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

Abstract

The present invention relates to a novel compound having histone deacetylase 6 (HDAC6) inhibitory activity, a method for preparing the same, and uses thereof. The novel compound according to the present invention, its stereoisomer, or its pharmaceutically acceptable salt has histone deacetylase 6 (HDAC6) inhibitory activity and is effective in the prevention or treatment of HDAC6-related diseases, including cancer, inflammatory diseases, autoimmune diseases, and neurological or degenerative neurological diseases.

Description

Technology Field

[0001] The present invention relates to a 1,3,4-oxadiazole derivative compound of a novel structure having histone deacetylase 6 (HDAC6) inhibitory activity, a method for preparing the same, and uses thereof. Background Technology

[0002] In cells, post-translational modifications such as acetylation are critical regulatory modules at the center of biological processes and are strictly controlled by numerous enzymes. Histones are central proteins that constitute chromatin; they act as axes for DNA coiling, facilitating DNA condensation. Furthermore, the balance between histone acetylation and deacetylation plays a vital role in gene expression.

[0003] Histone deacetylases (HDACs) are enzymes that remove acetyl groups from lysine residues of histone proteins constituting chromatin. They are associated with gene silencing and are known to induce cell cycle arrest, inhibition of angiogenesis, immunomodulation, and apoptosis (Hassig et al., Curr. Opin. Chem. Biol. 1997, 1, 300-308). Furthermore, inhibition of HDAC enzyme function has been reported to induce cancer cell self-destruction by reducing the activity of cancer cell survival-related factors and activating cancer cell death-related factors in vivo (Warrell et al, J. Natl. Cancer Inst. 1998, 90, 1621-1625).

[0004] In humans, 18 HDACs are known and are classified into four classes based on their homology with yeast HDACs. Among these, the 11 HDACs that use zinc as a cofactor can be divided into three groups: Class I (HDAC1, 2, 3, 8), Class II (IIa: HDAC4, 5, 7, 9; IIb: HDAC6, 10), and Class IV (HDAC11). Additionally, the seven HDACs in 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 in the preclinical or clinical development stages, only non-selective HDAC inhibitors are known as anticancer agents to date; vorinostat (SAHA) and romidepsin (FK228) have been approved as treatments for cutaneous T-cell lymphoma, and panobinostat (LBH-589) as a treatment for multiple myeloma. However, non-selective HDAC inhibitors are generally known to cause side effects such as fatigue and nausea at high doses (Piekarz et al., Pharmaceuticals 2010, 3, 2751-2767). These side effects are reported to be due to the inhibition of class I HDACs, and due to these side effects, the development of non-selective HDAC inhibitors has been limited to fields other than anticancer drugs (Witt et al., Cancer Letters 277, (2009), 8-21).

[0006] Meanwhile, there are reports that selective class II HDAC inhibition will not exhibit the toxicity seen in class I HDAC inhibition, and since the development of selective HDAC inhibitors could resolve side effects such as toxicity caused by non-selective HDAC inhibition, selective HDAC inhibitors have the potential to be developed as effective treatments for various diseases (Matthias et al., Mol. Cell. Biol. 2008, 28, 1688-1701).

[0007] HDAC6, one of the Class IIb HDACs, is known to be present mainly in the cytoplasm and involved in the deacetylation of numerous non-histone substrates (HSP90, cortactin, etc.), including tubulin proteins (Yao et al., Mol. Cell 2005, 18, 601-607). HDAC6 has two catalytic domains, and its C-terminal zinc finger domain can bind to ubiquitinated proteins. HDAC6 is known to play an important role in various diseases, including cancer, inflammatory diseases, autoimmune diseases, neurological diseases, and neurodegenerative disorders, because it has multiple non-histone proteins as substrates (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] A common structural feature of various HDAC inhibitors is that they consist of a cap group, a linker group, and a zinc-binding group (ZBG), as shown in the structure of the vorinostat below. Many researchers have investigated the inhibitory activity and selectivity toward enzymes through structural modifications of the cap and linker groups. Among these, the zinc-binding group is known to play a more important role in enzyme inhibitory activity and selectivity (Wiest et al., J. Org. Chem. 2013 78: 5051-5055; Methot et al., Bioorg. Med. Chem. Lett. 2008, 18, 973-978).

[0009]

[0010] Most of the zinc-binding groups mentioned above are hydroxamic acid or benzamide; among these, hydroxamic acid derivatives exhibit potent HDAC inhibitory effects but have problems with low bioavailability and serious off-target activity. In the case of benzamide, there is a problem in that it contains aniline, which can generate toxic metabolites in vivo (Woster et al., Med. Chem. Commun. 2015, online publication).

[0011] Accordingly, for the treatment of cancer, inflammatory diseases, autoimmune diseases, neurological diseases, and neurodegenerative disorders, there is a need to develop selective HDAC6 inhibitors having zinc-binding groups that are free from side effects and have improved bioavailability, unlike non-selective inhibitors that have side effects. Prior art literature

[0012] International Patent Publication WO 2011 / 091213 (Published July 28, 2011): ACY-1215 International Patent Publication WO 2011 / 011186 (Published January 27, 2011): Tubastatin International Patent Publication WO 2013 / 052110 (Published April 11, 2013): Sloan-K International Patent Publication WO 2013 / 041407 (Published March 28, 2013): Cellzome International Patent Publication WO 2013 / 134467 (Published September 12, 2013): Kozi International Patent Publication WO 2013 / 008162 (Published January 17, 2013): Novartis International Patent Publication WO No. 2013 / 080120 (Published June 6, 2013): Novartis International Patent Publication WO 2013 / 066835 (Published May 10, 2013): Tempero International Patent Publication WO 2013 / 066838 (Published May 10, 2013): Tempero International Patent Publication WO 2013 / 066833 (Published May 10, 2013): Tempero International Patent Publication WO 2013 / 066839 (Published May 10, 2013): Tempero The problem to be solved

[0013] The object of the present invention is to provide a compound having selective HDAC6 inhibitory activity, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0014] 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.

[0015] Another objective of the present invention is to provide a method for manufacturing the same.

[0016] Another objective of the present invention is to provide a pharmaceutical composition for the prevention or treatment of diseases related to HDAC6 activity.

[0017] Another objective of the present invention is to provide its use for the manufacture of a drug for the prevention or treatment of diseases related to HDAC6 activity.

[0018] Another objective of the present invention is to provide a method for preventing or treating diseases associated with HDAC6 activity, comprising administering a therapeutically effective amount of the said compounds.

[0019] Another objective of the present invention is to provide a preventive or therapeutic use for diseases related to HDAC6 activity. means of solving the problem

[0020] The inventors of the present invention discovered an oxadiazole derivative compound having histone deacetylase 6 (HDAC6) inhibitory activity and completed the present invention by using it to inhibit or treat diseases related to HDAC6 activity.

[0021] The following describes this in detail. All combinations of the various elements disclosed in this invention fall within the scope of this invention. Furthermore, the scope of this invention should not be considered limited by the following detailed description.

[0022] 1,3,4-oxadiazole derivative compounds

[0023] In accordance with the above purpose, the present invention provides a 1,3,4-oxadiazole derivative compound represented by the following formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0024] [Chemical Formula I]

[0025]

[0026] In the above chemical formula I,

[0027] R1 is -C 1-4 It is a haloalkyl;

[0028] X1 to X4 are each independently CR X or N and;

[0029] R X is -H, -C 1-4 Alkyl, -C 1-4 haloalkyl, or -haloic;

[0030] Y is CR Y or N and;

[0031] R Y -H or -C 1-4 It is alkyl;

[0032] Z is NR Z , O, or S and;

[0033] R Z -H or -C 1-4 It is alkyl;

[0034] W is O or S and;

[0035] m is 0 or 1 and;

[0036] Ring V is aryl, heteroaryl, or hydroheteroaryl and {wherein one or more H of the aryl, heteroaryl, or hydroheteroaryl ring are -C 1-4 Alkyl, -C 1-4 Aminoalkyl, -C 1-4 Hydroxyalkyl, -C 1-4It can be substituted with haloalkyl, -halo, -(CH2)n-cycloalkyl, -(CH2)n-heterocycloalkyl, or -(CH2)n-heteroaryl [wherein, one or more H of the -(CH2)n-cycloalkyl, -(CH2)n-heterocycloalkyl, or -(CH2)n-heteroaryl ring are -C 1-4 Alkyl, -C 1-4 It may be substituted with haloalkyl, -halo, cycloalkyl, or heterocycloalkyl (wherein one or more H of the cycloalkyl or heterocycloalkyl ring are -C 1-4 Can be substituted with alkyl groups)]};

[0037] n is 0, 1, or 2.

[0038] According to a specific embodiment of the present invention, the compound represented by Formula I of the present invention may be in the following range:

[0039] R1 is -C 1-4 It is a haloalkyl;

[0040] X1 is N and;

[0041] X2 through X4 are each independently CR X And;

[0042] R X is -H or -halo and;

[0043] Y is CR Y or N and;

[0044] R Y is -H and;

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

[0046] R Z is -C 1-4 It is alkyl;

[0047] W is O or S and;

[0048] m is 0 or 1 and;

[0049] Ring V is aryl, heteroaryl, or hydroheteroaryl and {wherein one or more H of the aryl, heteroaryl, or hydroheteroaryl ring are -C 1-4 Alkyl, -C 1-4 It can be substituted with aminoalkyl, -halo, -(CH2)n-cycloalkyl, -(CH2)n-heterocycloalkyl, or -(CH2)n-heteroaryl [wherein, one or more H of the -(CH2)n-cycloalkyl, -(CH2)n-heterocycloalkyl, or -(CH2)n-heteroaryl ring are -C 1-4 It may be substituted with alkyl, -halo, cycloalkyl, or heterocycloalkyl (wherein one or more H of the cycloalkyl or heterocycloalkyl ring are -C 1-4 Can be substituted with alkyl groups)]};

[0050] n is 0 or 1.

[0051] In addition, according to a specific embodiment of the present invention, the compound represented by Formula I of the present invention may be within the following range:

[0052] R1 is -CF2H or -CF3.

[0053] In addition, according to a specific embodiment of the present invention, the compound represented by Formula I of the present invention may be within the following range:

[0054] X1 is N; X2 to X4 are each independently CH or CF.

[0055] In addition, according to a specific embodiment of the present invention, the compound represented by Formula I of the present invention may be within the following range:

[0056] Y is CH or N;

[0057] Z is NC 1-4 It is alkyl, O, or S;

[0058] W is O or S and;

[0059] m is 0 or 1.

[0060] In addition, according to a specific embodiment of the present invention, the compound represented by Formula I of the present invention may be within the following range:

[0061] Ring V is phenyl, 5-10-membered heteroaryl, or 9-10-membered hydroheteroaryl, and {wherein one or more H of the phenyl, 5-10-membered heteroaryl, or 9-10-membered hydroheteroaryl ring are -C 1-4 Alkyl, -C 1-4 It can be substituted with aminoalkyl, -halo, -(CH2)n-cycloalkyl, -(CH2)n-heterocycloalkyl, or -(CH2)n-heteroaryl [wherein, one or more H of the -(CH2)n-cycloalkyl, -(CH2)n-heterocycloalkyl, or -(CH2)n-heteroaryl ring are -C 1-4 It may be substituted with alkyl, -halo, 4-6-membered cycloalkyl, or 4-6-membered heterocycloalkyl (wherein one or more H of the 4-6-membered cycloalkyl or 4-6-membered heterocycloalkyl ring is -C 1-4 Can be substituted with alkyl groups)]};

[0062] n is 0 or 1.

[0063] In addition, according to a specific embodiment of the present invention, the specific compound represented by Formula I of the present invention is as shown in Table 1 below:

[0064] [Table 1]

[0065]

[0066] delete

[0067] delete

[0068] delete

[0069] delete

[0070] delete

[0071] delete

[0072] In the present invention, "alkyl" may mean a straight-chain or branched-chain acyclic, cyclic, or saturated hydrocarbon combined with such acyclic hydrocarbon, unless otherwise specified. For example, "C 1-4 "alkyl" may refer to an alkyl containing 1 to 4 carbon atoms. Acyclic alkyls are, for example, methyl, ethyl, n -profile, n -Butyl, isopropyl, 2nd grade( sec )-butyl, isobutyl, or tertiary( tert Cyclic alkyls may include butyl, etc., but are not limited thereto. Cyclic alkyls may be used interchangeably with "cycloalkyl" in this specification and, as an example, may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, etc., but are not limited thereto.

[0073] In the present invention, "alkoxy" may mean an alkyl ether group -(O-alkyl), wherein alkyl is as defined above. For example, "C 1-4 "of alkoxy" is C 1-4 Alkoxy containing an alkyl group, i.e., -(OC 1-4 It can mean alkyl, and as an example, alkoxy can mean methoxy, ethoxy, n -Propoxi( n -propoxy), isopropoxy, n -Butoxy( n -butoxy), isobutoxy, sec -Butoxy( sec -butoxy), or tert -Butoxy( tert It may include but is not limited to -butoxy).

[0074] In the present invention, "halo" may be F, Cl, Br, or I.

[0075] In the present invention, "haloalkyl" may mean a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with one or more halos as defined herein. Examples of said haloalkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, or n-butyl independently substituted with one or more halogens, e.g., F, Cl, Br, or I.

[0076] In the present invention, "hydroxyalkyl" may mean a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with -OH. Examples of the hydroxyalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, or n-butyl independently substituted with one or more hydroxyl groups.

[0077] In the present invention, "aminoalkyl" may mean a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with amino-(NR'R"). Here, R' and R' are each independently hydrogen, and C 1-4 It can be selected from the group consisting of alkyls, and the selected R' and R" can each be independently substituted or unsubstituted.

[0078] In the present invention, "heterocycloalkyl" may mean a ring containing 1 to 5 heteroatoms selected from N, O, and S as ring-forming atoms, and may be saturated or partially unsaturated. Herein, if unsaturated, it may be referred to as a heterocycloalkene. Unless otherwise noted, a heterocycloalkyl may be a single ring or a polycyclic ring such as a spiro ring, a bridged ring, or a fused ring. Additionally, "heterocycloalkyl of 3 to 12 atoms" may mean a heterocycloalkyl containing 3 to 12 ring-forming atoms, and as an example, a heterocycloalkyl is pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(1 H ,3 H )-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine- S -Oxide, Thiomorpholine- S , S -oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidein, tropane, 2-azaspyro[3,3]heptane, (1 R ,5 S )-3-Azabicyclo[3.2.1]octane, (1 s ,4 s )-2-azabicyclo[2.2.2]octane, or (1 R ,4 R It may include )-2-oxa-5-azabicyclo[2.2.2]octane, but is not limited thereto.

[0079] In the present invention, "arene" may refer to an aromatic hydrocarbon ring. The arene may be a monocyclic arene or a polycyclic arene. The number of ring-forming carbon atoms of the arene may be 5 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less. Examples of arenes include, but are not limited to, benzene, naphthalene, fluorene, anthracene, phenanthrene, bibenzene, terbenzene, quaternbenzene, quinkbenzene, sexbenzene, triphenylene, pyrene, benzofluorantene, chrysene, etc. In this specification, a residue obtained by removing one hydrogen atom from the "arene" is referred to as "aryl".

