1, 3, 4-oxadiazole derivative compounds as histone deacetylase 6 inhibitors and uses thereof

Abstract

The present invention relates to a novel compound having histone deacetylase 6 (HDAC6) inhibitory activity, and a preparation method and use thereof. The novel compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to the present invention has HDAC6 inhibitory activity, and is effective for the prevention or treatment of HDAC6-related diseases, including cancer, inflammatory diseases, autoimmune diseases, nervous system diseases, or neurodegenerative diseases.

Description

Technical Field

[0001] The present invention relates to a 1,3,4-oxadiazole derivative compound with novel structure and histone deacetylase 6 (HDAC 6) inhibitory activity, a preparation method and use thereof. Background Art

[0002] Post-translational modifications in cells, such as acetylation, are very important regulatory modules at the center of biological processes and are strictly controlled by a variety of enzymes. Histones are core proteins that make up chromatin, which serve as the axis around which DNA is wound and help DNA condense. In addition, the balance between acetylation and deacetylation of histones plays a crucial role in gene expression.

[0003] Histone deacetylase (HDAC) is an enzyme that removes the acetyl group of the lysine residue of the histone constituting chromatin, which is known to be related to gene silencing, and induces cell cycle arrest, angiogenesis inhibition, immunomodulation, cell death, etc. (Hassig et al., Curr. Opin. Chem. Biol. 1997, 1, 300-308). In addition, it is reported that inhibiting HDAC enzyme function can reduce the activity of cancer cell survival-related factors in vivo, and activate cancer cell death-related factors, thereby inducing the self-death of cancer cells (Warrell et al., J. Natl. Cancer Inst. 1998, 90, 1621-1625).

[0004] There are 18 known HDACs in humans, which can be divided into four categories based on their homology with yeast HDACs. Among them, the 11 HDACs with zinc as cofactor can be divided into three groups: Class I (HDAC1, 2, 3, and 8), Class II (IIa: HDAC4, 5, 7, and 9; IIb: HDAC6 and 10) and Class IV (HDAC 11). In addition, the 7 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).

[0005] Although various HDAC inhibitors are all still in the preclinical or clinical development stage, so far, only non-selective HDAC inhibitors are known to be used as anticancer agents, wherein vorinostat (vorinostat) (SAHA) and romidepsin (romidepsin) (FK228) have been approved for the treatment of cutaneous T-cell lymphoma, and panobinostat (panobinostat) (LBH-589) has been approved for the treatment of multiple myeloma. However, non-selective HDAC inhibitors are generally known to cause side effects such as fatigue, nausea, etc. (Piekarz et al., Pharmaceuticals 2010, 3, 2751-2767) at high doses. It is reported that these side effects are caused by the inhibition of Class I HDAC, and due to these side effects, non-selective HDAC inhibitors are restricted in drug development in the field outside anticancer drugs (Witt et al., Cancer Letters 277, (2009), 8-21).

[0006] At the same time, it has been reported that selective class II HDAC inhibition may not produce the toxicity exhibited by class I HDAC inhibition, and the development of selective HDAC inhibitors can solve the side effects such as toxicity caused by non-selective HDAC inhibition. Therefore, selective HDAC inhibitors are expected to be developed as effective treatments for a variety of diseases (Matthias et al., Mol. Cell. Biol. 2008, 28, 1688-1701).

[0007] HDAC6 is one of class IIb HDACs, and it is known that it is mainly present in the cytoplasm, and participates in the deacetylation of various non-histone substrates (HSP90, coractin, etc.) including tubulin (Yao et al., Mol. Cell 2005, 18, 601-607). HDAC6 may have two catalytic domains, and the zinc finger domain at the C-terminus may bind to ubiquitinated proteins. Since HDAC6 uses various non-histone proteins as substrates, it is known that it plays an important role in various diseases such as cancer, inflammatory diseases, autoimmune diseases, nervous system diseases, neurodegenerative diseases, etc. (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).

[0008] The common structural feature of various HDAC inhibitors is that they are composed of a cap group, a linker group and a zinc binding group (ZBG), as shown in the structure of vorinostat below. Many researchers have studied the inhibitory activity and selectivity of the enzyme by modifying the structure of the cap group and the linker group. It is known that the zinc binding group plays a more important role in the inhibitory activity and selectivity of the enzyme (Wiest et al., J. Org. Chem. 2013 78: 5051-5065; Methot et al., Bioorg. Med. Chem. Lett. 2008, 18, 973-978).

[0009]

[0010] Most zinc binding groups are hydroxamic acid or benzamide, among which hydroxamic acid derivatives show strong HDAC inhibition effect, but there are some problems such as low bioavailability and serious off-target activity. Benzamide contains aniline, so there is also the problem of generating toxic metabolites in vivo (Woster et al., Med. Chem. Commun. 2015, online publication).

[0011] Therefore, in order to treat cancer, inflammatory diseases, autoimmune diseases, neurological diseases, neurodegenerative diseases, etc., it is necessary to develop a selective HDAC6 inhibitor with a zinc-binding group that has no side effects and has improved bioavailability, unlike non-selective inhibitors that have side effects.

[0012] Prior art literature

[0013] WO 2011 / 091213: ACY-1215

[0014] WO 2011 / 011186: Tubastatin

[0015] WO 2013 / 052110: Sloan-K

[0016] WO 2013 / 041407: Cellzome

[0017] WO 2013 / 134467: Kozi

[0018] WO 2013 / 008162: Novartis

[0019] WO 2013 / 080120: Novartis

[0020] WO 2013 / 066835: Tempero

[0021] WO 2013 / 066838: Tempero

[0022] WO 2013 / 066833: Tempero

[0023] WO 2013 / 066839: Tempero Summary of the invention

[0024] Technical issues

[0025] One object of the present invention is to provide a compound having selective histone deacetylase 6 (HDAC6) inhibitory activity, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0026] 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.

[0027] Another object of the present invention is to provide a method for preparing the same.

[0028] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating diseases related to HDAC6 activity.

[0029] Another object of the present invention is to provide a use of the compound in preparing a drug for preventing or treating diseases related to HDAC6 activity.

[0030] 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 compound as described above.

[0031] Another object of the present invention is to provide a method for preventing or treating diseases related to HDAC6 activity.

[0032] Solution to the problem

[0033] The present inventors have discovered an oxadiazole derivative compound having histone deacetylase 6 (HDAC6) inhibitory activity, and used the oxadiazole derivative compound to inhibit or treat diseases associated with HDAC6 activity, thereby completing the present invention.

[0034] The following will be described in detail. All combinations of the various elements disclosed herein are within the scope of the present invention. In addition, the scope of the present invention is not limited by the following specific description.

[0035] 1,3,4-Oxadiazole derivatives

[0036] In one general aspect, the present invention provides a 1,3,4-oxadiazole derivative compound represented by the following Chemical Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0037] [Chemical Formula I]

[0038]

[0039] In the above chemical formula I,

[0040] R1 is -C 1-4 Haloalkyl;

[0041] X1 to X4 are each independently CR X or N;

[0042] R X -H, -C 1-4 Alkyl, -C 1-4 Haloalkyl or -halogen;

[0043] Y is CR Y or N;

[0044] R Y -H or -C 1-4 alkyl;

[0045] Z is NR Z , O or S;

[0046] R Z -H or -C 1-4 alkyl;

[0047] W is O or S;

[0048] m is 0 or 1;

[0049] Ring V is aryl, heteroaryl or hydroheteroaryl {wherein at least one H in the aryl, heteroaryl or hydroheteroaryl ring may be replaced by -C 1-4 Alkyl, -C 1-4 Aminoalkyl, -C 1-4 Hydroxyalkyl, -C 1-4 The haloalkyl, -halogen, -(CH2)n-cycloalkyl, -(CH2)n-heterocyclyl or -(CH2)n-heteroaryl groups are substituted [wherein at least one H in the -(CH2)n-cycloalkyl, -(CH2)n-heterocyclyl or -(CH2)n-heteroaryl ring may be replaced by -C 1-4 Alkyl, -C 1-4 Haloalkyl, -halogen, cycloalkyl or heterocyclyl substituted (wherein at least one H in the cycloalkyl or heterocyclyl ring may be replaced by -C 1-4 alkyl substituted)]}; and

[0050] n is 0, 1 or 2.

[0051] According to one embodiment of the present invention, the compound represented by Chemical Formula I may be within the following range:

[0052] R1 is -C 1-4 Haloalkyl;

[0053] X1 is N;

[0054] X2 to X4 are each independently CR X ;

[0055] R X is -H or -halogen;

[0056] Y is CR Y or N;

[0057] R Y -H

[0058] Z is NR Z , O or S;

[0059] R Z For -C 1-4 alkyl;

[0060] W is O or S;

[0061] m is 0 or 1;

[0062] Ring V is aryl, heteroaryl or hydroheteroaryl {wherein at least one H on the aryl, heteroaryl or hydroheteroaryl ring may be replaced by -C 1-4 Alkyl, -C 1-4 aminoalkyl, -halogen, -(CH2)n-cycloalkyl, -(CH2)n-heterocyclyl or -(CH2)n-heteroaryl [wherein, at least one H on the -(CH2)n-cycloalkyl, -(CH2)n-heterocyclyl or -(CH2)n-heteroaryl ring may be replaced by -C 1-4 Alkyl, -halogen, cycloalkyl or heterocyclic group is substituted (wherein at least one H on the cycloalkyl or heterocyclic ring can be replaced by -C 1-4 alkyl substituted)]}; and

[0063] n is 0 or 1.

[0064] In addition, according to one embodiment of the present invention, the compound represented by Chemical Formula I may be within the following range:

[0065] R1 is -CF2H or -CF3.

[0066] In addition, according to one embodiment of the present invention, the compound represented by Chemical Formula I may be within the following range:

[0067] X1 is N; and

[0068] X2 to X4 are each independently CH or CF.

[0069] In addition, according to one embodiment of the present invention, the compound represented by Chemical Formula I may be within the following range:

[0070] Y is CH or N;

[0071] Z is NC 1-4 Alkyl, O or S;

[0072] W is O or S; and

[0073] m is 0 or 1.

[0074] In addition, according to one embodiment of the present invention, the compound represented by Chemical Formula I may be within the following range:

[0075] Ring V is phenyl, 5-10 membered heteroaryl or 9-10 membered hydrogen heteroaryl {wherein at least one H in the phenyl, 5-10 membered heteroaryl or 9-10 membered hydrogen heteroaryl ring may be replaced by -C 1-4 Alkyl, -C 1-4 aminoalkyl, -halogen, -(CH2)n-cycloalkyl, -(CH2)n-heterocyclyl or -(CH2)n-heteroaryl [wherein at least one H in the -(CH2)n-cycloalkyl, -(CH2)n-heterocyclyl or -(CH2)n-heteroaryl ring may be replaced by -C 1-4 Alkyl, -halogen, 4-6 membered cycloalkyl or 4-6 membered heterocyclic group (wherein at least one H in the 4-6 membered cycloalkyl or 4-6 membered heterocyclic ring may be replaced by -C 1-4 alkyl substituted)]}; and

[0076] n is 0 or 1.

[0077] In addition, according to one embodiment of the present invention, the specific compounds represented by Chemical Formula I of the present invention are shown in Table 1 below:

[0078] [Table 1]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086] In the present invention, unless otherwise specified, the term "alkyl" as used herein may refer to a linear or branched acyclic, cyclic or saturated hydrocarbon in which carbon atoms are linked. For example, "C 1-4 "Alkyl" may refer to an alkyl group containing 1 to 4 carbon atoms. Non-cyclic alkyl groups may include, for example, methyl, ethyl, n-propyl, n-butyl, isopropyl, sec-butyl, isobutyl, tert-butyl, etc., but are not limited thereto. Cyclic alkyl groups may be used interchangeably with "cycloalkyl" in this specification, and may include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc., but are not limited thereto.

[0087] In the present invention, "alkoxy" may refer to -(O-alkyl) as an alkyl ether group, wherein alkyl is as defined above. For example, "C 1-4 "Alkoxy" may refer to a C 1-4 Alkoxy of an alkyl group, i.e., -(OC 1-4 alkyl); examples of alkoxy may include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

[0088] In the present invention, "halogen" may be F, Cl, Br or I.

[0089] In the present invention, the term "haloalkyl" may refer to a straight or branched alkyl (hydrocarbon) having a carbon atom substituted by at least one halogen as defined herein. Examples of haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl or n-butyl independently substituted by at least one halogen (e.g., F, Cl, Br or I).

[0090] In the present invention, the term "hydroxyalkyl" may refer to a straight or branched alkyl (hydrocarbon) group in which a carbon atom is substituted by -OH. Examples of hydroxyalkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl or n-butyl groups independently substituted by at least one hydroxyl group.

[0091] In the present invention, the term "aminoalkyl" may refer to a straight or branched alkyl (hydrocarbon) chain whose carbon atom is substituted by an amino group-(NR'R"). In this context, R' and R" may be independently selected from hydrogen and C 1-4 The selected R' and R" may each independently be substituted or unsubstituted.

[0092] In the present invention, the term "heterocyclic group" may refer to a ring containing 1 to 5 heteroatoms selected from N, O and S as ring atoms, which may be saturated or partially unsaturated. In this article, when the heterocyclic group is unsaturated, it may be referred to as heterocyclic alkene. Unless otherwise specified, the heterocyclic group may be a monocyclic or polycyclic ring, such as a spirocyclic ring, a bridged ring or a condensed ring. In addition, "3 to 12 membered heterocyclic groups" may refer to heterocyclic groups containing 3 to 12 ring atoms. Examples of heterocyclic groups may include, but are not limited to, pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-24 (1H, 3H) -dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S, S-oxide, piperazine , pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1S,4S)-2-azabicyclo[2.2.2]octane or (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane, etc.

[0093] In the present invention, "aromatic hydrocarbon" refers to an aromatic hydrocarbon ring. The aromatic hydrocarbon may be a monocyclic aromatic hydrocarbon or a polycyclic aromatic hydrocarbon. The number of ring carbon atoms in the aromatic hydrocarbon may be 5 or more to 30 or less, 5 or more to 20 or less, or 5 or more to 15 or less. Examples of aromatic hydrocarbons may include, but are not limited to, benzene, naphthalene, fluorene, anthracene, phenanthrene, biphenyl, terphenyl, quaterphenyl, pentaphenyl, hexaphenyl, triphenylene, pyrene, benzofluoranthene, In the present specification, a part obtained by removing one hydrogen atom from the above-mentioned "aromatic hydrocarbon" is referred to as "aryl group".

[0094] In the present invention, "heteroaromatic hydrocarbon" may refer to a ring containing one or more of O, N, P, Si and S as a heteroelement. The number of carbon atoms in the ring of the heteroaromatic hydrocarbon may be 2 or more to 30 or less, or 2 or more to 20 or less. The heteroaromatic hydrocarbon may be a monocyclic heteroaromatic hydrocarbon or a polycyclic heteroaromatic hydrocarbon. The polycyclic heteroaromatic hydrocarbon may, for example, have a bicyclic structure or a tricyclic structure. Examples of heteroaromatic hydrocarbons include, but are not limited to, thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, bipyridine, triazine, acridine, pyridazine, pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazole In one embodiment of the present invention, heteroaromatic hydrocarbons may also include bicyclic heteroaromatic hydrocarbons, including aromatic hydrocarbon rings fused to heterocyclic rings or heteroaromatic hydrocarbons fused to cycloalkyl rings. In this specification, the part obtained by removing a hydrogen atom from the above-mentioned "heteroaromatic hydrocarbons" is referred to as "heteroaromatic hydrocarbons".

