KR20240035172A - 1,3,4-Oxadiazole Derivative Compounds as Histone Deacetylase 6 Inhibitor, and Uses thereof - Google Patents

Abstract

The present invention relates to a novel compound having histone deacetylase 6 (HDAC6) inhibitory activity, a method of producing the same, and a use thereof.
The novel compound according to the present invention, its stereoisomer or its pharmaceutically acceptable salt has histone deacetylase 6 (HDAC6) inhibitory activity and is effective in treating cancer, inflammatory diseases, autoimmune diseases, neurological or neurodegenerative diseases. It is effective in preventing or treating HDAC6-related diseases, including diseases.

Description

1,3,4-Oxadiazole Derivative Compounds as Histone Deacetylase 6 Inhibitor, and Uses thereof}

The present invention relates to a 1,3,4-oxadiazole derivative compound with a new structure having histone deacetylase 6 (HDAC6) inhibitory activity, a method of producing the same, and a use thereof.

In cells, post-translational modifications such as acetylation are very important regulatory modules at the heart of biological processes and are tightly controlled by multiple enzymes. Histones are central proteins that make up chromatin, and they serve as an axis around which DNA is wound, helping in condensation of DNA. Additionally, the balance between acetylation and deacetylation of histones plays a very important role in gene expression.

Histone deacetylases (HDACs) are enzymes that remove acetyl groups from lysine residues of histone proteins that make up chromatin, and are related to gene silencing, cell cycle arrest, and angiogenesis. It is known to induce suppression, immunomodulation, and cell death (Hassig et al., Curr. Opin. Chem. Biol. 1997, 1, 300-308). In addition, inhibition of HDAC enzyme function has been reported to induce cancer cell death by reducing the activity of cancer cell survival-related factors and activating cancer cell death-related factors in vivo (Warrell et al, J. Natl. Cancer Inst. 1998 , 90, 1621-1625).

In humans, 18 HDACs are known and are classified into 4 groups according to homology with yeast HDACs. At this time, the 11 HDACs that use zinc as a cofactor are Class I (HDAC1, 2, 3, 8), Class II (IIa: HDAC4, 5, 7, 9; IIb: HDAC6, 10), and Class IV (HDAC11). It can be divided into three groups. Additionally, seven HDACs of Class III (SIRT 1-7) use NAD+ as a cofactor instead of zinc (Bolden et al., Nat. Rev. Drug Discov. 2006, 5(9), 769-784).

Although various HDAC inhibitors are in preclinical or clinical development, only non-selective HDAC inhibitors are currently known as anticancer drugs, and vorinostat (SAHA) and romidepsin (FK228) are treatments for cutaneous T-cell lymphoma. Panobinostat (LBH-589) is approved for the treatment of multiple myeloma. However, non-selective HDACs inhibitors are generally known to cause side effects such as fatigue and vomiting at high doses (Piekarz et al., Pharmaceuticals 2010, 3, 2751-2767). It has been reported that these side effects are due to the inhibition of class I HDACs, and due to these side effects, non-selective HDACs inhibitors have been limited in drug development in fields other than anticancer drugs (Witt et al., Cancer Letters 277, (2009) , 8-21).

Meanwhile, it has been reported that in the case of selective class II HDAC inhibition, the toxicity seen in class I HDAC inhibition will not be observed, and if a selective HDAC inhibitor is developed, side effects such as toxicity due to non-selective HDAC inhibition will be resolved. Selective HDAC inhibitors have the potential to be developed as effective treatments for various diseases (Matthias et al., Mol. Cell. Biol. 2008, 28, 1688-1701).

HDAC6, one of the Class IIb HDACs, mainly exists in the cytoplasm and is known to be involved in the deacetylation of many non-histone substrates (HSP90, cortactin, etc.), including tubulin proteins (Yao et al., Mol. Cell 2005, 18, 601-607). HDAC6 has two catalytic domains, and the zinc finger domain at the C-terminus can bind to ubiquitinated proteins. Since HDAC6 has many non-histone proteins as substrates, it is involved in various diseases such as cancer, inflammatory diseases, autoimmune diseases, neurological diseases, and neurodegenerative disorders. It is known to play an important role in (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).

Common structural features of various HDAC inhibitors consist of a cap group, linker group, and zinc-binding group (ZBG), as shown in the structure of vorinostat below. Many researchers have conducted studies on the inhibitory activity and selectivity of enzymes through structural modification of the cap group and linker group. Among these, the zinc-binding group is known to play a more important role in enzyme inhibitory activity and selectivity (Wiest et al., J. Org. Chem. 2013 78: 5051-5055; Methot et al., Bioorg. Med. Chem. Lett. 2008, 18, 973-978).

Most of the zinc-binding groups are hydroxamic acid or benzamide, of which hydroxamic acid derivatives exhibit a strong HDAC inhibitory effect, but have low bioavailability and severe off-target activity. -target activity) problem. In the case of benzamide, because it contains aniline, there is a problem that toxic metabolites can be generated in vivo (Woster et al., Med. Chem. Commun. 2015, online publication).

Accordingly, unlike non-selective inhibitors that have side effects for the treatment of cancer, inflammatory diseases, autoimmune diseases, neurological diseases, and neurodegenerative disorders, There is a need to develop a selective HDAC6 inhibitor with a zinc-binding group with improved bioavailability and no side effects.

International Publication of Patent No. WO 2011/091213 (published on July 28, 2011): ACY-1215 International Patent Publication No. WO 2011/011186 (published on January 27, 2011): Tubastatin International Patent Publication No. WO 2013/052110 (published on April 11, 2013): Sloan-K International Publication of Patent No. WO 2013/041407 (published March 28, 2013): Cellzome International Publication of Patent No. WO 2013/134467 (published on September 12, 2013): Kozi International Patent Publication No. WO 2013/008162 (published on January 17, 2013): Novartis International Patent Publication No. WO 2013/080120 (published on June 6, 2013): Novartis International Patent Publication WO 2013/066835 (published May 10, 2013): Tempero International Patent Publication WO 2013/066838 (published May 10, 2013): Tempero International Patent Publication WO 2013/066833 (published May 10, 2013): Tempero International Patent Publication WO 2013/066839 (published May 10, 2013): Tempero

The object of the present invention is to provide a compound having selective HDAC6 inhibitory activity, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

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

Another object of the present invention is to provide a method for producing the same.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating diseases related to HDAC6 activity.

Another object of the present invention is to provide its use for the production of a medicament for the prevention or treatment of diseases related to HDAC6 activity.

Another object of the present invention is to provide a method for preventing or treating diseases related to HDAC6 activity, comprising administering a therapeutically effective amount of the above compounds.

Another object of the present invention is to provide a preventive or therapeutic use for diseases related to HDAC6 activity.

The present inventors completed the present invention by discovering an oxadiazole derivative compound with histone deacetylase 6 (HDAC6) inhibitory activity and using it to inhibit or treat diseases related to HDAC6 activity.

This will be explained in detail below. All combinations of the various elements disclosed herein fall within the scope of the present invention. Additionally, the scope of the present invention cannot be considered limited by the specific description below.

1,3,4-oxadiazole derivative compounds

In accordance with the above object, the present invention provides a 1,3,4-oxadiazole derivative compound represented by the following formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula I]

In Formula I above,

R ₁ is -C _1-4 haloalkyl;

X ₁ to X ₄ are each independently _CR

R _X is -H, -C _1-4 alkyl, -C _1-4 haloalkyl, or -halo;

Y is CR _Y or N;

_RY is -H or -C _1-4 alkyl;

Z is NR _Z , O, or S;

R _Z is -H or -C _1-4 alkyl;

W is O or S;

m is 0 or 1;

Ring V is aryl, heteroaryl, or hydroheteroaryl {wherein one or more H of the aryl, heteroaryl, or hydroheteroaryl ring is -C _1-4 alkyl, -C _1-4 aminoalkyl, -C _{1 -4} hydroxyalkyl, -C _1-4 haloalkyl, -halo, -(CH ₂ )n-cycloalkyl, -(CH ₂ )n-heterocycloalkyl, or -(CH ₂ )n-heteroaryl. [In this case, at least one H of the -(CH ₂ )n-cycloalkyl, -(CH ₂ )n-heterocycloalkyl, or -(CH ₂ )n-heteroaryl ring is -C _1-4 alkyl. , -C _1-4 haloalkyl, -halo, cycloalkyl, or heterocycloalkyl (wherein one or more H of the cycloalkyl or heterocycloalkyl ring may be substituted with -C _1-4 alkyl) )]};

n is 0, 1, or 2.

According to an embodiment of the present invention, the compound represented by formula (I) of the present invention may be in the following range:

R ₁ is -C _1-4 haloalkyl;

X ₁ is N;

X ₂ to X ₄ are each independently _CR

_R

Y is CR _Y or N;

R _Y is -H;

Z is NR _Z , O, or S;

R _Z is -C _1-4 alkyl;

W is O or S;

m is 0 or 1;

Ring V is aryl, heteroaryl, or hydroheteroaryl {wherein one or more H of the aryl, heteroaryl, or hydroheteroaryl ring is -C _1-4 alkyl, -C _1-4 aminoalkyl, -halo, -(CH ₂ )n-cycloalkyl, -(CH ₂ )n-heterocycloalkyl, or -(CH ₂ )n-heteroaryl [In this case, the -(CH ₂ )n-cycloalkyl, -(CH ₂ )n-heterocycloalkyl, or -(CH ₂ )n-heteroaryl One or more H of the ring may be substituted with -C _1-4 alkyl, -halo, cycloalkyl, or heterocycloalkyl ( above, one or more H of the cycloalkyl or heterocycloalkyl ring may be substituted with -C _1-4 alkyl)]};

n is 0 or 1.

Also, according to an embodiment of the present invention, the compound represented by Formula I of the present invention may be in the following range:

R ₁ is -CF ₂ H or -CF ₃ .

Also, according to an embodiment of the present invention, the compound represented by Formula I of the present invention may be in the following range:

X is CH or CF.

Also, according to an embodiment of the present invention, the compound represented by Formula I of the present invention may be in the following range:

Y is CH or N;

Z is NC _1-4 alkyl, O, or S;

W is O or S;

m is 0 or 1.

Also, according to an embodiment of the present invention, the compound represented by Formula I of the present invention may be in the following range:

Ring V is phenyl, 5-10 membered heteroaryl, or 9-10 membered hydroheteroaryl {wherein at least one H of the phenyl, 5-10 membered heteroaryl, or 9-10 membered hydroheteroaryl ring is -C _1-4 alkyl, -C _1-4 aminoalkyl, -halo, -(CH ₂ )n-cycloalkyl, -(CH ₂ )n-heterocycloalkyl, or -(CH ₂ )n-heteroaryl. [In this case, one or more H of the -(CH ₂ )n-cycloalkyl, -(CH ₂ )n-heterocycloalkyl, or -(CH ₂ )n-heteroaryl ring is -C _1-4 alkyl, -Can be substituted with halo, 4-6 membered cycloalkyl, or 4-6 membered heterocycloalkyl (wherein one or more H of the 4-6 membered cycloalkyl or 4-6 membered heterocycloalkyl ring is -C _{1- 4} may be substituted with alkyl)]};

n is 0 or 1.

In addition, according to an embodiment of the present invention, specific compounds represented by Formula I of the present invention are shown in Table 1 below:

[Table 1]

In the present invention, “alkyl”, unless otherwise specified, may mean a straight-chain or branched-chain acyclic, cyclic, or saturated hydrocarbon in which these are combined. For example, “C _1-4 alkyl” can mean alkyl containing 1 to 4 carbon atoms. Acyclic alkyl may include, for example, methyl, ethyl, n -propyl, n -butyl, isopropyl, sec )-butyl, isobutyl, or tertiary ( tert )-butyl, etc. It is not limited to this. Cyclic alkyl may be used interchangeably with “cycloalkyl” herein and may include, but is limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, as examples. It doesn't work.

In the present invention, “alkoxy” may mean -(O-alkyl) as an alkyl ether group, where alkyl is as defined above. For example, “C _1-4 alkoxy” may mean alkoxy containing C _1-4 alkyl, that is, -(OC _1-4 alkyl). As an example, alkoxy is methoxy (methoxy). ), ethoxy , n -propoxy, isopropoxy, n -butoxy , isobutoxy , sec -butoxy ), or tert -butoxy, etc., but is not limited thereto.

In the present invention, “halo” may be F, Cl, Br, or I.

In the present invention, “haloalkyl” may mean a straight or branched chain alkyl (hydrocarbon) having carbon atoms substituted with one or more halo as defined herein. Examples of such haloalkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, or n-butyl independently substituted with one or more halogens, such as F, Cl, Br, or I. .

In the present invention, “hydroxyalkyl” may mean straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with -OH. Examples of the hydroxyalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, or n-butyl independently substituted with one or more hydroxy.

In the present invention, "aminoalkyl" may mean a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with amino-(NR'R"). Here, R' and R" are each independently It may be selected from the group consisting of hydrogen, and C _1-4 alkyl, and the selected R' and R" may each independently be substituted or unsubstituted.

In the present invention, “heterocycloalkyl” may mean a ring containing 1 to 5 heteroatoms selected from N, O, and S as ring-forming atoms, and may be saturated or partially unsaturated. Here, when unsaturated, it may be referred to as a heterocycloalkene. Unless otherwise stated, heterocycloalkyl may be a single ring or multiple rings such as spiro rings, bridged rings, or fused rings. In addition, “heterocycloalkyl of 3 to 12 atoms” may mean heterocycloalkyl containing 3 to 12 atoms forming a ring. As an example, heterocycloalkyl includes pyrrolidine, piperidine, Imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4 (1 H , 3 H ) -Dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine- S -oxide, thiomorpholine- S , S -oxide , piperazine, pyran, pyridone, 3-pyrroline , thiophyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1 R ,5 S )-3-azabicyclo[3.2.1 ]Including octane, (1 s ,4 s )-2-azabicyclo[2.2.2]octane, or (1 R ,4 R )-2-oxa-5-azabicyclo[2.2.2]octane, etc. It can be done, but is not limited to this.

In the present invention, “arene” may mean an aromatic hydrocarbon ring. The arenes may be monocyclic arenes or polycyclic arenes. The number of ring-forming carbon atoms of the arene may be 5 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less. Examples of arenes include benzene, naphthalene, fluorene, anthracene, phenanthrene, bibenzene, terbenzene, quarterbenzene, quincbenzene, sexybenzene, triphenylene, pyrene, benzofluoranthene, chrysene, etc. , but is not limited to these. In this specification, the residue obtained by removing one hydrogen atom from the “arene” is referred to as “aryl.”

In the present invention, “heteroarene” may be a ring containing one or more of O, N, P, Si, and S as a heterogeneous element. The number of ring-forming carbon atoms of the heteroarene may be 2 to 30 or 2 to 20. The heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene. Polycyclic heteroarene may have, for example, a 2-ring or 3-ring structure. Examples of heteroarenes include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, bipyridyl, triazine, acridyl, and pyridazine. , pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyrido pyrimidine, pyrido pyrazine, pyrazino pyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine. , imidazopyrimidine, pyrazolopyrimidine, imidazopyrazine or pyrazolopyridine, N -arylcarbazole, N -heteroarylcarbazole, N -alkylcarbazole, benzoxazole, benzoimidazole, benzothiazole , benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenothiazine , dibenzosilol, and dibenzofuran, etc., but are not limited to these. In one embodiment of the invention, heteroarenes may also include bicyclic heterocyclo-arenes, including an arene ring fused to a heterocycloalkyl ring or a heteroarene fused to a cycloalkyl ring. In this specification, the residue obtained by removing one hydrogen atom from the “heteroarene” is referred to as “heteroaryl.”

The compound represented by formula (I) of the present invention may contain one or more asymmetric carbons, and thus may exist as a racemate, a racemic mixture, a single enantiomer, a diastereomeric mixture, and individual diastereomers. there is. These stereoisomers can be separated using conventional techniques, for example, the compound represented by Formula I can be separated by column chromatography or HPLC. Alternatively, each stereoisomer of the compound represented by Formula I can be stereospecifically synthesized using a known array of optically pure starting materials and/or reagents.

