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

Abstract

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

Description

Technical Field

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

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

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

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

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

[0006] Meanwhile, it has been reported that selective class II HDAC inhibition may not show the toxicity seen in class I HDAC inhibition, and if selective class II HDAC inhibitors are developed, side effects (such as toxicity, etc.) caused by non-selective HDAC inhibition may be resolved, and thus selective HDAC inhibitors have the potential to be developed as effective therapeutic agents for various diseases (Matthias et al., Mol. Cell. Biol. 2008, 28, 1688-1701).

[0007] HDAC6 (one of class IIb HDACs) is mainly present in the cytoplasm and is known to be involved in the deacetylation of many non-histone substrates including tubulin (HSP90, cortactin, etc.) (Yao et al., Mol. Cell 2005, 18, 601-607). HDAC6 has two catalytic domains, and the C-terminus of the zinc finger domain can bind to ubiquitinated proteins. Since HDAC6 has a large amount of non-histone as a substrate, it is known that it plays an important role in various diseases such as cancer, inflammatory diseases, autoimmune diseases, nervous system diseases and neurodegenerative diseases (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).

[0008] A common structural feature of various HDAC inhibitors is that they are composed of a cap group, a linker group and a zinc binding group (ZBG), as shown in the structure of vorinostat below. Many researchers have studied the inhibitory activity and selectivity of enzymes by structural modification of cap groups and linker groups. Among these groups, it is known that zinc binding groups play a more important role in enzyme inhibitory activity and selectivity (Wiest et al., J.Org.Chem.2013 78:5051-5065; Methot et al., Bioorg.Med.Chem.Lett.2008,18,973-978).

[0009]

[0010] Most zinc-binding groups are hydroxamic acid or benzamide, and among them, hydroxamic acid derivatives exhibit strong HDAC inhibition, but have problems such as low bioavailability and severe off-target activity, etc. Since benzamide contains aniline, there is a problem that toxic metabolites may be caused in vivo (Woster et al., Med. Chem. Commun. 2015, published online).

[0011] Therefore, in order to treat cancer, inflammatory diseases, autoimmune diseases, neurological diseases, neurodegenerative disorders, etc., it is necessary to develop a selective HDAC6 inhibitor with a zinc-binding group, which has improved bioavailability without side effects, unlike non-selective inhibitors with side effects. Summary of the invention

[0012] Technical issues

[0013] An object of the present invention is to provide a 1,3,4-oxadiazole derivative compound having selective histone deacetylase 6 (HDAC6) inhibitory activity, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

[0014] Another object of the present invention is to provide a pharmaceutical composition comprising a 1,3,4-oxadiazole derivative compound having selective HDAC6 inhibitory activity, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

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

[0016] Another object of the present invention is to provide a pharmaceutical composition comprising the compound for preventing or treating diseases mediated by histone deacetylase 6 (HDAC6), including infectious diseases; neoplasms; endocrine, nutritional and metabolic diseases; mental and behavioral disorders; nervous system diseases; eye and appendage diseases; circulatory system diseases; respiratory system diseases; digestive system diseases; skin and subcutaneous tissue diseases; musculoskeletal and connective tissue diseases; or congenital malformations, changes and chromosomal abnormalities.

[0017] Another object of the present invention is to provide use of the compound for preparing a medicament for preventing or treating a disease mediated by HDAC6.

[0018] Another object of the present invention is to provide a method for preventing or treating HDAC6-mediated diseases, which comprises administering a therapeutically effective amount of a composition comprising the compound as described above.

[0019] Solution to the problem

[0020] The present inventors have discovered 1,3,4-oxadiazole derivative compounds having histone deacetylase 6 (HDAC6) inhibitory activity, which are useful for inhibiting or treating HDAC6-mediated diseases, and have completed the present invention.

[0021] 1,3,4-Oxadiazole derivative compounds

[0022] In one general aspect, the present invention provides a 1,3,4-oxadiazole derivative compound represented by the following chemical formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[0023] [Chemical Formula I]

[0024]

[0025] In the above chemical formula I,

[0026] Z 1 To Z 4 are each independently N, CH or CX, wherein Z 1 To Z 4 It cannot be three or more Ns at the same time;

[0027] L, L 1 or L 2 Each independently is -(C 0 -C 2 Alkylene)-;

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

[0029] R2 is an aryl or heteroaryl group, wherein at least one -H of the aryl or heteroaryl group can be independently replaced by -X, -OH, -(C 1 -C 4 alkyl) or -O(C 1 -C 4 Alkyl) substituted;

[0030] R is

[0031] R a To R d are independently -H or -(C 1 -C 4 alkyl);

[0032] 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), where -(C 1 -C 4 alkyl) or -C(=O)-(C 1 -C 4 At least one -H of the alkyl group may be replaced by -X, -OH, -N(CH 3 ) 2 or -O(C 1 -C 4 alkyl) substituted, and -(C 3 -C 7 Cycloalkyl), -(C 2 -C 6 Heterocycloalkyl), -(C 1 -C 4Alkyl)-(C 3 -C 7 Cycloalkyl), -(C 1 -C 4 Alkyl)-(C 2 -C 6 heterocycloalkyl) or -C(=O)-(C 3 -C 7 At least one -H of the cycloalkyl) ring may be replaced by -X, -OH or -(C 1 -C 4 Alkyl) substituted;

[0033] m or n are each independently 1, 2 or 3; and

[0034] X is F, Cl, Br or I.

[0035] Furthermore, according to one embodiment of the present invention, in the above Chemical Formula I,

[0036] Z 1 To Z 4 are each independently N, CH or CX, wherein Z 1 To Z 4 It cannot be two or more N at the same time;

[0037] L, L 1 or L 2 Each independently is -(C 0 -C 2 Alkylene)-;

[0038] R 1 Yes-CH 2 X or -CX 3 ;

[0039] R 2 is an aryl group, wherein at least one -H of the aryl group can be independently replaced by -X, -OH, -(C 1 -C 4 alkyl) or -O(C 1 -C 4 Alkyl) substituted;

[0040] R is

[0041] R a To R d Each is independently -H or -(C 1 -C 4 alkyl);

[0042] R' and R" are each independently -H, -(C 1 -C 4 Alkyl), -(C3 -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), where -(C 1 -C 4 alkyl) or -C(=O)-(C 1 -C 4 At least one -H of the alkyl group may be replaced by -X, -OH, -N(CH 3 ) 2 or -O(C 1 -C 4 alkyl) substituted, and -(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 At least one -H of the cycloalkyl) ring may be replaced by -X, -OH or -(C 1 -C 4 Alkyl) substituted;

[0043] m or n are each independently 1, 2 or 3; and

[0044] X is F, Cl or Br.

[0045] Furthermore, according to one embodiment of the present invention, in the above Chemical Formula I,

[0046] Z 1 To Z 4 are each independently N, CH or CX, wherein Z 1 To Z 4 It cannot be two or more N at the same time;

[0047] L is -(C 1 Alkylene)-;

[0048] L 1 or L 2 Each independently is -(C 0 Alkylene)-;

[0049] R 1 Yes-CH 2 X or -CX 3 ;

[0050] R 2 is an aryl group, wherein at least one -H of the aryl group may be independently substituted by -X;

[0051] R is

[0052] R a To R d Each independently is -H;

[0053] 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), where -(C 1 -C 4alkyl) or -C(=O)-(C 1 -C 4 At least one -H of the alkyl group may be replaced by -X, -OH, -N(CH 3 ) 2 or -O(C 1 -C 4 alkyl) substituted, and -(C 3 -C 7 At least one -H of the cycloalkyl) ring may be substituted with -X;

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

[0055] X is F or Cl.

[0056] Furthermore, according to one embodiment of the present invention, in the above Chemical Formula I,

[0057] Z 1 To Z 4 are each independently N, CH or CF, wherein Z 1 To Z 4 It cannot be two or more N at the same time;

[0058] L is -(C 1 Alkylene)-;

[0059] L 1 or L 2 Each independently is -(C 0 Alkylene)-;

[0060] R 1 Yes - CF 2 H or -CF 3 ;

[0061] R 2 is an aryl group, wherein at least one -H of the aryl group may be independently substituted with -F;

[0062] R is

[0063] R a To R d Each independently is -H;

[0064] R' is -H, -(C 1 -C 4 Alkyl), -(C 3 -C 7 Cycloalkyl), -(C 2 -C 6 Heterocycloalkyl), -(C 1 -C 4 Alkyl)-(C 3 -C7 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), where -(C 1 -C 4 alkyl) or -C(=O)-(C 1 -C 4 At least one -H of the alkyl group may be replaced by -X, -OH, -N(CH 3 ) 2 or -O(C 1 -C 4 alkyl) substituted, and -(C 3 -C 7 At least one -H of the cycloalkyl) ring may be substituted with -X;

[0065] R" is -(C 1 -C 4 Alkyl), -(C 3 -C 7 Cycloalkyl) or -(C 2 -C 6 Heterocycloalkyl);

[0066] m or n are each independently 1 or 2; and

[0067] X is F or Cl.

[0068] In addition, according to one embodiment of the present invention, the specific compounds represented by Chemical Formula I of the present invention are shown in the following Table 1:

[0069] [Table 1]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078] In the present invention, pharmaceutically acceptable salts refer to salts commonly used in the pharmaceutical industry, such as inorganic ion salts prepared from calcium, potassium, sodium and magnesium, inorganic acid salts prepared from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid and sulfuric acid, etc.; organic acid salts prepared from acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc.; sulfonates prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid, etc.; amino acid salts prepared from glycine, arginine, lysine, etc.; and amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc., but the types of salts mentioned in the present invention are not limited to these salts listed above.

[0079] The compounds represented by chemical formula I of the present invention may contain one or more asymmetric carbons, thereby being able to exist as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. These isomers can be separated using conventional techniques, for example, by distribution (such as by column chromatography, HPLC, etc.) by the compounds represented by chemical formula I. Alternatively, the stereoisomers of each of the compounds represented by chemical formula I can be stereoselectively synthesized using optically pure starting materials and / or reagents with known arrangements.

[0080] Method for preparing 1,3,4-oxadiazole derivative compounds

[0081] The present invention provides a method for preparing a 1,3,4-oxadiazole derivative compound represented by Chemical Formula I, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

[0082] A preferred method for preparing the 1,3,4-oxadiazole derivative compound represented by Chemical Formula I according to the present invention, its optical isomer or a pharmaceutically acceptable salt thereof is the same as the following Reaction Schemes 1 and 2, which also include preparation methods modified at a level obvious to those skilled in the art.

[0083] [Reaction Scheme 1]

[0084]

[0085] [Reaction Scheme 1] shows a method for synthesizing a compound having an α-fluoroamide structure. First, compound 1-1 is reacted with hydrazine to synthesize hydrazide compound 1-2. A cyclization reaction with difluoroacetic anhydride or trifluoroacetic anhydride is performed to synthesize compound 1-3, followed by a bromination reaction to synthesize compound 1-4. Compound 1-5 is synthesized by reacting with aniline into which a substituent is introduced. Compound 1-6 is synthesized by reacting oxalyl chloride with a carboxylic acid into which fluorine is introduced at the α position, and then reacting it with compound 1-5 to synthesize compound 1-7. Compound 1-8 from which a protecting group is removed under acid conditions is synthesized, and the title compound 1-9 is synthesized by introducing various functional groups.

[0086] The compounds prepared by the above reaction scheme are 2865, 2866, 2867, 2868, 2869, 2951, 2952, 2953, 2954, 2969, 2970, 2971, 2972, 2973, 2974, 2975, 2976, 2995, 2996, 2997, 2998, 2999, 3000, 3001, 3002, 3003, 3004, 3005, 3006, 3007, 3047, 3048, 3049, 3050, 3051, 3052, 3053, 3054, 3055, 3090, 3091, 3092, 3093, 3094, 3095, 3096, 3097, 3098, 3152, 3153, 3154, 3155, 3156, 3157, 3158, 3159, 3160, 3161, 3162, 3163, 3164, 3165, 3166, 3167, 3168, 3169, 3170, 3171, 3172, 3216, 3217, 3218, 3429, 3430, 3431, 3432, 3433, 3434, 3435, 3436, 3437, 3438, 3439, 3440, 3441, 3442, 3443, 6890, and 6891.

[0087] [Reaction Scheme 2]

[0088]

[0089] [Reaction Scheme 2] also shows a method for synthesizing a compound having an α-fluoroamide 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 from which a protecting group is removed under acid conditions is synthesized, and the title compound 2-3 is synthesized by introducing various functional groups.

[0090] Compounds prepared by the above reaction scheme are 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.

[0091] Compositions containing 1,3,4-oxadiazole derivative compounds, uses thereof, and methods of treatment using the same

[0092] The present invention provides a pharmaceutical composition for preventing or treating a disease mediated by histone deacetylase 6, wherein the pharmaceutical composition contains a compound represented by the following chemical formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient:

[0093] [Chemical Formula I]

[0094]

[0095] Formula I is the same as defined above.

[0096] The pharmaceutical composition of the present invention exhibits a significant effect in preventing or treating diseases mediated by histone deacetylase 6 by selectively inhibiting histone deacetylase 6.

[0097] Diseases mediated by histone deacetylase 6 include infectious diseases, such as prion diseases; neoplasms, such as benign tumors (e.g., myelodysplastic syndrome) or malignant tumors (e.g., multiple myeloma, lymphoma, leukemia, lung cancer, colorectal cancer, colon cancer, prostate cancer, urothelial cancer, breast cancer, melanoma, skin cancer, liver cancer, brain cancer, stomach cancer, ovarian cancer, pancreatic cancer, head and neck cancer, oral cancer, or glioma); endocrine, nutritional and metabolic diseases, such as Wilson's disease, amyloidosis, or diabetes; mental and behavioral disorders, such as depression or Rett syndrome; nervous system diseases, such as central nervous system atrophy (e.g., Huntington's disease, spinal muscular atrophy (SMA), spinocerebellar ataxia (SCA)), neurodegenerative diseases (e.g., Alzheimer's disease), movement disorders (e.g., Parkinson's disease), and leukemia. disease), neuropathy (e.g., hereditary neuropathy (Charcot-Marie-Tooth disease), sporadic neuropathy, inflammatory neuropathy, drug-induced neuropathy), motor neuropathy (e.g., amyotrophic lateral sclerosis (ALS)), or central nervous system demyelination (e.g., multiple sclerosis (MS)); eye and appendage diseases, such as uveitis; circulatory system diseases, such as atrial fibrillation, stroke, etc.; respiratory system diseases, such as asthma; digestive system diseases, such as alcoholic liver disease, inflammatory bowel disease, Crohn's disease, ulcerative bowel disease, etc.; skin and subcutaneous tissue diseases, such as psoriasis; musculoskeletal and connective tissue diseases, such as rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus (SLE), etc.; or congenital malformations, changes and chromosomal abnormalities, such as autosomal dominant polycystic kidney disease, and also include symptoms or diseases associated with abnormal histone deacetylase function.

[0098] The pharmaceutically acceptable salts are the same as described above in terms of the pharmaceutically acceptable salts of the compounds represented by Chemical Formula I of the present invention.

[0099] In addition to the compound represented by chemical formula I, its optical isomer or its pharmaceutical salt, the pharmaceutical composition of the present invention can also include one or more pharmaceutical carriers for administration. Pharmaceutical carriers can be used by mixing saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components, and if necessary, other conventional additives such as antioxidants, buffers, antibacterial agents, etc. can also be added. In addition, injectable preparations (such as aqueous solutions, suspensions, emulsions, etc.), pills, capsules, granules or tablets can be prepared by further adding diluents, dispersants, surfactants, adhesives and lubricants. Therefore, the composition of the present invention can be a patch, a liquid, a pill, a capsule, a granule, a tablet, a suppository, etc. These preparations can be prepared by the conventional methods used for preparations in the art or by the method disclosed in Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton PA, and various preparations can be formulated according to corresponding diseases or ingredients.

[0100] The composition of the present invention can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage range varies depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate and disease severity, etc. The daily dose of the compound represented by Chemical Formula I of the present invention can be about 1 to 1000 mg / kg, preferably 5 to 100 mg / kg, and can be administered once a day or divided into several doses a day.

[0101] In addition to the above-mentioned compound represented by Chemical Formula I, its optical isomers or pharmaceutically acceptable salts thereof, the pharmaceutical composition of the present invention may further comprise one or more active ingredients exhibiting the same or similar pharmaceutical effects.

[0102] The present invention provides a method for preventing or treating a disease mediated by histone deacetylase 6, comprising administering a therapeutically effective amount of a compound represented by Chemical Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0103] The term "therapeutically effective amount" used in the present invention refers to an amount of the compound represented by Chemical Formula I that is effective for preventing or treating a disease mediated by histone deacetylase 6.

[0104] In addition, the present invention provides a method for selectively inhibiting HDAC6 by administering a compound represented by Chemical Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof to mammals including humans.

[0105] The method for preventing or treating a disease mediated by histone deacetylase 6 of the present invention also includes administering a compound represented by chemical formula I before the onset of symptoms to treat the disease itself, and to suppress or avoid its symptoms. In the management of the disease, the preventive or therapeutic dose of a specific active ingredient will vary according to the characteristics and severity of the disease or condition and the route of administration of the active ingredient. The dosage and frequency of administration will vary according to the age, weight and response of the individual patient. Taking these factors into account, it is natural that a suitable dosage regimen can be easily selected by a person of ordinary skill in the art. In addition, the method for preventing or treating a disease mediated by histone deacetylase 6 of the present invention can also include administering a therapeutically effective amount of another activating agent that can be used to treat the disease together with the compound represented by chemical formula I, wherein the other activating agent can show a synergistic or auxiliary effect together with the compound represented by chemical formula I.

[0106] The present invention also aims to provide the use of the compound represented by the above chemical formula I, its optical isomer or its pharmaceutically acceptable salt for preparing a drug for treating diseases mediated by histone deacetylase 6. The compound represented by the above chemical formula I for preparing the drug can be mixed with an acceptable adjuvant, diluent, carrier, etc., and can be prepared into a composite preparation together with other active agents to have a synergistic effect of the active ingredients.

[0107] Matters mentioned in the uses, compositions and methods of treatment of the present invention are equally applicable, as long as they are not inconsistent with each other.

[0108] Advantageous Effects of the Invention

[0109] The compound represented by the chemical formula I, its optical isomer or a pharmaceutically acceptable salt thereof can selectively inhibit histone deacetylase 6 (HDAC6), thereby having a significantly excellent preventive or therapeutic effect on HDAC6-mediated diseases. DETAILED DESCRIPTION

[0110] Hereinafter, the present invention will be described in more detail through examples and experimental examples. However, these examples and the like are merely examples of the present invention, and the scope of the present invention is not limited thereto.

[0111] Preparation of 1,3,4-oxadiazole derivatives

[0112] A specific method for preparing the compound represented by Chemical Formula I is shown below.

[0113] 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

[0114] [Step 1] Synthesis of N-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-fluorobenzyl)aniline

[0115]

[0116] 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) were 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 obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 80 g column; ethyl acetate / hexane = 5% to 50%) and concentrated to obtain the title compound (1.900 g, 55.4%) as a colorless oil.

[0117] [Step 2] Synthesis of tert-butyl 4-(chlorocarbonyl)-4-fluoropiperidine-1-carboxylate

[0118]

[0119] 1-(tert-Butyloxycarbonyl)-4-fluoropiperidine-4-carboxylic acid (1,000 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, 0.404 mmol) were added at 0° C. and stirred at room temperature for 2 hours. After the solvent was removed from the reaction mixture under reduced pressure, the title compound (1.070 g, 99.6%) was obtained as a colorless oil.