[0080] In the present invention, "heteroarene" may be a ring comprising one or more of O, N, P, Si, and S as heteroelements. The number of carbon atoms forming the ring of the heteroarene may be 2 or more and 30 or less, or 2 or more and 20 or less. The heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene. The polycyclic heteroarene may have, for example, a two-ring or three-ring structure. Examples of heteroalenes include thiophene, purine, pyrrole, pyrazol, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, bipyridyl, triazine, acryl, pyridazine, pyrazine, quinoline, quinazolin, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyrimidine, pyrazolopyrimidine, imidazopyrazine or pyrazolopyridine. N -Arylcarbazole, N -heteroarylcarbazole, NExamples include, but are not limited to, alkylcarbazole, benzoxazole, benzimidazole, benzothiazole, benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isooxazole, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenothiazine, dibenzosilol, and dibenzofuran. In one embodiment of the present invention, the heteroarene may also include a bicyclic heterocyclo-arene comprising an arene ring fused to a heterocycloalkyl ring or a heteroarene fused to a cycloalkyl ring. In this specification, a residue obtained by removing one hydrogen atom from the "heteroarene" is referred to as "heteroaryl".

[0081] The compound represented by Formula I of the present invention may contain one or more asymmetric carbons and, accordingly, may exist as a racemic mixture, a racemic mixture, a single enantiomer, a mixture of diastereomers, and each diastereomer. Such stereoisomers can be separated by the prior art, for example, by column chromatography or HPLC. Alternatively, each stereoisomer of the compound represented by Formula I may be synthesized stereospecifically using optically pure starting materials and / or reagents of a known arrangement.

[0082] In the present invention, the term "enantiomer" refers to a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but differing stereochemically. Each of these enantiomers and mixtures thereof are also included within the scope of the present invention. Unless otherwise noted, a solid line (-) connected to an asymmetric carbon atom is a wedge-shaped solid line representing an absolute stereocenter arrangement. or wedge-shaped dotted joint It may include.

[0083] The compound of Formula 1 of the present invention may exist in the form of a "pharmaceutically acceptable salt." As the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The term "pharmaceutically acceptable salt" of the present invention refers to any organic or inorganic acid addition salt of said compound at a concentration having a relatively non-toxic and harmless active effect on the patient, such that side effects caused by said salt do not reduce the beneficial efficacy of the compound represented by Formula 1.

[0084] Acid addition salts are prepared by conventional methods, for example, by dissolving a compound in an excess amount of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent, for example, methanol, ethanol, acetone, or acetonitrile. An equal molar amount of the compound and an acid or alcohol in water may be heated, and then the mixture may be dried by evaporation or the precipitated salt may be filtered by suction.

[0085] In this case, organic and inorganic acids may be used as free acids; hydrochloric acid, phosphoric acid, sulfuric acid, or nitric acid may be used as inorganic acids, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid, vanillic acid, or hydroiodic acid may be used as organic acids. However, they are not limited to these.

[0086] In addition, pharmaceutically acceptable metal salts can be prepared using a base. Alkali metal salts or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium, or calcium salts as the metal salts, but is not limited to these. 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).

[0087] The pharmaceutically acceptable salts of the present invention comprise salts of acidic or basic groups that may be present in the compound of Formula 1, unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of hydroxyl groups, and other pharmaceutically acceptable salts of amino groups include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p-toluenesulfonate (tosylate) salts, and may be prepared through methods for preparing salts known in the art.

[0088] Method for preparing 1,3,4-oxadiazole derivative compounds

[0089] 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.

[0090] [Chemical Formula I]

[0091]

[0092] The above chemical formula I is as defined above.

[0093] In the present invention, preferred methods for preparing an oxadiazole derivative compound represented by the above formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof are as shown in [Reaction Scheme 1] to [Reaction Scheme 8] below, and methods for preparation modified to a level obvious to those skilled in the art are also included.

[0094] [Reaction Equation 1]

[0095]

[0096] According to the above reaction scheme 1, compound 1-2 is prepared by adding hydrazine to compound 1-1, compound 1-3 is prepared by reacting with trifluoroacetic anhydride or difluoroacetic anhydride, and then compound 1-4 is synthesized through a bromination reaction. Compound 1-4 is used as the Zn-Binder portion of an HDAC 6 inhibitor and serves as an intermediate in the synthesis of all compounds.

[0097] [Reaction Equation 2]

[0098]

[0099] 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)-one and 1,3,4-oxadiazole-2(3H)-thion compound 2-4 are prepared using CDI and potassium ethylxanthate. Additionally, compound 2-3 can be prepared by adding Lawesson reagent to compound 2-2, and then 1,3,4-thiadiazole-2(3H)-one compound 2-4 can be prepared using CDI. Compound 2-5 is prepared through a substitution reaction between compound 2-4 and compound 1-4. Compound 2-5 prepared by the above reaction formula 2 may be 1, 5, 15, 16, 17, 18, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 59, 60, 61, 62, etc.

[0100] [Reaction Equation 3]

[0101]

[0102] In the above reaction scheme 3, compound 3-2 is prepared by reductively amination of compound 3-1, which has an aldehyde structure, and compound 3-3 is prepared using hydrazine. Then, 1,3,4-oxadiazole-2(3H)-one compound 3-4 is prepared using CDI. Subsequently, compound 3-5 can be prepared through a substitution reaction with compound 1-4. Examples of compound 3-5 prepared by the above reaction scheme 3 include compounds 2 and 4.

[0103] [Reaction Equation 3-1]

[0104]

[0105] In the above reaction scheme 3-1, compound 3-1-1 is prepared by using ethylene glycol to protect the aldehyde structure of compound 3-1, and then compound 3-1-2 is prepared using hydrazine. Subsequently, 1,3,4-oxadiazole-2(3H)-one and 1,3,4-oxadiazole-2(3H)-thion compound 3-1-3 are prepared using CDI and potassium ethixanthate. Afterwards, compound 3-1-4 is prepared through 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. Subsequently, compound 3-5 can be prepared through a reductive amination reaction. Examples of compounds 3-5 prepared by the above reaction formula 3-1 include 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.

[0106] [Reaction Equation 3-2]

[0107]

[0108] In the above reaction scheme 3-2, compound 3-2-1 is prepared by reductively aminating compound 3-1 having an aldehyde structure, compound 3-2-2 is prepared using hydrazine, and then 1,3,4-oxadiazole-2(3H)-one is prepared using CDI and 1,3,4-oxadiazole-2(3H)-thion compound 3-2-4 is prepared using potassium ethylxanthate. Additionally, compound 3-2-3 is prepared from compound 3-2-2 using Lawesson reagent, and then 1,3,4-thionazole-2(3H)-one compound 3-2-4 is prepared using CDI. Subsequently, compound 3-2-5 is prepared by using a substitution reaction between compound 3-2-4 and compound 1-4, compound 3-2-6 is prepared by removing the amine protecting group, and compound 3-2-7 is prepared through a reductive amination reaction. Examples of compound 3-2-7 prepared by the above reaction scheme 3-2 include 63, 64, 65, 66, 67, 68, 77, 78, 79, 83, etc.

[0109] [Reaction Equation 4]

[0110]

[0111] In the above reaction scheme 4, compound 4-2 is prepared from ester compound 4-1 containing a halogen element through a CC coupling (Suzuki-coupling) reaction, and then compound 4-3 is prepared through a reduction reaction. Additionally, compound 4-3 is prepared from compound 4-1 through a CN coupling (Buchwald-raction) and substitution reaction. Subsequently, compound 4-4 is prepared using hydrazine, and 1,3,4-oxadiazole-2(3H)-one is prepared using CDI, and 1,3,4-oxadiazole-2(3H)-thion compound 4-6 is prepared using potassium ethylxanthate. Furthermore, compound 4-5 is prepared from compound 4-4 using Lawesson reagent, and then 1,3,4-thion-2(3H)-one compound 4-6 is prepared using CDI. Subsequently, Compound 4-7 is prepared through a substitution reaction with Compound 1-4, and Compound 4-8 is prepared by removing the amine protecting group, such as Compounds 20, 23, and 36. Additionally, Compound 4-9 can be prepared through a reductive amination reaction. Compound 4-9 prepared according to the above reaction scheme 4 includes Compounds 8, 9, 10, 21, 22, 24, 25, 37, 38, 39, 40, 26, 29, 30, 41, 55, 56, 57, 58, 75, 76, 80, 81, 82, 100, 101, 102, 103, 104, 105, 106, 115, 116, 126, and 127.

[0112] In addition, compound 4-10 can be prepared by reductively amination of compound 4-8 prepared according to the above reaction scheme 4, compound 4-11 can be prepared by removing the amine protecting group, and compound 4-12 can be prepared by reductively amination. Examples of compound 4-12 include compounds 27, 28, etc.

[0113] [Reaction Equation 4-1]

[0114]

[0115] In the above reaction scheme 4-1, compound 4-2 is prepared using hydrazine from ester compound 4-1 containing a halogen element, and 1,3,4-oxadiazole-2(3H)-one compound 4-3 is prepared using CDI. Subsequently, compound 4-4 is prepared through a substitution reaction with compound 1-4, and compound 4-9 is prepared through an amine substitution reaction. The compounds prepared by the above reaction scheme 4-1 may be 6, 7, etc.

[0116] [Reaction Equation 5]

[0117]

[0118] In the above reaction scheme 5, compound 5-2 is prepared by alkylating compound 5-1, which contains an amine, with an amine protecting group, and compound 5-3 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)-thion compound 5-4. Subsequently, compound 5-5 is prepared through a substitution reaction with compound 1-4. Examples of compounds 5-5 prepared according to the above reaction scheme 5 include compounds 19, 31, 32, etc.

[0119] In addition, compound 5-6 can be prepared by removing the amine protecting group of compound 5-5 prepared according to the above reaction scheme 5, and compounds 3, 11, 33, 34, 35, etc. can be used as compounds 5-6.

[0120] Subsequently, compounds 5-7 are prepared through a reductive amination reaction. Examples of compounds 5-7 prepared according to the above reaction scheme 5 include compounds 12, 13, 14, 135, 136, 137, 138, 139, 140, 141, etc.

[0121] [Reaction Equation 6]

[0122]

[0123] In the above reaction scheme 6, acetate compound 6-2 is prepared by substituting bromo compound 6-1, and hydrazine carboxylate compound 6-3 is prepared by substituting, and then 1,3,4-oxadiazine-2-one compound 6-4 is prepared using sodium ethylate. Subsequently, compound 6-5 is prepared through a substitution reaction with compound 1-4. Examples of compound 6-5 prepared according to the above reaction scheme 6 include compounds 69, 70, 71, 72, 73, 74, etc.

[0124] [Reaction Equation 7]

[0125]

[0126] The above reaction scheme 7 prepares compound 7-2 protected by the amine protecting group of compound 7-1, prepares triple-bonded compound 7-4 through a substitution reaction with compound 7-3, and prepares oxazole-2(3H)-one compound 7-5 using silver bis(trifluoromethanesulfonyl)imide. Subsequently, compound 7-6 is prepared using hydrazine, and then compound 7-7 can be prepared by reacting with trifluoroacetic anhydride or difluoroacetic anhydride. The compounds prepared by the above reaction scheme 7 may be 142, 143, etc.

[0127] [Reaction Equation 8]

[0128]

[0129] The above reaction scheme 8 can produce compound 8-2 by substitution reaction of imidazole-2-one compound 8-1 with compound 1-4. The compounds produced by the above reaction scheme 8 may be 144, etc.

[0130] Uses of 1,3,4-oxadiazole derivative compounds

[0131] The present invention provides the use of a compound represented by the following chemical formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0132] [Chemical Formula I]

[0133]

[0134] The above chemical formula I is as defined above.

[0135] According to one embodiment of the present invention, the present invention provides a pharmaceutical composition comprising, as an active ingredient, a compound represented by the formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0136] In addition, according to one embodiment of the present invention, the present invention provides a pharmaceutical composition for the prevention or treatment of diseases related to histone deacetylase 6 activity, comprising as an active ingredient a compound represented by the formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of the present invention exhibits a significant effect in the prevention or treatment of diseases related to histone deacetylase 6 activity by selectively inhibiting histone deacetylase 6.

[0137] Diseases associated with the activity of the above-mentioned histone deacetylase 6 include cancer, inflammatory diseases, autoimmune diseases, neurological or degenerative neurological diseases, specifically including lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, brain cancer, ovarian cancer, stomach cancer, skin cancer, pancreatic cancer, glioma, neuroporomatous erythematoma, leukemia, lymphoma, multiple myeloma, solid tumors, Wilson's disease, spinocerebellar ataxia, prion disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, amyloidosis, Alzheimer's disease, alcoholic liver disease, spinal muscular atrophy, rheumatoid arthritis, or osteoarthritis, and also include symptoms or diseases associated with abnormal function of the histone deacetylase.

[0138] According to one embodiment of the present invention, examples of histone deacetylase-mediated diseases include infectious diseases; neoplasms; endocrine, nutritional, and metabolic diseases; mental and behavioral disorders; neurological diseases; diseases of the eye and adnexa; circulatory diseases; respiratory diseases; digestive diseases; skin and subcutaneous tissue diseases; musculoskeletal and connective tissue diseases; or congenital malformations, deformities, and chromosomal abnormalities. In addition, it includes symptoms or diseases associated with the abnormal function of histone deacetylase 6.

[0139] In the present invention, the infectious disease may be a prion disease. Additionally, the neoplasm may be a benign tumor (e.g., myelodysplastic syndrome) or a malignant tumor (e.g., multiple myeloma, lymphoma, leukemia, lung cancer, colorectal cancer, colon cancer, prostate cancer, urothelial carcinoma, breast cancer, melanoma, skin cancer, liver cancer, brain cancer, stomach cancer, ovarian cancer, pancreatic cancer, head and neck cancer, oral cancer, or glioma). Additionally, the endocrine, nutritional, and metabolic disease may be Wilson's disease, amyloidosis, or diabetes mellitus. Additionally, the mental and behavioral disorder may be depression or Rett syndrome. In addition, the above neurological disease may be a central nervous system atrophy (e.g., Huntington's disease, spinal muscular atrophy (SMA), spinocerebellar ataxia (SCA)), neurodegenerative disease (e.g., Alzheimer's disease), movement disorder (e.g., Parkinson's disease), neuropathy (e.g., hereditary neuropathy (Charcot-Marie-Tooth disease), sporadic neuropathy, inflammatory neuropathy, drug-induced neuropathy), motor neuron disease (e.g., amyotrophic lateral sclerosis (ALS)), or central nervous system demyelinating disease (e.g., multiple sclerosis (MS)). In addition, the above eye and adnexal disease may be uveitis. In addition, the above circulatory disease may be atrial fibrillation or stroke. In addition, the above respiratory disease may be asthma. In addition, the above digestive disease may be alcoholic liver disease, inflammatory bowel disease, Crohn's disease, or ulcerative colitis. In addition, the above skin and subcutaneous tissue disease may be psoriasis. In addition, the musculoskeletal and connective tissue diseases mentioned above may be rheumatoid arthritis, osteoarthritis, or systemic lupus erythematosus (SLE). In addition, the congenital malformations, deformities, and chromosomal abnormalities mentioned above may be autosomal dominant polycystic kidney disease.

[0140] The stereoisomer and pharmaceutically acceptable salt above are as described above in the stereoisomer and pharmaceutically acceptable salt of the compound represented by Formula I of the present invention.

[0141] The pharmaceutical composition of the present invention may further comprise one or more pharmaceutically acceptable carriers in addition to the compound represented by Formula I, its stereoisomers, or pharmaceutically acceptable salts thereof for administration. In this case, the pharmaceutically acceptable carrier may be a mixture of saline solution, sterile water, Ringer's solution, buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components, and other conventional additives such as antioxidants, buffers, and bacteriostatic agents may be added as needed. Additionally, diluents, dispersants, surfactants, binders, and lubricants may be added to formulate the composition into injectable formulations such as aqueous solutions, suspensions, and emulsions, or into pills, capsules, granules, or tablets. Accordingly, the composition of the present invention may be a patch, liquid, pill, capsule, granule, tablet, suppository, etc. These formulations may be manufactured by conventional methods used in the field of formulation or by methods disclosed in Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton PA, and may be formulated into various formulations depending on each disease or component.