In the present invention, the term “enantiomer” refers to a compound of the present invention or a salt thereof that has the same chemical or molecular formula but is sterically different. Each of these optical isomers and mixtures thereof are also included within the scope of the present invention. Unless otherwise stated, the solid bond (-) connecting an asymmetric carbon atom is a solid wedge bond indicating the absolute configuration of the stereocenter. or wedge-dotted join may include.

The compound of Formula 1 of the present invention may exist in the form of a “pharmaceutically acceptable salt.” As a salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The term “pharmaceutically acceptable salt” of the present invention refers to any of the compounds at a concentration that is relatively non-toxic and harmless to patients and has an effective effect, where side effects due to the salt do not reduce the beneficial efficacy of the compound represented by Formula 1. refers to all organic or inorganic acid addition salts.

Acid addition salts are prepared by conventional methods, for example, by dissolving the compound in an excess of aqueous acid solution and precipitating the salt using a water-miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. Equimolar amounts of the compound and acid or alcohol in water can be heated, and the mixture can then be evaporated to dryness, or the precipitated salt can be filtered off with suction.

At this time, organic acids and inorganic acids can be used as free acids. Hydrochloric acid, phosphoric acid, sulfuric acid, or nitric acid can be used as inorganic acids, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, etc. can be used as organic acids. Maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, glue Gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, or hydroiodic acid, etc. can be used. However, it is not limited to these.

Additionally, a pharmaceutically acceptable metal salt can be prepared using a base. The alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare metal salts, especially sodium, potassium, or calcium salts, but is not limited to these. Additionally, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with an appropriate silver salt (e.g., silver nitrate).

Pharmaceutically acceptable salts of the present invention include salts of acidic or basic groups that may be present in the compound of formula (1), unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group may include hydrobromide, sulfate, hydrogen sulfate, phosphate, Hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p-toluenesulfonate (tosylate) salts are known in the art. It can be produced through a known salt production method.

Method for producing 1,3,4-oxadiazole derivative compounds

The present invention provides a method for producing a 1,3,4-oxadiazole derivative compound represented by the following formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula I]

The formula (I) is as defined above.

In the present invention, the preferred method for producing the oxadiazole derivative compound represented by the formula (I), its stereoisomer, or its pharmaceutically acceptable salt is as shown in [Scheme 1] to [Scheme 4] below, and is obvious to those skilled in the art. This includes manufacturing methods that have been modified to the same level.

[Scheme 1]

According to Scheme 1, compound 1-2 was prepared by adding hydrazine to compound 1-1, reacted with trifluoroacetic anhydride or difluoroacetic anhydride to prepare compound 1-3, and then subjected to bromination reaction. Compound 1-4 is synthesized. Compound 1-4 is the Zn-Binder portion of the HDAC 6 inhibitor and is used as an intermediate in the synthesis of all compounds.

[Scheme 2]

According to Scheme 2, Compound 2-1 was prepared using hydrazine, and then 1,3,4-oxadiazol-2(3H)-one and potassium ethylxanthate were prepared using CDI. 1,3,4-oxadiazole-2(3H)-thion compound 2-4 is prepared using. In addition, after adding Lawesson's reagent to compound 2-2 to prepare compound 2-3, 1,3,4-thiadiazol-2(3H)-one compound 2-4 can be prepared using CDI. . Compound 2-5 is prepared through a substitution reaction between compound 2-4 and compound 1-4. Compound 2-5 prepared according to Scheme 2, 18849, 19358, 19529, 19530, 19542, 19543, 19793, 19839, 19844, 19846, 19847, 19849, 19863, 19927, 19928, 199 68, 19970, 20012, 20017, It may be 20018, 20020, 20023, etc.

[Scheme 3]

In Scheme 3, compound 3-2 is prepared through a reductive amination reaction of compound 3-1 having an aldehyde structure, compound 3-3 is prepared using hydrazine, and then compound 3-3 is synthesized using CDI. -Oxadiazol-2(3H)-one Compound 3-4 is prepared. Afterwards, compound 3-5 can be prepared through a substitution reaction with compound 1-4. Compounds 3-5 prepared according to Scheme 3 include compounds 19331 and 19060.

[Reaction Scheme 3-1]

In Scheme 3-1, dioxolane compound 3-1-1, which protects the aldehyde structure of compound 3-1, is prepared using ethylene glycol, and then compound 3-1-2 is prepared using hydrazine. Then, 1,3,4-oxadiazole-2(3H)-one using CDI and 1,3,4-oxadiazole-2(3H)-thion compound using potassium et?Kxanthate. Produce 3-1-3. Afterwards, compound 3-1-4 is prepared through a substitution reaction with compound 1-4, and dioxolane, an aldehyde protecting group, is removed using iron (III) chloride hexahydrate to prepare compound 3-1-5. Afterwards, compound 3-5 can be prepared through a reductive amination reaction. Compound 3-5 prepared according to Scheme 3-1, 20468, 20469, 20470, 20471, 20472, 20473, 20474, 20528, 20529, 20530, 20531, 20532, 20533, 20534, 20535, 2 0536, 20616, 20617, 20618, 20619, 20620, 20669, 20670, 20678, 20757, 20758, 20759, 20760, 20766, 20767, 20768, 20769, 20770, 20861, 20862, 2086 3, 20873, 20877, 20878, 20965, etc.

[Reaction Scheme 3-2]

In Scheme 3-2, compound 3-2-1 is prepared through a reductive amination reaction of compound 3-1 having an aldehyde structure, compound 3-2-2 is prepared using hydrazine, and then CDI is used. Prepare 1,3,4-oxadiazole-2(3H)-thion compound 3-2-4 using 1,3,4-oxadiazole-2(3H)-one and potassium ethylxanthate. do. In addition, after preparing compound 3-2-2 using Lawesson reagent, 1,3,4-thiadiazol-2(3H)-one compound 3-2 was obtained using CDI. Produce -4. Afterwards, compound 3-2-5 was prepared using a substitution reaction with compound 3-2-4 and compound 1-4, and compound 3-2-6 was prepared by removing the amine protecting group, followed by reductive amination. Compound 3-2-7 is prepared through reaction. Compound 3-2-7 prepared according to Scheme 3-2 includes 20096, 20097, 20098, 20099, 20100, 20101, 20373, 20374, 20375, 20376, 20443, etc.

[Scheme 4]

In Scheme 4, compound 4-2 is prepared from ester compound 4-1 with a halogen element through a C-C coupling reaction, and then compound 4-3 is prepared through a reduction reaction. Additionally, compound 4-3 is prepared from compound 4-1 through C-N coupling (Buchwald-raction) and substitution reaction. Thereafter, compound 4-4 was prepared using hydrazine, 1,3,4-oxadiazol-2(3H)-one using CDI, and 1,3,4-oxadiazol-one using potassium ethylxanthate. Sol-2(3H)-thion compound 4-6 is prepared. Additionally, compound 4-5 is prepared from compound 4-4 using Lawesson's reagent, and then 1,3,4-thiadiazol-2(3H)-one compound 4-6 is prepared using CDI. Thereafter, compound 4-7 is prepared through a substitution reaction with compound 1-4, and compound 4-8 prepared by removing the amine protecting group includes compounds 19557, 19561, and 19652. Additionally, compound 4-9 can be prepared through a reductive amination reaction. Compound 4-9 prepared according to Scheme 4, Compound 19458, 19459, 19460, 19558, 19559, 19562, 19563, 19653, 19654, 19655, 19656, 19616, 19619, 19620, 19682, 2 0013, 20014, 20015, Examples include 20016, 20366, 20367, 20377, 20378, 20566, 20567, 20568, 20569, 20570, 20575, 20576, 20754, 20755, 20785, 20786, etc.

In addition, compound 4-8 prepared according to Scheme 4 was subjected to a reductive amination reaction to prepare compound 4-10, and the amine protecting group was removed to prepare compound 4-11, followed by a reductive amination reaction. Compound 4-12 can be prepared. Examples of the compound 4-12 include compounds 19617 and 19618.

[Reaction Scheme 4-1]

Scheme 4-1 shows that ester compound 4-1 with a halogen element is prepared using hydrazine to prepare compound 4-2, and 1,3,4-oxadiazol-2(3H)-one compound 4 is prepared using CDI. Produce -3. Afterwards, compound 4-4 is prepared through a substitution reaction with compound 1-4, and compound 4-9 is prepared through an amine substitution reaction. Compounds prepared according to Scheme 4-1 may be 19454, 19455, etc.

[Scheme 5]

In Scheme 5, compound 5-2 is prepared from compound 5-1 containing an amine through an amine protecting group and alkylation, compound 5-3 is prepared using hydrazine, and then compound 5-3 is prepared using CDI. 1,3,4-oxadiazole-2(3H)-thion compound 5-4 is prepared using 3,4-oxadiazole-2(3H)-one and potassium ethylxanthate. Afterwards, compound 5-5 is prepared through a substitution reaction with compound 1-4. Compound 5-5 prepared according to Scheme 5 includes compounds 19544, 19632, and 19633.

In addition, compound 5-6 can be prepared by removing the amine protecting group of compound 5-5 prepared according to Scheme 5, and examples of compound 5-6 include compounds 19204, 19469, 19642, 19645, and 19647.

Afterwards, compounds 5-7 are prepared through a reductive amination reaction. Compounds 5-7 prepared according to Scheme 5 include compounds 19497, 19498, 19499, 21116, 21117, 21118, 21120, 21133, 21134, 21135, etc.

[Scheme 6]

In Scheme 6, acetate compound 6-2 is prepared through a substitution reaction of bromo compound 6-1, hydrazine carboxylate compound 6-3 is prepared through a substitution reaction, and then sodium ethylate is used to prepare acetate compound 6-2. , 4-oxadiazin-2-one compound 6-4 is prepared. Afterwards, compound 6-5 is prepared through a substitution reaction with compound 1-4. Compound 6-5 prepared according to Scheme 6 includes compounds 20137, 20138, 20146, 20147, 20148, 20352, etc.

[Scheme 7]

Scheme 7 shows that compound 7-2 is protected with the amine protecting group of compound 7-1, triple bond compound 7-4 is prepared through a substitution reaction with compound 7-3, and silver bis (trifluoromethane sulfur) is prepared. Oxazol-2(3H)-one compound 7-5 is prepared using ponyl)imide. Thereafter, Compound 7-6 can be prepared using hydrazine, and then reacted with trifluoroacetic anhydride or difluoroacetic anhydride to prepare Compound 7-7. Compounds prepared according to Scheme 7 may be 16974, 17195, etc.

[Scheme 8]

In Scheme 8, compound 8-2 can be prepared through a substitution reaction of imidazol-2-one compound 8-1 with compound 1-4. The compound prepared by Scheme 8 may be 17738, etc.

Uses of 1,3,4-oxadiazole derivative compounds

The present invention provides the use of a compound represented by the following formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula I]

The formula (I) is as defined above.

According to one embodiment of the present invention, the present invention provides a pharmaceutical composition comprising the compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, according to one embodiment of the present invention, the present invention provides a histone deacetylase 6 (Histone deacetylase) comprising the compound represented by Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. 6) Provides a pharmaceutical composition for preventing or treating an activity-related disease. The pharmaceutical composition of the present invention shows a significant effect in preventing or treating diseases related to histone deacetylase 6 activity by selectively inhibiting histone deacetylase 6.

Diseases related to the activity of the histone deacetylase 6 include cancer, inflammatory diseases, autoimmune diseases, and neurological or degenerative diseases, specifically, lung cancer, colon cancer, breast cancer, prostate cancer, and liver cancer. , brain cancer, ovarian cancer, stomach cancer, skin cancer, pancreatic cancer, glioma, neuroblastoma, 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, and also includes symptoms or diseases related to the abnormal function of histone deacetylase.

According to one embodiment of the present invention, examples of the histone deacetylase enzyme-mediated diseases include infectious diseases; neoplasm; Endocrine, nutritional and metabolic diseases; mental and behavioral disorders; neurological disease; eye and appendage diseases; circulatory diseases; Respiratory diseases; digestive diseases; Skin and subcutaneous tissue diseases; Musculoskeletal and connective tissue diseases; Or congenital abnormalities, deformities, and chromosomal abnormalities. In addition, it includes symptoms or diseases related to abnormal function of histone deacetylase 6.

In the present invention, the infectious disease may be prion disease. In addition, the neoplasms may be benign tumors (e.g., myelodysplastic syndrome) or malignant tumors (e.g., multiple myeloma, lymphoma, leukemia, lung cancer, colon cancer, colon cancer, prostate cancer, urothelial cancer, breast cancer, melanoma, and skin cancer). , liver cancer, brain cancer, stomach cancer, ovarian cancer, pancreatic cancer, head and neck cancer, oral cancer, or glioma). Additionally, the endocrine, nutritional, and metabolic disease may be Wilson's disease, amyloidosis, or diabetes. Additionally, the mental and behavioral disorder may be depression or Rett syndrome. In addition, the above neurological diseases include central nervous system atrophy (e.g., Huntington's disease, spinal muscular atrophy (SMA), spinocerebellar ataxia (SCA)), neurodegenerative disease (e.g., Alzheimer's disease), and movement disorder (e.g., Parkinson's disease). ), neuropathy (e.g., hereditary neuropathy (Charcot-Marie-Tooth disease), sporadic neuropathy, inflammatory neuropathy, drug-induced neuropathy), motor neuron disease (e.g., amyotrophic lateral sclerosis (ALS)), or It may be a demyelinating disease of the central nervous system (e.g., multiple sclerosis (MS)). Additionally, the eye and adnexal disease may be uveitis. Additionally, the circulatory disease may be atrial fibrillation or stroke. Additionally, the respiratory disease may be asthma. Additionally, the digestive disease may be alcoholic liver disease, inflammatory bowel disease, Crohn's disease, or ulcerative bowel disease. Additionally, the skin and subcutaneous tissue disease may be psoriasis. Additionally, the musculoskeletal and connective tissue diseases may be rheumatoid arthritis, osteoarthritis, or systemic lupus erythematosus (SLE). Additionally, the congenital malformations, deformities, and chromosomal abnormalities may be autosomal dominant polycystic new types.

The stereoisomers and pharmaceutically acceptable salts are the same as previously described in the stereoisomers and 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 include one or more pharmaceutically acceptable carriers in addition to the compound represented by Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. At this time, the pharmaceutically acceptable carrier may be saline, sterilized water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and a mixture of one or more of these ingredients, and if necessary, antioxidants. , other common additives such as buffer solutions and bacteriostatic agents can be added. In addition, diluents, dispersants, surfactants, binders, and lubricants can be additionally added to formulate injectable formulations such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules, or tablets. Accordingly, the composition of the present invention may be a patch, solution, pill, capsule, granule, tablet, suppository, etc. These preparations can be manufactured by conventional methods used for formulation in the art or by methods disclosed in Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton PA, and can be formulated into various preparations depending on each disease or ingredient. It can be.

The composition of the present invention can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) depending on the desired method, and the dosage is determined by the patient's weight, age, gender, and health status. , the range varies depending on diet, administration time, administration method, excretion rate, and severity of disease. The daily dosage of the compound represented by Formula I of the present invention is about 1 to 1000 mg/kg, preferably 5 to 100 mg/kg, and can be administered once or in divided doses several times a day.

The pharmaceutical composition of the present invention may further include one or more active ingredients that exhibit the same or similar medicinal efficacy in addition to the compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

According to an embodiment of the present invention, the present invention provides a step of administering a therapeutically effective amount of a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof. Provided is a method for preventing or treating diseases related to histone deacetylase 6 activity, including: The subject may be a mammal, including humans.

The method for preventing or treating diseases related to histone deacetylase 6 activity of the present invention is by administering the compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, before the onset of symptoms. It involves not only dealing with the disease itself, but also inhibiting or avoiding its symptoms. In addition, the method for preventing or treating diseases related to histone deacetylase 6 activity of the present invention includes the compound represented by Formula 1, as well as a therapeutically effective amount of an additional active agent helpful in treating the disease. It may further include administration, and additional active agents may have a synergistic or auxiliary effect with the compound of formula (I).

