RU2810081C1 - 1,3,4-oxadiazole derivatives as histone deacetylase 6 inhibitor and pharmaceutical composition containing them - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a 1,3,4-oxadiazole derivative represented by the chemical formula I, or to a pharmaceutically acceptable salt thereof, where in the chemical formula I Z₁-Z₄ each independently represents N, CH or CX, where Z₁-Z₄ is not may be three or more N's at the same time; L, L¹ or L² are each independently -(C₀-C₂alkylene)-; R₁ represents -CX₂H or -CX₃; R₂ represents C₆ aryl, wherein at least one -H of C₆ aryl can each be independently substituted with -X, -OH, -(C₁-C₄alkyl) or -O(C₁-C₄alkyl); R represents or; R_a-R_d are each independently -H or -(C₁-C₄alkyl); R´ and R˝ are each independently -H, -(C₁-C₄alkyl), -(C₃-C₇cycloalkyl), -(C₂-C₆heterocycloalkyl) containing one O atom or one S atom in the ring, -(C₁-C₄alkyl)-(C₃-C₇cycloalkyl), -(C₁-C₄alkyl)-(C₂-C₆heterocycloalkyl), containing one O atom in the ring, -C (=O)-(C₁-C₄alkyl), -C(=O)-(C₃-C₇cycloalkyl), -C(=O)-O(C₁-C₄alkyl) or -S( =O)₂ -(C₁-C₄alkyl), wherein at least one -H of -(C₁-C₄alkyl) or -C(=O)-(C₁-C₄alkyl) may be is substituted by -X, -OH, -N(CH₃)₂ or -O(C₁-C₄alkyl) and at least one -H in the ring of -(C₃-C₇cycloalkyl) may be substituted by - X, -OH or -(C₁-C₄alkyl); m or n are each independently 1, 2 or 3; and X represents either F, Cl, Br or I. The invention also relates to a pharmaceutical composition having inhibitory activity against histone deacetylase 6 (HDAC6), based on the specified derivative of Chemical formula I.

EFFECT: obtaining new compounds and a pharmaceutical composition based on them which may have medical applications to prevent or treat HDAC6-mediated diseases, including cancer, inflammatory diseases, autoimmune diseases, neurological or neurodegenerative diseases.

9 cl, 2 tbl, 128 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 obtaining a therapeutic medicinal product; a method of treatment using said compound; a pharmaceutical composition containing the specified compound; and the method of obtaining it.

State of the art

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 acetyl groups from lysine residues of histone proteins that make up chromatin. They 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. Opin. Chem. Biol. 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 that use zinc as a cofactor can be divided into three groups: Class I (HDAC 1, 2, 3 and 8), Class II (IIA: HDAC 4, 5, 7 and 9; IV: HDAC 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 Mb class 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 tubupin 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, online publication).

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 problem

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.

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 and 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.

Thus, the technical result of the present invention is to provide new 1,3,4-oxadiazole derivatives having selective inhibitory activity against histone deacetylase 6 (HDAC6).

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 above

Z ₁ -Z ₄ each independently represents N, CH or CX, where Z ₁ -Z ₄ cannot represent three or more N at the same time;

L, L ¹ or L ² each independently represents -(C ₀ -C ₂ alkylene)-;

R ₁ represents -CH ₂ X or -CX ₃ ;

R ₂ is aryl or heteroaryl, wherein at least one -H of aryl or heteroaryl may each independently be substituted by -X, -OH, -(C ₁ -C ₄ alkyl) or -O(C ₁ -C ₄ alkyl);

R represents or ;

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

R' and R'' are each independently -H, -(C ₁ -C ₄ alkyl), -(C ₃ -C ₇ cycloalkyl), -(C ₂ -C ₆ heterocycloalkyl), -(C ₁ -C ₄ alkyl)-(C ₃ -C ₇ cycloalkyl), -(C ₁ -C ₄ alkyl)-(C ₂ -C ₆ heterocycloalkyl), -C(=O)-(C ₁ -C ₄ alkyl), -C( =O)-(C ₃ -C ₇ cycloalkyl), -C(=O)-O(C ₁ -C ₄ alkyl) or -S(=O) ₂ -(C ₁ -C ₄ alkyl), while at least one -H of -(C ₁ -C ₄ alkyl) or -C(=O)-(C ₁ -C ₄ alkyl) may be substituted by -X, -OH, -N(CH ₃ ) ₂ or - O(C ₁ -C ₄ alkyl), and at least one -H in the ring y -(C ₃ -C ₇ cycloalkyl), -(C ₂ -C ₆ heterocycloalkyl), -(C ₁ -C ₄ alkyl)- (C ₃ -C ₇ cycloalkyl), -(C ₁ -C ₄ alkyl)-(C ₂ -C ₆ heterocycloalkyl) or -C(=O)-(C ₃ -C ₇ cycloalkyl) may be substituted by -X, -OH or -(C ₁ -C ₄ alkyl);

m or n are each independently 1, 2 or 3; And

X represents F, Cl, Br or I.

Also, according to one embodiment of the present invention, in chemical formula I above

Z ₁ -Z ₄ each independently represents N, CH or CX, where Z ₁ -Z ₄ cannot represent two or more N at the same time;

L, L ¹ or L ² each independently represents -(C ₀ -C ₂ alkylene)-;

R ₁ represents -CH ₂ X or -CX ₃ ;

R ₂ represents aryl, wherein at least one -H of aryl can each independently be substituted by -X, -OH, -(C ₁ -C ₄ alkyl) or -O(C ₁ -C ₄ alkyl);

R represents or ;

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

R' and R'' are each independently -H, -(C ₁ -C ₄ alkyl), -(C ₃ -C ₇ cycloalkyl), -(C ₂ -C ₆ heterocycloalkyl), -(C ₁ -C ₄ alkyl)-(C ₃ -C ₇ cycloalkyl), -(C ₁ -C ₄ alkyl)-(C ₂ -C ₆ heterocycloalkyl), -C(=O)-(C ₁ -C ₄ alkyl), -C( =O)-(C ₃ -C ₇ cycloalkyl), -C(=O)-O(C ₁ -C ₄ alkyl) or -S(=O) ₂ -(C ₁ -C ₄ alkyl), with at least one -H of -(C ₁ -C ₄ alkyl) or -C(=O)-(C ₁ -C ₄ alkyl) may be substituted by -X, -OH, -N(CH ₃ ) ₂ or - O(C ₁ -C ₄ alkyl), and at least one -H in the ring y -(C ₃ -C ₇ cycloalkyl), -(C ₂ -C ₆ heterocycloalkyl), -(C ₁ -C ₄ alkyl)- (C ₃ -C ₇ cycloalkyl), -(C ₁ -C ₄ alkyl)-(C ₂ -C ₆ heterocycloalkyl) or -C(=O)-(C ₃ -C ₇ cycloalkyl) may be substituted by -X, -OH or -(C ₁ -C ₄ alkyl);

m or n are each independently 1, 2 or 3; And

X represents F, Cl or Br.

Also, according to one embodiment of the present invention, in chemical formula I above

Z ₁ -Z ₄ each independently represents N, CH or CX, where Z ₁ -Z ₄ cannot represent two or more N at the same time;

L represents -(C ₁ alkylene)-;

L ₁ or L ₂ each independently represents -(C ₀ alkylene)-;

R ₁ represents -CH ₂ X or -CX ₃ ;

R ₂ represents aryl, wherein at least one -H of aryl can each independently be substituted by -X;

R represents or ;

R _a -R _d each independently represents - H;

R' and R'' are each independently -H, -(C ₁ -C ₄ alkyl), -(C ₃ -C ₇ cycloalkyl), -(C ₂ -C ₆ heterocycloalkyl), -(C ₁ -C ₄ alkyl)-(C ₃ -C ₇ cycloalkyl), -(C ₁ -C ₄ alkyl)-(C ₂ -C ₆ heterocycloalkyl), -C(=O)-(C ₁ -C ₄ alkyl), -C( =O)-(C ₃ -C ₇ cycloalkyl), -C(=O)-O(C ₁ -C ₄ alkyl) or -S(=O)2-(C ₁ -C ₄ alkyl), while at least one -H of -(C ₁ -C ₄ alkyl) or -C(=O)-(C ₁ -C ₄ alkyl) may be substituted by -X, -OH, -N(CH ₃ ) ₂ or - O(C ₁ -C ₄ alkyl), and at least one -H on the y-(C ₃ -C ₇ cycloalkyl) ring may be substituted by -X;

m or n are each independently 1 or 2; And

X represents F or Cl.

Also, according to one embodiment of the present invention, in chemical formula I above

Z ₁ -Z ₄ each independently represents N, CH or CF, where Z ₁ -Z ₄ cannot represent two or more N at the same time;

L represents -(C ₁ alkylene)-;

L ¹ or L ² each independently represents -(C ₀ alkylene)-;

R ₁ represents -CF ₂ H or -CF ₃ ;

R ₂ represents aryl, wherein at least one -H of aryl can each independently be substituted by -F;

R represents or ;

R _a -R _d are each independently -H;

R' represents -H, -(C ₁ -C ₄ alkyl), -(C ₃ -C ₇ cycloalkyl), -(C ₂ -C ₆ heterocycloalkyl), -(C ₁ -C ₄ alkyl)-(C ₃ -C ₇ cycloalkyl), -(C ₁ -C ₄ alkyl)-(C ₂ -C ₆ heterocycloalkyl), -C(=O)-(C ₁ -C ₄ alkyl), -C(=O)-(C ₃ -C ₇ cycloalkyl), -C(=O)-O(C ₁ -C ₄ alkyl) or -S(=O) ₂ -(C ₁ -C ₄ alkyl), wherein at least one -H from -(C ₁ -C ₄ alkyl) or -C(=O)-(C ₁ -C ₄ alkyl) may be substituted by -X, -OH, -N(CH ₃ ) ₂ or -O(C ₁ -C ₄ alkyl), and at least one -H in the ring y -(C ₃ -C ₇ cycloalkyl) may be substituted by -X;

R'' represents -(C ₁ -C ₄ alkyl), -(C ₃ -C ₇ cycloalkyl) or -(C ₂ -C ₆ heterocycloalkyl);

m or n are each independently 1 or 2; And

X represents F or Cl.

Moreover, according to one embodiment of the present invention, specific compounds represented by Chemical Formula I according to the present invention are shown in Table 1 below:

Table 1

Etc. Conn. Structure Etc. Conn. Structure 1 2865 2 2866 3 2867 4 2868 5 2869 6 2951 7 2952 8 2953 9 2954 10 2969 eleven 2970 12 2971 13 2972 14 2973 15 2974 16 2975 17 2976 18 2995 19 2996 20 2997 21 2998 22 2999 23 3000 24 3001 25 3002 26 3003 27 3004 28 3005 29 3006 thirty 3007 31 3047 32 3048 33 3049 34 3050 35 3051 36 3052 37 3053 38 3054 39 3055 40 3090 41 3091 42 3092 43 3093 44 3094 45 3095 46 3096 47 3097 48 3098 49 3105 50 3106 51 3107 52 3108 53 3109 54 3110 55 3111 56 3112 57 3113 58 3114 59 3115 60 3152 61 3153 62 3154 63 3155 64 3156 65 3157 66 3158 67 3159 68 3160 69 3161 70 3162 71 3163 72 3164 73 3165 74 3166 75 3167 76 3168 77 3169 78 3170 79 3171 80 3172 81 3216 82 3217 83 3218 84 3219 85 3220 86 3221 87 3222 88 3223 89 3224 90 3389 91 3390 92 3391 93 3392 94 3393 95 3394 96 3395 97 3396 98 3397 99 3398 100 3399 101 3400 102 3401 103 3402 104 3403 105 3404 106 3405 107 3406 108 3407 109 3408 110 3409 111 3410 112 3429 113 3430 114 3431 115 3432 116 3433 117 3434 118 3435 119 3436 120 3437 121 3438 122 3439 123 3440 124 3441 125 3442 126 3443 127 6890 128 6891

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 those salts listed above.

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 preparing the 1,3,4-oxadiazole derivative represented by chemical formula I, its optical isomer or a pharmaceutically acceptable salt thereof.

The preferred method for preparing the 1,3,4-oxadiazole derivative represented by Chemical Formula I, its optical isomer or a pharmaceutically acceptable salt according to the present invention is the same as in Reaction Schemes 1 and 2 below, which also includes production methods modified in to the extent apparent to those skilled in the art.

[Reaction Scheme 1]

[Reaction Scheme 1] illustrates a method for preparing a compound having the structure of an alpha-fluoramide. First, compound 1-1 is reacted with hydrazine to synthesize hydrazide compound 1-2. A cyclization reaction with difluoroacetic anhydride or trifluoroacetic anhydride is carried out to synthesize compound 1-3, followed by a bromination reaction to synthesize compound 1-4. When interacting with aniline, into which a substituent is introduced, compound 1-5 is synthesized. Compound 1-6 is synthesized by reacting oxalyl chloride with a carboxylic acid containing fluorine at the alpha position and then reacting with compound 1-5 to synthesize compound 1-7. Compound 1-8 is synthesized and deprotected under acidic conditions, and the title compound 1-9 is synthesized by introducing various functional groups.

The compounds obtained from the above reaction scheme are 2865, 2866, 2867, 2868, 2869, 2951, 2952, 2953, 2954, 2969, 2970, 2971, 2972, 2973, 2974, 2975, 2976, 2995, 2 996, 2997 , 2998, 2999, 3000, 3001, 3002, 3003, 3004, 3005, 3006, 3007, 3047, 3048, 3049, 3050, 3051, 3052, 3053, 3054, 3055, 3090, 3 091, 3092, 3093, 3094, 3095 , 3096, 3097, 3098, 3152, 3153, 3154, 3155, 3156, 3157, 3158, 3159, 3160, 3161, 3162, 3163, 3164, 3165, 3166, 3167, 3168, 3 169, 3170, 3171, 3172, 3216 , 3217 3218, 3429, 3430, 3431, 3432, 3433, 3434, 3435, 3436, 3437, 3438, 3439, 3440, 3441, 3442, 3443, 6890 and 6891.

[Reaction scheme 2]

[Reaction Scheme 2] also illustrates a method for preparing a compound having an alpha-fluoramide structure. First, compound 1-8 synthesized in Reaction Scheme 1 is subjected to a reductive amination reaction to synthesize compound 2-1. Compound 2-2 is synthesized and deprotected under acidic conditions, and the title compound 2-3 is synthesized by introducing various functional groups.

The compounds obtained from the above reaction scheme are compounds 3105, 3106, 3107, 3108, 3109, 3110, 3111, 3112, 3113, 3114, 3115, 3219, 3220, 3221, 3222, 3223, 3224, 3389, 3390, 3391, 3392, 3393, 3394, 3395, 3396, 3397, 3398, 3399, 3400, 3401, 3402, 3403, 3404, 3405, 3406, 3407, 3408, 3409 and 3410.

A composition comprising a 1,3,4-oxadiazole derivative, its use, and a 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 a compound represented by chemical formula I below, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient:

[Chemical formula I]

Chemical formula I is 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. Moreover, 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 formulations 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 formulated into 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. An appropriate 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 include 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 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.

[Advantageous effects 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 surprisingly excellent preventive or therapeutic effect on HDAC6-mediated diseases.

Best implementation option

Hereinafter, the present invention will be described in more detail with the help of examples and experimental examples. However, these Examples and the like 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 derivative

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

Example 1: Synthesis of compound 2865, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2, 2,2-trifluoroacetate

[Step 1] Synthesis of N-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-fluorobenzyl)aniline

Aniline (0.980 ml, 10.738 mmol), 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (4.286 g, 13.959 mmol), potassium carbonate (2.968 g, 21.475 mmol), and potassium iodide (0.178 g, 1.074 mmol) was dissolved in N,N-dimethylformamide (25 ml) at room temperature. The resulting solution was stirred at the same temperature for 16 hours. Water 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 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, 80 g; ethyl acetate/hexane = 5% to 50%) and concentrated to give the title compound (1.900 g, 55.4%) as a colorless oil.

[Step 2] Synthesis of tert-butyl 4-(chlorocarbonyl)-4-fluoropiperidine-1-carboxylate

1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid (1000 g, 4.044 mmol) was dissolved in dichloromethane (25 ml), and oxalyl chloride (0.417 ml, 4.853 mmol) and N,N-dimethylformamide (0.031 ml) were added , 0.404 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 (1.070 g, 99.6%) was obtained as a colorless oil.

[Step 3] Synthesis of tert-butyl 4-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)(phenyl)carbamoyl)-4-fluoropiperidin-1- carboxylate

To a solution of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)aniline (0.900 g, 2.819 mmol) obtained in step 1 and triethylamine (1.179 ml, 8.456 mmol) was dissolved in dichloromethane (35 ml) at room temperature, tert-butyl 4-(chlorocarbonyl)-4-fluoropiperidine-1-carboxylate (0.974 g, 3.664 mmol) obtained in step 2 was added and stirred at the same temperature for 16 hours. A saturated aqueous solution of ammonium chloride was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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, 40 g; ethyl acetate/hexane = 5% to 35%) and concentrated to give the title compound (0.570 g, 36.9%) as a foamy solid.

[Step 4] Synthesis of compound 2865

Tert-butyl 4-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)(phenyl)carbamoyl)-4-fluoropiperidine-1-carboxylate (0.350 g, 0.638 mmol) obtained in step 3 was dissolved in dichloromethane (20 ml), and trifluoroacetic acid (0.977 ml, 12.761 mmol) was added at 0°C and stirred at room temperature for 16 hours. After removing the solvent from the reaction mixture under reduced pressure, the title compound (0.355 g, 98.9%) was obtained as a foamy solid.

^1H NMR (400 MHz, MeOD) δ 7.91 (m, 1H), 7.76 (m, 1H), 7.60 (m, 1H), 7.36-7.71 (m, 6H) , 5.08 (s, 2H), 3.11 (m, 2H), 2.84 (m, 2H), 2.44-2.27 (m, 2H), 2.04 (m, 2H);

LRMS (ES) m/z 449.4 (M ⁺ +1).

Example 2: Synthesis of Compound 2866, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-1-methyl-N-phenylpiperidin-4 -carboxamide

N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2-trifluoroacetate (0.070 g, 0.124 mmol) obtained in step 4 of Example 1, paraformaldehyde (0.007 g, 0.249 mmol), and acetic acid (0.007 ml, 0.124 mmol) were dissolved in dichloromethane (4 ml), and the resulting solution was stirred at room temperature for 1 hours. Sodium triacetoxyborohydride (0.079 g, 0.373 mmol) was added and further stirred at the same temperature for 16 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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; methanol/dichloromethane = 0% to 10%) and concentrated to give the title compound (0.025 g, 43.4%) as a foamy solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 7.89 (m, 1H), 7.74 (m, 1H), 7.58 (m, 1H), 7.33 (m, 3H), 7 .06-6.80 (m, 3H), 5.03 (s, 2H), 2.96 (m, 2H), 2.56-2.34 (m, 7H), 1.99 (m, 2H );

LRMS (ES) m/z 463.6 (M ⁺ +1).

Example 3: Synthesis of Compound 2867, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-ethyl-4-fluoro-N-phenylpiperidin-4 -carboxamide

N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2-trifluoroacetate (0.070 g, 0.124 mmol) obtained in step 4 of Example 1, acetaldehyde (0.011 g, 0.249 mmol), and acetic acid (0.007 ml, 0.124 mmol) were dissolved in dichloromethane (4 ml), and the resulting solution was stirred at room temperature for 1 hours. Sodium triacetoxyborohydride (0.079 g, 0.373 mmol) was added and further stirred at the same temperature for 16 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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; methanol/dichloromethane = 0% to 10%) and concentrated to give the title compound (0.024 g, 40.5%) as a foamy solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 7.89 (m, 1H), 7.74 (m, 1H), 7.71 (m, 1H), 7.57 (m, 3H), 7 .06-6.80 (m, 3H), 5.03 (s, 2H), 3.04 (m, 2H), 2.64-2.35 (m, 6H), 2.00 (m, 2H ), 1.15 (m, 3H);

LRMS (ES) m/z 477.6 (M ⁺ +1).

Example 4: Synthesis of Compound 2868, 1-Cyclobutyl-N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-N-phenylpiperidin-4 -carboxamide

N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2-trifluoroacetate (0.070 g, 0.124 mmol) obtained in step 4 of Example 1, cyclobutanone (0.019 g, 0.249 mmol), and acetic acid (0.007 ml, 0.124 mmol) were dissolved in dichloromethane (4 ml), and the resulting solution was stirred at room temperature for 1 hours. Sodium triacetoxyborohydride (0.079 g, 0.373 mmol) was added and further stirred at the same temperature for 16 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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; methanol/dichloromethane = 0% to 10%) and concentrated to give the title compound (0.022 g, 35.2%) as a foamy solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 7.89 (m, 1H), 7.74 (m, 1H), 7.71 (m, 1H), 7.32 (m, 3H), 7 .06-6.60 (m, 3H), 5.03 (s, 2H), 2.75 (m, 3H), 2.45-2.31 (m, 2H), 2.02-1.90 (m, 8H), 1.73-1.63 (m, 2H);

LRMS (ES) m/z 503.4 (M ⁺ +1).

Example 5: Synthesis of Compound 2869, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-1-(oxetan-3-yl) -N-phenylpiperidine-4-carboxamide

N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2-trifluoroacetate (0.070 g, 0.124 mmol) obtained in step 4 of Example 1, oxetan-3-one (0.016 g, 0.249 mmol), and acetic acid (0.007 ml, 0.124 mmol) were dissolved in dichloromethane (4 ml), and the resulting solution was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.079 g, 0.373 mmol) was added and further stirred at the same temperature for 16 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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; methanol/dichloromethane = 0% to 10%) and concentrated to give the title compound (0.022 g, 35.0%) as a foamy solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 7.89 (m, 1H), 7.74 (m, 1H), 7.59 (m, 1H), 7.33 (m, 3H), 7 .06-6.80 (m, 3H), 5.04 (s, 2H), 4.61 (m, 4H), 3.44 (m, 1H), 2.58 (m, 2H), 2 .47-2.31 (m, 2H), 2.02-1.91 (m, 4H);

LRMS (ES) m/z 505.4 (M ⁺ +1).

