New 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, its stereoisomers, its pharmaceutically acceptable salts, its use in preparing drugs, a pharmaceutical composition containing the same, its preventive or therapeutic methods, and a method for preparing novel 1,3,4-oxadiazoletriazole derivatives, wherein the compound having selective HDAC6 inhibitory activity is represented by the following formula I. #imgabs0#

Description

Technical Field

[0001] The present invention relates to a novel compound having histone deacetylase 6 (HDAC6) inhibitory activity, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, use thereof for preparing a medicament, a pharmaceutical composition comprising the compound, a preventive or therapeutic method thereof, and a preparation method thereof. Existing technology

[0002] In cells, post-translational modifications such as acetylation serve as crucial regulatory modules at the heart of biological processes and are strictly controlled by a variety of enzymes. As core proteins constituting chromatin, histones function as spindles around which DNA is coiled, thus contributing to DNA condensation. Furthermore, the balance between acetylation and deacetylation of histones plays a crucial role in gene expression.

[0003] As an enzyme for removing acetyl groups from lysine residues of histone proteins that constitute chromatin, histone deacetylase (HDAC) is known to be associated with gene silencing and induces cell cycle arrest, angiogenesis inhibition, immune regulation, apoptosis, etc. (Hassig et al., Curr. Opin. Chem. Biol. 1997, 1, 300-308). In addition, it is reported that inhibition of HDAC enzyme function induces cancer cell apoptosis by reducing the activity of cancer cell survival-related factors and activating cancer cell death-related factors in vivo (Warrell et al., J. Natl. Cancer Inst. 1998, 90, 1621-1625).

[0004] In humans, 18 HDACs are known and are divided into four classes based on their homology to yeast HDACs. Eleven HDACs that use zinc as a cofactor can be divided into three classes: 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 (HDAC 11). Furthermore, seven class III HDACs (SIRTs 1-7) use NAD+ as a cofactor instead of zinc (Bolden et al., Nat. Rev. Drug Discov. 2006, 5(9), 769-784).

[0005] Various HDAC inhibitors are currently in the preclinical or clinical development stage, but only non-selective HDAC inhibitors are known to be anticancer agents. 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 known that non-selective HDAC inhibitors generally produce side effects at high doses, such as fatigue, nausea, etc. (Piekarz et al., Pharmaceuticals 2010, 3, 2751-2767). It is reported that the side effects are caused by the inhibition of Class I HDAC. Due to the side effects, non-selective HDAC inhibitors are limited in drug development in other fields other than anticancer agents (Witt et al., Cancer Letters 277 (2009) 8-21).

[0006] At the same time, it has been reported that selective inhibition of class II HDACs will not show the toxicity that occurs when inhibiting class I HDACs. If selective HDAC inhibitors are developed, it will be possible to address the side effects caused by non-selective inhibition of HDACs, such as toxicity. Therefore, there is an opportunity to develop selective HDAC inhibitors as effective therapeutic agents for various diseases (Matthias et al., Mol. Cell. Biol. 2008, 28, 1688-1701).

[0007] It is known that HDAC6 (a class IIb HDAC) is mainly present in the cytoplasm and contains tubulin, and is therefore involved in the deacetylation of various non-histone substrates (HSP90, cortical actin (cortactin) etc.) (Yao et al., Mol. Cell 2005, 18, 601-607). HDAC6 has two catalytic domains, wherein the zinc finger domain at the C-terminus can bind to ubiquitinated proteins. It is known that HDAC6 has a variety of non-histone proteins as substrates, and therefore plays an important role in various diseases, such as cancer, inflammatory diseases, autoimmune diseases, neurological diseases, neurodegenerative disorders, etc. (Santo et al., Blood 2012 119, 2579-2589; Vishwakarma et al., International Immunopharmacology 2013, 16, 72-78; Hu et al., J. Neurol. Sci. 2011, 304, 1-8).

[0008] The structural features common to various HDAC inhibitors are composed of a capping 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 capping groups and linker groups. In addition to the groups, zinc binding groups are known to play a more important role in enzyme inhibitory activity and selectivity (Wiest et al., J.Org.Chem.2013 78:5051-5055; Methot et al., Bioorg.Med.Chem.Lett.2008,18,973-978).

[0009]

[0010] Most zinc-binding groups are composed of hydroxamic acid or benzamide. Among these zinc-binding groups, hydroxamic acid derivatives exhibit strong HDAC inhibition but suffer from low bioavailability and severe off-target activity. Benzamide contains aniline and therefore has the potential to produce toxic metabolites in vivo (Woster et al., Med. Chem. Commun. 2015, online publication).

[0011] Therefore, for the treatment of cancer, inflammatory diseases, autoimmune diseases, neurological diseases, neurodegenerative disorders, etc., it is necessary to develop a selective HDAC6 inhibitor having a zinc-binding group with improved bioavailability without side effects, unlike non-selective inhibitors with side effects.

[0012] <Citation of Prior Art>

[0013] <Patent Document>

[0014] International Patent Publication No. WO 2011 / 091213 (published on July 28, 2011): ACY-1215

[0015] International Patent Publication No. WO 2011 / 011186 (published on January 27, 2011): Tubastatin

[0016] International Patent Publication No. WO 2013 / 052110 (published on April 11, 2013): Sloan-K

[0017] International Patent Publication No. WO 2013 / 041407 (published on March 28, 2013): Cellzome

[0018] International Patent Publication No. WO 2013 / 134467 (published on September 12, 2013): Kozi

[0019] International Patent Publication No. WO 2013 / 008162 (published on January 17, 2013): Novartis

[0020] International Patent Publication No. WO 2013 / 080120 (published on June 6, 2013): Novartis

[0021] International Patent Publication No. WO 2013 / 066835 (published on May 10, 2013): Tempero

[0022] International Patent Publication No. WO 2013 / 066838 (published on May 10, 2013): Tempero

[0023] International Patent Publication No. WO 2013 / 066833 (published on May 10, 2013): Tempero

[0024] International Patent Publication No. WO 2013 / 066839 (published on May 10, 2013): Tempero Summary of the Invention

[0025] Technical issues

[0026] One object of the present invention is to provide a compound having selective HDAC6 inhibitory activity, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0027] Another object of the present invention is to provide a pharmaceutical composition comprising a compound having selective HDAC6 inhibitory activity, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0028] Another object of the present invention is to provide a method for preparing the compound.

[0029] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating diseases related to HDAC6 activity.

[0030] Another object of the present invention is to provide use of the compound in preparing a drug for preventing or treating diseases related to HDAC6 activity.

[0031] Another object of the present invention is to provide a method for preventing or treating diseases related to HDAC6 activity, which comprises administering a therapeutically effective amount of a compound.

[0032] Another object of the present invention is to provide use thereof for preventing or treating diseases related to HDAC6 activity.

[0033] Technical Solution

[0034] The present inventors have discovered oxadiazole derivative compounds having histone deacetylase 6 (HDAC6) inhibitory activity and have used them for inhibiting or treating diseases associated with HDAC6 activity, thereby completing the present invention.

[0035] The present invention will be described in more detail below. In other words, all combinations of the various components disclosed in the present invention fall within the scope of the present invention. In addition, it can be found that the scope of the present invention is not limited to the specific description below.