The term “therapeutically effective amount” used in the present invention refers to the amount of the compound represented by Formula I that is effective in preventing or treating diseases related to histone deacetylase 6 activity. Specifically, “therapeutically effective amount” means an amount sufficient to treat the disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type and severity of the individual, age, gender, type of disease, It can be determined based on factors including the activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, drugs used simultaneously, and other factors well known in the medical field. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with commercially available therapeutic agents. And it can be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can achieve maximum effect with the minimum amount without side effects, and can be easily determined by a person skilled in the art. The administered dose of the pharmaceutical composition of the present invention may be determined by an expert depending on various factors such as the patient's condition, age, gender, and complications. Since the active ingredient of the pharmaceutical composition of the present invention has excellent safety, it can be used at a dose exceeding the determined dosage.

In addition, according to one embodiment of the present invention, the present invention provides a method of selectively inhibiting HDAC6 by administering a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to mammals, including humans. to provide.

According to one embodiment of the present invention, the present invention provides a use of a compound represented by Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

According to one embodiment of the present invention, the present invention also provides a compound represented by the formula (I), a stereoisomer thereof, or a pharmaceutical agent thereof for the production of a medicament for the treatment of diseases related to histone deacetylase 6 activity. Provides acceptable uses of salts. The compound represented by formula (I) for the preparation of a drug can be mixed with acceptable auxiliaries, diluents, carriers, etc., and can be prepared as a complex preparation with other active agents to have a synergistic effect of the active ingredients.

Matters mentioned in the uses, compositions, and treatment methods of the present invention apply equally unless they contradict each other.

The embodiments of the present invention may be modified into various other forms, and the scope of the present invention is not limited to the embodiments described below. Additionally, embodiments of the present invention are provided to more completely explain the present invention to those with average knowledge in the relevant technical field. Furthermore, “including” a certain element throughout the specification means that other elements may be further included, rather than excluding other elements, unless specifically stated to the contrary.

The compound represented by the formula (I) of the present invention, its stereoisomer, or its pharmaceutically acceptable salt can selectively inhibit HDAC6, thereby providing a preventive or therapeutic effect on diseases related to histone deacetylase 6 (Histone deacetylase) activity. is significantly superior.

Hereinafter, the present invention will be described in more detail through examples and experimental examples. However, these examples are only illustrative of the present invention, and the scope of the present invention is not limited to these only.

Preparation of 1,3,4-oxadiazole derivative compounds

The specific manufacturing method of the compound represented by Formula I is as follows.

Example 5: 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(2-thiene Synthesis of 1)-1,3,4-oxadiazol-2-one (19358)

[Step 1] Synthesis of 6-methylnicotinohydrazide

Hydrazine monohydrate (32.151 mL, 661.507 mmol) was added to a solution of methyl 6-methylnicotinate (10.000 g, 66.151 mmol) dissolved in ethanol (200 mL) at room temperature, and stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, water was added to the obtained concentrate, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (8.248 g, 82.5 %, white solid).

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

Triethylamine (38.024 mL, 272.805 mmol) was added to a solution of 6-methylnicotinohydrazide (8.248 g, 54.561 mmol) synthesized in Step 1 in tetrahydrofuran (200 mL) at 0 °C, and added at the same temperature. Stirred for 10 minutes. 2,2-difluoroacetic anhydride (20.349 mL, 163.683 mmol) was added to the reaction mixture and stirred for additional 3 hours at 80°C, and then the temperature was lowered to room temperature to complete the reaction. A saturated aqueous solution of sodium hydrogen carbonate was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 80 g cartridge; ethyl acetate/hexane = 0 % to 50 %) to obtain the title compound (8.019 g, 69.6 %) as a yellow solid.

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

2-(difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole (8.019 g, 37.974 mmol), 1-bromopyrrolidine, synthesized in Step 2 -2,5-one (NBS, 8.110 g, 45.569 mmol) and azobisisobutyronitrile (AIBN, 0.624 g, 3.797 mmol) were dissolved in 1,2-dichloroethane (120 mL) at room temperature. It was stirred at the same temperature for 6 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous ammonium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 80 g cartridge; ethyl acetate/hexane = 0 % to 40 %) to obtain the title compound (3.960 g, 36.0 %) as a brown solid.

[Step 4] Synthesis of thiophene-2-carbohydrazide

Hydrazine monohydrate (100.00 % solution, 1.367 mL, 28.100 mmol) was added to a solution of methyl thiophene-2-carboxylate (100.00 % solution, 0.163 mL, 1.410 mmol) dissolved in ethanol (10 mL) at room temperature and incubated at 60°C. After stirring for 5 hours, the temperature was lowered to room temperature to terminate the reaction. The solvent was removed from the reaction mixture under reduced pressure, and 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, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (0.2 g, 99.8 %, pale yellow solid).

[Step 5] Synthesis of 5-(2-thienyl)-3H-1,3,4-oxadiazol-2-one

Thiophene-2-carbohydrazide (100.00 %, 0.200 g, 1.407 mmol) and 1,1'-carbonylbis-1H-imidazole (100.00 %, 0.274 g, 1.690 mmol) synthesized in step 4 were stored at room temperature. Triethylamine (100.00 % solution, 0.273 mL, 2.000 mmol) was added to the solution dissolved in tetrahydrofuran (10 mL) and stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0 % to 10 %) to obtain the title compound (0.143 g, 60.450 %, pale yellow solid).

[Step 6] Synthesis of compound 19358

5-(2-thienyl)-3H-1,3,4-oxadiazol-2-one (100.00 %, 0.063 g, 0.350 mmol) and potassium carbonate (100.00 %, 0.049 g, 0.494 mmol) was dissolved in N,N-dimethylformamide (2 mL) at room temperature and 2-[6-(bromomethyl)-3-pyridyl]-5-(difluorofluoroethylene) synthesized in step 3. Methyl)-1,3,4-oxadiazole (100.00%, 0.122 g, 0.421 mmol) was added and stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0 % to 10 %), and then the obtained product was again chromatographed (SiO ₂ , 4 g cartridge; Purification and concentration (methanol/dichloromethane = 0% to 10%) gave the title compound (0.036 g, 26.44%, yellow solid).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.34-9.33 (m, 1H), 8.44 (dd, J = 8.2, 2.2 Hz, 1H), 7.65 (dd, J = 4.0, 1.2 Hz, 1H), 7.55- 7.52 (m, 2H), 7.17-7.15 (m, 1H), 6.96 (t, J = 51.6 Hz, 1H), 5.22 (s, 2H); LRMS (ES) m/z 378.7 (M ⁺ +1).

The compounds in Table 2 below were synthesized according to substantially the same method as in Example 5.

[Table 2]

Example 45: 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-phenyl-1,3 , Synthesis of 4-oxadiazole-2(3H)-thion (19844)

[Step 1] Synthesis of benzohydrazine

A solution of methyl benzoate (0.500 g, 2.203 mmol) and hydrazine monohydrate (0.920 mL, 7.308 mmol) dissolved in ethanol (12 mL) at room temperature was heated to reflux for 18 hours, and then the temperature was lowered to room temperature to terminate the reaction. . After removing the solvent from the reaction mixture under reduced pressure, the obtained product was used without further purification (0.500 g, 100.0 %, white solid).

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

Potassium ethylxanthate (100.00 %, 0.589 g, 3.674 mmol) was added to a solution of benzohydrazide (100.00 %, 0.500 g, 3.672 mmol) synthesized in Step 1 in ethanol (12 mL) at room temperature, and then added at the same temperature. It was stirred. After removing the solvent from the reaction mixture under reduced pressure, the precipitated solid was filtered, washed with water, and dried to obtain the title compound (0.45 g, 68.759%) as a light yellow solid.

[Step 3] Synthesis of Compound 19844

5-phenyl-1,3,4-oxadiazole-2(3H)-thion (100.00%, 50.000 mg, 0.281 mmol) synthesized in step 1 was mixed with N,N-dimethylformamide (2 mL) at room temperature. ) was added to the solution dissolved in potassium carbonate (100.00%, 40.000 mg, 0.404 mmol) and stirred at the same temperature for 0.3 hours. Add 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 100.000 mg, 0.345 mmol) to the reaction mixture. and stirred for additional 18 hours at 35°C. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; hexane/ethyl acetate = 100 % to 50 %) to obtain the title compound (58 mg, 53.36 %) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.32 (d, J = 1.6 Hz, 1H), 8.40 (dd, J = 8.2, 2.2 Hz, 1H), 8.01 (dd, J = 8.2, 1.4 Hz, 2H) , 7.83 (d, J = 8.4 Hz, 1H), 7.56-7.51 (m, 3H), 6.96 (t, J = 51.6 Hz, 1H), 4.75 (s, 2H); LRMS (ES) m/z 388.8 (M ⁺ +1).

The compounds shown in Table 3 below were synthesized according to substantially the same method as that of Example 45.

[Table 3]

Example 43: 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-phenyl-1,3 , Synthesis of 4-thiadiazol-2-one (19838)

[Step 1] Synthesis of benzohydrazide

A solution of methyl benzoate (100.00 %, 1.000 g, 7.345 mmol) and hydrazine monohydrate (100.00 %, 3.677 g, 73.452 mmol) in ethanol (80 mL) at 90°C was stirred at the same temperature overnight, and then the temperature was adjusted to The reaction was terminated by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, water was added to the obtained concentrate, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (0.88 g, 88.000 %, white solid).

[Step 2] Synthesis of benzenecarbothiohydrazide

A solution of benzohydrazide (100.00 %, 0.500 g, 3.672 mmol) synthesized in Step 1 and Lawesson's reagent (100.00 %, 1.782 g, 4.406 mmol) was dissolved in toluene (20 mL) at 100 °C overnight at the same temperature. After stirring, the temperature was lowered to room temperature to complete the reaction. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 0 % to 30 %) to obtain the title compound (0.31 g, 55.455 %, white solid).

[Step 3] Synthesis of 5-phenyl-3H-1,3,4-thiadiazol-2-one

Benzenecarbothiohydrazide (100.00 %, 0.280 g, 1.839 mmol) and 1,1'-carbonylweis-1H-imidazole (100.00 %, 0.358 g, 2.208 mmol) synthesized in step 2 were reacted at 50°C. The solution dissolved in dichloromethane (20 mL) was stirred at the same temperature overnight, and then the temperature was lowered to room temperature to complete the reaction. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane = 0 % to 30 %) to obtain the title compound (0.25 g, 76.264 %, white solid).

[Step 4] Synthesis of Compound 19838

5-phenyl-3H-1,3,4-thiadiazol-2-one (100.00 %, 0.050 g, 0.281 mmol) and potassium carbonate (100.00 %, 0.058 g, 0.420 mmol) synthesized in step 4 were added to N , A solution dissolved in N-dimethylformamide (5 mL) was stirred at room temperature for 30 minutes and 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1, 3,4-oxadiazole (100.00 %, 0.085 g, 0.293 mmol) and potassium iodide (100.00 %, 0.023 g, 0.139 mmol) were added and stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane = 0 % to 50 %) to obtain the title compound (0.054 g, 49.68 %, white solid).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.33 (d, J = 1.6 Hz, 1H), 8.42 (dd, J = 8.2, 2.2 Hz, 1H), 7.71-7.69 (m, 2H), 7.48-7.43 ( m, 4H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H), 5.43 (s, 2H); LRMS (ES) m/z 388.0 (M ⁺ +1).

The compounds shown in Table 4 below were synthesized according to substantially the same method as that of Example 43.

[Table 4]

Example 4: 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluoro Synthesis of -4-[(4-methyl-1-piperidyl)methyl]phenyl]-1,3,4-oxadiazol-2-one (19331)

[Step 1] Methyl 2-fluoro-4-[(4-methyl-1-piperidyl)methyl]benzoate

Methyl 2-fluoro-4-formyl-benzoate (100.00 %, 0.300 g, 1.647 mmol), 4-methylpiperidine (100.00 %, 2.000 eq, 3.294 mmol) and sodium triacetoxyborohydride (100.00 %, 2.000 equivalent, 3.294 mmol) was dissolved in dichloromethane (10 mL) at room temperature and stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane = 0 % to 100 %) to obtain the title compound (0.43 g, 98.41 %, yellow oil).

[Step 2] 2-Fluoro-4-[(4-methyl-1-piperidyl)methyl]benzohydrazide

Methyl 2-fluoro-4-[(4-methyl-1-piperidyl)methyl]benzoate (100.00%, 0.420 g, 1.583 mmol) and hydrazine monohydrate (100.00%, 10.000 equivalents, synthesized in Step 1) A solution of 15.830 mmol) dissolved in ethanol (10 mL) at 80°C was stirred at the same temperature overnight, and then the temperature was lowered to room temperature to terminate the reaction. After removing the solvent from the reaction mixture under reduced pressure, the obtained product was used without further purification (0.42 g, 100.0 %, white solid).

[Step 3] 5-[2-fluoro-4-[(4-methyl-1-piperidyl)methyl]phenyl]-3H-1,3,4-oxadiazol-2-one

2-Fluoro-4-[(4-methyl-1-piperidyl)methyl]benzohydrazide (100.00%, 0.420 g, 1.583 mmol), triphosgene (100.00%, 0.400 equiv, synthesized in step 2) 0.633 mmol) and N,N-diisopropylethylamine (100.00%, 2.000 equivalents, 3.166 mmol) were dissolved in dichloromethane (10 mL) at room temperature and stirred at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 0 % to 100 %) to obtain the title compound (0.275 g, 59.63 %, white solid).

[Step 4] Synthesis of Compound 19331

5-[2-fluoro-4-[(4-methyl-1-piperidyl)methyl]phenyl]-3H-1,3,4-oxadiazol-2-one (100.00%) synthesized in Step 3 , 0.090 g, 0.309 mmol), 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.200 equivalent, 0.371 mmol), potassium carbonate (100.00 %, 2.000 equivalents, 0.618 mmol), and potassium iodide (100.00 %, 1.100 equivalents, 0.340 mmol) were dissolved in N,N-dimethylformamide (5 mL) at room temperature. It was stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane = 0 % to 100 %) to obtain the title compound (0.07 g, 45.27 %, white solid).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.25 (s, 1H), 8.37 (d, J = 10.0 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.49 (d, J = 8.0 Hz) , 1H), 7.21-7.18 (m, 2H), 6.93 (t, J = 51.6 Hz, 1H), 5.22 (s, 2H), 3.47 (s, 2H), 2.76 (d, J = 11.2 Hz, 2H) , 1.95 (t, J = 10.8 Hz, 2H), 1.57 (d, J = 12.0 Hz, 2H), 1.34-1.20 (m, 3H), 0.89 (d, J = 6.0 Hz, 3H); LRMS (ES) m/z 501.4 (M ⁺ +1).

The compounds shown in Table 5 below were synthesized according to substantially the same method as that of Example 4.

[Table 5]

Example 84: 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-(3-(( Synthesis of dimethylamino)methyl)phenyl)-1,3,4-oxadiazole-2(3H)-thion (20468)

[Step 1] Synthesis of methyl 3-(1,3-dioxolan-2-yl)benzoate

Methyl 3-formylbenzoate (100.00 %, 2.000 g, 12.183 mmol), ethylene glycol (100.00 %, 3.781 g, 60.920 mmol) and 4-methylbenzenesulfonic acid hydrate (100.00 %, 0.232 g, 1.220 mmol) The mixture mixed with toluene (120 mL) at room temperature was heated and refluxed overnight. The temperature was lowered to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 80 g cartridge; ethyl acetate/hexane = 0 % to 10 %) to obtain the title compound (1.8 g, 70.959 %, white solid).

[Step 2] Synthesis of 3-(1,3-dioxolan-2-yl)benzohydrazide

Methyl 3-(1,3-dioxolan-2-yl)benzoate (100.00%, 1.130 g, 5.427 mmol) and hydrazine monohydrate (100.00%, 2.717 g, 54.275 mmol) synthesized in Step 1 were reacted at 80°C. The solution dissolved in ethanol (80 mL) was stirred at the same temperature overnight, and then the temperature was lowered to room temperature to complete the reaction. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 24 g cartridge; methanol/dichloromethane = 0 % to 5 %) to obtain the title compound (1.1 g, 97.345 %, white solid).

