5-(difluoromethyl)-1,3 ,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)azetidine-1-carboxylate (0.155 g, 79.7%) as light yellow solid matter.

[Step 3] Synthesis of 2-(4-((4-(4-(azetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5 -(difluoromethyl)-1,3,4-oxadiazole

Tert-butyl 3-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4 -yl)phenyl)azetidine-1-carboxylate (0.155 g, 0.294 mmol) obtained in step 2 and trifluoroacetic acid (0.225 ml, 2.944 mmol) were dissolved in dichloromethane (2 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 4 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Then, the resulting product is used without an additional purification process (2-(4-((4-(4-(azetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3 -fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole, 0.120 g, 95.6%, yellow oil).

[Step 4] Synthesis of compound 17698

2-(4-((4-(4-(Azetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)- 1,3,4-oxadiazole (0.040 g, 0.094 mmol) obtained in step 3 and formaldehyde (37.00% solution in water, 0.019 ml, 0.188 mmol) are dissolved in dichloromethane (1 ml), after which the resulting solution is stirred at room temperature for 15 minutes, and then sodium triacetoxyborohydride (0.060 g, 0.281 mmol) was added thereto, and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give 2-(4-((4-(4-(1-cyclobutyl azetidin-3-yl)phenyl)- 1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.013 g, 31.5%) as a white solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.43 (s, 1H), 8.00-7.94 (m, 2H), 7.82 (d, J= 8.2 Hz, 2H), 7.60 (t, J= 7.7 Hz, 1H), 7.41 (d, J= 8.3 Hz, 2H), 7.24 (t, J= 51.6 Hz, 1H), 5, 85 (s, 2H), 3.98-3.80 (m, 3H), 3.42 (t, J= 7.5 Hz, 2H), 2.50 (s, 3H); MSNR (ER) m/z 441.3 (M ⁺ +1).

The compounds of Table 151 are synthesized in accordance with substantially the same method as described above in the synthesis of compound 17698 except for the use of 2-(4-((4-(4-(azetidin-3-yl)phenyl)-1H-1, 2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole and the reagent from Table 150.

Table 150 Example Connection no. Reagent Exit (%) 503 17699 Cyclobutanone 58 504 17700 Oxetan-3-one 82

Table 151 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 503 17699 2-(4-((4-(4-(1-cyclobutylazetidin-3-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl )-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.42 (s, 1H), 8.00-7.94 (m, 2H), 7.82 (d, J=8.2 Hz, 2H), 7.60 (t, J=7.7 Hz, 1H), 7.39 (d, J=8.3 Hz, 2H), 7.24 (t, J=51.6 Hz, 1H), 5, 85 (s, 2H), 3.84-3.75 (m, 3H), 3.35-3.33 (m, 3H), 2.13-2.05 (m, 2H), 1.99- 1.92 (m, 2H), 1.90-1.73 (m, 2H); MS (ESI) m/z 481.3 (M ⁺ + H). 504 17700 2-(difluoromethyl)-5-(3-fluoro-4-((4-(4-(1-(oxetan-3-yl)azetidin-3-yl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.43 (s, 1H), 8.00-7.95 (m, 2H), 7.82 (d, J=8.2 Hz, 2H), 7.60 (t, J=7.7 Hz, 1H), 7.43 (d, J=8.2 Hz, 2H), 7.24 (t, J=51.6 Hz, 1H), 5, 85 (s, 2H), 4.78 (t, J=6.7 Hz, 2H), 4.57-4.54 (m, 2H), 3.92-3.81 (m, 4H), 3 .38-3.35 (m, 2H); MS (ESI) m/z 483.3 (M ⁺ + H).

Example 505: Synthesis of Compound 17773, (S)-2-(difluoromethyl)-5-(3-fluoro-4-((4-(6-((3-fluoropyrrolidin-1-yl)methyl)pyridin-3-yl )-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 5-((trimethylsilyl)ethynyl)picolinaldehyde

5-bromopicolinaldehyde (2.000 g, 10.752 mmol), trimethylsilylacetylene (3.039 ml, 21.504 mmol), bis(triphenylphosphine) palladium dichloride (0.755 g, 1.075 mmol), copper iodide (I/II, 0.205 g, 1.075 mmol) and triphenylphosphine triphenylphosphine (0.282 g, 1.075 mmol) was mixed in tetrahydrofuran (20 ml)/triethylamine (8 ml), heated at 100°C for 0.5 hours by microwave irradiation, and the reaction was completed by reducing the temperature to room temperature. The reaction mixture is filtered through a pad of celite to remove solid matter, after which the solvent is removed from the resulting filtrate without solid matter under reduced pressure. The resulting concentrate was then purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 5-((trimethylsilyl)ethynyl)picolinaldehyde (0.780 g, 35.7%) as light -brown solid.

[Step 2] 5-ethynylpicolinaldehyde

5-((Trimethylsilyl)ethynyl)picolinaldehyde (0.247 g, 1.215 mmol) obtained in step 1 and potassium carbonate (0.504 g, 3.645 mmol) are dissolved in methanol (10 ml) at room temperature, after which the resulting solution is stirred at same temperature for 18 hours. The solvent is removed from the reaction mixture under reduced pressure, after which a saturated aqueous ammonium chloride solution is poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give 5-ethynylpicolinaldehyde (0.120 g, 75.3%) as a yellow solid.

[Step 3] Synthesis of 5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4- yl)picolinaldehyde

5-Ethynylpicolinaldehyde (0.150 g, 1.144 mmol) obtained in step 2, and 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.308 g, 1.144 mmol ) obtained in step 1 of example 2 is dissolved in tert-butanol (2 ml)/water (2 ml) at room temperature, followed by sodium ascorbate (1.00 M solution, 0.114 ml, 0.114 mmol) and copper (I) sulfate /II, 0.50 M solution, 0.114 ml, 0.057 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution is poured into the reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give 5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazole-2 -yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)picolinaldehyde (0.350 g, 76.4%) in the form of a light yellow solid.

[Step 4] Synthesis of compound 17773

5-(1-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)picolinaldehyde (0.040 g, 0.100 mmol) obtained in step 3, (S)-(+)-3-fluoropyrrolidine and hydrochloric acid (0.025 g, 0.200 mmol) are dissolved in dichloromethane (1 ml) at room temperature, after which sodium triacetoxyborohydride (0.106 g , 0.500 mmol) is added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-80%) and concentrated to give (S)-2-(difluoromethyl)-5-(3-fluoro-4-((4-( 6-((3-fluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.029 g , 61.3%) in the form of a white solid.

¹ H NMR(400 MHz, CDCl₃) δ 8.97 (s, 1H), 8.80 (s, 1H), 8.25-8.18 (m, 1H), 7.96 (d, J=9.1 Hz, 2H), 7 .61 (t, J=7.7 Hz, 1H), 7.56 (t, J=51.3 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 5.87 (s, 2H), 5.34-5.09 (m, J=55.8 Hz, 1H), 3.77 (s, 2H), 2.86 (dd, J=25.6, 11.1 Hz, 2H), 2.77-2.61 (m, 1H), 2.44-2.36 (m, J=7.2 Hz, 1H), 2.26-2.04 (m, 1H) , 2.01-1.79 (m, 1H).;MCNR(ER) m/z 474.28 (M⁺+1).

The compounds of Table 153 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 17773 except for the use of 5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl )-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)picolinaldehyde and the reagent from Table 152.

Table 152 Example Connection no. Reagent Exit (%) 506 17774 (R)-(-)-3-fluoropyrrolidine 67 507 17775 3,3-difluoropyrrolidine 67 508 17777 4,4-dimethylpiperidine 58 509 17778 4,4-difluoropiperidine 53 525 18174 Azetidine 52 526 18175 Pyrrolidine 61 527 18176 Dimethylamine 51 528 18177 4-methylpiperidine 55

Table 153 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 506 17774 (R)-2-(difluoromethyl)-5-(3-fluoro-4-((4-(6-((3-fluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-1H-1,2 ,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, DMSO- _d6 ) δ 8.98 (s, 1H), 8.79 (s, 1H), 8.25-8.18 (m, 1H), 7.96 (d, J=9.1 Hz, 2H), 7.61 (t, J=7.7 Hz, 1H), 7.56 (t, J=51.3 Hz, 1H), 7.51 (d, J= 8.1 Hz, 1H), 5.87 (s, 2H), 5.34-5.09 (m, J=55.8 Hz, 1H), 3.77 (s, 2H), 2.86 ( dd, J=25.6, 11.1 Hz, 2H), 2.77-2.61 (m, 1H), 2.44-2.36 (m, J=7.2 Hz, 1H), 2 .26-2.04 (m, 1H), 2.01-1.79 (m, 1H); MSNR (IER) m/z 474.21 (M ⁺ + 1). 507 17775 2-(difluoromethyl)-5-(4-((4-(6-((3,3-difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-1H-1,2,3-triazol-1 -yl)methyl)-3-fluorophenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.99 (d, J=2.0 Hz, 1H), 8.80 (s, 1H), 8.23 (dd, J=8.0, 2.2 Hz, 1H), 7.97 (s, 1H), 7.95 (s, 1H), 7.61 (t, J=9.0 Hz, 1H), 7.56 (t, J= 51.3 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 5.88 (s, 2H), 3.78 (s, 2H), 2.96 (t, J= 13.4 Hz, 2H), 2.78 (t, J=6.9 Hz, 2H), 2.26 (td, J=15.4, 7.6 Hz, 2H); MSNR (IER) m/z 492.32 (M ⁺ + 1). 508 17777 2-(difluoromethyl)-5-(4-((4-(6-((4,4-dimethylpiperidin-1-yl)methyl)pyridin-3-yl)-1H-1,2,3-triazol-1 -yl)methyl)-3-fluorophenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.96 (d, J=2.2 Hz, 1H), 8.78 (s, 1H), 8.19 (dd, J=8.1, 2.2 Hz, 1H), 7.97 (s, 1H), 7.94 (s, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.56 (t, J= 51.3 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 5.87 (s, 2H), 3.62 (s, 2H), 2.40 (s, 4H) , 1.40-1.30 (m, 4H), 0.91 (s, 6H); MSNR (IER) m/z 498.17 (M ⁺ + 1). 509 17778 2-(difluoromethyl)-5-(4-((4-(6-((4,4-difluoropiperidin-1-yl)methyl)pyridin-3-yl)-1H-1,2,3-triazol-1 -yl)methyl)-3-fluorophenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (d, J=2.2 Hz, 1H), 8.80 (s, 1H), 8.22 (dd, J=8.1, 2.2 Hz, 1H), 7.97 (s, 1H), 7.95 (s, 1H), 7.61 (t, J=7.7 Hz, 1H), 7.56 (t, J= 51.2 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 5.87 (s, 2H), 3.71 (s, 2H), 2.61-2.53 ( m, 4H), 2.07-1.88 (m, 4H); MSNR (IER) m/z 506.29 (M ⁺ + 1). 525 18174 2-(4-((4-(6-(azetidin-1-ylmethyl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5- (difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.99 (s, 1H), 8.59 (s, 1H), 8.26 (d, J=7.9 Hz, 1H), 7.98 ( dd, J=12.0, 9.1 Hz, 2H), 7.63 (t, J=7.7 Hz, 1H), 7.50 (d, J=8.3 Hz, 1H), 7, 24 (t, J=51.6 Hz, 1H), 5.88 (s, 2H), 3.88 (s, 2H), 3.50 (s, 4H), 2.27-2.17 (m , 2H); MSNR (IER) m/z 442.32 (M ⁺ + 1). 526 18175 2-(difluoromethyl)-5-(3-fluoro-4-((4-(6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl) methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.99 (s, 1H), 8.59 (s, 1H), 8.27 (d, J=5.8 Hz, 1H), 7.98 ( dd, J=11.9, 9.1 Hz, 2H), 7.62 (dd, J=14.0, 6.5 Hz, 2H), 7.24 (t, J=51.6 Hz, 1H ), 5.88 (s, 2H), 3.87 (s, 2H), 2.68 (s, 4H), 1.86 (s, 4H); MSNR (IER) m/z 456.76 (M ⁺ + 1). 527 18176 1-(5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) pyridin-2-yl)-N,N-dimethylmethanamine
¹ H NMR (400 MHz, CD ₃ OD) δ 9.00 (s, 1H), 8.60 (s, 1H), 8.27 (s, 1H), 7.98 (dd, J=11.9 , 9.1 Hz, 2H), 7.70-7.51 (m, J=7.7 Hz, 2H), 7.24 (t, J=51.6 Hz, 1H), 5.88 (s , 2H), 3.67 (s, 2H), 2.33 (s, 6H); MSNR (IER) m/z 430.77 (M ⁺ + 1). 528 18177 2-(difluoromethyl)-5-(3-fluoro-4-((4-(6-((4-methylpiperidin-1-yl)methyl)pyridin-3-yl)-1H-1,2,3-triazole -1-yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.98 (s, 1H), 8.59 (s, 1H), 8.26 (d, J=8.1 Hz, 1H), 7.98 ( dd, J=11.7, 9.1 Hz, 2H), 7.63 (t, J=7.5 Hz, 2H), 7.24 (t, J=51.6 Hz, 1H), 5, 88 (s, 2H), 3.69 (s, 2H), 2.92 (d, J=12.3 Hz, 2H), 2.19-2.08 (m, 2H), 1.66 (d , J=13.0 Hz, 2H), 1.49-1.36 (m, 1H), 1.31 (t, J=10.2 Hz, 2H), 0.96 (d, J=6, 3 Hz, 3H); MSNR (IER) m/z 484.74 (M ⁺ + 1).

Example 514: Synthesis of compound 17912, 2-(4-((4-(5-(azetidin-1-ylmethyl)thiophen-2-yl)-1H-1,2,3-triazol-1-yl)methyl)- 3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole

[Step 1] 5-((trimethylsilyl)ethynyl)thiophene-2-carbaldehyde

5-Bromothiophene-2-carbaldehyde (0.622 ml, 5.210 mmol), bis(triphenylphosphine) palladium dichloride (0.073 g, 0.104 mmol), copper iodide (I/II, 0.010 g, 0.052 mmol) and diethylamine (10.778 ml, 104.199 mmol ) was dissolved in tetrahydrofuran, after which trimethylsilylacetylene (0.810 ml, 5.731 mmol) was added to the resulting solution at 0°C, stirred at the same temperature for 0.5 hours, and then stirred at room temperature for 18 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting concentrate is poured into water, followed by extraction with diethyl ether. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/hexane=0-50%) and concentrated to give 5-((trimethylsilyl)ethynyl)thiophene-2-carbaldehyde (0.600 g, 55.3%) as brown solid.

[Step 2] Synthesis of 5-ethynylthiophene-2-carbaldehyde

5-((Trimethylsilyl)ethynyl)thiophene-2-carbaldehyde (0.550 g, 2.640 mmol) obtained in step 1 and potassium carbonate (1.094 g, 7.919 mmol) were dissolved in methanol (5 ml) at room temperature, after which the resulting the solution is stirred at the same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-20%) and concentrated to give 5-ethynylthiophene-2-carbaldehyde (0.300 g, 83.5%) as a light yellow solid.

[Step 3] Synthesis of 5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4- yl)thiophene-2-carbaldehyde

5-ethynylthiophene-2-carbaldehyde (0.250 g, 1.836 mmol) obtained in step 2, and 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.494 g, 1.836 mmol) obtained in step 1 of example 2 is dissolved in tert-butanol (1 ml)/water (1 ml) at room temperature, followed by sodium ascorbate (1.00 M solution, 0.184 ml, 0.184 mmol) and Copper sulfate (I/II, 0.50 M solution, 0.184 ml, 0.092 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution is poured into the reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=100-40%) and concentrated to give 5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazole-2 -yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)thiophene-2-carbaldehyde (0.590 g, 79.3%) in the form of a light yellow solid.

[Step 4] Synthesis of compound 17912

5-(1-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)thiophene-2 The β-carbaldehyde (0.050 g, 0.123 mmol) obtained in step 3, azetidine and hydrochloric acid (0.023 g, 0.247 mmol) are dissolved in dichloromethane (1 ml) at room temperature, after which sodium triacetoxyborohydride (0.131 g, 0.617 mmol) is added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-80%) and concentrated to give 2-(4-((4-(5-(azetidin-1-ylmethyl)thiophen-2-yl )-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.042 g, 76.3%) as a beige solid substances.

¹ H NMR(400 MHz, DMSO-d₆) δ 8.54 (s, 1H), 7.96 (s, 1H), 7.94 (s, 1H), 7.58 (d, J=7.6 Hz, 1H), 7.56 (t , J=51.3 Hz, 1H), 7.26 (d, J=3.5 Hz, 1H), 6.91 (d, J=3.6 Hz, 1H), 5.82 (s, 2H ), 3.68 (s, 2H), 3.16 (t, J=7.0 Hz, 4H), 2.05-1.93 (m, 2H).;MCNR(ER) m/z 447.31 (M⁺+1).

The compounds of Table 155 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 17912 except for the use of 5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl )-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)thiophene-2-carbaldehyde and the reagent from Table 154.

Table 154 Example Connection no. Reagent Exit (%) 515 17913 Pyrrolidine 72 516 17914 Dimethylamine 72 517 17915 4-methylpiperidine 71 518 17916 (S)-(+)-3-fluoropyrrolidine 76 519 17917 (R)-(-)-3-fluoropyrrolidine 72 520 17922 - eleven

Table 155 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 515 17913 2-(difluoromethyl)-5-(3-fluoro-4-((4-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)-1H-1,2,3-triazol-1-yl) methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.54 (s, 1H), 7.96 (s, 1H), 7.94 (s, 1H), 7.59 (d, J=7, 8 Hz, 1H), 7.56 (t, J=51.3 Hz, 1H), 7.26 (d, J=3.6 Hz, 1H), 6.93 (d, J=3.5 Hz , 1H), 5.82 (s, 2H), 3.77 (s, 2H), 2.51-2.43 (m, 4H), 1.71 (s, 4H); MSNR (IER) m/z 461.34 (M ⁺ + 1). 516 17914 1-(5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) thiophen-2-yl)-N,N-dimethylmethanamine
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.55 (s, 1H), 7.96 (s, 1H), 7.94 (s, 1H), 7.59 (d, J=7, 6 Hz, 1H), 7.56 (t, J=51.3 Hz, 1H), 7.28 (d, J=3.5 Hz, 1H), 6.94 (d, J=3.5 Hz , 1H), 5.83 (s, 2H), 3.60 (s, 2H), 2.19 (s, 6H); MSNR (IER) m/z 435.26 (M ⁺ + 1). 517 17915 2-(difluoromethyl)-5-(3-fluoro-4-((4-(5-((4-methylpiperidin-1-yl)methyl)thiophen-2-yl)-1H-1,2,3-triazole -1-yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.54 (s, 3H), 7.96 (s, 1H), 7.94 (s, 1H), 7.58 (d, J=7, 9 Hz, 1H), 7.56 (t, J=51.3 Hz, 1H), 7.27 (d, J=3.5 Hz, 1H), 6.92 (d, J=3.6 Hz , 1H), 5.82 (s, 2H), 3.64 (s, 2H), 2.84 (d, J=11.2 Hz, 2H), 1.95 (t, J=10.6 Hz , 2H), 1.58 (d, J=10.7 Hz, 2H), 1.32 (s, 1H), 1.21-1.06 (m, 2H), 0.89 (d, J= 6.5 Hz, 3H); MSNR (IER) m/z 489.34 (M ⁺ + 1). 518 17916 (S)-2-(difluoromethyl)-5-(3-fluoro-4-((4-(5-((3-fluoropyrrolidin-1-yl)methyl)thiophen-2-yl)-1H-1,2 ,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, DMSO) δ 8.56 (s, 2H), 7.96 (s, 1H), 7.94 (s, 1H), 7.59 (d, J=7.7 Hz, 1H), 7.56 (t, J=51.3 Hz, 1H), 7.28 (d, J=3.6 Hz, 1H), 6.96 (d, J=3.6 Hz, 1H) , 5.83 (s, 2H), 5.31-5.10 (m, J=54.7 Hz, 1H), 3.82 (s, 2H), 2.91-2.76 (m, 2H ), 2.74-2.60 (m, 1H), 2.45-2.36 (m, 1H), 2.24-2.04 (m, 1H), 2.00-1.80 (m , 1H); MSNR (IER) m/z 479.28 (M ⁺ + 1). 519 17917 (R)-2-(difluoromethyl)-5-(3-fluoro-4-((4-(5-((3-fluoropyrrolidin-1-yl)methyl)thiophen-2-yl)-1H-1,2 ,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.56 (s, 2H), 7.96 (s, 1H), 7.94 (s, 1H), 7.59 (d, J=7, 7 Hz, 1H), 7.56 (t, J=51.3 Hz, 1H), 7.28 (d, J=3.6 Hz, 1H), 6.96 (d, J=3.6 Hz , 1H), 5.83 (s, 2H), 5.31-5.10 (m, J=54.7 Hz, 1H), 3.82 (s, 2H), 2.91-2.76 ( m, 2H), 2.74-2.60 (m, 1H), 2.45-2.36 (m, 1H), 2.24-2.04 (m, 1H), 2.00-1. 80 (m, 1H); MSNR (IER) m/z 479.34 (M ⁺ + 1). 520 17922 ¹ H NMR (400 MHz, DMSO-d₆) δ 9.93 (s, 1H), 8.86 (s, 1H), 8.05 (d, J=3.9 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H ), 7.68 (d, J=4.0 Hz, 1H), 7.64 (t, J=7.6 Hz, 1H), 7.56 (t, J=51.3 Hz, 1H), 5.88 (s, 2H), 3.29 (s, 2H);MCNR (IER) m/z 406.67 (M⁺ + 1).

Example 523: Synthesis of Compound 18058, 2-(difluoromethyl)-5-(5-fluoro-6-((4-(4-(pyrrolidin-1-ylmethyl)phenyl)-1H-1,2,3-triazol-1 -yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of 4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2 ,3-triazol-4-yl)benzaldehyde

4-Ethynylbenzaldehyde (0.050 ml, 0.423 mmol), 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.114 g, 0.423 mmol), obtained in step 1 of example 490, sodium ascorbate (0.50 M solution in water, 0.085 ml, 0.042 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.004 ml, 0.004 mmol) are dissolved in tert. butanol (1 ml)/water (1 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate is purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol = 0-10%) and concentrated, after which dichloromethane (5 ml) and hexane (100 ml) are added to the resulting solution and stirred to filter out the precipitated solid substances, washed with hexane and dried to obtain 4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H- 1,2,3-triazol-4-yl)benzaldehyde (0.089 g, 52.6%) as a yellow solid.

[Step 2] Synthesis of compound 18058

4-(1-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)benzaldehyde (0.089 g, 0.222 mmol) obtained in step 1, pyrrolidine (0.036 ml, 0.444 mmol) and acetic acid (0.013 ml, 0.222 mmol) are dissolved in dichloromethane (0.5 ml)/methanol (0. 5 ml), after which the resulting solution was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (0.141 g, 0.666 mmol) was added thereto and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give 2-(difluoromethyl)-5-(5-fluoro-6-((4-(4-(pyrrolidine -1-ylmethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.032 g, 31.6%) as yellow solid matter.

¹ H NMR (400 MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.49 (s, 1H), 8.39 (dd, J=9.6, 1.7 Hz, 1H), 7.83 (d, J=8.2 Hz, 2H), 7.45 (d, J=8.2 Hz, 2H), 7.27 (t, J=51.5 Hz, 1H), 6, 30 (d, J=238.5 Hz, 2H), 3.71 (s, 2H), 2.62 (s, 4H), 1.87-1.83 (m, 4H); MSNR (ER) m/z 456.4 (M ⁺ +1).

