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] L 1 , L 2 and L 3 Each independently is -(C 0 -C 2 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(C 1 -C 4 alkyl)};

[0027] Z is N, O, S or absent (none) {wherein when Z is absent (none), R 2 does not exist (nothing), and L2 and L 3 Direct connection};

[0028] R 1 Yes-CX 2 H or -CX 3 ;

[0029] R 2 Yes-H, -(C 1 -C 4 alkyl), -C(=O)-R A 、-C(=O)-OR B or -C(=O)-NR C R D {When Z is O or S, R 2 does not exist (none)};

[0030] R A Yes-(C 1 -C 4 Alkyl), -(C 1 -C 4 alkyl)-O-(C 1 -C 4 Alkyl), -(C 1 -C 4 alkyl)-C(=O)-O(C 1 -C 4 alkyl), -aryl, -heteroaryl, -NR A1 R A2 ,

[0031]

[0032] R B To R D are independently -H, -(C 1 -C 4 Alkyl), -(C 1 -C 4 alkyl)-O-(C 1 -C 4 Alkyl), -(C 1 -C 4 alkyl)-C(=O)-O(C 1 -C 4 Alkyl), -(C 3 -C 7 cycloalkyl), -aryl or -heteroaryl;

[0033] Y is N, CH, O or S(=O) 2 ,

[0034] When Y is N or CH, R Y1 To R Y4 are independently -H, -X, -OH, -(C 1 -C 4 Alkyl), -(C 3 -C 7 Cycloalkyl), -(C 2 -C 6 Heterocycloalkyl), -(C 1 -C 4 alkyl)-O-(C 1 -C 4 Alkyl), -(C 1 -C 4 alkyl)-C(=O)-O(C 1 -C 4 alkyl), -C(=O)-(C 1 -C 4 alkyl), -C(=O)-O(C 1 -C 4 alkyl), -C(=O)-NR A3 R A4 、-C(=O)-(C 3 -C 7 Cycloalkyl), -C(=O)-(C 2 -C 6 Heterocycloalkyl), -S(=O) 2 -(C 1 -C 4 alkyl), -aryl, -(C 1 -C 4 alkyl)-aryl, -heteroaryl, -(C 1 -C 4 alkyl)-heteroaryl, amine protecting group or

[0035] {where -(C 1 -C 4 Alkyl), -(C 3 -C 7 Cycloalkyl), -(C 1 -C 4 alkyl)-O-(C 1 -C 4 Alkyl), -(C 1 -C 4 alkyl)-C(=O)-O(C 1 -C 4 alkyl), -C(=O)-(C 1 -C 4 alkyl), -C(=O)-(C 3 -C 7Cycloalkyl), -C(=O)-(C 2 -C 6 Heterocycloalkyl) and -S(=O) 2 -(C 1 -C 4 At least one H of the alkyl group may be substituted by -X or -OH; 1 -C 4 alkyl)-aryl, heteroaryl and -(C 1 -C 4 At least one H of the heteroaryl group may be replaced by -(C 1 -C 4 Alkyl), -O-(C 1 -C 4 alkyl), -X, -OH or -CF 3 Replace; -(C 2 -C 6 Heterocycloalkyl), -heteroaryl or -(C 1 -C 4 alkyl)heteroaryl may contain N, O or S atoms in the ring; and W is NH, CH 2 or O};

[0036] When Y is O or S (=O) 2 When R Y1 To R Y4 does not exist (none);

[0037] m and n are each independently an integer of 1, 2 or 3;

[0038] R a To R d are independently -H or -(C 1 -C 4 alkyl);

[0039] R 3 Yes-H, -(C 1 -C 4 Alkyl), -(C 1 -C 4 Alkyl)-O(C 1 -C 4 Alkyl), -(C 1 -C 4 alkyl)-C(=O)-O(C 1 -C 4 alkyl), -C(=O)-O(C 1 -C 4 Alkyl), -(C 3 -C 7 Cycloalkyl), -(C 2 -C 6heterocycloalkyl), -adamantyl, -aryl or -heteroaryl {wherein -(C 1 -C 4 At least one H of -(C 3 -C 7 Cycloalkyl), -(C 2 -C 6 At least one -H of -(C 1 -C 4 Alkyl), -O(C 1 -C 4 alkyl), -(C=O)-(C 1 -C 4 alkyl), -C(=O)-O(C 1 -C 4 Alkyl), -CF 3 , -CF 2 H, -OCF 3 、-NR A5 R A6 、-S(=O) 2 -(C 1 -C 4 alkyl), -aryl or -heteroaryl};

[0040] R A1 To R A6 are independently -H or -(C 1 -C 4 alkyl); and

[0041] X is F, Cl, Br or I.

[0042] According to one embodiment of the present invention,

[0043] In the above chemical formula I,

[0044] L 1 , L 2 and L 3 Each independently is -(C 0 -C 1 alkyl)-;

[0045] 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};

[0046] Z is N, O or absent (none) {wherein when Z is absent (none), R 2 does not exist (nothing), and L 2 and L3 Direct connection};

[0047] R 1 Yes-CX 2 H or -CX 3 ;

[0048] R 2 Yes-H, -(C 1 -C 4 alkyl) or -C(=O)-R A {When Z is O, R 2 does not exist (none)};

[0049] R A Yes - NR A1 R A2 ,

[0050] Y is N, CH, O or S(=O) 2 ;

[0051] When Y is N or CH, R Y1 To R Y4 are independently -H, -(C 1 -C 4 Alkyl), -(C 3 -C 7 Cycloalkyl), -(C 2 -C 6 Heterocycloalkyl), -C(=O)-(C 1 -C 4 alkyl), -C(=O)-O(C 1 -C 4 alkyl), -C(=O)-NR A3 R A4 、-C(=O)-(C 3 -C 7 Cycloalkyl), -C(=O)-(C 2 -C 6 Heterocycloalkyl), -S(=O) 2 -(C 1 -C 4 alkyl), -aryl, -heteroaryl or

[0052] {where -(C 1 -C 4 Alkyl), -(C 3 -C 7 Cycloalkyl), -C(=O)-(C 1 -C 4 alkyl), -C(=O)-(C3 -C 7 Cycloalkyl), -C(=O)-(C 2 -C 6 Heterocycloalkyl) and -S(=O) 2 -(C 1 -C 4 At least one H of an alkyl group may be substituted with -X or -OH; at least one H of an aryl group or a heteroaryl group may be substituted with -(C 1 -C 4 Alkyl), -O-(C 1 -C 4 alkyl), -X, -OH or -CF 3 Replace; -(C 2 -C 6 heterocycloalkyl) or -heteroaryl may contain N, O or S atoms in the ring; and W is NH, CH 2 or O};

[0053] When Y is O or S (=O) 2 When R Y1 To R Y4 does not exist (none);

[0054] m and n are each independently an integer of 1 or 2;

[0055] R a To R d are independently -H or -(C 1 -C 4 alkyl);

[0056] R 3 Yes-(C 3 -C 7 Cycloalkyl), -(C 2 -C 6 heterocycloalkyl), -adamantyl, -aryl or -heteroaryl {wherein -(C 3 -C 7 Cycloalkyl), -(C 2 -C 6 At least one -H of -(C 1 -C 4 Alkyl), -O(C 1 -C 4 alkyl), -(C=O)-(C 1 -C 4 alkyl), -C(=O)-O(C 1 -C 4 Alkyl), -CF 3 , -CF 2 H, -OCF3 、-NR A5 R A6 、-S(=O) 2 -(C 1 -C 4 alkyl), -aryl or -heteroaryl};

[0057] R A1 To R A6 are independently -H or -(C 1 -C 4 alkyl); and

[0058] X can be F, Cl or Br.

[0059] Furthermore, according to another embodiment of the present invention,

[0060] In the above chemical formula I,

[0061] L 1 and L 3 Each independently is -(C 0 alkyl)-;

[0062] L 2 Yes-(C 1 alkyl)-;

[0063] a, b and c are each independently CR 4 {where R 4 is -H or -X};

[0064] Z is N, O or absent (none) {wherein when Z is absent (none), R 2 does not exist (nothing), and L 2 and L 3 Direct connection};

[0065] R 1 Yes - CF 2 H or -CF 3 ;

[0066] R 2 is -H or -C(=O)-R A {When Z is O, R 2 does not exist (none)};

[0067] R A yes

[0068] Y is N;

[0069] R Y1 To R Y4Each independently is -(C 1 -C 4 Alkyl), -(C 3 -C 7 Cycloalkyl), -(C 2 -C 6 Heterocycloalkyl), -C(=O)-(C 1 -C 4 alkyl), -C(=O)-O(C 1 -C 4 alkyl), -C(=O)-NR A3 R A4 、-C(=O)-(C 3 -C 7 Cycloalkyl), -C(=O)-(C 2 -C 6 Heterocycloalkyl), -S(=O) 2 -(C 1 -C 4 alkyl), -heteroaryl or

[0070] {where -(C 1 -C 4 Alkyl), -(C 3 -C 7 Cycloalkyl), -C(=O)-(C 1 -C 4 alkyl), -C(=O)-(C 3 -C 7 Cycloalkyl), -C(=O)-(C 2 -C 6 Heterocycloalkyl) and -S(=O) 2 -(C 1 -C 4 At least one H of -(C 2 -C 6 Heterocycloalkyl) may contain N, O or S atoms in the ring; and W is CH 2 or O};

[0071] m and n are each independently an integer of 1 or 2;

[0072] R a To R d are independently -H or -(C 1 -C 4 alkyl);

[0073] R 3 Yes-(C 3 -C 7 cycloalkyl), -adamantyl, -aryl or -heteroaryl {wherein -(C3 -C 7 At least one -H of -(cycloalkyl), -adamantyl, -aryl and -heteroaryl may be independently replaced by -X, -(C 1 -C 4 Alkyl), -O(C 1 -C 4 alkyl), -(C=O)-(C 1 -C 4 Alkyl), -CF 3 or -S(=O) 2 -(C 1 -C 4 alkyl) substituted};

[0074] R A1 To R A6 are independently -H or -(C 1 -C 4 alkyl); and

[0075] X may be F or Cl.

[0076] Furthermore, according to yet another embodiment of the present invention,

[0077] In the above chemical formula I,

[0078] L 1 , L 2 or L 3 Each independently is -(C 0 -C 1 alkyl)-;

[0079] 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};

[0080] Z is N;

[0081] R 1 Yes-CX 2 H or -CX 3 ;

[0082] R 2 Yes -C(=O)-R A ;

[0083] R A yes

[0084] Y is N, CH, O or S(=O) 2 ;

[0085] When Y is N or CH, R Y1 and RY3 are independently -H, -(C 1 -C 4 Alkyl), -(C 3 -C 7 Cycloalkyl), -(C 2 -C 6 Heterocycloalkyl), -C(=O)-(C 1 -C 4 alkyl), -C(=O)-O(C 1 -C 4 alkyl), -C(=O)-NR A3 R A4 、-C(=O)-(C 3 -C 7 Cycloalkyl), -C(=O)-(C 2 -C 6 Heterocycloalkyl), -S(=O) 2 -(C 1 -C 4 alkyl), -aryl, -heteroaryl or

[0086] {where -(C 1 -C 4 Alkyl), -(C 3 -C 7 Cycloalkyl), -C(=O)-(C 1 -C 4 alkyl), -C(=O)-(C 3 -C 7 Cycloalkyl), -C(=O)-(C 2 -C 6 Heterocycloalkyl) and -S(=O) 2 -(C 1 -C 4 At least one H of an alkyl group may be substituted with -X or -OH; at least one H of an aryl group or a heteroaryl group may be substituted with -(C 1 -C 4 Alkyl), -O-(C 1 -C 4 alkyl), -X, -OH or -CF 3 Replace; -(C 2 -C 6 heterocycloalkyl) or -heteroaryl may contain N, O or S atoms in the ring; and W is NH, CH 2 or O};

[0087] When Y is O or S (=O) 2 When R Y1 and R Y3 does not exist (none);

[0088] m and n are each independently an integer of 1 or 2;

[0089] R a To R d are independently -H or -(C 1 -C 4 alkyl);

[0090] R 3 is -C(=O)-O(C 1 -C 4 Alkyl), -(C 3 -C 7 Cycloalkyl), -(C 2 -C 6 heterocycloalkyl), -adamantyl, -aryl or -heteroaryl {wherein -(C 3 -C 7 Cycloalkyl), -(C 2 -C 6 At least one -H of -(C 1 -C 4 Alkyl), -O(C 1 -C 4 alkyl), -(C=O)-(C 1 -C 4 alkyl), -C(=O)-O(C 1 -C 4 Alkyl), -CF 3 , -CF 2 H, -OCF 3 、-NR A5 R A6 、-S(=O) 2 -(C 1 -C 4 alkyl), -aryl or -heteroaryl};

[0091] R A3 To R A6 are independently -H or -(C 1 -C 4 alkyl); and

[0092] X can be F, Cl or Br.

[0093] Furthermore, according to yet another embodiment of the present invention,

[0094] In the above chemical formula I,

[0095] L 1 , L 2 and L 3Each independently is -(C 0 -C 1 alkyl)-;

[0096] 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};

[0097] Z is N;

[0098] R 1 Yes-CX 2 H or -CX 3 ;

[0099] R 2 Yes -C(=O)-R A ;

[0100] R A Yes - NR A1 R A2 ,

[0101] m and n are each independently an integer of 1 or 2;

[0102] R a To R d are independently -H or -(C 1 -C 4 alkyl);

[0103] Y is N, CH, O or S(=O) 2 ;

[0104] When Y is N or CH, R Y2 and R Y4 are independently -H, -(C 1 -C 4 Alkyl), -(C 3 -C 7 Cycloalkyl), -(C 2 -C 6 Heterocycloalkyl), -C(=O)-(C 1 -C 4 alkyl), -C(=O)-O(C 1 -C 4 alkyl), -C(=O)-NR A3 R A4 、-C(=O)-(C 3 -C 7 Cycloalkyl), -C(=O)-(C 2 -C 6 Heterocycloalkyl), -S(=O) 2 -(C1 -C 4 alkyl), -aryl or -heteroaryl {wherein -(C 1 -C 4 Alkyl), -(C 3 -C 7 Cycloalkyl), -C(=O)-(C 1 -C 4 alkyl), -C(=O)-(C 3 -C 7 Cycloalkyl), -C(=O)-(C 2 -C 6 Heterocycloalkyl) and -S(=O) 2 -(C 1 -C 4 At least one H of an alkyl group may be substituted with -X or -OH; at least one H of an aryl group or a heteroaryl group may be substituted with -(C 1 -C 4 Alkyl), -O-(C 1 -C 4 alkyl), -X, -OH or -CF 3 Replace; and - (C 2 -C 6 -heterocycloalkyl) or -heteroaryl may contain N, O or S atoms in the ring};

[0105] When Y is O or S (=O) 2 When R Y2 and R Y4 does not exist (none);

[0106] R 3 is -C(=O)-O(C 1 -C 4 Alkyl), -(C 3 -C 7 Cycloalkyl), -(C 2 -C 6 heterocycloalkyl), -adamantyl, -aryl or -heteroaryl {wherein -(C 3 -C 7 Cycloalkyl), -(C 2 -C 6 At least one -H of -(C 1 -C 4 Alkyl), -O(C 1 -C 4 alkyl), -(C=O)-(C 1 -C 4 alkyl), -C(=O)-O(C 1 -C 4Alkyl), -CF 3 , -CF 2 H, -OCF 3 、-NR A5 R A6 、-S(=O) 2 -(C 1 -C 4 alkyl), -aryl or -heteroaryl};

[0107] R A1 To R A6 are independently -H or -(C 1 -C 4 alkyl); and

[0108] X can be F, Cl or Br.

[0109] Furthermore, according to yet another embodiment of the present invention,

[0110] In the above chemical formula I,

[0111] L 1 , L 2 and L 3 Each independently is -(C 0 -C 1 alkyl)-;

[0112] 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};

[0113] Z is N, O or absent (none) {wherein when Z is absent (none), R 2 does not exist (nothing), and L 2 and L 3 Direct connection};

[0114] R 1 Yes-CX 2 H or -CX 3 ;

[0115] R 2 Yes-H, -(C 1 -C 4 alkyl) {wherein when Z is O, R 2 does not exist (none)};

[0116] R 3 is -C(=O)-O(C 1 -C 4 Alkyl), -(C 3 -C 7 Cycloalkyl), -(C2 -C 6 heterocycloalkyl), -adamantyl, -aryl or -heteroaryl {wherein -(C 3 -C 7 Cycloalkyl), -(C 2 -C 6 At least one -H of -(C 1 -C 4 Alkyl), -O(C 1 -C 4 alkyl), -(C=O)-(C 1 -C 4 alkyl), -C(=O)-O(C 1 -C 4 Alkyl), -CF 3 , -CF 2 H, -OCF 3 、-NR A5 R A6 、-S(=O) 2 -(C 1 -C 4 alkyl), -aryl or -heteroaryl};

[0117] R A5 and R A6 are independently -H or -(C 1 -C 4 alkyl); and

[0118] X can be F, Cl or Br.

[0119] Specific compounds represented by Chemical Formula I of the present invention are shown in Table 1 below.

[0120] [Table 1]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132] According to one embodiment of the present invention, the specific compound represented by Chemical Formula I of the present invention may be as shown in the following Table 2:

[0133] [Table 2]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141] According to another embodiment of the present invention, the specific compound represented by Chemical Formula I of the present invention may be as shown in the following Table 3:

[0142] [Table 3]

[0143]

[0144]

[0145]

[0146]

[0147] According to another embodiment of the present invention, the specific compound represented by Chemical Formula I of the present invention may be as shown in the following Table 4:

[0148] [Table 4]

[0149]

[0150]

[0151]

[0152] 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.

[0153] Preferred salts in the present invention include hydrochloride, phosphate, sulfate, trifluoroacetate, citrate, bromate, maleate or tartrate.

[0154] 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.

[0155] Method for preparing 1,3,4-oxadiazole derivative compounds

[0156] 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.

[0157] A preferred method for preparing the 1,3,4-oxadiazole derivative compound represented by Chemical Formula I according to the present invention, its optical isomer or a pharmaceutically acceptable salt thereof is the same as the following Reaction Schemes 1-4, which also includes preparation methods modified at a level obvious to those skilled in the art.

[0158] [Reaction Scheme 1]

[0159]

[0160] In Reaction Scheme 1, compound 1-1 is reacted with 1,3-dichloropropane-2-one to synthesize bicyclic compound 1-2, followed by substitution with various functional groups to synthesize compound 1-3, followed by reaction with hydrazine to synthesize hydrazide compound 1-4. Finally, a cyclization reaction with difluoroacetic anhydride is performed to synthesize the title compound 1-5.

[0161] The compound prepared by the above reaction scheme is compound 3009.

[0162] [Reaction Scheme 2]

[0163]

[0164] In Reaction Scheme 2, compound 2-1 in which a protecting group is introduced into compound 1-1 is synthesized, and then reacted with hydrazine to synthesize hydrazide compound 2-2. A cyclization reaction with fluorine-substituted acetic anhydride is performed to synthesize compound 2-3, and then the protecting group is removed under acidic conditions to synthesize compound 2-4. Bicyclic compound 2-5 is synthesized by reacting with 1,3-dichloropropane-2-one, and is reacted with various functional groups to synthesize the title compound 2-6.

[0165] Compounds prepared by the above reaction scheme are compounds 3585, 3586, 3587, 3588, 3589, 3590, 3591, 3592, 3593, 3594, 3595, 3596, 3668, 3669, 3670, 3671, 3672, 3673, 3674, 3675, 3676, 3677, 3678, 3679, 3719, 3720, 3721, 3722, 3723, 3724 and 3725.

[0166] [Reaction Scheme 3]

[0167]

[0168] Reaction Scheme 3 shows a method for synthesizing a compound having an amide structure, wherein compound 2-6 synthesized in Reaction Scheme 2 is reacted with compound 3-2 having an acetyl chloride functional group under basic conditions, thereby synthesizing compound 3-3. Compound 3-4 from which a protecting group is removed under acidic conditions is synthesized, and reacted with various functional groups to synthesize the title compound 3-5.

[0169] The compounds prepared by the above reaction scheme are compounds 3782, 3783, 4115, 4116, 4117, 4118, 4119, 4120, 4121, 4122, 4123, 4124, 4125, 4126, 4127, 4128, 4129, 4130, 4131, 4132, 4137, 4138, 4139, 4140, 4141, 4142, 4143, 4144, 4145, 4146, 4147, 4148, 4150, 4151, 4152, 4153, 4154, 4155, 4156, 4157 4194, 4195, 4196, 4197, 4198, 4199, 4200, 4201, 4202, 4203, 4204, 4205, 4206, 4207, 4618, and 4619.

[0170] [Reaction Scheme 4]

[0171]

[0172] Reaction Scheme 4 shows a method for synthesizing a compound having a urea structure, wherein the compound 2-6 synthesized in Reaction Scheme 2 is reacted with triphosgene and an amine compound under alkaline conditions, thereby synthesizing compound 4-1. Compound 4-2 from which a protecting group is removed under acidic conditions is synthesized, and reacts with various functional groups to synthesize the title compound 4-3.

[0173] Compounds prepared by the above reaction scheme are compounds 3784, 3785, 4033, 4034, 4035, 4036, 4037, 4038, 4039, 4040, 4041, 4042, 4043, 4044, 4045, 4046, 4047, 4048, 4049, 4083, 4084, 4085, 4086, 4087, 4088, 4089, 4090, 4091, 4092, 4093, 4094, 4095, 4096, 4097, 4098, 4099, 4100, 4101, 4102, 4103, 4620, 4621, 4625, and 6892.

[0174] Compositions containing 1,3,4-oxadiazole derivative compounds, uses thereof, and methods of treatment using the same

[0175] 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:

[0176] [Chemical Formula I]

[0177]

[0178] Formula I is the same as defined above.

[0179] 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.

[0180] 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.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] 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.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] 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.

[0191] Advantageous Effects of the Invention

[0192] 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

[0193] 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.

[0194] Preparation of 1,3,4-oxadiazole derivative compounds of the present invention

[0195] A specific method for preparing the compound represented by Chemical Formula I is shown below.

[0196] Example 1: Synthesis of Compound 3009, 2-(2-benzylimidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0197] [Step 1] Synthesis of methyl 2-(chloromethyl)imidazo[1,2-a]pyridine-7-carboxylate

[0198]

[0199] 2-aminoisonicotinate (1.000 g, 6.572 mmol) and 1,3-dichloropropane-2-one (1.085 g, 8.544 mmol) were dissolved in ethanol (5 mL) / 1,2-dimethoxyethane (6 mL), and the resulting solution was stirred at room temperature for 1 hour and at 90 ° C for another 16 hours. Then, the temperature was lowered to room temperature to terminate the reaction. Water 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 column chromatography (SiO 2 , 24 g column; ethyl acetate / hexanes = 5% to 70%) and concentrated to afford the title compound (0.200 g, 13.5%) as a beige solid.

[0200] [Step 2] Synthesis of methyl 2-benzylimidazolo[1,2-a]pyridine-7-carboxylate

[0201]

[0202] The 2-(chloromethyl)imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (0.200 g, 0.890 mmol), phenylboronic acid (0.217 g, 1.781 mmol), bis(triphenyl)phosphine)palladium(II) chloride (Pd(PPh 3 ) 2 Cl 2 , 0.062g, 0.089mmol) and potassium carbonate (0.369g, 2.671mmol) were dissolved in 1,4-dioxane (8mL) / water (2mL), and the resulting solution was stirred at 105°C for 16 hours. Then, the temperature was lowered to room temperature to terminate the reaction. Water 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 column chromatography (SiO 2 , 24 g column; ethyl acetate / hexanes = 5% to 70%) and concentrated to obtain the title compound (0.076 g, 32.1%) as a white solid.

[0203] [Step 3] Synthesis of 2-benzylimidazolo[1,2-a]pyridine-7-carboxylic acid hydrazide

[0204]

[0205] 2-Benzyl imidazo [1,2-a] pyridine-7-carboxylic acid methyl ester (0.075 g, 0.282 mmol) and hydrazine monohydrate (0.068 mL, 1.408 mmol) prepared in step 2 were dissolved in ethanol (5 mL) at room temperature, and the resulting solution was heated to reflux for 16 hours. Then, the temperature was lowered to room temperature to terminate the reaction. Water 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 obtain the title compound (0.074 g, 98.7%) as a white solid.

[0206] [Step 4] Synthesis of compound 3009

[0207]

[0208] 2-benzylimidazolo[1,2-a]pyridine-7-carboxylic acid hydrazide (0.065g, 0.244mmol) and imidazole (0.050g, 0.732mmol) prepared in step 3 were dissolved in dichloromethane (5mL), and 2,2-difluoroacetic anhydride (0.152mL, 1.220mmol) was added at room temperature and heated to reflux for 16 hours. Then, the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove solid residue and water layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 4 g column; ethyl acetate / hexanes = 5% to 60%) and concentrated to obtain the title compound (0.030 g, 37.7%) as a bright red solid.

[0209] 1 H NMR (400 MHz, CDCl 3 )δ8.29(m,1H),8.15-8.13(m,1H),7.49-7.46(m,1H),7.36-7.32(m,5H),7.29-7.26(m,1H),6.95(t,J=51.7Hz,1H),4.22(s,2H);

[0210] LRMS (ES) m / z 327.2 (M + +1).

[0211] Example 2: Synthesis of Compound 3585, 2-(difluoromethyl)-5-(2-(3-fluorobenzyl)imidazo[1,2-a]pyridin-7-yl)-1,3,4-oxadiazole

[0212] [Step 1] Synthesis of methyl 2-((tert-butoxycarbonyl)amino)isonicotinate

[0213]

[0214] 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.

[0215] [Step 2] Synthesis of tert-butyl (4-(hydrazinecarbonyl)pyridin-2-yl)carbamate

[0216]

[0217] 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 obtained organic layer was concentrated to obtain the title compound (25.000 g, 96.2%) as a white solid.

[0218] [Step 3] Synthesis of tert-butyl (4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)carbamate ester

[0219]

[0220] The tert-butyl (4- (hydrazine carbonyl) 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. Then, the temperature was lowered to room temperature to terminate the reaction. Saturated aqueous ammonium chloride solution was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. 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.

[0221] [Step 4] Synthesis of 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine

[0222]

[0223] 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 and 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.

[0224] [Step 5] Synthesis of 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazol-1-yl Oxadiazole

[0225]

[0226] 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-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 reduced to room temperature to terminate the reaction. The reaction mixture was filtered through a plastic filter to remove solids, and the filtrate was purified by column chromatography (SiO 2 , 80 g column; ethyl acetate / hexanes = 10% to 90%) and concentrated to afford the title compound (7.000 g, 69.6%) as a beige solid.

[0227] [Step 6] Synthesis of compound 3585

[0228]

[0229] 2-(2-(Chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), (3-fluorophenyl)boronic acid (0.049 g, 0.351 mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh 3 ) 2 Cl 2, 0.012g, 0.018mmol) and potassium carbonate (0.073g, 0.527mmol) were dissolved in 1,4-dioxane (4mL) / water (1mL), and the resulting solution was stirred at 100°C for 1 hour. 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 a saturated aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 4 g column; ethyl acetate / hexanes = 0% to 70%) and concentrated to obtain the title compound (0.023 g, 38.0%) as a pink solid.

[0230] 1 H NMR (400 MHz, CDCl 3 )δ8.27-8.19(m,1H),8.10(dd,J=7.1,1.0Hz,1H),7.44(dd,J=7.1,1.7Hz,1H),7.34(s,1H) ,7.23(td,J=8.0,6.0Hz,1H),7.05(dt,J=7.6,1.2Hz,1H),7.00-6.70(m,3H),4.13(s,2H);

[0231] LRMS (ES) m / z 345.9 (M + +1).

[0232] Example 3: Synthesis of Compound 3586, 2-(difluoromethyl)-5-(2-(4-fluorobenzyl)imidazo[1,2-a]pyridin-7-yl)-1,3,4-oxadiazole

[0233]

[0234] 2-(2-(Chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), (4-fluorophenyl)boronic acid (0.049 g, 0.351 mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh 3 ) 2 Cl 2, 0.012g, 0.018mmol) and potassium carbonate (0.073g, 0.527mmol) were dissolved in 1,4-dioxane (4mL) / water (1mL), and the resulting solution was stirred at 100°C for 1 hour. 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 a saturated aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 4 g column; ethyl acetate / hexanes = 0% to 70%) and concentrated to obtain the title compound (0.030 g, 49.6%) as a pink solid.