[0036] Compound represented by formula I

[0037] The present invention may provide a compound represented by the following formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0038]

[0039] in

[0040] X1 to X4 are each independently CA or N;

[0041] A is H or halogen;

[0042] L is a C1-C2 alkylene group;

[0043] R1 is CF2H or CF3;

[0044] B is (wherein Y1 is CR2 or N, Y2 and Y3 are each independently CR' or N, and R' is H or C1-C5 alkyl), or (wherein Y1 is O or NR2);

[0045] R2 is H or C1-C5 alkyl, wherein at least one H in the C1-C5 alkyl may be substituted by OH or N(C1-C5 alkyl)2;

[0046] R3 is halogen; C1-C5 alkyl; C1-C5 haloalkyl; (wherein a, b and c are independently 0, 1, 2 or 3, wherein a and b cannot be 0 at the same time, and Z1 is CH2, NH or O); C4-C6 cycloalkenyl; C6-C12 aryl; 5- to 9-membered heteroaryl including at least one heteroatom selected from N, O and S; (wherein a and b are each independently an integer of 1 or 2); (where a is an integer of 0, 1 or 2); or pyridone;

[0047] At least one H in R3 may be replaced independently by halogen or -(CH2) n -Q1-Q2-Ra substituted (wherein n is 0 or 1);

[0048] Q1 is a single bond, -SO2-, -NH-, -N(C1-C5 alkyl)-, -NHC(=O)-, -N(C1-C5 alkyl)C(=O)-, or -C(=O)-;

[0049] Q2 is a single bond, C1-C5 alkylene, -NH-, -(C1-C5 alkylene)-NH-C(=O)-, or -N(C1-C5 alkyl)-;

[0050] Ra is OH; C1-C5 alkyl; C1-C5 haloalkyl; -NR4R5 (wherein R4 and R5 are each independently H or C1-C5 alkyl); C1-C5 alkoxy; (wherein a and b are each independently 1 or 2, M1 is CH2, O, NH or SO2, and M2 is CH or N); (wherein M3 is CH or N); diazabicycloheptane; or a 5-membered or 6-membered heteroaryl group containing 1 to 3 N atoms; and

[0051] At least one H in Ra may be independently replaced by OH; halogen; C1-C5 alkyl; (wherein a and b are each independently 0 or 1 but cannot be 0 at the same time, c is 0 or 1, M4 is CH2, NH or O, and at least one H in M4 can be substituted by halogen, C1-C5 alkyl, C3-C6 cycloalkyl or -C(=O)-O(C1-C5 alkyl)); C1-C6 haloalkyl; -NR6R7 (wherein R6 and R7 are each independently H or C1-C5 alkyl); -C(=O)-(C1-C5 alkyl); C(=O)-O(C1-C5 alkyl); or -NH-C(=O)-O(C1-C5 alkyl).

[0052] In one embodiment, the compound represented by the above formula I may include a compound represented by the following formula II:

[0053]

[0054] wherein X1 to X4, L, R1, R3 and Y1 to Y3 in Formula II are the same as those defined in Formula I.

[0055] In one embodiment, in Formula II above:

[0056] X1 to X4 are each independently CA or N;

[0057] A is H or halogen;

[0058] L is a C1-C2 alkylene group;

[0059] R1 is CF2H or CF3;

[0060] Y1 is CH or N;

[0061] R3 is phenyl; a 6-membered or 9-membered heteroaryl group comprising at least one heteroatom selected from N and O; or pyridone;

[0062] At least one H in R3 may be replaced independently by halogen or -(CH2) n -Q1-Q2-Ra substituted (wherein n is 0 or 1);

[0063] Q1 is a single bond, -NH, -NHC(=O)- or -C(=O)-;

[0064] Q2 is a single bond or -N(C1-C5 alkyl)-;

[0065] Ra is C1-C5 alkyl; C1-C5 haloalkyl; -NR4R5 (wherein R4 and R5 are each independently H or C1-C5 alkyl); C1-C5 alkoxy; (wherein a and b are each independently 1 or 2, M1 is CH2, O, NH or SO2, and M2 is CH or N); or (wherein M3 is CH or N); and

[0066] At least one H in Ra may be independently replaced by a C1-C5 alkyl group; (wherein a and b are each independently 0 or 1 but cannot be 0 at the same time, c is 0 or 1, M4 is CH2, NH or O, and at least one H in M4 can be substituted with halogen or C1-C5 alkyl); -NR6R7 (wherein R6 and R7 are each independently H or C1-C5 alkyl); or -NH-C(=O)-O(C1-C5 alkyl).

[0067] In one embodiment, in the above Formula II:

[0068] X1 to X4 are each independently CA or N;

[0069] A is H or halogen;

[0070] L is a C1-C2 alkylene group;

[0071] R1 is CF2H;

[0072] Y1 is CH;

[0073] R3 is phenyl; or a 9-membered heteroaryl group including at least one N;

[0074] At least one H in R3 may be independently replaced by -(CH2) n -Q1-Ra substituted (wherein n is 0 or 1);

[0075] Q1 is a single bond, NH or -NHC(=O)-;

[0076] Ra is (wherein a and b are each independently 1 or 2, M1 is CH2, O or NH, and M2 is N) or C1-C5 haloalkyl; and

[0077] At least one H in Ra may be independently substituted with a C1-C5 alkyl group.

[0078] In the present invention, "Cx-Cy" (wherein x and y are integers of 1 or greater) refers to the number of carbon atoms. For example, a C1-C5 alkyl group refers to an alkyl group having 1 or more and 5 or less carbon atoms, and a C6-C12 aryl group refers to an aryl group having 6 or more and 12 or less carbon atoms.

[0079] In the present invention, "halogen" refers to F, Cl, Br or I.

[0080] In the present invention, "alkyl" means a straight or branched saturated hydrocarbon group and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl and the like.

[0081] In the present invention, "alkylene" means a divalent functional group induced from an alkyl group as defined above (including both straight-chain and branched chains).

[0082] In the present invention, "haloalkyl" means a functional group in which at least one H in an alkyl group (including both linear and branched) as defined above is replaced by a halogen. For example, a haloalkyl group may include -CF3, -CF2H or -CFH2.

[0083] In the present invention, the "cycloalkyl group" may be a monocyclic cycloalkyl group or a polycyclic cycloalkyl group. The carbon number of the cycloalkyl group may be 3 or more and 9 or less.

[0084] In the present invention, the "heterocycloalkyl group" may be a monocyclic heterocycloalkyl group or a polycyclic heterocycloalkyl group, and the heterocycloalkyl group may be a 3-membered to 9-membered ring.

[0085] In the present invention, the cycloalkyl group or heterocycloalkyl group can be represented by the following general formula:

[0086]

[0087] Examples of cycloalkyl groups may include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Examples of heterocycloalkyl groups may include propylene oxide, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, piperidine, pyrrolidine, and the like.

[0088] In the present invention, "aryl" refers to a monocyclic aromatic or polycyclic aromatic functional group consisting only of carbon and hydrogen, and the carbon number of the aryl group may be 6 or more and 12 or less. Examples of the aryl group may include, but are not limited to, phenyl, naphthyl, and the like.

[0089] In the present invention, "heteroaryl" refers to a monocyclic or polycyclic heterocycle in which at least one carbon of the monocyclic or polycyclic aromatic functional group is substituted by a heteroatom, and may be monocyclic or polycyclic. Examples of heteroatoms may include nitrogen (N), oxygen (O), sulfur (S), etc. The heteroaryl group may be a 5- to 10-membered or 5- to 9-membered ring. When the heteroaryl group includes at least two heteroatoms, the two heteroatoms or more heteroatoms may be the same or different from each other. Examples of heteroaryl groups may include thiophene, benzothiophene, indazole, furan, benzofuran, indole, pyrazole, pyridine, imidazopyridine, pyrimidine, pyrrolopyridine, imidazole, benzimidazole, thiazole, oxazole, oxadiazole, triazole, pyrazine (pyrizine), bipyridine, triazine, pyridazine, pyrazine, quinoline, quinazoline or isoquinoline, but are not limited thereto.

[0090] In the present invention, Indicates the connection part.

[0091] In the present invention, pharmaceutically acceptable salts may refer to salts commonly used in the pharmaceutical industry, such as inorganic ion salts prepared from calcium, potassium, sodium, magnesium, etc.; inorganic acid salts prepared from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, 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, naphthalenesulfonic acid, etc.; amino acid salts prepared from glycine, arginine, lysine, etc.; amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, picolinidine, etc.; and the like, but the types of salts intended in the present invention are not limited to the salts listed above.

[0092] In the present invention, preferred salts may include hydrochloric acid, trifluoroacetic acid, citric acid, bromic acid, maleic acid, phosphoric acid, sulfuric acid, tartaric acid and the like.

[0093] As an example, the pharmaceutically acceptable salt of the present invention may be a salt of compound 3867 of the present invention.

[0094] The compounds represented by Formula I of the present invention may contain at least one asymmetric carbon and may therefore exist as racemates, racemic mixtures, single enantiomers, mixtures of diastereomers, and individual diastereomers thereof. Such isomers of compounds represented by Formula I may be separated by resolution thereof according to the prior art, for example, by column chromatography, HPLC, or the like. Alternatively, individual stereoisomers of compounds represented by Formula I may be stereospecifically synthesized using a known series of optically pure starting materials and / or reagents.

[0095] In the present invention, "stereoisomers" include diastereomers and optical isomers (enantiomers), wherein optical isomers include not only enantiomers but also mixtures of enantiomers and even racemates.

[0096] The compound represented by Formula I of the present invention may be any one selected from the compounds shown in Table 1 below.