[0142] The composition of the present invention may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) according to the intended method, and the dosage may vary depending on the patient's body weight, age, gender, health condition, diet, time of administration, method of administration, excretion rate, and severity of the disease. The daily dosage of the compound represented by Formula I of the present invention is about 1 to 1000 mg / kg, preferably 5 to 100 mg / kg, and may be administered once or several times a day.

[0143] The pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar medicinal effects in addition to the compound represented by the formula I, its stereoisomer, or its pharmaceutically acceptable salt.

[0144] According to a specific embodiment of the present invention, the present invention provides a method for preventing or treating a disease related to histone deacetylase 6 activity, comprising the step of administering a therapeutically effective amount of a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof. The subject may be a mammal, including humans.

[0145] The method for preventing or treating a histone deacetylase 6 activity-related disease according to the present invention comprises administering a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, thereby not only treating the disease itself before the onset of symptoms but also inhibiting or avoiding the symptoms thereof. Additionally, the method for preventing or treating a histone deacetylase 6 activity-related disease according to the present invention may further comprise administering a therapeutically effective amount of an additional active agent that aids in treating the disease together with the compound represented by Formula 1, wherein the additional active agent may exhibit a synergistic or auxiliary effect together with the compound of Formula I.

[0146] The term "therapeutically effective amount" as used in the present invention refers to an amount of the compound represented by Formula I that is effective for the prevention or treatment of diseases related to histone deacetylase 6 activity. Specifically, "therapeutically effective amount" means an amount sufficient to treat the disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level may be determined based on factors including individual type and severity, age, sex, type of disease, drug activity, sensitivity to the drug, time of administration, route of administration and elimination rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with commercially available therapeutic agents. It may also be administered as a single or multiple doses. It is important to administer an amount that obtains maximum effect with a minimum amount without side effects, taking all of the above factors into consideration, and this can be easily determined by a person skilled in the art. The dosage of the pharmaceutical composition of the present invention may be determined by an expert based on various factors such as the patient's condition, age, gender, and complications. Since the active ingredient of the pharmaceutical composition of the present invention has excellent safety, it may be used in doses exceeding the determined dosage.

[0147] In addition, according to one embodiment of the present invention, the present invention provides a method for selectively inhibiting HDAC6 by administering a compound represented by the formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to mammals including humans.

[0149] According to one embodiment of the present invention, the present invention provides the use of a compound represented by the formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0150] According to one embodiment of the present invention, the present invention also provides the use of a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for the preparation of a drug for the treatment of diseases related to histone deacetylase 6 activity. The compound represented by Formula I for the preparation of the drug may be mixed with acceptable adjuvants, diluents, carriers, etc., and may be prepared as a complex formulation with other active agents to have a synergistic effect of the active ingredients.

[0151] The matters mentioned in the uses, compositions, and treatment methods of the present invention apply equally unless they contradict one another.

[0152] Embodiments of the present invention may be modified in various different forms, and the scope of the present invention is not limited to the embodiments described below. Furthermore, embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art. Moreover, throughout the specification, the term "comprising" any component means that, unless specifically stated otherwise, it does not exclude other components but may include additional components. Effects of the invention

[0153] The compound represented by the above formula I of the present invention, its stereoisomers, or its pharmaceutically acceptable salts can selectively inhibit HDAC6, and thus have significantly superior preventive or therapeutic effects against diseases related to histone deacetylase 6 activity. Specific details for implementing the invention

[0154] The present invention will be explained in more detail below through examples and experimental examples. However, these examples are merely illustrative of the present invention, and the scope of the present invention is not limited thereto.

[0155] Preparation of 1,3,4-oxadiazole derivative compounds

[0156] The specific method for preparing the compound represented by chemical formula I is as follows.

[0157] Example 5: Synthesis of Compound 5, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-(2-thienyl)-1,3,4-oxadiazole-2-one

[0158] [Step 1] Synthesis of 6-Methylnicotinohydrazide

[0159]

[0160] Hydrazine monohydrate (32.151 mL, 661.507 mmol) was added to a solution of methyl 6-methylnicotinate (10.000 g, 66.151 mmol) dissolved in ethanol (200 mL) at room temperature, and the mixture was stirred at the same temperature for 18 hours. Water was added to the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water was removed with anhydrous magnesium sulfate, and the mixture was filtered and concentrated under reduced pressure. The product was used without further purification (8.248 g, 82.5%, white solid).

[0161] [Step 2] Synthesis of 2-(difluoromethyl)-5-(6-methylpyridine-3-yl)-1,3,4-oxadiazole

[0162]

[0163] Triethylamine (38.024 mL, 272.805 mmol) was added to a solution of 6-methylnicotinohydrazide (8.248 g, 54.561 mmol) synthesized in Step 1 in tetrahydrofuran (200 mL) at 0 °C, and the mixture was stirred for 10 minutes at the same temperature. 2,2-difluoroacetic anhydride (20.349 mL, 163.683 mmol) was added to the reaction mixture and stirred for an additional 3 hours at 80 °C, after which the temperature was lowered to room temperature to terminate the reaction. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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%) in the form of a yellow solid.

[0164] [Step 3] Synthesis of 2-(6-(bromomethyl)-pyridine-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0165]

[0166] The solution of 2-(difluoromethyl)-5-(6-methylpyridine-3-yl)-1,3,4-oxadiazole (8.019 g, 37.974 mmol), 1-bromopyrrolidin-2,5-one (NBS, 8.110 g, 45.569 mmol), and azobis-isobutyronitrile (AIBN, 0.624 g, 3.797 mmol) synthesized in Step 2, dissolved in 1,2-dichloroethane (120 mL) at room temperature, was stirred at the same temperature for 6 hours. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous ammonium chloride solution, water was removed with 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%) in the form of a brown solid.

[0167] [Step 4] Synthesis of Thiophene-2-Carbohydrazide

[0168]

[0169] Hydrazine monohydrate (100.00% solution, 1.367 mL, 28.100 mmol) was added to a solution of methylthiophene-2-carboxylate (100.00% solution, 0.163 mL, 1.410 mmol) dissolved in ethanol (10 mL) at room temperature, and the mixture was stirred at 60 °C for 5 hours, after which the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was subjected to solvent removal under reduced pressure to obtain a concentrate, to which an aqueous solution of saturated sodium bicarbonate was poured and extracted with dichloromethane. The organic layer was washed with an aqueous solution of saturated sodium chloride, water was removed with anhydrous magnesium sulfate, and the mixture was filtered and concentrated under reduced pressure. The product was used without further purification (0.2 g, 99.8%, pale yellow solid).

[0170] [Step 5] Synthesis of 5-(2-thienyl)-3H-1,3,4-oxadiazole-2-one

[0171]

[0172] Triethylamine (100.00% solution, 0.273 mL, 2.000 mmol) was added to a solution of thiophene-2-carbohydrazide (100.00%, 0.200 g, 1.407 mmol) and 1,1'-carbonylbese-1H-imidazole (100.00%, 0.274 g, 1.690 mmol) synthesized in Step 4 in tetrahydrofuran (10 mL) at room temperature, and the mixture was stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 obtain the title compound (0.143 g, 60.450%, pale yellow solid).

[0173] [Step 6] Synthesis of Compound 5

[0174]

[0175] To a solution in which 5-(2-thienyl)-3H-1,3,4-oxadiazole-2-one (100.00%, 0.063 g, 0.350 mmol) and potassium carbonate (100.00%, 0.049 g, 0.494 mmol) synthesized in Step 5 were 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 overnight at the same temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, and then filtered and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%), and the resulting product was further purified and concentrated by chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) to obtain the title compound (0.036 g, 26.44%, yellow solid).

[0176] 1 H NMR (400 MHz, CDCl3) δ 9.34-9.33 (m, 1H), 8.44 (dd, J = 8.2, 2.2 Hz, 1H), 7.65 (dd, J = 4.0, 1.2 Hz, 1H), 7.55-7.52 (m, 2H), 7.17-7.15 (m, 1H), 6.96 (t, J = 51.6 Hz, 1H), 5.22 (s, 2H); LRMS (ES) m / z 378.7 (M + +1).

[0177] The compounds in Table 2 below were synthesized according to a method substantially identical to the process of Example 5.

[0178] [Table 2]

[0179]

[0180] Example 45: Synthesis of Compound 45, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-5-phenyl-1,3,4-oxadiazole-2(3H)-thione

[0181] [Step 1] Synthesis of Benzohydrazine

[0182]

[0183] 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 under reflux for 18 hours, after which the temperature was lowered to room temperature to terminate the reaction. After removing the solvent from the reaction mixture under reduced pressure, the product was used without further purification (0.500 g, 100.0%, white solid).

[0184] [Step 2] Synthesis of 5-phenyl-1,3,4-oxadiazole-2(3H)-thione

[0185]

[0186] Potassium ethylxanthate (100.00%, 0.589 g, 3.674 mmol) was added to a solution of benzohydrazide (100.00%, 0.500 g, 3.672 mmol) synthesized in Step 1 dissolved in ethanol (12 mL) at room temperature, and the mixture was stirred at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the precipitated solid was filtered, washed with water, and dried to obtain the title compound (0.45 g, 68.759%) in the form of a pale yellow solid.

[0187] [Step 3] Synthesis of Compound 45

[0188]

[0189] Potassium carbonate (100.00%, 40.000 mg, 0.404 mmol) was added 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 in N,N-dimethylformamide (2 mL) at room temperature, and the mixture was stirred for 0.3 hours at the same temperature. 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 for 18 hours at 35 °C. Water was poured into the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium 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 obtain the title compound (58 mg, 53.36%) in the form of a white solid.

[0190] 1 H NMR (400 MHz, CDCl3) δ 9.32 (d, J = 1.6 Hz, 1H), 8.40 (dd, J = 8.2, 2.2 Hz, 1H), 8.01 (dd, J = 8.2, 1.4 Hz, 2H), 7.83 (d, J = 8.4 Hz, 1H), 7.56-7.51 (m, 3H), 6.96 (t, J = 51.6 Hz, 1H), 4.75 (s, 2H); LRMS (ES) m / z 388.8 (M + +1).

[0191] The compounds of Table 3 below were synthesized according to a method substantially identical to the process of Example 45.

[0192] [Table 3]

[0193]

[0194] delete

[0195] Example 43: Synthesis of Compound 43, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-phenyl-1,3,4-thiadiazole-2-one

[0196] [Step 1] Synthesis of Benzohydrazide

[0197]

[0198] Methyl benzoate (100.00%, 1.000 g, 7.345 mmol) and hydrazine monohydrate (100.00%, 3.677 g, 73.452 mmol) were dissolved in ethanol (80 mL) at 90 °C. The solution was stirred overnight at the same temperature, after which the temperature was lowered to room temperature to terminate the reaction. Water was added to the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water was removed with anhydrous magnesium sulfate, and the mixture was filtered and concentrated under reduced pressure. The product was used without further purification (0.88 g, 88.000%, white solid).

[0199] [Step 2] Synthesis of Benzene Carbothiohydrazide

[0200]

[0201] Benzohydrazide (100.00%, 0.500 g, 3.672 mmol) synthesized in Step 1 and Lawesson reagent (100.00%, 1.782 g, 4.406 mmol) were dissolved in toluene (20 mL) at 100 °C. The solution was stirred overnight at the same temperature, after which the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 (0.31 g, 55.455%, white solid).

[0202] [Step 3] Synthesis of 5-phenyl-3H-1,3,4-thiadiazole-2-one

[0203]

[0204] The benzene carbothiohydrazide (100.00%, 0.280 g, 1.839 mmol) and 1,1'-carbonylbese-1H-imidazole (100.00%, 0.358 g, 2.208 mmol) synthesized in Step 2 were dissolved in dichloromethane (20 mL) at 50 °C. The solution was stirred overnight at the same temperature, and then the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 30%) to obtain the title compound (0.25 g, 76.264%, white solid).

[0205] [Step 4] Synthesis of Compound 43

[0206]

[0207] A solution of 5-phenyl-3H-1,3,4-thiadiazole-2-one (100.00%, 0.050 g, 0.281 mmol) and potassium carbonate (100.00%, 0.058 g, 0.420 mmol) synthesized in Step 3, dissolved in N,N-dimethylformamide (5 mL), was stirred at room temperature for 30 minutes, and 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.085 g, 0.293 mmol) and potassium iodide (100.00%, 0.023 g, 0.139 mmol) were added and stirred additionally overnight at the same temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, water was removed with anhydrous magnesium sulfate, and then filtered and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 0% to 50%) to obtain the title compound (0.054 g, 49.68%, white solid).

[0208] 1 H NMR (400 MHz, CDCl3) δ 9.33 (d, J = 1.6 Hz, 1H), 8.42 (dd, J = 8.2, 2.2 Hz, 1H), 7.71-7.69 (m, 2H), 7.48-7.43 (m, 4H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H), 5.43 (s, 2H); LRMS (ES) m / z 388.0 (M + +1).

[0209] The compounds in Table 4 below were synthesized according to a method substantially identical to the process of Example 43.

[0210] [Table 4]

[0211]

[0212] Example 4: Synthesis of Compound 4,3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-4-[(4-methyl-1-piperidyl)methyl]phenyl]-1,3,4-oxadiazole-2-one

[0213] [Step 1] Methyl 2-fluoro-4-[(4-methyl-1-piperidyl)methyl]benzoate

[0214]

[0215] A solution of methyl 2-fluoro-4-formyl-benzoate (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 extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 obtain the title compound (0.43 g, 98.41%, yellow oil).

[0216] [Step 2] 2-fluoro-4-[(4-methyl-1-piperidyl)methyl]benzohydrazide

[0217]

[0218] Methyl 2-fluoro-4-[(4-methyl-1-piperidyl)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) were dissolved in ethanol (10 mL) at 80 °C. The solution was stirred overnight at the same temperature, after which the temperature was lowered to room temperature to terminate the reaction. After removing the solvent from the reaction mixture under reduced pressure, the product was used without further purification (0.42 g, 100.0%, white solid).

[0219] [Step 3] 5-[2-fluoro-4-[(4-methyl-1-piperidyl)methyl]phenyl]-3H-1,3,4-oxadiazole-2-one

[0220]

[0221] The solution of 2-fluoro-4-[(4-methyl-1-piperidyl)methyl]benzohydrazide (100.00%, 0.420 g, 1.583 mmol), triphosgene (100.00%, 0.400 equivalents, 0.633 mmol), and N,N-diisopropylethylamine (100.00%, 2.000 equivalents, 3.166 mmol) synthesized in Step 2, dissolved in dichloromethane (10 mL) at room temperature, was stirred at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 obtain the title compound (0.275 g, 59.63%, white solid).

[0222] [Step 4] Synthesis of Compound 4

[0223]

[0224] A solution of 5-[2-fluoro-4-[(4-methyl-1-piperidyl)methyl]phenyl]-3H-1,3,4-oxadiazole-2-one (100.00%, 0.090 g, 0.309 mmol), 2-[6-(bromomethyl)-3-pyridyl]-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) synthesized in Step 3, dissolved in N,N-dimethylformamide (5 mL) at room temperature, was stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 obtain the title compound (0.07 g, 45.27%, white solid).

[0225] 1 H NMR (400 MHz, CDCl3) δ 9.25 (s, 1H), 8.37 (d, J = 10.0 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.21-7.18 (m, 2H), 6.93 (t, J = 51.6 Hz, 1H), 5.22 (s, 2H), 3.47 (s, 2H), 2.76 (d, J = 11.2 Hz, 2H), 1.95 (t, J = 10.8 Hz, 2H), 1.57 (d, J = 12.0 Hz, 2H), 1.34-1.20 (m, 3H), 0.89 (d, J = 6.0 Hz, 3H); LRMS(ES) m / z 501.4 (M + +1).