[0235] 1 H NMR (400 MHz, CDCl 3 )δ8.37-8.29(m,1H),8.18(dd,J=7.1,1.0Hz,1H),7.53(dd,J=7.1,1.7Hz,1H ),7.39(d,J=0.9Hz,1H),7.36-7.30(m,2H),7.10-6.81(m,3H),4.20(s,2H);

[0236] LRMS (ES) m / z 346.0 (M + +1).

[0237] Example 4: Synthesis of Compound 3587, 2-(2-(3,4-difluorobenzyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0238]

[0239] 2-(2-(Chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), (3,4-difluorophenyl)boric acid (0.055 g, 0.351 mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh 3 ) 2 Cl 2 , 0.012g, 0.018mmol) and potassium carbonate (0.073g, 0.527mmol) were dissolved in 1,4-dioxane (4mL) / water (1mL), and the resulting solution was stirred at 100°C for 1 hour. 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 a saturated aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g column; ethyl acetate / hexanes = 0% to 70%) and concentrated to obtain the title compound (0.033 g, 51.9%) as a pink solid.

[0240] 1 H NMR (400 MHz, CDCl 3 )δ8.38-8.29(m,1H),8.21(dd,J=7.1,1.0Hz,1H),7.55(dd,J=7.1,1.7Hz,1H),7.45(s,1H),7.21-6.81(m,4H),4.19(s,2H);

[0241] LRMS(ES)m / z 364.0(M + +1).

[0242] Example 5: Synthesis of Compound 3588, 2-(2-(2,4-difluorobenzyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0243]

[0244] 2-(2-(Chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), (2,4-difluorophenyl)boronic acid (0.055 g, 0.351 mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh 3 ) 2 Cl 2 , 0.012g, 0.018mmol) and potassium carbonate (0.073g, 0.527mmol) were dissolved in 1,4-dioxane (4mL) / water (1mL), and the resulting solution was stirred at 100°C for 1 hour. 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 a saturated aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 4 g column; ethyl acetate / hexanes = 0% to 70%) and concentrated to obtain the title compound (0.031 g, 48.7%) as a pink solid.

[0245] 1 H NMR (400 MHz, CDCl 3)δ8.37-8.29(m,1H),8.20(dd,J=7.1,1.0Hz,1H),7.54(dd,J=7.1,1.7Hz,1H), 7.47(s,1H),7.37(td,J=8.7,8.3,6.4Hz,1H),7.11-6.80(m,3H),4.22(s,2H);

[0246] LRMS(ES)m / z 364.0(M + +1).

[0247] Example 6: Synthesis of Compound 3589, 2-(difluoromethyl)-5-(2-(4-methylbenzyl)imidazo[1,2-a]pyridin-7-yl)-1,3,4-oxadiazole

[0248]

[0249] 2-(2-(Chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), p-tolueneboric acid (0.048 g, 0.351 mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh 3 ) 2 Cl 2 , 0.012g, 0.018mmol) and potassium carbonate (0.073g, 0.527mmol) were dissolved in 1,4-dioxane (4mL) / water (1mL), and the resulting solution was stirred at 100°C for 1 hour. 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 a saturated aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 4 g column; ethyl acetate / hexanes = 0% to 70%) and concentrated to obtain the title compound (0.028 g, 46.8%) as a pink solid.

[0250] 1 H NMR (400 MHz, CDCl 3 )δ8.39-8.28(m,1H),8.15(dd,J=7.1,1.0Hz,1H),7.51(dd,J=7.1,1.7Hz,1H),7.37(t,J=0.8Hz, 1H),7.26(d,J=8.0Hz,2H),7.19-7.15(m,2H),6.95(t,J=51.7Hz,1H),4.20(s,2H),2.37(s,3H);

[0251] LRMS (ES) m / z 341.3 (M + +1).

[0252] Example 7: Synthesis of Compound 3590, 2-(difluoromethyl)-5-(2-(4-methoxybenzyl)imidazo[1,2-a]pyridin-7-yl)-1,3,4-oxadiazole

[0253]

[0254] 2-(2-(Chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), (4-methoxyphenyl)boronic acid (0.053 g, 0.351 mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh 3 ) 2 Cl 2 , 0.012 g, 0.018 mmol) and potassium carbonate (0.073 g, 0.527 mmol) were dissolved in 1,4-dioxane (4 mL) / water (1 mL), and the resulting solution was stirred at 100° C. for 1 hour. Then, the temperature was lowered to room temperature to terminate the reaction. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; ethyl acetate / hexane = 0% to 70%) and concentration gave the title compound (0.015 g, 24.0%) as a pink solid.

[0255] 1 H NMR (400 MHz, CDCl 3 )δ8.29-8.16(m,1H),8.06(dd,J=7.1,1.0Hz,1H),7.41(dd,J=7.1,1.7Hz,1H),7.19(t,J=4.3Hz,3H),7.00-6.71(m,3H),4.08(s,2H),3.73(s,3H);

[0256] LRMS (ES) m / z 356.9 (M + +1).

[0257] Example 8: Synthesis of Compound 3591, 2-(difluoromethyl)-5-(2-(4-trifluoromethyl)benzyl)imidazo[1,2-a]pyridin-7-yl)-1,3,4-oxadiazole

[0258]

[0259] 2-(2-(Chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), (4-(trifluoromethyl)phenyl)boric acid (0.067 g, 0.351 mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh 3 ) 2 Cl 2 , 0.012 g, 0.018 mmol) and potassium carbonate (0.073 g, 0.527 mmol) were dissolved in 1,4-dioxane (4 mL) / water (1 mL), and the resulting solution was stirred at 100° C. for 1 hour. Then, the temperature was lowered to room temperature to terminate the reaction. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; ethyl acetate / hexane = 0% to 70%) and concentration gave the title compound (0.029 g, 41.9%) as a pink solid.

[0260] 1 H NMR (400 MHz, CDCl 3 )δ8.40-8.27(m,1H),8.20(dd,J=7.1,0.9Hz,1H),7.61(d,J=8.0Hz,2H),7.54(dd,J=7. 1,1.7Hz,1H),7.48(d,J=8.0Hz,2H),7.44(s,1H),6.96(t,J=51.7Hz,1H),4.28(s,2H);

[0261] LRMS (ES) m / z 394.7 (M + +1).

[0262] Example 9: Synthesis of Compound 3592, 1-(4-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)phenyl)ethan-1-one

[0263]

[0264] 2-(2-(Chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), (4-acetylphenyl)boronic acid (0.058 g, 0.351 mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh 3 ) 2 Cl2 , 0.012 g, 0.018 mmol) and potassium carbonate (0.073 g, 0.527 mmol) were dissolved in 1,4-dioxane (4 mL) / water (1 mL), and the resulting solution was stirred at 100° C. for 1 hour. Then, the temperature was lowered to room temperature to terminate the reaction. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; ethyl acetate / hexane = 0% to 70%) and concentration gave the title compound (0.021 g, 32.5%) as a pink solid.

[0265] 1 H NMR (400 MHz, CDCl 3 )δ8.35-8.30(m,1H),8.19(dd,J=7.1,1.0Hz,1H),7.99-7.92(m,2H),7.70(ddd,J=12.0,8.3,1.4 Hz,1H),7.58-7.50(m,1H),7.49-7.43(m,3H),6.96(t,J=51.7Hz,1H),4.29(s,2H),2.62(s,3H);

[0266] LRMS (ES) m / z 369.3 (M + +1).

[0267] Example 10: Synthesis of Compound 3593, 2-(2-(4-chlorobenzyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0268]

[0269] 2-(2-(Chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), (4-fluorophenyl)boronic acid (0.055 g, 0.351 mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh 3 ) 2 Cl 2 , 0.012 g, 0.018 mmol) and potassium carbonate (0.073 g, 0.527 mmol) were dissolved in 1,4-dioxane (4 mL) / water (1 mL), and the resulting solution was stirred at 100° C. for 1 hour. Then, the temperature was lowered to room temperature to terminate the reaction. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified by chromatography (SiO 2Plate, 20x20x1 mm; ethyl acetate / hexane = 0% to 70%) and concentration gave the title compound (0.012 g, 18.9%) as a pink solid.

[0270] 1 H NMR (400 MHz, CDCl 3 )δ8.32(dt,J=1.7,0.8Hz,1H),8.18(dd,J=7.1,0.9Hz,1H),7.52(dd,J=7.1,1.7Hz, 1H),7.39(q,J=0.8Hz,1H),7.35-7.27(m,4H),6.95(t,J=51.7Hz,1H),4.19(s,2H);

[0271] LRMS (ES) m / z 362.9 (M + +1).

[0272] Example 11: Synthesis of Compound 3594, 2-(difluoromethyl)-5-(2-(3-isopropylbenzyl)imidazo[1,2-a]pyridin-7-yl)-1,3,4-oxadiazole

[0273]

[0274] 2-(2-(Chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), (3-isopropylphenyl)boronic acid (0.058 g, 0.351 mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh 3 ) 2 Cl 2 , 0.012 g, 0.018 mmol) and potassium carbonate (0.073 g, 0.527 mmol) were dissolved in 1,4-dioxane (4 mL) / water (1 mL), and the resulting solution was stirred at 100° C. for 1 hour. Then, the temperature was lowered to room temperature to terminate the reaction. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; ethyl acetate / hexane = 0% to 70%) and concentration gave the title compound (0.032 g, 49.5%) as a pink solid.

[0275] 1 H NMR (400 MHz, CDCl 3)δ8.33(s,1H),8.17(dd,J=7.1,0.9Hz,1H),7.52(dd,J=7.1,1.7Hz,1H),7.37(d,J=0.8Hz,1H),7.32-7.26(m,1H),7.23 (d,J=1.8Hz,1H),7.20-7.13(m,2H),6.95(t,J=51.7Hz,1H),4.22(s,2H),2.92(p,J=6.9Hz,1H),1.28(d,J=6.9Hz,6H);

[0276] LRMS (ES) m / z 370.0 (M + +1).

[0277] Example 12: Synthesis of Compound 3595, 2-(difluoromethyl)-5-(2-(4-(methylsulfonyl)benzyl)imidazo[1,2-a]pyridin-7-yl)-1,3,4-oxadiazole

[0278]

[0279] 2-(2-(Chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), (4-(methylsulfonyl)phenyl)boronic acid (0.070 g, 0.351 mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh 3 ) 2 Cl 2 , 0.012 g, 0.018 mmol) and potassium carbonate (0.073 g, 0.527 mmol) were dissolved in 1,4-dioxane (4 mL) / water (1 mL), and the resulting solution was stirred at 100° C. for 1 hour. Then, the temperature was lowered to room temperature to terminate the reaction. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.033 g, 46.5%) as a pink solid.

[0280] 1 H NMR (400 MHz, CDCl 3)δ8.33(dt,J=1.7,0.8Hz,1H),8.22(dd,J=7.1,0.9Hz,1H),7.95-7.87(m,2H),7.56(td,J =6.6,1.8Hz,3H),7.49(d,J=0.8Hz,1H),6.96(t,J=51.7Hz,1H),4.31(s,2H),3.06(s,3H);

[0281] LRMS (ES) m / z 405.1 (M + +1).

[0282] Example 13: Synthesis of Compound 3596, 2-(2-(Benzo[d][1,3]dioxol-5-ylmethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0283]

[0284] 2-(2-(Chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), benzo[d][1,3]dioxol-5-ylboronic acid (0.058 g, 0.351 mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh 3 ) 2 Cl 2 , 0.012 g, 0.018 mmol) and potassium carbonate (0.073 g, 0.527 mmol) were dissolved in 1,4-dioxane (4 mL) / water (1 mL), and the resulting solution was stirred at 100° C. for 1 hour. Then, the temperature was lowered to room temperature to terminate the reaction. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.041 g, 63.0%) as a pink solid.

[0285] 1 H NMR (400 MHz, CDCl 3 )δ8.32(d,J=1.6Hz,1H),8.18(dd,J=7.1,1.0Hz,1H),7.52(dd,J=7.1,1.7Hz,1H),7.41(s,1H),7.10-6.77(m,4H),5.96(s,2H),4.15(s,2H);

[0286] LRMS(ES)m / z 372.0(M + +1).

[0287] Example 14: Synthesis of Compound 3668, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)aniline

[0288]

[0289] 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), aniline (0.024 mL, 0.263 mmol), potassium carbonate (0.036 g, 0.263 mmol) and potassium iodide (0.015 g, 0.088 mmol) prepared in step 5 of Example 2 were dissolved in N,N-dimethylformamide (3 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 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 (SiO 2 , 4 g column; ethyl acetate / hexanes = 0% to 70%) and concentrated to obtain the title compound (0.050 g, 83.4%) as a yellow solid.

[0290] 1 H NMR (400 MHz, CDCl 3 )δ8.33(dt,J=1.7,0.8Hz,1H),8.21(dd,J=7.2,1.0Hz,1H),7.68(d,J=0.9Hz,1H),7.54(dd,J=7.1 ,1.7Hz,1H),7.25-7.18(m,2H),6.96(t,J=51.7Hz,1H),6.80-6.70(m,3H),4.62(d,J=0.8Hz,2H);

[0291] LRMS(ES)m / z 342.9(M + +1).

[0292] Example 15: Synthesis of Compound 3669, 1-(3-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)phenyl)ethan-1-one

[0293]

[0294] 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), m-toluidine (0.036 g, 0.263 mmol), potassium carbonate (0.036 g, 0.263 mmol) and potassium iodide (0.015 g, 0.088 mmol) prepared in step 5 of Example 2 were dissolved in N,N-dimethylformamide (3 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 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 (SiO 2 , 4 g column; ethyl acetate / hexanes = 0% to 70%) and concentrated to obtain the title compound (0.040 g, 59.4%) as a yellow solid.

[0295] 1 H NMR (400 MHz, CDCl 3 )δ8.38-8.29(m,1H),8.24(dd,J=7.1,1.0Hz,1H),7.74-7.67(m,1H),7.57(dd,J=7.1,1.7Hz, 1H),7.36-7.32(m,2H),7.31-7.28(m,1H),7.11-6.82(m,2H),4.68-4.64(m,2H),2.59(s,3H);

[0296] LRMS(ES)m / z 385.0(M + +1).

[0297] Example 16: Synthesis of Compound 3670, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-3-fluoroaniline

[0298]

[0299] 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), 3-fluoroaniline (0.036 g, 0.263 mmol), potassium carbonate (0.036 g, 0.263 mmol) and potassium iodide (0.015 g, 0.088 mmol) prepared in step 5 of Example 2 were dissolved in N,N-dimethylformamide (3 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 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 (SiO 2 , 4 g column; ethyl acetate / hexanes = 0% to 70%) and concentrated to obtain the title compound (0.040 g, 59.4%) as a yellow solid.

[0300] 1 H NMR (400 MHz, CDCl 3 )δ8.34(dt,J=1.7,0.8Hz,1H),8.23(dd,J=7.1,1.0Hz,1H),7.68(d,J=0.8Hz,1H),7.5 7(dd,J=7.1,1.7Hz,1H),7.18-6.76(m,2H),6.54-6.32(m,3H),4.59(d,J=0.8Hz,2H);

[0301] LRMS (ES) m / z 360.9 (M + +1).

[0302] Example 17: Synthesis of Compound 3671, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-3,4-difluoroaniline

[0303]

[0304] 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), 3,4-difluoroaniline (0.029 g, 0.263 mmol), potassium carbonate (0.036 g, 0.263 mmol) and potassium iodide (0.015 g, 0.088 mmol) prepared in step 5 of Example 2 were dissolved in N,N-dimethylformamide (3 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 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 (SiO 2 , 4 g column; ethyl acetate / hexanes = 0% to 70%) and concentrated to obtain the title compound (0.024 g, 38.0%) as a yellow solid.

[0305] 1 H NMR (400 MHz, CDCl 3 )δ8.38(s,1H),8.27(dd,J=7.1,1.0Hz,1H),7.69(d,J=0.8Hz,1H),7.63(dd,J=7.1,1.7Hz,1H),7.11-6. 80(m,2H),6.52(ddd,J=12.5,6.6,2.9Hz,1H),6.42(ddd,J=8.9,3.2,1.6Hz,1H),4.57(d,J=0.8Hz,2H);

[0306] LRMS (ES) m / z 378.1 (M + +1).

[0307] Example 18: Synthesis of Compound 3672, 3-chloro-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-fluoroaniline

[0308]

[0309] 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), 3-chloro-4-fluoroaniline (0.038 g, 0.263 mmol), potassium carbonate (0.036 g, 0.263 mmol) and potassium iodide (0.015 g, 0.088 mmol) prepared in step 5 of Example 2 were dissolved in N,N-dimethylformamide (3 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 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 (SiO 2 , 4 g column; ethyl acetate / hexanes = 0% to 70%) and concentrated to obtain the title compound (0.041 g, 59.3%) as a yellow solid.

[0310] 1 H NMR (400 MHz, CDCl 3 )δ8.37(d,J=1.5Hz,1H),8.26(dd,J=7.1,1.0Hz,1H),7.69(d,J=0.8Hz,1H),7.62(dd,J=7.1,1.7Hz,1H), 7.10-6.80(m,2H),6.73(dd,J=6.0,2.9Hz,1H),6.57(ddd,J=8.9,3.8,2.9Hz,1H),4.57(d,J=0.8Hz,2H);

[0311] LRMS (ES) m / z 396.0 (M + +1).

[0312] Example 19: Synthesis of Compound 3673, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-(trifluoromethyl)aniline

[0313]

[0314] 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), 4-(trifluoromethyl)aniline (0.042 g, 0.263 mmol), potassium carbonate (0.036 g, 0.263 mmol) and potassium iodide (0.015 g, 0.088 mmol) prepared in step 5 of Example 2 were dissolved in N,N-dimethylformamide (3 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 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 (SiO 2 , 4 g column; ethyl acetate / hexanes = 0% to 70%) and concentrated to obtain the title compound (0.029 g, 40.3%) as a yellow solid.

[0315] 1 H NMR (400 MHz, CDCl 3 )δ8.36(dt,J=1.6,0.7Hz,1H),8.25(dd,J=7.1,1.0Hz,1H),7.68(d,J=0.7Hz,1H),7.60(dd,J= 7.1,1.7Hz,1H),7.47-7.39(m,2H),6.97(t,J=51.7Hz,1H),6.74(d,J=8.6Hz,2H),4.66(s,2H);

[0316] LRMS(ES)m / z 411.0(M + +1).

[0317] Example 20: Synthesis of Compound 3674, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-(methylsulfonyl)aniline

[0318]

[0319] 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), 4-(methylsulfonyl)aniline (0.045 g, 0.263 mmol), potassium carbonate (0.036 g, 0.263 mmol) and potassium iodide (0.015 g, 0.088 mmol) prepared in step 5 of Example 2 were dissolved in N,N-dimethylformamide (3 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 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 (SiO 2 , 4 g column; dichloromethane / methanol = 0% to 10%) and concentrated to obtain the title compound (0.034 g, 46.2%) as a yellow solid.

[0320] 1 H NMR (400 MHz, CDCl 3 )δ8.33(dt,J=1.7,0.8Hz,1H),8.26(dd,J=7.1,1.0Hz,1H),7.76-7.71(m,2H),7.69(d,J=0.8Hz,1H),7. 58(dd,J=7.2,1.7Hz,1H),6.97(t,J=51.7Hz,1H),6.79-6.71(m,2H),4.66(d,J=4.3Hz,2H),3.02(s,3H);

[0321] LRMS (ES) m / z 420.3 (M + +1).

[0322] Example 21: Synthesis of Compound 3675, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)pyridin-3-amine

[0323]

[0324] 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), pyridine-3-amine (0.025 g, 0.263 mmol), potassium carbonate (0.036 g, 0.263 mmol) and potassium iodide (0.015 g, 0.088 mmol) prepared in step 5 of Example 2 were dissolved in N,N-dimethylformamide (3 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 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 (SiO 2 , 4 g column; dichloromethane / methanol = 0% to 10%) and concentrated to obtain the title compound (0.037 g, 61.5%) as a yellow solid.

[0325] 1 H NMR (400 MHz, CDCl 3 )δ8.33(dt,J=1.7,0.8Hz,1H),8.24(dd,J=7.1,1.0Hz,1H),8.19(d,J=2.8Hz,1H),8.05 -7.99(m,1H),7.70(s,1H),7.56(dd,J=7.1,1.7Hz,1H),7.17-6.82(m,3H),4.62(s,2H);

[0326] LRMS (ES) m / z 343.1 (M + +1).

[0327] Example 22: Synthesis of Compound 3676, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-6-fluoropyridin-3-amine

[0328]

[0329] 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), 6-fluoropyridine-3-amine (0.030 g, 0.263 mmol), potassium carbonate (0.036 g, 0.263 mmol) and potassium iodide (0.015 g, 0.088 mmol) prepared in step 5 of Example 2 were dissolved in N,N-dimethylformamide (3 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 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 (SiO 2 , 4 g column; dichloromethane / methanol = 0% to 10%) and concentrated to obtain the title compound (0.033 g, 52.1%) as a yellow solid.

[0330] 1 H NMR (400 MHz, CDCl 3 )δ8.35(dt,J=1.7,0.9Hz,1H),8.26(dd,J=7.1,1.0Hz,1H),7.73-7.68(m,1H),7.66(dd,J=3.1,1.9Hz,1H),7.60(dd,J=7 .1,1.7Hz,1H),7.16(ddd,J=8.8,6.7,3.1Hz,1H),6.97(t,J=51.7Hz,1H),6.79(ddd,J=8.7,3.4,0.6Hz,1H),4.59(s,2H);

[0331] LRMS (ES) m / z 362.1 (M + +1).

[0332] Example 23: Synthesis of Compound 3677, (3s, 5s, 7s)-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)adamantan-1-amine

[0333]

[0334] 2-(2-(Chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), (3s,5s,7s)-adamantan-1-amine (0.040 g, 0.263 mmol), potassium carbonate (0.036 g, 0.263 mmol) and potassium iodide (0.015 g, 0.088 mmol) prepared in step 5 of Example 2 were added to N,N-dimethylformamide (3 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 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 chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 25%) and concentrated to obtain the title compound (0.023 g, 32.8%) as a yellow solid.

[0335] 1 H NMR (400 MHz, CDCl 3 )δ8.29(p,J=0.8Hz,1H),8.23(dd,J=7.1,0.9Hz,1H),7.84(s,1H),7.50(dd,J=7.1,1.7Hz,1H),6.9 5(t,J=51.7Hz,1H),4.10(s,2H),2.18-2.09(m,3H),1.84(d,J=2.9Hz,6H),1.70(q,J=12.8Hz,6H);

[0336] LRMS (ES) m / z 399.8 (M + +1).

[0337] Example 24: Synthesis of Compound 3678, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)cyclohexylamine

[0338]

[0339] 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), cyclohexylamine (0.026 g, 0.263 mmol), potassium carbonate (0.036 g, 0.263 mmol) and potassium iodide (0.015 g, 0.088 mmol) prepared in step 5 of Example 2 were dissolved in N,N-dimethylformamide (3 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 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 chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 25%) and concentrated to obtain the title compound (0.024 g, 39.3%) as a yellow solid.

[0340] 1 H NMR (400 MHz, CDCl 3 )δ8.30(dt,J=1.7,0.8Hz,1H),8.24(dd,J=7.1,0.9Hz,1H),7.74(s,1H),7.53(dd,J=7.1,1.7Hz,1H),6.96(t,J=51.7Hz,1H),4.09( s,2H),2.61(tt,J=10.0,3.7Hz,1H),2.39(s,1H),2.01(d,J=12.0Hz,2H),1.85-1.71(m,2H),1.70-1.59(m,1H),1.39-1.13(m,4H);

[0341] LRMS (ES) m / z 347.7 (M + +1).

[0342] Example 25: Synthesis of Compound 3679, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-3-methylaniline

[0343]

[0344] 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), m-toluidine (0.028 g, 0.263 mmol), potassium carbonate (0.036 g, 0.263 mmol) and potassium iodide (0.015 g, 0.088 mmol) prepared in step 5 of Example 2 were dissolved in N,N-dimethylformamide (3 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 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 (SiO 2 , 4 g column; ethyl acetate / hexanes = 0% to 70%) and concentrated to obtain the title compound (0.032 g, 51.3%) as a yellow solid.

[0345] 1 H NMR (400 MHz, CDCl 3 )δ8.31(p,J=0.8Hz,1H),8.19(dd,J=7.1,1.0Hz,1H),7.67(d,J=0.9Hz,1H),7.52(dd,J=7 .1,1.7Hz,1H),7.14-6.77(m,2H),6.63-6.50(m,3H),4.60(d,J=0.9Hz,2H),2.29(s,3H);

[0346] LRMS (ES) m / z 356.2 (M + +1).

[0347] Example 26: Synthesis of Compound 3719, 2-(difluoromethyl)-5-(2-(phenoxymethyl)imidazo[1,2-a]pyridin-7-yl)-1,3,4-oxadiazole

[0348]

[0349] 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.040 g, 0.141 mmol), phenol (0.019 mL, 0.211 mmol) and potassium carbonate (0.039 g, 0.281 mmol) prepared in step 5 of Example 2 were dissolved in N,N-dimethylformamide (2 mL) at room temperature, and the resulting solution was stirred at the same temperature for 2 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. 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 chromatography (SiO 2 Plate, 20x20x1 mm; ethyl acetate / hexane = 0% to 50%) and concentration gave the title compound (0.032 g, 66.5%) as a white solid.

[0350] 1 H NMR (400 MHz, CDCl 3 )δ8.38(d,J=1.6Hz,1H),8.28(dd,J=7.1,1.0Hz,1H),7.86-7.79(m,1H),7.60( dd,J=7.1,1.7Hz,1H),7.38-7.30(m,2H),7.12-6.81(m,4H),5.39-5.35(m,2H);

[0351] LRMS (ES) m / z 342.7 (M + +1).

[0352] Example 27: Synthesis of Compound 3720, 2-(difluoromethyl)-5-(2-((m-tolyloxy)methyl)imidazo[1,2-a]pyridin-7-yl)-1,3,4-oxadiazole

[0353]

[0354] 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.040 g, 0.141 mmol), m-cresol (0.023 g, 0.211 mmol) and potassium carbonate (0.039 g, 0.281 mmol) prepared in step 5 of Example 2 were dissolved in N,N-dimethylformamide (2 mL) at room temperature, and the resulting solution was stirred at the same temperature for 2 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. 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 chromatography (SiO 2 Plate, 20x20x1 mm; ethyl acetate / hexane = 0% to 50%) and concentration gave the title compound (0.037 g, 73.9%) as a white solid.

[0355] 1 H NMR (400 MHz, CDCl 3 )δ8.38(dd,J=1.8,0.9Hz,1H),8.27(dd,J=7.2,1.0Hz,1H),7.82(d,J=0.9Hz,1H),7.59(dd,J= 7.1,1.7Hz,1H),7.22(t,J=7.8Hz,1H),7.12-6.78(m,4H),5.36(d,J=0.8Hz,2H),2.37(s,3H);

[0356] LRMS (ES) m / z 356.7 (M + +1).

[0357] Example 28: Synthesis of Compound 3721, 1-(3-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)ethan-1-one

[0358]

[0359] 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.040 g, 0.141 mmol), 1-(3-hydroxyphenyl)ethan-1-one (0.029 g, 0.211 mmol) and potassium carbonate (0.039 g, 0.281 mmol) prepared in step 5 of Example 2 were dissolved in N,N-dimethylformamide (2 mL) at room temperature, and the resulting solution was stirred at the same temperature for 2 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. 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 chromatography (SiO 2 Plate, 20x20x1 mm; ethyl acetate / hexane = 0% to 50%) and concentration gave the title compound (0.010 g, 18.5%) as a white solid.

[0360] 1 H NMR (400 MHz, CDCl 3 )δ8.28(dt,J=1.7,0.8Hz,1H),8.19(dd,J=7.1,1.0Hz,1H),7.91-7.86(m,2H),7.74(d,J=0. 8Hz,1H),7.50(dd,J=7.1,1.7Hz,1H),7.05-6.74(m,3H),5.33(d,J=0.7Hz,2H),2.50(s,3H);

[0361] LRMS (ES) m / z 384.8 (M + +1).