[0120] [Step 3] Synthesis of 4-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)(phenyl)amino (formyl)-4-fluoropiperidin-1-carboxylic acid tert-butyl ester

[0121]

[0122] To a solution in which N-(4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-2-fluorobenzyl)aniline (0.900 g, 2.819 mmol) and triethylamine (1.179 mL, 8.456 mmol) prepared in step 1 were dissolved in dichloromethane (35 mL) at room temperature, 4-(chlorocarbonyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester (0.974 g, 3.664 mmol) prepared in step 2 was added and stirred at the same temperature for 16 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 40 g column; ethyl acetate / hexanes = 5% to 35%) and concentrated to afford the title compound (0.570 g, 36.9%) as a foamy solid.

[0123] [Step 4] Synthesis of compound 2865

[0124]

[0125] 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) prepared 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.

[0126] 1 H NMR(400MHz,MeOD)δ7.91(m,1H),7.76(m,1H),7.60(m,1H),7.36-7.71(m,6 H),5.08(s,2H),3.11(m,2H),2.84(m,2H),2.44-2.27(m,2H),2.04(m,2H);

[0127] LRMS (ES) m / z 449.4 (M + +1).

[0128] Example 2: Synthesis of Compound 2866, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-1-methyl-N-phenylpiperidine-4-carboxamide

[0129]

[0130] N-(4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-2-fluorobenzyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2-trifluoroacetate (0.070 g, 0.124 mmol), paraformaldehyde (0.007 g, 0.249 mmol) and acetic acid (0.007 mL, 0.124 mmol) prepared in step 4 of Example 1 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 obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 4 g column; methanol / dichloromethane = 0% to 10%) and concentrated to afford the title compound (0.025 g, 43.4%) as a foamy solid.

[0131] 1 H NMR (400 MHz, CDCl 3 )δ7.89(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);

[0132] LRMS (ES) m / z 463.6 (M + +1).

[0133] Example 3: Synthesis of Compound 2867, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-ethyl-4-fluoro-N-phenylpiperidine-4-carboxamide

[0134]

[0135] N-(4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-2-fluorobenzyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2-trifluoroacetate (0.070 g, 0.124 mmol), acetaldehyde (0.011 g, 0.249 mmol) and acetic acid (0.007 mL, 0.124 mmol) prepared in step 4 of Example 1 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 obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 4 g column; methanol / dichloromethane = 0% to 10%) and concentrated to afford the title compound (0.024 g, 40.5%) as a foamy solid.

[0136] 1 H NMR (400 MHz, CDCl 3 )δ7.89(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);

[0137] LRMS(ES)m / z 477.6(M + +1).

[0138] Example 4: Synthesis of Compound 2868, 1-cyclobutyl-N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-N-phenylpiperidine-4-carboxamide

[0139]

[0140] N-(4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-2-fluorobenzyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2-trifluoroacetate (0.070 g, 0.124 mmol), cyclobutanone (0.019 mL, 0.249 mmol) and acetic acid (0.007 mL, 0.124 mmol) prepared in step 4 of Example 1 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 obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 4 g column; methanol / dichloromethane = 0% to 10%) and concentrated to afford the title compound (0.022 g, 35.2%) as a foamy solid.

[0141] 1 H NMR (400 MHz, CDCl 3 )δ7.89(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);

[0142] LRMS (ES) m / z 503.4 (M + +1).

[0143] Example 5: Synthesis of Compound 2869, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-1-(oxetane-3-yl)-N-phenylpiperidine-4-carboxamide

[0144]

[0145] N-(4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-2-fluorobenzyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2-trifluoroacetate (0.070 g, 0.124 mmol), oxetanes-3-one (0.016 mL, 0.249 mmol) and acetic acid (0.007 mL, 0.124 mmol) prepared in step 4 of Example 1 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 obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 4 g column; methanol / dichloromethane = 0% to 10%) and concentrated to afford the title compound (0.022 g, 35.0%) as a foamy solid.

[0146] 1 H NMR (400 MHz, CDCl 3 )δ7.89(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);

[0147] LRMS (ES) m / z 505.4 (M + +1).

[0148] 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

[0149] [Step 1] Synthesis of 6-methylnicotinic acid hydrazide

[0150]

[0151] A solution of 6-methylnicotinate (25.000 g, 165.377 mmol) and hydrazine monohydrate (40.188 mL, 826.884 mmol) dissolved in ethanol (220 mL) was heated to reflux for 16 hours at room temperature, and then the temperature was lowered to room temperature to terminate the reaction. The solvent was removed from the reaction mixture under reduced pressure. The precipitated solid was filtered, washed with hexane, and dried to obtain the title compound (25.000 g, 100.0%) as a white solid.

[0152] [Step 2] Synthesis of 2-(difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole

[0153]

[0154] 6-Methylnicotinamide hydrazide (15.000 g, 99.226 mmol) and imidazole (20.265 g, 297.678 mmol) prepared in step 1 were dissolved in dichloromethane (250 mL). 2,2-difluoroacetic anhydride (37.008 mL, 297.678 mmol) was added at 0 ° C and heated to reflux for 16 hours, and then the temperature was reduced to room temperature to terminate the reaction. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The obtained product was filtered and concentrated under reduced pressure to obtain the title compound (20.900 g, 99.7%) as a red solid.

[0155] [Step 3] Synthesis of 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0156]

[0157] 2-(Difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole (20.900 g, 98.972 mmol) prepared in step 2 was dissolved in 1,2-dichloroethane (200 mL). Azobisisobutyronitrile (AIBN, 0.813 g, 4.949 mmol) and 1-bromopyrrolidine-2,5-one (NBS, 22.900 g, 128.664 mmol) were added at room temperature and heated to reflux for 16 hours, and then the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 80 g column; ethyl acetate / hexane = 5% to 50%) and concentrated to obtain the title compound (5.400 g, 18.8%) as a red solid.

[0158] [Step 4] Synthesis of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)aniline

[0159]

[0160] 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) prepared 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 obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 80 g column; ethyl acetate / hexane = 5% to 50%) and concentrated to obtain the title compound (1.300 g, 80.1%) as a yellow solid.

[0161] [Step 5] Synthesis of 4-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(benzene tert-Butyl)carbamoyl)-4-fluoropiperidin-1-carboxylate

[0162]

[0163] To a solution in which N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)aniline (0.700 g, 2.316 mmol) and triethylamine (0.968 mL, 6.947 mmol) prepared in step 4 were dissolved in dichloromethane (35 mL) at room temperature, 4-(chlorocarbonyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester (0.861 g, 3.242 mmol) prepared in step 2 of Example 1 was added and stirred at the same temperature for 16 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 40 g column; ethyl acetate / hexanes = 5% to 35%) and concentrated to afford the title compound (0.400 g, 32.5%) as a foamy solid.

[0164] [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

[0165]

[0166] 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) prepared 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.

[0167] [Step 7] Synthesis of compound 2951

[0168]

[0169] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2-trifluoroacetate (0.075 g, 0.138 mmol), paraformaldehyde (0.008 g, 0.275 mmol) and acetic acid (0.008 mL, 0.138 mmol) prepared in step 6 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 for 16 hours at the same temperature. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 4 g column; methanol / dichloromethane = 0% to 10%) and concentrated to afford the title compound (0.023 g, 37.6%) as a foamy solid.

[0170] 1 H NMR (400 MHz, CDCl 3 )δ9.23(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);

[0171] LRMS (ES) m / z 446.4 (M + +1).

[0172] 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

[0173]

[0174] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2-trifluoroacetate (0.075 g, 0.138 mmol), acetone (0.020 mL, 0.275 mmol) and acetic acid (0.008 mL, 0.138 mmol) prepared in step 6 of Example 6 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 obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 4 g column; methanol / dichloromethane = 0% to 10%) and concentrated to afford the title compound (0.018 g, 27.6%) as a foamy solid.

[0175] 1 H NMR (400 MHz, CDCl 3 )δ9.24(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);

[0176] LRMS(ES)m / z 474.4(M + +1).

[0177] 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

[0178]

[0179] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2-trifluoroacetate (0.075 g, 0.138 mmol), cyclobutanone (0.021 mL, 0.275 mmol) and acetic acid (0.008 mL, 0.138 mmol) prepared in step 6 of Example 6 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 obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 4 g column; methanol / dichloromethane = 0% to 10%) and concentrated to afford the title compound (0.022 g, 33.0%) as a foamy solid.

[0180] 1 H NMR (400 MHz, CDCl 3 )δ9.24(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);

[0181] LRMS (ES) m / z 486.4 (M + +1).

[0182] 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

[0183]

[0184] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-phenylpiperidine-4-carboxamide 2,2,2-trifluoroacetate (0.075 g, 0.138 mmol), oxetanes-3-one (0.018 mL, 0.275 mmol) and acetic acid (0.008 mL, 0.138 mmol) prepared in step 6 of Example 6 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 obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 4 g column; methanol / dichloromethane = 0% to 10%) and concentrated to afford the title compound (0.024 g, 35.8%) as a foamy solid.

[0185] 1 H NMR (400 MHz, CDCl 3 )δ9.24(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);

[0186] LRMS (ES) m / z 488.5 (M + +1).

[0187] Example 10: Synthesis of Compound 2969, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-(3-fluorophenyl)-1-methylpiperidine-4-carboxamide

[0188] [Step 1] Synthesis of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro aniline

[0189]

[0190] To a solution in which 3-fluoroaniline (1.000 g, 8.999 mmol) and potassium carbonate (1.866 g, 13.499 mmol) were dissolved in N,N-dimethylformamide (40 mL) at room temperature, 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (2.480 g, 8.549 mmol) and potassium iodide (0.747 g, 4.500 mmol) prepared in step 3 of Example 6 were added 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 saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 40 g column; ethyl acetate / hexanes = 0% to 60%) and concentrated to obtain the title compound (2.340 g, 81.2%) as a yellow solid.

[0191] [Step 2] Synthesis of 4-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(3- tert-Butyl (4-fluorophenyl)carbamoyl)-4-fluoropiperidin-1-carboxylate

[0192]

[0193] To a solution in which N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoroaniline (0.490 g, 1.530 mmol) and triethylamine (0.640 mL, 4.590 mmol) prepared in step 1 were dissolved in dichloromethane (20 mL) at room temperature, 4-(chlorocarbonyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester (0.528 g, 1.989 mmol) prepared in step 2 of Example 1 was added and stirred at the same temperature for 16 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 12 g column; ethyl acetate / hexanes = 0% to 30%) and concentrated to obtain the title compound (0.430 g, 51.1%) as a yellow solid.

[0194] [Step 3] 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

[0195]

[0196] Tert-butyl 4-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(3-fluorophenyl)carbamoyl)-4-fluoropiperidine-1-carboxylate (0.430 g, 0.782 mmol) and trifluoroacetic acid (1.198 mL, 15.650 mmol) prepared in step 2 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.

[0197] [Step 4] Synthesis of compound 2969

[0198]

[0199] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-(3-fluorophenyl)piperidine-4-carboxamide 2,2,2-trifluoroacetate (0.088 g, 0.196 mmol), formaldehyde (0.012 g, 0.392 mmol), acetic acid (0.011 mL, 0.196 mmol) and sodium triacetoxyborohydride (0.125 g, 0.587 mmol) prepared in step 3 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. Saturated sodium bicarbonate aqueous solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.011 g, 12.1%) as a white solid.

[0200] 1 H NMR (400 MHz, CDCl 3 )δ9.32-9.19(m,1H),8.38(dd,J=8.2,2.2Hz,1H),7.53(d,J=8.2Hz,1H),7.32(ddd,J=13.5,6.8,4.2Hz,1H),7.09-6.81 (m,4H),5.06(s,2H),2.72(d,J=11.2Hz,2H),2.50-2.31(m,2H),2.28(s,3H),2.16(t,J=11.6Hz,2H),2.02-1.89(m,2H);

[0201] LRMS (ES) m / z 464.6 (M + +1).

[0202] 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

[0203]

[0204] 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), 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) prepared in step 3 of Example 10 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.024 g, 24.9%) as a white solid.

[0205] 1 H NMR (400 MHz, CDCl 3 )δ9.27(d,J=1.6Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.54(d,J=8.3Hz,1H),7.36-7.29(m,1H),7.00(ddd,J=73. 7,45.8,33.6Hz,4H),5.07(s,2H),2.74(s,2H),2.45-2.24(m,4H),1.98(d,J=11.1Hz,3H),1.04(d,J=6.5Hz,6H);

[0206] LRMS (ES) m / z 492.5 (M + +1).

[0207] 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

[0208]

[0209] 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), cyclobutanone (0.027 g, 0.392 mmol), acetic acid (0.011 mL, 0.196 mmol) and sodium triacetoxyborohydride (0.125 g, 0.587 mmol) prepared in step 3 of Example 10 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.035 g, 35.5%) as a white solid.

[0210] 1 H NMR (400 MHz, CDCl 3 )δ9.26(d,J=1.6Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.53(d,J=8.2Hz,1H),7.35-7.29(m,1H),7.10-6. 80(m,4H),5.07(s,2H),2.70(t,J=11.7Hz,3H),2.45-2.22(m,2H),2.07-1.83(m,7H),1.75-1.59(m,3H);

[0211] LRMS (ES) m / z 504.4 (M + +1).

[0212] 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-(oxetane-3-yl)piperidine-4-carboxamide

[0213]

[0214] 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), oxetanes-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) prepared in step 3 of Example 10 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.045 g, 45.5%) as a white solid.

[0215] 1 H NMR (400 MHz, CDCl 3 )δ9.28(d,J=1.5Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.53(d,J=8.3Hz,1H),7.36-7.29(m,1H),7.10-6.81(m,4H),5.07(s,2H) ,4.62(dt,J=15.9,6.4Hz,4H),3.47(p,J=6.6Hz,1H),2.59(d,J=8.6Hz,2H),2.49-2.27(m,2H),2.00(dt,J=24.8,12.4Hz,4H);

[0216] LRMS (ES) m / z 506.4 (M + +1).

[0217] 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

[0218] [Step 1] Synthesis of tert-butyl 3-(chlorocarbonyl)-3-fluoroazetidine-1-carboxylate

[0219]

[0220] 1-(tert-Butyloxycarbonyl)-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.

[0221] [Step 2] Synthesis of 3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(benzene tert-Butyl)carbamoyl)-3-fluoroazetidine-1-carboxylate

[0222]

[0223] 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) and triethylamine (0.692 mL, 4.962 mmol) prepared in step 4 of Example 6 were dissolved in dichloromethane (35 mL) at room temperature, tert-butyl 3-(chlorocarbonyl)-3-fluoroazetidine-1-carboxylate (0.511 g, 2.150 mmol) prepared in step 1 was added and stirred at the same temperature for 16 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 40 g column; ethyl acetate / hexane = 5% to 50%) and concentrated to obtain the title compound (0.610 g, 73.2%) as a foamy solid.

[0224] [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

[0225]

[0226] 3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)(phenyl)carbamoyl)-3-fluoroazetidine-1-carboxylic acid tert-butyl ester (0.200 g, 0.397 mmol) prepared 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.

[0227] [Step 4] Synthesis of compound 2973

[0228]

[0229] By N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050g, 0.097mmol), paraformaldehyde (0.006g, 0.193mmol) and acetic acid (0.006mL, 0.097mmol) prepared in step 3, dissolved in dichloromethane (4mL), and the resulting solution was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.061g, 0.290mmol) was added and further stirred for 16 hours at the same temperature. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and water layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 4 g column; methanol / dichloromethane = 0% to 10%) and concentrated to afford the title compound (0.021 g, 52.1%) as a foamy solid.

[0230] 1 H NMR (400 MHz, CDCl 3 )δ9.25(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);

[0231] LRMS (ES) m / z 418.5 (M + +1).

[0232] 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

[0233]

[0234] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.097 mmol), acetone (0.014 mL, 0.193 mmol) and acetic acid (0.006 mL, 0.097 mmol) prepared in step 3 of Example 14 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 for 16 hours at the same temperature. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 4 g column; methanol / dichloromethane = 0% to 10%) and concentrated to afford the title compound (0.022 g, 51.1%) as a foamy solid.

[0235] 1 H NMR (400 MHz, CDCl 3 )δ9.25(m,1H),8.38(m,1H),7.58(m,1H),7.35(m,3H),7.25(m,2H),6.95 (m,1H),5.12(s,2H),3.53(m,2H),3.11(m,2H),2.30(m,1H),0.90(m,6H);

[0236] LRMS (ES) m / z 446.6 (M + +1).

[0237] 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

[0238]

[0239] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.097 mmol), cyclobutanone (0.014 mL, 0.193 mmol) and acetic acid (0.006 mL, 0.097 mmol) prepared in step 3 of Example 14 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 for 16 hours at the same temperature. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 4 g column; methanol / dichloromethane = 0% to 10%) and concentrated to afford the title compound (0.025 g, 56.6%) as a white solid.

[0240] 1 H NMR (400 MHz, CDCl 3 )δ9.24(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);

[0241] LRMS (ES) m / z 458.5 (M + +1).

[0242] 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

[0243]

[0244] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.097 mmol), oxetane-3-one (0.012 mL, 0.193 mmol) and acetic acid (0.006 mL, 0.097 mmol) prepared in step 3 of Example 14 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 for 16 hours at the same temperature. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 4 g column; methanol / dichloromethane = 0% to 10%) and concentrated to afford the title compound (0.024 g, 54.1%) as a white solid.

[0245] 1 H NMR (400 MHz, CDCl 3 )δ9.26(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);

[0246] LRMS (ES) m / z 460.6 (M + +1).

[0247] 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]hept-6-yl)piperidine-4-carboxamide

[0248]

[0249] 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), 2-oxaspiro[3.3]heptan-6-one (0.050 g, 0.445 mmol), acetic acid (0.013 mL, 0.223 mmol) and sodium triacetoxyborohydride (0.141 g, 0.668 mmol) prepared in step 6 of Example 6 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.032 g, 27.3%) as a white solid.

[0250] 1 H NMR (400 MHz, CDCl 3 )δ9.25(d,J=2.2Hz,1H),8.37(dd,J=8.2,2.3Hz,1H),7.54(d,J=8.2Hz,1H),7.38 -7.29(m,3H),7.21(dd,J=7.9,1.6Hz,2H),6.95(t,J=51.7Hz,1H),5.09(s,2H),4. 70(s,2H),4.59(s,2H),2.66(d,J=11.7Hz,2H),2.48(dd,J=15.2,7.8Hz,1H),2.4 1-2.31(m,3H),2.26(dd,J=13.7,4.7Hz,1H),1.98(ddd,J=40.7,19.6,8.9Hz,6H);

[0251] LRMS (ES) m / z 529.4 (M + +1).

[0252] 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

[0253]

[0254] 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), cyclopentanone (0.037 g, 0.445 mmol), acetic acid (0.013 mL, 0.223 mmol) and sodium triacetoxyborohydride (0.141 g, 0.668 mmol) prepared in step 6 of Example 6 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.037 g, 33.3%) as a white solid.

