RU2822624C1 - 1,3,4-oxadiazole derivatives as histone deacetylase 6 inhibitor and pharmaceutical composition containing thereof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention relates to 1,3,4-oxadiazole derivatives having histone deacetylase 6 (HDAC6) inhibitory activity, specifically to a compound of formula I or a pharmaceutically acceptable salt thereof, in which L₁, L₂ and L₃ each independently represents -(C₀-C₁alkyl)-; a, b and c are each independently CR₄ and R₄ is -H; Z is N, O or is absent, wherein when Z is absent, R₂ is also absent, and L₂ and L₃ are directly connected; R₁ is -CF₂ or -CX₃; R₂ is -H, -(C₁-C₄alkyl) or -C(=O)-R^A, wherein when Z is O, R₂ is absent; R^A is

, or ;

Y is N, when Y is N, each of R^Y1, R^Y2 and R^Y4 independently represents -(C₁-C₄alkyl), -(C₃-C₇ cycloalkyl), -(C₂-C₆heterocycloalkyl), containing an N or O atom in the ring, -C(=O)-(C₁-C₄alkyl), -C(=O)-O(C₁-C₄alkyl), -C(=O)-NR^A3R^A4, -C(=O)-(C₃-C₇cycloalkyl), -C(=O)-(C₂-C₆heterocycloalkyl), containing one O atom in the ring, -S(=O)₂-(C₁-C₄alkyl), -C₄-C₅heteroaryl, containing one or two N atoms in a ring, or

,

where at least one H -(C₁-C₄alkyl), -(C₃-C₇cycloalkyl) and -C(=O)-(C₁-C₄ alkyl) can be substituted with -X or -OH; and W is CH₂ or O; m and n each independently represents integer 1 or 2; R_a-R_d each independently represents -H; R₃ is -(C₃-C₇ cycloalkyl), -adamantyl, -C₆aryl, -C₅heteroaryl containing one N atom in the ring, or C₇heteroaryl containing two O atoms in the ring, where at least one -H -C₆aryl or -C₅heteroaryl containing one N atom in the ring, each can be independently substituted with groups -X, -(C₁-C₄ alkyl), -O(C₁-C₄ alkyl), -(C=O)-(C₁-C₄ alkyl), -CF₃, or -S(=O)₂-(C₁-C₄alkyl); R^A3 and R^A4 each independently represents -(C₁-C₄alkyl); and X is F, Cl or Br. Invention also relates to a pharmaceutical composition, a method of inhibiting HDAC6 and use for preparing a drug for inhibiting HDAC6 based on said compounds.

EFFECT: obtaining alternative compounds having inhibitory activity to HDAC6, which can be used in medicine for treating HDAC6-mediated diseases.

13 cl, 5 tbl, 158 ex

Description

[Technical field]

The present invention relates to a 1,3,4-oxadiazole derivative having histone deacetylase 6 (HDAC6) inhibitory activity, its optical isomer, a pharmaceutically acceptable salt thereof, use for the preparation of a therapeutic drug, a method of treatment using the said compound, a pharmaceutical composition, containing the specified compound, and a method for its preparation.

[Technique level]

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

Histone deacetylases (HDACs) are enzymes that remove the acetyl group on lysine residues of histone proteins that make up chromatin, which are known to be associated with gene silencing and induce cell cycle arrest, inhibition of angiogenesis, immune regulation, cell death and the like ( Hassig et al., Curr. Chem. 1997, 1, 300-308). In addition, inhibition of HDAC enzyme function has been reported to induce cancer cell death by reducing the activity of factors associated with cancer cell survival and activating factors associated with cancer cell death in vivo (Warrell et al, J. Natl. Cancer Inst. 1998 , 90, 1621-1625).

There are 18 known HDACs in humans, which are divided into 4 groups based on their homology to yeast HDACs. Thus, 11 HDACs using 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 (SIRT 1-7) use NAD ⁺ as a cofactor instead of zinc (Bolden et al., Nat. Rev. Drug. Discov. 2006, 5(9), 769-784).

Various HDAC inhibitors are in preclinical or clinical development. However, so far only nonselective HDAC inhibitors are known as anticancer agents, with vorinostat (SAHA) and romidepsin (FK228) having been approved for the treatment of cutaneous T-cell lymphoma, and panobinostat (LBH-589) having been approved for the treatment of multiple myeloma. However, non-selective HDAC inhibitors are generally known to cause side effects at high doses such as fatigue and nausea and the like (Piekarz et al., Pharmaceuticals 2010, 3, 2751-2767). These side effects are reported to be caused by HDAC class I inhibition, and due to these side effects, non-selective HDAC inhibitors have been limited for drug development in areas other than anticancer agents (Witt et al., Cancer Letters 277 (2009) 8.21).

Meanwhile, it has been reported that selective HDAC class II inhibition may not exhibit the toxicity observed with class I HDAC inhibition, and if a selective class II HDAC inhibitor is developed, then side effects such as toxicity caused by non-selective HDAC inhibition can be eliminated, and thus, a selective HDAC inhibitor can be developed as an effective therapeutic agent for various diseases (Matthias et al., Mol. Cell. Biol. 2008, 28, 1688-1701). HDAC6, one of the class IIb HDACs, is mainly present in the cytoplasm and is known to be involved in the deacetylation of a number of non-histone substrates (HSP90, cortactin and the like), including tubulin proteins (Yao et al., Mol. Cell 2005, 18, 601 -607). HDAC6 has two catalytic domains, and the C-terminal zinc finger domain can bind to ubiquitinated proteins. Since HDAC6 substrates can be a variety of non-histone proteins, it is known to play an important role in various diseases such as cancer, inflammatory diseases, autoimmune diseases, neurological diseases and neurodegenerative disorders, and the like (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).

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

Most of the zinc-binding groups are hydroxamic acid or benzamide, and among them, hydroxamic acid derivatives exhibit strong HDAC inhibitory effects, but they suffer from problems such as low bioavailability and strong off-target activity. Because benzamide contains aniline, there is a problem with the formation of toxic metabolites in vivo (Woster et al., Med. Chem. Commun. 2015, published online).

Thus, for the treatment of cancer, inflammatory diseases, autoimmune diseases, neurological diseases and neurodegenerative disorders and the like, the development of a selective HDAC6 inhibitor containing a zinc-binding group with improved bioavailability without side effects is required, as opposed to non-selective inhibitors with side effects.

[Brief description of the invention]

[Technical challenge]

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

Another object of the present invention is to provide a pharmaceutical composition containing a 1,3,4-oxadiazole derivative having selective inhibitory activity against HDAC6, its optical isomer or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for their preparation.

Another object of the present invention is to provide a pharmaceutical composition containing these compounds for the prevention or treatment of diseases mediated by histone deacetylase 6 (HDAC6), including infectious diseases; neoplasms; endocrine, nutritional and metabolic diseases; mental and behavioral disorders; neurological diseases; diseases of the eye and its adnexa; diseases of the circulatory system; respiratory diseases; diseases of the digestive system; diseases of the skin and subcutaneous tissues; diseases of the musculoskeletal system and connective tissue; or congenital malformations, changes or chromosomal abnormalities.

Another object of the present invention is to provide the use of these compounds for the preparation of a medicament for the prevention or treatment of diseases mediated by HDAC6.

Another object of the present invention is to provide a method of preventing or treating diseases mediated by HDAC6, including the administration of a therapeutically effective amount of a composition containing compounds as described above.

[Technical solution]

The present inventors have discovered a 1,3,4-oxadiazole derivative having histone deacetylase 6 (HDAC6) inhibitory activity for inhibiting or treating HDAC6-mediated diseases and have made the present invention.

1,3,4-oxadiazole derivative

In one general aspect, the present invention provides a 1,3,4-oxadiazole derivative represented by Chemical Formula I below, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[Chemical formula I]

in chemical formula I,

L ₁ , L ₂ and L ₃ are each independently -(C ₀ -C ₂ alkyl)-;

a, b and c are each independently N or CR ₄ {wherein a, b and c cannot both be N and R ₄ is -H, -X or -O(C ₁ -C ₄ alkyl)};

Z is N, O, S or absent {where in the case where Z is absent, R ₂ is also absent and L ₂ and L ₃ are directly related};

R ₁ represents -CH ₂ X or -CX ₃ ;

R ₂ represents -H, - (C ₁ -C ₄ alkyl), -C (=O)-R ^A , -C(=O)-OR ^B or -C(=O)-NR ^C R ^D {where when Z is 0 or S, R ₂ is absent};

R ^A represents -(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 ,

R ^B - R ^D each independently represents -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; Y is N, CH, O or S(=O) ₂ when Y is N or CH, each of R ^Y1 - R ^Y4 independently represents -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, amino protecting group, or

{where at least one H -(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 ₇ cycloalkyl), -C(=O)-(C ₂ -C ₆ heterocycloalkyl) and -S(=O) ₂ -(C ₁ -C ₄ alkyl) may be substituted with -X or -OH; at least one H of aryl, -(C ₁ -C ₄ alkyl)-aryl, heteroaryl and -(C ₁ -C ₄ alkyl)-heteroaryl may be substituted by the group - (C ₁ -C ₄ alkyl), -O-( C ₁ -C ₄ alkyl), -X, -OH or -CF ₃ ; -(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};

when Y is O or S(=O) ₂ , R ^Y1 - R ^Y4 are absent;

m and n are each independently an integer 1, 2 or 3;

R _a - R _d are each independently -H or -(C ₁ -C ₄ alkyl);

R ₃ represents -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 ₆ heterocycloalkyl), -adamantyl, -aryl or -heteroaryl {wherein at least one H -(C ₁ -C ₄ alkyl) may be substituted with -X or -OH; at least one -H -(C ₃ -C ₇ cycloalkyl), -(C ₂ -C ₆ heterocycloalkyl), -adamantyl, -aryl and -heteroaryl may each be independently substituted with a -X, -OH, -(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};

R ^A1 - R ^A6 are each independently -H or -(C ₁ -C ₄ alkyl); And

X represents F, Cl, Br or I.

According to one embodiment of the present invention, in Chemical Formula I above,

L ₁ , L ₂ and L ₃ are each independently -(C ₀ -C ₁ alkyl)-;

a, b and c are each independently N or CR ⁴ {where a, b and c cannot both be N and R ⁴ is -H or -X};

Z is N, O or absent {where in the case where Z is absent, R ₂ is also absent), and L ₂ and L ₃ are directly related};

R ₁ represents -CH ₂ X or -CX ₃ ;

R ₂ is -H, -(C ₁ -C ₄ alkyl) or -C(=O)-R ^A {where when Z is O, R ₂ is absent};

R ^A is -NR ^A1 R ^A2 ,

Y is N, CH, O or S(=O) ₂ ;

when Y is N or CH, each of R ^Y1 -R ^Y4 is 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

{where at least one H - (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 alkyl) may be substituted by -X or -OH; at least one H of aryl and heteroaryl may be replaced by a -(C ₁ -C ₄ alkyl), -O-(C ₁ -C ₄ alkyl), -X, -OH or -CF ₃ group; -(C ₂ -C ₆ heterocycloalkyl) or -heteroaryl may contain N, O or S atoms in the ring; and W represents NH, CH ₂ or O};

when Y is O or S (=O) ₂ , R ^Y1 - R ^Y4 are absent;

m and n are each independently an integer 1 or 2;

R _a - R _d are each independently -H or -(C ₁ -C ₄ alkyl);

R ₃ represents - (C ₃ -C ₇ cycloalkyl), - (C ₂ -C ₆ heterocycloalkyl), -adamantyl, -aryl or -heteroaryl {where at least one -H - (C ₃ -C ₇ cycloalkyl), -(C ₂ -C ₆ heterocycloalkyl), -adamantyl, -aryl and -heteroaryl can each be independently substituted with -X, -OH, -(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;}

R ^A1 - R ^A6 are each independently -H or -(C ₁ -C ₄ alkyl); And

X may be F, Cl or Br.

Moreover, according to another embodiment of the present invention, in Chemical Formula I above,

L ₁ and L ₃ are each independently -(C ₀ alkyl)-;

L ₂ represents -(C ₁ alkyl)-;

a, b and c are each independently CR ₄ {wherein R ₄ is -H or -X};

Z is N, O or absent {where in the case where Z is absent, R ₂ is also absent and L ₂ and L ₃ are directly related};

R ₁ represents -CF ₂ H or CF ₃ ;

R ₂ is -H or -C(=O)-R ^A {where when Z is O, R ₂ is absent};

R _a represents

Y represents N;

R ^Y1 - R ^Y4 are each independently -(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

{where at least one H -(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 alkyl) may be substituted by -X or -OH; -(C ₂ -C ₆ heterocycloalkyl) may contain N, O or S atoms in the ring; and W represents CH ₂ or O};

m and n are each independently an integer 1 or 2;

R _a - R _d are each independently -H or -(C ₁ -C ₄ alkyl);

R ₃ represents -(C ₃ -C ₇ cycloalkyl), -adamantyl, -aryl or -heteroaryl {wherein at least one -H -(C ₃ -C ₇ cycloalkyl), -adamantyl, -aryl and -heteroaryl can each be independently substituted 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)};

R ^A1 - R ^A6 are each independently -H or -(C ₁ -C ₄ alkyl); And

X may be F or Cl.

Moreover, according to yet another embodiment of the present invention, in Chemical Formula I above,

L ₁ , L ₂ or L ₃ are each independently -(C ₀ -C ₁ alkyl)-;

a, b and c are each independently N or CR ⁴ {where a, b and c cannot both be N and R ⁴ is -H or -X};

Z represents N;

R ₁ represents -CH ₂ X or -CX ₃ ;

R ₂ represents -C (=O)-R ^A ;

R ^A represents or

Y is N, CH, O or S(=O) ₂ ;

when Y is N or CH, R ^Y1 and R ^Y3 are each 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

{where at least one H -(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 alkyl) may be substituted by -X or -OH; at least one H of aryl and heteroaryl may be replaced by a -(C ₁ -C ₄ alkyl), -O-(C ₁ -C ₄ alkyl), -X, -OH or -CF ₃ group; -(C ₂ -C ₆ heterocycloalkyl) or -heteroaryl may contain N, O or S atoms in the ring; and W represents NH, CH ₂ or O};

when Y is O or S (=O) ₂ , R ^Y1 and R ^Y3 are absent;

m and n are each independently an integer 1 or 2;

R _a - R _d are each independently -H or -(C ₁ -C ₄ alkyl);

R ₃ represents -C(=O)-O(C ₁ -C ₄ alkyl), -(C ₃ -C ₇ cycloalkyl), -(C ₂ -C ₆ heterocycloalkyl), -adamantyl, -aryl or -heteroaryl { where at least one -H -(C ₃ -C ₇ cycloalkyl), -(C ₂ -C ₆ heterocycloalkyl), -adamantyl, -aryl and -heteroaryl each independently can be substituted by the group -X, -OH, -(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;}

R ^A3 - R ^A6 are each independently -H or -(C ₁ -C ₄ alkyl); And

X may be F, Cl or Br.

Moreover, according to yet another embodiment of the present invention, in Chemical Formula I above,

L ₁ , L ₂ and L ₃ are each independently -(C ₀ -C ₁ alkyl)-;

a, b and c are each independently N or CR ₄ {where a, b and c cannot both be N and R ₄ is -H or -X};

Z represents N;

R ₁ represents -CH ₂ X or -CX ₃ ;

R ₂ represents -C(=O)-R ^A ;

R ^A is -NR ^A1 R ^A2 ,

m and n are each independently an integer 1 or 2;

R _a - R _d are each independently -H or -(C ₁ -C ₄ alkyl);

Y is N, CH, O or S(=O) ₂ ; when Y is N or CH, R ^Y2 and R ^Y4 are each 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 or -heteroaryl { where at least one H -(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 alkyl) may be substituted with -X or -OH; at least one H of aryl and heteroaryl may be replaced by a -(C ₁ -C ₄ alkyl), -O-(C ₁ -C ₄ alkyl), -X, -OH or -CF ₃ group; and -(C ₂ -C ₆ heterocycloalkyl) or -heteroaryl may contain N, O or S} atoms in the ring;

when Y is O or S(=O) ₂ , R ^Y2 and R ^Y4 are absent;

R ₃ represents -C(=O)-O(C ₁ -C ₄ alkyl), -(C ₃ -C ₇ cycloalkyl), -(C ₂ -C ₆ heterocycloalkyl), -adamantyl, -aryl or -heteroaryl { where at least one -H-(C ₃ -C ₇ cycloalkyl), -(C ₂ -C ₆ heterocycloalkyl), -adamantyl, -aryl and -heteroaryl each independently can be substituted by the group -X, -OH, -(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;}

R ^A1 - R ^A6 are each independently -H or -(C ₁ -C ₄ alkyl); And

X may be F, Cl or Br.

Moreover, according to yet another embodiment of the present invention, in Chemical Formula I above,

L ₁ , L ₂ and L ₃ are each independently -(C ₀ -C ₁ alkyl) -;

a, b and c are each independently N or CR ₄ {where a, b and c cannot both be N and R ₄ is -H or -X};

Z is N, O or absent {where in the case where Z is absent, R ₂ is also absent and L ₂ and L ₃ are directly related};

R ₁ represents -CH ₂ X or -CX ₃ ;

R ₂ represents -H, -(C ₁ -C ₄ alkyl) {where when Z represents O, R ₂ represents none};

R ₃ represents -C(=O)-O(C ₁ -C ₄ alkyl), -(C ₃ -C ₇ cycloalkyl), -(C ₂ -C ₆ heterocycloalkyl), -adamantyl, -aryl or -heteroaryl { where at least one -H -(C ₃ -C ₇ cycloalkyl), -(C ₂ -C ₆ heterocycloalkyl), -adamantyl, -aryl and -heteroaryl each independently can be substituted by the group -X, -OH, -(C1 -C4alkyl), -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;}

R ^A5 and R ^A6 are each independently -H or -(C ₁ -C ₄ alkyl); And

X may be F, Cl or Br.

Specific compounds represented by Chemical Formula I according to the present invention are shown in Table 1 below.

According to an embodiment of the present invention, specific compounds represented by Chemical Formula I according to the present invention can be shown in Table 2 below:

According to another embodiment of the present invention, specific compounds represented by Chemical Formula I according to the present invention can be shown in Table 3 below:

According to another embodiment of the present invention, specific compounds represented by Chemical Formula I according to the present invention can be shown in Table 4 below:

In the present invention, a pharmaceutically acceptable salt refers to a salt commonly used in the pharmaceutical industry, for example, may include inorganic ionic salts derived from calcium, potassium, sodium and magnesium and the like, inorganic acid salts derived from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid and sulfuric acid, and the like; organic acid salts derived 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, and the like; sulfonic acid salts derived from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid, and the like; amino acid salts derived from glycine, arginine, lysine, and the like; and amine salts derived from trimethylamine, triethylamine, ammonia, pyridine, picoline, and the like, but the types of salts specified in the present invention are not limited to these salts listed above.

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

The compound represented by chemical formula I according to the present invention may contain one or more asymmetric carbon atoms, thereby being able to exist as a racemate, a racemic mixture, a single enantiomer, a diastereomeric mixture, and each diastereomer. These isomers can be separated using conventional methods, for example, by separating, for example, by column chromatography, HPLC or the like, the compound represented by chemical formula I. Alternatively, stereoisomers of each of the compounds represented by chemical formula I can be stereospecifically synthesized using optically pure starting materials and/or reagents with a known spatial arrangement. Method for producing 1,3,4-oxadiazole derivative The present invention provides a method for producing 1,3,4-oxadiazole derivative represented by chemical formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

In the present invention, the preferred method for preparing the 1,3,4-oxadiazole derivative represented by Chemical Formula I, its optical isomer or a pharmaceutically acceptable salt is the same as in Reaction Schemes 1 to 4 below, which also includes production methods modified in to the extent apparent to those skilled in the art.

[Reaction Scheme 1]

In Reaction Scheme 1, compound 1-1 is reacted with 1,3-dichloropropan-2-one to synthesize the bicyclic compound 1-2, followed by substitution with various functional groups to synthesize compound 1-3, followed by reaction with hydrazine to synthesize the hydrazide compound 1-4. Finally, a cyclization reaction is carried out with difluoroacetic anhydride to synthesize the target compound 1-5.

The compound obtained by the above reaction scheme is compound 3009.

Reaction scheme 2

In Reaction Scheme 2, compound 2-1 is synthesized by protecting compound 1-1, which is then reacted with hydrazine to synthesize hydrazide compound 2-2. To synthesize compound 2-3, a cyclization reaction is carried out with fluoroacetic anhydride, and then the protecting group is removed under acidic conditions to synthesize compound 2-4. By reacting with 1,3-dichloropropan-2-one, bicyclic compound 2-5 is synthesized and reacted with various functional groups to synthesize the target compound 2-6.

The compounds obtained according to the above reaction scheme are compounds 3585, 3586, 3587, 3588, 3589, 3590, 3591, 3592, 3593, 3594, 3595, 3596, 3668, 3669, 3670, 3671, 3672, 673, 3674, 3675, 3676, 3677, 3678, 3679, 3719, 3720, 3721, 3722, 3723, 3724 and 3725.

Reaction scheme 3

Reaction Scheme 3 illustrates 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 containing an acetyl chloride functionality under basic conditions to synthesize Compound 3-3. Deprotected compound 3-4 is synthesized under acidic conditions and reacted with various functional groups to synthesize the target compound 3-5.

The compounds obtained according to the above reaction scheme are compounds 3782, 3783, 4115, 4116, 4117, 4118, 4119, 4120, 4121, 4122, 4123, 4124, 4125, 4126, 4127, 4128, 4129, 130, 4131, 4132, 4137, 4138, 4139, 4140, 4141, 4142, 4143, 4144, 4145, 4146, 4147, 4148, 4150, 4151, 4152, 4153, 4154, 4155, 56, 4157, 4158, 4159, 4160, 4161, 4162, 4163, 4164, 4165, 4166, 4167, 4168, 4169, 4170, 4171, 4172, 4173, 4174, 4175, 4176, 4177, 4188, 4189, 4190, 91, 4192, 4193, 4194, 4195, 4196, 4197, 4198, 4199, 4200, 4201, 4202, 4203, 4204, 4204, 4205, 4206, 4207, 4618 and 4619.

Reaction scheme 4

Reaction Scheme 4 illustrates a method for synthesizing a compound having a urea structure, wherein Compound 2-6 synthesized in Reaction Scheme 2 is reacted with triphosgene and an amine compound under basic conditions to synthesize Compound 4-1. Deprotected compound 4-2 is synthesized under acidic conditions and reacted with various functional groups to synthesize the target compound 4-3.

The compounds obtained according to the above reaction scheme are compounds 3784, 3785, 4033, 4034, 4035, 4036, 4037, 4038, 4039, 4040, 4041, 4042, 4043, 4044, 4045, 4046, 4047, 048, 4049, 4083, 4084, 4085, 4086, 4087, 4088, 4089, 4090, 4091, 4092, 4093, 4094, 4095, 4096, 4097, 4098, 4099, 4100, 4101, 02, 4103, 4620, 4621, 4625 and 6892.

Composition containing 1,3,4-oxadiazole derivatives, its use, and method of treatment using it

The present invention provides a pharmaceutical composition for the prevention or treatment of diseases mediated by histone deacetylase 6, containing as an active ingredient a compound represented by the chemical formula I below, its optical isomer or a pharmaceutically acceptable salt thereof:

[Chemical formula I]

Chemical formula I is the same as defined above.

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

Diseases mediated by histone deacetylase 6 include infectious diseases such as prion disease; neoplasms such as benign tumors (eg, myelodysplastic syndrome) or malignant tumors (eg, multiple myeloma, lymphoma, leukemia, lung cancer, colorectal cancer, colon cancer, prostate cancer, urinary tract epithelial carcinoma, 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; neurological diseases such as central nervous system atrophy (eg, Huntington's disease, spinal muscular atrophy (SMA), spinal cerebellar ataxia (SCA)), neurodegenerative diseases (eg, Alzheimer's disease), movement disorders (eg, Parkinson's disease), neuropathy ( eg, hereditary neuropathy (Charcot-Marie-Tooth disease), sporadic neuropathy, inflammatory neuropathy, drug-induced neuropathy), motor neuropathy (eg, amyotrophic lateral sclerosis (ALS)) or central nervous system demyelination (eg, multiple sclerosis (MS)); diseases of the eyes and adjacent organs, such as uveitis; diseases of the circulatory system, such as atrial fibrillation, stroke and the like; respiratory diseases such as asthma; diseases of the digestive tract such as alcoholic liver disease, inflammatory bowel disease, Crohn's disease, peptic ulcer disease and the like; diseases of the skin and subcutaneous tissues, such as psoriasis; diseases of the musculoskeletal system and connective tissue, such as rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus (SLE) and the like; 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 functions.

The pharmaceutically acceptable salt is the same as described above for the pharmaceutically acceptable salt of the compound represented by Chemical Formula I according to the present invention.

The pharmaceutical composition according to the present invention may further contain one or more pharmaceutically acceptable carriers for administration, in addition to the compound represented by chemical formula I, its optical isomer or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable carrier 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 ingredients, and other conventional additives may be added, if necessary, such as as antioxidants, buffers, bacteriostatic agents and the like. In addition, injectable formulations such as aqueous solutions, suspensions, emulsions and the like, pills, capsules, granules or tablets can be prepared by further adding diluents, dispersants, surfactants, binders and lubricants. Accordingly, the composition according to the present invention may be a patch, liquid, pill, capsule, granule, tablet, suppository or the like. These compositions can be prepared by the usual method used in the art or by the method described in Remington's Pharmaceutical Science (latest edition). Mack Publishing Company, Easton PA, and are prepared in various formulations depending on the respective diseases or ingredients.