[Step 3] Synthesis of 5-[3-(1,3-dioxolan-2-yl)phenyl]-3H-1,3,4-oxadiazole-2-thion

3-(1,3-dioxolan-2-yl)benzohydrazide (100.00 %, 0.900 g, 4.323 mmol) and potassium ethylxanthate (100.00 %, 0.762 g, 4.754 mmol) synthesized in step 2 were mixed at 80 °C. The solution dissolved in ethanol (50 mL) at ℃ was stirred at the same temperature overnight, and then the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane = 0 % to 30 %) to obtain the title compound (0.7 g, 64.70 %, white solid).

[Step 4] 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[3-(1 Synthesis of ,3-dioxolan-2-yl)phenyl]-1,3,4-oxadiazole-2-thion

5-[3-(1,3-dioxolan-2-yl)phenyl]-3H-1,3,4-oxadiazole-2-thion (100.00%, 0.350 g, 1.398 mmol) synthesized in step 3 ), 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00 %, 0.426 g, 1.469 mmol), potassium carbonate A solution of (100.00 %, 0.208 g, 2.099 mmol) and potassium iodide (100.00 %, 0.116 g, 0.699 mmol) in N,N-dimethylformamide (30 mL) was stirred at room temperature for 30 minutes and mixed with the same solution. It was further stirred overnight at temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 0 % to 50 %) to obtain the title compound (0.51 g, 79.39 %, white solid).

[Step 5] 3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-thioxo Synthesis of -1,3,4-oxadiazol-2-yl]benzaldehyde

3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[3-(synthesized in step 4 1,3-dioxolan-2-yl)phenyl]-1,3,4-oxadiazole-2-thion (100.00 %, 0.500 g, 1.088 mmol) and ferric chloride hexahydrate (100.00 %, 1.030 g, A solution of 3.811 mmol) dissolved in dichloromethane (30 mL) at room temperature was stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 0 % to 40 %) to obtain the title compound (0.350 g, 77.41 %) as a white solid.

[Step 6] Synthesis of compound 20468

4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-cy synthesized in Step 5 Oxo-1,3,4-oxadiazol-2-yl] benzaldehyde (100.00 %, 0.030 g, 0.072 mmol) was dissolved in dichloromethane (5 mL) at room temperature and N-methylmethanamine (100.00 %, 0.007 g, 0.155 mmol) was added and stirred at the same temperature for 30 minutes. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0 % to 5 %) to obtain the title compound (0.011 g, 34.27 %, white solid).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.32 (d, J = 1.7 Hz, 1H), 8.39 (dd, J = 8.2, 2.2 Hz, 1H), 7.94-7.90 (m, 2H), 7.83 (d, J = 8.2 Hz, 1H), 7.52-7.45 (m, 2H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H), 4.74 (s, 2H), 3.50 ( s, 2H), 2.28 (s, 6H); LRMS (ES) m/z 445.23 (M ⁺ +1).

The compounds in Table 6 below were synthesized according to a method substantially the same as that of Example 84.

[Table 6]

Example 132: 5-[4-(azetidin-1-ylmethyl)phenyl]-3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl Synthesis of ]-2-pyridyl]methyl]-1,3,4-oxa-diazol-2-one (20877)

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

Methyl 4-formylbenzoate (100.00 %, 3.000 g, 18.275 mmol), ethylene glycol (100.00 %, 5.672 g, 91.380 mmol) and 4-methylbenzenesulfonic acid hydrate (100.00 %, 0.348 g, 1.830 mmol) The mixture mixed with toluene (150 mL) at room temperature was heated and refluxed overnight. The temperature was lowered to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 80 g cartridge; ethyl acetate/hexane = 0 % to 10 %) to obtain the title compound (3.5 g, 91.984 %, white solid).

[Step 2] Synthesis of 4-(1,3-dioxolan-2-yl)benzohydrazide

Methyl 4-(1,3-dioxolan-2-yl)benzoate (100.00 %, 2.000 g, 9.606 mmol) and hydrazine monohydrate (100.00 %, 4.809 g, 96.065 mmol) synthesized in Step 1 were dissolved in ethanol at room temperature. The mixture (100 mL) was heated and refluxed overnight. The temperature was lowered to room temperature, water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 40 g cartridge; methanol/dichloromethane = 0 % to 5 %) to obtain the title compound (1.8 g, 90.000 %, white solid).

[Step 3] Synthesis of 5-[4-(1,3-dioxolan-2-yl)phenyl]-3H-1,3,4-oxadiazol-2-one

4-(1,3-dioxolan-2-yl)benzohydrazide (100.00 %, 0.650 g, 3.122 mmol) and 1,1'-carbonylbis-1H-imidazole (100.00 %) synthesized in step 2. , 0.607 g, 3.744 mmol) was mixed with dichloromethane (50 mL) at room temperature and heated to reflux overnight. The temperature was lowered to room temperature, water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 0 % to 50 %) to obtain the title compound (0.45 g, 61.545 %, white solid).

[Step 4] 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-(1 Synthesis of ,3-dioxolan-2-yl)phenyl]-1,3,4-oxadiazol-2-one

5-[4-(1,3-dioxolan-2-yl)phenyl]-3H-1,3,4-oxadiazol-2-one (100.00 %, 0.500 g, 2.135 mmol) synthesized in Step 3 2-[6-(bromomethyl)-3-pyridyl]-5 in a solution of potassium carbonate (100.00%, 0.443 g, 3.205 mmol) in N,N-dimethylformamide (30 mL) at room temperature. -(Difluoromethyl)-1,3,4-oxadiazole (100.00 %, 0.650 g, 2.241 mmol) and potassium iodide (100.00 %, 0.177 g, 1.066 mmol) were added and incubated at the same temperature for 30 minutes. It was stirred. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Ethyl acetate (5 mL) was added to the concentrate, stirred, and the precipitated solid was filtered, washed with hexane, and dried to obtain the title compound (0.74 g, 78.18 %, white solid).

[Step 5] 4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-oxo- Synthesis of 1,3,4-oxadiazol-2-yl]benzaldehyde

3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-(synthesized in Step 4 1,3-dioxolan-2-yl)phenyl]-1,3,4-oxadiazol-2-one (100.00 %, 0.280 g, 0.632 mmol) and ferric chloride hexahydrate (100.00 %, 0.512 g, 1.894 mmol) mmol) was dissolved in dichloromethane (30 mL) at room temperature and stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 0 % to 50 %) to obtain the title compound (0.18 g, 71.39 %, white solid).

[Step 6] Synthesis of compound 20877 (132)

4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-oxo synthesized in Step 5 -1,3,4-oxadiazol-2-yl]benzaldehyde (100.00 %, 0.030 g, 0.075 mmol) and azetidine hydrochloride (100.00 %, 0.014 g, 0.150 mmol) were mixed with dichloromethane (5 mL). ) was stirred at room temperature for 30 minutes, sodium triacetoxyborohydride (100.00 %, 0.048 g, 0.227 mmol) was added, and it was further stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0 % to 5 %) to obtain the title compound (0.019 g, 57.42 %, white solid).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.33 (d, J = 1.5 Hz, 1H), 8.43 (dd, J = 8.2, 2.2 Hz, 1H), 7.82 (d, J = 8.3 Hz, 2H), 7.55 -7.52 (m, 1 H), 7.43 (d, J = 8.1 Hz, 2H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H), 5.24 (s, 2H) ), 3.67 (s, 2H), 3.32-3.28 (m, 4H), 2.19-2.12 (m, 2H); LRMS (ES) m/z 441.3 (M ⁺ +1).

The compounds shown in Table 7 below were synthesized according to substantially the same method as that of Example 132.

[Table 7]

Example 83: 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-[( Synthesis of 4-isopropylpiperazin-1-yl)methyl]phenyl]-1,3,4-oxadiazol-2-one (20443)

[Step 1] Synthesis of tert-butyl 4-[(4-methoxycarbonylphenyl)methyl]piperazine-1-carboxylate

Methyl 4-formylbenzoate (100.00 %, 0.500 g, 3.046 mmol), tert-butyl piperazine-1-carboxylate (100.00 %, 0.681 g, 3.656 mmol) and sodium triacetoxyborohydride (100.00 %, A solution of 1.291 g, 6.091 mmol) dissolved in dichloromethane (20 mL) at room temperature was stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane = 0 % to 30 %) to obtain the title compound (0.89 g, 87.38 %, white solid).

[Step 2] Synthesis of tert-butyl 4-[[4-(hydrazinecarbonyl)phenyl]methyl]piperazine-1-carboxylate

Tert-butyl 4-[(4-methoxycarbonylphenyl)methyl]piperazine-1-carboxylate (100.00%, 0.300 g, 0.897 mmol) and hydrazine monohydrate (100.00%, 0.449 g, synthesized in Step 1) A solution of 8.969 mmol) dissolved in ethanol (20 mL) at 90°C was stirred at the same temperature overnight, and then the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (0.29 g, 96.67 %, white solid).

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

Tert-butyl 4-[[4-(hydrazinecarbonyl)phenyl]methyl]piperazine-1-carboxylate (100.00%, 0.500 g, 1.495 mmol) synthesized in Step 2 and 1,1'-carbonylvice- Triethylamine (100.00 % solution, 0.29 mL, 2.100 mmol) was added to a solution of 1H-imidazole (100.00 %, 0.291 g, 1.795 mmol) dissolved in tetrahydrofuran (10 mL) at room temperature and stirred at the same temperature overnight. did. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 24 g cartridge; methanol/dichloromethane = 0 % to 10 %) to obtain the title compound (0.468 g, 86.85 %, white solid).

[Step 4] Tert-butyl 4-[[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl] Synthesis of methyl]-5-oxo-1,3,4-oxadiazol-2-yl]phenyl]methyl]piperazine-1-carboxylate

Tert-butyl 4-[[4-(2-oxo-3H-1,3,4-oxadiazol-5-yl)phenyl]methyl]piperazine-1-carboxylate (100.00%, 2-[ prepared in step 3 of Example 5 in a solution of 0.236 g, 0.655 mmol) and potassium carbonate (100.00%, 0.091 g, 0.918 mmol) in N,N-dimethyl formamide (3 mL) at room temperature. 6-(Bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.228 g, 0.786 mmol) was added and stirred at the same temperature overnight. . Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane = 0 % to 60 %), and then the obtained product was purified again by chromatography (SiO ₂ , 4 g cartridge; methanol). /dichloromethane = 0% to 10%) to obtain the title compound (0.37 g, 99.20%, white solid).

[Step 5] 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-(pipe Synthesis of razin-1-ylmethyl)phenyl]-1,3,4-oxadiazol-2-one

Tert-butyl 4-[[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl synthesized in Step 4 ]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]phenyl]methyl]piperazine-1-carboxylate (100.00 %, 0.370 g, 0.650 mmol) and trifluoroacetic acid (100.00 % solution, 0.497 mL, 6.490 mmol) was dissolved in dichloromethane (3 mL) at room temperature and stirred at the same temperature overnight. A saturated aqueous solution of sodium hydrogen carbonate was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (0.3 g, 98.39 %, yellow oil).

[Step 6] Synthesis of Compound 20443

3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-(synthesized in Step 5 piperazin-1-ylmethyl)phenyl]-1,3,4-oxadiazol-2-one (100.00 %, 0.075 g, 0.160 mmol), acetone (100.00 % solution, 0.019 mL, 0.257 mmol) and N- A solution of ethyl-N-isopropyl-propan-2-amine (100.00 % solution, 0.056 mL, 0.322 mmol) in dichloromethane (1 mL) was stirred at room temperature for 30 minutes and washed with sodium triacetoxyborohydride. Hydride (100.00 %, 0.101 g, 0.479 mmol) was added and stirred at the same temperature for additional 18 hours. A saturated aqueous solution of sodium hydrogen carbonate was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol = 0 % to 10 %) to obtain the title compound (0.014 g, 17.13 %, pale yellow solid).

¹ H NMR (400 MHz, CD ₃ OD) δ 9.25 (d, J = 1.6 Hz, 1H), 8.53 (dd, J = 8.2, 2.2 Hz, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.26 (t, J = 51.6 Hz, 1H), 5.26 (s, 2H), 3.63 (s, 2H), 2.74-2.59 (m, 9H), 1.15 (d, J = 6.8 Hz, 6H); LRMS (ES) m/z 512.8 (M ⁺ +1).

Example 66: 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-(4 Synthesis of -isopropylpiperazin-1-yl)phenyl]-1,3,4-thiadiazol-2-one (20099)

[Step 1] Synthesis of tert-butyl 4-[[4-(aminocarbamosioyl)phenyl]methyl]piperazine-1-carboxylate

Tert-butyl 4-[[4-(hydrazinecarbonyl)phenyl]methyl]piperazine-1-carboxylate (100.00%, 1.000 g, 2.990 mmol) synthesized in step 2 of Example 86 and Lawesson's reagent (100.00% , 1.451 g, 3.587 mmol) in toluene (40 mL) at 80°C was stirred overnight at the same temperature, and then the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane = 0 % to 60 %) to obtain the title compound (0.61 g, 58.20 %, white solid).

[Step 2] Synthesis of tert-butyl 4-[[4-(2-oxo-3H-1,3,4-thiadiazol-5-yl)phenyl]methyl]piperazine-1-carboxylate

Tert-butyl 4-[[4-(aminocarbamosthioyl)phenyl]methyl]piperazine-1-carboxylate (100.00%, 0.500 g, 1.427 mmol) and 1,1'-carbonyl synthesized in Step 1 A solution of Weiss-1H-imidazole (100.00%, 0.278 g, 1.715 mmol) dissolved in dichloromethane (30 mL) at 50°C was stirred at the same temperature overnight, and then the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous ammonium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 0 % to 40 %) to obtain the title compound (0.25 g, 46.55 %, white solid).

[Step 3] Tert-butyl 4-[[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl] Synthesis of methyl]-5-oxo-1,3,4-thiadiazol-2-yl]phenyl]methyl]piperazine-1-carboxylate

Tert-butyl 4-[[4-(2-oxo-3H-1,3,4-thiadiazol-5-yl)phenyl]methyl]piperazine-1-carboxylate (100.00%) synthesized in Step 2 , 0.100 g, 0.266 mmol) and potassium carbonate (100.00%, 0.055 g, 0.398 mmol) in N,N-dimethylformamide (10 mL) were stirred at room temperature for 30 minutes, and 2-[6- (bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00 %, 0.081 g, 0.279 mmol) and potassium iodide (100.00 %, 0.022 mmol) g, 0.133 mmol) was added and further stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 0 % to 40 %) to obtain the title compound (0.095 g, 61.08 %, white solid).

[Step 4] 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-(pipe Razin-1-ylmethyl)phenyl]-1,3,4-thiadiazol-2-one Synthesis of 2,2,2-trifluoroacetic acid

Tert-butyl 4-[[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl synthesized in Step 3 ]methyl]-5-oxo-1,3,4-thiadiazol-2-yl]phenyl]methyl]piperazine-1-carboxylate (100.00%, 0.090 g, 0.154 mmol) and trifluoroacetic acid ( A solution of 100.00 %, 0.053 g, 0.465 mmol) dissolved in dichloromethane (10 mL) at room temperature was stirred at the same temperature for 3 hours. After removing the solvent from the reaction mixture under reduced pressure, the obtained product was used without further purification (0.088 g, 95.51 %, yellow oil).

[Step 5] Synthesis of Compound 20099

3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(4-pipe synthesized in step 4 Razin-1-ylphenyl)-1,3,4-thiadiazol-2-one 2,2,2-trifluoroacetic acid (100.00 %, 0.030 g, 0.051 mmol), acetone (100.00 %, 0.006 g) , 0.103 mmol), N-ethyldiisopropylamine (100.00 % solution, 0.018 mL, 0.103 mmol) and sodium triacetoxyborohydride (100.00 %, 0.033 g, 0.156 mmol) were mixed with dichloromethane (5 mL). ) was stirred at room temperature for 30 minutes and further stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0 % to 5 %) to obtain the title compound (0.011 g, 41.80 %, white solid).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.33 (d, J = 1.6 Hz, 1H), 8.41 (dd, J = 8.2, 2.2 Hz, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 8.2 Hz, 2H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H), 5.42 (s) , 2H), 3.56 (s, 2H), 2.78-2.77 (m, 1H), 2.64-2.48 (m, 8H), 1.11 (d, J = 6.5 Hz, 6H); LRMS (ES) m/z 529.35 (M ⁺ +1).

The compounds in Table 8 below were synthesized according to a process substantially the same as that of Example 66.