[0095] The compound represented by the chemical formula I of the present invention may contain at least one asymmetric carbon, and therefore may exist in the form of a racemate, a racemic mixture, a single enantiomer, a diastereomeric mixture, and each diastereoisomer. These stereoisomers may be separated by conventional techniques, for example, the compound represented by the chemical formula I may be separated by column chromatography, HPLC, etc. In addition, each stereoisomer of the compound represented by the chemical formula I may be synthesized stereospecifically using optically pure starting materials and / or reagents of known configuration.

[0096] In the present invention, the term "enantiomer" used herein refers to a compound or salt thereof having the same chemical formula or molecular formula but different spatial arrangements. Each of these enantiomers and mixtures thereof are also included within the scope of the present invention. Unless otherwise specified, a solid bond (-) connected to an asymmetric carbon atom may include a wedge-shaped solid bond indicating the absolute arrangement of a stereocenter. or dotted wedge key

[0097] The compound represented by the chemical formula I of the present invention may exist in the form of a "pharmaceutically acceptable salt". As the salt, an acid addition salt formed from a pharmaceutically acceptable free acid may be used. The term "pharmaceutically acceptable salt" as used herein refers to a concentrate having a relatively non-toxic and harmless effective effect on the patient, including any organic acid or inorganic acid addition salt of the compound represented by the chemical formula I, wherein the side effects caused by these salts do not reduce the beneficial effects of the compound.

[0098] 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 with a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equimolar amounts of the compound and the acid or alcohol are dissolved in water and heated, and the mixture can then be evaporated to dryness, or the precipitated salt can be filtered by suction.

[0099] In this case, as the free acid, an organic acid and an inorganic acid may be used, wherein the inorganic acid may include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, etc., and the organic acid may include methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. However, the organic acid and the inorganic acid are not limited thereto.

[0100] In addition, a base can also be used to prepare a pharmaceutically acceptable metal salt. Alkali metal salts or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. Here, as metal salts, sodium salts, potassium salts or calcium salts are particularly suitable in pharmacy, but metal salts are not limited thereto. In addition, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0101] Unless otherwise indicated, the pharmaceutically acceptable salts of the present invention include salts of acidic or basic groups that may be present in the compounds represented by the above chemical formula I. For example, pharmaceutically acceptable salts may include sodium salts, calcium salts, potassium salts of hydroxyl groups, and other pharmaceutically acceptable salts of amino groups may include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), p-toluenesulfonate (tosylate), etc. These salts can be prepared by salt preparation methods known in the art.

[0102] Method for preparing 1,3,4-oxadiazole derivative compounds

[0103] The present invention provides a method for preparing a 1,3,4-oxadiazole derivative compound represented by the following chemical formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0104] [Chemical Formula I]

[0105]

[0106] Formula I is as defined above.

[0107] In the present invention, preferred methods for preparing the oxadiazole derivative compound represented by Chemical Formula I, its stereoisomers or pharmaceutically acceptable salts thereof are shown in the following [Reaction Scheme 1] to [Reaction Scheme 8], which also include modified preparation methods that are obvious to those skilled in the art.

[0108] [Reaction Scheme 1]

[0109]

[0110] According to the above reaction scheme 1, hydrazine is added to compound 1-1 to prepare compound 1-2, which is then reacted with trifluoroacetic anhydride or difluoroacetic anhydride to prepare compound 1-3, and then subjected to bromination reaction to synthesize compound 1-4. Compound 1-4 is the Zn binding sub-part of the HDAC 6 inhibitor and is used as an intermediate for the synthesis of all compounds.

[0111] [Reaction Scheme 2]

[0112]

[0113] According to the above reaction scheme 2, compound 2-2 is prepared from compound 2-1 using hydrazine, and then 1,3,4-oxadiazole-2(3H)-thione compound 2-4 is prepared using CDI using 1,3,4-oxadiazole-2(3H)-thione compound 2-4. In addition, compound 2-3 can be prepared by adding Lawesson's reagent to compound 2-2, and then 1,3,4-thiadiazole-2(3H)-one compound 2-4 is prepared by using CDI. Compound 2-5 is prepared by a substitution reaction of compound 2-4 with compound 1-4. Examples of compound 2-5 prepared by the above reaction scheme 2 may include compound numbers 1, 5, 15, 16, 17, 18, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60, 61, 62, and the like.

[0114] [Reaction Scheme 3]

[0115]

[0116] In reaction scheme 3, compound 3-1 having an aldehyde structure is subjected to a reductive amination reaction to prepare compound 3-2, and then hydrazine is used to prepare compound 3-3, and then CDI is used to prepare 1,3,4-oxadiazol-2(3H)-one compound 3-4. Then, compound 3-5 can be prepared by a substitution reaction with compound 1-4. Examples of compound 3-5 prepared by the above reaction scheme 3 may include compound numbers 2, 4, and the like.

[0117] [Reaction Scheme 3-1]

[0118]

[0119] In reaction scheme 3-1, dioxolane compound 3-1-1 with an aldehyde structure is prepared from compound 3-1 using ethylene glycol, and then compound 3-1-2 is prepared using hydrazine. Then, 1,3,4-oxadiazole-2(3H)-one and potassium ethylxanthate are used to prepare 1,3,4-oxadiazole-2(3H)-thione compound 3-1-3 using CDI. Then, compound 3-1-4 is prepared by a substitution reaction with compound 1-4, and compound 3-1-5 is prepared by removing the aldehyde protecting group dioxolane using iron (III) chloride hexahydrate. Then, compound 3-5 can be prepared by a reductive amination reaction. Examples of compound 3-5 prepared by reaction scheme 3-1 may include compound numbers 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 107, 108, 109, 110, 111, 112, 113, 114, 117, 118, 119, 120, 121, 122, 123, 124, 125, 128, 129, 130, 131, 132, 133, 134, etc.

[0120] [Reaction Scheme 3-2]

[0121]

[0122] In reaction scheme 3-2, compound 3-1 having an aldehyde structure is subjected to a reductive amination reaction to prepare compound 3-2-1, and then compound 3-2-2 is prepared using hydrazine, and then 1,3,4-oxadiazole-2(3H)-thione compound 3-2-4 is prepared using CDI by using 1,3,4-oxadiazole-2(3H)-one and potassium ethylxanthate. In addition, compound 3-2-3 is prepared by adding Lawesson's reagent to compound 3-2-2, and then 1,3,4-thiadiazole-2(3H)-one compound 3-2-4 is prepared by using CDI. Then, compound 3-2-5 is prepared by a substitution reaction of compound 3-2-4 with compound 1-4, compound 3-2-6 is prepared by removing the amine protecting group, and then a reductive amination reaction is performed to prepare compound 3-2-7. Examples of compound 3-2-7 prepared by the above reaction scheme 3-2 may include compound numbers 63, 64, 65, 66, 67, 68, 77, 78, 79, 83, and the like.

[0123] [Reaction Scheme 4]

[0124]

[0125] In reaction scheme 4, the ester compound 4-1 having a halogen element is subjected to a CC coupling (Suzuki coupling) reaction to prepare compound 4-2, and then a reduction reaction is performed to prepare compound 4-3. In addition, compound 4-3 is prepared from compound 4-1 by CN coupling (Buchwald reaction) and substitution reaction. Then, compound 4-4 is prepared using hydrazine, and then 1,3,4-oxadiazole-2 (3H) -thione compound 4-6 is prepared using CDI by using 1,3,4-oxadiazole-2 (3H) -one and potassium ethyl xanthate. In addition, compound 4-5 is prepared by adding Lawesson reagent to compound 4-4, and then 1,3,4-thiadiazole-2 (3H) -one compound 4-6 is prepared by using CDI. Subsequently, compound 4-7 is prepared by a substitution reaction with compound 1-4, and then compound 4-8 is prepared by removing the amino protecting group. Examples of compound 4-8 may include compound numbers 20, 23, 36, and the like. Then, compound 4-9 is prepared by a reductive amination reaction. Examples of compounds 4-9 prepared by the above reaction scheme 4 may include compound numbers 8, 9, 10, 21, 22, 24, 25, 26, 29, 30, 37, 38, 39, 40, 41, 55, 56, 57, 58, 75, 76, 80, 81, 82, 100, 101, 102, 103, 104, 105, 106, 115, 116, 126, 127, etc.

[0126] In addition, compound 4-10 can be prepared by reductive amination of compound 4-8 prepared according to Reaction Scheme 4, and compound 4-11 can be prepared by removing the amine protecting group and then reductive amination to prepare compound 4-12. Examples of compound 4-12 may include compound Nos. 27, 28, and the like.

[0127] [Reaction Scheme 4-1]

[0128]

[0129] In reaction scheme 4-1, compound 4-2 is prepared from ester compound 4-1 having a halogen element using hydrazine, and 1,3,4-oxadiazol-2(3H)-one compound 4-3 is prepared using CDI. Then, compound 4-4 is prepared by a substitution reaction with compound 1-4, and then an amine substitution reaction is performed to prepare compound 4-9. Examples of compounds prepared by the above reaction scheme 4-1 may include compound numbers 6, 7, etc.

[0130] [Reaction Scheme 5]

[0131]

[0132] In Reaction Scheme 5, Compound 5-1 containing an amine is subjected to an amine protecting group and alkylation reaction to prepare Compound 5-2, and then Compound 5-3 is prepared using hydrazine, and then 1,3,4-oxadiazole-2(3H)-one and potassium ethylxanthate are used to prepare 1,3,4-oxadiazole-2(3H)-thione Compound 5-4 using CDI. Then, Compound 5-5 is prepared by a substitution reaction with Compound 1-4. Examples of Compound 5-5 prepared by Reaction Scheme 5 may include Compound Nos. 19, 31, 32, and the like.

[0133] Furthermore, compound 5-6 can be prepared by removing the amine protecting group of compound 5-5 prepared according to reaction scheme 5, and examples of compound 5-6 may include compound numbers 3, 11, 33, 34, 35, and the like.

[0134] Then, compound 5-7 is prepared by reductive amination reaction. Examples of compound 5-7 prepared by the above reaction scheme 5 may include compound numbers 12, 13, 14, 135, 136, 137, 138, 139, 140, 141, and the like.

[0135] [Reaction Scheme 6]

[0136]

[0137] In reaction scheme 6, bromine compound 6-1 is subjected to substitution reaction to prepare acetate compound 6-2, and then subjected to substitution reaction to prepare hydrazine carboxylate compound 6-3, and then 1,3,4-oxadiazine-2-one compound 6-4 is prepared by using sodium ethoxide. Then, compound 6-5 is prepared by substitution reaction with compound 1-4. Examples of compound 6-5 prepared by the above reaction scheme 6 may include compound numbers 69, 70, 71, 72, 73, 74, and the like.

[0138] [Reaction Scheme 7]

[0139]

[0140] In reaction scheme 7, compound 7-1 is protected by an amine protecting group to prepare compound 7-2, and then a triple bond compound 7-4 is prepared by a substitution reaction with compound 7-3, and then bis(trifluoromethanesulfonyl)imide silver is used to prepare oxazol-2(3H)-one compound 7-5. Subsequently, hydrazine can be used to prepare compound 7-6, and then reacted with trifluoroacetic anhydride or difluoroacetic anhydride to prepare compound 7-7. Examples of compounds prepared by reaction scheme 7 may include compound numbers 142, 143, and the like.

[0141] [Reaction Scheme 8]

[0142]

[0143] In Reaction Scheme 8, Compound 8-2 can be prepared by a substitution reaction of imidazol-2-one Compound 8-1 with Compound 1-4. Examples of the compound prepared by Reaction Scheme 8 include Compound No. 144 and the like.

[0144] Uses of 1,3,4-oxadiazole derivatives

[0145] The present invention provides the use of the compound represented by the following chemical formula I, its stereoisomer or a pharmaceutically acceptable salt thereof:

[0146] [Chemical Formula I]

[0147]

[0148] Formula I is as defined above.

[0149] According to one embodiment of the present invention, the present invention provides a pharmaceutical composition comprising a compound represented by Chemical Formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

[0150] Further, according to one embodiment of the present invention, the present invention provides a pharmaceutical composition for preventing or treating diseases related to histone deacetylase 6 activity, which comprises a compound represented by the above chemical formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition of the present invention selectively inhibits histone deacetylase 6, thereby showing a significant effect in preventing or treating diseases related to histone deacetylase 6 activity.

[0151] Diseases associated with histone deacetylase 6 (HDAC6) activity include cancer, inflammatory diseases, autoimmune diseases, nervous system diseases or neurodegenerative diseases, specifically including lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, brain cancer, ovarian cancer, gastric 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, as well as symptoms or diseases associated with abnormal histone deacetylase function.

[0152] According to one embodiment of the present invention, examples of histone deacetylase-mediated diseases may include infectious diseases; tumors; endocrine, nutritional and metabolic diseases; mental and behavioral disorders; nervous system diseases; eye and eye appendage diseases; circulatory system diseases; respiratory system diseases; digestive system diseases; skin and subcutaneous tissue diseases; musculoskeletal and connective tissue diseases; or congenital malformations, mutations and chromosomal abnormalities. In addition, histone deacetylase-mediated diseases include symptoms or diseases associated with abnormal histone deacetylase 6 function.

[0153] In the present invention, infectious diseases can be prion diseases. In addition, tumors can be benign tumors (for example, myelodysplastic syndrome) or malignant tumors (for example, multiple myeloma, lymphoma, leukemia, lung cancer, colorectal cancer, colon cancer, prostate cancer, urothelial cell cancer, breast cancer, melanoma, skin cancer, liver cancer, brain cancer, gastric cancer, ovarian cancer, pancreatic cancer, head and neck cancer, oral cancer or glioma). In addition, endocrine, nutritional and metabolic diseases can be Wilson's disease, amyloidosis or diabetes. In addition, mental and behavioral disorders can be depression or Rett syndrome. In addition, nervous system diseases can include central nervous system atrophy (e.g., Huntington's disease, spinal muscular atrophy (SMA), spinocerebellar ataxia (SCA)), neurodegenerative diseases (e.g., Alzheimer's disease), movement disorders (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 central nervous system demyelinating disease (e.g., multiple sclerosis (MS)). In addition, eye and eye adnexa diseases can be uveitis. In addition, circulatory system diseases can be atrial fibrillation or stroke. In addition, respiratory system diseases can be asthma. In addition, digestive system diseases can be alcoholic liver disease, inflammatory bowel disease, Crohn's disease or ulcerative bowel disease. In addition, skin and subcutaneous tissue diseases can be psoriasis. In addition, musculoskeletal and connective tissue diseases can be rheumatoid arthritis, osteoarthritis or systemic lupus erythematosus (SLE). In addition, congenital malformations, mutations, and chromosomal abnormalities can cause autosomal dominant polycystic kidney disease.

[0154] The stereoisomers and pharmaceutically acceptable salts are as described above in the stereoisomers and pharmaceutically acceptable salts of the compound represented by Chemical Formula I of the present invention.

[0155] In order to apply, the pharmaceutical composition of the present invention can also include at least one or more pharmaceutically acceptable carriers in addition to the compound represented by chemical formula I, its stereoisomer or its pharmaceutically acceptable salt.Pharmaceutically acceptable carriers can be saline, sterile water, Ringer's solution, buffered saline, glucose solution, maltodextrin solution, glycerol, ethanol or a mixture of one or more of these components, and other conventional additives, such as antioxidants, buffers, antibacterial agents, etc., can be included if necessary.In addition, diluents, dispersants, surfactants, adhesives and lubricants can be added additionally, and injectable dosage forms (such as aqueous solutions, suspensions, emulsions, etc.), pills, capsules, granules or tablets can be formulated.Therefore, the pharmaceutical composition of the present invention can be a patch, a liquid, a pill, a capsule, a granule, a tablet, a suppository, etc. These preparations can be prepared by the conventional methods or documents disclosed in the art [see, Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton PA] for preparations, and various preparations can be formulated according to each disease or component.