[0255] 1 H NMR (400 MHz, CDCl 3 )δ9.25(d,J=2.2Hz,1H),8.38(dd,J=8.2,2.2Hz,1H),7.55(d,J=8.3Hz,1H),7.4 0-7.30(m,3H),7.22(dd,J=7.7,1.7Hz,2H),6.95(t,J=51.7Hz,1H),5.09(s,2H) ,3.01(d,J=11.4Hz,2H),2.67(d,J=7.2Hz,1H),2.59-2.38(m,2H),2.38-2.24(m ,2H),1.98(d,J=11.7Hz,2H),1.82(d,J=21.6Hz,2H),1.71(s,2H),1.54(s,4H);

[0256] LRMS (ES) m / z 501.4 (M + +1).

[0257] 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

[0258]

[0259] 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), cyclohexanone (0.044 g, 0.445 mmol), acetic acid (0.013 mL, 0.223 mmol) and sodium triacetoxyborohydride (0.141 g, 0.668 mmol) prepared in step 6 of Example 6 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.044 g, 38.5%) as a white solid.

[0260] 1 H NMR (400 MHz, CDCl 3 )δ9.25(d,J=2.2Hz,1H),8.38(dd,J=8.2,2.3Hz,1H),7.56(d,J=8.1Hz,1H),7.39-7.30(m,3H),7.24-7.19(m,2H),6. 97(dd,J=65.0,38.4Hz,1H),5.09(s,2H),2.78(s,2H),2.39(d,J=43.3Hz,5H),1.97(s,2H),1.78(s,5H),1.21(s,5H);

[0261] LRMS (ES) m / z 515.5 (M + +1).

[0262] 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

[0263]

[0264] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.090 g, 0.223 mmol), cyclopentanone (0.038 g, 0.446 mmol), acetic acid (0.013 mL, 0.223 mmol) and sodium triacetoxyborohydride (0.142 g, 0.669 mmol) prepared in step 3 of Example 14 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.051 g, 48.5%) as a white solid.

[0265] 1 H NMR (400 MHz, CDCl 3 )δ9.29-9.20(m,1H),8.38(dd,J=8.2,2.2Hz,1H),7.59(d,J=8.4Hz,1H), 7.41-7.31(m,3H),7.27-7.22(m,2H),6.95(t,J=51.7Hz,1H),5.12(s,2H) ,3.51(dd,J=23.8,10.3Hz,2H),3.11(dd,J=21.8,10.4Hz,2H),2.69(d,J =5.2Hz,1H),1.68-1.60(m,2H),1.60-1.43(m,4H),1.28(d,J=6.1Hz,2H);

[0266] LRMS(ES)m / z 473.4(M + +1).

[0267] 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

[0268]

[0269] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.090 g, 0.223 mmol), cyclohexanone (0.044 g, 0.445 mmol), acetic acid (0.013 mL, 0.223 mmol) and sodium triacetoxyborohydride (0.142 g, 0.669 mmol) prepared in step 3 of Example 14 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.050 g, 46.2%) as a white solid.

[0270] 1 H NMR (400 MHz, CDCl 3 )δ9.25(d,J=1.6Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.60(d,J=8.0Hz,1H),7.4 0–7.32(m,3H),7.25(d,J=8.1Hz,2H),6.95(t,J=51.7Hz,1H),5.13(s,2H),3.53 (dd,J=23.2,9.8Hz,2H),3.11(dd,J=21.4,9.4Hz,2H),2.01-1.85(m,2H),1.72( d,J=28.0Hz,2H),1.38-1.24(m,2H),1.24-1.10(m,3H),0.97(d,J=11.8Hz,2H);

[0271] LRMS (ES) m / z 487.5 (M + +1).

[0272] 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

[0273]

[0274] 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), 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) prepared in step 3 of Example 14 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.032 g, 29.4%) as a white solid.

[0275] 1 H NMR (400 MHz, CDCl 3 )δ9.28-9.23(m,1H),8.39(dd,J=8.2,2.2Hz,1H),7.59(d,J=8.3Hz,1H),7.41-7.32( m,3H),7.26(d,J=8.0Hz,2H),6.95(t,J=51.6Hz,1H),5.13(s,2H),3.93(dt,J=11.4, 3.6Hz, 2H), 3.57 (dd, J=23.2, 10.0Hz, 2H), 3.35 (td, J=11.2, 1.9Hz, 2H), 3.13 (dd, J= 21.6,10.1Hz,2H),2.24(s,1H),1.57(d,J=13.2Hz,2H),1.33(td,J=14.5,4.7Hz,2H);

[0276] LRMS (ES) m / z 488.5 (M + +1).

[0277] 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

[0278]

[0279] 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), acetaldehyde (0.010 g, 0.238 mmol), acetic acid (0.007 mL, 0.119 mmol) and sodium triacetoxyborohydride (0.076 g, 0.357 mmol) prepared in step 3 of Example 14 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.042 g, 81.8%) as a yellow solid.

[0280] 1 H NMR (400 MHz, CDCl 3 )δ9.26(d,J=1.6Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.61(d,J=8.2Hz,1H),7.40-7.34(m,3H),7.26(d,J=8.1Hz,2H),6.96(t,J=51 .7Hz,1H),5.13(s,2H),3.75(dd,J=22.9,10.9Hz,2H),3.24(dd,J=21.6,10.5Hz,2H),2.59(q,J=7.2Hz,2H),0.98(t,J=7.2Hz,3H);

[0281] LRMS (ES) m / z 433.4 (M + +1).

[0282] 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

[0283]

[0284] 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), propionaldehyde (0.014 g, 0.238 mmol), acetic acid (0.007 mL, 0.119 mmol) and sodium triacetoxyborohydride (0.076 g, 0.357 mmol) prepared in step 3 of Example 14 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.029 g, 54.7%) as a yellow solid.

[0285] 1 H NMR (400 MHz, CDCl 3 )δ9.25(d,J=1.5Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.59(d,J=8.4Hz,1H),7.41-7.30(m,3H),7.27-7.20(m,2H),6.95(t,J=51.7Hz,1H),5.13 (s,2H),3.56(dd,J=22.8,10.1Hz,2H),3.14(dd,J=21.6,9.3Hz,2H),2.40(t,J=7.4Hz,2H),1.32(dt,J=19.6,9.8Hz,2H),0.87(t,J=7.4Hz,3H);

[0286] LRMS (ES) m / z 447.5 (M + +1).

[0287] 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

[0288]

[0289] 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), butyraldehyde (0.017 g, 0.238 mmol), acetic acid (0.007 mL, 0.119 mmol) and sodium triacetoxyborohydride (0.076 g, 0.357 mmol) prepared in step 3 of Example 14 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.038 g, 69.5%) as a yellow solid.

[0290] 1 H NMR (400 MHz, CDCl 3 )δ9.25(d,J=1.5Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.59(d,J=8.1Hz,1H),7.41-7.32(m,3H),7.27-7.21(m,2H),6.95(t,J=51.7Hz, 1H),5.13(s,2H),3.55(dd,J=22.8,9.4Hz,2H),3.14(dd,J=21.5,10.3Hz,2H),2.42(s,2H),1.34-1.24(m,4H),0.88(t,J=7.1Hz,3H);

[0291] LRMS (ES) m / z 461.5 (M + +1).

[0292] 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

[0293]

[0294] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.048 g, 0.119 mmol), isobutyraldehyde (0.017 g, 0.238 mmol), acetic acid (0.007 mL, 0.119 mmol) and sodium triacetoxyborohydride (0.076 g, 0.357 mmol) prepared in step 3 of Example 14 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.040 g, 73.2%) as a yellow solid.

[0295] 1 H NMR (400 MHz, CDCl 3 )δ9.26(d,J=1.5Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.59(d,J=8.2Hz,1H),7.41-7.33(m,3H),7.27-7.20(m,2H),6.95(t,J=51.7Hz,1H) ,5.13(s,2H),3.62-3.46(m,2H),3.15(dd,J=21.8,9.7Hz,2H),2.25(d,J=7.1Hz,2H),1.54(dt,J=13.3,6.8Hz,1H),0.85(d,J=6.7Hz,6H);

[0296] LRMS (ES) m / z 460.4 (M + +1).

[0297] 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

[0298]

[0299] 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), 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) prepared in step 3 of Example 14 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.023 g, 41.9%) as a yellow solid.

[0300] 1 H NMR (400 MHz, CDCl 3 )δ9.27(d,J=1.6Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.57(d,J=8.2Hz,1H),7.38(dd,J=8.6,3.2Hz,3H),7.25(d,J=7.7Hz,2H),6 .96(t,J=51.7Hz,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=6.5Hz,3H);

[0301] LRMS (ES) m / z 463.5 (M + +1).

[0302] 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

[0303]

[0304] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.048 g, 0.119 mmol), 3-(dimethylamino)propanoyl chloride (0.021 g, 0.155 mmol) and triethylamine (0.050 mL, 0.357 mmol) prepared in step 3 of Example 14 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.029 g, 48.5%) as a yellow solid.

[0305] 1 H NMR (400 MHz, CDCl 3 )δ9.29(d,J=1.8Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.54(d,J=8.1Hz,1H),7.4 3-7.35(m,3H),7.32-7.24(m,2H),6.96(t,J=51.7Hz,1H),5.13(s,2H),4.76(dd, J=21.7,10.2Hz,1H),4.36(dd,J=22.7,12.1Hz,1H),4.04(dd,J=22.6,10.5Hz,1 H),3.69(dd,J=22.9,11.7Hz,1H),2.65(t,J=7.2Hz,2H),2.29(d,J=10.1Hz,8H);

[0306] LRMS (ES) m / z 504.4 (M + +1).

[0307] 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

[0308]

[0309] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.048 g, 0.119 mmol), 4-(dimethylamino)butyryl chloride (0.023 g, 0.155 mmol) and triethylamine (0.050 mL, 0.357 mmol) prepared in step 3 of Example 14 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.033 g, 53.7%) as a yellow solid.

[0310] 1 H NMR (400 MHz, CDCl 3 )δ9.28(d,J=1.8Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.54(d,J=8.2Hz,1H),7.44-7.36( m,3H),7.28(d,J=5.9Hz,2H),6.96(t,J=51.7Hz,1H),5.13(s,2H),4.73(dd,J=22.1,11.0 Hz,1H),4.38(dd,J=23.1,11.7Hz,1H),4.02(dd,J=22.7,10.4Hz,1H),3.70(dd,J=22.8,1 2.3Hz,1H),2.48(d,J=6.7Hz,2H),2.36(s,6H),2.16(t,J=7.1Hz,2H),1.90-1.79(m,2H);

[0311] LRMS (ES) m / z 517.4 (M + +1).

[0312] 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

[0313] [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

[0314]

[0315] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoroaniline (1.100 g, 3.434 mmol) and triethylamine (1.436 mL, 10.303 mmol) prepared in step 1 of Example 10 were dissolved in dichloromethane (20 mL) at room temperature. 3-(chlorocarbonyl)-3-fluoroazetidine-1-carboxylic acid tert-butyl ester (1.061 g, 4.465 mmol) prepared in step 1 of Example 14 was added and stirred at the same temperature for 16 hours. Saturated aqueous ammonium chloride solution 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 , 12 g column; ethyl acetate / hexanes = 0% to 30%) and concentrated to obtain the title compound (1.210 g, 67.6%) as a yellow solid.

[0316] [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

[0317]

[0318] Tert-butyl 3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(3-fluorophenyl)carbamoyl)-3-fluoroazetidine-1-carboxylate (1.080 g, 2.145 mmol) and trifluoroacetic acid (3.285 mL, 42.901 mmol) prepared in step 1 were dissolved in dichloromethane (30 mL) at room temperature, and the resulting solution was stirred at the same temperature for 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.

[0319] [Step 3] Synthesis of compound 3047

[0320]

[0321] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol), formaldehyde (0.007 g, 0.237 mmol), acetic acid (0.007 mL, 0.119 mmol) and sodium triacetoxyborohydride (0.075 g, 0.356 mmol) prepared in step 2 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. Saturated sodium bicarbonate aqueous solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.032 g, 61.9%) as a white solid.

[0322] 1 H NMR (400 MHz, CDCl 3 )δ9.28(d,J=1.5Hz,1H),8.40(dd,J=8.2,2.3Hz,1H),7.57(d,J=8.2Hz,1H),7.39-7.31(m ,1H),7.01(dt,J=83.3,28.8Hz,4H),5.10(s,2H),3.67(s,2H),3.21(s,2H),2.36(s,3H);

[0323] LRMS (ES) m / z 437.5 (M + +1).

[0324] 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

[0325]

[0326] 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), 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) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.026 g, 47.3%) as a white solid.

[0327] 1 H NMR (400 MHz, CDCl 3 )δ9.27(d,J=1.6Hz,1H),8.40(dd,J=8.2,2.3Hz,1H),7.58(d,J=7.8Hz,1H),7.39-7.31(m,1H),7.1 1-6.81(m,4H),5.10(s,2H),3.61(s,2H),3.16(s,2H),2.34(d,J=6.0Hz,1H),0.92(d,J=6.2Hz,6H);

[0328] LRMS(ES)m / z 465.4(M + +1).

[0329] 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

[0330]

[0331] 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), cyclobutanone (0.017 g, 0.237 mmol), acetic acid (0.007 mL, 0.119 mmol) and sodium triacetoxyborohydride (0.075 g, 0.356 mmol) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.019 g, 33.7%) as a white solid.

[0332] 1 H NMR (400 MHz, CDCl 3 )δ9.27(d,J=2.2Hz,1H),8.40(dd,J=8.2,2.3Hz,1H),7.58(d,J=8.1Hz,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=7.2Hz,3H),2.00-1.92(m,2H),1.78(dd,J=18.8,9.9Hz,2H),1.61(s,2H);

[0333] LRMS(ES)m / z 477.4(M + +1).

[0334] 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-(oxetane-3-yl)azetidine-3-carboxamide

[0335]

[0336] 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), oxetane-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) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.033 g, 58.3%) as a white solid.

[0337] 1 H NMR (400 MHz, CDCl 3 )δ9.29(d,J=1.5Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.56(d,J=8.1Hz,1H),7.40-7.32(m,1H),7.13-6.82 (m,4H),5.11(s,2H),4.69(t,J=6.9Hz,2H),4.54-4.47(m,2H),3.91-3.74(m,3H),3.34(d,J=22.0Hz,2H);

[0338] LRMS(ES)m / z 478.3(M + +1).

[0339] 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

[0340]

[0341] 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), cyclopentanone (0.020 g, 0.237 mmol), acetic acid (0.007 mL, 0.119 mmol) and sodium triacetoxyborohydride (0.075 g, 0.356 mmol) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.036 g, 62.0%) as a white solid.

[0342] 1 H NMR (400 MHz, CDCl 3 )δ9.27(d,J=1.5Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.57(d,J=8.1Hz,1H),7.38-7.30(m,1H),7.12-6.80(m,4H),5.10(s,2 H),3.56(d,J=23.0Hz,2H),3.18(d,J=13.0Hz,2H),2.73(s,1H),1.71-1.64(m,2H),1.60-1.44(m,4H),1.29(d,J=7.4Hz,2H);

[0343] LRMS (ES) m / z 491.5 (M + +1).

[0344] 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

[0345]

[0346] 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), dihydrofuran-3(2H)-one (0.020 g, 0.237 mmol), acetic acid (0.007 mL, 0.119 mmol) and sodium triacetoxyborohydride (0.075 g, 0.356 mmol) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.024 g, 41.2%) as a white solid.

[0347] 1 H NMR (400 MHz, CDCl 3 )δ9.27(d,J=1.5Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.57(d,J=8.1Hz,1H),7.38-7.30(m,1H),7.12-6.80(m,4H),5.10(s,2 H),3.56(d,J=23.0Hz,2H),3.18(d,J=13.0Hz,2H),2.73(s,1H),1.71-1.64(m,2H),1.60-1.44(m,4H),1.29(d,J=7.4Hz,2H);

[0348] LRMS(ES)m / z 492.3(M + +1).

[0349] 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

[0350]

[0351] 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), cyclohexanone (0.023 g, 0.237 mmol), acetic acid (0.007 mL, 0.119 mmol) and sodium triacetoxyborohydride (0.075 g, 0.356 mmol) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.030 g, 50.2%) as a white solid.

[0352] 1 H NMR (400 MHz, CDCl 3 )δ9.29-9.24(m,1H),8.39(dd,J=8.2,2.2Hz,1H),7.57(d,J=8.5Hz,1H),7.39-7.31(m,1H),7.10-6.81(m,4H),5.10(s,2H),3.6 9-3.52(m,3H),3.18(d,J=12.1Hz,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);

[0353] LRMS (ES) m / z 505.4 (M + +1).

[0354] 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

[0355]

[0356] 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), 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) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.027 g, 45.0%) as a white solid.

[0357] 1 H NMR (400 MHz, CDCl 3 )δ9.28(d,J=1.5Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.57(d,J=8.3Hz,1H),7.39-7.31(m,1H),7.12-6.81(m,4H),5.10(s,2H),3.94(dt,J= 7.2,3.8Hz,2H),3.63(d,J=11.9Hz,2H),3.36(td,J=11.2,2.2Hz,2H),3.21(d,J=22.0Hz,2H),2.28(s,1H),1.58(s,2H),1.41-1.29(m,2H);

[0358] LRMS (ES) m / z 507.4 (M + +1).

[0359] 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

[0360]

[0361] 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), triethylamine (0.033 mL, 0.237 mmol) and methanesulfonyl chloride (0.009 mL, 0.119 mmol) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, followed by extraction with dichloromethane. The obtained 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, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.041 g, 69.2%) as a white solid.

[0362] 1 H NMR (400 MHz, CDCl 3 )δ9.31(d,J=2.1Hz,1H),8.42(dd,J=8.2,2.2Hz,1H),7.54(d,J=8.2Hz,1H),7.39(dd,J=14.5,7.4Hz,1H), 7.16-6.82(m,4H),5.11(s,2H),4.46(dd,J=22.1,10.5Hz,2H),3.82(dd,J=22.1,10.3Hz,2H),2.91(s,3H);

[0363] LRMS (ES) m / z 500.4 (M + +1).

[0364] 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

[0365]

[0366] 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), acetaldehyde (0.010 g, 0.237 mmol), acetic acid (0.007 mL, 0.119 mmol) and sodium triacetoxyborohydride (0.075 g, 0.356 mmol) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.026 g, 48.8%) as a yellow gel.

[0367] 1 H NMR (400 MHz, CDCl 3 )δ9.18(d,J=1.8Hz,1H),8.30(dd,J=8.2,2.2Hz,1H),7.48(d,J=8.0Hz,1H),7.30-7.21(m,1H),6.93(ddd,J=86.8,42.3,27. 5Hz,4H),5.01(s,2H),3.53(dd,J=21.1,9.8Hz,2H),3.10(dd,J=22.0,9.2Hz,2H),2.40(q,J=7.1Hz,2H),0.91-0.82(m,3H);

[0368] LRMS (ES) m / z 450.5 (M + +1).

[0369] 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

[0370]

[0371] 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), propionaldehyde (0.014 g, 0.237 mmol), acetic acid (0.007 mL, 0.119 mmol) and sodium triacetoxyborohydride (0.075 g, 0.356 mmol) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.034 g, 61.8%) as a yellow gel.