[Table 8]

Example 77: 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-[( Synthesis of 4-isopropylpiperazin-1-yl)methyl]phenyl]-1,3,4-oxadiazole-2-thion (20373)

[Step 1] Synthesis of tert-butyl 4-(4-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)benzyl)piperazine-1-carboxylate

Tert-butyl 4-[[4-(hydrazinecarbonyl)phenyl]methyl]piperazine-1-carboxylate (100.00%, 1.000 g, 2.990 mmol) prepared in step 2 of Example 86 and potassium ethylxanthate ( A mixture of 100.00 %, 0.575 g, 3.587 mmol) mixed with ethanol (80 mL) at room temperature was heated and refluxed overnight. The temperature was lowered to room temperature, water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane = 0 % to 40 %) to obtain the title compound (0.85 g, 75.50 %, white solid).

[Step 2] Tert-butyl 4-[[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl] Synthesis of methyl]-5-thioxo-1,3,4-oxadiazol-2-yl]phenyl]methyl]piperazine-1-carboxylate

Tert-butyl 4-[[4-(2-thioxo-3H-1,3,4-oxadiazol-5-yl)phenyl]methyl]piperazine-1-carboxylate (100.00% , 0.500 g, 1.328 mmol) and potassium carbonate (100.00%, 0.197 g, 1.988 mmol) in N,N-dimethylformamide (30 mL) were stirred at room temperature for 30 minutes, and 2-[6- (bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00 %, 0.404 g, 1.393 mmol) and potassium iodide (100.00 %, 0.110 mmol) g, 0.663 mmol) was added and further stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane = 0 % to 40 %) to obtain the title compound (0.65 g, 83.58 %, white solid).

[Step 3] 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-(pipe Synthesis of razin-1-ylmethyl)phenyl]-1,3,4-oxadiazole-2-thion 2,2,2-trifluoroacetic acid

Tert-butyl 4-[[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl synthesized in Step 2 ]methyl]-5-thioxo-1,3,4-oxadiazol-2-yl]phenyl]methyl]piperazine-1-carboxylate (100.00%, 0.300 g, 0.512 mmol) and trifluoroacetic acid ( A solution of 100.00 %, 0.175 g, 1.535 mmol) dissolved in dichloromethane (20 mL) at room temperature was stirred at the same temperature for 3 hours. After removing the solvent from the reaction mixture under reduced pressure, the obtained product was used without further purification (0.28 g, 91.17 %, yellow oil).

[Step 4] Synthesis of Compound 20373

3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-(synthesized in Step 3 piperazin-1-ylmethyl)phenyl]-1,3,4-oxadiazole-2-thion 2,2,2-trifluoroacetic acid (100.00 %, 0.050 g, 0.083 mmol), acetone (100.00 % , 0.010 g, 0.172 mmol) and N-ethyldiisopropylamine (100.00% solution, 0.029 mL, 0.167 mmol) in dichloromethane (5 mL), stirred at room temperature for 30 minutes, and sodium triacetate. Toxiborohydride (100.00 %, 0.053 g, 0.250 mmol) was added and further stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0 % to 5 %) to obtain the title compound (0.022 g, 50.00 %, white solid).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.31 (d, J = 2.2 Hz, 1H), 8.39 (dd, J = 8.2, 2.2 Hz, 1H), 7.95 (d, J = 8.3 Hz, 2H), 7.82 (d, J = 8.2 Hz, 1H), 7.46 (d, J = 8.3 Hz, 2H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H), 4.73 (s) , 2H), 3.60 (s, 2H), 3.16-2.92 (m, 1H), 2.81-2.76 (m, 8H), 1.19 (d, J = 6.5 Hz, 6H); LRMS (ES) m/z 528.87 (M ⁺ +1).

The compounds in Table 9 below were synthesized according to substantially the same method as that of Example 77.

[Table 9]

Example 26: 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluoro Synthesis of -3-[1-(oxetan-3-yl)-4-piperidyl]phenyl]-1,3,4-oxadiazol-2-one (19616)

[Step 1] Synthesis of tert-butyl 4-(2-fluoro-3-methoxycarbonyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate

Methyl 3-bromo-2-fluoro-benzoate (100.00 %, 1.000 g, 4.291 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (100.00 %, 1.460 g, 4.722 mmol), bis(triphenylphosphine)palladium(II) dichloride (100.00 %, 0.301 g, 0.429 mmol) and sodium carbonate (100.00%, 1.365 g, 12.879 mmol) were dissolved in N,N-dimethylformamide (20 mL)/water (5 mL) at room temperature and stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane = 0 % to 30 %) to obtain the title compound (1.100 g, 76.43 %, white solid).

[Step 2] Synthesis of tert-butyl 4-(2-fluoro-3-methoxycarbonyl-phenyl)piperidine-1-carboxylate

Tert-butyl 4-(2-fluoro-3-methoxycarbonyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (100.00 %, 0.900 g, 2.683 mmol) synthesized in Step 1 ) and Pd/C (100.00 %, 0.286 g, 2.688 mmol) were dissolved in methanol (20 mL) at room temperature and stirred overnight at the same temperature. The reaction mixture was filtered through a Celite pad to remove solids, and the solvent was removed from the filtrate under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 0 % to 40 %) to obtain the title compound (0.74 g, 81.73 %, yellow oil).

[Step 3] Synthesis of tert-butyl 4-[2-fluoro-3-(hydrazinecarbonyl)phenyl]piperidine-1-carboxylate

Tert-butyl 4-(2-fluoro-3-methoxycarbonyl-phenyl)piperidine-1-carboxylate (100.00%, 0.700 g, 2.075 mmol) and hydrazine monohydrate (100.00%) synthesized in Step 2. , 1.039 g, 20.755 mmol) was dissolved in ethanol (30 mL) at room temperature and stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (0.65 g, 92.86 %, white solid).

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

Tert-butyl 4-[2-fluoro-3-(hydrazinecarbonyl)phenyl]piperidine-1-carboxylate (100.00%, 0.700 g, 2.075 mmol) and 1,1'-carboxylate synthesized in Step 3. A solution of Nilweis-1H-imidazole (100.00%, 0.404 g, 2.492 mmol) dissolved in dichloromethane (30 mL) at room temperature was stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous ammonium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 0 % to 40 %) to obtain the title compound (0.55 g, 72.95 %, white solid).

[Step 5] Tert-butyl 4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl Synthesis of ]-5-oxo-1,3,4-oxadiazol-2-yl]-2-flu-oro-phenyl]piperidine-1-carboxylate

Tert-butyl 4-[2-fluoro-3-(2-oxo-3H-1,3,4-oxadiazol-5-yl)phenyl]piperidine-1-carboxylate synthesized in Step 4 ( 2-[6-(bromomethyl) in a solution of 100.00 %, 0.400 g, 1.101 mmol) and potassium carbonate (100.00 %, 0.164 g, 1.655 mmol) in N,N-dimethylformamide (20 mL) at room temperature. )-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00 %, 0.335 g, 1.155 mmol) and potassium iodide (100.00 %, 0.091 g, 0.548 mmol) ) was added and stirred at the same temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 0 % to 40 %) to obtain the title compound (0.54 g, 85.69 %, white solid).

[Step 6] 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluoro -3-(4-piperidyl)phenyl]-1,3,4-oxadiazol-2-one Synthesis of 2,2,2-trifluoroacetic acid

Tert-butyl 4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl] synthesized in Step 5 methyl]-5-oxo-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]piperidine-1-carboxylate (100.00%, 0.300 g, 0.524 mmol) and 2, A solution of 2,2-trifluoroacetic acid (100.00 %, 0.179 g, 1.570 mmol) dissolved in dichloromethane (20 mL) at room temperature was stirred at the same temperature for 3 hours. After removing the solvent from the reaction mixture under reduced pressure, the obtained product was used without further purification (0.3 g, 97.63 %, yellow oil).

[Step 7] Synthesis of Compound 19616

3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluo synthesized in Step 6 Ro-3-(4-piperidyl)phenyl]-1,3,4-oxadiazol-2-one 2,2,2-trifluoroacetic acid (100.00 %, 0.050 g, 0.085 mmol), N- Ethyldiisopropylamine (100.00 % solution, 0.03 mL, 0.172 mmol), oxetan-3-one (100.00 %, 0.012 g, 0.167 mmol) and sodium triacetoxyborohydride (100.00 %, 0.054 g, 0.255 mmol) was dissolved in dichloromethane (5 mL) at room temperature and stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0 % to 5 %) to obtain the title compound (0.031 g, 68.79 %, white solid).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.32 (d, J = 1.6 Hz, 1H), 8.43 (dd, J = 8.2, 2.2 Hz, 1H), 7.70-7.66 (m, 1H), 7.53 (d. J = 8.2 Hz, 1H), 7.47-7.43 (m, 1H), 7.26-7.23 (m, 1H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H) 5.26 (s, 2H), 4.71-4.64 (m, 4H), 3.56-3.50 (m, 1H), 3.00-2.94 (m, 1H), 2.91-2.88 (m, 2H), 2.02-1.96 (m, 2H) , 1.87-1.81 (m, 4H); LRMS (ES) m/z 529.82 (M ⁺ +1).

The compounds in Table 10 below were synthesized according to substantially the same method as that of Example 26.

[Table 10]

Example 27: 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluoro Synthesis of -3-[1-(1-methylazetidin-3-yl)-4-piperidyl]phenyl]-1,3,4-oxadiazol-2-one (19617)

[Step 1] Tert-butyl 3-[4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyri Synthesis of diyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]-1-piperidyl]azetidine-1-carboxylate

3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5- synthesized in Step 6 of Example 26 [2-fluoro-3-(4-piperidyl)phenyl]-1,3,4-oxadiazol-2-one 2,2,2-trifluoroacetic acid (100.00 %, 0.150 g, 0.256 mmol) ), N-ethyldiisopropylamine (100.00 % solution, 0.089 mL, 0.511 mmol), tert-butyl 3-oxoazetidine-1-carboxylate (100.00 %, 0.088 g, 0.514 mmol) and sodium triacetoxy. A solution of ciborohydride (100.00%, 0.163 g, 0.769 mmol) dissolved in dichloromethane (5 mL) at room temperature was stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0 % to 5 %) to obtain the title compound (0.11 g, 68.52 %, white solid).

[Step 2] 5-[3-[1-(azetidin-3-yl)-4-piperidyl]-2-fluoro-phenyl]-3-[[5-[5-(difluoromethyl )-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-1,3,4-oxadiazol-2-one Synthesis of 2,2,2-trifluoroacetic acid

Tert-butyl 3-[4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2- synthesized in Step 1 pyridyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]-1-piperidyl]azetidine-1-carboxylate (100.00%, A solution of 0.110 g, 0.175 mmol) and 2,2,2-trifluoroacetic acid (100.00%, 0.060 g, 0.526 mmol) dissolved in dichloromethane (5 mL) at room temperature was stirred at the same temperature overnight. After removing the solvent from the reaction mixture under reduced pressure, the obtained product was used without further purification (0.100 g, 88.94 %, yellow oil).

[Step 3] Synthesis of Compound 19617

5-[3-[1-(azetidin-3-yl)-4-piperidyl]-2-fluoro-phenyl]-3-[[5-[5-(difluoro) synthesized in Step 2 methyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-1,3,4-oxadiazol-2-one 2,2,2-trifluoroacetic acid ( 100.00 %, 0.050 g, 0.078 mmol), formaldehyde (100.00 %, 0.005 g, 0.167 mmol), N-ethyldiisopropylamine (100.00 % solution, 0.027 mL, 0.155 mmol) and sodium triacetoxyborohydride ( A solution of 100.00 %, 0.050 g, 0.236 mmol) dissolved in dichloromethane (5 mL) at room temperature was stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0 % to 5 %) to obtain the title compound (0.029 g, 68.71 %, white solid).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.31 (d, J = 1.6 Hz, 1H), 8.43 (dd, J = 8.2, 2.2 Hz, 1H), 7.69-7.65 (m, 1H), 7.53 (d. J = 8.2 Hz, 1H), 7.45-7.41 (m, 1H), 7.25-7.21 (m, 1H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H) 5.26 (s, 2H), 3.76 (brs, 2H), 3.09 (brs, 3H), 2.99-2.90 (m, 3H), 2.50 (s, 3H), 2.09-1.94 (m, 2H), 1.87-1.80 (m , 4H); LRMS (ES) m/z 542.86 (M ⁺ +1).

The compounds in Table 11 below were synthesized according to substantially the same method as that of Example 27.

[Table 11]

Example 81: 5-[3-(1-cyclobutyl-4-piperidyl)-2-fluoro-phenyl]-3-[[5-[5-(difluoromethyl)-1,3, Synthesis of 4-oxadiazol-2-yl]-2-pyridyl]methyl]-1,3,4-oxadiazol-2-thion (20377)

[Step 1] of tert-butyl 4-[2-fluoro-3-(2-thioxo-3H-1,3,4-oxadiazol-5-yl)phenyl]piperidine-1-carboxylate synthesis

Tert-butyl 4-[2-fluoro-3-(hydrazinecarbonyl)phenyl]piperidine-1-carboxylate (100.00%, 1.100 g, 3.260 mmol) prepared in Step 3 of Example 26 and potassium ethyl A mixture of xanthate (100.00%, 0.627 g, 3.911 mmol) mixed with ethanol (80 mL) at room temperature was heated to reflux overnight. The temperature was lowered to room temperature, water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous ammonium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane = 0 % to 40 %) to obtain the title compound (0.9 g, 72.76 %, white solid).

[Step 2] Tert-butyl 4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl Synthesis of ]-5-thioxo-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]piperidine-1-carboxylate

Tert-butyl 4-[2-fluoro-3-(2-thioxo-3H-1,3,4-oxadiazol-5-yl)phenyl]piperidine-1-carboxylate synthesized in Step 1 A solution of (100.00 %, 0.500 g, 1.318 mmol) and potassium carbonate (100.00 %, 0.196 g, 1.978 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 30 minutes and 2-[ 6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00 %, 0.401 g, 1.383 mmol) and potassium iodide (100.00 % , 0.109 g, 0.657 mmol) was added and further stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane = 0 % to 30 %) to obtain the title compound (0.61 g, 78.64 %, white solid).

[Step 3] 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluoro Synthesis of -3-(4-piperidyl)phenyl]-1,3,4-oxadiazole-2-thion 2,2,2-trifluoroacetic acid

Tert-butyl 4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl] synthesized in Step 2 methyl]-5-thioxo-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]piperidine-1-carboxylate (100.00 %, 0.400 g, 0.680 mmol) and tri A solution of fluoroacetic acid (100.00 %, 0.232 g, 2.035 mmol) dissolved in dichloromethane (20 mL) at room temperature was stirred at the same temperature for 3 hours. After removing the solvent from the reaction mixture under reduced pressure, the obtained product was used without further purification (0.37 g, 90.37 %, yellow oil).

[Step 4] Synthesis of compound 20377

3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluo synthesized in Step 3 Ro-3-(4-piperidyl)phenyl]-1,3,4-oxadiazole-2-thion 2,2,2-trifluoroacetic acid (100.00 %, 0.050 g, 0.083 mmol), cyclo A solution of butanone (100.00 %, 0.012 g, 0.171 mmol) and N-ethyldiisopropylamine (100.00 % solution, 0.029 mL, 0.167 mmol) in dichloromethane (5 mL) was stirred at room temperature for 30 minutes. Then, sodium triacetoxyborohydride (100.00%, 0.053 g, 0.250 mmol) was added and stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0 % to 5 %) to obtain the title compound (0.029 g, 64.40 %, white solid).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.31 (d, J = 2.1 Hz, 1H), 8.38 (dd, J = 8.2, 2.3 Hz, 1H), 7.83-7.79 (m, 2H), 7.49-7.45 ( m, 1H), 7.26-7.22 (m, 1H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H), 4.73 (s, 2H), 3.15-3.12 (m , 2H), 3.03-3.00 (m, 1H), 2.88-2.84 (m, 1H), 2.12-2.02 (m, 6H), 1.98-1.88 (m, 4H), 1.79-1.68 (m, 2H); LRMS (ES) m/z 543.90 (M ⁺ +1).

The compounds shown in Table 12 below were synthesized according to substantially the same method as that of Example 81.