The composition of the present invention can be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally or locally) depending on the desired route, and the dosage range varies depending on the patient's body weight, age, gender, health status, nutrition, time of administration, route administration, rate of elimination and severity of the disease and the like. The daily dose of the compound represented by chemical formula I according to the present invention may be from about 1 to 1000 mg/kg, preferably from 5 to 100 mg/kg, and can be administered once a day or divided into several times a day.

The pharmaceutical composition according to the present invention may further contain one or more active ingredients exhibiting the same or similar medicinal effects in addition to the compound represented by Chemical Formula I above, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

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

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

Moreover, 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 a mammal, including a human.

The method of preventing or treating diseases mediated by histone deacetylase 6 according to the present invention also includes administering a compound represented by chemical formula I to treat the disease itself before the onset of a symptom, as well as to inhibit or prevent a symptom thereof. When treating a disease, the prophylactic or therapeutic dose of a particular active ingredient may vary depending on the nature and severity of the disease or condition, as well as the route of administration of the active ingredient. Dosage and frequency will vary depending on the age, body weight, and response of individual patients. A suitable dosage regimen can be readily selected by one of ordinary skill in the art, taking these factors into account. In addition, the method of preventing or treating diseases mediated by histone deacetylase 6 according to the present invention may further comprise administering a therapeutically effective amount of an additional active agent suitable for treating the disease together with a compound represented by Chemical Formula I, wherein the additional active agent may exhibit synergistic or auxiliary effect together with the compound represented by chemical formula I.

The present invention is also directed to providing the use of the compound represented by chemical formula I above, its optical isomer or a pharmaceutically acceptable salt thereof for the preparation of a drug for the treatment of diseases mediated by histone deacetylase 6. The compound represented by chemical formula I above for the production of a drug can be mixed with suitable adjuvants, diluents, carriers and the like, and can be formulated with other active agents to provide a synergistic effect of the active ingredients.

The entities mentioned in the applications, compositions and methods of treatment according to the present invention are used equally if they are incompatible with each other.

[Advantages of the invention]

The compound represented by chemical formula I above according to the present invention, its optical isomer or a pharmaceutically acceptable salt thereof, is capable of selectively inhibiting histone deacetylase 6 (HDAC6), thereby exerting a remarkably excellent preventive or therapeutic effect on HDAC6-mediated diseases.

[Best Implementation]

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

Preparation of 1,3,4-oxadiazole derivatives according to the present invention

A specific method for producing the compound represented by Chemical Formula I is as follows.

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

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

Methyl 2-aminoisonicotinate (1.000 g, 6.572 mmol) and 1,3-dichloropropan-2-one (1.085 g, 8.544 mmol) were dissolved in ethanol (5 ml)/1,2-dimethoxyethane (6 ml), and the resulting solution stirred at room temperature for 1 hour and then stirred at 90°C for 16 hours. The temperature was then lowered to room temperature to complete the reaction. Water was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane = 5% to 70%) and concentrated to give the title compound (0.200 g, 13.5%) as a beige solid.

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

Methyl 2-(chloromethyl)-imidazo[1,2-a]pyridine-7-carboxylate (0.200 g, 0.890 mmol) obtained in step 1, phenylboronic acid (0.217 g, 1.781 mmol), bis-((triphenyl) dichloride )-phosphine)-palladium(II) (Pd(PPh ₃ ) ₂ Cl ₂ , 0.062 g, 0.089 mmol) and potassium carbonate (0.369 g, 2.671 mmol) were dissolved in 1,4-dioxane (8 ml)/water (2 ml) at room temperature and the resulting solution was stirred at 105°C for 16 hours. The temperature was then lowered to room temperature to complete the reaction. Water was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane = 5% to 70%) and concentrated to give the title compound (0.076 g, 32.1%) as a white solid.

[Step 3] Synthesis of 2-benzylimidazo[1,2-a]pyridine-7-carbohydrazide

Methyl 2-benzylimidazo[1,2-a]pyridine-7-carboxylate (0.075 g, 0.282 mmol) obtained in step 2 and hydrazine monohydrate (0.068 ml, 1.408 mmol) were dissolved in ethanol (5 ml) at room temperature and the resulting solution was refluxed for 16 hours. The temperature was then lowered to room temperature to complete the reaction. The reaction mixture was poured with water, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure to obtain the title compound (0.074 g, 98.7%) as a white solid colors.

[Step 4] Synthesis of compound 3009

2-benzylimidazo[1,2-a]pyridine-7-carbohydrazide (0.065 g, 0.244 mmol) obtained in step 3 and imidazole (0.050 g, 0.732 mmol) were dissolved in dichloromethane (5 ml), and added at room temperature 2,2-difluoroacetic anhydride (0.152 ml, 1.220 mmol), and refluxed for 16 hours. The temperature was then lowered to room temperature to complete the reaction. Water was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 4 g; ethyl acetate/hexane = 5% to 60%) and concentrated to give the title compound (0.030 g, 37.7%) as a bright red solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (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=51.7 Hz, 1H), 4.22 (s, 2H);

MSNR (ER) m/z 327.2 (M ⁺ +1).

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

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

Methyl 2-aminoisonicotinate (20.000 g, 131.449 mmol) and di-tert-butyl dicarbonate (37.295 g, 170.884 mmol) were dissolved in tert-butanol (800 ml) at room temperature. The resulting solution was stirred at 60°C for 16 hours, and then the temperature was lowered to room temperature to stop the reaction. The precipitated solid was filtered, washed with ethanol and dried to give the title compound (26,000 g, 78.4%) as a white solid.

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

Methyl 2-((tert-butoxycarbonyl-)amino)-isonicotinate (26.000 g, 103.064 mmol) obtained 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 resulting product, then filtered through a plastic filter to obtain an organic layer, and the resulting organic layer was concentrated to obtain the target compound (25,000 g, 96.2%) as a white solid.

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

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

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

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

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

4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-pyridin-2-amine (7.500 g, 35.351 mmol) obtained in step 4, 1,3-dichloropropan-2-one ( 6.732 g, 53.026 mmol) and sodium hydrogen carbonate (14.848 g, 176.753 mmol) were dissolved in 1,4-dioxane (250 ml) at room temperature. The reaction mixture was refluxed for 16 hours and then 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 cartridge, 80 g; ethyl acetate/hexane = 10 to 90%) and concentrated to give the title compound (7,000 g, 69.6% ) in the form of a beige solid.

[Step 6] Synthesis of compound 3585

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) obtained in step 5, (3-fluorophenyl)-boronic acid (0.049 g, 0.351 mmol), bis-(triphenylphosphine)-palladium (II) dichloride (Pd(PPh ₃ ) ₂ Cl ₂ , 0.012 g, 0.018 mmol) and potassium carbonate (0.073 g, 0.527 mmol) was dissolved in 1,4-dioxane (4 ml)/water (1 ml) at room temperature, and the resulting solution was stirred at 100°C for 1 hour. The temperature was then lowered to room temperature to complete 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 cartridge, 4 g; ethyl acetate/hexane = 0% to 70%) and concentrated to give the title compound (0.023 g, 38.0%) as a pink solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.27-8.19 (m, 1H), 8.10 (dd, J=7.1, 1.0 Hz, 1H), 7.44 (dd, J=7.1, 1.7 Hz, 1H), 7.34 (s, 1H), 7.23 (td, J=8.0, 6.0 Hz, 1H), 7.05 (dt, J =7.6, 1.2 Hz, 1H), 7.00-6.70 (m, 3H), 4.13 (s, 2H);

MSNR (ER) m/z 345.9 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) prepared in step 5 of example 2, (4-fluorophenyl)-boronic acid (0.049 g, 0.351 mmol), bis-(triphenylphosphine)-palladium (II) dichloride (Pd(PPh ₃ ) ₂ Cl ₂ , 0.012 g, 0.018 mmol) and potassium carbonate (0.073 g, 0.527 mmol) was dissolved in 1,4-dioxane (4 ml)/water (1 ml) at room temperature, and the resulting solution was stirred at 100°C for 1 hour. The temperature was then lowered to room temperature to complete 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 cartridge, 4 g; ethyl acetate/hexane = 0% to 70%) and concentrated to give the title compound (0.030 g, 49.6%) as a pink solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37-8.29 (m, 1H), 8.18 (dd, J=7.1, 1.0 Hz, 1H), 7.53 (dd, J=7.1, 1.7 Hz, 1H), 7.39 (d, J=0.9 Hz, 1H), 7.36-7.30 (m, 2H), 7.10-6.81 (m, 3H), 4.20 (s, 2H);

MSNR (ER) m/z 346.0 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) prepared in step 5 of example 2, (3,4-difluorophenyl)-boronic acid (0.055 g, 0.351 mmol), bis-(triphenylphosphine)-palladium (II) dichloride (Pd(PPh ₃ ) ₂ Cl ₂ , 0.012 g, 0.018 mmol) and potassium carbonate (0.073 g, 0.527 mmol) was dissolved in 1,4-dioxane (4 ml)/water (1 ml) at room temperature, and the resulting solution was stirred at 100°C for 1 hour. The temperature was then lowered to room temperature to complete 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 cartridge, 4 g; ethyl acetate/hexane = 0% to 70%) and concentrated to give the title compound (0.033 g, 51.9%) as a pink solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38-8.29 (m, 1H), 8.21 (dd, J=7.1, 1.0 Hz, 1H), 7.55 (dd, J=7.1, 1.7 Hz, 1H), 7.45 (s, 1H), 7.21-6.81 (m, 4H), 4.19 (s, 2H);

MSNR (ER) m/z 364.0 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) prepared in step 5 of example 2, (2,4-difluorophenyl)-boronic acid (0.055 g, 0.351 mmol), bis-(triphenylphosphine)-palladium (II) dichloride (Pd(PPh ₃ ) ₂ Cl ₂ , 0.012 g, 0.018 mmol) and potassium carbonate (0.073 g, 0.527 mmol) was dissolved in 1,4-dioxane (4 ml)/water (1 ml) at room temperature, and the resulting solution was stirred at 100°C for 1 hour. The temperature was then lowered to room temperature to complete 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 cartridge, 4 g; ethyl acetate/hexane = 0% to 70%) and concentrated to give the title compound (0.031 g, 48.7%) as a pink solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37-8.29 (m, 1H), 8.20 (dd, J=7.1, 1.0 Hz, 1H), 7.54 (dd, J=7.1, 1.7 Hz, 1H), 7.47 (s, 1H), 7.37 (td, J=8.7, 8.3, 6.4 Hz, 1H), 7.11 -6.80 (m, 3H), 4.22 (s, 2H);

MSNR (ER) m/z 364.0 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) prepared in step 5 of example 2, p-tolylboronic acid (0.048 g, 0.351 mmol), bis-(triphenylphosphine)-palladium (II) dichloride (Pd(PPh ₃ ) ₂ Cl ₂ , 0.012 g, 0.018 mmol) and potassium carbonate (0.073 g, 0.527 mmol ) was dissolved in 1,4-dioxane (4 ml)/water (1 ml) at room temperature, and the resulting solution was stirred at 100°C for 1 hour. The temperature was then lowered to room temperature to complete 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 cartridge, 4 g; ethyl acetate/hexane = 0% to 70%) and concentrated to give the title compound (0.028 g, 46.8%) as a pink solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39-8.28 (m, 1H), 8.15 (dd, J=7.1, 1.0 Hz, 1H), 7.51 (dd, J=7.1, 1.7 Hz, 1H), 7.37 (t, J=0.8 Hz, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.19- 7.15 (m, 2H), 6.95 (t, J=51.7 Hz, 1H), 4.20 (s, 2H), 2.37 (s, 3H);

MSNR (ER) m/z 341.3 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) prepared in step 5 of example 2, (4-methoxyphenyl)-boronic acid (0.053 g, 0.351 mmol), bis-(triphenylphosphine)-palladium (II) dichloride (Pd(PPh ₃ ) ₂ Cl ₂ , 0.012 g, 0.018 mmol) and potassium carbonate (0.073 g, 0.527 mmol) was dissolved in 1,4-dioxane (4 ml)/water (1 ml) at room temperature, and the resulting solution was stirred at 100°C for 1 hour. The temperature was then lowered to room temperature to complete the reaction. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified by chromatography (SiO ₂ plate, 20 x 20 x 1 mm; ethyl acetate/hexane = 0% to 70%) and concentrated to give the title compound (0.015 g, 24. 0%) in the form of a pink solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29-8.16 (m, 1H), 8.06 (dd, J=7.1, 1.0 Hz, 1H), 7.41 (dd, J=7.1, 1.7 Hz, 1H), 7.19 (t, J=4.3 Hz, 3H), 7.00-6.71 (m, 3H), 4.08 (s, 2H ), 3.73 (s, 3H);

MSNR (ER) m/z 356.9 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) prepared in step 5 of example 2, (4-(trifluoromethyl)-phenyl)-boronic acid (0.067 g, 0.351 mmol), bis-(triphenylphosphine)-palladium (II) dichloride (Pd(PPh ₃ ) ₂ Cl ₂ , 0.012 g, 0.018 mmol) and Potassium carbonate (0.073 g, 0.527 mmol) was dissolved in 1,4-dioxane (4 ml)/water (1 ml) at room temperature, and the resulting solution was stirred at 100°C for 1 hour.

The temperature was then lowered to room temperature to complete the reaction. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; ethyl acetate/hexane = 0% to 70%) and concentrated to give the title compound (0.029 g, 41.9 %) in the form of a pink solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.40-8.27 (m, 1H), 8.20 (dd, J=7.1, 0.9 Hz, 1H), 7.61 (d, J=8.0 Hz, 2H), 7.54 (dd, J=7.1, 1.7 Hz, 1H), 7.48 (d, J=8.0 Hz, 2H), 7.44 ( s, 1H), 6.96 (t, J=51.7 Hz, 1H), 4.28 (s, 2H);

MSNR (ER) m/z 394.7 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) prepared in step 5 of example 2, (4-acetylphenyl)-boronic acid (0.058 g, 0.351 mmol), bis-(triphenylphosphine)-palladium (II) dichloride (Pd(PPh ₃ ) ₂ Cl ₂ , 0.012 g, 0.018 mmol) and potassium carbonate (0.073 g, 0.527 mmol) was dissolved in 1,4-dioxane (4 ml)/water (1 ml) at room temperature, and the resulting solution was stirred at 100°C for 1 hour. The temperature was then lowered to room temperature to complete the reaction. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; ethyl acetate/hexane = 0% to 70%) and concentrated to give the title compound (0.021 g, 32.5 %) in the form of a pink solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35-8.30 (m, 1H), 8.19 (dd, J=7.1, 1.0 Hz, 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=51.7 Hz, 1H), 4.29 (s, 2H), 2.62 (s, 3H);

MSNR (ER) m/z 369.3 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) prepared in step 5 of example 2, (4-fluorophenyl)-boronic acid (0.055 g, 0.351 mmol), bis-(triphenylphosphine)-palladium (II) dichloride (Pd(PPh ₃ ) ₂ Cl ₂ , 0.012 g, 0.018 mmol) and potassium carbonate (0.073 g, 0.527 mmol) was dissolved in 1,4-dioxane (4 ml)/water (1 ml) at room temperature, and the resulting solution was stirred at 100°C for 1 hour. The temperature was then lowered to room temperature to complete the reaction. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; ethyl acetate/hexane = 0% to 70%) and concentrated to give the title compound (0.012 g, 18.9 %) in the form of a pink solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (dt, J=1.7, 0.8 Hz, 1H), 8.18 (dd, J=7.1, 0.9 Hz, 1H) , 7.52 (dd, J=7.1, 1.7 Hz, 1H), 7.39 (kb, J=0.8 Hz, 1H), 7.35-7.27 (m, 4H), 6.95 (t, J=51.7 Hz, 1H), 4.19 (s, 2H);

MSNR (ER) m/z 362.9 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) prepared in step 5 of example 2, (3-isopropylphenyl)-boronic acid (0.058 g, 0.351 mmol), bis-(triphenylphosphine)-palladium (II) dichloride (Pd(PPh ₃ ) ₂ Cl ₂ , 0.012 g, 0.018 mmol) and potassium carbonate (0.073 g, 0.527 mmol) was dissolved in 1,4-dioxane (4 ml)/water (1 ml) at room temperature, and the resulting solution was stirred at 100°C for 1 hour. The temperature was then lowered to room temperature to complete the reaction. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; ethyl acetate/hexane = 0% to 70%) and concentrated to give the title compound (0.032 g, 49.5 %) in the form of a pink solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (s, 1H), 8.17 (dd, J=7.1, 0.9 Hz, 1H), 7.52 (dd, J=7, 1, 1.7 Hz, 1H), 7.37 (d, J=0.8 Hz, 1H), 7.32-7.26 (m, 1H), 7.23 (d, J=1.8 Hz, 1H), 7.20-7.13 (m, 2H), 6.95 (t, J=51.7 Hz, 1H), 4.22 (s, 2H), 2.92 (p, J =6.9 Hz, 1H), 1.28 (d, J=6.9 Hz, 6H);

MSNR (ER) m/z 370.0 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) prepared in step 5 of example 2, (4-(methylsulfonyl)-phenyl)-boronic acid (0.070 g, 0.351 mmol), bis-(triphenylphosphine)-palladium (II) dichloride (Pd(PPh ₃ ) ₂ Cl ₂ , 0.012 g, 0.018 mmol) and Potassium carbonate (0.073 g, 0.527 mmol) was dissolved in 1,4-dioxane (4 ml)/water (1 ml) at room temperature, and the resulting solution was stirred at 100°C for 1 hour.

The temperature was then lowered to room temperature to complete the reaction. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.033 g, 46.5 %) in the form of a pink solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (dt, J=1.7, 0.8 Hz, 1H), 8.22 (dd, J=7.1, 0.9 Hz, 1H) , 7.95-7.87 (m, 2H), 7.56 (td, J=6.6, 1.8 Hz, 3H), 7.49 (d, J=0.8 Hz, 1H), 6.96 (t, J=51.7 Hz, 1H), 4.31 (s, 2H), 3.06 (s, 3H);

MSNR (ER) m/z 405.1 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) prepared in step 5 of example 2, benzo[d][1,3]dioxol-5-ylboronic acid (0.058 g, 0.351 mmol), bis-(triphenylphosphine)-palladium (II) dichloride (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) at room temperature, and the resulting solution was stirred at 100°C for 1 hour.

The temperature was then lowered to room temperature to complete the reaction. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.041 g, 63.0 %) in the form of a pink solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (d, J=1.6 Hz, 1H), 8.18 (dd, J=7.1, 1.0 Hz, 1H), 7.52 (dd, J=7.1, 1.7 Hz, 1H), 7.41 (s, 1H), 7.10-6.77 (m, 4H), 5.96 (s, 2H), 4, 15 (s, 2H);

MSNR (ER) m/z 372.0 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) prepared in step 5 of example 2, aniline (0.024 ml, 0.263 mmol), potassium carbonate (0.036 g, 0.263 mmol) and potassium iodide (0.015 g, 0.088 mmol) were dissolved in N,N-dimethylformamide (3 ml) at room temperature and the resulting solution was stirred at that same temperature for 18 hours. A saturated aqueous solution of ammonium chloride was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The resulting product was then filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 4 g; ethyl acetate/hexane = 0% to 70%) and concentrated to give the title compound (0.050 g, 83.4%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (dt, J=1.7, 0.8 Hz, 1H), 8.21 (dd, J=7.2, 1.0 Hz, 1H) , 7.68 (d, J=0.9 Hz, 1H), 7.54 (dd, J=7.1, 1.7 Hz, 1H), 7.25-7.18 (m, 2H), 6.96 (t, J=51.7 Hz, 1H), 6.80-6.70 (m, 3H), 4.62 (d, J=0.8 Hz, 2H);

MSNR (ER) m/z 342.9 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) prepared in step 5 of example 2, 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) were dissolved in N,N-dimethylformamide (3 ml) at room temperature, and the resulting solution stirred at the same temperature for 18 hours. A saturated aqueous solution of ammonium chloride was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The resulting product was then filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 4 g; ethyl acetate/hexane = 0% to 70%) and concentrated to give the title compound (0.040 g, 59.4%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38-8.29 (m, 1H), 8.24 (dd, J=7.1, 1.0 Hz, 1H), 7.74-7, 67 (m, 1H), 7.57 (dd, J=7.1, 1.7 Hz, 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);

MSNR (ER) m/z 385.0 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) prepared in step 5 of example 2,3-fluoroaniline (0.036 g, 0.263 mmol), potassium carbonate (0.036 g, 0.263 mmol) and potassium iodide (0.015 g, 0.088 mmol) were dissolved in N,N-dimethylformamide (3 ml) at room temperature, and the resulting solution stirred at the same temperature for 18 hours. A saturated aqueous solution of ammonium chloride was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The resulting product was then filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 4 g; ethyl acetate/hexane = 0% to 70%) and concentrated to give the title compound (0.040 g, 59.4%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (dt, J=1.7, 0.8 Hz, 1H), 8.23 (dd, J=7.1, 1.0 Hz, 1H) , 7.68 (d, J=0.8 Hz, 1H), 7.57 (dd, J=7.1, 1.7 Hz, 1H), 7.18-6.76 (m, 2H), 6.54-6.32 (m, 3H), 4.59 (d, J=0.8 Hz, 2H);

MSNR (ER) m/z 360.9 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) prepared in step 5 of example 2,3,4-difluoroaniline (0.029 g, 0.263 mmol), potassium carbonate (0.036 g, 0.263 mmol) and potassium iodide (0.015 g, 0.088 mmol) were dissolved in N,N-dimethylformamide (3 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of ammonium chloride was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The resulting product was then filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 4 g; ethyl acetate/hexane = 0% to 70%) and concentrated to give the title compound (0.024 g, 38.0%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 8.27 (dd, J=7.1, 1.0 Hz, 1H), 7.69 (d, J=0, 8 Hz, 1H), 7.63 (dd, J=7.1, 1.7 Hz, 1H), 7.11-6.80 (m, 2H), 6.52 (dd, J=12.5 , 6.6, 2.9 Hz, 1H), 6.42 (ddd, J=8.9, 3.2, 1.6 Hz, 1H), 4.57 (d, J=0.8 Hz, 2H);

MSNR (ER) m/z 378.1 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) prepared in step 5 of example 2,3-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) were dissolved in N,N-dimethylformamide (3 ml) at room temperature , and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of ammonium chloride was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The resulting product was then filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 4 g; ethyl acetate/hexane = 0% to 70%) and concentrated to give the title compound (0.041 g, 59.3%) as a yellow solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.37 (d, J=1.5 Hz, 1H), 8.26 (dd, J=7.1, 1.0 Hz, 1H), 7.69 (d, J=0.8 Hz, 1H), 7.62 (dd, J=7.1, 1.7 Hz, 1H), 7.10-6.80 (m, 2H), 6.73 ( dd, J=6.0, 2.9 Hz, 1H), 6.57 (dd, J=8.9, 3.8, 2.9 Hz, 1H), 4.57 (d, J=0, 8 Hz, 2H);

MSNR (ER) m/z 396.0 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) prepared in step 5 of example 2,4-(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) were dissolved in N,N-dimethylformamide (3 ml) at room temperature , and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of ammonium chloride was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The resulting product was then filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 4 g; ethyl acetate/hexane = 0% to 70%) and concentrated to give the title compound (0.029 g, 40.3%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.36 (dt, J=1.6, 0.7 Hz, 1H), 8.25 (dd, J=7.1, 1.0 Hz, 1H) , 7.68 (d, J=0.7 Hz, 1H), 7.60 (dd, J=7.1, 1.7 Hz, 1H), 7.47-7.39 (m, 2H), 6.97 (t, J=51.7 Hz, 1H), 6.74 (d, J=8.6 Hz, 2H), 4.66 (s, 2H);

MSNR (ER) m/z 411.0 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) prepared in step 5 of example 2,4-(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) were dissolved in N,N-dimethylformamide (3 ml) at room temperature , and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of ammonium chloride was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The resulting product was then filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 4 g; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.034 g, 46.2%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (dt, J=1.7, 0.8 Hz, 1H), 8.26 (dd, J=7.1, 1.0 Hz, 1H) , 7.76-7.71 (m, 2H), 7.69 (d, J=0.8 Hz, 1H), 7.58 (dd, J=7.2, 1.7 Hz, 1H), 6.97 (t, J=51.7 Hz, 1H), 6.79-6.71 (m, 2H), 4.66 (d, J=4.3 Hz, 2H), 3.02 (s , 3H);

MSNR (ER) m/z 420.3 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) prepared in step 5 of example 2, pyridin-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) were dissolved in N,N-dimethylformamide (3 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of ammonium chloride was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The resulting product was then filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 4 g; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.037 g, 61.5%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (dt, J=1.7, 0.8 Hz, 1H), 8.24 (dd, J=7.1, 1.0 Hz, 1H) , 8.19 (d, J=2.8 Hz, 1H), 8.05-7.99 (m, 1H), 7.70 (s, 1H), 7.56 (dd, J=7.1 , 1.7 Hz, 1H), 7.17-6.82 (m, ZN), 4.62 (s, 2H);

MSNR (ER) m/z 343.1 (M ⁺ +1).

