1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitors and pharmaceutical compositions containing the same

Abstract

The present invention relates to a novel compound having histone deacetylase 6 (HDAC6) inhibitory activity, an isomer thereof or a pharmaceutically acceptable salt thereof, their use for preparing therapeutic drugs; a pharmaceutical composition containing them and a therapeutic method using the composition; and a preparation method thereof. The novel compound, its isomer or a pharmaceutically acceptable salt thereof according to the present invention has HDAC6 inhibitory activity, which effectively prevents or treats HDAC6-mediated diseases, including cancer, inflammatory diseases, autoimmune diseases, nervous system diseases or neurodegenerative diseases.

Description

Technical Field

[0001] The present invention relates to 1,3,4-oxadiazole derivative compounds having histone deacetylase 6 (HDAC6) inhibitory activity, optical isomers thereof, pharmaceutically acceptable salts thereof, uses thereof for preparing therapeutic drugs, therapeutic methods using the same, pharmaceutical compositions containing the same, and methods for preparing the same. Background Art

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

[0003] Histone deacetylase (HDAC) is an enzyme that removes the acetyl group of the histone lysine residues constituting chromatin, and it is known that these enzymes are associated with gene silencing and induce cell cycle arrest, angiogenesis inhibition, immunomodulation, cell death, etc. (Hassig et al., Curr. Opin. Chem. Biol. 1997, 1, 300-308). In addition, it is reported that the inhibition of HDAC enzyme function induces cancer cell death by reducing the activity of cancer cell survival-related factors in vivo and activating cancer cell death-related factors (Warrell et al., J. Natl. Cancer Inst. 1998, 90, 1621-1625).

[0004] In humans, 18 HDACs are known and divided into four groups based on their homology to yeast HDACs. Here, the 11 HDACs that use zinc as a cofactor can be divided into three groups: class I (HDACs 1, 2, 3, and 8), class II (IIa: HDACs 4, 5, 7, and 9; IIb: HDACs 6 and 10), and class IV (HDAC11). In addition, 7 class III HDACs (SIRTs 1-7) use NAD + Rather than zinc as a cofactor (Bolden et al., Nat. Rev. Drug. Discov. 2006, 5(9), 769-784).

[0005] Various HDAC inhibitors are in preclinical or clinical development stages. However, so far, only non-selective HDAC inhibitors are considered as anticancer agents, wherein vorinostat (vorinostat) (SAHA) and romidepsin (romidepsin) (FK228) have been approved as therapeutic agents for cutaneous T-cell lymphoma, and panobinostat (panobinostat) (LBH-589) has been approved as a therapeutic agent for multiple myeloma. However, it is generally known that non-selective HDAC inhibitors cause side effects such as fatigue and nausea at high doses (Piekarz et al., Pharmaceuticals 2010, 3, 2751-2767). It is reported that these side effects are caused by the inhibition of Class I HDAC, and due to these side effects, non-selective HDAC inhibitors are restricted in drug development in the field other than anticancer agents (Witt et al., Cancer Letters 277 (2009) 8.21).

[0006] Meanwhile, it is reported that selective class II HDAC inhibition may not show the toxicity seen in class I HDAC inhibition, and if selective class II HDAC inhibitors are developed, side effects (such as toxicity, etc.) caused by non-selective HDAC inhibition may be solved, and therefore selective HDAC inhibitors have the potential to be developed as effective therapeutic agents for various diseases (Matthias et al., Mol. Cell. Biol. 2008, 28, 1688-1701). HDAC6 (one of class IIb HDACs) is mainly present in the cytoplasm, and is known to participate in the deacetylation of many non-histone substrates (HSP90, cortactin, etc.) including tubulin (Yao et al., Mol. Cell 2005, 18, 601-607). HDAC6 has two catalytic domains, and the C-terminus of the zinc finger domain can bind to ubiquitinated proteins. Since HDAC6 has a large number of non-histone proteins as substrates, it is known to play an important role in various diseases such as cancer, inflammatory diseases, autoimmune diseases, nervous system diseases and neurodegenerative disorders (Santo et al., Blood 2012 119:2579-258; Vishwakarma et al., International Immunopharmacology 2013, 16, 72-78; Hu et al., J. Neurol. Sci. 2011, 304, 1-8).

[0007] A common structural feature of various HDAC inhibitors is that they are composed of a cap group, a linker group and a zinc binding group (ZBG), as shown in the structure of vorinostat below. Many researchers have studied the inhibitory activity and selectivity of enzymes by structural modification of cap groups and linker groups. Among these groups, it is known that zinc binding groups play a more important role in enzyme inhibitory activity and selectivity (Wiest et al., J.Org.Chem.2013 78:5051-5065; Methot et al., Bioorg.Med.Chem.Lett.2008,18,973-978).

[0008]

[0009] Most zinc-binding groups are hydroxamic acid or benzamide, and among them, hydroxamic acid derivatives exhibit strong HDAC inhibition, but have problems such as low bioavailability and severe off-target activity, etc. Since benzamide contains aniline, there is a problem that toxic metabolites may be caused in vivo (Woster et al., Med. Chem. Commun. 2015, published online).

[0010] Therefore, in order to treat cancer, inflammatory diseases, autoimmune diseases, neurological diseases, neurodegenerative disorders, etc., it is necessary to develop a selective HDAC6 inhibitor with a zinc-binding group, which has improved bioavailability without side effects, unlike non-selective inhibitors with side effects. Summary of the invention

[0011] Technical issues

[0012] An object of the present invention is to provide a 1,3,4-oxadiazole derivative compound having selective histone deacetylase 6 (HDAC6) inhibitory activity, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

[0013] Another object of the present invention is to provide a pharmaceutical composition comprising a 1,3,4-oxadiazole derivative compound having selective HDAC6 inhibitory activity, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

[0014] Another object of the present invention is to provide a method for preparing the same.

[0015] Another object of the present invention is to provide a pharmaceutical composition comprising the compound for preventing or treating diseases mediated by histone deacetylase 6 (HDAC6), including infectious diseases; neoplasms; endocrine, nutritional and metabolic diseases; mental and behavioral disorders; nervous system diseases; eye and appendage diseases; circulatory system diseases; respiratory system diseases; digestive system diseases; skin and subcutaneous tissue diseases; musculoskeletal and connective tissue diseases; or congenital malformations, changes or chromosomal abnormalities.

[0016] Another object of the present invention is to provide use of the compound for preparing a medicament for preventing or treating a disease mediated by HDAC6.

[0017] Another object of the present invention is to provide a method for preventing or treating HDAC6-mediated diseases, which comprises administering a therapeutically effective amount of a composition comprising the compound as described above.

[0018] Solution to the problem

[0019] The present invention has discovered 1,3,4-oxadiazole derivative compounds having histone deacetylase 6 (HDAC6) inhibitory activity for inhibiting or treating HDAC6-mediated diseases, and has completed the present invention.

[0020] 1,3,4-Oxadiazole derivative compounds

[0021] In one general aspect, the present invention provides a 1,3,4-oxadiazole derivative compound represented by the following chemical formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[0022] [Chemical Formula I]

[0023]

[0024] In the above chemical formula I,

[0025] L1, L2 and L3 are each independently -(C0-C2 alkyl)-;

[0026] a, b and c are each independently N or CR 4 , where a, b and c cannot be N at the same time, and R 4 is -H, -X or -O(C1-C4 alkyl);

[0027] R1 is -CX2H or -CX3;

[0028] R2 is -(C1-C4 alkyl), -(C1-C4 alkyl)-O-(C1-C4 alkyl), -NR A R B , aryl, heteroaryl,

[0029] Y is -N-, -CH-, -O- or -S(=O)2-;

[0030] When Y is -N- or -CH-, R5, R6, R7 and R8 are each independently -H, -X, -OH, -(C1-C4 alkyl), -(C1-C4 alkyl)-O(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -O(C1-C4 alkyl), -NR C R D , -CF3, -CF2H, -CN, -C(=O)-(C1-C4 alkyl), -C(=O)-(C3-C7 cycloalkyl), -C(=O)-(C2-C6 heterocycloalkyl), -C(=O)-O(C1-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(C1-C4 alkyl), -C(=O)-NR C R D 、-C(=O)-(C1-C4 alkyl)-NR C R D , -S(=O)2-(C1-C4 alkyl), -aryl, -heteroaryl, -(C1-C4 alkyl)-aryl, -(C1-C4 alkyl)heteroaryl, amine protecting group or

[0031] wherein at least one H of -(C1-C4 alkyl), -(C=O)-(C1-C4 alkyl), -(C3-C7 cycloalkyl) and -C(=O)-(C3-C7 cycloalkyl) may be substituted by -X, -OH, -O(C1-C4 alkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -CF3 or -CF2H; -aryl, -heteroaryl, -(C1-C4 alkyl)-aryl and -(C At least one H of the -(C1-C4 alkyl)heteroaryl may be substituted by -X, -OH, -(C1-C4 alkyl), -O(C1-C4 alkyl), -C(═O)-(C1-C4 alkyl), -C(═O)-O(C1-C4 alkyl), -CF3 or -CF2H; the -(C2-C6 heterocycloalkyl), -heteroaryl or -(C1-C4 alkyl)heteroaryl may contain N, O or S atoms in the ring; and Z is -NH-, -CH2- or -O-;

[0032] When Y is -O- or -S(=O)2-, R5, R6, R7 and R8 are absent (none);

[0033] R A To R Deach independently represents -H, -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -(C1-C4 alkyl)-(C2-C6 heterocycloalkyl), aryl, heteroaryl or -(C1-C4 alkyl)-aryl, wherein at least one H of -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -(C1-C4 alkyl)-(C2-C6 heterocycloalkyl), aryl, heteroaryl and -(C1-C4 alkyl)-aryl may be substituted by -(C1-C4 alkyl), -C(═O)-(C1-C4 alkyl), -S(═O)2-(C1-C4 alkyl) or -(C2-C6 heterocycloalkyl);

[0034] m and n are each independently an integer of 1, 2 or 3;

[0035] R a To R d Each is independently -H or -(C1-C4 alkyl);

[0036] R 3 is -H, -(C1-C4 alkyl), -(C1-C4 alkyl)-O(C1-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -aryl or -heteroaryl, wherein at least one H of -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -aryl and -heteroaryl can be each independently replaced by -X, -OH, -O(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -C(=O)-(C1-C4 alkyl), -CF3, -CF2H, -OCF3, -S(=O)2-(C1-C4 alkyl), -aryl, -O-aryl, -heteroaryl or -NR E R F Replace, and R E and R F are each independently -H or -(C1-C4 alkyl); and

[0037] X is F, Cl, Br or I.

[0038] According to one embodiment of the present invention,

[0039] In the above chemical formula I,

[0040] L1 to L3 are each independently -(C0-C1 alkyl)-;

[0041] a, b and c are each independently N or CR 4 , where a, b and c cannot be N at the same time, and R 4is -H or -X;

[0042] R1 is -CX2H or -CX3;

[0043] R2 is -(C1-C4 alkyl), -NR A R B ,

[0044] m and n are each independently an integer of 1 or 2;

[0045] R a To R d Each is independently -H or -(C1-C4 alkyl);

[0046] Y is -N-, -O- or -S(=O)2-;

[0047] When Y is -N-, R5, R6, R7 and R8 are each independently -H, -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-(C3-C7 cycloalkyl), -C(=O)-(C2-C6 heterocycloalkyl), -C(=O)-O(C1-C4 alkyl), -C(=O)-NR C R D , -S(=O)2-(C1-C4 alkyl), -heteroaryl or

[0048] wherein at least one -H of -(C1-C4 alkyl), -(C=O)-(C1-C4 alkyl) and -(C3-C7 cycloalkyl) may be substituted by -X or -OH; -(C2-C6 heterocycloalkyl) or -heteroaryl may contain N, O or S atoms in the ring; and Z is -NH-, -CH2- or -O-;

[0049] When Y is -O- or -S(=O)2-, R5, R6, R7 and R8 are absent (none);

[0050] R A To R D Each is independently -H or -(C1-C4 alkyl);

[0051] R 3 is -aryl or -heteroaryl, wherein at least one H of -aryl and -heteroaryl may be substituted with -X, respectively, independently; and

[0052] X can be F, Cl or Br.

[0053] Furthermore, according to another embodiment of the present invention,

[0054] In the above chemical formula I,

[0055] L1 and L3 are each independently -(C0 alkyl)-;

[0056] L2 is -(C1 alkyl)-;

[0057] a, b and c are each independently CR 4 , where R 4 is -H or -X;

[0058] R1 is -CX2H or -CX3;

[0059] R2 is

[0060] m and n are each independently an integer of 1 or 2;

[0061] R a and R b Each is independently -H or -(C1-C4 alkyl);

[0062] Y is -N-,

[0063] R5 and R6 are each independently -H, -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-(C3-C7 cycloalkyl), -C(=O)-(C2-C6 heterocycloalkyl), -C(=O)-O(C1-C4 alkyl), -C(=O)-NR C R D , -S(=O)2-(C1-C4 alkyl), -heteroaryl or

[0064] wherein at least one -H of -(C1-C4 alkyl), -(C=O)-(C1-C4 alkyl) and -(C3-C7 cycloalkyl) may be substituted by -X or -OH; -(C2-C6 heterocycloalkyl) or -heteroaryl may contain N, O or S atoms in the ring; and Z is -CH2- or -O-;

[0065] R C and R D Each is independently -H or -(C1-C4 alkyl);

[0066] R 3 is -aryl, wherein at least one H of the -aryl may be independently substituted by -X; and

[0067] X may be F or Cl.

[0068] Furthermore, according to yet another embodiment of the present invention,

[0069] In the above chemical formula I,

[0070] L1 to L3 are each independently -(C0-C1 alkyl)-;

[0071] a, b and c are each independently N or CR 4 , where a, b and c cannot be N at the same time, and R 4 is -H or -X;

[0072] R1 is -CX2H or -CX3;

[0073] R2 is -(C1-C4 alkyl),

[0074] m and n are each independently an integer of 1 or 2;

[0075] R a To R d Each is independently -H or -(C1-C4 alkyl);

[0076] Y is -N-, -O- or -S(=O)2-;

[0077] When Y is -N-, R5, R6, R7 and R8 are each independently -H, -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-(C3-C7 cycloalkyl), -C(=O)-(C2-C6 heterocycloalkyl), -C(=O)-O(C1-C4 alkyl), -C(=O)-NR C R D , -S(=O)2-(C1-C4 alkyl), -heteroaryl or

[0078] wherein at least one -H of -(C1-C4 alkyl), -(C=O)-(C1-C4 alkyl) and -(C3-C7 cycloalkyl) may be substituted by -X or -OH; -(C2-C6 heterocycloalkyl) or -heteroaryl may contain N, O or S atoms in the ring; and Z is -NH-, -CH2- or -O-;

[0079] When Y is -O- or -S(=O)2-, R5, R6, R7 and R8 are absent (none);

[0080] R C and R D Each is independently -H or -(C1-C4 alkyl);

[0081] R 3is -aryl or -heteroaryl, wherein at least one H of the -aryl or -heteroaryl may be substituted with -X, respectively; and

[0082] X can be F, Cl or Br.

[0083] Furthermore, according to yet another embodiment of the present invention,

[0084] In the above chemical formula I,

[0085] L1 to L3 are each independently -(C0-C1 alkyl)-;

[0086] a, b and c are each independently N or CR 4 , where a, b and c cannot be N at the same time, and R 4 is -H or -X;

[0087] R1 is -CX2H or -CX3;

[0088] R2 is -NR A R B ,

[0089] m and n are each independently an integer of 1 or 2;

[0090] R a To R d Each is independently -H or -(C1-C4 alkyl);

[0091] Y is -N-, -O- or -S(=O)2-;

[0092] When Y is -N-, R5, R6, R7 and R8 are each independently -H, -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-(C3-C7 cycloalkyl), -C(=O)-(C2-C6 heterocycloalkyl), -C(=O)-O(C1-C4 alkyl), -C(=O)-NR C R D , -S(=O)2-(C1-C4 alkyl), -heteroaryl or

[0093] wherein at least one -H of -(C1-C4 alkyl), -(C=O)-(C1-C4 alkyl) and -(C3-C7 cycloalkyl) may be substituted by -X or -OH; -(C2-C6 heterocycloalkyl) or -heteroaryl may contain N, O or S atoms in the ring; and Z is -NH-, -CH2- or -O-;

[0094] When Y is -O- or -S(=O)2-, R5, R6, R7 and R8 are absent (none);

[0095] R A To R D Each is independently -H or -(C1-C4 alkyl);

[0096] R 3 is -aryl or -heteroaryl, wherein at least one H of -aryl and -heteroaryl may be substituted with -X, respectively, independently; and

[0097] X can be F, Cl or Br.

[0098] Specific compounds represented by Chemical Formula I of the present invention are shown in Table 1 below.

[0099] [Table 1]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107] According to one embodiment of the present invention, it may be a specific compound represented by Chemical Formula I of the present invention:

[0108] [Table 2]

[0109]

[0110]

[0111]

[0112]

[0113] According to one embodiment of the present invention, it may be a specific compound represented by Chemical Formula I of the present invention:

[0114] [Table 3]

[0115]

[0116]

[0117]

[0118]

[0119] In the present invention, pharmaceutically acceptable salts refer to salts commonly used in the pharmaceutical industry, such as inorganic ion salts prepared from calcium, potassium, sodium and magnesium, inorganic acid salts prepared from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid and sulfuric acid, etc.; organic acid salts prepared from acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc.; sulfonates prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid, etc.; amino acid salts prepared from glycine, arginine, lysine, etc.; and amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc., but the types of salts mentioned in the present invention are not limited to these salts listed above.

[0120] Preferred salts in the present invention include hydrochloride, phosphate, sulfate, trifluoroacetate, citrate, bromate, maleate or tartrate.

[0121] The compounds represented by chemical formula I of the present invention may contain one or more asymmetric carbons, thereby being able to exist as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. These isomers can be separated using conventional techniques, for example, by distribution (such as by column chromatography, HPLC, etc.) by the compounds represented by chemical formula I. Alternatively, the stereoisomers of each of the compounds represented by chemical formula I can be stereoselectively synthesized using optically pure starting materials and / or reagents with known arrangements.

[0122] Method for preparing 1,3,4-oxadiazole derivative compounds

[0123] The present invention provides a method for preparing a 1,3,4-oxadiazole derivative compound represented by Chemical Formula I, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

[0124] In the present invention, the preferred method for preparing the 1,3,4-oxadiazole derivative compound represented by Chemical Formula I, its optical isomer or a pharmaceutically acceptable salt thereof is the same as the following Reaction Schemes 1 and 2, which also includes preparation methods improved at a level obvious to those skilled in the art.

[0125] [Reaction Scheme 1]

[0126]

[0127] Reaction scheme 1 shows a method for synthesizing a compound having a sulfonamide structure, wherein compound 1-2 in which a protecting group is introduced into compound 1-1 is synthesized, and then reacted with hydrazine to synthesize hydrazide compound 1-3. A cyclization reaction with difluoroacetic anhydride is performed to synthesize compound 1-4, and then the protecting group is removed under acidic conditions to synthesize compound 1-5. Bicyclic compound 1-6 is synthesized by reacting with 1,3-dichloropropane-2-one, and reacted with a sulfonamide functional group to synthesize compound 1-8. Compound 1-9 from which a protecting group is removed under acidic conditions is synthesized, and the title compound 1-10 is synthesized by introducing various functional groups.