Example 524: Synthesis of Compound 18059, 2-(difluoromethyl)-5-(5-fluoro-6-((4-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)-1H-1,2,3 -triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of 5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2 ,3-triazol-4-yl)thiophene-2-carbaldehyde

5-Ethynylthiophene-2-carbaldehyde (0.060 g, 0.441 mmol), 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.119 g, 0.441 mmol) obtained in step 1 of Example 490, sodium ascorbate (0.50 M solution in water, 0.088 ml, 0.044 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.004 ml, 0.004 mmol) dissolved in tert-butanol (1 ml)/water (1 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate is purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol = 0-10%) and concentrated, after which dichloromethane (5 ml) and hexane (100 ml) are added to the resulting solution and stirred to filter out the precipitated solid substances, washed with hexane and dried to obtain 5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H- 1,2,3-triazol-4-yl)thiophene-2-carbaldehyde (0.075 g, 41.9%) as a yellow solid.

[Step 2] Synthesis of compound 18059

5-(1-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)thiophene-2-carbaldehyde (0.075 g, 0.185 mmol) obtained in step 1, pyrrolidine (0.030 ml, 0.369 mmol) and acetic acid (0.011 ml, 0.185 mmol) are dissolved in dichloromethane (0.5 ml) / methanol (0.5 ml), after which the resulting solution was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (0.117 g, 0.554 mmol) was added thereto and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give 2-(difluoromethyl)-5-(5-fluoro-6-((4-(5-(pyrrolidine -1-ylmethyl)thiophen-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.023 g, 27.0% ) in the form of a yellow solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.40-8.37 (m, 2H), 7.30 (d, J=3.6 Hz, 1H), 7.27 (t, J=51.5 Hz, 1H), 7.01 (d, J=3.6 Hz, 1H), 5.98 (d, J=1.8 Hz, 2H), 3, 89 (s, 2H), 2.66-2.64 (m, 4H), 1.87-1.84 (m, 4H); MSNR (ER) m/z 462.4 (M ⁺ +1).

Example 529: Synthesis of compound 18178, 2-(4-((4-(5-(azetidin-1-ylmethyl)thiophen-3-yl)-1H-1,2,3-triazol-1-yl)methyl)- 3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 4-((trimethylsilyl)ethynyl)thiophene-2-carbaldehyde

4-Bromothiophene-2-carbaldehyde (2.000 g, 10.420 mmol), bis(triphenylphosphine) palladium dichloride (0.366 g, 0.521 mmol) and copper iodide (I/II, 0.198 g, 1.042 mmol) are dissolved in tetrahydrofuran (15 ml)/ triethylamine (15 ml), after which trimethylsilylacetylene (2.209 ml, 15.630 mmol) was added to the resulting solution at room temperature, and stirred at 60°C for 2 hours, and then the reaction was completed by lowering the temperature to room temperature. The reaction mixture is filtered through a pad of celite to remove solid matter, after which the solvent is removed from the resulting filtrate without solid matter under reduced pressure. The resulting concentrate was then purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane=0-10%) and concentrated to give 4-((trimethylsilyl)ethynyl)thiophene-2-carbaldehyde (1,200 g, 55.3% ) in the form of a brown solid.

[Step 2] Synthesis of 4-ethynylthiophene-2-carbaldehyde

4-((Trimethylsilyl)ethynyl)thiophene-2-carbaldehyde (1.500 g, 7.199 mmol) obtained in step 1 and potassium carbonate (2.985 g, 21.598 mmol) were dissolved in methanol (10 ml) at room temperature, after which the resulting the solution is stirred at the same temperature for 18 hours. The solvent is removed from the reaction mixture under reduced pressure, after which a saturated aqueous ammonium chloride solution is poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-20%) and concentrated to give 4-ethynylthiophene-2-carbaldehyde (0.650 g, 66.3%) as a yellow solid.

[Step 3] Synthesis of 4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4- yl)thiophene-2-carbaldehyde

4-Ethynylthiophene-2-carbaldehyde (0.150 g, 1.102 mmol) obtained in step 2, and 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.297 g, 1.102 mmol) obtained in step 1 of example 2 is dissolved in tert-butanol (2 ml)/water (2 ml) at room temperature, followed by sodium ascorbate (1.00 M solution, 0.110 ml, 0.110 mmol) and Copper sulfate (I/II, 0.50 M solution, 0.110 ml, 0.055 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution is poured into the reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give 4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazole-2 -yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)thiophene-2-carbaldehyde (0.370 g, 82.9%) as a beige solid.

[Step 4] Synthesis of compound 18178

4-(1-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)thiophene-2 α-carbaldehyde (0.040 g, 0.099 mmol) obtained in step 3 and azetidine (0.011 g, 0.197 mmol) are dissolved in dichloromethane (1 ml) at room temperature, after which sodium triacetoxyborohydride (0.105 g, 0.493 mmol) is added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=100-80%) and concentrated to give 2-(4-((4-(5-(azetidin-1-ylmethyl)thiophen-3-yl )-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.020 g, 45.4%) in the form of light yellow solid.

¹ H NMR (400 MHz, CD₃OD) δ 8.31 (s, 2H), 7.97 (dd, J=11.0, 9.2 Hz, 2H), 7.68 (d, J=1.2 Hz, 1H), 7, 59 (t, J=7.6 Hz, 1H), 7.36 (s, 1H), 7.24 (t, J=51.6 Hz, 1H), 5.83 (s, 2H), 3, 82 (s, 2H), 3.40-3.33 (m, 4H), 2.21-2.09 (m, 2H);MCNR(ER) m/z 447.69 (M⁺+1).

The compounds of Table 157 were synthesized in accordance with substantially the same method as described above for the synthesis of compound 18178 except for the use of 4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl )-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)thiophene-2-carbaldehyde and the reagent from Table 156.

Table 156 Example Connection no. Reagent Exit (%) 530 18180 (R)-(-)-3-fluoropyrrolidine 46 532 18187 Pyrrolidine 48 533 18188 Dimethylamine 44

Table 157 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 530 18180 (R)-2-(difluoromethyl)-5-(3-fluoro-4-((4-(5-((3-fluoropyrrolidin-1-yl)methyl)thiophen-3-yl)-1H-1,2 ,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.31 (s, 1H), 7.97 (dd, J=11.0, 9.1 Hz, 2H), 7.69 (d, J=1 ,2 Hz, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.39 (s, 1H), 7.24 (t, J=51.6 Hz, 1H), 5, 83 (s, 2H), 5.29-5.07 (m, 1H), 3.98-3.86 (m, 2H), 3.75 (dd, J=25.3, 15.5 Hz, 1H), 3.02-2.88 (m, 2H), 2.78 (dd, J=30.6, 11.7, 5.1 Hz, 1H), 2.55 (dd, J=14, 9, 8.4 Hz, 1H), 2.34-2.13 (m, 1H), 2.08-1.93 (m, 1H); MSNR (IER) m/z 479.73 (M ⁺ + 1). 532 18187 2-(difluoromethyl)-5-(3-fluoro-4-((4-(5-(pyrrolidin-1-ylmethyl)thiophen-3-yl)-1H-1,2,3-triazol-1-yl) methyl)phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.31 (s, 1H), 7.97 (dd, J=11.0, 9.1 Hz, 2H), 7.69 (d, J=1 ,3 Hz, 1H), 7.59 (t, J=7.6 Hz, 1H), 7.39 (s, 1H), 7.24 (t, J=51.6 Hz, 2H), 5, 84 (s, 2H), 3.89 (s, 2H), 2.64 (s, 4H), 1.85 (dd, J=6.8, 3.3 Hz, 4H); MSNR (IER) m/z 461.68 (M ⁺ + 1). 533 18188 1-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl) thiophen-2-yl)-N,N-dimethylmethanamine
¹ H NMR (400 MHz, CD ₃ OD) δ 8.31 (s, 1H), 7.98 (dd, J=10.8, 9.1 Hz, 2H), 7.71 (d, J=1 ,3 Hz, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.39 (s, 1H), 7.24 (t, J=51.6 Hz, 1H), 5, 84 (s, 2H), 3.74 (s, 2H), 2.31 (s, 6H); MSNR (IER) m/z 435.69 (M ⁺ + 1).

Example 537: Synthesis of Compound 18305, 2-(difluoromethyl)-5-(5-fluoro-6-((4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl) pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of 3-ethynylpyridine

Dimethyl (1-diazo-2-oxopropyl)phosphonate (0.462 ml, 3.081 mmol) and potassium carbonate (0.774 g, 5.602 mmol) are dissolved in methanol (10 ml) at room temperature, after which nicotinaldehyde (0.263 ml, 2.801 mmol) is added to the resulting solution and stir at the same temperature for 4 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 3-ethynylpyridine (0.130 g, 45.0%) as a yellow oil.

[Step 2] Synthesis of compound 18305

3-Ethynylpyridine (0.130 g, 1.261 mmol) prepared in Example 1, 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.341 g , 1.261 mmol) obtained in step 1 of Example 490, sodium ascorbate (0.50 M solution in water, 0.252 ml, 0.126 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.013 ml, 0.013 mmol ) is dissolved in tert-butanol (3 ml)/water (3 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Dichloromethane (5 ml) and hexane (50 ml) were added to the resulting concentrate and stirred to filter the precipitated solid, washed with hexane and dried to give 2-(difluoromethyl)-5-(5-fluoro-6-((4- (pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.121 g, 25.7%) as white solid matter.

^1H NMR (400 MHz, CD ₃ OD) δ 9.10-9.06 (m, 2H), 8.66 (s, 1H), 8.55 (s, 1H), 8.40 (dd, J =9.6, 1.4 Hz, 1H), 8.32 (d, J=8.0 Hz, 1H), 7.27-7.54 (m, 1H), 7.27 (t, J= 51.5 Hz, 1H), 6.04 (d, J=1.6 Hz, 2H); MSNR (ER) m/z 374.4 (M ⁺ +1).

The compounds of Table 159 are synthesized according to essentially the same process as described in the synthesis of compounds 3835, 4487, 4488 and 18305 using azide compound 1-2 and acetylene compound 2-3 in Table 158 for reagents and using a click reaction .

Table 158 Example Connection no. Reagent (acetylene) Reagent (azide) Exit (%) 48 3837 4-ethynylpyridine 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 71 49 3838 6-ethynyl-1H-indole 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 41 50 3839 4-ethynyl-1H-indole 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 32 51 3840 4-ethynyl-1H-pyrrolo[2,3-b]pyridine 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 28 52 3841 5-ethynyl-1H-pyrrolo[2,3-b]pyridine 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 44 53 3842 4-ethynyl-1-methyl-1H-indazole 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 27 54 3843 6-ethynyl-1H-benzo[d]imidazole 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 35 55 3844 3-ethynylpyridin-2(1H)-one 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 40 56 3845 5-ethynylpyridin-2(1H)-one 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 40 64 3866 4-(3-ethynylphenyl)morpholine 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 45 65 3867 1-(3-ethynylphenyl)-4-methylpiperazine 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 33 68 3881 2-ethynylpyridine 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 81 69 3882 2-chloro-5-ethynylpyridine 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 87 70 3883 3-chloro-5-ethynylpyridine 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 92 71 3884 3-ethynyl-5-methylpyridine 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 62 90 3925 5-ethynyl-2-methylpyridine 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 76 149 4071 7-ethynyl-1H-indole 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 67 150 4072 5-ethynyl-1H-indole 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 56 151 4073 5-ethynylbenzofuran 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 79 152 4074 5-ethynylbenzo[b]thiophene 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 49 153 4075 1-(3-ethynylphenyl)-1H-imidazole 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 67 154 4076 6-ethynyl-1H-indole 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 72 155 4077 6-ethynyl-1H-indole 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 64 156 4078 4-ethynyl-1H-indole 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 59 157 4079 4-ethynyl-1H-indole 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 70 158 4080 5-ethynyl-1H-indole 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 41 159 4081 7-ethynyl-1H-indole 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 48 160 4082 7-ethynyl-1H-indole 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 42 161 4104 4-(2-ethynylphenyl)morpholine 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 52 162 4105 4-(4-ethynylphenyl)morpholine 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 54 163 4106 1-(2-ethynylphenyl)-4-methylpiperazine 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 47 164 4107 1-(4-ethynylphenyl)-4-methylpiperazine 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 51 172 4135 5-ethynyl-1H-indole 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 79 174 4178 2-ethynyl-3-fluoropyridine 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 72 175 4179 2-ethynyl-4-fluoropyridine 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 52 176 4180 5-bromo-2-ethynylpyridine 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 71 177 4181 3-ethynyl-4-methylpyridine 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 56 178 4182 3-bromo-5-ethynylpyridine 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 90 179 4183 2-bromo-5-ethynylpyridine 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 56 180 4184 4-ethynyl-3-fluoropyridine 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 73 181 4185 4-ethynyl-2-fluoropyridine 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 81 205 4284 1-(4-ethynylphenyl)-1H-imidazole 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 66 206 4285 1-(4-ethynylphenyl)-1H-1,2,4-triazole 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 58 207 4286 1-(2-ethynylphenyl)-1H-1,2,4-triazole 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 74 210 4289 5-ethynyl-2-methyl-1H-indole 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 62 363 4489 1-(difluoromethyl)-3-ethynylbenzene 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 90 485 17198 7-ethynylimidazo[1,2-a]pyridine 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 68 486 17201 2-ethynylimidazo[1,2-a]pyridine 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 58 489 17263 2-bromo-6-ethynylpyridine 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 74 510 17848 2-ethynylthiazole 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 73 511 17851 5-ethynylthiazole 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 68 512 17854 2-ethynyl-4-methylthiazole 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 81 513 17857 2-ethynyl-5-methylthiazole 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 75