[0156] The composition of the present invention can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage varies according to the patient's weight, age, sex, health status, diet, administration time, administration method, excretion rate and disease severity. The daily dose of the compound represented by the chemical formula I of the present invention is about 1 to 1000 mg / kg, preferably 5 to 100 mg / kg, which can be divided and administered once or multiple times a day.

[0157] The pharmaceutical composition of the present invention may contain, in addition to the compound represented by Formula I, its stereoisomers or pharmaceutically acceptable salts thereof, at least one active ingredient exhibiting the same or similar efficacy.

[0158] According to one embodiment of the present invention, the present invention provides a method for preventing or treating a disease related to histone deacetylase 6 activity, comprising: administering to a subject in need thereof a therapeutically effective amount of a compound represented by chemical formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The subject may be a mammal, including a human.

[0159] The method for preventing or treating a disease related to histone deacetylase 6 activity includes not only treating the disease itself before the onset of symptoms, but also inhibiting or avoiding its symptoms by administering a compound represented by Chemical Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In addition, the method for preventing or treating a disease related to histone deacetylase 6 activity of the present invention may further administer a therapeutically effective amount of another active agent that helps treat the disease together with the compound represented by Chemical Formula I, wherein the other active agent may exhibit a synergistic or auxiliary effect together with the compound represented by the above-mentioned Chemical Formula I.

[0160] The term "therapeutically effective amount" as used herein refers to the amount of the compound represented by chemical formula I that effectively treats or prevents histone deacetylase 6 activity-related diseases. Specifically, "pharmaceutically effective amount" refers to the amount sufficient to treat the disease with a reasonable benefit / risk ratio suitable for medical treatment, and the effective dose level can be determined according to factors (including subject type and severity, age, sex, disease type, drug activity, sensitivity to drugs, administration time, administration route, excretion rate, treatment duration, drugs used simultaneously, and other factors well known in the medical field). The pharmaceutical composition of the present invention can be used as a separate therapeutic agent or in combination with other therapeutic agents, and can be used sequentially or simultaneously with commercially available therapeutic agents. In addition, the pharmaceutical composition of the present invention can be administered in single doses or multiple doses. Taking into account all of the above factors, it is important to administer with the minimum dose to obtain the maximum effect, and there are no side effects, which can be easily determined by those skilled in the art. The dosage of the pharmaceutical composition of the present invention can be determined by experts according to various factors such as the patient's condition, age, sex, complications, etc. Because the active ingredient of the pharmaceutical composition of the present invention has excellent safety, the active ingredient can also be used even above the predetermined dose.

[0161] According to one embodiment of the present invention, the present invention provides a method for selectively inhibiting histone deacetylase 6 (HDAC6) by administering a compound represented by Chemical Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to mammals, including humans.

[0162] According to one embodiment of the present invention, the present invention provides use of a compound represented by Chemical Formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0163] According to one embodiment of the present invention, the present invention provides the use of a compound represented by chemical formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating a disease associated with the activity of histone deacetylase 6. The compound represented by chemical formula I used to prepare the drug can be mixed with an acceptable excipient, diluent, carrier, etc., and can be prepared into a combined preparation with other active agents to exert the synergistic effect of the active ingredients.

[0164] According to one embodiment of the present invention, the present invention provides the use of a compound represented by Chemical Formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof for preventing or treating a disease mediated by histone deacetylase 6. The compound represented by Chemical Formula I for preventing or treating a disease mediated by histone deacetylase 6 can be mixed with an acceptable excipient, diluent, carrier, etc., and can be prepared into a combined preparation with other active agents to exert the synergistic effect of the active ingredients.

[0165] Matters mentioned in the uses, compositions and methods of treatment of the present invention are equally applicable unless they conflict with each other.

[0166] The exemplary embodiments of the present invention can be modified in various other forms, and the scope of the present invention is not limited to the exemplary embodiments described below. In addition, the exemplary embodiments of the present invention are provided to explain the present invention more completely to those of ordinary skill in the art. In addition, unless otherwise stated, "comprising" a component throughout the specification does not mean excluding other components, but means that other components may be further included.

[0167] Beneficial Effects of the Invention

[0168] The compound represented by Chemical Formula I of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof can selectively inhibit HDAC6, thereby having a very excellent preventive or therapeutic effect on diseases related to histone deacetylase 6 activity. DETAILED DESCRIPTION

[0169] Hereinafter, the present invention will be described in more detail by way of examples and experimental examples. However, these examples and the like are merely examples of the present invention, and the scope of the present invention is not limited to these examples.

[0170] Preparation of 1,3,4-oxadiazole derivatives

[0171] The specific method for preparing the compound represented by Chemical Formula I is described below.

[0172] Example 5: Synthesis of Compound 5, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(2-thienyl)-1,3,4-oxadiazol-2-one

[0173] [Step 1] Synthesis of 6-methylnicotinic acid hydrazide

[0174]

[0175] To a solution of methyl 6-methylnicotinate (10.000 g, 66.151 mmol) dissolved in ethanol (200 mL) at room temperature was added hydrazine monohydrate (32.151 mL, 661.507 mmol), and the mixture was stirred at the same temperature for 18 hours. The solvent in the reaction mixture was removed under reduced pressure to obtain a concentrate. Water was poured into the concentrate, and then extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (8.248 g, 82.5%, white solid).

[0176] [Step 2] Synthesis of 2-(difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole

[0177]

[0178] To a solution of 6-methylnicotinylhydrazide (8.248 g, 54.561 mmol) synthesized in step 1 dissolved in tetrahydrofuran (200 mL) at 0°C, triethylamine (38.024 mL, 272.805 mmol) was added and stirred at the same temperature for 10 minutes. 2,2-difluoroacetic anhydride (20.349 mL, 163.683 mmol) was added to the reaction mixture, stirring was continued at 80°C for 3 hours, and then the reaction was terminated by lowering the temperature to room temperature. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, and then extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 80 g cartridge; ethyl acetate / hexane = 0% to 50%) to obtain the title compound (8.019 g, 69.6%) as a yellow solid.

[0179] [Step 3] Synthesis of 2-(6-(bromomethyl)-pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0180]

[0181] The 2-(difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole (8.019 g, 37.974 mmol), 1-bromopyrrolidine-2,5-one (NBS, 8.110 g, 45.569 mmol) and azobisisobutyronitrile (AIBN, 0.624 g, 3.797 mmol) synthesized in step 2 were dissolved in 1,2-dichloroethane (120 mL) at room temperature and stirred at the same temperature for 6 hours. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 80 g cartridge; ethyl acetate / hexane = 0% to 40%) to obtain the title compound (3.960 g, 36.0%) as a brown solid.

[0182] [Step 4] Synthesis of Thiophene-2-Carbohydrazide

[0183]

[0184] To a solution of thiophene-2-carboxylic acid methyl ester (100.00% solution, 0.163 mL, 1.410 mmol) dissolved in ethanol (10 mL) at room temperature was added hydrazine monohydrate (100.00% solution, 1.367 mL, 28.100 mmol), stirred at 60°C for 5 hours, and then the reaction was terminated by lowering the temperature to room temperature. The solvent in the reaction mixture was removed under reduced pressure to obtain a concentrate. Saturated aqueous sodium bicarbonate solution was poured into the concentrate, and the reaction mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting product was used without further purification (0.2 g, 99.8%, light yellow solid).

[0185] [Step 5] Synthesis of 5-(2-thienyl)-3H-1,3,4-oxadiazol-2-one

[0186]

[0187] To a solution of 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 dissolved in tetrahydrofuran (10 mL) at room temperature, triethylamine (100.00% solution, 0.273 mL, 2.000 mmol) was added and stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) to give the title compound (0.143 g, 60.450%) as a light yellow solid.

[0188] [Step 6] Synthesis of Compound 5

[0189]

[0190] To a solution of 5-(2-thienyl)-3H-1,3,4-oxadiazol-2-one (100.00%, 0.063 g, 0.350 mmol) synthesized in step 5 and potassium carbonate (100.00%, 0.049 g, 0.494 mmol) dissolved in N,N-dimethylformamide (2 mL) at room temperature, 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.122 g, 0.421 mmol) synthesized in step 3 was added, and stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated, and the resulting product was then purified by chromatography (SiO2, 4g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to give the title compound (0.036 g, 26.44%, yellow solid).

[0191] 1 H NMR(400MHz, CDCl3) δ9.34-9.33(m,1H),8.44(dd,J=8.2,2.2Hz,1H),7.65(dd,J=4.0,1.2Hz, 1H),7.55-7.52(m,2H),7.17-7.15(m,1H),6.96(t,J=51.6Hz,1H),5.22(s,2H); LRMS(ES)m / z 378.7(M + +1).

[0192] The compounds in Table 2 below were synthesized according to substantially the same method as Example 5.

[0193] [Table 2]

[0194]

[0195]

[0196] Example 45: Synthesis of Compound 45, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-phenyl-1,3,4-oxadiazole-2(3H)-thione

[0197] [Step 1] Synthesis of benzohydrazine

[0198]

[0199] 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 reaction was terminated by lowering the temperature to room temperature. 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).

[0200] [Step 2] Synthesis of 5-phenyl-1,3,4-oxadiazole-2(3H)-thione

[0201]

[0202] To a solution of the benzohydrazide (100.00%, 0.500 g, 3.672 mmol) synthesized in step 1 dissolved in ethanol (12 mL) at room temperature was added potassium ethyl xanthate (100.00%, 0.589 g, 3.674 mmol), and the mixture was stirred at the same temperature. The solvent in the reaction mixture was removed under reduced pressure, and the precipitated solid was filtered, washed with water, and then dried to obtain the title compound (0.45 g, 68.759%) as a light yellow solid.

[0203] [Step 3] Synthesis of compound 45

[0204]

[0205] To a solution of 5-phenyl-1,3,4-oxadiazole-2(3H)-thione (100.00%, 50.000 mg, 0.281 mmol) synthesized in step 1 dissolved in N,N-dimethylformamide (2 mL) at room temperature, potassium carbonate (100.00%, 40.000 mg, 0.404 mmol) was added, and the mixture was stirred at the same temperature for 0.3 hours. 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 100.000 mg, 0.345 mmol) was added to the reaction mixture, and the mixture was further stirred at 35°C for 18 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; hexane / ethyl acetate = 100% to 50%) and concentrated to obtain the title compound (58 mg, 53.36%) as a white solid.

[0206] 1 H NMR (400MHz, CDCl3) δ9.32 (d, J=1.6Hz, 1H), 8.40 (dd, J=8.2, 2.2Hz, 1H), 8.01 (dd, J=8.2, 1.4Hz, 2H),7.83(d,J=8.4Hz,1H),7.56-7.51(m,3H),6.96(t,J=51.6Hz,1H),4.75(s,2H); LRMS(ES)m / z 388.8(M + +1).

[0207] The compounds in Table 3 below were synthesized according to substantially the same method as Example 45.

[0208] [Table 3]

[0209]

[0210]

[0211]

[0212] Example 43: Synthesis of Compound 43, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-phenyl-1,3,4-thiadiazol-2-one

[0213] [Step 1] Synthesis of benzohydrazide

[0214]

[0215] Methyl benzoate (100.00%, 1.000g, 7.345mmol) and hydrazine monohydrate (100.00%, 3.677g, 73.452mmol) were dissolved in ethanol (80mL) at 90°C and stirred overnight at the same temperature, and then the reaction was terminated by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure to obtain a concentrate. Water was poured into the concentrate, and then extracted with dichloromethane. The organic layer was washed with a saturated sodium bicarbonate aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting product can be used without further purification (0.88g, 88.000%, white solid).

[0216] [Step 2] Synthesis of phenylsulfhydrazide

[0217]

[0218] The solution of benzohydrazide (100.00%, 0.500g, 3.672mmol) and Lawesson reagent (100.00%, 1.782g, 4.406mmol) synthesized in step 1 was dissolved in toluene (20mL) at 100°C and stirred overnight at the same temperature, and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12g cartridge; ethyl acetate / hexane = 0% to 30%) to obtain the title compound (0.31g, 55.455%, white solid).

[0219] [Step 3] Synthesis of 5-phenyl-3H-1,3,4-thiadiazol-2-one

[0220]

[0221] The solution of phenylsulfhydrazide (100.00%, 0.280g, 1.839mmol) and 1,1'-carbonylbis-1H-imidazole (100.00%, 0.358g, 2.208mmol) synthesized in step 2 was dissolved in dichloromethane (20mL) at 50°C and stirred overnight at the same temperature. Then, the reaction was terminated by cooling the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 24g cartridge; ethyl acetate / hexane = 0% to 30%) to obtain the title compound (0.25g, 76.264%, white solid).

[0222] [Step 4] Synthesis of compound 43

[0223]

[0224] A solution of 5-phenyl-3H-1,3,4-thiadiazole-2-one (100.00%, 0.050 g, 0.281 mmol) synthesized in step 3 and potassium carbonate (100.00%, 0.058 g, 0.420 mmol) dissolved in N,N-dimethylformamide (5 mL) was stirred at room temperature for 30 minutes. Then, 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 stirring was continued at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 0% to 50%) and concentrated to obtain the title compound (0.054 g, 49.68%, white solid).

[0225] 1 H NMR (400MHz, CDCl3) δ9.33 (d, J=1.6Hz, 1H), 8.42 (dd, J=8.2, 2.2Hz, 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).

[0226] The compounds in Table 4 below were synthesized according to substantially the same method as Example 43.

[0227] [Table 4]

[0228]

[0229]

[0230] Example 4: Synthesis of Compound 4, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-4-[(4-methyl-1-piperidinyl)methyl]phenyl]-1,3,4-oxadiazol-2-one

[0231] [Step 1] Synthesis of methyl 2-fluoro-4-[(4-methyl-1-piperidinyl)methyl]benzoate

[0232]

[0233] A solution of methyl 2-fluoro-4-formylbenzoate (100.00%, 0.300 g, 1.647 mmol), 4-methylpiperidine (100.00%, 2.000 equivalents, 3.294 mmol) and sodium triacetoxyborohydride (100.00%, 2.000 equivalents, 3.294 mmol) dissolved in dichloromethane (10 mL) at room temperature was stirred overnight at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 0% to 100%) to give the title compound (0.43 g, 98.41%, yellow oil).

[0234] [Step 2] Synthesis of 2-fluoro-4-[(4-methyl-1-piperidinyl)methyl]benzohydrazide

[0235]

[0236] A solution of methyl 2-fluoro-4-[(4-methyl-1-piperidinyl)methyl]benzoate (100.00%, 0.420 g, 1.583 mmol) synthesized in step 1 and hydrazine monohydrate (100.00%, 10.000 equivalents, 15.830 mmol) dissolved in ethanol (10 mL) at 80°C was stirred overnight at the same temperature, and then the reaction was terminated by lowering the temperature to room temperature. 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).

[0237] [Step 3] Synthesis of 5-[2-fluoro-4-[(4-methyl-1-piperidinyl)methyl]phenyl]-3H-1,3,4-oxadiazol-2-one

[0238]

[0239] The 2-fluoro-4-[(4-methyl-1-piperidinyl)methyl]benzohydrazine (100.00%, 0.420g, 1.583mmol), triphosgene (100.00%, 0.400 equivalent, 0.633mmol) and N,N-diisopropylethylamine (100.00%, 2.000 equivalent, 3.166mmol) synthesized in step 2 were dissolved in dichloromethane (10mL) at room temperature and stirred at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12g cartridge; ethyl acetate / hexane = 0% to 100%) to give the title compound (0.275g, 59.63%, white solid).