Example 6: Synthesis of Compound 2951, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-1-methyl-N -phenylpiperidine-4-carboxamide

[Step 1] Synthesis of 6-methylnicotine hydrazide

A solution of methyl 6-methylnicotinate (25.000 g, 165.377 mmol) and hydrazine monohydrate (40.188 mL, 826.884 mmol) was dissolved in ethanol (220 mL) at room temperature, refluxed for 16 hours, and thereafter the temperature was reduced to room temperature to stop the reaction. The solvent was removed from the reaction mixture under reduced pressure. The precipitated solid was filtered, washed with hexane and dried to give the title compound (25,000 g, 100.0%) as a white solid.

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

6-Methylnicotinohydrazide (15.000 g, 99.226 mmol) obtained in step 1 and imidazole (20.265 g, 297.678 mmol) were dissolved in dichloromethane (250 ml). 2,2-difluoroacetic anhydride (37.008 ml, 297.678 mmol) was added at 0°C and refluxed for 16 hours, and then the temperature was lowered to room temperature to stop the reaction. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The resulting product was filtered and concentrated under reduced pressure to give the title compound (20.900 g, 99.7%) as a red solid.

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

2-(Difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole (20.900 g, 98.972 mmol) obtained in step 2 was dissolved in 1,2-dichloroethane (200 ml). Azobisisobutyronitrile (AIBN, 0.813 g, 4.949 mmol) and 1-bromopyrrolidin-2,5-one (NBS, 22.900 g, 128.664 mmol) were added at room temperature and refluxed for 16 hours, and then the temperature was lowered to room temperature to stop the reaction. 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 magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 80 g; ethyl acetate/hexane = 5% to 50%) and concentrated to give the title compound (5.400 g, 18.8%) as a red solid.

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

Aniline (0.490 ml, 5.369 mmol), 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (1.635 g, 5.637 mmol) obtained in step 3, Potassium carbonate (1.484 g, 10.738 mmol), and potassium iodide (0.089 g, 0.537 mmol) were dissolved in N,N-dimethylformamide (15 ml) at room temperature. The resulting solution was stirred at the same temperature for 16 hours. Water 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 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, 80 g; ethyl acetate/hexane = 5% to 50%) and concentrated to give the title compound (1,300 g, 80.1%) as a yellow solid.

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

To a solution in which N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)aniline (0.700 g, 2.316 mmol) obtained in step 4, and triethylamine (0.968 ml, 6.947 mmol) was dissolved in dichloromethane (35 ml) at room temperature, tert-butyl 4-(chlorocarbonyl)-4-fluoropiperidine-1-carboxylate (0.861 g, 3.242 mmol) obtained in step was added 2 of Example 1, and stirred at the same temperature for 16 hours. A saturated aqueous solution of ammonium chloride was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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, 40 g; ethyl acetate/hexane = 5% to 35%) and concentrated to give the title compound (0.400 g, 32.5%) as a foamy solid.

[Step 6] Synthesis of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2-trifluoroacetate

Tert-butyl 4-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(phenyl)carbamoyl)-4-fluoropiperidine-1-carboxylate (0.300 g, 0.564 mmol) obtained in step 5 was dissolved in dichloromethane (15 ml), and trifluoroacetic acid (0.432 ml, 5.644 mmol) was added at 0° C. and stirred at room temperature for 16 hours. After removing the solvent from the reaction mixture under reduced pressure, the title compound (0.305 g, 99.1%) was obtained as a foamy solid.

[Step 7] Synthesis of compound 2951

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2 β-trifluoroacetate (0.075 g, 0.138 mmol) obtained in step 6, paraformaldehyde (0.008 g, 0.275 mmol), and acetic acid (0.008 ml, 0.138 mmol) were dissolved in dichloromethane (4 ml), and the resulting solution was stirred at room temperature in within 1 hour. Sodium triacetoxyborohydride (0.087 g, 0.413 mmol) was added and further stirred at the same temperature for 16 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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; methanol/dichloromethane = 0% to 10%) and concentrated to give the title compound (0.023 g, 37.6%) as a foamy solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.23 (m, 1H), 8.33 (m, 1H), 7.46 (m, 1H), 7.33 (m, 3H), 7 .23 (m, 2H), 6.94 (m, 1H), 5.04 (s, 2H), 3.30 (m, 2H), 2.76 (m, 2H), 2.63 (m, 5H), 2.12 (m, 2H); LRMS (ES) m/z 446.4 (M ⁺ +1).

Example 7: Synthesis of Compound 2952, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-1-isopropyl-N -phenylpiperidine-4-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2 α-trifluoroacetate (0.075 g, 0.138 mmol) obtained in step 6 of Example 6, acetone (0.020 ml, 0.275 mmol), and acetic acid (0.008 ml, 0.138 mmol) were dissolved in dichloromethane (4 ml), and the resulting solution was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.087 g, 0.413 mmol) was added and further stirred at the same temperature for 16 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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; methanol/dichloromethane = 0% to 10%) and concentrated to give the title compound (0.018 g, 27.6%) as a foamy solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.24 (m, 1H), 8.36 (m, 1H), 7.47 (m, 1H), 7.34 (m, 3H), 7 .23 (m, 2H), 6.95 (m, 1H), 5.05 (s, 2H), 3.44 (m, 3H), 2.90-2.86 (m, 4H), 2, 18 (m, 2H), 1.28 (m, 6H);

LRMS (ES) m/z 474.4 (M ⁺ +1).

Example 8: Synthesis of Compound 2953, 1-Cyclobutyl-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N -phenylpiperidine-4-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2 α-trifluoroacetate (0.075 g, 0.138 mmol) obtained in step 6 of Example 6, cyclobutanone (0.021 ml, 0.275 mmol), and acetic acid (0.008 ml, 0.138 mmol) were dissolved in dichloromethane (4 ml), and the resulting solution was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.087 g, 0.413 mmol) was added and further stirred at the same temperature for 16 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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; methanol/dichloromethane = 0% to 10%) and concentrated to give the title compound (0.022 g, 33.0%) as a foamy solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.24 (m, 1H), 8.35 (m, 1H), 7.37 (m, 1H), 7.33 (m, 3H), 7 .23 (m, 2H), 6.95 (m, 1H), 5.06 (s, 2H), 3.18-3.08 (m, 3H), 2.63-2.52 (m, 4H ), 2.33 (m, 2H), 2.08 (m, 4H), 1.84-1.68 (m, 2H);

LRMS (ES) m/z 486.4 (M ⁺ +1).

Example 9: Synthesis of Compound 2954, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-1-(oxetane- 3-yl)-N-phenylpiperidine-4-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2 -trifluoroacetate (0.075 g, 0.138 mmol) obtained in step 6 of Example 6, oxetan-3-one (0.018 ml, 0.275 mmol), and acetic acid (0.008 ml, 0.138 mmol) were dissolved in dichloromethane (4 ml), and the resulting the solution was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.087 g, 0.413 mmol) was added and further stirred at the same temperature for 16 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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; methanol/dichloromethane = 0% to 10%) and concentrated to give the title compound (0.024 g, 35.8%) as a foamy solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.24 (m, 1H), 8.35 (m, 1H), 7.35 (m, 1H), 7.32 (m, 3H), 7.22 (m, 2H), 6.95 (m, 1H), 5.08 (s, 2H), 4.60 (m, 4H), 3.45 (m, 1H), 2.58 (m, 2H) , 2.43-2.33 (m, 2H), 1.97 (m, 4H);

LRMS (ES) m/z 488.5 (M ⁺ +1).

Example 10: Synthesis of compound 2969.1 N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-(3 -fluorophenyl)-1-methylpiperidine-4-carboxamide

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

2-(6-(bromomethyl)pyridine -3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (2.480 g, 8.549 mmol), obtained in step 3 of Example 6, and potassium iodide (0.747 g, 4.500 mmol), and 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 magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 40 g; ethyl acetate/hexane = 0% to 60%) and concentrated to give the title compound (2.340 g, 81.2%) as a yellow solid.

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

To a solution of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoroaniline (0.490 g, 1.530 mmol), obtained in step 1, and triethylamine (0.640 ml, 4.590 mmol) was dissolved in dichloromethane (20 ml) at room temperature, tert-butyl 4-(chlorocarbonyl)-4-fluoropiperidine-1-carboxylate (0.528 g, 1.989 mmol) was added, obtained in step 2 of Example 1, and stirred at the same temperature for 16 hours. A saturated aqueous solution of ammonium chloride 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 30%) and concentrated to give the title compound (0.430 g, 51.1%) as a yellow solid.

[Step 31 Synthesis of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-(3-fluorophenyl)piperidine -4-carboxamide 2,2,2-trifluoroacetate

Tert-butyl 4-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(3-fluorophenyl)carbamoyl)-4-fluoropiperidin-1 The β-carboxylate (0.430 g, 0.782 mmol) obtained in step 2 and trifluoroacetic acid (1.198 ml, 15.650 mmol) were dissolved in dichloromethane (30 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the title compound (0.350 g, 99.5%) was obtained as a brown liquid.

[Step 4] Synthesis of compound 2969

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-(3-fluorophenyl)piperidine-4-carboxamide 2,2,2-trifluoroacetate (0.088 g, 0.196 mmol) obtained in step 3, formaldehyde (0.012 g, 0.392 mmol), acetic acid (0.011 ml, 0.196 mmol), and sodium triacetoxyborohydride (0.125 g, 0.587 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.011 g, 12.1%) as a white solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.32-9.19 (m, 1H), 8.38 (dd, J=8.2, 2.2 Hz, 1H), 7.53 (d, J=8.2 Hz, 1 N), 7.32 (ddd, J=13.5, 6.8, 4.2 Hz, 1 N), 7.09-6.81 (m, 4H), 5 .06 (s, 2H), 2.72 (d, J=11.2 Hz, 2H), 2.50-2.31 (m, 2H), 2.28 (s, 3H), 2.16 ( t, J=11.6 Hz, 2H), 2.02-1.89 (m, 2H);

LRMS (ES) m/z 464.6 (M ⁺ +1).

Example 11: Synthesis of Compound 2970, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-(3- fluorophenyl)-1-isopropylpiperidine-4-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-(3-fluorophenyl)piperidine-4-carboxamide 2,2,2-trifluoroacetate (0.088 g, 0.196 mmol) obtained from step 3 of Example 10, propan-2-one (0.023 g, 0.392 mmol), acetic acid (0.011 ml, 0.196 mmol), and sodium triacetoxyborohydride (0.125 g, 0.587 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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, 24.9%) as a white solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.27 (d, J=1.6 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7, 54 (d, J=8.3 Hz, 1H), 7.36-7.29 (m, 1H), 7.00 (ddd, J=73.7, 45.8, 33.6 Hz, 4H) , 5.07 (s, 2H), 2.74 (s, 2H), 2.45-2.24 (m, 4H), 1.98 (d, J=11.1 Hz, 3H), 1, 04 (d, J=6.5 Hz, 6H);

LRMS (ES) m/z 492.5 (M ⁺ +1).

Example 12: Synthesis of Compound 2971, 1-Cyclobutyl-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N -(3-fluorophenyl)piperidine-4-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-(3-fluorophenyl)piperidine-4-carboxamide 2,2,2-trifluoroacetate (0.088 g, 0.196 mmol) obtained from step 3 of Example 10, cyclobutanone (0.027 g, 0.392 mmol), acetic acid (0.011 ml, 0.196 mmol), and sodium triacetoxyborohydride (0.125 g, 0.587 mmol ) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.035 g, 35.5%) as a white solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.26 (d, J=1.6 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.35-7.29 (m, 1H), 7.10-6.80 (m, 4H), 5.07 (s, 2H), 2, 70 (t, J=11.7 Hz, 3H), 2.45-2.22 (m, 2H), 2.07-1.83 (m, 7H), 1.75-1.59 (m, 3H);

LRMS (ES) m/z 504.4 (M ⁺ +1).

Example 13: Synthesis of Compound 2972, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-(3- fluorophenyl)-1-(oxetan-3-yl)piperidin-4-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-(3-fluorophenyl)piperidine-4-carboxamide 2,2,2-trifluoroacetate (0.088 g, 0.196 mmol) obtained in step 3 of Example 10, oxetan-3-one (0.028 g, 0.392 mmol), acetic acid (0.011 ml, 0.196 mmol), and sodium triacetoxyborohydride (0.125 g, 0.587 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.045 g, 45.5%) as a white solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.28 (d, J=1.5 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.36-7.29 (m, 1H), 7.10-6.81 (m, 4H), 5.07 (s, 2H), 4, 62 (dt, J=15.9, 6.4 Hz, 4H), 3.47 (p, J=6.6 Hz, 1H), 2.59 (d, J=8.6 Hz, 2H), 2.49-2.27 (m, 2H), 2.00 (dt, J=24.8, 12.4 Hz, 4H);

LRMS (ES) m/z 506.4 (M ⁺ +1).

Example 14: Synthesis of Compound 2973, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-1-methyl-N -phenylazetidine-3-carboxamide

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

1-(tert-butoxycarbonyl)-3-fluoroazetidine-3-carboxylic acid (0.500 g, 2.281 mmol) was dissolved in dichloromethane (20 ml). Oxalyl chloride (2.00 M solution in DCM, 1.483 ml, 2.965 mmol) and N,N-dimethylformamide (0.018 ml, 0.228 mmol) were added at 0°C, and stirred at room temperature for 2 hours. After removing the solvent from the reaction mixture under reduced pressure, the title compound (0.540 g, 99.6%) was obtained as a beige solid.

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

To a solution in which N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)aniline (0.500 g, 1.654 mmol) obtained in step 4 of Example 6, and triethylamine (0.692 ml, 4.962 mmol) was dissolved in dichloromethane (35 ml) at room temperature, tert-butyl 3-(chlorocarbonyl)-3-fluoroazetidine-1-carboxylate (0.511 g, 2.150 mmol) was added to obtain in step 1, and stirred at the same temperature for 16 hours. A saturated aqueous solution of ammonium chloride was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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, 40 g; ethyl acetate/hexane = 5% to 50%) and concentrated to give the title compound (0.610 g, 73.2%) as a foamy solid.

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

Tert-butyl 3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(phenyl)carbamoyl)-3-fluoroazetidine-1-carboxylate (0.200 g, 0.397 mmol) obtained in step 2 was dissolved in dichloromethane (12 ml). Trifluoroacetic acid (0.913 ml, 11.917 mmol) was added at 0°C, and stirred at room temperature for 16 hours. After removing the solvent from the reaction mixture under reduced pressure, the title compound (0.200 g, 97.3%) was obtained as a foamy solid.

[Step 4] Synthesis of compound 2973

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 β-trifluoroacetate (0.050 g, 0.097 mmol) obtained in step 3, paraformaldehyde (0.006 g, 0.193 mmol), and acetic acid (0.006 ml, 0.097 mmol) were dissolved in dichloromethane (4 ml), and the resulting solution was stirred at room temperature in within 1 hour. Sodium triacetoxyborohydride (0.061 g, 0.290 mmol) was added and further stirred at the same temperature for 16 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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; methanol/dichloromethane = 0% to 10%) and concentrated to give the title compound (0.021 g, 52.1%) as a foamy solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.25 (m, 1H), 8.39 (m, 1H), 7.59 (m, 1H), 7.35 (m, 3H), 7.25 (m, 2H), 6.95 (m, 1H), 5.12 (s, 2H), 3.60 (m, 2H), 3.18 (m, 2H), 2.34 (s, 3H) ;

LRMS (ES) m/z 418.5 (M ⁺ +1).

Example 15: Synthesis of Compound 2974, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-1-isopropyl-N -phenylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 α-trifluoroacetate (0.050 g, 0.097 mmol) obtained in step 3 of Example 14, acetone (0.014 ml, 0.193 mmol), and acetic acid (0.006 ml, 0.097 mmol) were dissolved in dichloromethane (4 ml), and the resulting solution was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.061 g, 0.290 mmol) was added and further stirred at the same temperature for 16 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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; methanol/dichloromethane = 0% to 10%) and concentrated to give the title compound (0.022 g, 51.1%) as a foamy solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.25 (hl, 1H), 8.38 (hl, 1H), 7.58 (hl, 1H), 7.35 (hl, 3H), 7.25 (m, 2H), 6.95 (m, 1H), 5.12 (s, 2H), 3.53 (hl, 2H), 3.11 (m, 2H), 2.30 (hl, 1H) , 0.90 (m, 6H);

LRMS (ES) m/z 446.6 (M ⁺ +1).

Example 16: Synthesis of Compound 2975, 1-Cyclobutyl-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N -phenylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 α-trifluoroacetate (0.050 g, 0.097 mmol) obtained in step 3 of Example 14, cyclobutanone (0.014 ml, 0.193 mmol), and acetic acid (0.006 ml, 0.097 mmol) were dissolved in dichloromethane (4 ml), and the resulting solution was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.061 g, 0.290 mmol) was added and further stirred at the same temperature for 16 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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; methanol/dichloromethane = 0% to 10%) and concentrated to give the title compound (0.025 g, 56.6%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.24 (m, 1H), 8.38 (m, 1H), 7.57 (m, 1H), 7.35 (m, 3H), 7.25 (m, 2H), 6.95 (m, 1H), 5.12 (s, 2H), 3.53 (m, 2H), 3.12 (m, 1H), 3.06 (m, 2H) , 1.91 (m, 2H), 1.66 (m, 4H);

LRMS (ES) m/z 458.5 (M ⁺ +1).

Example 17: Synthesis of Compound 2976, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-1-(oxetane- 3-yl)-N-phenylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 α-trifluoroacetate (0.050 g, 0.097 mmol) obtained in step 3 of Example 14, oxetan-3-one (0.012 ml, 0.193 mmol), and acetic acid (0.006 ml, 0.097 mmol) were dissolved in dichloromethane (4 ml), and the resulting the solution was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.061 g, 0.290 mmol) was added and further stirred at the same temperature for 16 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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; methanol/dichloromethane = 0% to 10%) and concentrated to give the title compound (0.024 g, 54.1%) as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.26 (m, 1H), 8.38 (m, 1H), 7.57 (m, 1H), 7.35 (m, 3H), 7.25 (m, 2H), 6.95 (m, 1H), 5.13 (s, 2H), 4.67 (m, 2H), 4.47 (m, 2H), 3.80 (m, 3H) , 3.25 (m, 2H);

LRMS (ES) m/z 460.6 (M ⁺ +1).

Example 18: Synthesis of Compound 2995, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-phenyl-1 -(2-oxaspiro[3.3]heptan-6-yl)piperidine-4-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2 -trifluoroacetate (0.096 g, 0.223 mmol) obtained from step 6 of Example 6,2-oxaspiro[3,3]heptan-6-one (0.050 g, 0.445 mmol), acetic acid (0.013 ml, 0.223 mmol), and triacetoxyborohydride sodium (0.141 g, 0.668 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.032 g, 27.3%) as a white solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.25 (d, J=2.2 Hz, 1H), 8.37 (dd, J=8.2, 2.3 Hz, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.38-7.29 (m, 3H), 7.21 (dd, J=7.9, 1.6 Hz, 2H), 6.95 ( t, J=51.7 Hz, 1H), 5.09 (s, 2H), 4.70 (s, 2H), 4.59 (s, 2H), 2.66 (d, J=11.7 Hz, 2H), 2.48 (dd, J=15.2, 7.8 Hz, 1H), 2.41-2.31 (m, 3H), 2.26 (dd, J=13.7, 4.7 Hz, 1H), 1.98 (ddd, J=40.7, 19.6, 8.9 Hz, 6H);

LRMS (ES) m/z 529.4 (M ⁺ +1).

Example 19: Synthesis of Compound 2996, 1-Cyclopentyl-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N -phenylpiperidine-4-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2 α-trifluoroacetate (0.096 g, 0.223 mmol) obtained in step 6 of Example 6, cyclopentanone (0.037 g, 0.445 mmol), acetic acid (0.013 ml, 0.223 mmol), and sodium triacetoxyborohydride (0.141 g, 0.668 mmol) were dissolved in dichloromethane ( 5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.037 g, 33.3%) as a white solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.25 (d, J=2.2 Hz, 1H), 8.38 (dd, J=8.2, 2.2 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.40-7.30 (m, 3H), 7.22 (dd, J=7.7, 1.7 Hz, 2H), 6.95 ( t, J=51.7 Hz, 1H), 5.09 (s, 2H), 3.01 (d, J=11.4 Hz, 2H), 2.67 (d, J=7.2 Hz, 1H), 2.59-2.38 (m, 2H), 2.38-2.24 (m, 2H), 1.98 (d, J=11.7 Hz, 2H), 1.82 (d , J=21.6 Hz, 2H), 1.71 (s, 2H), 1.54 (s, 4H);

LRMS (ES) m/z 501.4 (M ⁺ +1).

Example 20: Synthesis of Compound 2997, 1-Cyclohexyl-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N -phenylpiperidine-4-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2 α-trifluoroacetate (0.096 g, 0.223 mmol) obtained in step 6 of Example 6, cyclohexanone (0.044 g, 0.445 mmol), acetic acid (0.013 ml, 0.223 mmol), and sodium triacetoxyborohydride (0.141 g, 0.668 mmol) were dissolved in dichloromethane ( 5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.044 g, 38.5%) as a white solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.25 (d, J=2.2 Hz, 1H), 8.38 (dd, J=8.2, 2.3 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.39-7.30 (m, 3H), 7.24-7.19 (m, 2H), 6.97 (dd, J=65.0 , 38.4 Hz, 1H), 5.09 (s, 2H), 2.78 (s, 2H), 2.39 (d, J=43.3 Hz, 5H), 1.97 (s, 2H ), 1.78 (s, 5H), 1.21 (s, 5H);

LRMS (ES) m/z 515.5 (M ⁺ +1).