[0362] Example 29: Synthesis of Compound 3722, 2-(difluoromethyl)-5-(2-((3-fluorophenoxy)methyl)imidazo[1,2-a]pyridin-7-yl)-1,3,4-oxadiazole

[0363]

[0364] 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.040 g, 0.141 mmol), 3-fluorophenol (0.024 g, 0.211 mmol) and potassium carbonate (0.039 g, 0.281 mmol) prepared in step 5 of Example 2 were dissolved in N,N-dimethylformamide (2 mL) at room temperature, and the resulting solution was stirred at the same temperature for 2 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. 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 chromatography (SiO 2 Plate, 20x20x1 mm; ethyl acetate / hexane = 0% to 50%) and concentration gave the title compound (0.036 g, 71.1%) as a white solid.

[0365] 1 H NMR (400 MHz, CDCl 3 )δ8.38(dt,J=1.7,0.8Hz,1H),8.29(dd,J=7.1,0.9Hz,1H),7.83(t,J=0.8Hz,1H),7.61 (dd,J=7.1,1.7Hz,1H),7.28(d,J=6.9Hz,1H),7.11-6.68(m,4H),5.35(d,J=0.8Hz,2H);

[0366] LRMS (ES) m / z 360.7 (M + +1).

[0367] Example 30: Synthesis of Compound 3723, 2-(difluoromethyl)-5-(2-((3,4-difluorophenoxy)methyl)imidazo[1,2-a]pyridin-7-yl)-1,3,4-oxadiazole

[0368]

[0369] 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.040 g, 0.141 mmol), 3,4-difluorophenol (0.027 g, 0.211 mmol) and potassium carbonate (0.039 g, 0.281 mmol) prepared in step 5 of Example 2 were dissolved in N,N-dimethylformamide (2 mL) at room temperature, and the resulting solution was stirred at the same temperature for 2 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. 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 chromatography (SiO 2 Plate, 20x20x1 mm; ethyl acetate / hexane = 0% to 50%) and concentration gave the title compound (0.032 g, 60.2%) as a white solid.

[0370] 1 H NMR (400 MHz, CDCl 3 )δ8.37(dt,J=1.7,0.8Hz,1H),8.29(dd,J=7.1,1.0Hz,1H),7.82(d,J=0.8Hz ,1H),7.60(dd,J=7.1,1.7Hz,1H),7.15-6.73(m,4H),5.30(d,J=0.8Hz,2H);

[0371] LRMS(ES)m / z 378.7(M + +1).

[0372] Example 31: Synthesis of Compound 3724, 2-(difluoromethyl)-5-(2-((4-(trifluoromethyl)phenoxy)methyl)imidazo[1,2-a]pyridin-7-yl)-1,3,4-oxadiazole

[0373]

[0374] 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.040 g, 0.141 mmol), 4-(trifluoromethyl)phenol (0.034 g, 0.211 mmol) and potassium carbonate (0.039 g, 0.281 mmol) prepared in step 5 of Example 2 were dissolved in N,N-dimethylformamide (2 mL) at room temperature, and the resulting solution was stirred at the same temperature for 2 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. 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 chromatography (SiO 2 Plate, 20x20x1 mm; ethyl acetate / hexane = 0% to 50%) and concentration gave the title compound (0.051 g, 88.5%) as a white solid.

[0375] 1 H NMR (400 MHz, CDCl 3 )δ8.33-8.28(m,1H),8.20(dd,J=7.1,1.0Hz,1H),7.74(d,J=0.8Hz,1H),7. 52(ddd,J=10.9,8.1,1.3Hz,3H),7.08-6.71(m,3H),5.33(d,J=0.8Hz,2H);

[0376] LRMS (ES) m / z 410.7 (M + +1).

[0377] Example 32: Synthesis of Compound 3725, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-methylaniline

[0378]

[0379] 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol), N-methylaniline (0.028 g, 0.263 mmol), potassium carbonate (0.036 g, 0.263 mmol) and potassium iodide (0.015 g, 0.088 mmol) prepared in step 5 of Example 2 were dissolved in N,N-dimethylformamide (3 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 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 chromatography (SiO 2 Plate, 20x20x1 mm; hexane / ethyl acetate = 0% to 50%) and concentrated to obtain the title compound (0.051 g, 81.7%) as a white solid.

[0380] 1 H NMR (400 MHz, CDCl 3 )δ8.33(dt,J=1.7,0.9Hz,1H),8.15(dd,J=7.1,1.0Hz,1H),7.53-7.48(m,2H ),7.30-7.23(m,2H),7.10-6.75(m,4H),4.80(d,J=0.9Hz,2H),3.16(s,3H);

[0381] LRMS(ES)m / z 355.7(M + +1).

[0382] Example 33: Synthesis of Compound 3782, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-methyl-N-phenylpiperidine-4-carboxamide

[0383] [Step 1] Synthesis of tert-butyl 4-(chlorocarbonyl)piperidine-1-carboxylate

[0384]

[0385] 1-(tert-Butyloxycarbonyl)piperidine-4-carboxylic acid (0.200 g, 0.872 mmol) was dissolved in dichloromethane (10 mL), and oxalyl chloride (2.00 M solution, 0.567 mL, 1.134 mmol) and N,N-dimethylformamide (0.007 mL, 0.087 mmol) were added at 0° C. and stirred at room temperature for 2 hours. After removing the solvent from the reaction mixture under reduced pressure, the title compound (0.216 g, 100.0%) was obtained as a yellow solid without further purification.

[0386] [Step 2] Synthesis of 4-(((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridine- tert-Butyl (2-yl)methyl)(phenyl)carbamoyl)piperidine-1-carboxylate

[0387]

[0388] To a solution in which N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)aniline (0.200 g, 0.586 mmol) prepared in Example 14 was dissolved in dichloromethane (20 mL) at 0°C, tert-butyl 4-(chlorocarbonyl)piperidine-1-carboxylate (0.189 g, 0.762 mmol) and triethylamine (0.245 mL, 1.758 mmol) prepared in step 1 were added, and stirred at room temperature for 16 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 (SiO 2 , 12 g column; ethyl acetate / hexanes = 0% to 30%) and concentrated to obtain the title compound (0.200 g, 61.8%) as a yellow solid.

[0389] [Step 3] Synthesis of N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridine-2-yl) 4-(2-( ...piperidin-2-yl)methyl)-N-phenylpiperidin-4-carboxamide

[0390]

[0391] Tert-butyl 4-(((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)(phenyl)carbamoyl)piperidine-1-carboxylate (0.120 g, 0.217 mmol) and trifluoroacetic acid (0.333 mL, 4.343 mmol) prepared in step 2 were dissolved in dichloromethane (5 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, filtered, and concentrated under reduced pressure to obtain the title compound (0.098 g, 99.7%) as a brown gel without further purification.

[0392] [Step 4] Synthesis of compound 3782

[0393]

[0394] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-carboxamide (0.050 g, 0.111 mmol), formaldehyde (0.007 g, 0.221 mmol), acetic acid (0.006 mL, 0.111 mmol) and sodium triacetoxyborohydride (0.070 g, 0.332 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, 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, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.038 g, 73.7%) as a white solid.

[0395] 1 H NMR (400 MHz, CDCl 3 )δ8.29(dt,J=1.7,0.8Hz,1H),8.23(dd,J=7.1,1.0Hz,1H),7.78(s,1H),7.53(dd,J=7.1,1.7Hz,1H),7.46-7.36(m,3H),7. 27-7.21(m,2H),6.95(t,J=51.7Hz,1H),5.04(s,2H),2.89(s,2H),2.25(s,4H),1.93(q,J=11.6,11.0Hz,3H),1.71(s,3H);

[0396] LRMS (ES) m / z 468.1 (M + +1).

[0397] Example 34: Synthesis of Compound 3783, 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-carboxamide

[0398]

[0399] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-carboxamide (0.050 g, 0.111 mmol), oxetane-3-one (0.016 g, 0.221 mmol), acetic acid (0.006 mL, 0.111 mmol) and sodium triacetoxyborohydride (0.070 g, 0.332 mmol) prepared in step 3 of Example 33 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, 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, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.042 g, 74.7%) as a white solid.

[0400] 1 H NMR (400 MHz, CDCl 3 )δ8.29(dt,J=1.6,0.8Hz,1H),8.23(dd,J=7.1,0.9Hz,1H),7.79(s,1H), 7.53(dd,J=7.1,1.7Hz,1H),7.46-7.33(m,3H),7.27-7.22(m,2H),6.95( t,J=51.7Hz,1H),5.04(s,2H),4.59(d,J=6.6Hz,4H),3.38(s,1H),2.70( s,2H),2.25(d,J=12.0Hz,1H),1.92(q,J=11.8,11.2Hz,2H),1.67(s,4H);

[0401] LRMS (ES) m / z 508.9 (M + +1).

[0402] Example 35: Synthesis of Compound 3784, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-methyl-N-phenylpiperazine-1-carboxamide

[0403] [Step 1] Synthesis of 4-(((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridine- tert-Butyl (2-yl)methyl)(phenyl)carbamoyl)piperazine-1-carboxylate

[0404]

[0405] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)aniline (0.200 g, 0.586 mmol), triphosgene (0.174 g, 0.586 mmol) and N,N-diisopropylethylamine (0.510 mL, 2.930 mmol) prepared in Example 14 were dissolved in dichloromethane (15 mL), and the resulting solution was stirred at room temperature for 10 minutes. Then, tert-butyl piperazine-1-carboxylate (0.142 g, 0.762 mmol) was added and stirred for another 16 hours at the same temperature. Water 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 column chromatography (SiO 2 , 12 g column; ethyl acetate / hexanes = 5% to 50%) and concentrated to obtain the title compound (0.160 g, 49.3%) as a white solid.

[0406] [Step 2] Synthesis of N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridine-2-yl) 1-(2-(4-(2-(4-(2-methyl)piperazine)-1-carboxamide)

[0407]

[0408] Tert-butyl 4-(((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)(phenyl)carbamoyl)piperazine-1-carboxylate (0.100 g, 0.181 mmol) prepared in step 1 was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (0.277 mL, 3.613 mmol) was added at 0°C and stirred at room temperature for 16 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, extracted with dichloromethane, and then filtered through a plastic filter to remove the solid residue and the water layer. After concentration under reduced pressure, the title compound (0.099 g, 96.6%) was obtained as a foam solid without further purification.

[0409] [Step 3] Synthesis of compound 3784

[0410]

[0411] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-carboxamide (0.050 g, 0.110 mmol), paraformaldehyde (0.007 g, 0.221 mmol) and acetic acid (0.006 mL, 0.110 mmol) prepared in step 2 were dissolved in dichloromethane (5 mL), and the resulting solution was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (0.070 g, 0.331 mmol) was added and stirred for another 16 hours at the same temperature. Water 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 (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 10%) and concentrated to afford the title compound (0.030 g, 58.2%) as a white solid.

[0412] 1 H NMR(400MHz,MeOD)δ8.59(m,1H),8.20(m,1H),7.97(m,1H),7.56-7.54(m,1H),7.39- 7.35(m,2H),7.26-7.13(m,4H),5.03(s,2H),3.32(m,4H),2.36(m,4H),2.29(s,3H);

[0413] LRMS(ES)m / z 468.3(M + +1).

[0414] Example 36: Synthesis of Compound 3785, 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-carboxamide

[0415]

[0416] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-carboxamide (0.050 g, 0.110 mmol), oxetane-3-one (0.014 mL, 0.221 mmol) and acetic acid (0.006 mL, 0.110 mmol) prepared in step 2 of Example 35 were dissolved in dichloromethane (5 mL), and the resulting solution was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (0.070 g, 0.331 mmol) was added and stirred for another 16 hours at the same temperature. Water 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 (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 10%) and concentrated to afford the title compound (0.028 g, 49.8%) as a white solid.

[0417] 1 H NMR(400MHz,MeOD)δ8.58(m,1H),8.19(m,1H),7.96(s,1H),7.55-7.52(m,1H),7.39-7.34(m,2H), 7.26-7.13(m,4H),5.02(s,2H),4.63(m,2H),4.52(m,2H),3.41(m,1H),3.32(m,4H),2.17(m,4H);

[0418] LRMS (ES) m / z 510.1 (M + +1).

[0419] Example 37: Synthesis of Compound 4033, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-ethyl-N-phenylpiperazine-1-carboxamide

[0420]

[0421] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-carboxamide (0.100 g, 0.221 mmol), acetaldehyde (0.019 g, 0.441 mmol), acetic acid (0.013 mL, 0.221 mmol) and sodium triacetoxyborohydride (0.140 g, 0.662 mmol) prepared in step 2 of Example 35 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.027 g, 25.4%) as a yellow solid.

[0422] 1 H NMR(700MHz,MeOD)δ8.59(dd,J=7.2,1.0Hz,1H),8.21(dt,J=1.7,0.8Hz,1H),7.98(d,J=0.8Hz,1H),7.55(dd,J=7.1,1.7Hz,1H), 7.38-7.13(m,6H),5.03(d,J=0.8Hz,2H),3.32-3.27(m,4H),2.38(q,J=7.3Hz,2H),2.31(t,J=5.1Hz,4H),1.06(t,J=7.2Hz,3H);

[0423] LRMS(ES)m / z 482.2(M + +1).

[0424] Example 38: Synthesis of Compound 4034, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-isopropyl-N-phenylpiperazine-1-carboxamide

[0425]

[0426] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-carboxamide (0.050 g, 0.110 mmol), propan-2-one (0.013 g, 0.221 mmol), acetic acid (0.006 mL, 0.110 mmol) and sodium triacetoxyborohydride (0.070 g, 0.331 mmol) prepared in step 2 of Example 35 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.030 g, 54.9%) as a yellow solid.

[0427] 1 H NMR(400MHz,MeOD)δ8.53(dd,J=7.1,1.0Hz,1H),8.22(dt,J=1.8,0.8Hz,1H),7.92(s,1H),7.55(dd,J=7.1,1.7Hz,1H),7 .39-7.02(m,6H),5.02(s,2H),3.30(t,J=5.1Hz,4H),2.65(p,J=6.5Hz,1H),2.40(t,J=5.1Hz,4H),1.02(d,J=6.5Hz,6H);

[0428] LRMS (ES) m / z 496.5 (M + +1).

[0429] Example 39: Synthesis of Compound 4035, 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-carboxamide

[0430]

[0431] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-carboxamide (0.100 g, 0.221 mmol), 1-hydroxypropan-2-one (0.033 g, 0.441 mmol), acetic acid (0.013 mL, 0.221 mmol) and sodium triacetoxyborohydride (0.140 g, 0.662 mmol) prepared in step 2 of Example 35 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.011 g, 9.8%) as a yellow solid.

[0432] 1 H NMR (400 MHz, CDCl 3 )δ8.31-8.27(m,1H),8.20(dt,J=7.2,1.4Hz,1H),7.79-7.74(m,1H),7.51(tt,J=5.4,1.7Hz,1H),7.38-7.30(m,2H),7.27-7.21(m,2H),7.20 -7.09(m,1H),7.09-6.80(m,1H),5.07(s,2H),3.33(d,J=23.0Hz,4H), 3.24-3.15(m,2H),2.40(s,2H),2.12(s,2H),2.04(s,1H),1.28(s,3H);

[0433] LRMS (ES) m / z 512.3 (M + +1).

[0434] Example 40: Synthesis of Compound 4036, 4-cyclobutyl-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-carboxamide

[0435]

[0436] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-carboxamide (0.100 g, 0.221 mmol), cyclobutanone (0.031 g, 0.441 mmol), acetic acid (0.013 mL, 0.221 mmol) and sodium triacetoxyborohydride (0.140 g, 0.662 mmol) prepared in step 2 of Example 35 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.028 g, 25.0%) as a yellow solid.

[0437] 1 H NMR (700MHz, MeOD) δ8.60(dd,J=7.1,1.0Hz,1H),8.21(p,J=0.8Hz,1H),7.98(d,J=0.8Hz,1H),7.56(dd,J=7.1,1.7Hz,1H),7.40-7.14(m,6H),5.03(d,J =0.8Hz,2H),3.29(t,J=5.1Hz,4H),2.73-2.66(m,1H),2.18(t,J=5.1Hz,4H) ,2.06-1.98(m,2H),1.89-1.79(m,2H),1.70(ddt,J=12.8,10.0,5.7Hz,2H);

[0438] LRMS (ES) m / z 508.3 (M + +1).

[0439] Example 41: Synthesis of Compound 4037, 4-cyclohexyl-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-carboxamide

[0440]

[0441] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-carboxamide (0.100 g, 0.221 mmol), cyclohexanone (0.043 g, 0.441 mmol), acetic acid (0.013 mL, 0.221 mmol) and sodium triacetoxyborohydride (0.140 g, 0.662 mmol) prepared in step 2 of Example 35 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.031 g, 26.2%) as a yellow solid.

[0442] 1 H NMR(700MHz,MeOD)δ8.57(d,J=7.1Hz,1H),8.22-8.20(m,1H),7.96(s,1H),7.5 5(dd,J=7.1,1.7Hz,1H),7.41-7.09(m,6H),5.04-5.01(m,2H),3.29(t,J=5.1H z,4H),2.43(t,J=5.0Hz,4H),2.23(tt,J=11.9,3.6Hz,1H),1.86-1.74(m,4H), 1.63(dt,J=12.6,3.3Hz,1H),1.24(qt,J=12.9,3.2Hz,2H),1.19-1.07(m,3H);

[0443] LRMS (ES) m / z 536.2 (M + +1).

[0444] Example 42: Synthesis of Compound 4038, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenyl-4-(tetrahydro-2H-pyran-4-yl)piperazine-1-carboxamide

[0445]

[0446] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-carboxamide (0.100 g, 0.221 mmol), tetrahydro-4H-pyran-4-one (0.044 g, 0.441 mmol), acetic acid (0.013 mL, 0.221 mmol) and sodium triacetoxyborohydride (0.140 g, 0.662 mmol) prepared in step 2 of Example 35 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.016 g, 13.5%) as a yellow solid.

[0447] 1 H NMR(700MHz,MeOD)δ8.53(d,J=7.1Hz,1H),8.23-8.20(m,1H),7.92(s,1H),7.55(d d,J=7.1,1.7Hz,1H),7.36(dd,J=8.5,7.4Hz,2H),7.29-7.05(m,4H),5.02(s,2H),3 .97(dd,J=11.3,4.4Hz,2H),3.36(td,J=12.0,1.9Hz,2H),3.31-3.28(m,4H),2.43 (t,J=5.1Hz,5H),1.75(ddd,J=12.4,4.3,2.1Hz,2H),1.47(qd,J=12.2,4.5Hz,2H);

[0448] LRMS (ES) m / z 538.1 (M + +1).

[0449] Example 43: Synthesis of Compound 4039, 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-carboxamide

[0450]

[0451] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-carboxamide (0.100 g, 0.221 mmol), 4,4-difluorocyclohexan-1-one (0.059 g, 0.441 mmol), acetic acid (0.013 mL, 0.221 mmol) and sodium triacetoxyborohydride (0.140 g, 0.662 mmol) prepared in step 2 of Example 35 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentrated to obtain the title compound (0.034 g, 27.0%) as a yellow solid.

[0452] 1 H NMR(700MHz,MeOD)δ8.47(dd,J=7.1,1.0Hz,1H),8.21(dt,J=1.7,0.8Hz,1H),7.8 8(d,J=0.8Hz,1H),7.54(dd,J=7.1,1.7Hz,1H),7.37-7.32(m,2H),7.25-7.00(m, 4H),5.01(s,2H),3.30-3.26(m,4H),2.47-2.27(m,5H),2.08-2.04(m,2H),1.81( d,J=13.1Hz,2H),1.72(dddd,J=30.7,17.4,13.1,4.2Hz,2H),1.57-1.49(m,2H);

[0453] LRMS (ES) m / z 572.3 (M + +1).

[0454] Example 44: Synthesis of Compound 4040, 4-acetyl-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-carboxamide

[0455]

[0456] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-carboxamide (0.100 g, 0.221 mmol), acetyl chloride (0.031 mL, 0.441 mmol) and triethylamine (0.092 mL, 0.662 mmol) prepared in step 2 of Example 35 were dissolved in dichloromethane (4 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 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.018 g, 16.5%) as a yellow solid.

[0457] 1 H NMR (400 MHz, CDCl 3 )δ8.37(s,1H),8.24(d,J=7.1Hz,1H),7.79(s,1H),7.59(d,J=7.1Hz,1H),7.37(dd,J=8.4,7.2Hz,2H),7.33-7.28(m,2H),7. 21-7.13(m,1H),6.95(t,J=51.7Hz,1H),5.07(s,2H),3.43(t,J=5.3Hz,2H),3.30(s,4H),3.23(t,J=5.4Hz,2H),2.04(s,3H);

[0458] LRMS(ES)m / z 496.0(M + +1).

[0459] Example 45: Synthesis of Compound 4041, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenyl-4-propionylpiperazine-1-carboxamide

[0460]

[0461] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-carboxamide (0.100 g, 0.221 mmol), propionyl chloride (0.041 g, 0.441 mmol) and triethylamine (0.092 mL, 0.662 mmol) prepared in step 2 of Example 35 were dissolved in dichloromethane (4 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 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.014 g, 12.5%) as a yellow solid.

[0462] 1 H NMR(700MHz,MeOD)δ8.58(dd,J=7.1,1.0Hz,1H),8.20(dt,J=1.7,0.8Hz,1H),8.00-7.98(m,1H),7.54(dd,J=7.1,1.7Hz,1H ),7.40-7.14(m,6H),5.06-5.03(m,2H),3.44-3.38(m,4H),3.32-3.24(m,4H),2.35(q,J=7.5Hz,2H),1.07(t,J=7.5Hz,3H);

[0463] LRMS (ES) m / z 510.3 (M + +1).

[0464] Example 46: Synthesis of Compound 4042, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-(2-hydroxyacetyl)-N-phenylpiperazine-1-carboxamide

[0465]

[0466] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-carboxamide (0.100 g, 0.221 mmol), 2-hydroxyacetyl chloride (0.042 g, 0.441 mmol) and triethylamine (0.092 mL, 0.662 mmol) prepared in step 2 of Example 35 were dissolved in dichloromethane (4 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 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.029 g, 25.7%) as a yellow solid.

[0467] 1 H NMR (400 MHz, CDCl 3 )δ8.42(s,1H),8.26(d,J=7.1Hz,1H),7.80(s,1H),7.64(s,1H),7.43-7.30(m,4H),7.24-7.16(m,1H),6.95(t,J=5 1.7Hz, 1H), 5.07 (d, J = 0.7Hz, 2H), 4.09 (s, 2H), 3.50 (t, J = 5.3Hz, 2H), 3.29 (d, J = 9.9Hz, 4H), 3.10 (t, J = 5.2Hz, 2H);

[0468] LRMS (ES) m / z 513.2 (M + +1).

[0469] Example 47: Synthesis of Compound 4043, 4-(cyclobutanecarbonyl)-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-carboxamide

[0470]

[0471] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-carboxamide (0.100 g, 0.221 mmol), cyclobutanecarbonyl chloride (0.052 g, 0.441 mmol) and triethylamine (0.092 mL, 0.662 mmol) prepared in step 2 of Example 35 were dissolved in dichloromethane (4 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 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.030 g, 25.4%) as a yellow solid.

[0472] 1 H NMR(700MHz,MeOD)δ8.59(dd,J=7.1,1.0Hz,1H),8.21(dt,J=1.7,0.8Hz,1H) ,8.02-7.98(m,1H),7.56(dd,J=7.1,1.7Hz,1H),7.44-7.14(m,6H),5.06-5.0 3(m,2H),3.42-3.36(m,2H),3.29-3.22(m,6H),2.28-2.17(m,3H),2.14(ddd dd,J=12.2,11.0,8.8,3.7,1.8Hz,2H),2.02-1.94(m,1H),1.84-1.78(m,1H);

[0473] LRMS (ES) m / z 537.1 (M + +1).

[0474] Example 48: Synthesis of Compound 4044, 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-carboxamide

[0475]

[0476] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-carboxamide (0.050 g, 0.110 mmol), 1,1,1,5,5,5-hexafluoropentane-2,4-dione (0.046 g, 0.221 mmol) and triethylamine (0.046 mL, 0.331 mmol) prepared in step 2 of Example 35 were dissolved in dichloromethane (4 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 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.041 g, 67.7%) as a yellow solid.

[0477] 1 H NMR (400MHz, MeOD) δ8.59(dd,J=7.2,1.0Hz,1H),8.22(dt,J=1.7,0.8Hz,1H),8.00(d,J=0.7Hz,1H),7.56(dd,J =7.2,1.7Hz,1H),7.44-7.09(m,6H),5.06(d,J=0.8Hz,2H),3.51(q,J=5.3Hz,4H),3.36(dd,J=6.7,4.4Hz,4H);

[0478] LRMS (ES) m / z 550.4 (M + +1).

[0479] Example 49: Synthesis of Compound 4045, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-(methylsulfonyl)-N-phenylpiperazine-1-carboxamide

[0480]

[0481] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-carboxamide (0.050 g, 0.110 mmol), methanesulfonyl chloride (0.017 mL, 0.221 mmol) and triethylamine (0.046 mL, 0.331 mmol) prepared in step 2 of Example 35 were dissolved in dichloromethane (4 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 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.012 g, 20.5%) as a yellow solid.

[0482] 1 H NMR (400MHz, MeOD) δ8.59(dd,J=7.1,1.0Hz,1H),8.22(dt,J=1.7,0.8Hz,1H),7.99(d,J=0.8Hz,1H),7.56(dd,J =7.1,1.7Hz,1H),7.45-7.06(m,6H),5.04(d,J=0.7Hz,2H),3.39-3.35(m,4H),3.07-3.02(m,4H),2.80(s,3H);

[0483] LRMS (ES) m / z 532.4 (M + +1).

[0484] Example 50: Synthesis of Compound 4046, 4-(((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)(phenyl)carbamoyl)piperazine-1-carboxylic acid methyl ester

[0485]

[0486] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-carboxamide (0.100 g, 0.221 mmol), methyl chloroformate (0.042 g, 0.441 mmol) and triethylamine (0.092 mL, 0.662 mmol) prepared in step 2 of Example 35 were dissolved in dichloromethane (4 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 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.034 g, 30.1%) as a yellow solid.

[0487] 1 H NMR (700MHz, MeOD) δ8.59(dd,J=7.1,1.0Hz,1H),8.21(dt,J=1.7,0.8Hz,1H),7.99(d,J=0.8Hz,1H),7.55(dd,J=7.1, 1.7Hz,1H),7.44-7.11(m,6H),5.04(d,J=0.8Hz,2H),3.66(s,3H),3.29(d,J=5.9Hz,4H),3.26(dd,J=7.0,3.5Hz,4H);

[0488] LRMS (ES) m / z 511.8 (M + +1).

[0489] Example 51: Synthesis of Compound 4047, N1-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N4,N4-dimethyl-N1-phenylpiperazine-1,4-dicarboxamide

[0490]

[0491] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-carboxamide (0.100 g, 0.221 mmol), dimethylcarbamoyl chloride (0.047 g, 0.441 mmol) and triethylamine (0.092 mL, 0.662 mmol) prepared in step 2 of Example 35 were dissolved in dichloromethane (4 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 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.028 g, 24.2%) as a yellow solid.

[0492] 1 H NMR (700MHz, MeOD) δ8.59(dd,J=7.1,1.0Hz,1H),8.21(dt,J=1.7,0.8Hz,1H),7.99(d,J=0.8Hz,1H),7.55(dd,J =7.1,1.7Hz,1H),7.43-7.07(m,6H),5.04(d,J=0.8Hz,2H),3.32-3.28(m,4H),3.09-3.05(m,4H),2.81(s,6H);

[0493] LRMS(ES)m / z 525.0(M + +1).

[0494] Example 52: Synthesis of Compound 4048, 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-carboxamide

[0495]

[0496] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-carboxamide (0.065 g, 0.143 mmol), 2-chloropyridine (0.033 g, 0.287 mmol), cesium carbonate (0.093 g, 0.287 mmol) and RuPhos palladium G2 (0.006 g, 0.007 mmol) prepared in step 2 of Example 35 were dissolved in 1,4-dioxane (2 mL) at room temperature, and the resulting solution was stirred at 100° C. for 18 hours. Then, the temperature was lowered to room temperature to terminate the reaction. Saturated 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 30%) and concentration gave the title compound (0.011 g, 14.5%) as a white solid.