[0128] Compounds prepared by the above reaction scheme are compounds 3778, 3779, 4214, 4215, 4216, 4217, 4218, 4219, 4220, 4221, 4222, 4223, 4224, 4225, 4226, 4227, 4228, 4236, 4237, 4238, 4239, 4240, 4241, 4242, 4243, 4244, 4245, 4246, 4247, 4248, 4249, 4250, 4251, 4252, 4253, 4254, 4255, 4616, 4617, and 6893.

[0129] [Reaction Scheme 2]

[0130]

[0131] Reaction scheme 2 shows a method for synthesizing a compound having a sulfamide structure, wherein a compound 2-2 in which a leaving group is introduced into 1,1'-sulfonylbis(1-H-imidazole) is synthesized. The synthesized compound 2-2 is reacted with an amine compound to synthesize compound 2-3, and a leaving group is introduced again to synthesize compound 2-4. Compound 2-5 is synthesized by reacting with an amine compound, and is reacted with compound 1-6 synthesized in reaction scheme 1 to synthesize sulfonamide compound 2-6. Compound 2-7 from which a protecting group is removed under acidic conditions is synthesized, and the title compound 2-8 is synthesized by introducing various functional groups.

[0132] Compounds prepared by the above reaction scheme are compounds 4256, 4257, 4258, 4259, 4260, 4261, 4262, 4263, 4264, 4265, 4266, 4267, 4268, 4269, 4270, 4271, 4272, 4273, 4274, 4275, 4297, 4298, 4299, 4300, 4301, 4302, 4303, 4304, 4305, 4306, 4307, 4308, 4309, 4310, 4311, 4312, 4313, 4314, 4315, 4622, 4623, and 4624.

[0133] Compositions containing 1,3,4-oxadiazole derivative compounds, uses thereof, and methods of treatment using the same

[0134] The present invention provides a pharmaceutical composition for preventing or treating a disease mediated by histone deacetylase 6, wherein the pharmaceutical composition contains a compound represented by the following chemical formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient:

[0135] [Chemical Formula I]

[0136]

[0137] Formula I is the same as defined above.

[0138] The pharmaceutical composition of the present invention exhibits a significant effect in preventing or treating diseases mediated by histone deacetylase 6 by selectively inhibiting histone deacetylase 6.

[0139] Diseases mediated by histone deacetylase 6 include infectious diseases, such as prion diseases; neoplasms, such as benign tumors (e.g., myelodysplastic syndrome) or malignant tumors (e.g., multiple myeloma, lymphoma, leukemia, lung cancer, colorectal cancer, colon cancer, prostate cancer, urothelial cancer, breast cancer, melanoma, skin cancer, liver cancer, brain cancer, stomach cancer, ovarian cancer, pancreatic cancer, head and neck cancer, oral cancer, or glioma); endocrine, nutritional and metabolic diseases, such as Wilson's disease, amyloidosis, or diabetes; mental and behavioral disorders, such as depression or Rett syndrome; nervous system diseases, such as central nervous system atrophy (e.g., Huntington's disease, spinal muscular atrophy (SMA), spinocerebellar ataxia (SCA)), neurodegenerative diseases (e.g., Alzheimer's disease), movement disorders (e.g., Parkinson's disease), and leukemia. disease), neuropathy (e.g., hereditary neuropathy) (Charcot-Marie-Tooth disease), sporadic neuropathy, inflammatory neuropathy, drug-induced neuropathy), motor neuropathy (e.g., amyotrophic lateral sclerosis (ALS)) or central nervous system demyelination (e.g., multiple sclerosis (MS)); eye and appendage diseases, such as uveitis; circulatory system diseases, such as atrial fibrillation, stroke, etc.; respiratory system diseases, such as asthma; digestive system diseases, such as alcoholic liver disease, inflammatory bowel disease, Crohn's disease, ulcerative bowel disease, etc.; skin and subcutaneous tissue diseases, such as psoriasis; musculoskeletal and connective tissue diseases, such as rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus (SLE), etc.; or congenital malformations, changes and chromosomal abnormalities, such as autosomal dominant polycystic kidney disease, and also include symptoms or diseases associated with abnormal histone deacetylase function.

[0140] The pharmaceutically acceptable salts are the same as described above in terms of the pharmaceutically acceptable salts of the compounds represented by Chemical Formula I of the present invention.

[0141] In addition to the compound represented by chemical formula I, its optical isomer or its pharmaceutical salt, the pharmaceutical composition of the present invention can also include one or more pharmaceutical carriers for administration. Pharmaceutical carriers can be used by mixing saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components, and if necessary, other conventional additives such as antioxidants, buffers, antibacterial agents, etc. can also be added. In addition, injectable preparations such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules or tablets can be prepared by further adding diluents, dispersants, surfactants, adhesives and lubricants. Therefore, the composition of the present invention can be a patch, a liquid, a pill, a capsule, a granule, a tablet, a suppository, etc. These preparations can be prepared by the conventional methods used for preparations in the art or by the methods disclosed in Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton PA, and various preparations can be formulated according to corresponding diseases or ingredients.

[0142] The composition of the present invention can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage range varies depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate and disease severity, etc. The daily dose of the compound represented by Chemical Formula I of the present invention can be about 1 to 1000 mg / kg, preferably 5 to 100 mg / kg, and can be administered once a day or divided into several doses a day.

[0143] In addition to the above-mentioned compound represented by Chemical Formula I, its optical isomers or pharmaceutically acceptable salts thereof, the pharmaceutical composition of the present invention may further comprise one or more active ingredients exhibiting the same or similar pharmaceutical effects.

[0144] The present invention provides a method for preventing or treating a disease mediated by histone deacetylase 6, comprising administering a therapeutically effective amount of a compound represented by Chemical Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0145] The term "therapeutically effective amount" used in the present invention refers to an amount of the compound represented by Chemical Formula I that is effective for preventing or treating a disease mediated by histone deacetylase 6.

[0146] In addition, the present invention provides a method for selectively inhibiting HDAC6 by administering a compound represented by Chemical Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof to mammals including humans.

[0147] The method for preventing or treating a disease mediated by histone deacetylase 6 of the present invention also includes administering a compound represented by chemical formula I before the onset of symptoms to treat the disease itself, and to suppress or avoid its symptoms. In the management of the disease, the preventive or therapeutic dose of a specific active ingredient will vary according to the characteristics and severity of the disease or condition and the route of administration of the active ingredient. The dosage and frequency of administration will vary according to the age, weight and response of the individual patient. Taking these factors into account, it is natural that a suitable dosage regimen can be easily selected by a person of ordinary skill in the art. In addition, the method for preventing or treating a disease mediated by histone deacetylase 6 of the present invention can also include administering a therapeutically effective amount of another activating agent that can be used to treat the disease together with the compound represented by chemical formula I, wherein the other activating agent can show a synergistic or auxiliary effect together with the compound represented by chemical formula I.

[0148] The present invention also aims to provide the use of the compound represented by the above chemical formula I, its optical isomer or its pharmaceutically acceptable salt for preparing a drug for treating diseases mediated by histone deacetylase 6. The compound represented by the above chemical formula I for preparing the drug can be mixed with an acceptable adjuvant, diluent, carrier, etc., and can be prepared into a composite preparation together with other active agents to have a synergistic effect of the active ingredients.

[0149] Matters mentioned in the uses, compositions and methods of treatment of the present invention are equally applicable, as long as they are not inconsistent with each other.

[0150] Advantageous Effects of the Invention

[0151] The compound represented by the chemical formula I, its optical isomer or a pharmaceutically acceptable salt thereof can selectively inhibit histone deacetylase 6 (HDAC6), thereby having a significantly excellent preventive or therapeutic effect on HDAC6-mediated diseases. DETAILED DESCRIPTION

[0152] Hereinafter, the present invention will be described in more detail through embodiments and experimental examples. However, they are merely examples of the present invention, and the scope of the present invention is not limited thereto.

[0153] Preparation of 1,3,4-oxadiazole derivative compounds of the present invention

[0154] A specific method for preparing the compound represented by Chemical Formula I is shown below.

[0155] Example 1: Synthesis of Compound 3778, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-methyl-N-phenylpiperidine-4-sulfonamide

[0156] [Step 1] Synthesis of 2-((tert-butoxycarbonyl)amino)isonicotinic acid methyl ester

[0157]

[0158] At room temperature, 2-aminoisonicotinate (20.000 g, 131.449 mmol) and di-tert-butyl dicarbonate (37.295 g, 170.884 mmol) were dissolved in tert-butyl alcohol (800 mL). The resulting solution was stirred at 60 ° C for 16 hours, and then the temperature was lowered to room temperature to terminate the reaction. The precipitated solid was filtered, washed with ethanol, and dried to obtain the title compound (26.000 g, 78.4%) as a white solid.

[0159] [Step 2] Synthesis of tert-butyl (4-(hydrazinecarbonyl)pyridin-2-yl)carbamate

[0160]

[0161] The 2-((tert-butoxycarbonyl)amino)isonicotinic acid methyl ester (26.000 g, 103.064 mmol) prepared in step 1 and hydrazine monohydrate (100.182 mL, 2.061 mol) were dissolved in methanol (800 mL) at room temperature. The resulting solution was stirred at the same temperature for 16 hours. Methanol (500 mL) was added to the obtained product, followed by filtration through a plastic filter to obtain an organic layer, and the organic layer was concentrated to obtain the title compound (25.000 g, 96.2%) as a white solid.

[0162] [Step 3] Synthesis of tert-butyl (4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)carbamate ester

[0163]

[0164] The tert-butyl (4-(hydrazinecarbonyl)pyridin-2-yl)carbamate (20.000g, 79.280mmol) and triethylamine (55.250mL, 396.401mmol) prepared in step 2 were dissolved in tetrahydrofuran (600mL), and 2,2-difluoroacetic anhydride (49.281mL, 396.401mmol) was added at room temperature and heated to reflux for 16 hours, and then the temperature was reduced to room temperature to terminate the reaction. Saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Ethyl acetate (40mL) and hexane (200mL) were poured into the concentrate, suspended, and filtered to obtain a solid, and the obtained solid was washed with hexane and dried to obtain the title compound (11.500g, 46.5%) as a white solid.

[0165] [Step 4] Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine

[0166]

[0167] The tert-butyl (4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)carbamate (11.500g, 36.826mmol) prepared in step 3 was dissolved in dichloromethane (300mL), and trifluoroacetic acid (28.199mL, 368.259mmol) was added at 0°C. The resulting solution was stirred at room temperature for 4 hours. After removing the solvent from the reaction mixture under reduced pressure, saturated sodium bicarbonate aqueous solution (150mL) was poured into the concentrate and suspended, then filtered to obtain a solid. The obtained solid was washed with water and dried to obtain the title compound (7.500g, 96.0%) as a white solid.

[0168] [Step 5] Synthesis of 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazol-1-yl Oxadiazole

[0169]

[0170] 4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-amine (7.500 g, 35.351 mmol), 1,3-dichloropropane-2-one (6.732 g, 53.026 mmol) and sodium bicarbonate (14.848 g, 176.753 mmol) prepared in step 4 were dissolved in 1,4-dioxane (250 mL) at room temperature. The resulting solution was heated to reflux for 16 hours, and then the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a plastic filter to remove solids, and the filtrate was purified and concentrated by column chromatography (SiO2, 80 g column; ethyl acetate / hexane=10% to 90%) to obtain the title compound (7.000 g, 69.6%) as a beige solid.

[0171] [Step 6] Synthesis of 4-(N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyrrolidone tert-Butyl (2-pyridin-2-yl)methyl)-N-phenylsulfamoyl)piperidine-1-carboxylate

[0172]

[0173] At room temperature, tert-butyl 4-(N-phenylsulfamoyl)piperidine-1-carboxylate (0.050 g, 0.147 mmol), 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.040 g, 0.140 mmol), potassium carbonate (0.041 g, 0.294 mmol) and potassium iodide (0.002 g, 0.015 mmol) were dissolved in N,N-dimethylformamide (3 mL), and the resulting solution was stirred at the same temperature for 16 hours. Water (5 mL) was added to the reaction mixture and stirred to precipitate a solid. The precipitated solid was filtered, washed with water, and dried to obtain the title compound (0.055 g, 63.6%) as a beige solid.

[0174] [Step 7] Synthesis of N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-sulfonamide

[0175]

[0176] Tert-butyl 4-(N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylsulfamoyl)piperidine-1-carboxylate (0.100 g, 0.170 mmol) and trifluoroacetic acid (0.260 mL, 3.398 mmol) prepared in step 6 were dissolved in dichloromethane (3 mL) at room temperature, and the resulting solution was stirred for 3 hours at the same temperature. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution, dried over anhydrous magnesium sulfate, and filtered. After concentration under reduced pressure, the title compound (0.083 g, 100.0%) was obtained as a brown gel without further purification.

[0177] [Step 8] Synthesis of compound 3778

[0178]

[0179] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-sulfonamide (0.040 g, 0.082 mmol), formaldehyde (0.005 g, 0.164 mmol), acetic acid (0.005 mL, 0.082 mmol) and sodium triacetoxyborohydride (0.052 g, 0.246 mmol) prepared in step 7 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; dichloromethane / methanol = 0% to 10%) and concentrated to afford the title compound (0.016 g, 38.9%) as a white solid.

[0180] 1 H NMR (400MHz, CDCl3) δ8.26(s,1H),8.24-8.19(m,1H),7.80(s,1H),7.55-7.50(m,1H),7.47(d,J=7.8Hz,2H),7.35(d,J=9.2Hz,2H ),7.30(d,J=5.1Hz,1H),7.10-6.78(m,1H),5.16(d,J=3.0Hz,2H),3.00(d,J=10.2Hz,3H),2.31(s,3H),2.14(s,2H),2.01(s,4H);

[0181] LRMS (ES) m / z 503.2 (M + +1).

[0182] Example 2: Synthesis of Compound 3779, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(oxetane-3-yl)-N-phenylpiperidine-4-sulfonamide

[0183]

[0184] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-sulfonamide (0.040 g, 0.082 mmol), oxetane-3-one (0.012 g, 0.164 mmol), acetic acid (0.005 mL, 0.082 mmol) and sodium triacetoxyborohydride (0.052 g, 0.246 mmol) prepared in step 7 of Example 1 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 plate, 20×20×1 mm; dichloromethane / methanol=0% to 10%) and concentrated to afford the title compound (0.024 g, 53.8%) as a white solid.

[0185] 1 H NMR (400MHz, CDCl3) δ8.27(s,1H),8.22(d,J=6.9Hz,1H),7.79(s,1H),7.53(d,J=7.2Hz,1H),7.46(d,J=7.8Hz,2H),7.37(t,J=7.9Hz,2H),7.30(s,1H ),6.95(td,J=52.7,51.7,2.5Hz,1H),5.16(s,2H),4.70-4.55(m,4H),3.5 0(s,1H),3.09(s,1H),2.89(s,2H),2.16(s,2H),2.03(s,2H),1.85(s,2H);

[0186] LRMS (ES) m / z 545.3 (M + +1).

[0187] Example 3: Synthesis of Compound 4214, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-ethyl-N-phenylpiperidine-4-sulfonamide

[0188]

[0189] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-sulfonamide (0.050 g, 0.102 mmol), acetaldehyde (0.009 g, 0.205 mmol) and sodium triacetoxyborohydride (0.065 g, 0.307 mmol) prepared in step 7 of Example 1 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane=0% to 3%) and concentrated to obtain the title compound (0.014 g, 26.5%) as an ivory solid.

[0190] 1 H NMR (400MHz, CDCl3) δ8.25(s,1H),8.22(dd,1H,J=7.1,0.8Hz),7.80(s,1H),7.52(dd,1H,J=7.1,1.7Hz),7.49-7.45(m,2H),7.38-7.34 (m,2H),7.30-7.26(m,1H),6.95(t,1H,J=51.7Hz),5.17(s,2H),3.06-2.96(m,3H),2.29(s,3H),2.15-2.08(m,2H),2.05-1.89(m,4H);

[0191] LRMS (ES) m / z 517.4 (M + +1).

[0192] Example 4: Synthesis of Compound 4215, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-isopropyl-N-phenylpiperidine-4-sulfonamide

[0193]

[0194] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-sulfonamide (0.050 g, 0.102 mmol), propan-2-one (0.012 g, 0.205 mmol) and sodium triacetoxyborohydride (0.065 g, 0.307 mmol) prepared in step 7 of Example 1 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0% to 3%) and concentrated to afford the title compound (0.011 g, 20.3%) as an ivory solid.

[0195] 1 H NMR (400MHz, CDCl3) δ8.26 (s, 1H), 8.22 (dd, 1H, J = 7.1, 0.8Hz), 7.81 (s, 1H) ,7.52(dd,1H,J=7.1,1.7Hz),7.49-7.45(m,2H),7.38-7.34(m,2H),7.30-7 .26(m,1H),6.95(t,1H,J=51.7Hz),5.17(s,2H),3.09-2.99(m,3H),2.45-2 .39(m,1H),2.15-2.04(m,3H),2.04-1.88(m,3H),1.05(s,3H),1.03(s,3H);

[0196] LRMS (ES) m / z 531.4 (M + +1).

[0197] Example 5: Synthesis of Compound 4216, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(1-hydroxypropan-2-yl)-N-phenylpiperidine-4-sulfonamide

[0198]

[0199] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-sulfonamide (0.050 g, 0.102 mmol), 1-hydroxypropan-2-one (0.015 g, 0.205 mmol) and sodium triacetoxyborohydride (0.065 g, 0.307 mmol) prepared in step 7 of Example 1 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0% to 3%) and concentrated to afford the title compound (0.009 g, 16.1%) as an ivory solid.

[0200] 1 H NMR (400MHz, CDCl3) δ8.26 (s, 1H), 8.22 (dd, 1H, J = 7.1, 0.8Hz), 7.78 (s, 1H), 7.53 (dd, 1H, J=7.1,1.7Hz),7.48-7.44(m,2H),7.38-7.34(m,2H),7.30-7.26(m,1H),6.95(t,1H,J=51. 7Hz), 5.16 (s, 2H), 3.43-3.39 (m, 1H), 3.33 (t, 1H, J = 10.4Hz), 3.12-3.04 (m, 1H), 2.84-2. 30(m,3H),2.58-2.52(m,1H),2.20-2.15(m,2H),2.11-1.83(m,4H),0.89(d,3H,J=6.7Hz);

[0201] LRMS(ES)m / z 547.0(M + +1).

[0202] Example 6: Synthesis of Compound 4217, 1-cyclobutyl-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-sulfonamide

[0203]

[0204] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-sulfonamide (0.050 g, 0.102 mmol), cyclobutanone (0.014 g, 0.205 mmol) and sodium triacetoxyborohydride (0.065 g, 0.307 mmol) prepared in step 7 of Example 1 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane=0% to 3%) and concentrated to obtain the title compound (0.015 g, 27.0%) as an ivory solid.

[0205] 1 H NMR (400MHz, CDCl3) δ8.25(s,1H),8.21(dd,1H,J=7.1,0.9Hz),7.80(s,1H),7.52(dd,1H,J=7.1,1.7Hz),7.48-7.44(m,2H),7.38-7.33(m,2H),7.3 0-7.26(m,1H),6.95(t,1H,J=51.7Hz),5.16(s,2H),3.08-2.98(m,3H),2. 74-2.66(m,1H),2.15-2.11(m,2H),2.06-1.83(m,8H),1.74-1.53(m,2H);

[0206] LRMS (ES) m / z 543.4 (M + +1).