Example 21: Synthesis of Compound 2998, 1-Cyclopentyl-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N -phenylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 α-trifluoroacetate (0.090 g, 0.223 mmol) obtained in step 3 of Example 14, cyclopentanone (0.038 g, 0.446 mmol), acetic acid (0.013 ml, 0.223 mmol), and sodium triacetoxyborohydride (0.142 g, 0.669 mmol) were dissolved in dichloromethane ( 5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.051 g, 48.5%) as a white solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.29-9.20 (m, 1H), 8.38 (dd, J=8.2, 2.2 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.41-7.31 (m, 3H), 7.27-7.22 (m, 2H), 6.95 (t, J=51.7 Hz, 1H ), 5.12 (s, 2H), 3.51 (dd, J=23.8, 10.3 Hz, 2H), 3.11 (dd, J=21.8, 10.4 Hz, 2H) , 2.69 (d, J=5.2 Hz, 1H), 1.68-1.60 (m, 2H), 1.60-1.43 (m, 4H), 1.28 (d, J =6.1 Hz, 2H);

LRMS (ES) m/z 473.4 (M ⁺ +1).

Example 22: Synthesis of Compound 2999, 1-Cyclohexyl-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N -phenylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 α-trifluoroacetate (0.090 g, 0.223 mmol) obtained in step 3 of Example 14, cyclohexanone (0.044 g, 0.445 mmol), acetic acid (0.013 ml, 0.223 mmol), and sodium triacetoxyborohydride (0.142 g, 0.669 mmol) were dissolved in dichloromethane ( 5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.050 g, 46.2%) as a white solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.25 (d, J=1.6 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.40-7.32 (m, 3H), 7.25 (d, J=8.1 Hz, 2H), 6.95 (t, J= 51.7 Hz, 1H), 5.13 (s, 2H), 3.53 (dd, J=23.2, 9.8 Hz, 2H), 3.11 (dd, J=21.4, 9 ,4 Hz, 2H), 2.01-1.85 (m, 2H), 1.72 (d, J=28.0 Hz, 2H), 1.38-1.24 (m, 2H), 1 .24-1.10 (m, 3H), 0.97 (d, J=11.8 Hz, 2H);

LRMS (ES) m/z 487.5 (M ⁺ +1).

Example 23: Synthesis of Compound 3000, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-1 -(tetrahydro-2H-pyran-4-yl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 -trifluoroacetate (0.090 g, 0.223 mmol) obtained from step 3 of Example 14, tetrahydro-4H-pyran-4-one (0.045 g, 0.446 mmol), acetic acid (0.013 ml, 0.223 mmol), and sodium triacetoxyborohydride (0.142 g , 0.669 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.032 g, 29.4%) as a white solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.28-9.23 (m, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.41-7.32 (m, 3H), 7.26 (d, J=8.0 Hz, 2H), 6.95 (t, J=51.6 Hz, 1H), 5.13 (s, 2H), 3.93 (dt, J=11.4, 3.6 Hz, 2H), 3.57 (dd, J=23.2, 10.0 Hz , 2H), 3.35 (td, J=11.2, 1.9 Hz, 2H), 3.13 (dd, J=21.6, 10.1 Hz, 2H), 2.24 (s, 1H), 1.57 (d, J=13.2 Hz, 2H), 1.33 (td, J=14.5, 4.7 Hz, 2H);

LRMS (ES) m/z 488.5 (M ⁺ +1).

Example 24: Synthesis of Compound 3001, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-ethyl-3-fluoro-N -phenylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 β-trifluoroacetate (0.048 g, 0.119 mmol) obtained in step 3 of Example 14, acetaldehyde (0.010 g, 0.238 mmol), acetic acid (0.007 ml, 0.119 mmol), and sodium triacetoxyborohydride (0.076 g, 0.357 mmol) were dissolved in dichloromethane ( 5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.042 g, 81.8%) as a yellow solid colors.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.26 (d, J=1.6 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.40-7.34 (m, 3H), 7.26 (d, J=8.1 Hz, 2H), 6.96 (t, J= 51.7 Hz, 1H), 5.13 (s, 2H), 3.75 (dd, J=22.9, 10.9 Hz, 2H), 3.24 (dd, J=21.6, 10 .5 Hz, 2H), 2.59 (q, J=7.2 Hz, 2H), 0.98 (t, J=7.2 Hz, 3H);

LRMS (ES) m/z 433.4 (M ⁺ +1).

Example 25: Synthesis of Compound 3002, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-1 -propylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 α-trifluoroacetate (0.048 g, 0.119 mmol) obtained in step 3 of Example 14, propioaldehyde (0.014 g, 0.238 mmol), acetic acid (0.007 ml, 0.119 mmol), and sodium triacetoxyborohydride (0.076 g, 0.357 mmol) were dissolved in dichloromethane ( 5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.029 g, 54.7%) as a yellow solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.25 (d, J=1.5 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.41-7.30 (m, 3H), 7.27-7.20 (m, 2H), 6.95 (t, J=51.7 Hz, 1H), 5.13 (s, 2H), 3.56 (dd, J=22.8, 10.1 Hz, 2H), 3.14 (dd, J=21.6, 9.3 Hz , 2H), 2.40 (t, J=7.4 Hz, 2H), 1.32 (dt, J=19.6, 9.8 Hz, 2H), 0.87 (t, J=7, 4 Hz, 3H);

LRMS (ES) m/z 447.5 (M ⁺ +1).

Example 26: Synthesis of Compound 3003, 1-Butyl-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N -phenylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 β-trifluoroacetate (0.048 g, 0.119 mmol) obtained in step 3 of Example 14, butyraldehyde (0.017 g, 0.238 mmol), acetic acid (0.007 ml, 0.119 mmol), and sodium triacetoxyborohydride (0.076 g, 0.357 mmol) were dissolved in dichloromethane ( 5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.038 g, 69.5%) as a yellow solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.25 (d, J=1.5 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.41-7.32 (m, 3H), 7.27-7.21 (m, 2H), 6.95 (t, J=51.7 Hz, 1H), 5.13 (s, 2H), 3.55 (dd, J=22.8, 9.4 Hz, 2H), 3.14 (dd, J=21.5, 10.3 Hz , 2H), 2.42 (s, 2H), 1.34-1.24 (m, 4H), 0.88 (t, J=7.1 Hz, 3H);

LRMS (ES) m/z 461.5 (M ⁺ +1).

Example 27: Synthesis of Compound 3004, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-1-isobutyl-N -phenylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 α-trifluoroacetate (0.048 g, 0.119 mmol) obtained in step 3 of Example 14, isobutyraldehyde (0.017 g, 0.238 mmol), acetic acid (0.007 ml, 0.119 mmol), and sodium triacetoxyborohydride (0.076 g, 0.357 mmol) were dissolved in dichloromethane ( 5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.040 g, 73.2%) as a yellow solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.26 (d, J=1.5 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.41-7.33 (m, 3H), 7.27-7.20 (m, 2H), 6.95 (t, J=51.7 Hz, 1H), 5.13 (s, 2H), 3.62-3.46 (m, 2H), 3.15 (dd, J=21.8, 9.7 Hz, 2H), 2.25 (d, J=7.1 Hz, 2H), 1.54 (dt, J=13.3, 6.8 Hz, 1H), 0.85 (d, J=6.7 Hz, 6H);

LRMS (ES) m/z 460.4 (M ⁺ +1).

Example 28: Synthesis of Compound 3005, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-1-(1- Hydroxypropan-2-yl)-N-phenylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 -trifluoroacetate (0.048 g, 0.119 mmol) obtained from step 3 of Example 14,1-hydroxypropan-2-one (0.018 g, 0.238 mmol), acetic acid (0.007 ml, 0.119 mmol), and sodium triacetoxyborohydride (0.076 g, 0.357 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.023 g, 41.9%) as a yellow solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.27 (d, J=1.6 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.38 (dd, J=8.6, 3.2 Hz, 3H), 7.25 (d, J=7.7 Hz, 2H), 6 .96 (t, J=51.7 Hz, 1H), 5.12 (s, 2H), 3.94-3.75 (m, 2H), 3.62-3.51 (m, 1H), 3.47-3.26 (m, 3H), 2.60 (s, 1H), 0.99 (d, J=6.5 Hz, 3H);

LRMS (ES) m/z 463.5 (M ⁺ +1).

Example 29: Synthesis of Compound 3006, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-(3-(dimethylamino)propanoyl )-3-fluoro-N-phenylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 -trifluoroacetate (0.048 g, 0.119 mmol) obtained in step 3 of Example 14, 3-(dimethylamino)propanoyl chloride (0.021 g, 0.155 mmol), and triethylamine (0.050 ml, 0.357 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.029 g, 48.5%) as a yellow solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.29 (d, J=1.8 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.43-7.35 (m, 3H), 7.32-7.24 (m, 2H), 6.96 (t, J=51.7 Hz, 1H), 5.13 (s, 2H), 4.76 (dd, J=21.7, 10.2 Hz, 1H), 4.36 (dd, J=22.7, 12.1 Hz , 1H), 4.04 (dd, J=22.6, 10.5 Hz, 1H), 3.69 (dd, J=22.9, 11.7 Hz, 1H), 2.65 (t, J=7.2 Hz, 2H), 2.29 (d, J=10.1 Hz, 8H);

LRMS (ES) m/z 504.4 (M ⁺ +1).

Example 30: Synthesis of Compound 3007, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-(4-(dimethylamino)butanoyl )-3-fluoro-N-phenylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 β-trifluoroacetate (0.048 g, 0.119 mmol) obtained in step 3 of Example 14, 4-(dimethylamino)butanoyl chloride (0.023 g, 0.155 mmol), and triethylamine (0.050 ml, 0.357 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.033 g, 53.7%) as a yellow solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.28 (d, J=1.8 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.44-7.36 (m, 3H), 7.28 (d, J=5.9 Hz, 2H), 6.96 (t, J= 51.7 Hz, 1H), 5.13 (s, 2H), 4.73 (dd, J=22.1, 11.0 Hz, 1H), 4.38 (dd, J=23.1, 11 .7 Hz, 1H), 4.02 (dd, J=22.7, 10.4 Hz, 1H), 3.70 (dd, J=22.8, 12.3 Hz, 1H), 2.48 (d, J=6.7 Hz, 2H), 2.36 (s, 6H), 2.16 (t, J=7.1 Hz, 2H), 1.90-1.79 (m, 2H) ;

LRMS (ES) m/z 517.4 (M ⁺ +1).

Example 31: Synthesis of compound 3047,N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1-methylazetidine-3-carboxamide

[Step 1] Synthesis of 3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(3-fluorophenyl)carbamoyl)-3-fluoroazetidine -1-carboxylate

To a solution of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoroaniline (1.100 g, 3.434 mmol), obtained in step 1 of Example 10, and triethylamine (1.436 ml, 10.303 mmol) was dissolved in dichloromethane (20 ml) at room temperature, tert-butyl 3-(chlorocarbonyl)-3-fluoroazetidine-1-carboxylate (1.061 g, 4.465 mmol) was added ) obtained in step 1 of Example 14 and stirred at the same temperature for 16 hours. A saturated aqueous solution of ammonium chloride was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with water, 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 (1.210 g, 67.6%) as a yellow solid.

[Step 2] Synthesis of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl) Azetidine-3-carboxamide 2,2,2-trifluoroacetate

Tert-butyl 3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(3-fluorophenyl)carbamoyl)-3-fluoroazetidin-1 The β-carboxylate (1.080 g, 2.145 mmol) obtained in step 1 and trifluoroacetic acid (3.285 ml, 42.901 mmol) were dissolved in dichloromethane (30 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the title compound (0.865 g, 100.0%) was obtained as a brown gel.

[Step 3] Synthesis of compound 3047

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) from step 2, formaldehyde (0.007 g, 0.237 mmol), acetic acid (0.007 mL, 0.119 mmol), and sodium triacetoxyborohydride (0.075 g, 0.356 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.032 g, 61.9%) as a white solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.28 (d, J=1.5 Hz, 1H), 8.40 (dd, J=8.2, 2.3 Hz, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.39-7.31 (m, 1H), 7.01 (dt, J=83.3, 28.8 Hz, 4H), 5.10 ( s, 2H), 3.67 (s, 2H), 3.21 (s, 2H), 2.36 (s, 3H);

LRMS (ES) m/z 437.5 (M ⁺ +1).

Example 32: Synthesis of Compound 3048, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1-isopropylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained from step 2 of Example 31, propan-2-one (0.014 g, 0.237 mmol), acetic acid (0.011 ml, 0.119 mmol), and sodium triacetoxyborohydride (0.075 g, 0.356 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.026 g, 47.3%) as a white solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.27 (d, J=1.6 Hz, 1H), 8.40 (dd, J=8.2, 2.3 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.39-7.31 (m, 1H), 7.11-6.81 (m, 4H), 5.10 (s, 2H), 3, 61 (s, 2H), 3.16 (s, 2H), 2.34 (d, J=6.0 Hz, 1H), 0.92 (d, J=6.2 Hz, 6H);

LRMS (ES) m/z 465.4 (M ⁺ +1).

Example 33: Synthesis of Compound 3049, 1-Cyclobutyl-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N -(3-fluorophenyl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained from step 2 of Example 31, cyclobutanone (0.017 g, 0.237 mmol), acetic acid (0.007 ml, 0.119 mmol), and sodium triacetoxyborohydride (0.075 g, 0.356 mmol ) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.019 g, 33.7%) as a white solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.27 (d, J=2.2 Hz, 1H), 8.40 (dd, J=8.2, 2.3 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.39-7.31 (m, 1H), 7.01 (dt, J=86.0, 28.3 Hz, 4H), 5.10 ( s, 2H), 3.66 (s, 2H), 3.15 (d, J=7.2 Hz, 3H), 2.00-1.92 (m, 2H), 1.78 (dd, J =18.8, 9.9 Hz, 2H), 1.61 (s, 2H);

LRMS (ES) m/z 477.4 (M ⁺ +1).

Example 34: Synthesis of Compound 3050, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1-(oxetan-3-yl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained from step 2 of Example 31, oxetan-3-one (0.017 g, 0.237 mmol), acetic acid (0.007 ml, 0.119 mmol), and sodium triacetoxyborohydride (0.075 g, 0.356 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.033 g, 58.3%) as a white solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.29 (d, J=1.5 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.40-7.32 (m, 1H), 7.13-6.82 (m, 4H), 5.11 (s, 2H), 4, 69 (t, J=6.9 Hz, 2H), 4.54-4.47 (m, 2H), 3.91-3.74 (m, 3H), 3.34 (d, J=22, 0 Hz, 2H);

LRMS (ES) m/z 478.3 (M ⁺ +1).

Example 35: Synthesis of Compound 3051, 1-Cyclopentyl-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N -(3-fluorophenyl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained from step 2 of Example 31, cyclopentanone (0.020 g, 0.237 mmol), acetic acid (0.007 ml, 0.119 mmol), and sodium triacetoxyborohydride (0.075 g, 0.356 mmol ) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.036 g, 62.0%) as a white solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.27 (d, J=1.5 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.38-7.30 (m, 1H), 7.12-6.80 (m, 4H), 5.10 (s, 2H), 3, 56 (d, J=23.0 Hz, 2H), 3.18 (d, J=13.0 Hz, 2H), 2.73 (s, 1H), 1.71-1.64 (m, 2H ), 1.60-1.44 (m, 4H), 1.29 (d, J=7.4 Hz, 2H);

LRMS (ES) m/z 491.5 (M ⁺ +1).

Example 36: Synthesis of Compound 3052, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1-(tetrahydrofuran-3-yl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained from step 2 of Example 31, dihydrofuran-3(2H)-one (0.020 g, 0.237 mmol), acetic acid (0.007 ml, 0.119 mmol), and triacetoxyborohydride sodium (0.075 g, 0.356 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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, 41.2%) as a white solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.27 (d, J=1.5 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.38-7.30 (m, 1H), 7.12-6.80 (m, 4H), 5.10 (s, 2H), 3, 56 (d, J=23.0 Hz, 2H), 3.18 (d, J=13.0 Hz, 2H), 2.73 (s, 1H), 1.71-1.64 (m, 2H ), 1.60-1.44 (m, 4H), 1.29 (d, J=7.4 Hz, 2H);

LRMS (ES) m/z 492.3 (M ⁺ +1).

Example 37: Synthesis of Compound 3053, 1-Cyclohexyl-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N -(3-fluorophenyl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained from step 2 of Example 31, cyclohexanone (0.023 g, 0.237 mmol), acetic acid (0.007 ml, 0.119 mmol), and sodium triacetoxyborohydride (0.075 g, 0.356 mmol ) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.030 g, 50.2%) as a white solid colors.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.29-9.24 (m, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.39-7.31 (m, 1H), 7.10-6.81 (m, 4H), 5.10 (s, 2H), 3.69-3 .52 (m, 3H), 3.18 (d, J=12.1 Hz, 2H), 2.00 (s, 1H), 1.95-1.85 (m, 2H), 1.81- 1.69 (m, 3H), 1.36-1.25 (m, 2H), 1.24-1.14 (m, 2H);

LRMS (ES) m/z 505.4 (M ⁺ +1).

Example 38: Synthesis of Compound 3054, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1-(tetrahydro-2H-pyran-4-yl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained from step 2 of Example 31, tetrahydro-4H-pyran-4-one (0.024 g, 0.237 mmol), acetic acid (0.007 ml, 0.119 mmol), and Sodium triacetoxyborohydride (0.075 g, 0.356 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.027 g, 45.0%) as a white solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.28 (d, J=1.5 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.39-7.31 (m, 1H), 7.12-6.81 (m, 4H), 5.10 (s, 2H), 3, 94 (dt, J=7.2, 3.8 Hz, 2H), 3.63 (d, J=11.9 Hz, 2H), 3.36 (td, J=11.2, 2.2 Hz , 2H), 3.21 (d, J=22.0 Hz, 2H), 2.28 (s, 1H), 1.58 (s, 2H), 1.41-1.29 (m, 2H) ;

LRMS (ES) m/z 507.4 (M ⁺ +1).

Example 39: Synthesis of Compound 3055, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1-(methylsulfonyl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained in step 2 of Example 31, triethylamine (0.033 ml, 0.237 mmol), and methanesulfonyl chloride (0.009 ml, 0.119 mmol) were dissolved in dichloromethane (5 ml), and the resulting solution was stirred at 0°C for 1 hour and further stirred at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate 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 filtered through a plastic filter to remove the solid residue and the aqueous solution 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 (0.041 g, 69.2%) as a white solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.31 (d, J=2.1 Hz, 1H), 8.42 (dd, J=8.2, 2.2 Hz, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.39 (dd, J=14.5, 7.4 Hz, 1H), 7.16-6.82 (m, 4H), 5.11 ( s, 2H), 4.46 (dd, J=22.1, 10.5 Hz, 2H), 3.82 (dd, J=22.1, 10.3 Hz, 2H), 2.91 (s , 3H);

LRMS (ES) m/z 500.4 (M ⁺ +1).

Example 40: Synthesis of Compound 3090, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-ethyl-3-fluoro-N -(3-fluorophenyl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained from step 2 of Example 31, acetaldehyde (0.010 g, 0.237 mmol), acetic acid (0.007 ml, 0.119 mmol), and sodium triacetoxyborohydride (0.075 g, 0.356 mmol ) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.026 g, 48.8%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.18 (d, J=1.8 Hz, 1H), 8.30 (dd, J=8.2, 2.2 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.30-7.21 (m, 1H), 6.93 (ddd, J=86.8, 42.3, 27.5 Hz, 4H), 5.01 (s, 2H), 3.53 (dd, J=21.1, 9.8 Hz, 2H), 3.10 (dd, J=22.0, 9.2 Hz, 2H), 2 .40 (q, J=7.1 Hz, 2H), 0.91-0.82 (m, 3H);

LRMS (ES) m/z 450.5 (M ⁺ +1).

Example 41: Synthesis of Compound 3091, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1-propylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained in step 2 of Example 31, propioaldehyde (0.014 g, 0.237 mmol), acetic acid (0.007 ml, 0.119 mmol), and sodium triacetoxyborohydride (0.075 g, 0.356 mmol ) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.034 g, 61.8%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.18 (d, J=1.7 Hz, 1H), 8.30 (dd, J=8.2, 2.2 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.29-7.21 (m, 1H), 7.02-6.68 (m, 4H), 5.01 (s, 2H), 3, 52 (dd, J=22.8, 9.0 Hz, 2H), 3.11 (dd, J=21.4, 8.9 Hz, 2H), 2.33 (t, J=7.4 Hz , 2H), 1.26 (dq, J=14.9, 7.4 Hz, 2H), 0.79 (t, J=7.4 Hz, 3H);

LRMS (ES) m/z 464.3 (M ⁺ +1).

Example 42: Synthesis of Compound 3092, 1-Butyl-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N -(3-fluorophenyl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained from step 2 of Example 31, butyraldehyde (0.017 g, 0.237 mmol), acetic acid (0.007 ml, 0.119 mmol), and sodium triacetoxyborohydride (0.075 g, 0.356 mmol ) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.050 g, 88.3%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.27 (d, J=1.7 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.40-7.30 (m, 1H), 7.12-6.79 (m, 4H), 5.10 (s, 2H), 3, 61 (dd, J=22.3, 7.1 Hz, 2H), 3.27-3.10 (m, 2H), 2.44 (s, 2H), 1.34-1.24 (m, 4H), 0.89 (t, J=7.1 Hz, 3H);

LRMS (ES) m/z 478.3 (M ⁺ +1).

Example 43: Synthesis of Compound 3093, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1-isobutylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained in step 2 of Example 31, isobutyraldehyde (0.017 g, 0.237 mmol), acetic acid (0.007 ml, 0.119 mmol), and sodium triacetoxyborohydride (0.075 g, 0.356 mmol ) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.041 g, 72.4%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.28 (d, J=1.6 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.56 (t, J=7.3 Hz, 1H), 7.39-7.30 (m, 1H), 7.11-6.79 (m, 4H), 5.10 (s, 2H), 3, 56 (dd, J=13.2, 8.8 Hz, 2H), 3.21 (dd, J=22.0, 9.3 Hz, 2H), 2.26 (d, J=7.0 Hz , 2H), 1.55 (dt, J=13.6, 6.8 Hz, 1H), 0.87 (d, J=6.7 Hz, 6H);

LRMS (ES) m/z 479.4 (M ⁺ +1).