[0372] 1 H NMR (400 MHz, CDCl 3 )δ9.18(d,J=1.7Hz,1H),8.30(dd,J=8.2,2.2Hz,1H),7.48(d,J=8.2Hz,1H),7.29-7.21(m,1H),7.02-6.68(m,4H),5.01(s,2H),3.5 2(dd,J=22.8,9.0Hz,2H),3.11(dd,J=21.4,8.9Hz,2H),2.33(t,J=7.4Hz,2H),1.26(dq,J=14.9,7.4Hz,2H),0.79(t,J=7.4Hz,3H);

[0373] LRMS (ES) m / z 464.3 (M + +1).

[0374] 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

[0375]

[0376] 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), butyraldehyde (0.017 g, 0.237 mmol), acetic acid (0.007 mL, 0.119 mmol) and sodium triacetoxyborohydride (0.075 g, 0.356 mmol) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.050 g, 88.3%) as a yellow gel.

[0377] 1 H NMR (400 MHz, CDCl 3 )δ9.27(d,J=1.7Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.56(t,J=7.9Hz,1H),7.40-7.30(m,1H),7.12-6.79(m,4H),5 .10(s,2H),3.61(dd,J=22.3,7.1Hz,2H),3.27-3.10(m,2H),2.44(s,2H),1.34-1.24(m,4H),0.89(t,J=7.1Hz,3H);

[0378] LRMS(ES)m / z 478.3(M + +1).

[0379] 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

[0380]

[0381] 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), isobutyraldehyde (0.017 g, 0.237 mmol), acetic acid (0.007 mL, 0.119 mmol) and sodium triacetoxyborohydride (0.075 g, 0.356 mmol) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.041 g, 72.4%) as a yellow gel.

[0382] 1 H NMR (400 MHz, CDCl 3 )δ9.28(d,J=1.6Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.56(t,J=7.3Hz,1H),7.39-7.30(m,1H),7.11-6.79(m,4H),5.10(s,2H),3.5 6(dd,J=13.2,8.8Hz,2H),3.21(dd,J=22.0,9.3Hz,2H),2.26(d,J=7.0Hz,2H),1.55(dt,J=13.6,6.8Hz,1H),0.87(d,J=6.7Hz,6H);

[0383] LRMS(ES)m / z 479.4(M + +1).

[0384] 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

[0385]

[0386] 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), 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) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.041 g, 72.1%) as a yellow gel.

[0387] 1 H NMR (400 MHz, CDCl 3 )δ9.29(d,J=1.7Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.55(d,J=8.5Hz,1H),7.40-7.31(m,1H),7.13-6.78(m,4H),5.0 8(d,J=13.5Hz,2H),3.83(t,J=30.9Hz,2H),3.61-3.49(m,1H),3.44-3.27(m,3H),2.56(s,1H),0.99(d,J=6.5Hz,3H);

[0388] LRMS (ES) m / z 480.5 (M + +1).

[0389] 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

[0390]

[0391] 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), 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) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.037 g, 60.1%) as a yellow gel.

[0392] 1 H NMR (400 MHz, CDCl 3 )δ9.29(d,J=1.7Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.54(d,J=8.1Hz,1H),7.40-7.31(m,1H),7.01(dt,J 76.0,29.3Hz,4H),5.10(s,2H),3.63(dd,J=21.3,7.9Hz,2H),3.19(dd,J=21.3,9.0Hz,2H),3.00(t,J=8 .6Hz,2H),2.76(dd,J=19.4,13.1Hz,2H),2.53(d,J=10.0Hz,3H),2.36(s,1H),1.90(s,2H),1.57(s,2H);

[0393] LRMS (ES) m / z 519.4 (M + +1).

[0394] 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

[0395]

[0396] 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), 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) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.034 g, 53.1%) as a yellow gel.

[0397] 1 H NMR (400 MHz, CDCl 3 )δ9.28(d,J=1.7Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.56(d,J=8.3Hz,1H),7.41-7.31(m,1H),7.14-6.75(m,4H),5.10(s,2H),3.62(d d,J=22.1,8.6Hz,2H),3.19(dd,J=21.0,9.0Hz,2H),2.24(s,1H),2.12-1.97(m,2H),1.79-1.58(m,4H),1.47(dd,J=21.3,13.0Hz,2H);

[0398] LRMS (ES) m / z 541.6 (M + +1).

[0399] 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

[0400]

[0401] 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), 3-(dimethylamino)propanoyl chloride (0.021 g, 0.154 mmol) and triethylamine (0.050 mL, 0.356 mmol) prepared in step 3 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.035 g, 56.7%) as a yellow gel.

[0402] 1 H NMR (400 MHz, CDCl 3 )δ9.21(d,J=1.8Hz,1H),8.32(dd,J=8.2,2.2Hz,1H),7.45(d,J=8.1Hz,1H),7.2 9(dd,J=14.8,7.9Hz,1H),7.05-6.69(m,4H),5.01(s,2H),4.70(dd,J=21.2,10. 8Hz, 1H), 4.46 (dd, J=21.4, 12.0Hz, 1H), 3.99 (dd, J=21.8, 10.2Hz, 1H), 3.78 (dd ,J=21.7,11.7Hz,1H),3.07(q,J=7.3Hz,2H),2.70(s,6H),1.26(t,J=7.3Hz,2H);

[0403] LRMS (ES) m / z 521.5 (M + +1).

[0404] 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

[0405]

[0406] 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), 4-(dimethylamino)butyryl chloride (0.023 g, 0.154 mmol) and triethylamine (0.050 mL, 0.356 mmol) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.029 g, 45.7%) as a yellow gel.

[0407] 1 H NMR (400 MHz, CDCl 3 )δ9.30(d,J=1.8Hz,1H),8.41(dd,J=8.2,2.2Hz,1H),7.53(d,J=8.2Hz,1H),7. 38(dd,J=14.4,8.0Hz,1H),7.03(dt,J=75.6,30.1Hz,4H),5.10(d,J=1.9Hz,2H) ,4.72(dd,J=21.3,10.5Hz,1H),4.48(dd,J=21.6,11.6Hz,1H),4.03(dd,J=21.8 ,9.8Hz,1H),3.82(dd,J=22.8,11.9Hz,1H),2.78(s,6H),1.35(t,J=7.3Hz,6H);

[0408] LRMS (ES) m / z 535.3 (M + +1).

[0409] 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

[0410] [Step 1] Synthesis of 3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(benzene tert-Butyl)carbamoyl)-3-fluoro-[1,3'-aziridine]-1'-carboxylate

[0411]

[0412] 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), 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) prepared in step 3 of Example 14 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 12 g column; dichloromethane / methanol = 0% to 10%) and concentrated to afford the title compound (0.300 g, 86.7%) as a yellow gel.

[0413] [Step 2] Synthesis of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3- Fluoro-N-phenyl-[1,3'-aziridine]-3-carboxamide 2,2,2-trifluoroacetate

[0414]

[0415] Tert-butyl 3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(phenyl)carbamoyl)-3-fluoro-[1,3'-aziridine]-1'-carboxylate (0.262 g, 0.469 mmol) and trifluoroacetic acid (0.718 mL, 9.381 mmol) prepared in step 1 were dissolved in dichloromethane (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 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.

[0416] [Step 3] Synthesis of compound 3105

[0417]

[0418] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-[1,3'-aziridine]-3-carboxamide 2,2,2-trifluoroacetate (0.040 g, 0.087 mmol), formaldehyde (0.005 g, 0.175 mmol), acetic acid (0.005 mL, 0.087 mmol) and sodium triacetoxyborohydride (0.055 g, 0.262 mmol) prepared in step 2 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. Saturated sodium bicarbonate aqueous solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.014 g, 34.0%) as a yellow gel.

[0419] 1 H NMR (400 MHz, CDCl 3 )δ9.27(d,J=1.6Hz,1H),8.39(dd,J=8.1,2.2Hz,1H),7.57(d,J=8.0Hz,1H),7.40-7.34(m,3H),7.26(d,J=7.9Hz,2H),6.97(dd, J=64.5,38.9Hz,1H),5.12(s,2H),3.86(s,2H),3.69(dd,J=21.1,9.0Hz,2H),3.55-3.47(m,1H),3.31-3.12(m,4H),2.60(s,3H);

[0420] LRMS (ES) m / z 473.5 (M + +1).

[0421] 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'-aziridine]-3-carboxamide

[0422]

[0423] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-[1,3'-aziridine]-3-carboxamide 2,2,2-trifluoroacetate (0.040 g, 0.087 mmol), acetaldehyde (0.008 g, 0.175 mmol), acetic acid (0.007 mL, 0.087 mmol) and sodium triacetoxyborohydride (0.055 g, 0.262 mmol) prepared in step 2 of Example 49 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.022 g, 51.8%) as a yellow gel.

[0424] 1 H NMR (400 MHz, CDCl 3 )δ9.26(d,J=2.1Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.58(d,J=8.3Hz,1H),7.3 8(dt,J=10.6,3.6Hz,3H),7.25(d,J=8.0Hz,2H),6.97(dd,J=64.9,38.4Hz,1H), 5.12(s,2H),3.75-3.60(m,2H),3.43(dt,J=29.9,6.6Hz,3H),3.17(dd,J=21.7, 10.1Hz,2H),2.96(d,J=6.9Hz,2H),2.56(q,J=7.2Hz,2H),1.00(t,J=7.2Hz,3H);

[0425] LRMS (ES) m / z 488.5 (M + +1).

[0426] 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'-aziridine]-3-carboxamide

[0427]

[0428] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-[1,3'-aziridine]-3-carboxamide 2,2,2-trifluoroacetate (0.040 g, 0.087 mmol), propionaldehyde (0.010 g, 0.175 mmol), acetic acid (0.005 mL, 0.087 mmol) and sodium triacetoxyborohydride (0.055 g, 0.262 mmol) prepared in step 2 of Example 49 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.018 g, 41.2%) as a yellow gel.

[0429] 1 H NMR (400 MHz, CDCl 3 )δ9.27(d,J=1.7Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.57(d,J=8.3Hz,1H),7.38(d,J=7.1Hz,3H),7.25(d,J=5.4Hz,2H),6.96(t,J=51.7Hz,1H ),5.12(s,2H),3.97(s,2H),3.68(dd,J=23.3,12.6Hz,3H),3.34-3.11(m,4H),2.80(s,2H),1.54(dd,J=15.2,7.8Hz,2H),0.94(t,J=7.4Hz,3H);

[0430] LRMS (ES) m / z 501.3 (M + +1).

[0431] 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'-aziridine]-3-carboxamide

[0432]

[0433] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-[1,3'-aziridine]-3-carboxamide 2,2,2-trifluoroacetate (0.040 g, 0.087 mmol), butyraldehyde (0.013 g, 0.175 mmol), acetic acid (0.005 mL, 0.087 mmol) and sodium triacetoxyborohydride (0.055 g, 0.262 mmol) prepared in step 2 of Example 49 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.018 g, 40.1%) as a yellow gel.

[0434] 1 H NMR (400 MHz, CDCl 3 )δ9.26(d,J=1.6Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.58(d,J=8.3Hz,1H),7.37(d,J=7.3Hz,3H),7.25(d,J=8.1Hz,2H),6.96(t,J=51.7Hz,1H),5 .12(s,2H),3.66(d,J=21.7Hz,3H),3.46(s,1H),3.17(dd,J=21.7,9.9Hz ,2H),3.04(s,2H),2.59(s,2H),1.43-1.24(m,5H),0.91(t,J=7.2Hz,3H);

[0435] LRMS (ES) m / z 516.5 (M + +1).

[0436] 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'-aziridine]-3-carboxamide

[0437]

[0438] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenyl-[1,3'-aziridine]-3-carboxamide 2,2,2-trifluoroacetate (0.040 g, 0.087 mmol), isobutylaldehyde (0.013 g, 0.175 mmol), acetic acid (0.005 mL, 0.087 mmol) and sodium triacetoxyborohydride (0.055 g, 0.262 mmol) prepared in step 2 of Example 49 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.016 g, 35.6%) as a yellow gel.

[0439] 1 H NMR (400 MHz, CDCl 3 )δ9.26(d,J=2.1Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.59(d,J=8.2Hz,1H),7. 36(t,J=5.4Hz,3H),7.25(d,J=8.2Hz,2H),6.97(dd,J=64.8,38.6Hz,1H),5.13( s,2H),3.67(dd,J=22.5,9.8Hz,2H),3.37(s,3H),3.17(dd,J=22.4,10.4Hz,2H ),2.89(s,2H),2.26(d,J=6.6Hz,2H),1.67-1.49(m,1H),0.88(d,J=6.7Hz,6H);

[0440] LRMS (ES) m / z 516.5 (M + +1).

[0441] 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-phenylazetidine-3-carboxamide

[0442] [Step 1] Synthesis of 4-(3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl) tert-Butyl (phenyl)carbamoyl)-3-fluoroazetidin-1-yl)piperidine-1-carboxylate

[0443]

[0444] 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), 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) prepared in step 3 of Example 14 were 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained 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 , 40 g column; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the title compound (1.100 g, 75.6%) as a white solid.

[0445] [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

[0446]

[0447] Tert-butyl 4-(3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(phenyl)carbamoyl)-3-fluoroazetidine-1-yl)piperidine-1-carboxylate (1.000 g, 1.705 mmol) and trifluoroacetic acid (0.718 mL, 8.523 mmol) prepared in step 1 were dissolved in dichloromethane (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 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.

[0448] [Step 3] Synthesis of compound 3110

[0449]

[0450] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-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), formaldehyde (0.005 g, 0.164 mmol), acetic acid (0.005 mL, 0.082 mmol) and sodium triacetoxyborohydride (0.052 g, 0.247 mmol) prepared in step 2 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. Saturated sodium bicarbonate aqueous solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.020 g, 48.6%) as a yellow gel.

[0451] 1 H NMR (400 MHz, CDCl 3 )δ9.26(d,J=2.1Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.58(d,J=8.3Hz,1H),7.37(d,J=7.2Hz,3H),7.26(d,J=8.0Hz,2H),6.95(t,J=51.7Hz,1 H),5.13(s,2H),3.55(dd,J=23.1,9.9Hz,2H),3.12(dd,J=21.5,10.2Hz,2H),2.83(s,2H),2.35(s,3H),2.11(s,3H),1.71(s,2H),1.41(s,2H);

[0452] LRMS (ES) m / z 501.4 (M + +1).

[0453] 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

[0454]

[0455] 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), acetaldehyde (0.007 g, 0.164 mmol), acetic acid (0.007 mL, 0.082 mmol) and sodium triacetoxyborohydride (0.052 g, 0.247 mmol) prepared in step 2 of Example 54 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.017 g, 40.2%) as a yellow gel.

[0456] 1 H NMR (400 MHz, CDCl 3 )δ9.27(d,J=2.0Hz,1H),8.39(dd,J=8.3,2.2Hz,1H),7.57(d,J=7.8Hz,1H),7.38(d,J=7.4Hz,3H),7.25(s,2H),6.96(t,J=51.6Hz ,1H),5.13(s,2H),3.55(dd,J=23.4,9.9Hz,2H),3.12(dd,J=21.4,9.5Hz,2H),2.93(s,2H),1.72(s,7H),1.47(s,2H),1.20(s,3H);

[0457] LRMS (ES) m / z 515.5 (M + +1).

[0458] 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

[0459]

[0460] 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), propionaldehyde (0.010 g, 0.164 mmol), acetic acid (0.005 mL, 0.082 mmol) and sodium triacetoxyborohydride (0.052 g, 0.247 mmol) prepared in step 2 of Example 54 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.011 g, 25.3%) as a yellow gel.

[0461] 1 H NMR (400 MHz, CDCl 3 )δ9.26(d,J=1.6Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.58(d,J=8.2Hz,1H),7.37(d,J=7.2Hz,3H),7.26(d,J=7.9Hz,2H),6.96(t,J=51.6Hz, 1H),5.13(s,2H),3.55(dd,J=23.2,9.9Hz,2H),3.12(dd,J=21.4,10.2Hz,2H),2.90(s,2H),1.68(s,9H),1.42(s,2H),0.92(t,J=7.4Hz,3H);

[0462] LRMS (ES) m / z 529.6 (M + +1).

[0463] 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

[0464]

[0465] 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), butyraldehyde (0.012 g, 0.164 mmol), acetic acid (0.005 mL, 0.082 mmol) and sodium triacetoxyborohydride (0.052 g, 0.247 mmol) prepared in step 2 of Example 54 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.022 g, 49.3%) as a yellow gel.

[0466] 1 H NMR (400 MHz, CDCl 3 )δ9.27(d,J=1.8Hz,1H),8.39(dd,J=8.1,2.2Hz,1H),7.57(d,J=8.2Hz,1H),7.37(d,J=7.1Hz,3H),7.26(d,J=8.1Hz,2H),6.97(dd,J=64.6,3 8.7Hz,1H),5.13(s,2H),3.54(d,J=22.8Hz,2H),3.12(d,J=12.0Hz,2H),2.89(s,2H),1.66(s,10H),1.41-1.29(m,3H),0.93(t,J=7.3Hz,3H);

[0467] LRMS (ES) m / z 543.6 (M + +1).

[0468] 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

[0469]

[0470] 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), isobutyraldehyde (0.012 g, 0.164 mmol), acetic acid (0.005 mL, 0.082 mmol) and sodium triacetoxyborohydride (0.052 g, 0.247 mmol) prepared in step 2 of Example 54 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.017 g, 38.1%) as a yellow gel.

[0471] 1 H NMR (400 MHz, CDCl 3 )δ9.26(d,J=1.6Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.59(d,J=8.3Hz,1H),7. 40-7.34(m,3H),7.26(d,J=7.9Hz,2H),6.95(t,J=51.6Hz,1H),5.13(s,2H),3.5 4(dd,J=23.1,9.9Hz,2H),3.12(dd,J=21.2,10.2Hz,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=6.1Hz,6H);

[0472] LRMS (ES) m / z 544.5 (M + +1).

[0473] 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

[0474]

[0475] 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), 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) prepared in step 2 of Example 54 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.016 g, 36.8%) as a yellow gel.

[0476] 1 H NMR (400 MHz, CDCl 3 )δ9.28(d,J=2.2Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.55(d,J=7.9Hz,1H),7.39(d,J=7.1Hz,3H),7.26(s,2H),6.96(t,J=51.7Hz,1H),5.12( s,2H),3.55(dd,J=23.0,9.5Hz,2H),3.41(s,1H),3.12(dd,J=21.0,10.1Hz,3H),2.12(s,2H),1.85(s,4H),1.64(s,2H),1.30(d,J=6.7Hz,6H);

[0477] LRMS (ES) m / z 529.3 (M + +1).

[0478] 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

[0479]

[0480] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.060 g, 0.149 mmol), acetyl chloride (0.014 m, 0.193 mmol) and triethylamine (0.062 mL, 0.446 mmol) prepared in step 3 of Example 14 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 12 g column; ethyl acetate / hexanes = 0% to 30%) and concentration gave the title compound (0.015 g, 22.6%) as a yellow gel.

[0481] 1 H NMR (400 MHz, CDCl 3 )δ9.20(d,J=1.8Hz,1H),8.31(dd,J=8.2,2.2Hz,1H),7.45(d,J=8.2Hz,1H ),7.37-7.23(m,3H),7.20(d,J=4.3Hz,2H),6.88(dd,J=64.1,39.2Hz,1H), 5.04(s,2H),4.67(dd,J=21.4,10.4Hz,1H),4.25(dd,J=22.5,11.7Hz,1H) ,3.94(dd,J=22.7,9.6Hz,1H),3.58(dd,J=23.1,11.8Hz,1H),1.79(s,3H);

[0482] LRMS (ES) m / z 446.5 (M + +1).