[0207] Example 7: Synthesis of Compound 4218, 1-cyclohexyl-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-sulfonamide

[0208]

[0209] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-sulfonamide (0.050 g, 0.102 mmol), cyclohexanone (0.020 g, 0.205 mmol) and sodium triacetoxyborohydride (0.065 g, 0.307 mmol) prepared in step 7 of Example 1 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane=0% to 3%) and concentrated to obtain the title compound (0.014 g, 24.0%) as an ivory solid.

[0210] 1 H NMR (400MHz, CDCl3) δ8.25 (s, 1H), 8.21 (dd, 1H, J = 7.1, 0.8Hz), 7.81 (s, 1H), 7.5 2(dd,1H,J=7.1,1.7Hz),7.48-7.46(m,2H),7.38-7.34(m,2H),7.30-7.26(m,1H ),6.95(t,1H,J=51.7Hz),5.17(s,2H),3.05-3.02(m,3H),2.32(m,1H),2.23-2. 10(m,4H),1.99-1.91(m,2H),1.81(m,3H),1.66-1.62(m,1H),1.29-1.07(m,6H);

[0211] LRMS (ES) m / z 571.4 (M + +1).

[0212] Example 8: Synthesis of Compound 4219, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenyl-1-(tetrahydro-2H-pyran-4-yl)piperidine-4-sulfonamide

[0213]

[0214] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-sulfonamide (0.050 g, 0.102 mmol), tetrahydro-4H-pyran-4-one (0.020 g, 0.205 mmol) and sodium triacetoxyborohydride (0.065 g, 0.307 mmol) prepared in step 7 of Example 1 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0% to 3%) and concentrated to afford the title compound (0.012 g, 20.5%) as an ivory solid.

[0215] 1 H NMR (400MHz, CDCl3) δ8.26 (s, 1H), 8.21 (dd, 1H, J = 7.1, 0.8Hz), 7.80 (s, 1H), 7.52 (dd, 1 H,J=7.1,1.7Hz),7.48-7.45(m,2H),7.38-7.34(m,2H),7.30-7.25(m,1H),6.95(t,1H,J =51.7Hz),5.17(s,2H),4.04-3.99(m,2H),3.41-3.34(m,2H),3.09-3.02(m,3H),2.53-2 .48(m,1H),2.19-2.13(m,4H),2.01-1.92(m,2H),1.72-1.69(m,2H),1.63-1.54(m,2H);

[0216] LRMS (ES) m / z 573.4 (M + +1).

[0217] Example 9: Synthesis of Compound 4220, 1-(4,4-difluorocyclohexyl)-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-sulfonamide

[0218]

[0219] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-sulfonamide (0.050 g, 0.102 mmol), 4,4-difluorocyclohexan-1-one (0.027 g, 0.205 mmol) and sodium triacetoxyborohydride (0.065 g, 0.307 mmol) prepared in step 7 of Example 1 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0% to 3%) and concentrated to afford the title compound (0.009 g, 14.5%) as an ivory solid.

[0220] 1 H NMR (400MHz, CDCl3) δ8.24 (s, 1H), 8.21 (dd, 1H, J = 7.1, 0.9Hz), 7.78 (s, 1H), 7 .50(dd,1H,J=7.1,1.7Hz),7.47-7.43(m,2H),7.37-7.32(m,2H),7.29-7.24(m ,1H),6.95(t,1H,J=51.7Hz),5.15(s,2H),3.07-2.96(m,3H),2.46-2.41(m,1H ),2.21-2.08(m,6H),1.98-1.88(m,2H),1.80-1.73(m,3H),1.69-1.60(m,3H);

[0221] LRMS (ES) m / z 607.1 (M + +1).

[0222] Example 10: Synthesis of Compound 4221, 1-acetyl-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-sulfonamide

[0223]

[0224] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-sulfonamide (0.050 g, 0.102 mmol), acetyl chloride (0.015 mL, 0.205 mmol) and triethylamine (0.043 mL, 0.307 mmol) prepared in step 7 of Example 1 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane=70% to 100%) and concentrated to obtain the title compound (0.014 g, 25.8%) as an ivory solid.

[0225] 1 H NMR (400MHz, CDCl3) δ8.26 (t, 1H, J = 0.8Hz), 8.22 (dd, 1H, J = 7.1, 0.9Hz), 7.73 (s, 1H), 7.53 (d d,1H,J=7.1,1.7Hz),7.46-7.42(m,2H),7.38-7.34(m,2H),7.34-7.27(m,1H),6.95(t,1H,J=5 1.7Hz),5.13(s,2H),4.72(d,1H,J=13.5Hz),3.95(d,1H,J=13.8Hz),3.67-3.29(m,1H),3.11- 3.03(m,1H),2.58(td,1H,J=12.8,2.5Hz),2.27-2.16(m,2H),2.11(s,3H),1.94-1.76(m,2H);

[0226] LRMS (ES) m / z 531.3 (M + +1).

[0227] Example 11: Synthesis of Compound 4222, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenyl-1-propionylpiperidine-4-sulfonamide

[0228]

[0229] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-sulfonamide (0.050 g, 0.102 mmol), propionyl chloride (0.019 g, 0.205 mmol) and triethylamine (0.043 mL, 0.307 mmol) prepared in step 7 of Example 1 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane=70% to 100%) and concentrated to obtain the title compound (0.013 g, 23.3%) as an ivory solid.

[0230] 1 H NMR (400MHz, CDCl3) δ8.26(s,1H),8.22(dd,1H,J=7.1,0.9Hz),7.73(s,1H),7.53(dd,1H,J=7.1,1.7 Hz),7.46-7.42(m,2H),7.38-7.34(m,2H),7.32-7.27(m,1H),6.95(t,1H,J=51.7Hz),5.13(s,2H),4 .75(d,1H,J=13.4Hz),4.00(d,1H,J=13.5Hz),3.68-3.29(m,1H),3.03(t,1H,J=12.1Hz),2.58(t,1H ,J=11.9Hz),2.36(q,2H,J=7.4Hz),2.20(t,2H,J=15.4Hz),1.90-1.76(m,2H),1.15(t,3H,J=7.4Hz);

[0231] LRMS (ES) m / z 545.4 (M + +1).

[0232] Example 12: Synthesis of Compound 4223, 1-(cyclobutanecarbonyl)-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-sulfonamide

[0233]

[0234] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-sulfonamide (0.050 g, 0.102 mmol), cyclobutanecarbonyl chloride (0.024 g, 0.205 mmol) and triethylamine (0.043 mL, 0.307 mmol) prepared in step 7 of Example 1 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane=70% to 100%) and concentrated to obtain the title compound (0.010 g, 17.1%) as an ivory solid.

[0235] 1 H NMR (400MHz, CDCl3) δ8.27 (t, 1H, J = 0.8Hz), 8.22 (dd, 1H, J = 7.1, 0.9Hz), 7.74 (s, 1H), 7.54 (dd ,1H,J=7.1,1.7Hz),7.46-7.42(m,2H),7.38-7.34(m,2H),7.32-7.27(m,1H),6.95(t,1H,J=51. 7Hz),5.13(s,2H),4.78-4.76(m,1H),3.84(d,1H,J=13.6Hz),3.50(s,1H),3.33-3.24(m,2H), 3.23-2.90(m,1H),2.61-2.54(m,1H),2.40-2.33(m,2H),2.19-2.12(m,4H),2.06-1.74(m,3H);

[0236] LRMS(ES)m / z 571.0(M + +1).

[0237] Example 13: Synthesis of Compound 4224, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenyl-1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide

[0238]

[0239] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-sulfonamide (0.050 g, 0.102 mmol), 2,2,2-trifluoroacetic anhydride (0.043 g, 0.205 mmol) and triethylamine (0.043 mL, 0.307 mmol) prepared in step 7 of Example 1 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 70% to 100%) and concentrated to obtain the title compound (0.012 g, 20.1%) as an ivory solid.

[0240] 1 H NMR (400MHz, CDCl3) δ8.28 (s, 1H), 8.22 (dd, 1H, J = 7.1, 0.9Hz), 7.70 (s, 1H), 7.55 (d d,1H,J=7.1,1.7Hz),7.45-7.41(m,2H),7.39-7.34(m,2H),7.33-7.29(m,1H),6.95( t,1H,J=51.7Hz),5.12(s,2H),4.60(d,1H,J=13.6Hz),4.16-4.12(m,1H),3.48-3.40 (m,1H),3.23-3.16(m,1H),2.93-2.86(m,1H),2.33-2.27(m,2H),2.21-1.91(m,2H);

[0241] LRMS (ES) m / z 585.1 (M + +1).

[0242] Example 14: Synthesis of Compound 4225, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(methylsulfonyl)-N-phenylpiperidine-4-sulfonamide

[0243]

[0244] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-sulfonamide (0.050 g, 0.102 mmol), methanesulfonyl chloride (0.016 mL, 0.205 mmol) and triethylamine (0.043 mL, 0.307 mmol) prepared in step 7 of Example 1 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane=70% to 100%) and concentrated to obtain the title compound (0.012 g, 20.7%) as an ivory solid.

[0245] 1 H NMR (400MHz, CDCl3) δ8.28 (s, 1H), 8.23 ​​(dd, 1H, J = 7.1, 0.9Hz), 7.73 (s, 1H), 7.55(dd,1H,J=7.1,1.7Hz),7.45-7.42(m,2H),7.39-7.34(m,2H),7.33-7.2 8(m,1H),6.95(t,1H,J=51.7Hz),5.13(s,2H),3.90(dt,2H,J=12.6,3.5Hz), 3.28-3.20(m,1H),2.86-2.76(m,5H),2.30-2.25(m,2H),2.21-2.00(m,2H);

[0246] LRMS(ES)m / z 567.0(M + +1).

[0247] Example 15: Synthesis of Compound 4226, 4-(N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylsulfamoyl)piperidine-1-carboxylic acid methyl ester

[0248]

[0249] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-sulfonamide (0.050 g, 0.102 mmol), methyl chloroformate (0.019 g, 0.205 mmol) and triethylamine (0.043 mL, 0.307 mmol) prepared in step 7 of Example 1 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane=70% to 100%) and concentrated to obtain the title compound (0.015 g, 26.8%) as an ivory solid.

[0250] 1 H NMR (400MHz, CDCl3) δ8.27(s,1H),8.22(dd,1H,J=7.2,0.9Hz),7.75(s,1H),7.54(dd,1H,J=7.1,1.7Hz),7.46-7.43(m,2H),7.39-7.34(m,2H),7.32 -7.28(m,1H),6.95(t,1H,J=51.7Hz),5.14(s,2H),4.28(s,2H),3.72(s,3 H),3.28-3.22(m,1H),2.78(m,2H),2.18-2.14(m,2H),1.91-1.80(m,2H);

[0251] LRMS (ES) m / z 547.1 (M + +1).

[0252] Example 16: Synthesis of Compound 4227, 4-(N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylsulfamoyl)-N,N-dimethylpiperidine-1-carboxamide

[0253]

[0254] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-sulfonamide (0.050 g, 0.102 mmol), dimethylcarbamoyl chloride (0.022 g, 0.205 mmol) and triethylamine (0.043 mL, 0.307 mmol) prepared in step 7 of Example 1 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane=70% to 100%) and concentrated to obtain the title compound (0.013 g, 22.7%) as an ivory solid.

[0255] 1 H NMR (400MHz, CDCl3) δ8.27 (s, 1H), 8.22 (dd, 1H, J = 7.1, 0.9Hz), 7.76 (s, 1H), 7. 54(dd,1H,J=7.1,1.7Hz),7.47-7.44(m,2H),7.39-7.34(m,2H),7.32-7.27(m,1 H),6.95(t,1H,J=51.7Hz),5.15(s,2H),3.78(d,2H,J=13.3Hz),3.27-3.19(m,1 H),2.84-2.80(m,6H),2.76-2.67(m,2H),2.18-2.15(m,2H),1.98-1.87(m,2H);

[0256] LRMS (ES) m / z 560.1 (M + +1).

[0257] Example 17: Synthesis of Compound 4228, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenyl-1-(pyrimidin-2-yl)piperidine-4-sulfonamide

[0258]

[0259] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-sulfonamide (0.050 g, 0.102 mmol), 2-chloropyrimidine (0.023 g, 0.205 mmol) and potassium carbonate (0.042 g, 0.307 mmol) prepared in step 7 of Example 1 were dissolved in acetonitrile (1 mL) / N,N-dimethylformamide (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 70% to 100%) and concentrated to obtain the title compound (0.014 g, 24.1%) as an ivory solid.

[0260] 1 H NMR (400MHz, CDCl3) δ8.33 (d, 2H, J = 4.8Hz), 8.26 (s, 1H), 8.22 (dd, 1H, J = 7.1, 0.9Hz), 7. 77(s,1H),7.54(dd,1H,J=7.1,1.7Hz),7.48-7.45(m,2H),7.39-7.35(m,2H),7.31-7.29( m,1H),6.95(t,1H,J=51.7Hz),6.53(t,1H,J=4.7Hz),5.17(s,2H),4.94(d,2H,J=13.5Hz ),3.41-3.34(m,1H),2.89(td,2H,J=12.9,4.3Hz),2.24-2.21(m,2H),1.97-1.86(m,2H);

[0261] LRMS (ES) m / z 566.8 (M + +1).

[0262] Example 18: Synthesis of Compound 4236, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-1-methylpiperidine-4-sulfonamide

[0263] [Step 1] Synthesis of tert-butyl 4-(N-(3-fluorophenyl)sulfamoyl)piperidine-1-carboxylate

[0264]

[0265] At room temperature, tert-butyl 4-(chlorosulfonyl)piperidine-1-formate (5.000g, 17.620mmol), 3-fluoroaniline (2.937g, 26.430mmol) and triethylamine (2.947mL, 21.144mmol) were dissolved in dichloromethane (50mL), and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 40g column; ethyl acetate / hexane=0% to 30%) to obtain the title compound (3.200g, 50.7%) as a white solid.

[0266] [Step 2] Synthesis of 4-(N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyrrolidone tert-Butyl (2-piperidin-2-yl)methyl)-N-(3-fluorophenyl)sulfamoyl)piperidine-1-carboxylate

[0267]

[0268] Tert-butyl 4-(N-(3-fluorophenyl)sulfamoyl)piperidine-1-carboxylate (2.680 g, 7.477 mmol) prepared in step 1, 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (2.554 g, 8.972 mmol) prepared in step 5 of Example 1, potassium carbonate (1.550 g, 11.216 mmol) and potassium iodide (0.621 g, 3.739 mmol) were dissolved in N,N-dimethylformamide (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. Saturated aqueous ammonium chloride solution was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 40 g column; ethyl acetate / hexane = 0% to 90%) and concentrated to obtain the title compound (3.600 g, 79.4%) as a yellow solid.

[0269] [Step 3] Synthesis of N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide

[0270]

[0271] 4-(N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)sulfamoyl)piperidine-1-carboxylic acid tert-butyl ester (1.200 g, 1.978 mmol) and trifluoroacetic acid (3.030 mL, 39.563 mmol) prepared in step 2 were dissolved in dichloromethane (18 mL) at 0 ° C, and the resulting solution was stirred at room temperature for 4 hours. Saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and then filtered through a plastic filter to remove the solid residue and water layer. After concentration under reduced pressure, the title compound (0.990 g, 100.1%) was obtained as a yellow solid without further purification.

[0272] [Step 4] Synthesis of compound 4236

[0273]

[0274] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide (0.050 g, 0.099 mmol), formaldehyde (0.006 g, 0.197 mmol), acetic acid (0.006 mL, 0.099 mmol), sodium triacetoxyborohydride (0.063 g, 0.296 mmol) and triethylamine (0.014 mL, 0.099 mmol) prepared in step 3 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Aqueous sodium bicarbonate solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. To the concentrate was added dichloromethane (3 mL), followed by stirring, and the precipitated solid was filtered, washed with dichloromethane, and dried to obtain the title compound (0.028 g, 54.1%) as a white solid.

[0275] 1 H NMR (400MHz, CDCl3) δ8.27(p,J=0.7Hz,1H),8.23(dd,J=1.0,7.1Hz,1H),7.78(s,1H),7.54(dd,J=1.7,7.1Hz,1H),7.36- 7.23(m,3H),7.10-6.80(m,2H),5.15(s,2H),3.09-2.90(m,3H),2.28(s,3H),2.10(d,J=11.3Hz,2H),2.03-1.86(m,4H);

[0276] LRMS (ES) m / z 521.2 (M + +1).

[0277] Example 19: Synthesis of Compound 4237, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-ethyl-N-(3-fluorophenyl)-piperidine-4-sulfonamide

[0278]

[0279] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide (0.050 g, 0.099 mmol), acetaldehyde (0.009 g, 0.197 mmol), acetic acid (0.006 mL, 0.099 mmol), sodium triacetoxyborohydride (0.063 g, 0.296 mmol) and triethylamine (0.014 mL, 0.099 mmol) prepared in step 3 of Example 18 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 10%) and concentrated to afford the title compound (0.027 g, 51.9%) as a yellow solid.

[0280] 1 H NMR (400MHz, CDCl3) δ8.27(s,1H),8.22(d,J=7.1Hz,1H),7.78(s,1H),7.53(dd,J=1.7,7.1Hz,1H),7.34-7.24(m,3H),7.09-6.80(m,2H ),5.15(s,2H),3.12-2.99(m,3H),2.42(q,J=7.2Hz,2H),2.11(d,J=11.7Hz,2H),2.05-1.85(m,4H),1.08(t,J=7.2Hz,3H); LRMS(ES)m / z 535.1(M + +1).

[0281] Example 20: Synthesis of Compound 4238, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-1-isopropylpiperidine-4-sulfonamide

[0282]

[0283] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide (0.050 g, 0.099 mmol), propan-2-one (0.011 g, 0.197 mmol), acetic acid (0.006 mL, 0.099 mmol), sodium triacetoxyborohydride (0.063 g, 0.296 mmol) and triethylamine (0.014 mL, 0.099 mmol) prepared in step 3 of Example 18 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 10%) and concentrated to afford the title compound (0.018 g, 33.2%) as a white solid.

[0284] 1 H NMR (400MHz, CDCl3) δ8.27(s,1H),8.23(d,J=7.1Hz,1H),7.79(s,1H),7.53(dd,J=1.8,7.1Hz,1H),7.36-7.24(m,3H),7.09-6.81 (m,2H),5.15(s,2H),3.01(d,J=11.4Hz,3H),2.85-2.72(m,1H),2.12(d,J=13.4Hz,4H),2.02-1.87(m,2H),1.04(d,J=6.6Hz,6H);

[0285] LRMS (ES) m / z 549.4 (M + +1).

[0286] Example 21: Synthesis of Compound 4239, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-1-(1-hydroxypropan-2-yl)piperidine-4-sulfonamide

[0287]

[0288] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide (0.050 g, 0.099 mmol), 1-hydroxypropan-2-one (0.015 g, 0.197 mmol), acetic acid (0.006 mL, 0.099 mmol), sodium triacetoxyborohydride (0.063 g, 0.296 mmol) and triethylamine (0.014 mL, 0.099 mmol) prepared in step 3 of Example 18 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 10%) and concentrated to afford the title compound (0.019 g, 33.7%) as a yellow solid.

[0289] 1 H NMR(400MHz, CDCl3)δ8.28(s,1H),8.23(dd,J=7.1,1.0Hz,1H),7.77(s,1H),7.54( dd,J=7.1,1.7Hz,1H),7.37-7.22(m,3H),7.11-6.80(m,2H),5.15(s,2H),3.42(dd ,J=10.8,5.0Hz,1H),3.33(t,J=10.4Hz,1H),3.09(tt,J=11.9,3.8Hz,1H),2.96-2 .80(m,3H),2.55(td,J=11.6,2.4Hz,1H),2.21-1.81(m,5H),0.89(d,J=6.7Hz,3H);

[0290] LRMS (ES) m / z 565.4 (M + +1).