[0097] [Table 1]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125] In the present invention, the compound represented by the above formula I, its stereoisomer or a pharmaceutically acceptable salt thereof can be selected from the following compound group: 3825, 3826, 3838, 3839, 3840, 3841, 3843, 3845, 3944, 3962, 3986, 3987, 3988, 4072, 4075, 4108, 4109, 4110, 4111, 4112, 4134, 4186, 4187, 4233, 4340, 434 3, 4344, 4345, 4346, 4347, 4348, 4449, 4453, 4466, 4484, 4489, 4492, 4493, 4496, 4497, 4502, 4503, 4504, 4521, 4523, 4524, 4525, 4526, 4527, 4548, 4551, 4558, 4560, 4565, 4569, 4591, 4592, 4609, 4610, and 17255.

[0126] In the present invention, the compound represented by the above formula I, its stereoisomer or a pharmaceutically acceptable salt thereof can be selected from the following compound group: 3838, 3839, 3840, 3841, 3843, 3944, 3986, 3987, 4108, 4187, 4340, 4343, 4346, 4347, 4348, 4466, 4493, 4524, 4525, 4558, 4565 and 17255.

[0127] Process for preparing compounds of formula I

[0128] Preferred methods for preparing the compound represented by the above formula I, its stereoisomers or pharmaceutically acceptable salts thereof are the same as those shown in reaction formulas 1 to 19, and even therein also include preparation methods modified at a level obvious to those skilled in the art.

[0129] In the reaction formula below, symbols identical to those in formula (I) and not specifically described are identical to those defined in formula (I), and repeated descriptions are omitted. In addition, in the reaction formula, PG may represent an amine protecting group, and may be, for example, a tert-butyloxycarbonyl group (Boc).

[0130] Furthermore, in the reaction formula, Xa to Xc each independently represent H, halogen, C1-C5 alkyl or C1-C5 haloalkyl.

[0131] [Reaction formula 1]

[0132]

[0133] According to the above reaction formula 1, compound 1-2 can be synthesized by replacing the halide portion of compound 1-1 with azide.

[0134] Compound 1-2 can be used to synthesize all compounds with a triazole structure.

[0135] [Reaction formula 1-1]

[0136]

[0137] According to the above reaction formula 1-1, compound 1-4 can be synthesized by replacing the halide portion of compound 1-3 with an azide. Compound 1-4 can be used to synthesize all compounds having a triazole structure. In the above reaction formula 1-1, the alkyl group can be a C1-C5 alkyl group.

[0138] [Reaction formula 2]

[0139]

[0140] The above reaction formula 2 can be a reaction for synthesizing compound 2-3 having a triple bond, a precursor of a compound having a triazole structure, and compound 2-3 having a triple bond can be synthesized by reacting the aldehyde of compound 2-1 with compound 2-2 as a phosphonate reagent.

[0141] Compounds 2-3 can be used to synthesize all compounds with a triazole structure.

[0142] [Reaction formula 2-1]

[0143]

[0144] Similar to Reaction Formula 2, Reaction Formula 2-1 can be used to synthesize Compound 2-3 containing a triple bond, which is a precursor to a compound having a triazole structure. Based on Reaction Formula 2-1, Compound 2-3 containing a triple bond can be synthesized via a Corey-Fuchs reaction using the aldehyde of Compound 2-1. Compound 2-3 can be used to synthesize all compounds having a triazole structure.

[0145] [Reaction formula 3]

[0146]

[0147] The above reaction formula 3 can be a method for synthesizing a compound having a triazole structure. According to the above reaction formula 3, compound 3-2 can be prepared by a click reaction between formula 3-1 and compound 1-2.

[0148] The compound prepared by the above reaction formula 3 can be compounds 3657, 3658, 3661, 3662, 3695, 3696, 3697, 3698, 3733, 3734, 3735, 3736, 3737, 3738, 3820, 3822, 3831, 3832, 3833, 3834, 3835, 3837, 3838, 3839, 3840, 3841, 3842 42, 3843, 3844, 3845, 3846, 3853, 3854, 3855, 3856, 3860, 3861, 3879, 3880, 3881, 3882, 3883, 3884, 3902, 3925, 3960, 3985, 4071, 4072, 4073, 4074, 4075, 4076, 4077, 4078, 4079, 408 0, 4081, 4082, 4135, 4178, 4179, 4180, 4181, 4182, 4183, 4184, 4185, 4284, 4285, 4286, 4289, 4340, 4341, 4342, 4343, 4344, 4345, 4346, 4347, 4348, 4487, 4488, 4489, 4524, 4525, 4526 , 4527, 16781, 16928, 16930, 17261, 17263, 17347, 17983, 17984, 18256, 18258, 18305, 18470, 18736, 17198, 17201, 17848, 17851, 17854, 17857, 18918, 18919, 18920, 18921, 19058, etc.

[0149] [Reaction formula 3-1]

[0150]

[0151] The above reaction formula 3-1 can represent a reaction for preparing compound 3-1-3 through an amine substitution reaction between compound 3-1-1 and compound 3-1-2, which are prepared by substantially the same method as the method described in the above reaction formula 3. In this case, in the above reaction formula 3-1, X can be F, Cl, etc. in the form of a leaving group, and Ry can be OH; halogen; C1-C5 alkyl; C1-C6 haloalkyl; -NR6R7; -C(=O)-(C1-C5 alkyl); C(=O)-O(C1-C5 alkyl); or -NH-C(=O)-O(C1-C5 alkyl). It may refer to a heteroaryl group including N, for example, pyridyl.

[0152] The compounds prepared by the above reaction formula 3-1 can be 4582, 4591, 4592, 4593, 4594, 4633, 4634, 4635, 4636, 16789, etc.

[0153] [Reaction formula 3-2]

[0154]

[0155] In the above reaction formula 3-3, compound 3-1-5 can be prepared by an amine substitution reaction between compound 3-1-1 and compound 3-1-4, which are prepared by substantially the same method as described in the above reaction formula 3. After removing the amine protecting group, compound 3-1-3 is subjected to a reductive amination reaction by using a Ry-H compound. In this case, in the above reaction formula 3-2, X, Ry and It may be the same as defined in the above reaction formula 3-1.

[0156] For example, compound 3-2-1 prepared by the above reaction formula 3-2 can be compound 4640, 17362, 17363, 17364, 17635, etc.

[0157] [Reaction formula 3-3]

[0158]

[0159] According to the above reaction formula 3-3, compound 3-1-1 can be reacted with Compound 3-1-6 is prepared by Suzuki reaction between compounds 3-2-1. In the above reaction formula 3-3, ring A can be (wherein a and b are each independently 1 or 2, M1 is CH2, O, NH or SO2, and M2 is CH or N); (wherein M3 is CH or N); diazabicycloheptane; or a 5-membered or 6-membered heteroaryl group containing 1 to 3 N atoms.

[0160] The compound prepared according to the above reaction formula 3-2 can be compound 17058, etc.

[0161] [Reaction formula 4]

[0162]

[0163] According to the above reaction formula 4, compound 4-2 can be prepared by a click reaction between compound 4-1 having a triple bond and compound 1-2. In the above reaction formula 4, W1 represents N-(C1-C5 alkyl) or O.

[0164] The compounds prepared by the above reaction formula 4 can be compounds 3866, 3867, 4104, 4105, 4106, 4107, 4336, 4337, 4338, 4339, etc.

[0165] [Reaction formula 5]

[0166]

[0167] In the above reaction formula 5, a and b may each independently represent 1 or 2, Y may represent N or CH, and PG may be C(=O)-O(C1-C5 alkyl), such as Boc. Rz may be OH; halogen; C1-C5 alkyl; (wherein a and b are each independently 0 or 1, but cannot be both 0, c is 0 or 1, M4 is CH2, NH or O, and at least one H in M4 may be substituted with halogen or C1-C5 alkyl); C1-C6 haloalkyl; -NR6R7 (wherein R4 and R5 are each independently H or C1-C5 alkyl); -C(=O)-(C1-C5 alkyl); C(=O)-O(C1-C5 alkyl); or -NH-C(=O)-O(C1-C5 alkyl). Rw may be C1-C5 alkyl.

[0168] According to the above Reaction Formula 5, compound 18868 can be prepared as compound 5-2 having a triazole structure via a click reaction between compound 5-1 including a triple bond obtained from Reaction Formula 2 or Reaction Formula 2-1 and compound 1-2.