[0226] The compounds in Table 5 below were synthesized according to a method substantially identical to the process of Example 4.

[0227] [Table 5]

[0228]

[0229] Example 84: Synthesis of Compound 84, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-5-(3-((dimethylamino)methyl)phenyl)-1,3,4-oxadiazole-2(3H)-thione

[0230] [Step 1] Synthesis of Methyl 3-(1,3-dioxolane-2-yl)benzoate

[0231]

[0232] A mixture of methyl 3-formylbenzoate (100.00%, 2.000 g, 12.183 mmol), ethylene glycol (100.00%, 3.781 g, 60.920 mmol), and 4-methylbenzenesulfonic acid hydrate (100.00%, 0.232 g, 1.220 mmol) mixed in toluene (120 mL) was heated and refluxed overnight at room temperature. After cooling to room temperature, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, water was removed with 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 10%) to obtain the title compound (1.8 g, 70.959%, ​​white solid).

[0233] [Step 2] Synthesis of 3-(1,3-dioxolane-2-yl)benzohydrazide

[0234]

[0235] Methyl 3-(1,3-dioxolane-2-yl)benzoate (100.00%, 1.130 g, 5.427 mmol) and hydrazine monohydrate (100.00%, 2.717 g, 54.275 mmol) synthesized in Step 1 were dissolved in ethanol (80 mL) at 80 °C. The solution was stirred overnight at the same temperature, after which the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water was removed with anhydrous magnesium sulfate, and the mixture was filtered and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 24 g cartridge; methanol / dichloromethane = 0% to 5%) to obtain the title compound (1.1 g, 97.345%, white solid).

[0236] [Step 3] Synthesis of 5-[3-(1,3-dioxolan-2-yl)phenyl]-3H-1,3,4-oxadiazole-2-thione

[0237]

[0238] 3-(1,3-dioxolane-2-yl)benzohydrazide (100.00%, 0.900 g, 4.323 mmol) and potassium ethylxanthate (100.00%, 0.762 g, 4.754 mmol) synthesized in Step 2 were dissolved in ethanol (50 mL) at 80 °C. The solution was stirred overnight at the same temperature, after which the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, and the mixture was filtered and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 24 g cartridge; ethyl acetate / hexane = 0% to 30%) to obtain the title compound (0.7 g, 64.70%, white solid).

[0239] [Step 4] Synthesis of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[3-(1,3-dioxolane-2-yl)phenyl]-1,3,4-oxadiazole-2-thione

[0240]

[0241] A solution of 5-[3-(1,3-dioxolane-2-yl)phenyl]-3H-1,3,4-oxadiazole-2-thione (100.00%, 0.350 g, 1.398 mmol), 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) synthesized in Step 3, dissolved in N,N-dimethylformamide (30 mL), was stirred at room temperature for 30 minutes and further stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, water was removed with 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 obtain the title compound (0.51 g, 79.39%, white solid).

[0242] [Step 5] Synthesis of 3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-thioxo-1,3,4-oxadiazole-2-yl]benzaldehyde

[0243]

[0244] The solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[3-(1,3-dioxolane-2-yl)phenyl]-1,3,4-oxadiazole-2-thione (100.00%, 0.500 g, 1.088 mmol) and ferric chloride hexahydrate (100.00%, 1.030 g, 3.811 mmol) synthesized in Step 4, dissolved in dichloromethane (30 mL) at room temperature, was stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 40%) to obtain the title compound (0.350 g, 77.41%) in the form of a white solid.

[0245] [Step 6] Synthesis of Compound 84

[0246]

[0247] N-methylmethaneamine (100.00%, 0.007 g, 0.155 mmol) was added to a solution of 4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-thioxo-1,3,4-oxadiazole-2-yl]benzaldehyde (100.00%, 0.030 g, 0.072 mmol) synthesized in Step 5 in dichloromethane (5 mL) at room temperature, and the mixture was stirred for 30 minutes at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water was removed with 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, 34.27%, white solid).

[0248] 1 H NMR (400 MHz, CDCl3) δ 9.32 (d, J = 1.7 Hz, 1H), 8.39 (dd, J = 8.2, 2.2 Hz, 1H), 7.94-7.90 (m, 2H), 7.83 (d, J = 8.2 Hz, 1H), 7.52-7.45 (m, 2H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H), 4.74 (s, 2H), 3.50 (s, 2H), 2.28 (s, 6H); LRMS (ES) m / z 445.23 (M + +1).

[0249] The compounds of Table 6 below were synthesized according to a method substantially identical to the process of Example 84.

[0250] [Table 6]

[0251]

[0252] delete

[0253] delete

[0254] delete

[0255] delete

[0256] delete

[0257] delete

[0258] Example 132: Synthesis of Compound 132, 5-[4-(azetidine-1-ylmethyl)phenyl]-3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-1,3,4-oxa-diazole-2-one

[0259] [Step 1] Synthesis of Methyl 4-(1,3-dioxolane-2-yl)benzoate

[0260]

[0261] A mixture of methyl 4-formylbenzoate (100.00%, 3.000 g, 18.275 mmol), ethylene glycol (100.00%, 5.672 g, 91.380 mmol), and 4-methylbenzenesulfonic acid hydrate (100.00%, 0.348 g, 1.830 mmol) mixed in toluene (150 mL) was heated and refluxed overnight at room temperature. After cooling to room temperature, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 10%) to obtain the title compound (3.5 g, 91.984%, white solid).

[0262] [Step 2] Synthesis of 4-(1,3-dioxolane-2-yl)benzohydrazide

[0263]

[0264] A mixture of methyl 4-(1,3-dioxolane-2-yl)benzoate (100.00%, 2.000 g, 9.606 mmol) and hydrazine monohydrate (100.00%, 4.809 g, 96.065 mmol) synthesized in Step 1 was mixed in ethanol (100 mL) at room temperature and heated under reflux overnight. After cooling to room temperature, water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 40 g cartridge; methanol / dichloromethane = 0% to 5%) to obtain the title compound (1.8 g, 90.000%, white solid).

[0265] [Step 3] Synthesis of 5-[4-(1,3-dioxolan-2-yl)phenyl]-3H-1,3,4-oxadiazole-2-one

[0266]

[0267] A mixture of 4-(1,3-dioxolane-2-yl)benzohydrazide (100.00%, 0.650 g, 3.122 mmol) and 1,1'-carbonylbese-1H-imidazole (100.00%, 0.607 g, 3.744 mmol) synthesized in Step 2 and dichloromethane (50 mL) was heated and refluxed overnight at room temperature. After cooling to room temperature, water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 obtain the title compound (0.45 g, 61.545%, white solid).

[0268] [Step 4] Synthesis of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[4-(1,3-dioxolan-2-yl)phenyl]-1,3,4-oxadiazole-2-one

[0269]

[0270] To a solution in which 5-[4-(1,3-dioxolane-2-yl)phenyl]-3H-1,3,4-oxadiazole-2-one (100.00%, 0.500 g, 2.135 mmol) and potassium carbonate (100.00%, 0.443 g, 3.205 mmol) synthesized in Step 3 were dissolved in N,N-dimethylformamide (30 mL) at room temperature, 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.650 g, 2.241 mmol) and potassium iodide (100.00%, 0.177 g, 1.066 mmol) were added and stirred for 30 minutes at the same temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, water was removed with anhydrous magnesium sulfate, and then filtered and concentrated under reduced pressure. Ethyl acetate (5 mL) was added to the concentrate and stirred to filter the precipitated solid, which was then washed with hexane and dried to obtain the title compound (0.74 g, 78.18%, white solid).

[0271] [Step 5] Synthesis of 4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazole-2-yl]benzaldehyde

[0272]

[0273] The solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[4-(1,3-dioxolane-2-yl)phenyl]-1,3,4-oxadiazole-2-one (100.00%, 0.280 g, 0.632 mmol) and ferric chloride hexahydrate (100.00%, 0.512 g, 1.894 mmol) synthesized in Step 4, dissolved in dichloromethane (30 mL) at room temperature, was stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 obtain the title compound (0.18 g, 71.39%, white solid).

[0274] [Step 6] Synthesis of Compound 132

[0275]

[0276] A solution of 4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazole-2-yl]benzaldehyde (100.00%, 0.030 g, 0.075 mmol) and azetidine hydrochloride (100.00%, 0.014 g, 0.150 mmol) synthesized in Step 5, dissolved in dichloromethane (5 mL), was stirred at room temperature for 30 minutes, and sodium triacetoxyborohydride (100.00%, 0.048 g, 0.227 mmol) was added and stirred additionally overnight at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water was removed with anhydrous magnesium sulfate, and then 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 (0.019 g, 57.42%, white solid).

[0277] 1 H NMR (400 MHz, CDCl3) δ 9.33 (d, J = 1.5 Hz, 1H), 8.43 (dd, J = 8.2, 2.2 Hz, 1H), 7.82 (d, J = 8.3 Hz, 2H), 7.55-7.52 (m, 1 H), 7.43 (d, J = 8.1 Hz, 2H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H), 5.24 (s, 2H), 3.67 (s, 2H), 3.32-3.28 (m, 4H), 2.19-2.12 (m, 2H); LRMS (ES) m / z 441.3 (M + +1).

[0278] The compounds of Table 7 below were synthesized according to a method substantially identical to the process of Example 132.

[0279] [Table 7]

[0280]

[0281] Example 83: Synthesis of Compound 83, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[4-[(4-isopropylpiperazine-1-yl)methyl]phenyl]-1,3,4-oxadiazole-2-one

[0282] [Step 1] Synthesis of tert-butyl 4-[(4-methoxycarbonylphenyl)methyl]piperazine-1-carboxylate

[0283]

[0284] A solution of methyl 4-formylbenzoate (100.00%, 0.500 g, 3.046 mmol), tert-butyl piperazine-1-carboxylate (100.00%, 0.681 g, 3.656 mmol), and sodium triacetoxyborohydride (100.00%, 1.291 g, 6.091 mmol) dissolved in dichloromethane (20 mL) at room temperature was stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water was removed with 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 30%) to obtain the title compound (0.89 g, 87.38%, white solid).

[0285] [Step 2] Synthesis of Tert-Butyl 4-[[4-(hydrazine carbonyl)phenyl]methyl]piperazine-1-carboxylate

[0286]

[0287] 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 were dissolved in ethanol (20 mL) at 90 °C. The solution was stirred overnight at the same temperature, after which the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water was removed with anhydrous magnesium sulfate, and the mixture was filtered and concentrated under reduced pressure. The product was used without further purification (0.29 g, 96.67%, white solid).

[0288] [Step 3] Synthesis of Tert-Butyl 4-[[4-(2-oxo-3H-1,3,4-oxadiazole-5-yl)phenyl]methyl]piperazine-1-carboxylate

[0289]

[0290] Triethylamine (100.00% solution, 0.29 mL, 2.100 mmol) was added to a solution of tert-butyl 4-[[4-(hydrazine carbonyl)phenyl]methyl]piperazine-1-carboxylate (100.00%, 0.500 g, 1.495 mmol) and 1,1'-carbonylbese-1H-imidazole (100.00%, 0.291 g, 1.795 mmol) synthesized in Step 2 in tetrahydrofuran (10 mL) at room temperature, and the mixture was stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 24 g cartridge; methanol / dichloromethane = 0% to 10%) to obtain the title compound (0.468 g, 86.85%, white solid).

[0291] [Step 4] Synthesis of tert-butyl 4-[[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazole-2-yl]phenyl]methyl]piperazine-1-carboxylate

[0292]

[0293] To a solution prepared in Step 3 of Example 5, in which tert-butyl 4-[[4-(2-oxo-3H-1,3,4-oxadiazole-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 were 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) was added, and the mixture was stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 60%), and the resulting product was further purified and concentrated by chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) to obtain the title compound (0.37 g, 99.20%, white solid).

[0294] [Step 5] Synthesis of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[4-(piperazine-1-ylmethyl)phenyl]-1,3,4-oxadiazole-2-one

[0295]

[0296] The solution of tert-butyl 4-[[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazole-2-yl]phenyl]methyl]piperazine-1-carboxylate (100.00%, 0.370 g, 0.650 mmol) synthesized in Step 4 and trifluoroacetic acid (100.00% solution, 0.497 mL, 6.490 mmol) dissolved in dichloromethane (3 mL) at room temperature was stirred overnight at the same temperature. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The product was used without further purification (0.3 g, 98.39%, yellow oil).

[0297] [Step 6] Synthesis of Compound 83

[0298]

[0299] A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[4-(piperazine-1-ylmethyl)phenyl]-1,3,4-oxadiazole-2-one (100.00%, 0.075 g, 0.160 mmol), acetone (100.00% solution, 0.019 mL, 0.257 mmol), and N-ethyl-N-isopropyl-propane-2-amine (100.00% solution, 0.056 mL, 0.322 mmol) synthesized in Step 5, dissolved in dichloromethane (1 mL), was stirred at room temperature for 30 minutes, and sodium triacetoxyborohydride (100.00%, 0.101 g, 0.479 mmol) The mixture was added and stirred for an additional 18 hours at the same temperature. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 obtain the title compound (0.014 g, 17.13%, pale yellow solid).

[0300] 1 H NMR (400 MHz, CD3OD) δ 9.25 (d, J = 1.6 Hz, 1H), 8.53 (dd, J = 8.2, 2.2 Hz, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.26 (t, J = 51.6 Hz, 1H), 5.26 (s, 2H), 3.63 (s, 2H), 2.74-2.59 (m, 9H), 1.15 (d, J = 6.8 Hz, 6H); LRMS(ES) m / z 512.8 (M + +1).

[0301] Example 66: Synthesis of Compound 66, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[4-(4-isopropylpiperazine-1-yl)phenyl]-1,3,4-thiadiazole-2-one

[0302] [Step 1] Synthesis of Tert-Butyl 4-[[4-(aminocarbamothioyl)phenyl]methyl]piperazine-1-carboxylate

[0303]

[0304] Tert-butyl 4-[[4-(hydrazine carbonyl)phenyl]methyl]piperazine-1-carboxylate (100.00%, 1.000 g, 2.990 mmol) synthesized in Step 2 of Example 86 and Lawesson reagent (100.00%, 1.451 g, 3.587 mmol) were dissolved in toluene (40 mL) at 80 °C. The solution was stirred overnight at the same temperature, and then the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 obtain the title compound (0.61 g, 58.20%, white solid).

[0305] [Step 2] Synthesis of Tert-Butyl 4-[[4-(2-oxo-3H-1,3,4-thiadiazole-5-yl)phenyl]methyl]piperazine-1-carboxylate

[0306]

[0307] The tert-butyl 4-[[4-(aminocarbamothioyl)phenyl]methyl]piperazine-1-carboxylate (100.00%, 0.500 g, 1.427 mmol) and 1,1'-carbonylbese-1H-imidazole (100.00%, 0.278 g, 1.715 mmol) synthesized in Step 1 were dissolved in dichloromethane (30 mL) at 50 °C. The solution was stirred overnight at the same temperature, and then the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous ammonium chloride solution, water was removed with 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 40%) to obtain the title compound (0.25 g, 46.55%, white solid).

[0308] [Step 3] Synthesis of tert-butyl 4-[[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-thiadiazole-2-yl]phenyl]methyl]piperazine-1-carboxylate

[0309]

[0310] A solution of tert-butyl 4-[[4-(2-oxo-3H-1,3,4-thiadiazole-5-yl)phenyl]methyl]piperazine-1-carboxylate (100.00%, 0.100 g, 0.266 mmol) and potassium carbonate (100.00%, 0.055 g, 0.398 mmol) synthesized in Step 2, dissolved in N,N-dimethylformamide (10 mL), was stirred at room temperature for 30 minutes, and 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.081 g, 0.279 mmol) and potassium iodide (100.00%, 0.022 g, 0.133 mmol) was added and stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, water was removed with 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 40%) to obtain the title compound (0.095 g, 61.08%, white solid).