[0291] Example 22: Synthesis of Compound 4240, 1-cyclobutyl-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide

[0292]

[0293] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide (0.050 g, 0.099 mmol), cyclobutanone (0.014 g, 0.197 mmol), acetic acid (0.006 mL, 0.099 mmol), sodium triacetoxyborohydride (0.063 g, 0.296 mmol) and triethylamine (0.014 mL, 0.099 mmol) prepared in step 3 of Example 18 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 10%) and concentrated to afford the title compound (0.023 g, 41.9%) as a white solid.

[0294] 1 H NMR (400MHz, CDCl3) δ8.27(d,J=1.5Hz,1H),8.22(d,J=7.1Hz,1H),7.78(s,1H),7.53(dd,J=1.7,7.1Hz,1H),7.36-7.23(m,3H),7 .10-6.80(m,2H),5.14(s,2H),3.03(ddt,J=3.6,12.1,26.5Hz,3H),2.70(p,J=7.8Hz,1H),2.15-1.82(m,8H),1.79-1.59(m,4H);

[0295] LRMS (ES) m / z 561.1 (M + +1).

[0296] Example 23: Synthesis of Compound 4241, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-1-oxetane-3-yl)piperidine-4-sulfonamide

[0297]

[0298] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide (0.050 g, 0.099 mmol), oxetan-3-one (0.014 g, 0.197 mmol), acetic acid (0.006 mL, 0.099 mmol), sodium triacetoxyborohydride (0.063 g, 0.296 mmol) and triethylamine (0.014 mL, 0.099 mmol) prepared in step 3 of Example 18 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 10%) and concentrated to afford the title compound (0.027 g, 48.8%) as a white solid.

[0299] 1 H NMR (400MHz, CDCl3) δ8.27 (dt, J=0.8, 1.7Hz, 1H), 8.23 ​​(dd, J=1.0, 7.2Hz, 1H), 7.76 (s, 1H),7.53(dd,J=1.7,7.1Hz,1H),7.36-7.23(m,3H),7.10-6.81(m,2H),5.14(s,2H),4. 62(dt,J=6.4,21.5Hz,4H),3.53-3.43(m,1H),3.09(tt,J=3.9,11.7Hz,1H),2.87(dt,J =3.4,11.8Hz,2H),2.17-2.09(m,2H),1.99(qd,J=3.8,12.1Hz,2H),1.88-1.78(m,2H);

[0300] LRMS (ES) m / z 563.1 (M + +1).

[0301] Example 24: Synthesis of Compound 4242, 1-cyclohexyl-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide

[0302]

[0303] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-sulfonamide (0.050 g, 0.099 mmol), cyclohexanone (0.019 g, 0.197 mmol), acetic acid (0.006 mL, 0.099 mmol), sodium triacetoxyborohydride (0.063 g, 0.296 mmol) and triethylamine (0.014 mL, 0.099 mmol) prepared in step 3 of Example 18 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 10%) and concentrated to afford the title compound (0.030 g, 51.6%) as a white solid.

[0304] 1 H NMR (400MHz, CDCl3) δ8.29-8.25(m,1H),8.22(dd,J=1.0,7.1Hz,1H),7.78(s,1H),7.53(dd,J=1.7,7.1Hz,1H),7.35-7.23(m,3H),7.11-6.7 9(m,2H),5.15(s,2H),3.05(dq,J=4.0,11.9Hz,3H),2.40-1.87(m,7H),1.80(dd,J=5.6,10.2Hz,4H),1.68-1.59(m,1H),1.33-1.15(m,5H);

[0305] LRMS (ES) m / z 589.2 (M + +1).

[0306] Example 25: Synthesis of Compound 4243, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-1-(tetrahydro-2H-pyran-4-yl)piperidine-4-sulfonamide

[0307]

[0308] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide (0.050 g, 0.099 mmol), tetrahydro-4H-pyran-4-one (0.020 g, 0.197 mmol), acetic acid (0.006 mL, 0.099 mmol), sodium triacetoxyborohydride (0.063 g, 0.296 mmol) and triethylamine (0.014 mL, 0.099 mmol) prepared in step 3 of Example 18 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 10%) and concentrated to give the title compound (0.023 g, 40.1%) as a yellow gel.

[0309] 1 H NMR (400MHz, CDCl3) δ8.29-8.26 (m, 1H), 8.23 ​​(dd, J = 1.0, 7.1Hz, 1H), 7.77 (s, 1H), 7 .53(dd,J=1.7,7.1Hz,1H),7.37-7.23(m,3H),7.09-6.80(m,2H),5.15(s,2H),4.06- 3.97(m,2H),3.37(td,J=2.0,11.8Hz,2H),3.12-3.02(m,3H),2.56-2.46(m,1H),2. 20-2.06(m,4H),2.00-1.89(m,2H),1.71(dd,J=3.5,12.4Hz,2H),1.64-1.52(m,2H);

[0310] LRMS (ES) m / z 591.1 (M + +1).

[0311] Example 26: Synthesis of Compound 4244, 1-(4,4-difluorocyclohexyl)-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide

[0312]

[0313] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide (0.050 g, 0.099 mmol), 4,4-difluorocyclohexan-1-one (0.026 g, 0.197 mmol), acetic acid (0.006 mL, 0.099 mmol), sodium triacetoxyborohydride (0.063 g, 0.296 mmol) and triethylamine (0.014 mL, 0.099 mmol) prepared in step 3 of Example 18 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20x 20x 1mm; methanol / dichloromethane = 0% to 10%) and concentrated, and the obtained product was then purified again by chromatography (SiO2 plate, 20x 20x 1mm; methanol / 1%-dichloromethane aqueous solution = 0% to 7%) and concentrated to obtain the title compound (0.017 g, 27.9%) as a yellow gel.

[0314] 1 H NMR (400MHz, CDCl3) δ8.28(s,1H),8.23(d,J=7.5Hz,1H),7.77(s,1H),7.54(dd,J=1.7,7.1Hz,1H),7.36-7.23(m,3H), 7.09-6.79(m,2H),5.15(s,2H),3.03(t,J=9.3Hz,2H),2.45(s,1H),2.16(dt,J=11.7,22.3Hz,6H),2.00-1.56(m,9H);

[0315] LRMS (ES) m / z 625.2 (M + +1).

[0316] Example 27: Synthesis of Compound 4245, 1-acetyl-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide

[0317]

[0318] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide (0.050 g, 0.099 mmol), acetyl chloride (0.014 mL, 0.197 mmol) and triethylamine (0.041 mL, 0.296 mmol) prepared in step 3 of Example 18 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to give the title compound (0.020 g, 37.7%) as a white gel.

[0319] 1 H NMR (400MHz, CDCl3) δ8.30-8.27(m,1H),8.24(dd,J=1.0,7.1Hz,1H),7.73(s,1H),7.55(dd,J= 1.7,7.1Hz,1H),7.37-7.22(m,3H),7.10-6.81(m,2H),5.12(s,2H),4.72(d,J=13.3Hz,1H),3.9 5(d,J=13.6Hz,1H),3.33(tt,J=3.8,11.7Hz,1H),3.07(ddd,J=2.8,12.2,14.0Hz,1H),2.57(td ,J=2.9,12.9Hz,1H),2.22(d,J=12.6Hz,1H),2.11(s,3H),1.83(dtt,J=6.1,12.3,24.8Hz,3H);

[0320] LRMS (ES) m / z 548.9 (M + +1).

[0321] Example 28: Synthesis of Compound 4246, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-1-propionylpiperidine-4-sulfonamide

[0322]

[0323] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide (0.050 g, 0.099 mmol), propionyl chloride (0.018 g, 0.197 mmol) and triethylamine (0.041 mL, 0.296 mmol) prepared in step 3 of Example 18 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.017 g, 29.9%) as a yellow solid.

[0324] 1 H NMR (400MHz, CDCl3) δ8.30-8.28(m,1H),8.24(dd,J=1.0,7.1Hz,1H),7.76-7.71(m,1H),7.56(dd ,J=1.7,7.1Hz,1H),7.38-7.22(m,3H),7.11-6.82(m,2H),5.13(s,2H),4.75(d,J=13.5Hz,1H),4. 00(d,J=13.8Hz,1H),3.33(tt,J=3.8,11.7Hz,1H),3.03(t,J=12.9Hz,1H),2.57(t,J=12.8Hz,1H ),2.36(q,J=7.4Hz,2H),2.18(dd,J=13.1,25.6Hz,2H),1.90-1.70(m,2H),1.16(t,J=7.4Hz,3H);

[0325] LRMS(ES)m / z 563.0(M + +1).

[0326] Example 29: Synthesis of Compound 4247, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-1-(2-hydroxyacetyl)piperidine-4-sulfonamide

[0327]

[0328] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide (0.050 g, 0.099 mmol) prepared in Step 3 of Example 18, 2-hydroxyacetic acid (0.015 g, 0.197 mmol), triethylamine (0.028 mL, 0.197 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.056 g, 0.148 mmol) were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Sodium bicarbonate aqueous solution is poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove solid residue and water layer, then concentrated under reduced pressure. The concentrate is passed through chromatography (SiO Plate, 20x 20x 1mm; methanol / dichloromethane=0% to 7%) and concentrated, then the product obtained is again passed through chromatography (SiO Plate, 20x 20x 1mm; methanol / 1%-dichloromethane aqueous solution=5% to 7%) and concentrated to obtain title compound (0.017g, 31.2%), which is a white gel.

[0329] 1 H NMR (400MHz, CDCl3) δ8.30(dd,J=0.9,1.7Hz,1H),8.24(dd,J=1.0,7.2Hz,1H),7.71(s,1H),7.57(d d,J=1.7,7.1Hz,1H),7.34(td,J=6.2,8.0Hz,1H),7.30-7.22(m,2H),7.10-6.81(m,2H),5.11(s,2H ),4.68(d,J=13.5Hz,1H),4.18(d,J=1.2Hz,2H),3.65(d,J=13.7Hz,1H),3.39(tt,J=3.8,11.5Hz,1 H),3.07-2.96(m,1H),2.77(t,J=12.2Hz,1H),2.23(t,J=14.2Hz,2H),1.87(qd,J=4.3,12.4Hz,2H);

[0330] LRMS (ES) m / z 565.0 (M + +1).

[0331] Example 30: Synthesis of Compound 4248, 1-(cyclobutanecarbonyl)-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide

[0332]

[0333] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide (0.050 g, 0.099 mmol), cyclobutanecarbonyl chloride (0.023 g, 0.197 mmol) and triethylamine (0.041 mL, 0.296 mmol) prepared in step 3 of Example 18 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20x 20x 1mm; methanol / dichloromethane = 0% to 7%) and concentrated, and the obtained product was then purified again by chromatography (SiO2 plate, 20x 20x 1mm; methanol / 1%-dichloromethane aqueous solution = 0% to 7%) and concentrated to give the title compound (0.010 g, 17.2%) as a white solid.

[0334] 1 H NMR (400MHz, CDCl3) δ8.31-8.28(m,1H),8.24(dd,J=1.0,7.1Hz,1H),7.73(s,1H),7.5 7(dd,J=1.7,7.1Hz,1H),7.38-7.22(m,3H),7.10-6.81(m,2H),5.13(s,2H),4.72(d,J =13.4Hz,1H),3.84(d,J=13.7Hz,1H),3.37-3.17(m,2H),2.95(t,J=12.8Hz,1H),2.57 (t,J=12.8Hz,1H),2.42-2.27(m,2H),2.16(tt,J=4.8,8.8Hz,4H),2.05-1.68(m,4H);

[0335] LRMS (ES) m / z 588.9 (M + +1).

[0336] Example 31: Synthesis of Compound 4249, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-1-(oxetane-3-carbonyl)piperidine-4-sulfonamide

[0337]

[0338] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide (0.050 g, 0.099 mmol) prepared in Step 3 of Example 18, oxetane-3-carboxylic acid (0.020 g, 0.197 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.056 g, 0.148 mmol) and triethylamine (0.028 mL, 0.197 mmol) were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Sodium bicarbonate aqueous solution is poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove solid residue and water layer, then concentrated under reduced pressure. The concentrate is purified and concentrated by chromatography (SiO2 plate, 20x 20x1mm; methanol / dichloromethane=0% to 7%) to obtain the title compound (0.013g, 21.8%) as a yellow solid.

[0339] 1 H NMR (400MHz, CDCl3) δ8.33-8.28(m,1H),8.24(dd,J=1.0,7.1Hz,1H),7.71(s,1H),7.57(dd,J=1.7,7.1Hz,1H),7.38 -7.20(m,3H),7.10-6.81(m,2H),5.11(s,2H),4.92(ddd,J=5.8,7.1,16.4Hz,2H),4.81(dd,J=5.9,8.7Hz,2H),4.72( d,J=13.8Hz,1H),4.00(tt,J=7.1,8.7Hz,1H),3.47(d,J=13.8Hz,1H),3.35(tt,J=3.8,11.6Hz,1H),2.98(ddd,J=2.8 ,12.2,14.2Hz,1H),2.66(td,J=2.9,12.9,13.7Hz,1H),2.20(d,J=13.0Hz,1H),1.81(dtt,J=6.1,13.0,20.0Hz,3H);

[0340] LRMS(ES)m / z 591.0(M + +1).

[0341] Example 32: Synthesis of Compound 4250, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-1-(2,2,2-trifluoroacetyl)piperidine-4-sulfonamide

[0342]

[0343] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide (0.050 g, 0.099 mmol), 2,2,2-trifluoroacetic anhydride (0.041 g, 0.197 mmol) and triethylamine (0.041 mL, 0.296 mmol) prepared in step 3 of Example 18 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.025 g, 41.9%) as a yellow solid.

[0344] 1 H NMR (400MHz, CDCl3) δ8.30 (s, 1H), 8.27-8.21 (m, 1H), 7.71 (s, 1H), 7.57 (dd, J = 1.7 ,7.1Hz,1H),7.38-7.19(m,3H),7.11-6.81(m,2H),5.11(s,2H),4.60(d,J=13.5Hz ,1H),4.13(d,J=14.2Hz,1H),3.45(ddt,J=4.1,7.3,11.3Hz,1H),3.20(ddd,J=2.8 ,11.8,14.4Hz,1H),2.93-2.81(m,1H),2.27(d,J=13.6Hz,2H),2.04-1.88(m,2H);

[0345] LRMS (ES) m / z 602.7 (M + +1).

[0346] Example 33: Synthesis of Compound 4251, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-1-(methylsulfonyl)piperidine-4-sulfonamide

[0347]

[0348] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide (0.050 g, 0.099 mmol), methanesulfonyl chloride (0.015 mL, 0.197 mmol) and triethylamine (0.041 mL, 0.296 mmol) prepared in step 3 of Example 18 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.004 g, 6.2%) as a white solid.

[0349] 1 H NMR (400MHz, CDCl3) δ8.29(dt,J=0.8,1.7Hz,1H),8.24(dd,J=1.0,7.1Hz,1H),7.75-7.71(m,1H),7.56(dd,J=1.7,7.1Hz,1H),7.38-7.21(m,3H),7.09 -6.80(m,2H),5.12(s,2H),3.89(dt,J=4.2,13.3Hz,2H),3.24(ddt,J=3.8, 7.7,11.1Hz,1H),2.85-2.73(m,5H),2.30-2.17(m,2H),2.07-1.95(m,2H);

[0350] LRMS (ES) m / z 584.7 (M + +1).

[0351] Example 34: Synthesis of Compound 4252, 4-(N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)sulfamoyl)piperidine-1-carboxylic acid methyl ester

[0352]

[0353] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide (0.050 g, 0.099 mmol), methyl chloroformate (0.019 g, 0.197 mmol) and triethylamine (0.041 mL, 0.296 mmol) prepared in step 3 of Example 18 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.025 g, 45.6%) as a yellow solid.

[0354] 1 H NMR (400MHz, CDCl3) δ8.28(dt,J=0.8,1.7Hz,1H),8.23(dd,J=1.0,7.1Hz,1H),7.74(s,1H),7.55(dd,J=1.7,7.2Hz,1H),7.36-7.23(m,3H),7.09-6. 81(m,2H),5.12(s,2H),4.28(s,2H),3.71(s,3H),3.26(ddd,J=3.7,8.1,1 1.8Hz,1H),2.77(s,2H),2.18-2.07(m,2H),1.82(qd,J=4.5,12.4Hz,2H);

[0355] LRMS (ES) m / z 565.4 (M + +1).

[0356] Example 35: Synthesis of Compound 4253, 4-(N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)sulfamoyl)-N,N-dimethylpiperidine-1-carboxamide

[0357]

[0358] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide (0.050 g, 0.099 mmol), dimethylcarbamoyl chloride (0.021 g, 0.197 mmol) and triethylamine (0.041 mL, 0.296 mmol) prepared in step 3 of Example 18 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.022 g, 38.4%) as a white solid.

[0359] 1 H NMR (400MHz, CDCl3) δ8.28 (dt, J=0.8, 1.7Hz, 1H), 8.23 ​​(dd, J=1.0, 7.2Hz, 1H), 7.7 5(s,1H),7.55(dd,J=1.7,7.2Hz,1H),7.36-7.24(m,3H),7.10-6.81(m,2H),5.13( s,2H),3.77(dt,J=3.4,13.9Hz,2H),3.23(tt,J=3.8,11.9Hz,1H),2.84(s,6H),2. 71(td,J=2.5,12.9,13.4Hz,2H),2.19-2.06(m,2H),1.89(qd,J=4.1,12.4Hz,2H);

[0360] LRMS (ES) m / z 578.4 (M + +1).

[0361] Example 36: Synthesis of Compound 4254, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-1-(pyridin-2-yl)piperidine-4-sulfonamide

[0362]

[0363] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide (0.050 g, 0.099 mmol), 2-bromopyridine (0.031 g, 0.197 mmol), RuPhos palladium G2 (0.004 g, 0.005 mmol) and cesium carbonate (0.064 g, 0.197 mmol) prepared in step 3 of Example 18 were dissolved in 1,4-dioxane (1 mL) at room temperature, and the resulting solution was stirred at 120° C. for 18 hours. Then, the temperature was lowered to room temperature to terminate the reaction. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20x 20x 1mm; methanol / dichloromethane = 0% to 7%) and concentrated, and the obtained product was then purified again by chromatography (SiO2 plate, 20x 20x 1mm; methanol / 1%-dichloromethane aqueous solution = 0% to 7%) and concentrated to give the title compound (0.005 g, 8.0%) as a yellow solid.

[0364] 1 H NMR (400MHz, CDCl3) δ8.30-8.26(m,1H),8.23(dd,J=1.0,7.1Hz,1H),8.20(ddd,J=0.9,2.0,5.0Hz, 1H),7.76(d,J=0.7Hz,1H),7.55(dd,J=1.7,7.1Hz,1H),7.51(t,J=8.2Hz,1H),7.37-7.24(m,3H),7 .10-6.81(m,2H),6.67(dd,J=7.3,12.1Hz,2H),5.16(s,2H),4.46(d,J=13.3Hz,2H),3.35(ddd,J=3 .8,8.2,12.0Hz,1H),2.86(t,J=12.7Hz,2H),2.21(d,J=12.8Hz,2H),1.95(qd,J=4.2,12.3Hz,2H);

[0365] LRMS (ES) m / z 584.1 (M + +1).