Table 159 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 48 3837 2-(difluoromethyl)-5-(6-((4-(pyridin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3, 4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 9.27 (dd, J =2.3, 0.8 Hz, 1H), 8.76 (s, 1H), 8.62 (d, J =5 .5 Hz, 2H), 8.54 (dd, J =8.2, 2.2 Hz, 1H), 7.95-7.89 (m, 2H), 7.64 (dd, J =8, 2, 0.9 Hz, 1H), 7.26 (t, J =51.6 Hz, 1H), 5.96 (s, 2H); MSNR (ER) m/z 356.1 (M ⁺ +1). 49 3838 2-(6-((4-(1H-indol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1, 3,4-oxadiazole
^1H NMR (400 MHz, DMSO- _d6 ) δ 11.20 (s, 1H), 9.21 (dd, J =2.3, 0.8 Hz, 1H), 8.65 (s, 1H) , 8.50 (dd, J =8.2, 2.3 Hz, 1H), 7.93 (dt, J =1.6, 0.9 Hz, 1H), 7.60 (d, J =8 .3 Hz, 1H), 7.58 (t, J =51.3 Hz, 1H), 7.56 (dd, J =8.2, 0.9 Hz, 1H), 7.50 (dd, J =8.2, 1.5 Hz, 1H), 7.42-7.36 (m, 1H), 6.45 (ddd, J =3.0, 1.9, 0.9 Hz, 1H), 5.92 (s, 2H); MSNR (ER) m/z 394.3 (M ⁺ +1). 50 3839 2-(6-((4-(1H-indol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1, 3,4-oxadiazole
^1H NMR (400 MHz, DMSO- _d6 ) δ 9.21 (dd, J = 2.3, 0.9 Hz, 1H), 8.78 (s, 1H), 8.49 (dd, J = 8.2, 2.3 Hz, 1H), 7.60 (dd, J =7.4, 1.0 Hz, 1H), 7.55 (dd, J =8.2, 0.9 Hz, 1H ), 7.68-7.41 (m, 1H), 7.44 (d, J =3.2 Hz, 1H), 7.40 (d, J =1.3 Hz, 1H), 7.22 -7.13 (m, 1H), 6.97 (dd, J =3.2, 0.9 Hz, 1H), 5.96 (s, 2H); MSNR (ER) m/z 394.2 (M ⁺ +1). 51 3840 2-(6-((4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)- 5-(difluoromethyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 9.31 (s, 1H), 8.89 (s, 1H), 8.60-8.48 (m, 1H), 7.66 (d, J =8.5 Hz, 2H), 7.55 (d, J =3.5 Hz, 1H), 7.32 (t, J =51.5 Hz, 1H), 7.07 (d, J =3 .6 Hz, 1H), 6.03 (s, 2H); MSNR (ER) m/z 395.1 (M ⁺ +1). 52 3841 2-(6-((4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)- 5-(difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.74 (s, 1H), 9.22 (dd, J = 2.3, 0.9 Hz, 1H), 8.77-8.70 ( m, 2H), 8.50 (dd, J =8.2, 2.3 Hz, 1H), 8.41 (d, J =2.1 Hz, 1H), 7.60 (d, J =7 .9 Hz, 1H), 7.58 (t, J =51.3 Hz, 1H), 7.55-7.49 (m, 1H), 6.52 (dd, J =3.4, 1, 8 Hz, 1H), 5.95 (s, 2H); MSNR (ER) m/z 395.4 (M ⁺ +1). 53 3842 2-(difluoromethyl)-5-(6-((4-(1-methyl-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl )-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.31 (s, 1H), 8.78 (s, 1H), 8.58 (d, J =1.0 Hz, 1H), 8.56 ( dd, J =8.2, 2.2 Hz, 1H), 7.71 (dd, J =7.1, 0.9 Hz, 1H), 7.67-7.61 (m, 2H), 7 .54 (dd, J =8.5, 7.1 Hz, 1H), 7.32 (t, J =51.6 Hz, 1H), 6.01 (s, 2H); MSNR (ER) m/z 409.2 (M ⁺ +1). 54 3843 2-(6-((4-(1H-benzo[d]imidazol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl )-1,3,4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.24-9.19 (m, 1H), 8.71 (d, J = 6.6 Hz, 1H), 8.50 (dd, J = 8.2, 2.3 Hz, 1H), 8.28-8.12 (m, 1H), 7.78 (d, J =7.6 Hz, 1H), 7.71 (s, 1H), 7.61-7.44 (m, 2H), 5.93 (s, 2H); MSNR (ER) m/z 395.2 (M ⁺ +1). 55 3844 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl )pyridin-2(1H)-one
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.21-9.16 (m, 1H), 8.77 (s, 1H), 8.48 (dd, J = 8.2, 2.3 Hz, 1H), 8.32 (dd, J =7.0, 2.1 Hz, 1H), 7.74-7.42 (m, 2H), 7.52 (d, J =8.0 Hz , 1H), 6.39 (t, J =6.7 Hz, 1H), 5.96 (s, 2H); MSNR (ER) m/z 372.2 (M ⁺ +1). 56 3845 5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl )pyridin-2(1H)-one
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.19 (d, J = 2.0 Hz, 1H), 8.77 (s, 1H), 8.48 (dd, J = 8.2, 2.3 Hz, 1H), 8.32 (dd, J =7.1, 2.2 Hz, 1H), 7.72-7.41 (m, 2H), 7.52 (d, J =8 .5 Hz, 1H), 6.40 (d, J =6.5 Hz, 1H), 5.96 (s, 2H); MSNR (ER) m/z 372.2 (M ⁺ +1). 64 3866 4-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)phenyl)morpholine
¹ H NMR (400 MHz, CD ₃ OD) δ 9.28 (s, 1H), 8.53 (dd, J =8.2, 2.3 Hz, 1H), 8.48 (s, 1H), 7.60 (d, J =8.3 Hz, 1H), 7.49 (s, 1H), 7.34 (d, J =6.6 Hz, 2H), 7.26 (t, J =51 .5 Hz, 1H), 7.02-6.97 (m, 1H), 5.92 (s, 2H), 3.91-3.84 (m, 4H), 3.26-3.19 ( m, 4H); MSNR (ER) m/z 440.3 (M ⁺ +1). 65 3867 2-(difluoromethyl)-5-(6-((4-(3-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3- yl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 9.28 (dd, J =2.2, 0.9 Hz, 1H), 8.53 (dd, J =8.2, 2.2 Hz, 1H ), 8.48 (s, 1H), 7.59 (dd, J =8.2, 0.8 Hz, 1H), 7.50 (kv, J =1.3 Hz, 1H), 7.36 -7.30 (m, 2H), 7.26 (t, J =51.6 Hz, 1H), 7.00 (dt, J =6.6, 2.7 Hz, 1H), 5.92 ( s, 2H), 3.33-3.27 (m, 4H), 2.71-2.64 (m, 4H), 2.39 (s, 3H); MSNR (ER) m/z 453.3 (M ⁺ +1). 68 3881 2-(difluoromethyl)-5-(6-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3, 4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.20 (dd, J=2.2, 0.9 Hz, 1H), 8.76 (d, J=1.0 Hz, 1H), 8 .66-8.58 (m, 1H), 8.49 (dt, J=8.3, 1.8 Hz, 1H), 8.07 (dt, J=7.9, 1.1 Hz, 1H ), 7.92 (tt, J=7.8, 1.6 Hz, 1H), 7.72-7.45 (m, 2H), 7.40-7.34 (m, 1H), 5, 98 (s, 2H); MSNR (IER) m/z 356.2 (M ⁺ + H). 69 3882 2-(6-((4-(6-chloropyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.20 (dd, J=2.3, 0.8 Hz, 1H), 8.96-8.86 (m, 2H), 8.50 ( dd, J=8.2, 2.3 Hz, 1H), 8.32 (dd, J=8.3, 2.5 Hz, 1H), 7.63 (ddd, J=8.2, 2, 7, 0.8 Hz, 2H), 7.58 (t, J=51.2 Hz, 1H), 5.98 (s, 2H); MSNR (IER) m/z 390.2 (M ⁺ + H). 70 3883 2-(6-((4-(5-chloropyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.20 (dd, J=2.2, 0.8 Hz, 1H), 9.07 (dd, J=1.9, 0.4 Hz, 1H), 8.93 (s, 1H), 8.61 (dd, J=2.3, 0.4 Hz, 1H), 8.51 (dd, J=8.2, 2.3 Hz, 1H ), 8.39 (dd, J=2.3, 1.9 Hz, 1H), 7.73-7.44 (m, 2H), 5.98 (s, 2H); MSNR (IER) m/z 390.1 (M ⁺ + H). 71 3884 2-(difluoromethyl)-5-(6-((4-(5-methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.20 (dd, J=2.3, 0.9 Hz, 1H), 8.91-8.86 (m, 1H), 8.82 ( s, 1H), 8.50 (dd, J=8.2, 2.3 Hz, 1H), 8.40 (dd, J=2.2, 0.9 Hz, 1H), 8.09 (td , J=2.1, 0.8 Hz, 1H), 7.61 (dd, J=8.2, 0.8 Hz, 1H), 7.58 (t, J=51.2 Hz, 1H) , 5.96 (s, 2H), 2.37 (kv, J=0.7 Hz, 3H); MSNR (IER) m/z 370.2 (M ⁺ + H). 90 3925 2-(difluoromethyl)-5-(6-((4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.34 (dd, J=2.2, 0.8 Hz, 1H), 8.90 (d, J=2.3 Hz, 1H), 8, 42 (dd, J=8.2, 2.2 Hz, 1H), 8.17 (dd, J=8.1, 2.3 Hz, 1H), 8.06 (s, 1H), 7.46 (dd, J=8.2, 0.8 Hz, 1H), 7.28 (d, J=8.1 Hz, 2H), 6.94 (t, J=51.6 Hz, 1H), 5 .83 (s, 2H), 2.63 (s, 3H); MSNR (IER) m/z 370.2 (M ⁺ + H). 149 4071 2-(6-((4-(1H-indol-7-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1, 3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 8.55 (s, 1H), 8.03-7.93 (m, 2H), 7.64-7.57 (m, 2H), 7.50 (dd, J =7.4, 1.0 Hz, 1H), 7.39 (d, J =3.2 Hz, 1H), 7.37-7.12 (m, 1H), 7.12- 7.08 (m, 1H), 6.54 (d, J =3.2 Hz, 1H), 5.90 (s, 2H); MSNR (ER) m/z 394.2 (M ⁺ +1). 150 4072 2-(6-((4-(1H-indol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1, 3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 9.30 (dd, J =2.3, 0.9 Hz, 1H), 8.52 (dd, J =8.2, 2.3 Hz, 1H ), 8.41 (s, 1H), 8.05 (dd, J =1.7, 0.7 Hz, 1H), 7.82 (s, 1H), 7.59 (dt, J =8, 4, 1.4 Hz, 2H), 7.47 (dd, J =8.5, 0.8 Hz, 1H), 7.28 (s, 1H), 7.40-7.06 (m, 1H ), 5.92 (s, 2H); MSNR (ER) m/z 394.3 (M ⁺ +1). 151 4073 2-(6-((4-(benzofuran-5-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3, 4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 9.29 (dd, J =2.2, 0.8 Hz, 1H), 8.52 (dd, J =8.2, 2.3 Hz, 1H ), 8.45 (s, 1H), 8.10 (dd, J =1.9, 0.7 Hz, 1H), 7.82 (s, 1H), 7.79 (dd, J =8, 9, 2.0 Hz, 2H), 7.63-7.54 (m, 2H), 7.22 (t, J =51.6 Hz, 1H), 6.89 (dd, J =2.2 , 1.0 Hz, 1H), 5.92 (s, 2H); MSNR (ER) m/z 395.3 (M ⁺ +1). 152 4074 2-(6-((4-(benzo[b]thiophen-5-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)- 1,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 9.29 (d, J =2.0 Hz, 1H), 8.56 (s, 1H), 8.54 (dd, J =8.2, 2 ,3 Hz, 1H), 8.38-8.33 (m, 1H), 8.00 (d, J =8.4 Hz, 1H), 7.85 (dd, J =8.4, 1, 7 Hz, 1H), 7.65 (d, J =5.5 Hz, 1H), 7.62 (d, J =8.1 Hz, 1H), 7.46 (dd, J =5.5, 0.8 Hz, 1H), 7.26 (t, J =51.6 Hz, 1H), 5.95 (s, 2H); MSNR (ER) m/z 411.3 (M ⁺ +1). 153 4075 2-(6-((4-(3-(1H-imidazol-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-( difluoromethyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 9.29 (dd, J =2.3, 0.9 Hz, 1H), 8.64 (s, 1H), 8.54 (dd, J =8 ,2, 2.2 Hz, 1H), 8.40-8.20 (m, 2H), 8.10 (s, 1H), 7.96-7.89 (m, 1H), 7.80- 7.57 (m, 4H), 7.26 (t, J =51.6 Hz, 1H), 5.95 (s, 2H); MSNR (ER) m/z 421.4 (M ⁺ +1). 154 4076 2-(4-((4-(1H-indol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4- oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.36 (s, 1H), 8.17 (d, J =8.4 Hz, 2H), 7.90 (d, J =1.0 Hz, 1H), 7.66-7.58 (m, 3H), 7.46 (dd, J =8.2, 1.5 Hz, 1H), 7.29 (d, J =3.1 Hz, 1H ), 7.23 (t, J =51.6 Hz, 1H), 6.47 (dd, J =3.2, 0.9 Hz, 1H), 5.80 (s, 2H); MSNR (ER) m/z 393.2 (M ⁺ +1). 155 4077 2-(4-((4-(1H-indol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3 ,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 8.35 (s, 1H), 8.02-7.92 (m, 2H), 7.90 (s, 1H), 7.65-7.56 (m, 2H), 7.45 (dd, J =8.2, 1.5 Hz, 1H), 7.31-7.26 (m, 1H), 7.20 (t, J =51.6 Hz, 1H), 6.48 (dd, J =3.2, 0.9 Hz, 1H), 5.85 (s, 2H); MSNR (ER) m/z 411.2 (M ⁺ +1). 156 4078 2-(4-((4-(1H-indol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4- oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 8.46 (s, 1H), 8.20-8.13 (m, 2H), 7.82 (s, 1H), 7.67-7.60 (m, 2H), 7.55 (dd, J =7.4, 0.9 Hz, 1H), 7.44 (dd, J =8.1, 0.9 Hz, 1H), 7.34 ( t, J =1.6 Hz, 1H), 7.21 (d, J =7.5 Hz, 1H), 7.32-7.04 (m, 1H), 5.84 (s, 2H); MSNR (ER) m/z 393.3 (M ⁺ +1). 157 4079 2-(4-((4-(1H-indol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3 ,4-oxadiazole (0.043 g, 70.5%)
¹ H NMR (400 MHz, CD ₃ OD) δ 8.51 (s, 1H), 8.02-7.93 (m, 2H), 7.61 (t, J = 7.8 Hz, 1H), 7.55 (dd, J =7.4, 0.9 Hz, 1H), 7.44 (dt, J =8.1, 0.9 Hz, 1H), 7.35 (d, J =3, 2 Hz, 1H), 7.24 (t, J =51.6 Hz, 1H), 7.20 (dd, J =8.1, 7.3 Hz, 1H), 6.86 (dd, J = 3.2, 1.0 Hz, 1H), 5.91 (s, 2H); MSNR (ER) m/z 411.4 (M ⁺ +1). 158 4080 2-(4-((4-(1H-indol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4- oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.32 (s, 1H), 8.20-8.13 (m, 2H), 8.03 (dd, J = 1.7, 0.7 Hz , 1H), 7.82 (s, 1H), 7.66-7.60 (m, 1H), 7.58 (dd, J =8.5, 1.7 Hz, 1H), 7.46 ( dd, J =8.4, 0.7 Hz, 1H), 7.27 (t, J =1.6 Hz, 1H), 7.19 (t, J =51.6 Hz, 1H), 6, 51 (dd, J =3.2, 0.9 Hz, 1H), 5.79 (s, 2H); MSNR (ER) m/z 393.2 (M ⁺ +1). 159 4081 2-(4-((4-(1H-indol-7-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4- oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.49 (s, 1H), 8.16 (d, J =8.4 Hz, 2H), 7.62 (d, J =8.3 Hz, 2H), 7.59 (dd, J =7.9, 1.0 Hz, 1H), 7.49 (d, J =7.5 Hz, 1H), 7.38 (s, 1H), 7, 18 (t, J =51.7 Hz, 1H), 7.12-7.07 (m, 1H), 6.54 (d, J =3.2 Hz, 1H), 5.83 (s, 2H ); MSNR (ER) m/z 393.1 (M ⁺ +1). 160 4082 2-(4-((4-(1H-indol-7-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3 ,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 8.49 (s, 1H), 8.01-7.91 (m, 2H), 7.82 (s, 1H), 7.64-7.55 (m, 2H), 7.49 (dd, J =7.4, 1.0 Hz, 1H), 7.38 (s, 1H), 7.20 (t, J =51.6 Hz, 1H) , 7.10 (dd, J =7.9, 7.4 Hz, 1H), 5.88 (s, 2H); MSNR (ER) m/z 411.3 (M ⁺ +1). 161 4104 4-(2-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)phenyl)morpholine
^1H NMR (400 MHz, CDCl ₃ ) δ 9.35 (dd, J =2.2, 0.7 Hz, 1H), 8.62 (s, 1H), 8.43 (dd, J =8, 2, 2.2 Hz, 1H), 8.15 (dd, J =7.7, 1.6 Hz, 1H), 7.47 (d, J =8.2 Hz, 1H), 7.36 ( ddd, J =7.9, 7.5, 1.7 Hz, 1H), 7.26-7.16 (m, 2H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H), 5.85 (s, 2H), 3.82-3.73 (m, 4H), 2.96-2.86 (m, 4H) ; MSNR (ER) m/z 440.4 (M ⁺ +1). 162 4105 4-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)phenyl)morpholine
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.35 (d, J = 1.5 Hz, 1H), 8.41 (dd, J = 8.2, 2.2 Hz, 1H), 7.89 (s, 1H), 7.83-7.72 (m, 2H), 7.41 (d, J =7.9 Hz, 1H), 7.09 (s, 0.2H), 7.00 ( d, J =8.5 Hz, 2H), 6.96 (s, 0.5H), 6.83 (s, 0.2H), 5.82 (s, 2H), 3.96-3.85 (m, 4H), 3.30-3.17 (m, 4H); MSNR (ER) m/z 440.4 (M ⁺ +1). 163 4106 2-(difluoromethyl)-5-(6-((4-(2-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3- yl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 9.36 (dd, J =2.1, 0.6 Hz, 1H), 8.57 (s, 1H), 8.41 (dd, J =8, 2, 2.2 Hz, 1H), 8.20-8.10 (m, 1H), 7.45 (d, J =8.2 Hz, 1H), 7.37-7.29 (m, 1H ), 7.25-7.15 (m, 2H), 7.06 (m, 0.3H), 6.96 (s, 0.5H), 6.83 (s, 0.2H), 5, 84 (s, 2H), 2.92 (t, J =4.8 Hz, 4H), 2.59-2.36 (m, 4H), 2.31 (s, 3H); MSNR (ER) m/z 453.2 (M ⁺ +1). 164 4107 2-(difluoromethyl)-5-(6-((4-(4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3- yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.34 (dd, J = 2.2, 0.7 Hz, 1H), 8.39 (dd, J = 8.2, 2.2 Hz, 1H) , 7.87 (s, 1H), 7.79-7.69 (m, 2H), 7.39 (dd, J =8.2, 0.6 Hz, 1H), 7.09 (s, 0 ,2H), 7.01-6.96 (m, 2H), 6.96 (s, 0.5H), 6.83 (s, 0.3H), 5.81 (s, 2H), 3, 34-3.23 (m, 4H), 2.60 (dd, J =16.1, 11.1 Hz, 4H), 2.39 (s, 3H); MSNR (ER) m/z 453.1 (M ⁺ +1). 172 4135 2-(4-((4-(1H-indol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3 ,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 8.04 (s, 1H), 7.94 (s, 1H), 7.84 (t, J =10.4 Hz, 3H), 7.51 (d , J =8.5 Hz, 2H), 7.39 (d, J =8.5 Hz, 1H), 7.17 (s, 1H), 6.89 (t, J =51.5 Hz, 1H ), 5.71 (s, 2H); MSNR (ER) m/z 411.91 (M ⁺ +1). 174 4178 2-(difluoromethyl)-5-(6-((4-(3-fluoropyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.27 (dd, J=2.2, 0.9 Hz, 1H), 8.67 (d, J=2.6 Hz, 1H), 8, 56-8.49 (m, 2H), 7.76 (dd, J=10.8, 8.4, 1.3 Hz, 1H), 7.62 (dd, J=8.2, 0.9 Hz, 1H), 7.48 (ddd, J=8.6, 4.7, 4.1 Hz, 1H), 7.26 (t, J=51.6 Hz, 1H), 5.99 (s , 2H); MSNR (IER) m/z 374.3 (M ⁺ + H). 175 4179 2-(difluoromethyl)-5-(6-((4-(4-fluoropyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.27 (dd, J=2.3, 0.9 Hz, 1H), 8.66 (s, 1H), 8.61 (dd, J=8 ,4, 5.7 Hz, 1H), 8.53 (dd, J=8.2, 2.2 Hz, 1H), 7.87 (dd, J=10.0, 2.5 Hz, 1H) , 7.63 (dd, J=8.2, 0.8 Hz, 1H), 7.26 (t, J=51.6 Hz, 1H), 7.20 (ddd, J=8.4, 5 ,7, 2.5 Hz, 1H), 5.97 (s, 2H); MSNR (IER) m/z 374.0 (M ⁺ + H). 176 4180 2-(6-((4-(5-bromopyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.27 (dd, J=2.2, 0.8 Hz, 1H), 8.69 (dd, J=2.3, 0.8 Hz, 1H ), 8.64 (s, 1H), 8.53 (ddd, J=8.2, 2.3, 1.2 Hz, 1H), 8.10 (dd, J=8.5, 2.3 Hz, 1H), 8.03 (dd, J=8.5, 0.8 Hz, 1H), 7.73-7.61 (m, 1H), 7.26 (td, J=51.6, 5.1 Hz, 1H), 5.96 (s, 2H); MSNR (IER) m/z 434.3 (M ⁺ + H). 177 4181 2-(difluoromethyl)-5-(6-((4-(4-methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.28 (dd, J=2.3, 0.9 Hz, 1H), 8.82 (s, 1H), 8.57-8.51 (m , 2H), 8.42 (d, J=5.2 Hz, 1H), 7.63 (dd, J=8.2, 0.8 Hz, 1H), 7.42 (d, J=5, 1 Hz, 1H), 7.26 (t, J=51.6 Hz, 1H), 5.98 (s, 2H), 2.56 (d, J=0.7 Hz, 3H); MSNR (IER) m/z 370.3 (M ⁺ + H). 178 4182 2-(6-((4-(5-bromopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.27 (dd, J=2.2, 0.9 Hz, 1H), 9.03 (d, J=1.8 Hz, 1H), 8, 70 (s, 1H), 8.65 (d, J=2.2 Hz, 1H), 8.57-8.49 (m, 2H), 7.64 (dd, J=8.2, 0, 8 Hz, 1H), 7.26 (t, J=51.6 Hz, 1H), 5.95 (s, 2H)); MSNR (IER) m/z 434.2 (M ⁺ + H). 179 4183 2-(6-((4-(6-bromopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.27 (dd, J=2.2, 0.9 Hz, 1H), 8.86 (dd, J=2.5, 0.8 Hz, 1H ), 8.66 (s, 1H), 8.53 (dd, J=8.3, 2.2 Hz, 1H), 8.19 (dd, J=8.3, 2.5 Hz, 1H) , 7.72 (dd, J=8.4, 0.8 Hz, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.26 (t, J=51.6 Hz, 1H), 5.95 (s, 2H); MSNR (IER) m/z 434.3 (M ⁺ + H). 180 4184 2-(difluoromethyl)-5-(6-((4-(3-fluoropyridin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.27 (dd, J=2.3, 0.9 Hz, 1H), 8.72 (d, J=3.4 Hz, 1H), 8, 60 (d, J=2.7 Hz, 1H), 8.57-8.47 (m, 2H), 8.22 (dd, J=6.4, 5.1 Hz, 1H), 7.63 (dd, J=8.2, 0.8 Hz, 1H), 7.26 (t, J=51.6 Hz, 1H), 5.99 (s, 2H); MSNR (IER) m/z 374.3 (M ⁺ + H). 181 4185 2-(difluoromethyl)-5-(6-((4-(2-fluoropyridin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.27 (dd, J=2.3, 0.9 Hz, 1H), 8.79 (s, 1H), 8.54 (dd, J=8 ,2, 2.3 Hz, 1H), 8.28 (dt, J=5.2, 0.7 Hz, 1H), 7.80 (ddd, J=5.3, 2.0, 1.3 Hz, 1H), 7.65 (dd, J=8.3, 0.8 Hz, 1H), 7.56 (kv, J=1.2 Hz, 1H), 7.26 (t, J=51 .6 Hz, 1H), 5.96 (s, 2H); MSNR (IER) m/z 374.4 (M ⁺ + H). 205 4284 2-(6-((4-(4-(1H-imidazol-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-( difluoromethyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, DMSO- _d6 ) δ 9.21 (d, J =2.0 Hz, 1H), 8.80 (s, 1H), 8.54-8.48 (m, 1H) , 8.34 (s, 1H), 8.02 (d, J =8.2 Hz, 2H), 7.83 (s, 1H), 7.77 (d, J =8.2 Hz, 2H) , 7.73-7.44 (m, 2H), 7.15 (s, 1H), 5.96 (s, 2H); MSNR (ER) m/z 421.2 (M ⁺ +1). 206 4285 2-(6-((4-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3- yl)-5-(difluoromethyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, DMSO- _d6 ) δ 9.36 (s, 1H), 9.21 (d, J =2.2 Hz, 1H), 8.82 (s, 1H), 8.51 (dd, J =8.3, 2.3 Hz, 1H), 8.27 (s, 1H), 8.11-8.04 (m, 2H), 7.98 (d, J =8.5 Hz, 2H), 7.73-7.44 (m, 2H), 5.96 (s, 2H); MSNR (ER) m/z 422.9 (M ⁺ +1). 207 4286 2-(6-((4-(2-(1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3- yl)-5-(difluoromethyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, DMSO- _d6 ) δ 9.18 (dd, J = 2.3, 0.8 Hz, 1H), 8.76 (s, 1H), 8.48 (dd, J = 8.2, 2.3 Hz, 1H), 8.21 (s, 1H), 8.09 (dd, J =7.9, 1.5 Hz, 1H), 7.71 (td, J =7 ,4, 1.6 Hz, 1H), 7.58 (pd, J = 7.9, 1.5 Hz, 3H), 7.48-7.40 (m, 1H), 7.35 (s, 1H), 5.85 (s, 2H); MSNR (ER) m/z 422.2 (M ⁺ +1). 210 4289 2-(difluoromethyl)-5-(6-((4-(2-methyl-1H-indol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl )-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.28 (dd, J=2.3, 0.9 Hz, 1H), 8.52 (dd, J=8.2, 2.2 Hz, 1H ), 8.36 (s, 1H), 7.89 (d, J=1.6 Hz, 1H), 7.64-7.54 (m, 1H), 7.54-7.43 (m, 1H), 7.39-7.12 (m, 2H), 6.21-6.16 (m, 1H), 5.90 (s, 2H), 2.44 (d, J=1.0 Hz , 3H); MSNR (IER) m/z 408.3 (M ⁺ + H). 363 4489 2-(difluoromethyl)-5-(6-((4-(3-(difluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3 ,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.31 (d, J=2.3 Hz, 1H), 8.39 (dd, J=8.2, 2.3 Hz, 1H), 8.10 &#8211; 7.92 (m, 3H), 7.47 (ddd, J=23.1, 15.2, 7.9 Hz, 3H), 7.10 &#8211; 6.47 (m, 2H), 5.81 (s, 2H); MSNR (ER) m/z (M++1). 485 17198 2-(difluoromethyl)-5-(3-fluoro-4-((4-(imidazo[1,2-a]pyridin-7-yl)-1H-1,2,3-triazol-1-yl)methyl )phenyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 8.65 (s, 1H), 8.59 (s, 1H), 8.09-7.89 (m, 4H), 7.68 (dt, J =27.7, 7.7 Hz, 2H), 7.48 (d, J=7.1 Hz, 1H), 7.24 (t, J=51.6 Hz, 1H), 5.89 (s , 2H); MSNR (ER) m/z 412.34 (M ⁺ +1). 486 17201 2-(difluoromethyl)-5-(3-fluoro-4-((4-(imidazo[1,2-a]pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl )phenyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.71-8.24 (m, 2H), 7.99 (dd, J=11.8, 8.9 Hz, 3H), 7.64 (t , J=7.5 Hz, 1H), 7.56 (s, 1H), 7.45-7.34 (m, 1H), 7.24 (t, J=51.6 Hz, 8H), 6 .98 (t, J=6.8 Hz, 1H), 5.91 (s, 2H), 4.87 (s, 119H), 3.33 (dt, J=3.3, 1.6 Hz, 196H), 3.30-3.16 (m, 6H), 1.93 (s, 5H), 1.24 (s, 1H); MSNR (ER) m/z 412.34 (M ⁺ +1). 489 17263 2-(4-((4-(6-bromopyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3 ,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.60 (s, 1H), 8.06 (d, J= 7.6 Hz, 1H), 8.00-7.95 (m, 2H), 7.79 (t, J= 7.8 Hz, 1H), 7.63 (t, J= 7.6 Hz, 1H), 7.55 (d, J= 7.8 Hz, 1H), 7. 24 (t, J= 51.6 Hz, 1H), 5.88 (s, 2H); MSNR (IER) m/z 451.1 (M ⁺ + H). 510 17848 2-(difluoromethyl)-5-(3-fluoro-4-((4-(thiazol-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3, 4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.84 (s, 1H), 7.96 (d, J=2.7 Hz, 1H), 7.95-7.92 (m, 2H) , 7.80 (d, J=3.2 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.56 (t, J=51.3 Hz, 1H), 5 .89 (s, 2H); ; MSNR (ER) m/z 379.64 (M ⁺ +1). 511 17851 2-(difluoromethyl)-5-(3-fluoro-4-((4-(thiazol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3, 4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.13 (s, 1H), 8.72 (s, 1H), 8.30 (s, 1H), 7.96 (d, J=8, 8 Hz, 2H), 7.62 (t, J=7.7 Hz, 1H), 7.56 (t, J=51.3 Hz, 1H), 5.87 (s, 2H); MSNR (ER) m/z 379.63 (M ⁺ +1). 512 17854 2-(difluoromethyl)-5-(3-fluoro-4-((4-(4-methylthiazol-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1, 3,4-oxadiazole
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.80 (s, 1H), 7.96 (s, 1H), 7.94 (s, 1H), 7.60 (t, J=7, 8 Hz, 1H), 7.56 (t, J=51.4 Hz, 1H), 7.33 (s, 1H), 5.88 (s, 2H), 2.41 (s, 3H); MSNR (ER) m/z 393.63 (M ⁺ +1). 513 17857 2-(difluoromethyl)-5-(3-fluoro-4-((4-(5-methylthiazol-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1, 3,4-oxadiazole
^1H NMR (400 MHz, DMSO- _d6 ) δ 8.76 (s, 1H), 7.96 (s, 1H), 7.93 (s, 1H), 7.64-7.57 (m, 2H), 7.56 (t, J=51.3 Hz, 1H), 5.88 (s, 2H), 2.47 (s, 3H); MSNR (ER) m/z 393.63 (M ⁺ +1).

Example 538: Synthesis of Compound 18306, 2-(6-((4-(4-(azetidin-1-ylmethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluoropyridin- 3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2 ,3-triazol-4-yl)benzaldehyde

4-ethynylbenzaldehyde (0.200 g, 1.537 mmol), 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.415 g, 1.537 mmol), obtained in step 1 of example 490, sodium ascorbate (0.50 M solution in water, 0.307 ml, 0.154 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.015 ml, 0.015 mmol) are dissolved in tert. butanol (3 ml)/water (3 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Dichloromethane (5 ml) and hexane (50 ml) were added to the resulting concentrate and stirred to filter the precipitated solid, washed with hexane and dried to obtain 4-(1-((5-(5-(difluoromethyl)-1,3 ,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzaldehyde (0.367 g, 59.7%) as a yellow solid .

[Step 2] Synthesis of compound 18306

4-(1-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)benzaldehyde (0.090 g, 0.225 mmol) obtained in step 1, azetidine (0.030 ml, 0.450 mmol) and acetic acid (0.013 ml, 0.225 mmol) are dissolved in dichloromethane (1 ml), after which the resulting solution is stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (0.143 g, 0.674 mmol) was added thereto, and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give 2-(6-((4-(4-(azetidin-1-ylmethyl)phenyl)-1H- 1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 50.4%) as a yellow solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.48 (s, 1H), 8.38 (dd, J=9.6, 1.7 Hz, 1H), 7.83 (d, J=8.2 Hz, 2H), 7.41-7.14 (m, 3H), 6.00 (d, J=1.8 Hz, 2H), 3.72 (s , 2H), 3.40 (t, J=7.3 Hz, 4H), 2.21-2.14 (m, 2H); MSNR (ER) m/z 442.4 (M ⁺ +1).

The compounds of Table 161 were synthesized in accordance with substantially the same method as described above for the synthesis of compound 18306 except for the use of 4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2- yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzaldehyde and the reagent from Table 160.