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-fluoropyridine-3-amine

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) prepared in step 5 of example 2,6-fluoropyridin-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) were dissolved in N,N-dimethylformamide (3 ml) at room temperature , and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of ammonium chloride was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The resulting product was then filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 4 g; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.033 g, 52.1%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35 (dt, J=1.7, 0.9 Hz, 1H), 8.26 (dd, J=7.1, 1.0 Hz, 1H) , 7.73-7.68 (m, 1H), 7.66 (dd, J=3.1, 1.9 Hz, 1H), 7.60 (dd, J=7.1, 1.7 Hz , 1H), 7.16 (ddd, J=8.8, 6.7, 3.1 Hz, 1H), 6.97 (t, J=51.7 Hz, 1H), 6.79 (ddd, J=8.7, 3.4, 0.6 Hz, 1H), 4.59 (s, 2H);

MSNR (ER) m/z 362.1 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) prepared in step 5 of example 2, (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) were added to N,N-dimethylformamide ( 3 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of ammonium chloride was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The resulting product was then filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 25%) and concentrated to give the title compound (0.023 g, 32.8%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (p, J=0.8 Hz, 1H), 8.23 (dd, J=7.1, 0.9 Hz, 1H), 7.84 (s, 1H), 7.50 (dd, J=7.1, 1.7 Hz, 1H), 6.95 (t, J=51.7 Hz, 1H), 4.10 (s, 2H) , 2.18-2.09 (m, 3H), 1.84 (d, J=2.9 Hz, 6H), 1.70 (kv, J=12.8 Hz, 6H);

MSNR (ER) m/z 399.8 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) prepared in step 5 of example 2, cyclohexanamine (0.026 g, 0.263 mmol), potassium carbonate (0.036 g, 0.263 mmol) and potassium iodide (0.015 g, 0.088 mmol) were dissolved in N,N-dimethylformamide (3 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of ammonium chloride was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The resulting product was then filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 25%) and concentrated to give the title compound (0.024 g, 39.3%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.30 (dt, J=1.7, 0.8 Hz, 1H), 8.24 (dd, J=7.1, 0.9 Hz, 1H) , 7.74 (s, 1H), 7.53 (dd, J=7.1, 1.7 Hz, 1H), 6.96 (t, J=51.7 Hz, 1H), 4.09 ( s, 2H), 2.61 (tt, J=10.0, 3.7 Hz, 1H), 2.39 (s, 1H), 2.01 (d, J=12.0 Hz, 2H), 1.85-1.71 (m, 2H), 1.70-1.59 (m, 1H), 1.39-1.13 (m, 4H);

MSNR (ER) m/z 347.7 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) prepared in step 5 of example 2, 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) were dissolved in N,N-dimethylformamide (3 ml) at room temperature, and the resulting solution stirred at the same temperature for 18 hours. A saturated aqueous solution of ammonium chloride was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The resulting product was then filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 4 g; ethyl acetate/hexane = 0% to 70%) and concentrated to give the title compound (0.032 g, 51.3%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (p, J=0.8 Hz, 1H), 8.19 (dd, J=7.1, 1.0 Hz, 1H), 7.67 (d, J=0.9 Hz, 1H), 7.52 (dd, J=7.1, 1.7 Hz, 1H), 7.14-6.77 (m, 2H), 6.63- 6.50 (m, 3H), 4.60 (d, J=0.9 Hz, 2H), 2.29 (s, 3H);

MSNR (ER) m/z 356.2 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.040 g, 0.141 mmol) prepared in step 5 of example 2, phenol (0.019 ml, 0.211 mmol) and potassium carbonate (0.039 g, 0.281 mmol) were dissolved in N,N-dimethylformamide (2 ml) at room temperature, and the resulting solution was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The resulting product was then filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; ethyl acetate/hexane = 0% to 50%) and concentrated to give the title compound (0.032 g, 66.5%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (d, J=1.6 Hz, 1H), 8.28 (dd, J=7.1, 1.0 Hz, 1H), 7.86 -7.79 (m, 1H), 7.60 (dd, J=7.1,1.7 Hz, 1H), 7.38-7.30 (m, 2H), 7.12-6.81 (m, 4H), 5.39-5.35 (m, 2H);

MSNR (ER) m/z 342.7 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.040 g, 0.141 mmol) prepared in step 5 of example 2, m-cresol (0.023 g, 0.211 mmol) and potassium carbonate (0.039 g, 0.281 mmol) were dissolved in N,N-dimethylformamide (2 ml) at room temperature, and the resulting solution was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The resulting product was then filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; ethyl acetate/hexane = 0% to 50%) and concentrated to give the title compound (0.037 g, 73.9%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (dd, J=1.8, 0.9 Hz, 1H), 8.27 (dd, J=7.2, 1.0 Hz, 1H) , 7.82 (d, J=0.9 Hz, 1H), 7.59 (dd, J=7.1, 1.7 Hz, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.12-6.78 (m, 4H), 5.36 (d, J=0.8 Hz, 2H), 2.37 (s, 3H);

MSNR (ER) m/z 356.7 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.040 g, 0.141 mmol) prepared in step 5 of example 2, 1-(3-hydroxyphenyl)-ethan-1-one (0.029 g, 0.211 mmol) and potassium carbonate (0.039 g, 0.281 mmol) were dissolved in N,N-dimethylformamide (2 ml) at room temperature, and the resulting solution stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The resulting product was then filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; ethyl acetate/hexane = 0% to 50%) and concentrated to give the title compound (0.010 g, 18.5%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (dt, J=1.7, 0.8 Hz, 1H), 8.19 (dd, J=7.1, 1.0 Hz, 1H) , 7.91-7.86 (m, 2H), 7.74 (d, J=0.8 Hz, 1H), 7.50 (dd, J=7.1, 1.7 Hz, 1H), 7.05-6.74 (m, 3H), 5.33 (d, J=0.7 Hz, 2H), 2.50 (s, 3H);

MSNR (ER) m/z 384.8 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.040 g, 0.141 mmol) prepared in step 5 of example 2,3-fluorophenol (0.024 g, 0.211 mmol) and potassium carbonate (0.039 g, 0.281 mmol) were dissolved in N,N-dimethylformamide (2 ml) at room temperature, and the resulting solution was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The resulting product was then filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; ethyl acetate/hexane = 0% to 50%) and concentrated to give the title compound (0.036 g, 71.1%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (dt, J=1.7, 0.8 Hz, 1H), 8.29 (dd, J=7.1, 0.9 Hz, 1H) , 7.83 (t, J=0.8 Hz, 1H), 7.61 (dd, J=7.1, 1.7 Hz, 1H), 7.28 (d, J=6.9 Hz, 1H), 7.11-6.68 (m, 4H), 5.35 (d, J=0.8 Hz, 2H);

MSNR (ER) m/z 360.7 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.040 g, 0.141 mmol) prepared in step 5 of example 2,3,4-difluorophenol (0.027 g, 0.211 mmol) and potassium carbonate (0.039 g, 0.281 mmol) were dissolved in N,N-dimethylformamide (2 ml) at room temperature, and the resulting solution was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The resulting product was then filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; ethyl acetate/hexane = 0% to 50%) and concentrated to give the title compound (0.032 g, 60.2%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (dt, J=1.7, 0.8 Hz, 1H), 8.29 (dd, J=7.1, 1.0 Hz, 1H) , 7.82 (d, J=0.8 Hz, 1H), 7.60 (dd, J=7.1, 1.7 Hz, 1H), 7.15-6.73 (m, 4H), 5.30 (d, J=0.8 Hz, 2H);

MSNR (ER) m/z 378.7 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.040 g, 0.141 mmol) prepared in step 5 of example 2,4-(trifluoromethyl)phenol (0.034 g, 0.211 mmol) and potassium carbonate (0.039 g, 0.281 mmol) were dissolved in N,N-dimethylformamide (2 ml) at room temperature, and the resulting solution was stirred at the same temperature in within 2 hours. A saturated aqueous solution of ammonium chloride was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The resulting product was then filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; ethyl acetate/hexane = 0% to 50%) and concentrated to give the title compound (0.051 g, 88.5%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33-8.28 (m, 1H), 8.20 (dd, J=7.1, 1.0 Hz, 1H), 7.74 (d, J=0.8 Hz, 1H), 7.52 (ddd, J=10.9, 8.1, 1.3 Hz, 3H), 7.08-6.71 (m, 3H), 5.33 (d, J=0.8 Hz, 2H);

MSNR (ER) m/z 410.7 (M ⁺ +1).

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

2-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.176 mmol) prepared in step 5 of example 2, 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) were dissolved in N,N-dimethylformamide (3 ml) at room temperature, and the resulting solution stirred at the same temperature for 18 hours. A saturated aqueous solution of ammonium chloride was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The resulting product was then filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; hexane/ethyl acetate = 0% to 50%) and concentrated to give the title compound (0.051 g, 81.7%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (dt, J=1.7, 0.9 Hz, 1H), 8.15 (dd, J=7.1, 1.0 Hz, 1H) , 7.53-7.48 (m, 2H), 7.30-7.23 (m, 2H), 7.10-6.75 (m, 4H), 4.80 (d, J=0, 9 Hz, 2H), 3.16 (s, 3H);

MSNR (ER) m/z 355.7 (M ⁺ +1).

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

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

1-(tert-butoxycarbonyl)-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 were added (0.007 ml, 0.087 mmol) 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.

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

To a solution in which N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-aniline (0.200 g, 0.586 mmol) obtained 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) was added. obtained in step 1, and triethylamine (0.245 ml, 1.758 mmol), and stirred at room temperature for 16 hours. A saturated aqueous solution of ammonium chloride 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 cartridge, 12 g; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (0.200 g, 61.8%) as a yellow solid.

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

Tert-butyl-4-(((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-( Phenyl)-carbamoyl)-piperidine-1-carboxylate (0.120 g, 0.217 mmol) obtained in step 2 and trifluoroacetic acid (0.333 ml, 4.343 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. A saturated aqueous solution of sodium hydrogen carbonate 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 give the title compound (0.098 g, 99.7%) as a brown gel without further purification.

[Step 4] Synthesis of compound 3782

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylpiperidin-4- carboxamide (0.050 g, 0.111 mmol) obtained in step 3, formaldehyde (0.007 g, 0.221 mmol), acetic acid (0.006 ml, 0.111 mmol) and sodium triacetoxyborohydride (0.070 g, 0.332 mmol) were dissolved in dichloromethane (3 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate 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 (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.038 g, 73.7%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.29 (dt, J=1.7, 0.8 Hz, 1H), 8.23 (dd, J=7.1, 1.0 Hz, 1H) , 7.78 (s, 1H), 7.53 (dd, J=7.1, 1.7 Hz, 1H), 7.46-7.36 (m, 3H), 7.27-7.21 (m, 2H), 6.95 (t, J=51.7 Hz, 1H), 5.04 (s, 2H), 2.89 (s, 2H), 2.25 (s, 4H), 1 .93 (kv, J=11.6, 11.0 Hz, 3H), 1.71 (s, 3H);

MSNR (ER) m/z 468.1 (M ⁺ +1).

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-(oxetan-3-yl)-N-phenylpiperidin-4-carboxamide

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylpiperidin-4- carboxamide (0.050 g, 0.111 mmol) obtained in step 3 of Example 33, oxetan-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) were dissolved in dichloromethane (3 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium hydrogen carbonate 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 (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.042 g, 74.7%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.29 (dt, J=1.6, 0.8 Hz, 1H), 8.23 (dd, J=7.1, 0.9 Hz, 1H) , 7.79 (s, 1H), 7.53 (dd, J=7.1, 1.7 Hz, 1H), 7.46-7.33 (m, 3H), 7.27-7.22 (m, 2H), 6.95 (t, J=51.7 Hz, 1H), 5.04 (s, 2H), 4.59 (d, J=6.6 Hz, 4H), 3.38 (s, 1H), 2.70 (s, 2H), 2.25 (d, J=12.0 Hz, 1H), 1.92 (kv, J=11.8, 11.2 Hz, 2H) , 1.67 (s, 4H);

MSNR (ER) m/z 508.9 (M ⁺ +1).

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

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-aniline (0.200 g, 0.586 mmol) obtained in Example 14, triphosgene (0.174 g, 0.586 mmol) and N,N-diisopropylethylamine (0.510 ml, 2.930 mmol) were dissolved in dichloromethane (15 ml), and the resulting solution was stirred at room temperature for 10 minutes. Tert-butylpiperazine-1-carboxylate (0.142 g, 0.762 mmol) was then added and further stirred at the same temperature for 16 hours. Water was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 12 g; ethyl acetate/hexane = 5% to 50%) and concentrated to give the title compound (0.160 g, 49.3%) as a white solid.

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

Tert-butyl-4-(((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)-methyl)-(phenyl )-Carbamoyl)-piperazine-1-carboxylate (0.100 g, 0.181 mmol) obtained 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 hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane, and then filtered through a plastic filter to remove the solid residue and aqueous layer. After concentration under reduced pressure, the title compound (0.099 g, 96.6%) was obtained as a foam solid without further purification.

[Step 3] Synthesis of compound 3784

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) obtained in step 2, paraformaldehyde (0.007 g, 0.221 mmol) and acetic acid (0.006 ml, 0.110 mmol) were dissolved in dichloromethane (5 ml), and the resulting solution was stirred at room temperature for 1 hours. Sodium triacetoxyborohydride (0.070 g, 0.331 mmol) was then added and further stirred at the same temperature for 16 hours. Water was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; methanol/dichloromethane = 10%) and concentrated to give the title compound (0.030 g, 58.2%) as a white solid.

^1H NMR (400 MHz, MeOD) δ 8.59 (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);

MSNR (ER) m/z 468.3 (M ⁺ +1).

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-(oxetan-3-yl)-N-phenylpiperazine-1-carboxamide

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) obtained in step 2 of Example 35, oxetan-3-one (0.014 ml, 0.221 mmol) and acetic acid (0.006 ml, 0.110 mmol) were dissolved in dichloromethane (5 ml), and the resulting solution was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.070 g, 0.331 mmol) was then added and further stirred at the same temperature for 16 hours. Water was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; methanol/dichloromethane = 10%) and concentrated to give the title compound (0.028 g, 49.8%) as a white solid.

^1H NMR (400 MHz, MeOD) δ 8.58 (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);

MSNR (ER) m/z 510.1 (M ⁺ +1).

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

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) obtained in step 2 of Example 35, acetaldehyde (0.019 g, 0.441 mmol), acetic acid (0.013 ml, 0.221 mmol) and sodium triacetoxyborohydride (0.140 g, 0.662 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 sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.027 g, 25.4%) as a yellow solid.

¹ H NMR (700 MHz, MeOD) δ 8.59 (dd, J=7.2, 1.0 Hz, 1H), 8.21 (dt, J=1.7, 0.8 Hz, 1H), 7.98 (d, J=0.8 Hz, 1H), 7.55 (dd, J=7.1, 1.7 Hz, 1H), 7.38-7.13 (m, 6H), 5 .03 (d, J=0.8 Hz, 2H), 3.32-3.27 (m, 4H), 2.38 (kv, J=7.3 Hz, 2H), 2.31 (t, J=5.1 Hz, 4H), 1.06 (t, J=7.2 Hz, 3H);

MSNR (ER) m/z 482.2 (M ⁺ +1).

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-isolrolyl-N-phenylpiperazine-1-carboxamide

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) obtained in step 2 of Example 35, 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) 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 hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.030 g, 54.9%) as a yellow solid.

¹ H NMR (400 MHz, MeOD) δ 8.53 (dd, J=7.1, 1.0 Hz, 1H), 8.22 (dt, J=1.8, 0.8 Hz, 1H), 7.92 (s, 1H), 7.55 (dd, J=7.1, 1.7 Hz, 1H), 7.39-7.02 (m, 6H), 5.02 (s, 2H) , 3.30 (t, J=5.1 Hz, 4H), 2.65 (p, J=6.5 Hz, 1H), 2.40 (t, J=5.1 Hz, 4H), 1 .02 (d, J=6.5 Hz, 6H);

MSNR (ER) m/z 496.5 (M ⁺ +1).

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

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) obtained from step 2 of Example 35, 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) dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.011 g, 9.8%) as a yellow solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.31-8.27 (m, 1H), 8.20 (dt, J=7.2, 1.4 Hz, 1H), 7.79-7, 74 (m, 1H), 7.51 (tm, J=5.4, 1.7 Hz, 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=23.0 Hz , 4H), 3.24-3.15 (m, 2H), 2.40 (s, 2H), 2.12 (s, 2H), 2.04 (s, 1H), 1.28 (s, 3H);

MSNR (ER) m/z 512.3 (M ⁺ +1).

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

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) obtained in step 2 of Example 35, cyclobutanone (0.031 g, 0.441 mmol), acetic acid (0.013 ml, 0.221 mmol) and sodium triacetoxyborohydride (0.140 g, 0.662 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 sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.028 g, 25.0%) as a yellow solid.

¹ H NMR (700 MHz, MeOD) δ 8.60 (dd, J=1.1, 1.0 Hz, 1H), 8.21 (p, J=0.8 Hz, 1H), 7.98 ( d, J=0.8 Hz, 1H), 7.56 (dd, J=7.1, 1.7 Hz, 1H), 7.40-7.14 (m, 6H), 5.03 (d , J=0.8 Hz, 2H), 3.29 (t, J=5.1 Hz, 4H), 2.73-2.66 (m, 1H), 2.18 (t, J=5, 1 Hz, 4H), 2.06-1.98 (m, 2H), 1.89-1.79 (m, 2H), 1.70 (ddt, J=12.8, 10.0, 5, 7 Hz, 2H);

MSNR (ER) m/z 508.3 (M ⁺ +1).

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

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) obtained in step 2 of Example 35, cyclohexanone (0.043 g, 0.441 mmol), acetic acid (0.013 ml, 0.221 mmol) and sodium triacetoxyborohydride (0.140 g, 0.662 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 sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.031 g, 26.2%) as a yellow solid.

¹ H NMR (700 MHz, MeOD) δ 8.57 (d, J=7.1 Hz, 1H), 8.22-8.20 (m, 1H), 7.96 (s, 1H), 7, 55 (dd, J=7.1, 1.7 Hz, 1H), 7.41-7.09 (m, 6H), 5.04-5.01 (m, 2H), 3.29 (t, J=5.1 Hz, 4H), 2.43 (t, J=5.0 Hz, 4H), 2.23 (tt, J=11.9, 3.6 Hz, 1H), 1.86- 1.74 (m, 4H), 1.63 (dt, J=12.6, 3.3 Hz, 1H), 1.24 (kW, J=12.9, 3.2 Hz, 2H), 1 .19-1.07 (m, 3H); MSNR (ER) m/z 536.2 (M ⁺ +1).

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

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) obtained in step 2 of Example 35, 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) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.016 g, 13.5%) as a yellow solid.

^1H NMR (700 MHz, MeOD) δ 8.53 (d, J=7.1 Hz, 1H), 8.23-8.20 (m, 1H), 7.92 (s, 1H), 7, 55 (dd, J=7.1, 1.7 Hz, 1H), 7.36 (dd, J=8.5, 7.4 Hz, 2H), 7.29-7.05 (m, 4H) , 5.02 (s, 2H), 3.97 (dd, J=11.3, 4.4 Hz, 2H), 3.36 (td, J=12.0, 1.9 Hz, 2H), 3.31-3.28 (m, 4H), 2.43 (t, J=5.1 Hz, 5H), 1.75 (ddd, J=12.4, 4.3, 2.1 Hz, 2H), 1.47 (kvd, J=12.2, 4.5 Hz, 2H);

MSNR (ER) m/z 538.1 (M ⁺ +1).

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

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) obtained in step 2 of Example 35, 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) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.034 g, 27.0%) as a yellow solid.

¹ H NMR (700 MHz, MeOD) δ 8.47 (dd, J=7.1, 1.0 Hz, 1H), 8.21 (dt, J=1.7, 0.8 Hz, 1H), 7.88 (d, J=0.8 Hz, 1H), 7.54 (dd, J=7.1, 1.7 Hz, 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=13.1 Hz, 2H), 1.72 (dddd, J=30.7, 17.4, 13.1, 4.2 Hz , 2H), 1.57-1.49 (m, 2H);

MSNR (ER) m/z 572.3 (M ⁺ +1).

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

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) obtained in step 2 of Example 35, acetyl chloride (0.031 ml, 0.441 mmol) and triethylamine (0.092 ml, 0.662 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at 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 solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.018 g, 16.5%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 8.24 (d, J=7.1 Hz, 1H), 7.79 (s, 1H), 7.59 (d , J=7.1 Hz, 1H), 7.37 (dd, J=8.4, 7.2 Hz, 2H), 7.33-7.28 (m, 2H), 7.21-7, 13 (m, 1H), 6.95 (t, J=51.7 Hz, 1H), 5.07 (s, 2H), 3.43 (t, J=5.3 Hz, 2H), 3, 30 (s, 4H), 3.23 (t, J=5.4 Hz, 2H), 2.04 (s, 3H);

MSNR (ER) m/z 496.0 (M ⁺ +1).

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

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) obtained in step 2 of Example 35, propionyl chloride (0.041 g, 0.441 mmol) and triethylamine (0.092 ml, 0.662 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at 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 solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.014 g, 12.5%) as a yellow solid.

^1H NMR (700 MHz, MeOD) δ 8.58 (dd, J=7.1, 1.0 Hz, 1H), 8.20 (dt, J=1.7, 0.8 Hz, 1H), 8.00-7.98 (m, 1H), 7.54 (dd, J=7.1, 1.7 Hz, 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 (kV, J=7.5 Hz, 2H) , 1.07 (t, J=7.5 Hz, 3H);

MSNR (ER) m/z 510.3 (M ⁺ +1).

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

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) obtained in step 2 of Example 35, 2-hydroxyacetyl chloride (0.042 g, 0.441 mmol) and triethylamine (0.092 ml, 0.662 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 solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.029 g, 25.7%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.42 (s, 1H), 8.26 (d, J=7.1 Hz, 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=51.7 Hz, 1H), 5.07 ( d, J=0.7 Hz, 2H), 4.09 (s, 2H), 3.50 (t, J=5.3 Hz, 2H), 3.29 (d, J=9.9 Hz, 4H), 3.10 (t, J=5.2 Hz, 2H);

MSNR (ER) m/z 513.2 (M ⁺ +1).

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

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) obtained in step 2 of Example 35, cyclobutanecarbonyl chloride (0.052 g, 0.441 mmol) and triethylamine (0.092 ml, 0.662 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at that 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 solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.030 g, 25.4%) as a yellow solid.

¹ H NMR (700 MHz, MeOD) δ 8.59 (dd, J=7.1, 1.0 Hz, 1H), 8.21 (dt, J=1.7, 0.8 Hz, 1H), 8.02-7.98 (m, 1H), 7.56 (dd, J=7.1, 1.7 Hz, 1H), 7.44-7.14 (m, 6H), 5.06- 5.03 (m, 2H), 3.42-3.36 (m, 2H), 3.29-3.22 (m, 6H), 2.28-2.17 (m, 3H), 2. 14 (dddddd, J=12.2, 11.0, 8.8, 3.7, 1.8 Hz, 2H), 2.02-1.94 (m, 1H), 1.84-1.78 (m, 1H);

MSNR (ER) m/z 537.1 (M ⁺ +1).

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

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) obtained in step 2 of Example 35, 1,1,1,5,5,5-hexafluoropentane-2,4-dione (0.046 g, 0.221 mmol) and triethylamine (0.046 ml, 0.331 mmol ) was 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 solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.041 g, 67.7%) as a yellow solid.

¹ H NMR (400 MHz, MeOD) δ 8.59 (dd, J=7.2, 1.0 Hz, 1H), 8.22 (dt, J=1.7, 0.8 Hz, 1H), 8.00 (d, J=0.7 Hz, 1H), 7.56 (dd, J=7.2, 1.7 Hz, 1H), 7.44-7.09 (m, 6H), 5 .06 (d, J=0.8 Hz, 2H), 3.51 (kv, J=5.3 Hz, 4H), 3.36 (dd, J=6.7, 4.4 Hz, 4H) ;

MSNR (ER) m/z 550.4 (M ⁺ +1).

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

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) obtained in step 2 of Example 35, methanesulfonyl chloride (0.017 ml, 0.221 mmol) and triethylamine (0.046 ml, 0.331 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at that 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 solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.012 g, 20.5%) as a yellow solid.

¹ H NMR (400 MHz, MeOD) δ 8.59 (dd, J=7.1, 1.0 Hz, 1H), 8.22 (dt, J=1.7, 0.8 Hz, 1H), 7.99 (d, J=0.8 Hz, 1H), 7.56 (dd, J=7.1, 1.7 Hz, 1H), 7.45-7.06 (m, 6H), 5 .04 (d, J=0.7 Hz, 2H), 3.39-3.35 (m, 4H), 3.07-3.02 (m, 4H), 2.80 (s, 3H); MSNR (ER) m/z 532.4 (M ⁺ +1).

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

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) obtained in step 2 of Example 35, methyl chloroformate (0.042 g, 0.441 mmol) and triethylamine (0.092 ml, 0.662 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at that 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 solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.034 g, 30.1%) as a yellow solid.

^1H NMR (700 MHz, MeOD) δ 8.59 (dd, J=7.1, 1.0 Hz, 1H), 8.21 (dt, J=1.7, 0.8 Hz, 1H), 7.99 (d, J=0.8 Hz, 1H), 7.55 (dd, J=7.1, 1.7 Hz, 1H), 7.44-7.11 (m, 6H), 5 .04 (d, J=0.8 Hz, 2H), 3.66 (s, 3H), 3.29 (d, J=5.9 Hz, 4H), 3.26 (dd, J=7, 0, 3.5 Hz, 4H);

MSNR (ER) m/z 511.8 (M ⁺ +1).

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

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) obtained in step 2 of Example 35, dimethylcarbamic acid chloride (0.047 g, 0.441 mmol) and triethylamine (0.092 ml, 0.662 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 solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.028 g, 24.2%) as a yellow solid.