Example 44: Synthesis of Compound 3094, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1-(1-hydroxypropan-2-yl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained from step 2 of Example 31, 1-hydroxypropan-2-one (0.018 g, 0.237 mmol), acetic acid (0.007 ml, 0.119 mmol), and sodium triacetoxyborohydride (0.075 g, 0.356 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.041 g, 72.1%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.29 (d, J=1.7 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.40-7.31 (m, 1H), 7.13-6.78 (m, 4H), 5.08 (d, J=13.5 Hz, 2H), 3.83 (t, J=30.9 Hz, 2H), 3.61-3.49 (m, 1H), 3.44-3.27 (m, 3H), 2.56 (s, 1H), 0.99 (d, J=6.5 Hz, 3H);

LRMS (ES) m/z 480.5 (M ⁺ +1).

Example 45: Synthesis of Compound 3095, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1-(1-methylpiperidin-4-yl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained from step 2 of Example 31, 1-methylpiperidin-4-one (0.027 g, 0.237 mmol), acetic acid (0.007 ml, 0.119 mmol), and sodium triacetoxyborohydride (0.075 g, 0.356 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.037 g, 60.1%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.29 (d, J=1.7 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.40-7.31 (m, 1H), 7.01 (dt, J 76.0, 29.3 Hz, 4H), 5.10 (s , 2H), 3.63 (dd, J=21.3, 7.9 Hz, 2H), 3.19 (dd, J=21.3, 9.0 Hz, 2H), 3.00 (t, J=8.6 Hz, 2H), 2.76 (dd, J=19.4, 13.1 Hz, 2H), 2.53 (d, J=10.0 Hz, 3H), 2.36 ( s, 1H), 1.90 (s, 2H), 1.57 (s, 2H);

LRMS (ES) m/z 519.4 (M ⁺ +1).

Example 46: Synthesis of Compound 3096, 1-(4,4-difluorocyclohexyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl) -3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained from step 2 of Example 31, 4,4-difluorocyclohexan-1-one (0.032 g, 0.237 mmol), acetic acid (0.007 ml, 0.119 mmol), and Sodium triacetoxyborohydride (0.075 g, 0.356 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.034 g, 53.1%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.28 (d, J=1.7 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.41-7.31 (m, 1H), 7.14-6.75 (m, 4H), 5.10 (s, 2H), 3, 62 (dd, J=22.1, 8.6 Hz, 2H), 3.19 (dd, J=21.0, 9.0 Hz, 2H), 2.24 (s, 1H), 2.12 -1.97 (m, 2H), 1.79-1.58 (m, 4H), 1.47 (dd, J=21.3, 13.0 Hz, 2H);

LRMS (ES) m/z 541.6 (M ⁺ +1).

Example 47: Synthesis of Compound 3097, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-(3-(dimethylamino)propanoyl )-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained in step 3 of Example 31, 3-(dimethylamino)propanoyl chloride (0.021 g, 0.154 mmol), and triethylamine (0.050 ml, 0.356 mmol) were dissolved in dichloromethane ( 5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.035 g, 56.7%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.21 (d, J=1.8 Hz, 1H), 8.32 (dd, J=8.2, 2.2 Hz, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.29 (dd, J=14.8, 7.9 Hz, 1H), 7.05-6.69 (m, 4H), 5.01 ( s, 2H), 4.70 (dd, J=21.2, 10.8 Hz, 1H), 4.46 (dd, J=21.4, 12.0 Hz, 1H), 3.99 (dd , J=21.8, 10.2 Hz, 1H), 3.78 (dd, J=21.7, 11.7 Hz, 1H), 3.07 (q, J=7.3 Hz, 2H) , 2.70 (s, 6H), 1.26 (t, J=7.3 Hz, 2H);

LRMS (ES) m/z 521.5 (M ⁺ +1).

Example 48: Synthesis of Compound 3098, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-(4-(dimethylamino)butanoyl )-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained in step 2 of Example 31, 4-(dimethylamino)butanoyl chloride (0.023 g, 0.154 mmol), and triethylamine (0.050 ml, 0.356 mmol) were dissolved in dichloromethane ( 5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.029 g, 45.7%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.30 (d, J=1.8 Hz, 1H), 8.41 (dd, J=8.2, 2.2 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.38 (dd, J=14.4, 8.0 Hz, 1H), 7.03 (dt, J=75.6, 30.1 Hz, 4H), 5.10 (d, J=1.9 Hz, 2H), 4.72 (dd, J=21.3, 10.5 Hz, 1H), 4.48 (dd, J=21.6 , 11.6 Hz, 1H), 4.03 (dd, J=21.8, 9.8 Hz, 1H), 3.82 (dd, J=22.8, 11.9 Hz, 1H), 2 .78 (s, 6H), 1.35 (t, J=7.3 Hz, 6H);

LRMS (ES) m/z 535.3 (M ⁺ +1).

Example 49: Synthesis of Compound 3105, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-1'-methyl- N-phenyl-[1,3'-biazetidine]-3-carboxamide

[Step 1] Synthesis of tert-butyl 3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(phenyl)carbamoyl)-3- fluoro-[1,3'-biazetidine]-1'-carboxylate

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 -trifluoroacetate (0.250 g, 0.620 mmol) obtained from step 3 of Example 14, tert-butyl 3-oxoazetidine-1-carboxylate (0.212 g, 1.240 mmol), acetic acid (0.035 ml, 0.620 mmol), and sodium triacetoxyborohydride (0.394 g, 1.859 mmol) was dissolved in dichloromethane (20 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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, 12 g; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.300 g, 86.7%) as a yellow gel.

[Step 2] Synthesis of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-[1, 3'-biazetidine1-3-carboxamide 2,2,2-trifluoroacetate

Tert-butyl 3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(phenyl)carbamoyl)-3-fluoro-[1, 3'-Biazetidine]-1'-carboxylate (0.262 g, 0.469 mmol) obtained in step 1 and trifluoroacetic acid (0.718 ml, 9.381 mmol) were dissolved in dichloromethane (10 ml) at room temperature, and the resulting solution was stirred at same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the title compound (0.215 g, 100.0%) was obtained as a yellow gel.

[Step 3] Synthesis of compound 3105

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-[1,3'-biazetidine] -3-carboxamide 2,2,2-trifluoroacetate (0.040 g, 0.087 mmol) obtained in step 2, formaldehyde (0.005 g, 0.175 mmol), acetic acid (0.005 ml, 0.087 mmol), and sodium triacetoxyborohydride (0.055 g, 0.262 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.014 g, 34.0%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.27 (d, J=1.6 Hz, 1H), 8.39 (dd, J=8.1, 2.2 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.40-7.34 (m, 3H), 7.26 (d, J=7.9 Hz, 2H), 6.97 (dd, J= 64.5, 38.9 Hz, 1H), 5.12 (s, 2H), 3.86 (s, 2H), 3.69 (dd, J=21.1, 9.0 Hz, 2H), 3.55-3.47 (m, 1H), 3.31-3.12 (m, 4H), 2.60 (s, 3H);

LRMS (ES) m/z 473.5 (M ⁺ +1).

Example 50: Synthesis of Compound 3106, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1'-ethyl-3-fluoro- N-phenyl-[1,3'-biazetidine]-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-[1,3'-biazetidine] -3-carboxamide 2,2,2-trifluoroacetate (0.040 g, 0.087 mmol) obtained in step 2 of Example 49, acetaldehyde (0.008 g, 0.175 mmol), acetic acid (0.007 ml, 0.087 mmol), and sodium triacetoxyborohydride (0.055 g, 0.262 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.022 g, 51.8%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.26 (d, J=2.1 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.58 (d, J=8.3 Hz, 1H), 7.38 (dt, J=10.6, 3.6 Hz, 3H), 7.25 (d, J=8.0 Hz, 2H), 6 .97 (dd, J=64.9, 38.4 Hz, 1H), 5.12 (s, 2H), 3.75-3.60 (m, 2H), 3.43 (dt, J=29 ,9, 6.6 Hz, 3H), 3.17 (dd, J=21.7, 10.1 Hz, 2H), 2.96 (d, J=6.9 Hz, 2H), 2.56 (q, J=7.2 Hz, 2H), 1.00 (t, J=7.2 Hz, 3H);

LRMS (ES) m/z 488.5 (M ⁺ +1).

Example 51: Synthesis of Compound 3107, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-1 '-propyl-[1,3'-biazetidine]-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-[1,3'-biazetidine] -3-carboxamide 2,2,2-trifluoroacetate (0.040 g, 0.087 mmol) obtained in step 2 of Example 49, propioaldehyde (0.010 g, 0.175 mmol), acetic acid (0.005 ml, 0.087 mmol), and sodium triacetoxyborohydride (0.055 g, 0.262 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.018 g, 41.2%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.27 (d, J=1.7 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.38 (d, J=7.1 Hz, 3H), 7.25 (d, J=5.4 Hz, 2H), 6.96 (t , J=51.7 Hz, 1H), 5.12 (s, 2H), 3.97 (s, 2H), 3.68 (dd, J=23.3, 12.6 Hz, 3H), 3 .34-3.11 (m, 4H), 2.80 (s, 2H), 1.54 (dd, J=15.2, 7.8 Hz, 2H), 0.94 (t, J=7 ,4 Hz, 3H);

LRMS (ES) m/z 501.3 (M++1).

Example 52: Synthesis of Compound 3108, 1'-Butyl-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro- N-phenyl-[1,3'-biazetidine]-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-[1,3'-biazetidine] -3-carboxamide 2,2,2-trifluoroacetate (0.040 g, 0.087 mmol) obtained in step 2 of Example 49, butyraldehyde (0.013 g, 0.175 mmol), acetic acid (0.005 ml, 0.087 mmol), and sodium triacetoxyborohydride (0.055 g, 0.262 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.018 g, 40.1%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.26 (d, J=1.6 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.58 (d, J=8.3 Hz, 1H), 7.37 (d, J=7.3 Hz, 3H), 7.25 (d, J=8.1 Hz, 2H), 6.96 (t , J=51.7 Hz, 1H), 5.12 (s, 2H), 3.66 (d, J=21.7 Hz, 3H), 3.46 (s, 1H), 3.17 (dd , J=21.7, 9.9 Hz, 2H), 3.04 (s, 2H), 2.59 (s, 2H), 1.43-1.24 (m, 5H), 0.91 ( t, J=7.2 Hz, 3H);

LRMS (ES) m/z 516.5 (M ⁺ +1).

Example 53: Synthesis of Compound 3109, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-1'-isobutyl- N-phenyl-[1,3'-biazetidine]-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-[1,3'-biazetidine] -3-carboxamide 2,2,2-trifluoroacetate (0.040 g, 0.087 mmol) obtained in step 2 of Example 49, isobutyraldehyde (0.013 g, 0.175 mmol), acetic acid (0.005 ml, 0.087 mmol), and sodium triacetoxyborohydride (0.055 g, 0.262 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.016 g, 35.6%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.26 (d, J=2.1 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.36 (t, J=5.4 Hz, 3H), 7.25 (d, J=8.2 Hz, 2H), 6.97 (dd , J=64.8, 38.6 Hz, 1H), 5.13 (s, 2H), 3.67 (dd, J=22.5, 9.8 Hz, 2H), 3.37 (s, 3H), 3.17 (dd, J=22.4, 10.4 Hz, 2H), 2.89 (s, 2H), 2.26 (d, J=6.6 Hz, 2H), 1, 67-1.49 (m, 1H), 0.88 (d, J=6.7 Hz, 6H);

LRMS (ES) m/z 516.5 (M ⁺ +1).

Example 54: Synthesis of Compound 3110, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-1-(1- methylpiperidin-4-yl)-N-phenylazetidin-3-carboxamide

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

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 -trifluoroacetate (1.000 g, 2.479 mmol) obtained from step 3 of Example 14, tert-butyl 4-oxopiperidine-1-carboxylate (0.988 g, 4.958 mmol), acetic acid (0.142 ml, 2.479 mmol), and sodium triacetoxyborohydride (1.576 g, 7.437 mmol) was dissolved in dichloromethane (50 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, 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, 40 g; methanol/dichloromethane = 0% to 10%) and concentrated to give the title compound (1.100 g, 75.6%) as a white solid.

[Step 2] Synthesis of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-1-( piperidin-4-yl)azetidine-3-carboxamide 2,2,2-trifluoroacetate

Tert-butyl 4-(3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(phenyl)carbamoyl)-3-fluoroazetidin- 1-yl)piperidin-1-carboxylate (1.000 g, 1.705 mmol) obtained in step 1 and trifluoroacetic acid (0.718 ml, 8.523 mmol) were dissolved in dichloromethane (10 ml) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. After removing the solvent from the reaction mixture under reduced pressure, the title compound (0.800 g, 96.5%) was obtained as a yellow gel.

[Step 3] Synthesis of compound 3110

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-1-(piperidin-4-yl )azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.040 g, 0.082 mmol) obtained in step 2, formaldehyde (0.005 g, 0.164 mmol), acetic acid (0.005 ml, 0.082 mmol), and sodium triacetoxyborohydride (0.052 g, 0.247 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.020 g, 48.6%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.26 (d, J=2.1 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.58 (d, J=8.3 Hz, 1H), 7.37 (d, J=7.2 Hz, 3H), 7.26 (d, J=8.0 Hz, 2H), 6.95 (t , J=51.7 Hz, 1H), 5.13 (s, 2H), 3.55 (dd, J=23.1, 9.9 Hz, 2H), 3.12 (dd, J=21, 5, 10.2 Hz, 2H), 2.83 (s, 2H), 2.35 (s, 3H), 2.11 (s, 3H), 1.71 (s, 2H), 1.41 ( s, 2H);

LRMS (ES) m/z 501.4 (M ⁺ +1).

Example 55: Synthesis of Compound 3111, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-(1-ethylpiperidin-4- yl)-3-fluoro-N-phenylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-1-(piperidin-4-yl )azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.040 g, 0.082 mmol) prepared in step 2 of Example 54, acetaldehyde (0.007 g, 0.164 mmol), acetic acid (0.007 ml, 0.082 mmol), and sodium triacetoxyborohydride (0.052 g, 0.247 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.017 g, 40.2%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.27 (d, J=2.0 Hz, 1H), 8.39 (dd, J=8.3, 2.2 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.38 (d, J=7.4 Hz, 3H), 7.25 (s, 2H), 6.96 (t, J=51.6 Hz , 1H), 5.13 (s, 2H), 3.55 (dd, J=23.4, 9.9 Hz, 2H), 3.12 (dd, J=21.4, 9.5 Hz, 2H), 2.93 (s, 2H), 1.72 (s, 7H), 1.47 (s, 2H), 1.20 (s, 3H);

LRMS (ES) m/z 515.5 (M ⁺ +1).

Example 56: Synthesis of Compound 3112, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-1 -(1-propylpiperidin-4-yl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-1-(piperidin-4-yl )azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.040 g, 0.082 mmol) prepared in step 2 of Example 54, propioaldehyde (0.010 g, 0.164 mmol), acetic acid (0.005 ml, 0.082 mmol), and sodium triacetoxyborohydride (0.052 g, 0.247 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.011 g, 25.3%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.26 (d, J=1.6 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.37 (d, J=7.2 Hz, 3H), 7.26 (d, J=7.9 Hz, 2H), 6.96 (t , J=51.6 Hz, 1H), 5.13 (s, 2H), 3.55 (dd, J=23.2, 9.9 Hz, 2H), 3.12 (dd, J=21, 4, 10.2 Hz, 2H), 2.90 (s, 2H), 1.68 (s, 9H), 1.42 (s, 2H), 0.92 (t, J=7.4 Hz, 3H);

LRMS (ES) m/z 529.6 (M ⁺ +1).

Example 57: Synthesis of Compound 3113, 1-(1-Butylpiperidin-4-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl) methyl)-3-fluoro-N-phenylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-1-(piperidin-4-yl )azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.040 g, 0.082 mmol) prepared in step 2 of Example 54, butyraldehyde (0.012 g, 0.164 mmol), acetic acid (0.005 ml, 0.082 mmol), and sodium triacetoxyborohydride (0.052 g, 0.247 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.022 g, 49.3%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.27 (d, J=1.8 Hz, 1H), 8.39 (dd, J=8.1, 2.2 Hz, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.37 (d, J=7.1 Hz, 3H), 7.26 (d, J=8.1 Hz, 2H), 6.97 (dd , J=64.6, 38.7 Hz, 1H), 5.13 (s, 2H), 3.54 (d, J=22.8 Hz, 2H), 3.12 (d, J=12, 0 Hz, 2H), 2.89 (s, 2H), 1.66 (s, 10H), 1.41-1.29 (m, 3H), 0.93 (t, J=7.3 Hz, 3H);

LRMS (ES) m/z 543.6 (M ⁺ +1).

Example 58: Synthesis of Compound 3114, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-1-(1- isobutylpiperidin-4-yl)-N-phenylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-1-(piperidin-4-yl )azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.040 g, 0.082 mmol) prepared in step 2 of Example 54, isobutyraldehyde (0.012 g, 0.164 mmol), acetic acid (0.005 ml, 0.082 mmol), and sodium triacetoxyborohydride (0.052 g, 0.247 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.017 g, 38.1%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.26 (d, J=1.6 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.40-7.34 (m, 3H), 7.26 (d, J=7.9 Hz, 2H), 6.95 (t, J= 51.6 Hz, 1H), 5.13 (s, 2H), 3.54 (dd, J=23.1, 9.9 Hz, 2H), 3.12 (dd, J=21.2, 10 .2 Hz, 2H), 2.76 (s, 2H), 2.06 (s, 2H), 1.91 (s, 2H), 1.77 (s, 2H), 1.59 (s, 2H ), 1.28 (s, 2H), 0.89 (d, J=6.1 Hz, 6H);

LRMS (ES) m/z 544.5 (M ⁺ +1).

Example 59: Synthesis of Compound 3115, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-1-(1- isopropylpiperidin-4-yl)-N-phenylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-1-(piperidin-4-yl )azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.040 g, 0.082 mmol) prepared in step 2 of Example 54, propan-2-one (0.010 g, 0.164 mmol), acetic acid (0.005 ml, 0.082 mmol) , and sodium triacetoxyborohydride (0.052 g, 0.247 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.016 g, 36.8%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.28 (d, J=2.2 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.39 (d, J=7.1 Hz, 3H), 7.26 (s, 2H), 6.96 (t, J=51.7 Hz , 1H), 5.12 (s, 2H), 3.55 (dd, J=23.0, 9.5 Hz, 2H), 3.41 (s, 1H), 3.12 (dd, J= 21.0, 10.1 Hz, 3H), 2.12 (s, 2H), 1.85 (s, 4H), 1.64 (s, 2H), 1.30 (d, J=6.7 Hz, 6H);

LRMS (ES) m/z 529.3 (M ⁺ +1).

Example 60: Synthesis of Compound 3152, 1-Acetyl-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N -phenylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 α-trifluoroacetate (0.060 g, 0.149 mmol) obtained in step 3 of Example 14, acetyl chloride (0.014 ml, 0.193 mmol), and triethylamine (0.062 ml, 0.446 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 (0.015 g, 22.6%) as a yellow gel.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.20 (d, J=1.8 Hz, 1H), 8.31 (dd, J=8.2, 2.2 Hz, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.37-7.23 (m, 3H), 7.20 (d, J=4.3 Hz, 2H), 6.88 (dd, J= 64.1, 39.2 Hz, 1H), 5.04 (s, 2H), 4.67 (dd, J=21.4, 10.4 Hz, 1H), 4.25 (dd, J=22 ,5, 11.7 Hz, 1H), 3.94 (dd, J=22.7, 9.6 Hz, 1H), 3.58 (dd, J=23.1, 11.8 Hz, 1H) , 1.79 (s, 3H);

LRMS (ES) m/z 446.5 (M ⁺ +1).

Example 61: Synthesis of Compound 3153, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-1 -propionylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 α-trifluoroacetate (0.060 g, 0.149 mmol) obtained in step 3 of Example 14, propionyl chloride (0.018 g, 0.193 mmol), and triethylamine (0.062 ml, 0.446 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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, 35.1%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.29 (d, J=1.7 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.48-7.34 (m, 3H), 7.28 (d, J=4.5 Hz, 2H), 6.97 (dd, J= 64.2, 39.1 Hz, 1H), 5.13 (s, 2H), 4.74 (dd, J=21.6, 10.4 Hz, 1H), 4.35 (dd, J=22 ,6, 11.8 Hz, 1H), 4.02 (dd, J=22.8, 9.9 Hz, 1H), 3.68 (dd, J=23.1, 11.7 Hz, 1H) , 2.11 (q, J=7.5 Hz, 2H), 1.12 (t, J=7.5 Hz, 3H); LRMS (ES) m/z 460.2 (M ⁺ +1).

Example 62: Synthesis of Compound 3154, 1-Butyryl-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N -phenylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 α-trifluoroacetate (0.060 g, 0.149 mmol) obtained in step 3 of Example 14, butyryl chloride (0.021 g, 0.193 mmol), and triethylamine (0.062 ml, 0.446 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.021 g, 29.8%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.20 (d, J=1.8 Hz, 1H), 8.31 (dd, J=8.2, 2.2 Hz, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.36-7.26 (m, 3H), 7.19 (d, J=4.5 Hz, 2H), 6.88 (dd, J= 64.1, 39.2 Hz, 1H), 5.04 (s, 2H), 4.66 (dd, J=21.7, 10.4 Hz, 1H), 4.25 (dd, J=22 ,4, 12.2 Hz, 1H), 3.93 (dd, J=22.6, 10.0 Hz, 1H), 3.58 (dd, J=23.5, 12.0 Hz, 1H) , 1.97 (t, J=7.5 Hz, 2H), 1.54 (dq, J=14.8, 7.5 Hz, 2H), 0.85 (t, J=7.4 Hz, 3H);

LRMS (ES) m/z 475.5 (M ⁺ +1).