[0483] 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

[0484]

[0485] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.060 g, 0.149 mmol), propionyl chloride (0.018 g, 0.193 mmol) and triethylamine (0.062 mL, 0.446 mmol) prepared in step 3 of Example 14 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.024 g, 35.1%) as a yellow gel.

[0486] 1 H NMR (400 MHz, CDCl 3 )δ9.29(d,J=1.7Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.54(d,J=8.2Hz,1H),7.48- 7.34(m,3H),7.28(d,J=4.5Hz,2H),6.97(dd,J=64.2,39.1Hz,1H),5.13(s,2H),4. 74(dd,J=21.6,10.4Hz,1H),4.35(dd,J=22.6,11.8Hz,1H),4.02(dd,J=22.8,9.9H z,1H),3.68(dd,J=23.1,11.7Hz,1H),2.11(q,J=7.5Hz,2H),1.12(t,J=7.5Hz,3H);

[0487] LRMS (ES) m / z 460.2 (M + +1).

[0488] 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

[0489]

[0490] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.060 g, 0.149 mmol), butyryl chloride (0.021 g, 0.193 mmol) and triethylamine (0.062 mL, 0.446 mmol) prepared in step 3 of Example 14 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.021 g, 29.8%) as a yellow gel.

[0491] 1 H NMR (400 MHz, CDCl 3 )δ9.20(d,J=1.8Hz,1H),8.31(dd,J=8.2,2.2Hz,1H),7.45(d,J=8.2Hz,1H),7.36-7.26(m ,3H),7.19(d,J=4.5Hz,2H),6.88(dd,J=64.1,39.2Hz,1H),5.04(s,2H),4.66(dd,J=21.7, 10.4Hz, 1H), 4.25 (dd, J=22.4, 12.2Hz, 1H), 3.93 (dd, J=22.6, 10.0Hz, 1H), 3.58 (dd, J=23. 5,12.0Hz,1H),1.97(t,J=7.5Hz,2H),1.54(dq,J=14.8,7.5Hz,2H),0.85(t,J=7.4Hz,3H);

[0492] LRMS (ES) m / z 475.5 (M + +1).

[0493] 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

[0494]

[0495] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.060 g, 0.149 mmol), 3-methylbutyryl chloride (0.023 g, 0.193 mmol) and triethylamine (0.062 mL, 0.446 mmol) prepared in step 3 of Example 14 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.019 g, 26.2%) as a yellow gel.

[0496] 1 H NMR (400 MHz, CDCl 3 )δ9.29(d,J=1.8Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.54(d,J=8.2Hz,1H),7.45-7.35(m ,3H),7.28(d,J=5.0Hz,2H),6.97(dd,J=64.2,39.1Hz,1H),5.13(s,2H),4.76(dd,J=21.6, 10.4Hz, 1H), 4.34 (dd, J=22.8, 12.3Hz, 1H), 4.03 (dd, J=22.8, 10.1Hz, 1H), 3.67 (dd, J=23. 2,12.4Hz,1H),2.11(td,J=13.5,6.7Hz,1H),1.96(d,J=7.1Hz,2H),0.95(t,J=6.5Hz,6H);

[0497] LRMS(ES)m / z 488.3(M + +1).

[0498] 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

[0499]

[0500] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.060 g, 0.149 mmol), cyclohexanecarboxaldehyde (0.033 g, 0.297 mmol), acetic acid (0.009 mL, 0.149 mmol) and sodium triacetoxyborohydride (0.095 g, 0.446 mmol) prepared in step 3 of Example 14 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.024 g, 32.3%) as a yellow gel.

[0501] 1 H NMR (400 MHz, CDCl 3 )δ9.16(d,J=1.7Hz,1H),8.29(dd,J=8.2,2.2Hz,1H),7.50(d,J=8.2Hz,1H),7.31- 7.23(m,3H),7.16(dd,J=8.0,1.4Hz,2H),6.88(dd,J=65.1,38.3Hz,1H),5.03(s,2H ),3.45(dd,J=22.6,8.4Hz,2H),3.06(dd,J=20.8,9.5Hz,2H),2.19(d,J=6.6Hz,2H) ,1.77-1.64(m,2H),1.60(s,2H),1.27-0.95(m,5H),0.76(dd,J=21.4,11.4Hz,2H);

[0502] LRMS (ES) m / z 501.4 (M + +1).

[0503] 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

[0504]

[0505] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.060 g, 0.149 mmol), 3-methoxypropanoyl chloride (0.024 g, 0.193 mmol) and triethylamine (0.062 mL, 0.446 mmol) prepared in step 3 of Example 14 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.031 g, 42.6%) as a yellow gel.

[0506] 1 H NMR (400 MHz, CDCl 3 )δ9.19(d,J=1.8Hz,1H),8.31(dd,J=8.2,2.2Hz,1H),7.45(d,J=8.2Hz,1H),7.40-7 .26(m,3H),7.19(d,J=4.9Hz,2H),6.88(dd,J=64.4,38.9Hz,1H),5.04(s,2H),4.67 (dd,J=21.5,10.2Hz,1H),4.27(dd,J=22.5,12.3Hz,1H),3.96(dd,J=22.7,10.1Hz, 1H),3.71-3.58(m,1H),3.58-3.50(m,2H),3.28-3.23(m,3H),2.24(t,J=6.2Hz,2H);

[0507] LRMS (ES) m / z 490.2 (M + +1).

[0508] 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

[0509]

[0510] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.060 g, 0.149 mmol), cyclopropanecarbonyl chloride (0.020 g, 0.193 mmol) and triethylamine (0.062 mL, 0.446 mmol) prepared in step 3 of Example 14 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.019 g, 27.1%) as a yellow gel.

[0511] 1 H NMR (400 MHz, CDCl 3 )δ9.29(d,J=1.8Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.55(d,J=8.1Hz,1H),7.46-7.33(m,3H),7.33-7.2 0(m,2H),6.97(dd,J=64.1,39.2Hz,1H),5.14(s,2H),4.88(dd,J=21.1,10.1Hz,1H),4.35(dd,J=22.9,11 .2Hz,1H),4.15(dd,J=22.1,9.9Hz,1H),3.68(dd,J=23.5,11.9Hz,1H),3.46(d,J=27.5Hz,1H),1.71(ddd ,J=12.7,8.0,4.7Hz,1H),1.36(ddd,J=12.5,8.1,4.6Hz,1H),1.16(d,J=12.6Hz,1H),0.83-0.77(m,1H);

[0512] LRMS (ES) m / z 472.2 (M + +1).

[0513] 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

[0514]

[0515] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.060 g, 0.149 mmol), cyclobutanecarbonyl chloride (0.023 g, 0.193 mmol) and triethylamine (0.062 mL, 0.446 mmol) prepared in step 3 of Example 14 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.020 g, 27.7%) as a yellow gel.

[0516] 1 H NMR (400 MHz, CDCl 3 )δ9.19(d,J=1.8Hz,1H),8.30(dd,J=8.2,2.2Hz,1H),7.44(d,J=8.2Hz,1H),7.37-7.25(m, 3H),7.18(d,J=8.3Hz,2H),6.88(dd,J=64.3,39.0Hz,1H),5.03(s,2H),4.58(dd,J=21.8,10 .3Hz,1H),4.24(dd,J=22.7,11.7Hz,1H),3.86(dd,J=22.7,10.5Hz,1H),3.57(dd,J=23.3,1 1.6Hz,1H),2.92(p,J=8.5Hz,1H),2.31-2.12(m,2H),2.06-1.96(m,2H),1.96-1.74(m,2H);

[0517] LRMS (ES) m / z 486.3 (M + +1).

[0518] 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

[0519]

[0520] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.060 g, 0.149 mmol), cyclopentanecarbonyl chloride (0.026 g, 0.193 mmol) and triethylamine (0.062 mL, 0.446 mmol) prepared in step 3 of Example 14 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.011 g, 14.8%) as a yellow gel.

[0521] 1 H NMR (400 MHz, CDCl 3 )δ9.29(d,J=1.8Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.55(d,J=8.2Hz,1H),7.4 0(dd,J=8.5,3.1Hz,3H),7.28(s,2H),6.97(dd,J=64.1,39.2Hz,1H),5.14(s,2H) ,4.78(dd,J=21.7,10.1Hz,1H),4.33(dd,J=22.7,11.9Hz,1H),4.05(dd,J=22.9 ,10.1Hz,1H),3.67(dd,J=23.3,11.4Hz,1H),2.53(d,J=7.8Hz,1H),1.74(s,8H);

[0522] LRMS (ES) m / z 500.2 (M + +1).

[0523] 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

[0524]

[0525] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.060 g, 0.149 mmol), cyclohexanecarbonyl chloride (0.028 g, 0.193 mmol) and triethylamine (0.062 mL, 0.446 mmol) prepared in step 3 of Example 14 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.032 g, 41.9%) as a yellow gel.

[0526] 1 H NMR (400 MHz, CDCl 3 )δ9.28(d,J=1.8Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.54(d,J=8.2Hz,1H),7.46-7.36(m,3H),7.2 8(d,J=6.9Hz,2H),6.97(dd,J=64.2,39.1Hz,1H),5.13(s,2H),4.80(dd,J=21.2,10.3Hz,1H),4.32 (dd,J=22.4,11.9Hz,1H),4.07(dd,J=22.6,10.3Hz,1H),3.65(dd,J=23.2,12.2Hz,1H),2.10(ddd, J=11.6,7.5,3.2Hz,1H),1.86-1.68(m,4H),1.44(dt,J=33.2,16.7Hz,2H),1.26(d,J=15.1Hz,4H);

[0527] LRMS (ES) m / z 514.3 (M + +1).

[0528] 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

[0529]

[0530] 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), 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) prepared in step 3 of Example 14 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.019 g, 25.4%) as a yellow gel.

[0531] 1 H NMR (400 MHz, CDCl 3 )δ9.17(d,J=1.8Hz,1H),8.30(dd,J=8.2,2.2Hz,1H),7.49(d,J=8.2Hz,1H),7.2 9(dt,J=10.5,3.6Hz,3H),7.22-7.10(m,2H),6.86(t,J=51.7Hz,1H),5.03(s,2H ),3.47(dd,J=22.9,8.7Hz,2H),3.04(dd,J=21.3,9.1Hz,2H),2.59(t,J=11.8Hz ,2H),2.49-2.37(m,2H),1.98(s,1H),1.81(d,J=13.0Hz,2H),1.48-1.30(m,2H);

[0532] LRMS (ES) m / z 505.3 (M + +1).

[0533] 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

[0534]

[0535] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol), propionyl chloride (0.014 g, 0.154 mmol) and triethylamine (0.050 mL, 0.356 mmol) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.023 g, 40.6%) as a yellow gel.

[0536] 1 H NMR (400 MHz, CDCl 3 )δ9.21(d,J=1.8Hz,1H),8.32(dd,J=8.2,2.2Hz,1H),7.44(d,J=8.2Hz,1H),7. 29(dd,J=14.8,8.2Hz,1H),6.93(dt,J=75.5,30.1Hz,4H),5.01(s,2H),4.67(dd ,J=21.3,9.9Hz,1H),4.30(dd,J=21.9,11.3Hz,1H),3.97(dd,J=22.3,9.6Hz,1 H), 3.68 (dd, J = 23.6, 12.3Hz, 1H), 2.03 (q, J = 7.5Hz, 2H), 1.03 (t, J = 7.5Hz, 3H);

[0537] LRMS (ES) m / z 478.6 (M + +1).

[0538] 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

[0539]

[0540] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol), acetyl chloride (0.011 m, 0.154 mmol) and triethylamine (0.050 mL, 0.356 mmol) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.022 g, 40.0%) as a yellow gel.

[0541] 1 H NMR (400 MHz, CDCl 3 )δ9.31(d,J=1.8Hz,1H),8.41(dd,J=8.2,2.2Hz,1H),7.53(d,J=8.3Hz,1H),7.38(dd,J=14.6,8.3Hz,1H),7.19-6.74(m,4H),5.10(s,2H) ,4.78(dd,J=21.3,9.6Hz,1H),4.39(dd,J=22.1,11.3Hz,1H),4.08(dd,J=22.0,10.1Hz,1H),3.76(dd,J=22.7,12.1Hz,1H),1.90(s,3H);

[0542] LRMS (ES) m / z 464.2 (M + +1).

[0543] 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

[0544]

[0545] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol), butyryl chloride (0.016 g, 0.154 mmol) and triethylamine (0.050 mL, 0.356 mmol) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.021 g, 36.0%) as a yellow gel.

[0546] 1 H NMR (400 MHz, CDCl 3 )δ9.21(d,J=1.8Hz,1H),8.32(dd,J=8.2,2.2Hz,1H),7.44(d,J=8.2Hz,1H),7.29(dd,J =14.7,8.1Hz,1H),6.93(dt,J=75.8,30.1Hz,4H),5.01(s,2H),4.68(dd,J=21.0,10.0H z,1H),4.29(dd,J=22.1,11.7Hz,1H),3.98(dd,J=22.3,10.0Hz,1H),3.67(dd,J=22.8, 11.7Hz,1H),1.98(t,J=7.4Hz,2H),1.55(dq,J=14.7,7.4Hz,2H),0.86(t,J=7.4Hz,3H);

[0547] LRMS (ES) m / z 493.5 (M + +1).

[0548] 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

[0549]

[0550] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol), 3-methylbutyryl chloride (0.019 g, 0.154 mmol) and triethylamine (0.050 mL, 0.356 mmol) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.025 g, 41.7%) as a yellow gel.

[0551] 1 H NMR (400 MHz, CDCl 3 )δ9.21(d,J=1.8Hz,1H),8.32(dd,J=8.2,2.2Hz,1H),7.44(d,J=8.1Hz,1H),7.29(d d,J=14.9,7.8Hz,1H),6.93(dt,J=75.7,30.1Hz,4H),5.01(s,2H),4.68(dd,J=21.2 ,10.3Hz,1H),4.29(dd,J=22.0,11.5Hz,1H),3.98(dd,J=22.3,10.4Hz,1H),3.67(d d,J=23.0,11.6Hz,1H),2.10-1.97(m,1H),1.88(d,J=7.1Hz,2H),0.89-0.84(m,6H);

[0552] LRMS (ES) m / z 506.2 (M + +1).

[0553] 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

[0554]

[0555] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol), 3-methoxypropanoyl chloride (0.019 g, 0.154 mmol) and triethylamine (0.050 mL, 0.356 mmol) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.025 g, 41.5%) as a yellow gel.

[0556] 1 H NMR (400 MHz, CDCl 3 )δ9.21(d,J=1.7Hz,1H),8.32(dd,J=8.2,2.2Hz,1H),7.44(d,J=8.1Hz,1H), 7.28(dd,J=14.6,8.3Hz,1H),7.09-6.68(m,4H),5.01(s,2H),4.69(dd,J=21. 9,10.1Hz,1H),4.31(dd,J=22.3,11.9Hz,1H),4.01(dd,J=22.6,10.6Hz,1H), 3.81-3.64(m,1H),3.57(q,J=6.2Hz,2H),3.25(s,3H),2.26(t,J=6.2Hz,2H);

[0557] LRMS (ES) m / z 508.2 (M + +1).

[0558] Example 76: Synthesis of Compound 3168, 1-(cyclobutanecarbonyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide

[0559]

[0560] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol), cyclobutanecarbonyl chloride (0.018 g, 0.154 mmol) and triethylamine (0.050 mL, 0.356 mmol) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.025 g, 41.8%) as a yellow gel.

[0561] 1 H NMR (400 MHz, CDCl 3 )δ9.21(d,J=1.9Hz,1H),8.31(dd,J=8.2,2.2Hz,1H),7.43(d,J=8.2Hz,1H),7.28(dd,J=14.5,8 .0Hz,1H),6.95(ddd,J=99.3,44.9,30.2Hz,4H),5.00(s,2H),4.60(dd,J=21.5,10.1Hz,1H),4.2 8(dd,J=22.2,11.7Hz,1H),3.90(dd,J=22.4,10.5Hz,1H),3.66(dd,J=23.3,11.9Hz,1H),2.93( p,J=8.6Hz,1H),2.22(tt,J=17.6,8.7Hz,2H),2.00(dt,J=25.6,12.9Hz,2H),1.93–1.76(m,2H);

[0562] LRMS (ES) m / z 504.2 (M + +1).

[0563] 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

[0564]

[0565] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol), cyclopentanecarbonyl chloride (0.020 g, 0.154 mmol) and triethylamine (0.050 mL, 0.356 mmol) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.033 g, 53.7%) as a yellow gel.

[0566] 1 H NMR (400 MHz, CDCl 3 )δ9.21(d,J=1.8Hz,1H),8.32(dd,J=8.2,2.2Hz,1H),7.44(d,J=8.1Hz,1H),7.29( dd,J=14.7,8.0Hz,1H),6.93(dt,J=75.6,30.1Hz,4H),5.01(s,2H),4.70(dd,J=21. 3,10.3Hz,1H),4.28(dd,J=22.2,11.7Hz,1H),4.00(dd,J=22.4,9.8Hz,1H),3.66( dd,J=23.0,11.9Hz,1H),2.45(d,J=7.5Hz,1H),1.66(s,6H),1.47(d,J=5.1Hz,2H);

[0567] LRMS (ES) m / z 518.2 (M + +1).

[0568] 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

[0569]

[0570] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol), cyclohexanecarbonyl chloride (0.023 g, 0.154 mmol) and triethylamine (0.050 mL, 0.356 mmol) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.031 g, 49.2%) as a yellow gel.

[0571] 1 H NMR (400 MHz, CDCl 3 )δ9.21(d,J=1.8Hz,1H),8.32(dd,J=8.2,2.2Hz,1H),7.44(d,J=8.4Hz,1H),7.29(d d,J=14.7,8.1Hz,1H),7.08-6.69(m,4H),5.01(s,2H),4.72(dd,J=21.2,9.5Hz,1H) ,4.27(dd,J=21.4,11.8Hz,1H), 4.02(dd,J=22.4,9.1Hz,1H), 3.65(dd,J=22.4,11. 7Hz,1H),2.03(t,J=11.7Hz,1H),1.70(s,3H),1.44-1.31(m,3H),1.23-1.09(m,4H);

[0572] LRMS(ES)m / z 532.3(M + +1).

[0573] 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

[0574]

[0575] 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), cyclohexanecarboxaldehyde (0.027 g, 0.237 mmol), acetic acid (0.007 mL, 0.119 mmol) and sodium triacetoxyborohydride (0.075 g, 0.356 mmol) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.028 g, 45.6%) as a yellow gel.

[0576] 1 H NMR (400 MHz, CDCl 3 )δ9.18(d,J=1.7Hz,1H),8.30(dd,J=8.2,2.2Hz,1H),7.48(d,J=8.2Hz,1H),7.25(td,J=8.2,6.4Hz,1H),6.91(dt,J=84.0,29.1Hz,4H),5. 00(s,2H),3.52(dd,J=25.3,13.7Hz,2H),3.12(d,J=12.5Hz,2H),2.19(t,J=13.2Hz,2H),1.77-1.52(m,9H),0.77(dd,J=22.1,11.5Hz,2H);

[0577] LRMS (ES) m / z 519.3 (M + +1).

[0578] 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

[0579]

[0580] 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), 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) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.018 g, 29.1%) as a yellow gel.