[Table 12]

Example 100: 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[6-(4 Synthesis of -ethylpiperazin-1-yl)-2-pyridyl]-1,3,4-oxadiazole-2-thion (20566)

[Step 1] Synthesis of tert-butyl 4-(6-methoxycarbonyl-2-pyridyl)piperazine-1-carboxylate

Methyl 6-fluoropyridine-2-carboxylate (100.00 %, 0.500 g, 3.223 mmol), tert-butyl piperazine-1-carboxylate (100.00 %, 1.200 g, 6.443 mmol) and N,N-diisopropyl A solution of ethylamine (100.00 % solution, 0.844 mL, 4.800 mmol) dissolved in dimethyl sulfoxide (15 mL) at 130°C was stirred at the same temperature overnight, and then the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane = 0 % to 60 %) to obtain the title compound (0.736 g, 71.05 %, yellow solid).

[Step 2] Synthesis of tert-butyl 4-[6-(hydrazinecarbonyl)-2-pyridyl]piperazine-1-carboxylate

Tert-butyl 4-(6-methoxycarbonyl-2-pyridyl)piperazine-1-carboxylate (100.00%, 0.736 g, 2.290 mmol) synthesized in step 1 was dissolved in ethanol (10 mL) at room temperature. Hydrazine monohydrate (100.00 % solution, 1.113 mL, 22.900 mmol) was added to the solution and stirred at 60°C for 18 hours, then the temperature was lowered to room temperature to complete the reaction. A saturated aqueous ammonium chloride solution was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0 % to 10 %) to obtain the title compound (0.73 g, 99.18 %, yellow solid).

[Step 3] Synthesis of tert-butyl 4-[6-(2-thioxo-3H-1,3,4-oxadiazol-5-yl)-2-pyridyl]piperazine-1-carboxylate

Tert-butyl 4-[6-(hydrazinecarbonyl)-2-pyridyl]piperazine-1-carboxylate (100.00%, 0.730 g, 2.271 mmol) and potassium ethylate (100.00%, 2.271 mmol) synthesized in step 2. A solution of 0.364 g, 2.271 mmol) dissolved in ethanol (10 mL) at room temperature was stirred at 90°C overnight, and then the temperature was lowered to room temperature to terminate the reaction. A saturated aqueous ammonium chloride solution was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 40 g cartridge; dichloromethane/methanol = 0 % to 10 %) to obtain the title compound (0.604 g, 73.18 %, yellow solid).

[Step 4] Tert-butyl 4-[6-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl Synthesis of ]-5-thioxo-1,3,4-oxadiazol-2-yl]-2-pyridyl]piperazine-1-carboxylate

Tert-butyl 4-[3-(2-thioxo-3H-1,3,4-oxadiazol-5-yl)phenyl]piperazine-1-carboxylate (100.00 %, 0.700 g) synthesized in Step 3 , 1.932 mmol), 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.000 equivalent, 1.932 mmol) , a solution of potassium carbonate (100.00%, 2.000 equivalents, 3.863 mmol) and potassium iodide (100.00%, 2.000 equivalents, 3.863 mmol) dissolved in N,N-dimethylformamide (5 mL) at room temperature at the same temperature. Stirred overnight. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 0 % to 50 %) to obtain the title compound (0.14 g, 12.68 %, yellow solid).

[Step 5] 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(6-piperazine Synthesis of -1-yl-2-pyridyl)-1,3,4-oxadiazole-2-thion

Tert-butyl 4-[6-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl] synthesized in Step 4 methyl]-5-thioxo-1,3,4-oxadiazol-2-yl]-2-pyridyl]piperazine-1-carboxylate (100.00 %, 0.384 g, 0.671 mmol) and trifluoroacetic acid (100.00 % solution, 0.513 mL, 6.700 mmol) was dissolved in dichloromethane (3 mL) at room temperature and stirred at the same temperature overnight. A saturated aqueous solution of sodium hydrogen carbonate was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (0.31 g, 97.83 %, yellow oil).

[Step 6] Synthesis of compound 20566

3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(6-pipe synthesized in Step 5 Razin-1-yl-2-pyridyl)-1,3,4-oxadiazole-2-thion (100.00 %, 0.100 g, 0.212 mmol), acetaldehyde (100.00 % solution, 0.024 mL, 0.429 mmol) A solution of N-ethyl-N-isopropyl-propan-2-amine (100.00 % solution, 0.074 mL, 0.425 mmol) in dichloromethane (1 mL) was stirred at room temperature for 30 minutes and added with sodium triacetoxy. Ciborohydride (100.00 %, 0.134 g, 0.635 mmol) was added and stirred at the same temperature for additional 18 hours. A saturated aqueous solution of sodium hydrogen carbonate was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol = 0 % to 10 %) to obtain the title compound (0.026 g, 24.55 %, yellow solid).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.32 (d, J = 1.6 Hz, 1H), 8.37 (dd, J = 8.2, 2.2 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.63 -7.59 (m, 1H), 7.43 (d, J = 7.2 Hz, 1H), 6.96 (t, J = 51.6 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 4.75 (s, 2H) , 3.69 (t, J = 5.0 Hz, 4H), 2.59 (t, J = 5.0 Hz, 4H), 2.50 (q, J = 7.2 Hz, 2H), 1.16 (t, J = 7.2 Hz, 3H); LRMS (ES) m/z 501.5 (M ⁺ +1).

The compounds shown in Table 13 below were synthesized according to substantially the same method as that of Example 100.

[Table 13]

Example 41: 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluoro Synthesis of -3-(1-methyl-4-piperidyl)phenyl]-1,3,4-thiadiazol-2-one (19682)

[Step 1] Synthesis of tert-butyl 4-[3-(aminocarbamosioyl)-2-fluoro-phenyl]piperidine-1-carboxylate

Tert-butyl 4-[2-fluoro-3-(hydrazinecarbonyl)phenyl]piperidine-1-carboxylate (100.00%, 0.200 g, 0.593 mmol) prepared in Step 3 of Example 26 and Lawesson's reagent (100.00 %, 0.288 g, 0.712 mmol) was dissolved in toluene (20 mL) at room temperature and stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous ammonium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (0.11 g, 52.51 %, yellow oil).

[Step 2] of tert-butyl 4-[2-fluoro-3-(2-oxo-3H-1,3,4-thiadiazol-5-yl)phenyl]piperidine-1-carboxylate synthesis

Tert-butyl 4-[3-(aminocarbamosthioyl)-2-fluoro-phenyl]piperidine-1-carboxylate (100.00%, 0.200 g, 0.566 mmol) synthesized in Step 1 and 1,1 A solution of '-carbonylbis-1H-imidazole (100.00 %, 0.110 g, 0.678 mmol) dissolved in dichloromethane (20 mL) at room temperature was stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous ammonium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 0 % to 40 %) to obtain the title compound (0.15 g, 69.86 %, white solid).

[Step 3] Tert-butyl 4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl Synthesis of ]-5-oxo-1,3,4-thiadiazol-2-yl]-2-flu-oro-phenyl]piperidine-1-carboxylate

Tert-butyl 4-[2-fluoro-3-(2-oxo-3H-1,3,4-thiadiazol-5-yl)phenyl]piperidine-1-carboxylate synthesized in Step 2 2-[6-(Bromo Methyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00 %, 0.059 g, 0.203 mmol) and potassium iodide (100.00 %, 0.016 g, 0.096 mmol) mmol) was added and stirred at the same temperature for 30 minutes. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 0 % to 30 %) to obtain the title compound (0.05 g, 44.15 %, white solid).

[Step 4] 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluoro -3-(4-piperidyl)phenyl]-1,3,4-thiadiazol-2-one Synthesis of 2,2,2-trifluoroacetic acid

Tert-butyl 4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl] synthesized in Step 3 methyl]-5-oxo-1,3,4-thiadiazol-2-yl]-2-fluoro-phenyl]piperidine-1-carboxylate (100.00%, 0.058 g, 0.099 mmol) and tri A solution of fluoroacetic acid (100.00 %, 0.034 g, 0.298 mmol) dissolved in dichloromethane (10 mL) at room temperature was stirred at the same temperature for 3 hours. After removing the solvent from the reaction mixture under reduced pressure, the obtained product was used without further purification (0.055 g, 92.64 %, yellow oil).

[Step 5] Synthesis of Compound 19682

3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluo synthesized in Step 4 Ro-3-(4-piperidyl)phenyl]-1,3,4-thiadiazol-2-one 2,2,2-trifluoroacetic acid (100.00 %, 0.055 g, 0.091 mmol), N -Ethyldiisopropylamine (100.00 % solution, 0.032 mL, 0.184 mmol), formaldehyde (100.00 %, 0.005 g, 0.167 mmol) and sodium triacetoxy-borohydride (100.00 %, 0.039 g, 0.184 mmol) at room temperature. A solution dissolved in dichloromethane (5 mL) was stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0 % to 5 %) to obtain the title compound (0.031 g, 67.58 %, white solid).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.32 (d, J = 1.6 Hz, 1H), 8.41 (dd, J = 8.2, 2.2 Hz, 1H), 7.77-7.73 (m, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.40-7.36 (m, 1H), 7.28-7.17 (m, 1H), 5.44 (s, 2H), 3.13-3.10 (m, 2H), 2.99-2.92 (m, 1H) , 2.43 (s, 3H), 2.26-2.20 (m, 2H), 1.98-1.86 (m, 4H); LRMS (ES) m/z 503.7 (M ⁺ +1).

The compounds shown in Table 14 below were synthesized according to substantially the same method as that of Example 41.

[Table 14]

Example 20 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(4-piperazine- Synthesis of 1-ylphenyl)-1,3,4-oxadiazol-2-one (19557)

[Step 1] Tert-butyl 4-(4-methoxycarbonylphenyl)piperazine-1-carboxylate

Methyl 4-bromobenzoate (100.00 %, 0.500 g, 2.325 mmol), tert-butyl piperazine-1-carboxylate (100.00 %, 1.200 equivalents, 2.790 mmol), tris(dibenzylideneacetone)dipalladium ( A solution of 100.00 %, 5.000 mol%, 0.116 mmol), After stirring at room temperature overnight, the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 0 % to 30 %) to obtain the title compound (0.73 g, 97.99 %, brown solid).

[Step 2] Tert-butyl 4-[4-(hydrazinecarbonyl)phenyl]piperazine-1-carboxylate

Tert-butyl 4-(4-methoxycarbonylphenyl)piperazine-1-carboxylate (100.00 %, 0.770 g, 2.403 mmol) and hydrazine monohydrate (100.00 %, 10.000 eq, 24.030 mmol) synthesized in Step 1. A solution dissolved in dichloromethane (5 mL) at room temperature was stirred at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 0 % to 30 %) to obtain the title compound (0.77 g, 100.0 %, yellow solid).

[Step 3] Tert-butyl 4-[4-(2-oxo-3H-1,3,4-oxadiazol-5-yl)phenyl]piperazine-1-carboxylate

Tert-butyl 4-[4-(hydrazinecarbonyl)phenyl]piperazine-1-carboxylate (100.00 %, 0.770 g, 2.403 mmol) and 1,1'-carbonylvice-1H-imit synthesized in step 2. A solution of Dazole (100.00%, 1.500 equivalent, 3.605 mmol) dissolved in dichloromethane (5 mL) at room temperature was heated to reflux overnight, and then the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 0 % to 100 %) to obtain the title compound (0.5 g, 60.06 %, yellow solid).

[Step 4] Tert-butyl 4-[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl ]-5-oxo-1,3,4-oxadiazol-2-yl]phenyl]piperazine-1-carboxylate

Tert-butyl 4-[4-(2-oxo-3H-1,3,4-oxadiazol-5-yl)phenyl]piperazine-1-carboxylate (100.00%, 0.500 g, synthesized in step 3) 1.443 mmol), 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.200 equivalents, 1.732 mmol), A solution of potassium carbonate (100.00 %, 2.000 equivalents, 2.887 mmol) and potassium iodide (100.00 %, 1.100 equivalents, 1.588 mmol) dissolved in N,N-dimethylformamide (25 mL) at room temperature was stirred at the same temperature. did. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 0 % to 50 %) to obtain the title compound (0.9 g, 112.2 %, yellow solid).

[Step 5] 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(4-piperazine -1-ylphenyl)-1,3,4-oxadiazol-2-one

Tert-butyl 4-[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl] synthesized in Step 4 methyl]-5-oxo-1,3,4-oxadiazol-2-yl]phenyl]piperazine-1-carboxylate (100.00 %, 0.900 g, 1.620 mmol) and 2,2,2-trifluoro A solution of acetic acid (100.00%, 10.000 equivalents, 16.200 mmol) dissolved in dichloromethane (50 mL) at room temperature was stirred at the same temperature. An aqueous N-sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol = 0 % to 10 %) to obtain the title compound (0.12 g, 16.26 %, white solid).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.29 (s, 1H), 8.39 (d, J = 10.0 Hz, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.0 Hz) , 1H), 7.06-6.80 (m, 3H), 5.18 (s, 2H), 3.27 (s, 4H), 3.02 (s, 4H); LRMS (ES) m/z 455.5 (M ⁺ +1).

The compounds in Table 15 below were synthesized according to substantially the same method as that of Example 20.

[Table 15]

Example 21: 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-(4 Synthesis of -methylpiperazin-1-yl)phenyl]-1,3,4-oxadiazol-2-one (19558)

3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5- synthesized in Step 5 of Example 20 (4-piperazine-1-ylphenyl)-1,3,4-oxadiazol-2-one (100.00 %, 0.060 g, 0.132 mmol), sodium triacetoxyborohydride (100.00 %, 2.000 eq. , 0.264 mmol) and formaldehyde (37.00%, 2.000 equivalents, 0.264 mmol) dissolved in dichloromethane (5 mL) at room temperature and stirred at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol = 0 % to 10 %) to obtain the title compound (0.025 g, 40.42 %, yellow solid).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.29 (s, 1H), 8.39 (d, J = 10.4 Hz, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.0 Hz) , 1H), 6.93-6.80 (m, 3H), 5.18 (s, 2H), 3.34 (s, 4H), 2.59 (s, 4H), 2.36 (s, 3H); LRMS (ES) m/z 470.6 (M ⁺ +1).

The compounds in Table 16 below were synthesized according to substantially the same method as that of Example 21.

[Table 16]

Example 6: 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[6-(4 Synthesis of -isopropylpiperazin-1-yl)-2-pyridyl]-1,3,4-oxadiazol-2-one (19454)

[Step 1] Synthesis of 6-fluoropyridine-2-carbohydrazide

Hydrazine monohydrate (100.00 % solution, 6.266 mL, 129.000 mmol) was added to a solution of methyl 6-fluoropyridine-2-carboxylate (100.00 %, 1.000 g, 6.446 mmol) dissolved in ethanol (30 mL) at room temperature. It was stirred overnight at temperature. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured with a saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (1 g, 100.00 %, pale yellow solid).

[Step 2] Synthesis of 5-(6-fluoro-2-pyridyl)-3H-1,3,4-oxadiazol-2-one

6-Fluoropyridine-2-carbohydrazide (100.00 %, 1.000 g, 6.446 mmol) and 1,1'-carbonylweis-1H-imidazole (100.00 %, 1.254 g, 7.734 mmol) synthesized in Step 1 ) was dissolved in tetrahydrofuran (30 mL) at room temperature, triethylamine (100.00 % solution, 1.251 mL, 9.000 mmol) was added and stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0 % to 10 %) to obtain the title compound (0.21 g, 17.987 %, yellow solid).

[Step 3] 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(6-fluoro Synthesis of -2-pyridyl)-1,3,4-oxadiazol-2-one

5-(6-fluoro-2-pyridyl)-3H-1,3,4-oxadiazol-2-one (100.00 %, 0.210 g, 1.160 mmol) and potassium carbonate (100.00 %) synthesized in step 2. , 0.244 g, 1.765 mmol) was dissolved in N,N-dimethylformamide (5 mL) at room temperature and 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl) )-1,3,4-oxadiazole (100.00%, 0.404 g, 1.393 mmol) was added and stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0 % to 10 %) to obtain the title compound (0.185 g, 40.88 %, pale yellow solid).