[0366] Example 37: Synthesis of Compound 4255, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-1-(pyrimidin-2-yl)piperidine-4-sulfonamide

[0367]

[0368] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide (0.050 g, 0.099 mmol), 2-chloropyrimidine (0.023 g, 0.197 mmol) and potassium carbonate (0.041 g, 0.296 mmol) prepared in step 3 of Example 18 were dissolved in N,N-dimethylformamide (0.5 mL) / acetonitrile (0.5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The sodium bicarbonate aqueous solution was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. Next, the obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. To the concentrate was added dichloromethane (3 mL), followed by stirring, and the precipitated solid was filtered, washed with dichloromethane, and dried to obtain the title compound (0.012 g, 21.5%) as a yellow solid.

[0369] 1 H NMR (400MHz, CDCl3) δ8.32 (d, J = 4.7Hz, 2H), 8.27 (dt, J = 0.8, 1.7Hz, 1H), 8.23 ​​(dd, J = 1. 0,7.1Hz,1H),7.76(d,J=0.7Hz,1H),7.55(dd,J=1.7,7.1Hz,1H),7.37-7.25(m,4H),7. 10-6.81(m,2H),6.53(t,J=4.7Hz,1H),5.15(s,2H),4.99-4.86(m,2H),3.38(ddt,J=3. 7,7.5,11.9Hz,1H),2.95-2.82(m,2H),2.26-2.18(m,2H),1.89(qd,J=4.4,12.4Hz,2H);

[0370] LRMS (ES) m / z 585.1 (M + +1).

[0371] Example 38: Synthesis of Compound 4256, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-methyl-N-phenylpiperazine-1-sulfonamide

[0372] [Step 1] Synthesis of 1-((1H-imidazol-1-yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate

[0373]

[0374] 1,1'-Sulfonylbis(1H-imidazole, 10.000 g, 50.454 mmol) and methyl trifluoromethanesulfonate (4.981 mL, 45.409 mmol) were dissolved in dichloromethane (150 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. After removing the solvent from the reaction mixture under reduced pressure, the title compound (18.280 g, 100.0%) was obtained as a white solid without further purification.

[0375] [Step 2] Synthesis of tert-butyl 4-((1H-imidazol-1-yl)sulfonyl)piperazine-1-carboxylate

[0376]

[0377] 1-((1H-imidazole-1-yl)sulfonyl)-3-methyl-1H-imidazole-3-ium trifluoromethanesulfonate (18.000 g, 49.684 mmol) and tert-butyl piperazine-1-carboxylate (10.642 g, 57.137 mmol) prepared in step 1 were dissolved in acetonitrile (100 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous ammonium chloride solution was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 80 g column; hexane / ethyl acetate = 0% to 100%) to obtain the title compound (5.830 g, 37.1%) as a white solid.

[0378] [Step 3] Synthesis of 1-((4-(tert-butoxycarbonyl)piperazin-1-yl)sulfonyl)-3-methyl-1H-imidazol-3-ium Triflate

[0379]

[0380] Tert-butyl 4-((1H-imidazol-1-yl)sulfonyl)piperazine-1-carboxylate (5.830 g, 18.427 mmol) prepared in step 2 and methyl trifluoromethanesulfonate (2.223 mL, 20.270 mmol) were dissolved in dichloromethane (150 mL) at 0° C., and the resulting solution was stirred at room temperature for 3 hours. After removing the solvent from the reaction mixture under reduced pressure, the title compound (8.850 g, 100.0%) was obtained as a white solid without further purification.

[0381] [Step 4] Synthesis of tert-butyl 4-(N-(phenylsulfamoyl)piperazine-1-carboxylate

[0382]

[0383] 1-((4-(tert-butoxycarbonyl)piperazine-1-yl)sulfonyl)-3-methyl-1H-imidazole-3-ium trifluoromethanesulfonate (4.400 g, 9.158 mmol) and aniline (1.003 mL, 10.989 mmol) prepared in step 3 were dissolved in acetonitrile (50 mL) at room temperature, and the resulting solution was heated to reflux for 18 hours. Then, the temperature was lowered to room temperature to terminate the reaction. Saturated aqueous ammonium chloride solution was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 24 g column; ethyl acetate / hexane=0% to 20%) to obtain the title compound (1.200 g, 38.4%) as a beige solid.

[0384] [Step 5] Synthesis of 4-(N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyrrolidone tert-Butyl (2-pyridin-2-yl)methyl)-N-phenylsulfamoyl)piperazine-1-carboxylate

[0385]

[0386] 4-(N-phenylsulfamoyl)piperazine-1-carboxylic acid tert-butyl ester (0.300 g, 0.879 mmol) prepared in step 4, 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.300 g, 1.054 mmol) prepared in step 5 of Example 1, potassium carbonate (0.182 g, 1.318 mmol) and potassium iodide (0.073 g, 0.439 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. Saturated aqueous ammonium chloride solution was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 40 g column; ethyl acetate / hexane = 0% to 70%) and concentrated to obtain the title compound (0.450 g, 86.9%) as a white solid.

[0387] [Step 6] Synthesis of N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridine-2-yl) 1-(2-(4 ...piperazine-1-yl)methyl)-N-phenylpiperazine-1-sulfonamide)

[0388]

[0389] 4-(N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylsulfamoyl) prepared in step 5 was added to the mixture at room temperature. Piperazine-1- tert-Butyl formate (0.470g, 0.797mmol) and trifluoroacetic acid (1.221mL, 15.942mmol) were dissolved in dichloromethane (10mL), and the resulting solution was stirred for 3 hours at the same temperature. Saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution, dried over anhydrous magnesium sulfate, and filtered. After concentrating under reduced pressure, the title compound (0.390g, 100.0%) was obtained as a brown gel without further purification.

[0390] [Step 7] Synthesis of compound 4256

[0391]

[0392] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide (0.050 g, 0.102 mmol), formaldehyde (0.006 g, 0.204 mmol), acetic acid (0.006 mL, 0.102 mmol) and sodium triacetoxyborohydride (0.065 g, 0.306 mmol) prepared in step 6 were dissolved in dichloromethane (3 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; dichloromethane / methanol = 0% to 10%) and concentrated to obtain the title compound (0.020 g, 38.9%) as a yellow solid.

[0393] 1 H NMR (700MHz, CDCl3) δ8.30(s,1H),8.23(dd,J=7.1,1.0Hz,1H),7.76(s,1H),7.54(dd,J=7.1,1.7Hz,1H),7.48(d,J= 7.9Hz,2H),7.36(t,J=7.8Hz,2H),7.30(s,1H),6.95(t,J=51.7Hz,1H),5.11(s,2H),3.39(s,4H),2.71-2.28(m,7H);

[0394] LRMS (ES) m / z 504.3 (M + +1).

[0395] Example 39: Synthesis of Compound 4257, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-ethyl-N-phenylpiperazine-1-sulfonamide

[0396]

[0397] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide (0.050 g, 0.102 mmol), acetaldehyde (0.009 g, 0.204 mmol), acetic acid (0.006 mL, 0.102 mmol) and sodium triacetoxyborohydride (0.065 g, 0.306 mmol) prepared in step 6 of Example 38 were dissolved in dichloromethane (3 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; dichloromethane / methanol = 0% to 10%) and concentrated to afford the title compound (0.024 g, 45.4%) as a yellow solid.

[0398] 1 H NMR (700MHz, CDCl3) δ8.28(d,J=1.7Hz,1H),8.22(dd,J=7.1,1.0Hz,1H),7.79(s,1H),7.52(dd,J=7.1,1.7Hz,1H),7.51-7.4 7(m,2H),7.38-7.33(m,2H),7.28-7.25(m,1H),6.95(t,J=51.7Hz,1H),5.12(s,2H),3.31(s,4H),2.45(s,6H),1.10(s,3H);

[0399] LRMS (ES) m / z 518.2 (M + +1).

[0400] Example 40: Synthesis of Compound 4258, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-isopropyl-N-phenylpiperazine-1-sulfonamide

[0401]

[0402] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide (0.050 g, 0.102 mmol), propan-2-one (0.012 g, 0.204 mmol), acetic acid (0.006 mL, 0.102 mmol) and sodium triacetoxyborohydride (0.065 g, 0.306 mmol) prepared in step 6 of Example 38 were dissolved in dichloromethane (3 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; dichloromethane / methanol = 0% to 10%) and concentrated to obtain the title compound (0.032 g, 58.9%) as a yellow solid.

[0403] 1 H NMR (700MHz, CDCl3) δ8.28(s,1H),8.22(d,J=7.1Hz,1H),7.80(d,J=0.8Hz,1H),7.52(dd,J=7.1,1.7Hz,1H),7.51-7.48(m,2H) ,7.35(t,J=7.7Hz,2H),7.28-7.25(m,1H),7.03-6.86(m,1H),5.12(s,2H),3.27(s,4H),2.70(s,1H),2.48(s,4H),1.02(s,6H);

[0404] LRMS(ES)m / z 532.3(M + +1).

[0405] Example 41: Synthesis of Compound 4259, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-(1-hydroxypropan-2-yl)-N-phenylpiperazine-1-sulfonamide

[0406]

[0407] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide (0.050 g, 0.102 mmol), 1-hydroxypropan-2-one (0.015 g, 0.204 mmol), acetic acid (0.006 mL, 0.102 mmol) and sodium triacetoxyborohydride (0.065 g, 0.306 mmol) prepared in step 6 of Example 38 were dissolved in dichloromethane (3 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; dichloromethane / methanol = 0% to 10%) and concentrated to obtain the title compound (0.019 g, 34.0%) as a yellow solid.

[0408] 1 H NMR (400MHz, CDCl3) δ8.28 (dt, J=1.7, 0.8Hz, 1H), 8.21 (dd, J=7.1, 1.0Hz, 1H), 7.76 (d,J=0.7Hz,1H),7.52(dd,J=7.1,1.7Hz,1H),7.51-7.46(m,2H),7.39-7.32(m,2H) ,7.30-7.25(m,1H),6.95(t,J=51.7Hz,1H),5.11(d,J=0.7Hz,2H),3.45(d,J=12.0H z,1H),3.41-3.20(m,5H),2.85(s,1H),2.66(s,2H),2.44(s,2H),0.92-0.87(m,3H);

[0409] LRMS (ES) m / z 548.3 (M + +1).

[0410] Example 42: Synthesis of Compound 4260, 4-cyclobutyl-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide

[0411]

[0412] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide (0.050 g, 0.102 mmol), cyclobutanone (0.014 g, 0.204 mmol), acetic acid (0.006 mL, 0.102 mmol) and sodium triacetoxyborohydride (0.065 g, 0.306 mmol) prepared in step 6 of Example 38 were dissolved in dichloromethane (3 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; dichloromethane / methanol = 0% to 10%) and concentrated to afford the title compound (0.022 g, 39.6%) as a yellow solid.

[0413] 1 H NMR (700MHz, CDCl3) δ8.28(s,1H),8.22(d,J=7.1Hz,1H),7.78(s,1H),7.52(dd,J=7.1,1.7Hz,1H),7.49(d,J=7.9Hz,2H),7.35(t,J=7.7Hz, 2H),7.28-7.25(m,1H),6.95(t,J=51.7Hz,1H),5.12(s,2H),3.27(s, 4H),2.71(s,1H),2.29(s,4H),2.03(s,2H),1.83(s,2H),1.70(s,2H);

[0414] LRMS (ES) m / z 544.1 (M + +1).

[0415] Example 43: Synthesis of Compound 4261, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-(oxetane-3-yl)-N-phenylpiperazine-1-sulfonamide

[0416]

[0417] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide (0.050 g, 0.102 mmol), oxetan-3-one (0.015 g, 0.204 mmol), acetic acid (0.006 mL, 0.102 mmol) and sodium triacetoxyborohydride (0.065 g, 0.306 mmol) prepared in step 6 of Example 38 were dissolved in dichloromethane (3 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; dichloromethane / methanol = 0% to 10%) and concentrated to afford the title compound (0.022 g, 39.5%) as a yellow solid.

[0418] 1 H NMR(700MHz, CDCl3)δ8.29(s,1H),8.22(dd,J=7.1,1.0Hz,1H),7.76(s,1H),7.54(dd,J=7.1,1.7Hz,1H),7.50-7.47(m,2H),7 .38-7.35(m,2H),7.29(s,1H),7.04-6.86(m,1H),5.11(s,2H),4.67(t,J=6.5Hz,4H),3.54(s,1H),3.36(s,4H),2.37(s,4H);

[0419] LRMS (ES) m / z 545.9 (M + +1).

[0420] Example 44: Synthesis of Compound 4262, 4-cyclohexyl-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide

[0421]

[0422] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide (0.050 g, 0.102 mmol), cyclohexanone (0.020 g, 0.204 mmol), acetic acid (0.006 mL, 0.102 mmol) and sodium triacetoxyborohydride (0.065 g, 0.306 mmol) prepared in step 6 of Example 38 were dissolved in dichloromethane (3 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; dichloromethane / methanol = 0% to 10%) and concentrated to afford the title compound (0.029 g, 49.7%) as a yellow solid.

[0423] 1 H NMR (700MHz, CDCl3) δ8.28(s,1H),8.24-8.20(m,1H),7.80(d,J=0.7Hz,1H),7.53(dd,J=7.1,1.7Hz,1H),7.49(d,J=7.9Hz,2H),7.35(t,J=7.7Hz ,2H),7.28-7.24(m,1H),6.95(t,J=51.7Hz,1H),5.12(s,2H),3.25(s,4 H),2.53(s,4H),2.31-2.20(m,1H),1.80(s,4H),1.17(d,J=86.7Hz,6H);

[0424] LRMS(ES)m / z 572.2(M + +1).

[0425] Example 45: Synthesis of Compound 4263, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenyl-1-(tetrahydro-2H-pyran-4-yl)piperazine-1-sulfonamide

[0426]

[0427] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide (0.050 g, 0.102 mmol), tetrahydro-4H-pyran-4-one (0.015 g, 0.153 mmol), acetic acid (0.006 mL, 0.102 mmol), sodium triacetoxyborohydride (0.065 g, 0.306 mmol) and triethylamine (0.014 mL, 0.102 mmol) prepared in step 6 of Example 38 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20x 20x 1mm; methanol / dichloromethane = 0% to 7%) and concentrated, and the obtained product was then purified again by chromatography (SiO2 plate, 20x 20x 1mm; methanol / 1%-dichloromethane aqueous solution = 0% to 7%) and concentrated to give the title compound (0.017 g, 29.5%) as a white solid.

[0428] 1 H NMR (400MHz, CDCl3) δ8.27 (s, 1H), 8.21 (d, J = 7.1Hz, 1H), 7.77 (s, 1H), 7.55-7.45 (m, 3H) ,7.35(t,J=7.7Hz,2H),7.26(t,J=8.1Hz,1H),6.95(t,J=51.7Hz,1H),5.12(s,2H),4.02 (dd,J=4.3,11.3Hz,2H),3.36(td,J=1.9,11.9Hz,2H),3.27(t,J=4.9Hz,4H),2.53(t,J= 4.9Hz,4H),2.43(d,J=12.9Hz,2H),1.70(d,J=12.7Hz,1H),1.53(qd,J=4.5,12.0Hz,2H);

[0429] LRMS (ES) m / z 574.4 (M + +1).

[0430] Example 46: Synthesis of Compound 4264, 4-(4,4-difluorocyclohexyl)-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide

[0431]

[0432] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide (0.050 g, 0.102 mmol), 4,4-difluorocyclohexan-1-one (0.021 g, 0.153 mmol), acetic acid (0.006 mL, 0.102 mmol), sodium triacetoxyborohydride (0.065 g, 0.306 mmol) and triethylamine (0.014 mL, 0.102 mmol) prepared in step 6 of Example 38 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20x 20x 1mm; methanol / dichloromethane = 0% to 7%) and concentrated, and the obtained product was then purified again by chromatography (SiO2 plate, 20x 20x 1mm; methanol / 1%-dichloromethane aqueous solution = 0% to 7%) and concentrated to give the title compound (0.011 g, 18.2%) as a white solid.

[0433] 1 H NMR (400MHz, CDCl3) δ8.27(s,1H),8.21(d,J=7.1Hz,1H),7.77(s,1H),7.50(ddd,J=1.7,7.5,13.0Hz,3H),7.35(dd,J=6.9,8.6Hz,2H),7.2 6(d,J=7.4Hz,1H),6.95(t,J=51.7Hz,1H),5.11(s,2H),3.25(s,4H),2.51(s,4H),2.39(s,1H),2.13(d,J=10.7Hz,2H),1.83-1.53(m,6H);

[0434] LRMS (ES) m / z 608.5 (M + +1).

[0435] Example 47: Synthesis of Compound 4265, 4-acetyl-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide

[0436]

[0437] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide (0.050 g, 0.102 mmol), acetyl chloride (0.011 mL, 0.153 mmol) and triethylamine (0.043 mL, 0.306 mmol) prepared in step 6 of Example 38 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Aqueous sodium bicarbonate solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane=0% to 5%) and concentrated to obtain the title compound (0.024 g, 43.5%) as a white solid.

[0438] 1 H NMR (400MHz, CDCl3) δ8.29 (dd, J=0.9, 1.8Hz, 1H), 8.21 (dd, J=1.0, 7.1Hz, 1H), 7.73(s,1H),7.53(dd,J=1.7,7.1Hz,1H),7.49-7.43(m,2H),7.36(ddd,J=1.4,6 .8,7.8Hz,2H),7.31-7.26(m,1H),6.95(t,J=51.7Hz,1H),5.08(s,2H),3.59(t, J=5.2Hz,2H),3.42(t,J=5.1Hz,2H),3.22(dt,J=5.2,10.9Hz,4H),2.08(s,3H);

[0439] LRMS (ES) m / z 532.4 (M + +1).

[0440] Example 48: Synthesis of Compound 4266, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenyl-4-propionylpiperazine-1-sulfonamide

[0441]

[0442] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide (0.050 g, 0.102 mmol), propionyl chloride (0.014 g, 0.153 mmol) and triethylamine (0.043 mL, 0.306 mmol) prepared in step 6 of Example 38 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Aqueous sodium bicarbonate solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to obtain the title compound (0.017 g, 30.9%) as a white solid.

[0443] 1 H NMR (400MHz, CDCl3) δ8.28 (dt, J=0.8, 1.7Hz, 1H), 8.21 (dd, J=1.0, 7.1Hz, 1H), 7. 73(d,J=0.7Hz,1H),7.53(dd,J=1.7,7.2Hz,1H),7.50-7.42(m,2H),7.40-7.24(m ,3H),6.95(t,J=51.7Hz,1H),5.11-5.06(m,2H),3.60(t,J=5.2Hz,2H),3.42(t,J =5.1Hz,2H),3.22(q,J=5.6Hz,4H),2.32(q,J=7.4Hz,2H),1.14(t,J=7.4Hz,3H);

[0444] LRMS (ES) m / z 546.0 (M + +1).

[0445] Example 49: Synthesis of Compound 4267, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-(2-hydroxyacetyl)-N-phenylpiperazine-1-sulfonamide

[0446]

[0447] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide (0.050 g, 0.102 mmol), 2-hydroxyacetic acid (0.012 g, 0.153 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.058 g, 0.153 mmol) and triethylamine (0.043 mL, 0.306 mmol) prepared in step 6 of Example 38 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.017 g, 30.9%) as a white solid.