Example 63: Synthesis of Compound 3155, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-1-(3- methylbutanoyl)-N-phenylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 -trifluoroacetate (0.060 g, 0.149 mmol) obtained in step 3 of Example 14, 3-methylbutanoyl chloride (0.023 g, 0.193 mmol), and triethylamine (0.062 ml, 0.446 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting the solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.019 g, 26.2%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.29 (d, J=1.8 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.45-7.35 (m, 3H), 7.28 (d, J=5.0 Hz, 2H), 6.97 (dd, J= 64.2, 39.1 Hz, 1H), 5.13 (s, 2H), 4.76 (dd, J=21.6, 10.4 Hz, 1H), 4.34 (dd, J=22 ,8, 12.3 Hz, 1H), 4.03 (dd, J=22.8, 10.1 Hz, 1H), 3.67 (dd, J=23.2, 12.4 Hz, 1H) , 2.11 (td, J=13.5, 6.7 Hz, 1H), 1.96 (d, J=7.1 Hz, 2H), 0.95 (t, J=6.5 Hz, 6H);

LRMS (ES) m/z 488.3 (M ⁺ +1).

Example 64: Synthesis of Compound 3156, 1-(cyclohexylmethyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro -N-phenylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 α-trifluoroacetate (0.060 g, 0.149 mmol) obtained in step 3 of Example 14, cyclohexanecarbaldehyde (0.033 g, 0.297 mmol), acetic acid (0.009 ml, 0.149 mmol), and sodium triacetoxyborohydride (0.095 g, 0.446 mmol) were dissolved in dichloromethane ( 5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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, 32.3%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.16 (d, J=1.7 Hz, 1H), 8.29 (dd, J=8.2, 2.2 Hz, 1H), 7.50 (d, J=8.2 Hz, 1H), 7.31-7.23 (m, 3H), 7.16 (dd, J=8.0, 1.4 Hz, 2H), 6.88 ( dd, J=65.1, 38.3 Hz, 1H), 5.03 (s, 2H), 3.45 (dd, J=22.6, 8.4 Hz, 2H), 3.06 (dd , J=20.8, 9.5 Hz, 2H), 2.19 (d, J=6.6 Hz, 2H), 1.77-1.64 (m, 2H), 1.60 (s, 2H), 1.27-0.95 (m, 5H), 0.76 (dd, J=21.4, 11.4 Hz, 2H);

LRMS (ES) m/z 501.4 (M ⁺ +1).

Example 65: Synthesis of compound 3157,N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-1-(3- methoxypropanoyl)-N-phenylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 -trifluoroacetate (0.060 g, 0.149 mmol) obtained in step 3 of Example 14, 3-methoxypropanoyl chloride (0.024 g, 0.193 mmol), and triethylamine (0.062 ml, 0.446 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting the solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.031 g, 42.6%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=1.8 Hz, 1H), 8.31 (dd, J=8.2, 2.2 Hz, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.40-7.26 (m, 3H), 7.19 (d, J=4.9 Hz, 2H), 6.88 (dd, J= 64.4, 38.9 Hz, 1H), 5.04 (s, 2H), 4.67 (dd, J=21.5, 10.2 Hz, 1H), 4.27 (dd, J=22 ,5, 12.3 Hz, 1H), 3.96 (dd, J=22.7, 10.1 Hz, 1H), 3.71-3.58 (m, 1H), 3.58-3, 50 (m, 2H), 3.28-3.23 (m, 3H), 2.24 (t, J=6.2 Hz, 2H);

LRMS (ES) m/z 490.2 (M ⁺ +1).

Example 66: Synthesis of Compound 3158, 1-(Cyclopropanecarbonyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro -N-phenylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 α-trifluoroacetate (0.060 g, 0.149 mmol) obtained in step 3 of Example 14, cyclopropanecarbonyl chloride (0.020 g, 0.193 mmol), and triethylamine (0.062 ml, 0.446 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.019 g, 27.1%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.29 (d, J=1.8 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.46-7.33 (m, 3H), 7.33-7.20 (m, 2H), 6.97 (dd, J=64.1 , 39.2 Hz, 1H), 5.14 (s, 2H), 4.88 (dd, J=21.1, 10.1 Hz, 1H), 4.35 (dd, J=22.9, 11.2 Hz, 1H), 4.15 (dd, J=22.1, 9.9 Hz, 1H), 3.68 (dd, J=23.5, 11.9 Hz, 1H), 3, 46 (d, J=27.5 Hz, 1H), 1.71 (ddd, J=12.7, 8.0, 4.7 Hz, 1H), 1.36 (ddd, J=12.5, 8.1, 4.6 Hz, 1H), 1.16 (d, J=12.6 Hz, 1H), 0.83-0.77 (m, 1H);

LRMS (ES) m/z 472.2 (M ⁺ +1).

Example 67: Synthesis of Compound 3159, 1-(Cyclobutanecarbonyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro -N-phenylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 β-trifluoroacetate (0.060 g, 0.149 mmol) obtained in step 3 of Example 14, cyclobutanecarbonyl chloride (0.023 g, 0.193 mmol), and triethylamine (0.062 ml, 0.446 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.020 g, 27.7%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=1.8 Hz, 1H), 8.30 (dd, J=8.2, 2.2 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.37-7.25 (m, 3H), 7.18 (d, J=8.3 Hz, 2H), 6.88 (dd, J= 64.3, 39.0 Hz, 1H), 5.03 (s, 2H), 4.58 (dd, J=21.8, 10.3 Hz, 1H), 4.24 (dd, J=22 ,7, 11.7 Hz, 1H), 3.86 (dd, J=22.7, 10.5 Hz, 1H), 3.57 (dd, J=23.3, 11.6 Hz, 1H ), 2.92 (p, J=8.5 Hz, 1H), 2.31-2.12 (m, 2H), 2.06-1.96 (m, 2H), 1.96-1, 74 (m, 2H);

LRMS (ES) m/z 486.3 (M ⁺ +1).

Example 68: Synthesis of Compound 3160, 1-(cyclopentanecarbonyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro -N-phenylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 α-trifluoroacetate (0.060 g, 0.149 mmol) obtained in step 3 of Example 14, cyclopentanecarbonyl chloride (0.026 g, 0.193 mmol), and triethylamine (0.062 ml, 0.446 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.011 g, 14.8%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.29 (d, J=1.8 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.40 (dd, J=8.5, 3.1 Hz, 3H), 7.28 (s, 2H), 6.97 (dd, J= 64.1, 39.2 Hz, 1H), 5.14 (s, 2H), 4.78 (dd, J=21.7, 10.1 Hz, 1H), 4.33 (dd, J=22 ,7, 11.9 Hz, 1H), 4.05 (dd, J=22.9, 10.1 Hz, 1H), 3.67 (dd, J=23.3, 11.4 Hz, 1H) , 2.53 (d, J=7.8 Hz, 1H), 1.74 (s, 8H);

LRMS (ES) m/z 500.2 (M ⁺ +1).

Example 69: Synthesis of Compound 3161, 1-(cyclohexanecarbonyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro -N-phenylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 α-trifluoroacetate (0.060 g, 0.149 mmol) obtained in step 3 of Example 14, cyclohexanecarbonyl chloride (0.028 g, 0.193 mmol), and triethylamine (0.062 ml, 0.446 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.032 g, 41.9%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.28 (d, J=1.8 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.46-7.36 (m, 3H), 7.28 (d, J=6.9 Hz, 2H), 6.97 (dd, J= 64.2, 39.1 Hz, 1H), 5.13 (s, 2H), 4.80 (dd, J=21.2, 10.3 Hz, 1H), 4.32 (dd, J=22 ,4, 11.9 Hz, 1H), 4.07 (dd, J=22.6, 10.3 Hz, 1H), 3.65 (dd, J=23.2, 12.2 Hz, 1H) , 2.10 (ddd, J=11.6, 7.5, 3.2 Hz, 1H), 1.86-1.68 (m, 4H), 1.44 (dt, J=33.2, 16.7 Hz, 2H), 1.26 (d, J=15.1 Hz, 4H);

LRMS (ES) m/z 514.3 (M ⁺ +1).

Example 70: Synthesis of Compound 3162, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-1 -(tetrahydro-2H-thiopyran-4-yl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 -trifluoroacetate (0.060 g, 0.149 mmol) obtained from step 3 of Example 14, tetrahydro-4H-thiopyran-4-one (0.035 g, 0.297 mmol), acetic acid (0.009 ml, 0.149 mmol), and sodium triacetoxyborohydride (0.095 g , 0.446 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.019 g, 25.4%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₂ ) δ 9.17 (d, J=1.8 Hz, 1 H), 8.30 (dd, J=8.2, 2.2 Hz, 1 H), 7 .49 (d, J=8.2 Hz, 1H), 7.29 (dt, J=10.5, 3.6 Hz, 3H), 7.22-7.10 (m, 2H), 6, 86 (t, J=51.7 Hz, 1H), 5.03 (s, 2H), 3.47 (dd, J=22.9, 8.7 Hz, 2H), 3.04 (dd, J =21.3, 9.1 Hz, 2H), 2.59 (t, J=11.8 Hz, 2H), 2.49-2.37 (m, 2H), 1.98 (s, 1H) , 1.81 (d, J=13.0 Hz, 2H), 1.48-1.30 (m, 2H);

LRMS (ES) m/z 505.3 (M ⁺ +1).

Example 71: Synthesis of Compound 3163, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1-propionylazetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained in step 2 of Example 31, propionyl chloride (0.014 g, 0.154 mmol), and triethylamine (0.050 ml, 0.356 mmol) were dissolved in dichloromethane (5 ml) at room temperature temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.023 g, 40.6%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₂ ) δ 9.21 (d, J=1.8 Hz, 1H), 8.32 (dd, J=8.2, 2.2 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.29 (dd, J=14.8, 8.2 Hz, 1H), 6.93 (dt, J=75.5, 30.1 Hz, 4H), 5.01 (s, 2H), 4.67 (dd, J=21.3, 9.9 Hz, 1H), 4.30 (dd, J=21.9, 11.3 Hz, 1H), 3.97 (dd, J=22.3, 9.6 Hz, 1H), 3.68 (dd, J=23.6, 12.3 Hz, 1H), 2.03 (q, J=7, 5 Hz, 2H), 1.03 (t, J=7.5 Hz, 3H);

LRMS (ES) m/z 478.6 (M ⁺ +1).

Example 72: Synthesis of Compound 3164, 1-Acetyl-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N -(3-fluorophenyl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained in step 2 of Example 31, acetyl chloride (0.011 ml, 0.154 mmol), and triethylamine (0.050 ml, 0.356 mmol) were dissolved in dichloromethane (5 ml) at room temperature , and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.022 g, 40.0%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.31 (d, J=1.8 Hz, 1H), 8.41 (dd, J=8.2, 2.2 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.38 (dd, J=14.6, 8.3 Hz, 1H), 7.19-6.74 (m, 4H), 5.10 ( s, 2H), 4.78 (dd, J=21.3, 9.6 Hz, 1H), 4.39 (dd, J=22.1, 11.3 Hz, 1H), 4.08 (dd , J=22.0, 10.1 Hz, 1H), 3.76 (dd, J=22.7, 12.1 Hz, 1H), 1.90 (s, 3H);

LRMS (ES) m/z 464.2 (M ⁺ +1).

Example 73: Synthesis of Compound 3165, 1-Butyryl-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N -(3-fluorophenyl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained in step 2 of Example 31, butyryl chloride (0.016 g, 0.154 mmol), and triethylamine (0.050 ml, 0.356 mmol) were dissolved in dichloromethane (5 ml) at room temperature temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.021 g, 36.0%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (d, J=1.8 Hz, 1H), 8.32 (dd, J=8.2, 2.2 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.29 (dd, J=14.7, 8.1 Hz, 1H), 6.93 (dt, J=75.8, 30.1 Hz, 4H), 5.01 (s, 2H), 4.68 (dd, J=21.0, 10.0 Hz, 1H), 4.29 (dd, J=22.1, 11.7 Hz, 1H ), 3.98 (dd, J=22.3, 10.0 Hz, 1H), 3.67 (dd, J=22.8, 11.7 Hz, 1H), 1.98 (t, J= 7.4 Hz, 2H), 1.55 (dq, J=14.7, 7.4 Hz, 2H), 0.86 (t, J=7.4 Hz, 3H);

LRMS (ES) m/z 493.5 (M ⁺ +1).

Example 74: Synthesis of Compound 3166, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1-(3-methylbutanoyl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained from step 2 of Example 31, 3-methylbutanoyl chloride (0.019 g, 0.154 mmol), and triethylamine (0.050 ml, 0.356 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.025 g, 41.7%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (d, J=1.8 Hz, 1H), 8.32 (dd, J=8.2, 2.2 Hz, 1H), 7.44 (d, J=8.1 Hz, 1H), 7.29 (dd, J=14.9, 7.8 Hz, 1H), 6.93 (dt, J=75.7, 30.1 Hz, 4H), 5.01 (s, 2H), 4.68 (dd, J=21.2, 10.3 Hz, 1H), 4.29 (dd, J=22.0, 11.5 Hz, 1H ), 3.98 (dd, J=22.3, 10.4 Hz, 1H), 3.67 (dd, J=23.0, 11.6 Hz, 1H), 2.10-1.97 ( m, 1H), 1.88 (d, J=7.1 Hz, 2H), 0.89-0.84 (m, 6H);

LRMS (ES) m/z 506.2 (M ⁺ +1).

Example 75: Synthesis of Compound 3167, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1-(3-methoxypropanoyl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained from step 2 of Example 31, 3-methoxypropanoyl chloride (0.019 g, 0.154 mmol), and triethylamine (0.050 ml, 0.356 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.025 g, 41.5%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (d, J=1.7 Hz, 1H), 8.32 (dd, J=8.2, 2.2 Hz, 1H), 7.44 (d, J=8.1 Hz, 1H), 7.28 (dd, J=14.6, 8.3 Hz, 1H), 7.09-6.68 (m, 4H), 5.01 ( s, 2H), 4.69 (dd, J=21.9, 10.1 Hz, 1H), 4.31 (dd, J=22.3, 11.9 Hz, 1H), 4.01 (dd , J=22.6, 10.6 Hz, 1H), 3.81-3.64 (m, 1H), 3.57 (q, J=6.2 Hz, 2H), 3.25 (s, 3H), 2.26 (t, J=6.2 Hz, 2H);

LRMS (ES) m/z 508.2 (M ⁺ +1).

Example 76: Synthesis of Compound 3168, 1-(Cyclobutancarbonyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro -N-(3-fluorophenyl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained in step 2 of Example 31, cyclobutanecarbonyl chloride (0.018 g, 0.154 mmol), and triethylamine (0.050 ml, 0.356 mmol) were dissolved in dichloromethane (5 ml) at room temperature temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.025 g, 41.8%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (d, J=1.9 Hz, 1H), 8.31 (dd, J=8.2, 2.2 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H), 7.28 (dd, J=14.5, 8.0 Hz, 1H), 6.95 (ddd, J=99.3, 44.9, 30 ,2 Hz, 4H), 5.00 (s, 2H), 4.60 (dd, J=21.5, 10.1 Hz, 1H), 4.28 (dd, J=22.2, 11, 7 Hz, 1H), 3.90 (dd, J=22.4, 10.5 Hz, 1H), 3.66 (dd, J=23.3, 11.9 Hz, 1H), 2.93 ( p, J=8.6 Hz, 1H), 2.22 (tt, J=17.6, 8.7 Hz, 2H), 2.00 (dt, J=25.6, 12.9 Hz, 2H ), 1.93-1.76 (m, 2H);

LRMS (ES) m/z 504.2 (M ⁺ +1).

Example 77: Synthesis of Compound 3169, 1-(cyclopentanecarbonyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro -N-(3-fluorophenyl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained in step 2 of Example 31, cyclopentanecarbonyl chloride (0.020 g, 0.154 mmol), and triethylamine (0.050 ml, 0.356 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.033 g, 53.7%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (d, J=1.8 Hz, 1H), 8.32 (dd, J=8.2, 2.2 Hz, 1H), 7.44 (d, J=8.1 Hz, 1H), 7.29 (dd, J=14.7, 8.0 Hz, 1H), 6.93 (dt, J=75.6, 30.1 Hz, 4H), 5.01 (s, 2H), 4.70 (dd, J=21.3, 10.3 Hz, 1H), 4.28 (dd, J=22.2, 11.7 Hz, 1H ), 4.00 (dd, J=22.4, 9.8 Hz, 1H), 3.66 (dd, J=23.0, 11.9 Hz, 1H), 2.45 (d, J= 7.5 Hz, 1H), 1.66 (s, 6H), 1.47 (d, J=5.1 Hz, 2H);

LRMS (ES) m/z 518.2 (M ⁺ +1).

Example 78: Synthesis of Compound 3170, 1-(cyclohexanecarbonyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro -N-(3-fluorophenyl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained in step 2 of Example 31, cyclohexanecarbonyl chloride (0.023 g, 0.154 mmol), and triethylamine (0.050 ml, 0.356 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.031 g, 49.2%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (d, J=1.8 Hz, 1H), 8.32 (dd, J=8.2, 2.2 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.29 (dd, J=14.7, 8.1 Hz, 1H), 7.08-6.69 (m, 4H), 5.01 ( s, 2H), 4.72 (dd, J=21.2, 9.5 Hz, 1H), 4.27 (dd, J=21.4, 11.8 Hz, 1H), 4.02 (dd , J=22.4, 9.1 Hz, 1H), 3.65 (dd, J=22.4, 11.7 Hz, 1H), 2.03 (t, J=11.7 Hz, 1H) , 1.70 (s, 3H), 1.44-1.31 (m, 3H), 1.23-1.09 (m, 4H);

LRMS (ES) m/z 532.3 (M ⁺ +1).

Example 79: Synthesis of Compound 3171, 1-(cyclohexylmethyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro -N-(3-fluorophenyl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained from step 2 of Example 31, cyclohexanecarbaldehyde (0.027 g, 0.237 mmol), acetic acid (0.007 ml, 0.119 mmol), and sodium triacetoxyborohydride (0.075 g, 0.356 mmol ) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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, 45.6%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 (d, J=1.7 Hz, 1H), 8.30 (dd, J=8.2, 2.2 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.25 (td, J=8.2, 6.4 Hz, 1H), 6.91 (dt, J=84.0, 29.1 Hz, 4H), 5.00 (s, 2H), 3.52 (dd, J=25.3, 13.7 Hz, 2H), 3.12 (d, J=12.5 Hz, 2H), 2, 19 (t, J=13.2 Hz, 2H), 1.77-1.52 (m, 9H), 0.77 (dd, J=22.1, 11.5 Hz, 2H);

LRMS (ES) m/z 519.3 (M ⁺ +1).

Example 80: Synthesis of Compound 3172, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1-(tetrahydro-2H-thiopyran-4-yl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained from step 2 of Example 31, tetrahydro-4H-thiopyran-4-one (0.028 g, 0.237 mmol), acetic acid (0.007 ml, 0.119 mmol), and Sodium triacetoxyborohydride (0.075 g, 0.356 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.018 g, 29.1%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=1.7 Hz, 1H), 8.30 (dd, J=8.2, 2.2 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.33-7.21 (m, 1H), 7.04-6.70 (m, 4H), 5.01 (s, 2H), 3, 64-3.39 (m, 2H), 3.22-3.02 (m, 2H), 2.61 (d, J=13.9 Hz, 2H), 2.52-2.35 (m, 2H), 1.99 (d, J=10.9 Hz, 1H), 1.83 (d, J=13.0 Hz, 2H), 1.39 (dd, J=20.5, 10.2 Hz, 2H);

LRMS (ES) m/z 523.2 (M ⁺ +1).

Example 81: Synthesis of Compound 3216, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-1 -(tetrahydro-2H-pyran-4-yl)methyl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2 -trifluoroacetate (0.060 g, 0.149 mmol) obtained from step 3 of Example 14, tetrahydro-2H-pyran-4-carbaldehyde (0.034 g, 0.297 mmol), acetic acid (0.009 ml, 0.149 mmol), and sodium triacetoxyborohydride (0.095 g , 0.446 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.022 g, 29.5%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.26 (d, J=1.7 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.57 (t, J=9.6 Hz, 1H), 7.37 (d, J=7.1 Hz, 3H), 7.25 (d, J=7.9 Hz, 2H), 6.97 (dd , J=64.8, 38.5 Hz, 1H), 5.12 (s, 2H), 3.99-3.89 (m, 2H), 3.65-3.44 (m, 2H), 3.34 (dd, J=11.6, 10.2 Hz, 2H), 3.17 (d, J=13.5 Hz, 2H), 2.34 (s, 2H), 1.58 (d , J=13.1 Hz, 2H), 1.32-1.16 (m, 3H);

LRMS (ES) m/z 503.3 (M ⁺ +1).

Example 82: Synthesis of Compound 3217, 1-(Cyclopropanecarbonyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro -N-(3-fluorophenyl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained in step 2 of Example 31, cyclopropanecarbonyl chloride (0.016 g, 0.154 mmol), and triethylamine (0.050 ml, 0.356 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.014 g, 24.1%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.31 (d, J=1.8 Hz, 1H), 8.41 (dd, J=8.2, 2.2 Hz, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.38 (dd, J=14.6, 8.3 Hz, 1H), 7.15-6.82 (m, 4H), 5.11 ( s, 2H), 4.91 (s, 1H), 4.40 (s, 1H), 4.20 (d, J=15.3 Hz, 1H), 3.76 (s, 1H), 3, 47 (s, 1H), 1.02-0.96 (m, 2H), 0.83-0.75 (m, 2H);

LRMS (ES) m/z 490.5 (M ⁺ +1).

Example 83: Synthesis of compound 3218, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1-(tetrahydro-2H-pyran-4-yl)methyl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained from step 2 of Example 31, tetrahydro-2H-pyran-4-carbaldehyde (0.027 g, 0.237 mmol), acetic acid (0.007 ml, 0.119 mmol), and Sodium triacetoxyborohydride (0.075 g, 0.356 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.022 g, 35.7%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.28 (d, J=1.8 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.40-7.31 (m, 1H), 7.02 (ddd, J=86.4, 42.5, 28.2 Hz, 4H), 5.10 (s, 2H), 3.99-3.88 (m, 2H), 3.65 (s, 2H), 3.56-3.46 (m, 1H), 3.42-3, 30 (m, 2H), 3.21 (s, 2H), 2.37 (s, 2H), 1.37-1.16 (m, 4H);

LRMS (ES) m/z 521.4 (M ⁺ +1).