[Step 4] Synthesis of compound 19454

3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(6-fluoromethyl) synthesized in Step 3 Ro-2-pyridyl)-1,3,4-oxadiazol-2-one (100.00 %, 0.040 g, 0.103 mmol), 1-isopropylpiperazine (100.00 % solution, 0.029 mL, 0.203 mmol) and A solution of N,N-diisopropylethylamine (100.00 % solution, 0.027 mL, 0.150 mmol) dissolved in dimethyl sulfoxide (1 mL) at 130°C was stirred at the same temperature overnight, then lowered to room temperature. The reaction was terminated. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol/dichloromethane = 0 % to 10 %) to obtain the title compound (0.02 g, 39.15 %) as an orange solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.32 (d, J = 1.6 Hz, 1H), 8.43 (dd, J = 8.2, 2.2 Hz, 1H), 7.61-7.57 (m, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 6.96 (t, J = 51.6 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 5.27 (s, 2H) , 3.76 (s, 4H), 2.89-2.75 (m, 5H), 1.18 (d, J = 5.6 Hz, 6H); LRMS (ES) m/z 499.8 (M ⁺ +1).

The compounds in Table 17 below were synthesized according to substantially the same method as in Example 6.

[Table 17]

Example 19: 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-(1-methyl- Synthesis of 1H-indole-5-yl)-1,3,4-oxadiazole-2(3H)-thion (19544)

[Step 1] Synthesis of methyl 1-methylindole-5-carboxylate

Sodium hydride (60.00 %, 140.000 mg, 3.500 mg) was added to a solution of methyl 1H-indole-5-carboxylate (100.00 %, 0.500 g, 2.854 mmol) in N,N-dimethylformamide (7 mL) at 0 °C. mmol) was added and stirred at the same temperature for 0.2 hours. Iodomethane (100.00 % solution, 0.27 mL, 4.340 mmol) was added to the reaction mixture and stirred for additional 4 hours at room temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 0 % to 30 %) to obtain the title compound (0.27 g, 49.996 %, white solid).

[Step 2] Synthesis of 1-methylindole-5-carbohydrazide

Methyl 1-methylindole-5-carboxylate (100.00 %, 160.000 mg, 0.846 mmol) synthesized in Step 1 was dissolved in ethanol (2.5 mL) and hydrazine monohydrate (100.00 % solution, 0.8 mL, 16.490 mmol) was added at room temperature. After addition and stirring at 60°C for 18 hours, the temperature was lowered to room temperature to complete the reaction. After removing the solvent from the reaction mixture under reduced pressure, the obtained product was used without further purification (160 mg, 100.00 %, light yellow solid).

[Step 3] Synthesis of 5-(1-methylindol-5-yl)-3H-1,3,4-oxadiazol-2-one

1-Methylindole-5-carbohydrazide (100.00 %, 160.000 mg, 0.846 mmol) and N,N-diisopropylethylamine (Dipea, 100.00 % solution, 0.3 mL, 1.700 mmol) synthesized in step 2. Triphosgene (100.00%, 100.000 mg, 0.337 mmol) was added to a solution dissolved in dichloromethane (3 mL) at 0°C and stirred at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 10 % to 50 %) to obtain the title compound (270 mg, 148.36 %). , white solid) was obtained.

[Step 4] Synthesis of Compound 19544

5-(1-methylindol-5-yl)-3H-1,3,4-oxadiazol-2-one (100.00%, 50.000 mg, 0.232 mmol) synthesized in step 3 was reacted with N,N- Potassium carbonate (100.00 %, 35.000 mg, 0.353 mmol) was added to the solution dissolved in dimethylformamide (2 mL) and stirred at the same temperature for 0.3 hours. Add 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 80.000 mg, 0.276 mmol) to the reaction mixture. and stirred for additional 18 hours at 35°C. Saturated aqueous sodium chloride solution was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; hexane/ethyl acetate = 100 % to 50 %) to obtain the title compound (43 mg, 43.61 %, white solid).

¹ H NMR (400 MHz, CD ₃ OD) δ 9.27 (d, J = 1.2 Hz, 1H), 8.52 (dd, J = 8.4, 2.4 Hz, 1H), 8.10 (d, J = 0.8 Hz, 1H), 7.80 (s, 1H), 7.70 (t, J = 8.8 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 3.2 Hz, 1H), 7.21 (t, J = 51.6 Hz, 1H), 6.57 (dd, J = 3.2, 0.4 Hz, 1H), 5.25 (s, 2H), 3.86 (s, 3H); LRMS (ES) m/z 425.7 (M ⁺ +1).

The compounds shown in Table 18 below were synthesized according to substantially the same method as that of Example 19.

[Table 18]

Example 33: 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(1H-indole- Synthesis of 6-day)-1,3,4-oxadiazol-2-one (19642)

[Step 1] Synthesis of 1-tert-butoxycarbonylindole-6-carboxylic acid

4 in a solution of 1H-indole-6-carboxylic acid (100.00 %, 1.000 g, 6.205 mmol) and di-tert-butyl dicarbonate (100.00 %, 2.000 g, 9.164 mmol) in tetrahydrofuran (12 mL) at room temperature. -(Dimethylamino)pyridine (100.00 %, 0.150 g, 1.228 mmol) was added and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane = 0 % to 30 %) to obtain the title compound (0.8 g, 49.34 %, white solid).

[Step 2] Synthesis of tert-butyl 6-(hydrazinecarbonyl)-1H-indole-1-carboxylate

1-tert-butoxycarbonylindole-6-carboxylic acid (100.00%, 250 mg, 0.9568 mmol) synthesized in Step 1 was dissolved in tetrahydrofuran (5 mL) at room temperature and 1,1'-carbonylweiss was added to the solution. -1H-imidazole (100.00 %, 200.000 mg, 1.233 mmol) was added and stirred at the same temperature for 3 hours. Hydrazine monohydrate (100.00%, 145.000 mg, 2.897 mmol) was added to the reaction mixture and stirred for additional 18 hours at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the obtained product was used without additional purification (mixture, light yellow solid).

[Step 3] Synthesis of tert-butyl 6-(2-oxo-3H-1,3,4-oxadiazol-5-yl)indole-1-carboxylate

Tert-butyl 6-(hydrazinecarbonyl)indole-1-carboxylate (100.00 %, 450.000 mg, 1.635 mmol) and N,N-diisopropylethylamine (100.00 % solution, 0.56 mL, 3.200 mmol) synthesized in step 2. mmol) was dissolved in dichloromethane (5 mL), triphosgene (100.00 %, 190.000 mg, 0.640 mmol) was added at 0°C, and the mixture was stirred at room temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 10 % to 50 %) to obtain the title compound (270 mg, 54.82 %). , white solid) was obtained.

[Step 4] Tert-butyl 6-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5 Synthesis of -oxo-1,3,4-oxadiazol-2-yl]indole-1-carboxylate

Tert-butyl 6-(2-oxo-3H-1,3,4-oxadiazol-5-yl)indole-1-carboxylate (100.00%, 55.000 mg, 0.183 mmol) synthesized in step 3 was stirred at room temperature. Potassium carbonate (100.00 %, 25.000 mg, 0.252 mmol) was added to a solution dissolved in N,N-dimethylformamide (2 mL) and stirred at the same temperature for 0.3 hours. Add 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 64.000 mg, 0.221 mmol) to the reaction mixture. and stirred for additional 18 hours at 35°C. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; hexane/ethyl acetate = 100 % to 50 %) to obtain the title compound (58 mg, 62.25 %, white solid).

[Step 5] Synthesis of Compound 19642

Tert-butyl 6-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]- synthesized in Step 4 5-oxo-1,3,4-oxadiazol-2-yl] indole-1-carboxylate (100.00 %, 50.000 mg, 0.098 mmol) was dissolved in dichloromethane (1 mL) at room temperature. Fluoroacetic acid (100.00 % solution, 0.3 mL, 3.918 mmol) was added and stirred at the same temperature for 1 hour. The solvent was removed from the reaction mixture under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was poured into the resulting concentrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol = 100 % to 80 %) to obtain the title compound (34 mg, 84.59 %, light yellow solid).

¹ H NMR (400 MHz, CD ₃ OD) δ 9.27 (d, J = 1.6 Hz, 1H), 8.54 (dd, J = 8.2, 2.2 Hz, 1H), 7.93 (d, J = 0.8 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.53 (dd, J = 8.4, 1.6 Hz, 1H), 7.44 (d, J = 1.2 Hz, 1H), 7.26 (t, J = 51.6 Hz, 1H), 5.26 (s, 2H); LRMS (ES) m/z 412.8 (M ⁺ +1).

The compounds in Table 19 below were synthesized according to substantially the same method as that of Example 33.

[Table 19]

Example 11: 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(1,2, Synthesis of 3,4-tetrahydroisoquinolin-6-yl)-1,3,4-oxadiazol-2-one (19469)

[Step 1] Tert-butyl 7-(hydrazinecarbonyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate

2-tert-butyl,7-methyl 3,4-dihydro-1H-isoquinoline-2,7-dicarboxylate (100.00 %, 0.603 g, 2.070 mmol) and hydrazine monohydrate (100.00 %, 10.000 eq, 20.700 mmol) in ethanol (20 mL) at 70°C was stirred overnight at the same temperature, and then the temperature was lowered to room temperature to terminate the reaction. After removing the solvent from the reaction mixture under reduced pressure, the obtained product was used without further purification (0.603 g, 100.0 %, white solid).

[Step 2] Tert-butyl 7-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate

Tert-butyl 7-(hydrazinecarbonyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (100.00%, 0.640 g, 2.197 mmol) and 1,1'-carbonyl synthesized in Step 1 A solution of Weiss-1H-imidazole (100.00%, 1.500 equivalents, 3.296 mmol) dissolved in dichloromethane (5 mL) at 50°C was stirred at the same temperature overnight, and then the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane = 0 % to 100 %) to obtain the title compound (0.42 g, 60.25 %, white solid).

[Step 3] Tert-butyl 7-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5 -oxo-1,3,4-oxadiazol-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate

Tert-butyl 7-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate synthesized in Step 2 (100.00 %, 0.420 g, 1.324 mmol), 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00 %, 1.200 eq. , 1.588 mmol), potassium carbonate (100.00 %, 2.000 equivalents, 2.647 mmol) and potassium iodide (100.00 %, 1.100 equivalents, 1.456 mmol) dissolved in N,N-dimethylformamide (25 mL) at room temperature. was stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 0 % to 100 %) to obtain the title compound (0.55 g, 78.92 %, yellow solid).

[Step 4] Synthesis of Compound 19469

Tert-butyl 7-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]- synthesized in Step 3 5-oxo-1,3,4-oxadiazol-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (100.00 %, 0.550 g, 1.045 mmol) and 2,2, A solution of 2-trifluoroacetic acid (100.00%, 10.000 equivalents, 10.450 mmol) dissolved in dichloromethane (20 mL) at room temperature was stirred at the same temperature overnight. An aqueous N-sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol = 0 % to 10 %) to obtain the title compound (0.42 g, 94.29 %, yellow solid).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.31 (s, 1H), 8.42 (d, J = 8.4 Hz, 1H), 7.60 (s, 2H), 7.51 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.93 (t, J = 51.6 Hz, 1H), 5.21 (s, 2H), 4.09 (s, 2H), 3.19 (s, 2H), 2.88 (s, 2H) ; LRMS (ES) m/z 427.4 (M ⁺ +1).

Example 12: 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(2-methyl- Synthesis of 3,4-dihydro-1H-isoquinolin-7-yl)-1,3,4-oxadiazol-2-one (19497)

3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5- synthesized in step 4 of Example 11 (1,2,3,4-tetrahydroisoquinolin-7-yl)-1,3,4-oxadiazol-2-one (100.00 %, 0.080 g, 0.188 mmol), formaldehyde (100.00 %, 1.500 equivalents) , 0.281 mmol) and sodium triacetoxyborohydride (100.00 %, 2.000 equiv., 0.375 mmol) were dissolved in dichloromethane (5 mL) at room temperature and stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol = 0 % to 10 %) to obtain the title compound (0.02 g, 24.21 %, yellow solid).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.27 (s, 1H), 8.38 (d, J = 10.4 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 25.6 Hz) , 2H), 7.17 (d, J = 8.0 Hz, 1H), 6.93 (t, J = 51.6 Hz, 1H), 5.18 (s, 2H), 3.60 (s, 2H), 2.95 (t, J = 5.6 Hz) , 2H), 2.72 (t, J = 6.0 Hz, 2H), 2.45 (s, 3H); LRMS (ES) m/z 441.4 (M ⁺ +1).

The compounds in Table 20 below were synthesized according to substantially the same method as that of Example 12.

[Table 20]

Example 135: 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]-5- Synthesis of (2-methyl-3,4-dihydro-1H-isoquinolin-6-yl)-1,3,4-oxadiazole-2-thion (21116)

[Step 1] Synthesis of tert-butyl 6-(hydrazinecarbonyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate

2-tert-butyl,6-methyl 3,4-dihydro-1H-isoquinoline-2,6-dica-boxylate (100.00 %, 1.000 g, 3.433 mmol) was dissolved in ethanol (20 mL) at room temperature. Hydrazine monohydrate (100.00 % solution, 1.668 mL, 34.320 mmol) was added to the solution and stirred at 60°C overnight, and then the temperature was lowered to room temperature to terminate the reaction. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified and concentrated by column chromatography (SiO ₂ , 24 g cartridge; methanol/dichloromethane = 0% to 10%) to obtain the title compound (1 g, 100.0%). %, white solid) was obtained.

[Step 2] Synthesis of tert-butyl 6-(2-thioxo-3H-1,3,4-oxadiazol-5-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate

Tert-butyl 6-(hydrazinecarbonyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (100.00%, 0.642 g, 2.204 mmol) and potassium ethylxanthate (100.00%) synthesized in Step 1. , 0.353 g, 2.202 mmol) in ethanol (10 mL) at room temperature was stirred at 90°C overnight, and then the temperature was lowered to room temperature to terminate the reaction. A saturated aqueous ammonium chloride solution was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol = 0 % to 10 %) to obtain the title compound (0.03 g, 4.083 %, colorless oil).

[Step 3] Tert-Butyl 6-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl Synthesis of ]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate

Tert-butyl 6-(2-thioxo-3H-1,3,4-oxadiazol-5-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate synthesized in Step 2 ( 2-[6-(bromomethyl) in a solution of 100.00 %, 0.550 g, 1.650 mmol) and potassium carbonate (100.00 %, 0.229 g, 2.311 mmol) in N,N-dimethylformamide (10 mL) at room temperature. )-5-Fluoro-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.610 g, 1.980 mmol) was added and stirred at the same temperature overnight. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane = 0 % to 60 %) to obtain the title compound (0.395 g, 42.71 %, yellow solid).

[Step 4] 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]-5- Synthesis of (1,2,3,4-tetrahydroisoquinolin-6-yl)-1,3,4-oxadiazole-2-thion

Tert-butyl 6-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyri synthesized in Step 3 dil]methyl]-5-thioxo-1,3,4-oxadiazol-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (100.00 %, 0.395 g, 0.705 mmol ) and trifluoroacetic acid (100.00 % solution, 0.539 mL, 7.040 mmol) dissolved in dichloromethane (5 mL) at room temperature and stirred at the same temperature overnight. An aqueous N-sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (0.32 g, 98.64 %, yellow oil).

[Step 5] Synthesis of compound 21116

3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]-5 synthesized in Step 4 -(1,2,3,4-Tetrahydroisoquinolin-6-yl)-1,3,4-oxadiazole-2-thion (100.00 %, 0.060 g, 0.130 mmol), formaldehyde (37.00 % solution , 0.026 mL, 0.261 mmol) and N-ethyl-N-isopropyl-propan-2-amine (100.00 % solution, 0.045 mL, 0.258 mmol) in dichloromethane (1 mL) at room temperature for 30 minutes. After stirring, sodium triacetoxyborohydride (100.00%, 0.082 g, 0.389 mmol) was added and stirred at the same temperature for additional 18 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol = 0 % to 10 %) to obtain the title compound (0.021 g, 33.96 %, pale yellow solid).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.12 (s, 1H), 8.15 (dd, J = 9.0, 1.8 Hz, 1H), 7.79-7.76 (m, 2H), 7.17 (d, J = 8.0 Hz, 1H), 6.96 (t, J = 52.2 Hz, 1H), 4.80 (d, J = 1.6 Hz, 2H), 3.65 (s, 2H), 3.01 (t, J = 5.8 Hz, 2H), 2.76-2.73 ( m, 2H), 2.50 (s, 3H); LRMS (ES) m/z 475.9 (M ⁺ +1).