[0240] [Step 4] Synthesis of Compound 4

[0241]

[0242] The 5-[2-fluoro-4-[(4-methyl-1-piperidinyl)methyl]phenyl]-3H-1,3,4-oxadiazol-2-one synthesized in step 3 (100.00%, 0.090 g, 0.309 mmol), 2-[6-(bromomethyl)-3-pyridinyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.200 equivalents, 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 and stirred overnight at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 0% to 100%) and concentrated to obtain the title compound (0.07 g, 45.27%, white solid).

[0243] 1H NMR (400MHz, CDCl3) δ9.25 (s, 1H), 8.37 (d, J = 10.0Hz, 1H), 7.69 (t, J = 7.6Hz, 1H), 7.49 (d, J = 8.0Hz, 1H), 7.21-7.18 (m, 2H), 6.93 (t, J = 51.6Hz, 1H), 5. 22(s,2H),3.47(s,2H),2.76(d,J=11.2Hz,2H),1.95(t,J=10.8Hz,2H),1.5 7(d,J=12.0Hz,2H),1.34-1.20(m,3H),0.89(d,J=6.0Hz,3H); LRMS(ES)m / z 501.4(M + +1).

[0244] The compounds in Table 5 below were synthesized according to substantially the same method as Example 4.

[0245] [Table 5]

[0246]

[0247]

[0248] Example 84: Synthesis of Compound 84, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-(3-((dimethylamino)methyl)phenyl)-1,3,4-oxadiazole-2(3H)-thione

[0249] [Step 1] Synthesis of methyl 3-(1,3-dioxolan-2-yl)benzoate

[0250]

[0251] Methyl 3-formylbenzoate (100.00%, 2.000g, 12.183mmol), ethylene glycol (100.00%, 3.781g, 60.920mmol) and 4-methylbenzenesulfonic acid hydrate (100.00%, 0.232g, 1.220mmol) were dissolved in toluene (120mL) at room temperature, and the resulting mixture was heated under reflux overnight. The mixture was cooled to room temperature, water was poured into the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 80g cartridge; ethyl acetate / hexane = 0% to 10%) to obtain the title compound (1.8g, 70.959%, ​​white solid).

[0252] [Step 2] Synthesis of 3-(1,3-dioxolan-2-yl)benzohydrazide

[0253]

[0254] The solution of 3-(1,3-dioxolan-2-yl)benzoic acid methyl ester (100.00%, 1.130g, 5.427mmol) and hydrazine monohydrate (100.00%, 2.717g, 54.275mmol) synthesized in step 1 was dissolved in ethanol (80mL) at 80°C and stirred overnight at the same temperature, and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 24g cartridge; methanol / dichloromethane = 0% to 5%) to obtain the title compound (1.1g, 97.345%, white solid).

[0255] [Step 3] Synthesis of 5-[3-(1,3-dioxolan-2-yl)phenyl]-3H-1,3,4-oxadiazole-2-thione

[0256]

[0257] The 3-(1,3-dioxolan-2-yl)benzohydrazide (100.00%, 0.900g, 4.323mmol) synthesized in step 2 and potassium ethylxanthate (100.00%, 0.762g, 4.754mmol) were dissolved in ethanol (50mL) at 80°C and stirred overnight at the same temperature, and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 24g cartridge; ethyl acetate / hexane = 0% to 30%) to give the title compound (0.7g, 64.70%, white solid).

[0258] [Step 4] Synthesis of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[3-(1,3-dioxolan-2-yl)phenyl]-1,3,4-oxadiazole-2-thione

[0259]

[0260] A solution of 5-[3-(1,3-dioxolan-2-yl)phenyl]-3H-1,3,4-oxadiazole-2-thione (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 (100.00%, 0.208 g, 2.099 mmol) and potassium iodide (100.00%, 0.116 g, 0.699 mmol) dissolved in N,N-dimethylformamide (30 mL) was stirred at room temperature for 30 minutes and then further stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 50%) and concentrated to obtain the title compound (0.51 g, 79.39%, white solid).

[0261] [Step 5] Synthesis of 3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-thioxo-1,3,4-oxadiazol-2-yl]benzaldehyde

[0262]

[0263] The solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[3-(1,3-dioxolan-2-yl)phenyl]-1,3,4-oxadiazole-2-thione (100.00%, 0.500 g, 1.088 mmol) synthesized in step 4 and ferric chloride hexahydrate (100.00%, 1.030 g, 3.811 mmol) dissolved in dichloromethane (30 mL) was stirred overnight at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 40%) and concentrated to give the title compound (0.350 g, 77.41%) as a white solid.

[0264] [Step 6] Synthesis of Compound 84

[0265]

[0266] To a solution of 4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-thioxo-1,3,4-oxadiazol-2-yl]benzaldehyde (100.00%, 0.030 g, 0.072 mmol) synthesized in step 5 dissolved in dichloromethane (5 mL) at room temperature, N-methylmethylamine (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 the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 5%) to give the title compound (0.011 g, 34.27%, white solid).

[0267] 1 H NMR(400MHz, CDCl3)δ9.32(d,J=1.7Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.94-7.90(m,2H),7.83(d,J=8.2Hz,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).

[0268] The compounds in Table 6 below were synthesized in substantially the same manner as Example 84.

[0269] [Table 6]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278] Example 132: Synthesis of Compound 132, 5-[4-(azetidin-1-ylmethyl)phenyl]-3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-1,3,4-oxadiazol-2-one

[0279] [Step 1] Synthesis of methyl 4-(1,3-dioxolan-2-yl)benzoate

[0280]

[0281] Methyl 4-formylbenzoate (100.00%, 3.000g, 18.275mmol), ethylene glycol (100.00%, 5.672g, 91.380mmol) and 4-methylbenzenesulfonic acid hydrate (100.00%, 0.348g, 1.830mmol) were dissolved in toluene (150mL) at room temperature, and the resulting mixture was heated under reflux overnight. The mixture was cooled to room temperature, water was poured into the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 80g cartridge; ethyl acetate / hexane = 0% to 10%) to obtain the title compound (3.5g, 91.984%, white solid).

[0282] [Step 2] Synthesis of 4-(1,3-dioxolan-2-yl)benzohydrazide

[0283]

[0284] The 4-(1,3-dioxolan-2-yl)benzoic acid methyl ester (100.00%, 2.000g, 9.606mmol) synthesized in step 1 and hydrazine monohydrate (100.00%, 4.809g, 96.065mmol) were dissolved in ethanol (100mL) at room temperature, and the resulting mixture was heated under reflux overnight. The mixture was cooled to room temperature, water was poured into the reaction mixture, and then extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 40g cartridge; methanol / dichloromethane = 0% to 5%) to obtain the title compound (1.8g, 90.000%, white solid).

[0285] [Step 3] Synthesis of 5-[4-(1,3-dioxolan-2-yl)phenyl]-3H-1,3,4-oxadiazol-2-one

[0286]

[0287] The 4-(1,3-dioxolan-2-yl)benzohydrazide (100.00%, 0.650g, 3.122mmol) and 1,1'-carbonylbis-1H-imidazole (100.00%, 0.607g, 3.744mmol) synthesized in step 2 were dissolved in dichloromethane (50mL) at room temperature, and the resulting mixture was heated under reflux overnight. The mixture was cooled to room temperature, water was poured into the reaction mixture, and then extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12g cartridge; ethyl acetate / hexane = 0% to 50%) to give the title compound (0.45g, 61.545%, white solid).

[0288] [Step 4] Synthesis of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-(1,3-dioxolan-2-yl)phenyl]-1,3,4-oxadiazol-2-one

[0289]

[0290] 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.650g, 2.241mmol) and potassium iodide (100.00%, 0.177g, 1.066mmol) were added to a solution of 5-[4-(1,3-dioxolan-2-yl)phenyl]-3H-1,3,4-oxadiazol-2-one (100.00%, 0.500g, 2.135mmol) synthesized in step 3 and potassium carbonate (100.00%, 0.443g, 3.205mmol) dissolved in N,N-dimethylformamide (30mL) at room temperature, and stirred at the same temperature for 30 minutes. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Ethyl acetate (5 mL) was added to the concentrate and stirred to precipitate a solid. The precipitated solid was filtered, washed with hexane, and dried to obtain the title compound (0.74 g, 78.18%, white solid).

[0291] [Step 5] Synthesis of 4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]benzaldehyde

[0292]

[0293] The solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-(1,3-dioxolan-2-yl)phenyl]-1,3,4-oxadiazol-2-one (100.00%, 0.280g, 0.632mmol) and ferric chloride hexahydrate (100.00%, 0.512g, 1.894mmol) synthesized in step 4 was dissolved in dichloromethane (30mL) and stirred overnight at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12g cartridge; ethyl acetate / hexane = 0% to 50%) to give the title compound (0.18g, 71.39%, white solid).

[0294] [Step 6] Synthesis of compound 132

[0295]

[0296] The 4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]benzaldehyde (100.00%, 0.030g, 0.075mmol) synthesized in step 5 and azetidine hydrochloride (100.00%, 0.014g, 0.150mmol) were dissolved in dichloromethane (5mL) and stirred at room temperature for 30 minutes. Then, sodium triacetoxyborohydride (100.00%, 0.048g, 0.227mmol) was added and stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 5%) and concentrated to obtain the title compound (0.019 g, 57.42%, white solid).

[0297] 1H NMR (400MHz, CDCl3) δ9.33(d,J=1.5Hz,1H),8.43(dd,J=8.2,2.2Hz,1H),7.82(d,J=8.3Hz,2H),7.55-7.52(m,1H),7.43(d,J=8.1H z,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).

[0298] The compounds in Table 7 below were synthesized according to essentially the same method as Example 132.

[0299] [Table 7]

[0300]

[0301] Example 83: Synthesis of Compound 83, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-[(4-isopropylpiperazin-1-yl)methyl]phenyl]-1,3,4-oxadiazol-2-one

[0302] [Step 1] Synthesis of tert-butyl 4-[(4-methoxycarbonylphenyl)methyl]piperazine-1-carboxylate

[0303]

[0304] A solution of methyl 4-formylbenzoate (100.00%, 0.500g, 3.046mmol), tert-butyl piperazine-1-carboxylate (100.00%, 0.681g, 3.656mmol) and sodium triacetoxyborohydride (100.00%, 1.291g, 6.091mmol) dissolved in dichloromethane (20mL) at room temperature was stirred overnight at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 24g cartridge; ethyl acetate / hexane = 0% to 30%) to give the title compound (0.89g, 87.38%, white solid).

[0305] [Step 2] Synthesis of tert-butyl 4-[[4-(hydrazinecarbonyl)phenyl]methyl]piperazine-1-carboxylate

[0306]

[0307] A solution of 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, 8.969 mmol) synthesized in step 1 was dissolved in ethanol (20 mL) at 90°C and stirred overnight at the same temperature, and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (0.29 g, 96.67%, white solid).

[0308] [Step 3] Synthesis of tert-butyl 4-[[4-(2-oxo-3H-1,3,4-oxadiazol-5-yl)phenyl]methyl]piperazine-1-carboxylate

[0309]

[0310] To the solution of tert-butyl 4-[[4-(hydrazinecarbonyl)phenyl]methyl]piperazine-1-carboxylate (100.00%, 0.500g, 1.495mmol) and 1,1'-carbonylbis-1H-imidazole (100.00%, 0.291g, 1.795mmol) synthesized in step 2 dissolved in tetrahydrofuran (10mL) at room temperature, triethylamine (100.00% solution, 0.29mL, 2.100mmol) was added and stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 24g cartridge; methanol / dichloromethane = 0% to 10%) to give the title compound (0.468g, 86.85%, white solid).

[0311] [Step 4] Synthesis of tert-butyl 4-[[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]phenyl]methyl]piperazine-1-carboxylate

[0312]

[0313] To the solution of tert-butyl 4-[[4-(2-oxo-3H-1,3,4-oxadiazol-5-yl)phenyl]methyl]piperazine-1-carboxylate (100.00%, 0.236 g, 0.655 mmol) and potassium carbonate (100.00%, 0.091 g, 0.918 mmol) synthesized in step 3 dissolved in N,N-dimethylformamide (3 mL) at room temperature, 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.228 g, 0.786 mmol) prepared in step 3 of Example 5 was added, and stirred overnight at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4g cartridge; ethyl acetate / hexane = 0% to 60%), and the resulting product was then purified and concentrated by chromatography (SiO2, 4g cartridge; methanol / dichloromethane = 0% to 10%) to obtain the title compound (0.37 g, 99.20%, white solid).

[0314] [Step 5] Synthesis of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-(piperazin-1-ylmethyl)phenyl]-1,3,4-oxadiazol-2-one

[0315]

[0316] A solution of 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]methyl]piperazine-1-carboxylate (100.00%, 0.370 g, 0.650 mmol) and trifluoroacetic acid (100.00% solution, 0.497 mL, 6.490 mmol) dissolved in dichloromethane (3 mL) at room temperature was stirred overnight at room temperature. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, and then extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (0.3 g, 98.39%, yellow oil).

[0317] [Step 6] Synthesis of Compound 83

[0318]

[0319] A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-(piperazin-1-ylmethyl)phenyl]-1,3,4-oxadiazol-2-one (100.00%, 0.075 g, 0.160 mmol) synthesized in step 5, acetone (100.00% solution, 0.019 mL, 0.257 mmol) and N-ethyl-N-isopropyl-propan-2-amine (100.00% solution, 0.056 mL, 0.322 mmol) dissolved in dichloromethane (1 mL) was stirred at room temperature for 30 minutes. Then, sodium triacetoxyborohydride (100.00%, 0.101 g, 0.479 mmol) was added and stirred at the same temperature for another 18 hours. A saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, and then extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = 0% to 10%) to give the title compound (0.014 g, 17.13%) as a light yellow solid.

[0320] 1 H NMR (400MHz, CD3OD) δ9.25(d,J=1.6Hz,1H),8.53(dd,J=8.2,2.2Hz,1H),7.85(d,J=8.4Hz,2H),7.72(d,J=8.0Hz,1H),7.53 (d,J=8.4Hz,2H),7.26(t,J=51.6Hz,1H),5.26(s,2H),3.63(s,2H),2.74-2.59(m,9H),1.15(d,J=6.8Hz,6H); LRMS(ES)m / z 512.8(M + +1).

[0321] Example 66: Synthesis of Compound 66, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-[4-(4-isopropylpiperazin-1-yl)phenyl]-1,3,4-thiadiazol-2-one

[0322] [Step 1] Synthesis of tert-butyl 4-[[4-(aminothiocarbamoyl)phenyl]methyl]piperazine-1-carboxylate

[0323]

[0324] A solution of tert-butyl 4-[[4-(hydrazinecarbonyl)phenyl]methyl]piperazine-1-carboxylate (100.00%, 1.000 g, 2.990 mmol) and Lawesson's reagent (100.00%, 1.451 g, 3.587 mmol) synthesized in step 2 of Example 86 was dissolved in toluene (40 mL) at 80°C and stirred overnight at the same temperature. Then, the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 24 g cartridge; ethyl acetate / hexane = 0% to 60%) to give the title compound (0.61 g, 58.20%, white solid).

[0325] [Step 2] Synthesis of tert-butyl 4-[[4-(2-oxo-3H-1,3,4-thiadiazol-5-yl)phenyl]methyl]piperazine-1-carboxylate

[0326]

[0327] The solution of tert-butyl 4-[[4-(aminothiocarbamoyl)phenyl]methyl]piperazine-1-carboxylate (100.00%, 0.500g, 1.427mmol) and 1,1'-carbonylbis-1H-imidazole (100.00%, 0.278g, 1.715mmol) synthesized in step 1 was dissolved in dichloromethane (30mL) at 50°C and stirred overnight at the same temperature. Then, the reaction was terminated by cooling the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12g cartridge; ethyl acetate / hexane = 0% to 40%) to give the title compound (0.25g, 46.55%, white solid).