[0311] [Step 4] Synthesis of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[4-(piperazine-1-ylmethyl)phenyl]-1,3,4-thiadiazole-2-one 2,2,2-trifluoroacetic acid

[0312]

[0313] A solution of tert-butyl 4-[[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-thiadiazole-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, dissolved in dichloromethane (10 mL) at room temperature, was stirred at the same temperature for 3 hours. After removing the solvent from the reaction mixture under reduced pressure, the product was used without further purification (0.088 g, 95.51%, yellow oil).

[0314] [Step 5] Synthesis of Compound 66

[0315]

[0316] A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[4-(piperazine-1-ylmethyl)phenyl]-1,3,4-thiadiazole-2-one, 2,2,2-trifluoroacetic acid (100.00%, 0.030 g, 0.051 mmol), acetone (100.00%, 0.006 g, 0.103 mmol), N-ethyldiisopropylamine (100.00% solution, 0.018 mL, 0.103 mmol), and sodium triacetoxyborohydride (100.00%, 0.033 g, 0.156 mmol) synthesized in Step 4, dissolved in dichloromethane (5 mL), was heated at room temperature for 30 minutes The mixture was stirred for minutes and further stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water was removed with 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).

[0317] 1 H NMR (400 MHz, CDCl3) δ 9.33 (d, J = 1.6 Hz, 1H), 8.41 (dd, J = 8.2, 2.2 Hz, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 1H), 7.41 (d, J= 8.2 Hz, 2H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H), 5.42 (s, 2H), 3.56 (s, 2H), 2.78-2.77 (m, 1H), 2.64-2.48 (m, 8H), 1.11 (d, J = 6.5 Hz, 6H); LRMS (ES) m / z 529.35 (M + +1).

[0318] The compounds in Table 8 below were synthesized according to a process substantially identical to that of Example 66.

[0319] [Table 8]

[0320]

[0321] Example 77: Synthesis of Compound 77, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[4-[(4-isopropylpiperazine-1-yl)methyl]phenyl]-1,3,4-oxadiazole-2-thione

[0322] [Step 1] Synthesis of tert-butyl 4-(4-(5-thioxo-4,5-dihydro-1,3,4-oxadiazole-2-yl)benzyl)piperazine-1-carboxylate

[0323]

[0324] A mixture of tert-butyl 4-[[4-(hydrazine carbonyl)phenyl]methyl]piperazine-1-carboxylate (100.00%, 1.000 g, 2.990 mmol) and potassium ethylxanthate (100.00%, 0.575 g, 3.587 mmol) prepared in Step 2 of Example 86 and mixed in ethanol (80 mL) was heated and refluxed overnight at room temperature. After cooling to room temperature, water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 obtain the title compound (0.85 g, 75.50%, white solid).

[0325] [Step 2] Synthesis of tert-butyl 4-[[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-thioxo-1,3,4-oxadiazole-2-yl]phenyl]methyl]piperazine-1-carboxylate

[0326]

[0327] A solution of tert-butyl 4-[[4-(2-thioxo-3H-1,3,4-oxadiazole-5-yl)phenyl]methyl]piperazine-1-carboxylate (100.00%, 0.500 g, 1.328 mmol) and potassium carbonate (100.00%, 0.197 g, 1.988 mmol) synthesized in Step 1 in N,N-dimethylformamide (30 mL) was stirred at room temperature for 30 minutes, and 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.404 g, 1.393 mmol) and potassium iodide (100.00%, 0.110 g, 0.663 mmol was added, and the mixture was stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, water was removed with 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 obtain the title compound (0.65 g, 83.58%, white solid).

[0328] [Step 3] Synthesis of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[4-(piperazine-1-ylmethyl)phenyl]-1,3,4-oxadiazole-2-thione 2,2,2-trifluoroacetic acid

[0329]

[0330] A solution of tert-butyl 4-[[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-thioxo-1,3,4-oxadiazole-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, dissolved in dichloromethane (20 mL) at room temperature, was stirred at the same temperature for 3 hours. After removing the solvent from the reaction mixture under reduced pressure, the product was used without further purification (0.28 g, 91.17%, yellow oil).

[0331] [Step 4] Synthesis of Compound 77

[0332]

[0333] A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[4-(piperazine-1-ylmethyl)phenyl]-1,3,4-oxadiazole-2-thione 2,2,2-trifluoroacetic acid (100.00%, 0.050 g, 0.083 mmol), acetone (100.00%, 0.010 g, 0.172 mmol), and N-ethyldiisopropylamine (100.00% solution, 0.029 mL, 0.167 mmol) synthesized in Step 3, dissolved in dichloromethane (5 mL), was stirred at room temperature for 30 minutes, and sodium triacetoxyborohydride (100.00%, 0.053 g, 0.250 mmol was added, and the mixture was stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water was removed with 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 (0.022 g, 50.00%, white solid).

[0334] 1 H NMR (400 MHz, CDCl3) δ 9.31 (d, J = 2.2 Hz, 1H), 8.39 (dd, J = 8.2, 2.2 Hz, 1H), 7.95 (d, J = 8.3 Hz, 2H), 7.82 (d, J = 8.2 Hz, 1H), 7.46 (d, J= 8.3 Hz, 2H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H), 4.73 (s, 2H), 3.60 (s, 2H), 3.16-2.92 (m, 1H), 2.81-2.76 (m, 8H), 1.19 (d, J = 6.5 Hz, 6H); LRMS (ES) m / z 528.87 (M + +1).

[0335] The compounds in Table 9 below were synthesized according to a method substantially identical to the process of Example 77.

[0336] [Table 9]

[0337]

[0338] Example 26: Synthesis of Compound 26, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-[1-(oxetane-3-yl)-4-piperidyl]phenyl]-1,3,4-oxadiazole-2-one

[0339] [Step 1] Synthesis of tert-butyl 4-(2-fluoro-3-methoxycarbonyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate

[0340]

[0341] A solution of methyl 3-bromo-2-fluoro-benzoate (100.00%, 1.000 g, 4.291 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (100.00%, 1.460 g, 4.722 mmol), bis(triphenylphosphine)palladium(II) dichloride (100.00%, 0.301 g, 0.429 mmol) and sodium carbonate (100.00%, 1.365 g, 12.879 mmol) 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 extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, water was removed with 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 30%) to obtain the title compound (1.100 g, 76.43%, white solid).

[0342] [Step 2] Synthesis of Tert-Butyl 4-(2-fluoro-3-methoxycarbonyl-phenyl)piperidine-1-carboxylate

[0343]

[0344] A solution of tert-butyl 4-(2-fluoro-3-methoxycarbonyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (100.00%, 0.900 g, 2.683 mmol) and Pd / C (100.00%, 0.286 g, 2.688 mmol) synthesized in Step 1, dissolved in methanol (20 mL) at room temperature, was stirred overnight at the same temperature. The reaction mixture was filtered through a Celite pad to remove the solid, and the solvent was removed from the filtrate under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 40%) to obtain the title compound (0.74 g, 81.73%, yellow oil).

[0345] [Step 3] Synthesis of Tert-Butyl 4-[2-Fluoro-3-(Hydrazine Carbonyl)phenyl]Piperidine-1-Carboxylate

[0346]

[0347] Tert-butyl 4-(2-fluoro-3-methoxycarbonyl-phenyl)piperidine-1-carboxylate (100.00%, 0.700 g, 2.075 mmol) and hydrazine monohydrate (100.00%, 1.039 g, 20.755 mmol) synthesized in Step 2 were dissolved in ethanol (30 mL) at room temperature and stirred overnight at the same temperature. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water was removed with anhydrous magnesium sulfate, and the mixture was filtered and concentrated under reduced pressure. The product was used without further purification (0.65 g, 92.86%, white solid).

[0348] [Step 4] Synthesis of tert-butyl 4-[2-fluoro-3-(2-oxo-3H-1,3,4-oxadiazole-5-yl)phenyl]piperidine-1-carboxylate

[0349]

[0350] The solution of tert-butyl 4-[2-fluoro-3-(hydrazine carbonyl)phenyl]piperidine-1-carboxylate (100.00%, 0.700 g, 2.075 mmol) and 1,1'-carbonylbese-1H-imidazole (100.00%, 0.404 g, 2.492 mmol) synthesized in Step 3, dissolved in dichloromethane (30 mL) at room temperature, was stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous ammonium chloride solution, water was removed with 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 40%) to obtain the title compound (0.55 g, 72.95%, white solid).

[0351] [Step 5] Synthesis of tert-butyl 4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazole-2-yl]-2-flu-oro-phenyl]piperidine-1-carboxylate

[0352]

[0353] To a solution in which tert-butyl 4-[2-fluoro-3-(2-oxo-3H-1,3,4-oxadiazole-5-yl)phenyl]piperidine-1-carboxylate (100.00%, 0.400 g, 1.101 mmol) and potassium carbonate (100.00%, 0.164 g, 1.655 mmol) synthesized in Step 4 were dissolved in N,N-dimethylformamide (20 mL) at room temperature, 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.335 g, 1.155 mmol) and potassium iodide (100.00%, 0.091 g, 0.548 mmol) were added, and at the same temperature The mixture was stirred. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, water was removed with 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 40%) to obtain the title compound (0.54 g, 85.69%, white solid).

[0354] [Step 6] Synthesis of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-(4-piperidyl)phenyl]-1,3,4-oxadiazole-2-one 2,2,2-trifluoroacetic acid

[0355]

[0356] A solution of tert-butyl 4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazole-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) at room temperature, was stirred at the same temperature for 3 hours. After removing the solvent from the reaction mixture under reduced pressure, the product was used without further purification (0.3 g, 97.63%, yellow oil).

[0357] [Step 7] Synthesis of Compound 26

[0358]

[0359] A solution prepared by dissolving 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-(4-piperidyl)phenyl]-1,3,4-oxadiazole-2-one, 2,2,2-trifluoroacetic acid (100.00%, 0.050 g, 0.085 mmol), N-ethyldiisopropylamine (100.00% solution, 0.03 mL, 0.172 mmol), oxetan-3-one (100.00%, 0.012 g, 0.167 mmol), and sodium triacetoxyborohydride (100.00%, 0.054 g, 0.255 mmol) synthesized in Step 6 in dichloromethane (5 mL) at room temperature The mixture was stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water was removed with 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).

[0360] 1 H NMR (400 MHz, CDCl3) δ 9.32 (d, J = 1.6 Hz, 1H), 8.43 (dd, J = 8.2, 2.2 Hz, 1H), 7.70-7.66 (m, 1H), 7.53 (d. J= 8.2 Hz, 1H), 7.47-7.43 (m, 1H), 7.26-7.23 (m, 1H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H) 5.26 (s, 2H), 4.71-4.64 (m, 4H), 3.56-3.50 (m, 1H), 3.00-2.94 (m, 1H), 2.91-2.88 (m, 2H), 2.02-1.96 (m, 2H), 1.87-1.81 (m, 4H); LRMS (ES) m / z 529.82 (M + +1).

[0361] The compounds of Table 10 below were synthesized according to a method substantially identical to the process of Example 26.

[0362] [Table 10]

[0363]

[0364] Example 27: Synthesis of Compound 27, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-[1-(1-methylazetidin-3-yl)-4-piperidyl]phenyl]-1,3,4-oxadiazole-2-one

[0365] [Step 1] Synthesis of tert-butyl 3-[4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazole-2-yl]-2-fluoro-phenyl]-1-piperidyl]azetidine-1-carboxylate

[0366]

[0367] 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-(4-piperidyl)phenyl]-1,3,4-oxadiazole-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-oxozetidine-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 A solution of mmol was dissolved in dichloromethane (5 mL) at room temperature and stirred overnight at the same temperature. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water was removed with 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).

[0368] [Step 2] Synthesis of 5-[3-[1-(azetidine-3-yl)-4-piperidyl]-2-fluoro-phenyl]-3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-1,3,4-oxadiazole-2-one 2,2,2-trifluoroacetic acid

[0369]

[0370] A solution of tert-butyl 3-[4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazole-2-yl]-2-fluoro-phenyl]-1-piperidyl]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 in dichloromethane (5 mL) was stirred overnight at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the product was used without further purification (0.100 g, 88.94%, yellow oil).

[0371] [Step 3] Synthesis of Compound 27

[0372]

[0373] 5-[3-[1-(azetidine-3-yl)-4-piperidyl]-2-fluoro-phenyl]-3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-1,3,4-oxadiazole-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 at room temperature The solution dissolved in dichloromethane (5 mL) was stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water was removed with 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).

[0374] 1 H NMR (400 MHz, CDCl3) δ 9.31 (d, J = 1.6 Hz, 1H), 8.43 (dd, J = 8.2, 2.2 Hz, 1H), 7.69-7.65 (m, 1H), 7.53 (d. J = 8.2 Hz, 1H), 7.45-7.41 (m, 1H), 7.25-7.21 (m, 1H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H) 5.26 (s, 2H), 3.76 (brs, 2H), 3.09 (brs, 3H), 2.99-2.90 (m, 3H), 2.50 (s, 3H), 2.09-1.94 (m, 2H), 1.87-1.80 (m, 4H); LRMS(ES) m / z 542.86 (M + +1).

[0375] The compounds of Table 11 below were synthesized according to a method substantially identical to the process of Example 27.

[0376] [Table 11]

[0377]

[0378] Example 81: Synthesis of Compound 81, 5-[3-(1-cyclobutyl-4-piperidyl)-2-fluoro-phenyl]-3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-1,3,4-oxadiazole-2-thione

[0379] [Step 1] Synthesis of tert-butyl 4-[2-fluoro-3-(2-thioxo-3H-1,3,4-oxadiazole-5-yl)phenyl]piperidine-1-carboxylate

[0380]

[0381] A mixture of tert-butyl 4-[2-fluoro-3-(hydrazine carbonyl)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 and mixed in ethanol (80 mL) was heated and refluxed overnight at room temperature. After cooling to room temperature, water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous ammonium chloride solution, water was removed with 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 obtain the title compound (0.9 g, 72.76%, white solid).

[0382] [Step 2] Synthesis of tert-butyl 4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-thioxo-1,3,4-oxadiazole-2-yl]-2-fluoro-phenyl]piperidine-1-carboxylate

[0383]

[0384] A 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) and potassium carbonate (100.00%, 0.196 g, 1.978 mmol) synthesized in Step 1 in N,N-dimethylformamide (20 mL) was stirred at room temperature for 30 minutes, and 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.401 g, 1.383 mmol) and potassium iodide (100.00%, 0.109 g, 0.657 mmol was added, and the mixture was stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, water was removed with 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 30%) to obtain the title compound (0.61 g, 78.64%, white solid).

[0385] [Step 3] Synthesis of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-(4-piperidyl)phenyl]-1,3,4-oxadiazole-2-thione 2,2,2-trifluoroacetic acid

[0386]

[0387] A solution of tert-butyl 4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-thioxo-1,3,4-oxadiazole-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, dissolved in dichloromethane (20 mL) at room temperature, was stirred at the same temperature for 3 hours. After removing the solvent from the reaction mixture under reduced pressure, the product was used without further purification (0.37 g, 90.37%, yellow oil).

[0388] [Step 4] Synthesis of Compound 81

[0389]

[0390] A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-(4-piperidyl)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, dissolved in dichloromethane (5 mL), was stirred at room temperature for 30 minutes, and sodium triacetoxyborohydride (100.00%, 0.053 g, 0.250 mmol was added, and the mixture was stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water was removed with 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, 64.40%, white solid).