[0169] Thereafter, the amine protecting group can be removed from compound 5-2 and subjected to a reductive amination reaction (preparation of compound 5-3) to prepare compounds 3988, 3989, 3990, 3991, 4070, 4368, 4369, 4370, 4371, 4373, 4374, 4375, 4376, 4460, 4461, 4462, 4502, 4503, 4504, 4505, 4506, 4507, 4508, 4509, 4510, 4511, 4528, 17698, 17699, 17700, 18869, 18870, 18871, 18924, 18926, etc. as compound 5-4.

[0170] Alternatively, according to the above Reaction Scheme 5, compounds 4372 and 4377 as compound 5-5 can be prepared via acylation reaction of compound 5-3.

[0171] [Reaction Formula 5-1]

[0172]

[0173] In the above reaction formula 5-1, a and b may each independently represent 1 or 2, Y may represent N or CH, and PG may be C(═O)—O(C1-C5 alkyl), such as Boc. In the above reaction formula 5-1, Rz may represent halogen, C1-C5 alkyl, or C3-C6 cycloalkyl.

[0174] According to the above Reaction Formula 5-1, compound 18872 as compound 5-3-1 can be prepared via a reductive amination reaction between compound 5-3 prepared according to Reaction Formula 5 and compound 8-2-1 having an amine protecting group.

[0175] Thereafter, the amine protecting group can be removed from compound 5-3-1 to prepare compound 5-3-2 and compounds 18877 and 18878 as compound 5-3-3 can be prepared via reductive amination reaction.

[0176] [Reaction formula 6]

[0177]

[0178] In the above Reaction Formula 6, a and b may each independently represent 1 or 2, and Rz may be the same as described in Reaction Formula 5 or Reaction Formula 5-1.

[0179] According to the above reaction formula 6, compound 6-2 in which the aldehyde group of compound 6-1 is protected by an acetal group can be prepared, and compound 6-4 can be prepared via C-N coupling (Buchwald reaction) with compound 6-3. Thereafter, compound 6-5 having an aldehyde structure can be prepared by removing the acetal protecting group, and compound 6-7 having a triple bond can be prepared by performing a Corey-Fuchs reaction, and then compound 6-8 having a triazole structure can be prepared by a click reaction with compound 1-2. The amine protecting group (PG) of compound 6-8 can be removed to synthesize compounds 4316, 4317, 4396, 4397, 4398, 4399, 4439, 4440, 4450, 16797, and 18893 corresponding to compound 6-9. Compound 6-9 can be used to perform a reductive amination reaction to prepare compound 6-10.

[0180] Compound 6-10 prepared by the above reaction formula 6 can be compound 4318, 4319, 4320, 4321, 4322, 4419, 4420, 4421, 4422, 4424, 4425, 4426, 4427, 4429, 4430, 4441, 4442, 4443, 4444, 4451, 4452, 4453, 4454, 4455, 4483, 4484, 4485, 4486, 4569, 4570, 4571, 4572, 4573, 4576, 4577, 4578, 4579, 4580, 4600, 4601, 4602, 4603, 18327, 18961, etc.

[0181] [Reaction formula 7]

[0182]

[0183] In the above Reaction Formula 7, a and b may each independently represent 1 or 2, n may represent an integer from 0 to 5, and Rz and Rw may be the same as described in Reaction Formula 5.

[0184] According to the above reaction formula 7, compounds 3805, 3926, 3961, 3999, 4000, etc. can be prepared as compound 7-2 having a triazole structure via a click reaction between compound 7-1 having a triple bond and compound 1-2. In addition, the amine protecting group can be removed from compound 7-2 to prepare compound 7-3, and then compound 7-4 can be prepared via a reductive amination reaction.

[0185] Compound 7-4 prepared by the above reaction formula 7 can be compounds 3806, 3807, 3808, 3809, 3810, 3951, 3952, 3953, 3954, 3955, 4002, 4003, 4005, 4006, 4007, 4008, 4014, 4026, 4027, etc.

[0186] In addition, compound 7-3 can be subjected to acylation reaction or amide reaction to prepare amide compound 7-5, such as compounds 3811, 3812, 3813, 3891, 3892, 3893, 3894, 3956, 3957, 3958, 3959, 4004, 4009, 4015, 4028, 4029, etc.

[0187] [Reaction Formula 7-1]

[0188]

[0189] In the above reaction formula 7-1, a and b may each independently represent 1 or 2, n may represent an integer from 0 to 5, the alkyl group may be a C1-C5 alkyl group, and R5 and R6 may each independently represent H, halogen or a C1-C5 alkyl group.

[0190] According to the above reaction formula 7-1, compound 7-1-1 having a triazole structure can be prepared by a click reaction between compound 7-1 and compound 1-4, and the amine protecting group can be removed with an acid to prepare compound 7-1-2. Thereafter, compound 7-1-4 can be prepared by reacting with compound 7-1-3, which is an oxirane compound, and compound 7-1-5 can be prepared by replacing the hydroxyl group with fluorine, and then compound 7-1-6 can be prepared by using hydrazine. Thereafter, compound 7-1-7 can be prepared by reacting with trifluoroacetic anhydride or difluoroacetic anhydride. The compound prepared by reaction formula 7-1 may be compound 3895, 3896, etc.

[0191] [Reaction formula 8]

[0192]

[0193] In the above Reaction Formula 8, a and b may each independently represent 1 or 2, the alkyl group may be a C1-C5 alkyl group, and Rz may be the same as described in Reaction Formula 5.

[0194] According to the above reaction formula 8, compound 8-2 having a triazole structure can be prepared via a click reaction between compound 8-1 having a triple bond and compound 1-4, and then compound 8-4 can be prepared via CC coupling (Suzuki reaction) with compound 8-3 having a protecting group. Thereafter, compound 8-5 can be prepared via a reduction reaction, and compound 8-6 can be prepared using hydrazine and then reacted with trifluoroacetic anhydride or difluoroacetic anhydride to prepare compound 4001 as compound 8-7. After preparing compound 8-8 by removing the amine protecting group of compound 8-7, compound 8-9 can be prepared via a reductive amination reaction, and compounds 4010, 4011, 4012, 4013, 4290, 4291, 4292, 4293, 19087, etc. may exist as compound 8-9.

[0195] [Reaction formula 8-1]

[0196]

[0197] In the above reaction formula 8-1, the alkyl group may be a C1-C5 alkyl group, and R8 and R9 may each independently represent H, halogen or a C1-C5 alkyl group.

[0198] According to the above reaction formula 8-1, compound 8-1-1 can be prepared by removing the amine protecting group of compound 8-5 prepared by reaction formula 8 with an acid, and then reacting with compound 7-1-3, which is an oxirane compound, to prepare compound 8-1-2. After preparing compound 8-1-3 by replacing the hydroxyl group of compound 8-1-2 with a fluoride, compound 8-1-4 can be prepared by using hydrazine, and then reacting with trifluoroacetic anhydride or difluoroacetic anhydride to prepare compound 8-1-5.

[0199] The compound prepared by reaction formula 8-1 may be compound 4349, 4350, etc.

[0200] [Reaction formula 8-2]

[0201]

[0202] In the above reaction formula 8-2, R 10 It may represent H, halogen or C1-C5 alkyl.

[0203] According to the above reaction formula 8-2, compound 8-2-2 can be prepared via a reductive amination reaction between compound 8-8 prepared by reaction formula 8 and compound 8-2-1 having an amine protecting group, and the amine protecting group can be removed to prepare compound 8-2-3, and then compound 8-2-4 can be prepared via a reductive amination reaction.

[0204] The compound prepared by reaction formula 8-2 may be compound 4294, 4295, 4296, etc.

[0205] [Reaction formula 9]

[0206]

[0207] In the above reaction formula 9, R 11 Can The H of the functional group can be independently substituted by OH, halogen, C1-C5 alkyl, C1-C6 haloalkyl, etc.

[0208] According to the above reaction formula 9, compound 9-2 having a triazole structure can be prepared via a click reaction between compound 9-1 and compound 1-2, and then compound 9-3 can be prepared via a reductive amination reaction.