¹ H NMR (700 MHz, MeOD) δ 8.59 (dd, J=7.1, 1.0 Hz, 1H), 8.21 (dt, J=1.7, 0.8 Hz, 1H), 7.99 (d, J=0.8 Hz, 1H), 7.55 (dd, J=7.1, 1.7 Hz, 1H), 7.43-7.07 (m, 6H), 5 .04 (d, J=0.8 Hz, 2H), 3.32-3.28 (m, 4H), 3.09-3.05 (m, 4H), 2.81 (s, 6H);

MSNR (ER) m/z 525.0 (M ⁺ +1).

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

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) obtained in step 2 of Example 35, 2-chloropyridine (0.033 g, 0.287 mmol), cesium carbonate (0.093 g, 0.287 mmol) and palladium RuPhos G2 (0.006 g, 0.007 mmol) were dissolved in 1 ,4-dioxane (2 ml) at room temperature, and the resulting solution was stirred at 100°C for 18 hours. The temperature was then lowered to room temperature to complete the reaction. Saturated aqueous sodium hydrogen carbonate was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 30%) and concentrated to give the title compound (0.011 g, 14.5%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 8.24 (d, J=7.1 Hz, 1H), 8.20-8.16 (m, 1H), 7 .79 (s, 1H), 7.53 (d, J=7.1 Hz, 1H), 7.39-7.29 (m, 5H), 7.16 (t, J=7.1 Hz, 1H), 6.95 (t, J=51.7 Hz, 1H), 6.74 (s, 2H), 5.10 (d, J=2.3 Hz, 2H), 3.45 (s, 6H), 1.63 (s, 2H);

MSNR (ER) m/z 531.4 (M ⁺ +1).

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

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) obtained in step 2 of Example 35, 2-chloropyrimidine (0.051 g, 0.441 mmol) and potassium carbonate (0.061 g, 0.441 mmol) 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 solution of ammonium chloride was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The resulting product was then filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.015 g, 12.8%) as a yellow solid.

¹ H NMR (700 MHz, MeOD) δ 8.56 (d, J=7.0 Hz, 1H), 8.31-8.23 (m, 2H), 7.97 (d, J=9.4 Hz, 1H), 7.76-7.73 (m, 1H), 7.59 (d, J=7.1 Hz, 1H), 7.40-7.08 (m, 6H), 6.58 (t, J=4.8 Hz, 1H), 5.06 (s, 2H), 3.66-3.62 (m, 4H), 3.36-3.34 (m, 4H);

MSNR (ER) m/z 532.0 (M ⁺ +1).

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

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-3-fluoroaniline (0.200 g . 15 ml), and the resulting solution was stirred at 0°C for 1 hour and further stirred at room temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane = 0% to 60%) and concentrated to give the title compound (0.240 g, 75.4%) as a white solid.

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

Tert-butyl-4-(((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-( 3-fluorophenyl)-carbamoyl)-piperazine-1-carboxylate (2.000 g, 3.499 mmol) obtained in step 1 and trifluoroacetic acid (5.359 ml, 69.984 mmol) were dissolved in dichloromethane (30 ml) at room temperature, and the resulting solution stirred at the same temperature for 3 hours. A saturated aqueous solution of sodium hydrogen carbonate 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 give the title compound (1.650 g, 100.0%) as a brown gel without further purification.

[Step 3] 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 )-piperazine-1-carboxamide (0.080 g, 0.170 mmol) obtained in step 2, formaldehyde (0.010 g, 0.339 mmol), acetic acid (0.010 ml, 0.170 mmol) and sodium triacetoxyborohydride (0.108 g, 0.509 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 sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.018 g, 21.8%) as a yellow solid.

¹ H NMR (700 MHz, MeOD) δ 8.59 (dd, J=7.2, 1.0 Hz, 1H), 8.22 (dt, J=1.8, 0.9 Hz, 1H), 7.99 (d, J=0.7 Hz, 1H), 7.56 (dd, J=7.1, 1.7 Hz, 1H), 7.37 (td, J=8.4, 6, 6 Hz, 1H), 7.26 (t, J=51.6 Hz, 1H), 7.09-7.03 (m, 2H), 6.90 (tdd, J=8.3, 2.5 , 0.9 Hz, 1H), 5.04 (d, J=0.8 Hz, 2H), 3.32 (s, 2H), 3.28-3.25 (m, 2H), 2.31 (t, J=5.0 Hz, 4H), 2.25 (s, 3H);

MSNR (ER) m/z 486.1 (M ⁺ +1).

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

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) obtained in step 2 of Example 54, acetaldehyde (0.015 g, 0.339 mmol), acetic acid (0.010 ml, 0.170 mmol) and sodium triacetoxyborohydride (0.108 g, 0.509 mmol) dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.022 g, 26.0%) as a yellow solid.

¹ H NMR (700 MHz, MeOD) δ 8.59 (dd, J=7.1, 1.0 Hz, 1H), 8.21 (dt, J=1.7, 0.8 Hz, 1H), 7.99 (d, J=0.8 Hz, 1H), 7.56 (dd, J=7.1, 1.7 Hz, 1H), 7.37 (td, J=8.3, 6, 5 Hz, 1H), 7.27 (t, J=51.6 Hz, 1H), 7.09-7.04 (m, 2H), 6.90 (tdd, J=8.4, 2.4 , 0.9 Hz, 1H), 5.04 (d, J=0.8 Hz, 2H), 3.33 (dd, J=3.6, 2.0 Hz, 4H), 2.40 (kv , J=7.2 Hz, 2H), 2.35 (t, J=5.1 Hz, 4H), 1.07 (t, J=7.2 Hz, 3H);

MSNR (ER) m/z 500.1 (M ⁺ +1).

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

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) obtained from step 2 of Example 54, 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) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.024 g, 27.5%) as a yellow solid.

¹ H NMR (700 MHz, MeOD) δ 8.59 (dd, J=7.1, 1.0 Hz, 1H), 8.22 (dt, J=1.7, 0.8 Hz, 1H), 7.99 (d, J=0.8 Hz, 1H), 7.56 (dd, J=7.2, 1.7 Hz, 1H), 7.37 (td, J=8.3, 6, 6 Hz, 1H), 7.27 (t, J=51.6 Hz, 1H), 7.08-7.04 (m, 2H), 6.90 (tdd, J=8.4, 2.4 , 0.9 Hz, 1H), 5.04 (d, J=0.8 Hz, 2H), 3.33-3.31 (m, 4H), 2.65 (p, J=6.5 Hz , 1H), 2.42 (t, J=5.1 Hz, 4H), 1.03 (d, J=6.5 Hz, 6H);

MSNR (ER) m/z 514.4 (M ⁺ +1).

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

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) prepared in step 2 of Example 54, 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) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.022 g, 24.5%) as a yellow solid.

^1H NMR (700 MHz, MeOD) δ 8.60 (dd, J=1.1, 1.0 Hz, 1H), 8.23 (dt, J=1.8, 0.9 Hz, 1H), 8.00 (d, J=0.8 Hz, 1H), 7.56 (dd, J=1.1, 1.1 Hz, 1H), 7.36 (td, J=8.3, 6, 6 Hz, 1H), 7.26 (t, J=51.7 Hz, 1H), 7.08-7.03 (m, 2H), 6.92-6.86 (m, 1H), 5, 04 (d, J=0.8 Hz, 2H), 3.53 (dd, J=11.1, 6.8 Hz, 1H), 3.41 (dd, J=11.2, 5.6 Hz , 1H), 3.33-3.30 (m, 4H), 2.65 (td, J=6.8, 5.7 Hz, 1H), 2.50 (dd, J=10.6, 6 ,3, 3.8 Hz, 2H), 2.43 (dd, J=10.9, 6.2, 2H), 0.96 (d, 3H);

MSNR (ER) m/z 530.1 (M ⁺ +1).

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

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) obtained from step 2 of Example 54, cyclobutanone (0.024 g, 0.339 mmol), acetic acid (0.010 ml, 0.170 mmol) and sodium triacetoxyborohydride (0.108 g, 0.509 mmol) dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.025 g, 28.0%) as a yellow solid.

¹ H NMR (700 MHz, MeOD) δ 8.55 (dd, J=7.1, 1.0 Hz, 1H), 8.24-8.21 (m, 1H), 7.94 (s, 1H ), 7.56 (dd, J=7.1, 1.7 Hz, 1H), 7.34 (td, J=8.4, 6.5 Hz, 1H), 7.20 (t, J= 51.7 Hz, 1H), 7.05-6.99 (m, 2H), 6.90-6.85 (m, 1H), 5.03 (s, 2H), 3.31 (d, J =7.4 Hz, 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, 8.2 Hz, 2H);

MSNR (ER) m/z 526.1 (M ⁺ +1).

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-(oxetan-3-yl)-piperazine-1-carboxamide

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) prepared in step 2 of Example 54, oxetan-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) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.019 g, 21.2%) as a yellow solid.

¹ H NMR (700 MHz, MeOD) δ 8.54 (dd, J=7.1, 1.0 Hz, 1H), 8.23 (dt, J=1.8, 0.8 Hz, 1H), 7.94 (d, J=0.8 Hz, 1H), 7.56 (dd, J=7.1, 1.7 Hz, 1H), 7.34 (td, J=8.4, 6, 4 Hz, 1H), 7.20 (t, J=51.6 Hz, 1H), 7.05-6.99 (m, H), 6.88 (tdd, J=8.3, 2.5 , 0.9 Hz, 1H), 5.05-4.98 (m, 2H), 4.66 (t, J=6.7 Hz, 2H), 4.55 (t, J=6.2 Hz , 2H), 3.47 (s, 1H), 3.36-3.34 (m, 4H), 2.24 (s, 4H);

MSNR (ER) m/z 529.2 (M ⁺ +1).

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

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) obtained from step 2 of Example 54, cyclohexanone (0.033 g, 0.339 mmol), acetic acid (0.010 ml, 0.170 mmol) and sodium triacetoxyborohydride (0.108 g, 0.509 mmol) dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.018 g, 19.2%) as a yellow solid.

¹ H NMR (700 MHz, MeOD) δ 8.54 (dd, J=7.1, 1.0 Hz, 1H), 8.23 (t, J=1.1 Hz, 1H), 7.94 (s, 1H), 7.56 (dd, J=7.1, 1.7 Hz, 1H), 7.34 (td, J=8.5, 6.7 Hz, 1H), 7.20 (t, J =51.6 Hz, 1H), 7.07-6.95 (m, 2H), 6.87 (ddd, J=9.5, 8.0, 2.5 Hz, 1H), 5.03 ( s, 2H), 3.32 (s, 4H), 2.50 (s, 4H), 2.28 (s, 1H), 1.84 (d, J=11.2 Hz, 2H), 1, 82-1.76 (m, 2H), 1.64 (d, J=12.6 Hz, 1H), 1.24 (ddd, J=16.0, 11.2, 3.2 Hz, 2H), 1 ,21-1.13 (m, 2H), 1H (d, J=12.9, 1H);

MSNR (ER) m/z 554.4 (M ⁺ +1).

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)-piperazin-1-carboxamide

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) obtained from step 2 of Example 54, tetrahydro-4H-pyran-4-one (0.034 g, 0.339 mmol), acetic acid (0.010 ml, 0.170 mmol) and triacetoxyborohydride sodium (0.108 g, 0.509 mmol) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO ₂ plate 20 x 20 x 1 mm; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.028 g, 29.7%) as a yellow solid.

¹ H NMR (700 MHz, MeOD) δ 8.53 (dt, J=6.8, 3.2 Hz, 1H), 8.23 (s, 1H), 7.93 (d, J=2.5 Hz, 1H), 7.56 (d, J=7.0 Hz, 1H), 7.34 (kv, J=7.8 Hz, 1H), 7.18 (tt, J=51.7, 2 .9 Hz, 1H), 7.02 (t, J=10.6 Hz, 2H), 6.87 (td, J=8.3, 2.6 Hz, 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=12.5 Hz, 2H), 1.50 (dd, J=12.2, 4.3 Hz, 2H);

MSNR (ER) m/z 556.1 (M ⁺ +1).

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

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) obtained from step 2 of Example 54, 4,4-difluorocyclohexan-1-one (0.046 g, 0.339 mmol), acetic acid (0.010 ml, 0.170 mmol) and triacetoxyborohydride sodium (0.108 g, 0.509 mmol) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.030 g, 30.0%) as a yellow solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.28 (s, 1H), 8.21 (d, J=7.0 Hz, 1H), 7.75 (d, J=0.8 Hz, 1H ), 7.53 (d, J=7.2 Hz, 1H), 7.32 (d, J=7.8 Hz, 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, 6.3 Hz, 4H);

MSNR (ER) m/z 590.3 (M ⁺ +1).

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

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) obtained in step 2 of example 54, acetyl chloride (0.024 ml, 0.339 mmol) and triethylamine (0.071 ml, 0.509 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 solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.037 g, 42.5%) as a yellow solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 8.23 (dd, J=7.1, 1.0 Hz, 1H), 7.77 (s, 1H), 7 .56 (dd, J=7.1, 1.7 Hz, 1H), 7.32 (td, J=8.2, 6.5 Hz, 1H), 7.13-6.79 (m, 4H ), 5.07 (s, 2H), 3.47 (dd, J=6.6, 4.0 Hz, 2H), 3.33 (s, 4H), 3.26-3.22 (m, 2H), 2.05 (s, 3H);

MSNR (ER) m/z 514.3 (M ⁺ +1).

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

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) obtained in step 2 of Example 54, propionyl chloride (0.031 g, 0.339 mmol) and triethylamine (0.071 ml, 0.509 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 solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.031 g, 34.6%) as a yellow solid.

¹ H NMR (700 MHz, MeOD) δ 8.59 (dd, J=7.1, 1.0 Hz, 1H), 8.21 (dt, J=1.7, 0.8 Hz, 1H), 8.02-7.99 (m, 1H), 7.55 (dd, J=7.1, 1.7 Hz, 1H), 7.37 (td, J=8.2, 6.4 Hz, 1H), 7.27 (t, J=51.7 Hz, 1H), 7.13-7.06 (m, 2H), 6.91 (tdd, J=8.4, 2.5, 0, 9 Hz, 1H), 5.06 (d, J=0.8 Hz, 2H), 3, 49-3, 42 (m, 4H), 3.35-3.34 (m, 2H), 3, 30-3.27 (m, 2H), 2.37 (kv, J=7.5 Hz, 2H), 1.08 (t, J=7.5 Hz, 3H);

MSNR (ER) m/z 528.1 (M ⁺ +1).

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

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) obtained in step 2 of Example 54, 2-hydroxyacetyl chloride (0.032 g, 0.339 mmol) and triethylamine (0.071 ml, 0.509 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 solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.014 g, 15.6%) as a yellow solid.

¹ H NMR (700 MHz, MeOD) δ 8.60 (dd, J=1.1, 1.0 Hz, 1H), 8.23 (dt, J=1.7, 0.8 Hz, 1H), 8.01 (d, J=0.8 Hz, 1H), 7.57 (dd, J=7.1, 1.7 Hz, 1H), 7.38 (td, J=8.2, 6, 5 Hz, 1H), 7.26 (t, J=51.7 Hz, 1H), 7.13-7.06 (m, 2H), 6.92 (tdd, J=8.3, 2.5 , 0.9 Hz, 1H), 5.06 (d, J=0.8 Hz, 2H), 4.19 (s, 2H), 3.74 (p, J=6.6 Hz, 1H), 3.48 (t, J=5.3 Hz, 2H), 3.26-3.19 (m, 1H), 1.39 (d, J=6.7 Hz, 4H);

MSNR (ER) m/z 530.0 (M ⁺ +1).

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

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) obtained in step 2 of Example 54, cyclobutanecarbonyl chloride (0.040 g, 0.339 mmol) and triethylamine (0.071 ml, 0.509 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 solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO ₂ plate 2 0x20x1 mm; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.027 g, 28.7%) as a yellow solid.

¹ H NMR (700 MHz, MeOD) δ 8.60 (dd, J=1.1, 1.0 Hz, 1H), 8.24-8.21 (m, 1H), 8.01 (s, 1H ), 7.57 (dd, J=7.1, 1.7 Hz, 1H), 7.37 (td, J=8.2, 6.5 Hz, 1H), 7.26 (t, J= 51.7 Hz, 1H), 7.13-7.06 (m, 2H), 6.92 (tdd, J=8.4, 2.5, 0.9 Hz, 1H), 5.06 (s , 2Н), 3, 46-3, 43 (m, 2Н), 3.37 (td, J=8.7, 1.1 Hz, 1Н), 3.32 (s, 1Н), 3.3 0 -3.2 6 (m, 4H), 2.2 8-2.19 (m, 3H), 2.17-2.10 (m, 2H), 2.04-1.95 (m, 1H) , 1.84-1.78 (m, 1H);

MSNR (ER) m/z 553.9 (M ⁺ +1).

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

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) prepared in step 2 of Example 54, 1,1,1,5,5,5-hexafluoropentane-2,4-dione (0.044 g, 0.212 mmol) and triethylamine (0.044 ml, 0.318 mmol) was 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 solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.038 g, 63.1%) as a yellow solid.

^1H NMR (400 MHz, MeOD) δ 8.59 (dd, J=7.2, 1.0 Hz, 1H), 8.23 (dt, J=1.6, 0.8 Hz, 1H), 8.01 (d, J=0.7 Hz, 1H), 7.57 (dd, J=7.2, 1.7 Hz, 1H), 7.42-6.86 (m, 5H), 5 .07 (d, J=0.8 Hz, 2H), 3.56 (kv, J=5.0 Hz, 4H), 3.38 (td, J=7.2, 6.2, 4.0 Hz, 4H);

MSNR (ER) m/z 568.4 (M ⁺ +1).

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

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) obtained in step 2 of Example 54, methanesulfonyl chloride (0.016 ml, 0.212 mmol) and triethylamine (0.044 ml, 0.318 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 solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.015 g, 25.7%) as a yellow solid.

¹ H NMR (400 MHz, MeOD) δ 8.60 (dd, J=7.2, 1.0 Hz, 1H), 8.23 (dt, J=1.7, 0.8 Hz, 1H), 8.01 (d, J=0.8 Hz, 1H), 7.57 (dd, J=7.1, 1.7 Hz, 1H), 7.46-6.87 (m, 5H), 5 .06 (d, J=0.7 Hz, 2H), 3.43-3.36 (m, 4H), 3.13-3.0 6 (m, 4H), 2.81 (s, 3H) ;

MSNR (ER) m/z 550.4 (M ⁺ +1).

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

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) obtained in step 2 of Example 54, methyl chloroformate (0.032 g, 0.339 mmol) and triethylamine (0.071 ml, 0.509 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 solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.032 g, 35.6%) as a yellow solid.

¹ H NMR (700 MHz, MeOD) δ 8.55 (dd, J=7.1, 1.0 Hz, 1H), 8.24 (dt, J=1.8, 0.9 Hz, 1H), 7.96 (s, 1H), 7.57 (dd, J=7.1, 1.7 Hz, 1H), 7.35 (td, J=8.4, 6.5 Hz, 1H), 7 .20 (t, J=51.6 Hz, 1H), 7.07-7.02 (m, 2H), 6.92-6.8 6 (m, 1H), 5.05-5.02 ( m, 2H), 3.67 (s, 3H), 3.36-3.34 (m, 4H), 3.28 (dd, J=6.6, 3.7 Hz, 4H);

MSNR (ER) m/z 531.3 (M ⁺ +1).

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

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) obtained in step 2 of Example 54, dimethylcarbamic acid chloride (0.036 g, 0.339 mmol) and triethylamine (0.071 ml, 0.509 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 solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.018 g, 19.6%) as a yellow solid.

^1H NMR (700 MHz, MeOD) δ 8.58-8.55 (m, 1H), 8.26-8.24 (m, 1H), 7.97 (s, 1H), 7.59 (dd , J=7.1, 1.7 Hz, 1H), 7.36 (td, J=8.4, 6.4 Hz, 1H), 7.20 (t, J=51.7 Hz, 1H) , 7.06-7.02 (m, 2H), 6.89 (tdd, J=8.3, 2.4, 1.0 Hz, 1H), 5.05 (s, 2H), 3.32 -3.30 (m, 4H), 3.12-3.10 (m, 4H), 2.82 (s, 6H);

MSNR (ER) m/z 542.9 (M ⁺ +1).

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

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) obtained from step 2 of Example 54, 2-chloropyridine (0.032 g, 0.280 mmol), cesium carbonate (0.091 g, 0.280 mmol) and palladium RuPhos G2 ( 0.005 g, 0.007 mmol) was dissolved in 1,4-dioxane (2 ml) at room temperature, and the resulting solution was stirred at 100°C for 18 hours.

The temperature was then lowered to room temperature to complete the reaction. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 30%) and concentrated to give the title compound (0.014 g, 18.2%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 8.25 (d, J=7.0 Hz, 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, 1.6 Hz, 1H), 7.36-7 .29 (m, 1H), 7.14-6.79 (m, 5H), 6.61 (d, J=8.3 Hz, 1H), 5.10 (s, 2H), 3.55 ( d, J=57.6 Hz, 6H), 1.80-1.56 (m, 2H);

MSNR (ER) m/z 54 9.4 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-okeadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-(3-fluorophenyl )-piperazine-1-carboxamide (0.080 g, 0.170 mmol) prepared in step 2 of Example 54, 2-chloropyrimidine (0.039 g, 0.339 mmol) and potassium carbonate (0.047 g, 0.339 mmol) 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 solution of ammonium chloride was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The resulting product was then filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.015 g, 16.1%) as a yellow solid.

¹ H NMR (700 MHz, MeOD) δ 8.50 (dd, J=7.1, 1.8 Hz, 1H), 8.28 (d, J=4.8 Hz, 1H), 8.24 ( d, J=1.6 Hz, 1H), 7.93 (s, 1H), 7.56 (dd, J=7.1, 1.7 Hz, 1H), 7.34 (td, J=8 ,1, 6.4 Hz, 1H), 7.15 (td, J=51.7, 2.0 Hz, 1H), 7.07-7.02 (m, 2H), 6.87 (td, J=8.3, 2.4 Hz, 1H), 6.57 (t, J=4.7 Hz, 1H), 5.06 (s, 2H), 3.70-3.66 (m, 4H ), 3.4 0-3.35 (m, 4H);

MSNR (ER) m/z 550.2 (M ⁺ +1).

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

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) obtained 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 in within 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a 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 cartridge, 12 g; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (0.015 g, 25.3%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34-8.29 (m, 1H), 8.24 (dt, J=7.1, 1.0 Hz, 1H), 7.77 (dd, J= 5.3, 0.7 Hz, 1H), 7.55 (dd, J=7.2, 1.7 Hz, 1H), 7.36 (tt, J=7.4, 1.9 Hz, 2H), 7.28-7.25 (m, 2H), 7.21-7.13 (m, 1H), 6.95 (t, J=51.7 Hz, 1H), 5.07 (d, J= 3.3 Hz, 2H), 4.85 (dd, J=7.1, 5.9 Hz, 1H), 4.76 (dd, J=8.7, 5.9 Hz, 1H), 3, 44 (dt, J=10.2, 5.4 Hz, 2H), 3.31 (s, 2H), 3.24 (ddt, J=10.3, 7.4, 3.5 Hz, 4H) , 3.01 (t, J=5.3 Hz, 1H), 2.04 (s, 2H);

MSNR (ER) m/z 538.5 (M ⁺ +1).

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

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) obtained in step 2 of example 54, oxetane-3-carboxylic acid (0.022 g, 0.212 mmol), 1-[bis-(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium hexafluorophosphate 3-oxide (HATU, 0.048 g, 0.127 mmol) and triethylamine (0.044 ml, 0.318 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting the solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 12 g; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (0.024 g, 40.7%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (dd, J=1.7, 0.9 Hz, 1H), 8.23 (dd, J=7.1, 1.0 Hz, 1H) , 7.76 (dd, J=4.5, 0.7 Hz, 1H), 7.55 (dd, J=7.1, 1.8 Hz, 1H), 7.32 (tdd, J=8 ,5, 6.6, 2.0 Hz, 1H), 7.11-6.79 (m, 4H), 5.07 (d, J=3.0 Hz, 2H), 4.87 (dd, J=7.1, 5.9 Hz, 1H), 4.77 (dd, J=8.7, 6.0 Hz, 1H), 3.48 (dt, J=10.5, 5.4 Hz , 2H), 3.34 (s, 2H), 3.31-3.16 (m, 4H), 3.05 (t, J=5.3 Hz, 1H);

MSNR (ER) m/z 556.5 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylpiperidin-4- carboxamide (0.040 g, 0.088 mmol) obtained in step 3 of Example 33, acetaldehyde (0.010 ml, 0.177 mmol) and acetic acid (0.005 ml, 0.088 mmol) were dissolved in dichloromethane (0.5 ml), and the resulting solution was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.056 g, 0.265 mmol) was then added and further stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO ₂ plate 20x20x1mm; methanol/dichloromethane = 0% to 20%) and concentrated to give the title compound (0.003 g, 7.8%) as a yellow gel.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.30 (d, J=1.6 Hz, 1H), 8.24 (dd, J=0.9, 7.1 Hz, 1H), 7.77 (s, 1H), 7.54 (dd, J=1.8, 7.1 Hz, 1H), 7.4 6-7.3 6 (m, 3H), 7.27-7.21 (m , 2H), 6.95 (t, J=51.7 Hz, 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=10.3 Hz, 3H), 1.80 (s, 2H), 1.28 (s, 1H), 1 .15 (s, 3H);

MSNR (ER) m/z 481.3 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylpiperidin-4- carboxamide (0.024 g, 0.053 mmol) obtained in step 3 of Example 33, propan-2-one (0.006 g, 0.106 mmol) and acetic acid (0.003 ml, 0.053 mmol) were dissolved in dichloromethane (1 ml), and the resulting solution was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.034 g, 0.159 mmol) was then added and further stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; methanol/dichloromethane = 0% to 20%) and concentrated to give the title compound (0.006 g, 22.5%) as a yellow solid.