[0391] 1 H NMR (400 MHz, CDCl3) δ 9.31 (d, J = 2.1 Hz, 1H), 8.38 (dd, J= 8.2, 2.3 Hz, 1H), 7.83-7.79 (m, 2H), 7.49-7.45 (m, 1H), 7.26-7.22 (m, 1H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H), 4.73 (s, 2H), 3.15-3.12 (m, 2H), 3.03-3.00 (m, 1H), 2.88-2.84 (m, 1H), 2.12-2.02 (m, 6H), 1.98-1.88 (m, 4H), 1.79-1.68 (m, 2H); LRMS (ES) m / z 543.90 (M + +1).

[0392] The compounds of Table 12 below were synthesized according to a method substantially identical to the process of Example 81.

[0393] [Table 12]

[0394]

[0395] Example 100: Synthesis of Compound 100, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[6-(4-ethylpiperazine-1-yl)-2-pyridyl]-1,3,4-oxadiazole-2-thione

[0396] [Step 1] Synthesis of Tert-Butyl 4-(6-Methoxycarbonyl-2-Pyridyl)Piperazine-1-Carboxylate

[0397]

[0398] Methyl 6-fluoropyridine-2-carboxylate (100.00%, 0.500 g, 3.223 mmol), tert-butyl piperazine-1-carboxylate (100.00%, 1.200 g, 6.443 mmol), and N,N-diisopropylethylamine (100.00% solution, 0.844 mL, 4.800 mmol) were dissolved in dimethyl sulfoxide (15 mL) at 130 °C. The solution was stirred overnight at the same temperature, and then the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 obtain the title compound (0.736 g, 71.05%, yellow solid).

[0399] [Step 2] Synthesis of Tert-Butyl 4-[6-(Hydrazine Carbonyl)-2-Pyridyl]Piperazine-1-Carboxylate

[0400]

[0401] Hydrazine monohydrate (100.00% solution, 1.113 mL, 22.900 mmol) was added to a solution prepared by dissolving tert-butyl 4-(6-methoxycarbonyl-2-pyridyl)piperazine-1-carboxylate (100.00%, 0.736 g, 2.290 mmol) synthesized in Step 1 in ethanol (10 mL) at room temperature, and the mixture was stirred at 60 °C for 18 hours, after which the temperature was lowered to room temperature to terminate the reaction. A saturated aqueous ammonium chloride solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 obtain the title compound (0.73 g, 99.18%, yellow solid).

[0402] [Step 3] Synthesis of tert-butyl 4-[6-(2-thioxo-3H-1,3,4-oxadiazole-5-yl)-2-pyridyl]piperazine-1-carboxylate

[0403]

[0404] Tert-butyl 4-[6-(hydrazine carbonyl)-2-pyridyl]piperazine-1-carboxylate (100.00%, 0.730 g, 2.271 mmol) and potassium ethyl phosphate (100.00%, 0.364 g, 2.271 mmol) synthesized in Step 2 were dissolved in ethanol (10 mL) at room temperature. The solution was stirred overnight at 90 °C, after which the temperature was lowered to room temperature to terminate the reaction. A saturated aqueous ammonium chloride solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 40 g cartridge; dichloromethane / methanol = 0% to 10%) to obtain the title compound (0.604 g, 73.18%, yellow solid).

[0405] [Step 4] Synthesis of tert-butyl 4-[6-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-thioxo-1,3,4-oxadiazole-2-yl]-2-pyridyl]piperazine-1-carboxylate

[0406]

[0407] A solution of tert-butyl 4-[3-(2-thioxo-3H-1,3,4-oxadiazole-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 equivalents, 1.932 mmol), potassium carbonate (100.00%, 2.000 equivalents, 3.863 mmol), and potassium iodide (100.00%, 2.000 equivalents, 3.863 mmol) synthesized in Step 3, dissolved in N,N-dimethylformamide (5 mL) at room temperature, was stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 obtain the title compound (0.14 g, 12.68%, yellow solid).

[0408] [Step 5] Synthesis of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-(6-piperazine-1-yl-2-pyridyl)-1,3,4-oxadiazole-2-thione

[0409]

[0410] The solution of tert-butyl 4-[6-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-thioxo-1,3,4-oxadiazole-2-yl]-2-pyridyl]piperazine-1-carboxylate (100.00%, 0.384 g, 0.671 mmol) synthesized in Step 4 and trifluoroacetic acid (100.00% solution, 0.513 mL, 6.700 mmol) dissolved in dichloromethane (3 mL) at room temperature was stirred overnight at the same temperature. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The product was used without further purification (0.31 g, 97.83%, yellow oil).

[0411] [Step 6] Synthesis of Compound 100

[0412]

[0413] A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-(6-piperazine-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-propane-2-amine (100.00% solution, 0.074 mL, 0.425 mmol) synthesized in Step 5, dissolved in dichloromethane (1 mL), was stirred at room temperature for 30 minutes, and sodium triacetoxyborohydride (100.00%, 0.134 g, 0.635 mmol was added, and the mixture was stirred for an additional 18 hours at the same temperature. An aqueous solution of saturated sodium bicarbonate was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, water was removed with 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 obtain the title compound (0.026 g, 24.55%, yellow solid).

[0414] 1 H NMR (400 MHz, CDCl3) δ 9.32 (d, J = 1.6 Hz, 1H), 8.37 (dd, J = 8.2, 2.2 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.63-7.59 (m, 1H), 7.43 (d, J = 7.2 Hz, 1H), 6.96 (t, J = 51.6 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 4.75 (s, 2H), 3.69 (t, J = 5.0 Hz, 4H), 2.59 (t, J= 5.0 Hz, 4H), 2.50 (q, J = 7.2 Hz, 2H), 1.16 (t, J = 7.2 Hz, 3H); LRMS (ES) m / z 501.5 (M + +1).

[0415] The compounds of Table 13 below were synthesized according to a method substantially identical to the process of Example 100.

[0416] [Table 13]

[0417]

[0418] delete

[0419] Example 41: Synthesis of Compound 41, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-(1-methyl-4-piperidyl)phenyl]-1,3,4-thiadiazole-2-one

[0420] [Step 1] Synthesis of Tert-Butyl 4-[3-(aminocarbamothiol)-2-fluoro-phenyl]piperidine-1-carboxylate

[0421]

[0422] A solution of tert-butyl 4-[2-fluoro-3-(hydrazine carbonyl)phenyl]piperidine-1-carboxylate (100.00%, 0.200 g, 0.593 mmol) prepared in Step 3 of Example 26 and Lawesson reagent (100.00%, 0.288 g, 0.712 mmol) dissolved in toluene (20 mL) at room temperature was stirred overnight at the same temperature. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous ammonium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The product was used without further purification (0.11 g, 52.51%, yellow oil).

[0423] [Step 2] Synthesis of tert-butyl 4-[2-fluoro-3-(2-oxo-3H-1,3,4-thiadiazole-5-yl)phenyl]piperidine-1-carboxylate

[0424]

[0425] The solution of tert-butyl 4-[3-(aminocarbamothioyl)-2-fluorophenyl]piperidine-1-carboxylate (100.00%, 0.200 g, 0.566 mmol) and 1,1'-carbonylbese-1H-imidazole (100.00%, 0.110 g, 0.678 mmol) synthesized in Step 1, dissolved in dichloromethane (20 mL) at room temperature, was stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous ammonium chloride solution, water was removed with 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 40%) to obtain the title compound (0.15 g, 69.86%, white solid).

[0426] [Step 3] Synthesis of tert-butyl 4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-thiadiazole-2-yl]-2-flu-oro-phenyl]piperidine-1-carboxylate

[0427]

[0428] To the solution prepared by dissolving tert-butyl 4-[2-fluoro-3-(2-oxo-3H-1,3,4-thiadiazole-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 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 the same The mixture was stirred at the temperature for 30 minutes. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, water was removed with 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).

[0429] [Step 4] Synthesis of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-(4-piperidyl)phenyl]-1,3,4-thiadiazole-2-one 2,2,2-trifluoroacetic acid

[0430]

[0431] A solution of tert-butyl 4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-thiadiazole-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) at room temperature, was stirred at the same temperature for 3 hours. After removing the solvent from the reaction mixture under reduced pressure, the product was used without further purification (0.055 g, 92.64%, yellow oil).

[0432] [Step 5] Synthesis of Compound 41

[0433]

[0434] A solution prepared by dissolving 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-(4-piperidyl)phenyl]-1,3,4-thiadiazole-2-one 2,2,2-trifluoroacetic acid (100.00%, 0.055 g, 0.091 mmol), N-ethyldiisopropylamine (100.00% solution, 0.032 mL, 0.184 mmol), formaldehyde (100.00%, 0.005 g, 0.167 mmol), and sodium triacetoxy-borohydride (100.00%, 0.039 g, 0.184 mmol) synthesized in Step 4 in dichloromethane (5 mL) at room temperature The mixture was stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water was removed with 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).

[0435] 1 H NMR (400 MHz, CDCl3) δ 9.32 (d, J = 1.6 Hz, 1H), 8.41 (dd, J = 8.2, 2.2 Hz, 1H), 7.77-7.73 (m, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.40-7.36 (m, 1H), 7.28-7.17 (m, 1H), 5.44 (s, 2H), 3.13-3.10 (m, 2H), 2.99-2.92 (m, 1H), 2.43 (s, 3H), 2.26-2.20 (m, 2H), 1.98-1.86 (m, 4H); LRMS(ES) m / z 503.7 (M + +1).

[0436] The compounds of Table 14 below were synthesized according to a method substantially identical to the process of Example 41.

[0437] [Table 14]

[0438]

[0439] Example 20: Synthesis of Compound 20, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-(4-piperazine-1-ylphenyl)-1,3,4-oxadiazole-2-one

[0440] [Step 1] Tert-butyl 4-(4-methoxycarbonylphenyl)piperazine-1-carboxylate

[0441]

[0442] A solution of methyl 4-bromobenzoate (100.00%, 0.500 g, 2.325 mmol), tert-butyl piperazine-1-carboxylate (100.00%, 1.200 equivalents, 2.790 mmol), tris(dibenzylideneacetone)dipalladium (100.00%, 5.000 mol%, 0.116 mmol), Xphos (100.00%, 5.000 mol%, 0.116 mmol), and cesium carbonate (100.00%, 2.000 equivalents, 4.650 mmol) dissolved in toluene (50 mL) at 110 °C was stirred overnight at the same temperature, after which the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 (0.73 g, 97.99%, brown solid).

[0443] [Step 2] Tert-butyl 4-[4-(hydrazine carbonyl)phenyl]piperazine-1-carboxylate

[0444]

[0445] A solution of tert-butyl 4-(4-methoxycarbonylphenyl)piperazine-1-carboxylate (100.00%, 0.770 g, 2.403 mmol) and hydrazine monohydrate (100.00%, 10,000 equivalents, 24.030 mmol) synthesized in Step 1, dissolved in dichloromethane (5 mL) at room temperature, was stirred at the same temperature. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 (0.77 g, 100.0%, yellow solid).

[0446] [Step 3] Tert-butyl 4-[4-(2-oxo-3H-1,3,4-oxadiazole-5-yl)phenyl]piperazine-1-carboxylate

[0447]

[0448] The solution of tert-butyl 4-[4-(hydrazine carbonyl)phenyl]piperazine-1-carboxylate (100.00%, 0.770 g, 2.403 mmol) synthesized in Step 2 and 1,1'-carbonylbese-1H-imidazole (100.00%, 1.500 equivalents, 3.605 mmol) dissolved in dichloromethane (5 mL) at room temperature was heated under reflux overnight, after which the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 obtain the title compound (0.5 g, 60.06%, yellow solid).

[0449] [Step 4] Tert-butyl 4-[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazole-2-yl]phenyl]piperazine-1-carboxylate

[0450]

[0451] A solution of tert-butyl 4-[4-(2-oxo-3H-1,3,4-oxadiazole-5-yl)phenyl]piperazine-1-carboxylate (100.00%, 0.500 g, 1.443 mmol), 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) synthesized in Step 3, dissolved in N,N-dimethylformamide (25 mL) at room temperature, was stirred at the same temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 obtain the title compound (0.9 g, 112.2%, yellow solid).

[0452] [Step 5] 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-(4-piperazine-1-ylphenyl)-1,3,4-oxadiazole-2-one

[0453]

[0454] A solution of tert-butyl 4-[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazole-2-yl]phenyl]piperazine-1-carboxylate (100.00%, 0.900 g, 1.620 mmol) and 2,2,2-trifluoroacetic acid (100.00%, 10,000 equivalents, 16.200 mmol) synthesized in Step 4, dissolved in dichloromethane (50 mL) at room temperature, was stirred at the same temperature. An aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 obtain the title compound (0.12 g, 16.26%, white solid).

[0455] 1 H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 8.39 (d, J = 10.0 Hz, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.06-6.80 (m, 3H), 5.18 (s, 2H), 3.27 (s, 4H), 3.02 (s, 4H); LRMS (ES) m / z 455.5 (M + +1).

[0456] The compounds of Table 15 below were synthesized according to a method substantially identical to the process of Example 20.

[0457] [Table 15]

[0458]

[0459] Example 21: Synthesis of Compound 21, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[4-(4-methylpiperazine-1-yl)phenyl]-1,3,4-oxadiazole-2-one

[0460]

[0461] A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-(4-piperazine-1-ylphenyl)-1,3,4-oxadiazole-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, dissolved in dichloromethane (5 mL) at room temperature, was stirred at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, and then 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 obtain the title compound (0.025 g, 40.42%, yellow solid).

[0462] 1 H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 8.39 (d, J = 10.4 Hz, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.0 Hz, 1H), 6.93-6.80 (m, 3H), 5.18 (s, 2H), 3.34 (s, 4H), 2.59 (s, 4H), 2.36 (s, 3H); LRMS (ES) m / z 470.6 (M + +1).

[0463] The compounds of Table 16 below were synthesized according to a method substantially identical to the process of Example 21.

[0464] [Table 16]

[0465]

[0466] delete

[0467] Example 6: Synthesis of Compound 6, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[6-(4-isopropylpiperazine-1-yl)-2-pyridyl]-1,3,4-oxadiazole-2-one

[0468] [Step 1] Synthesis of 6-fluoropyridine-2-carbohydrazide

[0469]

[0470] Hydrazine monohydrate (100.00% solution, 6.266 mL, 129.000 mmol) was added to a solution of methyl 6-fluoropyridine-2-carboxylate (100.00%, 1.000 g, 6.446 mmol) dissolved in ethanol (30 mL) at room temperature, and the mixture was stirred overnight at the same temperature. The reaction mixture was subjected to solvent removal under reduced pressure to obtain a concentrate, to which an aqueous solution of saturated sodium bicarbonate was poured, and the mixture was extracted with dichloromethane. The organic layer was washed with an aqueous solution of saturated sodium chloride, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting product was used without further purification (1 g, 100.00%, pale yellow solid).

[0471] [Step 2] Synthesis of 5-(6-fluoro-2-pyridyl)-3H-1,3,4-oxadiazole-2-one

[0472]

[0473] Triethylamine (100.00% solution, 1.251 mL, 9.000 mmol) was added to a solution of 6-fluoropyridine-2-carbohydrazide (100.00%, 1.000 g, 6.446 mmol) and 1,1'-carbonylbese-1H-imidazole (100.00%, 1.254 g, 7.734 mmol) synthesized in Step 1 in tetrahydrofuran (30 mL) at room temperature, and the mixture was stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 obtain the title compound (0.21 g, 17.987%, yellow solid).

[0474] [Step 3] Synthesis of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-(6-fluoro-2-pyridyl)-1,3,4-oxadiazole-2-one

[0475]

[0476] 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole-2-one (100.00%, 0.210 g, 1.160 mmol) and potassium carbonate (100.00%, 0.244 g, 1.765 mmol) synthesized in Step 2 were dissolved in N,N-dimethylformamide (5 mL) at room temperature, to which 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.404 g, 1.393 mmol) was added and stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 obtain the title compound (0.185 g, 40.88%, pale yellow solid).