[0497] 1 H NMR (400 MHz, CDCl 3 )δ8.32(s,1H),8.24(d,J=7.1Hz,1H),8.20-8.16(m,1H),7.79(s,1H),7.53(d,J=7.1Hz,1H),7.39-7.29(m,5H ),7.16(t,J=7.1Hz,1H),6.95(t,J=51.7Hz,1H),6.74(s,2H),5.10(d,J=2.3Hz,2H),3.45(s,6H),1.63(s,2H);

[0498] LRMS (ES) m / z 531.4 (M + +1).

[0499] Example 53: Synthesis of Compound 4049, 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-carboxamide

[0500]

[0501] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-carboxamide (0.100 g, 0.221 mmol), 2-chloropyrimidine (0.051 g, 0.441 mmol) and potassium carbonate (0.061 g, 0.441 mmol) prepared in step 2 of Example 35 were dissolved in acetonitrile (2 mL) / N,N-dimethylformamide (2 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. 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. 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.015 g, 12.8%) as a yellow solid.

[0502] 1 H NMR (700MHz, MeOD) δ8.56(d,J=7.0Hz,1H),8.31-8.23(m,2H),7.97(d,J=9.4Hz,1H),7.76-7.73(m,1H),7.59( d,J=7.1Hz,1H),7.40-7.08(m,6H),6.58(t,J=4.8Hz,1H),5.06(s,2H),3.66-3.62(m,4H),3.36-3.34(m,4H);

[0503] LRMS(ES)m / z 532.0(M + +1).

[0504] Example 54: Synthesis of Compound 4083, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-4-methylpiperazine-1-carboxamide

[0505] [Step 1] Synthesis of 4-(((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridine- tert-Butyl (2-yl)methyl)(3-fluorophenyl)carbamoyl)piperazine-1-carboxylate

[0506]

[0507] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-3-fluoroaniline (0.200 g, 0.557 mmol), tert-butyl piperazine-1-carboxylate (0.135 g, 0.724 mmol), triphosgene (0.165 g, 0.557 mmol) and N,N-diisopropylethylamine (0.485 mL, 2.783 mmol) prepared in Example 16 were dissolved in dichloromethane (15 mL), and the resulting solution was stirred at 0 ° C for 1 hour and at room temperature for another 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 by column chromatography (SiO 2 , 40 g column; ethyl acetate / hexanes = 0% to 60%) and concentrated to obtain the title compound (0.240 g, 75.4%) as a white solid.

[0508] [Step 2] Synthesis of N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridine-2-yl) 1-(4-(4-(2 ...methyl-1-yl)methyl)piperazine-1-carboxamide)

[0509]

[0510] Tert-butyl 4-(((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)(3-fluorophenyl)carbamoyl)piperazine-1-carboxylate (2.000 g, 3.499 mmol) and trifluoroacetic acid (5.359 mL, 69.984 mmol) prepared in step 1 were dissolved in dichloromethane (30 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, 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 to obtain the title compound (1.650 g, 100.0%) as a brown gel without further purification.

[0511] [Step 3] Synthesis of compound 4083

[0512]

[0513] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-carboxamide (0.080 g, 0.170 mmol), formaldehyde (0.010 g, 0.339 mmol), acetic acid (0.010 mL, 0.170 mmol) and sodium triacetoxyborohydride (0.108 g, 0.509 mmol) prepared in step 2 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.018 g, 21.8%) as a yellow solid.

[0514] 1 H NMR (700MHz, MeOD) δ8.59 (dd, J=7.2, 1.0Hz, 1H), 8.22 (dt, J=1.8, 0.9Hz, 1H), 7.9 9(d,J=0.7Hz,1H),7.56(dd,J=7.1,1.7Hz,1H),7.37(td,J=8.4,6.6Hz,1H),7.26 (t,J=51.6Hz,1H),7.09-7.03(m,2H),6.90(tdd,J=8.3,2.5,0.9Hz,1H),5.04(d, J=0.8Hz,2H),3.32(s,2H),3.28-3.25(m,2H),2.31(t,J=5.0Hz,4H),2.25(s,3H);

[0515] LRMS (ES) m / z 486.1 (M + +1).

[0516] Example 55: Synthesis of Compound 4084, 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-carboxamide

[0517]

[0518] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-carboxamide (0.080 g, 0.170 mmol), acetaldehyde (0.015 g, 0.339 mmol), acetic acid (0.010 mL, 0.170 mmol) and sodium triacetoxyborohydride (0.108 g, 0.509 mmol) prepared in step 2 of Example 54 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentrated to obtain the title compound (0.022 g, 26.0%) as a yellow solid.

[0519] 1 H NMR (700MHz, MeOD) δ8.59 (dd, J=7.1, 1.0Hz, 1H), 8.21 (dt, J=1.7, 0.8Hz, 1H), 7.99 (d, J= 0.8Hz,1H),7.56(dd,J=7.1,1.7Hz,1H),7.37(td,J=8.3,6.5Hz,1H),7.27(t,J=51.6Hz, 1H),7.09-7.04(m,2H),6.90(tdd,J=8.4,2.4,0.9Hz,1H),5.04(d,J=0.8Hz,2H),3.33(d d,J=3.6,2.0Hz,4H),2.40(q,J=7.2Hz,2H),2.35(t,J=5.1Hz,4H),1.07(t,J=7.2Hz,3H);

[0520] LRMS (ES) m / z 500.1 (M + +1).

[0521] Example 56: Synthesis of Compound 4085, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-4-isopropylpiperazine-1-carboxamide

[0522]

[0523] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-carboxamide (0.080 g, 0.170 mmol), propan-2-one (0.020 g, 0.339 mmol), acetic acid (0.010 mL, 0.170 mmol) and sodium triacetoxyborohydride (0.108 g, 0.509 mmol) prepared in step 2 of Example 54 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.024 g, 27.5%) as a yellow solid.

[0524] 1 H NMR(700MHz,MeOD)δ8.59(dd,J=7.1,1.0Hz,1H),8.22(dt,J=1.7,0.8Hz,1H),7.99(d, J=0.8Hz,1H),7.56(dd,J=7.2,1.7Hz,1H),7.37(td,J=8.3,6.6Hz,1H),7.27(t,J=51. 6Hz,1H),7.08-7.04(m,2H),6.90(tdd,J=8.4,2.4,0.9Hz,1H),5.04(d,J=0.8Hz,2H), 3.33-3.31(m,4H),2.65(p,J=6.5Hz,1H),2.42(t,J=5.1Hz,4H),1.03(d,J=6.5Hz,6H);

[0525] LRMS (ES) m / z 514.4 (M + +1).

[0526] Example 57: Synthesis of Compound 4086, 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-carboxamide

[0527]

[0528] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-carboxamide (0.080 g, 0.170 mmol), 1-hydroxypropan-2-one (0.025 g, 0.339 mmol), acetic acid (0.010 mL, 0.170 mmol) and sodium triacetoxyborohydride (0.108 g, 0.509 mmol) prepared in step 2 of Example 54 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.022 g, 24.5%) as a yellow solid.

[0529] 1 H NMR(700MHz,MeOD)δ8.60(dd,J=7.1,1.0Hz,1H),8.23(dt,J=1.8,0.9Hz,1H),8.00(d,J=0.8Hz,1H),7.56(dd,J =7.1,1.7Hz,1H),7.36(td,J=8.3,6.6Hz,1H),7.26(t,J=51.7Hz,1H),7.08-7.03(m,2H),6.92-6.86(m,1H),5. 04(d,J=0.8Hz,2H),3.53(dd,J=11.1,6.8Hz,1H),3.41(dd,J=11.2,5.6Hz,1H),3.33-3.30(m,4H),2.65(td,J= 6.8,5.7Hz,1H),2.50(ddd,J=10.6,6.3,3.8Hz,2H),2.43(ddd,J=10.9,6.3,4.2Hz,2H),0.96(d,J=6.7Hz,3H);

[0530] LRMS (ES) m / z 530.1 (M + +1).

[0531] Example 58: Synthesis of Compound 4087, 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-carboxamide

[0532]

[0533] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-carboxamide (0.080 g, 0.170 mmol), cyclobutanone (0.024 g, 0.339 mmol), acetic acid (0.010 mL, 0.170 mmol) and sodium triacetoxyborohydride (0.108 g, 0.509 mmol) prepared in step 2 of Example 54 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentrated to obtain the title compound (0.025 g, 28.0%) as a yellow solid.

[0534] 1 H NMR(700MHz,MeOD)δ8.55(dd,J=7.1,1.0Hz,1H),8.24-8.21(m,1H),7.94(s,1H),7.56 (dd,J=7.1,1.7Hz,1H),7.34(td,J=8.4,6.5Hz,1H),7.20(t,J=51.7Hz,1H),7.05-6.9 9(m,2H),6.90-6.85(m,1H),5.03(s,2H),3.31(d,J=7.4Hz,4H),2.74(s,1H),2.24(s, 4H),2.06-2.00(m,2H),1.90-1.79(m,2H),1.71(dtd,J=15.6,10.8,10.3,8.2Hz,2H);

[0535] LRMS (ES) m / z 526.1 (M + +1).

[0536] Example 59: Synthesis of Compound 4088, 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-carboxamide

[0537]

[0538] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-carboxamide (0.080 g, 0.170 mmol), oxetane-3-one (0.024 g, 0.339 mmol), acetic acid (0.010 mL, 0.170 mmol) and sodium triacetoxyborohydride (0.108 g, 0.509 mmol) prepared in step 2 of Example 54 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.019 g, 21.2%) as a yellow solid.

[0539] 1 H NMR(700MHz,MeOD)δ8.54(dd,J=7.1,1.0Hz,1H),8.23(dt,J=1.8,0.8Hz,1H),7.94(d, J=0.8Hz, 1H), 7.56 (dd, J=7.1, 1.7Hz, 1H), 7.34 (td, J=8.4, 6.4Hz, 1H), 7.20 (t, J=51. 6Hz,1H),7.05-6.99(m,H),6.88(tdd,J=8.3,2.5,0.9Hz,1H),5.05-4.98(m,2H),4.66 (t,J=6.7Hz,2H),4.55(t,J=6.2Hz,2H),3.47(s,1H),3.36-3.34(m,4H),2.24(s,4H);

[0540] LRMS (ES) m / z 529.2 (M + +1).

[0541] Example 60: Synthesis of Compound 4089, 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-carboxamide

[0542]

[0543] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-carboxamide (0.080 g, 0.170 mmol), cyclohexanone (0.033 g, 0.339 mmol), acetic acid (0.010 mL, 0.170 mmol) and sodium triacetoxyborohydride (0.108 g, 0.509 mmol) prepared in step 2 of Example 54 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.018 g, 19.2%) as a yellow solid.

[0544] 1 H NMR(700MHz,MeOD)δ8.54(dd,J=7.1,1.0Hz,1H),8.23(t,J=1.1Hz,1H),7.94(s,1H),7.56(dd,J=7.1,1.7H z,1H),7.34(td,J=8.5,6.7Hz,1H),7.20(t,J=51.6Hz,1H),7.07-6.95(m,2H),6.87(ddd,J=9.5,8.0,2.5H z,1H),5.03(s,2H),3.32(s,4H),2.50(s,4H),2.28(s,1H),1.84(d,J=11.2Hz,2H),1.82-1.76(m,2H),1.6 4(d,J=12.6Hz,1H),1.24(ddd,J=16.0,11.2,3.2Hz,2H),1.21-1.13(m,2H),1.11(dt,J=12.9,3.6Hz,1H);

[0545] LRMS (ES) m / z 554.4 (M + +1).

[0546] Example 61: Synthesis of Compound 4090, 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-carboxamide

[0547]

[0548] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-carboxamide (0.080 g, 0.170 mmol), tetrahydro-4H-pyran-4-one (0.034 g, 0.339 mmol), acetic acid (0.010 mL, 0.170 mmol) and sodium triacetoxyborohydride (0.108 g, 0.509 mmol) prepared in step 2 of Example 54 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.028 g, 29.7%) as a yellow solid.

[0549] 1 H NMR(700MHz,MeOD)δ8.53(dt,J=6.8,3.2Hz,1H),8.23(s,1H),7.93(d,J=2.5Hz,1H ),7.56(d,J=7.0Hz,1H),7.34(q,J=7.8Hz,1H),7.18(tt,J=51.7,2.9Hz,1H),7.02 (t,J=10.6Hz,2H),6.87(td,J=8.3,2.6Hz,1H),5.03(s,2H),4.00-3.96(m,2H),3. 41-3.32(m,7H),2.48(s,4H),1.77(d,J=12.5Hz,2H),1.50(dd,J=12.2,4.3Hz,2H);

[0550] LRMS (ES) m / z 556.1 (M + +1).

[0551] Example 62: Synthesis of Compound 4091, 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-carboxamide

[0552]

[0553] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-carboxamide (0.080 g, 0.170 mmol), 4,4-difluorocyclohexan-1-one (0.046 g, 0.339 mmol), acetic acid (0.010 mL, 0.170 mmol) and sodium triacetoxyborohydride (0.108 g, 0.509 mmol) prepared in step 2 of Example 54 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.030 g, 30.0%) as a yellow solid.

[0554] 1 H NMR (400 MHz, CDCl 3 )δ8.28(s,1H),8.21(d,J=7.0Hz,1H),7.75(d,J=0.8Hz,1H),7.53(d,J=7.2Hz,1H),7.32(d,J=7.8Hz,1H),7.09-6.78(m,4H), 5.07(s,2H),4.01-3.87(m,1H),3.30(s,2H),2.40(s,3H),2.23-2.05(m,3H),1.98-1.83(m,4H),1.76(dt,J=12.3,6.3Hz,4H);

[0555] LRMS (ES) m / z 590.3 (M + +1).

[0556] Example 63: Synthesis of Compound 4092, 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-carboxamide

[0557]

[0558] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-carboxamide (0.080 g, 0.170 mmol), acetyl chloride (0.024 mL, 0.339 mmol) and triethylamine (0.071 mL, 0.509 mmol) prepared in step 2 of Example 54 were dissolved in dichloromethane (4 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 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.037 g, 42.5%) as a yellow solid.

[0559] 1 H NMR (400 MHz, CDCl 3 )δ8.32(s,1H),8.23(dd,J=7.1,1.0Hz,1H),7.77(s,1H),7.56(dd,J=7.1,1.7Hz,1H),7.32(td,J=8.2,6.5Hz, 1H),7.13-6.79(m,4H),5.07(s,2H),3.47(dd,J=6.6,4.0Hz,2H),3.33(s,4H),3.26-3.22(m,2H),2.05(s,3H);

[0560] LRMS (ES) m / z 514.3 (M + +1).

[0561] Example 64: Synthesis of Compound 4093, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-4-propionylpiperazine-1-carboxamide

[0562]

[0563] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-carboxamide (0.080 g, 0.170 mmol), propionyl chloride (0.031 g, 0.339 mmol) and triethylamine (0.071 mL, 0.509 mmol) prepared in step 2 of Example 54 were dissolved in dichloromethane (4 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 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.031 g, 34.6%) as a yellow solid.

[0564] 1 H NMR(700MHz,MeOD)δ8.59(dd,J=7.1,1.0Hz,1H),8.21(dt,J=1.7,0.8Hz,1H),8.02-7.99 (m,1H),7.55(dd,J=7.1,1.7Hz,1H),7.37(td,J=8.2,6.4Hz,1H),7.27(t,J=51.7Hz,1H), 7.13-7.06(m,2H),6.91(tdd,J=8.4,2.5,0.9Hz,1H),5.06(d,J=0.8Hz,2H),3.49-3.42(m ,4H),3.35-3.34(m,2H),3.30-3.27(m,2H),2.37(q,J=7.5Hz,2H),1.08(t,J=7.5Hz,3H);

[0565] LRMS(ES)m / z 528.1(M + +1).

[0566] Example 65: Synthesis of Compound 4094, 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-carboxamide

[0567]

[0568] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-carboxamide (0.080 g, 0.170 mmol), 2-hydroxyacetyl chloride (0.032 g, 0.339 mmol) and triethylamine (0.071 mL, 0.509 mmol) prepared in step 2 of Example 54 were dissolved in dichloromethane (4 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 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.014 g, 15.6%) as a yellow solid.

[0569] 1 H NMR(700MHz,MeOD)δ8.60(dd,J=7.1,1.0Hz,1H),8.23(dt,J=1.7,0.8Hz,1H),8.01(d,J=0 .8Hz,1H),7.57(dd,J=7.1,1.7Hz,1H),7.38(td,J=8.2,6.5Hz,1H),7.26(t,J=51.7Hz,1H ),7.13-7.06(m,2H),6.92(tdd,J=8.3,2.5,0.9Hz,1H),5.06(d,J=0.8Hz,2H),4.19(s,2H ),3.74(p,J=6.6Hz,1H),3.48(t,J=5.3Hz,2H),3.26-3.19(m,1H),1.39(d,J=6.7Hz,4H);

[0570] LRMS (ES) m / z 530.0 (M + +1).

[0571] Example 66: Synthesis of Compound 4095, 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-carboxamide

[0572]

[0573] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-carboxamide (0.080 g, 0.170 mmol), cyclobutanecarbonyl chloride (0.040 g, 0.339 mmol) and triethylamine (0.071 mL, 0.509 mmol) prepared in step 2 of Example 54 were dissolved in dichloromethane (4 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 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.027 g, 28.7%) as a yellow solid.

[0574] 1 H NMR (700MHz, MeOD) δ8.60 (dd, J = 7.1, 1.0 Hz, 1H), 8.24-8.21 (m, 1H), 8.01 (s, 1H), 7.57 (dd, J = 7. 1,1.7Hz,1H),7.37(td,J=8.2,6.5Hz,1H),7.26(t,J=51.7Hz,1H),7.13-7.06(m,2H),6.92(tdd, J=8.4,2.5,0.9Hz,1H),5.06(s,2H),3.46-3.43(m,2H),3.37(td,J=8.7,1.1Hz,1H),3.32(s,1H) ,3.30-3.26(m,4H),2.28-2.19(m,3H),2.17-2.10(m,2H),2.04-1.95(m,1H),1.84-1.78(m,1H);

[0575] LRMS (ES) m / z 553.9 (M + +1).

[0576] Example 67: Synthesis of Compound 4096, 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-carboxamide

[0577]

[0578] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-carboxamide (0.050 g, 0.106 mmol), 1,1,1,5,5,5-hexafluoropentane-2,4-dione (0.044 g, 0.212 mmol) and triethylamine (0.044 mL, 0.318 mmol) prepared in step 2 of Example 54 were dissolved in dichloromethane (4 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 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.038 g, 63.1%) as a yellow solid.

[0579] 1 H NMR (400MHz, MeOD) δ8.59(dd,J=7.2,1.0Hz,1H),8.23(dt,J=1.6,0.8Hz,1H),8.01(d,J=0.7Hz,1H),7.57(dd,J=7 .2,1.7Hz,1H),7.42-6.86(m,5H),5.07(d,J=0.8Hz,2H),3.56(q,J=5.0Hz,4H),3.38(td,J=7.2,6.2,4.0Hz,4H);

[0580] LRMS (ES) m / z 568.4 (M + +1).

[0581] Example 68: Synthesis of Compound 4097, 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-carboxamide

[0582]

[0583] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-carboxamide (0.050 g, 0.106 mmol), methanesulfonyl chloride (0.016 mL, 0.212 mmol) and triethylamine (0.044 mL, 0.318 mmol) prepared in step 2 of Example 54 were dissolved in dichloromethane (4 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 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.015 g, 25.7%) as a yellow solid.

[0584] 1 H NMR (400MHz, MeOD) δ8.60(dd,J=7.2,1.0Hz,1H),8.23(dt,J=1.7,0.8Hz,1H),8.01(d,J=0.8Hz,1H),7.57(dd,J =7.1,1.7Hz,1H),7.46-6.87(m,5H),5.06(d,J=0.7Hz,2H),3.43-3.36(m,4H),3.13-3.06(m,4H),2.81(s,3H);

[0585] LRMS (ES) m / z 550.4 (M + +1).

[0586] Example 69: Synthesis of Compound 4098, methyl 4-(((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)(3-fluorophenyl)carbamoyl)piperazine-1-carboxylate

[0587]

[0588] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-carboxamide (0.080 g, 0.170 mmol), methyl chloroformate (0.032 g, 0.339 mmol) and triethylamine (0.071 mL, 0.509 mmol) prepared in step 2 of Example 54 were dissolved in dichloromethane (4 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 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.032 g, 35.6%) as a yellow solid.

[0589] 1 H NMR(700MHz,MeOD)δ8.55(dd,J=7.1,1.0Hz,1H),8.24(dt,J=1.8,0.9Hz,1H),7.96(s,1H),7.57(dd,J=7.1,1.7Hz,1H),7.35(td,J=8.4,6.5Hz,1 H),7.20(t,J=51.6Hz,1H),7.07-7.02(m,2H),6.92-6.86(m,1H),5.05-5 .02(m,2H),3.67(s,3H),3.36-3.34(m,4H),3.28(dd,J=6.6,3.7Hz,4H);

[0590] LRMS (ES) m / z 531.3 (M + +1).

[0591] Example 70: Synthesis of Compound 4099, N1-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N1-(3-fluorophenyl)-N4,N4-dimethylpiperazine-1,4-dicarboxamide

[0592]

[0593] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-carboxamide (0.080 g, 0.170 mmol), dimethylcarbamoyl chloride (0.036 g, 0.339 mmol) and triethylamine (0.071 mL, 0.509 mmol) prepared in step 2 of Example 54 were dissolved in dichloromethane (4 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 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.018 g, 19.6%) as a yellow solid.

[0594] 1 H NMR (700MHz, MeOD) δ8.58-8.55(m,1H),8.26-8.24(m,1H),7.97(s,1H),7.59(dd,J=7.1,1.7Hz,1H),7.36(td,J=8.4,6.4Hz,1H),7.20( t,J=51.7Hz,1H),7.06-7.02(m,2H),6.89(tdd,J=8.3,2.4,1.0Hz,1H),5.05(s,2H),3.32-3.30(m,4H),3.12-3.10(m,4H),2.82(s,6H);

[0595] LRMS (ES) m / z 542.9 (M + +1).

[0596] Example 71: Synthesis of Compound 4100, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-4-(pyridin-2-yl)piperazine-1-carboxamide

[0597]

[0598] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-carboxamide (0.066 g, 0.140 mmol), 2-chloropyridine (0.032 g, 0.280 mmol), cesium carbonate (0.091 g, 0.280 mmol) and RuPhos palladium G2 (0.005 g, 0.007 mmol) prepared in step 2 of Example 54 were dissolved in 1,4-dioxane (2 mL) at room temperature, and the resulting solution was stirred at 100° C. for 18 hours. Then, the temperature was lowered to room temperature to terminate the reaction. 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 water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 30%) and concentration gave the title compound (0.014 g, 18.2%) as a white solid.

[0599] 1 H NMR (400 MHz, CDCl 3 )δ8.32(s,1H),8.25(d,J=7.0Hz,1H),8.21-8.17(m,1H),7.78(s,1H),7.59-7.52(m,1H),7.42(ddt,J=10.9,7.4,1.6Hz, 1H),7.36-7.29(m,1H),7.14-6.79(m,5H),6.61(d,J=8.3Hz,1H),5.10(s,2H),3.55(d,J=57.6Hz,6H),1.80-1.56(m,2H);

[0600] LRMS (ES) m / z 549.4 (M + +1).

[0601] Example 72: Synthesis of Compound 4101, 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-carboxamide

[0602]

[0603] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-carboxamide (0.080 g, 0.170 mmol), 2-chloropyrimidine (0.039 g, 0.339 mmol) and potassium carbonate (0.047 g, 0.339 mmol) prepared in step 2 of Example 54 were dissolved in acetonitrile (2 mL) / N,N-dimethylformamide (2 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. 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. 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.015 g, 16.1%) as a yellow solid.

[0604] 1 H NMR(700MHz,MeOD)δ8.50(dd,J=7.1,1.8Hz,1H),8.28(d,J=4.8Hz,1H),8.24(d ,J=1.6Hz,1H),7.93(s,1H),7.56(dd,J=7.1,1.7Hz,1H),7.34(td,J=8.1,6.4H z,1H),7.15(td,J=51.7,2.0Hz,1H),7.07-7.02(m,2H),6.87(td,J=8.3,2.4Hz ,1H),6.57(t,J=4.7Hz,1H),5.06(s,2H),3.70-3.66(m,4H),3.40-3.35(m,4H);

[0605] LRMS (ES) m / z 550.2 (M + +1).

[0606] Example 73: Synthesis of Compound 4102, 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-carboxamide

[0607]

[0608] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperazine-1-carboxamide (0.050 g, 0.110 mmol) prepared in step 2 of Example 35, oxetane-3-carboxylic acid (0.023 g, 0.221 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.050 g, 0.132 mmol) and triethylamine (0.043 mL, 0.331 mmol) 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 (SiO 2 , 12 g column; ethyl acetate / hexanes = 0% to 30%) and concentrated to afford the title compound (0.015 g, 25.3%) as a white solid.

[0609] 1 H NMR (400 MHz, CDCl 3 )δ8.34-8.29(m,1H),8.24(dt,J=7.1,1.0Hz,1H),7.77(dd,J=5.3,0.7Hz,1H),7.55(dd,J=7.2,1. 7Hz,1H),7.36(tt,J=7.4,1.9Hz,2H),7.28-7.25(m,2H),7.21-7.13(m,1H),6.95(t,J=51.7Hz,1H ), 5.07 (d, J = 3.3Hz, 2H), 4.85 (dd, J = 7.1, 5.9Hz, 1H), 4.76 (dd, J = 8.7, 5.9Hz, 1H), 3.44 (dt, J = 10. 2,5.4Hz,2H),3.31(s,2H),3.24(ddt,J=10.3,7.4,3.5Hz,4H),3.01(t,J=5.3Hz,1H),2.04(s,2H);

[0610] LRMS (ES) m / z 538.5 (M + +1).

[0611] Example 74: Synthesis of Compound 4103, 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-carboxamide

[0612]

[0613] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-carboxamide (0.050 g, 0.106 mmol), oxetane-3-carboxylic acid (0.022 g, 0.212 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.048 g, 0.127 mmol) and triethylamine (0.044 mL, 0.318 mmol) prepared in step 2 of Example 54 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 (SiO 2 , 12 g column; ethyl acetate / hexanes = 0% to 30%) and concentrated to obtain the title compound (0.024 g, 40.7%) as a white solid.

[0614] 1 H NMR (400 MHz, CDCl 3 )δ8.31(dd,J=1.7,0.9Hz,1H),8.23(dd,J=7.1,1.0Hz,1H),7.76(dd,J=4.5,0.7Hz,1H) ,7.55(dd,J=7.1,1.8Hz,1H),7.32(tdd,J=8.5,6.6,2.0Hz,1H),7.11-6.79(m,4H),5.0 7(d,J=3.0Hz,2H),4.87(dd,J=7.1,5.9Hz,1H),4.77(dd,J=8.7,6.0Hz,1H),3.48(dt,J =10.5,5.4Hz,2H),3.34(s,2H),3.31-3.16(m,4H),3.05(t,J=5.3Hz,1H),2.06(s,2H);

[0615] LRMS (ES) m / z 556.5 (M + +1).

[0616] Example 75: Synthesis of Compound 4115, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-ethyl-N-phenylpiperidine-4-carboxamide

[0617]

[0618] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-carboxamide (0.040 g, 0.088 mmol), acetaldehyde (0.010 mL, 0.177 mmol) and acetic acid (0.005 mL, 0.088 mmol) prepared in step 3 of Example 33 were dissolved in dichloromethane (0.5 mL), and the resulting solution was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (0.056 g, 0.265 mmol) was added and stirred for another 18 hours at the same temperature. Saturated 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 water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 20%) and concentration gave the title compound (0.003 g, 7.8%) as a yellow gel.

[0619] 1 H NMR (400 MHz, CDCl 3 )δ8.30(d,J=1.6Hz,1H),8.24(dd,J=0.9,7.1Hz,1H),7.77(s,1H),7.54(dd,J=1.8,7.1Hz,1H),7.46-7.36(m,3H),7.27-7.21(m,2H),6.95(t,J =51.7Hz,1H),5.04(s,2H),3.09(s,2H),2.55(s,2H),2.41(s,1H),2.02 (s,1H),1.97(d,J=10.3Hz,3H),1.80(s,2H),1.28(s,1H),1.15(s,3H);

[0620] LRMS(ES)m / z 481.3(M + +1).