Example 84: Synthesis of Compound 3219, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1,-methyl-[1,3'-biazetidine]-3-carboxamide

[Step 1] Synthesis of tert-butyl 3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(3-fluorophenyl)carbamoyl)- 3-fluoro-[1,3'-biazetidine]-1'-carboxylate

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.250 g, 0.593 mmol) obtained from step 2 of Example 31, tert-butyl 3-oxoazetidine-1-carboxylate (0.203 g, 1.187 mmol), acetic acid (0.034 ml, 0.593 mmol), and sodium triacetoxyborohydride (0.377 g, 1.780 mmol) were dissolved in dichloromethane (20 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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, 12 g; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.300 g, 87.7%) as a yellow gel.

[Step 2] Synthesis of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl) -[1,3'-biazetidine1-3-carboxamide 2,2,2-trifluoroacetate

Tert-butyl 3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(3-fluorophenyl)carbamoyl)-3-fluoro-[ 1,3'-Biazetidine]-1'-carboxylate (0.380 g, 0.659 mmol) obtained in step 1 and trifluoroacetic acid (1.009 ml, 13.182 mmol) were dissolved in dichloromethane (10 ml) at room temperature, and the resulting solution was stirred at the same temperature for 2 hours. After removing the solvent from the reaction mixture under reduced pressure, the title compound (0.314 g, 100.0%) was obtained as a brown gel.

[Step 3] Synthesis of compound 3219

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-[1,3 '-biazetidine]-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.105 mmol) obtained in step 2, formaldehyde (0.006 g, 0.210 mmol), acetic acid (0.006 ml, 0.105 mmol), and sodium triacetoxyborohydride (0.067 g, 0.315 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.023 g, 44.7%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.28 (d, J=2.1 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.36 (dd, J=14.5,8.1 Hz, 1H), 7.13-6.80 (m, 4H), 5.10 ( s, 2H), 3.82-3.67 (m, 2H), 3.61 (s, 2H), 3.44 (s, 1H), 3.32-3.19 (m, 2H), 3 .13 (s, 2H), 2.48 (s, 3H);

LRMS (ES) m/z 492.3 (M ⁺ +1).

Example 85: Synthesis of Compound 3220, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1'-ethyl-3-fluoro- N-(3-fluorophenyl)-[1,3'-biazetidine]-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-[1,3 '-biazetidine]-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.105 mmol) prepared in step 2 of Example 84, acetaldehyde (0.009 g, 0.210 mmol), acetic acid (0.006 ml, 0.105 mmol), and Sodium triacetoxyborohydride (0.067 g, 0.315 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.025 g, 47.2%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=1.7 Hz, 1H), 8.31 (dd, J=8.2, 2.2 Hz, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.31-7.21 (m, 1H), 7.04-6.70 (m, 4H), 5.00 (s, 2H), 3, 74-3.56 (m, 2H), 3.39 (d, J=27.2 Hz, 3H), 3.23-3.06 (m, 2H), 2.91 (s, 2H), 2 .50 (s, 2H), 0.93 (t, J=7.1 Hz, 3H);

LRMS (ES) m/z 506.3 (M ⁺ +1).

Example 86: Synthesis of compound 3221, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1'-propyl-[1,3'-biazetidine]-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-[1,3 '-biazetidine]-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.105 mmol) obtained in step 2 of Example 84, propioaldehyde (0.012 g, 0.210 mmol), acetic acid (0.006 ml, 0.105 mmol), and Sodium triacetoxyborohydride (0.067 g, 0.315 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.025 g, 45.9%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.28 (d, J=1.6 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.40-7.31 (m, 1H), 7.02 (ddd, J=87.4, 42.7, 28.5 Hz, 4H), 5.10 (s, 2H), 3.81-3.65 (m, 2H), 3.44 (s, 3H), 3.25 (dd, J=21.9, 8.9 Hz, 2H) , 3.00 (s, 2H), 2.49 (s, 2H), 1.42 (dd, J=14.5, 7.4 Hz, 2H), 0.91 (t, J=7.4 Hz, 3H);

LRMS (ES) m/z 520.4 (M ⁺ +1).

Example 87: Synthesis of Compound 3222, 1'-Butyl-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro- N-(3-fluorophenyl)-[1,3'-biazetidine]-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-[1,3 '-biazetidine]-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.105 mmol) prepared in step 2 of Example 84, butyraldehyde (0.015 g, 0.210 mmol), acetic acid (0.006 ml, 0.105 mmol), and Sodium triacetoxyborohydride (0.067 g, 0.315 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.022 g, 39.4%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.28 (d, J=2.0 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.40-7.31 (m, 1H), 7.13-6.80 (m, 4H), 5.09 (s, 2H), 3, 72 (d, J=22.8 Hz, 2H), 3.50 (d, J=34.3 Hz, 3H), 3.33-3.16 (m, 2H), 3.03 (s, 2H ), 2.56 (s, 2H), 1.44-1.30 (m, 4H), 0.91 (t, J=7.1 Hz, 3H);

LRMS (ES) m/z 534.3 (M ⁺ +1).

Example 88: Synthesis of Compound 3223, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1'-isobutyl-[1,3'-biazetidine]-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-[1,3 '-biazetidine]-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.105 mmol) prepared in step 2 of Example 84, isobutyraldehyde (0.015 g, 0.210 mmol), acetic acid (0.006 ml, 0.105 mmol), and Sodium triacetoxyborohydride (0.067 g, 0.315 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.021 g, 37.6%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.28 (d, J=1.9 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.40-7.31 (m, 1H), 7.02 (ddd, J=87.3, 42.4, 27.7 Hz, 4H), 5.10 (s, 2H), 3.72 (dd, J=21.4, 9.1 Hz, 2H), 3.42 (s, 3H), 3.24 (dd, J=22.3, 9.7 Hz, 2H), 2.94 (s, 2H), 2.29 (d, J=6.3 Hz, 2H), 1.62 (dt, J=13.1, 6.7 Hz, 1H), 0.89 (d, J=6.7 Hz, 6H);

LRMS (ES) m/z 534.4 (M ⁺ +1).

Example 89: Synthesis of Compound 3224, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1'-isobutyl-[1,3'-biazetidine]-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-[1,3 '-biazetidine]-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.105 mmol) prepared in step 2 of Example 84, propan-2-one (0.012 g, 0.210 mmol), acetic acid (0.006 ml, 0.105 mmol), and sodium triacetoxyborohydride (0.067 g, 0.315 mmol) was dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The resulting product was 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 (0.015 g, 27.6%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.28 (d, J=1.7 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.40-7.30 (m, 1H), 7.12-6.79 (m, 4H), 5.09 (s, 2H), 3, 80-3.63 (m, 2H), 3.53 (s, 2H), 3.42 (s, 1H), 3.24 (dd, J=21.0, 9.7 Hz, 2H), 3 .01 (s, 2H), 2.50 (s, 1H), 1.02 (d, J=5.6 Hz, 6H);

LRMS (ES) m/z 520.4 (M ⁺ +1).

Example 90: Synthesis of Compound 3389, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-(3- fluorophenyl)-1-(1-methylazetidin-3-yl)piperidine-4-carboxamide

[Step 1] Synthesis of 3-(4-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(3-fluorophenyl)carbamoyl)- 4-fluoropiperidin-1-yl)azetidine-1-carboxylate

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-(3-fluorophenyl)piperidine-4-carboxamide 2,2,2-trifluoroacetate (0.458 g, 1.019 mmol) obtained from step 3 of Example 10, tert-butyl 3-oxoazetidine-1-carboxylate (0.349 g, 2.038 mmol), acetic acid (0.058 ml, 1.019 mmol), and sodium triacetoxyborohydride (0.648 g, 3.057 mmol) were dissolved in dichloromethane (10 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 24 g; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.300 g, 48.7%) as a yellow gel.

[Step 2] Synthesis of 1-(azetidin-3-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4 -fluoro-N-(3-fluorophenyl)piperidine-4-carboxamide 2,2,2-trifluoroacetate

Tert-butyl 3-(4-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(3-fluorophenyl)carbamoyl)-4- fluoropiperidin-1-yl)azetidine-1-carboxylate (0.300 g, 0.496 mmol) obtained in step 1 and trifluoroacetic acid (0.760 ml, 9.924 mmol) were dissolved in dichloromethane (10 ml) at room temperature, and the resulting solution was stirred at same temperature for 2 hours. After removing the solvent from the reaction mixture under reduced pressure, the title compound (0.250 g, 99.9%) was obtained as a yellow gel.

[Step 3] Synthesis of compound 3389

1-(Azetidin-3-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N- (3-fluorophenyl)piperidine-4-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.099 mmol) obtained in step 2, formaldehyde (0.006 g, 0.198 mmol), acetic acid (0.006 ml, 0.099 mmol), and Sodium triacetoxyborohydride (0.063 g, 0.297 mmol) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.015 g, 29.2%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=2.0 Hz, 1H), 8.29 (dd, J=8.2, 2.2 Hz, 1H), 7.50 -7.33 (m, 1H), 7.27-7.21 (m, 1H), 7.02-6.74 (m, 4H), 4.97 (s, 2H), 4.16 (s , 1H), 3.39 (d, J=21.9 Hz, 2H), 3.33-3.18 (m, 1H), 2.87-2.61 (m, 2H), 2.46 ( d, J=9.9 Hz, 1H), 2.22 (ddd, J=30.1, 16.9, 8.7 Hz, 3H), 1.93 (dt, J=25.0, 11, 9 Hz, 4H), 1.25-1.19 (m, 1H), 0.84-0.72 (m, 1H);

LRMS (ES) m/z 519.2 (M ⁺ +1).

Example 91: Synthesis of Compound 3390, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-(3- fluorophenyl)-1-(1-propylazetidin-3-yl)piperidine-4-carboxamide

1-(Azetidin-3-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N- (3-fluorophenyl)piperidine-4-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.099 mmol) prepared in step 2 of Example 90, propioaldehyde (0.012 g, 0.198 mmol), acetic acid (0.006 ml, 0.099 mmol) , and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.015 g, 27.7%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.22-9.15 (m, 1H), 8.29 (dd, J=8.2, 2.2 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H), 7.26-7.20 (m, 1H), 7.01-6.72 (m, 4H), 4.97 (s, 2H), 3.69 (d , J=25.8 Hz, 2H), 3.03 (dd, J=11.9, 5.6 Hz, 3H), 2.60-2.52 (m, 2H), 2.52-2, 42 (m, 2H), 2.33-2.13 (m, 2H), 1.90 (dt, J=32.9, 11.9 Hz, 4H), 1.47-1.36 (m, 2H), 0.85 (t, J=7.4 Hz, 3H);

LRMS (ES) m/z 547.0 (M ⁺ +1).

Example 92: Synthesis of Compound 3391, 1-(1-Butylazetidin-3-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl) methyl)-4-fluoro-N-(3-fluorophenyl)piperidine-4-carboxamide

1-(Azetidin-3-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N- (3-fluorophenyl)piperidine-4-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.099 mmol) prepared in step 2 of Example 90, butyraldehyde (0.014 g, 0.198 mmol), acetic acid (0.006 ml, 0.099 mmol) , and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.015 g, 27.0%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.25-9.10 (m, 1H), 8.29 (dd, J=8.2, 2.2 Hz, 1H), 7.43 (t, J=9.3 Hz, 1H), 7.26-7.20 (m, 1H), 7.01-6.71 (m, 4H), 4.97 (s, 2H), 3.71 (s , 2H), 3.02 (dd, J=14.8, 6.1 Hz, 3H), 2.62-2.53 (m, 2H), 2.53-2.43 (m, 2H), 2.22 (dtd, J=25.2, 13.0, 8.2 Hz, 2H), 1.99-1.80 (m, 4H), 1.41-1.31 (m, 2H), 1.25 (td, J=14.4, 7.1 Hz, 2H), 0.83 (t, J=7.3 Hz, 3H);

LRMS (ES) m/z 561.1 (M ⁺ +1).

Example 93: Synthesis of Compound 3392, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-(3- fluorophenyl)-1-(1-isobutylazetidin-3-yl)piperidine-4-carboxamide

1-(Azetidin-3-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N- (3-fluorophenyl)piperidine-4-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.099 mmol) prepared in step 2 of Example 90, isobutyraldehyde (0.014 g, 0.198 mmol), acetic acid (0.006 ml, 0.099 mmol) , and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.015 g, 27.0%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 (d, J=1.6 Hz, 1H), 8.29 (dd, J=8.2, 2.2 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H), 7.27-7.20 (m, 1H), 7.02-6.70 (m, 4H), 4.97 (s, 2H), 3, 66 (s, 2H), 3.05-2.85 (m, 3H), 2.53-2.43 (m, 2H), 2.40-2.13 (m, 4H), 1.97- 1.80 (m, 4H), 1.65 (dt, J=13.1, 6.7 Hz, 1H), 0.84 (d, J=6.7 Hz, 6H);

LRMS (ES) m/z 561.1 (M ⁺ +1).

Example 94: Synthesis of Compound 3393, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-(3- fluorophenyl)-1-(1-isopropylazetidin-3-yl)piperidine-4-carboxamide

1-(Azetidin-3-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N- (3-fluorophenyl)piperidin-4-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.099 mmol) prepared in step 2 of Example 90, propan-2-one (0.012 g, 0.198 mmol), acetic acid (0.006 ml , 0.099 mmol), and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.015 g, 27.7%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 (d, J=1.6 Hz, 1H), 8.29 (dd, J=8.2, 2.2 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H), 7.28-7.16 (m, 1H), 7.03-6.71 (m, 4H), 4.99 (d, J=13.6 Hz, 2H), 3.64 (s, 2H), 2.96 (s, 3H), 2.58-2.44 (m, 3H), 2.34-2.11 (m, 2H), 1 .90 (dt, J=31.4, 11.9 Hz, 4H), 0.98 (d, J=6.3 Hz, 6H);

LRMS (ES) m/z 547.1 (M ⁺ +1).

Example 95: Synthesis of Compound 3394, 1'-Cyclobutyl-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro- N-(3-fluorophenyl)-[1,3'-biazetidine]-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-[1,3 '-biazetidine]-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.105 mmol) prepared in step 2 of Example 84, cyclobutanone (0.015 g, 0.210 mmol), acetic acid (0.006 ml, 0.105 mmol), and Sodium triacetoxyborohydride (0.067 g, 0.315 mmol) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.015 g, 26.9%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 (d, J=1.6 Hz, 1H), 8.30 (dd, J=8.2, 2.2 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.26 (dt, J=8.0, 7.2 Hz, 1H), 6.92 (dt, J=85.9, 29.1 Hz, 4H), 5.00 (s, 2H), 3.63 (dd, J=21.5, 9.2 Hz, 2H), 3.40-3.27 (m, 3H), 3.15 (dd , J=17.6, 9.8 Hz, 3H), 2.93 (s, 2H), 1.96-1.84 (m, 2H), 1.80 (dd, J=19.3, 9 ,6 Hz, 2H), 1.75-1.66 (m, 1H), 1.60 (dt, J=10.3, 8.6 Hz, 1H);

LRMS (ES) m/z 531.0 (M ⁺ +1).

Example 96: Synthesis of Compound 3395, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1'-(oxetan-3-yl)-[1,3'-biazetidine]-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-[1,3 '-biazetidine]-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.105 mmol) prepared in step 2 of Example 84, oxetan-3-one (0.015 g, 0.210 mmol), acetic acid (0.006 ml, 0.105 mmol), and sodium triacetoxyborohydride (0.067 g, 0.315 mmol) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.015 g, 26.8%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.19 (dd, J=4.2, 1.9 Hz, 1H), 8.31 (dd, J=8.2, 1.5 Hz, 1H) , 7.49-7.42 (m, 1H), 7.32-7.22 (m, 1H), 7.04-6.69 (m, 4H), 5.00 (s, 2H), 4 .60 (t, J=6.7 Hz, 1H), 4.48-4.37 (m, 1H), 4.06-3.91 (m, 1H), 3.88 (s, 1H), 3.66 (ddd, J=63.0, 30.5, 14.3 Hz, 4H), 3.34 (s, 1H), 3.25-3.13 (m, 2H), 3.00 ( s, 1H), 1.30-1.20 (m, 1H), 0.83-0.72 (m, 1H);

LRMS (ES) m/z 533.4 (M ⁺ +1).

Example 97: Synthesis of Compound 3396, 1'-Cyclopentyl-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro- N-(3-fluorophenyl)-[1,3'-biazetidine]-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-[1,3 '-biazetidine]-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.105 mmol) prepared in step 2 of Example 84, cyclopentanone (0.018 g, 0.210 mmol), acetic acid (0.006 ml, 0.105 mmol), and Sodium triacetoxyborohydride (0.067 g, 0.315 mmol) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.015 g, 26.2%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.22-9.13 (m, 1H), 8.31 (dd, J=8.2, 2.2 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.30-7.22 (m, 1H), 6.92 (dt, J=85.4, 29.4 Hz, 4H), 5.00 (s, 2H ), 3.63 (dd, J=21.8, 9.3 Hz, 2H), 3.46 (t, J=7.3 Hz, 2H), 3.41-3.30 (m, 1H) , 3.15 (dd, J=21.7, 9.2 Hz, 2H), 2.95 (d, J=7.0 Hz, 2H), 2.83 (dd, J=11.8, 6 ,0 Hz, 1H), 1.71-1.53 (m, 4H), 1.46 (ddd, J=9.2, 7.6, 2.5 Hz, 2H), 1.39-1, 29 (m, 2H);

LRMS (ES) m/z 546.3 (M ⁺ +1).

Example 98: Synthesis of Compound 3397, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1'-(tetrahydrofuran-3-yl)-[1,3'-biazetidine]-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-[1,3 '-biazetidine]-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.105 mmol) prepared in step 2 of Example 84, dihydrofuran-3(2H)-one (0.018 g, 0.210 mmol), acetic acid (0.006 ml, 0.105 mmol), and sodium triacetoxyborohydride (0.067 g, 0.315 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.015 g, 26.2%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 (d, J=1.6 Hz, 1H), 8.30 (dd, J=8.2, 2.2 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.26 (td, J=8.1, 6.4 Hz, 1H), 7.02-6.70 (m, 4H), 5.00 ( s, 2H), 3.80 (dd, J=15.6, 7.6 Hz, 1H), 3.59 (dddd, J=26.6, 12.0, 8.7, 3.9 Hz, 5H), 3.27 (s, 3H), 3.15 (dd, J=21.9, 9.2 Hz, 2H), 2.93 (td, J=8.0,2.9 Hz, 1H ), 2.82 (d, J=11.4 Hz, 2H), 1.78 (ddd, J=15.1, 12.8, 7.5 Hz, 1H), 1.60 (dddd, J= 12.5, 7.5, 4.9, 2.9 Hz, 1H);

LRMS (ES) m/z 548.1 (M ⁺ +1).

Example 99: Synthesis of Compound 3398, 1'-Cyclohexyl-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro- N-(3-fluorophenyl)-[1,3'-biazetidine]-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-[1,3 '-biazetidine]-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.105 mmol) prepared in step 2 of Example 84, cyclohexanone (0.021 g, 0.210 mmol), acetic acid (0.006 ml, 0.105 mmol), and Sodium triacetoxyborohydride (0.067 g, 0.315 mmol) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.015 g, 25.6%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=1.7 Hz, 1H), 8.31 (dd, J=8.2, 2.2 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.26 (dt, J=8.0, 7.2 Hz, 1H), 6.92 (dt, J=85.6, 29.2 Hz, 4H), 5.00 (s, 2H), 3.64 (dd, J=21.3, 9.1 Hz, 2H), 3.54 (t, J=7.2 Hz, 2H), 3, 46-3.35 (m, 1H), 3.15 (dd, J=21.5, 9.1 Hz, 2H), 3.00 (s, 2H), 2.15 (d, J=4, 2 Hz, 1H), 1.68 (d, J=5.6 Hz, 4H), 1.54 (s, 1H), 1.09 (d, J=5.2 Hz, 5H);

LRMS (ES) m/z 559.1 (M ⁺ +1).

Example 100: Synthesis of Compound 3399, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1'-(tetrahydro-2H-pyran-4-yl)-[1,3'-biazetidine]-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-[1,3 '-biazetidine]-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.105 mmol) prepared in step 2 of Example 84, tetrahydro-4H-pyran-4-one (0.021 g, 0.210 mmol), acetic acid ( 0.006 ml, 0.105 mmol), and sodium triacetoxyborohydride (0.067 g, 0.315 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.015 g, 25.5%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.21-9.16 (m, 1H), 8.30 (dd, J=8.2, 2.2 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.31-7.22 (m, 1H), 7.03-6.71 (m, 4H), 5.00 (s, 2H), 3.90-3 .80 (m, 2H), 3.63 (dd, J=21.7, 9.2 Hz, 2H), 3.35-3.21 (m, 5H), 3.15 (dd, J=22 ,1, 9.2 Hz, 2H), 2.81 (d, J=6.6 Hz, 2H), 2.14 (ddd, J=14.0, 10.0, 3.9 Hz, 1H) , 1.53 (d, J=11.9 Hz, 2H), 1.25 (ddd, J=13.9, 10.6, 3.9 Hz, 2H);

LRMS (ES) m/z 562.2 (M ⁺ +1).

Example 101: Synthesis of Compound 3400, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-(1-ethylpiperidin-4- yl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide

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

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.513 g, 1.217 mmol) obtained from step 2 of Example 31, tert-butyl 4-oxopiperidine-1-carboxylate (0.485 g, 2.435 mmol), acetic acid (0.070 ml, 1.217 mmol), and sodium triacetoxyborohydride (0.774 g, 3.652 mmol) were dissolved in dichloromethane (10 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 24 g; methanol/dichloromethane = 0% to 10%) and concentrated to give the title compound (0.610 g, 82.9%) as a white solid.

[Step 2] Synthesis of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl) -1-(piperidin-4-yl)azetidine-3-carboxamide 2,2,2-trifluoroacetate

Tert-butyl 4-(3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(3-fluorophenyl)carbamoyl)-3- fluoroazetidin-1-yl)piperidin-1-carboxylate (0.610 g, 1.009 mmol) obtained in step 1 and trifluoroacetic acid (1.545 ml, 20.178 mmol) were dissolved in dichloromethane (10 ml) at room temperature, and the resulting solution was stirred at the same temperature for 2 hours. After removing the solvent from the reaction mixture under reduced pressure, the title compound (0.500 g, 98.2%) was obtained as a yellow gel.