[0448] 1 H NMR (400MHz, CDCl3) δ8.29(dt,J=1.7,0.8Hz,1H),8.21(dd,J=7.1,1.0Hz,1H),7.70(s,1H),7.54(dd,J=7.1,1.7Hz,1H),7.48-7.42(m,2 H),7.40-7.33(m,2H),7.32-7.28(m,1H),6.96(t,J=51.7Hz,1H),5.07(s,2H),4.15(s,2H),3.66(t,J=5.2Hz,2H),3.26(d,J=6.5Hz,6H);

[0449] LRMS (ES) m / z 546.0 (M + +1).

[0450] Example 50: Synthesis of Compound 4268, 4-(cyclobutanecarbonyl)-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide

[0451]

[0452] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide (0.050 g, 0.102 mmol), cyclobutanecarbonyl chloride (0.018 g, 0.153 mmol) and triethylamine (0.043 mL, 0.306 mmol) prepared in step 6 of Example 38 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20x 20x 1mm; methanol / dichloromethane = 0% to 7%) and concentrated, and the obtained product was then purified again by chromatography (SiO2 plate, 20x 20x 1mm; methanol / 1%-dichloromethane aqueous solution = 0% to 7%) and concentrated to give the title compound (0.010 g, 17.6%) as a white solid.

[0453] 1 H NMR (400MHz, CDCl3) δ8.30 (s, 1H), 8.22 (dd, J = 0.9, 7.1Hz, 1H), 7.73 (s, 1H), 7.55 (dd, J = 1.7, 7.2Hz,1H),7.46(dd,J=1.8,7.5Hz,2H),7.35(t,J=7.7Hz,2H),7.29(d,J=7.6Hz,1H),6.95(t, J=51.7Hz,1H),5.09(s,2H),3.59(t,J=5.1Hz,2H),3.31(t,J=5.0Hz,2H),3.20(ddd,J=3.1,5 .5,10.8Hz,5H),2.33(dq,J=9.1,11.5Hz,2H),2.14(qd,J=4.6,8.8Hz,2H),2.03-1.81(m,2H);

[0454] LRMS (ES) m / z 571.9 (M + +1).

[0455] Example 51: Synthesis of Compound 4269, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-(oxetane-3-carbonyl)-N-phenylpiperazine-1-sulfonamide

[0456]

[0457] N-((7-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide (0.050 g, 0.102 mmol) prepared in Step 6 of Example 38, oxetane-3-carboxylic acid (0.016 g, 0.153 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.058 g, 0.153 mmol) and triethylamine (0.043 mL, 0.306 mmol) were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Sodium bicarbonate aqueous solution is poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residue and water layer, then concentrated under reduced pressure. The concentrate is purified and concentrated by column chromatography (SiO2 plate, 4g column; methanol / dichloromethane=0% to 5%), then the obtained product is purified and concentrated by chromatography (SiO2 plate, 20x 20x 1mm; methanol / 1%-dichloromethane aqueous solution=0% to 7%) again to obtain the title compound (0.006g, 10.2%) as a white solid.

[0458] 1 H NMR (400MHz, CDCl3) δ8.32 (s, 1H), 8.22 (dd, J = 0.9, 7.2Hz, 1H), 7.71 (s, 1H), 7.56 (dd,J=1.7,7.2Hz,1H),7.49-7.42(m,2H),7.40-7.33(m,2H),7.35-7.27(m,1H),6 .96(t,J=51.7Hz,1H),5.08(s,2H),4.89(dd,J=5.9,7.1Hz,2H),4.79(dd,J=5.9, 8.7Hz,2H),3.97(tt,J=7.0,8.7Hz,1H),3.64(t,J=5.2Hz,2H),3.28-3.10(m,6H);

[0459] LRMS(ES)m / z 574.1(M + +1).

[0460] Example 52: Synthesis of Compound 4270, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenyl-4-(2,2,2-trifluoroacetyl)piperazine-1-sulfonamide

[0461]

[0462] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide (0.050 g, 0.102 mmol), 2,2,2-trifluoroacetic anhydride (0.026 g, 0.123 mmol) and triethylamine (0.043 mL, 0.306 mmol) prepared in step 6 of Example 38 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.021 g, 35.3%) as a yellow solid.

[0463] 1 H NMR (400MHz, CDCl3) δ8.29(dd,J=1.0,1.9Hz,1H),8.21(dd,J=1.0,7.1Hz,1H),7.69(s,1H),7.55(dd,J=1.7,7.1Hz,1H ),7.49-7.26(m,5H),6.96(t,J=51.7Hz,1H),5.07(s,2H),3.71-3.64(m,2H),3.59(t,J=5.0Hz,2H),3.37-3.29(m,4H);

[0464] LRMS (ES) m / z 585.8 (M + +1).

[0465] Example 53: Synthesis of Compound 4271, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-(methylsulfonyl)-N-phenylpiperazine-1-sulfonamide

[0466]

[0467] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide (0.050 g, 0.102 mmol), methanesulfonyl chloride (0.012 mL, 0.153 mmol) and triethylamine (0.043 mL, 0.306 mmol) prepared in step 6 of Example 38 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20x 20x 1mm; methanol / dichloromethane = 0% to 7%) and concentrated, and the obtained product was then purified again by chromatography (SiO2 plate, 20x 20x 1mm; methanol / 1%-dichloromethane aqueous solution = 0% to 5%) and concentrated to give the title compound (0.002 g, 2.9%) as a yellow solid.

[0468] 1 H NMR (400MHz, CDCl3) δ8.37(s,1H),8.25(d,J=7.0Hz,1H),7.74(s,1H),7.62(d,J=6.9Hz,1H),7.49(d,J=7.8Hz,2H),7.39(t, J=7.6Hz,2H),7.33(d,J=7.2Hz,1H),7.10-6.82(m,1H),5.12(s,2H),3.41-3.29(m,4H),3.22(t,J=5.0Hz,4H),2.78(s,3H);

[0469] LRMS (ES) m / z 567.9 (M + +1).

[0470] Example 54: Synthesis of Compound 4272, 4-(N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylsulfamoyl)piperazine-1-carboxylic acid methyl ester

[0471]

[0472] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide (0.050 g, 0.102 mmol), methyl chloroformate (0.014 g, 0.153 mmol) and triethylamine (0.043 mL, 0.306 mmol) prepared in step 6 of Example 38 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Aqueous sodium bicarbonate solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to obtain the title compound (0.012 g, 21.8%) as a white solid.

[0473] 1 H NMR (400MHz, CDCl3) δ8.29(dt,J=0.9,1.8Hz,1H),8.22(dd,J=1.0,7.2Hz,1H),7.74(d,J=0.7Hz,1H),7.54(dd,J=1.7,7.1Hz,1H),7.51-7.43(m,2H) ,7.41-7.31(m,2H),7.29(d,J=7.1Hz,1H),6.95(t,J=51.7Hz,1H),5.10(d ,J=0.7Hz,2H),3.71(s,3H),3.45(t,J=5.1Hz,4H),3.20(t,J=5.1Hz,4H);

[0474] LRMS (ES) m / z 547.8 (M + +1).

[0475] Example 55: Synthesis of Compound 4273, 4-(N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylsulfamoyl)-N,N-dimethylpiperazine-1-carboxamide

[0476]

[0477] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide (0.050 g, 0.102 mmol), dimethylcarbamoyl chloride (0.016 g, 0.153 mmol) and triethylamine (0.043 mL, 0.306 mmol) prepared in step 6 of Example 38 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to obtain the title compound (0.020 g, 35.3%) as a white solid.

[0478] 1 H NMR (400MHz, CDCl3) δ8.27(dt,J=0.8,1.7Hz,1H),8.21(dd,J=1.0,7.2Hz,1H),7.74(s,1H),7.51(dd,J=1.7,7.2Hz,1H),7. 48-7.42(m,2H),7.39-7.29(m,2H),7.34-7.22(m,1H),6.95(t,J=51.7Hz,1H),5.09(s,2H),3.29-3.15(m,8H),2.82(s,6H);

[0479] LRMS (ES) m / z 547.8 (M + +1).

[0480] Example 56: Synthesis of Compound 4274, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenyl-4-(pyridin-2-yl)piperazine-1-sulfonamide

[0481]

[0482] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide (0.050 g, 0.102 mmol), 2-chloropyridine (0.032 g, 0.204 mmol), RuPhos palladium G2 (0.004 g, 0.005 mmol) and cesium carbonate (0.067 g, 0.204 mmol) prepared in step 6 of Example 38 were dissolved in 1,4-dioxane (1 mL) at room temperature, and the resulting solution was stirred at 120° C. for 18 hours. Then, the temperature was lowered to room temperature to terminate the reaction. An aqueous sodium bicarbonate solution was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. Next, the obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.003 g, 5.7%) as a white solid.

[0483] 1 H NMR (400MHz, CDCl3) δ8.27(dd,J=1.7,0.9Hz,1H),8.24-8.18(m,2H),7.77(d,J=0.7Hz,1H),7.55-7.47(m,4H),7.38-7.30(m,2H), 7.27-7.23(m,1H),6.95(t,J=51.7Hz,1H),6.71-6.60(m,2H),5.13(s,2H),3.53(q,J=4.6,4.0Hz,4H),3.35(dd,J=6.4,3.9Hz,4H);

[0484] LRMS (ES) m / z 567.5 (M + +1).

[0485] Example 57: Synthesis of Compound 4275, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenyl-4-(pyrimidin-2-yl)piperazine-1-sulfonamide

[0486]

[0487] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-sulfonamide (0.050 g, 0.102 mmol), 2-chloropyrimidine (0.023 g, 0.204 mmol) and potassium carbonate (0.042 g, 0.306 mmol) prepared in Step 6 of Example 38 were dissolved in N,N-dimethylformamide (0.5 mL) / acetonitrile (0.5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. Next, the obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.023 g, 39.2%) as a white solid.

[0488] 1 H NMR (400MHz, CDCl3) δ8.31(d,J=4.7Hz,2H),8.28-8.25(m,1H),8.21(dd,J=1.0,7.1Hz,1H),7.77(s,1H),7.55-7.47(m,3H),7.37- 7.31(m,2H),7.28-7.23(m,1H),6.95(t,J=51.7Hz,1H),6.54(t,J=4.7Hz,1H),5.12(s,2H),3.83-3.77(m,4H),3.32-3.23(m,4H);

[0489] LRMS(ES)m / z 568.0(M + +1).

[0490] Example 58: Synthesis of Compound 4297, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-4-methylpiperazine-1-sulfonamide

[0491] [Step 1] Synthesis of tert-butyl 4-(N-(3-fluorophenyl)sulfamoyl)piperazine-1-carboxylate

[0492]

[0493] 1-((4-(tert-Butyloxycarbonyl)piperazin-1-yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (4.400 g, 9.158 mmol) and 3-fluoroaniline (1.221 g, 10.989 mmol) prepared in Step 3 of Example 38 were dissolved in acetonitrile (50 mL) at room temperature, and the resulting solution was heated to reflux for 18 hours. Then, the temperature was lowered to room temperature to terminate the reaction. A saturated aqueous ammonium chloride solution was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 24 g column; ethyl acetate / hexane=0% to 20%) and concentrated to obtain the title compound (2.400 g, 72.9%) as a beige solid.

[0494] [Step 2] Synthesis of 4-(N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyrrolidone tert-Butyl (2-piperidin-2-yl)methyl)-N-(3-fluorophenyl)sulfamoyl)piperazine-1-carboxylate

[0495]

[0496] Tert-butyl 4-(N-(3-fluorophenyl)sulfamoyl)piperazine-1-carboxylate (0.300 g, 0.835 mmol) prepared in step 1, 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.285 g, 1.002 mmol) prepared in step 5 of Example 1, potassium carbonate (0.173 g, 1.252 mmol) and potassium iodide (0.069 g, 0.417 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. Saturated aqueous ammonium chloride solution was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 40 g column; ethyl acetate / hexane = 0% to 70%) and concentrated to obtain the title compound (0.400 g, 78.9%) as a white solid.

[0497] [Step 3] Synthesis of N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridine-2-yl) 1-(4-(4-(2-fluorophenyl)piperazine)sulfonamide

[0498]

[0499] Tert-butyl 4-(N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)sulfamoyl)piperazine-1-carboxylate (0.450 g, 0.741 mmol) and trifluoroacetic acid (1.134 mL, 4.812 mmol) prepared in step 2 were dissolved in dichloromethane (10 mL) at room temperature, and the resulting solution was stirred for 3 hours at the same temperature. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution, dried over anhydrous magnesium sulfate, and filtered. After concentration under reduced pressure, the title compound (0.376 g, 100.0%) was obtained as a brown gel without further purification.

[0500] [Step 4] Synthesis of compound 4297

[0501]

[0502] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide (0.050 g, 0.099 mmol), formaldehyde (0.006 g, 0.197 mmol), acetic acid (0.006 mL, 0.099 mmol) and sodium triacetoxyborohydride (0.063 g, 0.296 mmol) prepared in step 3 were dissolved in dichloromethane (3 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; dichloromethane / methanol = 0% to 10%) and concentrated to obtain the title compound (0.024 g, 46.7%) as a yellow solid.

[0503] 1 H NMR (700MHz, CDCl3) δ8.31 (s, 1H), 8.24 (dd, J = 7.1, 1.0 Hz, 1H), 7.77 (s, 1H), 7.55 (dd, J = 7. 1,1.7Hz,1H),7.35-7.28(m,3H),7.05-6.84(m,2H),5.09(s,2H),3.38(s,4H),2.39(s,7H);

[0504] LRMS (ES) m / z 523.1 (M + +1).

[0505] Example 59: Synthesis of Compound 4298, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-ethyl-N-(3-fluorophenyl)-piperazine-1-sulfonamide

[0506]

[0507] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide (0.050 g, 0.099 mmol), acetaldehyde (0.009 g, 0.197 mmol), acetic acid (0.006 mL, 0.099 mmol) and sodium triacetoxyborohydride (0.063 g, 0.296 mmol) prepared in step 3 of Example 58 were dissolved in dichloromethane (3 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; dichloromethane / methanol = 0% to 10%) and concentrated to obtain the title compound (0.019 g, 36.0%) as a yellow solid.

[0508] 1 H NMR (700MHz, CDCl3) δ8.30 (s, 1H), 8.26-8.22 (m, 1H), 7.79-7.76 (m, 1H), 7.55 (dd, J=7.1, 1.7Hz ,1H),7.34-7.29(m,3H),7.06-6.84(m,2H),5.10(s,2H),3.32(s,4H),2.46(s,6H),1.12(s,3H);

[0509] LRMS (ES) m / z 536.3 (M + +1).

[0510] Example 60: Synthesis of Compound 4299, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-4-isopropylpiperazine-1-sulfonamide

[0511]

[0512] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide (0.050 g, 0.099 mmol), propan-2-one (0.011 g, 0.197 mmol), acetic acid (0.006 mL, 0.099 mmol) and sodium triacetoxyborohydride (0.063 g, 0.296 mmol) prepared in step 3 of Example 58 were dissolved in dichloromethane (3 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; dichloromethane / methanol = 0% to 10%) and concentrated to afford the title compound (0.024 g, 44.3%) as a yellow solid.

[0513] 1 H NMR (700MHz, CDCl3) δ8.31-8.28(m,1H),8.25-8.21(m,1H),7.79(d,J=0.8Hz,1H),7.54(dd,J=7.1,1.7Hz,1 H),7.34-7.28(m,3H),7.04-6.80(m,2H),5.11(s,2H),3.27(s,4H),2.71(s,1H),2.49(s,4H),1.03(s,6H);

[0514] LRMS (ES) m / z 549.9 (M + +1).

[0515] Example 61: Synthesis of Compound 4300, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-4-(1-hydroxypropan-2-yl)piperazine-1-sulfonamide

[0516]

[0517] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide (0.050 g, 0.099 mmol), 1-hydroxypropan-2-one (0.015 g, 0.197 mmol), acetic acid (0.006 mL, 0.099 mmol) and sodium triacetoxyborohydride (0.063 g, 0.296 mmol) prepared in step 3 of Example 58 were dissolved in dichloromethane (3 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; dichloromethane / methanol = 0% to 10%) and concentrated to obtain the title compound (0.032 g, 57.4%) as a yellow solid.

[0518] 1 H NMR (400MHz, CDCl3) δ8.30(dt,J=1.7,0.9Hz,1H),8.23(dd,J=7.1,1.0Hz,1H),7.76(d,J=0.7Hz,1H),7.54(dd,J=7.1,1.7Hz,1H),7.35-7.29(m,3H),7 .11-6.77(m,2H),5.09(d,J=0.7Hz,2H),3.46(d,J=11.5Hz,1H),3.33(d,J= 18.2Hz,5H),2.86(s,1H),2.67(s,2H),2.44(s,2H),0.91(d,J=6.6Hz,3H);

[0519] LRMS (ES) m / z 566.4 (M + +1).

[0520] Example 62: Synthesis of Compound 4301, 4-cyclobutyl-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide

[0521]

[0522] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide (0.050 g, 0.099 mmol), cyclobutanone (0.014 g, 0.197 mmol), acetic acid (0.006 mL, 0.099 mmol) and sodium triacetoxyborohydride (0.063 g, 0.296 mmol) prepared in step 3 of Example 58 were dissolved in dichloromethane (3 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; dichloromethane / methanol = 0% to 10%) and concentrated to afford the title compound (0.022 g, 39.8%) as a yellow solid.

[0523] 1 H NMR (700MHz, CDCl3) δ8.29(s,1H),8.23(d,J=7.1Hz,1H),7.78(d,J=0.7Hz,1H),7.54(dd,J=7.1,1.7Hz,1H),7.33-7.29 (m,3H),7.05-6.86(m,2H),5.10(s,2H),3.27(s,4H),2.71(s,1H),2.29(s,4H),2.03(s,2H),1.83(s,2H),1.70(s,2H);

[0524] LRMS (ES) m / z 562.2 (M + +1).

[0525] Example 63: Synthesis of Compound 4302, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-4-oxetane-3-yl)piperazine-1-sulfonamide

[0526]

[0527] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide (0.050 g, 0.099 mmol), oxetan-3-one (0.014 g, 0.197 mmol), acetic acid (0.006 mL, 0.099 mmol) and sodium triacetoxyborohydride (0.063 g, 0.296 mmol) prepared in step 3 of Example 58 were dissolved in dichloromethane (3 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; dichloromethane / methanol = 0% to 10%) and concentrated to afford the title compound (0.017 g, 30.6%) as a yellow solid.

[0528] 1 H NMR(700MHz, CDCl3)δ8.31(dt,J=1.8,0.8Hz,1H),8.24(dd,J=7.1,1.0Hz,1H),7.78-7.74(m,1H),7.55(dd,J=7.1,1.7Hz ,1H),7.36-7.29(m,3H),7.05-6.83(m,2H),5.11-5.07(m,2H),4.71-4.55(m,4H),3.53(s,1H),3.35(s,4H),2.36(s,4H);

[0529] LRMS (ES) m / z 564.5 (M + +1).

[0530] Example 64: Synthesis of Compound 4303, 4-cyclohexyl-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide

[0531]

[0532] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide (0.050 g, 0.099 mmol), cyclohexanone (0.019 g, 0.197 mmol), acetic acid (0.006 mL, 0.099 mmol) and sodium triacetoxyborohydride (0.063 g, 0.296 mmol) prepared in step 3 of Example 58 were dissolved in dichloromethane (3 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; dichloromethane / methanol = 0% to 10%) and concentrated to obtain the title compound (0.029 g, 49.9%) as a yellow solid.