[0621] Example 76: Synthesis of Compound 4116, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-isopropyl-N-phenylpiperidine-4-carboxamide

[0622]

[0623] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-carboxamide (0.024 g, 0.053 mmol), propan-2-one (0.006 g, 0.106 mmol) and acetic acid (0.003 mL, 0.053 mmol) prepared in step 3 of Example 33 were dissolved in dichloromethane (1 mL), and the resulting solution was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (0.034 g, 0.159 mmol) was added and stirred for another 18 hours at the same temperature. Saturated 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 water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 20%) and concentration gave the title compound (0.006 g, 22.5%) as a yellow solid.

[0624] 1 H NMR(700MHz,MeOD)δ8.58(dd,J=1.0,7.1Hz,1H),8.23(dt,J=0.8,1.8Hz,1H), 7.94-7.89(m,1H),7.58(dd,J=1.7,7.1Hz,1H),7.47-7.38(m,3H),7.32-7.27 (m,2H),5.11(s,2H),3.40(d,J=12.2Hz,2H),2.78(s,2H),2.65(d,J=11.8Hz, 1H),2.12-2.05(m,2H),2.04-1.99(m,2H),1.96(s,1H),1.27(d,J=6.7Hz,6H);

[0625] LRMS (ES) m / z 495.4 (M + +1).

[0626] Example 77: Synthesis of Compound 4117, 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-carboxamide

[0627]

[0628] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-carboxamide (0.040 g, 0.088 mmol), 1-hydroxypropan-2-one (0.012 m, 0.177 mmol), acetic acid (0.005 mL, 0.088 mmol) and sodium triacetoxyborohydride (0.056 g, 0.265 mmol) prepared in step 3 of Example 33 were dissolved in dichloromethane (1 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, 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 (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 20%) and concentration gave the title compound (0.009 g, 19.1%) as a white solid.

[0629] 1 H NMR (400 MHz, CDCl 3 )δ8.31(s,1H),8.24(d,J=7.1Hz,1H),7.74(s,1H),7.55(dd,J=1.7,7.1Hz,1H),7.41 (td,J=5.8,8.3Hz,3H),7.26-7.18(m,2H),6.96(t,J=51.7Hz,1H),5.04(s,2H),3.71( dd,J=4.2,12.2Hz,1H),3.48(dd,J=8.6,12.0Hz,1H),3.30(s,1H),3.14(s,2H),2.80( s,1H),2.50(d,J=26.3Hz,2H),2.05(s,2H),1.97-1.82(m,2H),1.06(d,J=6.7Hz,3H);

[0630] LRMS (ES) m / z 510.55 (M + +1).

[0631] Example 78: Synthesis of Compound 4118, 1-cyclobutyl-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-carboxamide

[0632]

[0633] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-carboxamide (0.040 g, 0.088 mmol), cyclobutanone (0.013 mL, 0.177 mmol) and acetic acid (0.005 mL, 0.088 mmol) prepared in step 3 of Example 33 were dissolved in dichloromethane (0.5 mL), and the resulting solution was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (0.056 g, 0.265 mmol) was added and stirred for another 18 hours at the same temperature. Saturated 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 water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 20%) and concentration gave the title compound (0.012 g, 27.2%) as a light red solid.

[0634] 1 H NMR (400 MHz, CDCl 3 )δ8.31(s,1H),8.24(d,J=7.1Hz,1H),7.74(s,1H),7.55(dd,J=1.7,7.1Hz,1H),7.41 (td,J=5.8,8.3Hz,3H),7.26-7.18(m,2H),6.96(t,J=51.7Hz,1H),5.04(s,2H),3.71( dd,J=4.2,12.2Hz,1H),3.48(dd,J=8.6,12.0Hz,1H),3.30(s,1H),3.14(s,2H),2.80( s,1H),2.50(d,J=26.3Hz,2H),2.05(s,2H),1.97-1.82(m,2H),1.06(d,J=6.7Hz,3H);

[0635] LRMS (ES) m / z 507.3 (M + +1).

[0636] Example 79: Synthesis of Compound 4119, 1-cyclohexyl-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-carboxamide

[0637]

[0638] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-carboxamide (0.040 g, 0.088 mmol), cyclohexanone (0.018 mL, 0.177 mmol) and acetic acid (0.005 mL, 0.088 mmol) prepared in step 3 of Example 33 were dissolved in dichloromethane (0.5 mL), and the resulting solution was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (0.056 g, 0.265 mmol) was added and stirred for another 18 hours at the same temperature. Saturated 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 water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 20%) and concentration gave the title compound (0.004 g, 7.6%) as a white solid.

[0639] 1 H NMR(400MHz,MeOD)δ8.58(dd,J=1.0,7.1Hz,1H),8.25-8.22(m,1H),7.92(s,1H),7.57(dd,J=1.7,7.1Hz,1H),7.47-7.36(m,3H),7.31-7.15(m,3H),5 .10(s,2H),2.84(s,1H),2.58(dd,J=12.7,22.7Hz,3H),2.11-1.81(m,8H) ,1.68(d,J=13.0Hz,1H),1.41-1.31(m,5H),1.20(dd,J=11.7,23.7Hz,2H);

[0640] LRMS (ES) m / z 535.3 (M + +1).

[0641] Example 80: Synthesis of Compound 4120, 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-carboxamide

[0642]

[0643] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-carboxamide (0.050 g, 0.111 mmol), tetrahydro-4H-pyran-4-one (0.020 mL, 0.221 mmol), acetic acid (0.006 mL, 0.111 mmol) and sodium triacetoxyborohydride (0.070 g, 0.332 mmol) prepared in step 3 of Example 33 were dissolved in dichloromethane (1 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, 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 (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 20%) and concentration gave the title compound (0.012 g, 20.7%) as a white solid.

[0644] 1 H NMR (400 MHz, CDCl 3 )δ8.31-8.28(m,1H),8.23(dd,J=1.0,7.1Hz,1H),7.78(s,1H),7.53(dd,J=1 .7,7.1Hz,1H),7.46-7.32(m,3H),7.27-7.20(m,2H),6.95(t,J=51.7Hz,1H) ,5.04(s,2H),3.99(dd,J=4.2,11.4Hz,2H),3.34(td,J=2.0,11.8Hz,2H),2. 92(s,2H),2.34(d,J=64.4Hz,2H),1.88(d,J=14.6Hz,4H),1.76-1.48(m,6H);

[0645] LRMS (ES) m / z 537.3 (M + +1).

[0646] Example 81: Synthesis of Compound 4121, 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-carboxamide

[0647]

[0648] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-carboxamide (0.040 g, 0.088 mmol), 4,4-difluorocyclohexan-1-one (0.024 g, 0.177 mmol), acetic acid (0.005 mL, 0.088 mmol) and sodium triacetoxyborohydride (0.056 g, 0.265 mmol) prepared in step 3 of Example 33 were dissolved in dichloromethane (1 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, 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 (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 20%) and concentration gave the title compound (0.014 g, 28.2%) as a white solid.

[0649] 1 H NMR (400 MHz, CDCl 3 )δ8.29(s,1H),8.23(d,J=7.1Hz,1H),7.78(s,1H),7.53(dd,J=1.8,7.1Hz,1H),7.46-7.32(m,3H ),7.27-7.19(m,2H),5.04(s,2H),3.93(dt,J=3.5,7.0Hz,1H),2.85(s,2H),2.41-1.51(m,15H);

[0650] LRMS (ES) m / z 571.4 (M + +1).

[0651] Example 82: Synthesis of Compound 4122, 1-acetyl-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-carboxamide

[0652]

[0653] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-carboxamide (0.041 g, 0.091 mmol), acetyl chloride (0.031 mL, 0.181 mmol) and triethylamine (0.038 mL, 0.272 mmol) prepared in step 3 of Example 33 were dissolved in dichloromethane (1 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, 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 (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 7%) and concentration gave the title compound (0.012 g, 26.6%) as a white solid.

[0654] 1 H NMR (400 MHz, CDCl 3 )δ8.30(s,1H),8.23(d,J=7.2Hz,1H),7.77(s,1H),7.54(d,J=7.2Hz,1H),7.41(dq ,J=7.0,13.7Hz,3H),7.31-7.22(m,3H),6.95(t,J=51.7Hz,1H),5.14-4.95(m,2H) ,4.53(d,J=13.3Hz,1H),3.77(d,J=13.5Hz,1H),2.84(t,J=13.0Hz,1H),2.49(d,J =11.1Hz,1H),2.34(t,J=12.4Hz,1H),2.06(s,3H),1.75(dd,J=14.2,49.2Hz,4H);

[0655] LRMS(ES)m / z 494.9(M + +1).

[0656] Example 83: Synthesis of Compound 4123, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenyl-1-propionylpiperidine-4-carboxamide

[0657]

[0658] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-carboxamide (0.041 g, 0.091 mmol), propionyl chloride (0.017 g, 0.181 mmol) and triethylamine (0.038 mL, 0.272 mmol) prepared in step 3 of Example 33 were dissolved in dichloromethane (1 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, 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 (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.023 g, 49.0%) as an orange solid.

[0659] 1 H NMR (400 MHz, CDCl 3 )δ8.32-8.26(m,1H),8.23(dd,J=0.9,7.1Hz,1H),7.76(s,1H),7.53(dd,J=1.7,7.1Hz, 1H),7.47-7.33(m,3H),7.29-7.21(m,2H),6.95(t,J=51.7Hz,1H),5.10-4.95(m,2H),4. 55(d,J=13.4Hz,1H),3.81(d,J=13.6Hz,1H),2.84-2.74(m,1H),2.50(ddt,J=4.3,10.3, 15.0Hz,1H),2.31(pd,J=4.1,7.5,8.6Hz,3H),1.85-1.59(m,4H),1.12(t,J=7.5Hz,3H);

[0660] LRMS (ES) m / z 509.2 (M + +1).

[0661] Example 84: Synthesis of Compound 4124, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(2-hydroxyacetyl)-N-phenylpiperidine-4-carboxamide

[0662]

[0663] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-carboxamide (0.041 g, 0.091 mmol), 2-hydroxyacetic acid (0.014 g, 0.181 mmol), triethylamine (0.038 mL, 0.272 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.052 g, 0.136 mmol) prepared in step 3 of Example 33 were dissolved in dichloromethane (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, 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 (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.012 g, 25.5%) as an orange solid.

[0664] 1 H NMR (400 MHz, CDCl 3 )δ8.33-8.29(m,1H),8.23(dd,J=0.9,7.1Hz,1H),7.76(s,1H),7.54(dd,J=1.7,7.1 Hz,1H),7.47-7.38(m,3H),7.27(d,J=7.7Hz,3H),6.95(t,J=51.7Hz,1H),5.03(d,J =2.9Hz,2H),4.48(d,J=13.3Hz,1H),4.18-4.03(m,2H),3.62(s,1H),3.47(d,J=13. 7Hz,1H),2.83-2.72(m,1H),2.54(td,J=4.1,10.1,10.5Hz,2H),1.85-1.64(m,4H);

[0665] LRMS (ES) m / z 511.3 (M + +1).

[0666] Example 85: Synthesis of Compound 4125, 1-(cyclobutanecarbonyl)-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-carboxamide

[0667]

[0668] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-carboxamide (0.041 g, 0.091 mmol), cyclobutanecarbonyl chloride (0.021 g, 0.181 mmol) and triethylamine (0.038 mL, 0.272 mmol) prepared in step 3 of Example 33 were dissolved in dichloromethane (1 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, 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 (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 7%) and concentration gave the title compound (0.020 g, 40.9%) as an orange gel.

[0669] 1 H NMR (400 MHz, CDCl 3 )δ8.30(dt,J=0.8,1.7Hz,1H),8.23(dd,J=1.0,7.1Hz,1H),7.77(s,1H),7.53(dd,J=1.7,7.1Hz, 1H),7.46-7.35(m,3H),7.28-7.24(m,2H),6.95(t,J=51.7Hz,1H),5.10-4.95(m,2H),4.52(d,J= 13.6Hz,1H),3.66(d,J=13.4Hz,1H),3.25-3.15(m,1H),2.71(t,J=11.7Hz,1H),2.48(ddt,J=4.4 ,10.4,15.0Hz,1H),2.39-2.25(m,4H),2.19-2.03(m,1H),1.99-1.79(m,2H),1.77-1.61(m,4H);

[0670] LRMS (ES) m / z 535.1 (M + +1).

[0671] Example 86: Synthesis of Compound 4126, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(oxetane-3-carbonyl)-N-phenylpiperidine-4-carboxamide

[0672]

[0673] N-((7-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-carboxamide (0.050 g, 0.111 mmol) prepared in Step 3 of Example 33, oxetane-3-carboxylic acid (0.023 g, 0.221 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.063 g, 0.166 mmol) and triethylamine (0.043 mL, 0.332 mmol) were dissolved in dichloromethane (1 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, 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 (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.007 g, 12.0%) as a white solid.

[0674] 1 H NMR (400 MHz, CDCl 3 )δ8.31(s,1H),8.23(dd,J=1.0,7.1Hz,1H),7.76(s,1H),7.55(dd,J=1.7,7.1Hz,1H),7.48-7.35(m,3H),7 .30-7.23(m,2H),7.02(d,J=51.7Hz,1H),5.03(d,J=4.3Hz,2H),4.93(dd,J=5.9,7.2Hz,1H),4.85(dd,J=5. 9,7.2Hz,1H),4.76(ddd,J=5.8,8.7,10.1Hz,2H),4.52(d,J=13.4Hz,1H),3.96(tt,J=7.2,8.7Hz,1H),3.3 0(d,J=13.6Hz,1H),2.78-2.70(m,1H),2.50(dq,J=4.8,10.1Hz,1H),2.46-2.38(m,1H),1.75-1.62(m,4H);

[0675] LRMS (ES) m / z 537.2 (M + +1).

[0676] Example 87: Synthesis of Compound 4127, 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-carboxamide

[0677]

[0678] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-carboxamide (0.041 g, 0.091 mmol), 2,2,2-trifluoroacetic anhydride (0.025 mL, 0.181 mmol) and triethylamine (0.038 mL, 0.272 mmol) prepared in step 3 of Example 33 were dissolved in dichloromethane (1 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, 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 (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 7%) and concentration gave the title compound (0.020 g, 40.0%) as a light red solid.

[0679] 1 H NMR (400 MHz, CDCl 3 )δ8.33-8.26(m,1H),8.23(dd,J=0.9,7.1Hz,1H),7.77(s,1H),7.54(dd,J=1.7,7.1Hz,1H),7.43(ddd,J=5.9,7.9,10.5Hz,3H),7.28(d,J=6.2H z,2H),6.95(t,J=51.7Hz,1H),5.03(s,2H),4.45-4.33(m,1H),3.97(d, J=14.0Hz,1H),3.01-2.88(m,1H),2.72-2.53(m,2H),1.94-1.65(m,4H);

[0680] LRMS (ES) m / z 549.3 (M + +1).

[0681] Example 88: Synthesis of Compound 4128, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(methylsulfonyl)-N-phenylpiperidine-4-carboxamide

[0682]

[0683] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-carboxamide (0.041 g, 0.091 mmol), methanesulfonyl chloride (0.014 mL, 0.181 mmol) and triethylamine (0.038 mL, 0.272 mmol) prepared in step 3 of Example 33 were dissolved in dichloromethane (1 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, 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 (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 7%) and concentration gave the title compound (0.008 g, 15.6%) as a white solid.

[0684] 1 H NMR (400 MHz, CDCl 3 )δ8.32(s,1H),8.25(dd,J=1.0,7.1Hz,1H),7.78(s,1H),7.56(dd,J=1.7,7 .1Hz,1H),7.48-7.36(m,3H),7.28-7.25(m,2H),6.95(t,J=51.7Hz,1H),5. 05(s,2H),3.74(dd,J=6.0,10.1Hz,2H),2.74(s,3H),2.54(td,J=2.9,11.9 Hz,2H),2.43-2.34(m,1H),2.00-1.86(m,2H),1.75(dd,J=3.6,13.6Hz,2H);

[0685] LRMS (ES) m / z 531.1 (M + +1).

[0686] Example 89: Synthesis of Compound 4129, methyl 4-(((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)(phenyl)carbamoyl)piperidine-1-carboxylate

[0687]

[0688] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-carboxamide (0.041 g, 0.091 mmol), methyl chloroformate (0.017 g, 0.181 mmol) and triethylamine (0.025 mL, 0.181 mmol) prepared in step 3 of Example 33 were dissolved in dichloromethane (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, 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 (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 7%) and concentration gave the title compound (0.020 g, 43.7%) as a light orange solid.

[0689] 1 H NMR (400 MHz, CDCl 3 )δ8.29(dt,J=0.9,1.8Hz,1H),8.23(dd,J=0.9,7.1Hz,1H),7.77(s,1H),7.5 3(dd,J=1.7,7.1Hz,1H),7.46-7.35(m,3H),7.26-7.23(m,2H),6.95(t,J=51 .7Hz,1H),5.03(s,2H),4.09(s,2H),3.67(s,3H),2.53(s,2H),2.43(tt,J=3 .8,11.2Hz,1H),1.76(qd,J=4.4,11.9,12.4Hz,2H),1.62(d,J=12.8Hz,2H);

[0690] LRMS (ES) m / z 511.1 (M + +1).

[0691] Example 90: Synthesis of Compound 4130, N4-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N1,N1-dimethyl-N4-phenylpiperidine-1,4-dicarboxamide

[0692]

[0693] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-carboxamide (0.041 g, 0.091 mmol), dimethylcarbamoyl chloride (0.019 g, 0.181 mmol) and triethylamine (0.025 mL, 0.181 mmol) prepared in step 3 of Example 33 were dissolved in dichloromethane (1 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, 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 (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 7%) and concentration gave the title compound (0.024 g, 51.4%) as a red gel.

[0694] 1 H NMR (400 MHz, CDCl 3 )δ8.29(dt,J=0.8,1.7Hz,1H),8.23(dd,J=1.0,7.1Hz,1H),7.77(s,1H),7.53(dd,J=1 .7,7.1Hz,1H),7.40(dddd,J=2.3,4.6,6.8,11.7Hz,3H),7.27-7.23(m,2H),6.95(t,J =51.7Hz,1H),5.03(s,2H),3.59(dd,J=3.8,13.3Hz,2H),2.79(s,6H),2.44(dtd,J=5. 1,11.5,12.2,16.5Hz,3H),1.82(qd,J=4.0,12.6Hz,2H),1.64(dd,J=3.5,13.7Hz,2H);

[0695] LRMS(ES)m / z 524.4(M + +1).

[0696] Example 91: Synthesis of Compound 4131, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenyl-1-(pyridin-2-yl)piperidine-4-carboxamide

[0697]

[0698] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-carboxamide (0.025 g, 0.055 mmol), 2-bromopyridine (0.017 g, 0.111 mmol), cesium carbonate (0.036 g, 0.111 mmol) and RuPhos palladium G2 (0.002 g, 0.003 mmol) prepared in step 3 of Example 33 were dissolved in 1,4-dioxane (0.5 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. Saturated aqueous sodium bicarbonate solution was poured into 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. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 7%) and concentration gave the title compound (0.006 g, 19.1%) as a yellow solid.

[0699] 1 H NMR (400 MHz, CDCl 3 )δ8.30(p,J=0.8Hz,1H),8.23(dd,J=1.0,7.1Hz,1H),8.15(ddd,J=0.9,2.0,4.9Hz ,1H),7.79(s,1H),7.54(dd,J=1.7,7.1Hz,1H),7.48-7.37(m,4H),7.31-7.26(m,2H ),6.95(t,J=51.7Hz,1H),6.63-6.55(m,2H),5.05(s,2H),4.25(d,J=13.1Hz,2H),2 .57(dt,J=11.9,34.6Hz,3H), 1.90(qd,J=4.2,12.7Hz,2H), 1.73(d,J=13.1Hz,2H);

[0700] LRMS (ES) m / z 530.3 (M + +1).

[0701] Example 92: Synthesis of Compound 4132, 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-carboxamide

[0702]

[0703] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylpiperidine-4-carboxamide (0.041 g, 0.091 mmol), 2-chloropyrimidine (0.021 g, 0.181 mmol) and potassium carbonate (0.038 g, 0.272 mmol) prepared in step 3 of Example 33 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. Saturated 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 ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 7%) and concentration gave the title compound (0.022 g, 45.6%) as a white solid.

[0704] 1 H NMR (400 MHz, CDCl 3 )δ8.29-8.25(m,3H),8.22(dd,J=1.0,7.1Hz,1H),7.78(s,1H),7.52(dd,J= 1.7,7.1Hz,1H),7.47-7.36(m,3H),7.29-7.26(m,2H),6.95(t,J=51.7Hz,1H ),6.44(t,J=4.7Hz,1H),5.04(s,2H),4.71(dt,J=3.4,13.5Hz,2H),2.70-2 .52(m,3H),1.83(dq,J=5.8,7.6,19.8Hz,2H),1.70(dd,J=3.6,13.9Hz,2H);

[0705] LRMS (ES) m / z 531.3 (M + +1).

[0706] Example 93: Synthesis of Compound 4137, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-1-methylpiperidine-4-carboxamide

[0707] [Step 1] Synthesis of tert-butyl 4-(chlorocarbonyl)piperidine-1-carboxylate

[0708]

[0709] 1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid (1,000 g, 4.361 mmol), oxalyl chloride (2.00 M solution (anhydrous) in DCM, 2.835 mL, 5.670 mmol) and N,N-dimethylformamide (0.034 mL, 0.436 mmol) were dissolved in dichloromethane (25 mL) at 0°C, and the resulting solution was stirred at room temperature for 2 hours. After removing the solvent from the reaction mixture under reduced pressure, the title compound (1.080 g, 100.0%) was obtained as a yellow solid without further purification.

[0710] [Step 2] Synthesis of 4-(((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridine- tert-Butyl (2-yl)methyl) (3-fluorophenyl)carbamoyl)piperidine-1-carboxylate

[0711]

[0712] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-3-fluoroaniline (1.000 g, 2.783 mmol), tert-butyl 4-(chlorocarbonyl)piperidine-1-carboxylate (1.034 g, 4.175 mmol) and triethylamine (1.164 mL, 8.349 mmol) prepared in Example 16 were dissolved in dichloromethane (15 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. N-ammonium chloride aqueous solution was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 24 g column; ethyl acetate / hexanes = 0% to 90%) and concentrated to afford the title compound (0.680 g, 42.8%) as a light orange solid.

[0713] [Step 3] Synthesis of N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridine-2-yl) 4-(3-fluorophenyl)piperidine-4-carboxamide

[0714]

[0715] Tert-butyl 4-(((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)(3-fluorophenyl)carbamoyl)piperidine-1-carboxylate (1,000 g, 1.753 mmol) and trifluoroacetic acid (2.684 mL, 35.053 mmol) prepared in step 2 were dissolved in dichloromethane (30 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, filtered, and concentrated under reduced pressure to obtain the title compound (0.824 g, 99.9%) as a brown gel without further purification.

[0716] [Step 4] Synthesis of compound 4137

[0717]

[0718] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-carboxamide (0.060 g, 0.128 mmol), formaldehyde (35.00%, 0.022 g, 0.255 mmol), acetic acid (0.007 mL, 0.128 mmol) and sodium triacetoxyborohydride (0.081 g, 0.383 mmol) prepared in step 3 were dissolved in dichloromethane (4 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 water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.024 g, 38.8%) as a yellow solid.

[0719] 1 H NMR (700 MHz, CDCl 3 )δ8.29(d,J=1.7Hz,1H),8.24(dd,J=7.1,1.0Hz,1H),7.79(s,1H),7.54(dd,J=7.1,1.7Hz,1H),7.39(td,J=8.1,6.2 Hz,1H),7.12-6.86(m,4H),5.01(s,2H),2.92-2.80(m,2H),2.29-2.16(m,5H),1.94-1.86(m,2H),1.82-1.72(m,3H);

[0720] LRMS (ES) m / z 485.3 (M + +1).

[0721] Example 94: Synthesis of Compound 4138, 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-carboxamide

[0722]

[0723] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-carboxamide (0.060 g, 0.128 mmol), acetaldehyde (0.011 g, 0.255 mmol), acetic acid (0.007 mL, 0.128 mmol) and sodium triacetoxyborohydride (0.081 g, 0.383 mmol) prepared in step 3 of Example 93 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.031 g, 48.8%) as a yellow solid.

[0724] 1 H NMR (400 MHz, CDCl 3 )δ8.30(dt,J=1.7,0.8Hz,1H),8.24(ddd,J=7.1,2.9,1.0Hz,1H),7.78(d,J=8.3Hz,1H),7.55(dd,J=7.2,1.7Hz,1H),7.40(t dd,J=8.2,6.3,1.8Hz,1H),7.13-6.80(m,4H),5.02(s,2H),3.00(s,1H),2.50-2.21(m,3H),1.99-1.62(m,7H),1.12(s,3H);

[0725] LRMS (ES) m / z 499.3 (M + +1).

[0726] Example 95: Synthesis of Compound 4139, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-1-isopropylpiperidine-4-carboxamide

[0727]

[0728] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-carboxamide (0.060 g, 0.128 mmol), propan-2-one (0.015 g, 0.255 mmol), acetic acid (0.007 mL, 0.128 mmol) and sodium triacetoxyborohydride (0.081 g, 0.383 mmol) prepared in step 3 of Example 93 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.018 g, 27.5%) as a yellow solid.

[0729] 1 H NMR (700 MHz, CDCl 3 )δ8.30(d,J=1.6Hz,1H),8.24(dd,J=7.1,1.0Hz,1H),7.78(s,1H),7.55(dd,J=7.1,1.7Hz,1H),7.39(td,J=8.1,6.3Hz,1 H),7.13-6.85(m,4H),5.02(s,2H),2.86(s,2H),2.68(s,1H),2.29-2.19(m,1H),1.91(s,4H),1.66(s,2H),1.00(s,6H);

[0730] LRMS (ES) m / z 512.9 (M + +1).

[0731] Example 96: Synthesis of Compound 4140, 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-carboxamide

[0732]

[0733] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-carboxamide (0.060 g, 0.128 mmol), 1-hydroxypropan-2-one (0.019 g, 0.255 mmol), acetic acid (0.007 mL, 0.128 mmol) and sodium triacetoxyborohydride (0.081 g, 0.383 mmol) prepared in step 3 of Example 93 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.019 g, 28.2%) as a yellow solid.

[0734] 1 H NMR (700 MHz, CDCl 3 )δ8.31(dt,J=1.7,0.8Hz,1H),8.25(dd,J=7.1,1.0Hz,1H),7.78(s,1H),7.5 6(dd,J=7.1,1.7Hz,1H),7.41(td,J=8.1,6.3Hz,1H),7.12(dt,J=8.3,4.6Hz, 1H),7.09-7.04(m,2H),7.04-6.88(m,1H),5.02(s,2H),3.40(d,J=64.6Hz,3H ),2.98-2.69(m,3H),1.96(d,J=11.2Hz,2H),1.84(s,2H),0.93-0.80(m,5H);

[0735] LRMS (ES) m / z 529.3 (M + +1).

[0736] Example 97: Synthesis of Compound 4141, 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-carboxamide

[0737]

[0738] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-carboxamide (0.060 g, 0.128 mmol), cyclobutanone (0.018 g, 0.255 mmol), acetic acid (0.007 mL, 0.128 mmol) and sodium triacetoxyborohydride (0.081 g, 0.383 mmol) prepared in step 3 of Example 93 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.022 g, 32.9%) as a yellow solid.

[0739] 1 H NMR (700 MHz, CDCl 3 )δ8.29(d,J=1.6Hz,1H),8.24(dd,J=7.1,1.0Hz,1H),7.78(s,1H),7.55(d d,J=7.1,1.7Hz,1H),7.39(td,J=8.1,6.3Hz,1H),7.10(dt,J=8.7,4.7Hz,1 H),7.07-6.87(m,3H),5.02(s,2H),2.87(s,2H),2.61(s,1H),2.30-2.19(m ,1H),1.98(s,2H),1.90(d,J=10.9Hz,4H),1.65(s,4H),1.56-1.44(m,2H);

[0740] LRMS (ES) m / z 525.2 (M + +1).