[0477] [Step 4] Synthesis of Compound 6

[0478]

[0479] The 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-(6-fluoro-2-pyridyl)-1,3,4-oxadiazole-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 were dissolved in dimethyl sulfoxide (1 mL) at 130 °C. The solution was stirred overnight at the same temperature, and then the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, and then 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 obtain the title compound (0.02 g, 39.15%) in the form of an orange solid.

[0480] 1 H NMR (400 MHz, CDCl3) δ 9.32 (d, J = 1.6 Hz, 1H), 8.43 (dd, J = 8.2, 2.2 Hz, 1H), 7.61-7.57 (m, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 6.96 (t, J = 51.6 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 5.27 (s, 2H), 3.76 (s, 4H), 2.89-2.75 (m, 5H), 1.18 (d, J = 5.6 Hz, 6H); LRMS (ES) m / z 499.8 (M + +1).

[0481] The compounds of Table 17 below were synthesized according to a method substantially identical to the process of Example 6.

[0482] [Table 17]

[0483]

[0484] Example 19: Synthesis of Compound 19, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-5-(1-methyl-1H-indole-5-yl)-1,3,4-oxadiazole-2(3H)-one

[0485] [Step 1] Synthesis of Methyl 1-Methylindole-5-Carboxylate

[0486]

[0487] Sodium hydride (60.00%, 140.000 mg, 3.500 mmol) was added to a solution of methyl 1H-indole-5-carboxylate (100.00%, 0.500 g, 2.854 mmol) dissolved in N,N-dimethylformamide (7 mL) at 0 °C, and the mixture was stirred at the same temperature for 0.2 hours. Iodomethane (100.00% solution, 0.27 mL, 4.340 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 4 hours. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 (0.27 g, 49.996%, white solid).

[0488] [Step 2] Synthesis of 1-Methylindole-5-Carbohydrazide

[0489]

[0490] Methyl 1-methylindole-5-carboxylate (100.00%, 160.000 mg, 0.846 mmol) synthesized in Step 1 was dissolved in ethanol (2.5 mL), and hydrazine monohydrate (100.00% solution, 0.8 mL, 16.490 mmol) was added at room temperature. The mixture was stirred at 60 °C for 18 hours, after which the temperature was lowered to room temperature to terminate the reaction. After removing the solvent from the reaction mixture under reduced pressure, the product was used without further purification (160 mg, 100.00%, pale yellow solid).

[0491] [Step 3] Synthesis of 5-(1-methylindole-5-yl)-3H-1,3,4-oxadiazole-2-one

[0492]

[0493] Triphosgene (100.00%, 100.000 mg, 0.337 mmol) was added to a solution prepared by dissolving 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) in dichloromethane (3 mL) at 0 °C, and the mixture was stirred at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 10% to 50%) to obtain the title compound (270 mg, 148.36%, white solid).

[0494] [Step 4] Synthesis of Compound 19

[0495]

[0496] Potassium carbonate (100.00%, 35.000 mg, 0.353 mmol) was added to a solution of 5-(1-methylindole-5-yl)-3H-1,3,4-oxadiazole-2-one (100.00%, 50.000 mg, 0.232 mmol) synthesized in Step 3 in N,N-dimethylformamide (2 mL) at room temperature, and the mixture was stirred for 0.3 hours at the same temperature. 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 for 18 hours at 35 °C. A saturated aqueous sodium chloride solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, and then filtered and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; hexane / ethyl acetate = 50% to 100%) to obtain the title compound (43 mg, 43.61%, white solid).

[0497] 1 H NMR (400 MHz, CD3OD) δ 9.27 (d, J = 1.2 Hz, 1H), 8.52 (dd, J = 8.4, 2.4 Hz, 1H), 8.10 (d, J = 0.8 Hz, 1H), 7.80 (s, 1H), 7.70 (t, J = 8.8 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 3.2 Hz, 1H), 7.21 (t, J = 51.6 Hz, 1H), 6.57 (dd, J = 3.2, 0.4 Hz, 1H), 5.25 (s, 2H), 3.86 (s, 3H); LRMS (ES) m / z 425.7 (M + +1).

[0498] The compounds of Table 18 below were synthesized according to a method substantially identical to the process of Example 19.

[0499] [Table 18]

[0500]

[0501] Example 33: Synthesis of Compound 33, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-(1H-indole-6-yl)-1,3,4-oxadiazole-2-one

[0502] [Step 1] Synthesis of 1-Tert-Butoxycarbonylindole-6-Carboxylic Acid

[0503]

[0504] 4-(dimethylamino)pyridine (100.00%, 0.150 g, 1.228 mmol) was added to a solution of 1H-indole-6-carboxylic acid (100.00%, 1.000 g, 6.205 mmol) and di-tert-butyl dicarbonate (100.00%, 2.000 g, 9.164 mmol) dissolved in tetrahydrofuran (12 mL) at room temperature, and the mixture was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 30%) to obtain the title compound (0.8 g, 49.34%, white solid).

[0505] [Step 2] Synthesis of Tert-Butyl 6-(Hydrazine Carbonyl)-1H-Indole-1-Carboxylate

[0506]

[0507] 1,1'-carbonylbis-1H-imidazole (100.00%, 200.000 mg, 1.233 mmol) was added to a solution of 1-tert-butoxycarbonylindole-6-carboxylic acid (100.00%, 250 mg, 0.9568 mmol) synthesized in Step 1 dissolved in tetrahydrofuran (5 mL) at room temperature, and the mixture was stirred for 3 hours at the same temperature. Hydrazine monohydrate (100.00%, 145.000 mg, 2.897 mmol) was added to the reaction mixture, and the mixture was further stirred for 18 hours at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the product was used without further purification (mixture, pale yellow solid).

[0508] [Step 3] Synthesis of tert-butyl 6-(2-oxo-3H-1,3,4-oxadiazole-5-yl)indole-1-carboxylate

[0509]

[0510] Tert-butyl 6-(hydrazine carbonyl)indole-1-carboxylate (100.00%, 450.000 mg, 1.635 mmol) synthesized in Step 2 and N,N-diisopropylethylamine (100.00% solution, 0.56 mL, 3.200 mmol) were dissolved in dichloromethane (5 mL), and at 0 °C, triphosgene (100.00%, 190.000 mg, 0.640 mmol) was added and stirred at room temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 10% to 50%) to obtain the title compound (270 mg, 54.82%, white solid).

[0511] [Step 4] Synthesis of tert-butyl 6-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazole-2-yl]indole-1-carboxylate

[0512]

[0513] Potassium carbonate (100.00%, 25.000 mg, 0.252 mmol) was added to a solution of tert-butyl 6-(2-oxo-3H-1,3,4-oxadiazole-5-yl)indole-1-carboxylate (100.00%, 55.000 mg, 0.183 mmol) synthesized in Step 3 in N,N-dimethylformamide (2 mL) at room temperature, and the mixture was stirred for 0.3 hours at the same temperature. 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 the mixture was further stirred for 18 hours at 35 °C. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; hexane / ethyl acetate = 50% to 100%) to obtain the title compound (58 mg, 62.25%, white solid).

[0514] [Step 5] Synthesis of Compound 33

[0515]

[0516] Trifluoroacetic acid (100.00% solution, 0.3 mL, 3.918 mmol) was added to a solution in which tert-butyl 6-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazole-2-yl]indole-1-carboxylate (100.00%, 50.000 mg, 0.098 mmol) synthesized in Step 4 was dissolved in dichloromethane (1 mL) at room temperature, and the mixture was stirred for 1 hour at the same temperature. A saturated aqueous sodium bicarbonate solution was poured over the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = 80% to 100%) to obtain the title compound (34 mg, 84.59%, pale yellow solid).

[0517] 1 H NMR (400 MHz, CD3OD) δ 9.27 (d, J = 1.6 Hz, 1H), 8.54 (dd, J = 8.2, 2.2 Hz, 1H), 7.93 (d, J = 0.8 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.53 (dd, J = 8.4, 1.6 Hz, 1H), 7.44 (d, J = 1.2 Hz, 1H), 7.26 (t, J = 51.6 Hz, 1H), 5.26 (s, 2H); LRMS (ES) m / z 412.8 (M + +1).

[0518] The compounds of Table 19 below were synthesized according to substantially the same method as the process of Example 33.

[0519] [Table 19]

[0520]

[0521] Example 11: Synthesis of Compound 11, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-(1,2,3,4-tetrahydroisoquinoline-6-yl)-1,3,4-oxadiazole-2-one

[0522] [Step 1] Tert-butyl 7-(hydrazine carbonyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate

[0523]

[0524] 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, after which the temperature was lowered to room temperature to terminate the reaction. After removing the solvent from the reaction mixture under reduced pressure, the product was used without further purification (0.603 g, 100.0%, white solid).

[0525] [Step 2] Tert-butyl 7-(2-oxo-3H-1,3,4-oxadiazole-5-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate

[0526]

[0527] Tert-butyl 7-(hydrazine carbonyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (100.00%, 0.640 g, 2.197 mmol) and 1,1'-carbonylbese-1H-imidazole (100.00%, 1.500 equivalents, 3.296 mmol) synthesized in Step 1 were dissolved in dichloromethane (5 mL) at 50 °C. The solution was stirred overnight at the same temperature, and then the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 obtain the title compound (0.42 g, 60.25%, white solid).

[0528] [Step 3] Tert-butyl 7-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazole-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate

[0529]

[0530] Tert-butyl 7-(2-oxo-3H-1,3,4-oxadiazole-5-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (100.00%, 0.420 g, 1.324 mmol), 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.200 equivalents, 1.588 mmol), potassium carbonate (100.00%, 2.000 equivalents, 2.647 mmol), and potassium iodide (100.00%, 1.100 equivalents, 1.456 mmol) synthesized in Step 2 were dissolved in N,N-dimethylformamide (25 mL) at room temperature. The solution was stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 obtain the title compound (0.55 g, 78.92%, yellow solid).

[0531] [Step 4] Synthesis of Compound 11

[0532]

[0533] A solution of tert-butyl 7-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazole-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (100.00%, 0.550 g, 1.045 mmol) and 2,2,2-trifluoroacetic acid (100.00%, 10.000 equivalents, 10.450 mmol) synthesized in Step 3, dissolved in dichloromethane (20 mL) at room temperature, was stirred overnight at the same temperature. An aqueous solution of sodium bicarbonate was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, and then 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 obtain the title compound (0.42 g, 94.29%, yellow solid).

[0534] 1 H NMR (400 MHz, CDCl3) δ 9.31 (s, 1H), 8.42 (d, J = 8.4 Hz, 1H), 7.60 (s, 2H), 7.51 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.93 (t, J = 51.6 Hz, 1H), 5.21 (s, 2H), 4.09 (s, 2H), 3.19 (s, 2H), 2.88 (s, 2H); LRMS (ES) m / z 427.4 (M + +1).

[0535] Example 12: Synthesis of Compound 12, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-(2-methyl-3,4-dihydro-1H-isoquinoline-7-yl)-1,3,4-oxadiazole-2-one

[0536]

[0537] A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-(1,2,3,4-tetrahydroisoquinoline-7-yl)-1,3,4-oxadiazole-2-one (100.00%, 0.080 g, 0.188 mmol), formaldehyde (100.00%, 1.500 equivalents, 0.281 mmol), and sodium triacetoxyborohydride (100.00%, 2.000 equiv., 0.375 mmol) synthesized in Step 4 of Example 11, dissolved in dichloromethane (5 mL) at room temperature, was stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, and then 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 obtain the title compound (0.02 g, 24.21%, yellow solid).

[0538] 1 H NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 8.38 (d, J = 10.4 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 25.6 Hz, 2H), 7.17 (d, J = 8.0 Hz, 1H), 6.93 (t, J = 51.6 Hz, 1H), 5.18 (s, 2H), 3.60 (s, 2H), 2.95 (t, J = 5.6 Hz, 2H), 2.72 (t, J = 6.0 Hz, 2H), 2.45 (s, 3H); LRMS (ES) m / z 441.4 (M + +1).

[0539] The compounds of Table 20 below were synthesized according to a method substantially identical to the process of Example 12.

[0540] [Table 20]

[0541]

[0542] Example 135: Synthesis of Compound 135, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-3-fluoro-2-pyridyl]methyl]-5-(2-methyl-3,4-dihydro-1H-isoquinoline-6-yl)-1,3,4-oxadiazole-2-thione

[0543] [Step 1] Synthesis of Tert-Butyl 6-(Hydrazine Carbonyl)-3,4-Dihydro-1H-Isoquinoline-2-Carboxylate

[0544]

[0545] Hydrazine monohydrate (100.00% solution, 1.668 mL, 34.320 mmol) was added to a solution of 2-tert-butyl,6-methyl 3,4-dihydro-1H-isoquinoline-2,6-dica-boxylate (100.00%, 1.000 g, 3.433 mmol) dissolved in ethanol (20 mL) at room temperature, and the mixture was stirred overnight at 60 °C, after which the temperature was lowered to room temperature to terminate the reaction. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified and concentrated by column chromatography (SiO2, 24 g cartridge; methanol / dichloromethane = 0% to 10%) to obtain the title compound (1 g, 100.0%, white solid).

[0546] [Step 2] Synthesis of tert-butyl 6-(2-thioxo-3H-1,3,4-oxadiazole-5-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate

[0547]

[0548] Tert-butyl 6-(hydrazine carbonyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (100.00%, 0.642 g, 2.204 mmol) and potassium ethylxanthate (100.00%, 0.353 g, 2.202 mmol) synthesized in Step 1 were dissolved in ethanol (10 mL) at room temperature. The solution was stirred overnight at 90 °C, after which the temperature was lowered to room temperature to terminate the reaction. A saturated aqueous ammonium chloride solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 obtain the title compound (0.03 g, 4.083%, colorless oil).

[0549] [Step 3] Synthesis of tert-butyl 6-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-3-fluoro-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazole-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate

[0550]

[0551] To a solution in which tert-butyl 6-(2-thioxo-3H-1,3,4-oxadiazole-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 were 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 overnight at the same temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 60%) to obtain the title compound (0.395 g, 42.71%, yellow solid).

[0552] [Step 4] Synthesis of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-3-fluoro-2-pyridyl]methyl]-5-(1,2,3,4-tetrahydroisoquinoline-6-yl)-1,3,4-oxadiazole-2-thione

[0553]

[0554] A solution of tert-butyl 6-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-3-fluoro-2-pyridyl]methyl]-5-thioxo-1,3,4-oxadiazole-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (100.00%, 0.395 g, 0.705 mmol) and trifluoroacetic acid (100.00% solution, 0.539 mL, 7.040 mmol) synthesized in Step 3 was dissolved in dichloromethane (5 mL) at room temperature and stirred overnight at the same temperature. An aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The product was used without further purification (0.32 g, 98.64%, yellow oil).

[0555] [Step 5] Synthesis of Compound 135

[0556]

[0557] A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-3-fluoro-2-pyridyl]methyl]-5-(1,2,3,4-tetrahydroisoquinoline-6-yl)-1,3,4-oxadiazole-2-thione (100.00%, 0.060 g, 0.130 mmol), formaldehyde (37.00% solution, 0.026 mL, 0.261 mmol), and N-ethyl-N-isopropyl-propane-2-amine (100.00% solution, 0.045 mL, 0.258 mmol) synthesized in Step 4, dissolved in dichloromethane (1 mL), was stirred at room temperature for 30 minutes, and sodium triacetoxyborohydride (100.00%, 0.082 g (0.389 mmol) was added and stirred for an additional 18 hours at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 obtain the title compound (0.021 g, 33.96%, pale yellow solid).