[0328] [Step 3] Synthesis of tert-butyl 4-[[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-oxo-1,3,4-thiadiazol-2-yl]phenyl]methyl]piperazine-1-carboxylate

[0329]

[0330] The solution of tert-butyl 4-[[4-(2-oxo-3H-1,3,4-thiadiazol-5-yl)phenyl]methyl]piperazine-1-carboxylate (100.00%, 0.100 g, 0.266 mmol) synthesized in step 2 and potassium carbonate (100.00%, 0.055 g, 0.398 mmol) dissolved in N,N-dimethylformamide (10 mL) was stirred at room temperature for 30 minutes. Then, 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 g, 0.133 mmol) were added and stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 40%) and concentrated to give the title compound (0.095 g, 61.08%, white solid).

[0331] [Step 4] Synthesis of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-(piperazin-1-ylmethyl)phenyl]-1,3,4-thiadiazol-2-one 2,2,2-trifluoroacetic acid

[0332]

[0333] A solution of tert-butyl 4-[[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]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 (100.00%, 0.053 g, 0.465 mmol) synthesized in step 3 was dissolved in dichloromethane (10 mL) at room temperature and stirred overnight at the same temperature. 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).

[0334] [Step 5] Synthesis of Compound 66

[0335]

[0336] A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-(piperazin-1-ylmethyl)phenyl]-1,3,4-thiadiazol-2-one 2,2,2-trifluoroacetic acid (100.00%, 0.030 g, 0.051 mmol) synthesized in step 4, 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) dissolved in dichloromethane (5 mL) was stirred at room temperature for 30 minutes and then stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 5%) to obtain the title compound (0.011 g, 41.80%, white solid).

[0337] 1 H NMR (400MHz, CDCl3) δ9.33(d,J=1.6Hz,1H),8.41(dd,J=8.2,2.2Hz,1H),7.64(d,J=8.2Hz,2H),7.47(d,J=8.2Hz,1H),7.41(d,J=8.2Hz,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=6.5Hz,6H); LRMS(ES)m / z 529.35(M + +1).

[0338] The compounds in Table 8 below were synthesized according to essentially the same method as Example 66.

[0339] [Table 8]

[0340]

[0341]

[0342] Example 77: Synthesis of Compound 77, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[4-[(4-isopropylpiperazin-1-yl)methyl]phenyl]-1,3,4-oxadiazole-2-thione

[0343] [Step 1] Synthesis of tert-butyl 4-(4-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)benzyl)piperazine-1-carboxylate

[0344]

[0345] A mixture of 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 (100.00%, 0.575 g, 3.587 mmol) was mixed in ethanol (80 mL) at room temperature and heated under reflux overnight. The mixture was cooled to room temperature, water was poured into the reaction mixture, and then extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 24 g cartridge; ethyl acetate / hexane = 0% to 40%) to give the title compound (0.85 g, 75.50%, white solid).

[0346] [Step 2] Synthesis of tert-butyl 4-[[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-thioxo-1,3,4-oxadiazol-2-yl]phenyl]methyl]piperazine-1-carboxylate

[0347]

[0348] The solution of 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) synthesized in step 1 and potassium carbonate (100.00%, 0.197 g, 1.988 mmol) dissolved in N,N-dimethylformamide (30 mL) was stirred at room temperature for 30 minutes. Then, 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 g, 0.663 mmol) were added and stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 24 g cartridge; ethyl acetate / hexane = 0% to 40%) and concentrated to give the title compound (0.65 g, 83.58%, white solid).

[0349] [Step 3] Synthesis of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[4-(piperazin-1-ylmethyl)phenyl]-1,3,4-oxadiazole-2-thione 2,2,2-trifluoroacetic acid

[0350]

[0351] A solution of tert-butyl 4-[[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]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 (100.00%, 0.175 g, 1.535 mmol) synthesized in step 2 was dissolved in dichloromethane (20 mL) at room temperature and stirred at the same temperature for 3 hours. After removing the solvent in the reaction mixture under reduced pressure, the obtained product was used without further purification (0.28 g, 91.17%, yellow oil).

[0352] [Step 4] Synthesis of Compound 77

[0353]

[0354] A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[4-(piperazin-1-ylmethyl)phenyl]-1,3,4-oxadiazole-2-thione 2,2,2-trifluoroacetic acid (100.00%, 0.050 g, 0.083 mmol) synthesized in step 3, acetone (100.00%, 0.010 g, 0.172 mmol) and N-ethyldiisopropylamine (100.00% solution, 0.029 mL, 0.167 mmol) dissolved 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 stirring was continued at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 5%) to give the title compound (0.022 g, 50.00%, white solid).

[0355] 1H NMR (400MHz, CDCl3) δ9.31(d,J=2.2Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.95(d,J=8.3Hz,2H),7.82(d,J=8.2Hz,1H),7.46(d,J=8.3Hz,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=6.5Hz,6H); LRMS(ES)m / z 528.87(M + +1).

[0356] The compounds in Table 9 below were synthesized using essentially the same method as Example 77.

[0357] [Table 9]

[0358]

[0359] Example 26: Synthesis of Compound 26, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-[1-(oxetane-3-yl)-4-piperidinyl]phenyl]-1,3,4-oxadiazol-2-one

[0360] [Step 1] Synthesis of tert-butyl 4-(2-fluoro-3-methoxycarbonyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate

[0361]

[0362] A solution of 3-bromo-2-fluoro-benzoic acid methyl ester (100.00%, 1.000 g, 4.291 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (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) dissolved in N,N-dimethylformamide (20 mL) / water (5 mL) at room temperature was stirred overnight at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 24 g cartridge; ethyl acetate / hexane = 0% to 30%) and concentrated to obtain the title compound (1.100 g, 76.43%, white solid).

[0363] [Step 2] Synthesis of tert-butyl 4-(2-fluoro-3-methoxycarbonyl-phenyl)piperidine-1-carboxylate

[0364]

[0365] The solution of 4-(2-fluoro-3-methoxycarbonyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (100.00%, 0.900g, 2.683mmol) and Pd / C (100.00%, 0.286g, 2.688mmol) synthesized in step 1 was dissolved in methanol (20mL) and stirred overnight at the same temperature. The reaction mixture was filtered through a diatomaceous earth pad to remove solids, and the solvent in the filtrate was removed under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12g cartridge; ethyl acetate / hexane = 0% to 40%) to give the title compound (0.74g, 81.73%, yellow oil).

[0366] [Step 3] Synthesis of tert-butyl 4-[2-fluoro-3-(hydrazinecarbonyl)phenyl]piperidine-1-carboxylate

[0367]

[0368] The solution of tert-butyl 4-(2-fluoro-3-methoxycarbonyl-phenyl)piperidine-1-carboxylate (100.00%, 0.700g, 2.075mmol) and hydrazine monohydrate (100.00%, 1.039g, 20.755mmol) synthesized in step 2 was dissolved in ethanol (30mL) at room temperature and stirred overnight at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (0.65g, 92.86%, white solid).

[0369] [Step 4] Synthesis of tert-butyl 4-[2-fluoro-3-(2-oxo-3H-1,3,4-oxadiazol-5-yl)phenyl]piperidine-1-carboxylate

[0370]

[0371] The solution of tert-butyl 4-[2-fluoro-3-(hydrazinecarbonyl)phenyl]piperidine-1-carboxylate (100.00%, 0.700g, 2.075mmol) and 1,1'-carbonylbis-1H-imidazole (100.00%, 0.404g, 2.492mmol) synthesized in step 3 was dissolved in dichloromethane (30mL) at room temperature and stirred overnight at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12g cartridge; ethyl acetate / hexane = 0% to 40%) to obtain the title compound (0.55g, 72.95%, white solid).

[0372] [Step 5] Synthesis of tert-butyl 4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]piperidine-1-carboxylate

[0373]

[0374] To the solution of tert-butyl 4-[2-fluoro-3-(2-oxo-3H-1,3,4-oxadiazole-5-yl)phenyl]piperidine-1-carboxylate (100.00%, 0.400g, 1.101mmol) and potassium carbonate (100.00%, 0.164g, 1.655mmol) synthesized in step 4 dissolved in N,N-dimethylformamide (20mL) at room temperature, 2-[6-bromomethyl-3-pyridyl]-5-difluoromethyl-1,3,4-oxadiazole (100.00%, 0.335g, 1.155mmol) and potassium iodide (100.00%, 0.091g, 0.548mmol) were added and stirred at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 40%) and concentrated to give the title compound (0.54 g, 85.69%, white solid).

[0375] [Step 6] Synthesis of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-(4-piperidinyl)phenyl]-1,3,4-oxadiazol-2-one 2,2,2-trifluoroacetic acid

[0376]

[0377] A solution of tert-butyl 4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]piperidine-1-carboxylate (100.00%, 0.300 g, 0.524 mmol) and 2,2,2-trifluoroacetic acid (100.00%, 0.179 g, 1.570 mmol) synthesized in step 5 dissolved in dichloromethane (20 mL) was stirred at the same temperature for 3 hours. After the solvent in the reaction mixture was removed under reduced pressure, the obtained product was used without further purification (0.3 g, 97.63%, yellow oil).

[0378] [Step 7] Synthesis of Compound 26

[0379]

[0380] A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-(4-piperidinyl)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), oxetane-3-one (100.00%, 0.012 g, 0.167 mmol) and sodium triacetoxyborohydride (100.00%, 0.054 g, 0.255 mmol) synthesized in step 6 was dissolved in dichloromethane (5 mL) at room temperature and stirred overnight at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 5%) to obtain the title compound (0.031 g, 68.79%, white solid).

[0381] 1 H NMR (400MHz, CDCl3) δ9.32 (d, J=1.6Hz, 1H), 8.43 (dd, J=8.2, 2.2Hz, 1H), 7.70-7.66 (m ,1H),7.53(dJ=8.2Hz,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 / z529.82(M + +1).

[0382] The compounds in Table 10 below were synthesized according to substantially the same method as Example 26.

[0383] [Table 10]

[0384]

[0385]

[0386] Example 27: Synthesis of Compound 27, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-[1-(1-methylazetidin-3-yl)-4-piperidinyl]phenyl]-1,3,4-oxadiazol-2-one

[0387] [Step 1] Synthesis of tert-butyl 3-[4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]-1-piperidinyl]azetidine-1-carboxylate

[0388]

[0389] A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-(4-piperidinyl)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 triacetoxyborohydride (100.00%, 0.163 g, 0.769 mmol) synthesized in step 6 of Example 26 was dissolved in dichloromethane (5 mL) at room temperature and stirred overnight at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 5%) to obtain the title compound (0.11 g, 68.52%, white solid).

[0390] [Step 2] Synthesis of 5-[3-[1-(azetidin-3-yl)-4-piperidinyl]-2-fluoro-phenyl]-3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-1,3,4-oxadiazol-2-one 2,2,2-trifluoroacetic acid

[0391]

[0392] The solution of tert-butyl 3-[4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]-1-piperidinyl]azetidine-1-carboxylate (100.00%, 0.110 g, 0.175 mmol) and 2,2,2-trifluoroacetic acid (100.00%, 0.060 g, 0.526 mmol) synthesized in step 1 dissolved in dichloromethane (5 mL) was stirred at the same temperature overnight. After the solvent in the reaction mixture was removed under reduced pressure, the obtained product was used without further purification (0.100 g, 88.94%, yellow oil).

[0393] [Step 3] Synthesis of compound 27

[0394]

[0395] A solution of 5-[3-[1-(azetidin-3-yl)-4-piperidinyl]-2-fluoro-phenyl]-3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]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 (100.00%, 0.050 g, 0.236 mmol) synthesized in step 2 was dissolved in dichloromethane (5 mL) at room temperature and stirred overnight at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 5%) to obtain the title compound (0.029 g, 68.71%, white solid).

[0396] 1H NMR (400MHz, CDCl3) δ9.31 (d, J=1.6Hz, 1H), 8.43 (dd, J=8.2, 2.2Hz, 1H), 7.69-7.65 (m,1H),7.53(dJ=8.2Hz,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),2.99-2.9 0(m,3H),2.50(s,3H),2.09-1.94(m,2H),1.87-1.80(m,4H); LRMS(ES)m / z542.86(M + +1).

[0397] The compounds in Table 11 below were synthesized according to substantially the same method as Example 27.

[0398] [Table 11]

[0399]

[0400] Example 81: Synthesis of Compound 81, 5-[3-(1-cyclobutyl-4-piperidinyl)-2-fluoro-phenyl]-3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridinyl]methyl]-1,3,4-oxadiazole-2-thione

[0401] [Step 1] Synthesis of tert-butyl 4-[2-fluoro-3-(2-thioxo-3H-1,3,4-oxadiazol-5-yl)phenyl]piperidine-1-carboxylate

[0402]

[0403] A mixture of tert-butyl 4-[2-fluoro-3-(hydrazinecarbonyl)phenyl]piperidine-1-carboxylate (100.00%, 1.100 g, 3.260 mmol) and potassium ethylxanthate (100.00%, 0.627 g, 3.911 mmol) prepared in step 3 of Example 26 was mixed in ethanol (80 mL) at room temperature and heated to reflux overnight. The mixture was cooled to room temperature, water was poured into the reaction mixture, and then extracted with dichloromethane. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 24 g cartridge; ethyl acetate / hexane = 0% to 40%) to give the title compound (0.9 g, 72.76%, white solid).

[0404] [Step 2] Synthesis of tert-butyl 4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-thioxo-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]piperidine-1-carboxylate

[0405]

[0406] The solution of tert-butyl 4-[2-fluoro-3-(2-thioxo-3H-1,3,4-oxadiazole-5-yl)phenyl]piperidine-1-carboxylate (100.00%, 0.500 g, 1.318 mmol) synthesized in step 1 and potassium carbonate (100.00%, 0.196 g, 1.978 mmol) dissolved in N,N-dimethylformamide (20 mL) was stirred at room temperature for 30 minutes. Then, 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) were added and stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 24 g cartridge; ethyl acetate / hexane=0% to 30%) and concentrated to give the title compound (0.61 g, 78.64%, white solid).

[0407] [Step 3] Synthesis of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-(4-piperidinyl)phenyl]-1,3,4-oxadiazole-2-thione 2,2,2-trifluoroacetic acid

[0408]

[0409] A solution of tert-butyl 4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-thioxo-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]piperidine-1-carboxylate (100.00%, 0.400 g, 0.680 mmol) and trifluoroacetic acid (100.00%, 0.232 g, 2.035 mmol) synthesized in step 2 was dissolved in dichloromethane (20 mL) at room temperature and stirred at the same temperature for 3 hours. After removing the solvent in the reaction mixture under reduced pressure, the obtained product was used without further purification (0.37 g, 90.37%, yellow oil).

[0410] [Step 4] Synthesis of Compound 81

[0411]

[0412] A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-(4-piperidinyl)phenyl]-1,3,4-oxadiazole-2-thione 2,2,2-trifluoroacetic acid (100.00%, 0.050 g, 0.083 mmol), cyclobutanone (100.00%, 0.012 g, 0.171 mmol) and N-ethyldiisopropylamine (100.00% solution, 0.029 mL, 0.167 mmol) synthesized in step 3 was dissolved in dichloromethane (5 mL) and stirred at room temperature for 30 minutes. Then, sodium triacetoxyborohydride (100.00%, 0.053 g, 0.250 mmol) was added and stirring was continued at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 5%) to give the title compound (0.029 g, 64.40%, white solid).

[0413] 1 H NMR (400MHz, CDCl3) δ9.31 (d, J=2.1Hz, 1H), 8.38 (dd, J=8.2, 2.3Hz, 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),2.88-2.8 4(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).

[0414] The compounds in Table 12 below were synthesized according to substantially the same method as Example 81.