[0741] Example 98: Synthesis of Compound 4142, 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-carboxamide

[0742]

[0743] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-carboxamide (0.060 g, 0.128 mmol), oxetane-3-one (0.018 g, 0.255 mmol), acetic acid (0.007 mL, 0.128 mmol) and sodium triacetoxyborohydride (0.081 g, 0.383 mmol) prepared in step 3 of Example 93 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.032 g, 47.7%) as a yellow solid.

[0744] 1 H NMR (700 MHz, CDCl 3 )δ8.30(dd,J=1.8,0.9Hz,1H),8.24(dd,J=7.1,1.0Hz,1H),7.78(s,1H),7.55(dd,J=7.1,1.7Hz,1H),7.40(td,J=8.1,6.3Hz,1H),7.15-7. 09(m,1H),7.09-6.84(m,3H),5.02(s,2H),4.61(s,4H),3.40(s,1H),2.73(s,2H),2.34-2.21(m,1H),1.93(d,J=12.2Hz,2H),1.66(s,4H);

[0745] LRMS(ES)m / z 527.0(M + +1).

[0746] Example 99: Synthesis of Compound 4143, 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-carboxamide

[0747]

[0748] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-carboxamide (0.060 g, 0.128 mmol), cyclohexanone (0.025 g, 0.255 mmol), acetic acid (0.007 mL, 0.128 mmol) and sodium triacetoxyborohydride (0.081 g, 0.383 mmol) prepared in step 3 of Example 93 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.014 g, 19.9%) as a yellow solid.

[0749] 1 H NMR (700 MHz, CDCl 3 )δ8.32-8.26(m,1H),8.23(dd,J=7.1,1.0Hz,1H),7.78(s,1H),7.53(dd,J=7.1,1.7Hz,1H),7.38(td,J=8.1,6.3Hz,1H),7.13-6.85(m, 4H),5.01(s,2H),2.92(s,2H),2.35-2.19(m,2H),2.10-1.95(m,2H),1.92-1.73(m,8H),1.61(d,J=13.1Hz,2H),1.21(d,J=14.6Hz,4H);

[0750] LRMS (ES) m / z 553.1 (M + +1).

[0751] Example 100: Synthesis of Compound 4144, 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-carboxamide

[0752]

[0753] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-carboxamide (0.060 g, 0.128 mmol), tetrahydro-4H-pyran-4-one (0.026 g, 0.255 mmol), acetic acid (0.007 mL, 0.128 mmol) and sodium triacetoxyborohydride (0.081 g, 0.383 mmol) prepared in step 3 of Example 93 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.016 g, 22.6%) as a yellow solid.

[0754] 1 H NMR (700 MHz, CDCl 3 )δ8.33-8.27(m,1H),8.24(dd,J=7.1,1.0Hz,1H),7.83-7.74(m,1H),7.55(dd,J=7.1,1. 7Hz,1H),7.40(td,J=8.1,6.3Hz,1H),7.10(ddd,J=8.4,5.5,2.2Hz,1H),7.09-6.86(m,3 H),5.02(s,2H),4.04-3.95(m,2H),3.35(t,J=11.7Hz,2H),2.93(s,2H),2.45(d,J=22.4 Hz,1H),2.31-2.20(m,1H),1.89(d,J=10.6Hz,4H),1.67(s,4H),1.56(d,J=11.5Hz,2H);

[0755] LRMS (ES) m / z 555.3 (M + +1).

[0756] Example 101: Synthesis of Compound 4145, 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-carboxamide

[0757]

[0758] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-carboxamide (0.060 g, 0.128 mmol), 4,4-difluorocyclohexan-1-one (0.034 g, 0.255 mmol), acetic acid (0.007 mL, 0.128 mmol) and sodium triacetoxyborohydride (0.081 g, 0.383 mmol) prepared in step 3 of Example 93 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.026 g, 34.6%) as a yellow solid.

[0759] 1 H NMR (400 MHz, CDCl 3 )δ8.31-8.27(m,1H),8.23(dd,J=7.1,1.0Hz,1H),7.78(s,1H),7.53(dd,J=7.1,1.7Hz,1H),7.39(td,J=8.1,6.3Hz,1H),7.15-6 .77(m,4H),5.01(s,2H),2.87(s,2H),2.36(s,1H),2.30-2.21(m,1H),2.10(d,J=11.6Hz,2H),1.96(s,2H),1.92-1.54(m,10H);

[0760] LRMS (ES) m / z 589.2 (M + +1).

[0761] Example 102: Synthesis of Compound 4146, 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-carboxamide

[0762]

[0763] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-carboxamide (0.060 g, 0.128 mmol), acetyl chloride (0.018 mL, 0.255 mmol) and triethylamine (0.053 mL, 0.383 mmol) prepared in step 3 of Example 93 were dissolved in dichloromethane (4 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 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.021 g, 32.1%) as a yellow solid.

[0764] 1 H NMR (700 MHz, CDCl 3 )δ8.46(s,1H),8.34-8.26(m,1H),7.82(s,1H),7.69(dd,J=7.1,1.7Hz,1H),7.45 (td,J=8.2,6.3Hz,1H),7.17-7.13(m,2H),7.12-7.09(m,1H),6.97(t,J=51.7Hz,1 H),5.06(s,2H),4.55(d,J=13.6Hz,1H),3.80(d,J=13.6Hz,1H),2.88(t,J=13.8H z,1H),2.53(d,J=11.2Hz,1H),2.44-2.34(m,1H),2.07(s,3H),1.84-1.63(m,4H);

[0765] LRMS (ES) m / z 513.0 (M + +1).

[0766] Example 103: Synthesis of Compound 4147, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-1-propionylpiperidine-4-carboxamide

[0767]

[0768] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-carboxamide (0.060 g, 0.128 mmol), propionyl chloride (0.024 g, 0.255 mmol) and triethylamine (0.053 mL, 0.383 mmol) prepared in step 3 of Example 93 were dissolved in dichloromethane (4 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 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.010 g, 14.9%) as a yellow solid.

[0769] 1 H NMR (700 MHz, CDCl 3 )δ8.33(s,1H),8.25(dd,J=7.1,1.0Hz,1H),7.78(s,1H),7.57(dd,J=7.2,1.6Hz,1H),7.42(td,J= 8.1,6.2Hz,1H),7.16-7.05(m,3H),6.96(t,J=51.7Hz,1H),5.08-4.94(m,2H),4.57(dd,J=11.2,6 .8Hz,1H),3.83(d,J=13.7Hz,1H),2.88-2.74(m,1H),2.52(td,J=11.8,11.0,5.7Hz,1H),2.33(dd dd,J=23.0,17.7,15.3,10.0Hz,4H),1.83-1.74(m,1H),1.74-1.61(m,2H),1.13(t,J=7.5Hz,3H);

[0770] LRMS(ES)m / z 527.0(M + +1).

[0771] Example 104: Synthesis of Compound 4149, 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-carboxamide

[0772]

[0773] N-((7-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-carboxamide (0.060 g, 0.128 mmol) prepared in Step 3 of Example 93, 2-hydroxyacetyl chloride (0.024 g, 0.255 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.097 g, 0.255 mmol) and N,N-diisopropylethylamine (0.044 mL, 0.255 mmol) were dissolved in dichloromethane (4 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 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.017 g, 25.2%) as a yellow solid.

[0774] 1 H NMR (400 MHz, CDCl 3 )δ8.31(dt,J=1.7,0.9Hz,1H),8.24(dd,J=7.1,1.0Hz,1H),7.76(s,1H),7.55(dd,J=7.1,1.7Hz,1H),7.42(td,J=8.3,6.3Hz,1H),7.16-6.78(m ,4H),5.01(s,2H),4.48(d,J=13.7Hz,1H),4.18-4.01(m,2H),3.48(d,J =13.7Hz,1H),2.86-2.73(m,1H),2.63-2.44(m,2H),1.84-1.62(m,4H);

[0775] LRMS(ES)m / z 529.0(M + +1).

[0776] Example 105: Synthesis of Compound 4150, 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-carboxamide

[0777]

[0778] 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 93 were dissolved in dichloromethane (1 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, 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 (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 7%) and concentrated, and then the obtained product was chromatographed again (SiO 2 Plate, 20x20x1 mm; methanol / 1%-aqueous dichloromethane = 0% to 7%) and concentration gave the title compound (0.011 g, 20.0%) as a yellow gel.

[0779] 1 H NMR (400 MHz, CDCl 3 )δ8.31(d,J=1.6Hz,1H),8.24(dd,J=1.0,7.1Hz,1H),7.77(s,1H),7.55(dt,J=1.2,7.0Hz,1H ),7.41(td,J=6.3,8.3Hz,1H),7.16-6.80(m,4H),5.01(d,J=3.4Hz,2H),4.53(d,J=13.3Hz,1H ),3.68(d,J=13.6Hz,1H),3.21(p,J=8.5Hz,1H),2.74(t,J=12.7Hz,1H),2.48(d,J=12.2Hz,1H ),2.34(ddd,J=9.3,11.8,20.7Hz,3H),2.12(ddt,J=3.6,8.2,11.8Hz,2H),2.00-1.59(m,6H);

[0780] LRMS (ES) m / z 553.4 (M + +1).

[0781] Example 106: Synthesis of Compound 4151, 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-carboxamide

[0782]

[0783] N-((7-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-carboxamide (0.050 g, 0.106 mmol) prepared in Step 3 of Example 93, oxetane-3-carboxylic acid (0.022 g, 0.213 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.061 g, 0.159 mmol) and triethylamine (0.044 mL, 0.319 mmol) were dissolved in dichloromethane (1 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, 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 (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 7%) and concentrated, and then the obtained product was chromatographed again (SiO 2 Plate, 20x20x1 mm; methanol / 1%-aqueous dichloromethane = 0% to 7%) and concentrated to obtain the title compound (0.016 g, 27.3%) as a yellow solid.

[0784] 1 H NMR (400 MHz, CDCl 3 )δ8.34-8.28(m,1H),8.24(dd,J=1.0,7.1Hz,1H),7.76(s,1H),7.56(dd,J=1.7,7.2Hz,1H),7.4 2(td,J=6.2,8.2Hz,1H),7.16-6.82(m,4H),5.01(d,J=1.6Hz,2H),4.93(dd,J=5.9,7.2Hz,1H), 4.86(dd,J=5.9,7.2Hz,1H),4.77(td,J=5.9,8.6Hz,2H),4.53(d,J=13.4Hz,1H),4.01-3.91(m, 1H),3.31(d,J=13.5Hz,1H),2.77(t,J=11.9Hz,1H),2.56-2.38(m,2H),1.71(d,J=18.8Hz,4H);

[0785] LRMS (ES) m / z 555.4 (M + +1).

[0786] Example 107: Synthesis of Compound 4152, 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-carboxamide

[0787]

[0788] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-carboxamide (0.050 g, 0.106 mmol), 2,2,2-trifluoroacetic anhydride (0.045 g, 0.213 mmol) and triethylamine (0.044 mL, 0.319 mmol) prepared in step 3 of Example 93 were dissolved in dichloromethane (1 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, 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 (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.020 g, 33.6%) as a brown solid.

[0789] 1 H NMR (400 MHz, CDCl 3 )δ8.33-8.28(m,1H),8.24(dd,J=1.0,7.1Hz,1H),7.77(s,1H),7.56(dd,J=1.7,7.2Hz,1H),7.43(td,J=6.3,8.3Hz,1H),7.17- 6.77(m,4H),5.01(s,2H),4.46-4.34(m,1H),3.98(d,J=14.0Hz,1H),3.06-2.94(m,1H),2.74-2.53(m,1H),1.94-1.68(m,4H);

[0790] LRMS (ES) m / z 566.7 (M + +1).

[0791] Example 108: Synthesis of Compound 4153, 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-carboxamide

[0792]

[0793] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-carboxamide (0.050 g, 0.106 mmol), methanesulfonyl chloride (0.016 mL, 0.213 mmol) and triethylamine (0.044 mL, 0.319 mmol) prepared in step 3 of Example 93 were dissolved in dichloromethane (1 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, 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 (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 7%) and concentration gave the title compound (0.005 g, 8.7%) as a brown solid.

[0794] 1 H NMR (400 MHz, CDCl 3 )δ8.32(d,J=1.5Hz,1H),8.25(dd,J=1.0,7.2Hz,1H),7.78(s,1H),7.57(dd,J=1.7,7.1Hz,1H),7.46-7.39(m,1H),7.16-6.77(m,4H),5.0 2(s,2H),3.76(d,J=12.3Hz,2H),2.75(s,3H),2.57(t,J=11.6Hz,2H),2.40(d,J=11.4Hz,1H),2.01-1.84(m,2H),1.75(d,J=13.5Hz,2H);

[0795] LRMS (ES) m / z 549.4 (M + +1).

[0796] Example 109: Synthesis of Compound 4154, methyl 4-(((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)(3-fluorophenyl)carbamoyl)piperidine-1-carboxylate

[0797]

[0798] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-carboxamide (0.050 g, 0.106 mmol), methyl chloroformate (0.020 g, 0.213 mmol) and triethylamine (0.044 mL, 0.319 mmol) prepared in step 3 of Example 93 were dissolved in dichloromethane (1 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, 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 (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.021 g, 35.2%) as a red solid.

[0799] 1 H NMR (400 MHz, CDCl 3 )δ8.32-8.27(m,1H),8.23(dd,J=1.0,7.2Hz,1H),7.77(s,1H),7.54(dd,J=1.7,7.1Hz,1H),7.40(td,J=6.4,8.3Hz,1H),7.16-6. 80(m,4H),5.01(s,2H),4.10(s,2H),3.67(s,3H),2.65-2.37(m,3H),1.75(qd,J=4.4,11.9,12.4Hz,2H),1.62(d,J=13.1Hz,2H);

[0800] LRMS (ES) m / z 529.1 (M + +1).

[0801] Example 110: Synthesis of Compound 4155, N4-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N4-(3-fluorophenyl)-N1,N1-dimethylpiperidine-1,4-dicarboxamide

[0802]

[0803] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-carboxamide (0.050 g, 0.106 mmol), dimethylcarbamoyl chloride (0.023 g, 0.213 mmol) and triethylamine (0.044 mL, 0.319 mmol) prepared in step 3 of Example 93 were dissolved in dichloromethane (1 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, 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 (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 7%) and concentration gave the title compound (0.019 g, 33.5%) as a light red solid.

[0804] 1 H NMR (400 MHz, CDCl 3 )δ8.32-8.28(m,1H),8.24(dd,J=1.0,7.1Hz,1H),7.78(s,1H),7.55(dd,J=1.7,7.1Hz,1H),7.41(td,J=6.4,8.3Hz,1H),7.15-6.81 (m,4H),5.02(s,2H),3.61(d,J=13.2Hz,2H),2.80(s,6H),2.57-2.37(m,3H),1.82(qd,J=4.0,12.6Hz,2H),1.64(d,J=12.8Hz,2H);

[0805] LRMS(ES)m / z 542.0(M + +1).

[0806] Example 111: Synthesis of Compound 4156, 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-carboxamide

[0807]

[0808] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-carboxamide (0.050 g, 0.106 mmol), 2-bromopyridine (0.034 g, 0.213 mmol), RuPhos palladium G2 (0.004 g, 0.005 mmol) and cesium carbonate (0.069 g, 0.213 mmol) prepared in step 3 of Example 93 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 reaction was terminated by lowering the temperature to room temperature. Saturated 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 ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; methanol / dichloromethane = 0% to 7%) and concentrated to afford the title compound (0.013 g, 22.2%) as a brown solid.

[0809] 1 H NMR (400 MHz, CDCl 3 )δ8.33-8.29(m,1H),8.23(dd,J=1.0,7.1Hz,1H),8.16(ddd,J=0.8,2.0,5.0H z,1H),7.79(s,1H),7.55(dd,J=1.7,7.1Hz,1H),7.48-7.36(m,2H),7.16-6.8 0(m,4H),6.65-6.55(m,2H),5.03(s,2H),4.26(d,J=13.5Hz,2H),2.65(t,J=1 2.6Hz,2H),2.53(s,1H),1.89(qd,J=4.1,12.5Hz,2H),1.72(d,J=13.1Hz,2H);

[0810] LRMS (ES) m / z 548.2 (M + +1).

[0811] Example 112: Synthesis of Compound 4157, 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-carboxamide

[0812]

[0813] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-carboxamide (0.050 g, 0.106 mmol), 2-chloropyrimidine (0.024 g, 0.213 mmol) and potassium carbonate (0.044 g, 0.319 mmol) prepared in step 3 of Example 93 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 saturated 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. Methylene chloride (3 mL) was added to the concentrate, followed by stirring, and the precipitated solid was filtered, washed with methylene chloride, and dried to obtain the title compound (0.018 g, 30.5%) as a white solid.

[0814] 1 H NMR (400 MHz, CDCl 3 )δ8.31-8.26(m,3H),8.23(dd,J=0.9,7.1Hz,1H),7.78(s,1H),7.54(dd,J=1. 7,7.1Hz,1H),7.43(td,J=6.5,8.3Hz,1H),7.15-6.81(m,4H),6.46(t,J=4.7Hz ,1H),5.02(s,2H),4.73(dt,J=3.5,13.4Hz,2H),2.69(t,J=13.0Hz,2H),2.56 (d,J=11.5Hz,1H),1.83(qd,J=4.2,12.0,12.5Hz,2H),1.71(d,J=13.0Hz,2H);

[0815] LRMS (ES) m / z 549.4 (M + +1).

[0816] Example 113: Synthesis of Compound 4158, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-methyl-N-phenylazetidine-3-carboxamide

[0817] [Step 1] Synthesis of tert-butyl 3-(chlorocarbonyl)azetidine-1-carboxylate

[0818]

[0819] 1-(tert-Butyloxycarbonyl)azetidine-3-carboxylic acid (1.200 g, 5.964 mmol) was dissolved in dichloromethane (150 mL), and oxalyl chloride (2.00 M solution in DCM, 3.578 mL, 7.156 mmol) and N,N-dimethylformamide (0.046 mL, 0.596 mmol) were added at 0° C. and stirred at room temperature for 2 hours. After removing the solvent from the reaction mixture under reduced pressure, the title compound (1.250 g, 95.4%) was obtained as a colorless oil without further purification.

[0820] [Step 2] Synthesis of 3-(((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridine- tert-Butyl (2-yl)methyl)(phenyl)carbamoyl)azetidine-1-carboxylate

[0821]

[0822] To a solution in which N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)aniline (1.500 g, 4.395 mmol) and triethylamine (1.838 mL, 13.184 mmol) prepared in Example 14 were dissolved in dichloromethane (150 mL) at room temperature, tert-butyl 3-(chlorocarbonyl)azetidine-1-carboxylate (1.255 g, 5.713 mmol) was added and stirred at the same temperature for 16 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture, extracted with dichloromethane, 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 (SiO 2 , 40 g column; ethyl acetate / hexanes = 5% to 60%) and concentrated to afford the title compound (1.600 g, 69.4%) as a beige solid.

[0823] [Step 3] Synthesis of N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridine-2-yl) (2-(4-(4-(2 ...

[0824]

[0825] Tert-butyl 3-(((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)(phenyl)carbamoyl)azetidine-1-carboxylate (0.600 g, 1.144 mmol) and trifluoroacetic acid (1.752 mL, 22.878 mmol) prepared in step 2 were dissolved in dichloromethane (7 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, filtered, and concentrated under reduced pressure to obtain the title compound (0.485 g, 99.9%) as a brown gel without further purification.

[0826] [Step 4] Synthesis of compound 4158

[0827]

[0828] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide (0.050 g, 0.118 mmol), formaldehyde (0.007 g, 0.236 mmol), acetic acid (0.007 mL, 0.118 mmol) and sodium triacetoxyborohydride (0.075 g, 0.353 mmol) prepared in step 3 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.014 g, 27.1%) as a white solid.

[0829] 1 H NMR (400 MHz, CDCl 3 )δ8.31(dt,J=1.8,0.8Hz,1H),8.23(dd,J=7.1,1.0Hz,1H),7.79(s,1H),7.54(dd,J=7.1,1.7Hz,1H),7. 44-7.34(m,3H),7.19-7.13(m,2H),6.95(t,J=51.7Hz,1H),5.05(s,2H),3.39-3.28(m,5H),2.35(s,3H);

[0830] LRMS (ES) m / z 439.3 (M + +1).

[0831] Example 114: Synthesis of Compound 4159, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-ethyl-N-phenylazetidine-3-carboxamide

[0832]

[0833] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide (0.050 g, 0.118 mmol), acetaldehyde (0.010 g, 0.236 mmol), acetic acid (0.007 mL, 0.118 mmol) and sodium triacetoxyborohydride (0.075 g, 0.353 mmol) prepared in step 3 of Example 113 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.022 g, 41.3%) as a white solid.

[0834] 1 H NMR (400 MHz, CDCl 3 )δ8.31(dt,J=1.7,0.8Hz,1H),8.23(dd,J=7.1,1.0Hz,1H),7.78(s,1H),7.54(dd,J=7.1,1.7Hz,1H),7.45-7.34 (m,3H),7.21-7.13(m,2H),6.95(t,J=51.7Hz,1H),5.06(s,2H),3.39(s,5H),2.60(s,2H),0.99(t,J=7.1Hz,3H);

[0835] LRMS (ES) m / z 453.4 (M + +1).

[0836] Example 115: Synthesis of Compound 4160, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-isopropyl-N-phenylazetidine-3-carboxamide

[0837]

[0838] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide (0.050 g, 0.118 mmol), propan-2-one (0.014 g, 0.236 mmol), acetic acid (0.007 mL, 0.118 mmol) and sodium triacetoxyborohydride (0.075 g, 0.353 mmol) prepared in step 3 of Example 113 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.024 g, 43.7%) as a white solid.

[0839] 1 H NMR (400 MHz, CDCl 3 )δ8.31(dt,J=1.8,0.8Hz,1H),8.23(dd,J=7.2,1.0Hz,1H),7.76(s,1H),7.54(dd,J=7.1,1.7Hz,1H),7.44-7.35 (m,3H),7.20-7.13(m,2H),6.95(t,J=51.7Hz,1H),5.06(s,2H),3.40(s,5H),2.63(s,1H),1.01(d,J=5.4Hz,6H);

[0840] LRMS(ES)m / z 467.4(M + +1).

[0841] Example 116: Synthesis of Compound 4161, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(1-hydroxypropan-2-yl)-N-phenylazetidine-3-carboxamide

[0842]

[0843] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide (0.050 g, 0.118 mmol), 1-hydroxypropan-2-one (0.017 g, 0.236 mmol), acetic acid (0.007 mL, 0.118 mmol) and sodium triacetoxyborohydride (0.075 g, 0.353 mmol) prepared in step 3 of Example 113 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.029 g, 51.0%) as a white solid.

[0844] 1 H NMR (400 MHz, CDCl 3 )δ8.32(dt,J=1.7,0.8Hz,1H),8.24(dd,J=7.1,1.0Hz,1H),7.80-7.73(m,1H),7.55(dd,J=7.1,1.7Hz,1H),7.44-7.36 (m,3H),7.20-7.14(m,2H),6.95(t,J=51.7Hz,1H),5.06(s,2H),3.64-3.28(m,7H),2.64(s,1H),1.02(d,J=6.5Hz,3H);

[0845] LRMS(ES)m / z 483.4(M + +1).

[0846] Example 117: Synthesis of Compound 4162, 1-cyclobutyl-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide

[0847]

[0848] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide (0.050 g, 0.118 mmol), cyclobutanone (0.017 g, 0.236 mmol), acetic acid (0.007 mL, 0.118 mmol) and sodium triacetoxyborohydride (0.075 g, 0.353 mmol) prepared in step 3 of Example 113 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.018 g, 31.9%) as a white solid.

[0849] 1 H NMR (400 MHz, CDCl 3 )δ8.32(dt,J=1.7,0.8Hz,1H),8.23(dd,J=7.2,1.0Hz,1H),7.76(s,1H),7.55(dd,J=7.1,1.7Hz,1H),7.44-7.35(m,3H),7.16(dd,J= 7.8,1.9Hz,2H),6.95(t,J=51.7Hz,1H),5.06(s,2H),3.60-3.28(m,5H),2.04(d,J=11.2Hz,4H),1.84(s,1H),1.71(q,J=9.2Hz,2H);

[0850] LRMS(ES)m / z 479.0(M + +1).

[0851] Example 118: Synthesis of Compound 4163, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(oxetane-3-yl)-N-phenylazetidine-3-carboxamide

[0852]

[0853] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide (0.050 g, 0.118 mmol), oxetane-3-one (0.017 g, 0.236 mmol), acetic acid (0.007 mL, 0.118 mmol) and sodium triacetoxyborohydride (0.075 g, 0.353 mmol) prepared in step 3 of Example 113 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.019 g, 33.6%) as a white solid.

[0854] 1 H NMR (400 MHz, CDCl 3 )δ8.32(dt,J=1.6,0.8Hz,1H),8.23(dd,J=7.1,1.0Hz,1H),7.78(s,1H),7.54(dd,J=7.1,1.7Hz,1H),7.45-7.36(m,3H),7.21- 7.15(m,2H),6.95(t,J=51.7Hz,1H),5.06(s,2H),4.69(t,J=6.8Hz,2H),4.53(t,J=6.1Hz,2H),3.81(s,1H),3.54-3.29(m,5H);

[0855] LRMS (ES) m / z 481.4 (M + +1).

[0856] Example 119: Synthesis of Compound 4164, 1-cyclohexyl-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide

[0857]

[0858] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide (0.050 g, 0.118 mmol), cyclohexanone (0.023 g, 0.236 mmol), acetic acid (0.007 mL, 0.118 mmol) and sodium triacetoxyborohydride (0.075 g, 0.353 mmol) prepared in step 3 of Example 113 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.028 g, 46.9%) as a white solid.

[0859] 1 H NMR (400 MHz, CDCl 3 )δ8.34-8.29(m,1H),8.23(dd,J=7.2,1.0Hz,1H),7.77(s,1H),7.54(dd,J=7.1,1.7Hz,1H),7.44-7.34(m,3H),7.17(dd,J=8 .0,1.7Hz,2H),6.95(t,J=51.7Hz,1H),5.06(s,2H),3.40(s,4H),1.73(d,J=10.2Hz,5H),1.61(s,2H),1.17(d,J=9.2Hz,5H);

[0860] LRMS (ES) m / z 507.4 (M + +1).

[0861] Example 120: Synthesis of Compound 4165, 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)azetidine-3-carboxamide

[0862]

[0863] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide (0.050 g, 0.118 mmol), tetrahydro-4H-pyran-4-one (0.024 g, 0.236 mmol), acetic acid (0.007 mL, 0.118 mmol) and sodium triacetoxyborohydride (0.075 g, 0.353 mmol) prepared in step 3 of Example 113 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.023 g, 38.4%) as a white solid.

[0864] 1 H NMR (400 MHz, CDCl 3 )δ8.32-8.30(m,1H),8.23(dd,J=7.1,1.0Hz,1H),7.77(s,1H),7.54(dd ,J=7.1,1.7Hz,1H),7.44-7.34(m,3H),7.20-7.14(m,2H),6.95(t,J=51. 7Hz,1H),5.06(s,2H),3.94(d,J=11.8Hz,2H),3.35(td,J=11.4,2.3Hz,6 H),2.35(s,1H),1.84-1.69(m,1H),1.64(d,J=12.8Hz,2H),1.28(s,2H);

[0865] LRMS (ES) m / z 509.0 (M + +1).

[0866] Example 121: Synthesis of Compound 4166, 1-(4,4-difluorocyclohexyl)-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide

[0867]

[0868] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide (0.050 g, 0.118 mmol), 4,4-difluorocyclohexan-1-one (0.032 g, 0.236 mmol), acetic acid (0.007 mL, 0.118 mmol) and sodium triacetoxyborohydride (0.075 g, 0.353 mmol) prepared in step 3 of Example 113 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.031 g, 48.5%) as a white solid.

[0869] 1 H NMR (400 MHz, CDCl 3 )δ8.31(dt,J=1.7,0.8Hz,1H),8.23(dd,J=7.1,1.0Hz,1H),7.78(s,1H),7.54(dd,J=7.1,1.7Hz,1H),7.44-7.34(m,3H),7.22-7.16(m,2H), 6.95(t,J=51.7Hz,1H),5.05(s,2H),3.28(q,J=7.5,6.9Hz,1H),3.19(s,4H),2.21(s,1H),2.00(s,2H),1.68(q,J=14.1Hz,4H),1.39(s,2H);

[0870] LRMS (ES) m / z 543.5 (M + +1).