¹ H NMR (700 MHz, MeOD) δ 8.58 (dd, J=1.0, 7.1 Hz, 1H), 8.23 (dt, J = 0.8, 1.8 Hz, 1H), 7.94-7.89 (m, 1H), 7.58 (dd, J = 1.7, 7.1 Hz, 1H), 7.47-7.38 (m, 3H), 7.32- 7.27 (m, 2H), 5.11 (s, 2H), 3.40 (d, J=12.2 Hz, 2H), 2.78 (s, 2H), 2.65 (d, J =11.8 Hz, 1H), 2.12-2.05 (m, 2H), 2.04-1.99 (m, 2H), 1.96 (s, 1H), 1.27 (d, J=6.7 Hz, 6H);

MSNR (ER) m/z 4 95.4 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-okeadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylpiperidin-4- carboxamide (0.040 g, 0.088 mmol) obtained in step 3 of Example 33, 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) was dissolved in dichloromethane (1 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO ₂ plate 20x20x1mm; methanol/dichloromethane = 0% to 20%) and concentrated to give the title compound (0.009 g, 19.1%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (s, 1H), 8.24 (d, J=7.1 Hz, 1H), 7.74 (s, 1H), 7.55 (dd , J=1.7, 7.1 Hz, 1H), 7.41 (td, J=5.8, 8.3 Hz, 3H), 7.26-7.18 (m, 2H), 6, 96 (t, J=51.7 Hz, 1H), 5.04 (s, 2H), 3.71 (dd, J=4.2, 12.2 Hz, 1H), 3.48 (dd, J =8.6, 12.0 Hz, 1H), 3.30 (s, 1H), 3.14 (s, 2H), 2.80 (s, 1H), 2.50 (d, J=26, 3 Hz, 2H), 2.05 (s, 2H), 1.97-1.82 (m, 2H), 1.06 (d, J=6.7 Hz, 3H);

MSNR (ER) m/z 510.55 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylpiperidin-4- carboxamide (0.040 g, 0.088 mmol) obtained in step 3 of Example 33, cyclobutanone (0.013 ml, 0.177 mmol) and acetic acid (0.005 ml, 0.088 mmol) were dissolved in dichloromethane (0.5 ml), and the resulting solution was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.056 g, 0.265 mmol) was then added and further stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO ₂ plate 20x20x1mm; methanol/dichloromethane = 0% to 20%) and concentrated to give the title compound (0.012 g, 27.2%) as a pale red solid colors.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (s, 1H), 8.24 (d, J=7.1 Hz, 1H), 7.74 (s, 1H), 7.55 (dd , J=1.7, 7.1 Hz, 1H), 7.41 (td, J=5.8, 8.3 Hz, 3H), 7.26-7.18 (m, 2H), 6, 96 (t, J=51.7 Hz, 1H), 5.04 (s, 2H), 3.71 (dd, J=4.2, 12.2 Hz, 1H), 3.48 (dd, J =8.6, 12.0 Hz, 1H), 3.30 (s, 1H), 3.14 (s, 2H), 2.80 (s, 1H), 2.50 (d, J=26, 3 Hz, 2H), 2.05 (s, 2H), 1.97-1.82 (m, 2H), 1.06 (d, J=6.7 Hz, 3H);

MSNR (ER) m/z 507.3 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylpiperidin-4- carboxamide (0.040 g, 0.088 mmol) obtained in step 3 of Example 33, cyclohexanone (0.018 ml, 0.177 mmol) and acetic acid (0.005 ml, 0.088 mmol) were dissolved in dichloromethane (0.5 ml), and the resulting solution was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.056 g, 0.265 mmol) was then added and further stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; methanol/dichloromethane = 0% to 20%) and concentrated to give the title compound (0.004 g, 7.6%) as a white solid.

¹ H NMR (400 MHz, MeOD) δ 8.58 (dd, J=1.0, 7.1 Hz, 1H), 8.25-8.22 (m, 1H), 7.92 (s, 1H ), 7.57 (dd, J=1.7, 7.1 Hz, 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, 22.7 Hz, 3H), 2.11-1.81 (m, 8H), 1 .68 (d, J=13.0 Hz, 1H), 1.41-1.31 (m, 5H), 1.20 (dd, J=11.7, 23.7 Hz, 2H);

MSNR (ER) m/z 535.3 (M ⁺ +1).

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)-piperidin-4-carboxamide

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylpiperidin-4- carboxamide (0.050 g, 0.111 mmol) obtained in step 3 of Example 33, 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) was dissolved in dichloromethane (1 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residue and 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 concentrated to give the title compound (0.012 g, 20.7%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) 5 8.31-8.28 (m, 1H), 8.23 (dd, J=1.0, 7.1 Hz, 1H), 7.78 (s, 1H), 7.53 (dd, J=1.7, 7.1 Hz, 1H), 7.46-7.32 (m, 3H), 7.27-7.20 (m, 2H), 6 .95 (t, J=51.7 Hz, 1H), 5.04 (s, 2H), 3.99 (dd, J=4.2, 11.4 Hz, 2H), 3.34 (td, J=2.0, 11.8 Hz, 2H), 2.92 (s, 2H), 2.34 (d, J=64.4 Hz, 2H), 1.88 (d, J=14.6 Hz, 4H), 1.76-1.48 (m, 6H);

MSNR (ER) m/z 537.3 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylpiperidin-4- carboxamide (0.040 g, 0.088 mmol) obtained in step 3 of Example 33, 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) was dissolved in dichloromethane (1 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO ₂ plate 20 x 20 x 1 mm; methanol/dichloromethane = 0% to 20%) and concentrated to give the title compound (0.014 g, 2 8.2%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (s, 1H), 8.23 (d, J=7.1 Hz, 1H), 7.78 (s, 1H), 7.53 (dd , J=1.8, 7.1 Hz, 1H), 7.46-7.32 (m, 3H), 7.27-7.19 (m, 2H), 5.04 (s, 2H), 3.93 (dt, J=3.5, 7.0 Hz, 1H), 2.85 (s, 2H), 2.41-1.51 (m, 15H);

MSNR (ER) m/z 571.4 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylpiperidin-4- carboxamide (0.041 g, 0.091 mmol) obtained in step 3 of Example 33, acetyl chloride (0.031 ml, 0.181 mmol) and triethylamine (0.038 ml, 0.272 mmol) were dissolved in dichloromethane (1 ml) at room temperature, and the resulting solution was stirred at same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; methanol/dichloromethane = 0% to 7%) and concentrated to give the title compound (0.012 g, 26.6%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.30 (s, 1H), 8.23 (d, J=7.2 Hz, 1H), 7.77 (s, 1H), 7.54 (d , J=7.2 Hz, 1H), 7.41 (dkv, J=7.0, 13.7 Hz, 3H), 7.31-7.22 (m, 3H), 6.95 (t, J=51.7 Hz, 1H), 5.14-4.95 (m, 2H), 4.53 (d, J - 13.3 Hz, 1H), 3.77 (d, J=13.5 Hz, 1H), 2.84 (t, J - 13.0 Hz, 1H), 2.49 (d, J=11.1 Hz, 1H), 2.34 (t, J=12.4 Hz, 1H), 2.06 (s, 3H), 1.75 (dd, J=14.2, 4 9.2 Hz, 4H);

MSNR (ER) m/z 4 94.9 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-okeadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylpiperidin-4- carboxamide (0.041 g, 0.091 mmol) obtained in step 3 of Example 33, propionyl chloride (0.017 g, 0.181 mmol) and triethylamine (0.038 ml, 0.272 mmol) were dissolved in dichloromethane (1 ml) at room temperature, and the resulting solution was stirred at that same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; methanol/dichloromethane = 0% to 7%) and concentrated to give the title compound (0.023 g, 49.0%) as an orange solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32-8.26 (m, 1H), 8.23 (dd, J=0.9, 7.1 Hz, 1H), 7.76 (s, 1H), 7.53 (dd, J=1.7, 7.1 Hz, 1H), 7.47-7.33 (m, 3H), 7.29-7.21 (m, 2H), 6 .95 (t, J=51.7 Hz, 1H), 5.10-4.95 (m, 2H), 4.55 (d, J=13.4 Hz, 1H), 3.81 (d, J=13.6 Hz, 1H), 2, 84-2, 74 (m, 1H), 2.50 (ddt, J=4.3, 10.3, 15.0 Hz, 1H), 2.31 (pd, J=4.11, 7.5, 8.6 Hz, 3H), 1.85-1.59 (m, 4H), 1.12 (t, J=7.5 Hz, 3H);

MSNR (ER) m/z 509.2 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylpiperidin-4- carboxamide (0.041 g, 0.091 mmol) obtained in step 3 of example 33,2-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 hexafluorophosphate 3-oxide (HATU, 0.052 g, 0.136 mmol) was 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 solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; methanol/dichloromethane = 0% to 7%) and concentrated to give the title compound (0.012 g, 25.5%) as an orange solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33-8.29 (m, 1H), 8.23 (dd, J=0.9, 7.1 Hz, 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=1.1 Hz, 3H ), 6.95 (t, J=51.7 Hz, 1H), 5.03 (d, J=2.9 Hz, 2H), 4.48 (d, J=13.3 Hz, 1H), 4.18-4.03 (m, 2H), 3.62 (s, 1H), 3.47 (d, J=13.7 Hz, 1H), 2.83-2.72 (m, 1H) , 2.54 (td, J=4.1, 10.1, 10.5 Hz, 2H), 1.85-1.64 (m, 4H);

MSNR (ER) m/z 511.3 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylpiperidin-4- carboxamide (0.041 g, 0.091 mmol) obtained in step 3 of Example 33, cyclobutanecarbonyl chloride (0.021 g, 0.181 mmol) and triethylamine (0.038 ml, 0.272 mmol) were dissolved in dichloromethane (1 ml) at room temperature, and the resulting solution was stirred at that same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO ₂ plate, 20 x 20 x 1 mm; methanol/dichloromethane = 0% to 7%) and concentrated to give the title compound (0.020 g, 40.9%) as an orange gel.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.30 (dt, J=0.8, 1.7 Hz, 1H), 8.23 (dd, J=1.0, 7.1 Hz, 1H) , 7.77 (s, 1H), 7.53 (dd, J=1.7, 7.1 Hz, 1H), 7.4 6-7.35 (m, 3H), 7.2 8-7 .24 (m, 2H), 6.95 (t, J=51.7 Hz, 1H), 5.10-4.95 (m, 2H), 4.52 (d, J=13.6 Hz, 1H), 3.66 (d, J=13.4 Hz, 1H), 3.25-3.15 (m, 1H), 2.71 (t, J=11.7 Hz, 1H), 2, 48 (ddt, J=4.4, 10.4, 15.0 Hz, 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);

MSNR (ER) m/z 535.1 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylpiperidin-4- carboxamide (0.050 g, 0.111 mmol) obtained 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 hexafluorophosphate 3-oxide (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 within 18 hours. Saturated aqueous sodium hydrogen carbonate was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; methanol/dichloromethane = 0% to 7%) and concentrated to give the title compound (0.007 g, 12.0%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (s, 1H), 8.23 (dd, J=1.0, 7.1 Hz, 1H), 7.76 (s, 1H), 7 .55 (dd, J=1.7, 7.1 Hz, 1H), 7.48-7.35 (m, 3H), 7.30-7.23 (m, 2H), 7.02 (d , J=51.7 Hz, 1H), 5.03 (D, J=4.3 Hz, 2H), 4.93 (dd, J - 5.9, 7.2 Hz, 1H), 4.85 (dd, J=5.9, 7.2 Hz, 1H), 4.76 (dd, J - 5.8, 8.7, 10.1 Hz, 2H), 4.52 (d, J=13 .4 Hz, 1H), 3.96 (tt, J=7.2, 8.7 Hz, 1H), 3.30 (d, J=13.6, 1H), 2.78-2.70 ( m, 1H), 2.50 (d, J=4.8, 1H), 2.46-2.38 (m, 1H), 1H);

MSNR (ER) m/z 537.2 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-okeadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylpiperidin-4- carboxamide (0.041 g, 0.091 mmol) obtained in step 3 of Example 33, 2,2,2-trifluoroacetic anhydride (0.025 ml, 0.181 mmol) and triethylamine (0.038 ml, 0.272 mmol) 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 hydrogen carbonate was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO ₂ plate 20 x 20 x 1 mm; methanol/dichloromethane = 0% to 7%) and concentrated to give the title compound (0.020 g, 4 0.0%) as a pale red solid colors.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33-8.26 (m, 1H), 8.23 (dd, J=0.9, 7.1 Hz, 1H), 7.77 (s, 1H), 7.54 (dd, J=1.7, 7.1 Hz, 1H), 7.43 (ddd, J=5.9, 7.9, 10.5 Hz, 3H), 7.28 (d, J=6.2 Hz, 2H), 6.95 (t, J=51.7 Hz, 1H), 5.03 (s, 2H), 4.45-4.33 (m, 1H) , 3.97 (d, J=14.0 Hz, 1H), 3.01-2.88 (m, 1H), 2.72-2.53 (m, 2H), 1.94-1.65 (m, 4H);

MSNR (ER) m/z 549.3 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylpiperidin-4- carboxamide (0.041 g, 0.091 mmol) obtained in step 3 of example 33, methanesulfonyl chloride (0.014 ml, 0.181 mmol) and triethylamine

(0.038 ml, 0.272 mmol) was dissolved in dichloromethane (1 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; methanol/dichloromethane = 0% to 7%) and concentrated to give the title compound (0.008 g, 15.6%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 8.25 (dd, J=1.0, 7.1 Hz, 1H), 7.78 (s, 1H), 7 .56 (dd, J=1.7, 7.1 Hz, 1H), 7.48-7.36 (m, 3H), 7.28-7.25 (m, 2H), 6.95 (t , J=51.7 Hz, 1H), 5.05 (s, 2H), 3.74 (dd, J=6.0, 10.1 Hz, 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, 13.6 Hz, 2H);

MSNR (ER) m/z 531.1 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylpiperidin-4- carboxamide (0.041 g, 0.091 mmol) obtained in step 3 of Example 33, methyl chloroformate (0.017 g, 0.181 mmol) and triethylamine (0.025 ml, 0.181 mmol) were dissolved in dichloromethane (1 ml) at room temperature, and the resulting solution was stirred at that same temperature for 18 hours. Water was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO ₂ plate 20 x 20 x 1 mm; methanol/dichloromethane = 0% to 7%) and concentrated to give the title compound (0.020 g, 43.7%) as a pale orange solid .

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (dt, J=0.9, 1.8 Hz, 1H), 8.23 (dd, J=0.9, 7.1 Hz, 1H) , 7.77 (s, 1H), 7.53 (dd, J=1.7, 7.1 Hz, 1H), 7.4 6-7.35 (m, 3H), 7.2 6-7 .23 (m, 2H), 6.95 (t, J=51.7 Hz, 1H), 5.03 (s, 2H), 4.09 (s, 2H), 3.67 (s, 3H) , 2.53 (s, 2H), 2.43 (tt, J=3.8, 11.2 Hz, 1H), 1.76 (kvd, J=4.4, 11.9, 12.4 Hz , 2H), 1.62 (d, J=12.8 Hz, 2H);

MSNR (ER) m/z 511.1 (M ⁺ +1).

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-N-phenylpiperidine-1,4-dicarboxamide

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylpiperidin-4- carboxamide (0.041 g, 0.091 mmol) obtained in step 3 of Example 33, dimethylcarbamic acid chloride (0.019 g, 0.181 mmol) and triethylamine (0.025 ml, 0.181 mmol) were dissolved in dichloromethane (1 ml) at room temperature, and the resulting the solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; methanol/dichloromethane = 0% to 7%) and concentrated to give the title compound (0.024 g, 51.4%) as a red gel.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (dt, J=0.8, 1.7 Hz, 1H), 8.23 (dd, J=1.0, 7.1 Hz, 1H) , 7.77 (s, 1H), 7.53 (dd, J=1.7, 7.1 Hz, 1H), 7.40 (dddd, J=2.3, 4.6, 6.8, 11.7 Hz, 3H), 7.27-7.23 (m, 2H), 6.95 (t, J=51.7 Hz, 1H), 5.03 (s, 2H), 3.59 ( dd, J=3.8, 13.3 Hz, 2H), 2.79 (s, 6H), 2.44 (dtd, J=5.1, 11.5, 12.2, 16.5 Hz, 3H), 1.82 (kvd, J=4.0, 12.6 Hz, 2H), 1.64 (dd, J=3.5, 13.7 Hz, 2H);

MSNR (ER) m/z 524.4 (M ⁺ +1).

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)-piperidin-4-carboxamide

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylpiperidin-4- carboxamide (0.025 g, 0.055 mmol) obtained in step 3 of Example 33, 2-bromopyridine (0.017 g, 0.111 mmol), cesium carbonate (0.036 g, 0.111 mmol) and palladium RuPhos G2 (0.002 g, 0.003 mmol) were dissolved in 1 ,4-dioxane (0.5 ml) at room temperature, and the resulting

the solution was stirred at 120°C for 18 hours. The temperature was then lowered to room temperature to complete the reaction. A saturated aqueous solution of sodium hydrogen carbonate was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; methanol/dichloromethane = 0% to 7%) and concentrated to give the title compound (0.006 g, 19.1%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.30 (p, J=0.8 Hz, 1H), 8.23 (dd, J=1.0, 7.1 Hz, 1H), 8.15 (ddd, J=0.9, 2.0, 4.9 Hz, 1H), 7.79 (s, 1H), 7.54 (dd, J=1.7, 7.1 Hz, 1H), 7.48-7.37 (m, 4H), 7.31-7.26 (m, 2H), 6.95 (t, J=51.7 Hz, 1H), 6.63-6.55 ( m, 2H), 5.05 (s, 2H), 4.25 (d, J=13.1 Hz, 2H), 2.57 (dt, J=11.9, 34.6 Hz, 3H), 1.90 (kvd, J=4.2, 12.7 Hz, 2H), 1.73 (d, J=13.1 Hz, 2H);

MSNR (ER) m/z 530.3 (M ⁺ +1).

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)-piperidin-4-carboxamide

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylpiperidin-4- carboxamide (0.041 g, 0.091 mmol) obtained in step 3 of example 33, 2-chloropyrimidine (0.021 g, 0.181 mmol) and potassium carbonate (0.038 g, 0.272 mmol) 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 solution of sodium hydrogen carbonate was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; methanol/dichloromethane = 0% to 7%) and concentrated to give the title compound (0.022 g, 45.6%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29-8.25 (m, 3H), 8.22 (dd, J=1.0, 7.1 Hz, 1H), 7.78 (s, 1H), 7.52 (dd, J=1.7, 7.1 Hz, 1H), 7.47-7.36 (m, 3H), 7.29-7.26 (m, 2H), 6 .95 (t, J=51.7 Hz, 1H), 6.44 (t, J=4.7 Hz, 1H), 5.04 (s, 2H), 4.71 (dt, J=3, 4, 13.5 Hz, 2H), 2.70-2.52 (m, 3H), 1.83 (dkv, J=5.8, 7.6, 19.8 Hz, 2H), 1.70 (dd, J=3.6, 13.9 Hz, 2H);

MSNR (ER) m/z 531.3 (M ⁺ +1).

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

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

1-(tert-butoxycarbonyl)-piperidine-4-carboxylic acid (1.000 g, 4.361 mmol), oxalyl chloride (2.00 M dry solution in DCM, 2.835 ml, 5.670 mmol) and N,N-dimethylformamide (0.034 ml, 0.436 mmol) was 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.

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-3-fluoroaniline (1,000 g , 2.783 mmol) obtained in Example 16, tert-butyl-4-(chlorocarbonyl)-piperidine-1-carboxylate (1.034 g, 4.175 mmol) and triethylamine (1.164 ml, 8.349 mmol) were dissolved in dichloromethane (15 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. An aqueous solution of ammonium chloride was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate/hexane = 0% to 90%) and concentrated to give the title compound (0.680 g, 4 2.8%) as a pale orange solid.

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

Tert-butyl-4-(((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-( 3-fluorophenyl)-carbamoyl)-piperidine-1-carboxylate (1000 g, 1.753 mmol) obtained in step 2 and trifluoroacetic acid (2.684 ml, 35.053 mmol) were dissolved in dichloromethane (30 ml) at room temperature, and the resulting solution stirred at the same temperature for 3 hours. A saturated aqueous solution of sodium hydrogen carbonate 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 give the title compound (0.824 g, 99.9%) as a brown gel without further purification.

[Step 4] 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 )-piperidine-4-carboxamide (0.060 g, 0.128 mmol) obtained in step 3, 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) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.024 g, 38.8%) as a yellow solid.

^1H NMR (700 MHz, CDCl ₃ ) δ 8.29 (d, J=1.7 Hz, 1H), 8.24 (dd, J=7.1, 1.0 Hz, 1H), 7.79 (s, 1H), 7.54 (dd, J=7.1, 1.7 Hz, 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);

MSNR (ER) m/z 485.3 (M ⁺ +1).

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

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) obtained in step 3 of Example 93, acetaldehyde (0.011 g, 0.255 mmol), acetic acid (0.007 ml, 0.128 mmol) and sodium triacetoxyborohydride (0.081 g, 0.383 mmol) dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.031 g, 48.8%) as a yellow solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.30 (dt, J=1.7, 0.8 Hz, 1H), 8.24 (ddd, J=7.1, 2.9, 1.0 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 7.55 (dd, J=7.2, 1.7 Hz, 1H), 7.40 (tdd, J=8 ,2, 6.3, 1.8 Hz, 1H), 7.13-6.80 (m, 4H), 5.02 (s, 2H), 3.00 (s, 1H), 2.50- 2.21 (m, 3H), 1.9 9-1.62 (m, 7H), 1.12 (s, 3H); MSNR (ER) m/z 499.3 (M ⁺ +1).

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

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) obtained from step 3 of Example 93, 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) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.018 g, 27.5%) as a yellow solid.

^1H NMR (700 MHz, CDCl ₃ ) δ 8.30 (d, J=1.6 Hz, 1H), 8.24 (dd, J=7.1, 1.0 Hz, 1H), 7.78 (s, 1H), 7.55 (dd, J=7.1, 1.7 Hz, 1H), 7.39 (td, J=8.1, 6.3 Hz, 1H), 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);

MSNR (ER) m/z 512.9 (M ⁺ +1).

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)-piperidin-4-carboxamide

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, 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) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.019 g, 28.2%) as a yellow solid.

¹ H NMR (700 MHz, CDCl ₃ ) δ 8.31 (dt, J=1.7, 0.8 Hz, 1H), 8.25 (dd, J=7.1, 1.0 Hz, 1H) , 7.78 (s, 1H), 7.56 (dd, J=7.1, 1.7 Hz, 1H), 7.41 (td, J=8.1, 6.3 Hz, 1H), 7.12 (dt, J=8.3, 4.6 Hz, 1H), 7.0 9-7.04 (m, 2H), 7.04-6.8 8 (m, 1H), 5, 02 (s, 2H), 3.40 (d, J=64.6 Hz, 3H), 2.98-2.69 (m, 3H), 1.96 (d, J=11.2 Hz, 2H ), 1.84 (s, 2H), 0.93-0.8 0 (m, 5H);

MSNR (ER) m/z 529.3 (M ⁺ +1).

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

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) obtained from step 3 of Example 93, cyclobutanone (0.018 g, 0.255 mmol), acetic acid (0.007 ml, 0.128 mmol) and sodium triacetoxyborohydride (0.081 g, 0.383 mmol) dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.022 g, 32.9%) as a yellow solid.

¹ H NMR (700 MHz, CDCl ₃ ) δ 8.29 (d, J=1.6 Hz, 1H), 8.24 (dd, J=7.1, 1.0 Hz, 1H), 7.78 (s, 1H), 7.55 (dd, J=7.1, 1.7 Hz, 1H), 7.39 (td, J=8.1, 6.3 Hz, 1H), 7.10 ( dt, J=8.7, 4.7 Hz, 1H), 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=10.9 Hz, 4H), 1.65 (s, 4H), 1.56-1.44 (m, 2H);

MSNR (ER) m/z 525.2 (M ⁺ +1).

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-(oxetan-3-yl)-piperidin-4-carboxamide

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, oxetan-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) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.032 g, 47.7%) as a yellow solid.

¹ H NMR (700 MHz, CDCl ₃ ) δ 8.30 (dd, J=1.8, 0.9 Hz, 1H), 8.24 (dd, J=7.1, 1.0 Hz, 1H) , 7.78 (s, 1H), 7.55 (dd, J=7.1, 1.7 Hz, 1H), 7.40 (td, J=8.1, 6.3 Hz, 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=12.2 Hz, 2H), 1.66 (s, 4H);

MSNR (ER) m/z 527.0 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-okeadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-(3-fluorophenyl )-piperidine-4-carboxamide (0.060 g, 0.128 mmol) obtained from step 3 of Example 93, cyclohexanone (0.025 g, 0.255 mmol), acetic acid (0.007 ml, 0.128 mmol) and sodium triacetoxyborohydride (0.081 g, 0.383 mmol) dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.014 g, 19.9%) as a yellow solid.

¹ H NMR (700 MHz, CDCl ₃ ) δ 8.32-8.26 (m, 1H), 8.23 (dd, J=7.1, 1.0 Hz, 1H), 7.78 (s, 1H), 7.53 (dd, J=7.1, 1.7 Hz, 1H), 7.38 (td, J=8.1, 6.3 Hz, 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=13.1 Hz, 2H), 1.21 (d, J=14.6 Hz, 4H); MSNR (ER) m/z 553.1 (M ⁺ +1).