Table 160 Example Connection no. Reagent Exit (%) 539 18307 4-methylpiperidine 60 540 18308 Dimethylamine 58

Table 161 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 539 18307 2-(difluoromethyl)-5-(5-fluoro-6-((4-(4-((4-methylpiperidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)pyridin-3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.11 (s, 1H), 8.48 (s, 1H), 8.39 (dd, J=9.6, 1.7 Hz, 1H), 7.82 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H), 5.27 (t, J=1200.0 Hz, 1H), 6, 00 (d, J=1.8 Hz, 2H), 3.58 (s, 2H), 2.92 (d, J=11.7 Hz, 2H), 2.07 (t, J=10.7 Hz, 2H), 1.67 (d, J=14.1 Hz, 2H), 1.44-1.38 (m, 1H), 1.32-1.22 (m, 2H), 0.95 (d, J=6.4 Hz, 3H); MSNR (IER) m/z 484.4 (M ⁺ + H). 540 18308 1-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3 -triazol-4-yl)phenyl)-N,N-dimethylmethanamine
¹ H NMR (400 MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.49 (s, 1H), 8.39 (dd, J=9.6, 1.7 Hz, 1H), 7.84 (d, J=8.2 Hz, 2H), 7.43 (d, J=8.2 Hz, 2H), 7.27 (t, J=51.5 Hz, 1H), 6, 00 (d, J=1.7 Hz, 2H), 3.53 (s, 2H), 2.29 (s, 6H); MSNR (IER) m/z 430.3 (M ⁺ + H).

Example 541: Synthesis of compound 18309, 2-(6-((4-(5-(azetidin-1-ylmethyl)thiophen-2-yl)-1H-1,2,3-triazol-1-yl)methyl)- 5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2 ,3-triazol-4-yl)thiophene-2-carbaldehyde

5-ethynylthiophene-2-carbaldehyde (0.171 ml, 1.469 mmol), 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.397 g, 1.469 mmol) obtained in step 1 of Example 490, sodium ascorbate (0.50 M solution in water, 0.294 ml, 0.147 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.015 ml, 0.015 mmol) dissolved in tert-butanol (3 ml)/water (3 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Dichloromethane (5 ml) and hexane (50 ml) were added to the resulting concentrate and stirred to filter the precipitated solid, washed with hexane and dried to obtain 5-(1-((5-(5-(difluoromethyl)-1,3 ,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)thiophene-2-carbaldehyde (0.370 g, 62.0%) in form of a yellow solid.

[Step 2] Synthesis of compound 18309

5-(1-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)thiophene-2-carbaldehyde (0.090 g, 0.221 mmol) obtained in step 1, azetidine (0.030 ml, 0.443 mmol) and acetic acid (0.013 ml, 0.221 mmol) are dissolved in dichloromethane (1 ml), then the resulting solution was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (0.141 g, 0.664 mmol) was added thereto, and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give 2-(6-((4-(5-(azetidin-1-ylmethyl)thiophen-2-yl )-1H-1,2,3-triazol-1-yl)methyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.042 g, 42.4%) in the form of a light yellow solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.40-8.36 (m, 2H), 7.30 (d, J=3.6 Hz, 1H), 7.27 (t, J=51.5 Hz, 1H), 6.97 (d, J=3.6 Hz, 1H), 5.98 (d, J=1.7 Hz, 2H), 3, 82 (s, 2H), 3.37-3.32 (m, 4H), 2.18-2.11 (m, 2H); MSNR (ER) m/z 448.4 (M ⁺ +1).

The compounds of Table 163 were synthesized in accordance with substantially the same method as described above for the synthesis of compound 18309 except for the use of 5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2- yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)thiophene-2-carbaldehyde and the reagent from Table 162.

Table 162 Example Connection no. Reagent Exit (%) 542 18310 4-methylpiperidine 84 543 18311 Dimethylamine 24

Table 163 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 542 18310 2-(difluoromethyl)-5-(5-fluoro-6-((4-(5-((4-methylpiperidin-1-yl)methyl)thiophen-2-yl)-1H-1,2,3-triazole -1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.40-8.36 (m, 2H), 7.30 (d, J=3.6 Hz, 1H), 7.27 (t, J=51.6 Hz, 1H), 6.98 (d, J=3.6 Hz, 1H), 5.98 (d, J=1.6 Hz, 2H), 3, 76 (s, 2H), 2.96 (d, J=11.6 Hz, 2H), 2.10 (t, J=10.6 Hz, 2H), 1.67 (d, J=11.2 Hz, 2H), 1.42-1.36 (m, 1H), 1.33-1.23 (m, 2H), 0.96 (d, J=6.4 Hz, 3H); MSNR (IER) m/z 490.5 (M ⁺ + H). 543 18311 1-(5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3 -triazol-4-yl)thiophen-2-yl)-N,N-dimethylmethanamine
¹ H NMR (400 MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.40-8.37 (m, 2H), 7.32 (d, J=3.6 Hz, 1H), 7.27 (t, J=51.6 Hz, 1H), 7.00 (d, J=3.6 Hz, 1H), 5.98 (d, J=1.7 Hz, 2H), 3, 73 (s, 2H), 2.32 (s, 6H); MSNR (IER) m/z 436.3 (M ⁺ + H).

Example 544: Synthesis of Compound 18327

2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-fluoro-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)-1H -1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 2-(4-bromo-3-fluorophenyl)-1,3-dioxolane

4-Bromo-3-fluorobenzaldehyde (10.000 g, 49.259 mmol), p-toluenesulfonic acid (0.094 g, 0.493 mmol) and ethylene glycol (13.157 ml, 59.110 mmol) are dissolved in toluene (50 ml) at room temperature, then the resulting solution heated at reflux for 18 hours, and then the reaction is completed by reducing the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane=0-10%) and concentrated to give 2-(4-bromo-3-fluorophenyl)-1,3-dioxolane (11.410 g, 93.8 %) in the form of a clear liquid.

[Step 2] Synthesis of tert-butyl 4-(4-(1,3-dioxolan-2-yl)-2-fluorophenyl)piperazine-1-carboxylate

2-(4-Bromo-3-fluorophenyl)-1,3-dioxolane (5.000 g, 20.238 mmol), tert-butyl piperazine-1-carboxylate (4.523 g, 24.286 mmol), tris(dibenzylideneacetone)dipalladium (Pd ₂ ( dba) ₃ , 0.185 g, 0.202 mmol), rac-BINAP (0.252 g, 0.405 mmol) and NaOBut (3.890 g, 40.476 mmol) are dissolved in toluene (50 ml) at room temperature, after which the resulting solution is heated at reflux refrigerator for 18 hours, and then the reaction is completed by lowering the temperature to room temperature. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl 4-(4-(1,3-dioxolan-2-yl)-2-fluorophenyl) piperazine-1-carboxylate (7.200 g, 101.0%) as a yellow solid.

[Step 3] Synthesis of tert-butyl 4-(2-fluoro-4-formylphenyl)piperazine-1-carboxylate

Tert-butyl 4-(4-(1,3-dioxolan-2-yl)-2-fluorophenyl)piperazine-1-carboxylate (7.200 g, 20.431 mmol) and hydrochloric acid (1.00 M solution, 61.292 ml, 61.292 mmol) was dissolved in methanol (20 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 3 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The precipitated solid was filtered, washed with hexane and dried to give tert-butyl 4-(2-fluoro-4-formylphenyl)piperazine-1-carboxylate (6.550 g, 104.0%) as a yellow solid.

[Step 4] Synthesis of tert-butyl 4-(4-(2,2-dibromovinyl)-2-fluorophenyl)piperazine-1-carboxylate

Tert-butyl 4-(2-fluoro-4-formylphenyl)piperazine-1-carboxylate (6.550 g, 21.242 mmol), carbon tetrabromide (14.089 g, 42.484 mmol) and triphenylphosphine triphenylphosphine (16.715 g, 63.726 mmol) are dissolved in dichloromethane ( 150 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane=0-20%) and concentrated to give tert-butyl 4-(4-(2,2-dibromovinyl)-2-fluorophenyl)piperazine-1- carboxylate (5.670 g, 57.5%) in the form of a white solid.

[Step 5] Synthesis of tert-butyl 4-(4-ethynyl-2-fluorophenyl)piperazine-1-carboxylate

Tert-butyl 4-(4-(2,2-dibromovinyl)-2-fluorophenyl)piperazine-1-carboxylate (5.670 g, 12.215 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido [1,2-a]azepine (DBU, 7.307 ml, 48.861 mmol) was dissolved in acetonitrile (50 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting concentrate is poured into water, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl 4-(4-ethynyl-2-fluorophenyl)piperazine-1-carboxylate (1.100 g, 29 .6%) in the form of a white solid.

[Step 6] Synthesis of tert-butyl 4-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2, 3-triazol-4-yl)-2-fluorophenyl)piperazine-1-carboxylate

Tert-butyl 4-(4-ethynyl-2-fluorophenyl)piperazine-1-carboxylate (0.430 g, 1.413 mmol), 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3 ,4-oxadiazole (0.418 g, 1.554 mmol) obtained in step 1 of Example 2, copper(II) sulfate pentahydrate (0.004 g, 0.014 mmol) and sodium ascorbate (0.028 g, 0.141 mmol) were dissolved in tert-butanol (20 ml )/water (10 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl 4-(4-(1-(4-(5-(difluoromethyl)-1,3 ,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-2-fluorophenyl)piperazine-1-carboxylate (0.330 g, 40.7%) as white solid.

[Step 7] Synthesis of 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-fluoro-4-(piperazin-1-yl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)phenyl)-1,3,4-oxadiazole

Tert-butyl 4-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4 -yl)-2-fluorophenyl)piperazine-1-carboxylate (0.380 g, 0.663 mmol) and trifluoroacetic acid (0.507 ml, 6.625 mmol) were dissolved in dichloromethane (25 ml) at room temperature, after which the resulting solution was stirred at the same temperature within 12 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without additional purification process (2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-fluoro-4-(piperazine-1- yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole, 0.300 g, 95.6%, yellow oil).

[Step 8] Synthesis of compound 18327

2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-fluoro-4-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl) Methyl)phenyl)-1,3,4-oxadiazole (0.080 g, 0.169 mmol), tetrahydro-4H-pyran-4-one (0.034 g, 0.338 mmol) and sodium triacetoxyborohydride (0.072 g, 0.338 mmol) are dissolved in dichloromethane ( 5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-fluoro- 4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4- oxadiazole (0.035 g, 37.2%) in the form of a white solid.

¹ H NMR(400 MHz, CDCl₃) δ d 7.91 ~ 7.88 (m, 2H), 7.75 (s, 1H), 7.52 ~ 7.42 (m, 3H), 7.04 ~ 6.79 (m, 2H), 5 .70 (s, 1H), 4.04 (dd, J=11.3, 3.4 Hz, 2H), 3.40 (t, J=11.3 Hz, 2H), 3.18 (t, J=0.0 Hz, 4H), 2.79 (t, J=2.0 Hz, 4H), 2.53 (t, J=11.3 Hz, 1H), 1.83 (d, J= 12.2Hz, 2H), 1.68~1.58(m, 2H);MCNR(ER) m/z 558.4 (M⁺+1).

Example 545: Synthesis of compound 18457 , 1-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)- 1H-1,2,3-triazol-4-yl)phenyl)-N,N-dimethylmethanamine

[Step 1] Synthesis of 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2 ,3-triazol-4-yl)benzaldehyde

3-ethynylbenzaldehyde (0.200 g, 1.537 mmol), 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.415 g, 1.537 mmol), obtained in step 1 of example 490, sodium ascorbate (0.50 M solution in water, 0.307 ml, 0.154 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.015 ml, 0.015 mmol) are dissolved in tert. butanol (3 ml)/water (3 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol- 2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzaldehyde (0.420 g, 68.3%) in the form of a light yellow solid.

[Step 2] Synthesis of compound 18457

3-(1-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)benzaldehyde (0.100 g, 0.250 mmol), dimethylamine (2.00 M solution in MeOH, 0.250 ml, 0.500 mmol) and acetic acid (0.014 ml, 0.250 mmol) were dissolved in dichloromethane (1 ml), and the resulting the solution was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (0.159 g, 0.749 mmol) was added thereto, and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give 1-(3-(1-((5-(5-(difluoromethyl)-1,3,4 -oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-N,N-dimethylmethanamine (0.031 g, 28.9%) in the form of a yellow solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 9.11 (s, 1H), 8.49 (s, 1H), 8.39 (dd, J=9.6, 1.7 Hz, 1H), 7.82-7.79 (m, 2H), 7.45 (t, J=7.6 Hz, 1H), 7.35 (d, J=7.7 Hz, 1H), 7.27 (t , J=51.5 Hz, 1H), 6.01 (d, J=1.8 Hz, 2H), 3.57 (s, 2H), 2.30 (s, 6H); MSNR (ER) m/z 430.4 (M ⁺ +1).

The compound of Table 165 was synthesized in accordance with substantially the same method as described above in the synthesis of compound 18457 using 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl )-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzaldehyde and the reagent from Table 164.

Table 164 Example Connection no. Reagent Exit (%) 546 18459 4-methylpiperidine 55

Table 165 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 546 18459 2-(difluoromethyl)-5-(5-fluoro-6-((4-(3-((4-methylpiperidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)pyridin-3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.11 (s, 1H), 8.48 (s, 1H), 8.39 (dd, J=9.6, 1.6 Hz, 1H), 7.83 (s, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.45-7.14 (m, 3H), 6.01 (d, J=1.6 Hz , 2H), 3.59 (s, 2H), 2.93 (d, J=11.8 Hz, 2H), 2.07 (t, J=10.7 Hz, 2H), 1.66 (d , J=12.1 Hz, 2H), 1.43-1.37 (m, 1H), 1.32-1.22 (m, 2H), 0.95 (d, J=6.4 Hz, 3H); MSNR (IER) m/z 484.4 (M ⁺ + H).

Example 548: Synthesis of compound 18483 , 1-(3-chloro-5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1 ,2,3-triazol-4-yl)phenyl)-N,N-dimethylmethanamine

[Step 1] Synthesis of 3-chloro-5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3- triazol-4-yl)benzaldehyde

3-Chloro-5-ethynylbenzaldehyde (0.112 g, 0.680 mmol), 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.183 g, 0.680 mmol), obtained in step 1 of example 2, sodium ascorbate (0.50 M solution in water, 0.136 ml, 0.068 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.007 ml, 0.007 mmol) are dissolved in tert. butanol (2 ml)/water (2 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. An aqueous solution of tert-ammonium chloride is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 3-chloro-5-(1-(4-(5-(difluoromethyl)-1,3,4 -oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)benzaldehyde (0.110 g, 37.3%) as a yellow solid.

[Step 2] Synthesis of compound 18483

3-Chloro-5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl )benzaldehyde (0.055 g, 0.127 mmol) from step 1, dimethylamine (2.00 M solution in MeOH, 0.127 ml, 0.254 mmol) and acetic acid (0.007 ml, 0.127 mmol) were dissolved in dichloromethane (1 ml), then the resulting the solution was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (0.081 g, 0.380 mmol) was added thereto, and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give 1-(3-chloro-5-(1-(4-(5-(difluoromethyl)-1, 3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-N,N-dimethylmethanamine (0.041 g, 69.9%) as yellow solid matter.

^1H NMR (400 MHz, CD ₃ OD) δ 8.51 (s, 1H), 8.00-7.95 (m, 2H), 7.83 (s, 1H), 7.74 (s, 1H ), 7.61 (t, J=7.7 Hz, 1H), 7.24 (t, J=51.6 Hz, 1H), 5.86 (s, 2H), 3.53 (s, 2H ), 2.28 (s, 6H); MSNR (ER) m/z 463.3 (M ⁺ +1).

Example 549: Synthesis of compound 18554 , 1-(2-chloro-3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1 ,2,3-triazol-4-yl)phenyl)-N,N-dimethylmethanamine

[Step 1] Synthesis of 2-chloro-3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3- triazol-4-yl)benzaldehyde

2-Chloro-3-ethynylbenzaldehyde (0.095 g, 0.577 mmol), 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.156 g, 0.577 mmol), obtained in step 1 of example 2, sodium ascorbate (0.50 M solution in water, 0.115 ml, 0.058 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.006 ml, 0.006 mmol) are dissolved in tert. butanol (1 ml)/water (1 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Dichloromethane (5 ml) and hexane (100 ml) were added to the resulting concentrate and stirred to filter the precipitated solid, washed with hexane, and dried to give 2-chloro-3-(1-(4-(5-(difluoromethyl) -1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)benzaldehyde (0.046 g, 18.4%) as a light yellow solid .

[Step 2] Synthesis of compound 18554

2-Chloro-3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl )benzaldehyde (0.046 g, 0.106 mmol) from step 1, dimethylamine (2.00 M solution in MeOH, 0.106 ml, 0.212 mmol) and acetic acid (0.006 ml, 0.106 mmol) were dissolved in dichloromethane (1 ml), then the resulting the solution was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (0.067 g, 0.318 mmol) was added thereto, and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate is purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0-15%) and concentrated, after which the resulting product is purified again by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0-10%) and concentrate to give 1-(2-chloro-3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2, 3-triazol-4-yl)phenyl)-N,N-dimethylmethanamine (0.014 g, 28.5%) as a white solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.60 (s, 1H), 8.00-7.91 (m, 3H), 7.60 (t, J=7.6 Hz, 1H), 7.52-7.51 (m, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.24 (t, J=51.5 Hz, 1H), 5.90 (s , 2H), 3.70 (s, 2H), 2.33 (s, 6H); MSNR (ER) m/z 463.3 (M ⁺ +1).

Example 550: Synthesis of compound 18622, 2-(6-((4-(5-(azetidin-1-ylmethyl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)- 5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 6-((trimethylsilyl)ethynyl)nicotinaldehyde

6-bromonicotinaldehyde (1.000 g, 5.376 mmol), bis(triphenylphosphine) palladium dichloride (0.189 g, 0.269 mmol) and copper iodide (I/II, 0.102 g, 0.538 mmol) are dissolved in tetrahydrofuran (20 ml)/triethylamine (4 ml) ), after which trimethylsilylacetylene (1.081 ml, 8.064 mmol) was added to the resulting solution at room temperature and stirred at the same temperature for 5 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane=0-10%) and concentrated to give 6-((trimethylsilyl)ethynyl)nicotinaldehyde (0.527 g, 48.3%) as a yellow solid. .

[Step 2] Synthesis of 6-ethynylnicotinaldehyde

6-((Trimethylsilyl)ethynyl)nicotinaldehyde (0.527 g, 2.595 mmol) obtained in step 1 and potassium carbonate (1.076 g, 7.785 mmol) are dissolved in methanol (10 ml) at room temperature, after which the resulting solution is stirred at same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 6-ethynylnicotinaldehyde (0.340 g, 99.9%) as a yellow solid.

[Step 3] Synthesis of 6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2 ,3-triazol-4-yl)nicotinaldehyde

6-Ethynylnicotinaldehyde (0.150 g, 1.144 mmol) prepared in Example 2, 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.309 g , 1.144 mmol) obtained in step 1 of Example 490, sodium ascorbate (0.50 M solution in water, 0.229 ml, 0.114 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.011 ml, 0.011 mmol ) is dissolved in tert-butanol (3 ml)/water (3 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Dichloromethane (3 ml) and hexane (50 ml) were added to the resulting concentrate and stirred to filter the precipitated solid, washed with hexane and dried to obtain 6-(1-((5-(5-(difluoromethyl)-1,3 ,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)nicotinaldehyde (0.138 g, 30.1%) as a yellow solid .

[Step 4] Synthesis of compound 18622

6-(1-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)nicotinaldehyde (0.050 g, 0.125 mmol) obtained in step 3, azetidine (0.017 ml, 0.249 mmol) and acetic acid (0.007 ml, 0.125 mmol) are dissolved in dichloromethane (1 ml), after which the resulting solution is stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (0.079 g, 0.374 mmol) was added thereto, and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-15%) and concentrated to give 2-(6-((4-(5-(azetidin-1-ylmethyl)pyridin-2-yl )-1H-1,2,3-triazol-1-yl)methyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.016 g, 29.0%) in the form of a light yellow solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.60 (s, 1H), 8.53 (d, J=1.8 Hz, 1H), 8.39 ( dd, J=9.5, 1.5 Hz, 1H), 8.07 (d, J=8.2 Hz, 1H), 7.87 (dd, J=8.1, 2.1 Hz, 1H ), 7.26 (t, J=51.5 Hz, 1H), 6.04 (d, J=1.6 Hz, 2H), 3.70 (s, 2H), 3.37-3.33 (m, 4H), 2.20-2.13 (m, 2H); MSNR (ER) m/z 443.4 (M ⁺ +1).

Example 551: Synthesis of compound 18711 , 1-(2-chloro-4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1 ,2,3-triazol-4-yl)phenyl)-N,N-dimethylmethanamine

[Step 1] Synthesis of 2-chloro-4-((trimethylsilyl)ethynyl)benzaldehyde

4-bromo-2-chlorobenzaldehyde (1.000 g, 4.557 mmol), bis(triphenylphosphine) palladium(II) dichloride (0.160 g, 0.228 mmol) and copper iodide (I/II, 0.087 g, 0.456 mmol) are dissolved in tetrahydrofuran (20 ml)/triethylamine (4 ml), after which trimethylsilylacetylene (0.917 ml, 6.835 mmol) was added to the resulting solution at room temperature and stirred at the same temperature for 5 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane=0-10%) and concentrated to give 2-chloro-4-((trimethylsilyl)ethynyl)benzaldehyde (1.000 g, 92.7%) in form of a brown liquid.

[Step 2] Synthesis of 2-chloro-4-ethynylbenzaldehyde

2-Chloro-4-((trimethylsilyl)ethynyl)benzaldehyde (1.000 g, 4.224 mmol) obtained in step 1 and potassium carbonate (1.751 g, 12.671 mmol) were dissolved in methanol (20 ml) at room temperature, after which the resulting the solution is stirred at the same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 2-chloro-4-ethynylbenzaldehyde (0.528 g, 76.0%) as a yellow solid.

[Step 3] Synthesis of 2-chloro-4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3- triazol-4-yl)benzaldehyde

2-Chloro-4-ethynylbenzaldehyde (0.170 g, 1.033 mmol) obtained in step 2, 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.278 g , 1.033 mmol) obtained in step 1 of example 2, sodium ascorbate (0.50 M solution in water, 0.207 ml, 0.103 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.010 ml, 0.010 mmol ) was dissolved in tert-butanol (2 ml)/water (2 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Dichloromethane (5 ml) and hexane (100 ml) were added to the resulting concentrate and stirred to filter the precipitated solid, washed with hexane and dried to give 2-chloro-4-(1-(4-(5-(difluoromethyl)- 1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)benzaldehyde (0.332 g, 74.1%) as a yellow solid.

[Step 4] Synthesis of compound 18711

2-Chloro-4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl )benzaldehyde (0.080 g, 0.184 mmol) from step 3, dimethylamine (2.00 M solution in MeOH, 0.184 ml, 0.369 mmol) and acetic acid (0.011 ml, 0.184 mmol) were dissolved in dichloromethane (1 ml), then the resulting the solution was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (0.117 g, 0.553 mmol) was added thereto, and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol = 0-15%) and concentrated to give 1-(2-chloro-4-(1-(4-(5-(difluoromethyl)-1, 3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-N,N-dimethylmethanamine (0.024 g, 28.1%) in the form of light -yellow solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.51 (s, 1H), 8.00-7.93 (m, 3H), 7.78 (dd, J=8.0, 1.7 Hz , 1H), 7.61 (t, J=7.7 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.24 (t, J=51.6 Hz, 1H ), 5.86 (s, 2H), 3.65 (s, 2H), 2.32 (s, 6H); MSNR (ER) m/z 463.2 (M ⁺ +1).

The compounds of Table 167 were synthesized according to substantially the same method as described above for the synthesis of compound 18711 except for the use of 2-chloro-4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazole -2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)benzaldehyde and the reagent from Table 166.