[0415] [Table 12]

[0416]

[0417]

[0418] Example 100: Synthesis of Compound 100, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-[6-(4-ethylpiperazin-1-yl)-2-pyridinyl]-1,3,4-oxadiazole-2-thione

[0419] [Step 1] Synthesis of tert-butyl 4-(6-methoxycarbonyl-2-pyridyl)piperazine-1-carboxylate

[0420]

[0421] A solution of 6-fluoropyridine-2-carboxylic acid methyl ester (100.00%, 0.500g, 3.223mmol), piperazine-1-carboxylic acid tert-butyl ester (100.00%, 1.200g, 6.443mmol) and N,N-diisopropylethylamine (100.00% solution, 0.844mL, 4.800mmol) dissolved in dimethyl sulfoxide (15mL) at 130°C was stirred overnight at the same temperature, and the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 24g cartridge; ethyl acetate / hexane = 0% to 60%) to give the title compound (0.736g, 71.05%, yellow solid).

[0422] [Step 2] Synthesis of tert-butyl 4-[6-(hydrazinecarbonyl)-2-pyridyl]piperazine-1-carboxylate

[0423]

[0424] To the solution of tert-butyl 4-(6-methoxycarbonyl-2-pyridyl)piperazine-1-carboxylate (100.00%, 0.736g, 2.290mmol) synthesized in step 1 dissolved in ethanol (10mL) was added hydrazine monohydrate (100.00% solution, 1.113mL, 22.900mmol) and stirred at 60°C for 18 hours. Then, the reaction was terminated by lowering the temperature to room temperature. A saturated aqueous solution of ammonium chloride was poured into the reaction mixture, and then extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4g cartridge; methanol / dichloromethane = 0% to 10%) to give the title compound (0.73g, 99.18%, yellow solid).

[0425] [Step 3] Synthesis of tert-butyl 4-[6-(2-thioxo-3H-1,3,4-oxadiazol-5-yl)-2-pyridinyl]piperazine-1-carboxylate

[0426]

[0427] The solution of tert-butyl 4-[6-(hydrazinecarbonyl)-2-pyridyl]piperazine-1-carboxylate (100.00%, 0.730g, 2.271mmol) and potassium ethylxanthate (100.00%, 0.364g, 2.271mmol) synthesized in step 2 was dissolved in ethanol (10mL) at room temperature and stirred overnight at 90°C. Then, the reaction was terminated by lowering the temperature to room temperature. A saturated aqueous solution of ammonium chloride was poured into the reaction mixture, and then extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 40g cartridge; dichloromethane / methanol = 0% to 10%) to give the title compound (0.604g, 73.18%, yellow solid).

[0428] [Step 4] Synthesis of tert-butyl 4-[6-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-thioxo-1,3,4-oxadiazol-2-yl]-2-pyridinyl]piperazine-1-carboxylate

[0429]

[0430] The solution of tert-butyl 4-[3-(2-thioxo-3H-1,3,4-oxadiazol-5-yl)phenyl]piperazine-1-carboxylate (100.00%, 0.700 g, 1.932 mmol), 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.000 equivalent, 1.932 mmol), potassium carbonate (100.00%, 2.000 equivalent, 3.863 mmol) and potassium iodide (100.00%, 2.000 equivalent, 3.863 mmol) synthesized in step 3 was dissolved in N,N-dimethylformamide (5 mL) at room temperature and stirred overnight at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 50%) and concentrated to obtain the title compound (0.14 g, 12.68%, yellow solid).

[0431] [Step 5] Synthesis of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(6-piperazin-1-yl-2-pyridyl)-1,3,4-oxadiazole-2-thione

[0432]

[0433] The solution of tert-butyl 4-[6-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-thioxo-1,3,4-oxadiazol-2-yl]-2-pyridinyl]piperazine-1-carboxylate (100.00%, 0.384g, 0.671mmol) and trifluoroacetic acid (100.00% solution, 0.513mL, 6.700mmol) synthesized in step 4 was dissolved in dichloromethane (3mL) at room temperature and stirred overnight at the same temperature. Saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, and then extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (0.31g, 97.83%, yellow oil).

[0434] [Step 6] Synthesis of Compound 100

[0435]

[0436] The solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-(6-piperazin-1-yl-2-pyridyl)-1,3,4-oxadiazole-2-thione (100.00%, 0.100 g, 0.212 mmol), acetaldehyde (100.00% solution, 0.024 mL, 0.429 mmol) and N-ethyl-N-isopropyl-propan-2-amine (100.00% solution, 0.074 mL, 0.425 mmol) synthesized in step 5 was dissolved in dichloromethane (1 mL) and stirred at room temperature for 30 minutes, sodium triacetoxyborohydride (100.00%, 0.134 g, 0.635 mmol) was added, and stirring was continued at the same temperature for 18 hours. Saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, and then extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = 0% to 10%) to give the title compound (0.026 g, 24.55%, yellow solid).

[0437] 1H NMR (400MHz, CDCl3) δ9.32(d,J=1.6Hz,1H),8.37(dd,J=8.2,2.2Hz,1H),7.84(d,J=8.4Hz,1H),7.63-7.59(m,1H),7.43(d,J=7.2Hz,1H),6.96(t,J=51 .6Hz,1H),6.78(d,J=8.8Hz,1H),4.75(s,2H),3.69(t,J=5.0Hz,4H),2.59( t,J=5.0Hz,4H),2.50(q,J=7.2Hz,2H),1.16(t,J=7.2Hz,3H); LRMS(ES)m / z 501.5(M + +1).

[0438] The compounds in Table 13 below were synthesized according to substantially the same method as Example 100.

[0439] [Table 13]

[0440]

[0441]

[0442]

[0443] Example 41: Synthesis of Compound 41, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-[2-fluoro-3-(1-methyl-4-piperidinyl)phenyl]-1,3,4-thiadiazole-2-one

[0444] [Step 1] Synthesis of tert-butyl 4-[3-(aminothiocarbamoyl)-2-fluoro-phenyl]piperidine-1-carboxylate

[0445]

[0446] A solution of tert-butyl 4-[2-fluoro-3-(hydrazinecarbonyl)phenyl]piperidine-1-carboxylate (100.00%, 0.200 g, 0.593 mmol) and Lawesson's reagent (100.00%, 0.288 g, 0.712 mmol) prepared in step 3 of Example 26 was dissolved in toluene (20 mL) at room temperature and stirred overnight at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (0.11 g, 52.51%, yellow oil).

[0447] [Step 2] Synthesis of tert-butyl 4-[2-fluoro-3-(2-oxo-3H-1,3,4-thiadiazol-5-yl)phenyl]piperidine-1-carboxylate

[0448]

[0449] The solution of tert-butyl 4-[3-(aminothiocarbamoyl)-2-fluoro-phenyl]piperidine-1-carboxylate (100.00%, 0.200g, 0.566mmol) and 1,1'-carbonylbis-1H-imidazole (100.00%, 0.110g, 0.678mmol) synthesized in step 1 was dissolved in dichloromethane (20mL) at room temperature and stirred overnight at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12g cartridge; ethyl acetate / hexane = 0% to 40%) to give the title compound (0.15g, 69.86%, white solid).

[0450] [Step 3] Synthesis of tert-butyl 4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-oxo-1,3,4-thiadiazol-2-yl]-2-fluoro-phenyl]piperidine-1-carboxylate

[0451]

[0452] To a solution of tert-butyl 4-[2-fluoro-3-(2-oxo-3H-1,3,4-thiadiazol-5-yl)phenyl]piperidine-1-carboxylate (100.00%, 0.073 g, 0.192 mmol) and potassium carbonate (100.00%, 0.029 g, 0.293 mmol) synthesized in step 2 dissolved in N,N-dimethylformamide (20 mL) at room temperature, 2-[6-(bromomethyl)-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) were added, and stirred at the same temperature for 30 minutes. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 30%) to obtain the title compound (0.05 g, 44.15%, white solid).

[0453] [Step 4] Synthesis of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-(4-piperidinyl)phenyl]-1,3,4-thiadiazol-2-one 2,2,2-trifluoroacetic acid

[0454]

[0455] A solution of tert-butyl 4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-thiadiazol-2-yl]-2-fluoro-phenyl]piperidine-1-carboxylate (100.00%, 0.058 g, 0.099 mmol) and trifluoroacetic acid (100.00%, 0.034 g, 0.298 mmol) synthesized in step 3 dissolved in dichloromethane (10 mL) was stirred at the same temperature for 3 hours. After the solvent in the reaction mixture was removed under reduced pressure, the obtained product was used without further purification (0.055 g, 92.64%, yellow oil).

[0456] [Step 5] Synthesis of compound 41

[0457]

[0458] A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-(4-piperidinyl)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 triacetoxyborohydride (100.00%, 0.039 g, 0.184 mmol) synthesized in step 4 was dissolved in dichloromethane (5 mL) at room temperature and stirred overnight at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 5%) to obtain the title compound (0.031 g, 67.58%, white solid).

[0459] 1H NMR(400MHz, CDCl3)δ9.32(d,J=1.6Hz,1H),8.41(dd,J=8.2,2.2Hz,1H),7.77-7.73(m,1H),7.46(d,J=8.2Hz,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).

[0460] The compounds in Table 14 below were synthesized according to substantially the same method as Example 41.

[0461] [Table 14]

[0462]

[0463]

[0464] Example 20: Synthesis of Compound 20, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(4-piperazin-1-ylphenyl)-1,3,4-oxadiazol-2-one

[0465] [Step 1] Synthesis of tert-butyl 4-(4-methoxycarbonylphenyl)piperazine-1-carboxylate

[0466]

[0467] A solution of methyl 4-bromobenzoate (100.00%, 0.500 g, 2.325 mmol), tert-butyl piperazine-1-carboxylate (100.00%, 1.200 equiv., 2.790 mmol), tris(dibenzylideneacetone)dipalladium (100.00%, 5.000 mol%, 0.116 mmol), Xphos (100.00%, 5.000 mol%, 0.116 mmol) and cesium carbonate (100.00%, 2.000 equiv., 4.650 mmol) dissolved in toluene (50 mL) at 110°C was stirred overnight at the same temperature. Then, the reaction was terminated by lowering the temperature 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 sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 30%) and concentrated to obtain the title compound (0.73 g, 97.99%, brown solid).

[0468] [Step 2] Synthesis of tert-butyl 4-[4-(hydrazinecarbonyl)phenyl]piperazine-1-carboxylate

[0469]

[0470] The solution of tert-butyl 4-(4-methoxycarbonylphenyl)piperazine-1-carboxylate (100.00%, 0.770g, 2.403 mmol) and hydrazine monohydrate (100.00%, 10.000 equivalents, 24.030 mmol) synthesized in step 1 was dissolved in dichloromethane (5 mL) at room temperature and stirred at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 30%) to give the title compound (0.77 g, 100.0%, yellow solid).

[0471] [Step 3] Synthesis of tert-butyl 4-[4-(2-oxo-3H-1,3,4-oxadiazol-5-yl)phenyl]piperazine-1-carboxylate

[0472]

[0473] The solution of tert-butyl 4-[4-(hydrazinecarbonyl)phenyl]piperazine-1-carboxylate (100.00%, 0.770 g, 2.403 mmol) and 1,1'-carbonylbis-1H-imidazole (100.00%, 1.500 equivalents, 3.605 mmol) synthesized in step 2 was dissolved in dichloromethane (5 mL) and heated to reflux overnight at room temperature. Then, the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 100%) to give the title compound (0.5 g, 60.06%, yellow solid).

[0474] [Step 4] Synthesis of 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

[0475]

[0476] The tert-butyl 4-[4-(2-oxo-3H-1,3,4-oxadiazol-5-yl)phenyl]piperazine-1-carboxylate (100.00%, 0.500 g, 1.443 mmol) synthesized in step 3 and 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.200 equivalents, 1.732 mmol), potassium carbonate (100.00%, 2.000 equivalents, 2.887 mmol) and potassium iodide (100.00%, 1.100 equivalents, 1.588 mmol) were dissolved in N,N-dimethylformamide (25 mL) at room temperature and stirred at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 50%) and concentrated to obtain the title compound (0.9 g, 112.2%, yellow solid).

[0477] [Step 5] Synthesis of Compound 20, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(4-piperazin-1-ylphenyl)-1,3,4-oxadiazol-2-one

[0478]

[0479] The solution of 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 (100.00%, 0.900 g, 1.620 mmol) synthesized in step 4 and 2,2,2-trifluoroacetic acid (100.00%, 10.000 equivalents, 16.200 mmol) was dissolved in dichloromethane (50 mL) at room temperature and stirred at the same temperature. N-sodium bicarbonate aqueous solution was poured into the reaction mixture, and then extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = 0% to 10%) and concentrated to give the title compound (0.12 g, 16.26%, white solid).

[0480] 1H NMR (400MHz, CDCl3) δ9.29(s,1H),8.39(d,J=10.0Hz,1H),7.70(d,J=8.8Hz,2H),7.49( d,J=8.0Hz,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).

[0481] The compounds in Table 15 below were synthesized according to substantially the same method as Example 20.

[0482] [Table 15]

[0483]

[0484] Example 21: Synthesis of Compound 21, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-[4-(4-methylpiperazin-1-yl)phenyl]-1,3,4-oxadiazol-2-one

[0485]

[0486] A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(4-piperazin-1-ylphenyl)-1,3,4-oxadiazol-2-one (100.00%, 0.060 g, 0.132 mmol), sodium triacetoxyborohydride (100.00%, 2.000 equivalents, 0.264 mmol) and formaldehyde (37.00%, 2.000 equivalents, 0.264 mmol) synthesized in step 5 of Example 20 was dissolved in dichloromethane (5 mL) at room temperature and stirred at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = 0% to 10%) and concentrated to obtain the title compound (0.025 g, 40.42%, yellow solid).

[0487] 1H NMR (400MHz, CDCl3) δ9.29 (s, 1H), 8.39 (d, J = 10.4Hz, 1H), 7.70 (d, J = 8.8Hz, 2H), 7.50 (d, J = 8. 0Hz,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).

[0488] The compounds in Table 16 below were synthesized according to substantially the same method as Example 21.

[0489] [Table 16]

[0490]

[0491]

[0492] Example 6: Synthesis of Compound 6, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-[6-(4-isopropylpiperazin-1-yl)-2-pyridinyl]-1,3,4-oxadiazol-2-one

[0493] [Step 1] Synthesis of 6-fluoropyridine-2-carbohydrazide

[0494]

[0495] To a solution of 6-fluoropyridine-2-carboxylic acid methyl ester (100.00%, 1.000g, 6.446mmol) dissolved in ethanol (30mL) at room temperature, hydrazine monohydrate (100.00% solution, 6.266mL, 129.000mmol) was added and stirred overnight at the same temperature. Saturated sodium bicarbonate aqueous solution was poured into the concentrate obtained by removing the solvent in the reaction mixture under reduced pressure, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting product can be used without further purification (1g, 100.00%, light yellow solid).

[0496] [Step 2] Synthesis of 5-(6-fluoro-2-pyridyl)-3H-1,3,4-oxadiazol-2-one

[0497]

[0498] To a solution of 6-fluoropyridine-2-carbohydrazide (100.00%, 1.000g, 6.446mmol) and 1,1'-carbonylbis-1H-imidazole (100.00%, 1.254g, 7.734mmol) synthesized in step 1 dissolved in tetrahydrofuran (30mL) at room temperature, triethylamine (100.00% solution, 1.251mL, 9.000mmol) was added and stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4g cartridge; methanol / dichloromethane = 0% to 10%) to give the title compound (0.21g, 17.987%, yellow solid).