[0209] The compound prepared by the above reaction formula 9 can be compound 3915, 3916, 3917, 3918, 3919, 3963, 3964, 3965, 3966, 4400, 4401, 4402, 4403, 4404, 4405, 4406, 4407, 4408, 4409, 4410, 4411, 4412, 4413, 4414, 4415, 4416, 4417, 4418, 4466, 4467, 4468, 4469, 4470, 4471, 4472, 4473, 4474, 4475, 4476, 4477, 4494, 4521, 4522, 4523, 4548, 4549, 4550, 4551, 4552, 4553, 4554, 4555, 4556, 4557, 4558, 4559, 4560, 4561, 4562, 4563, 4564, 4565, 4566, 4567, 4583, 4585, 4586, 4587, 4588, 4589, 4590, 18058, 18306, 18307, 18308, 18457, 18459, 18822, 18823, 18882, 4604, 4605, 4606, 4607, 4608, 4609, 4610, 4611, etc.

[0210] [Reaction formula 9-1]

[0211]

[0212] In the above reaction formula 9-1, ring A can be a C4-C6 cycloalkenyl group; a C6-C12 aryl group; a 5- to 9-membered heteroaryl group including at least one heteroatom selected from N, O and S; (wherein a or b are each independently an integer of 1 or 2); (wherein a is an integer of 0, 1 or 2); or pyridone. In this case, R 11 It may be halogen or -Q1-Q2-Ra. In addition, X bonded to the A ring may represent F, Cl or Br.

[0213] According to the above reaction formula 9-1, compound 9-1-3 having a trimethylsilyl protecting group can be prepared via CC coupling (Sonogashira) between halide 9-1-1 and compound 9-1-2 having a triple bond, and then compound 9-1-4 having an aldehyde structure can be prepared by removing the trimethylsilyl protecting group.

[0214] Compound 9-1-5 having a triazole structure can be prepared via a click reaction between compound 9-1-4 and compound 1-2, and then compound 9-1-6 can be prepared via a reductive amination reaction.

[0215] The compound prepared by the above reaction formula 9-1 can be compound 18059, 18309, 18310, 18311, 18483, 18554, 18622, 18711, 18712, 18713, 19088, 19089, 19090, 19091, 19092, 19093, 19094, 19096, 19098, 19099, 19100, 17532, 17533, 17534, 1 7535, 17545, 17773, 17774, 17775, 17777, 17778, 17912, 17913, 17914, 17915, 17916, 17917, 17922, 18174, 18175, 18176, 18177, 18178, 18180, 18185, 18187, 18188, 18260, 18947, 18948, 18949 and 18950.

[0216] [Reaction formula 10]

[0217]

[0218] In the above reaction formula 10, a and b may each independently be 1 or 2, and W2 may be O, CH2, CH(C1-C5 alkyl), NH or N-(C1-C5)alkyl.

[0219] In the above reaction formula 10, R4 and R5 can each independently be H or C1-C5 alkyl, and at least one H can each independently be (wherein a and b are each independently 0 or 1 but cannot be 0 at the same time, c is 0 or 1, M4 is CH2, NH or O, and at least one H in M4 can be substituted by halogen, C1-C5 alkyl, C3-C6 cycloalkyl or -C(=O)-O(C1-C5 alkyl)); or -NR6R7 (wherein R6 and R7 are each independently H or C1-C5 alkyl).

[0220] According to the above reaction formula 10, compounds 3659, 3660, 3731, 3732 and 3739 can be prepared as compound 10-2 having a triazole structure via a click reaction between compound 10-1 and compound 1-2.

[0221] Compounds 3829, 3885, 3886, 3887, 4448, 4482, etc. can be prepared as amide compound 10-3 via an amide bond with compound 10-2, and compounds 4449 and 4480 can be prepared as compound 10-4.

[0222] [Reaction formula 11]

[0223]

[0224] In the above reaction formula 11, R4 and R5 can each independently be H or C1-C5 alkyl, and at least one H can each independently be replaced by OH, halogen, etc. to replace.

[0225] According to the above reaction formula 11, compound 11-2 having a triazole structure can be prepared via a click reaction between compound 11-1 and compound 1-2, and then compounds 3774, 3824, 3827, 3828, 3830, 4323, 4324, 4325, 4326, 4330, 4331, 4332, 4431, 4432, 4433, 4434, 4435, 4436, 4437 and 4438 can be prepared as compound 11-3 via a reductive amination reaction.

[0226] Compound 11-2 can be subjected to acylation reaction and amide reaction to prepare compounds 3775, 3776, 3777, 3825, 3826, 3987, 4229, 4230, 4231, 4327, 4328, 4329, 4333, 4334, 4335, 4351, 4352, 4353, etc. as compound 11-4.

[0227] [Reaction formula 11-1]

[0228]

[0229] In the above reaction formula 11-1, R 12It can be OH; halogen; C1-C5 alkyl; C1-C6 haloalkyl; -NR6R7 (wherein R6 and R7 may each independently be H or C1-C5 alkyl); -C(=O)-(C1-C5 alkyl); C(=O)-O(C1-C5 alkyl); or -NH-C(=O)-O(C1-C5 alkyl).

[0230] According to Reaction Formula 11-1, after preparing Compound 11-4 by forming an amide bond between Compound 11-2 prepared in Reaction Formula 11 and Compound 11-3 having an amine protecting group, Compound 4463 can be prepared as Compound 11-5 by removing the amine protecting group.

[0231] Compound 11-5 can be subjected to a reductive amination reaction to prepare compounds 4464 and 4465 as compound 11-6.

[0232] [Reaction formula 11-2]

[0233]

[0234] In the above reaction formula 11-2, n can be 1 or 2.

[0235] According to the above reaction formula 11-2, compounds 4495 and 4496 can be prepared as compound 11-2-2, which forms an amide bond between compound 11-2 prepared by reaction formula 11 and compound 11-2-1 having an amine protecting group. Thereafter, the amine protecting group can be removed to prepare compounds 4497 and 4498 as compound 11-2-3.

[0236] [Reaction formula 11-3]

[0237]

[0238] According to the above reaction formula 11-3, compound 3741 having the structure of compound 11-3-2 containing a triazole structure can be prepared via a click reaction between compound 11-3-1 having an amine protecting group and compound 1-2. Thereafter, the amine protecting group can be removed to prepare compound 11-2, and then compound 11-3-3 can be prepared via a reductive amination reaction.

[0239] [Reaction formula 11-4]

[0240]

[0241] In the above reaction formula 11-4, Rx can be a C1-C5 alkyl group or a C1-C5 alkoxy group.

[0242] According to the above reaction formula 11-4, compound 11-1 having a triple bond can be subjected to a reductive amination reaction to prepare compound 11-4-1, and compound 11-4-2 having a triazole structure can be prepared through a click reaction with compound 1-2. Thereafter, compounds 3889 and 3890 can be prepared as compound 11-4-3 through an acylation reaction.

[0243] [Reaction formula 12]

[0244]

[0245] In the above reaction formula 12, R 13 It can be -Q1-Q2-Ra.

[0246] According to the above reaction formula 12, compound 12-1 having an aldehyde structure can be subjected to a Mannich reaction to produce compound 12-2, which can then be synthesized using compound 2-2, a phosphonate reagent, to form compound 12-3 having a triple bond structure. Subsequently, compounds 3944, 3962, 3986, 4108, 4109, 4110, 4111, 4112, 4134, 4492, 4493, and 17255 can be prepared as compound 12-4 having a triazole structure via a click reaction with compound 1-2.

[0247] [Reaction formula 12-1]

[0248]

[0249] In the above reaction formula 12-1, R 13 Can be -(CH2) n -Q1-Q2-Ra (wherein n is 0 or 1).

[0250] According to the above reaction formula 12-1, compound 12-1 having an aldehyde structure can be subjected to a reductive amination reaction to prepare compound 12-1-1. Compound 2-2, a phosphonate reagent, can then be used to synthesize compound 12-1-2 having a triple bond structure. Subsequently, compounds 3914 and 4136 can be prepared as compound 12-1-3 having a triazole structure via a click reaction with compound 1-2.

[0251] [Reaction formula 12-2]

[0252]

[0253] According to the above reaction formula 12-2, compound 12-2-2 having a triazole structure can be prepared via a click reaction between compound 12-2-1 obtained by reaction formula 2 and compound 1-2, and then compounds 4023, 4186 and 4187 can be prepared as compound 12-2-4 via a Mannich reaction with compound 12-2-3.

[0254] [Reaction formula 12-3]

[0255]

[0256] According to the above reaction formula 12-3, compound 12-3-1 can be subjected to Pd(II)-catalyzed indole synthesis to produce compound 12-3-2, and compound 12-3-3 having an alcohol structure can be prepared via a reduction reaction. Subsequently, compound 12-3-4 having an aldehyde structure can be prepared via an oxidation reaction, and compound 2-2, a phosphonate reagent, can be used to prepare compound 12-3-5 having a triple bond structure. Thereafter, compounds 4287 and 4288 can be prepared as compound 12-3-6 having a triazole structure via a click reaction with compound 1-2, a 1,3,4-oxadiazole.