Table 166 Example Connection no. Reagent Exit (%) 552 18712 Azetidine 27 553 18713 Pyrrolidine 29

Table 167 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 552 18712 2-(4-((4-(4-(azetidin-1-ylmethyl)-3-chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-( difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.50 (s, 1H), 8.00-7.92 (m, 3H), 7.77 (d, J=7.3 Hz, 1H), 7.61 (t, J=7.5 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.24 (t, J=51.6 Hz, 1H), 5, 85 (s, 2H), 3.79 (s, 2H), 3.40 (t, J=7.1 Hz, 4H), 2.20-2.13 (m, 2H); MSNR (IER) m/z 475.4 (M ⁺ + H). 553 18713 2-(4-((4-(3-chloro-4-(pyrrolidin-1-ylmethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5- (difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 8.51 (s, 1H), 8.00-7.93 (m, 3H), 7.78 (dd, J=8.0, 1.6 Hz , 1H), 7.63-7.57 (m, 2H), 7.24 (t, J=51.6 Hz, 1H), 5.86 (s, 2H), 3.86 (s, 2H) , 2.69 (s, 4H), 1.87-1.84 (m, 4H); MSNR (IER) m/z 489.3 (M ⁺ + H).

Example 554: Synthesis of Compound 18736, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(6-methoxypyridin-2-yl)-1H-1,2,3-triazol-1-yl) methyl)phenyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 2-(2,2-dibromovinyl)-6-methoxypyridine

6-Methoxypicolinaldehyde (0.200 g, 1.458 mmol), carbon tetrabromide (0.967 g, 2.917 mmol) and triphenylphosphine triphenylphosphine (1.148 g, 4.375 mmol) were dissolved in dichloromethane (10 ml) at room temperature, after which the resulting solution was stirred at the same temperature within 12 hours. Water is poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove solid residue and a layer of aqueous solution, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-20%) and concentrated to give 2-(2,2-dibromovinyl)-6-methoxypyridine (0.180 g, 42.1%) as yellow oil.

[Step 2] Synthesis of 2-ethynyl-6-methoxypyridine

2-(2,2-Dibromovinyl)-6-methoxypyridine (0.200 g, 0.683 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (DBU, 0.306 ml, 2.048 mmol) was dissolved in acetonitrile (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 2-ethynyl-6-methoxypyridine (0.090 g, 99.0%) as a white solid.

[Step 3] Synthesis of compound 18736

2-Ethynyl-6-methoxypyridine (0.100 g, 0.751 mmol), 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.202 g, 0.751 mmol), obtained in step 1 of example 2, copper(II) sulfate pentahydrate (0.002 g, 0.008 mmol) and sodium ascorbate (0.015 g, 0.075 mmol) were dissolved in dichloromethane (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature within 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(6-methoxypyridinium- 2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.035 g, 11.6%) as a white solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.99 (d,J=4.0 Hz, 1H), 7.92-7.83 (m, 3H), 7.42 (t,J=7.8 Hz, 1H), 7.15 (t,J=7.9 Hz, 1H), 7.03-6.78 (m, 2H), 5.72 (s, 2H), 3.10 (sq,J=8.2, 6.4 Hz, 4H), 2.68-2.54 (m, 9H), 2.23 (ddd,J=21.2, 10.3, 4.7 Hz, 2H);MCNR(ER) m/z 578.4 (M⁺+1).

Example 555 Synthesis of compound 18822, 2-(6-((4-(2-(azetidin-1-ylmethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluoropyridin-3 -yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 2-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2 ,3-triazol-4-yl)benzaldehyde

2-ethynylbenzaldehyde (0.100 g, 0.768 mmol), (6-(azidomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.208 g, 0.768 mmol), obtained from step 1 of example 490, sodium ascorbate (0.50 M solution in water, 0.154 ml, 0.077 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.008 ml, 0.008 mmol) are dissolved in tert-butanol ( 2 ml)/water (2 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate is purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol = 0-10%) and concentrated, after which dichloromethane (5 ml) and hexane (100 ml) are added to the resulting solution and stirred to filter out the precipitated solid substances, washed with hexane and dried to obtain 2-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H- 1,2,3-triazol-4-yl)benzaldehyde (0.108 g, 35.1%) as a yellow solid.

[Step 2] Synthesis of compound 18822

2-(1-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)benzaldehyde (0.050 g, 0.125 mmol) obtained in step 1, azetidine (0.017 ml, 0.250 mmol) and acetic acid (0.007 ml, 0.125 mmol) are dissolved in dichloromethane (0.5 ml), and the resulting solution stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (0.079 g, 0.375 mmol) was added thereto, and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give 2-(6-((4-(2-(azetidin-1-ylmethyl)phenyl)-1H- 1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.010 g, 18.1%) in the form of red oil.

¹ H NMR (400 MHz, CD ₃ OD) δ 9.11 (s, 1H), 8.45 (s, 1H), 8.40 (d, J=9.9 Hz, 1H), 7.68- 7.66 (m, 1H), 7.48-7.46 (m, 1H), 7.42-7.14 (m, 3H), 6.04 (s, 2H), 3.84 (s, 2H), 3.38-3.33 (m, 4H), 2.17-2.10 (m, 2H); MSNR (ER) m/z 442.4 (M ⁺ +1).

The compound of Table 169 was synthesized in accordance with substantially the same method as described above for the synthesis of compound 18822 except for the use of 2-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2- yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzaldehyde and the reagent from Table 168.

Table 168 Example Connection no. Reagent Exit (%) 556 18823 Pyrrolidine 18

Table 169 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 556 18823 2-(difluoromethyl)-5-(5-fluoro-6-((4-(2-(pyrrolidin-1-ylmethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin- 3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.11 (s, 1H), 8.52 (s, 1H), 8.40 (dd, J=9.6, 1.4 Hz, 1H), 7.73-7.71 (m, 1H), 7.54-7.51 (m, 1H), 7.45-7.14 (m, 3H), 6.04 (d, J=1.4 Hz, 2H), 3.87 (s, 2H), 2.68 (s, 4H), 1.84 (s, 4H); MSNR (IER) m/z 456.4 (M ⁺ + H).

Example 558: Synthesis of Compound 18869, 2-(difluoromethyl)-5-(5-fluoro-6-((4-(3-(1-methylpiperidin-4-yl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of 2-(difluoromethyl)-5-(5-fluoro-6-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)pyridin-3-yl)-1,3,4-oxadiazole 2,2,2-trifluoroacetate

TFC

Tert-butyl 4-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1, 2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate (0.320 g, 0.576 mmol), corresponding to compound 18868 according to Example 557, and trifluoroacetic acid (0.132 ml, 1.728 mmol) were dissolved in dichloromethane (20 ml ) at room temperature, after which the resulting solution is stirred at the same temperature for 3 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without further purification process (2,2,2-trifluoroacetate 2-(difluoromethyl)-5-(5-fluoro-6-((4-(3-(piperidine -4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole, 0.300 g, 94.3%, yellow oil) .

[Step 2] Synthesis of compound 18869

2,2,2-Trifluoroacetate 2-(difluoromethyl)-5-(5-fluoro-6-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1 -yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.050 g, 0.091 mmol) obtained in step 1 and N,N-diisopropylethylamine (0.032 ml, 0.181 mmol) were dissolved in dichloromethane (5 ml), after which the resulting solution was stirred at room temperature for 30 minutes, and then formaldehyde (0.005 g, 0.181 mmol) was added thereto and then stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give 2-(difluoromethyl)-5-(5-fluoro-6-((4-(3-(1 -methylpiperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.027 g, 63.5%) in form of a yellow solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.99 (d,J=4.0 Hz, 1H), 7.92-7.83 (m, 3H), 7.42 (t,J=7.8 Hz, 1H), 7.15 (t,J=7.9 Hz, 1H), 7.03-6.78 (m, 2H), 5.72 (s, 2H), 3.10 (sq,J=8.2, 6.4 Hz, 4H), 2.68-2.54 (m, 9H), 2.23 (ddd,J=21.2, 10.3, 4.7 Hz, 2H);MCNR(ER) m/z 578.4 (M⁺+1).

The compounds of Table 171 were synthesized in accordance with substantially the same method as described above in the synthesis of compound 18869 except for the use of 2-(difluoromethyl)-5-(5-fluoro-6-((4-(3-(piperidine-4 -yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole 2,2,2-trifluoroacetate and the reagent from Table 170.

Table 170 Example Connection no. Reagent Exit (%) 559 18870 Cyclobutanone 73 560 18871 Oxetan-3-one 54

Table 171 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 559 18870 2-(6-((4-(3-(1-cyclobutylpiperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluoropyridin-3-yl)- 5-(difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.17 (s, 1H), 8.21 (d, J =9.0 Hz, 1 H), 8.00 (s, 1H), 7.73- 7.69 (m, 2H), 7.37 (t, J =7.6 Hz, 1H), 7.24-7.22 (m, 2H), 7.09 (s, 0.2H), 6 .96 (s, 0.5H), 6.83 (s, 0.2H), 5.89 (s, 2H), 3.11 (shs, 2H), 2.84 (shs, 1H), 2, 59 (shs, 1H), 2.19-1.91 (m, 10H), 1.79-1.68 (m, 2H); MSNR (ER) m/z 510.43 (M ⁺ +1). 560 18871 2-(difluoromethyl)-5-(5-fluoro-6-((4-(3-(1-(oxetan-3-yl)piperidin-4-yl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 9.16 (s, 1H), 8.21 (d, J =9.0 Hz, 1H), 8.01 (s, 1H), 7.76 ( s, 1H), 7.68 (d, J =7.6 Hz, 1H), 7.38 (t, J =7.7 Hz, 1H), 7.23 (d, J =7.7 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.2H), 5.89 (s, 2H), 4.70 (d, J =6.5 Hz, 4H), 3.57-3.53 (m, 1H), 2.92 (d, J =9.8 Hz, 2H), 2.62-2.58 ( m, 1H), 1.98-1.91 (m, 6H); MSNR (ER) m/z 512.13 (M ⁺ +1).

Example 561: Synthesis of compound 18872 , tert-butyl 3-(4-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2 -yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidin-1-yl)azetidine-1-carboxylate

2,2,2-Trifluoroacetate 2-(difluoromethyl)-5-(5-fluoro-6-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1 -yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.120 g, 0.217 mmol) prepared in step 1 of Example 558, tert-butyl 3-oxoazetidine-1-carboxylate (0.045 g, 0.260 mmol ) and N,N-diisopropylethylamine (0.076 ml, 0.434 mmol) are dissolved in dichloromethane (10 ml), after which the resulting solution is stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (0.138 g, 0.650 mmol) is added thereto and then stir at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate is purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give tert-butyl 3-(4-(3-(1-((5-(5-(difluoromethyl) -1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidin-1-yl)azetidine-1 -carboxylate (0.100 g, 75.5%) in the form of a yellow solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.99 (d,J=4.0 Hz, 1H), 7.92-7.83 (m, 3H), 7.42 (t,J=7.8 Hz, 1H), 7.15 (t,J=7.9 Hz, 1H), 7.03-6.78 (m, 2H), 5.72 (s, 2H), 3.10 (sq,J=8.2, 6.4 Hz, 4H), 2.68-2.54 (m, 9H), 2.23 (ddd,J=21.2, 10.3, 4.7 Hz, 2H);MCNR(ER) m/z 578.4 (M⁺+1).

Example 562: Synthesis of compound 18877, 2-(difluoromethyl)-5-(5-fluoro-6-((4-(3-(1-(1-methylazetidin-3-yl)piperidin-4-yl)phenyl)- 1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of 2,2,2-trifluoroacetate 2-(6-((4-(3-(1-(azetidin-3-yl)piperidin-4-yl)phenyl)-1H-1,2,3 -triazol-1-yl)methyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

Tert-butyl 3-(4-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H -1,2,3-triazol-4-yl)phenyl)piperidin-1-yl)azetidine-1-carboxylate (0.100 g, 0.164 mmol) prepared in Example 561 and trifluoroacetic acid (0.050 ml, 0.655 mmol) were dissolved in dichloromethane (10 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 3 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without additional purification process (2,2,2-trifluoroacetate 2-(6-((4-(3-(1-(azetidin-3-yl)piperidin- 4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole, 0.090 g, 90.5%, yellow oil)

[Step 2] Synthesis of compound 18877

2,2,2-Trifluoroacetate 2-(6-((4-(3-(1-(azetidin-3-yl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1- yl)methyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.045 g, 0.074 mmol) obtained in step 1 and formaldehyde (0.004 g, 0.148 mmol) are dissolved in dichloromethane (5 ml), after which the resulting solution was stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (0.031 g, 0.148 mmol) was added thereto and then stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 2-(difluoromethyl)-5-(5-fluoro-6-((4-(3-(1 -(1-methylazetidin-3-yl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole ( 0.019 g, 48.9%) as a yellow solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.99 (d,J=4.0 Hz, 1H), 7.92-7.83 (m, 3H), 7.42 (t,J=7.8 Hz, 1H), 7.15 (t,J=7.9 Hz, 1H), 7.03-6.78 (m, 2H), 5.72 (s, 2H), 3.10 (sq,J=8.2, 6.4 Hz, 4H), 2.68-2.54 (m, 9H), 2.23 (ddd,J=21.2, 10.3, 4.7 Hz, 2H);MCNR(ER) m/z 578.4 (M⁺+1).

The compound of Table 173 was synthesized in accordance with substantially the same method as described above in the synthesis of compound 18877 except for the use of 2-(6-((4-(3-(1-(azetidine-3) 2,2,2-trifluoroacetate -yl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4- oxadiazole and the reagent from table 172.

Table 172 Example Connection no. Reagent Exit (%) 563 18878 Cyclobutanone 50

Table 173 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 563 18878 2-(6-((4-(3-(1-(1-cyclobutylazetidin-3-yl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)- 5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 9.15 (s, 1H), 8.21 (d, J =9.0 Hz, 1H), 8.01 (s, 1H), 7.77 ( s, 1H), 7.66 (d, J =7.7 Hz, 1H), 7.36 (t, J =7.7 Hz, 1H), 7.20 (d, J =7.6 Hz, 1H), 7.09 (s, 0.2H), 6.96 (s, 0.5H), 6.83 (s, 0.2H), 5.89 (s, 2H), 3.84 (shs, 1H), 3.75 (s, 2H), 3.47-3.43 (m, 1H), 3.22-3.19 (m, 3H), 2.87 (d, J =11 .0 Hz, 2H), 2.56-2.54 (m, 1H), 2.13-2.09 (m, 3H), 2.06-2.00 (m, 2H), 1.97- 1.71 (m, 6H); MSNR (ER) m/z 565.46 (M ⁺ +1).

Example 564: Synthesis of compound 18882, 2-(6-((4-(5-(azetidin-1-ylmethyl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)- 5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 5-((trimethylsilyl)ethynyl)nicotinaldehyde

5-Bromonicotinaldehyde (0.300 g, 1.613 mmol), bis(triphenylphosphine) palladium dichloride (0.057 g, 0.081 mmol) and copper iodide (I/II, 0.031 g, 0.161 mmol) are dissolved in tetrahydrofuran (5 ml)/triethylamine (1 ml) ), after which trimethylsilylacetylene (0.324 ml, 2.419 mmol) was added to the resulting solution at room temperature and stirred at the same temperature for 5 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane=0-10%) and concentrated to give 5-((trimethylsilyl)ethynyl)nicotinaldehyde (0.097 g, 29.6%) as a brown solid. .

[Step 2] Synthesis of 5-ethynylnicotinaldehyde

5-((Trimethylsilyl)ethynyl)nicotinaldehyde (0.097 g, 0.477 mmol) obtained in step 1 and potassium carbonate (0.198 g, 1.431 mmol) are dissolved in methanol (2 ml) at room temperature, after which the resulting solution is stirred at same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give 5-ethynylnicotinaldehyde (0.023 g, 36.8%) as a white solid.

[Step 3] Synthesis of 5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2 ,3-triazol-4-yl)nicotinaldehyde

5-Ethynylnicotinaldehyde (0.023 g, 0.175 mmol) obtained in step 2, 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.047 g , 0.175 mmol) obtained in step 1 of Example 490, sodium ascorbate (0.50 M solution in water, 0.035 ml, 0.018 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.002 ml, 0.002 mmol ) was dissolved in tert-butanol (0.5 ml)/water (0.5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate is purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol = 0-10%) and concentrated, after which dichloromethane (5 ml) and hexane (100 ml) are added to the resulting solution and stirred to filter out the precipitated solid substances, washed with hexane and dried to obtain 5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H- 1,2,3-triazol-4-yl)nicotinaldehyde (0.035 g, 49.7%) as a white solid.

[Step 4] Synthesis of compound 18882

5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)nicotinaldehyde (0.035 g, 0.087 mmol) obtained in step 3, azetidine (0.012 ml, 0.174 mmol) and acetic acid (0.005 ml, 0.087 mmol) are dissolved in dichloromethane (0.5 ml), and the resulting solution stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (0.055 g, 0.262 mmol) was added thereto, and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give 2-(6-((4-(5-(azetidin-1-ylmethyl)pyridin-3-yl )-1H-1,2,3-triazol-1-yl)methyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.014 g, 36.3%) in the form of a pink solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.96 (d, J=1.6 Hz, 1H), 8.67 (s, 1H), 8.48 ( s, 1H), 8.40 (d, J=9.6 Hz, 1H), 8.25 (s, 1H), 7.27 (t, J=51.6 Hz, 1H), 6.04 ( s, 2H), 3.75 (s, 2H), 3.38 (t, J=7.1 Hz, 4H), 2.21-2.13 (m, 2H); MSNR (ER) m/z 443.6 (M ⁺ +1).

Example 565: Synthesis of Compound 18893, 2-(difluoromethyl)-5-(6-((4-(3-((3R,5S)-3,5-dimethylpiperazin-1-yl)phenyl)-1H-1,2 ,3-triazol-1-yl)methyl)-5-fluoropyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl (2R,6S)-4-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin- 2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-2,6-dimethylpiperazine-1-carboxylate

Tert-butyl (2R,6S)-4-(3-ethynylphenyl)-2,6-dimethylpiperazine-1-carboxylate (0.300 g, 0.954 mmol) prepared in step 5 of Example 321, 2-(6-(azidomethyl)- 5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.387 g, 1.431 mmol) prepared in Step 1 of Example 490, copper(II) sulfate pentahydrate (0.002 g, 0.010 mmol) and sodium ascorbate (0.019 g, 0.095 mmol) are dissolved in tert-butanol (4 ml)/water (2 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-100%) and concentrated to give tert-butyl (2R,6S)-4-(3-(1-((5-(5- (difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-2,6-dimethylpiperazine -1-carboxylate (0.400 g, 71.7%) in the form of a brown solid.

[Stage 2] Synthesis of compound 18893

Tert-butyl (2R,6S)-4-(3-ethynylphenyl)-2,6-dimethylpiperazin-1-carboxylate (0.300 g, 0.954 mmol), 2-(6-(azidomethyl)-5-fluoropyridin-3-yl )-5-(difluoromethyl)-1,3,4-oxadiazole (0.387 g, 1.431 mmol), copper(II) sulfate pentahydrate (0.002 g, 0.010 mmol) and sodium ascorbate (0.019 g, 0.095 mmol) are dissolved in tert. butanol (4 ml)/water (2 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-100%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(3-((3R,5S) -3,5-dimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluoropyridin-3-yl)-1,3,4-oxadiazole (0.400 g , 71.7%) in the form of a brown solid.

¹ H NMR(400 MHz, CDCl₃) δ 9.09 (s, 1H), 8.15 (dd, J=9.0, 1.7 Hz, 1H), 8.00 (s, 1H), 7.47 (s, 1H), 7 .28 ~ 7.24 (m, 1H), 7.18 (d, J=7.6 Hz, 1H), 7.07 ~ 6.82 (m, 2H), 5.85 (s, 2H), 3.54 (d, J=11.3Hz, 2H), 2.74 (t, J=11.5Hz, 2H), 2.59 ~ 2.54 (m, 2H), 1.23 (d , J=6.3 Hz, 6H);MCNR(ER) m/z 485.8 (M⁺+1).

Example 570: Synthesis of Compound 18924, 2-(difluoromethyl)-5-(5-fluoro-6-((4-(3-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 4-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl) -1H-1,2,3-triazol-4-yl)phenyl)piperazine-1-carboxylate

Tert-butyl 4-(3-ethynylphenyl)piperazine-1-carboxylate (0.300 g, 1.048 mmol) prepared in Step 1 of Example 117, 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5- (difluoromethyl)-1,3,4-oxadiazole (0.425 g, 1.571 mmol) prepared in step 1 of Example 490, copper(II) sulfate pentahydrate (0.003 g, 0.010 mmol) and sodium ascorbate (0.021 g, 0.105 mmol) were dissolved in tert-butanol (4 ml)/water (2 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-100%) and concentrated to give tert-butyl 4-(3-(1-((5-(5-(difluoromethyl)-1, 3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)piperazine-1-carboxylate (0.400 g, 68.6 %) in the form of a brown solid.

[Step 2] Synthesis of 2-(difluoromethyl)-5-(5-fluoro-6-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl )methyl)pyridin-3-yl)-1,3,4-oxadiazole

Tert-butyl 4-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1, 2,3-triazol-4-yl)phenyl)piperazine-1-carboxylate (0.500 g, 0.898 mmol) and trifluoroacetic acid (0.688 ml, 8.984 mmol) were dissolved in dichloromethane (10 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without further purification process (2-(difluoromethyl)-5-(5-fluoro-6-((4-(3-(piperazin-1-yl)phenyl) -1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole, 0.400 g, 97.5%, brown solid).

[Step 3] Synthesis of compound 18924

2-(difluoromethyl)-5-(5-fluoro-6-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin- 3-yl)-1,3,4-oxadiazole (0.100 g, 0.219 mmol), formaldehyde (0.013 g, 0.438 mmol) and sodium triacetoxyborohydride (0.093 g, 0.438 mmol) are dissolved in dichloromethane (5 ml) at room temperature, after whereupon the resulting solution is stirred at the same temperature for 12 hours. Water is poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove solid residue and a layer of aqueous solution, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(5-fluoro-6-((4-(3-(4 -methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.035 g, 34.0%) in form of a yellow solid.

¹ H NMR(400 MHz, CDCl₃) δ 9.10 (s, 1H), 8.16 (dd, J=9.0, 1.7 Hz, 1H), 7.99 (s, 1H), 7.47 (s, 1H), 7 ,30 ~ 7.21 (m, 2H), 7.07 ~ 6.81 (m, 2H), 5.85 (s, 2H), 3.32 (t, J=4.9 Hz, 4H), 2.74 (t, J=4.9 Hz, 4H), 2.43 (s, 3H);MCNR(ER) m/z 471.7 (M⁺+1).

The compound of Table 175 was synthesized in accordance with substantially the same method as described above for the synthesis of compound 18924 except for the use of 2-(difluoromethyl)-5-(5-fluoro-6-((4-(3-(piperazine-1 -yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reagent from Table 174.

Table 174 Example Connection no. Reagent Exit (%) 571 18926 Propan-2-one 39

Table 175 Example Connection no. Name of compound, 1H-NMR, MS (ESI) 571 18926 2-(difluoromethyl)-5-(5-fluoro-6-((4-(3-(4-isopropylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl) pyridin-3-yl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CDCl ₃ ) δ 9.04 (s, 1H), 8.10 (dd, J=9.0, 1.7 Hz, 1H), 8.01 (s, 1H), 7 .40 (s, 1H), 7.26-7.22 (m, 2H), 7.07-6.80 (m, 2H), 5.82 (s, 2H), 3.40 (t, J =4.8 Hz, 4H), 3.21-3.17 (m, 1H), 3.01 (t, J=4.6 Hz, 4H), 1.23 (d, J=6.6 Hz , 6H); MSNR (ER) m/z 499.8 (M ⁺ +1).