[0581] 1 H NMR (400 MHz, CDCl 3 )δ9.19(d,J=1.7Hz,1H),8.30(dd,J=8.2,2.2Hz,1H),7.47(d,J=8.1Hz,1H),7.33-7.21(m,1H),7.04-6.70(m,4H),5.01(s,2H),3.64-3.39(m,2 H),3.22-3.02(m,2H),2.61(d,J=13.9Hz,2H),2.52-2.35(m,2H),1.99(d,J=10.9Hz,1H),1.83(d,J=13.0Hz,2H),1.39(dd,J=20.5,10.2Hz,2H);

[0582] LRMS (ES) m / z 523.2 (M + +1).

[0583] 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

[0584]

[0585] 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), 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) prepared in step 3 of Example 14 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.022 g, 29.5%) as a yellow gel.

[0586] 1 H NMR (400 MHz, CDCl 3 )δ9.26(d,J=1.7Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.57(t,J=9.6Hz,1H),7. 37(d,J=7.1Hz,3H),7.25(d,J=7.9Hz,2H),6.97(dd,J=64.8,38.5Hz,1H),5.12 (s,2H),3.99-3.89(m,2H),3.65-3.44(m,2H),3.34(dd,J=11.6,10.2Hz,2H),3 .17(d,J=13.5Hz,2H),2.34(s,2H),1.58(d,J=13.1Hz,2H),1.32-1.16(m,3H);

[0587] LRMS (ES) m / z 503.3 (M + +1).

[0588] 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

[0589]

[0590] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol), cyclopropanecarbonyl chloride (0.016 g, 0.154 mmol) and triethylamine (0.050 mL, 0.356 mmol) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.014 g, 24.1%) as a yellow gel.

[0591] 1 H NMR (400 MHz, CDCl 3 )δ9.31(d,J=1.8Hz,1H),8.41(dd,J=8.2,2.2Hz,1H),7.54(d,J=8.2Hz,1H),7.38(dd,J=14.6,8.3Hz,1H),7.15-6.82(m,4H),5 .11(s,2H),4.91(s,1H),4.40(s,1H),4.20(d,J=15.3Hz,1H),3.76(s,1H),3.47(s,1H),1.02-0.96(m,2H),0.83-0.75(m,2H);

[0592] LRMS (ES) m / z 490.5 (M + +1).

[0593] 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

[0594]

[0595] 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), 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) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.022 g, 35.7%) as a yellow gel.

[0596] 1 H NMR (400 MHz, CDCl 3 )δ9.28(d,J=1.8Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.56(d,J=8.0Hz,1H),7.40-7.31(m,1H),7.02(ddd,J=86.4,42.5,28.2Hz,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);

[0597] LRMS (ES) m / z 521.4 (M + +1).

[0598] 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'-aziridine]-3-carboxamide

[0599] [Step 1] Synthesis of 3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(3- tert-Butyl (1,3'-azoline)-3-fluoro-[1,3'-phenyl]carbamoyl)-1'-carboxylate

[0600]

[0601] 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), 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) prepared in step 2 of Example 31 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 12 g column; dichloromethane / methanol = 0% to 10%) and concentrated to afford the title compound (0.300 g, 87.7%) as a yellow gel.

[0602] [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'-aziridine]-3-carboxamide 2,2,2-trifluoroacetate

[0603]

[0604] Tert-butyl 3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(3-fluorophenyl)carbamoyl)-3-fluoro-[1,3'-aziridine]-1'-carboxylate (0.380 g, 0.659 mmol) and trifluoroacetic acid (1.009 mL, 13.182 mmol) prepared in step 1 were dissolved in dichloromethane (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 2 hours. 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.

[0605] [Step 3] Synthesis of compound 3219

[0606]

[0607] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-[1,3'-aziridine]-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.105 mmol), formaldehyde (0.006 g, 0.210 mmol), acetic acid (0.006 mL, 0.105 mmol) and sodium triacetoxyborohydride (0.067 g, 0.315 mmol) prepared in step 2 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure. Saturated sodium bicarbonate aqueous solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.023 g, 44.7%) as a yellow gel.

[0608] 1 H NMR (400 MHz, CDCl 3 )δ9.28(d,J=2.1Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.56(d,J=7.8Hz,1H),7.36(dd,J=14.5,8.1Hz,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);

[0609] LRMS(ES)m / z 492.3(M + +1).

[0610] 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'-aziridine]-3-carboxamide

[0611]

[0612] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-[1,3'-aziridine]-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.105 mmol), acetaldehyde (0.009 g, 0.210 mmol), acetic acid (0.006 mL, 0.105 mmol) and sodium triacetoxyborohydride (0.067 g, 0.315 mmol) prepared in step 2 of Example 84 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.025 g, 47.2%) as a yellow gel.

[0613] 1 H NMR (400 MHz, CDCl 3 )δ9.19(d,J=1.7Hz,1H),8.31(dd,J=8.2,2.2Hz,1H),7.47(d,J=8.2Hz,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=27.2Hz,3H),3.23-3.06(m,2H),2.91(s,2H),2.50(s,2H),0.93(t,J=7.1Hz,3H);

[0614] LRMS (ES) m / z 506.3 (M + +1).

[0615] 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'-aziridine]-3-carboxamide

[0616]

[0617] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-[1,3'-aziridine]-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.105 mmol), propionaldehyde (0.012 g, 0.210 mmol), acetic acid (0.006 mL, 0.105 mmol) and sodium triacetoxyborohydride (0.067 g, 0.315 mmol) prepared in step 2 of Example 84 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.025 g, 45.9%) as a yellow gel.

[0618] 1 H NMR (400 MHz, CDCl 3 )δ9.28(d,J=1.6Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.56(d,J=8.2Hz,1H),7.40-7.31(m,1H),7.02(ddd,J=87.4,42.7,28.5Hz,4H),5.10(s,2 H),3.81-3.65(m,2H),3.44(s,3H),3.25(dd,J=21.9,8.9Hz,2H),3.00(s,2H),2.49(s,2H),1.42(dd,J=14.5,7.4Hz,2H),0.91(t,J=7.4Hz,3H);

[0619] LRMS (ES) m / z 520.4 (M + +1).

[0620] 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'-aziridine]-3-carboxamide

[0621]

[0622] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-[1,3'-aziridine]-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.105 mmol), butyraldehyde (0.015 g, 0.210 mmol), acetic acid (0.006 mL, 0.105 mmol) and sodium triacetoxyborohydride (0.067 g, 0.315 mmol) prepared in step 2 of Example 84 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.022 g, 39.4%) as a yellow gel.

[0623] 1 H NMR (400 MHz, CDCl 3 )δ9.28(d,J=2.0Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.56(d,J=8.1Hz,1H),7.40-7.31(m,1H),7.13-6.80(m,4H),5.09(s,2H),3.7 2(d,J=22.8Hz,2H),3.50(d,J=34.3Hz,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=7.1Hz,3H);

[0624] LRMS (ES) m / z 534.3 (M + +1).

[0625] 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'-aziridine]-3-carboxamide

[0626]

[0627] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-[1,3'-aziridine]-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.105 mmol), isobutyraldehyde (0.015 g, 0.210 mmol), acetic acid (0.006 mL, 0.105 mmol) and sodium triacetoxyborohydride (0.067 g, 0.315 mmol) prepared in step 2 of Example 84 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.021 g, 37.6%) as a yellow gel.

[0628] 1 H NMR (400 MHz, CDCl 3 )δ9.28(d,J=1.9Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.56(d,J=8.1Hz,1H), 7.40-7.31(m,1H),7.02(ddd,J=87.3,42.4,27.7Hz,4H),5.10(s,2H),3.72(d d,J=21.4,9.1Hz,2H),3.42(s,3H),3.24(dd,J=22.3,9.7Hz,2H),2.94(s,2H ), 2.29 (d, J = 6.3Hz, 2H), 1.62 (dt, J = 13.1, 6.7Hz, 1H), 0.89 (d, J = 6.7Hz, 6H);

[0629] LRMS (ES) m / z 534.4 (M + +1).

[0630] 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'-aziridine]-3-carboxamide

[0631]

[0632] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-[1,3'-aziridine]-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.105 mmol), 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) prepared in step 2 of Example 84 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. Saturated aqueous sodium bicarbonate solution was poured into the obtained concentrate, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.015 g, 27.6%) as a yellow gel.

[0633] 1 H NMR (400 MHz, CDCl 3 )δ9.28(d,J=1.7Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.56(d,J=8.1Hz,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=21.0,9.7Hz,2H),3.01(s,2H),2.50(s,1H),1.02(d,J=5.6Hz,6H);

[0634] LRMS (ES) m / z 520.4 (M + +1).

[0635] 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

[0636] [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

[0637]

[0638] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-(3-fluorophenyl)piperidine-4-carboxamide 2,2,2-trifluoroacetate (0.458 g, 1.019 mmol), 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) prepared in step 3 of Example 10 were dissolved in dichloromethane (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 24 g column; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.300 g, 48.7%) as a yellow gel.

[0639] [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

[0640]

[0641] 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) and trifluoroacetic acid (0.760 mL, 9.924 mmol) prepared in step 1 were dissolved in dichloromethane (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 2 hours. 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.

[0642] [Step 3] Synthesis of compound 3389

[0643]

[0644] 1-(azetidine-3-yl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-4-fluoro-N-(3-fluorophenyl)piperidine-4-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.099 mmol), formaldehyde (0.006 g, 0.198 mmol), acetic acid (0.006 mL, 0.099 mmol) and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) prepared in step 2 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.015 g, 29.2%) as a yellow gel.

[0645] 1 H NMR (400 MHz, CDCl 3 )δ9.19(d,J=2.0Hz,1H),8.29(dd,J=8.2,2.2Hz,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=21.9Hz,2H),3. 33-3.18(m,1H),2.87-2.61(m,2H),2.46(d,J=9.9Hz,1H),2.22(ddd,J=30.1,16.9 ,8.7Hz,3H),1.93(dt,J=25.0,11.9Hz,4H),1.25-1.19(m,1H),0.84-0.72(m,1H);

[0646] LRMS (ES) m / z 519.2 (M + +1).

[0647] 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

[0648]

[0649] 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), propionaldehyde (0.012 g, 0.198 mmol), acetic acid (0.006 mL, 0.099 mmol) and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) prepared in step 2 of Example 90 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.015 g, 27.7%) as a yellow gel.

[0650] 1 H NMR (400 MHz, CDCl 3 )δ9.22-9.15(m,1H),8.29(dd,J=8.2,2.2Hz,1H),7.42(d,J=8.2Hz,1H),7.2 6-7.20(m,1H),7.01-6.72(m,4H),4.97(s,2H),3.69(d,J=25.8Hz,2H),3.03( dd,J=11.9,5.6Hz,3H),2.60-2.52(m,2H),2.52-2.42(m,2H),2.33-2.13(m, 2H),1.90(dt,J=32.9,11.9Hz,4H),1.47-1.36(m,2H),0.85(t,J=7.4Hz,3H);

[0651] LRMS(ES)m / z 547.0(M + +1).

[0652] 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

[0653]

[0654] 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), butyraldehyde (0.014 g, 0.198 mmol), acetic acid (0.006 mL, 0.099 mmol) and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) prepared in step 2 of Example 90 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.015 g, 27.0%) as a yellow gel.

[0655] 1 H NMR (400 MHz, CDCl 3 )δ9.25-9.10(m,1H),8.29(dd,J=8.2,2.2Hz,1H),7.43(t,J=9.3Hz,1H),7.26-7.2 0(m,1H),7.01-6.71(m,4H),4.97(s,2H),3.71(s,2H),3.02(dd,J=14.8,6.1Hz,3H) ,2.62-2.53(m,2H),2.53-2.43(m,2H),2.22(dtd,J=25.2,13.0,8.2Hz,2H),1.99-1 .80(m,4H),1.41-1.31(m,2H),1.25(td,J=14.4,7.1Hz,2H),0.83(t,J=7.3Hz,3H);

[0656] LRMS (ES) m / z 561.1 (M + +1).

[0657] 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

[0658]

[0659] 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), isobutyraldehyde (0.014 g, 0.198 mmol), acetic acid (0.006 mL, 0.099 mmol) and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) prepared in step 2 of Example 90 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.015 g, 27.0%) as a yellow gel.

[0660] 1 H NMR (400 MHz, CDCl 3 )δ9.18(d,J=1.6Hz,1H),8.29(dd,J=8.2,2.2Hz,1H),7.42(d,J=8.2Hz,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=13.1,6.7Hz,1H),0.84(d,J=6.7Hz,6H);

[0661] LRMS (ES) m / z 561.1 (M + +1).

[0662] 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

[0663]

[0664] 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), 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) prepared in step 2 of Example 90 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.015 g, 27.7%) as a yellow gel.

[0665] 1 H NMR (400 MHz, CDCl 3 )δ9.18(d,J=1.6Hz,1H),8.29(dd,J=8.2,2.2Hz,1H),7.42(d,J=8.2Hz,1H),7.28-7.16(m,1H),7.03-6.71(m,4H),4.99(d,J=13 .6Hz,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=31.4,11.9Hz,4H),0.98(d,J=6.3Hz,6H);

[0666] LRMS (ES) m / z 547.1 (M + +1).

[0667] 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'-aziridine]-3-carboxamide

[0668]

[0669] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-[1,3'-aziridine]-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.105 mmol), cyclobutanone (0.015 g, 0.210 mmol), acetic acid (0.006 mL, 0.105 mmol) and sodium triacetoxyborohydride (0.067 g, 0.315 mmol) prepared in step 2 of Example 84 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.015 g, 26.9%) as a yellow gel.

[0670] 1 H NMR (400 MHz, CDCl 3 )δ9.18(d,J=1.6Hz,1H),8.30(dd,J=8.2,2.2Hz,1H),7.47(d,J=8.1Hz,1H),7.26(dt ,J=8.0,7.2Hz,1H),6.92(dt,J=85.9,29.1Hz,4H),5.00(s,2H),3.63(dd,J=21.5,9. 2Hz,2H),3.40-3.27(m,3H),3.15(dd,J=17.6,9.8Hz,3H),2.93(s,2H),1.96-1.84(m ,2H),1.80(dd,J=19.3,9.6Hz,2H),1.75-1.66(m,1H),1.60(dt,J=10.3,8.6Hz,1H);

[0671] LRMS(ES)m / z 531.0(M + +1).

[0672] 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'-(oxetane-3-yl)-[1,3'-aziridine]-3-carboxamide

[0673]

[0674] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-[1,3'-diazetidine]-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.105 mmol), oxetane-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) prepared in step 2 of Example 84 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.015 g, 26.8%) as a yellow gel.

[0675] 1 H NMR (400 MHz, CDCl 3 )δ9.19(dd,J=4.2,1.9Hz,1H),8.31(dd,J=8.2,1.5Hz,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=6.7Hz,1H),4.48-4.3 7(m,1H),4.06-3.91(m,1H),3.88(s,1H),3.66(ddd,J=63.0,30.5,14.3Hz,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);

[0676] LRMS (ES) m / z 533.4 (M + +1).

[0677] 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'-aziridine]-3-carboxamide

[0678]

[0679] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-[1,3'-aziridine]-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.105 mmol), cyclopentanone (0.018 g, 0.210 mmol), acetic acid (0.006 mL, 0.105 mmol) and sodium triacetoxyborohydride (0.067 g, 0.315 mmol) prepared in step 2 of Example 84 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.015 g, 26.2%) as a yellow gel.

[0680] 1 H NMR (400 MHz, CDCl 3 )δ9.22-9.13(m,1H),8.31(dd,J=8.2,2.2Hz,1H),7.47(d,J=8.1Hz,1H),7.30-7.22(m,1H) ,6.92(dt,J=85.4,29.4Hz,4H),5.00(s,2H),3.63(dd,J=21.8,9.3Hz,2H),3.46(t,J=7.3H z,2H),3.41-3.30(m,1H),3.15(dd,J=21.7,9.2Hz,2H),2.95(d,J=7.0Hz,2H),2.83(dd,J= 11.8,6.0Hz,1H),1.71-1.53(m,4H),1.46(ddd,J=9.2,7.6,2.5Hz,2H),1.39-1.29(m,2H);

[0681] LRMS (ES) m / z 546.3 (M + +1).

[0682] 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'-aziridine]-3-carboxamide

[0683]

[0684] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-[1,3'-diazetidine]-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.105 mmol), 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) prepared in step 2 of Example 84 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.015 g, 26.2%) as a yellow gel.

[0685] 1 H NMR (400 MHz, CDCl 3 )δ9.18(d,J=1.6Hz,1H),8.30(dd,J=8.2,2.2Hz,1H),7.46(d,J=8.1Hz,1H),7.26(td,J=8.1,6. 4Hz,1H),7.02-6.70(m,4H),5.00(s,2H),3.80(dd,J=15.6,7.6Hz,1H),3.59(dddd,J=26.6,12.0 ,8.7,3.9Hz,5H),3.27(s,3H),3.15(dd,J=21.9,9.2Hz,2H),2.93(td,J=8.0,2.9Hz,1H),2.82( d,J=11.4Hz,2H),1.78(ddd,J=15.1,12.8,7.5Hz,1H),1.60(dddd,J=12.5,7.5,4.9,2.9Hz,1H);

[0686] LRMS (ES) m / z 548.1 (M + +1).

[0687] 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'-aziridine]-3-carboxamide

[0688]

[0689] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-[1,3'-aziridine]-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.105 mmol), cyclohexanone (0.021 g, 0.210 mmol), acetic acid (0.006 mL, 0.105 mmol) and sodium triacetoxyborohydride (0.067 g, 0.315 mmol) prepared in step 2 of Example 84 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.015 g, 25.6%) as a yellow gel.

[0690] 1 H NMR (400 MHz, CDCl 3 )δ9.19(d,J=1.7Hz,1H),8.31(dd,J=8.2,2.2Hz,1H),7.47(d,J=8.1Hz,1H),7.26(dt, J=8.0,7.2Hz,1H),6.92(dt,J=85.6,29.2Hz,4H),5.00(s,2H),3.64(dd,J=21.3,9.1H z,2H),3.54(t,J=7.2Hz,2H),3.46-3.35(m,1H),3.15(dd,J=21.5,9.1Hz,2H),3.00(s ,2H),2.15(d,J=4.2Hz,1H),1.68(d,J=5.6Hz,4H),1.54(s,1H),1.09(d,J=5.2Hz,5H);

[0691] LRMS (ES) m / z 559.1 (M + +1).

[0692] 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'-aziridine]-3-carboxamide

[0693]

[0694] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-[1,3'-diazetidine]-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.105 mmol), 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) prepared in step 2 of Example 84 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.015 g, 25.5%) as a yellow gel.

[0695] 1 H NMR (400 MHz, CDCl 3 )δ9.21-9.16(m,1H),8.30(dd,J=8.2,2.2Hz,1H),7.46(d,J=8.1Hz,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=21.7,9.2Hz,2H ),3.35-3.21(m,5H),3.15(dd,J=22.1,9.2Hz,2H),2.81(d,J=6.6Hz,2H),2.14(ddd,J =14.0,10.0,3.9Hz,1H),1.53(d,J=11.9Hz,2H),1.25(ddd,J=13.9,10.6,3.9Hz,2H);

[0696] LRMS (ES) m / z 562.2 (M + +1).

[0697] 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

[0698] [Step 1] Synthesis of 4-(3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl) tert-Butyl (3-fluorophenyl)carbamoyl)-3-fluoroazetidin-1-yl)piperidine-1-carboxylate

[0699]

[0700] 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), 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) prepared in step 2 of Example 31 were dissolved in dichloromethane (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 24 g column; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the title compound (0.610 g, 82.9%) as a white solid.