[Step 3] Synthesis of compound 3400

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-1-(piperidine -4-yl)azetidin-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.099 mmol) obtained in step 2, acetaldehyde (0.009 g, 0.198 mmol), acetic acid (0.006 ml, 0.099 mmol), and Sodium triacetoxyborohydride (0.063 g, 0.297 mmol) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.015 g, 28.4%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=1.6 Hz, 1H), 8.30 (dd, J=8.2, 2.2 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.32-7.22 (m, 1H), 6.90 (ddd, J=51.7, 26.5, 17.8 Hz, 4H), 5.75-5.43 (m, 2H), 5.00 (s, 2H), 3.60-3.43 (m, 2H), 3.08 (d, J=20.8 Hz, 4H) , 2.82 (s, 2H), 1.84 (s, 2H), 1.65 (d, J=5.9 Hz, 3H), 1.51-1.33 (m, 3H);

LRMS (ES) m/z 533.4 (M ⁺ +1).

Example 102: Synthesis of Compound 3401, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1-(1-propylpiperidin-4-yl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-1-(piperidine -4-yl)azetidin-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.099 mmol) prepared in step 2 of Example 101, propioaldehyde (0.012 g, 0.198 mmol), acetic acid (0.006 ml, 0.099 mmol) , and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.015 g, 27.7%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=1.6 Hz, 1H), 8.30 (dd, J=8.2, 2.2 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.30-7.22 (m, 1H), 7.04-6.72 (m, 4H), 5.00 (s, 2H), 3, 61-3.44 (m, 2H), 3.09 (dd, J=21.3, 9.3 Hz, 2H), 2.86 (t, J=8.3 Hz, 2H), 2.50 (t, J=16.0 Hz, 4H), 2.20 (d, J=25.1 Hz, 1H), 1.89 (s, 2H), 1.61 (dd, J=15.6, 7.7 Hz, 2H), 1.47-1.37 (m, 2H), 0.85 (t, J=7.4 Hz, 3H);

LRMS (ES) m/z 547.3 (M ⁺ +1).

Example 103: Synthesis of Compound 3402, 1-(1-Butylpiperidin-4-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl) methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-1-(piperidine -4-yl)azetidin-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.099 mmol) prepared in step 2 of Example 101, butyraldehyde (0.014 g, 0.198 mmol), acetic acid (0.006 ml, 0.099 mmol) , and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.015 g, 27.0%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=1.6 Hz, 1H), 8.30 (dd, J=8.2, 2.2 Hz, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.32-7.23 (m, 1H), 6.93 (dt, J=88.2, 28.3 Hz, 4H), 5.00 ( s, 2H), 3.53 (dd, J=22.5, 9.0 Hz, 2H), 3.08 (dd, J=20.9, 9.0 Hz, 2H), 2.91 (t , J=9.2 Hz, 2H), 2.63 (dd, J=21.6, 13.8 Hz, 4H), 2.31 (s, 1H), 2.00 (d, J=5, 0 Hz, 2H), 1.68-1.55 (m, 2H), 1.53-1.41 (m, 2H), 1.32-1.21 (m, 2H), 0.85 (t , J=7.4 Hz, 3H);

LRMS (ES) m/z 561.2 (M ⁺ +1).

Example 104: Synthesis of Compound 3403, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1-(1-isobutylpiperidin-4-yl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-1-(piperidine -4-yl)azetidin-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.099 mmol) prepared in step 2 of Example 101, isobutyraldehyde (0.014 g, 0.198 mmol), acetic acid (0.006 ml, 0.099 mmol) , and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.015 g, 27.0%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.18 (d, J=1.6 Hz, 1H), 8.30 (dd, J=8.2, 2.2 Hz, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.29-7.21 (m, 1H), 7.02-6.72 (m, 4H), 5.00 (s, 2H), 3, 61-3.42 (m, 2H), 3.09 (dd, J=21.4, 9.1 Hz, 2H), 2.77-2.68 (m, 2H), 2.13 (dd, J=21.2, 13.2 Hz, 5H), 1.70 (d, J=31.3 Hz, 3H), 1.28 (dd, J=9.0, 3.5 Hz, 2H), 0.83 (d, J=6.5 Hz, 6H);

LRMS (ES) m/z 561.1 (M ⁺ +1).

Example 105: Synthesis of Compound 3404, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1-(1-isopropylpiperidin-4-yl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-1-(piperidine -4-yl)azetidin-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.099 mmol) prepared in step 2 of Example 101, propan-2-one (0.012 g, 0.198 mmol), acetic acid (0.006 ml , 0.099 mmol), and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.015 g, 27.7%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (d, J=1.6 Hz, 1H), 8.31 (dd, J=8.2, 2.2 Hz, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.32-7.22 (m, 1H), 6.93 (dt, J=76.2, 29.2 Hz, 4H), 5.00 ( s, 2H), 3.59-3.45 (m, 2H), 3.09 (dd, J=21.3, 9.8 Hz, 3H), 2.95 (t, J=10.1 Hz , 2H), 2.79 (s, 2H), 2.38 (s, 1H), 2.28-2.15 (m, 2H), 1.53 (d, J=13.5 Hz, 2H) , 1.25 (d, J=6.4 Hz, 6H);

LRMS (ES) m/z 547.2 (M ⁺ +1).

Example 106: Synthesis of Compound 3405, 1-(1-Cyclobutylpiperidin-4-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl) methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-1-(piperidine -4-yl)azetidin-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.099 mmol) prepared in step 2 of Example 101, cyclobutanone (0.014 g, 0.198 mmol), acetic acid (0.006 ml, 0.099 mmol) , and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.015 g, 27.1%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.22-9.15 (m, 1H), 8.30 (dd, J=8.2, 2.2 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.30-7.21 (m, 1H), 7.04-6.69 (m, 4H), 5.00 (s, 2H), 3.58-3 .40 (m, 2H), 3.08 (dd, J=21.5, 9.3 Hz, 2H), 2.85 (s, 1H), 2.68 (d, J=7.6 Hz, 2H), 2.16 (dd, J=15.3, 7.8 Hz, 4H), 1.99 (dd, J=16.1, 8.2 Hz, 3H), 1.81 (d, J =27.2 Hz, 2H), 1.77-1.65 (m, 1H), 1.58 (dt, J=18.8, 9.5 Hz, 1H), 1.33 (d, J= 23.7 Hz, 2H);

LRMS (ES) m/z 559.5 (M ⁺ +1).

Example 107: Synthesis of Compound 3406, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1-(1-(oxetan-3-yl)piperidin-4-yl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-1-(piperidine -4-yl)azetidin-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.099 mmol) prepared in step 2 of Example 101, oxetan-3-one (0.014 g, 0.198 mmol), acetic acid (0.006 ml , 0.099 mmol), and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.015 g, 27.0%) as a yellow gel .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=1.6 Hz, 1H), 8.30 (dd, J=8.2, 2.2 Hz, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.31-7.21 (m, 1H), 7.03-6.70 (m, 4H), 5.00 (s, 2H), 4, 55 (d, J=6.4 Hz, 4H), 3.52 (dd, J=22.3, 8.6 Hz, 2H), 3.41 (s, 1H), 3.11 (dd, J =21.4, 8.2 Hz, 2H), 2.55 (d, J=10.7 Hz, 2H), 2.05 (s, 1H), 1.85 (s, 2H), 1.58 (s, 2H), 1.34-1.21 (m, 2H);

LRMS (ES) m/z 561.1 (M ⁺ +1).

Example 108: Synthesis of Compound 3407, 1-(1-cyclopentylpiperidin-4-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl) methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-1-(piperidine -4-yl)azetidin-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.099 mmol) prepared in step 2 of Example 101, cyclopentanone (0.017 g, 0.198 mmol), acetic acid (0.006 ml, 0.099 mmol) , and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.015 g, 26.4%) as a yellow gel .

1H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=1.5 Hz, 1 H), 8.30 (dd, J=8.2, 2.2 Hz, 1 H), 7, 45 (d, J=8.1 Hz, 1H), 7.31-7.22 (m, 1H), 7.05-6.70 (m, 4H), 5.00 (s, 2H), 3 ,61-3.41 (m, 2H), 3.08 (dd, J=21.4, 9.1 Hz, 2H), 3.01-2.69 (m, 5H), 2.33 (s , 1H), 2.13 (dd, J=22.8, 15.0 Hz, 2H), 1.88 (d, J=10.2 Hz, 4H), 1.75 (s, 2H), 1 .55-1.42 (m, 4H);

LRMS (ES) m/z 573.3 (M ⁺ +1).

Example 109: Synthesis of Compound 3408, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1-(1-(tetrahydrofuran-3-yl)piperidin-4-yl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-1-(piperidine -4-yl)azetidin-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.099 mmol) prepared in step 2 of Example 101, dihydrofuran-3(2H)-one (0.017 g, 0.198 mmol), acetic acid (0.006 ml, 0.099 mmol), and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.005 g, 8.8%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=1.5 Hz, 1H), 8.30 (dd, J=8.2, 2.2 Hz, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.30-7.21 (m, 1H), 7.03-6.71 (m, 4H), 5.00 (s, 2H), 3, 86 (td, J=8.6, 4.4 Hz, 1H), 3.77 (dd, J=8.7, 6.9 Hz, 1H), 3.69 (dd, J=16.2, 8.0 Hz, 1H), 3.63-3.41 (m, 3H), 3.10 (dd, J=21.6, 9.4 Hz, 2H), 2.92 (s, 1H), 2.77 (s, 1H), 2.61 (s, 1H), 2.15-1.93 (m, 4H), 1.80 (s, 1H), 1.59 (s, 2H), 1 .29 (dd, J=27.5, 16.4 Hz, 2H);

LRMS (ES) m/z 575.4 (M ⁺ +1).

Example 110: Synthesis of Compound 3409, 1-(1-cyclohexylpiperidin-4-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl) methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-1-(piperidine -4-yl)azetidin-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.099 mmol) prepared in step 2 of Example 101, cyclohexanone (0.019 g, 0.198 mmol), acetic acid (0.006 ml, 0.099 mmol) , and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.005 g, 8.6%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.20 (d, J=1.7 Hz, 1H), 8.31 (dd, J=8.1, 2.2 Hz, 1H), 7.44 (d, J=7.0 Hz, 1H), 7.28 (dd, J=14.6, 8.1 Hz, 1H), 7.05-6.70 (m, 4H), 5.00 ( s, 2H), 3.04 (s, 4H), 2.46 (s, 2H), 2.16 (dd, J=18.4, 10.9 Hz, 2H), 1.83 (d, J =12.8 Hz, 2H), 1.58 (dd, J=32.7, 12.5 Hz, 6H), 1.37 (dt, J=26.8, 13.2 Hz, 3H), 1 .23 (dd, J=17.5, 8.8 Hz, 5H);

LRMS (ES) m/z 587.5 (M ⁺ +1).

Example 111: Synthesis of Compound 3410, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3- fluorophenyl)-1-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)azetidine-3-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-1-(piperidine -4-yl)azetidin-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.099 mmol), prepared in step 2 of Example 101, tetrahydro-4H-pyran-4-one (0.020 g, 0.198 mmol), acetic acid acid (0.006 ml, 0.099 mmol), and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.005 g, 8.6%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 9.20 (d, J=1.6 Hz, 1H), 8.30 (dd, J=8.2, 2.2 Hz, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.27 (dd, J=14.5, 8.2 Hz, 1H), 7.04-6.70 (m, 4H), 5.00 ( s, 2H), 3.97 (d, J=10.7 Hz, 2H), 3.59-3.44 (m, 2H), 3.30 (t, J=11.2 Hz, 2H), 3.09 (dd, J=21.6, 9.4 Hz, 2H), 2.92 (s, 2H), 2.02-1.76 (m, 3H), 1.67 (s, 3H) , 1.57 (s, 2H), 1.48 (s, 2H), 1.33-1.21 (m, 2H);

LRMS (ES) m/z 589.2 (M ⁺ +1).

Example 112: Synthesis of Compound 3429, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-3-fluoro-1-methyl-N-phenylazetidin-3 -carboxamide

[Step 1] Synthesis of tert-butyl 3-(((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)(phenyl)carbamoyl)-3-fluoroazetidin-1 -carboxylate

To a solution in which N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)aniline (1.000 g, 3.132 mmol) obtained in step 1 of Example 1, and triethylamine (1.436 ml, 9.396 mmol) was dissolved in dichloromethane (20 ml) at room temperature, tert-butyl 3-(chlorocarbonyl)-3-fluoroazetidine-1-carboxylate (0.968 g, 4.072 mmol) obtained in step 1 of Example was added 14, and stirred at the same temperature for 16 hours. A saturated aqueous solution of ammonium chloride was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with water, 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 (0.527 g, 32.3%) as a yellow solid.

[Step 2] Synthesis of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2, 2-trifluoroacetate

Tert-butyl 3-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)(phenyl)carbamoyl)-3-fluoroazetidine-1-carboxylate (0.527 g, 1.013 mmol) obtained in step 1, and trifluoroacetic acid (1.551 ml, 20.251 mmol) was dissolved in dichloromethane (10 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the title compound (0.425 g, 99.9%) was obtained as a brown gel.

[Step 3] Synthesis of compound 3429

N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained in step 2, formaldehyde (0.007 g, 0.238 mmol), acetic acid (0.007 ml, 0.119 mmol), and sodium triacetoxyborohydride (0.076 g, 0.357 mmol) were dissolved in dichloromethane (4 ml) at room temperature , and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.020 g, 38.7%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 7.80 (dd, J=8.0, 1.5 Hz, 1H), 7.65 (dd, J=9.8, 1.6 Hz, 1H) , 7.52 (t, J=7.6 Hz, 1H), 7.26 (dd, J=6.8, 3.9 Hz, 3H), 7.04-6.97 (m, 2H), 6.84 (t, J=51.7 Hz, 1H), 4.98 (s, 2H), 3.54 (dd, J=22.2, 10.5 Hz, 2H), 3.15-2 .99 (m, 2H), 2.27 (s, 3H);

LRMS (ES) m/z 436.1 (M ⁺ +1).

Example 113: Synthesis of Compound 3430, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-ethyl-3-fluoro-N-phenylazetidin-3 -carboxamide

N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained in step 2 of Example 112, acetaldehyde (0.010 g, 0.238 mmol), acetic acid (0.007 ml, 0.119 mmol), and sodium triacetoxyborohydride (0.076 g, 0.357 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.020 g, 37.5%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 7.89 (dd, J=8.0, 1.5 Hz, 1H), 7.74 (dd, J=9.8, 1.6 Hz, 1H) , 7.62 (t, J=7.6 Hz, 1H), 7.38-7.32 (m, 3H), 7.13-7.07 (m, 2H), 6.95 (dd, J =70.2, 33.2 Hz, 1H), 5.07 (s, 2H), 3.57 (dd, J=22.5, 10.3 Hz, 2H), 3.11 (dd, J= 21.7, 10.4 Hz, 2H), 2.48 (q, J=7.1 Hz, 2H), 0.95 (t, J=7.2 Hz, 3H);

LRMS (ES) m/z 450.1 (M ⁺ +1).

Example 114: Synthesis of Compound 3431, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-3-fluoro-1-isopropyl-N-phenylazetidin-3 -carboxamide

N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-3-fluoro-N-phenylazetidin-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained in step 2 of Example 112, propan-2-one (0.014 g, 0.238 mmol), acetic acid (0.007 ml, 0.119 mmol), and sodium triacetoxyborohydride (0.076 g, 0.357 mmol) were dissolved in dichloromethane ( 4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.020 g, 36.4%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 7.80 (dd, J=8.0, 1.5 Hz, 1H), 7.64 (dd, J=9.8, 1.6 Hz, 1H) , 7.53 (t, J=7.6 Hz, 1H), 7.25 (dd, J=6.9, 3.7 Hz, 3H), 7.05-6.98 (m, 2H), 6.84 (t, J=51.7 Hz, 1H), 4.98 (s, 2H), 3.46 (dd, J=22.7, 10.3 Hz, 2H), 3.00 (dd , J=21.6, 10.4 Hz, 2H), 2.28-2.15 (m, 1H), 0.81 (d, J=6.2 Hz, 6H);

LRMS (ES) m/z 464.4 (M ⁺ +1).

Example 115: Synthesis of Compound 3432, 1-Acetyl-N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-3-fluoro-N-phenylazetidine-3 -carboxamide

N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained in step 2 of Example 112, acetyl chloride (0.013 ml, 0.178 mmol), and triethylamine (0.050 ml, 0.357 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.020 g, 36.4%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 7.90 (dd, J=8.0, 1.4 Hz, 1H), 7.76 (dd, J=9.8, 1.5 Hz, 1H) , 7.56 (t, J=7.6 Hz, 1H), 7.41-7.35 (m, 3H), 7.12-6.78 (m, 3H), 5.14 (d, J =14.6 Hz, 1H), 5.03 (d, J=14.8 Hz, 1H), 4.77 (dd, J=21.6, 10.9 Hz, 1H), 4.29 (dd , J=22.7, 12.4 Hz, 1H), 4.03 (dd, J=22.4, 10.2 Hz, 1H), 3.63 (dd, J=23.4, 11.9 Hz, 1H), 1.89 (s, 3H);

LRMS (ES) m/z 463.4 (M ⁺ +1).

Example 116: Synthesis of Compound 3433, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-3-fluoro-N-phenyl-1-propionylazetidine-3 -carboxamide

N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained in step 2 of Example 112, propionyl chloride (0.017 g, 0.178 mmol), and triethylamine (0.050 ml, 0.357 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.020 g, 35.3%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 7.90 (dd, J=8.0, 1.5 Hz, 1H), 7.76 (dd, J=9.8, 1.6 Hz, 1H) , 7.56 (t, J=7.6 Hz, 1H), 7.40-7.35 (m, 3H), 7.11-6.78 (m, 3H), 5.19-4.98 (m, 2H), 4.82-4.67 (m, 1H), 4.29 (dd, J=22.1, 11.3 Hz, 1H), 4.00 (dd, J=22.2 , 8.8 Hz, 1H), 3.63 (dd, J=22.3, 10.6 Hz, 1H), 2.11 (q, J=7.5 Hz, 2H), 1.12 (t , J=7.5 Hz, 3H);

LRMS (ES) m/z 478.2 (M ⁺ +1).

Example 117: Synthesis of Compound 3434, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-3-fluoro-1-isobutyryl-N-phenylazetidine-3 -carboxamide

N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained in step 2 of Example 112, isobutyryl chloride (0.019 g, 0.178 mmol), and triethylamine (0.050 ml, 0.357 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.020 g, 34.3%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 7.90 (dd, J=8.0, 1.5 Hz, 1H), 7.76 (dd, J=9.8, 1.6 Hz, 1H) , 7.56 (t, J=7.6 Hz, 1H), 7.41-7.35 (m, 3H), 7.13-6.79 (m, 3H), 5.20-4.98 (m, 2H), 4.80 (dd, J=21.6, 10.1 Hz, 1H), 4.28 (dd, J=22.6, 11.9 Hz, 1H), 4.04 ( dd, J=22.6, 10.2 Hz, 1H), 3.62 (dd, J=23.4, 11.8 Hz, 1H), 2.41 (dt, J=13.6, 6, 8 Hz, 1H), 1.09 (t, J=7.8 Hz, 6H);

LRMS (ES) m/z 492.3 (M ⁺ +1).

Example 118: Synthesis of Compound 3435, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-3-fluoro-N-phenyl-1-(2, 2,2-trifluoroacetyl)azetidine-3-carboxamide

N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained in step 2 of Example 112, 3,3,3-trifluoropropane anhydride (0.042 g, 0.178 mmol), and triethylamine (0.050 ml, 0.357 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.020 g, 32.6%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 7.91 (dd, J=8.0, 1.6 Hz, 1H), 7.77 (dd, J=9.8, 1.6 Hz, 1H) , 7.56 (t, J=7.6 Hz, 1H), 7.44-7.38 (m, 3H), 7.11-6.78 (m, 3H), 5.10 (dd, J =37.8, 14.6 Hz, 2H), 4.96 (dd, J=22.4, 11.8 Hz, 1H), 4.49 (dd, J=22.2, 12.5 Hz, 1H), 4.23 (dd, J=22.0, 11.9 Hz, 1H), 3.81 (dd, J=23.2, 13.5 Hz, 1H);

LRMS (ES) m/z 516.9 (M ⁺ +1).

Example 119: Synthesis of Compound 3436, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-3-fluoro-1-(methylsulfonyl)-N-phenylazetidine -3-carboxamide

N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-3-fluoro-N-phenylazetidin-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol) obtained in step 2 of Example 112, methanesulfonyl chloride (0.014 ml, 0.178 mmol), and triethylamine (0.050 ml, 0.357 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.020 g, 33.7%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 7.90 (dd, J=8.0, 1.6 Hz, 1H), 7.76 (dd, J=9.8, 1.6 Hz, 1H) , 7.57 (t, J=7.6 Hz, 1H), 7.42-7.35 (m, 3H), 7.12-6.78 (m, 3H), 5.09 (s, 2H ), 4.40 (dd, J=23.1, 11.7 Hz, 2H), 3.68 (dd, J=22.2, 11.7 Hz, 2H), 2.89 (s, 3H) ;

LRMS (ES) m/z 499.0 (M ⁺ +1).

Example 120: Synthesis of Compound 3437, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-1-isopropyl-N-phenylpiperidin-4 -carboxamide

N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.112 mmol) obtained in step 4 of Example 1, propan-2-one (0.013 g, 0.223 mmol), acetic acid (0.007 ml, 0.112 mmol), and sodium triacetoxyborohydride (0.071 g, 0.335 mmol) were dissolved in dichloromethane ( 4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.020 g, 36.6%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 7.89 (dd, J=8.0, 1.6 Hz, 1H), 7.73 (dd, J=9.8, 1.6 Hz, 1H) , 7.59 (t, J=7.6 Hz, 1H), 7.35-7.30 (m, 3H), 6.99 (ddd, J=92.0, 32.0, 26.7 Hz , 3H), 5.04 (s, 2H), 2.84 (d, J=29.5 Hz, 3H), 2.47 (d, J=46.4 Hz, 4H), 1.97 (s , 2H), 1.08 (d, J=6.3 Hz, 6H);

LRMS (ES) m/z 491.0 (M ⁺ +1).