Example 572: Synthesis of Compound 18947, 2-(6-((4-(4-(azetidin-1-ylmethyl)-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-5 -fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[Step 1] Synthesis of 4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2 ,3-triazol-4-yl)-2-fluorobenzaldehyde

4-Ethynyl-2-fluorobenzaldehyde (0.200 g, 1.350 mmol) and 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.365 g, 1.350 mmol) , obtained in step 1 of example 490, is dissolved in tert-butanol (2 ml)/water (2 ml) at room temperature, followed by sodium ascorbate (1.00 M solution, 0.135 ml, 0.135 mmol) and copper sulfate (I/ II, 0.50 M solution, 0.135 ml, 0.068 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution is poured into the reaction mixture, and extraction is carried out with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=100-70%) and concentrated to give 4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol- 2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-fluorobenzaldehyde (0.420 g, 74.4%) as a light yellow solid .

[Step 2] Synthesis of compound 18947

4-(1-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol- 4-yl)-2-fluorobenzaldehyde (0.050 g, 0.120 mmol) obtained in step 1, azetidine (0.014 g, 0.239 mmol) and sodium triacetoxyborohydride (0.127 g, 0.598 mmol) are dissolved in dichloromethane (3 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=100-80%) and concentrated to give 2-(6-((4-(4-(azetidin-1-ylmethyl)-3-fluorophenyl) -1H-1,2,3-triazol-1-yl)methyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.028 g, 51.0%) in form of a white solid.

¹ H NMR(400 MHz, CD₃OD) δ 9.10 (s, 1H), 8.54 (s, 1H), 8.39 (dd, J=9.6, 1.7 Hz, 1H), 7.69-7.58 (m , 2H), 7.44 (t, J=7.8 Hz, 1H), 7.27 (t, J=51.6 Hz, 2H), 6.01 (s, J=1.8 Hz, 2H ), 3.71 (s, 2H), 3.41-3.34 (m, 4H), 2.20-2.06 (m, 2H);MCNR(ER) m/z 461.58 (M⁺+1).

The compounds of Table 177 were synthesized in accordance with substantially the same method as described above for the synthesis of compound 18947 except for the use of 4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2- yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-fluorobenzaldehyde and the reagent from Table 176.

Table 176 Example Connection no. Reagent Exit (%) 573 18948 Pyrrolidine 51 574 18949 Dimethylamine 33 575 18950 Piperidine 36

Table 177 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 573 18948 2-(difluoromethyl)-5-(5-fluoro-6-((4-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-1H-1,2,3-triazol-1-yl) methyl)pyridin-3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.55 (s, 1H), 8.39 (dd, J=9.6, 1.7 Hz, 1H), 7.65 (ddd, J=12.6, 9.5, 1.6 Hz, 3H), 7.51 (t, J=7.8 Hz, 1H), 7.27 (t, J=51, 6 Hz, 2H), 6.01 (s, J=5.5 Hz, 2H), 3.77 (s, 2H), 2.64 (s, 4H), 1.89-1.78 (m, 4H); MSNR (ER) m/z 475.76 (M ⁺ +1). 574 18949 1-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3 -triazol-4-yl)-2-fluorophenyl)-N,N-dimethylmethanamine
¹ H NMR (400 MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.55 (s, 1H), 8.39 (dd, J=9.6, 1.7 Hz, 1H), 7.65 (ddd, J=12.6, 9.5, 1.6 Hz, 2H), 7.48 (t, J=7.8 Hz, 1H), 7.27 (t, J=51, 6 Hz, 2H), 6.01 (s, J=1.8 Hz, 2H), 3.60 (s, 2H), 2.30 (s, 6H); MSNR (ER) m/z 449.86 (M ⁺ +1). 575 18950 2-(difluoromethyl)-5-(5-fluoro-6-((4-(3-fluoro-4-(piperidin-1-ylmethyl)phenyl)-1H-1,2,3-triazol-1-yl) methyl)pyridin-3-yl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.11 (s, 1H), 8.54 (s, 1H), 8.39 (dd, J=9.6, 1.7 Hz, 1H), 7.64 (ddd, J=12.5, 9.4, 1.6 Hz, 2H), 7.50 (t, J=7.7 Hz, 1H), 7.27 (t, J=51, 6 Hz, 2H), 6.01 (d, J=1.8 Hz, 2H), 3.63 (s, 2H), 2.52 (s, 4H), 1.69-1.56 (m, 4H), 1.48 (s, 2H); MSNR (ER) m/z 489.75 (M ⁺ +1).

Example 576: Synthesis of Compound 18961, 2-(difluoromethyl)-5-(5-fluoro-6-((4-(3-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)phenyl) -1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

2-(Difluoromethyl)-5-(6-((4-(3-((3R,5S)-3,5-dimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1- yl)methyl)-5-fluoropyridin-3-yl)-1,3,4-oxadiazole (0.100 g, 0.206 mmol) prepared in step 2 of Example 569, formaldehyde (0.012 g, 0.413 mmol) and sodium triacetoxyborohydride (0.087 g , 0.413 mmol) was dissolved in dichloromethane (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. Water is poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove solid residue and a layer of aqueous solution, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(5-fluoro-6-((4-(3-(( 3R,5S)-3,4,5-trimethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.040 g, 38.9%) as a yellow solid.

¹ H NMR(400 MHz, CDCl₃) δ 9.09 (s, 1H), 8.15 (dd, J=9.0, 1.7 Hz, 1H), 8.00 (s, 1H), 7.47 (s, 1H), 7 .28 ~ 7.24 (m, 1H), 7.18 (d, J=7.6 Hz, 1H), 7.07 ~ 6.82 (m, 2H), 5.85 (s, 2H), 3.54 (d, J=11.3 Hz, 2H), 2.74 (t, J=11.5 Hz, 2H), 2.59 ~ 2.54 (m, 2H), 2.39 (s , 3H), 1.23 (d, J=6.3 Hz, 6H);MCNR(ER) m/z 499.7 (M⁺+1).

Example 577: Synthesis of compound 19002, 2-(difluoromethyl)-5-(5-fluoro-6-((4-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1, 2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of tert-butyl 7-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H- 1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

Tert-butyl 7-ethynyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.350 g, 1.360 mmol) prepared in Step 1 of Example 261, 2-(6-(azidomethyl)-5-fluoropyridin-3-yl )-5-(difluoromethyl)-1,3,4-oxadiazole (0.441 g, 1.632 mmol) obtained from step 1 of Example 490, copper(II) sulfate pentahydrate (0.003 g, 0.014 mmol) and sodium ascorbate (0.027 g, 0.136 mmol) was dissolved in tert-butanol (4 ml)/water (2 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution is poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove solid residue and a layer of aqueous solution, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-100%) and concentrated to give tert-butyl 7-(1-((5-(5-(difluoromethyl)-1,3,4 -oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.630 g, 87.8%) in the form of a brown solid.

[Step 2] Synthesis of 2-(difluoromethyl)-5-(5-fluoro-6-((4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol- 1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

Tert-butyl 7-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3 -triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.630 g, 1.194 mmol) and trifluoroacetic acid (0.915 ml, 11.943 mmol) were dissolved in dichloromethane (50 ml) at room temperature, then the resulting solution is stirred at the same temperature for 12 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(5-fluoro-6-((4-(1,2, 3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.500 g, 98.0%) in the form of brown butter.

[Step 3] Synthesis of compound 19002

2-(difluoromethyl)-5-(5-fluoro-6-((4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl )pyridin-3-yl)-1,3,4-oxadiazole (0.070 g, 0.164 mmol), formaldehyde (0.010 g, 0.328 mmol) and sodium triacetoxyborohydride (0.069 g, 0.328 mmol) are dissolved in dichloromethane (5 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution is poured into the reaction mixture, followed by extraction with dichloromethane, then filtered through a plastic filter to remove solid residue and a layer of aqueous solution, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol=0-10%) and concentrated to give 2-(difluoromethyl)-5-(5-fluoro-6-((4-(2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.020 g, 27 .7%) in the form of a yellow solid.

¹ H NMR(400 MHz, CDCl₃) δ 9.09 (s, 1H), 8.14 (d, J=8.8 Hz, 1H), 7.96 (s, 1H), 7.56 ~ 7.50 (m, 2H), 7 .14 ~ 6.81 (m, 2H), 5.83 (s, 2H), 3.66 (s, 2H), 2.96 (t, J=0.0 Hz, 2H), 2.85 ( t, J=0.0 Hz, 2H), 2.52 (s, 3H);MCNR(ER) m/z 442.3 (M⁺+1).

The compound of Table 179 was synthesized in accordance with substantially the same method as described above in the synthesis of compound 19002 except for the use of 2-(difluoromethyl)-5-(5-fluoro-6-((4-(1,2,3, 4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reagent from Table 178.

Table 178 Example Connection no. Reagent Exit (%) 578 19004 Cyclobutanone 28

Table 179 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 578 19004 2-(6-((4-(2-cyclobutyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluoropyridin- 3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.10 (s, 1H), 8.15 (d, J=8.8 Hz, 1H), 7.95 (s, 1H), 7.56-7 .52 (m, 2H), 7.13 (d, J=7.8 Hz, 1H), 6.94 (t, J=51.6 Hz, 1H), 5.84 (s, 2H), 3 .65 (s, 2H), 3.04-3.01 (m, 1H), 2.92 (t, J=2.9 Hz, 2H), 2.75 (t, J=5.6 Hz, 2H), 2.15-2.10 (m, 4H), 1.79-1.69 (m, 2H); MSNR (ER) m/z 482.4 (M ⁺ +1).

Example 580: Synthesis of Compound 19087, 2-(difluoromethyl)-5-(5-fluoro-6-((4-(4-(1-methylpiperidin-4-yl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[Step 1] Synthesis of 1-bromo-4-ethynylbenzene

4-bromobenzaldehyde (1.000 g, 5.405 mmol), potassium carbonate (0.896 g, 6.486 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.142 g, 5.945 mmol) are dissolved in methanol (30 ml) at room temperature, after which the resulting solution is stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting product was used without further purification process (1-bromo-4-ethynylbenzene, 0.800 g, 81.8%, yellow solid).

[Step 2] Synthesis of methyl 6-(azidomethyl)-5-fluoronicotinate

Methyl 6-(bromomethyl)-5-fluoronicotinate (1.000 g, 4.031 mmol) and sodium azide (0.315 g, 4.838 mmol) were dissolved in N,N-dimethylformamide (20 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-40%) and concentrated to give methyl 6-(azidomethyl)-5-fluoronicotinate (0.650 g, 76.7%) as a yellow solid. substances.

[Step 3] Synthesis of methyl 6-((4-(4-bromophenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluoronicotinate

1-Bromo-4-ethynylbenzene (0.400 g, 2.210 mmol) obtained in step 1, methyl 6-(azidomethyl)-5-fluoronicotinate (0.441 g, 2.099 mmol) obtained in step 2, sodium ascorbate (1.00 M solution in H ₂ O, 0.221 ml, 0.221 mmol) and copper(II) sulfate pentahydrate (0.50 M solution in H ₂ O, 0.044 ml, 0.022 mmol) dissolved in tert-butanol (5 ml)/water (5 ml ) at room temperature, after which the resulting solution is stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give methyl 6-((4-(4-bromophenyl)-1H-1,2,3-triazol- 1-yl)methyl)-5-fluoronicotinate (0.300 g, 34.7%) as a yellow solid.

[Step 4] Synthesis of methyl 6-((4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-1,2,3-triazole -1-yl)methyl)-5-fluoronicotinate

Methyl 6-((4-(4-bromophenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluoronicotinate (0.500 g, 1.278 mmol) obtained in step 3, tert-butyl 4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.474 g, 1.534 mmol), bis(triphenylphosphine) dichloride palladium(II) (0.090 g, 0.128 mmol) and sodium carbonate (0.271 g, 2.556 mmol) are mixed in N,N-dimethylformamide (10 ml)/water (5 ml) at 80°C, after which the resulting mixture is stirred at that same temperature for 5 hours, and then the reaction is completed by lowering the temperature to room temperature. The reaction mixture is filtered through a pad of celite to remove solid matter, after which the resulting concentrate is poured into water and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give methyl 6-((4-(4-(1-(tert-butoxycarbonyl)-1,2,3 ,6-tetrahydropyridin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluoronicotinate (0.290 g, 46.0%) as a white solid.

[Step 5] Synthesis of methyl 6-((4-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5 -fluoronicotinate

Methyl 6-((4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl) Methyl)-5-fluoronicotinate (0.290 g, 0.588 mmol) obtained in step 4 was dissolved in methanol (20 ml) at room temperature, after which the resulting solution was stirred for 5 hours. The reaction mixture was filtered through a pad of celite to remove solid matter, after which the solvent was removed from the resulting filtrate under reduced pressure, and then the resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-30%) and concentrated to give methyl 6-((4-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluoronicotinate ( 0.150 g, 51.5%) in the form of a yellow solid.

[Step 6] Synthesis of tert-butyl 4-(4-(1-((3-fluoro-5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl) phenyl)piperidine-1-carboxylate

Methyl 6-((4-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluoronicotinate (0.150 g , 0.303 mmol) obtained in step 5 and hydrazine monohydrate (0.147 ml, 3.027 mmol) is dissolved in ethanol (20 ml) at 90°C, after which the resulting solution is stirred at the same temperature for 12 hours, and then the reaction is completed by reducing temperature to room temperature. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without additional purification process (tert-butyl 4-(4-(1-((3-fluoro-5-(hydrazinecarbonyl)pyridin-2-yl)methyl)- 1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate, 0.140 g, 93.3%, white solid).

[Step 7] Synthesis of tert-butyl 4-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl) -1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate

Tert-butyl 4-(4-(1-((3-fluoro-5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidin-1 The -carboxylate (0.150 g, 0.303 mmol) obtained in step 6, imidazole (0.062 g, 0.908 mmol) and 2,2-difluoroacetic anhydride (0.113 ml, 0.908 mmol) are mixed in dichloromethane (30 ml) at room temperature, then the resulting mixture is heated at reflux for 12 hours and cooled to room temperature. Then, water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane=0-50%) and concentrated to give tert-butyl 4-(4-(1-((5-(5-(difluoromethyl)-1, 3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidin-1-carboxylate (0.100 g, 59.5 %) in the form of a white solid.

[Step 8] Synthesis of 2,2,2-trifluoroacetate 2-(difluoromethyl)-5-(5-fluoro-6-((4-(4-(piperidin-4-yl)phenyl)-1H-1,2, 3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

Tert-butyl 4-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1, 2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate (0.100 g, 0.180 mmol) obtained in step 7 and trifluoroacetic acid (0.041 ml, 0.540 mmol) are dissolved in dichloromethane (10 ml) at room temperature , after which the resulting solution is stirred at the same temperature for 3 hours. The solvent is removed from the reaction mixture under reduced pressure, after which the resulting product is used without further purification process (2,2,2-trifluoroacetate 2-(difluoromethyl)-5-(5-fluoro-6-((4-(4-(piperidine -4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole, 0.090 g, 87.8%, yellow oil) .

[Step 9] Synthesis of compound 19087

2,2,2-Trifluoroacetate 2-(difluoromethyl)-5-(5-fluoro-6-((4-(4-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1 -yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.080 g, 0.140 mmol) obtained in step 8 was dissolved in dichloromethane (5 ml), after which the resulting solution was stirred at room temperature for 30 minutes and N,N-diisopropylethylamine (0.049 ml, 0.281 mmol), formaldehyde (0.008 g, 0.281 mmol) and sodium triacetoxyborohydride (0.089 g, 0.421 mmol) were added and stirred at the same temperature for 12 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-5%) and concentrated to give 2-(difluoromethyl)-5-(5-fluoro-6-((4-(4-(1 -methylpiperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.029 g, 44.0%) in form of a white solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.99 (d,J=4.0 Hz, 1H), 7.92-7.83 (m, 3H), 7.42 (t,J=7.8 Hz, 1H), 7.15 (t,J=7.9 Hz, 1H), 7.03-6.78 (m, 2H), 5.72 (s, 2H), 3.10 (sq,J=8.2, 6.4 Hz, 4H), 2.68-2.54 (m, 9H), 2.23 (ddd,J=21.2, 10.3, 4.7 Hz, 2H);MCNR(ER) m/z 578.4 (M⁺+1).

Example 581: Synthesis of compound 19088 , 1-(2-chloro-3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl )methyl)-1H-1,2,3-triazol-4-yl)phenyl)-N,N-dimethylmethanamine

[Step 1] Synthesis of 2-chloro-3-((trimethylsilyl)ethynyl)benzaldehyde

3-bromo-2-chlorobenzaldehyde (1.000 g, 4.557 mmol), bis(triphenylphosphine) palladium dichloride (0.160 g, 0.228 mmol) and copper iodide (I/II, 0.087 g, 0.456 mmol) are dissolved in tetrahydrofuran (20 ml)/ triethylamine (4 ml), after which trimethylsilylacetylene (0.917 ml, 6.835 mmol) was added to the resulting solution at room temperature and stirred at the same temperature for 5 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-10%) and concentrated to give 2-chloro-3-((trimethylsilyl)ethynyl)benzaldehyde (0.718 g, 66.6%) in orange liquid form.

[Step 2] Synthesis of 2-chloro-3-ethynylbenzaldehyde

2-Chloro-3-((trimethylsilyl)ethynyl)benzaldehyde (0.718 g, 3.032 mmol) obtained in step 1 and potassium carbonate (1.257 g, 9.097 mmol) were dissolved in methanol (10 ml) at room temperature, after which the resulting the solution is stirred at the same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-10%) and concentrated to give 2-chloro-3-ethynylbenzaldehyde (0.480 g, 96.2%) as a light yellow solid.

[Step 3] Synthesis of 2-chloro-3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H -1,2,3-triazol-4-yl)benzaldehyde

2-Chloro-3-ethynylbenzaldehyde (0.480 g, 2.916 mmol) obtained in step 2, 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4- oxadiazole (0.788 g, 2.916 mmol) obtained in step 1 of Example 490, sodium ascorbate (0.50 M solution in water, 0.583 ml, 0.292 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.029 ml, 0.029 mmol) was dissolved in tert-butanol (5 ml)/water (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate is purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol = 0-10%) and concentrated, after which dichloromethane (5 ml) and hexane (100 ml) are added to the resulting solution and stirred to filter out the precipitated solid substances, washed with hexane and dried to obtain 2-chloro-3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl )-1H-1,2,3-triazol-4-yl)benzaldehyde (0.210 g, 16.6%) as a green solid.

[Step 4] Synthesis of compound 19088

2-Chloro-3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2, 3-triazol-4-yl)benzaldehyde (0.100 g, 0.230 mmol) obtained in step 3, dimethylamine (2.00 M solution in MeOH, 0.230 ml, 0.460 mmol) and acetic acid (0.013 ml, 0.230 mmol) are dissolved in dichloromethane (1 ml), after which the resulting solution was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (0.146 g, 0.690 mmol) was added thereto and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-10%) and concentrated to give 1-(2-chloro-3-(1-((5-(5-(difluoromethyl)-1 ,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-N,N-dimethylmethanamine (0.076 g, 71 .2%) in the form of a brown solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.66 (s, 1H), 8.39 (dd, J=9.6, 1.6 Hz, 1H), 7.93 (dd, J=7.7, 1.6 Hz, 1H), 7.51 (dd, J=7.6, 1.5 Hz, 1H), 7.45-7.14 (m, 2H), 6.04 (d, J=1.5 Hz, 2H), 3.71 (s, 2H), 2.34 (s, 6H); MSNR (ER) m/z 464.3 (M ⁺ +1).

The compound of Table 181 was synthesized in accordance with substantially the same method as described above for the synthesis of compound 19088 except for the use of 2-chloro-3-(1-((5-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzaldehyde and the reagent from Table 180.

Table 180 Example Connection no. Reagent Exit (%) 582 19089 Pyrrolidine 10

Table 181 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 582 19089 2-(6-((4-(2-chloro-3-(pyrrolidin-1-ylmethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluoropyridin-3-yl )-5-(difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.10 (d, J=0.6 Hz, 1H), 8.65 (s, 1H), 8.38 (dd, J=9.6, 1 .7 Hz, 1H), 7.92 (dd, J=7.8, 1.7 Hz, 1H), 7.55 (dd, J=7.6, 1.7 Hz, 1H), 7.45 -7.14 (m, 2H), 6.04 (d, J=1.8 Hz, 2H), 3.91 (s, 2H), 2.71-2.68 (m, 4H), 1, 87-1.84 (m, 4H); MSNR (IER) m/z 490.3 (M ⁺ + H).

Example 583: Synthesis of compound 19090 , 1-(3-chloro-5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl )methyl)-1H-1,2,3-triazol-4-yl)phenyl)-N,N-dimethylmethanamine

[Step 1] Synthesis of 3-chloro-5-((trimethylsilyl)ethynyl)benzaldehyde

3-Bromo-5-chlorobenzaldehyde (1.000 g, 4.557 mmol), bis(triphenylphosphine) palladium dichloride (0.160 g, 0.228 mmol) and copper iodide (I/II, 0.087 g, 0.456 mmol) are dissolved in tetrahydrofuran (20 ml)/ triethylamine (4 ml), after which trimethylsilylacetylene (0.917 ml, 6.835 mmol) was added to the resulting solution at room temperature and stirred at the same temperature for 5 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-10%) and concentrated to give 3-chloro-5-((trimethylsilyl)ethynyl)benzaldehyde (1.019 g, 94.5%) in form of a brown liquid.

[Step 2] Synthesis of 3-chloro-5-ethynylbenzaldehyde

3-Chloro-5-((trimethylsilyl)ethynyl)benzaldehyde (1.019 g, 4.304 mmol) obtained in step 1 and potassium carbonate (1.784 g, 12.911 mmol) were dissolved in methanol (10 ml) at room temperature, after which the resulting the solution is stirred at the same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-10%) and concentrated to give 3-chloro-5-ethynylbenzaldehyde (0.530 g, 74.8%) as a light yellow solid.

[Step 3] Synthesis of 3-chloro-5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H -1,2,3-triazol-4-yl)benzaldehyde

3-Chloro-5-ethynylbenzaldehyde (0.530 g, 3.220 mmol) obtained in step 2, 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4- oxadiazole (0.870 g, 3.220 mmol) obtained in step 1 of Example 490, sodium ascorbate (0.50 M solution in water, 0.644 ml, 0.322 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.032 ml, 0.032 mmol) was dissolved in tert-butanol (5 ml)/water (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate is purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol = 0-10%) and concentrated, after which dichloromethane (5 ml) and hexane (100 ml) are added to the resulting solution and stirred to filter out the precipitated solid substances, washed with hexane and dried to obtain 3-chloro-5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl )-1H-1,2,3-triazol-4-yl)benzaldehyde (0.571 g, 40.8%) as a green solid.

[Step 4] Synthesis of compound 19090

3-Chloro-5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2, 3-triazol-4-yl)benzaldehyde (0.100 g, 0.230 mmol) obtained in step 3, dimethylamine (2.00 M solution in MeOH, 0.230 ml, 0.460 mmol) and acetic acid (0.013 ml, 0.230 mmol) are dissolved in dichloromethane (1 ml), after which the resulting solution was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (0.146 g, 0.690 mmol) was added thereto and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-15%) and concentrated to give 1-(3-chloro-5-(1-((5-(5-(difluoromethyl)-1 ,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-N,N-dimethylmethanamine (0.067 g, 62 .8%) in the form of a light yellow solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 9.09 (d, J=0.6 Hz, 1H), 8.55 (s, 1H), 8.38 (dd, J=9.6, 1 .7 Hz, 1H), 7.83-7.82 (m, 1H), 7.75 (s, 1H), 7.37-7.37 (m, 1H), 7.27 (t, J= 51.5 Hz, 1H), 6.01 (d, J=1.8 Hz, 2H), 3.53 (s, 2H), 2.29 (s, 6H); MSNR (ER) m/z 464.3 (M ⁺ +1).