[0871] Example 122: Synthesis of Compound 4167, 1-acetyl-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide

[0872]

[0873] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide (0.050 g, 0.118 mmol), acetyl chloride (0.017 mL, 0.236 mmol) and triethylamine (0.049 mL, 0.353 mmol) prepared in step 3 of Example 113 were dissolved in dichloromethane (4 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 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.020 g, 36.4%) as a white solid.

[0874] 1 H NMR (400 MHz, CDCl 3 )δ8.39(s,1H),8.29(d,J=7.0Hz,1H),7.82(s,1H),7.62(d,J=7.1Hz,1H),7. 42(dt,J=9.3,6.4Hz,3H),7.25-7.19(m,2H),6.96(t,J=51.7Hz,1H),5.13-5 .06(m,2H),4.54-4.40(m,1H),4.06(dd,J=9.6,6.5Hz,1H),3.93(t,J=8.5Hz ,1H),3.71(t,J=9.4Hz,1H),3.37(ddd,J=15.3,9.0,6.3Hz,1H),1.83(s,3H);

[0875] LRMS (ES) m / z 466.9 (M + +1).

[0876] Example 123: Synthesis of Compound 4168, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenyl-1-propionylazetidine-3-carboxamide

[0877]

[0878] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide (0.050 g, 0.118 mmol), propionyl chloride (0.022 g, 0.236 mmol) and triethylamine (0.049 mL, 0.353 mmol) prepared in step 3 of Example 113 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 (SiO 2 , 12 g column; ethyl acetate / hexanes = 0% to 30%) and concentrated to obtain the title compound (0.032 g, 56.5%) as a white solid.

[0879] 1 H NMR (400 MHz, CDCl 3 )δ8.36-8.31(m,1H),8.25(dd,J=7.1,1.0Hz,1H),7.80(d,J=0.7Hz,1H),7.57(dd,J=7.1,1. 7Hz,1H),7.46-7.36(m,3H),7.20(dd,J=8.1,1.6Hz,2H),6.96(t,J=51.7Hz,1H),5.18-4.96 (m,2H),4.45(dd,J=8.1,6.2Hz,1H),4.05(dd,J=9.5,6.5Hz,1H),3.91(t,J=8.4Hz,1H),3.7 1(t,J=9.3Hz,1H),3.36(tt,J=9.0,6.3Hz,1H),2.07(p,J=7.5Hz,2H),1.09(t,J=7.5Hz,3H);

[0880] LRMS (ES) m / z 480.9 (M + +1).

[0881] Example 124: Synthesis of Compound 4169, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(2-hydroxyacetyl)-N-phenylazetidine-3-carboxamide

[0882]

[0883] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide (0.050 g, 0.118 mmol), 2-hydroxyacetyl chloride (0.022 g, 0.236 mmol) and triethylamine (0.049 mL, 0.353 mmol) prepared in step 3 of Example 113 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 (SiO 2 , 12 g column; ethyl acetate / hexanes = 0% to 30%) and concentrated to obtain the title compound (0.030 g, 52.8%) as a white solid.

[0884] 1 H NMR (400MHz, MeOD) δ8.58 (dd, J=7.1, 1.0Hz, 1H), 8.23 ​​(dt, J=1.7, 0.8Hz, 1H) ,7.98(d,J=0.7Hz,1H),7.57(dd,J=7.2,1.7Hz,1H),7.48-7.11(m,6H),5.14( dd,J=2.2,0.7Hz,2H),4.48(dd,J=9.0,6.2Hz,1H),4.22-4.17(m,1H),4.14- 4.07(m,1H),3.82(t,J=9.4Hz,1H),3.57-3.48(m,1H),3.22(q,J=7.3Hz,2H);

[0885] LRMS(ES)m / z 483.0(M + +1).

[0886] Example 125: Synthesis of Compound 4170, 1-(cyclobutanecarbonyl)-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide

[0887]

[0888] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide (0.050 g, 0.118 mmol), cyclobutanecarbonyl chloride (0.028 g, 0.236 mmol) and triethylamine (0.049 mL, 0.353 mmol) prepared in step 3 of Example 113 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 (SiO 2 , 12 g column; ethyl acetate / hexanes = 0% to 30%) and concentrated to obtain the title compound (0.029 g, 48.6%) as a white solid.

[0889] 1 H NMR (400 MHz, CDCl 3 )δ8.35(s,1H),8.25(dd,J=7.1,1.0Hz,1H),7.80(d,J=0.7Hz,1H),7.58(dd,J=7.2,1.7H z,1H),7.47-7.36(m,3H),7.22-7.15(m,2H),6.96(t,J=51.7Hz,1H),5.15-4.96(m,2H),4 .44-4.30(m,1H),4.04(dd,J=9.5,6.5Hz,1H),3.85(t,J=8.4Hz,1H),3.70(t,J=9.4Hz,1 H),3.35(tt,J=8.9,6.4Hz,1H),3.09-2.92(m,1H),2.43-2.21(m,3H),2.14-1.89(m,3H);

[0890] LRMS (ES) m / z 507.4 (M + +1).

[0891] Example 126: Synthesis of Compound 4171, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(oxetane-3-carbonyl)-N-phenylazetidine-3-carboxamide

[0892]

[0893] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide (0.050 g, 0.118 mmol), oxetane-3-carbonyl chloride (0.028 g, 0.236 mmol) and triethylamine (0.049 mL, 0.353 mmol) prepared in step 3 of Example 113 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 (SiO 2 , 12 g column; ethyl acetate / hexanes = 0% to 30%) and concentrated to obtain the title compound (0.039 g, 65.1%) as a white solid.

[0894] 1 H NMR (400 MHz, CDCl 3 )δ8.38(s,1H),8.26(dd,J=7.0,1.0Hz,1H),7.78(s,1H),7.61(d,J=7.1Hz,1H),7.47-7.38(m ,3H),7.24-7.18(m,2H),6.96(t,J=51.7Hz,1H),5.09(d,J=2.9Hz,2H),4.90(dd,J=7.0,5.8H z,1H),4.83(dd,J=7.0,5.7Hz,1H),4.72(ddd,J=14.5,8.6,5.8Hz,2H),4.40-4.32(m,1H),4. 11-4.04(m,1H),3.83(t,J=8.4Hz,1H),3.79-3.71(m,2H),3.39(ddd,J=15.1,8.9,6.3Hz,1H);

[0895] LRMS (ES) m / z 509.4 (M + +1).

[0896] Example 127: Synthesis of Compound 4172, 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)azetidine-3-carboxamide

[0897]

[0898] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide (0.050 g, 0.118 mmol), 1,1,1,5,5,5-hexafluoropentane-2,4-dione (0.049 g, 0.236 mmol) and triethylamine (0.049 mL, 0.353 mmol) prepared in step 3 of Example 113 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 (SiO 2 , 12 g column; ethyl acetate / hexanes = 0% to 30%) and concentrated to obtain the title compound (0.034 g, 55.5%) as a white solid.

[0899] 1 H NMR (400 MHz, CDCl 3 )δ8.36(s,1H),8.26(dd,J=7.1,1.0Hz,1H),7.79(s,1H),7.59(dd,J=7.1,1.7Hz,1H),7.51-7.37(m,3H),7.25-7.19(m,2H),6.96(t,J=51.7Hz,1 H),5.09(d,J=2.9Hz,2H),4.76-4.60(m,1H),4.27(dd,J=10.4,6.6Hz,1H ),4.22-4.10(m,1H),3.87(t,J=9.9Hz,1H),3.51(tt,J=9.1,6.5Hz,1H);

[0900] LRMS (ES) m / z 520.9 (M + +1).

[0901] Example 128: Synthesis of Compound 4173, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(methylsulfonyl)-N-phenylazetidine-3-carboxamide

[0902]

[0903] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide (0.050 g, 0.118 mmol), methanesulfonyl chloride (0.018 mL, 0.236 mmol) and triethylamine (0.049 mL, 0.353 mmol) prepared in step 3 of Example 113 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 (SiO 2 , 12 g column; ethyl acetate / hexanes = 0% to 30%) and concentrated to obtain the title compound (0.032 g, 54.1%) as a white solid.

[0904] 1 H NMR (400 MHz, CDCl 3 )δ8.37(s,1H),8.26(dd,J=7.2,1.0Hz,1H),7.80-7.75(m,1H),7.60(dd,J=7.1,1.7Hz,1H),7.47-7.38(m,3H),7.24-7.15(m, 2H),6.96(t,J=51.7Hz,1H),5.09(s,2H),4.16(dd,J=8.1,7.1Hz,2H),3.71(t,J=8.3Hz,2H),3.47-3.32(m,1H),2.91(s,3H);

[0905] LRMS (ES) m / z 503.4 (M + +1).

[0906] Example 129: Synthesis of Compound 4174, methyl 3-(((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)(phenyl)carbamoyl)azetidine-1-carboxylate

[0907]

[0908] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide (0.050 g, 0.118 mmol), methyl chloroformate (0.022 g, 0.236 mmol) and triethylamine (0.049 mL, 0.353 mmol) prepared in step 3 of Example 113 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 (SiO 2 , 12 g column; ethyl acetate / hexanes = 0% to 30%) and concentrated to obtain the title compound (0.023 g, 40.5%) as a white solid.

[0909] 1 H NMR (400 MHz, CDCl 3 )δ8.36(s,1H),8.26(dd,J=7.1,1.0Hz,1H),7.82(s,1H),7.59(dd,J=7.2,1.7Hz,1H),7.46-7.36(m,3H),7.22-7.16(m, 2H),6.96(t,J=51.7Hz,1H),5.08(s,2H),4.19(s,2H),3.74(t,J=8.6Hz,2H),3.64(s,3H),3.36(tt,J=8.8,6.4Hz,1H);

[0910] LRMS(ES)m / z 482.8(M + +1).

[0911] Example 130: Synthesis of Compound 4175, N3-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N1,N1-dimethyl-N3-phenylazetidine-1,3-dicarboxamide

[0912]

[0913] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide (0.050 g, 0.118 mmol), dimethylcarbamoyl chloride (0.025 g, 0.236 mmol) and triethylamine (0.049 mL, 0.353 mmol) prepared in step 3 of Example 113 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 (SiO 2 , 12 g column; ethyl acetate / hexanes = 0% to 30%) and concentrated to obtain the title compound (0.030 g, 51.4%) as a white solid.

[0914] 1 H NMR (400 MHz, CDCl 3 )δ8.34(s,1H),8.26(dd,J=7.1,1.0Hz,1H),7.84-7.80(m,1H),7.58(dd,J=7.1,1.7Hz,1H),7.45-7.34(m,3H),7.22-7.15(m,2H),6. 95(t,J=51.7Hz,1H),5.08(s,2H),4.18(dd,J=8.0,6.8Hz,2H),3.70(dd,J=9.0,8.0Hz,2H),3.35(tt,J=9.0,6.8Hz,1H),2.82(s,6H);

[0915] LRMS (ES) m / z 495.9 (M + +1).

[0916] Example 131: Synthesis of Compound 4176, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenyl-1-(pyridin-2-yl)azetidine-3-carboxamide

[0917]

[0918] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide (0.050 g, 0.118 mmol), 2-chloropyridine (0.027 g, 0.236 mmol), cesium carbonate (0.077 g, 0.236 mmol) and RuPhos palladium G2 (0.005 g, 0.006 mmol) prepared in step 2 of Example 113 were dissolved in 1,4-dioxane (2 mL) at room temperature, and the resulting solution was stirred at 100 ° C for 18 hours. Then, the temperature was lowered to room temperature to terminate the reaction. 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 30%) and concentration gave the title compound (0.028 g, 47.4%) as a white solid.

[0919] 1 H NMR (400 MHz, CDCl 3 )δ8.31(dt,J=1.7,0.8Hz,1H),8.23(dd,J=7.1,1.0Hz,1H),8.11(ddd,J=5.1,1.8,0. 9Hz,1H),7.82(d,J=0.7Hz,1H),7.54(dd,J=7.1,1.7Hz,1H),7.49-7.35(m,4H),7.25 -7.21(m,2H),6.95(t,J=51.7Hz,1H),6.61(ddd,J=7.1,5.1,1.0Hz,1H),6.35-6.27( m,1H),5.08(s,2H),4.23(t,J=7.2Hz,2H),3.86(t,J=8.1Hz,2H),3.61-3.48(m,1H);

[0920] LRMS (ES) m / z 502.4 (M + +1).

[0921] Example 132: Synthesis of Compound 4177, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenyl-1-(pyrimidin-2-yl)azetidine-3-carboxamide

[0922]

[0923] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-phenylazetidine-3-carboxamide (0.050 g, 0.118 mmol), 2-chloropyrimidine (0.027 g, 0.236 mmol) and potassium carbonate (0.033 g, 0.236 mmol) prepared in step 3 of Example 113 were dissolved in acetonitrile (2 mL) / N,N-dimethylformamide (2 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 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.018 g, 30.4%) as a white solid.

[0924] 1 H NMR (400 MHz, CDCl 3 )δ8.33-8.28(m,3H),8.23(dd,J=7.1,1.0Hz,1H),7.82(d,J=0.7Hz,1H),7.54(dd,J=7.2,1.7Hz,1H),7.47-7.36(m,3H),7.26-7.18(m,2H), 6.95(t,J=51.7Hz,1H),6.54(t,J=4.8Hz,1H),5.09(s,2H),4.36(dd,J=8.5,6.5Hz,2H),3.95(t,J=8.6Hz,2H),3.51(tt,J=8.7,6.5Hz,1H);

[0925] LRMS (ES) m / z 503.4 (M + +1).

[0926] Example 133: Synthesis of Compound 4188, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-1-methylazetidine-3-carboxamide

[0927] [Step 1] Synthesis of 3-(((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridine- tert-Butyl (2-yl)methyl) (3-fluorophenyl)carbamoyl)azetidine-1-carboxylate

[0928]

[0929] To a solution in which N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-3-fluoroaniline (1.500 g, 4.175 mmol) and triethylamine (1.746 mL, 12.524 mmol) prepared in Example 16 were dissolved in dichloromethane (150 mL) at room temperature, tert-butyl 3-(chlorocarbonyl)azetidine-1-carboxylate (1.192 g, 5.427 mmol) prepared in step 1 of Example 113 was added and stirred at the same temperature for 16 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture, extracted with dichloromethane, 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 (SiO 2 , 40 g column; ethyl acetate / hexane = 5% to 60%) and concentrated to obtain the title compound (1.200 g, 53.0%) as a yellow solid.

[0930] [Step 2] Synthesis of N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridine-2-yl) (3-fluorophenyl)azetidine-3-carboxamide

[0931]

[0932] Tert-butyl 4-(((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)(3-fluorophenyl)carbamoyl)azetidine-1-carboxylate (0.700 g, 1.290 mmol) and trifluoroacetic acid (1.976 mL, 25.806 mmol) prepared in step 1 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, filtered, and concentrated under reduced pressure to obtain the title compound (0.570 g, 99.9%) as a brown gel without further purification.

[0933] [Step 3] Synthesis of compound 4188

[0934]

[0935] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)azetidine-3-carboxamide (0.050 g, 0.113 mmol), formaldehyde (0.007 g, 0.226 mmol), acetic acid (0.006 mL, 0.113 mmol) and sodium triacetoxyborohydride (0.072 g, 0.339 mmol) prepared in step 2 were dissolved in dichloromethane (4 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, 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.016 g, 31.0%) as a white solid.

[0936] 1 H NMR (400 MHz, CDCl 3 )δ8.33-8.30(m,1H),8.24(dd,J=7.1,1.0Hz,1H),7.79(s,1H),7.55(dd,J=7.1,1.7Hz,1H),7.3 8(td,J=8.3,6.3Hz,1H),7.14-6.80(m,4H),5.03(s,2H),3.45(s,2H),3.36(s,3H),2.39(s,3H);

[0937] LRMS(ES)m / z 457.4(M + +1).

[0938] Example 134: Synthesis of Compound 4189, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-ethyl-N-(3-fluorophenyl)azetidine-3-carboxamide

[0939]

[0940] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)azetidine-3-carboxamide (0.060 g, 0.136 mmol), acetaldehyde (0.012 g, 0.271 mmol), acetic acid (0.008 mL, 0.136 mmol) and sodium triacetoxyborohydride (0.086 g, 0.407 mmol) prepared in step 2 of Example 133 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 (SiO 2 , 12 g column; ethyl acetate / hexanes = 0% to 30%) and concentrated to obtain the title compound (0.021 g, 32.9%) as a white solid.

[0941] 1 H NMR (400 MHz, CDCl 3 )δ8.33-8.30(m,1H),8.24(dd,J=7.1,1.0Hz,1H),7.78(s,1H),7.56(dd,J=7.1,1.7Hz,1H) ,7.43-7.34(m,1H),7.14-6.78(m,4H),5.04(s,2H),3.38(s,4H),2.59(s,1H),1.68(s,5H);

[0942] LRMS (ES) m / z 471.5 (M + +1).

[0943] Example 135: Synthesis of Compound 4190, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-1-isopropylazetidine-3-carboxamide

[0944]

[0945] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)azetidine-3-carboxamide (0.060 g, 0.136 mmol), propan-2-one (0.016 g, 0.271 mmol), acetic acid (0.008 mL, 0.136 mmol) and sodium triacetoxyborohydride (0.086 g, 0.407 mmol) prepared in step 2 of Example 133 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.025 g, 38.0%) as a white solid.

[0946] 1 H NMR (400 MHz, CDCl 3 )δ8.32(dd,J=1.7,0.9Hz,1H),8.24(dd,J=7.1,1.0Hz,1H),7.78(s,1H),7.55(dd,J=7.1,1.7Hz,1H),7.38(td,J =8.3,6.3Hz,1H),7.14-6.80(m,4H),5.03(s,2H),3.43(s,2H),3.35(s,3H),2.54(s,1H),0.97(d,J=6.3Hz,6H);

[0947] LRMS (ES) m / z 485.5 (M + +1).

[0948] Example 136: Synthesis of Compound 4191, 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)azetidine-3-carboxamide

[0949]

[0950] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)azetidine-3-carboxamide (0.050 g, 0.113 mmol), 1-hydroxypropan-2-one (0.017 g, 0.226 mmol), acetic acid (0.006 mL, 0.113 mmol) and sodium triacetoxyborohydride (0.072 g, 0.339 mmol) prepared in step 2 of Example 133 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.020 g, 35.4%) as a white solid.

[0951] 1 H NMR (400 MHz, CDCl 3 )δ8.32(dd,J=1.7,0.9Hz,1H),8.24(dd,J=7.1,1.0Hz,1H),7.78(s,1H),7.55(dd,J=7.1,1.7Hz,1H),7.43-7.34(m,1H ),7.13-6.81(m,4H),5.03(s,2H),3.60-3.45(m,4H),3.43-3.30(m,3H),2.62(d,J=9.4Hz,1H),1.00(d,J=6.5Hz,3H);

[0952] LRMS (ES) m / z 501.4 (M + +1).

[0953] Example 137: Synthesis of Compound 4192, 1-cyclobutyl-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)azetidine-3-carboxamide

[0954]

[0955] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)azetidine-3-carboxamide (0.050 g, 0.113 mmol), cyclobutanone (0.016 g, 0.226 mmol), acetic acid (0.006 mL, 0.113 mmol) and sodium triacetoxyborohydride (0.072 g, 0.339 mmol) prepared in step 2 of Example 133 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.024 g, 42.8%) as a white solid.

[0956] 1 H NMR (400 MHz, CDCl 3 )δ8.32(dt,J=1.7,0.8Hz,1H),8.24(dd,J=7.1,1.0Hz,1H),7.79(s,1H),7.55(dd,J=7.1,1.7Hz,1H),7.38(td,J =8.2,6.2Hz,1H),7.12-6.81(m,4H),5.03(s,2H),3.23(d,J=61.3Hz,5H),2.01-1.94(m,2H),1.86-1.59(m,5H);

[0957] LRMS (ES) m / z 497.4 (M + +1).

[0958] Example 138: Synthesis of Compound 4193, 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)azetidine-3-carboxamide

[0959]

[0960] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)azetidine-3-carboxamide (0.050 g, 0.113 mmol), oxetane-3-one (0.016 g, 0.226 mmol), acetic acid (0.006 mL, 0.113 mmol) and sodium triacetoxyborohydride (0.072 g, 0.339 mmol) prepared in step 2 of Example 133 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.032 g, 56.8%) as a white solid.

[0961] 1 H NMR (400 MHz, CDCl 3 )δ8.32(dt,J=1.7,0.8Hz,1H),8.24(dd,J=7.1,1.0Hz,1H),7.79(s,1H),7.55(dd,J=7.1,1.7Hz,1H),7.39(td,J=8.2,6.2Hz,1H),7.14-6.79(m,4 H),5.03(s,2H),4.67(t,J=6.7Hz,2H),4.49(dd,J=6.7,5.2Hz,2H),3.74(ddd,J=11.9,6.7,5.2Hz,1H),3.44-3.32(m,3H),3.28(d,J=5.6Hz,2H);

[0962] LRMS (ES) m / z 499.4 (M + +1).

[0963] Example 139: Synthesis of Compound 4194, 1-cyclohexyl-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)azetidine-3-carboxamide

[0964]

[0965] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)azetidine-3-carboxamide (0.050 g, 0.113 mmol), cyclohexanone (0.022 g, 0.226 mmol), acetic acid (0.006 mL, 0.113 mmol) and sodium triacetoxyborohydride (0.072 g, 0.339 mmol) prepared in step 2 of Example 133 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.034 g, 57.4%) as a white solid.

[0966] 1 H NMR (400 MHz, CDCl 3 )δ8.32(dt,J=1.6,0.8Hz,1H),8.24(dd,J=7.1,1.0Hz,1H),7.77(s,1H),7.55(dd,J=7.1,1.7Hz,1H),7.38(td,J=8.3,6.3Hz,1H ),7.14-6.78(m,4H),5.03(s,2H),3.45(d,J=29.4Hz,5H),2.28(s,1H),1.74(d,J=10.1Hz,4H),1.61(s,1H),1.23-1.05(m,5H);

[0967] LRMS (ES) m / z 525.1 (M + +1).

[0968] Example 140: Synthesis of Compound 4195, 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)azetidine-3-carboxamide

[0969]

[0970] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)azetidine-3-carboxamide (0.050 g, 0.113 mmol), tetrahydro-4H-pyran-4-one (0.023 g, 0.226 mmol), acetic acid (0.006 mL, 0.113 mmol) and sodium triacetoxyborohydride (0.072 g, 0.339 mmol) prepared in step 2 of Example 133 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.015 g, 25.2%) as a white solid.

[0971] 1 H NMR (400 MHz, CDCl 3 )δ8.32(dt,J=1.6,0.8Hz,1H),8.23(dd,J=7.1,1.0Hz,1H),7.78(s,1H),7.55(dd,J=7.1,1.7Hz,1H),7.38(td,J=8.3,6.3Hz,1H),7.13-6. 79(m,4H),5.03(s,2H),3.92(dt,J=11.6,3.7Hz,2H),3.41-3.15(m,7H),2.36-2.22(m,1H),1.61(d,J=13.0Hz,2H),1.31(d,J=4.3Hz,2H);

[0972] LRMS (ES) m / z 527.5 (M + +1).

[0973] Example 141: Synthesis of Compound 4196, 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)azetidine-3-carboxamide

[0974]

[0975] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)azetidine-3-carboxamide (0.050 g, 0.113 mmol), 4,4-difluorocyclohexan-1-one (0.030 g, 0.226 mmol), acetic acid (0.006 mL, 0.113 mmol) and sodium triacetoxyborohydride (0.072 g, 0.339 mmol) prepared in step 2 of Example 133 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.021 g, 33.1%) as a white solid.

[0976] 1 H NMR (400 MHz, CDCl 3 )δ8.32(dt,J=1.7,0.8Hz,1H),8.23(dd,J=7.1,1.0Hz,1H),7.78(s,1H),7.55(dd,J=7.1,1.7Hz,1H),7.38(td,J=8.4,6.5Hz,1H),7.15-6. 77(m,4H),5.03(s,2H),3.34-3.12(m,5H),2.22(s,1H),2.00(dd,J=12.7,5.4Hz,2H),1.69(q,J=17.0,15.4Hz,4H),1.40(d,J=11.4Hz,2H);

[0977] LRMS (ES) m / z 561.3 (M + +1).

[0978] Example 142: Synthesis of Compound 4197, 1-acetyl-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)azetidine-3-carboxamide

[0979]

[0980] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)azetidine-3-carboxamide (0.050 g, 0.113 mmol), acetyl chloride (0.016 mL, 0.226 mmol) and triethylamine (0.047 mL, 0.339 mmol) prepared in step 2 of Example 133 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.024 g, 43.8%) as a white solid.

[0981] 1 H NMR (400 MHz, CDCl 3 )δ8.36(d,J=1.6Hz,1H),8.26(dd,J=7.2,1.0Hz,1H),7.81(s,1H),7.60( dd,J=7.2,1.7Hz,1H),7.41(td,J=8.0,6.4Hz,1H),7.18-6.77(m,4H),5.1 5-4.97(m,2H),4.50-4.42(m,1H),4.06(dd,J=9.5,6.4Hz,1H),3.97(t,J =8.5Hz,1H),3.81-3.69(m,1H),3.38(tt,J=8.9,6.3Hz,1H),1.84(s,3H);

[0982] LRMS(ES)m / z 485.0(M + +1).

[0983] Example 143: Synthesis of Compound 4198, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-1-isopropylazetidine-3-carboxamide

[0984]

[0985] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)azetidine-3-carboxamide (0.050 g, 0.113 mmol), propionyl chloride (0.021 g, 0.226 mmol) and triethylamine (0.047 mL, 0.339 mmol) prepared in step 2 of Example 133 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.027 g, 47.9%) as a white solid.

[0986] 1 H NMR (400 MHz, CDCl 3 )δ8.35(s,1H),8.26(d,J=7.1Hz,1H),7.80(s,1H),7.58(dd,J=7.1,1.7Hz, 1H),7.41(q,J=7.6Hz,1H),7.17-6.81(m,4H),5.14-4.97(m,2H),4.51-4.38 (m,1H),4.06(dd,J=9.5,6.5Hz,1H),3.95(t,J=8.4Hz,1H),3.76(t,J=9.3Hz ,1H),3.38(tt,J=8.8,6.2Hz,1H),2.14-2.00(m,2H),1.10(t,J=7.5Hz,3H);

[0987] LRMS (ES) m / z 499.5 (M + +1).

[0988] Example 144: Synthesis of Compound 4199, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-1-(2-hydroxyacetyl)azetidine-3-carboxamide

[0989]

[0990] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)azetidine-3-carboxamide (0.050 g, 0.113 mmol), 2-hydroxyacetyl chloride (0.021 g, 0.226 mmol) and triethylamine (0.047 mL, 0.339 mmol) prepared in step 2 of Example 133 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.012 g, 21.2%) as a white solid.

[0991] 1 H NMR (400 MHz, CDCl 3 )δ8.33(d,J=2.0Hz,1H),8.25(dd,J=7.2,1.1Hz,1H),7.79(s,1H),7.57(dt,J=7.1,1.6Hz,1H),7.42(td,J=8.1,6.2Hz,1H),7.18-6 .79(m,4H),5.05(d,J=4.0Hz,2H),4.38(t,J=7.3Hz,1H),4.21-4.14(m,1H),4.03-3.81(m,4H),3.49(ddd,J=15.2,8.9,6.3Hz,1H);

[0992] LRMS (ES) m / z 501.0 (M + +1).

[0993] Example 145: Synthesis of Compound 4200, 1-(cyclobutanecarbonyl)-N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)azetidine-3-carboxamide

[0994]

[0995] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)azetidine-3-carboxamide (0.050 g, 0.113 mmol), cyclobutanecarbonyl chloride (0.027 g, 0.226 mmol) and triethylamine (0.047 mL, 0.339 mmol) prepared in step 2 of Example 133 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.038 g, 64.1%) as a white solid.