Example 121: Synthesis of Compound 3438, 1-Acetyl-N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-N-phenylpiperidine-4 -carboxamide

N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.112 mmol) obtained in step 4 of Example 1, acetyl chloride (0.012 ml, 0.167 mmol), and triethylamine (0.047 ml, 0.335 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.020 g, 36.6%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 7.89 (dd, J=8.0, 1.6 Hz, 1H), 7.75 (dd, J=9.8, 1.6 Hz, 1H) , 7.55 (t, J=7.6 Hz, 1H), 7.34 (dd, J=6.9, 3.7 Hz, 3H), 7.08-6.78 (m, 3H), 5.04 (d, J=7.9 Hz, 2H), 4.49 (d, J=10.3 Hz, 1H), 3.68 (s, 1H), 3.23 (s, 1H), 2.73 (s, 1H), 2.42-2.22 (m, 2H), 2.11 (s, 3H), 1.96 (d, J=8.9 Hz, 2H);

LRMS (ES) m/z 491.1 (M ⁺ +1).

Example 122: Synthesis of Compound 3439, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-N-phenyl-1-propionylpiperidin-4 -carboxamide

N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.112 mmol) obtained in step 4 of Example 1, propionyl chloride (0.015 ml, 0.167 mmol), and triethylamine (0.047 ml, 0.335 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.020 g, 35.6%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 7.89 (dd, J=8.0, 1.5 Hz, 1H), 7.75 (dd, J=9.8, 1.6 Hz, 1H) , 7.56 (t, J=7.6 Hz, 1H), 7.37-7.31 (m, 3H), 6.99 (ddd, J=88.9, 33.1, 28.3 Hz , 3H), 5.04 (s, 2H), 4.49 (s, 1H), 3.74 (s, 1H), 3.16 (s, 1H), 2.73 (s, 1H), 2 .41-2.12 (m, 4H), 1.95 (s, 2H), 1.16 (dd, J=8.9, 6.0 Hz, 3H);

LRMS (ES) m/z 505.3 (M ⁺ +1).

Example 123: Synthesis of Compound 3440, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-1-isobutyryl-N-phenylpiperidin-4 -carboxamide

N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.112 mmol) obtained in step 4 of Example 1, isobutyryl chloride (0.018 ml, 0.167 mmol), and triethylamine (0.047 ml, 0.335 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.020 g, 34.6%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 7.89 (dd, J=8.0, 1.6 Hz, 1H), 7.75 (dd, J=9.8, 1.6 Hz, 1H) , 7.56 (t, J=7.6 Hz, 1H), 7.34 (dd, J=6.9, 3.7 Hz, 3H), 6.99 (ddd, J=90.2, 32 .5, 27.7 Hz, 3H), 5.04 (d, J=9.1 Hz, 2H), 4.52 (d, J=11.0 Hz, 1H), 3.82 (d, J =9.3 Hz, 1H), 3.18 (d, J=14.5 Hz, 1H), 2.85-2.56 (m, 2H), 2.25 (ddd, J=52.7, 39.7, 12.9 Hz, 2H), 1.96 (d, J=10.4 Hz, 2H), 1.14 (dd, J=7.3, 4.9 Hz, 6H);

LRMS (ES) m/z 519.4 (M ⁺ +1).

Example 124: Synthesis of Compound 3441, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-N-phenyl-1-(2, 2,2-trifluoroacetyl)piperidine-4-carboxamide

N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.112 mmol) obtained in step 4 of Example 1, 3,3,3-trifluoropropane anhydride (0.040 g, 0.167 mmol), and triethylamine (0.047 ml, 0.335 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.020 g, 32.9%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 7.89 (dd, J=8.0, 1.6 Hz, 1H), 7.76 (dd, J=9.8, 1.6 Hz, 1H) , 7.55 (t, J=7.6 Hz, 1H), 7.38-7.33 (m, 3H), 7.08-6.79 (m, 3H), 5.04 (d, J =4.7 Hz, 2H), 4.42 (d, J=13.1 Hz, 1H), 3.91 (d, J=13.1 Hz, 1H), 3.29 (t, J=12 .8 Hz, 1H), 2.94 (t, J=12.7 Hz, 1H), 2.46-2.22 (m, 2H), 2.08-1.98 (m, 2H);

LRMS (ES) m/z 546.2 (M ⁺ +1).

Example 125: Synthesis of Compound 3442, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-1-(methylsulfonyl)-N-phenylpiperidine -4-carboxamide

N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.112 mmol) obtained in step 4 of Example 1, methanesulfonyl chloride (0.013 ml, 0.167 mmol), and triethylamine (0.047 ml, 0.335 mmol) were dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.020 g, 34.1%) as a yellow gel .

^1H NMR (400 MHz, CDCl ₃ ) δ 7.90 (dd, J=8.0, 1.6 Hz, 1H), 7.75 (dd, J=9.9, 1.6 Hz, 1H) , 7.56 (t, J=7.6 Hz, 1H), 7.38-7.31 (m, 3H), 7.10-6.79 (m, 3H), 5.05 (s, 2H ), 3.69 (d, J=11.3 Hz, 2H), 2.89-2.78 (m, 2H), 2.75 (s, 3H), 2.57-2.32 (m, 2H), 2.06 (d, J=9.1 Hz, 2H);

LRMS (ES) m/z 527.1 (M ⁺ +1).

Example 126: Synthesis of Compound 3443, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-ethyl-4-fluoro-N -(3-fluorophenyl)piperidine-4-carboxamide

N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-(3-fluorophenyl)piperidine-4-carboxamide 2,2,2-trifluoroacetate (0.200 g, 0.445 mmol) obtained from step 3 of Example 10, acetaldehyde (0.039 g, 0.890 mmol), acetic acid (0.025 ml, 0.445 mmol), and sodium triacetoxyborohydride (0.283 g, 1.335 mmol ) was dissolved in dichloromethane (4 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.080 g, 37.7%) as a white solid colors.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.27 (d, J=1.6 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.37-7.29 (m, 1H), 7.11-6.78 (m, 4H), 5.07 (s, 2H), 2, 86 (s, 2H), 2.43 (dd, J=39.0, 9.5 Hz, 4H), 2.24 (d, J=10.4 Hz, 2H), 2.02 (d, J =18.6 Hz, 2H), 1.12 (t, J=7.2 Hz, 3H);

LRMS (ES) m/z 478.3 (M ⁺ +1).

Example 127: Synthesis of Compound 6890, tert-butyl 3-fluoro-3-((3-fluorophenyl)((5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl )methyl)carbamoyl)azetidine-1-carboxylate

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

6-Methylnicotinohydrazide (2.000 g, 13.230 mmol) obtained in step 1 of Example 6 and imidazole (2.702 g, 39.690 mmol) were dissolved in dichloromethane (5 ml) and trifluoroacetic anhydride (5.606 ml, 39.690 mmol) was added at 0°C and then refluxed for 16 hours. The temperature was then lowered to room temperature to stop the reaction. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The resulting product was filtered and concentrated under reduced pressure to give the title compound (2.650 g, 87.4%) as a yellow solid.

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

2-(6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole (2.650 g, 11.564 mmol) obtained in step 1 was dissolved in 1,2-dichloroethane (100 ml), and at room temperature azobisisobutyronitrile (AIBN, 0.190 g, 1.156 mmol) and 1-bromopyrrolidin-2,5-one (NBS, 2.676 g, 15.033 mmol) and refluxed for 16 hours. The reaction was stopped by lowering the temperature to room temperature. 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 magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 80 g; ethyl acetate/hexane = 15%) and concentrated to give the title compound (0.750 g, 21.1%) as a red solid.

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

2-(6-(Bromomethyl)pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole (0.500 g, 1.623 mmol) obtained in step 2, 3-fluoroaniline (0.271 g, 2.435 mmol ), potassium carbonate (0.336 g, 2.435 mmol), and potassium iodide (0.135 g, 0.812 mmol) were dissolved in N,N-dimethylformamide (50 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of ammonium chloride was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 24 g; ethyl acetate/hexane = 0% to 70%) and concentrated to give the title compound (0.280 g, 51.0%) as a yellow solid.

[Step 4] Synthesis of compound 6890

To a solution in which tert-butyl 3-(chlorocarbonyl)-3-fluoroazetidine-1-carboxylate (0.137 g, 0.576 mmol) obtained in step 1 of Example 14 was dissolved in dichloromethane (20 ml) at room temperature, 3- fluoro-N-((5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)aniline (0.150 g, 0.443 mmol) obtained in step 3, and stirred at the same temperature. Triethylamine (0.185 mL, 1.330 mmol) was added to the reaction mixture and further stirred at the same temperature for 16 hours. The solvent was removed from the reaction mixture under reduced pressure. A saturated aqueous solution of ammonium chloride was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ cartridge, 24 g; ethyl acetate/hexane = 0% to 60%) and concentrated to give the title compound (0.150 g, 62.7%) as a yellow solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.30 (d, J=2.1 Hz, 1H), 8.41 (dt, J=7.8, 3.9 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.37 (dd, J=14.7, 7.6 Hz, 1H), 7.09 (t, J=10.5 Hz, 3H), 5 .10 (s, 2H), 4.63-4.33 (m, 2H), 3.83 (d, J=45.0 Hz, 2H), 1.44 (s, 9H).

Example 128: Synthesis of compound 6891, 3-fluoro-N-(3-fluorophenyl)-1-methyl-N-((5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin- 2-yl)methyl)azetidine-3-carboxamide

[Step 1] Synthesis of 3-fluoro-N-(3-fluorophenyl)-N-((5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl) Azetidine-3-carboxamide 2,2,2-trifluoroacetate

Tert-butyl 3-fluoro-3-((3-fluorophenyl)((5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)carbamoyl)azetidin- 1-carboxylate (0.080 g, 0.148 mmol) obtained in step 4 of Example 127 and trifluoroacetic acid (0.227 ml, 2.966 mmol) were dissolved in dichloromethane (5 ml) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the title compound (0.065 g, 99.8%) was obtained as a yellow gel.

[Step 2] Synthesis of compound 6891

3-Fluoro-N-(3-fluorophenyl)-N-((5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.070 g, 0.159 mmol) obtained in step 1, formaldehyde (0.010 g, 0.319 mmol), acetic acid (0.009 ml, 0.159 mmol) and sodium triacetoxyborohydride (0.101 g, 0.478 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 bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The resulting product was 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 (0.050 g, 69.2%) as a yellow gel.

^1H NMR (400 MHz, CDCl ₃ ) δ 9.28 (d, J=2.0 Hz, 1H), 8.40 (dd, J=8.2, 2.2 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.39-7.31 (m, 1H), 7.13-7.00 (m, 3H), 5.10 (s, 2H), 3, 68 (dd, J=21.6, 9.4 Hz, 2H), 3.25 (dd, J=21.5, 8.8 Hz, 2H), 2.37 (s, 3H);

LRMS (ES) m/z 453.6 (M ⁺ +1).

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

<Experimental Example 1> HDAC Enzyme Activity Inhibition Assay (in vitro)

To confirm the selectivity of the compounds represented by Chemical Formula I of the present invention for HDAC6 in the HDAC1 and HDAC6 enzyme activity inhibition experiments, a comparison experiment was conducted using a compound 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). To test HDAC1 enzyme activity, 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 to a 96-well plate, 0.3 μg of enzyme and 10 μM of 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 plate reader (Flexstation 3, Molecular Device). HDAC6 enzymes were tested using recombinant human HDAC6 (382180) from Calbiochem Inc., according to the same protocol as the HDAC1 enzyme activity test method. Regarding the final outcome values, the corresponding ICso values were calculated using GraphPad Prism 4.0 (Table 2).

As shown in Table 2 above, from the results of the activity inhibition assay for HDAC1 and HDAC6, it was found that the 1,3,4-oxadiazole derivative of the present invention, its optical isomer or a pharmaceutically acceptable salt exhibits selective HDAC6 inhibitory activity that is from about 30 to approximately 2906 times higher than HDAC1.

Experimental Example 2> Analysis of the effect of HD6C6-specific inhibitor on mitochondrial axonal transport (in vitro)

The effect of a specific HDAC6 inhibitor on mitochondrial axonal transport was analyzed. In particular, to confirm whether the compound represented by Chemical Formula I according to the present invention selectively inhibits the activity of HDAC6 to 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 amyloid-beta N peptide fragments. After 24 hours, the compound was treated on day 8 of in vitro culture, and after 3 hours, treated with MitoTracker Red CMXRos (Life Technologies, New York, USA) for the last 5 minutes to stain mitochondria. For 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 within 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 improved the speed of mitochondrial axonal transport.

Claims (53)

1. A 1,3,4-oxadiazole derivative represented by the following chemical formula I, or a pharmaceutically acceptable salt thereof: [Chemical formula I] , where in the above chemical formula I Z ₁ - Z ₄ each independently represents N, CH or CX, where Z ₁ - Z ₄ cannot represent three or more N at the same time; L, L ¹ or L ² are each independently -(C ₀ -C ₂ alkylene)-; R ₁ represents -CX ₂ H or -CX ₃ ; R ₂ represents C ₆ aryl, wherein at least one -H of C ₆ aryl can each be independently substituted with -X, -OH, -(C ₁ -C ₄ alkyl) or -O(C ₁ -C ₄ alkyl ); R represents or ; R _a - R _d are each independently -H or -(C ₁ -C ₄ alkyl); R' and Rʺ each independently represent -H, -(C ₁ -C ₄ alkyl), -(C ₃ -C ₇ cycloalkyl), -(C ₂ -C ₆ heterocycloalkyl) containing one O atom or one S atom in ring, -(C ₁ -C ₄ alkyl)-(C ₃ -C ₇ cycloalkyl), -(C ₁ -C ₄ alkyl)-(C ₂ -C ₆ heterocycloalkyl), containing one O atom in the ring, -C( =O)-(C ₁ -C ₄ alkyl), -C(=O)-(C ₃ -C ₇ cycloalkyl), -C(=O)-O(C ₁ -C ₄ alkyl) or -S(= O) ₂ -(C ₁ -C ₄ alkyl), wherein at least one -H of -(C ₁ -C ₄ alkyl) or -C(=O)-(C ₁ -C ₄ alkyl) may be substituted by -X, -OH, -N(CH ₃ ) ₂ or -O(C ₁ -C ₄ alkyl) and at least one -H on the y -(C ₃ -C ₇ cycloalkyl) ring may be substituted by -X , -OH or -(C ₁ -C ₄ alkyl); m or n are each independently 1, 2 or 3; And X represents F, Cl, Br or I. 2. A 1,3,4-oxadiazole derivative represented by chemical formula I, or a pharmaceutically acceptable salt thereof according to claim 1, wherein in the above chemical formula I Z ₁ - Z ₄ each independently represents N, CH or CX, where Z ₁ - Z ₄ cannot represent two or more N at the same time; L, L ¹ or L ² are each independently -(C ₀ -C ₂ alkylene)-; R ₁ represents -CX ₂ H or -CX ₃ ; R ₂ is C ₆ aryl, wherein at least one -H of C ₆ aryl may each independently be substituted by -X, -OH, -(C ₁ -C ₄ alkyl) or -O(C ₁ -C ₄ alkyl); R represents or ; R _a - R _d are each independently -H or -(C ₁ -C ₄ alkyl); R' and Rʺ each independently represent -H, -(C ₁ -C ₄ alkyl), -(C ₃ -C ₇ cycloalkyl), -(C ₂ -C ₆ heterocycloalkyl) containing one O atom or one S atom in ring, -(C ₁ -C ₄ alkyl)-(C ₃ -C ₇ cycloalkyl), -(C ₁ -C ₄ alkyl)-(C ₂ -C ₆ heterocycloalkyl), containing one O atom in the ring, -C( =O)-(C ₁ -C ₄ alkyl), -C(=O)-(C ₃ -C ₇ cycloalkyl), -C(=O)-O(C ₁ -C ₄ alkyl) or -S(= O) ₂ -(C ₁ -C ₄ alkyl), wherein at least one -H of -(C ₁ -C ₄ alkyl) or -C(=O)-(C ₁ -C ₄ alkyl) may be substituted by -X, -OH, -N(CH ₃ ) ₂ or -O(C ₁ -C ₄ alkyl) and at least one -H on the y -(C ₃ -C ₇ cycloalkyl) ring may be substituted by -X , -OH or -(C ₁ -C ₄ alkyl); m or n are each independently 1, 2 or 3; And X represents F, Cl or Br. 3. A 1,3,4-oxadiazole derivative represented by chemical formula I, or a pharmaceutically acceptable salt thereof according to claim 2, wherein in the above chemical formula I Z ₁ - Z ₄ each independently represents N, CH or CX, where Z ₁ - Z ₄ cannot represent two or more N at the same time; L represents -(C ₁ alkylene)-; L ¹ or L ² each independently represents -(C ₀ alkylene)-; R ₁ represents -CX ₂ H or -CX ₃ ; R ₂ represents C ₆ aryl, wherein at least one -H of C ₆ aryl can each independently be substituted by -X; R represents or ; R _a - R _d are each independently -H; R' and Rʺ each independently represent -H, -(C ₁ -C ₄ alkyl), -(C ₃ -C ₇ cycloalkyl), -(C ₂ -C ₆ heterocycloalkyl) containing one O atom or one S atom in ring, -(C ₁ -C ₄ alkyl)-(C ₃ -C ₇ cycloalkyl), -(C ₁ -C ₄ alkyl)-(C ₂ -C ₆ heterocycloalkyl), containing one O atom in the ring, -C( =O)-(C ₁ -C ₄ alkyl), -C(=O)-(C ₃ -C ₇ cycloalkyl), -C(=O)-O(C ₁ -C ₄ alkyl) or -S(= O) ₂ -(C ₁ -C ₄ alkyl), wherein at least one -H of -(C ₁ -C ₄ alkyl) or -C(=O)-(C ₁ -C ₄ alkyl) may be substituted by -X, -OH, -N(CH ₃ ) ₂ or -O(C ₁ -C ₄ alkyl) and at least one -H on the y -(C ₃ -C ₇ cycloalkyl) ring may be substituted by -X ; m or n are each independently 1 or 2; And X represents F or Cl. 4. A 1,3,4-oxadiazole derivative represented by chemical formula I, or a pharmaceutically acceptable salt thereof according to claim 3, wherein in the above chemical formula I Z ₁ - Z ₄ each independently represents N, CH or CF, where Z ₁ - Z ₄ cannot represent two or more N at the same time; L represents -(C ₁ alkylene)-; L ¹ or L ² each independently represents -(C ₀ alkylene)-; R ₁ represents -CF ₂ H or -CF ₃ ; R ₂ represents C ₆ aryl, wherein at least one -H of the C ₆ aryl can each independently be substituted by -F; R represents or ; R _a - R _d are each independently -H; R' represents -H, -(C ₁ -C ₄ alkyl), -(C ₃ -C ₇ cycloalkyl), -(C ₂ -C ₆ heterocycloalkyl), containing one O atom or one S atom in the ring, -( C ₁ -C ₄ alkyl)-(C ₃ -C ₇ cycloalkyl), -(C ₁ -C ₄ alkyl)-(C ₂ -C ₆ heterocycloalkyl), containing one O atom in the ring, -C(=O)- (C ₁ -C ₄ alkyl), -C(=O)-(C ₃ -C ₇ cycloalkyl), -C(=O)-O(C ₁ -C ₄ alkyl) or -S(=O) ₂ - (C ₁ -C ₄ alkyl), wherein at least one -H of -(C ₁ -C ₄ alkyl) or -C(=O)-(C ₁ -C ₄ alkyl) may be substituted by -X, -OH, -N(CH ₃ ) ₂ or -O(C ₁ -C ₄ alkyl) and at least one -H on the -(C ₃ -C ₇ cycloalkyl) ring may be substituted by -X; Rʺ represents -(C ₁ -C ₄ alkyl), -(C ₃ -C ₇ cycloalkyl) or -(C ₂ -C ₆ heterocycloalkyl) containing one O atom in the ring; m or n are each independently 1 or 2; And X represents F or Cl. 5. The 1,3,4-oxadiazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is any of the compounds listed in the following table: Etc. Conn. Structure Etc. Conn. Structure 1 2865 2 2866 3 2867 4 2868 5 2869 6 2951 7 2952 8 2953 9 2954 10 2969 eleven 2970 12 2971 13 2972 14 2973 15 2974 16 2975 17 2976 18 2995 19 2996 20 2997 21 2998 22 2999 23 3000 24 3001 25 3002 26 3003 27 3004 28 3005 29 3006 thirty 3007 31 3047 32 3048 33 3049 34 3050 35 3051 36 3052 37 3053 38 3054 39 3055 40 3090 41 3091 42 3092 43 3093 44 3094 45 3095 46 3096 47 3097 48 3098 49 3105 50 3106 51 3107 52 3108 53 3109 54 3110 55 3111 56 3112 57 3113 58 3114 59 3115 60 3152 61 3153 62 3154 63 3155 64 3156 65 3157 66 3158 67 3159 68 3160 69 3161 70 3162 71 3163 72 3164 73 3165 74 3166 75 3167 76 3168 77 3169 78 3170 79 3171 80 3172 81 3216 82 3217 83 3218 84 3219 85 3220 86 3221 87 3222 88 3223 89 3224 90 3389 91 3390 92 3391 93 3392 94 3393 95 3394 96 3395 97 3396 98 3397 99 3398 100 3399 101 3400 102 3401 103 3402 104 3403 105 3404 106 3405 107 3406 108 3407 109 3408 110 3409 111 3410 112 3429 113 3430 114 3431 115 3432 116 3433 117 3434 118 3435 119 3436 120 3437 121 3438 122 3439 123 3440 124 3441 125 3442 126 3443 127 6890 128 6891 6. 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. 1-5 and a pharmaceutically acceptable carrier. 7. The pharmaceutical composition according to claim 6, which is used for the prevention or treatment of diseases mediated by histone deacetylase 6, and at the same time these 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. 8. 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. 1-5. 9. The use of a compound represented by chemical formula I, or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-5 to obtain a drug for inhibiting histone deacetylase 6.