[0533] 1 H NMR(700MHz, CDCl3)δ8.29(dt,J=1.8,0.8Hz,1H),8.23(d,J=7.1Hz,1H),7.80-7.78(m,1H),7.54(dd,J=7.1,1.7Hz,1H),7.3 3-7.29(m,3H),7.05-6.86(m,2H),5.10(s,2H),3.25(s,4H),2.53(s,4H),2.31-2.18(m,1H),1.80(s,4H),1.25-1.06(m,6H);

[0534] LRMS (ES) m / z 590.0 (M + +1).

[0535] Example 65: Synthesis of Compound 4304, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazine-1-sulfonamide

[0536]

[0537] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide (0.050 g, 0.099 mmol), tetrahydro-4H-pyran-4-one (0.015 g, 0.148 mmol), acetic acid (0.006 mL, 0.099 mmol), sodium triacetoxyborohydride (0.063 g, 0.296 mmol) and triethylamine (0.014 mL, 0.099 mmol) prepared in step 3 of Example 58 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.021 g, 35.7%) as a white solid.

[0538] 1 H NMR (400MHz, CDCl3) δ8.30-8.27(m,1H),8.22(dd,J=1.0,7.1Hz,1H),7.77(s,1H ),7.53(dd,J=1.7,7.1Hz,1H),7.33-7.25(m,4H),7.10-6.80(m,2H),5.10(s,2H) ,4.06-3.97(m,2H),3.36(td,J=2.0,11.8Hz,2H),3.27(t,J=4.9Hz,4H),2.53(t, J=4.8Hz,4H),2.44(s,1H),1.69(d,J=12.0Hz,2H),1.53(qd,J=4.6,12.0Hz,2H);

[0539] LRMS (ES) m / z 592.2 (M + +1).

[0540] Example 66: Synthesis of Compound 4305, 4-(4,4-difluorocyclohexyl)-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide

[0541]

[0542] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide (0.050 g, 0.099 mmol), 4,4-difluorocyclohexan-1-one (0.020 g, 0.148 mmol), acetic acid (0.006 mL, 0.099 mmol), sodium triacetoxyborohydride (0.063 g, 0.296 mmol) and triethylamine (0.014 mL, 0.099 mmol) prepared in step 3 of Example 58 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.020 g, 31.8%) as a white solid.

[0543] 1 H NMR (400MHz, CDCl3) δ8.31-8.27(m,1H),8.23(dd,J=1.0,7.1Hz,1H),7.77(s,1H),7.54(dd,J=1.7,7.1Hz,1H),7.33-7.25(m,3H),7.09-6.8 1(m,2H),5.10(s,2H),3.25(t,J=4.7Hz,4H),2.51(t,J=4.9Hz,4H),2.38(d,J=11.2Hz,1H),2.13(q,J=10.2,10.8Hz,2H),1.84-1.53(m,6H);

[0544] LRMS(ES)m / z 626.0(M + +1).

[0545] Example 67: Synthesis of Compound 4306, 4-acetyl-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide

[0546]

[0547] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide (0.050 g, 0.099 mmol), acetyl chloride (0.011 mL, 0.148 mmol) and triethylamine (0.041 mL, 0.296 mmol) prepared in step 3 of Example 58 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.020 g, 36.2%) as a white solid.

[0548] 1 H NMR (400MHz, CDCl3) δ8.30(dt,J=0.8,1.7Hz,1H),8.23(dd,J=1.0,7.2Hz,1H),7.73(d,J=0.7Hz,1H),7.55(dd,J=1.7,7.1Hz,1H) ,7.38-7.22(m,3H),7.11-6.80(m,2H),5.07(s,2H),3.59(t,J=5.2Hz,2H),3.43(t,J=5.1Hz,2H),3.29-3.17(m,4H),2.09(s,3H);

[0549] LRMS (ES) m / z 550.4 (M + +1).

[0550] Example 68: Synthesis of Compound 4307, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-4-propionylpiperazine-1-sulfonamide

[0551]

[0552] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide (0.050 g, 0.099 mmol), propionyl chloride (0.014 g, 0.148 mmol) and triethylamine (0.041 mL, 0.296 mmol) prepared in step 3 of Example 58 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.013 g, 23.8%) as a white solid.

[0553] 1 H NMR (400MHz, CDCl3) δ8.34-8.28(m,1H),8.23(dd,J=1.0,7.1Hz,1H),7.74(d,J=0.7Hz,1H),7.56(dd,J=1.7,7.1Hz,1H),7.38-7.23(m,3H),7.11 -6.80(m,2H),5.07(s,2H),3.61(t,J=5.2Hz,2H),3.48-3.40(m,2H),3. 23(dt,J=5.1,11.2Hz,4H), 2.33(q,J=7.4Hz,2H), 1.15(t,J=7.4Hz,3H);

[0554] LRMS (ES) m / z 563.9 (M + +1).

[0555] Example 69: Synthesis of Compound 4308, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-4-(2-hydroxyacetyl)piperazine-1-sulfonamide

[0556]

[0557] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide (0.050 g, 0.099 mmol), 2-hydroxyacetic acid (0.011 g, 0.148 mmol), triethylamine (0.041 mL, 0.296 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.056 g, 0.148 mmol) prepared in Step 3 of Example 58 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Sodium bicarbonate aqueous solution is poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, then concentrated under reduced pressure. The concentrate is purified by chromatography (SiO2 plate, 20x 20x 1mm; methanol / dichloromethane=0% to 7%) and concentrated to obtain the title compound (0.019 g, 33.4%) as a white solid.

[0558] 1 H NMR (400MHz, CDCl3) δ8.33-8.28(m,1H),8.23(dd,J=1.0,7.2Hz,1H),7.71(s,1H),7.56(dd,J=1.7,7.1Hz,1H) ,7.39-7.22(m,3H),7.12-6.81(m,2H),5.05(s,2H),4.15(s,2H),3.66(t,J=5.1Hz,2H),3.28(d,J=7.3Hz,6H);

[0559] LRMS (ES) m / z 566.3 (M + +1).

[0560] Example 70: Synthesis of Compound 4309, 4-(cyclobutanecarbonyl)-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide

[0561]

[0562] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide (0.050 g, 0.099 mmol), cyclobutanecarbonyl chloride (0.018 g, 0.148 mmol) and triethylamine (0.041 mL, 0.296 mmol) prepared in step 3 of Example 58 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.014 g, 23.4%) as a white solid.

[0563] 1 H NMR (400MHz, CDCl3) δ8.31(s,1H),8.23(d,J=7.1Hz,1H),7.73(s,1H),7.56(dd,J=1.6,7.1Hz,1H),7.36-7.23(m,3H),7.10-6.81(m,2H),5.0 8(s,2H),3.59(t,J=5.2Hz,2H),3.32(t,J=5.0Hz,2H),3.22-3.15(m,4H),2.32(td,J=2.7,9.0Hz,3H),2.18-2.09(m,2H),2.03-1.84(m,2H);

[0564] LRMS (ES) m / z 590.0 (M + +1).

[0565] Example 71: Synthesis of Compound 4310, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-4-(oxetane-3-carbonyl)piperazine-1-sulfonamide

[0566]

[0567] N-((7-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide (0.050 g, 0.099 mmol) prepared in Step 3 of Example 58, oxetane-3-carboxylic acid (0.015 g, 0.148 mmol), triethylamine (0.041 mL, 0.296 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.056 g, 0.148 mmol) were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Sodium bicarbonate aqueous solution is poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, then concentrated under reduced pressure. The concentrate is purified by chromatography (SiO2 plate, 20x 20x 1mm; methanol / dichloromethane=0% to 7%) and concentrated to obtain the title compound (0.006 g, 10.8%) as a white solid.

[0568] 1 H NMR (400MHz, CDCl3) δ8.32 (s, 1H), 8.23 ​​(d, J = 7.1Hz, 1H), 7.71 (s, 1H), 7.5 7(d,J=7.1Hz,1H),7.36-7.22(m,3H),7.11-6.81(m,2H),5.06(s,2H),4.89 (t,J=6.6Hz,2H),4.79(dd,J=6.2,8.5Hz,2H),3.97(p,J=7.7,8.2Hz,1H), 3.64(t,J=5.0Hz,2H), 3.24(dt,J=4.8,10.2Hz,4H), 3.16(d,J=5.4Hz,2H);

[0569] LRMS (ES) m / z 592.5 (M + +1).

[0570] Example 72: Synthesis of Compound 4311, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-4-(2,2,2-trifluoroacetyl)piperazine-1-sulfonamide

[0571]

[0572] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide (0.050 g, 0.099 mmol), 2,2,2-trifluoroacetic anhydride (0.031 g, 0.148 mmol) and triethylamine (0.041 mL, 0.296 mmol) prepared in step 3 of Example 58 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.016 g, 26.7%) as a white solid.

[0573] 1 H NMR (400MHz, CDCl3) δ8.31(s,1H),8.23(dd,J=1.0,7.1Hz,1H),7.70(s,1H),7.57(dd,J=1.7,7.1Hz,1H),7.38-7.2 3(m,3H),7.11-6.81(m,2H),5.05(s,2H),3.69(t,J=5.2Hz,2H),3.60(t,J=5.0Hz,2H),3.34(dq,J=2.5,7.8Hz,4H);

[0574] LRMS (ES) m / z 604.0 (M + +1).

[0575] Example 73: Synthesis of Compound 4312, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-4-(methylsulfonyl)piperazine-1-sulfonamide

[0576]

[0577] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide (0.040 g, 0.079 mmol), methanesulfonyl chloride (0.009 mL, 0.118 mmol) and triethylamine (0.033 mL, 0.236 mmol) prepared in step 3 of Example 58 were dissolved in dichloromethane (1 mL) at 0° C., and the resulting solution was stirred at room temperature for 10 minutes. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.015 g, 33.1%) as a white solid.

[0578] 1 H NMR (400MHz, CDCl3) δ8.31(dt,J=0.8,1.7Hz,1H),8.23(dd,J=1.0,7.2Hz,1H),7.74-7.69(m,1H),7.56(dd,J=1.7,7.1H z,1H),7.40-7.24(m,3H),7.11-6.80(m,2H),5.06(s,2H),3.40-3.32(m,4H),3.22(dd,J=3.6,6.3Hz,4H),2.78(s,3H);

[0579] LRMS(ES)m / z 586.0(M + +1).

[0580] Example 74: Synthesis of Compound 4313, 4-(N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)sulfamoyl)piperazine-1-carboxylic acid methyl ester

[0581]

[0582] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide (0.050 g, 0.099 mmol), methyl chloroformate (0.014 g, 0.148 mmol) and triethylamine (0.041 mL, 0.296 mmol) prepared in step 3 of Example 58 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.014 g, 24.4%) as a white solid.

[0583] 1 H NMR (400MHz, CDCl3) δ8.33-8.27(m,1H),8.23(dd,J=1.0,7.1Hz,1H),7.77-7.72(m,1H),7.55(dd,J=1.7,7.1Hz,1H) ,7.38-7.24(m,3H),7.11-6.80(m,2H),5.07(s,2H),3.71(s,3H),3.45(t,J=5.0Hz,4H),3.21(dd,J=4.0,6.3Hz,4H);

[0584] LRMS (ES) m / z 566.4 (M + +1).

[0585] Example 75: Synthesis of Compound 4314, 4-(N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)sulfamoyl)-N,N-dimethylpiperazine-1-carboxamide

[0586]

[0587] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide (0.050 g, 0.099 mmol), cyclobutanecarbonyl chloride (0.016 g, 0.148 mmol) and triethylamine (0.041 mL, 0.296 mmol) prepared in step 3 of Example 58 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.016 g, 27.5%) as a white solid.

[0588] 1 H NMR (400MHz, CDCl3) δ8.32-8.27(m,1H),8.23(dd,J=1.0,7.2Hz,1H),7.74(s,1H),7.54(dd,J=1.7,7.2Hz, 1H),7.37-7.21(m,3H),7.11-6.79(m,2H),5.08(s,2H),3.30-3.22(m,4H),3.24-3.16(m,4H),2.83(s,6H);

[0589] LRMS (ES) m / z 579.3 (M + +1).

[0590] Example 76: Synthesis of Compound 4315, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-4-(pyrimidin-2-yl)piperazine-1-sulfonamide

[0591]

[0592] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide (0.050 g, 0.099 mmol), 2-chloropyrimidine (0.023 g, 0.197 mmol) and potassium carbonate (0.041 g, 0.296 mmol) prepared in step 3 of Example 58 were dissolved in N,N-dimethylformamide (0.5 mL) / acetonitrile (0.5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A sodium bicarbonate aqueous solution was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.012 g, 20.3%) as a white solid.

[0593] 1 H NMR (400MHz, CDCl3) δ8.32(d,J=4.7Hz,2H),8.28(s,1H),8.23(dd,J=0.9,7.2Hz,1H),7.77(s,1H),7.55(dd,J=1.7,7.1Hz ,1H),7.37-7.25(m,3H),7.11-6.80(m,2H),6.55(t,J=4.8Hz,1H),5.11(s,2H),3.86-3.78(m,4H),3.30(t,J=5.1Hz,4H);

[0594] LRMS (ES) m / z 586.5 (M + +1).

[0595] Example 77: Synthesis of Compound 4616, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-1-(spiro[3.3]hept-2-yl)piperidine-4-sulfonamide

[0596]

[0597] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide (0.100 g, 0.197 mmol), spiro[3.3]heptan-2-one (0.043 g, 0.395 mmol), acetic acid (0.011 mL, 0.197 mmol) and sodium triacetoxyborohydride (0.126 g, 0.592 mmol) prepared in step 3 of Example 18 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. A saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; dichloromethane / methanol = 0% to 10%) and concentrated to afford the title compound (0.100 g, 84.3%) as a white solid.

[0598] 1 H NMR (400MHz, CDCl3) δ8.28(s,1H),8.23(d,J=7.1Hz,1H),7.78(s,1H),7.54(dd,J=7.1,1.5Hz,1H),7.36-7.23(m,3H),7.10-6.79(m,2 H),5.14(s,2H),3.12-2.87(m,3H),2.49(d,J=39.3Hz,1H),2.41(ddd,J=9.2,6.1,2.7Hz,1H),2.19-2.04(m,4H),2.04-1.61(m,11H);

[0599] LRMS (ES) m / z 601.1 (M + +1).

[0600] Example 78: Synthesis of Compound 4617, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-1-(2-oxaspiro[3.3]hept-6-yl)piperidine-4-sulfonamide

[0601]

[0602] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-sulfonamide (0.100 g, 0.197 mmol), 2-oxaspiro[3.3]heptan-6-one (0.044 g, 0.395 mmol), acetic acid (0.011 mL, 0.197 mmol) and sodium triacetoxyborohydride (0.126 g, 0.592 mmol) prepared in step 3 of Example 18 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; dichloromethane / methanol = 0% to 10%) and concentrated to obtain the title compound (0.100 g, 84.0%) as a white solid.

[0603] 1 H NMR (400MHz, CDCl3) δ8.28 (s, 1H), 8.23 ​​(d, J = 7.1Hz, 1H), 7.77 (s, 1H), 7.54 (d,J=7.2Hz,1H),7.36-7.21(m,3H),7.11-6.79(m,2H),5.14(s,2H),4.75- 4.64(m,2H),4.61(s,2H),3.13-2.88(m,3H),2.59-2.31(m,3H),2.08(ddd, J=49.8,24.9,14.0Hz,4H),1.89(d,J=35.1Hz,2H),1.70(d,J=12.6Hz,2H);

[0604] LRMS (ES) m / z 603.3 (M + +1).

[0605] Example 79: Synthesis of Compound 4622, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-4-(spiro[3.3]hept-2-yl)piperazine-1-sulfonamide

[0606]

[0607] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide (0.090 g, 0.177 mmol), spiro[3.3]heptan-2-one (0.039 g, 0.355 mmol), acetic acid (0.010 mL, 0.177 mmol) and sodium triacetoxyborohydride (0.113 g, 0.532 mmol) prepared in step 3 of Example 58 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. Saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; dichloromethane / methanol = 0% to 10%) and concentrated to afford the title compound (0.050 g, 46.9%) as a white solid.

[0608] 1 H NMR (400MHz, CDCl3) δ8.29(s,1H),8.23(d,J=7.1Hz,1H),7.78(s,1H),7.54(dd,J=7.1,1.7Hz,1H),7.35-7.23(m, 3H),7.09-6.80(m,2H),5.09(s,2H),3.28(s,4H),2.57(s,1H),2.39-2.18(m,3H),2.13(s,2H),2.04-1.77(m,9H);

[0609] LRMS (ES) m / z 602.4 (M + +1).

[0610] Example 80: Synthesis of Compound 4623, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-4-(2-oxaspiro[3.3]hept-6-yl)piperazine-1-sulfonamide

[0611]

[0612] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-sulfonamide (0.090 g, 0.177 mmol), 2-oxaspiro[3.3]heptan-6-one (0.040 g, 0.355 mmol), acetic acid (0.010 mL, 0.177 mmol) and sodium triacetoxyborohydride (0.113 g, 0.532 mmol) prepared in step 3 of Example 58 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. Saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; dichloromethane / methanol = 0% to 10%) and concentrated to afford the title compound (0.050 g, 46.7%) as a white solid.

[0613] 1 H NMR (400MHz, CDCl3) δ8.29(s,1H),8.23(d,J=7.1Hz,1H),7.76(s,1H),7.54(dd,J=7.1,1.6Hz,1H),7.36-7.23(m,3H),7. 10-6.81(m,2H),5.08(s,2H),4.71(s,2H),4.60(s,2H),3.24(s,4H),2.50(s,1H),2.39(s,2H),2.26(s,4H),1.99(s,2H);

[0614] LRMS (ES) m / z 604.2 (M + +1).

[0615] Example 81: Synthesis of Compound 4624, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-6-methyl-N-phenyl-2,6-diazaspiro[3.3]heptane-2-sulfonamide

[0616] [Step 1] Synthesis of tert-butyl 6-((1H-imidazol-1-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0617]

[0618] 1-((1H-imidazole-1-yl)sulfonyl)-3-methyl-1H-imidazole-3-ium trifluoromethanesulfonate (3.600 g, 9.937 mmol) prepared in step 1 of Example 38 was dissolved in acetonitrile (25 mL). Then, tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate oxalate (2.659 g, 5.465 mmol) and N,N-diisopropylethylamine (8.654 mL, 49.683 mmol) were added at 0°C, stirred at the same temperature for 0.2 hours, and stirred at room temperature for another 3 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 24 g column; ethyl acetate / hexane = 10% to 80%) and concentrated to obtain the title compound (1.300 g, 39.8%) as a white solid.

[0619] [Step 2] Synthesis of (1-((6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]hept-2-yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate

[0620]

[0621] The tert-butyl 6-((1H-imidazole-1-yl)sulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1.300 g, 3.959 mmol) prepared in step 1 was dissolved in dichloromethane (20 mL). Then, methyl trifluoromethanesulfonate (0.499 mL, 4.553 mmol) was added at 0 ° C, stirred at the same temperature for 0.2 hours, and stirred at room temperature for another 3 hours. After removing the solvent from the reaction mixture under reduced pressure, the title compound (1.850 g, 94.9%) was obtained as a white solid without further purification.

[0622] [Step 3] Synthesis of tert-butyl 6-(N-(phenylsulfamoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0623]

[0624] (1-((6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]hept-2-yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (1.140 g, 2.315 mmol) and aniline (0.254 mL, 2.778 mmol) prepared in step 2 were dissolved in acetonitrile (15 mL) at room temperature and stirred at 85° C. for 18 hours. Then, the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 24 g column; ethyl acetate / hexane=0% to 30%) and concentrated to obtain the title compound (0.500 g, 61.1%) as a yellow solid.