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)-piperidin-4-carboxamide

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) obtained from step 3 of Example 93, tetrahydro-4H-pyran-4-one (0.026 g, 0.255 mmol), acetic acid (0.007 ml, 0.128 mmol) and triacetoxyborohydride sodium (0.081 g, 0.383 mmol) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.016 g, 22.6%) as a yellow solid.

¹ H NMR (700 MHz, CDCl ₃ ) δ 8.33-8.27 (m, 1H), 8.24 (dd, J=7.1, 1.0 Hz, 1H), 7.83-7, 74 (m, 1H), 7.55 (dd, J=7.1, 1.7 Hz, 1H), 7.40 (td, J=8.1, 6.3 Hz, 1H), 7.10 (ddd, J=8.4, 5.5, 2.2 Hz, 1H), 7.09-6.86 (m, 3H), 5.02 (s, 2H), 4.04-3.95 (m, 2H), 3.35 (t, J=11.7 Hz, 2H), 2.93 (s, 2H), 2.45 (d, J=22.4 Hz, 1H), 2.31 -2.20 (m, 1H), 1.89 (d, J=10.6 Hz, 4H), 1.67 (s, 4H), 1.56 (d, J=11.5 Hz, 2H) ;

MSNR (ER) m/z 555.3 (M ⁺ +1).

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)-piperidin-4-carboxamide

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-(3-fluorophenyl )-piperidin-4-carboxamide (0.060 g, 0.128 mmol) obtained from step 3 of Example 93, 4,4-difluorocyclohexan-1-one (0.034 g, 0.255 mmol), acetic acid (0.007 ml, 0.128 mmol) and triacetoxyborohydride sodium (0.081 g, 0.383 mmol) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.026 g, 34.6%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31-8.27 (m, 1H), 8.23 (dd, J=7.1, 1.0 Hz, 1H), 7.78 (s, 1H), 7.53 (dd, J=7.1, 1.7 Hz, 1H), 7.39 (td, J=8.1, 6.3 Hz, 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=11.6 Hz, 2H), 1.9 6 (s, 2H), 1.92-1.54 (m, 1H);

MSNR (ER) m/z 589.2 (M ⁺ +1).

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

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) obtained in step 3 of Example 93, acetyl chloride (0.018 ml, 0.255 mmol) and triethylamine (0.053 ml, 0.383 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 solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.021 g, 32.1%) as a yellow solid.

¹ H NMR (700 MHz, CDCl ₃ ) δ 8.46 (s, 1H), 8.34-8.26 (m, 1H), 7.82 (s, 1H), 7.69 (dd, J= 7.1, 1.7 Hz, 1H), 7.45 (td, J=8.2, 6.3 Hz, 1H), 7.17-7.13 (m, 2H), 7.12-7 .09 (m, 1H), 6.97 (t, J=51.7 Hz, 1H), 5.06 (s, 2H), 4.55 (d, J=13.6 Hz, 1H), 3 .80 (d, J=13.6 Hz, 1H), 2.88 (t, J=13.8 Hz, 1H), 2.53 (d, J=11.2 Hz, 1H), 2, 4 4-2.34 (m, 1H), 2.07 (s, 3H), 1.84-1.63 (m, 4H);

MSNR (ER) m/z 513.0 (M ⁺ +1).

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

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) obtained in step 3 of Example 93, propionyl chloride (0.024 g, 0.255 mmol) and triethylamine (0.053 ml, 0.383 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 solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.010 g, 14.9%) as a yellow solid.

¹ H NMR (700 MHz, CDCl ₃ ) δ 8.33 (s, 1H), 8.25 (dd, J=7.1, 1.0 Hz, 1H), 7.78 (s, 1H), 7 .57 (dd, J=7.2, 1.6 Hz, 1H), 7.42 (td, J=8.1, 6.2 Hz, 1H), 7.16-7.05 (m, 3H ), 6.96 (t, J=51.7 Hz, 1H), 5.08-4.94 (m, 2H), 4.57 (dd, J=11.2, 6.8 Hz, 1H) , 3.83 (d, J=13.7 Hz, 1H), 2.88-2.74 (m, 1H), 2.52 (td, J=11.8, 11.0, 5.7 Hz , 1H), 2.33 (dddd, J=23.0, 17.7, 15.3, 10.0 Hz, 4H), 1.83-1.74 (m, 1H), 1.74-1 .61 (m, 2H), 1.13 (t, J=7.5, 3H);

MSNR (ER) m/z 527.0 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-okeadiazol-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 hexafluorophosphate 3-oxide (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 solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.017 g, 25.2%) as a yellow solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.31 (dt, J=1.7, 0.9 Hz, 1H), 8.24 (dd, J=7.1, 1.0 Hz, 1H) , 7.76 (s, 1H), 7.55 (dd, J=7.1, 1.7 Hz, 1H), 7.42 (td, J=8.3, 6.3 Hz, 1H), 7.16-6.78 (m, 4H), 5.01 (s, 2H), 4.48 (d, J=13.7 Hz, 1H), 4.18-4.01 (m, 2H) , 3.48 (d, J=13.7 Hz, 1H), 2.86-2.73 (m, 1H), 2.63-2.44 (m, 2H), 1.84-1.62 (m, 4H);

MSNR (ER) m/z 529.0 (M ⁺ +1).

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

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) obtained in step 3 of Example 93, cyclobutanecarbonyl chloride (0.023 g, 0.197 mmol) and triethylamine (0.041 ml, 0.296 mmol) 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 hydrogen carbonate was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residue and 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 resulting product was purified again by chromatography (SiO ₂ plate 20x20x1 mm; methanol /1% aqueous dichloromethane = 0% to 7%) and concentrated to give the title compound (0.011 g, 20.0%) as a yellow gel.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (d, J=1.6 Hz, 1H), 8.24 (dd, J=1.0, 7.1 Hz, 1H), 7.77 (s, 1H), 7.55 (dt, J=1.2, 7.0 Hz, 1H), 7.41 (td, J=6.3, 8.3 Hz, 1H), 7.16- 6.80 (m, 4H), 5.01 (d, J=3.4 Hz, 2H), 4.53 (d, J=13.3 Hz, 1H), 3.68 (d, J=13 .6 Hz, 1H), 3.21 (p, J=8.5 Hz, 1H), 2.74 (t, J=12.7 Hz, 1H), 2.48 (d, J=12.2 Hz, 1H), 2.34 (dd, J=9.3, 11.8, 20.7 Hz, 3H), 2.12 (dd, J=3.6, 8.2, 11.8 Hz, 2H), 2.00-1.59 (m, 6H);

MSNR (ER) m/z 553.4 (M ⁺ +1).

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

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 hexafluorophosphate 3-oxide (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 the solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residue and 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 resulting product was purified again by chromatography (SiO ₂ plate 20x20x1 mm; methanol /1% aqueous dichloromethane = 0% to 7%) and concentrated to give the title compound (0.016 g, 27.3%) as a yellow solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.34-8.28 (m, 1H), 8.24 (dd, J=1.0, 7.1 Hz, 1H), 7.76 (s, 1H), 7.56 (dd, J=1.7, 7.2 Hz, 1H), 7.42 (td, J=6.2, 8.2 Hz, 1H), 7.16-6.82 (m, 4H), 5.01 (d, J=1.6 Hz, 2H), 4.93 (dd, J=5.9, 7.2 Hz, 1H), 4.86 (dd, J= 5.9, 7.2 Hz, 1H), 4.77 (td, J=5.9, 8.6 Hz, 2H), 4.53 (d, J=13.4 Hz, 1H), 4, 01-3.91 (m, 1H), 3.31 (d, J=13.5 Hz, 1H), 2.77 (t, J=11.9, 1H), 2.56-2.38 ( m, 2H), 1.71 (d, J=18.8 Hz, 4H);

MSNR (ER) m/z 555.4 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-okeadiazol-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, 2,2,2-trifluoroacetic anhydride (0.045 g, 0.213 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 aqueous sodium hydrogen carbonate was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; methanol/dichloromethane = 0% to 7%) and concentrated to give the title compound (0.020 g, 33.6%) as a brown solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33-8.28 (m, 1H), 8.24 (dd, J=1.0, 7.1 Hz, 1H), 7.77 (s, 1H), 7.56 (dd, J=1.7, 7.2 Hz, 1H), 7.43 (td, J=6.3, 8.3 Hz, 1H), 7.17-6.77 (m, 4H), 5.01 (s, 2H), 4.46-4.34 (m, 1H), 3.98 (d, J=14.0 Hz, 1H), 3.06-2, 94 (m, 1H), 2.74-2.53 (m, 1H), 1.94-1.68 (m, 4H);

MSNR (ER) m/z 566.7 (M ⁺ +1).

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

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) obtained in step 3 of Example 93, methanesulfonyl chloride (0.016 ml, 0.213 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 aqueous sodium hydrogen carbonate was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; methanol/dichloromethane = 0% to 7%) and concentrated to give the title compound (0.005 g, 8.7%) as a brown solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.32 (d, J=1.5 Hz, 1H), 8.25 (dd, J=1.0, 7.2 Hz, 1H), 7.78 (s, 1H), 7.57 (dd, J=1.7, 7.1 Hz, 1H), 7.46-7.39 (m, 1H), 7.16-6.77 (m, 4H ), 5.02 (s, 2H), 3.76 (d, J=12.3 Hz, 2H), 2.75 (s, 3H), 2.57 (t, J=11.6 Hz, 2H ), 2.40 (d, J=11.4 Hz, 1H), 2.01-1.84 (m, 2H), 1.75 (d, J=13.5 Hz, 2H);

MSNR (ER) m/z 549.4 (M ⁺ +1).

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

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) obtained in step 3 of Example 93, methyl chloroformate (0.020 g, 0.213 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 aqueous sodium hydrogen carbonate was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; methanol/dichloromethane = 0% to 7%) and concentrated to give the title compound (0.021 g, 35.2%) as a red solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32-8.27 (m, 1H), 8.23 (dd, J=1.0, 7.2 Hz, 1H), 7.77 (s, 1H), 7.54 (dd, J=1.7, 7.1 Hz, 1H), 7.40 (td, J=6.4, 8.3 Hz, 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 ( kvd, J=4.4, 11.9, 12.4 Hz, 2H), 1.62 (d, J=13.1 Hz, 2H);

MSNR (ER) m/z 529.1 (M ⁺ +1).

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

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) obtained in step 3 of Example 93, dimethylcarbamic acid chloride (0.023 g, 0.213 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 aqueous sodium hydrogen carbonate was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO ₂ plate 20 x 20 x 1 mm; methanol/dichloromethane = 0% to 7%) and concentrated to give the title compound (0.019 g, 33.5%) as a pale red solid .

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32-8.28 (m, 1H), 8.24 (dd, J=1.0, 7.1 Hz, 1H), 7.78 (s, 1H), 7.55 (dd, J=1.7, 7.1 Hz, 1H), 7.41 (td, J=6.4, 8.3 Hz, 1H), 7.15-6.81 (m, 4H), 5.02 (s, 2H), 3.61 (d, J=13.2 Hz, 2H), 2.80 (s, 6H), 2.57-2.37 (m, 3H), 1.82 (kvd, J=4.0, 12.6 Hz, 2H), 1.64 (d, J=12.8 Hz, 2H);

MSNR (ER) m/z 542.0 (M ⁺ +1).

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)-piperidin-4-carboxamide

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, 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) was dissolved in 1,4-dioxane (1 ml) at room temperature, and the resulting solution was stirred at 120°C for 18 hours. The temperature was then lowered to room temperature to complete the reaction. A saturated aqueous solution of sodium hydrogen carbonate was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; methanol/dichloromethane = 0% to 7%) and concentrated to give the title compound (0.013 g, 22.2%) as a brown solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33-8.29 (m, 1H), 8.23 (dd, J=1.0, 7.1 Hz, 1H), 8.16 (dd, J=0.8, 2.0, 5.0 Hz, 1H), 7.79 (s, 1H), 7.55 (dd, J=1.7, 7.1 Hz, 1H), 7.48 -7.36 (m, 2H), 7.16-6.80 (m, 4H), 6.65-6.55 (m, 2H), 5.03 (s, 2H), 4.26 (d , J=13.5 Hz, 2H), 2.65 (t, J=12.6 Hz, 2H), 2.53 (s, 1H), 1.89 (kvd, J=4.1, 12, 5 Hz, 2H), 1.72 (d, J=13.1 Hz, 2H);

MSNR (ER) m/z 548.2 (M ⁺ +1).

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)-piperidin-4-carboxamide

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, 2-chloropyrimidine (0.024 g, 0.213 mmol) and potassium carbonate (0.044 g, 0.319 mmol) 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 solution of sodium hydrogen carbonate was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The resulting product was then filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. Dichloromethane (3 mL) was added to the concentrate, then stirred, and the precipitated solid was filtered, washed with dichloromethane, and dried to give the title compound (0.018 g, 30.5%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31-8.26 (m, 3H), 8.23 (dd, J=0.9, 7.1 Hz, 1H), 7.78 (s, 1H), 7.54 (dd, J=1.7, 7.1 Hz, 1H), 7.43 (td, J=6.5, 8.3 Hz, 1H), 7.15-6.81 (m, 4H), 6.46 (t, J=4.7 Hz, 1H), 5.02 (s, 2H), 4.73 (dt, J=3.5, 13.4 Hz, 2H) , 2.69 (t, J=13.0 Hz, 2H), 2.56 (d, J=11.5 Hz, 1H), 1.83 (kvd, J=4.2, 12.0, 12 .5 Hz, 2H), 1.71 (d, J=13.0 Hz, 2H);

MSNR (ER) m/z 549.4 (M ⁺ +1).

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

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

1-(tert-butoxycarbonyl)-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 were added. N-dimethylformamide (0.046 mL, 0.596 mmol) 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.

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

To a solution in which N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)- aniline (1.500 g, 4.395 mmol) obtained in Example 14 and triethylamine (1.838 ml, 13.184 mmol) in dichloromethane (150 ml) at room temperature, tert-butyl 3-(chlorocarbonyl)-azetidine-1-carboxylate ( 1.255 g, 5.713 mmol) 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 solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane = 5% to 60%) and concentrated to give the title compound (1.600 g, 69.4%) as a beige solid.

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

Tert-butyl-3-(((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-( Phenyl)-carbamoyl)-azetidine-1-carboxylate (0.600 g, 1.144 mmol) obtained in step 2 and trifluoroacetic acid (1.752 ml, 22.87 8 mmol) were dissolved in dichloromethane (7 ml) at room temperature, and the resulting solution was stirred at the same temperature for 2 hours. A saturated aqueous solution of sodium hydrogen carbonate 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 give the title compound (0.485 g, 99.9%) as a brown gel without further purification.

[Step 4] Synthesis of compound 4158

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylazetidin-3- carboxamide (0.050 g, 0.118 mmol) obtained in step 3, formaldehyde (0.007 g, 0.236 mmol), acetic acid (0.007 ml, 0.118 mmol) and sodium triacetoxyborohydride (0.075 g, 0.353 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 sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.014 g, 27.1%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (dt, J=1.8, 0.8 Hz, 1H), 8.23 (dd, J=7.1, 1.0 Hz, 1H) , 7.79 (s, 1H), 7.54 (dd, J=7.1, 1.7 Hz, 1H), 7.44-7.34 (m, 3H), 7.19-7.13 (m, 2H), 6.95 (t, J=51.7 Hz, 1H), 5.05 (s, 2H), 3.3 9-3.2 8 (m, 5H), 2.35 ( s, 3H);

MSNR (ER) m/z 439.3 (M ⁺ +1).

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

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) obtained from step 3 of Example 113, acetaldehyde (0.010 g, 0.236 mmol), acetic acid (0.007 ml, 0.118 mmol) and sodium triacetoxyborohydride (0.075 g, 0.353 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 sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.022 g, 41.3%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (dt, J=1.7, 0.8 Hz, 1H), 8.23 (dd, J=7.1, 1.0 Hz, 1H) , 7.78 (s, 1H), 7.54 (dd, J=7.1, 1.7 Hz, 1H), 7.4 5-7.34 (m, 3H), 7.21-7, 13 (m, 2H), 6.95 (t, J=51.7 Hz, 1H), 5.06 (s, 2H), 3.39 (s, 5H), 2.60 (s, 2H), 0.99 (t, J=7.1 Hz, 3H);

MSNR (ER) m/z 453.4 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylazetidin-3- carboxamide (0.050 g, 0.118 mmol) obtained in step 3 of Example 113, 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) 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 hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO ₂ plate 20 x 20 x 1 mm; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.024 g, 4 3.7%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.31 (dt, J=1.8, 0.8 Hz, 1H), 8.23 (dd, J=7.2, 1.0 Hz, 1H) , 7.76 (s, 1H), 7.54 (dd, J=7.1, 1.7 Hz, 1H), 7.4 4-7.35 (m, 3H), 7.2 0-7 .13 (m, 2H), 6.95 (t, J=51.7 Hz, 1H), 5.06 (s, 2H), 3.40 (s, 5H), 2.63 (s, 1H) , 1.01 (d, J=5.4 Hz, 6H);

MSNR (ER) m/z 467.4 (M ⁺ +1).

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-phenylazetidin-3-carboxamide

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylazetidin-3- carboxamide (0.050 g, 0.118 mmol) obtained from step 3 of Example 113, 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) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.029 g, 51.0%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (dt, J=1.7, 0.8 Hz, 1H), 8.24 (dd, J=7.1, 1.0 Hz, 1H) , 7.80-7.73 (m, 1H), 7.55 (dd, J=7.1, 1.7 Hz, 1H), 7.44-7.36 (m, 3H), 7.20 -7.14 (m, 2H), 6.95 (t, J=51.7 Hz, 1H), 5.06 (s, 2H), 3.64-3.28 (m, 7H), 2, 64 (s, 1H), 1.02 (d, J=6.5 Hz, 3H);

MSNR (ER) m/z 483.4 (M ⁺ +1).

Example 117: Synthesis of Compound 4162, 1-cyclobutyl-17-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl )-methyl)-N-phenylazetidine-3-carboxamide

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylazetidin-3- carboxamide (0.050 g, 0.118 mmol) obtained in step 3 of Example 113, cyclobutanone (0.017 g, 0.236 mmol), acetic acid (0.007 ml, 0.118 mmol) and sodium triacetoxyborohydride (0.075 g, 0.353 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 sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.018 g, 31.9%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (dt, J=1.7, 0.8 Hz, 1H), 8.23 (dd, J=7.2, 1.0 Hz, 1H) , 7.76 (s, 1H), 7.55 (dd, J=7.1, 1.7 Hz, 1H), 7.44-7.35 (m, 3H), 7.16 (dd, J =7.8, 1.9 Hz, 2H), 6.95 (t, J=51.7 Hz, 1H), 5.06 (s, 2H), 3.60-3.28 (m, 5H) , 2.04 (d, J=11.2 Hz, 4H), 1.84 (s, 1H), 1.71 (kv, J=9.2 Hz, 2H);

MSNR (ER) m/z 479.0 (M ⁺ +1).

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-(oxetan-3-yl)-N-phenylazetidin-3-carboxamide

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylazetidin-3- carboxamide (0.050 g, 0.118 mmol) obtained in step 3 of Example 113, oxetan-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) 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 hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.019 g, 33.6%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.32 (dt, J=1.6, 0.8 Hz, 1H), 8.23 (dd, J=7.1, 1.0 Hz, 1H) , 7.78 (s, 1H), 7.54 (dd, J=7.1, 1.7 Hz, 1H), 7.4 5-7.3 6 (m, 3H), 7.21-7 .15 (m, 2H), 6.95 (t, J=51.7 Hz, 1H), 5.06 (s, 2H), 4.69 (t, J=6.8 Hz, 2H), 4 .53 (t, J=6.1 Hz, 2H), 3.81 (s, 1H), 3.54-3.29 (m, 5H);

MSNR (ER) m/z 481.4 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylazetidin-3- carboxamide (0.050 g, 0.118 mmol) obtained in step 3 of Example 113, cyclohexanone (0.023 g, 0.236 mmol), acetic acid (0.007 ml, 0.118 mmol) and sodium triacetoxyborohydride (0.075 g, 0.353 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 sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.028 g, 4 to 6.9%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34-8.29 (m, 1H), 8.23 (dd, J=7.2, 1.0 Hz, 1H), 7.77 (s, 1H), 7.54 (dd, J=7.1, 1.7 Hz, 1H), 7.44-7.34 (m, 3H), 7.17 (dd, J=8.0, 1, 7 Hz, 2H), 6.95 (t, J=51.7 Hz, 1H), 5.06 (s, 2H), 3.40 (s, 4H), 1.73 (d, J=10, 2 Hz, 5H), 1.61 (s, 2H), 1.17 (d, J=9.2 Hz, 5H);

MSNR (ER) m/z 507.4 (M ⁺ +1).

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)-azetidin-3-carboxamide

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylazetidin-3- carboxamide (0.050 g, 0.118 mmol) obtained in step 3 of Example 113, 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) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.023 g, 38.4%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.32-8.30 (m, 1H), 8.23 (dd, J=7.1, 1.0 Hz, 1H), 7.77 (s, 1H), 7.54 (dd, J=7.1, 1.7 Hz, 1H), 7, 44-7, 34 (m, 3H), 7.20-7.14 (m, 2H), 6 .95 (t, J=51.7 Hz, 1H), 5.06 (s, 2H), 3.94 (d, J=11.8 Hz, 2H), 3.35 (td, J=11, 4, 2.3 Hz, 6H), 2.35 (s, 1H), 1.84-1.69 (m, 1H), 1.64 (d, J=12.8 Hz, 2H), 1, 28 (s, 2H);

MSNR (ER) m/z 509.0 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylazetidin-3- carboxamide (0.050 g, 0.118 mmol) obtained in step 3 of Example 113, 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) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.031 g, 48.5%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (dt, J=1.7, 0.8 Hz, 1H), 8.23 (dd, J=7.1, 1.0 Hz, 1H) , 7.78 (s, 1H), 7.54 (dd, J=7.1, 1.7 Hz, 1H), 7.44-7.34 (m, 3H), 7.22-7.16 (m, 2H), 6.95 (t, J=51.7 Hz, 1H), 5.05 (s, 2H), 3.28 (kv, J=7.5, 6.9 Hz, 1H) , 3.19 (s, 4H), 2.21 (s, 1H), 2.00 (s, 2H), 1.68 (kV, J=14.1 Hz, 4H), 1.39 (s, 2H);

MSNR (ER) m/z 543.5 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-okeadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylazetidin-3- carboxamide (0.050 g, 0.118 mmol) obtained in step 3 of Example 113, acetyl chloride (0.017 ml, 0.236 mmol) and triethylamine (0.049 ml, 0.353 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at 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 solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.020 g, 36.4%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39 (s, 1H), 8.29 (d, J=7.0 Hz, 1H), 7.82 (s, 1H), 7.62 (d , J=7.1 Hz, 1H), 7.42 (dt, J=9.3, 6.4 Hz, 3H), 7.25-7.19 (m, 2H), 6.96 (t, J=51.7 Hz, 1H), 5.13-5.06 (m, 2H), 4.54-4.40 (m, 1H), 4.06 (dd, J=9.6, 6, 5 Hz, 1H), 3.93 (t, J=8.5 Hz, 1H), 3.71 (t, J=9.4 Hz, 1H), 3.37 (ddd, J=15.3, 9.0, 6.3 Hz, 1H), 1.83 (s, 3H);

MSNR (ER) m/z 466.9 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-okeadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylazetidin-3- carboxamide (0.050 g, 0.118 mmol) obtained in step 3 of Example 113, propionyl chloride (0.022 g, 0.236 mmol) and triethylamine (0.049 ml, 0.353 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 12 g; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (0.032 g, 5 to 6.5%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.36-8.31 (m, 1H), 8.25 (dd, J=7.1, 1.0 Hz, 1H), 7.80 (d, J=0.7 Hz, 1H), 7.57 (dd, J=7.1, 1.7 Hz, 1H), 7.46-7.36 (m, 3H), 7.20 (dd, J =8.1, 1.6 Hz, 2H), 6.96 (t, J=51.7 Hz, 1H), 5.18-4.96 (m, 2H), 4.45 (dd, J= 8.1, 6.2 Hz, 1H), 4.05 (dd, J=9.5, 6.5 Hz, 1H), 3.91 (t, J=8.4 Hz, 1H), 3, 71 (t, J=9.3 Hz, 1H), 3.36 (tt, J=9.0, 6.3 Hz, 1H), 2.07 (n, J=7.5 Hz, 2H), 1.09 (t, J=7.5 Hz, 3H);

MSNR (ER) m/z 480.9 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylazetidin-3- carboxamide (0.050 g, 0.118 mmol) obtained in step 3 of Example 113, 2-hydroxyacetyl chloride (0.022 g, 0.236 mmol) and triethylamine (0.049 ml, 0.353 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 a 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 cartridge, 12 g; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (0.030 g, 52.8%) as a white solid.