[0257] [Reaction formula 13]

[0258]

[0259] In the above reaction formula 13, n can be 1 or 2, the alkyl group can be a C1-C5 alkyl group, and R 13 Can be -(CH2) n -Q1-Q2-Ra (wherein n is 0 or 1).

[0260] According to the above reaction formula 13, compound 13-2 having a triazole structure can be prepared by a click reaction between compound 13-1 obtained by reaction formula 2 and compound 1-4, followed by preparation of compound 13-3 using hydrazine, and then reacting with trifluoroacetic anhydride or difluoroacetic anhydride to prepare compound 13-4. Thereafter, the amine protecting group can be removed to prepare compound 4539 as compound 13-5, and then compound 13-6 can be prepared through a reductive amination reaction.

[0261] The compound prepared by the above reaction formula 13 can be compounds 4051, 4052, 4053, 4054, 4055, 4209, 4210, 4211, 4212, 4213, 4358, 4359, 4360, 4361, 4362, 4363, 4364, 4365, 4366, 4367, 4513, 4515, 4516, 4517, 4518, 4519, 4529, 4530, 4531, 4532, 4533, 4534, 4535, 4536, 4537, 4538, 4540, 4541, 4542, 4543, 4595, 4596, 4597, 4598, 4599, 17458, 17460, 19002, 19004, etc.

[0262] [Reaction formula 13-1]

[0263]

[0264] In the above reaction formula 13-1, R 14 It can be OH; halogen; C1-C5 alkyl; C1-C6 haloalkyl; -NR6R7; -C(=O)-(C1-C5 alkyl); C(=O)-O(C1-C5 alkyl); or -NH-C(=O)-O(C1-C5 alkyl).

[0265] According to the above reaction formula 13-1, compound 13-4 having a triazole structure can be prepared via a click reaction between compound 13-1 obtained via reaction formula 2 and compound 1-2, after which the amine protecting group can be removed to prepare compound 13-5. Thereafter, compound 13-1-1 can be prepared via a reductive amination reaction with compound 8-2-1 having an amine protecting group, and the amine protecting group can be removed to prepare compound 13-1-2, and then compound 13-1-3 can be prepared via a reductive amination reaction.

[0266] The compound prepared by the above reaction formula 13-1 may be compound 4392, 4393, 4394, 4395, etc.

[0267] [Reaction formula 14]

[0268]

[0269] In the above reaction formula 14, R 13 Can be -(CH2) n -Q1-Q2-Ra (wherein n is 0 or 1).

[0270] According to the above reaction formula 14, a triazole-structured compound 14-2 can be prepared via a click reaction between compound 14-1 having an amine protecting group obtained via reaction formula 2-1 and compound 1-2. The amine protecting group can then be removed to prepare compound 4499 as compound 14-3. Subsequently, compounds 4500, 4501, etc. can be prepared as compound 14-4 via a reductive amination reaction.

[0271] [Reaction formula 15]

[0272]

[0273] According to the above reaction formula 15, compound 15-2 having a triazole structure can be prepared via a click reaction between compound 15-1 having a triple bond and compound 1-2. Compounds prepared by the above reaction formula may be 4276, 4277, 4278, and 4279. Subsequently, the hydroxyl group of compound 15-2 can be substituted with a fluoride to prepare compounds 4280, 4281, 4282, and 4283 having the structure of compound 15-3.

[0274] [Reaction formula 16]

[0275]

[0276] In the above reaction formula 16, R2′ can be H, C1-C5 alkyl, OH or N(C1-C5 alkyl)2.

[0277] According to the above reaction formula 16, the triazole compound 16-2 can be prepared via a click reaction between the aldehyde compound 16-1 having a triple bond and the compound 1-2, and then the compound 16-3 can be prepared via a reduction reaction and a reductive amination reaction.

[0278] The compounds prepared by the above reaction formula 16 may be compounds 4478, 4479, 4490 and 4491.

[0279] [Reaction 17]

[0280]

[0281] According to the above reaction formula 17, compound 3949 can be prepared as compound 17-2 via a substitution reaction between compound 17-1 and compound 1-1. Thereafter, compound 17-4 can be prepared via CC coupling (Suzuki reaction) with compound 17-3.

[0282] The compound prepared by the above reaction formula 17 may be compounds 3945, 3950, 4133, 4208, etc.

[0283] [Reaction formula 18]

[0284]

[0285] In the above reaction formula 18, the alkyl group may be a C1-C5 alkyl group.

[0286] According to the above reaction formula 18, compound 18-1 can be used to prepare compound 18-2 as a tetrazole, and compound 18-3 can be prepared by substitution reaction with compound 1-3 under basic conditions. Thereafter, compound 18-4 can be prepared by using hydrazine and then reacted with trifluoroacetic anhydride or difluoroacetic anhydride to prepare compound 18-5.

[0287] The compound prepared by the above reaction formula 18 may be compounds 4232, 4233, 4234, 4235, etc.

[0288] [Reaction formula 19]

[0289]

[0290] In the above reaction formula 19, the alkyl group may be a C1-C5 alkyl group.

[0291] According to the above reaction formula 19, compound 19-3 can be prepared by an amide bond reaction between compound 19-1 and compound 19-2, and then reacted with 1-methoxy-N-triethylammoniumsulfonyl-formimide ester (Burgess reagent) to prepare compound 19-4 having an oxadiazole structure. Thereafter, compound 19-5 can be prepared by using hydrazine, and then reacted with trifluoroacetic anhydride or difluoroacetic anhydride to prepare compound 3980 as compound 19-6.

[0292] Additionally, compound 19-4 can be subjected to methylamine (2.0 M in THF) to prepare compound 19-7, which can then be prepared by using hydrazine to prepare compound 19-8, and subsequently reacted with trifluoroacetic anhydride or difluoroacetic anhydride to prepare compound 3981 as compound 19-9.

[0293] Compositions comprising compounds represented by formula I, uses thereof, and methods of treatment using the same

[0294] The present invention may provide a pharmaceutical composition comprising the compound represented by the above formula I, its stereoisomers or pharmaceutically acceptable salts thereof as an active ingredient.

[0295] In addition, the present invention can provide a pharmaceutical composition for preventing or treating diseases related to histone deacetylase 6 activity, which comprises the compound represented by the above formula I, its stereoisomers or pharmaceutically acceptable salts thereof as an active ingredient.

[0296] The pharmaceutical composition of the present invention can selectively inhibit histone deacetylase 6, thereby showing a significant effect in preventing or treating diseases related to histone deacetylase 6 activity.

[0297] In addition to symptoms or diseases associated with abnormal function of histone deacetylase, diseases associated with histone deacetylase 6 activity may also include cancer, inflammatory diseases, autoimmune diseases, neurological or degenerative neurological diseases, specifically including lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, brain cancer, ovarian cancer, gastric cancer, skin cancer, pancreatic cancer, glioma, glioblastoma, leukemia, lymphoma, multiple myeloma, solid cancer, Wilson's disease, spinocerebellar ataxia, prion disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, amyloidosis, Alzheimer's disease, alcoholic liver disease, spinal muscular atrophy, rheumatoid arthritis or osteoarthritis.

[0298] Examples of histone deacetylase-mediated diseases may include infectious diseases; tumors, endocrine diseases, nutritional and metabolic diseases; mental and behavioral disorders; neurological diseases; eye and ocular adnexa diseases; circulatory system diseases; respiratory diseases; digestive tract problems; skin and subcutaneous tissue diseases; musculoskeletal system and connective tissue diseases; or deformities, deformations and chromosomal aberrations.

[0299] The endocrine, nutritional and metabolic diseases may be Wilson's disease, amyloidosis or diabetes, the mental and behavioral disorders may be depression or Rett syndrome, and the neurological diseases may be central nervous system atrophy, neurodegenerative diseases, movement disorders, neuropathy, motor neuron disease or central nervous system demyelinating diseases, the eye and ocular adnexa diseases may be uveitis, the skin and subcutaneous tissue diseases may be psoriasis, the musculoskeletal system and connective tissue diseases may be rheumatoid arthritis, osteoarthritis or systemic lupus erythematosus, the deformity, deformation and chromosomal aberration may be autosomal dominant polycystic kidney disease, the infectious disease may be prion disease, the tumor may be benign or malignant, the circulatory system disease may be atrial fibrillation or stroke, the respiratory tract disease may be asthma, and the digestive tract disease may be alcoholic liver disease, inflammatory bowel disease, Crohn's disease or ulcerative bowel disease.