The compounds of Table 183 were synthesized in accordance with substantially the same method as described above for the synthesis of compound 19090 except for the use of 2-chloro-3-(1-((5-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzaldehyde and the reagent from Table 182.

Table 182 Example Connection no. Reagent Exit (%) 584 19091 Azetidine 14 585 19092 Pyrrolidine 42 586 19093 4-methylpiperidine 76

Table 183 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 584 19091 2-(6-((4-(3-(azetidin-1-ylmethyl)-5-chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluoropyridin-3-yl) -5-(difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.55 (s, 1H), 8.39 (dd, J=9.6, 1.7 Hz, 1H), 7.81 (t, J=1.7 Hz, 1H), 7.72 (s, 1H), 7.33 (s, 1H), 7.27 (t, J=51.5 Hz, 1H), 6.01 (d, J=1.8 Hz, 2H), 3.68 (s, 2H), 3.38-3.34 (m, 4H), 2.20-2.12 (m, 2H) ; MSNR (IER) m/z 476.4 (M ⁺ + H). 585 19092 2-(6-((4-(3-chloro-5-(pyrrolidin-1-ylmethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluoropyridin-3-yl )-5-(difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.55 (s, 1H), 8.39 (dd, J=9.6, 1.7 Hz, 1H), 7.83-7.78 (m, 2H), 7.41-7.14 (m, 2H), 6.01 (d, J=1.8 Hz, 2H), 3.73 (s, 2H) , 2.63-2.61 (m, 4H), 1.87-1.84 (m, 4H); MSNR (IER) m/z 490.3 (M ⁺ + H). 586 19093 2-(6-((4-(3-chloro-5-((4-methylpiperidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5- fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole
^1H NMR (400 MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.55 (s, 1H), 8.40-8.38 (m, 1H), 7.81 (s, 1H ), 7.76 (s, 1H), 7.40-7.14 (m, 2H), 6.01 (s, 2H), 3.57 (s, 2H), 2.92-2.86 ( m, 2H), 2.18-2.05 (m, 2H), 1.67 (d, J=12.5 Hz, 2H), 1.33-1.23 (m, 3H), 0.95 (d, J=6.4 Hz, 3H); MSNR (IER) m/z 518.4 (M ⁺ + H).

Example 587: Synthesis of compound 19094 , 1-(2-chloro-4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl )methyl)-1H-1,2,3-triazol-4-yl)phenyl)-N,N-dimethylmethanamine

[Step 1] Synthesis of 2-chloro-4-((trimethylsilyl)ethynyl)benzaldehyde

4-bromo-2-chlorobenzaldehyde (1.000 g, 4.557 mmol), bis(triphenylphosphine) palladium dichloride (0.160 g, 0.228 mmol) and copper iodide (I/II, 0.087 g, 0.456 mmol) are dissolved in tetrahydrofuran (20 ml)/ triethylamine (4 ml), after which trimethylsilylacetylene (0.917 ml, 6.835 mmol) was added to the resulting solution at room temperature and stirred at the same temperature for 5 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-10%) and concentrated to give 2-chloro-4-((trimethylsilyl)ethynyl)benzaldehyde (0.691 g, 64.0%) in form of a brown liquid.

[Step 2] Synthesis of 2-chloro-4-ethynylbenzaldehyde

2-Chloro-4-((trimethylsilyl)ethynyl)benzaldehyde (0.691 g, 2.918 mmol) obtained in step 1 and potassium carbonate (1.210 g, 8.755 mmol) were dissolved in methanol (10 ml) at room temperature, after which the resulting the solution is stirred at the same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-10%) and concentrated to give 2-chloro-4-ethynylbenzaldehyde (0.380 g, 79.1%) as a light yellow solid.

[Step 3] Synthesis of 2-chloro-4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H -1,2,3-triazol-4-yl)benzaldehyde

2-Chloro-4-ethynylbenzaldehyde (0.380 g, 2.309 mmol) obtained in step 2, 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4- oxadiazole (0.624 g, 2.309 mmol) obtained in step 1 of Example 490, sodium ascorbate (0.50 M solution in water, 0.462 ml, 0.231 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.023 ml, 0.023 mmol) was dissolved in tert-butanol (5 ml)/water (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate is purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol = 0-10%) and concentrated, after which dichloromethane (5 ml) and hexane (100 ml) are added to the resulting solution and stirred to filter out the precipitated solid substances, washed with hexane, and dried to obtain 2-chloro-4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl) methyl)-1H-1,2,3-triazol-4-yl)benzaldehyde (0.537 g, 53.5%) as a green solid.

[Step 4] Synthesis of compound 19094

2-Chloro-4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2, 3-triazol-4-yl)benzaldehyde (0.100 g, 0.230 mmol) obtained in step 3, dimethylamine (2.00 M solution in MeOH, 0.230 ml, 0.460 mmol) and acetic acid (0.013 ml, 0.230 mmol) are dissolved in dichloromethane (1 ml), after which the resulting solution was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (0.146 g, 0.690 mmol) was added thereto and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-15%) and concentrated to give 1-(2-chloro-4-(1-((5-(5-(difluoromethyl)-1 ,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-N,N-dimethylmethanamine (0.072 g, 67 .5%) in the form of a yellow solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.56 (s, 1H), 8.39 (d, J=9.6 Hz, 1H), 7.94 ( s, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.27 (t, J=51.5 Hz, 1H), 6.01 (s, 2H), 3.66 (s, 2H), 2.33 (s, 6H); MSNR (ER) m/z 464.3 (M ⁺ +1).

The compound of Table 185 was synthesized in accordance with substantially the same method as described above for the synthesis of compound 19094 except for the use of 2-chloro-4-(1-((5-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzaldehyde and the reagent from Table 184.

Table 184 Example Connection no. Reagent Exit (%) 588 19096 Pyrrolidine 36

Table 185 Example Connection no. Name of compound, 1H-NMR, MS (ESI) 588 19096 2-(6-((4-(3-chloro-4-(pyrrolidin-1-ylmethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluoropyridin-3-yl )-5-(difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.68 (s, 1H), 8.39 (dd, J=9.6, 1.7 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.54 (d, J=1.6 Hz, 1H), 7.41-7.14 (m, 2H), 6.04 (d , J=1.8 Hz, 2H), 3.53 (s, 2H), 2.29 (s, 6H); MSNR (IER) m/z 490.3 (M ⁺ + H).

Example 589: Synthesis of compound 19098 , 1-(3-chloro-4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl )methyl)-1H-1,2,3-triazol-4-yl)phenyl)-N,N-dimethylmethanamine

[Step 1] Synthesis of 3-chloro-4-((trimethylsilyl)ethynyl)benzaldehyde

4-bromo-3-chlorobenzaldehyde (1.000 g, 4.557 mmol), bis(triphenylphosphine) palladium dichloride (0.160 g, 0.228 mmol) and copper iodide (I/II, 0.087 g, 0.456 mmol) are dissolved in tetrahydrofuran (20 ml)/ triethylamine (4 ml), after which trimethylsilylacetylene (0.917 ml, 6.835 mmol) was added to the resulting solution at room temperature and stirred at the same temperature for 5 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-10%) and concentrated to give 3-chloro-4-((trimethylsilyl)ethynyl)benzaldehyde (0.736 g, 68.2%) in orange liquid form.

[Step 2] Synthesis of 3-chloro-4-ethynylbenzaldehyde

3-Chloro-4-((trimethylsilyl)ethynyl)benzaldehyde (0.736 g, 3.109 mmol) obtained in step 1 and potassium carbonate (1.289 g, 9.326 mmol) were dissolved in methanol (10 ml) at room temperature, after which the resulting the solution is stirred at the same temperature for 18 hours. Water is poured into the reaction mixture and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane=0-10%) and concentrated to give 3-chloro-4-ethynylbenzaldehyde (0.398 g, 77.8%) as a light yellow solid.

[Step 3] Synthesis of 3-chloro-4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H -1,2,3-triazol-4-yl)benzaldehyde

3-Chloro-4-ethynylbenzaldehyde (0.230 g, 1.397 mmol) obtained in step 2, 2-(6-(azidomethyl)-5-fluoropyridin-3-yl)-5-(difluoromethyl)-1,3,4- oxadiazole (0.378 g, 1.397 mmol) obtained in step 1 of Example 490, sodium ascorbate (0.50 M solution in water, 0.279 ml, 0.140 mmol) and copper(II) sulfate pentahydrate (1.00 M solution in water, 0.014 ml, 0.014 mmol) was dissolved in tert-butanol (5 ml)/water (5 ml) at room temperature, after which the resulting solution was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate is purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol = 0-10%) and concentrated, after which dichloromethane (5 ml) and hexane (100 ml) are added to the resulting solution and stirred to filter out the precipitated solid substances, washed with hexane and dried to obtain 3-chloro-4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl )-1H-1,2,3-triazol-4-yl)benzaldehyde (0.310 g, 51.0%) as a yellow solid.

[Step 4] Synthesis of compound 19098

3-chloro-4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2, 3-triazol-4-yl)benzaldehyde (0.100 g, 0.230 mmol) obtained in step 3, dimethylamine (2.00 M solution in MeOH, 0.230 ml, 0.460 mmol) and acetic acid (0.013 ml, 0.230 mmol) are dissolved in dichloromethane (1 ml), after which the resulting solution was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (0.146 g, 0.690 mmol) was added thereto and then stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate is poured into the reaction mixture, and extraction is carried out with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane=0-15%) and concentrated to give 1-(3-chloro-4-(1-((5-(5-(difluoromethyl)-1 ,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-N,N-dimethylmethanamine (0.065 g, 60 .9%) in the form of a light yellow solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.68 (s, 1H), 8.39 (dd, J=9.6, 1.7 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.54 (d, J=1.6 Hz, 1H), 7.41-7.14 (m, 2H), 6.04 (d , J=1.8 Hz, 2H), 3.53 (s, 2H), 2.29 (s, 6H); MSNR (ER) m/z 464.4 (M ⁺ +1).

The compounds of Table 187 were synthesized in accordance with substantially the same method as described above for the synthesis of compound 19098 except for the use of 3-chloro-4-(1-((5-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzaldehyde and the reagent from Table 186.

Table 186 Example Connection no. Reagent Exit (%) 590 19099 Azetidine 25 591 19100 Pyrrolidine 23

Table 187 Example Connection no. Name of compound, ¹ H-NMR, MS (ESI) 590 19099 2-(6-((4-(4-(azetidin-1-ylmethyl)-2-chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluoropyridin-3-yl) -5-(difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.67 (s, 1H), 8.39 (dd, J=9.6, 1.7 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.50 (d, J=1.5 Hz, 1H), 7.37 (dd, J=8.1, 1.6 Hz, 1H ), 7.26 (t, J=51.5 Hz, 1H), 6.04 (d, J=1.8 Hz, 2H), 3.68 (s, 2H), 3.38-3.33 (m, 4H), 2.20-2.13 (m, 2H); MSNR (IER) m/z 476.0 (M ⁺ + H). 591 19100 2-(6-((4-(2-chloro-4-(pyrrolidin-1-ylmethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-fluoropyridin-3-yl )-5-(difluoromethyl)-1,3,4-oxadiazole
¹ H NMR (400 MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.68 (s, 1H), 8.39 (dd, J=9.6, 1.7 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.57 (d, J=1.5 Hz, 1H), 7.43 (dd, J=8.1, 1.6 Hz, 1H ), 7.27 (t, J=51.5 Hz, 1H), 6.04 (d, J=1.7 Hz, 2H), 3.72 (s, 2H), 2.63 (s, 4H ), 1.88-1.85 (m, 4H); MSNR (IER) m/z 490.4 (M ⁺ + H).

Protocol for measuring and analyzing the activity of compounds of the present invention

Experimental Example 1: Search for Inhibition of HDAC Enzyme Activity ( in vitro )

An experiment was carried out to identify the selectivity of the compound represented by Formula I of the present invention to HDAC6 through an experiment to inhibit the enzyme activity of HDAC1 and HDAC6.

HDAC enzyme activity is measured using the HDAC Fluorimetric Drug Discovery Kit (BML-AK511, 516) from Enzo Life Science, Inc. To test the enzyme activity of HDAC1, recombinant human HDAC1 (BML-SE456) is used as the enzyme source and Fluor de Lys® -“SIRT1 (BNL-KI177)” is used as the substrate. A 5-fold dilution of the compound is divided into a 96-well plate, after which 0.3 µg enzyme and 10 µM substrate are added to each well and reacted at 30°C for 60 minutes, for example, Fluor de Lys® Developer II (BML- KI176) is added therein and reacted for 30 minutes and terminated. After this, the fluorescence value (Exc. 360, Ex. 460) is measured using a multiplate reader (Flexstation 3, Molecular Device). The HDAC6 enzyme experiment was carried out according to the same protocol used in the HDAC1 enzyme activity test method using recombinant human HDAC6 (382180) from Calbiochem Inc. As final test values, each IC ₅₀ value was calculated in GraphPad Prism 4.0.