[0499] [Step 3] Synthesis of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-(6-fluoro-2-pyridinyl)-1,3,4-oxadiazol-2-one

[0500]

[0501] 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.404g, 1.393mmol) was added to a solution of 5-(6-fluoro-2-pyridyl)-3H-1,3,4-oxadiazole-2-one (100.00%, 0.210g, 1.160mmol) synthesized in step 2 and potassium carbonate (100.00%, 0.244g, 1.765mmol) dissolved in N,N-dimethylformamide (5mL) at room temperature, and stirred overnight at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to give the title compound (0.185 g, 40.88%, light yellow solid).

[0502] [Step 4] Synthesis of Compound 6

[0503]

[0504] A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-(6-fluoro-2-pyridinyl)-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 N,N-diisopropylethylamine (100.00% solution, 0.027 mL, 0.150 mmol) synthesized in step 3 was dissolved in dimethyl sulfoxide (1 mL) at 130°C and stirred overnight at the same temperature, and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to give the title compound (0.02 g, 39.15%) in the form of an orange solid.

[0505] 1 H NMR (400MHz, CDCl3) δ9.32(d,J=1.6Hz,1H),8.43(dd,J=8.2,2.2Hz,1H),7.61-7.57(m,1H),7.52(d,J=8.0Hz,1H),7.23(d,J=7.6Hz, 1H),6.96(t,J=51.6Hz,1H),6.78(d,J=8.8Hz,1H),5.27(s,2H),3.76(s,4H),2.89-2.75(m,5H),1.18(d,J=5.6Hz,6H); LRMS(ES)m / z 499.8(M + +1).

[0506] The compounds in Table 17 below were synthesized according to substantially the same method as Example 6.

[0507] [Table 17]

[0508]

[0509] Example 19: Synthesis of Compound 19, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-(1-methyl-1H-indol-5-yl)-1,3,4-oxadiazole-2(3H)-thione

[0510] [Step 1] Synthesis of methyl 1-methylindole-5-carboxylate

[0511]

[0512] To a solution of 1H-indole-5-carboxylic acid methyl ester (100.00%, 0.500g, 2.854mmol) dissolved in N,N-dimethylformamide (7mL) at 0°C, sodium hydride (60.00%, 140.000mg, 3.500mmol) was added and stirred at the same temperature for 0.2 hours. Iodomethane (100.00% solution, 0.27mL, 4.340mmol) was added to the reaction mixture and stirred at room temperature for another 4 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12g cartridge; ethyl acetate / hexane = 0% to 30%) to give the title compound (0.27g, 49.996%, white solid).

[0513] [Step 2] Synthesis of 1-methylindole-5-carbohydrazide

[0514]

[0515] The 1-methylindole-5-carboxylic acid methyl ester (100.00%, 160.000 mg, 0.846 mmol) synthesized in step 1 was dissolved in ethanol (2.5 mL), hydrazine monohydrate (100.00% solution, 0.8 mL, 16.490 mmol) was added at room temperature, and stirred at 60 ° C for 18 hours. Then, the temperature was lowered to room temperature to terminate the reaction. After the solvent in the reaction mixture was removed under reduced pressure, the resulting product was used without further purification (160 mg, 100.00%, light yellow solid).

[0516] [Step 3] Synthesis of 5-(1-methylindol-5-yl)-3H-1,3,4-oxadiazol-2-one

[0517]

[0518] To a solution of 1-methylindole-5-carbohydrazide (100.00%, 160.000 mg, 0.846 mmol) synthesized in step 2 and N,N-diisopropylethylamine (DIPEA, 100.00% solution, 0.3 mL, 1.700 mmol) dissolved in dichloromethane (3 mL) at 0°C, triphosgene (100.00%, 100.000 mg, 0.337 mmol) was added and stirred at the same temperature. The solvent in the reaction mixture was removed under reduced pressure, and the concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 10% to 50%) to obtain the title compound (270 mg, 148.36%, white solid).

[0519] [Step 4] Synthesis of compound 19

[0520]

[0521] To a solution of 5-(1-methylindol-5-yl)-3H-1,3,4-oxadiazol-2-one (100.00%, 50.000 mg, 0.232 mmol) synthesized in step 3 dissolved in N,N-dimethylformamide (2 mL) at room temperature, potassium carbonate (100.00%, 35,000 mg, 0.353 mmol) was added, and the mixture was stirred at the same temperature for 0.3 hours. 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 80,000 mg, 0.276 mmol) was added to the reaction mixture, and the mixture was further stirred at 35°C for 18 hours. A 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, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; hexane / ethyl acetate = 100% to 50%) and concentrated to obtain the title compound (43 mg, 43.61%, white solid).

[0522] 1 H NMR (400MHz, CD3OD) δ9.27(d,J=1.2Hz,1H),8.52(dd,J=8.4,2.4Hz,1H),8.10(d,J=0.8Hz,1H),7.80(s,1H),7.70(t,J=8.8Hz,1H),7. 48(d,J=8.8Hz,1H),7.26(d,J=3.2Hz,1H),7.21(t,J=51.6Hz,1H),6.57(dd,J=3.2,0.4Hz,1H),5.25(s,2H),3.86(s,3H); LRMS(ES)m / z 425.7(M + +1).

[0523] The compounds in Table 18 below were synthesized according to substantially the same method as Example 19.

[0524] [Table 18]

[0525]

[0526]

[0527] Example 33: Synthesis of Compound 33, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(1H-indol-6-yl)-1,3,4-oxadiazol-2-one

[0528] [Step 1] Synthesis of 1-tert-butoxycarbonylindole-6-carboxylic acid

[0529]

[0530] 4-(Dimethylamino)pyridine (100.00%, 0.150g, 1.228mmol) was added to a solution of 1H-indole-6-carboxylic acid (100.00%, 1.000g, 6.205mmol) and di-tert-butyl carbonate (100.00%, 2.000g, 9.164mmol) dissolved in tetrahydrofuran (12mL) at room temperature, and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 24g cartridge; ethyl acetate / hexane = 0% to 30%) to give the title compound (0.8g, 49.34%, white solid).

[0531] [Step 2] Synthesis of tert-butyl 6-(hydrazinecarbonyl)-1H-indole-1-carboxylate

[0532]

[0533] To a solution of 1-tert-butoxycarbonyl indole-6-carboxylic acid (100.00%, 250 mg, 0.9568 mmol) synthesized in step 1 dissolved in tetrahydrofuran (5 mL) at room temperature, 1,1'-carbonylbis-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 at the same temperature for another 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the obtained product was used without further purification (mixture, light yellow solid).

[0534] [Step 3] Synthesis of tert-butyl 6-(2-oxo-3H-1,3,4-oxadiazol-5-yl)indole-1-carboxylate

[0535]

[0536] The tert-butyl 6-(hydrazinecarbonyl)indole-1-carboxylate (100.00%, 450.000mg, 1.635mmol) synthesized in step 2 and N,N-diisopropylethylamine (100.00% solution, 0.56mL, 3.200mmol) were dissolved in dichloromethane (5mL), triphosgene (100.00%, 190.000mg, 0.640mmol) was added at 0°C, and stirred at room temperature for 18 hours. The solvent in the reaction mixture was removed under reduced pressure, and the concentrate was purified and concentrated by column chromatography (SiO2, 12g cartridge; ethyl acetate / hexane = 10% to 50%) to obtain the title compound (270mg, 54.82%, white solid).

[0537] [Step 4] Synthesis of tert-butyl 6-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]indole-1-carboxylate

[0538]

[0539] To a solution of 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 dissolved in N,N-dimethylformamide (2 mL) at room temperature, potassium carbonate (100.00%, 25.000 mg, 0.252 mmol) was added and stirred at the same temperature for 0.3 hours. 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 64,000 mg, 0.221 mmol) was added to the reaction mixture and further stirred at 35°C for 18 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; hexane / ethyl acetate = 100% to 50%) and concentrated to obtain the title compound (58 mg, 62.25%, white solid).

[0540] [Step 5] Synthesis of compound 33

[0541]

[0542] To a solution of tert-butyl 6-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]indole-1-carboxylate (100.00%, 50.000mg, 0.098mmol) synthesized in step 4 dissolved in dichloromethane (1mL) at room temperature, trifluoroacetic acid (100.00% solution, 0.3mL, 3.918mmol) was added, and stirred at the same temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was poured into the concentrate obtained by removing the solvent in the reaction mixture under reduced pressure, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = 100% to 80%) and concentrated to give the title compound (34 mg, 84.59%, light yellow solid).

[0543] 1 H NMR (400MHz, CD3OD) δ9.27(d,J=1.6Hz,1H),8.54(dd,J=8.2,2.2Hz,1H),7.93(d,J=0.8Hz,1H),7.73(d,J=8.4Hz,1H),7. 67(d,J=8.4Hz,1H),7.53(dd,J=8.4,1.6Hz,1H),7.44(d,J=1.2Hz,1H),7.26(t,J=51.6Hz,1H),5.26(s,2H); LRMS(ES)m / z 412.8(M + +1).

[0544] The compounds in Table 19 below were synthesized according to substantially the same method as Example 33.

[0545] [Table 19]

[0546]

[0547]

[0548] Example 11: Synthesis of Compound 11, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1,3,4-oxadiazol-2-one

[0549] [Step 1] Synthesis of tert-butyl 7-(hydrazinecarbonyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate

[0550]

[0551] A solution of 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 equivalents, 20.700 mmol) dissolved in ethanol (20 mL) at 70°C was stirred overnight at the same temperature, and then the reaction was terminated by lowering the temperature to room temperature. 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).

[0552] [Step 2] Synthesis of tert-butyl 7-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate

[0553]

[0554] The solution of tert-butyl 7-(hydrazinecarbonyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (100.00%, 0.640g, 2.197mmol) and 1,1'-carbonylbis-1H-imidazole (100.00%, 1.500 equivalents, 3.296mmol) synthesized in step 1 was dissolved in dichloromethane (5mL) at 50°C and stirred overnight at the same temperature, and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4g cartridge; ethyl acetate / hexane = 0% to 100%) to give the title compound (0.42g, 60.25%, white solid).

[0555] [Step 3] Synthesis of 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

[0556]

[0557] A solution of tert-butyl 7-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (100.00%, 0.420 g, 1.324 mmol) synthesized in step 2, 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.200 equiv., 1.588 mmol), potassium carbonate (100.00%, 2.000 equiv., 2.647 mmol) and potassium iodide (100.00%, 1.100 equiv., 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 the mixture was extracted with dichloromethane, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12g cartridge; ethyl acetate / hexane=0% to 100%) to obtain the title compound (0.55 g, 78.92%, yellow solid).

[0558] [Step 4] Synthesis of compound 11

[0559]

[0560] The solution of 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 (100.00%, 0.550 g, 1.045 mmol) synthesized in step 3 and 2,2,2-trifluoroacetic acid (100.00%, 10.000 equivalents, 10.450 mmol) dissolved in dichloromethane (20 mL) at room temperature was stirred overnight at the same temperature. N-sodium bicarbonate aqueous solution was poured into the reaction mixture, and then extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = 0% to 10%) and concentrated to obtain the title compound (0.42 g, 94.29%, yellow solid).

[0561] 1H NMR (400MHz, CDCl3) δ9.31(s,1H),8.42(d,J=8.4Hz,1H),7.60(s,2H),7.51(d,J=7.6Hz,1H),7.12(d,J =8.4Hz,1H),6.93(t,J=51.6Hz,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).

[0562] Example 12: Synthesis of Compound 12, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)-1,3,4-oxadiazol-2-one

[0563]

[0564] A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(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 equivalents, 0.375 mmol) synthesized in step 4 of Example 11 was dissolved in dichloromethane (5 mL) at room temperature and stirred at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = 0% to 10%) and concentrated to obtain the title compound (0.02 g, 24.21%, yellow solid).

[0565] 1 H NMR (400MHz, CDCl3) δ9.27(s,1H),8.38(d,J=10.4Hz,1H),7.57(d,J=8.0Hz,1H),7.52(d,J=25.6Hz,2H),7.17(d,J=8.0Hz,1H),6 .93(t,J=51.6Hz,1H),5.18(s,2H),3.60(s,2H),2.95(t,J=5.6Hz,2H),2.72(t,J=6.0Hz,2H),2.45(s,3H); LRMS(ES)m / z441.4(M + +1).

[0566] The compounds in Table 20 below were synthesized according to substantially the same method as Example 12.

[0567] [Table 20]

[0568]

[0569] Example 135: Synthesis of Compound 135, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]-5-(2-methyl-3,4-dihydro-1H-isoquinolin-6-yl)-1,3,4-oxadiazole-2-thione

[0570] [Step 1] Synthesis of tert-butyl 6-(hydrazinecarbonyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate

[0571]

[0572] To a solution of 2-tert-butyl, 6-methyl 3,4-dihydro-1H-isoquinoline-2,6-dicarboxylate (100.00%, 1.000 g, 3.433 mmol) dissolved in ethanol (20 mL) at room temperature, hydrazine monohydrate (100.00% solution, 1.668 mL, 34.320 mmol) was added and stirred at 60°C overnight. Then, the reaction was terminated by lowering the temperature to room temperature. The solvent in the reaction mixture was removed under reduced pressure, and the concentrate was purified and concentrated by column chromatography (SiO2, 24 g cartridge; methanol / dichloromethane = 0% to 10%) to obtain the title compound (1 g, 100.0%, white solid).

[0573] [Step 2] Synthesis of tert-butyl 6-(2-thioxo-3H-1,3,4-oxadiazol-5-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate

[0574]

[0575] The solution of tert-butyl 6-(hydrazinecarbonyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (100.00%, 0.642g, 2.204mmol) and potassium ethylxanthate (100.00%, 0.353g, 2.202mmol) synthesized in step 1 was dissolved in ethanol (10mL) at room temperature and stirred overnight at 90°C. Then, the reaction was terminated by lowering the temperature to room temperature. A saturated aqueous solution of ammonium chloride was poured into the reaction mixture, and then extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4g cartridge; dichloromethane / methanol = 0% to 10%) to give the title compound (0.03g, 4.083%, colorless oil).

[0576] [Step 3] Synthesis of tert-butyl 6-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate

[0577]

[0578] To the solution of tert-butyl 6-(2-thioxo-3H-1,3,4-oxadiazol-5-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (100.00%, 0.550 g, 1.650 mmol) and potassium carbonate (100.00%, 0.229 g, 2.311 mmol) synthesized in step 2 dissolved in N,N-dimethylformamide (10 mL) at room temperature, 2-[6-(bromomethyl)-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 the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 0% to 60%) and concentrated to obtain the title compound (0.395 g, 42.71%, yellow solid).

[0579] [Step 4] Synthesis of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1,3,4-oxadiazole-2-thione

[0580]

[0581] The solution of 6-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]-5-thioxo-1,3,4-oxadiazol-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (100.00%, 0.395g, 0.705mmol) and trifluoroacetic acid (100.00% solution, 0.539mL, 7.040mmol) synthesized in step 3 dissolved in dichloromethane (5mL) was stirred overnight at the same temperature. N-Sodium bicarbonate aqueous solution was poured into the reaction mixture, and then extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (0.32g, 98.64%, yellow oil).

[0582] [Step 5] Synthesis of Compound 135

[0583]

[0584] A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1,3,4-oxadiazole-2-thione (100.00%, 0.060 g, 0.130 mmol) synthesized in step 4, 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) was dissolved in dichloromethane (1 mL) and stirred at room temperature for 30 minutes, sodium triacetoxyborohydride (100.00%, 0.082 g, 0.389 mmol) was added, and stirring was continued at the same temperature for 18 hours. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4g cartridge; dichloromethane / methanol = 0% to 10%) to give the title compound (0.021 g, 33.96%, light yellow solid).