The compounds shown in Table 21 below were synthesized according to substantially the same method as that of Example 135.

[Table 21]

Example 69: 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(2-thiene 1) Synthesis of -6H-1,3,4-oxadiazin-2-one (20137)

[Step 1] Synthesis of [2-oxo-2-(2-thienyl)ethyl]acetate

Potassium acetate (100.00%) was added to a solution of 2-bromo-1-(2-thienyl)ethanone (100.00%, 0.500 g, 2.438 mmol) in N,N-dimethylformamide (10 mL) at room temperature. , 0.718 g, 7.316 mmol) and potassium iodide (100.00 %, 0.405 g, 2.440 mmol) were added and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (0.445 g, 99.078 %, yellow oil).

[Step 2] Synthesis of [(2E)-2-(methoxycarbonylhydrazono)-2-(2-thienyl)ethyl] acetate

[2-oxo-2-(2-thienyl)ethyl]acetate (100.00 %, 0.445 g, 2.416 mmol) and hydrogen chloride (1.00 M solution, 0.048 mL, 0.048 mmol) synthesized in Step 1 at room temperature. Methyl hydrazinocarboxylate (100.00 %, 0.239 g, 2.653 mmol) was added to the solution dissolved in methanol (10 mL) and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 0 % to 50 %) to obtain the title compound (0.425 g, 68.648 %, yellow solid).

[Step 3] Synthesis of 5-(2-thienyl)-3,6-dihydro-1,3,4-oxadiazin-2-one

[(2E)-2-(methoxycarbonylhydrazono)-2-(2-thienyl)ethyl]acetate (100.00%, 0.425 g, 1.658 mmol) synthesized in step 2 and sodium ethoxide (ca A solution of 20% in ethanol, 20.00 % solution, 0.962 mL, 2.500 mmol) dissolved in ethanol (10 mL) at room temperature was stirred at the same temperature for 30 minutes. A saturated aqueous ammonium chloride solution was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 0 % to 30 %) to obtain the title compound (0.2 g, 66.192 %, yellow solid).

[Step 4] Synthesis of Compound 20137

5-(2-thienyl)-3,6-dihydro-1,3,4-oxadiazin-2-one (100.00 %, 0.045 g, 0.247 mmol), 2-[6, synthesized in step 3 -(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00 %, 0.075 g, 0.259 mmol), potassium carbonate (100.00 %, 0.037 g , 0.373 mmol) and potassium iodide (100.00%, 0.020 g, 0.120 mmol) were dissolved in N,N-dimethylformamide (1 mL) at room temperature and stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, moisture was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane = 0 % to 60 %) to obtain the title compound (0.042 g, 43.45 %, pale yellow solid).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.32 (d, J = 1.6 Hz, 1H), 8.40 (dd, J = 8.2, 2.2 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.47 (dd, J = 5.2, 1.2 Hz, 1H), 7.25-7.24 (m, 1H), 7.11-7.09 (m, 1H), 6.96 (t, J = 51.6 Hz, 1H), 5.27 (s, 2H), 5.25 (s, 2H); LRMS (ES) m/z 392.3 (M ⁺ +1).

The compounds in Table 22 below were synthesized according to substantially the same method as in Example 69.

[Table 22]

Example 142: 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-phenyloxazol-2 Synthesis of (3H)-one (16974)

[Step 1] Synthesis of methyl 6-(((tert-butoxycarbonyl)amino)methyl)nicotinate

Di-tert-butyl dicarbonate (3.152 g, 14.442 mmol) and triethylamine were added to a solution of methyl 6-(aminomethyl)nicotinate (2.000 g, 12.035 mmol) in dichloromethane (20 mL) at room temperature. (2.516 mL, 18.053 mmol) was added and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, moisture was removed with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane = 0 % to 40 %) to obtain the title compound (1.700 g, 53.0 %, white solid).

[Step 2] Synthesis of methyl 6-(((tert-butoxycarbonyl)(phenylethanyl)amino)methyl) nicotinate

(Bromoethyneyl)benzene (0.200 g, 1.105 mmol) was dissolved in toluene (5 mL) and dissolved in methyl 6-(((tert-butoxycarbonyl)amino)methyl)nicotinate ( 80 by adding 0.353 g, 1.326 mmol), cooper(II) sulfate pentahydrate (0.055 g, 0.221 mmol), potassium phosphate (0.563 g, 2.651 mmol) and 1,10-phenanthroline (0.080 g, 0.442 mmol). After stirring at ℃ for 36 hours, the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a Celite pad to remove solids, the filtrate was removed under reduced pressure to remove the solvent, and the concentrate was subjected to column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate/hexane = 0% to 70%). Purification and concentration gave the title compound (0.110 g, 27.2 %, light yellow solid).

[Step 3] Synthesis of methyl 6-((2-oxo-5-phenyloxazol-3(2H)-yl)methyl)nicotinate

Methyl 6-(((tert-butoxycarbonyl)(phenylethanyl)amino)methyl)nicotinate (0.050 g, 0.136 mmol) synthesized in step 2 was dissolved in dichloromethane (0.5 mL) at room temperature. Silver bis(trifluoromethanesulfonyl)imide (0.003 g, 0.007 mmol) was added to the dissolved solution and stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, moisture was removed with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate/hexane = 0 % to 30 %) to obtain the title compound (0.030 g, 70.8 %, yellow solid).

[Step 4] Synthesis of 6-((2-oxo-5-phenyloxazol-3(2H)-yl)methyl)nicotinohydrazide

Methyl 6-((2-oxo-5-phenyloxazol-3(2H)-yl)methyl)nicotinate (0.016 g, 0.052 mmol) and hydrazine monohydrate (0.050 mL, 1.031 mmol) synthesized in Step 3. A solution dissolved in ethanol (1 mL) at 80°C was stirred at the same temperature for 18 hours, and then the temperature was lowered to room temperature to complete the reaction. After removing the solvent from the reaction mixture under reduced pressure, the obtained product was used without further purification (0.016 g, 100.0 %, white solid).

[Step 5] Synthesis of compound 16974

6-((2-oxo-5-phenyloxazol-3(2H)-yl)methyl)nicotinohydrazide (0.015 g, 0.048 mmol) and triethylamine (0.040 mL, 0.290 mmol) synthesized in step 4 ) was dissolved in tetrahydrofuran (0.7 mL) at room temperature, 2,2-difluoroacetic anhydride (0.024 mL, 0.193 mmol) was added and stirred at 80°C for 6 hours, then the temperature was lowered to room temperature for reaction. has ended. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, moisture was removed with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; hexane/ethyl acetate = 100 % to 50 %) to obtain the title compound (0.008 g, 44.7 %, white solid).

^1H NMR (400 MHz, CD ₃ OD) δ 9.28 (s, 1H), 8.53 (dd, J = 7.8, 2.2 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 7.6 Hz, 2H), 7.44-7.40 (m, 3H), 7.33 (t, J = 7.4 Hz, 1H), 7.26 (t, J = 51.4 Hz, 1H), 7.26 (t, J = 51.4 Hz, 1H) ), 5.09 (s, 2H); LRMS (ES) m/z 371.2 (M ⁺ +1).

The compounds shown in Table 23 below were synthesized according to substantially the same method as that of Example 142.

[Table 23]

Example 144: 1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-methyl-4-phenyl Synthesis of -1,3-dihydro-2H-imidazol-2-one (17738)

1-Methyl-5-phenyl-1,3-dihydro-2H-imidazol-2-one (0.050 g, 0.287 mmol) and 2-(6-(bromomethyl)pyridin-3-yl)-5- Potassium carbonate (0.060 g, 0.431 mmol) was added to a solution of (difluoromethyl)-1,3,4-oxadiazole (0.100 g, 0.345 mmol) in N,N-dimethylformamide (1 mL) at room temperature. ) and potassium iodide (0.010 g, 0.057 mmol) were added and stirred at 80°C for 18 hours, then the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, moisture was removed with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane/methanol = 100 % to 80 %) to obtain the title compound (0.012 g, 10.9 %, white solid).

^1H NMR (400 MHz, CDCl ₃ ) δ 8.18 (d, J = 8.4 Hz, 2H), 8.15 (dd, J = 4.2, 1.8 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.62 ~7.57 (m, 2H), 7.51 ~ 7.37 (m, 3H), 6.95 (t, J = 51.8 Hz, 1H), 6.79 (s, 1H), 5.66 (s, 2H), 3.51 (s, 3H); LRMS (ES) m/z 384.2 (M ⁺ +1).

Protocol for measuring and analyzing the activity of compounds of the present invention

<Experimental Example 1> Confirmation of inhibition of HDAC enzyme activity ( in vitro )

An experiment was conducted to confirm the selectivity of the compound represented by Formula I of the present invention for HDAC6 through HDAC1 and HDAC6 enzyme activity inhibition experiments.

HDAC enzyme activity was measured using the HDAC Fluorimetric Drug Discovery Kit (BML-AK511, 516) from Enzo Life Science. To test HDAC1 enzyme activity, human recombinant HDAC1 (BML-SE456) was used as an enzyme source and Fluor de Lys ^ⓡ -“SIRT1 (BNL-KI177) was used as a substrate. After dispensing 5-fold diluted compounds into a 96-well plate, 0.3 μg of enzyme and 10 μM substrate were added to each well and reacted at 30°C for 60 minutes. Fluor de Lys ^ⓡ Developer II (BML-KI176) was added and reacted for 30 minutes. After completion, the fluorescence values (Ex 360, Em 460) were measured using a multi-plate reader (Flexstation 3, Molecular Device). HDAC6 enzyme was tested using the same protocol as the HDAC1 enzyme activity test using human recombinant HDAC6 (382180) from Calbiochem. The final result was calculated by calculating each IC ₅₀ value using the GraphPad Prism 4.0 program. The results are summarized in Table 24 below.

[Table 24]

As described in Table 24 above, the activity inhibition test results for HDAC1 and HDAC6 show that the 1,3,4-oxadiazole derivative compounds of the present invention, their stereoisomers or pharmaceutically acceptable salts thereof have an inhibitory effect of about 185 to about It was confirmed that it exhibits excellent selective HDAC6 inhibitory activity of 3497 times.

Claims (10)

A 1,3,4-oxadiazole derivative compound represented by the following formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula I]

In Formula I above,
R ₁ is -C _1-4 haloalkyl;
X ₁ to X ₄ are each independently _CR
R _X is -H, -C _1-4 alkyl, -C _1-4 haloalkyl, or -halo;
Y is CR _Y or N;
_RY is -H or -C _1-4 alkyl;
Z is NR _Z , O, or S;
R _Z is -H or -C _1-4 alkyl;
W is O or S;
m is 0 or 1;
Ring V is aryl, heteroaryl, or hydroheteroaryl {wherein one or more H of the aryl, heteroaryl, or hydroheteroaryl ring is -C _1-4 alkyl, -C _1-4 aminoalkyl, -C _{1 -4} hydroxyalkyl, -C _1-4 haloalkyl, -halo, -(CH ₂ )n-cycloalkyl, -(CH ₂ )n-heterocycloalkyl, or -(CH ₂ )n-heteroaryl. [In this case, at least one H of the -(CH ₂ )n-cycloalkyl, -(CH ₂ )n-heterocycloalkyl, or -(CH ₂ )n-heteroaryl ring is -C _1-4 alkyl. , -C _1-4 may be substituted with haloalkyl, -halo, cycloalkyl, or heterocycloalkyl (wherein one or more H of the cycloalkyl or heterocycloalkyl ring may be substituted with -C _1-4 alkyl) )]};
n is 0, 1, or 2. According to claim 1,
R ₁ is -C _1-4 haloalkyl;
X ₁ is N;
X ₂ to X ₄ are each independently _CR
R
Y is CR _Y or N;
R _Y is -H;
Z is NR _Z , O, or S;
R _Z is -C _1-4 alkyl;
W is O or S;
m is 0 or 1;
Ring V is aryl, heteroaryl, or hydroheteroaryl {wherein one or more H of the aryl, heteroaryl, or hydroheteroaryl ring is -C _1-4 alkyl, -C _1-4 aminoalkyl, -halo, -(CH ₂ )n-cycloalkyl, -(CH ₂ )n-heterocycloalkyl, or -(CH ₂ )n-heteroaryl [In this case, the -(CH ₂ )n-cycloalkyl, -(CH ₂ )n-heterocycloalkyl, or -(CH ₂ )n-heteroaryl One or more H of the ring may be substituted with -C _1-4 alkyl, -halo, cycloalkyl, or heterocycloalkyl ( above, one or more H of the cycloalkyl or heterocycloalkyl ring may be substituted with -C _1-4 alkyl)]};
n is 0 or 1;
A 1,3,4-oxadiazole derivative compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. According to claim 1,
R ₁ is -CF ₂ H or -CF ₃ ;
A 1,3,4-oxadiazole derivative compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. According to claim 1,
X is CH or CF;
A 1,3,4-oxadiazole derivative compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. According to claim 1,
Y is CH or N;
Z is NC _1-4 alkyl, O, or S;
W is O or S;
m is 0 or 1;
A 1,3,4-oxadiazole derivative compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. According to claim 1,
Ring V is phenyl, 5-10 membered heteroaryl, or 9-10 membered hydroheteroaryl {wherein at least one H of the phenyl, 5-10 membered heteroaryl, or 9-10 membered hydroheteroaryl ring is -C _1-4 alkyl, -C _1-4 aminoalkyl, -halo, -(CH ₂ )n-cycloalkyl, -(CH ₂ )n-heterocycloalkyl, or -(CH ₂ )n-heteroaryl. [In this case, one or more H of the -(CH ₂ )n-cycloalkyl, -(CH ₂ )n-heterocycloalkyl, or -(CH ₂ )n-heteroaryl ring is -C _1-4 alkyl, -Can be substituted with halo, 4-6 membered cycloalkyl, or 4-6 membered heterocycloalkyl (wherein one or more H of the 4-6 membered cycloalkyl or 4-6 membered heterocycloalkyl ring is -C _{1- 4} may be substituted with alkyl)]};
n is 0 or 1;
A 1,3,4-oxadiazole derivative compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. According to claim 1,
The compound represented by Formula I is any one selected from the group consisting of the following compounds, a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:






. For the prevention or treatment of histone deacetylase 6-mediated diseases, comprising a compound represented by formula (I) according to any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Pharmaceutical composition. According to claim 8,
The histone deacetylase 6-mediated diseases include infectious diseases; neoplasm; Endocrine, nutritional and metabolic diseases; mental and behavioral disorders; neurological disease; eye and adnexal diseases; circulatory diseases; Respiratory diseases; digestive diseases; Skin and subcutaneous tissue diseases; Musculoskeletal and connective tissue diseases; or congenital malformations, deformities and chromosomal abnormalities;
Pharmaceutical composition for preventing or treating histone deacetylase 6-mediated diseases. According to clause 9,
The endocrine, nutritional and metabolic diseases are Wilson's disease, amyloidosis or diabetes,
The mental and behavioral disorder is depression or Rett syndrome,
The neurological disease is central nervous system atrophy, neurodegenerative disease, movement disorder, neuropathy, motor neuron disease, or central nervous system demyelinating disease,
The eye and adnexal disease is uveitis,
The skin and subcutaneous tissue disease is psoriasis,
The musculoskeletal and connective tissue diseases are rheumatoid arthritis, osteoarthritis, or systemic lupus erythematosus,
The above congenital malformations, deformities, and chromosomal abnormalities are autosomal dominant polycystic new types,
The infectious disease is prion disease,
The neoplasm is a benign tumor or a malignant tumor,
The circulatory disease is atrial fibrillation or stroke,
The respiratory disease is asthma,
The digestive disease is alcoholic liver disease, inflammatory bowel disease, Crohn's disease, or ulcerative bowel disease,
Pharmaceutical composition for preventing or treating histone deacetylase 6-mediated diseases.