[0625] [Step 4] Synthesis of tert-butyl 6-(N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylsulfamoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0626]

[0627] The tert-butyl 6-(N-phenylsulfamoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.100 g, 0.283 mmol), 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.097 g, 0.340 mmol), potassium carbonate (0.059 g, 0.424 mmol) and potassium iodide (0.023 g, 0.141 mmol) prepared in step 3 were dissolved in N,N-dimethylformamide (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. Saturated aqueous ammonium chloride solution was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 40 g column; ethyl acetate / hexane = 0% to 70%) and concentrated to obtain the title compound (0.120 g, 70.5%) as a white solid.

[0628] [Step 5] Synthesis of N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenyl-2,6-diazaspiro[3.3]heptane-2-sulfonamide

[0629]

[0630] 6-(N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylsulfamoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (0.120 g, 0.199 mmol) and trifluoroacetic acid (0.305 mL, 3.989 mmol) prepared in step 4 were dissolved in dichloromethane (10 mL) at room temperature, and the resulting solution was stirred for 2 hours at the same temperature. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution, dried over anhydrous magnesium sulfate, and filtered. After concentration under reduced pressure, the title compound (0.100 g, 100.0%) was obtained as a yellow gel without further purification.

[0631] [Step 6] Synthesis of compound 4624

[0632]

[0633] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenyl-2,6-diazaspiro[3.3]heptane-2-sulfonamide (0.100 g, 0.199 mmol), formaldehyde (0.012 g, 0.399 mmol), acetic acid (0.011 mL, 0.199 mmol) and sodium triacetoxyborohydride (0.127 g, 0.598 mmol) prepared in step 5 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. Saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO2 plate, 20 x 20 x 1 mm; dichloromethane / methanol = 0% to 10%) and concentrated to afford the title compound (0.080 g, 77.8%) as a white solid.

[0634] 1 H NMR (400MHz, CDCl3) δ8.28(s,1H),8.21(d,J=7.1Hz,1H),7.75(s,1H),7.52(dd,J=7.1,1.7Hz,1H),7.47-7.41(m, 2H),7.38-7.31(m,2H),7.30-7.25(m,1H),7.09-6.80(m,1H),5.07(s,2H),4.00(s,4H),3.33(s,4H),2.31(s,3H);

[0635] LRMS (ES) m / z 516.2 (M + +1).

[0636] Example 82: Synthesis of Compound 6893, tert-butyl 4-(N-(3-fluorophenyl)-N-((7-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)sulfamoyl)piperidine-1-carboxylate

[0637] [Step 1] Synthesis of tert-butyl (4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)carbamate

[0638]

[0639] The tert-butyl (4-(hydrazinecarbonyl)pyridin-2-yl)carbamate (2.600g, 10.306mmol) and triethylamine (14.365mL, 103.064mmol) prepared in step 2 of Example 1 were dissolved in tetrahydrofuran (150mL), and trifluoroacetic anhydride (7.279mL, 51.532mmol) was added at room temperature and heated to reflux for 16 hours. Then, the temperature was lowered to room temperature to terminate the reaction. Saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Ethyl acetate (30mL) and hexane (100mL) were poured into the concentrate, suspended, and filtered to obtain a solid, and the obtained solid was washed with hexane and dried to obtain the title compound (1.500g, 44.1%) as a white solid.

[0640] [Step 2] Synthesis of 4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine

[0641]

[0642] The tert-butyl (4-(5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)carbamate (1.500g, 4.542mmol) prepared in step 1 was dissolved in dichloromethane (70mL). Then, trifluoroacetic acid (6.956mL, 90.835mmol) was added at 0°C, and the resulting solution was stirred at room temperature for 4 hours. After removing the solvent from the reaction mixture under reduced pressure, saturated sodium bicarbonate aqueous solution (50mL) was poured into the concentrate and suspended, then filtered to obtain a solid. The obtained solid was washed with water and dried to obtain the title compound (1.030g, 98.5%) as a yellow solid.

[0643] [Step 3] Synthesis of 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole

[0644]

[0645] 4-(5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-amine (1.100 g, 4.779 mmol), 1,3-dichloropropane-2-one (1.214 g, 9.559 mmol) and sodium bicarbonate (2.008 g, 23.897 mmol) prepared in step 2 were dissolved in 1,4-dioxane (60 mL) at room temperature. The resulting solution was heated to reflux for 16 hours, and then the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a plastic filter to remove solids, and the filtrate was purified and concentrated by column chromatography (SiO2, 40 g column; ethyl acetate / hexane=5% to 70%) to obtain the title compound (0.850 g, 58.8%) as a beige solid.

[0646] [Step 4] Synthesis of compound 6893

[0647]

[0648] Tert-butyl 4-(N-(3-fluorophenyl)sulfamoyl)piperidine-1-carboxylate (0.250 g, 0.697 mmol) prepared in step 1 of Example 18, 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole (0.201 g, 0.663 mmol) prepared in step 3, potassium carbonate (0.193 g, 1.395 mmol) and potassium iodide (0.012 g, 0.070 mmol) were dissolved in N,N-dimethylformamide (6 mL) at room temperature, and the resulting solution was stirred at 60° C. for 16 hours. Then, the temperature was lowered to room temperature to terminate the reaction. Water was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. Next, the obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 24 g column; ethyl acetate / hexane = 10% to 90%) and concentrated to obtain the title compound (0.150 g, 34.4%) as a colorless oil.

[0649] 1H NMR(400MHz, CDCl3)δ8.08(s,1H),7.98(m,1H),7.59(s,1H),7.28-7.15(m,4H),6.87(m,1H) ,5.11(s,2H),4.19(m,2H),3.21(m,1H),2.67(m,2H),2.05(m,2H),1.75(m,2H),1.41(s,9H).

[0650] Activity Measurement and Analytical Protocols for Compounds of the Invention

[0651] <Experimental Example 1> In vitro HDAC enzyme activity inhibition assay

[0652] In order to confirm the selectivity of the compound represented by Chemical Formula I of the present invention to HDAC6 through HDAC1 and HDAC6 enzyme activity inhibition experiments, a comparative experiment was performed using the developed material as a control group.

[0653] HDAC enzyme activity was measured using the HDAC Fluorescence Drug Discovery Kit (Enzo Life Sciences, Inc., BML-AK511,516). For HDAC1 enzyme activity testing, human recombinant HDAC1 (BML-SE456) was used as the enzyme source, and Fluor de -SIRT1 (BNL-KI177) as a substrate. After dispensing the 5-fold diluted compound into a 96-well plate, 0.3 μg of enzyme and 10 μM substrate were added to each well of the plate and allowed to react at 30°C for 60 minutes. Next, Fluor de Developer II (BML-KI176) and react for 30 minutes to complete the reaction, then use a multi-plate reader (Flexstation 3, Molecular Device) to measure fluorescence values ​​(Ex 360, Em 460). According to the same scheme as the HDAC1 enzyme activity test method, the human recombinant HDAC6 (382180) from Calbiochem Inc. is used to test the HDAC6 enzyme. For the final result value, the corresponding IC50 value is calculated using GraphPad Prism 4.0 program, and the results are summarized in the following table 4.

[0654] [Table 4] Results of HDAC enzyme activity inhibition assay

[0655]

[0656]

[0657]

[0658] As shown in Table 4 above, according to the results of HDAC1 and HDAC6 activity inhibition assays, it was found that the 1,3,4-oxadiazole derivative compound of the present invention, its optical isomer or a pharmaceutically acceptable salt thereof exhibited about 16 to about 1055 times higher selective HDAC6 inhibitory activity than HDAC1.

[0659] <Experimental Example 2> In vitro analysis of the effects of HDAC6-specific inhibitors on mitochondrial axonal transport

[0660] The effect of HDAC6 specific inhibitors on mitochondrial axonal transport was analyzed. Specifically, in order to confirm whether the compound represented by Chemical Formula I of the present invention selectively inhibits HDAC6 activity and increases the acetylation of tubulin, which is the main substrate of HDAC6, thereby improving the mitochondrial axonal transport rate reduced by amyloid-β treatment in neuronal axons, a comparative experiment was carried out using the developed material as a control group.

[0661] The hippocampal neurons from Sprague-Dawley (SD) rat embryos at embryonic day 17-18 (E17-18) were cultured in a culture dish coated with extracellular matrix for 7 days for imaging, and then treated with 1M amyloid-β peptide fragments. After 24 hours, the 8th day of in vitro culture was treated with compounds, and after 3 hours, the last 5 minutes were treated with MitoTrackerRed CMXRos (Life Technologies, NY, USA) to dye mitochondria. About the axonal transport of stained neuronal mitochondria, by using a confocal microscope (Leica 5P8; Leica Microsystems, UK) to take images (at 1 second intervals for 1 minute), the transport rate of each mitochondria was determined using IMARIS analysis software (BITPLANE, Zurich, Switzerland).

[0662] As a result, it was confirmed that the 1,3,4-oxadiazole derivative compound of the present invention, an optical isomer thereof, or a pharmaceutically acceptable salt thereof exhibits an improving effect on the mitochondrial axonal transport rate.

Claims

1. A 1,3,4-oxadiazole derivative compound represented by the following chemical formula I, an optical isomer thereof or a pharmaceutically acceptable salt thereof: [Chemical Formula I] In the above chemical formula I, L1, L2 and L3 are each independently -(C0-C2 alkyl)-; a, b and c are each independently N or CR 4 , where a, b and c cannot be N at the same time, and R 4 is -H, -X or -O(C1-C4 alkyl); R1 is -CX2H or -CX3; R2 is Y is -N-, -O- or -S(=O)2-; When Y is -N-, R5, R6 and R8 are each independently -H, -X, -OH, -(C1-C4 alkyl), -(C1-C4 alkyl)-O(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -O(C1-C4 alkyl), -NR C R D , -CF3, -CF2H, -CN, -C(=O)-(C1-C4 alkyl), -C(=O)-(C3-C7 cycloalkyl), -C(=O)-(C2-C6 heterocycloalkyl), -C(=O)-O(C1-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(C1-C4 alkyl), -C(=O)-NR C R D 、-C(=O)-(C1-C4 alkyl)-NR C R D , -S(=O)2-(C1-C4 alkyl), -aryl, -heteroaryl, -(C1-C4 alkyl)-aryl, -(C1-C4 alkyl)heteroaryl or wherein at least one H of -(C1-C4 alkyl), -(C=O)-(C1-C4 alkyl), -(C3-C7 cycloalkyl) and -C(=O)-(C3-C7 cycloalkyl) may be substituted by -X, -OH, -O(C1-C4 alkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -CF3 or -CF2H; -aryl, -heteroaryl, -(C1-C4 alkyl)-aryl and -(C At least one H of the -(C1-C4 alkyl)heteroaryl may be substituted by -X, -OH, -(C1-C4 alkyl), -O(C1-C4 alkyl), -C(═O)-(C1-C4 alkyl), -C(═O)-O(C1-C4 alkyl), -CF3 or -CF2H; the -(C2-C6 heterocycloalkyl), -heteroaryl or -(C1-C4 alkyl)heteroaryl may contain N, O or S atoms in the ring; and Z is -NH-, -CH2- or -O-; When Y is -O- or -S(=O)2-, R5, R6 and R8 are absent (none); R C To R D each independently represents -H, -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -(C1-C4 alkyl)-(C2-C6 heterocycloalkyl), aryl, heteroaryl or -(C1-C4 alkyl)-aryl, wherein at least one H of -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -(C1-C4 alkyl)-(C2-C6 heterocycloalkyl), aryl, heteroaryl and -(C1-C4 alkyl)-aryl may be substituted by -(C1-C4 alkyl), -C(═O)-(C1-C4 alkyl), -S(═O)2-(C1-C4 alkyl) or -(C2-C6 heterocycloalkyl); m and n are each independently an integer of 1, 2 or 3; R a To R d Each is independently -H or -(C1-C4 alkyl); R 3 is -aryl or -heteroaryl, wherein at least one H of -aryl and -heteroaryl can be independently replaced by -X, -OH, -O(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -C(=O)-(C1-C4 alkyl), -CF3, -CF2H, -OCF3, -S(=O)2-(C1-C4 alkyl), -aryl, -O-aryl, -heteroaryl or -NR E R F Replace, and R E and R F are each independently -H or -(C1-C4 alkyl); and X is F, Cl, Br or I.

2. The 1,3,4-oxadiazole derivative compound represented by Chemical Formula I, its optical isomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein in the above Chemical Formula I, L1 to L3 are each independently -(C0-C1 alkyl)-; a, b and c are each independently N or CR 4 , where a, b and c cannot be N at the same time, and R 4 is -H or -X; R1 is -CX2H or -CX3; R2 is Y is -N-, -O- or -S(=O)2-; When Y is -N-, R5, R6 and R8 are each independently -H, -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-(C3-C7 cycloalkyl), -C(=O)-(C2-C6 heterocycloalkyl), -C(=O)-O(C1-C4 alkyl), -C(=O)-NR C R D , -S(=O)2-(C1-C4 alkyl), -heteroaryl or wherein at least one -H of -(C1-C4 alkyl), -(C=O)-(C1-C4 alkyl) and -(C3-C7 cycloalkyl) may be substituted by -X or -OH; -(C2-C6 heterocycloalkyl) or -heteroaryl may contain N, O or S atoms in the ring; and Z is -NH-, -CH2- or -O-; When Y is -O- or -S(=O)2-, R5, R6 and R8 are absent (none); R C To R D Each is independently -H or -(C1-C4 alkyl); m and n are each independently an integer of 1 or 2; R a To R d Each is independently -H or -(C1-C4 alkyl); R 3 is -aryl or -heteroaryl, wherein at least one H of -aryl and -heteroaryl may be substituted with -X, respectively, independently; and X is F, Cl or Br.

3. The 1,3,4-oxadiazole derivative compound represented by Chemical Formula I according to claim 2, its optical isomer or a pharmaceutically acceptable salt thereof, wherein in the above Chemical Formula I, L1 and L3 are each independently -(C0 alkyl)-; L2 is -(C1 alkyl)-; a, b and c are each independently CR 4 , where R 4 is -H or -X; R1 is -CX2H or -CX3; R2 is Y is -N-, R5 and R6 are each independently -H, -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-(C3-C7 cycloalkyl), -C(=O)-(C2-C6 heterocycloalkyl), -C(=O)-O(C1-C4 alkyl), -C(=O)-NR C R D , -S(=O)2-(C1-C4 alkyl), -heteroaryl or wherein at least one -H of -(C1-C4 alkyl), -(C=O)-(C1-C4 alkyl) and -(C3-C7 cycloalkyl) may be substituted by -X or -OH; -(C2-C6 heterocycloalkyl) or -heteroaryl may contain N, O or S atoms in the ring; and Z is -CH2- or -O-; R C and R D Each is independently -H or -(C1-C4 alkyl); m and n are each independently an integer of 1 or 2; R a To R d Each is independently -H or -(C1-C4 alkyl); R 3 is -aryl, wherein at least one H of the -aryl may be independently substituted by -X; and X is F or Cl.

4. The 1,3,4-oxadiazole derivative compound represented by Chemical Formula I, its optical isomer or a pharmaceutically acceptable salt thereof according to claim 2, wherein in the above Chemical Formula I, L1 to L3 are each independently -(C0-C1 alkyl)-; a, b and c are each independently N or CR 4 , where a, b and c cannot be N at the same time, and R 4 is -H or -X; R1 is -CX2H or -CX3; R2 is Y is -N-, -O- or -S(=O)2-; When Y is -N-, R5 is -H, -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-(C3-C7 cycloalkyl), -C(=O)-(C2-C6 heterocycloalkyl), -C(=O)-O(C1-C4 alkyl), -C(=O)-NR C R D , -S(=O)2-(C1-C4 alkyl), -heteroaryl or wherein at least one -H of -(C1-C4 alkyl), -(C=O)-(C1-C4 alkyl) and -(C3-C7 cycloalkyl) may be substituted by -X or -OH; -(C2-C6 heterocycloalkyl) or -heteroaryl may contain N, O or S atoms in the ring; and Z is -NH-, -CH2- or -O-; When Y is -O- or -S(=O)2-, R5 is absent (none); R C and R D Each is independently -H or -(C1-C4 alkyl); m and n are each independently an integer of 1 or 2; R a To R d Each is independently -H or -(C1-C4 alkyl); R 3 is -aryl or -heteroaryl, wherein at least one H of -aryl and -heteroaryl may be substituted with -X, respectively, independently; and X is F, Cl or Br.

5. The 1,3,4-oxadiazole derivative compound represented by Chemical Formula I, its optical isomer or a pharmaceutically acceptable salt thereof according to claim 2, wherein in the above Chemical Formula I, L1 to L3 are each independently -(C0-C1 alkyl)-; a, b and c are each independently N or CR 4 , where a, b and c cannot be N at the same time, and R 4 is -H or -X; R1 is -CX2H or -CX3; R2 is Y is -N-, -O- or -S(=O)2-; When Y is -N-, R6 and R8 are each independently -H, -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-(C3-C7 cycloalkyl), -C(=O)-(C2-C6 heterocycloalkyl), -C(=O)-O(C1-C4 alkyl), -C(=O)-NR C R D , -S(=O)2-(C1-C4 alkyl), -heteroaryl or wherein at least one -H of -(C1-C4 alkyl), -(C=O)-(C1-C4 alkyl) and -(C3-C7 cycloalkyl) may be substituted by -X or -OH; -(C2-C6 heterocycloalkyl) or -heteroaryl may contain N, O or S atoms in the ring; and Z is -NH-, -CH2- or -O-; When Y is -O- or -S(=O)2-, R6 and R8 are absent (none); R C To R D Each is independently -H or -(C1-C4 alkyl); m and n are each independently an integer of 1 or 2; R a To R d Each is independently -H or -(C1-C4 alkyl); R 3 is -aryl or -heteroaryl, wherein at least one H of -aryl and -heteroaryl may be substituted with -X, respectively, independently; and X is F, Cl or Br.

6. The 1,3,4-oxadiazole derivative compound, its optical isomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is any one of the compounds listed in the following table:

7. The 1,3,4-oxadiazole derivative compound, its optical isomer or a pharmaceutically acceptable salt thereof according to claim 6, wherein the compound is any one of the compounds listed in the following table:

8. The 1,3,4-oxadiazole derivative compound, its optical isomer or a pharmaceutically acceptable salt thereof according to claim 6, wherein the compound is any one of the compounds listed in the following table:

9. A pharmaceutical composition for preventing or treating a disease mediated by histone deacetylase 6, comprising the compound according to any one of claims 1 to 8, its optical isomer or a pharmaceutically acceptable salt thereof as an active ingredient.

10. The pharmaceutical composition for preventing or treating a disease mediated by histone deacetylase 6 according to claim 9, wherein The diseases mediated by histone deacetylase 6 are infectious diseases; neoplasms; endocrine, nutritional and metabolic diseases; mental and behavioral disorders; nervous system diseases; eye and appendage diseases; respiratory system diseases; Digestive system diseases; Skin and subcutaneous tissue disorders; musculoskeletal and connective tissue disorders; or congenital malformations, alterations, or chromosomal abnormalities.

11. Use of the compound according to any one of claims 1 to 8, its optical isomer or a pharmaceutically acceptable salt thereof for preparing a medicament for preventing or treating a disease mediated by histone deacetylase 6.

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