Table 188 Example Connection HDAC1
(µM) HDAC6
(µM) HDAC6 selectivity (fold) Example Connection HDAC1
(µM) HDAC6
(µM) HDAC6 selectivity (fold) 1 3657 >50 0.0948 527 29 3809 >50 0.1976 253 2 3658 >50 0.0579 863 thirty 3810 >50 0.2799 178 3 3659 >50 0.4089 122 31 3811 >50 0.2069 241 4 3660 >50 0.2854 175 32 3812 >50 0.1119 446 5 3661 >50 0.3987 125 33 3813 >50 0.2998 166 6 3662 >50 0.1730 289 34 3820 >50 0.1697 294 7 3695 >50 1,186 42 35 3822 >50 0.2047 244 8 3696 >50 0.9453 52 36 3824 >50 0.0205 2439 9 3697 >50 0.0454 1101 37 3825 >50 0.0112 4464 10 3698 >50 0.0456 1096 38 3826 >50 0.0121 4132 eleven 3731 >50 1.723 29 39 3827 >50 0.0201 2487 12 3732 >50 0.6722 74 40 3828 >50 0.0418 1196 13 3733 >50 0.2325 215 41 3829 >50 0.0302 1655 14 3734 >50 0.2438 500 42 3830 >50 0.0228 219 15 3735 >50 0.1562 320 43 3831 >50 0.1454 343 16 3736 >50 0.0222 2252 44 3832 >50 0.1896 263 17 3737 >50 0.0479 1043 45 3833 >50 0.4244 117 18 3738 >50 0.0440 1136 46 3834 >50 0.2380 217 19 3739 >50 0.0639 782 47 3835 >50 0.0427 1170 20 3741 >50 0.0285 1754 48 3837 >50 0.0518 965 21 3774 >50 0.1211 412 49 3838 >50 0.0070 7142 22 3775 >50 0.0292 1712 50 3839 >50 0.0074 6756 23 3776 >50 0.0252 1984 51 3840 >50 0.0088 5681 24 3777 >50 0.0225 2222 52 3841 >50 0.0084 5952 25 3805 >50 0.0592 844 53 3842 >50 0.0246 2032 26 3806 >50 0.3717 134 54 3843 >50 0.0084 5952 27 3807 >50 0.3012 166 55 3844 >50 0.0207 2415 28 3808 >50 0.3480 143 56 3845 >50 0.0161 3105 57 3846 >50 0.0793 630 85 3915 >50 0.0382 1308 58 3853 >50 0.0310 1612 86 3916 >50 0.0285 1754 59 3854 >50 0.0397 1259 87 3917 >50 0.0328 1524 60 3855 >50 0.0275 1818 88 3918 >50 0.0420 1190 61 3856 >50 0.0332 1506 89 3919 >50 0.0368 1358 62 3860 >50 0.1278 391 90 3925 >50 0.0351 1424 63 3861 >50 0.0542 922 91 3926 >50 0.1621 308 64 3866 >50 0.0186 2688 92 3944 >50 0.0067 7462 65 3867 >50 0.0256 1953 93 3945 >50 0.1931 258 66 3879 >50 0.0646 773 94 3949 >50 0.1122 445 67 3880 >50 0.0797 627 95 3950 >50 0.0524 954 68 3881 >50 0.0340 1470 96 3951 >50 0.6132 81 69 3882 >50 0.0506 988 97 3952 >50 0.6529 76 70 3883 >50 0.0339 1474 98 3953 >50 0.4981 100 71 3884 >50 0.0376 1329 99 3954 >50 0.4286 116 72 3885 >50 0.0543 920 100 3955 >50 0.5216 95 73 3886 >50 0.0447 1118 101 3956 >50 0.5363 93 74 3887 >50 0.0571 875 102 3957 >50 0.4959 100 75 3889 >50 0.0413 1210 103 3958 >50 0.4291 116 76 3890 >50 0.0379 1319 104 3959 >50 0.2386 209 77 3891 >50 0.1741 287 105 3960 >50 0.1055 473 78 3892 >50 0.1398 357 106 3961 >50 0.1294 386 79 3893 >50 0.1532 326 107 3962 >50 0.0108 4629 80 3894 >50 0.1004 498 108 3963 >50 0.0594 841 81 3895 >50 0.2927 171 109 3964 >50 0.0262 1908 82 3896 >50 0.2671 187 110 3965 >50 0.0359 1392 83 3902 >50 0.0207 2415 111 3966 >50 0.0295 1694 84 3914 >50 0.0432 1190 112 3980 >50 0.1836 272 113 3981 >50 1,200 41 140 4027 >50 5,000 10 114 3985 >50 0.0342 1461 141 4028 >50 0.2098 238 115 3986 >50 0.0074 6756 142 4029 >50 0.2084 239 116 3987 >50 0.0091 5494 143 4051 >50 0.0308 1623 117 3988 >50 0.0106 4716 144 4052 >50 0.0443 1128 118 3989 >50 0.0313 1597 145 4053 >50 0.0568 880 119 3990 >50 0.0190 2631 146 4054 >50 0.0457 1094 120 3991 >50 0.0282 1773 147 4055 >50 0.0576 868 121 3999 >50 0.0869 575 148 4070 >50 0.0385 1298 122 4000 >50 0.3431 145 149 4071 >50 0.1438 347 123 4001 >50 0.1687 296 150 4072 >50 0.0103 4854 124 4002 >50 0.5198 96 151 4073 >50 0.0608 822 125 4003 >50 0.4839 103 152 4074 >50 0.0830 602 126 4004 >50 0.3325 150 153 4075 >50 0.0164 3048 127 4005 >50 0.1317 379 154 4076 >50 0.0676 739 128 4006 >50 0.1332 375 155 4077 >50 0.0845 591 129 4007 >50 0.0174 2873 156 4078 >50 0.0351 1424 130 4008 >50 0.1224 408 157 4079 >50 0.0251 1992 131 4009 >50 0.1234 405 158 4080 >50 0.0233 2145 132 4010 >50 0.0211 2369 159 4081 >50 0.1045 478 133 4011 >50 0.0244 2049 160 4082 >50 0.1432 349 134 4012 >50 0.0212 2358 161 4104 33 0.0660 500 135 4013 >50 0.0229 2183 162 4105 34 0.0347 979 136 4014 >50 0.2029 246 163 4106 >50 0.0570 877 137 4015 >50 0.4711 106 164 4107 >50 0.0398 1256 138 4023 >50 1,560 32 165 4108 >50 0.0085 5882 139 4026 >50 0.2634 189 166 4109 >50 0.0137 3649 167 4110 >50 0.0165 3030 192 4231 >50 0.0547 914 168 4111 >50 0.0109 4587 193 4232 >50 0.0224 2232 169 4112 >50 0.0160 3125 194 4233 >50 0.0130 3846 170 4133 >50 0.1125 444 195 4234 >50 0.0168 2976 171 4134 >50 0.0165 3030 196 4235 >50 0.1719 290 172 4135 >50 0.0167 2941 197 4276 >50 0.3485 143 173 4136 >50 0.0174 2873 198 4277 >50 0.2349 212 174 4178 >50 0.0558 896 199 4278 >50 0.3113 160 175 4179 >50 0.0744 672 200 4279 >50 0.2741 182 176 4180 >50 0.0332 1506 201 4280 >50 0.1712 292 177 4181 >50 0.0357 1400 202 4281 >50 0.1213 412 178 4182 >50 0.0222 2252 203 4282 >50 0.2383 209 179 4183 >50 0.0558 896 204 4283 >50 0.2456 203 180 4184 >50 0.0387 1291 205 4284 >50 0.0261 1915 181 4185 >50 0.0685 729 206 4285 >50 0.0317 1577 182 4186 >50 0.0112 4464 207 4286 >50 0.3242 154 183 4187 >50 0.0089 5617 208 4287 >50 0.0239 2092 184 4208 >50 0.0338 1479 209 4288 >50 0.1028 486 185 4209 >50 0.0385 1298 210 4289 >50 0.0120 416 186 4210 >50 0.0519 963 211 4290 >50 0.0550 909 187 4211 >50 0.0481 1039 212 4291 >50 0.0427 1170 188 4212 >50 0.0312 1602 213 4292 >50 0.0517 967 189 4213 >50 0.0289 1730 214 4293 >50 0.0809 618 190 4229 >50 0.0287 1742 215 4294 >50 0.0632 791 191 4230 >50 0.0230 2173 216 4295 >50 0.0452 1106 217 4296 >50 0.0323 1547 242 4340 >50 0.0066 7575 218 4316 >50 0.2423 206 243 4341 >50 0.0409 1222 219 4317 >50 0.0836 598 244 4342 >50 0.0344 1453 220 4318 >50 0.0364 1373 245 4343 >50 0.0085 5882 221 4319 >50 0.0340 1470 246 4344 >50 0.0116 4310 222 4320 >50 0.0695 719 247 4345 >50 0.0129 3875 223 4321 >50 0.1115 434 248 4346 >50 0.0055 9090 224 4322 >50 0.0940 531 249 4347 >50 0.0073 6849 225 4323 >50 0.1611 310 250 4348 >50 0.0068 7352 226 4324 >50 0.2939 170 251 4349 >50 0.3629 137 227 4325 >50 0.0602 830 252 4350 >50 0.6049 82 228 4326 >50 0.0562 889 253 4351 >50 0.0419 1193 229 4327 >50 0.0358 1396 254 4352 >50 0.0332 1562 230 4328 >50 0.0591 846 255 4353 >50 0.0416 1201 231 4329 >50 0.0613 815 256 4358 >50 0.0330 1515 232 4330 >50 0.1859 268 257 4359 >50 0.0423 1182 233 4331 >50 0.0452 1106 258 4360 >50 0.0567 881 234 4332 >50 0.0416 1201 259 4361 >50 0.0748 668 235 4333 >50 0.0226 2212 260 4362 >50 0.0656 762 236 4334 >50 0.0263 1901 261 4363 >50 0.0361 1385 237 4335 >50 0.0627 797 262 4364 >50 0.0431 1160 238 4336 >50 0.0324 1543 263 4365 >50 0.0459 1089 239 4337 >50 0.0239 2092 264 4366 >50 0.0368 1358 240 4338 >50 0.0653 765 265 4367 >50 0.0413 1210 241 4339 >50 0.0308 1623 266 4368 >50 0.0326 1533 267 4369 >50 0.0548 912 292 4408 >50 0.0515 970 268 4370 >50 0.0699 715 293 4409 >50 0.5189 96 269 4371 >50 0.0545 917 294 4410 >50 0.0640 781 270 4372 >50 0.0690 724 295 4411 >50 0.0755 662 271 4373 >50 0.0149 335 296 4412 >50 0.1156 432 272 4374 >50 0.0219 228 297 4413 >50 0.1435 348 273 4375 >50 0.0350 1428 298 4414 >50 0.0797 627 274 4376 >50 0.0457 1094 299 4415 >50 0.0917 545 275 4377 >50 0.0481 1039 300 4416 >50 0.1117 427 276 4392 >50 0.0396 1262 301 4417 >50 0.1025 487 277 4393 >50 0.0362 1381 302 4418 >50 0.0597 837 278 4394 >50 0.0708 706 303 4419 >50 0.1586 315 279 4395 >50 0.0488 1024 304 4420 >50 0.1739 287 280 4396 >50 0.0807 619 305 4421 >50 0.2465 202 281 4397 >50 0.0652 766 306 4422 >50 0.3920 127 282 4398 >50 0.0506 988 307 4424 >50 0.0894 559 283 4399 >50 0.1085 460 308 4425 >50 0.1160 431 284 4400 >50 0.0307 1628 309 4426 >50 0.1497 334 285 4401 >50 0.0444 1126 310 4427 >50 0.0912 548 286 4402 >50 0.0738 677 311 4429 >50 0.0669 747 287 4403 >50 0.0412 1213 312 4430 >50 0.1424 351 288 4404 >50 0.0597 837 313 4431 >50 0.0190 2631 289 4405 >50 0.0629 794 314 4432 >50 0.0206 2427 290 4406 >50 0.0560 892 315 4433 >50 0.0331 1510 291 4407 >50 0.0397 1259 316 4434 >50 0.0209 2392 317 4435 >50 0.0298 1677 342 4467 >50 0.0219 2283 318 4436 >50 0.0365 1369 343 4468 >50 0.0135 370 319 4437 >50 0.0833 600 344 4469 >50 0.0590 847 320 4438 >50 0.0535 934 345 4470 >50 0.0546 915 321 4439 >50 0.0273 1831 346 4471 >50 0.0448 1116 322 4440 >50 0.0302 1655 347 4472 >50 0.1228 407 323 4441 >50 0.0380 1315 348 4473 >50 0.0399 1253 324 4442 >50 0.0398 1256 349 4474 >50 0.0412 1213 325 4443 >50 0.0229 2183 350 4475 >50 0.0394 1269 326 4444 >50 0.0267 1872 351 4476 >50 0.0489 1022 327 4448 >50 0.0174 2873 352 4477 >50 0.0249 2008 328 4449 >50 0.0133 3759 353 4478 >50 0.1142 437 329 4450 >50 0.0192 2604 354 4479 >50 0.4835 103 330 4451 >50 0.0168 1976 355 4480 >50 0.0360 1388 331 4452 >50 0.0203 2463 356 4482 >50 0.0530 943 332 4453 >50 0.0159 3144 357 4483 >50 0.0341 1466 333 4454 >50 0.0791 632 358 4484 >50 0.0163 3067 334 4455 >50 0.0961 520 359 4485 >50 0.0227 2202 335 4460 >50 0.3374 148 360 4486 >50 0.0309 1618 336 4461 >50 0.0658 759 361 4487 >50 0.0797 627 337 4462 >50 0.0925 540 362 4488 >50 0.0472 1059 338 4463 >50 0.0478 1046 363 4489 >50 0.0147 3401 339 4464 >50 0.0303 1650 364 4490 >50 0.0875 571 340 4465 >50 0.0225 2222 365 4491 >50 0.1154 433 341 4466 >50 0.0072 6944 366 4492 >50 0.0150 3333 367 4493 >50 0.0065 7692 392 4521 >50 0.0112 4464 368 4494 >50 0.0341 1466 393 4522 >50 0.0207 2415 369 4495 >50 0.0221 2262 394 4523 >50 0.0111 4504 370 4496 >50 0.0149 3355 395 4524 >50 0.0083 6024 371 4497 >50 0.0133 3759 396 4525 >50 0.0088 5681 372 4498 >50 0.0307 1628 397 4526 >50 0.0130 3846 373 4499 >50 0.0542 922 398 4527 >50 0.0116 4310 374 4500 >50 0.1210 413 399 4528 >50 0.1346 371 375 4501 >50 0.1367 365 400 4529 >50 0.1596 313 376 4502 >50 0.0142 3571 401 4530 >50 0.1113 449 377 4503 >50 0.0107 4672 402 4531 >50 0.1211 412 378 4504 >50 0.0135 3703 403 4532 >50 0.1526 327 379 4505 >50 0.0246 2032 404 4533 >50 0.1569 318 380 4506 >50 0.0221 2262 405 4534 >50 0.0944 529 381 4507 >50 0.0281 1779 406 4535 >50 0.0975 512 382 4508 >50 0.0362 1381 407 4536 >50 0.0874 572 383 4509 >50 0.0209 2392 408 4537 >50 0.0760 657 384 4510 >50 0.0230 2173 409 4538 >50 0.0927 539 385 4511 >50 0.0642 325 410 4539 >50 0.0644 776 386 4513 >50 0.1010 495 411 4540 >50 0.0857 583 387 4515 >50 0.0555 900 412 4541 >50 0.0340 1470 388 4516 >50 0.0735 680 413 4542 >50 0.0374 1336 389 4517 >50 0.0406 1231 414 4543 >50 0.0377 1326 390 4518 >50 0.0507 986 415 4548 >50 0.0131 4545 391 4519 >50 0.0503 994 416 4549 >50 0.0412 1213 417 4550 >50 0.0181 2762 442 4578 >50 0.0260 1923 418 4551 >50 0.0105 4761 443 4579 >50 0.0398 1256 419 4552 >50 0.0422 1184 444 4580 >50 0.0262 1908 420 4553 >50 0.0507 986 445 4582 >50 0.0219 2283 421 4554 >50 0.0646 773 446 4583 >50 0.3602 138 422 4555 >50 0.0238 2100 447 4585 >50 0.2104 237 423 4556 >50 0.0733 682 448 4586 >50 0.2220 225 424 4557 >50 0.0624 801 449 4587 >50 0.1820 274 425 4558 >50 0.0085 5882 450 4588 >50 0.2178 229 426 4559 >50 0.0213 2347 451 4589 >50 0.2904 172 427 4560 >50 0.0107 4672 452 4590 >50 0.1620 308 428 4561 >50 0.0140 3571 453 4591 >50 0.0141 3546 429 4562 >50 0.0240 2083 454 4592 >50 0.0154 3246 430 4563 >50 0.0225 2222 455 4593 >50 0.0235 2127 431 4564 >50 0.0212 2358 456 4594 >50 0.0243 2057 432 4565 >50 0.0083 6024 457 4595 >50 0.0478 1046 433 4566 >50 0.0398 1256 458 4596 >50 0.0639 782 434 4567 >50 0.0375 1333 459 4597 >50 0.0615 813 435 4569 >50 0.0137 3649 460 4598 >50 0.0451 1108 436 4570 >50 0.0202 2475 461 4599 >50 0.0755 662 437 4571 >50 0.0183 2732 462 4600 >50 0.0326 1533 438 4572 >50 0.0195 2564 463 4601 >50 0.0359 1392 439 4573 >50 0.0216 2314 464 4602 >50 0.1597 313 440 4576 >50 0.0175 2857 465 4603 >50 0.0672 744 441 4577 >50 0.0186 2688 466 4604 >50 0.0213 2347 467 4605 >50 0.0210 2380 469 4607 >50 0.0199 2512 468 4606 >50 0.0207 2415 470 4608 >50 0.0264 1893 471 4609 >50 0.0158 3164 496 17460 >50 0.0874 572 472 4610 >50 0.0143 3496 497 17532 >50 0.0238 2100 473 4611 >50 0.0179 2793 498 17533 >50 0.0220 2272 474 4633 >50 0.0168 2976 499 17534 >50 0.0379 1319 475 4634 >50 0.0241 2074 500 1535 >50 0.0467 1070 476 4635 >50 0.0198 2525 501 17545 >50 0.0568 880 477 4636 >50 0.0319 1567 502 17698 >50 0.0406 1231 478 4640 >50 0.0619 807 503 17699 >50 0.0479 1043 479 16781 >50 0.0915 546 504 17700 >50 0.0798 626 480 16789 >50 0.0795 628 505 17773 >50 0.0650 769 481 16797 >50 0.0677 738 506 17774 >50 0.0557 897 482 16928 >50 0.0853 586 507 17775 >50 0.0941 531 483 16930 >50 0.0479 1043 508 17777 >50 0.0525 952 484 17058 >50 0.0180 2777 509 17778 >50 0.0829 603 485 17198 >50 0.0964 518 510 17848 >50 0.0773 646 486 17201 >50 0.0782 639 511 17851 >50 0.0849 588 487 17255 >50 0.0097 5154 512 17854 >50 0.0834 599 488 17261 >50 0.0494 1012 513 17857 >50 0.0618 809 489 17263 >50 0.0444 1126 514 17912 >50 0.0404 1237 490 17347 >50 0.0796 628 515 17913 >50 0.0323 1547 491 17362 >50 0.0246 2032 516 17914 >50 0.0440 1136 492 17363 >50 0.0226 2212 517 17915 >50 0.0879 568 493 17364 >50 0.0512 976 518 17916 >50 0.0898 556 494 17365 >50 0.0363 1377 519 17917 >50 0.0567 881 495 17458 >50 0.0807 619 520 17922 >50 0.0976 512 521 17983 >50 0.0789 633 546 18459 >50 0.0642 778 522 17984 >50 0.0565 884 547 18470 >50 0.0987 506 523 18058 >50 0.0220 2272 548 18483 >50 0.0515 970 524 18059 >50 0.0386 1295 549 18554 >50 0.0494 1012 525 18174 >50 0.0510 980 550 18622 >50 0.0824 606 526 18175 >50 0.0422 1184 551 18711 >50 0.0954 524 527 18176 >50 0.0709 705 552 18712 >50 0.0436 1146 528 18177 >50 0.0637 784 553 18713 >50 0.0729 685 529 18178 >50 0.0761 657 554 18736 >50 0.0803 622 530 18180 >50 0.0743 672 555 18822 >50 0.5052 98 531 18185 >50 0.0620 806 556 18823 >50 0.3795 131 532 18187 >50 0.0826 605 557 18868 >50 0.5509 90 533 18188 >50 0.0748 668 558 18869 >50 0.0465 1075 534 18256 >50 0.0437 1144 559 18870 >50 0.0445 1123 535 18258 >50 0.0859 582 560 18871 >50 0.0740 675 536 18260 >50 0.0645 775 561 18872 >50 0.2988 167 537 18305 >50 0.0927 539 562 18877 >50 0.1359 367 538 18306 >50 0.0422 1184 563 18878 >50 0.1165 429 539 18307 >50 0.0486 1028 564 18882 >50 0.1629 306 540 18308 >50 0.0649 770 565 18893 >50 0.1288 388 541 18309 >50 0.0431 1160 566 18918 >50 0.0459 1089 542 18310 >50 0.0507 986 567 18919 >50 0.0602 830 543 18311 >50 0.0535 934 568 18920 >50 0.0420 1190 544 18327 >50 0.0995 502 569 18921 >50 0.0314 1592 545 18457 >50 0.0901 554 570 18924 >50 0.0800 625 571 18926 >50 0.0639 782 582 19089 >50 0.0751 665 572 18947 >50 0.0396 1262 583 19090 >50 0.0686 728 573 18948 >50 0.0584 856 584 19091 >50 0.1147 435 574 18949 >50 0.0658 759 585 19092 >50 0.0924 541 575 18950 >50 0.0876 570 586 19093 >50 0.2359 211 576 18961 >50 0.0639 782 587 19094 >50 0.0980 510 577 19002 >50 0.0851 587 588 19096 >50 0.0944 529 578 19004 >50 0.0781 640 589 19098 >50 0.0380 1315 579 19058 >50 0.0217 2304 590 19099 >50 0.0471 1061 580 19087 >50 0.0769 650 591 19100 >50 0.0576 868 581 19088 >50 0.0782 639

As described above in Table 188, based on the results of testing the inhibition activity against HDAC1 and HDAC6, it was confirmed that the 1,3,4-oxadiazole triazole derivative compounds of the present invention, stereoisomers thereof, or pharmaceutically acceptable salts thereof exhibit excellent selective inhibitory activity against HDAC6 from about 10 to about 9090 times.

Experimental example 2. Analysis of the effect of HDAC6-specific inhibitor on axonal transport of mitochondria (in vitro)

By analyzing the effect of an HDAC6-specific inhibitor on mitochondrial axonal transport, an experiment was conducted to determine whether the compound represented by Formula I of the present invention selectively inhibits HDAC6 activity and thereby increases acetylation of tubulin, a key substrate of HDAC6, i.e. to show the effect of improving the rate of mitochondrial transport, which is reduced by beta-amyloid treatment in the neuron axon.

From days 17 to 18 (E17-18) of insemination, fetal Sprague-Dawley (SD) rat hippocampal neurons are cultured in an imaging culture container that is coated with extracellular matrix and treated with 1 M amyloid-beta protein fragments. After 24 hours, neurons are treated with the compound on day 8 of in vitro culture. Three hours later, the resulting neurons were treated with MitoTracker Red CMXRos (Life Technologies, NY, USA) for a final five minutes to stain mitochondria. Axonal transport of stained neuronal mitochondria was imaged using a confocal microscope (Leica SP8; Leica microsystems, UK) at one-second intervals for one minute to measure the transport rate of each mitochondria per second using the IMARIS analysis program (BITPLANE, Zurich, Switzerland).

As a result, after establishing a section in which the amyloid-beta-treated group showed a significant decrease in the mitochondrial transport rate compared with the vehicle, this is confirmed for the 1,3,4-oxadiazoletriazole derivative compounds of the present invention, their stereoisomers or their pharmaceutically acceptable salts , where carriers are represented as 100%, beta-amyloid treatment group is represented as 0%, the distribution of connection rate after normalization is presented as *, 0%~50%; **, 50%~100%; ***, >100%.

Table 189 Example Compound Speed distribution (%) Example Compound Speed distribution (%) Carrier - 100% 165 4108 *** Amyloid beta - 0% 166 4109 *** 2 3658 * 167 4110 ** 16 3736 *** 168 4111 ** 18 3738 *** 169 4112 *** 22 3775 * 171 4134 ** 23 3776 *** 172 4135 ** 24 3777 * 173 4136 ** 37 3825 *** 178 4182 ** 38 3826 * 181 4185 *** 39 3827 *** 183 4187 * 40 3828 * 184 4208 ** 49 3838 * 186 4210 * 50 3839 * 193 4232 ** 51 3840 ** 195 4234 *** 52 3841 *** 208 4287 *** 53 3842 ** 210 4289 *** 58 3853 ** 217 4296 ** 59 3854 *** 238 4336 *** 61 3856 *** 239 4337 *** 64 3866 ** 243 4341 ** 65 3867 ** 244 4342 * 68 3881 *** 247 4345 * 70 3883 * 248 4346 *** 73 3886 * 249 4347 * 83 3902 *** 250 4348 ** 84 3914 * 259 4361 ** 86 3916 *** 264 4366 *** 90 3925 *** 268 4370 *** 92 3944 * 269 4371 ** 107 3962 *** 271 4373 *** 115 3986 *** 273 4375 * 116 3987 * 313 4431 *** 119 3990 ** 314 4432 *** 120 3991 ** 486 17201 * 132 4010 *** 492 17363 ** 134 4012 *** 497 17532 *** 135 4013 ** 498 17533 * 144 4052 ** 499 17534 *** 147 4055 * 521 17983 *** 148 4070 ** 523 18058 *** 150 4072 ** 527 18176 ** 151 4073 ** 531 18185 *** 153 4075 *** 538 18306 *** 154 4076 *** 539 18307 *** 157 4079 ** 540 18308 *** 158 4080 *** 541 18309 ** 164 4107 ** 579 19058 ***

Claims (76)

1. The compound represented by the following formula I, its stereoisomers or its pharmaceutically acceptable salts: [Formula I] , where each X ₁ -X ₄ independently represents CA or N; A represents H or halogen; L represents C1-C2 alkylene; R ₁ represents CF ₂ H or CF ₃ ; B represents (as used herein, Y ₁ is CR ₂ or N, Y ₂ and Y ₃ are each independently CR' or N and R' is H or C1-C5 alkyl) or (as used herein, Y ₁ is O or NR ₂ ); R ₂ represents H or C1-C5 alkyl, wherein in C1-C5 alkyl at least one H may be replaced by OH or N(C1-C5 alkyl) ₂ ; R ₃ represents halogen; C1-C5 alkyl; (as used herein, a, b and c independently represent 0, 1, 2 or 3, where a and b cannot be 0 at the same time, and Z ₁ represents CH ₂ , NH or O); C4-C6 cycloalkenyl; C6-C12 aryl; 5-9 membered heteroaryl, including at least one heteroatom selected from N, O and S; (as used herein, each a or b is independently an integer 1 or 2); ; (as used herein, a is an integer 0, 1 or 2); or pyridinone; at least one H of R ₃ may each be independently substituted with halogen or -(CH ₂ ) _n -Q1-Q2-Ra (n is 0 or 1 herein); Q1 is a single bond, -SO ₂ -, -NH-, -N(C1-C5 alkyl)-, -NHC(=O)-, -N(C1-C5 alkyl)C(=O)- or -C (=O)-; Q2 represents a single bond, C1-C5 alkylene, -NH- or -N(C1-C5 alkyl)-; Ra represents OH; C1-C5 alkyl; C1-C5 haloalkyl; -NR ₄ R ₅ (herein, each R ₄ and R ₅ independently represents H or C1-C5 alkyl); C1-C5 alkoxy; (as used herein, a and b are each independently 1 or 2, M ₁ is CH ₂ , O, NH or SO ₂ and M ₂ is CH or N); (herein M ₃ represents CH or N); diazabicycloheptane; or 5- or 6-membered heteroaryl, including 1-3 of N; And at least one H of Ra may each be independently substituted with OH; halogen; C1-C5 alkyl; (as used herein, a and b are each independently 0 or 1 but cannot be 0 at the same time, c is 0 or 1, M ₄ is CH ₂ , NH or O, and at least one H of M ₄ may be substituted halogen, C1-C5 alkyl, C3-C6 cycloalkyl or -C(=O)-O(C1-C5 alkyl)); -NR ₆ R ₇ (herein, each R ₆ and R ₇ independently represents H or C1-C5 alkyl); -C(=O)-(C1-C5 alkyl); C(=O)-O(C1-C5 alkyl); or -NH-C(=O)-O(C1-C5 alkyl). 2. The compound represented by formula I, its stereoisomers or pharmaceutically acceptable salts thereof according to claim 1, characterized in that the compound represented by the above formula I is a compound represented by formula II [Formula II] , where X ₁ -X ₄ , L, R ₁ , R ₃ and Y ₁ -Y ₃ are as defined in formula I according to claim 1. 3. The compound represented by formula I, its stereoisomers or its pharmaceutically acceptable salts according to claim 2, characterized in that in formula II: each X ₁ -X ₄ independently represents CA or N; A represents H or halogen; L represents C1-C2 alkylene; R ₁ represents CF ₂ H or CF ₃ ; Y ₁ represents CH or N; R ₃ represents phenyl; 6- or 9-membered heteroaryl, including at least one heteroatom selected from N and O; or pyridinone; at least one H of R ₃ may each be independently substituted with halogen or -(CH ₂ ) _n -Q1-Q2-Ra (n is 0 or 1 herein); Q1 is a single bond, -NH-, -NHC(=O)- or -C(=O)-; Q2 represents a single bond or -N(C1-C5 alkyl)-; Ra represents C1-C5 alkyl; C1-C5 haloalkyl; -NR ₄ R ₅ (herein, each R ₄ and R ₅ independently represents H or C1-C5 alkyl); C1-C5 alkoxy; (as used herein, a and b are each independently 1 or 2, M ₁ is CH ₂ , O, NH or SO ₂ and M ₂ is CH or N); or (herein M ₃ represents CH or N); And at least one H of Ra may each be independently substituted with C1-C5 alkyl; (as used herein, a and b are each independently 0 or 1 but cannot be 0 at the same time, c is 0 or 1, M ₄ is CH ₂ , NH or O, and at least one H of M ₄ may be substituted halogen or C1-C5 alkyl); -NR ₆ R ₇ (herein, each R ₆ and R ₇ independently represents H or C1-C5 alkyl); or -NH-C(=O)-O(C1-C5 alkyl). 4. The compound represented by formula I, its stereoisomers or its pharmaceutically acceptable salts according to claim 2, characterized in that in formula II: each X ₁ -X ₄ independently represents CA or N; A represents H or halogen; L represents C1-C2 alkylene; R ₁ represents CF ₂ H; Y ₁ represents CH; R ₃ represents phenyl; or 9-membered heteroaryl, including at least one of N; at least one H of R ₃ may each be independently substituted with -(CH ₂ ) _n -Q1-Ra (n is 0 or 1 herein); Q1 represents a single bond, NH or -NHC(=O)-; Ra represents (herein, each a and b independently represents 1 or 2, M ₁ represents CH ₂ , O or NH and M ₂ represents N) or C1-C5 haloalkyl; And at least one H of Ra may each be independently substituted with C1-C5 alkyl. 5. A compound, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that the compound is a compound selected from the group consisting of the following compounds: 6. A pharmaceutical composition having inhibitory activity against histone deacetylase 6 (HDAC6), containing as an effective ingredient a therapeutically effective amount of a compound according to any one of claims. 1-5, stereoisomers thereof or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. 7. The pharmaceutical composition according to claim 6, characterized in that the pharmaceutical composition is used for the prevention or treatment of diseases mediated by histone deacetylase (HDAC). 8. The pharmaceutical composition according to claim 7, characterized in that diseases mediated by histone deacetylase (HDAC) are infectious diseases; neoplasm; endocrinopathies, nutritional and metabolic disorders; mental and behavioral disorders; neurological diseases; diseases of the eyes and ocular appendages; circulatory diseases; respiratory diseases; digestive problems; diseases of the skin and subcutaneous tissue; diseases of the musculoskeletal system and connective tissue; or teratosis, deformations and chromosomal aberrations. 9. The pharmaceutical composition according to claim 8, characterized in that the endocrinopathy, nutritional and metabolic diseases are Wilson's disease, amyloidosis or diabetes; mental and behavioral disorders are depression or Rett syndrome; the neurological diseases are central nervous system atrophy, neurodegenerative disease, movement disorder, neuropathy, motor neuron disease or demyelinating disease of the central nervous system; diseases of the eyes and ocular appendages are uveitis; diseases of the skin and subcutaneous tissue are psoriasis; diseases of the musculoskeletal system and connective tissue are rheumatoid arthritis, osteoarthritis or systemic lupus erythematosus; teratoses, deformations and chromosomal aberrations represent autosomal dominant polycystic kidney disease; infectious diseases are prion diseases; the neoplasm is a benign tumor or a malignant tumor; diseases of the circulatory system are atrial fibrillation or stroke; respiratory diseases are asthma; and digestive problems are alcoholic liver disease, inflammatory bowel disease, Crohn's disease or peptic ulcer disease. 10. A method of inhibiting histone deacetylase 6, comprising administering a therapeutically effective amount of a compound according to any one of claims. 1-5, its stereoisomers or its pharmaceutically acceptable salts to the subject. 11. Use of the compound according to any one of paragraphs. 1-5, its stereoisomers or pharmaceutically acceptable salts thereof for inhibiting histone deacetylase 6. 12. Use of the compound according to any one of paragraphs. 1-5, its stereoisomers or pharmaceutically acceptable salts thereof in the preparation of a medicament for inhibiting histone deacetylase 6.