¹ H NMR (400 MHz, MeOD) δ 8.58 (dd, J=7.1, 1.0 Hz, 1H), 8.23 (dt, J=1.7, 0.8 Hz, 1H), 7.98 (d, J=0.7 Hz, 1H), 7.57 (dd, J=7.2, 1.7 Hz, 1H), 7.48-7.11 (m, 6H), 5 .14 (dd, J=2.2, 0.7 Hz, 2H), 4.48 (dd, J=9.0, 6.2 Hz, 1H), 4.22-4.17 (m, 1H ), 4.14-4.07 (m, 1H), 3.82 (t, J=9.4 Hz, 1H), 3.57-3.48 (m, 1H), 3.22 (sq, J=7.3 Hz, 2H);

MSNR (ER) m/z 483.0 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylazetidin-3- carboxamide (0.050 g, 0.118 mmol) obtained in step 3 of Example 113, cyclobutanecarbonyl chloride (0.028 g, 0.236 mmol) and triethylamine (0.049 ml, 0.353 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at that same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 12 g; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (0.029 g, 48.6%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35 (s, 1H), 8.25 (dd, J=7.1, 1.0 Hz, 1H), 7.80 (d, J=0, 7 Hz, 1H), 7.58 (dd, J=7.2, 1.7 Hz, 1H), 7.4 7-7.3 6 (m, 3H), 7.22-7.15 (m , 2H), 6.9 6 (t, J=51.7 Hz, 1H), 5.15-4.9 6 (m, 2H), 4, 44-4, 30 (m, 1H), 4, 04 (dd, J=9.5, 6.5 Hz, 1H), 3.85 (t, J=8.4 Hz, 1H), 3.70 (t, J=9.4 Hz, 1H), 3.35 (tm, J=8.9, 6.4 Hz, 1H), 3.09-2.92 (m, 1H), 2.43-2.21 (m, 3H), 2.14- 1.8 9 (m, 3H);

MSNR (ER) m/z 507.4 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylazetidin-3- carboxamide (0.050 g, 0.118 mmol) obtained in step 3 of Example 113, oxetane-3-carbonyl chloride (0.028 g, 0.236 mmol) and triethylamine (0.049 ml, 0.353 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting the solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 12 g; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (0.039 g, 65.1%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 8.26 (dd, J=7.0, 1.0 Hz, 1H), 7.78 (s, 1H), 7 .61 (d, J=7.1 Hz, 1H), 7.47-7.38 (m, 3H), 7.24-7.18 (m, 2H), 6.96 (t, J=51 .7 Hz, 1H), 5.09 (d, J=2.9 Hz, 2H), 4.90 (dd, J=7.0, 5.8 Hz, 1H), 4.83 (dd, J =7.0, 5.7 Hz, 1H), 4.72 (ddd, J=14.5, 8.6, 5.8 Hz, 2H), 4.40-4.32 (m, 1H), 4.11-4.04 (m, 1H), 3.83 (t, J=8.4 Hz, 1H), 3.79-3.71 (m, 2H), 3.39 (ddd, J= 15.1, 8.9, 8.3 Hz, 1H);

MSNR (ER) m/z 509.4 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylazetidin-3- carboxamide (0.050 g, 0.118 mmol) obtained from step 3 of Example 113, 1,1,1,5,5,5-hexafluoropentane-2,4-dione (0.049 g, 0.236 mmol) and triethylamine (0.049 ml, 0.353 mmol ) was 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 a 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 cartridge, 12 g; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (0.034 g, 55.5%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.36 (s, 1H), 8.26 (dd, J=7.1, 1.0 Hz, 1H), 7.79 (s, 1H), 7 .59 (dd, J=7.1, 1.7 Hz, 1H), 7.51-7.37 (m, 3H), 7.25-7.19 (m, 2H), 6.96 (t , J=51.7 Hz, 1H), 5.09 (d, J=2.9 Hz, 2H), 4.76-4.60 (m, 1H), 4.27 (dd, J=10, 4, 6.6 Hz, 1H), 4.22-4.10 (m, 1H), 3.87 (t, J=9.9 Hz, 1H), 3.51 (tt, J=9.1 , 6.5 Hz, 1H);

MSNR (ER) m/z 520.9 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylazetidin-3- carboxamide (0.050 g, 0.118 mmol) obtained in step 3 of Example 113, methanesulfonyl chloride (0.018 ml, 0.236 mmol) and triethylamine (0.049 ml, 0.353 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at that same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 12 g; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (0.032 g, 54.1%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 8.26 (dd, J=7.2, 1.0 Hz, 1H), 7.80-7.75 (m, 1H), 7.60 (dd, J=7.1, 1.7 Hz, 1H), 7, 47-7, 38 (m, 3H), 7.24-7.15 (m, 2H), 6 .96 (t, J=51.7 Hz, 1H), 5.09 (s, 2H), 4.16 (dd, J=8.1, 7.1 Hz, 2H), 3.71 (t, J=8.3 Hz, 2H), 3.4 7-3.32 (m, 1H), 2.91 (s, 3H);

MSNR (ER) m/z 503.4 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylazetidin-3- carboxamide (0.050 g, 0.118 mmol) obtained in step 3 of Example 113, methyl chloroformate (0.022 g, 0.236 mmol) and triethylamine (0.049 ml, 0.353 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at that same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 12 g; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (0.023 g, 40.5%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.36 (s, 1H), 8.26 (dd, J=7.1, 1.0 Hz, 1H), 7.82 (s, 1H), 7 .59 (dd, J=7.2, 1.7 Hz, 1H), 7.46-7.36 (m, 3H), 7.22-7.16 (m, 2H), 6.96 (t , J=51.7 Hz, 1H), 5.08 (s, 2H), 4.19 (s, 2H), 3.74 (t, J=8.6 Hz, 2H), 3.64 (s , 3H), 3.36 (tt, J=8.8, 6.4 Hz, 1H);

MSNR (ER) m/z 482.8 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylazetidin-3- carboxamide (0.050 g, 0.118 mmol) obtained in step 3 of Example 113, dimethylcarbamic acid chloride (0.025 g, 0.236 mmol) and triethylamine (0.04 9 ml, 0.353 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 a 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 cartridge, 12 g; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (0.030 g, 51.4%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.34 (s, 1H), 8.26 (dd, 77=7.1, 1.0 Hz, 1H), 7.84-7.80 (m, 1H), 7.58 (dd, J=7.1, 1.7 Hz, 1H), 7.45-7.34 (m, 3H), 7.22-7.15 (m, 2H), 6 .95 (t, J=51.7 Hz, 1H), 5.08 (s, 2H), 4.18 (dd, 77=8.0, 6.8 Hz, 2H), 3.70 (dd, 77=9.0, 8.0 Hz, 2H), 3.35 (tt, J=9.0, 6.8 Hz, 1H), 2.82 (s, 6H);

MSNR (ER) m/z 4 95.9 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-okeadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylazetidin-3- carboxamide (0.050 g, 0.118 mmol) obtained in step 2 of Example 113, 2-chloropyridine (0.027 g, 0.236 mmol), cesium carbonate (0.077 g, 0.236 mmol) and palladium RuPhos G2 (0.005 g, 0.006 mmol) were dissolved in 1 ,4-dioxane (2 ml) at room temperature, and the resulting solution was stirred at 10 0°C for 18 hours. The temperature was then lowered to room temperature to complete the reaction. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 30%) and concentrated to give the title compound (0.028 g, 47.4%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (dt, J=1.7, 0.8 Hz, 1H), 8.23 (dd, J=7.1, 1.0 Hz, 1H) , 8.11 (ddd, J=5.1, 1.8, 0.9 Hz, 1H), 7.82 (d, J=0.7 Hz, 1H), 7.54 (dd, J=7 ,1, 1.7 Hz, 1H), 7, 49-7, 35 (m, 4H), 7.25-7.21 (m, 2H), 6.95 (t, J=51.7 Hz, 1H), 6.61 (ddd, J=7.1, 5.1, 1.0 Hz, 1H), 6.35-6.27 (m, 1H), 5.08 (s, 2H), 4 .23 (t, J=7.2 Hz, 2H), 3.86 (t, J=8.1 Hz, 2H), 3.61-3.48 (m, 1H);

MSNR (ER) m/z 502.4 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-phenylazetidin-3- carboxamide (0.050 g, 0.118 mmol) obtained in step 3 of Example 113, 2-chloropyrimidine (0.027 g, 0.236 mmol) and potassium carbonate (0.033 g, 0.236 mmol) 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 solution of ammonium chloride was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The resulting product was then filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.018 g, 30.4%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.33-8.28 (m, 3H), 8.23 (dd, J=7.1, 1.0 Hz, 1H), 7.82 (d, J=0.7 Hz, 1H), 7.54 (dd, J=7.2, 1.7 Hz, 1H), 7.47-7.36 (m, 3H), 7.26-7.18 (m, 2H), 6.95 (t, J=51.7 Hz, 1H), 6.54 (t, J=4.8 Hz, 1H), 5.09 (s, 2H), 4.36 (dd, J=8.5, 6.5 Hz, 2H), 3.95 (t, J=8.6 Hz, 2H), 3.51 (tt, J=8.7, 6.5 Hz, 1H);

MSNR (ER) m/z 503.4 (M ⁺ +1).

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

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

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) prepared in Example 16 and triethylamine (1.746 ml, 12.524 mmol) in dichloromethane (150 ml) at room temperature, tert-butyl-3-(chlorocarbonyl)-azetidine-1- carboxylate (1.192 g, 5.427 mmol) obtained in step 1 of Example 113 and stirred at the same temperature for 1-6 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate/hexane = 5% to 60%) and concentrated to give the title compound (1200 g, 53.0%) as a yellow solid.

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

Tert-butyl-4-(((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-( 3-fluorophenyl)-carbamoyl)-azetidine-1-carboxylate (0.700 g, 1.290 mmol) obtained in step 1 and trifluoroacetic acid (1.976 ml, 25.806 mmol) were dissolved in dichloromethane (10 ml) at room temperature, and the resulting solution stirred at the same temperature for 2 hours. A saturated aqueous solution of sodium hydrogen carbonate 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 give the title compound (0.570 g, 9.9.9%) as a brown gel without further purification.

[Step 3] 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 )-azetidine-3-carboxamide (0.050 g, 0.113 mmol) obtained in step 2, formaldehyde (0.007 g, 0.226 mmol), acetic acid (0.006 ml, 0.113 mmol) and sodium triacetoxyborohydride (0.072 g, 0.339 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 sodium hydrogen carbonate was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.016 g, 31.0%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.33-8.30 (m, 1H), 8.24 (dd, J=7.1, 1.0 Hz, 1H), 7.79 (s, 1H), 7.55 (dd, J=7.1, 1.7 Hz, 1H), 7.38 (td, J=8.3, 6.3 Hz, 1H), 7.14-6.80 (m, 4H), 5.03 (s, 2H), 3.45 (s, 2H), 3.36 (s, 3H), 2.39 (s, 3H);

MSNR (ER) m/z 457.4 (M ⁺ +1).

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

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) obtained in step 2 of Example 133, acetaldehyde (0.012 g, 0.271 mmol), acetic acid (0.008 ml, 0.136 mmol) and sodium triacetoxyborohydride (0.086 g, 0.407 mmol) was 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 a 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 cartridge, 12 g; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (0.021 g, 32.9%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.33-8.30 (m, 1H), 8.24 (dd, J=7.1, 1.0 Hz, 1H), 7.78 (s, 1H), 7.56 (dd, J=7.1, 1.7 Hz, 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);

MSNR (ER) m/z 471.5 (M ⁺ +1).

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

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) prepared in step 2 of Example 133, 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) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.025 g, 38.0%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (dd, J=1.7, 0.9 Hz, 1H), 8.24 (dd, J=7.1, 1.0 Hz, 1H) , 7.78 (s, 1H), 7.55 (dd, J=7.1, 1.7 Hz, 1H), 7.38 (td, J=8.3, 6.3 Hz, 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=6.3 Hz, 6H);

MSNR (ER) m/z 485.5 (M ⁺ +1).

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

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) prepared in step 2 of Example 133, 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) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.020 g, 35.4%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (dd, J=1.7, 0.9 Hz, 1H), 8.24 (dd, J=7.1, 1.0 Hz, 1H) , 7.78 (s, 1H), 7.55 (dd, J=7.1, 1.7 Hz, 1H), 7.4 3-7, 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= 9.4 Hz, 1H), 1.00 (d, J=6.5 Hz, 3H);

MSNR (ER) m/z 501.4 (M ⁺ +1).

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

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) obtained in step 2 of Example 133, cyclobutanone (0.016 g, 0.226 mmol), acetic acid (0.006 ml, 0.113 mmol) and sodium triacetoxyborohydride (0.072 g, 0.339 mmol) dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.024 g, 42.8%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (dt, J=1.7, 0.8 Hz, 1H), 8.24 (dd, J=7.1, 1.0 Hz, 1H) , 7.79 (s, 1H), 7.55 (dd, J=7.1, 1.7 Hz, 1H), 7.38 (td, J=8.2, 6.2 Hz, 1H), 7.12-6.81 (m, 4H), 5.03 (s, 2H), 3.23 (d, J=61.3 Hz, 5H), 2.01-1.94 (m, 2H) , 1.86-1.59 (m, 5H);

MSNR (ER) m/z 497.4 (M ⁺ +1).

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-(oxetan-3-yl)-azetidin-3-carboxamide

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) prepared in step 2 of Example 133, oxetan-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) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.032 g, 56.8%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (dt, J=1.7, 0.8 Hz, 1H), 8.24 (dd, J=7.1, 1.0 Hz, 1H) , 7.79 (s, 1H), 7.55 (dd, J=7.1, 1.7 Hz, 1H), 7.39 (td, J=8.2, 6.2 Hz, 1H), 7.14-6.79 (m, 4H), 5.03 (s, 2H), 4.67 (t, J=6.7 Hz, 2H), 4.49 (dd, J=6.7, 5.2 Hz, 2H), 3.74 (ddd, J=11.9, 6.7, 5.2 Hz, 1H), 3.44-3.32 (m, 3H), 3.28 (d , J=5.6 Hz, 2H);

MSNR (ER) m/z 499.4 (M ⁺ +1).

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

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) prepared in step 2 of Example 133, cyclohexanone (0.022 g, 0.226 mmol), acetic acid (0.006 ml, 0.113 mmol) and sodium triacetoxyborohydride (0.072 g, 0.339 mmol) dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.034 g, 57.4%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.32 (dt, J=1.6, 0.8 Hz, 1H), 8.24 (dd, J=7.1, 1.0 Hz, 1H) , 7.77 (s, 1H), 7.55 (dd, J=7.1, 1.7 Hz, 1H), 7.38 (td, J=8.3, 6.3 Hz, 1H), 7.14-6.78 (m, 4H), 5.03 (s, 2H), 3.45 (d, J=29.4 Hz, 5H), 2.28 (s, 1H), 1.74 (d, J=10.1 Hz, 4H), 1.61 (s, 1H), 1.23-1.05 (m, 5H);

MSNR (ER) m/z 525.1 (M ⁺ +1).

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)-azetidin-3-carboxamide

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) prepared in step 2 of Example 133, tetrahydro-4H-pyran-4-one (0.023 g, 0.226 mmol), acetic acid (0.006 ml, 0.113 mmol) and triacetoxyborohydride sodium (0.072 g, 0.339 mmol) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.015 g, 25.2%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.32 (dt, J=1.6, 0.8 Hz, 1H), 8.23 (dd, J=7.1, 1.0 Hz, 1H) , 7.78 (s, 1H), 7.55 (dd, J=7.1, 1.7 Hz, 1H), 7.38 (td, J=8.3, 6.3 Hz, 1H), 7.13-6.79 (m, 4H), 5.03 (s, 2H), 3.92 (dt, J=11.6, 3.7 Hz, 2H), 3.41-3.15 ( m, 7H), 2.36-2.22 (m, 1H), 1.61 (d, J=13.0 Hz, 2H), 1.31 (d, J=4.3 Hz, 2H);

MSNR (ER) m/z 527.5 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-okeadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-(3-fluorophenyl )-azetidine-3-carboxamide (0.050 g, 0.113 mmol) prepared in step 2 of Example 133, 4,4-difluorocyclohexan-1-one (0.030 g, 0.226 mmol), acetic acid (0.006 ml, 0.113 mmol) and triacetoxyborohydride sodium (0.072 g, 0.339 mmol) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.021 g, 33.1%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (dt, J=1.7, 0.8 Hz, 1H), 8.23 (dd, J=7.1, 1.0 Hz, 1H) , 7.78 (s, 1H), 7.55 (dd, J=7.1, 1.7 Hz, 1H), 7.38 (td, J=8.4, 6.5 Hz, 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, 5.4 Hz, 2H), 1.69 (kv, J=17.0, 15.4 Hz, 4H), 1.40 (d, J=11.4 Hz, 2H);

MSNR (ER) m/z 561.3 (M ⁺ +1).

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

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) obtained in step 2 of example 133, acetyl chloride (0.016 ml, 0.226 mmol) and triethylamine (0.047 ml, 0.339 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 sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.024 g, 43.8%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.36 (d, J=1.6 Hz, 1H), 8.26 (dd, J=7.2, 1.0 Hz, 1H), 7.81 (s, 1H), 7.60 (dd, J=7.2, 1.7 Hz, 1H), 7.41 (td, J=8.0, 6.4 Hz, 1H), 7.18- 6.77 (m, 4H), 5.15-4.97 (m, 2H), 4.50-4.42 (m, 1H), 4.06 (dd, J=9.5, 6.4 Hz, 1H), 3.97 (t, J=8.5 Hz, 1H), 3.81-3.69 (m, 1H), 3.38 (tt, J=8.9, 6.3 Hz , 1H), 1.84 (s, 3H);

MSNR (ER) m/z 485.0 (M ⁺ +1).

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

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) obtained in step 2 of example 133, propionyl chloride (0.021 g, 0.226 mmol) and triethylamine (0.047 ml, 0.339 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 sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.027 g, 47.9%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.35 (s, 1H), 8.26 (d, J=7.1 Hz, 1H), 7.80 (s, 1H), 7.58 (dd , J=7.1, 1.7 Hz, 1H), 7.41 (kv, J=7.6 Hz, 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, 6.5 Hz, 1H), 3.95 (t, J=8, 4 Hz, 1H), 3.76 (t, J=9.3 Hz, 1H), 3.38 (tt, J=8.8, 6.2 Hz, 1H), 2.14-2.0 0 (m, 2H), 1.10 (t, J=7.5 Hz, 3H);

MSNR (ER) m/z 499.5 (M ⁺ +1).

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

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) prepared in step 2 of Example 133, 2-hydroxyacetyl chloride (0.021 g, 0.226 mmol) and triethylamine (0.047 ml, 0.339 mmol) were dissolved in dichloromethane (4 ml) at room temperature temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.012 g, 21.2%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.33 (d, J=2.0 Hz, 1H), 8.25 (dd, J=7.2, 1.1 Hz, 1H), 7.79 (s, 1H), 7.57 (dt, J=7.1, 1.6 Hz, 1H), 7.42 (td, J=8.1, 6.2 Hz, 1H), 7.18- 6.79 (m, 4H), 5.05 (d, J=4.0 Hz, 2H), 4.38 (t, J=7.3 Hz, 1H), 4.21-4.14 (m , 1H), 4.03-3.81 (m, 4H), 3.49 (ddd, J=15.2, 8.9, 6.3 Hz, 1H); MSNR (ER) m/z 501.0 (M ⁺ +1).

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

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) obtained in step 2 of Example 133, cyclobutanecarbonyl chloride (0.027 g, 0.226 mmol) and triethylamine (0.047 ml, 0.339 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 sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.038 g, 64.1%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 8.27 (d, J=7.1 Hz, 1H), 7.81 (s, 1H), 7.62 (d , J=7.1 Hz, 1H), 7.41 (td, J=8.3, 6.2 Hz, 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, 6.5 Hz, 1H), 3.89 (t, J=8, 4 Hz, 1H), 3.75 (t, J=9.3 Hz, 1H), 3.38 (ddd, J=15.1, 8.9, 6.3 Hz, 1H), 3.00 ( dd, J=9.4, 7.6 Hz, 1H), 2.28 (dp, J=27.9, 9.2, 8.8 Hz, 3H), 2.13-1.90 (m, 3H);

MSNR (ER) m/z 525.1 (M ⁺ +1).

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

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) obtained in step 2 of Example 133, oxetane-3-carbonyl chloride (0.027 g, 0.226 mmol) and triethylamine (0.047 ml, 0.339 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 sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.033 g, 55.5%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.35 (d, J=1.7 Hz, 1H), 8.25 (dd, J = 7.1, 1.0 Hz, 1H), 7.78 (s, 1H), 7.58 (dd, J = 7.1, 1.7 Hz, 1H), 7.42 (td, J = 8.0, 6.1 Hz, 1H), 7.17- 6.79 (m, 4H), 5.14-4.98 (m, 2H), 4.90 (dd, J = 7.0, 5.8 Hz, 1H), 4.83 (dd, J = 7.0, 5.8 Hz, 1H), 4.72 (dd, J = 12.0, 8.6, 5.8 Hz, 2H), 4.36 (dd, J = 8.1, 6, 1 Hz, 1H), 4.09 (dd, J = 9.7, 6.4 Hz, 1H), 3.89-3.71 (m, 3H), 3.39 (tt, J = 8.8 , 6.3 Hz, 1H);

MSNR (ER) m/z 527.1 (M ⁺ +1).

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

N-((7-(5-(difluoromethyl)-1,3,4-okeadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-(3-fluorophenyl )-azetidine-3-carboxamide (0.060 g, 0.136 mmol) prepared in step 2 of Example 133, 1,1,1,5,5,5-hexafluoropentane-2,4-dione (0.056 g, 0.271 mmol) and triethylamine (0.057 ml, 0.407 mmol) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.031 g, 42.5%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 8.27 (dd, J=7.1, 1.0 Hz, 1H), 7.80 (s, 1H), 7 .60 (dd, J=7.2, 1.7 Hz, 1H), 7.44 (tdd, J=8.3, 6.3 Hz, 1H), 7.15 (tdd, J=8.3 , 2.5, 1.1 Hz, 1H), 7.11-6.81 (m, 3H), 5.07 (d, J=2.3 Hz, 2H), 4, 74-4, 62 ( m, 1H), 4.33-4.12 (m, 2H), 3.92 (t, J=9.8 Hz, 1H), 3.53 (tt, J=9.1, 6.5 Hz , 1H);

MSNR (ER) m/z 539.0 (M ⁺ +1).

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

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) obtained in step 2 of Example 133, methanesulfonyl chloride (0.021 ml, 0.271 mmol) and triethylamine (0.057 ml, 0.407 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 sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.030 g, 42.5%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 8.27 (dd, J=7.2, 1.0 Hz, 1H), 7.79 (d, J=0, 7 Hz, 1H), 7.61 (dd, J=7.1, 1.7 Hz, 1H), 7.5 0-7.3 6 (m, 1H), 7.19-7.10 (m , 1H), 7.10-6.7 9 (m, 3H), 5.07 (s, 2H), 4.17 (dd, J=8.1, 7.1 Hz, 2H), 3.75 (t, J=8.4 Hz, 2H), 3.49-3.35 (m, 1H), 2.91 (s, 3H); MSNR (ER) m/z 521.1 (M ⁺ +1).

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

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) obtained in step 2 of Example 133, methyl chloroformate (0.021 g, 0.226 mmol) and triethylamine (0.047 ml, 0.339 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 sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.031 g, 54.8%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.37-8.33 (m, 1H), 8.26 (dd, J=7.1, 1.0 Hz, 1H), 7.82 (s, 1H), 7.59 (dd, J=7.2, 1.8 Hz, 1H), 7.41 (td, J=8.3, 6.2 Hz, 1H), 7.17-6.78 (m, 4H), 5.06 (s, 2H), 4.19 (s, 2H), 3.78 (t, J=8.6 Hz, 2H), 3.65 (s, 3H), 3 .37 (tm, J=8.9, 6.4 Hz, 1H);

MSNR (ER) m/z 501.0 (M ⁺ +1).

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

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) obtained in step 2 of Example 133, dimethylcarbamic acid chloride (0.024 g, 0.226 mmol) and triethylamine (0.047 ml, 0.339 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 sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.024 g, 41.4%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.34 (dd, J=1.8, 0.9 Hz, 1H), 8.26 (dd, J=7.1, 1.0 Hz, 1H) , 7.82 (s, 1H), 7.58 (dd, J=7.2, 1.7 Hz, 1H), 7.40 (td, J=8.3, 6.3 Hz, 1H), 7.15-6.77 (m, 4H), 5.05 (s, 2H), 4.17 (dd, J=8.0, 6.7 Hz, 2H), 3.74 (t, J= 8.5 Hz, 2H), 3.36 (tt, J=8.9, 6.7 Hz, 1H), 2.82 (s, 6H);

MSNR (ER) m/z 514.0 (M ⁺ +1).

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

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) prepared in step 2 of Example 133, 2-chloropyridine (0.026 g, 0.226 mmol), cesium carbonate (0.074 g, 0.226 mmol) and palladium RuPhos G2 (0.004 g, 0.006 mmol) was dissolved in 1,4-dioxane (2 ml) at room temperature, and the resulting solution was stirred at 100°C for 18 hours.

The temperature was then lowered to room temperature to complete the reaction. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO ₂ plate 20x20x1mm; dichloromethane/methanol = 0% to 30%) and concentrated to give the title compound (0.012 g, 20.4%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.36-8.30 (m, 1H), 8.24 (ddd, J=7.1, 6.0, 1.0 Hz, 1H), 8, 12 (ddd, J=5.1, 1.9, 0.9 Hz, 1H), 7.80 (d, J=8.0 Hz, 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, 1.0 Hz, 1H) , 6.29 (d, J=8.4 Hz, 1H), 5.06 (s, 2H), 4.21 (t, J=7.1 Hz, 2H), 3.88 (t, J= 8.2 Hz, 2H), 3.64 - 3.54 (m, 1H); MSNR (ER) m/z 520.5 (M ⁺ +1).

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

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) prepared in step 2 of Example 133, 2-chloropyrimidine (0.026 g, 0.226 mmol) and potassium carbonate (0.031 g, 0.226 mmol) 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 solution of ammonium chloride was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The resulting product was then filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.041 g, 69.7%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35-8.29 (m, 3H), 8.24 (dd, J=7.1, 1.0 Hz, 1H), 7.82 (s, 1H), 7.56 (dd, J=7.1, 1.7 Hz, 1H), 7.41 (td, J=8.2, 6.3 Hz, 1H), 7.16-6.80 (m, 4H), 6.56 (t, J=4.8 Hz, 1H), 5.07 (s, 2H), 4.36 (dd, J=8.6, 6.5 Hz, 2H) , 4.00 (t, J=8.6 Hz, 2H), 3.54 (tt, J=8.7, 6.4 Hz, 1H);

MSNR (ER) m/z 521.4 (M ⁺ +1).