[0300] The pharmaceutically acceptable salts are the same as those described for the pharmaceutically acceptable salts of the compounds represented by formula I of the present invention.

[0301] For its administration, in addition to the compound represented by Formula I, its stereoisomer or its pharmaceutically acceptable salt, the pharmaceutical composition of the present invention may additionally contain at least one type of pharmaceutically acceptable carrier. In this case, the pharmaceutically acceptable carrier to be used may include a mixture of physiological saline solution, sterile water, Ringer's solution, buffered physiological saline, dextrose solution, maltodextrin solution, glycerol, ethanol and at least one component thereof, and other conventional additives such as antioxidants, buffer solutions, antibacterial agents, etc. may be added as needed. In addition, diluents, dispersants, surfactants, adhesives and lubricants may be added to formulate injectable dosage forms such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules or tablets. Therefore, the composition of the present invention may be a patch, liquid medicine, pills, capsules, granules, tablets, suppositories, etc. Preparations can be prepared according to conventional methods for preparations in the art or methods disclosed in Remington's Pharmaceutical Science (latest version), Merck Publishing Company, Easton PA, and the composition can be formulated into various preparations depending on each disease or component.

[0302] The composition of the present invention can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) according to a targeted method, wherein the dosage varies within its range depending on the patient's weight, age, sex, health status and diet, administration time, administration method, excretion rate, severity of the disease, and similar factors. The daily dose of the compound represented by Formula I of the present invention may be about 1 to 1000 mg / kg, preferably 5 to 100 mg / kg, and can be administered once a day or several times a day by dividing the daily dose of the compound.

[0303] In addition to the compound represented by Formula I, its stereoisomers, or pharmaceutically acceptable salts thereof, the pharmaceutical composition of the present invention may further contain at least one active ingredient that exhibits the same or similar medical effects. The present invention may provide a method for preventing or treating diseases related to histone deacetylase 6 activity, comprising administering a therapeutically effective amount of the compound represented by Formula I, its stereoisomers, or pharmaceutically acceptable salts thereof.

[0304] As used herein, the term "therapeutically effective amount" may refer to an amount of the compound represented by the above Formula I, which can effectively prevent or treat histone deacetylase 6 activity-related diseases.

[0305] In addition, the present invention may provide a method for selectively inhibiting HDAC6 by administering the compound represented by the above Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to mammals including humans.

[0306] The method for preventing or treating histone deacetylase 6 activity-related diseases according to the present invention may include not only treating the disease itself before the symptoms of the disease appear, but also suppressing or avoiding such symptoms by administering a compound represented by the above formula I. In terms of managing the disease, the preventive dose or therapeutic dose of a certain active ingredient may vary depending on the nature and severity of the disease or condition and the route of administration of the active ingredient. Its dosage and frequency may vary depending on the age, weight and response of the individual patient. Suitable dosage and usage can be easily selected by those skilled in the art naturally considering such factors. In addition, in addition to the compound represented by the above formula I, the method for preventing or treating histone deacetylase 6 activity-related diseases of the present invention may further include administering a therapeutically effective amount of an additional active agent that helps to treat the disease, wherein the additional active agent can exhibit a synergistic or adjuvant effect together with the compound of the above formula I.

[0307] The present invention also provides a use of a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for preparing a medicament for treating diseases associated with histone deacetylase 6 activity. The compound represented by Formula I used to prepare the medicament can be combined with an acceptable adjuvant, diluent, carrier, etc., and can be prepared into a complex formulation with other active agents, thereby achieving a synergistic effect of the active ingredients.

[0308] Unless otherwise in conflict, the matters mentioned in the uses, compositions and therapeutic methods of the present invention also apply.

[0309] Beneficial effects

[0310] According to the present invention, the compound represented by the above formula I, its stereoisomers or pharmaceutically acceptable salts thereof can selectively inhibit HDAC6, and thus has a significantly excellent effect in preventing or treating diseases related to histone deacetylase 6 activity.

[0311] Mode for the Invention

[0312] Hereinafter, the present invention will be described in detail through preferred embodiments for better understanding of the present invention. However, the following embodiments are provided only for the purpose of illustrating the present invention, and therefore the present invention is not limited thereto.

[0313] Unless otherwise specified, the reagents and solvents mentioned below were purchased from Sigma-Aldrich, TCI, and Waters e2695 was used for HPLC, and Merck (230-400 mesh) was used for silica gel for column chromatography. 1 H NMR data and mass spectrometry were performed on an Agilent 1100 series instrument.

[0314] Example 1: Synthesis of Compound 3657, 2-(difluoromethyl)-5-(4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[0315] [Step 1] Synthesis of 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0316]

[0317] 2-(4-(Bromomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (1.500 g, 5.189 mmol) and sodium azide (0.405 g, 6.227 mmol) were dissolved in N,N-dimethylformamide (15 mL) at room temperature, and the resulting solution was stirred at 40 ° C for 18 hours, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 30%) and concentrated to give 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.950 g, 72.9%) as a colorless oil.

[0318] [Step 2] Synthesis of compound 3657

[0319]

[0320] 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.080 g, 0.318 mmol) prepared in Step 1 was dissolved in tert-butanol (1 mL) / water (1 mL) at room temperature. Ethylenebenzene (0.035 mL, 0.318 mmol) was then added to the resulting solution and stirred at the same temperature. Sodium ascorbate (1.00 M solution, 0.032 mL, 0.032 mmol) and copper (II) sulfate pentahydrate (0.001 g, 0.003 mmol) were added to the reaction mixture and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 10% to 50%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.070 g, 62.2%) as a white solid.

[0321] 1 H NMR(700MHz,CD3OD)δ8.44(s,1H),8.19-8.15(m,2H),7.86-7.82(m,2H),7.64-7.60(m,2H ),7.48-7.42(m,2H),7.39-7.34(m,1H),7.23(t,J=51.6Hz,1H),5.80(s,2H); LRMS(ES)m / z 354.2(M + +1).

[0322] Example 2: Synthesis of Compound 3658, 2-(difluoromethyl)-5-(3-fluoro-4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[0323] [Step 1] Synthesis of 2-(4-(azidomethyl)fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0324]

[0325] 2-(4-(Bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (1.500 g, 4.885 mmol) and sodium azide (0.381 g, 5.862 mmol) were dissolved in N,N-dimethylformamide (15 mL) at room temperature, and the resulting solution was stirred at 40 ° C for 18 hours, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 30%) and concentrated to give 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.930 g, 70.7%) as a colorless oil.

[0326] [Step 2] Synthesis of compound 3658

[0327]

[0328] 2-(4-(Azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.080 g, 0.297 mmol) prepared in Step 1 was dissolved in tert-butyl alcohol (1 mL) / water (1 mL) at room temperature. Ethylenebenzene (0.033 mL, 0.297 mmol) was then added to the resulting solution and stirred at the same temperature. Sodium ascorbate (1.00 M solution, 0.030 mL, 0.030 mmol) and copper (II) sulfate pentahydrate (0.001 g, 0.003 mmol) were added to the reaction mixture and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 10% to 50%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.065 g, 58.9%) as a white solid.

[0329] 1 H NMR (700MHz, CD3OD) δ8.45(s,1H),8.00(dd,J=8.0,1.7Hz,1H),7.97(dd,J=10.1,1.7Hz,1H),7.88-7.82(m,2H),7.61(t ,J=7.7Hz,1H),7.48-7.43(m,2H),7.37(ddt,J=7.9,6.9,1.3Hz,2H),7.24(t,J=51.6Hz,1H),5.86(s,2H); LRMS(ES)m / z 372.3(M + +1).

[0330] Example 16: Synthesis of Compound 3736, 2-(difluoromethyl)-5-(6-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0331] [Step 1] Synthesis of 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0332]

[0333] 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (1.000 g, 3.447 mmol) was dissolved in N,N-dimethylformamide (10 mL) at room temperature, after which sodium azide (0.224 g, 3.447 mmol) was added to the resulting solution and stirred at 40 ° C for 2 hours, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified and concentrated via column chromatography (SiO2, 24 g chromatographic column; ethyl acetate / hexane = 0 to 50%) to give 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.800 g, 92.0%) as a yellow solid.