[0558] 1 H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 8.15 (dd, J = 9.0, 1.8 Hz, 1H), 7.79-7.76 (m, 2H), 7.17 (d, J = 8.0 Hz, 1H), 6.96 (t, J = 52.2 Hz, 1H), 4.80 (d, J = 1.6 Hz, 2H), 3.65 (s, 2H), 3.01 (t, J = 5.8 Hz, 2H), 2.76-2.73 (m, 2H), 2.50 (s, 3H); LRMS (ES) m / z 475.9 (M + +1).

[0559] The compounds of Table 21 below were synthesized according to a method substantially identical to the process of Example 135.

[0560] [Table 21]

[0561]

[0562] delete

[0563] Example 69: Synthesis of Compound 69, 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-(2-thienyl)-6H-1,3,4-oxadiazine-2-one

[0564] [Step 1] Synthesis of [2-oxo-2-(2-thienyl)ethyl]acetate

[0565]

[0566] Potassium acetate (100.00%, 0.718 g, 7.316 mmol) and potassium iodide (100.00%, 0.405 g, 2.440 mmol) were added to a solution of 2-bromo-1-(2-thienyl)ethanol (100.00%, 0.500 g, 2.438 mmol) dissolved in N,N-dimethylformamide (10 mL) at room temperature, and the mixture was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The product was used without further purification (0.445 g, 99.078%, yellow oil).

[0567] [Step 2] Synthesis of [(2E)-2-(methoxycarbonylhydrazono)-2-(2-thienyl)ethyl]acetate

[0568]

[0569] Methyl hydrazinocarboxylate (100.00%, 0.239 g, 2.653 mmol) was added to a solution prepared by dissolving [2-oxo-2-(2-thienyl)ethyl]acetate (100.00%, 0.445 g, 2.416 mmol) and hydrogen chloride (1.00 M solution, 0.048 mL, 0.048 mmol) synthesized in Step 1 in methanol (10 mL) at room temperature, and the mixture was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 obtain the title compound (0.425 g, 68.648%, yellow solid).

[0570] [Step 3] Synthesis of 5-(2-cyanyl)-3,6-dihydro-1,3,4-oxadiazine-2-one

[0571]

[0572] [(2E)-2-(methoxycarbonylhydrazono)-2-(2-thienyl)ethyl] acetate (100.00%, 0.425 g, 1.658 mmol) synthesized in Step 2 and sodium ethoxide (ca. 20% in ethanol, 20.00% solution, 0.962 mL, 2.500 mmol) were dissolved in ethanol (10 mL) at room temperature and stirred for 30 minutes at the same temperature. A saturated aqueous ammonium chloride solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 (0.2 g, 66.192%, yellow solid).

[0573] [Step 4] Synthesis of Compound 69

[0574]

[0575] A solution of 5-(2-thienyl)-3,6-dihydro-1,3,4-oxadiazine-2-one (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) synthesized in Step 3, dissolved in N,N-dimethylformamide (1 mL) at room temperature, was stirred overnight at the same temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous magnesium sulfate, and then filtered and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 0% to 60%) to obtain the title compound (0.042 g, 43.45%, pale yellow solid).

[0576] 1 H NMR (400 MHz, CDCl3) δ 9.32 (d, J = 1.6 Hz, 1H), 8.40 (dd, J = 8.2, 2.2 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.47 (dd, J = 5.2, 1.2 Hz, 1H), 7.25-7.24 (m, 1H), 7.11-7.09 (m, 1H), 6.96 (t, J = 51.6 Hz, 1H), 5.27 (s, 2H), 5.25 (s, 2H); LRMS (ES) m / z 392.3 (M + +1).

[0577] The compounds of Table 22 below were synthesized according to substantially the same method as the process of Example 69.

[0578] [Table 22]

[0579]

[0580] Example 142: Synthesis of Compound 142, 3-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-5-phenyloxazole-2(3H)-one

[0581] [Step 1] Synthesis of Methyl 6-(((tert-butoxycarbonyl)amino)methyl)nicotinate

[0582]

[0583] Di-tert-butyl dicarbonate (3.152 g, 14.442 mmol) and triethylamine (2.516 mL, 18.053 mmol) were added to a solution of methyl 6-(aminomethyl)nicotinate (2.000 g, 12.035 mmol) dissolved in dichloromethane (20 mL) at room temperature, and the mixture was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 obtain the title compound (1.700 g, 53.0%, white solid).

[0584] [Step 2] Synthesis of Methyl 6-(((tert-butoxycarbonyl)(phenylethyneyl)amino)methyl) nicotinate

[0585]

[0586] (Bromothyninyl)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, after which the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a Celite pad to remove the solid, and the solvent was removed from the filtrate under reduced pressure. The concentrate was then 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%, pale yellow solid).

[0587] [Step 3] Synthesis of Methyl 6-((2-oxo-5-phenyloxazole-3(2H)-yl)methyl)nicotinate

[0588]

[0589] Silver bis(trifluoromethanesulfonyl)imide (0.003 g, 0.007 mmol) was added to a solution of methyl 6-(((tert-butoxycarbonyl)(phenylethyneyl)amino)methyl)nicotinate (0.050 g, 0.136 mmol) synthesized in Step 2 in dichloromethane (0.5 mL) at room temperature, and the mixture was stirred for 1 hour at the same temperature. A saturated aqueous ammonium 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, water was removed with 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 obtain the title compound (0.030 g, 70.8%, yellow solid).

[0590] [Step 4] Synthesis of 6-((2-oxo-5-phenyloxazole-3(2H)-yl)methyl)nicotinohydrazide

[0591]

[0592] Methyl 6-((2-oxo-5-phenyloxazole-3(2H)-yl)methyl)nicotinate (0.016 g, 0.052 mmol) and hydrazine monohydrate (0.050 mL, 1.031 mmol) synthesized in Step 3 were dissolved in ethanol (1 mL) at 80 °C. The solution was stirred at the same temperature for 18 hours, after which the temperature was lowered to room temperature to terminate the reaction. After removing the solvent from the reaction mixture under reduced pressure, the product was used without further purification (0.016 g, 100.0%, white solid).

[0593] [Step 5] Synthesis of Compound 142

[0594]

[0595] 2,2-difluoroacetic anhydride (0.024 mL, 0.193 mmol) was added to a solution prepared by dissolving 6-((2-oxo-5-phenyloxazole-3(2H)-yl)methyl)nicotinohydrazide (0.015 g, 0.048 mmol) and triethylamine (0.040 mL, 0.290 mmol) synthesized in Step 4 in tetrahydrofuran (0.7 mL) at room temperature, and the mixture was stirred at 80 °C for 6 hours, after which the temperature was lowered to room temperature to terminate the reaction. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with 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 = 50% to 100%) to obtain the title compound (0.008 g, 44.7%, white solid).

[0596] 1 H NMR (400 MHz, CD3OD) δ 9.28 (s, 1H), 8.53 (dd, J= 7.8, 2.2 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 7.6 Hz, 2H), 7.44-7.40 (m, 3H), 7.33 (t, J = 7.4 Hz, 1H), 7.26 (t, J = 51.4 Hz, 1H), 7.26 (t, J = 51.4 Hz, 1H), 5.09 (s, 2H); LRMS (ES) m / z 371.2 (M + +1).

[0597] The compounds of Table 23 below were synthesized according to a method substantially identical to the process of Example 142.

[0598] [Table 23]

[0599]

[0600] Example 144: Synthesis of Compound 144, 1-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-3-methyl-4-phenyl-1,3-dihydro-2H-imidazole-2-one

[0601]

[0602] Potassium carbonate (0.060 g, 0.431 mmol) and potassium iodide (0.010 g, 0.057 mmol) were added 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)pyridine-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.100 g, 0.345 mmol) dissolved in N,N-dimethylformamide (1 mL) at room temperature, and the mixture was stirred at 80 °C for 18 hours, after which the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, water was removed with anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; dichloromethane / methanol = 80% to 100%) to obtain the title compound (0.012 g, 10.9%, white solid).

[0603] 1 H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.4 Hz, 2H), 8.15 (dd, J = 4.2, 1.8 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.62 to 7.57 (m, 2H), 7.51 to 7.37 (m, 3H), 6.95 (t, J = 51.8 Hz, 1H), 6.79 (s, 1H), 5.66 (s, 2H), 3.51 (s, 3H); LRMS (ES) m / z 384.2 (M + +1).

[0604] Protocol for the measurement and analysis of the activity of the compound of the present invention

[0605] <Experimental Example 1> Confirmation of HDAC enzyme activity inhibition ( in vitro )

[0606] Experiments were conducted to confirm the selectivity of the compound represented by Formula I of the present invention toward HDAC6 through experiments on the inhibition of HDAC1 and HDAC6 enzyme activity.

[0607] HDAC enzyme activity was measured using Enzo Life Science’s HDAC Fluorimetric Drug Discovery Kit (BML-AK511, 516). For the HDAC1 enzyme activity test, human recombinant HDAC1 (BML-SE456) was used as the enzyme source. Fluor de Lys ⓡ - "SIRT1 (BNL-KI177) was used as the substrate. After dispensing the compound diluted 5-fold into a 96-well plate, 0.3 μg of enzyme and 10 μM of substrate were added to each well, and the reaction was carried out at 30 ℃ for 60 minutes, Fluor de Lys ⓡ After adding Developer II (BML-KI176) and reacting for 30 minutes to terminate the reaction, fluorescence values ​​(Ex 360, Em 460) were measured using a multi-plate reader (Flexstation 3, Molecular Device). The HDAC6 enzyme was tested using Calbiochem’s human recombinant HDAC6 (382180) following the same protocol as the HDAC1 enzyme activity assay. The final results were analyzed using GraphPad Prism 4.0 software to determine each IC 50 The values ​​were calculated. The results are summarized in Table 24 below.

[0608] [Table 24]

[0609]

[0610] delete

[0611] delete

[0612] As described in Table 24 above, the results of the activity inhibition tests for HDAC1 and HDAC6 confirmed that the 1,3,4-oxadiazole derivative compounds of the present invention, stereoisomers thereof, or pharmaceutically acceptable salts thereof exhibited excellent selective HDAC6 inhibitory activity of about 185 to about 3497 times.

Claims

Claim 1 1,3,4-oxadiazole derivative compounds represented by the following chemical formula I, stereoisomers thereof, or pharmaceutically acceptable salts thereof: [Chemical Formula I] In the above chemical formula I, R1 is -C 1-4 It is a haloalkyl; X1 to X4 are each independently CR X or N and;R X is -H, -C 1-4 Alkyl, -C 1-4 haloalkyl, or -halo and;Y is CR Y or N and;R Y -H or -C 1-4 alkyl; Z is O or S; W is O or S; m is 0 or 1; ring V is aryl, heteroaryl, or hydroheteroaryl {wherein one or more H of the aryl, heteroaryl, or hydroheteroaryl ring are -C 1-4 Alkyl, -C 1-4 Aminoalkyl, -C 1-4 Hydroxyalkyl, -C 1-4 It can be substituted with haloalkyl, -halo, -(CH2)n-cycloalkyl, -(CH2)n-heterocycloalkyl, or -(CH2)n-heteroaryl [wherein, one or more H of the -(CH2)n-cycloalkyl, -(CH2)n-heterocycloalkyl, or -(CH2)n-heteroaryl ring are -C 1-4 Alkyl, -C 1-4 It may be substituted with haloalkyl, -halo, cycloalkyl, or heterocycloalkyl (wherein one or more H of the cycloalkyl or heterocycloalkyl ring are -C 1-4 n is 0, 1, or 2. Claim 2 In claim 1, R1 is -C 1-4 It is a haloalkyl; X1 is N; X2 to X4 are each independently CR X Igo;R X is -H or -halo and;Y is CR Y or N and;R Y is -H; Z is O or S; W is O or S; m is 0 or 1; ring V is aryl, heteroaryl, or hydroheteroaryl {wherein one or more Hs of the aryl, heteroaryl, or hydroheteroaryl ring are -C 1-4 Alkyl, -C 1-4 It can be substituted with aminoalkyl, -halo, -(CH2)n-cycloalkyl, -(CH2)n-heterocycloalkyl, or -(CH2)n-heteroaryl [wherein, one or more H of the -(CH2)n-cycloalkyl, -(CH2)n-heterocycloalkyl, or -(CH2)n-heteroaryl ring are -C 1-4 It may be substituted with alkyl, -halo, cycloalkyl, or heterocycloalkyl (wherein one or more H of the cycloalkyl or heterocycloalkyl ring are -C 1-4 1,3,4-oxadiazole derivative compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein n is 0 or 1; can be substituted with alkyl groups. Claim 3 In claim 1, R1 is -CF2H or -CF3; a 1,3,4-oxadiazole derivative compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Claim 4 In claim 1, X1 is N; X2 to X4 are each independently CH or CF; a 1,3,4-oxadiazole derivative compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Claim 5 In claim 1, Y is CH or N; Z is O or S; W is O or S; m is 0 or 1; a 1,3,4-oxadiazole derivative compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Claim 6 In claim 1, ring V is phenyl, 5-10-membered heteroaryl, or 9-10-membered hydroheteroaryl, {wherein one or more H of the phenyl, 5-10-membered heteroaryl, or 9-10-membered hydroheteroaryl ring is -C 1-4 Alkyl, -C 1-4 It can be substituted with aminoalkyl, -halo, -(CH2)n-cycloalkyl, -(CH2)n-heterocycloalkyl, or -(CH2)n-heteroaryl [wherein, one or more H of the -(CH2)n-cycloalkyl, -(CH2)n-heterocycloalkyl, or -(CH2)n-heteroaryl ring are -C 1-4 It may be substituted with alkyl, -halo, 4-6-membered cycloalkyl, or 4-6-membered heterocycloalkyl (wherein one or more H of the 4-6-membered cycloalkyl or 4-6-membered heterocycloalkyl ring is -C 1-4 1,3,4-oxadiazole derivative compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein n is 0 or 1; can be substituted with alkyl groups. Claim 7 In claim 1, the compound represented by Formula I is any one selected from the group consisting of the following compounds, a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: . Claim 8 A pharmaceutical composition for the prevention or treatment of histone deacetylase 6-mediated diseases comprising, as an active ingredient, a compound represented by Formula I according to any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the histone deacetylase 6-mediated diseases are infectious diseases; neoplasms; endocrine, nutritional, and metabolic diseases; mental and behavioral disorders; neurological diseases; diseases of the eye and adnexa; respiratory diseases; digestive diseases; skin and subcutaneous tissue diseases; musculoskeletal and connective tissue diseases; A pharmaceutical composition for the prevention or treatment of histone deacetylase 6-mediated diseases, wherein the above-mentioned endocrine, nutritional, and metabolic diseases are Wilson's disease, amyloidosis, or diabetes mellitus; the above-mentioned mental and behavioral disorders are depression or Rett syndrome; the above-mentioned neurological diseases are central nervous system atrophy, neurodegenerative diseases, movement disorders, neuropathy, motor neuron diseases, or central nervous system demyelinating diseases; the above-mentioned eye and adnexal disease is uveitis; the above-mentioned skin and subcutaneous tissue disease is psoriasis; the above-mentioned musculoskeletal and connective tissue diseases are rheumatoid arthritis, osteoarthritis, or systemic lupus erythematosus; the above-mentioned congenital malformations, deformities, and chromosomal abnormalities are autosomal dominant polycystic kidney disease; the above-mentioned infectious diseases are prion diseases; the above-mentioned neoplasms are benign or malignant tumors; the above-mentioned respiratory diseases are asthma; and the above-mentioned digestive diseases are alcoholic liver disease, inflammatory bowel disease, Crohn's disease, or ulcerative colitis. Claim 9 delete Claim 10 delete

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