[0996] 1 H NMR (400 MHz, CDCl 3 )δ8.38(s,1H),8.27(d,J=7.1Hz,1H),7.81(s,1H),7.62(d,J=7.1Hz,1H),7.41(td,J=8 .3,6.2Hz,1H),7.17-6.77(m,4H),5.15-4.96(m,2H),4.43-4.31(m,1H),4.04(dd,J=9.4 ,6.5Hz,1H),3.89(t,J=8.4Hz,1H),3.75(t,J=9.3Hz,1H),3.38(ddd,J=15.1,8.9,6.3Hz ,1H),3.00(dd,J=9.4,7.6Hz,1H),2.28(dp,J=27.9,9.2,8.8Hz,3H),2.13-1.90(m,3H);

[0997] LRMS (ES) m / z 525.1 (M + +1).

[0998] Example 146: Synthesis of Compound 4201, 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)azetidine-3-carboxamide

[0999]

[1000] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)azetidine-3-carboxamide (0.050 g, 0.113 mmol), oxetane-3-carbonyl chloride (0.027 g, 0.226 mmol) and triethylamine (0.047 mL, 0.339 mmol) prepared in step 2 of Example 133 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.033 g, 55.5%) as a white solid.

[1001] 1 H NMR (400 MHz, CDCl 3 )δ8.35(d,J=1.7Hz,1H),8.25(dd,J=7.1,1.0Hz,1H),7.78(s,1H),7.58(dd,J=7.1,1.7Hz ,1H),7.42(td,J=8.0,6.1Hz,1H),7.17-6.79(m,4H),5.14-4.98(m,2H),4.90(dd,J=7.0,5 .8Hz, 1H), 4.83 (dd, J=7.0, 5.8Hz, 1H), 4.72 (ddd, J=12.0, 8.6, 5.8Hz, 2H), 4.36 (dd, J=8. 1,6.1Hz,1H),4.09(dd,J=9.7,6.4Hz,1H),3.89-3.71(m,3H),3.39(tt,J=8.8,6.3Hz,1H);

[1002] LRMS (ES) m / z 527.1 (M + +1).

[1003] Example 147: Synthesis of Compound 4202, 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)azetidine-3-carboxamide

[1004]

[1005] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)azetidine-3-carboxamide (0.060 g, 0.136 mmol), 1,1,1,5,5,5-hexafluoropentane-2,4-dione (0.056 g, 0.271 mmol) and triethylamine (0.057 mL, 0.407 mmol) prepared in step 2 of Example 133 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.031 g, 42.5%) as a white solid.

[1006] 1 H NMR (400 MHz, CDCl 3 )δ8.37(s,1H),8.27(dd,J=7.1,1.0Hz,1H),7.80(s,1H),7.60(dd,J=7.2,1.7Hz,1H),7.44(td,J=8.3,6.3Hz,1H),7.15(tdd,J=8.3,2.5,1. 1Hz,1H),7.11-6.81(m,3H),5.07(d,J=2.3Hz,2H),4.74-4.62(m,1H),4.33-4.12(m,2H),3.92(t,J=9.8Hz,1H),3.53(tt,J=9.1,6.5Hz,1H);

[1007] LRMS(ES)m / z 539.0(M + +1).

[1008] Example 148: Synthesis of Compound 4203, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)-1-(methylsulfonyl)azetidine-3-carboxamide

[1009]

[1010] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)azetidine-3-carboxamide (0.060 g, 0.136 mmol), methanesulfonyl chloride (0.021 mL, 0.271 mmol) and triethylamine (0.057 mL, 0.407 mmol) prepared in step 2 of Example 133 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.030 g, 42.5%) as a white solid.

[1011] 1 H NMR (400 MHz, CDCl 3 )δ8.37(s,1H),8.27(dd,J=7.2,1.0Hz,1H),7.79(d,J=0.7Hz,1H),7.61(dd,J=7.1,1.7Hz,1H),7.50-7.36(m,1H),7.19-7.1 0(m,1H),7.10-6.79(m,3H),5.07(s,2H),4.17(dd,J=8.1,7.1Hz,2H),3.75(t,J=8.4Hz,2H),3.49-3.35(m,1H),2.91(s,3H);

[1012] LRMS (ES) m / z 521.1 (M + +1).

[1013] Example 149: Synthesis of Compound 4204, methyl 3-(((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)(3-fluorophenyl)carbamoyl)azetidine-1-carboxylate

[1014]

[1015] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)azetidine-3-carboxamide (0.050 g, 0.113 mmol), methyl chloroformate (0.021 g, 0.226 mmol) and triethylamine (0.047 mL, 0.339 mmol) prepared in step 2 of Example 133 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.031 g, 54.8%) as a white solid.

[1016] 1 H NMR (400 MHz, CDCl 3 )δ8.37-8.33(m,1H),8.26(dd,J=7.1,1.0Hz,1H),7.82(s,1H),7.59(dd,J=7.2,1.8Hz,1H),7.41(td,J=8.3,6.2Hz ,1H),7.17-6.78(m,4H),5.06(s,2H),4.19(s,2H),3.78(t,J=8.6Hz,2H),3.65(s,3H),3.37(tt,J=8.9,6.4Hz,1H);

[1017] LRMS (ES) m / z 501.0 (M + +1).

[1018] Example 150: Synthesis of Compound 4205, N3-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N3-(3-fluorophenyl)-N1,N1-dimethylazetidine-1,3-dicarboxamide

[1019]

[1020] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)azetidine-3-carboxamide (0.050 g, 0.113 mmol), dimethylcarbamoyl chloride (0.024 g, 0.226 mmol) and triethylamine (0.047 mL, 0.339 mmol) prepared in step 2 of Example 133 were dissolved in dichloromethane (4 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.024 g, 41.4%) as a white solid.

[1021] 1 H NMR (400 MHz, CDCl 3 )δ8.34(dd,J=1.8,0.9Hz,1H),8.26(dd,J=7.1,1.0Hz,1H),7.82(s,1H),7.58(dd,J=7.2,1.7Hz,1H),7.40(td,J=8.3,6.3Hz,1H ),7.15-6.77(m,4H),5.05(s,2H),4.17(dd,J=8.0,6.7Hz,2H),3.74(t,J=8.5Hz,2H),3.36(tt,J=8.9,6.7Hz,1H),2.82(s,6H);

[1022] LRMS (ES) m / z 514.0 (M + +1).

[1023] Example 151: Synthesis of Compound 4206, 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)azetidine-3-carboxamide

[1024]

[1025] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)azetidine-3-carboxamide (0.050 g, 0.113 mmol), 2-chloropyridine (0.026 g, 0.226 mmol), cesium carbonate (0.074 g, 0.226 mmol) and RuPhos palladium G2 (0.004 g, 0.006 mmol) prepared in step 2 of Example 133 were dissolved in 1,4-dioxane (2 mL) at room temperature, and the resulting solution was stirred at 100 ° C for 18 hours. Then, the temperature was lowered to room temperature to terminate the reaction. 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 30%) and concentration gave the title compound (0.012 g, 20.4%) as a white solid.

[1026] 1 H NMR (400 MHz, CDCl 3 )δ8.36-8.30(m,1H),8.24(ddd,J=7.1,6.0,1.0Hz,1H),8.12(ddd,J=5.1,1. 9,0.9Hz,1H),7.80(d,J=8.0Hz,1H),7.59-7.51(m,1H),7.50-7.37(m,2H),7 .15-6.81(m,4H),6.62(ddd,J=7.2,5.0,1.0Hz,1H),6.29(d,J=8.4Hz,1H),5 .06(s,2H),4.21(t,J=7.1Hz,2H),3.88(t,J=8.2Hz,2H),3.64-3.54(m,1H);

[1027] LRMS (ES) m / z 520.5 (M + +1).

[1028] Example 152: Synthesis of Compound 4207, 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)azetidine-3-carboxamide

[1029]

[1030] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)azetidine-3-carboxamide (0.050 g, 0.113 mmol), 2-chloropyrimidine (0.026 g, 0.226 mmol) and potassium carbonate (0.031 g, 0.226 mmol) prepared in step 2 of Example 133 were dissolved in acetonitrile (2 mL) / N,N-dimethylformamide (2 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 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.041 g, 69.7%) as a white solid.

[1031] 1 H NMR (400 MHz, CDCl 3 )δ8.35-8.29(m,3H),8.24(dd,J=7.1,1.0Hz,1H),7.82(s,1H),7.56(dd,J=7.1,1.7Hz,1H),7.41(td,J=8.2,6.3Hz,1H),7.16-6 .80(m,4H),6.56(t,J=4.8Hz,1H),5.07(s,2H),4.36(dd,J=8.6,6.5Hz,2H),4.00(t,J=8.6Hz,2H),3.54(tt,J=8.7,6.4Hz,1H);

[1032] LRMS (ES) m / z 521.4 (M + +1).

[1033] Example 153: Synthesis of Compound 4618, 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-carboxamide

[1034]

[1035] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-carboxamide (0.040 g, 0.085 mmol), spiro[3.3]heptan-2-one (0.019 g, 0.170 mmol), acetic acid (0.011 mL, 0.085 mmol) and sodium triacetoxyborohydride (0.054 g, 0.255 mmol) prepared in step 3 of Example 93 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.020 g, 41.7%) as a white solid.

[1036] 1 H NMR (400 MHz, CDCl 3 )δ8.30(s,1H),8.23(d,J=7.1Hz,1H),7.55(d,J=6.9Hz,1H),7.39(dd,J=14.6,8.2Hz,1H),7.14-6.79(m,5H),5. 01(s,2H),3.13(d,J=41.6Hz,1H),2.84(s,2H),2.24(s,2H),1.89(dt,J=53.6,40.7Hz,12H),1.57-1.37(m,2H);

[1037] LRMS (ES) m / z 565.5 (M + +1).

[1038] Example 154: Synthesis of Compound 4619, 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-carboxamide

[1039]

[1040] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperidine-4-carboxamide (0.040 g, 0.085 mmol), 2-oxaspiro[3.3]heptan-6-one (0.019 g, 0.170 mmol), acetic acid (0.005 mL, 0.085 mmol) and sodium triacetoxyborohydride (0.054 g, 0.255 mmol) prepared in step 3 of Example 93 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.020 g, 41.5%) as a white solid.

[1041] 1 H NMR (400 MHz, CDCl 3 )δ8.30(s,1H),8.23(d,J=7.1Hz,1H),7.55(d,J=7.1Hz,1H),7.39(dd,J=14.5,8.1Hz,1H),7.14-6.79(m,5H),5.01(s,2H) ,4.69(s,2H),4.59(s,2H),3.23(s,1H),2.83(s,2H),2.30(d,J=47.7Hz,4H),2.04(s,2H),1.96-1.77(m,2H),1.50(s,2H);

[1042] LRMS (ES) m / z 568.2 (M + +1).

[1043] Example 155: Synthesis of Compound 4620, 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-carboxamide

[1044]

[1045] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-carboxamide (0.040 g, 0.085 mmol), spiro[3.3]heptan-2-one (0.019 g, 0.170 mmol), acetic acid (0.005 mL, 0.085 mmol) and sodium triacetoxyborohydride (0.054 g, 0.255 mmol) prepared in step 2 of Example 54 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.020 g, 41.7%) as a white solid.

[1046] 1 H NMR (400 MHz, CDCl 3 )δ8.28(s,1H),8.20(d,J=7.1Hz,1H),7.74(s,1H),7.51(dd,J=7.1,1.6Hz,1H),7.32-7.23(m,1H),7.09-6.76(m,4H) ,5.06(s,2H),3.33(s,4H),2.14(d,J=27.7Hz,6H),2.03-1.94(m,3H),1.94-1.86(m,2H),1.82(dt,J=8.1,6.0Hz,3H);

[1047] LRMS (ES) m / z 566.4 (M + +1).

[1048] Example 156: Synthesis of Compound 4621, 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-carboxamide

[1049]

[1050] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-N-(3-fluorophenyl)piperazine-1-carboxamide (0.040 g, 0.085 mmol), 2-oxaspiro[3.3]heptan-6-one (0.019 g, 0.170 mmol), acetic acid (0.005 mL, 0.085 mmol) and sodium triacetoxyborohydride (0.054 g, 0.255 mmol) prepared in step 2 of Example 54 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.020 g, 41.5%) as a white solid.

[1051] 1 H NMR (400MHz, CDCl3) δ8.28(s,1H),8.20(d,J=7.1Hz,1H),7.74(s,1H),7.51(dd,J=7.1,1.6Hz,1H),7.33-7.23(m,1H),7.09-6.75 (m,4H),5.05(s,2H),4.69(s,2H),4.58(s,2H),3.30(s,4H),2.46(s,1H),2.37(s,2H),2.25-2.04(m,3H),1.95(d,J=17.0Hz,2H);

[1052] LRMS(ES)m / z 568.0(M + +1).

[1053] Example 157: Synthesis of Compound 4625, 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-carboxamide

[1054] [Step 1] Synthesis of tert-butyl 6-(((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)(phenyl)carbamoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[1055]

[1056] N-((7-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)aniline (0.200 g, 0.586 mmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (0.081 g, 0.410 mmol), triphosgene (0.174 g, 0.586 mmol) and N,N-diisopropylethylamine (0.510 mL, 2.930 mmol) prepared in Example 14 were dissolved in dichloromethane (10 mL), and the resulting solution was stirred at 0 ° C for 1 hour and at room temperature for another 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 by column chromatography (SiO 2 , 12 g column; ethyl acetate / hexanes = 0% to 60%) and concentrated to obtain the title compound (0.210 g, 63.4%) as a brown solid.

[1057] [Step 2] 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-carboxamide

[1058]

[1059] Tert-butyl 6-(((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)(phenyl)carbamoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.210 g, 0.371 mmol) and trifluoroacetic acid (0.569 mL, 7.426 mmol) prepared in step 1 were dissolved in dichloromethane (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 2 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 to obtain the title compound (0.172 g, 99.5%) as a yellow gel without further purification.

[1060] [Step 3] Synthesis of compound 4625

[1061]

[1062] 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-carboxamide (0.172 g, 0.370 mmol), formaldehyde (0.022 g, 0.739 mmol), acetic acid (0.021 mL, 0.370 mmol) and sodium triacetoxyborohydride (0.235 g, 1.109 mmol) prepared in step 2 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, 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 (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 20%) and concentration gave the title compound (0.100 g, 56.4%) as a yellow solid.

[1063] 1 H NMR (400 MHz, CDCl 3 )δ8.27(s,1H),8.19(dt,J=7.8,3.9Hz,1H),7.81(s,1H),7.50(dd,J=7.1,1.7Hz,1H),7.38-7.29(m,4H) ,7.25-7.19(m,1H),6.94(dd,J=54.3,49.1Hz,1H),5.02(s,2H),3.64(s,4H),3.18(s,4H),2.21(s,3H);

[1064] LRMS (ES) m / z 480.3 (M + +1).

[1065] Example 158: Synthesis of Compound 6892, tert-butyl 4-((3-fluorophenyl)((7-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)carbamoyl)piperazine-1-carboxylate

[1066] [Step 1] Synthesis of tert-butyl (4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)carbamate

[1067]

[1068] 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 2 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 sodium chloride aqueous 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.

[1069] [Step 2] Synthesis of 4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine

[1070]

[1071] 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.

[1072] [Step 3] Synthesis of 2-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole

[1073]

[1074] 4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-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 by column chromatography (SiO 2 , 40 g column; ethyl acetate / hexanes = 5% to 70%) and concentrated to afford the title compound (0.850 g, 58.8%) as a beige solid.

[1075] [Step 4] Synthesis of 3-fluoro-N-((7-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)aniline

[1076]

[1077] 3-(2-(chloromethyl)imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.311 g, 1.028 mmol), 3-fluoroaniline (0.228 g, 2.055 mmol), potassium carbonate (0.213 g, 1.541 mmol) and potassium iodide (0.085 g, 0.514 mmol) prepared in step 3 were dissolved in N,N-dimethylformamide (6 mL) at room temperature, and the resulting solution was stirred at 60 ° C for 18 hours. Then, the temperature was lowered to room temperature to terminate the reaction. N-ammonium chloride aqueous solution was poured into the reaction mixture, 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 by chromatography (SiO 2 Plate, 20x20x1 mm; ethyl acetate / hexane = 0% to 50%) and concentration gave the title compound (0.050 g, 12.9%) as a yellow solid.

[1078] [Step 5] Synthesis of compound 6892

[1079]

[1080] 3-Fluoro-N-((7-(5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)aniline (0.050 g, 0.133 mmol), bis(trichloromethyl)carbonate (0.039 g, 0.133 mmol) and N,N-diisopropylethylamine (0.115 mL, 0.663 mmol) prepared in step 4 were dissolved in dichloromethane (4 mL), and the resulting solution was stirred at room temperature for 10 minutes. Then, tert-butyl piperazine-1-carboxylate (0.032 g, 0.172 mmol) was added and stirred for another 18 hours at the same temperature. Water 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 (SiO 2 Plate, 20x20x1 mm; ethyl acetate / hexane = 0% to 100%) and concentration gave the title compound (0.040 g, 51.3%) as a brown solid.

[1081] 1 H NMR (400MHz, acetone-d6) δ8.69(d,J=7.1Hz,1H),8.25(d,J=1.7Hz,1H),8.08(s,1H),7.53(dd,J=7.1,1.8Hz,1H),7.36(td,J=8.3,6.7H z,1H),7.14(ddt,J=8.0,5.3,2.3Hz,2H),6.86(td,J=8.4,2.4Hz,1H),5.09(s,2H),3.28(qd,J=6.2,5.0,2.5Hz,8H),1.42(s,10H);

[1082] LRMS (ES) m / z 591.1 (M + +1).

[1083] Activity Measurement and Analytical Protocols for Compounds of the Invention

[1084] <Experimental Example 1> In vitro HDAC enzyme activity inhibition assay

[1085] 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.

[1086] 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 (BNL-KI177) was used as a substrate. After dispensing the 5-fold diluted compound into a 96-well plate, 0.3 μg of the enzyme and 10 μM of the 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 5.

[1087] [Table 5] Results of HDAC enzyme activity inhibition assay

[1088]

[1089]

[1090]

[1091]

[1092]

[1093] As shown in Table 5 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 21 to about 740 times higher selective HDAC6 inhibition activity.

[1094] <Experimental Example 2> In vitro analysis of the effects of HDAC6-specific inhibitors on mitochondrial axonal transport

[1095] 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.

[1096] 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).

[1097] 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 CR4, wherein a, b and c cannot be N at the same time, and R4 is -H, -X or -O(C1-C4 alkyl); Z is N, O, S or absent (none), wherein when Z is absent (none), R2 is also absent (none), and L2 and L3 are directly connected; R1 is -CX2H or -CX3; R2 is -H, -(C1-C4 alkyl), -C(=O)-R A 、-C(=O)-OR B or -C(=O)-NR C R D , wherein when Z is O or S, R2 is absent (none); R A is -(C1-C4 alkyl), -(C1-C4 alkyl)-O-(C1-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(C1-C4 alkyl), -NR A1 R A2 , R B To R D Each is independently -H, -(C1-C4 alkyl), -(C1-C4 alkyl)-O-(C1-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(C1-C4 alkyl) or -(C3-C7 cycloalkyl); Y is N, When Y is N, R Y1 To R Y4 each independently represents -H, -X, -OH, -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -(C1-C4 alkyl)-O-(C1-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(C1-C4 alkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -C(=O)-NR A3 R A4 , -C(=O)-(C3-C7 cycloalkyl), -C(=O)-(C2-C6 heterocycloalkyl), -S(=O)2-(C1-C4 alkyl), -heteroaryl, Amine protecting group or wherein at least one H of -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C1-C4 alkyl)-O-(C1-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(C1-C4 alkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-(C3-C7 cycloalkyl), -C(=O)-(C2-C6 heterocycloalkyl) and -S(=O)2-(C1-C4 alkyl) may be substituted by -X or -OH; at least one H of the heteroaryl may be substituted by -(C1-C4 alkyl), -O-(C1-C4 alkyl), -X, -OH or -CF3; -(C2-C6 heterocycloalkyl) or -heteroaryl may contain N, O or S atoms in the ring; and W is NH, CH2 or O; 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); R3 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), -adamantyl, -aryl or -heteroaryl, wherein at least one H of -(C1-C4 alkyl) may be substituted by -X or -OH; at least one -H of -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -adamantyl, -aryl or -heteroaryl may be independently substituted by -X, -OH, -(C1-C4 alkyl), -O(C1-C4 alkyl), -(C=O)-(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -CF3, -CF2H, -OCF3, -NR A5 R A6 and -S(=O)2-(C1-C4alkyl); R A1 To R A6 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, L2 and L3 are each independently -(C0-C1 alkyl)-; a, b and c are each independently N or CR4, wherein a, b and c cannot be N at the same time, and R4 is -H or -X; Z is N, O or absent (none), wherein when Z is absent (none), R2 is also absent (none), and L2 and L3 are directly connected; R1 is -CX2H or -CX3; R2 is -H, -(C1-C4 alkyl) or -C(=O)-R A , wherein when Z is O, R2 is absent (none); R A Yes - NR A1 R A2 , Y is N; When Y is N, R Y1 To R Y4 Each is independently -H, -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -C(=O)-NR A3 R A4 , -C(=O)-(C3-C7 cycloalkyl), -C(=O)-(C2-C6 heterocycloalkyl), -S(=O)2-(C1-C4 alkyl), -heteroaryl or wherein at least one H of -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-(C3-C7 cycloalkyl), -C(=O)-(C2-C6 heterocycloalkyl) and -S(=O)2-(C1-C4 alkyl) may be substituted by -X or -OH; at least one H of the heteroaryl may be substituted by -(C1-C4 alkyl), -O-(C1-C4 alkyl), -X, -OH or -CF3; -(C2-C6 heterocycloalkyl) or -heteroaryl may contain N, O or S atoms in the ring; and W is NH, CH2 or O; m or n is each independently an integer of 1 or 2; R a To R d Each is independently -H or -(C1-C4 alkyl); R3 is -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -adamantyl, -aryl or -heteroaryl, wherein at least one -H of -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -adamantyl, -aryl or -heteroaryl can be independently replaced by -X, -OH, -(C1-C4 alkyl), -O(C1-C4 alkyl), -(C=O)-(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -CF3, -CF2H, -OCF3, -NR A5 R A6 or -S(=O)2-(C1-C4alkyl) substituted; R A1 To R A6 are each independently -H or -(C1-C4 alkyl); 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 CR4, wherein R4 is -H or -X; Z is N, O or absent (none), wherein when Z is absent (none), R2 is also absent (none), and L2 and L3 are directly connected; R1 is -CF2H or -CF3; R2 is -H or -C(=O)-R A , wherein Z is O, and R2 is absent (none); R A yes Y is N; R Y1 To R Y4 Each is independently -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -C(=O)-NR A3 R A4 , -C(=O)-(C3-C7 cycloalkyl), -C(=O)-(C2-C6 heterocycloalkyl), -S(=O)2-(C1-C4 alkyl), -heteroaryl or wherein at least one H of -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-(C3-C7 cycloalkyl), -C(=O)-(C2-C6 heterocycloalkyl) and -S(=O)2-(C1-C4 alkyl) may be substituted by -X or -OH; at least one H of the heteroaryl may be substituted by -(C1-C4 alkyl), -O-(C1-C4 alkyl), -X, -OH or -CF3; -(C2-C6 heterocycloalkyl) or -heteroaryl may contain N, O or S atoms in the ring; and W is CH2 or O; 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); R3 is -(C3-C7 cycloalkyl), -adamantyl, -aryl or -heteroaryl, wherein at least one -H of -(C3-C7 cycloalkyl), -adamantyl, -aryl or -heteroaryl can be independently substituted by -X, -(C1-C4 alkyl), -O(C1-C4 alkyl), -(C=O)-(C1-C4 alkyl), -CF3 or -S(=O)2-(C1-C4 alkyl); R A1 To R A6 are each independently -H or -(C1-C4 alkyl); 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, L2 or L3 are each independently -(C0-C1 alkyl)-; a, b and c are each independently N or CR4, wherein a, b and c cannot be N at the same time, and R4 is -H or -X; Z is N; R1 is -CX2H or -CX3; R2 is -C(=O)-R A ; R A yes Y is N; When Y is N, R Y1 and R Y3 Each is independently -H, -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -C(=O)-NR A3 R A4 , -C(=O)-(C3-C7 cycloalkyl), -C(=O)-(C2-C6 heterocycloalkyl), -S(=O)2-(C1-C4 alkyl), -heteroaryl or wherein at least one H of -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-(C3-C7 cycloalkyl), -C(=O)-(C2-C6 heterocycloalkyl) and -S(=O)2-(C1-C4 alkyl) may be substituted by -X or -OH; at least one H of the heteroaryl may be substituted by -(C1-C4 alkyl), -O-(C1-C4 alkyl), -X, -OH or -CF3; -(C2-C6 heterocycloalkyl) or -heteroaryl may contain N, O or S atoms in the ring; and W is NH, CH2 or O; 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); R3 is -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -adamantyl, -aryl or -heteroaryl, wherein at least one -H of -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -adamantyl, -aryl and -heteroaryl can be independently replaced by -X, -OH, -(C1-C4 alkyl), -O(C1-C4 alkyl), -(C=O)-(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -CF3, -CF2H, -OCF3, -NR A5 R A6 or -S(=O)2-(C1-C4alkyl) substituted; R A3 To R A6 are each independently -H or -(C1-C4 alkyl); 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, L2 and L3 are each independently -(C0-C1 alkyl)-; a, b and c are each independently N or CR4, wherein a, b and c cannot be N at the same time, and R4 is -H or -X; Z is N; R1 is -CX2H or -CX3; R2 is -C(=O)-R A ; R A Yes - NR A1 R A2 , Y is N; When Y is N, R Y2 and R Y4 Each is independently -H, -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -C(=O)-NR A3 R A4 , -C(=O)-(C3-C7 cycloalkyl), -C(=O)-(C2-C6 heterocycloalkyl), -S(=O)2-(C1-C4 alkyl), -heteroaryl or wherein at least one H of -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-(C3-C7 cycloalkyl), -C(=O)-(C2-C6 heterocycloalkyl) and -S(=O)2-(C1-C4 alkyl) may be substituted by -X or -OH; at least one H of the heteroaryl may be substituted by -(C1-C4 alkyl), -O-(C1-C4 alkyl), -X, -OH or -CF3; -(C2-C6 heterocycloalkyl) or -heteroaryl may contain N, O or S atoms in the ring; and W is NH, CH2 or O; 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); R3 is -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -adamantyl, -aryl or -heteroaryl, wherein at least one -H of -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -adamantyl, -aryl and -heteroaryl can be independently replaced by -X, -OH, -(C1-C4 alkyl), -O(C1-C4 alkyl), -(C=O)-(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -CF3, -CF2H, -OCF3, -NR A5 R A6 or -S(=O)2-(C1-C4alkyl) substituted; R A1 To R A6 are each independently -H or -(C1-C4 alkyl); and X is F, Cl or Br.

6. 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, L2 and L3 are each independently -(C0-C1 alkyl)-; a, b and c are each independently N or CR4, wherein a, b and c cannot be N at the same time, and R4 is -H or -X; Z is N, O or absent (none), wherein when Z is absent (none), R2 is also absent (none), and L2 and L3 are directly connected; R1 is -CX2H or -CX3; R2 is -H, -(C1-C4 alkyl), wherein when Z is O, R2 is absent (none); R3 is -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -adamantyl, -aryl or -heteroaryl, wherein at least one -H of -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -adamantyl, -aryl and -heteroaryl can be independently replaced by -X, -OH, -(C1-C4 alkyl), -O(C1-C4 alkyl), -(C=O)-(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -CF3, -CF2H, -OCF3, -NR A5 R A6 or -S(=O)2-(C1-C4alkyl) substituted; R A5 and R A6 are each independently -H or -(C1-C4 alkyl); and X is F, Cl or Br.

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

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

9. 1,3,4-oxadiazole derivative compound, its optical isomer or pharmaceutically acceptable salt thereof, wherein the compound is any one of the compounds listed in the following table:

10. 1,3,4-oxadiazole derivative compound, its optical isomer or pharmaceutically acceptable salt thereof, wherein the compound is any one of the compounds listed in the following table:

11. 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 10, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

12. The pharmaceutical composition for preventing or treating a disease mediated by histone deacetylase 6 according to claim 11, 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.

13. Use of the compound according to any one of claims 1 to 10, 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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