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]heptan-2-yl)-piperidin-4-carboxamide

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) obtained in step 3 of Example 93, 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) 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 hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.020 g, 41.7%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.30 (s, 1H), 8.23 (d, J=7.1 Hz, 1H), 7.55 (d, J=6.9 Hz, 1H ), 7.39 (dd, J=14.6, 8.2 Hz, 1H), 7.14-6.79 (m, 5H), 5.01 (s, 2H), 3.13 (d, J=41.6 Hz, 1H), 2.84 (s, 2H), 2.24 (s, 2H), 1.89 (dt, J=53.6, 40.7 Hz, 12H), 1, 57-1.37 (m, 2H);

MSNR (ER) m/z 565.5 (M ⁺ +1).

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]heptan-6-yl)-piperidin-4-carboxamide

N-((7-(5-(difluoromethyl)-1,3,4-okeadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-N-(3-fluorophenyl )-piperidine-4-carboxamide (0.040 g, 0.085 mmol) prepared in step 3 of Example 93, 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) 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 hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.020 g, 41.5%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.30 (s, 1H), 8.23 (d, J=7.1 Hz, 1H), 7.55 (d, J=7.1 Hz, 1H ), 7.39 (dd, J=14.5, 8.1 Hz, 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=47.7 Hz, 4H), 2.04 ( s, 2H), 1.96-1.77 (m, 2H), 1.50 (s, 2H);

MSNR (ER) m/z 568.2 (M ⁺ +1).

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]heptan-2-yl)-piperidin-4-carboxamide

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) prepared in step 2 of Example 54, 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) 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 hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.020 g, 41.7%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (s, 1H), 8.20 (d, J=7.1 Hz, 1H), 7.74 (s, 1H), 7.51 (dd , J=7.1, 1.6 Hz, 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=27.7 Hz, 6H), 2.03-1.94 (m, 3H), 1.94-1.8 6 (m, 2H ), 1.82 (dt, J=8.1, 6.0 Hz, 3H);

MSNR (ER) m/z 566.4 (M ⁺ +1).

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]heptan-6-yl)-piperidin-4-carboxamide

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) prepared in step 2 of Example 54, 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) 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 hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.020 g, 41.5%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.28 (s, 1H), 8.20 (d, J=7.1 Hz, 1H), 7.74 (s, 1H), 7.51 (dd , J=7.1, 1.6 Hz, 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=17.0 Hz, 2H);

MSNR (ER) m/z 568.0 (M ⁺ +1).

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

[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

N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-aniline (0.200 g, 0.586 mmol) obtained in Example 14, 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) was dissolved in dichloromethane (10 ml), and the resulting solution was stirred at 0°C for 1 hour and further stirred at room temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 12 g; ethyl acetate/hexane = 0% to 60%) and concentrated to give the title compound (0.210 g, 63.4%) as a brown solid.

[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

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) obtained in step 1 and trifluoroacetic acid (0.569 ml, 7.426 mmol) were dissolved in dichloromethane (10 ml) at room temperature, and the resulting solution was stirred at the same temperature for 2 hours. A saturated aqueous solution of sodium hydrogen carbonate 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 give the title compound (0.172 g, 99.5%) as a yellow gel without further purification.

[Step 3] Synthesis of compound 4625

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) obtained in step 2, formaldehyde (0.022 g, 0.739 mmol), acetic acid (0.021 ml, 0.370 mmol) and sodium triacetoxyborohydride (0.235 g, 1.109 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO ₂ plate 20x20x1mm; dichloromethane/methanol = 0% to 20%) and concentrated to give the title compound (0.100 g, 56.4%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.27 (s, 1H), 8.19 (dt, J=7.8, 3.9 Hz, 1H), 7.81 (s, 1H), 7 .50 (dd, J=7.1, 1.7 Hz, 1H), 7.38-7.29 (m, 4H), 7.25-7.19 (m, 1H), 6.94 (dd , J=54.3, 49.1 Hz, 1H), 5.02 (s, 2H), 3.64 (s, 4H), 3.18 (s, 4H), 2.21 (s, 3H) ;

MSNR (ER) m/z 480.3 (M ⁺ +1).

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

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

Tert-butyl-(4-(hydrazinecarbonyl)-pyridin-2-yl)-carbamate (2.600 g, 10.306 mmol) obtained in step 2 of Example 2 and triethylamine (14.365 ml, 103.064 mmol) were dissolved in tetrahydrofuran (150 ml) , trifluoroacetic anhydride (7.279 mL, 51.532 mmol) was added at room temperature and refluxed for 16 hours. The temperature was then lowered to room temperature to complete the reaction. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Ethyl acetate (30 ml) and hexane (10 0 ml) were poured into the concentrate, suspended and filtered to obtain a solid, the resulting solid was washed with hexane and dried to obtain the title compound (1,500 g, 44.1%) as a white solid .

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

Tert-butyl-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)-pyridin-2-yl)-carbamate (1.500 g, 4.542 mmol) obtained in step 1 was dissolved in dichloromethane (70 ml). Trifluoroacetic acid (6.956 mL, 90.835 mmol) was then 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 aqueous sodium hydrogen carbonate (50 ml) was poured into the concentrate and suspended, followed by filtration to obtain a solid. The resulting solid was washed with water and dried to obtain the title compound (1.030 g, 98.5%) as a yellow solid.

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

4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)-pyridin-2-amine (1.100 g, 4.779 mmol) obtained in step 2, 1,3-dichloropropan-2-one ( 1.214 g, 9.559 mmol) and sodium hydrogen carbonate (2.008 g, 23.897 mmol) were dissolved in 1,4-dioxane (60 ml) at room temperature. The reaction mixture was refluxed for 1-6 hours and then lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a plastic filter to remove solids, the filtrate was purified by column chromatography (SiO ₂ cartridge, 4 0 g; ethyl acetate/hexane = 5% to 7 0%) and concentrated to give the title compound (0.850 g, 5 8 .8%) in the form of a beige solid.

[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

3-(2-(chloromethyl)-imidazo[1,2-a]pyridin-7-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.311 g, 1.028 mmol) obtained in step 3, 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) were dissolved in N,N-dimethylformamide (6 ml) at room temperature, and the resulting solution was stirred at 60°C for 18 hours. The temperature was then lowered to room temperature to complete the reaction. An aqueous solution of ammonium chloride 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 20x20x1mm; ethyl acetate/hexane = 0% to 50%) and concentrated to give the title compound (0.050 g, 12.9%) as a yellow solid.

[Step 5] Synthesis of compound 6892

3-fluoro-N-((7-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)-imidazo[1,2-a]pyridin-2-yl)-methyl)-aniline ( 0.050 g, 0.133 mmol) obtained in step 4, bis-(trichloromethyl)carbonate (0.039 g, 0.133 mmol) and N,N-diisopropylethylamine (0.115 ml, 0.663 mmol) were dissolved in dichloromethane (4 ml), and the resulting solution stirred at room temperature for 10 minutes. Tert-butylpiperazine-1-carboxylate (0.032 g, 0.172 mmol) was then added and further 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 solid residue and aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (20 x 20 x 1 mm SiO ₂ plate; ethyl acetate/hexane = 0% to 100%) and concentrated to give the title compound (0.040 g, 51.3%) as a brown solid.

¹ H NMR (400 MHz, acetone-d6) δ 8.69 (d, J=7.1 Hz, 1H), 8.25 (d, J=1.7 Hz, 1H), 8.08 (s, 1H), 7.53 (dd, J=7.1, 1.8 Hz, 1H), 7.36 (td, J=8.3, 6.7 Hz, 1H), 7.14 (ddt, J =8.0, 5.3, 2.3 Hz, 2H), 6.86 (td, J=8.4, 2.4 Hz, 1H), 5.09 (s, 2H), 3.28 ( kvd, J=6.2, 5.0, 2.5 Hz, 8H), 1.42 (s, 10H);

MSNR (ER) m/z 591.1 (M ⁺ +1).

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

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

To confirm the selectivity of the compounds represented by Chemical Formula I of the present invention to HDAC6 in the HDAC1 and HDAC6 enzyme activity inhibition experiments, a comparison experiment was conducted using a material that had already been developed as a control group.

HDAC enzyme activity was measured using the HDAC Fluorimetric Drug Discovery Kit (Enzo Life Sciences, Inc., BML-AK511, 516). For the HDAC1 enzyme activity test, recombinant human HDAC1 (BML-SE456) was used as the enzyme source and Fluor de Lys ^® -SIRT1 (BNL-KI177) as the substrate. After adding a 5-fold dilution of the compounds into a 9 6-well plate, 0.3 μg of enzyme and 10 μM substrate were added to each well of the plate and allowed to react at 30°C for 60 minutes. Fluor de ^Lys® Developer II (BML-KI176) was then added and reacted for 30 minutes to complete the reaction, and then fluorescence values (Ex 360, Em 460) were measured using a multiplate reader (Flexstation 3, Molecular Device). HDAC6 enzymes were tested using recombinant human HDAC6 (382180) from Calbiochem Inc., following the same protocol as the HDAC1 enzyme activity test method. Regarding the final result values, the corresponding IC50 values were calculated using GraphPad Prism 4.0 and the results are shown below in Table 5.

As shown in Table 5 above, from the results of the activity inhibition assay for HDAC1 and HDAC6, it was found that the 1,3,4-oxadiazole derivatives of the present invention, the optical isomer thereof, or a pharmaceutically acceptable salt thereof exhibited selective HDAC6 inhibitory activity, which ranged from about 21 up to approximately 740 times higher than HDAC1.

<Experimental Example 2> In vitro analysis of the effect of HDAC6-specific inhibitors on mitochondrial axonal transport

The effect of specific HDAC6 inhibitors on mitochondrial axonal transport was analyzed. In particular, to confirm whether the compounds represented by Chemical Formula I according to the present invention selectively inhibit the activity of HDAC6 and increase the acetylation of tubulin, which is the main substrate of HDAC6, thereby improving the rate of mitochondrial axonal transport reduced by amyloid-beta treatment in neuronal axons , a comparison experiment was conducted using material that had already been developed as a control group.

Hippocampal neurons from embryonic day 17–18 (E17–18) Sprague-Dawley (SD) rat embryos were cultured for 7 days in a matrix-coated extracellular culture dish for imaging and then treated with 1 M amyloid-beta peptide fragments. After 24 hours, they were treated with compound on day 8 of in vitro culture, and after 3 hours, they were treated with MitoTracker Red CMXRos (Life Technologies, New York, USA) for the last 5 minutes to stain mitochondria. Regarding the axonal transport of stained neuronal mitochondria, transport rates of each mitochondria were determined using IMARIS analysis software (BITPLANE, Zurich, Switzerland) by acquiring images using a confocal microscope (Leica 5P8; Leica Microsystems, UK) at 1 second intervals per for 1 minute.

As a result, it was confirmed that the 1,3,4-oxadiazole derivative of the present invention, its optical isomer or pharmaceutically acceptable salts thereof showed an improving effect on the speed of mitochondrial axonal transport.

Claims (93)

1. A 1,3,4-oxadiazole derivative having selective inhibitory activity against histone deacetylase 6 (HDAC6), represented by chemical formula I, or a pharmaceutically acceptable salt thereof: [Chemical formula I] , where in the above chemical formula I: L ₁ , L ₂ and L ₃ are each independently -(C ₀ -C ₁ alkyl)-; a, b and c are each independently CR ₄ and R ₄ is -H; Z represents N, O or is absent, and when Z is absent, R ₂ is also absent and L ₂ and L ₃ are directly related; R ₁ represents -CF ₂ H or -CX ₃ ; R₂ represents -H, -(C₁-C₄alkyl) or -C(=O)-R^A, wherein when Z is O, R₂ absent; R ^A represents , or ; Y represents N, when Y is N, each of R ^Y1 , R ^Y2 and R ^Y4 independently represents -(C ₁ -C ₄ alkyl), -(C ₃ -C ₇ cycloalkyl), -(C ₂ -C ₆ heterocycloalkyl), containing N or O atom in the ring, -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), containing one O atom in the ring, -S(=O) ₂ -( C ₁ -C ₄ alkyl), -C ₄ -C ₅ heteroaryl containing one or two N atoms in the ring, or , wherein at least one H -(C ₁ -C ₄ alkyl), -(C ₃ -C ₇ cycloalkyl) and -C(=O)-(C ₁ -C ₄ alkyl) may be substituted by -X or -OH; and W is CH ₂ or O; m and n are each independently an integer 1 or 2; R _a - R _d are each independently -H; R ₃ represents -(C ₃ -C ₇ cycloalkyl), -adamantyl, -C ₆ aryl, -C ₅ heteroaryl containing one N atom in the ring, or -C ₇ heteroaryl containing two O atoms in the ring, where at least at least one -H -C ₆ aryl or -C ₅ heteroaryl containing one N atom in the ring may each be independently substituted with -X, -(C ₁ -C ₄ alkyl), -O(C ₁ -C ₄ alkyl) groups , -(C=O)-(C ₁ -C ₄ alkyl), -CF ₃ or -S(=O) ₂ -(C ₁ -C ₄ alkyl); R ^A3 and R ^A4 are each independently -(C ₁ -C ₄ alkyl); And X represents F, Cl or Br. 2. A 1,3,4-oxadiazole derivative having selective inhibitory activity against histone deacetylase 6 (HDAC6), represented by chemical formula I, or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that in chemical formula I above: L ₁ and L ₃ are each independently -(C ₀ alkyl)-; L ₂ represents -(C ₁ alkyl)-; a, b and c are CR ₄ where R ₄ is -H; Z represents N, O or is absent, and when Z is absent, R ₂ is also absent and L ₂ and L ₃ are directly related; R ₁ represents -CF ₂ H or CF ₃ ; R ₂ represents -H or -C(=O)-R ^A where Z represents O, R ₂ is absent; R ^A represents , or ; Y represents N; R ^Y1 , R ^Y2 and R ^Y4 each independently represent -(C ₁ -C ₄ alkyl), -(C ₃ -C ₇ cycloalkyl), -(C ₂ -C ₆ heterocycloalkyl) containing a N or O atom in the ring, -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), containing one O atom in the ring, -S(=O) ₂ -(C ₁ -C ₄ alkyl) , -C ₄ -C ₅ heteroaryl containing one or two N atoms in the ring, or , wherein at least one H -(C ₁ -C ₄ alkyl), -(C ₃ -C ₇ cycloalkyl) or -C(=O)-(C ₁ -C ₄ alkyl) may be substituted by -X or -OH; and W is CH ₂ or O; m and n are each independently an integer 1 or 2; R _a - R _d are each independently -H; R ₃ represents -(C ₃ -C ₇ cycloalkyl), -adamantyl, -C ₆ aryl, -C ₅ heteroaryl containing one N atom in the ring, or -C ₇ heteroaryl containing two O atoms in the ring, where each of at least one -H in -C ₆ aryl or -C ₅ heteroaryl containing one N atom in the ring may be independently substituted by the groups -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); R ^A3 and R ^A4 are each independently -(C ₁ -C ₄ alkyl); And X represents F or Cl. 3. A 1,3,4-oxadiazole derivative having selective inhibitory activity against histone deacetylase 6 (HDAC6), represented by chemical formula I, or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that in chemical formula I above: L ₁ , L ₂ or L ₃ are each independently -(C ₀ -C ₁ alkyl)-; a, b and c are each independently CR ₄ and R ₄ is -H; Z represents N; R ₁ represents -CF ₂ H or -CX ₃ ; R ₂ represents -C(=O)-R ^A ; R ^A represents ; Y represents N; when Y is N, R ^Y1 is -(C ₁ -C ₄ alkyl), -(C ₃ -C ₇ cycloalkyl), -(C ₂ -C ₆ heterocycloalkyl) containing a N or O atom in the ring, -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), containing one O atom in the ring, -S(=O) ₂ -(C ₁ -C ₄ alkyl), - C ₄ -C ₅ heteroaryl containing one or two N atoms in the ring, or , wherein at least one H -(C ₁ -C ₄ alkyl), -(C ₃ -C ₇ cycloalkyl) or -C(=O)-(C ₁ -C ₄ alkyl) may be substituted by -X or -OH; and W is CH ₂ or O; m and n are each independently an integer 1 or 2; R _a - R _d are each independently -H; R ₃ represents -(C ₃ -C ₇ cycloalkyl), -adamantyl, -C ₆ aryl, -C ₅ heteroaryl containing one N atom in the ring, or -C ₇ heteroaryl containing two O atoms in the ring, where at least at least one -H -C ₆ aryl or -C ₅ heteroaryl containing one N atom in the ring, each independently can be substituted by the groups -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); R ^A3 and R ^A4 are each independently -(C ₁ -C ₄ alkyl); And X represents F, Cl or Br. 4. A 1,3,4-oxadiazole derivative having selective inhibitory activity against histone deacetylase 6 (HDAC6), represented by chemical formula I, or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that in the above chemical formula I: L ₁ , L ₂ and L ₃ are each independently -(C ₀ -C ₁ alkyl)-; a, b and c are each independently CR ₄ and R ₄ is -H; Z represents N; R ₁ represents -CF ₂ H or -CX ₃ ; R ₂ represents -C(=O)-R ^A ; R ^A represents or ; Y represents N; when Y is N, R ^Y2 and R ^Y4 are each independently -(C ₁ -C ₄ alkyl), -(C ₃ -C ₇ cycloalkyl), -(C ₂ -C ₆ heterocycloalkyl) containing an N atom or O in the ring, -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), containing one O atom in the ring, -S(=O) ₂ -(C ₁ - C ₄ alkyl), -C ₄ -C ₅ heteroaryl containing one or two N atoms in the ring, or , wherein at least one H -(C ₁ -C ₄ alkyl), -(C ₃ -C ₇ cycloalkyl) or -C(=O)-(C ₁ -C ₄ alkyl) may be substituted by -X or -OH; and W is CH ₂ or O; m and n are each independently an integer 1 or 2; R _a - R _d are each independently -H; R ₃ represents -(C ₃ -C ₇ cycloalkyl), -adamantyl, -C ₆ aryl, -C ₅ heteroaryl containing one N atom in the ring, or -C ₇ heteroaryl containing two O atoms in the ring, where at least at least one -H -C ₆ aryl or -C ₅ heteroaryl containing one N atom in the ring, each independently can be substituted by the groups -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); R ^A3 and R ^A4 are each independently -(C ₁ -C ₄ alkyl); And X represents F, Cl or Br. 5. A 1,3,4-oxadiazole derivative having selective inhibitory activity against histone deacetylase 6 (HDAC6), represented by chemical formula I, or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that in the above chemical formula I: L ₁ , L ₂ and L ₃ are each independently -(C ₀ -C ₁ alkyl)-; a, b and c are each independently CR ₄ and R ₄ is -H; Z represents N, O or is absent, and when Z is absent, R ₂ is also absent and L ₂ and L ₃ are directly related; R ₁ represents -CF ₂ H or -CX ₃ ; R ₂ represents -H or -(C ₁ -C ₄ alkyl), and when Z represents O, R ₂ is absent; R ₃ represents -(C ₃ -C ₇ cycloalkyl), -adamantyl, -C ₆ aryl, -C ₅ heteroaryl containing one N atom in the ring, or –C ₇ heteroaryl containing two O atoms in the ring, where at least at least one -H in -C ₆ aryl or -C ₅ heteroaryl containing one N atom in the ring, each independently can be substituted by the groups -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); And X represents F, Cl or Br. 6. A 1,3,4-oxadiazole derivative having selective histone deacetylase 6 (HDAC6) inhibitory activity, or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that it is any of the compounds listed in the following table: Etc. Conn. Structure Etc. Conn. Structure 1 3009 2 3585 3 3586 4 3587 5 3588 6 3589 7 3590 8 3591 9 3592 10 3593 eleven 3594 12 3595 13 3596 14 3668 15 3669 16 3670 17 3671 18 3672 19 3673 20 3674 21 3675 22 3676 23 3677 24 3678 25 3679 26 3719 27 3720 28 3721 29 3722 thirty 3723 31 3724 32 3725 33 3782 34 3783 35 3784 36 3785 37 4033 38 4034 39 4035 40 4036 41 4037 42 4038 43 4039 44 4040 45 4041 46 4042 47 4043 48 4044 49 4045 50 4046 51 4047 52 4048 53 4049 54 4083 55 4084 56 4085 57 4086 58 4087 59 4088 60 4089 61 4090 62 4091 63 4092 64 4093 65 4094 66 4095 67 4096 68 4097 69 4098 70 4099 71 4100 72 4101 73 4102 74 4103 75 4115 76 4116 77 4117 78 4118 79 4119 80 4120 81 4121 82 4122 83 4123 84 4124 85 4125 86 4126 87 4127 88 4128 89 4129 90 4130 91 4131 92 4132 93 4137 94 4138 95 4139 96 4140 97 4141 98 4142 99 4143 100 4144 101 4145 102 4146 103 4147 104 4149 105 4150 106 4151 107 4152 108 4153 109 4154 110 4155 111 4156 112 4157 113 4158 114 4159 115 4160 116 4161 117 4162 118 4163 119 4164 120 4165 121 4166 122 4167 123 4168 124 4169 125 4170 126 4171 127 4172 128 4173 129 4174 130 4175 131 4176 132 4177 133 4188 134 4189 135 4190 136 4191 137 4192 138 4193 139 4194 140 4195 141 4196 142 4197 143 4198 144 4199 145 4200 146 4201 147 4202 148 4203 149 4204 150 4205 151 4206 152 4207 153 4618 154 4619 155 4620 156 4621 157 4625 158 6892 7. A 1,3,4-oxadiazole derivative having selective histone deacetylase 6 (HDAC6) inhibitory activity, or a pharmaceutically acceptable salt thereof according to claim 6, characterized in that it is any of the compounds listed in the following table: Etc. Conn. Structure Etc. Conn. Structure 33 3782 34 3783 40 4036 75 4115 76 4116 77 4117 78 4118 79 4119 80 4120 81 4121 82 4122 83 4123 84 4124 85 4125 86 4126 87 4127 88 4128 89 4129 90 4130 91 4131 92 4132 93 4137 94 4138 95 4139 96 4140 97 4141 98 4142 99 4143 100 4144 101 4145 102 4146 103 4147 104 4149 105 4150 106 4151 107 4152 108 4153 109 4154 110 4155 111 4156 112 4157 113 4158 114 4159 115 4160 116 4161 117 4162 118 4163 119 4164 120 4165 121 4166 122 4167 123 4168 124 4169 125 4170 126 4171 127 4172 128 4173 129 4174 130 4175 131 4176 132 4177 133 4188 134 4189 135 4190 136 4191 137 4192 138 4193 139 4194 140 4195 141 4196 142 4197 143 4198 144 4199 145 4200 146 4201 147 4202 148 4203 149 4204 150 4205 151 4206 152 4207 153 4618 154 4619 8. A 1,3,4-oxadiazole derivative having selective histone deacetylase 6 (HDAC6) inhibitory activity, or a pharmaceutically acceptable salt thereof according to claim 6, characterized in that it is any of the compounds listed in the following table: Etc. Conn. Structure Etc. Conn. Structure 35 3784 36 3785 37 4033 38 4034 39 4035 41 4037 42 4038 43 4039 44 4040 45 4041 46 4042 47 4043 48 4044 49 4045 50 4046 51 4047 52 4048 53 4049 54 4083 55 4084 56 4085 57 4086 58 4087 59 4088 60 4089 61 4090 62 4091 63 4092 64 4093 65 4094 66 4095 67 4096 68 4097 69 4098 70 4099 71 4100 72 4101 73 4102 74 4103 155 4620 156 4621 157 4625 158 6892 9. A 1,3,4-oxadiazole derivative having selective histone deacetylase 6 (HDAC6) inhibitory activity, or a pharmaceutically acceptable salt thereof according to claim 6, characterized in that it is any of the compounds listed in the following table: Etc. Conn. Structure Etc. Conn. Structure 1 3009 2 3585 3 3586 4 3587 5 3588 6 3589 7 3590 8 3591 9 3592 10 3593 eleven 3594 12 3595 13 3596 14 3668 15 3669 16 3670 17 3671 18 3672 19 3673 20 3674 21 3675 22 3676 23 3677 24 3678 25 3679 26 3719 27 3720 28 3721 29 3722 thirty 3723 31 3724 32 3725 10. A pharmaceutical composition having inhibitory activity against histone deacetylase-6, containing as an active ingredient a therapeutically effective amount of a compound represented by chemical formula I, or a pharmaceutically acceptable salt thereof according to any one of claims. 1-9 and a pharmaceutically acceptable carrier. 11. The pharmaceutical composition according to claim 10, characterized in that said composition is used for the prevention or treatment of diseases mediated by histone deacetylase-6, and wherein said histone deacetylase 6-mediated diseases are infectious diseases; neoplasms; endocrine, nutritional and metabolic diseases; mental and behavioral disorders; neurological diseases; diseases of the eye and its adnexa; diseases of the circulatory system; respiratory diseases; diseases of the digestive system; diseases of the skin and subcutaneous tissues; diseases of the musculoskeletal system and connective tissue; or congenital malformations, changes or chromosomal abnormalities. 12. A method of inhibiting histone deacetylase 6, comprising administering as an active ingredient a therapeutically effective amount of a compound represented by chemical formula I, or a pharmaceutically acceptable salt thereof according to any one of claims. 1-9. 13. The use of a compound represented by chemical formula I, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-9 for the preparation of a drug for inhibiting histone deacetylase-6.