[0585] 1H NMR(400MHz, CDCl3)δ9.12(s,1H),8.15(dd,J=9.0,1.8Hz,1H),7.79-7.76(m,2H),7.17(d,J=8.0Hz,1H),6.96(t,J=52.2 Hz,1H),4.80(d,J=1.6Hz,2H),3.65(s,2H),3.01(t,J=5.8Hz,2H),2.76-2.73(m,2H),2.50(s,3H); LRMS(ES)m / z475.9(M + +1).

[0586] The compounds in Table 21 below were synthesized according to essentially the same method as Example 135.

[0587] [Table 21]

[0588]

[0589]

[0590] Example 69: Synthesis of Compound 69, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(2-thienyl)-6H-1,3,4-oxadiazin-2-one

[0591] [Step 1] Synthesis of [2-oxo-2-(2-thienyl)ethyl]acetate

[0592]

[0593] To a solution of 2-bromo-1-(2-thienyl)ethanone (100.00%, 0.500 g, 2.438 mmol) dissolved in N,N-dimethylformamide (10 mL) at room temperature, potassium acetate (100.00%, 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 the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (0.445 g, 99.078%, yellow oil).

[0594] [Step 2] Synthesis of [(2E)-2-(methoxycarbonylhydrazine)-2-(2-thienyl)ethyl]acetate

[0595]

[0596] To a solution of [2-oxo-2-(2-thienyl)ethyl]acetate (100.00%, 0.445 g, 2.416 mmol) synthesized in step 1 and hydrogen chloride (1.00 M solution, 0.048 mL, 0.048 mmol) dissolved in methanol (10 mL) at room temperature, methyl hydrazinecarboxylate (100.00%, 0.239 g, 2.653 mmol) was added and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 50%) to give the title compound (0.425 g, 68.648%, yellow solid).

[0597] [Step 3] Synthesis of 5-(2-thienyl)-3,6-dihydro-1,3,4-oxadiazin-2-one

[0598]

[0599] A solution of [(2E)-2-(methoxycarbonylhydrazono)-2-(2-thienyl)ethyl]acetate (100.00%, 0.425 g, 1.658 mmol) synthesized in step 2 and sodium ethoxide (about 20% ethanol solution, 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, which was then extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 30%) to give the title compound (0.2 g, 66.192%, yellow solid).

[0600] [Step 4] Synthesis of Compound 69

[0601]

[0602] The 5-(2-thienyl)-3,6-dihydro-1,3,4-oxadiazine-2-one synthesized in step 3 (100.00%, 0.045 g, 0.247 mmol), 2-[6-(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 the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 0% to 60%) and concentrated to obtain the title compound (0.042 g, 43.45%, light yellow solid).

[0603] 1 H NMR (400MHz, CDCl3) δ9.32(d,J=1.6Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.53(d,J=8.4Hz,1H),7.47(dd,J=5.2, 1.2Hz,1H),7.25-7.24(m,1H),7.11-7.09(m,1H),6.96(t,J=51.6Hz,1H),5.27(s,2H),5.25(s,2H); LRMS(ES)m / z 392.3(M + +1).

[0604] The compounds in Table 22 below were synthesized according to essentially the same method as Example 69.

[0605] [Table 22]

[0606]

[0607]

[0608] Example 142: Synthesis of Compound 142, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-5-phenyloxazol-2(3H)-one

[0609] [Step 1] Synthesis of methyl 6-(((tert-butoxycarbonyl)amino)methyl)nicotinate

[0610]

[0611] To a solution of 6-(aminomethyl)nicotinate (2.000 g, 12.035 mmol) dissolved in dichloromethane (20 mL) at room temperature, di-tert-butyl dicarbonate (3.152 g, 14.442 mmol) and triethylamine (2.516 mL, 18.053 mmol) were added and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 24 g cartridge; ethyl acetate / hexane = 0% to 40%) to give the title compound (1.700 g, 53.0%, white solid).

[0612] [Step 2] Synthesis of methyl 6-(((tert-butoxycarbonyl)(phenylethynyl)amino)methyl)nicotinate

[0613]

[0614] (Bromoethynyl)benzene (0.200 g, 1.105 mmol) was dissolved in toluene (5 mL), and methyl 6-(((tert-butoxycarbonyl)amino)methyl)nicotinate (0.353 g, 1.326 mmol), copper(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) synthesized in step 1 were added at room temperature and stirred at 80 ° C for 36 hours. Then, the reaction was terminated by lowering the temperature to room temperature. The reaction mixture was filtered through a celite pad to remove solids, and the solvent in the filtrate was removed under reduced pressure. Then, the concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 70%) to obtain the title compound (0.110 g, 27.2%, light yellow solid).

[0615] [Step 3] Synthesis of methyl 6-((2-oxo-5-phenyloxazol-3(2H)-yl)methyl)nicotinate

[0616]

[0617] To a solution of 6-(((tert-butoxycarbonyl)(phenylethynyl)amino)methyl)nicotinate (0.050 g, 0.136 mmol) synthesized in step 2 dissolved in dichloromethane (0.5 mL) at room temperature was added silver bis(trifluoromethanesulfonyl)imide (0.003 g, 0.007 mmol), and stirred at the same temperature for 1 hour. 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, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane=0% to 30%) to give the title compound (0.030 g, 70.8%, yellow solid).

[0618] [Step 4] Synthesis of 6-((2-oxo-5-phenyloxazol-3(2H)-yl)methyl)nicotinic acid hydrazide

[0619]

[0620] A solution of 6-((2-oxo-5-phenyloxazol-3(2H)-yl)methyl)nicotinate (0.016 g, 0.052 mmol) synthesized in step 3 and hydrazine monohydrate (0.050 mL, 1.031 mmol) dissolved in ethanol (1 mL) at 80°C was stirred at the same temperature for 18 hours. Then, the reaction was terminated by lowering the temperature to room temperature. 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).

[0621] [Step 5] Synthesis of Compound 142

[0622]

[0623] To a solution of 6-((2-oxo-5-phenyloxazol-3(2H)-yl)methyl)nicotinamide hydrazide (0.015 g, 0.048 mmol) and triethylamine (0.040 mL, 0.290 mmol) synthesized in step 4 dissolved in tetrahydrofuran (0.7 mL) at room temperature was added 2,2-difluoroacetic anhydride (0.024 mL, 0.193 mmol), and stirred at 80°C for 6 hours. Then, the reaction was terminated by lowering the temperature to room temperature. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; hexane / ethyl acetate = 100% to 50%) to give the title compound (0.008 g, 44.7%, white solid).

[0624] 1H NMR (400MHz, CD3OD) δ9.28(s,1H),8.53(dd,J=7.8,2.2Hz,1H),7.67(d,J=8.4Hz,1H),7.56(d,J=7.6Hz,2H),7.4 4-7.40(m,3H),7.33(t,J=7.4Hz,1H),7.26(t,J=51.4Hz,1H),7.26(t,J=51.4Hz,1H),5.09(s,2H); LRMS(ES)m / z 371.2(M + +1).

[0625] The compounds in Table 23 below were synthesized in substantially the same manner as in Example 142.

[0626] [Table 23]

[0627]

[0628] Example 144: Synthesis of Compound 144, 1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-methyl-4-phenyl-1,3-dihydro-2H-imidazol-2-one

[0629]

[0630] To a solution of 1-methyl-5-phenyl-1,3-dihydro-2H-imidazole-2-one (0.050 g, 0.287 mmol) and 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.100 g, 0.345 mmol) dissolved in N,N-dimethylformamide (1 mL) at room temperature, potassium carbonate (0.060 g, 0.431 mmol) and potassium iodide (0.010 g, 0.057 mmol) were added and stirred at 80°C for 18 hours. Then, the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = 100% to 80%) and concentrated to give the title compound (0.012 g, 10.9%, white solid).

[0631] 1H NMR (400MHz, CDCl3) δ8.18(d,J=8.4Hz,2H),8.15(dd,J=4.2,1.8Hz,1H),7.71(d,J=8.0Hz,2H),7.62-7.5 7(m,2H),7.51-7.37(m,3H),6.95(t,J=51.8Hz,1H),6.79(s,1H),5.66(s,2H),3.51(s,3H); LRMS(ES)m / z 384.2(M + +1).

[0632] Activity Measurement and Analytical Protocols for Compounds of the Invention

[0633] <Experimental Example 1> Confirmation of Inhibition of HDAC Enzyme Activity (In Vitro)

[0634] The following experiment was performed to confirm the HDAC6 selectivity of the compound represented by Chemical Formula I of the present invention by HDAC1 and HDAC6 enzyme activity inhibition test.

[0635] HDAC enzyme activity was determined using the HDAC Fluorometric Drug Discovery Kit (BML-AK511,516) produced by Enzo Life Science. For HDAC1 enzyme activity determination, human recombinant HDAC1 (BML-SE456) was used as the enzyme source and - "SIRT1 (BNL-KI177) was used as a substrate. The 5-fold diluted compound was dispensed into a 96-well plate, 0.3 μg enzyme and 10 μM substrate were added to each well, reacted at 30°C for 60 minutes, and then Developer II (BML-KI176), react for 30 minutes to complete the reaction. Then, use a multi-plate reader (Flexstation 3, Molecular Device) to measure the fluorescence value (Ex 360, Em 460). Using the same protocol as the HDAC1 enzyme activity test method, the human recombinant HDAC6 (382180) from Calbiochem was used to measure the HDAC6 enzyme. For the final result, the GraphPad Prism 4.0 program was used to calculate each IC 50 The results are shown in Table 24 below.

[0636] [Table 24]

[0637]

[0638]

[0639]

[0640] As shown in Table 24 above, the results of the HDAC1 and HDAC6 activity inhibition test confirmed that the 1,3,4-oxadiazole derivative compound of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof exhibited about 185 to about 3497 times excellent selective HDAC6 inhibition activity.

Claims

1. A 1,3,4-oxadiazole derivative compound represented by the following chemical formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula I] In the above chemical formula I, R1 is -C 1-4 Haloalkyl; X1 to X4 are each independently CR X or N; R X -H, -C 1-4 Alkyl, -C 1-4 Haloalkyl or -halogen; Y is CR Y or N; R Y -H or -C 1-4 alkyl; Z is NR Z , O or S; R Z -H or -C 1-4 alkyl; W is O or S; m is 0 or 1; Ring V is aryl, heteroaryl or hydroheteroaryl, wherein at least one H in the aryl, heteroaryl or hydroheteroaryl ring may be replaced by -C 1-4 Alkyl, -C 1-4 Aminoalkyl, -C 1-4 Hydroxyalkyl, -C 1-4 The group is substituted with a haloalkyl, -halogen, -(CH2)n-cycloalkyl, -(CH2)n-heterocyclyl or -(CH2)n-heteroaryl group, wherein at least one H in the -(CH2)n-cycloalkyl, -(CH2)n-heterocyclyl or -(CH2)n-heteroaryl ring may be replaced with -C 1-4 Alkyl, -C 1-4 Haloalkyl, -halogen, cycloalkyl or heterocyclyl substituted (wherein at least one H in the cycloalkyl or heterocyclyl ring may be replaced by -C 1-4 alkyl substituted); and n is 0, 1 or 2.

2. The 1,3,4-oxadiazole derivative compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R1 is -C 1-4 Haloalkyl; X1 is N; X2 to X4 are each independently CR X ; R X is -H or -halogen; Y is CR Y or N; R Y is -H; Z is NR Z , O or S; R Z For -C 1-4 alkyl; W is O or S; m is 0 or 1; The ring V is an aryl, heteroaryl or hydroheteroaryl group, wherein at least one H on the aryl, heteroaryl or hydroheteroaryl ring can be replaced by -C 1-4 Alkyl, -C 1-4 The aminoalkyl, -halogen, -(CH2)n-cycloalkyl, -(CH2)n-heterocyclyl or -(CH2)n-heteroaryl groups are substituted, wherein at least one of the H groups on the -(CH2)n-cycloalkyl, -(CH2)n-heterocyclyl or -(CH2)n-heteroaryl rings may be replaced by -C 1-4 Alkyl, -halogen, cycloalkyl or heterocyclic substitution (wherein, At least one H on the cycloalkyl or heterocyclyl ring may be replaced by -C 1-4 alkyl substituted); and n is 0 or 1.

3. The 1,3,4-oxadiazole derivative compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R1 is -CF2H or -CF3.

4. The 1,3,4-oxadiazole derivative compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein X1 is N; and X2 to X4 are each independently CH or CF.

5. The 1,3,4-oxadiazole derivative compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein Y is CH or N; Z is NC 1-4 Alkyl, O or S; W is O or S; and m is 0 or 1.

6. The 1,3,4-oxadiazole derivative compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein The ring V is phenyl, 5-10 membered heteroaryl or 9-10 membered hydrogen heteroaryl, wherein at least one H in the phenyl, 5-10 membered heteroaryl or 9-10 membered hydrogen heteroaryl ring can be replaced by -C 1-4 Alkyl, -C 1-4 The aminoalkyl, -halogen, -(CH2)n-cycloalkyl, -(CH2)n-heterocyclyl or -(CH2)n-heteroaryl groups are substituted, wherein at least one H in the -(CH2)n-cycloalkyl, -(CH2)n-heterocyclyl or -(CH2)n-heteroaryl ring may be replaced by -C 1-4 Alkyl, -halogen, 4-6 membered cycloalkyl or 4-6 membered heterocyclyl (wherein at least one H in the 4-6 membered cycloalkyl or 4-6 membered heterocyclyl ring may be replaced by -C 1-4 alkyl substituted); and n is 0 or 1.

7. The 1,3,4-oxadiazole derivative compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein The compound represented by the chemical formula I is any one selected from the following compounds:

8. A pharmaceutical composition for preventing or treating a disease mediated by histone deacetylase 6, comprising: The compound represented by Chemical Formula I according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof as an active ingredient.

9. The pharmaceutical composition for preventing or treating a disease mediated by histone deacetylase 6 according to claim 8, wherein The diseases mediated by histone deacetylase 6 are infectious diseases; tumors; endocrine, nutritional and metabolic diseases; mental and behavioral disorders; and nervous system diseases. Diseases of the eye and ocular appendages; Circulatory system diseases; Respiratory diseases; Digestive system diseases; Skin and subcutaneous tissue disorders; musculoskeletal and connective tissue disorders; or congenital malformations, mutations, and chromosomal abnormalities.

10. The pharmaceutical composition for preventing or treating a disease mediated by histone deacetylase 6 according to claim 9, wherein The endocrine, nutritional and metabolic disease is Wilson's disease, amyloidosis or diabetes, The mental and behavioral disorders are depression or Rett syndrome, The nervous system disease is central nervous system atrophy, neurodegenerative disease, movement disorder, neuropathy, motor neuron disease and central nervous system demyelinating disease, The eye and ocular adnexal disease is uveitis, The skin and subcutaneous tissue disease is psoriasis, The musculoskeletal and connective tissue disease is rheumatoid arthritis, osteoarthritis or systemic lupus erythematosus (SLE), The congenital malformation, variation and chromosomal abnormality is autosomal dominant polycystic kidney disease, The infectious disease is prion disease, The tumor is a benign tumor or a malignant tumor, The circulatory system disease is atrial fibrillation or stroke, The respiratory disease is asthma, and The digestive system disease is alcoholic liver disease, inflammatory bowel disease, Crohn's disease or ulcerative bowel disease.

11. A method for preventing or treating a disease mediated by histone deacetylase 6, comprising administering a therapeutically effective amount of a compound represented by Chemical Formula I according to any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

12. Use of a compound represented by Chemical Formula I according to any one of claims 1 to 7, a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease mediated by histone deacetylase 6.

13. Use of the compound represented by Chemical Formula I according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof for preventing or treating a disease mediated by histone deacetylase 6.

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