[0701] [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

[0702]

[0703] Tert-butyl 4-(3-(((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(3-fluorophenyl)carbamoyl)-3-fluoroazetidine-1-yl)piperidine-1-carboxylate (0.610 g, 1.009 mmol) and trifluoroacetic acid (1.545 mL, 20.178 mmol) prepared in step 1 were dissolved in dichloromethane (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 2 hours. 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.

[0704] [Step 3] Synthesis of compound 3400

[0705]

[0706] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-3-fluoro-N-(3-fluorophenyl)-1-(piperidin-4-yl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.099 mmol), acetaldehyde (0.009 g, 0.198 mmol), acetic acid (0.006 mL, 0.099 mmol) and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) prepared in step 2 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.015 g, 28.4%) as a yellow gel.

[0707] 1 H NMR (400 MHz, CDCl 3 )δ9.19(d,J=1.6Hz,1H),8.30(dd,J=8.2,2.2Hz,1H),7.46(d,J=8.0Hz,1H),7.32-7.22(m,1H),6.90(ddd,J=51.7,26.5,17.8Hz,4H),5.75 -5.43(m,2H),5.00(s,2H),3.60-3.43(m,2H),3.08(d,J=20.8Hz,4H),2.82(s,2H),1.84(s,2H),1.65(d,J=5.9Hz,3H),1.51–1.33(m,3H);

[0708] LRMS (ES) m / z 533.4 (M + +1).

[0709] 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

[0710]

[0711] 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 (0.050 g, 0.099 mmol), propionaldehyde (0.012 g, 0.198 mmol), acetic acid (0.006 mL, 0.099 mmol) and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) prepared in step 2 of Example 101 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.015 g, 27.7%) as a yellow gel.

[0712] 1 H NMR (400 MHz, CDCl 3 )δ9.19(d,J=1.6Hz,1H),8.30(dd,J=8.2,2.2Hz,1H),7.46(d,J=8.1Hz,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 .3Hz,2H),2.86(t,J=8.3Hz,2H),2.50(t,J=16.0Hz,4H),2.20(d,J=25.1Hz,1H),1 .89(s,2H),1.61(dd,J=15.6,7.7Hz,2H),1.47-1.37(m,2H),0.85(t,J=7.4Hz,3H);

[0713] LRMS (ES) m / z 547.3 (M + +1).

[0714] 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

[0715]

[0716] 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 (0.050 g, 0.099 mmol), butyraldehyde (0.014 g, 0.198 mmol), acetic acid (0.006 mL, 0.099 mmol) and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) prepared in step 2 of Example 101 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.015 g, 27.0%) as a yellow gel.

[0717] 1 H NMR (400 MHz, CDCl 3 )δ9.19(d,J=1.6Hz,1H),8.30(dd,J=8.2,2.2Hz,1H),7.45(d,J=8.1Hz,1H),7.32-7.23(m,1 H),6.93(dt,J=88.2,28.3Hz,4H),5.00(s,2H),3.53(dd,J=22.5,9.0Hz,2H),3.08(dd,J=20 .9,9.0Hz,2H),2.91(t,J=9.2Hz,2H),2.63(dd,J=21.6,13.8Hz,4H),2.31(s,1H),2.00(d,J =5.0Hz,2H),1.68-1.55(m,2H),1.53-1.41(m,2H),1.32-1.21(m,2H),0.85(t,J=7.4Hz,3H);

[0718] LRMS (ES) m / z 561.2 (M + +1).

[0719] 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

[0720]

[0721] 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 (0.050 g, 0.099 mmol), isobutyraldehyde (0.014 g, 0.198 mmol), acetic acid (0.006 mL, 0.099 mmol) and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) prepared in step 2 of Example 101 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.015 g, 27.0%) as a yellow gel.

[0722] 1 H NMR (400 MHz, CDCl 3 )δ9.18(d,J=1.6Hz,1H),8.30(dd,J=8.2,2.2Hz,1H),7.47(d,J=8.2Hz,1H) ,7.29-7.21(m,1H),7.02-6.72(m,4H),5.00(s,2H),3.61-3.42(m,2H),3.0 9(dd,J=21.4,9.1Hz,2H),2.77-2.68(m,2H),2.13(dd,J=21.2,13.2Hz,5H) ,1.70(d,J=31.3Hz,3H),1.28(dd,J=9.0,3.5Hz,2H),0.83(d,J=6.5Hz,6H);

[0723] LRMS (ES) m / z 561.1 (M + +1).

[0724] 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

[0725]

[0726] 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 (0.050 g, 0.099 mmol), 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) prepared in step 2 of Example 101 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.015 g, 27.7%) as a yellow gel.

[0727] 1 H NMR (400 MHz, CDCl 3 )δ9.20(d,J=1.6Hz,1H),8.31(dd,J=8.2,2.2Hz,1H),7.45(d,J=8.1Hz,1H) ,7.32-7.22(m,1H),6.93(dt,J=76.2,29.2Hz,4H),5.00(s,2H),3.59-3.45( m,2H),3.09(dd,J=21.3,9.8Hz,3H),2.95(t,J=10.1Hz,2H),2.79(s,2H),2. 38(s,1H),2.28–2.15(m,2H),1.53(d,J=13.5Hz,2H),1.25(d,J=6.4Hz,6H);

[0728] LRMS (ES) m / z 547.2 (M + +1).

[0729] 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

[0730]

[0731] 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 (0.050 g, 0.099 mmol), cyclobutanone (0.014 g, 0.198 mmol), acetic acid (0.006 mL, 0.099 mmol) and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) prepared in step 2 of Example 101 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.015 g, 27.1%) as a yellow gel.

[0732] 1 H NMR (400 MHz, CDCl 3 )δ9.22-9.15(m,1H),8.30(dd,J=8.2,2.2Hz,1H),7.46(d,J=8.1Hz,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=21.5,9.3Hz,2H),2.85(s,1 H),2.68(d,J=7.6Hz,2H),2.16(dd,J=15.3,7.8Hz,4H),1.99(dd,J=16.1,8.2Hz,3H),1.81 (d,J=27.2Hz,2H),1.77-1.65(m,1H),1.58(dt,J=18.8,9.5Hz,1H),1.33(d,J=23.7Hz,2H);

[0733] LRMS (ES) m / z 559.5 (M + +1).

[0734] 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-(oxetane-3-yl)piperidin-4-yl)azetidine-3-carboxamide

[0735]

[0736] 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 (0.050 g, 0.099 mmol), oxetane-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) prepared in step 2 of Example 101 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.015 g, 27.0%) as a yellow gel.

[0737] 1 H NMR (400 MHz, CDCl 3 )δ9.19(d,J=1.6Hz,1H),8.30(dd,J=8.2,2.2Hz,1H),7.47(d,J=8.2Hz,1H), 7.31-7.21(m,1H),7.03-6.70(m,4H),5.00(s,2H),4.55(d,J=6.4Hz,4H),3. 52(dd,J=22.3,8.6Hz,2H),3.41(s,1H),3.11(dd,J=21.4,8.2Hz,2H),2.55( d,J=10.7Hz,2H),2.05(s,1H),1.85(s,2H),1.58(s,2H),1.34-1.21(m,2H);

[0738] LRMS (ES) m / z 561.1 (M + +1).

[0739] 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

[0740]

[0741] 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 (0.050 g, 0.099 mmol), cyclopentanone (0.017 g, 0.198 mmol), acetic acid (0.006 mL, 0.099 mmol) and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) prepared in step 2 of Example 101 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.015 g, 26.4%) as a yellow gel.

[0742] 1 H NMR (400 MHz, CDCl 3 )δ9.19(d,J=1.5Hz,1H),8.30(dd,J=8.2,2.2Hz,1H),7.45(d,J=8.1Hz,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=21.4,9.1Hz,2H),3.01-2.69(m,5H),2.33(s,1H),2.13(dd,J=2 2.8,15.0Hz,2H),1.88(d,J=10.2Hz,4H),1.75(s,2H),1.55-1.42(m,4H);

[0743] LRMS (ES) m / z 573.3 (M + +1).

[0744] 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

[0745]

[0746] 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 (0.050 g, 0.099 mmol), 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) prepared in step 2 of Example 101 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.005 g, 8.8%) as a yellow gel.

[0747] 1 H NMR (400 MHz, CDCl 3 )δ9.19(d,J=1.5Hz,1H),8.30(dd,J=8.2,2.2Hz,1H),7.47(d,J=8.2Hz,1H),7.30-7.21(m,1H) ,7.03-6.71(m,4H),5.00(s,2H),3.86(td,J=8.6,4.4Hz,1H),3.77(dd,J=8.7,6.9Hz,1H),3.69 (dd,J=16.2,8.0Hz,1H),3.63-3.41(m,3H),3.10(dd,J=21.6,9.4Hz,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=27.5,16.4Hz,2H);

[0748] LRMS (ES) m / z 575.4 (M + +1).

[0749] 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

[0750]

[0751] 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 (0.050 g, 0.099 mmol), cyclohexanone (0.019 g, 0.198 mmol), acetic acid (0.006 mL, 0.099 mmol) and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) prepared in step 2 of Example 101 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.005 g, 8.6%) as a yellow gel.

[0752] 1 H NMR (400 MHz, CDCl 3 )δ9.20(d,J=1.7Hz,1H),8.31(dd,J=8.1,2.2Hz,1H),7.44(d,J=7.0Hz,1H),7 .28(dd,J=14.6,8.1Hz,1H),7.05-6.70(m,4H),5.00(s,2H),3.04(s,4H),2.4 6(s,2H),2.16(dd,J=18.4,10.9Hz,2H),1.83(d,J=12.8Hz,2H),1.58(dd,J=3 2.7,12.5Hz,6H),1.37(dt,J=26.8,13.2Hz,3H),1.23(dd,J=17.5,8.8Hz,5H);

[0753] LRMS (ES) m / z 587.5 (M + +1).

[0754] 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

[0755]

[0756] 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 (0.050 g, 0.099 mmol), tetrahydro-4H-pyran-4-one (0.020 g, 0.198 mmol), acetic acid (0.006 mL, 0.099 mmol) and sodium triacetoxyborohydride (0.063 g, 0.297 mmol) prepared in step 2 of Example 101 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.005 g, 8.6%) as a yellow gel.

[0757] 1 H NMR (400 MHz, CDCl 3 )δ9.20(d,J=1.6Hz,1H),8.30(dd,J=8.2,2.2Hz,1H),7.45(d,J=8.1Hz,1H),7.27 (dd,J=14.5,8.2Hz,1H),7.04-6.70(m,4H),5.00(s,2H),3.97(d,J=10.7Hz,2H), 3.59-3.44(m,2H),3.30(t,J=11.2Hz,2H),3.09(dd,J=21.6,9.4Hz,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);

[0758] LRMS (ES) m / z 589.2 (M + +1).

[0759] Example 112: Synthesis of Compound 3429, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-3-fluoro-1-methyl-N-phenylazetidine-3-carboxamide

[0760] [Step 1] Synthesis of 3-(((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)(phenyl)amine tert-Butyl ((2-(4 ...

[0761]

[0762] To a solution in which N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)aniline (1.000 g, 3.132 mmol) and triethylamine (1.436 mL, 9.396 mmol) prepared in step 1 of Example 1 were dissolved in dichloromethane (20 mL) at room temperature, tert-butyl 3-(chlorocarbonyl)-3-fluoroazetidine-1-carboxylate (0.968 g, 4.072 mmol) prepared in step 1 of Example 14 was added and stirred at the same temperature for 16 hours. Saturated aqueous ammonium chloride solution 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 , 12 g column; ethyl acetate / hexanes = 0% to 30%) and concentrated to obtain the title compound (0.527 g, 32.3%) as a yellow solid.

[0763] [Step 2] Synthesis of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-3-fluoro-N-benzene Azetidine-3-carboxamide 2,2,2-trifluoroacetate

[0764]

[0765] 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) and trifluoroacetic acid (1.551 mL, 20.251 mmol) prepared in step 1 were dissolved in dichloromethane (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 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.

[0766] [Step 3] Synthesis of compound 3429

[0767]

[0768] N-(4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-2-fluorobenzyl)-3-fluoro-N-phenylazetidine-3-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.119 mmol), formaldehyde (0.007 g, 0.238 mmol), acetic acid (0.007 mL, 0.119 mmol) and sodium triacetoxyborohydride (0.076 g, 0.357 mmol) prepared in step 2 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.020 g, 38.7%) as a yellow gel.

[0769] 1 H NMR (400 MHz, CDCl 3 )δ7.80(dd,J=8.0,1.5Hz,1H),7.65(dd,J=9.8,1.6Hz,1H),7.52(t,J=7.6Hz,1H),7.26(dd,J=6.8,3.9Hz,3H),7.0 4-6.97(m,2H),6.84(t,J=51.7Hz,1H),4.98(s,2H),3.54(dd,J=22.2,10.5Hz,2H),3.15-2.99(m,2H),2.27(s,3H);

[0770] LRMS(ES)m / z 436.1(M + +1).

[0771] Example 113: Synthesis of Compound 3430, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-ethyl-3-fluoro-N-phenylazetidine-3-carboxamide

[0772]

[0773] 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), acetaldehyde (0.010 g, 0.238 mmol), acetic acid (0.007 mL, 0.119 mmol) and sodium triacetoxyborohydride (0.076 g, 0.357 mmol) prepared in step 2 of Example 112 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.020 g, 37.5%) as a yellow gel.

[0774] 1 H NMR (400 MHz, CDCl 3 )δ7.89(dd,J=8.0,1.5Hz,1H),7.74(dd,J=9.8,1.6Hz,1H),7.62(t,J=7.6Hz,1H),7.38-7.32(m,3H),7.13-7.07(m,2H),6.95(dd,J=70. 2,33.2Hz,1H),5.07(s,2H),3.57(dd,J=22.5,10.3Hz,2H),3.11(dd,J=21.7,10.4Hz,2H),2.48(q,J=7.1Hz,2H),0.95(t,J=7.2Hz,3H);

[0775] LRMS (ES) m / z 450.1 (M + +1).

[0776] Example 114: Synthesis of Compound 3431, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-3-fluoro-1-isopropyl-N-phenylazetidine-3-carboxamide

[0777]

[0778] 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), 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) prepared in step 2 of Example 112 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.020 g, 36.4%) as a yellow gel.

[0779] 1 H NMR (400 MHz, CDCl 3 )δ7.80(dd,J=8.0,1.5Hz,1H),7.64(dd,J=9.8,1.6Hz,1H),7.53(t,J=7.6Hz,1H),7.25(dd,J=6.9,3.7Hz,3H),7.05-6.98(m,2H),6.84 (t,J=51.7Hz,1H),4.98(s,2H),3.46(dd,J=22.7,10.3Hz,2H),3.00(dd,J=21.6,10.4Hz,2H),2.28-2.15(m,1H),0.81(d,J=6.2Hz,6H);

[0780] LRMS (ES) m / z 464.4 (M + +1).

[0781] 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

[0782]

[0783] 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), acetyl chloride (0.013 mL, 0.178 mmol) and triethylamine (0.050 mL, 0.357 mmol) prepared in step 2 of Example 112 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.020 g, 36.4%) as a yellow gel.

[0784] 1 H NMR (400 MHz, CDCl 3 )δ7.90(dd,J=8.0,1.4Hz,1H),7.76(dd,J=9.8,1.5Hz,1H),7.56(t,J=7.6Hz ,1H),7.41-7.35(m,3H),7.12-6.78(m,3H),5.14(d,J=14.6Hz,1H),5.03(d, J=14.8Hz,1H),4.77(dd,J=21.6,10.9Hz,1H),4.29(dd,J=22.7,12.4Hz,1H) ,4.03(dd,J=22.4,10.2Hz,1H),3.63(dd,J=23.4,11.9Hz,1H),1.89(s,3H);

[0785] LRMS (ES) m / z 463.4 (M + +1).

[0786] 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

[0787]

[0788] 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), propionyl chloride (0.017 g, 0.178 mmol) and triethylamine (0.050 mL, 0.357 mmol) prepared in step 2 of Example 112 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.020 g, 35.3%) as a yellow gel.

[0789] 1 H NMR (400 MHz, CDCl 3 )δ7.90(dd,J=8.0,1.5Hz,1H),7.76(dd,J=9.8,1.6Hz,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=22.1,11.3Hz,1H),4.00(dd,J=22.2,8.8Hz,1H),3. 63(dd,J=22.3,10.6Hz,1H),2.11(q,J=7.5Hz,2H),1.12(t,J=7.5Hz,3H);

[0790] LRMS(ES)m / z 478.2(M + +1).

[0791] 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

[0792]

[0793] 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), isobutyryl chloride (0.019 g, 0.178 mmol) and triethylamine (0.050 mL, 0.357 mmol) prepared in step 2 of Example 112 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.020 g, 34.3%) as a yellow gel.

[0794] 1 H NMR (400 MHz, CDCl 3 )δ7.90(dd,J=8.0,1.5Hz,1H),7.76(dd,J=9.8,1.6Hz,1H),7.56(t,J=7.6Hz,1 H),7.41-7.35(m,3H),7.13-6.79(m,3H),5.20-4.98(m,2H),4.80(dd,J=21.6, 10.1Hz,1H),4.28(dd,J=22.6,11.9Hz,1H),4.04(dd,J=22.6,10.2Hz,1H),3.6 2(dd,J=23.4,11.8Hz,1H),2.41(dt,J=13.6,6.8Hz,1H),1.09(t,J=7.8Hz,6H);

[0795] LRMS(ES)m / z 492.3(M + +1).

[0796] 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

[0797]

[0798] 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), 3,3,3-trifluoropropionic anhydride (0.042 g, 0.178 mmol) and triethylamine (0.050 mL, 0.357 mmol) prepared in step 2 of Example 112 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.020 g, 32.6%) as a yellow gel.

[0799] 1 H NMR (400 MHz, CDCl 3 )δ7.91(dd,J=8.0,1.6Hz,1H),7.77(dd,J=9.8,1.6Hz,1H),7.56(t,J=7.6Hz,1H),7.44-7.38(m,3H),7.11-6.78(m,3H),5.10(dd,J=37.8 ,14.6Hz,2H),4.96(dd,J=22.4,11.8Hz,1H),4.49(dd,J=22.2,12.5Hz,1H),4.23(dd,J=22.0,11.9Hz,1H),3.81(dd,J=23.2,13.5Hz,1H);

[0800] LRMS (ES) m / z 516.9 (M + +1).

[0801] 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

[0802]

[0803] 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), methanesulfonyl chloride (0.014 mL, 0.178 mmol) and triethylamine (0.050 mL, 0.357 mmol) prepared in step 2 of Example 112 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.020 g, 33.7%) as a yellow gel.

[0804] 1 H NMR (400MHz, CDCl3) δ7.90(dd,J=8.0,1.6Hz,1H),7.76(dd,J=9.8,1.6Hz,1H),7.57(t,J=7.6Hz,1H),7.42-7.35( m,3H),7.12-6.78(m,3H),5.09(s,2H),4.40(dd,J=23.1,11.7Hz,2H),3.68(dd,J=22.2,11.7Hz,2H),2.89(s,3H);

[0805] LRMS(ES)m / z 499.0(M + +1).

[0806] Example 120: Synthesis of Compound 3437, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-1-isopropyl-N-phenylpiperidine-4-carboxamide

[0807]

[0808] 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), 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) prepared in step 4 of Example 1 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.020 g, 36.6%) as a yellow gel.

[0809] 1 H NMR (400 MHz, CDCl 3 )δ7.89(dd,J=8.0,1.6Hz,1H),7.73(dd,J=9.8,1.6Hz,1H),7.59(t,J=7.6Hz,1H),7.35-7.30(m,3H),6.99(ddd,J=92. 0,32.0,26.7Hz,3H),5.04(s,2H),2.84(d,J=29.5Hz,3H),2.47(d,J=46.4Hz,4H),1.97(s,2H),1.08(d,J=6.3Hz,6H);

[0810] LRMS(ES)m / z 491.0(M + +1).

[0811] 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

[0812]

[0813] 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), acetyl chloride (0.012 mL, 0.167 mmol) and triethylamine (0.047 mL, 0.335 mmol) prepared in step 4 of Example 1 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.020 g, 36.6%) as a yellow gel.

[0814] 1 H NMR (400 MHz, CDCl 3 )δ7.89(dd,J=8.0,1.6Hz,1H),7.75(dd,J=9.8,1.6Hz,1H),7.55(t,J=7.6Hz,1H),7.34(dd,J=6.9,3.7Hz,3H),7.08-6.78(m,3H),5.04 (d,J=7.9Hz,2H),4.49(d,J=10.3Hz,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=8.9Hz,2H);

[0815] LRMS (ES) m / z 491.1 (M + +1).

[0816] Example 122: Synthesis of Compound 3439, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-N-phenyl-1-propionylpiperidine-4-carboxamide

[0817]

[0818] 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), propionyl chloride (0.015 mL, 0.167 mmol) and triethylamine (0.047 mL, 0.335 mmol) prepared in step 4 of Example 1 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.020 g, 35.6%) as a yellow gel.

[0819] 1 H NMR (400 MHz, CDCl 3 )δ7.89(dd,J=8.0,1.5Hz,1H),7.75(dd,J=9.8,1.6Hz,1H),7.56(t,J=7.6Hz,1H),7.37-7.31(m,3H),6.99(ddd,J=88.9,33.1,28.3H z,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=8.9,6.0Hz,3H);

[0820] LRMS (ES) m / z 505.3 (M + +1).

[0821] Example 123: Synthesis of Compound 3440, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-4-fluoro-1-isobutyryl-N-phenylpiperidine-4-carboxamide

[0822]

[0823] 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), isobutyryl chloride (0.018 mL, 0.167 mmol) and triethylamine (0.047 mL, 0.335 mmol) prepared in step 4 of Example 1 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.020 g, 34.6%) as a yellow gel.

[0824] 1 H NMR (400 MHz, CDCl 3 )δ7.89(dd,J=8.0,1.6Hz,1H),7.75(dd,J=9.8,1.6Hz,1H),7.56(t,J=7.6Hz,1H),7.34 (dd,J=6.9,3.7Hz,3H),6.99(ddd,J=90.2,32.5,27.7Hz,3H),5.04(d,J=9.1Hz,2H),4.5 2(d,J=11.0Hz,1H),3.82(d,J=9.3Hz,1H),3.18(d,J=14.5Hz,1H),2.85–2.56(m,2H),2. 25(ddd,J=52.7,39.7,12.9Hz,2H),1.96(d,J=10.4Hz,2H),1.14(dd,J=7.3,4.9Hz,6H);

[0825] LRMS (ES) m / z 519.4 (M + +1).

[0826] 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

[0827]

[0828] 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), 3,3,3-trifluoropropionic anhydride (0.040 g, 0.167 mmol) and triethylamine (0.047 mL, 0.335 mmol) prepared in step 4 of Example 1 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.020 g, 32.9%) as a yellow gel.

[0829] 1 H NMR (400 MHz, CDCl 3 )δ7.89(dd,J=8.0,1.6Hz,1H),7.76(dd,J=9.8,1.6Hz,1H),7.55(t,J=7.6Hz,1H),7.38-7.33(m,3H),7.08-6.79(m,3H),5.04(d,J=4.7Hz, 2H),4.42(d,J=13.1Hz,1H),3.91(d,J=13.1Hz,1H),3.29(t,J=12.8Hz,1H),2.94(t,J=12.7Hz,1H),2.46-2.22(m,2H),2.08-1.98(m,2H);

[0830] LRMS (ES) m / z 546.2 (M + +1).

[0831] 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

[0832]

[0833] 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), methanesulfonyl chloride (0.013 mL, 0.167 mmol) and triethylamine (0.047 mL, 0.335 mmol) prepared in step 4 of Example 1 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.020 g, 34.1%) as a yellow gel.

[0834] 1 H NMR (400 MHz, CDCl 3 )δ7.90(dd,J=8.0,1.6Hz,1H),7.75(dd,J=9.9,1.6Hz,1H),7.56(t,J=7.6Hz,1H),7.38-7.31(m,3H),7.10-6.79(m, 3H),5.05(s,2H),3.69(d,J=11.3Hz,2H),2.89-2.78(m,2H),2.75(s,3H),2.57-2.32(m,2H),2.06(d,J=9.1Hz,2H);

[0835] LRMS (ES) m / z 527.1 (M + +1).

[0836] 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

[0837]

[0838] 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), acetaldehyde (0.039 g, 0.890 mmol), acetic acid (0.025 mL, 0.445 mmol) and sodium triacetoxyborohydride (0.283 g, 1.335 mmol) prepared in step 3 of Example 10 were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 Plate, 20x20x1 mm; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.080 g, 37.7%) as a white solid.

[0839] 1 H NMR (400 MHz, CDCl 3 )δ9.27(d,J=1.6Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.53(d,J=8.3Hz,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=39.0,9.5Hz,4H),2.24(d,J=10.4Hz,2H),2.02(d,J=18.6Hz,2H),1.12(t,J=7.2Hz,3H);

[0840] LRMS(ES)m / z 478.3(M + +1).

[0841] 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

[0842] [Step 1] Synthesis of 2-(6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole

[0843]

[0844] 6-Methylnicotinamide hydrazide (2.000 g, 13.230 mmol) and imidazole (2.702 g, 39.690 mmol) prepared in step 1 of Example 6 were dissolved in dichloromethane (5 mL), and trifluoroacetic anhydride (5.606 mL, 39.690 mmol) was added at 0°C, and then heated to reflux for 16 hours. Next, the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The obtained product was filtered and concentrated under reduced pressure to obtain the title compound (2.650 g, 87.4%) as a yellow solid.

[0845] [Step 2] Synthesis of 2-(6-(bromomethyl)pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole

[0846]

[0847] 2-(6-methylpyridin-3-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole (2.650 g, 11.564 mmol) prepared in step 1 was dissolved in 1,2-dichloroethane (100 mL), and azobisisobutyronitrile (AIBN, 0.190 g, 1.156 mmol) and 1-bromopyrrolidine-2,5-one (NBS, 2.676 g, 15.033 mmol) were added at room temperature and heated to reflux for 16 hours. The reaction was terminated 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 saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 80 g column; ethyl acetate / hexane = 15%) and concentrated to obtain the title compound (0.750 g, 21.1%) as a red solid.

[0848] [Step 3] Synthesis of 3-fluoro-N-((5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl) aniline

[0849]

[0850] 2-(6-(bromomethyl)pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole (0.500 g, 1.623 mmol), 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) prepared in step 2 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. Saturated aqueous ammonium chloride solution was poured into the obtained 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 , 24 g column; ethyl acetate / hexanes = 0% to 70%) and concentrated to obtain the title compound (0.280 g, 51.0%) as a yellow solid.

[0851] [Step 4] Synthesis of compound 6890

[0852]

[0853] To a solution in which tert-butyl 3-(chlorocarbonyl)-3-fluoroazetidine-1-carboxylate (0.137 g, 0.576 mmol) prepared in step 1 of Example 14 was dissolved in dichloromethane (20 mL) at room temperature, 3-fluoro-N-((5-(5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)aniline (0.150 g, 0.443 mmol) prepared in step 3 was added and stirred at the same temperature. Triethylamine (0.185 mL, 1.330 mmol) was added to the reaction mixture and further stirred for 16 hours at the same temperature. The solvent was removed from the reaction mixture under reduced pressure. Saturated aqueous ammonium chloride solution was poured into the obtained 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 , 24 g column; ethyl acetate / hexanes = 0% to 60%) and concentrated to obtain the title compound (0.150 g, 62.7%) as a yellow solid.

[0854] 1 H NMR (400 MHz, CDCl 3)δ9.30(d,J=2.1Hz,1H),8.41(dt,J=7.8,3.9Hz,1H),7.56(d,J=8.3Hz,1H),7.37(dd,J=14.7,7.6H z, 1H), 7.09 (t, J = 10.5Hz, 3H), 5.10 (s, 2H), 4.63-4.33 (m, 2H), 3.83 (d, J = 45.0Hz, 2H), 1.44 (s, 9H).

[0855] 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

[0856] [Step 1] Synthesis of 3-fluoro-N-(3-fluorophenyl)-N-((5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyrrolidone (2-pyridin-2-yl)methyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate

[0857]

[0858] Tert-butyl 3-fluoro-3-((3-fluorophenyl)((5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)carbamoyl)azetidine-1-carboxylate (0.080 g, 0.148 mmol) prepared 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.

[0859] [Step 2] Synthesis of compound 6891

[0860]

[0861] 3-Fluoro-N-(3-fluorophenyl)-N-((5-(5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (0.070 g, 0.159 mmol), formaldehyde (0.010 g, 0.319 mmol), acetic acid (0.009 mL, 0.159 mmol) and sodium triacetoxyborohydride (0.101 g, 0.478 mmol) prepared in step 1 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The obtained product was filtered through a plastic filter to remove the solid residue and the water layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 , 4 g column; dichloromethane / methanol = 0% to 10%) and concentration gave the title compound (0.050 g, 69.2%) as a yellow gel.

[0862] 1 H NMR (400 MHz, CDCl 3 )δ9.28(d,J=2.0Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.59(d,J=8.2Hz,1H),7.39-7.31(m,1H),7.13 -7.00(m,3H),5.10(s,2H),3.68(dd,J=21.6,9.4Hz,2H),3.25(dd,J=21.5,8.8Hz,2H),2.37(s,3H);

[0863] LRMS (ES) m / z 453.6 (M + +1).

[0864] Activity Measurement and Analytical Protocols for Compounds of the Invention

[0865] <Experimental Example 1> HDAC enzyme activity inhibition assay (in vitro)

[0866] In order to confirm the selectivity of the compound represented by Chemical Formula I of the present invention for HDAC6 through HDAC1 and HDAC6 enzyme activity inhibition experiments, a comparative experiment was performed using a developed compound as a control group.

[0867] HDAC enzyme activity was measured using the HDAC Fluorescence Drug Discovery Kit (Enzo Life Sciences, Inc., BML-AK511,516). For HDAC1 enzyme activity testing, human recombinant HDAC1 (BML-SE456) was used as the enzyme source, and Fluor de -SIRT1 (BNL-KI177) as a substrate. After dispensing the 5-fold diluted compound into a 96-well plate, 0.3 μg of enzyme and 10 μM substrate were added to each well of the plate and allowed to react at 30°C for 60 minutes. Next, Fluor de Developer II (BML-KI176) and react for 30 minutes to complete the reaction, and then use a multi-plate reader (Flexstation 3, Molecular Device) to measure the fluorescence value (Ex 360, Em 460). According to the same protocol as the HDAC1 enzyme activity test method, human recombinant HDAC6 (382180) from Calbiochem Inc. was used to test the HDAC6 enzyme. For the final result value, the corresponding IC was calculated using the GraphPad Prism 4.0 program 50 Values ​​(Table 2).

[0868] [Table 2] Results of HDAC enzyme activity inhibition assay

[0869]

[0870]

[0871]

[0872]

[0873] As shown in Table 2 above, according to the results of HDAC1 and HDAC6 activity inhibition assays, it was found that the 1,3,4-oxadiazole derivative compound of the present invention, its optical isomer or a pharmaceutically acceptable salt thereof exhibited about 30 to about 2906 times higher selective HDAC6 inhibition activity.

[0874] <Experimental Example 2> Analysis of the effects of HDAC6-specific inhibitors on mitochondrial axonal transport (in vitro)

[0875] The effect of HDAC6 specific inhibitors on mitochondrial axonal transport was analyzed. Specifically, in order to confirm whether the compound represented by Chemical Formula I of the present invention selectively inhibits HDAC6 activity to increase the acetylation of tubulin, which is the main substrate of HDAC6, thereby improving the mitochondrial axonal transport rate reduced by amyloid-β treatment in neuronal axons, a comparative experiment was performed using the developed material as a control group.

[0876] The hippocampal neurons from Sprague-Dawley (SD) rat embryos at embryonic day 17-18 (E17-18) were cultured in a culture dish coated with extracellular matrix for 7 days for imaging, and then treated with 1M amyloid-β peptide fragments. After 24 hours, the 8th day of in vitro culture was treated with compounds, and after 3 hours, the last 5 minutes were treated with MitoTrackerRed CMXRos (Life Technologies, NY, USA) to dye mitochondria. About the axonal transport of stained neuronal mitochondria, by using a confocal microscope (Leica 5P8; Leica Microsystems, UK) to take images (at 1 second intervals for 1 minute), the transport rate of each mitochondria was determined using IMARIS analysis software (BITPLANE, Zurich, Switzerland).

[0877] As a result, it was confirmed that the 1,3,4-oxadiazole derivative compound of the present invention, an optical isomer thereof, or a pharmaceutically acceptable salt thereof exhibits an improving effect on the mitochondrial axonal transport rate.

Claims

1. A 1,3,4-oxadiazole derivative compound represented by the following chemical formula I or a pharmaceutically acceptable salt thereof: [Chemical Formula I] In the above chemical formula I, Z1 to Z4 are each independently N, CH or CX, wherein Z1 to Z4 cannot be three or more N at the same time; L, L 1 or L 2 Each is independently -(C0-C2alkylene)-; R1 is -CX2H or -CX3; R2 is phenyl, wherein at least one -H of the phenyl group may be independently substituted by -X, -OH, -(C1-C4 alkyl) or -O(C1-C4 alkyl); R a To R d Each is independently -H or -(C1-C4 alkyl); R' and R'' are each independently -H, -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -(C1-C4 alkyl)-(C3-C7 cycloalkyl), -(C1-C4 alkyl)-(C2-C6 heterocycloalkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-(C3-C7 cycloalkyl), -C(=O)-O(C1-C4 alkyl) or -S(=O)2-(C1-C4 alkyl), wherein -(C1-C4 alkyl) ) or -C(═O)-(C1-C4 alkyl) may be substituted by -X, -OH, -N(CH3)2 or -O(C1-C4 alkyl), and at least one -H of the -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -(C1-C4 alkyl)-(C3-C7 cycloalkyl), -(C1-C4 alkyl)-(C2-C6 heterocycloalkyl) or -C(═O)-(C3-C7 cycloalkyl) ring may be substituted by -X, -OH or -(C1-C4 alkyl); m or n are each independently 1, 2 or 3; and X is F, Cl, Br or I.

2. The 1,3,4-oxadiazole derivative compound represented by Chemical Formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein in the above Chemical Formula I, Z1 to Z4 are each independently N, CH or CX, wherein Z1 to Z4 cannot be two or more N at the same time; L, L 1 or L 2 Each is independently -(C0-C2alkylene)-; R1 is -CX2H or -CX3; R2 is phenyl, wherein at least one -H of the phenyl group may be independently substituted by -X, -OH, -(C1-C4 alkyl) or -O(C1-C4 alkyl); R a To R d Each is independently -H or -(C1-C4 alkyl); R' and R'' are each independently -H, -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -(C1-C4 alkyl)-(C3-C7 cycloalkyl), -(C1-C4 alkyl)-(C2-C6 heterocycloalkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-(C3-C7 cycloalkyl), -C(=O)-O(C1-C4 alkyl) or -S(=O)2-(C1-C4 alkyl), wherein -(C1-C4 alkyl) ) or -C(═O)-(C1-C4 alkyl) may be substituted by -X, -OH, -N(CH3)2 or -O(C1-C4 alkyl), and at least one -H of the -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -(C1-C4 alkyl)-(C3-C7 cycloalkyl), -(C1-C4 alkyl)-(C2-C6 heterocycloalkyl) or -C(═O)-(C3-C7 cycloalkyl) ring may be substituted by -X, -OH or -(C1-C4 alkyl); m or n are each independently 1, 2 or 3; and X is F, Cl or Br.

3. The 1,3,4-oxadiazole derivative compound represented by Chemical Formula I or a pharmaceutically acceptable salt thereof according to claim 2, wherein in the above Chemical Formula I, Z1 to Z4 are each independently N, CH or CX, wherein Z1 to Z4 cannot be two or more N at the same time; L is -(C1 alkylene)-; L 1 or L 2 Each is independently -(C0 alkylene)-; R1 is -CX2H or -CX3; R2 is a phenyl group, wherein at least one -H of the phenyl group may be independently substituted by -X; R a To R d each independently is -H; R' and R'' are each independently -H, -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -(C1-C4 alkyl)-(C3-C7 cycloalkyl), -(C1-C4 alkyl)-(C2-C6 heterocycloalkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-(C3-C7 cycloalkyl), -C(=O)-O(C1-C4 alkyl), or -S(=O)2-(C1-C4 alkyl), wherein at least one -H of -(C1-C4 alkyl) or -C(=O)-(C1-C4 alkyl) may be substituted with -X, -OH, -N(CH3)2, or -O(C1-C4 alkyl), and at least one -H of the -(C3-C7 cycloalkyl) ring may be substituted with -X; m or n are each independently 1 or 2; and X is F or Cl.

4. The 1,3,4-oxadiazole derivative compound represented by Chemical Formula I or a pharmaceutically acceptable salt thereof according to claim 3, wherein in the above Chemical Formula I, Z1 to Z4 are each independently N, CH or CF, wherein Z1 to Z4 cannot be two or more N at the same time; L is -(C1 alkylene)-; L 1 or L 2 Each is independently -(C0 alkylene)-; R1 is -CF2H or -CF3; R2 is phenyl, wherein at least one -H of the phenyl group may be independently substituted by -F; R a To R d each independently is -H; R' is -H, -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -(C1-C4 alkyl)-(C3-C7 cycloalkyl), -(C1-C4 alkyl)-(C2-C6 heterocycloalkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-(C3-C7 cycloalkyl), -C(=O)-O(C1-C4 alkyl), or -S(=O)2-(C1-C4 alkyl), wherein at least one -H of -(C1-C4 alkyl) or -C(=O)-(C1-C4 alkyl) may be substituted by -X, -OH, -N(CH3)2, or -O(C1-C4 alkyl), and at least one -H of the -(C3-C7 cycloalkyl) ring may be substituted by -X; R'' is -(C1-C4 alkyl), -(C3-C7 cycloalkyl), or -(C2-C6 heterocycloalkyl); m or n are each independently 1 or 2; and X is F or Cl.

5. The 1,3,4-oxadiazole derivative compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is any one of the following compounds: 。 6. A pharmaceutical composition for preventing or treating a disease mediated by histone deacetylase 6, comprising a compound represented by Chemical Formula I according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient.

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

8. Use of a compound represented by Chemical Formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 for preparing a medicament for preventing or treating a disease mediated by histone deacetylase 6.

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