[0334] [Step 2] Synthesis of compound 3736

[0335]

[0336] 2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.198 mmol) prepared in Step 1 was dissolved in tert-butanol (1 mL) / water (1 mL) at room temperature. Ethylenebenzene (0.022 mL, 0.198 mmol) was then added to the resulting solution and stirred at the same temperature. Sodium ascorbate (1.00 M solution, 0.020 mL, 0.020 mmol) and copper (II) sulfate pentahydrate (0.50 M solution, 0.004 g, 0.002 mmol) were added to the reaction mixture and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; dichloromethane / methanol = 0 to 10%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.035 g, 49.8%) as a white solid.

[0337] 1H NMR (400MHz, CDCl3) δ9.31(d,J=1.8Hz,1H),8.41(dt,J=8.1,1.8Hz,1H),8.03(d,J=1.4Hz,1H),7.81(dt,J=8.1,1. 3Hz,2H),7.48-7.35(m,4H),7.33(d,J=8.2Hz,1H),6.95(t,J=51.6,1.4Hz,1H),5.81(d,J=1.5Hz,2H); LRMS(ES)m / z 356.1(M + +1).

[0338] Example 21: Synthesis of Compound 3774, 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylaniline

[0339] [Step 1] Synthesis of 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)aniline

[0340]

[0341] 2-(4-(Azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.200 g, 0.743 mmol) prepared in Step 1 of Example 2 was dissolved in tert-butanol (1 mL) / water (1 mL) at room temperature. 3-Ethynylaniline (0.087 g, 0.743 mmol) was then added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. A saturated aqueous ammonium chloride solution was poured into the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; dichloromethane / methanol = 0 to 40%) and concentrated to give 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)aniline (0.198 g, 69.0%) as a beige solid.

[0342] [Step 2] Synthesis of compound 3774

[0343]

[0344] 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)aniline (0.030 g, 0.078 mmol) prepared in Step 1 and formaldehyde (37.00%, 0.063 g, 0.777 mmol) were dissolved in acetonitrile (1 mL) / acetic acid (0.01 mL). The resulting solution was stirred at room temperature for 0.5 hours, and sodium cyanoborohydride (0.015 g, 0.233 mmol) was added and stirred at the same temperature for another 1 hour. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO 2 , 12 g column; ethyl acetate / hexane = 0 to 30%) and concentrated to give 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylaniline (0.020 g, 62.2%) as a pale yellow oil.

[0345] 1 H NMR (400MHz, CD3OD) δ8.40(s,1H),8.02-7.92(m,2H),7.59(t,J=7.7Hz,1H),7.30-7.24(m,2H),7.24(t,J=51.6 Hz,1H),7.13(dt,J=7.6,1.2Hz,1H),6.79(ddd,J=8.4,2.7,0.9Hz,1H),5.84(s,2H),3.00(s,6H); LRMS(ES)m / z 415.3(M + +1).

[0346] The compounds in Table 3 were synthesized according to substantially the same procedures described above for the synthesis of compound 3774, except using 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)aniline and the reactants in Table 2.

[0347] [Table 2]

[0348] Example Compound number reactants Yield (%) 232 4330 Cyclohexanone 69 233 4331 Tetrahydro-4H-pyran-4-one 67 234 4332 Oxetane-3-one 52

[0349] [Table 3]

[0350]

[0351] Example 22: Synthesis of Compound 3775, N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)acetamide

[0352]

[0353] 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)aniline (0.030 g, 0.078 mmol) and triethylamine (0.013 mL, 0.093 mmol) prepared in Step 1 of Example 21 were dissolved in dichloromethane (1 mL) at room temperature. Acetyl chloride (0.006 mL, 0.078 mmol) was then added to the resulting solution, and the mixture was stirred at the same temperature for 1 hour. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 30%) and concentrated to give N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)acetamide (0.022 g, 66.1%) as a white solid.

[0354] 1 H NMR(400MHz,CD3OD)δ8.42(s,1H),8.05(s,1H),8.02-7.93(m,2H),7.58(dt,J=17.6,8.6Hz,3H ),7.40(t,J=7.9Hz,1H),7.24(t,J=51.6Hz,1H),5.88-5.84(m,2H),2.16(s,3H); LRMS(ES)m / z 429.2(M + +1).

[0355] The compounds in Table 5 were synthesized according to substantially the same procedures described above for the synthesis of Compound 3775, except using 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)aniline and the reactants in Table 4.

[0356] [Table 4]

[0357] Example Compound number reactants Yield (%) 23 3776 Methyl chloroformate 66 24 3777 Trifluoroacetic anhydride 72 235 4333 Trimethylacetyl chloride 82

[0358] [Table 5]

[0359]

[0360] Example 25: Synthesis of Compound 3805, tert-Butyl 4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate

[0361]

[0362] 2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.800 g, 3.172 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (0.730 g, 3.490 mmol), sodium ascorbate (1.00 M solution in H₂O, 0.317 mL, 0.317 mmol), and copper (II) sulfate pentahydrate (0.50 M solution in H₂O, 0.063 mL, 0.032 mmol) were dissolved in tert-butanol (10 mL) / water (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 24 g column; ethyl acetate / hexane = 0 to 70%) and concentrated to give tert-butyl 4-(1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate (1.100 g, 75.1%) as a white solid.

[0363] 1 H NMR (400MHz, CDCl3) δ9.33(dd,J=2.2,0.8Hz,1H),8.41(dd,J=8.2,2.2Hz,1H),7.49(d,J=0.4Hz,1H),7.37(dd,J=8.2,0.6Hz,1H),7.09(s,0.2H),6. 96(s,0.5H),6.83(s,0.3H),5.75(s,2H),4.16(s,2H),3.09-2.75(m,3H), 2.05(dd,J=12.9,2.3Hz,2H),1.73-1.54(m,2H),1.48(s,9H); LRMS(ES)m / z 462.22(M + +1).

[0364] Example 26: Synthesis of Compound 3806, 2-(difluoromethyl)-5-(6-((4-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0365] [Step 1] Synthesis of 2-(difluoromethyl)-5-(6-((4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0366]

[0367] Tert-butyl 4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate (1.100 g, 2.384 mmol) and trifluoroacetic acid (0.548 mL, 7.151 mmol) prepared in Example 25 were dissolved in dichloromethane (80 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting product (2-(difluoromethyl)-5-(6-((4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole, 0.700 g, 81.3%, yellow oil) was used without additional purification.

[0368] [Step 2] Synthesis of compound 3806

[0369]

[0370] 2-(Difluoromethyl)-5-(6-((4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.050 g, 0.138 mmol) prepared in Step 1, N,N-diisopropylethylamine (0.048 mL, 0.277 mmol), and formaldehyde (0.008 g, 0.277 mmol) were dissolved in dichloromethane (20 mL), and the resulting solution was stirred at room temperature for 30 minutes. Then, sodium triacetoxyborohydride (0.059 g, 0.277 mmol) was added thereto and stirred at the same temperature for further 12 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 5%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.029 g, 55.8%) as a white solid.

[0371] 1 H NMR (400MHz, CDCl3) δ9.33(d,J=1.5Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.50(s,1H),7.35(d,J=8.2Hz,1H),7.09(s,0.2H),6.96(s,0.5H), 6.83(s,0.3H),5.75(s,2H),3.02(d,J=11.6Hz,2H),2.85(t,J=11.5Hz,1H),2.39(s,3H),2.29-2.01(m,4H),1.95-1.65(m,2H); LRMS(ES)m / z 376.2(M + +1).

[0372] The compounds of Table 7 were synthesized according to substantially the same procedures described above for the synthesis of compound 3806, except using 2-(difluoromethyl)-5-(6-((4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reactants of Table 6.

[0373] [Table 6]

[0374] Example Compound number reactants Yield (%) 27 3807 acetaldehyde 55 28 3808 Propan-2-one 66 29 3809 Oxetane-3-one 58 30 3810 2-Oxaspiro[3.3]heptan-6-one 61

[0375] [Table 7]

[0376]

[0377] Example 31: Synthesis of Compound 38n, 1-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)ethan-1-one

[0378]

[0379] 2-(Difluoromethyl)-5-(6-((4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.050 g, 0.138 mmol), triethylamine (0.023 mL, 0.166 mmol), and acetic anhydride (0.026 mL, 0.277 mmol) prepared in Step 1 of Example 26 were dissolved in dichloromethane (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 5%) and concentrated to give 1-(4-(1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)ethan-1-one (0.041 g, 73.5%) as a white solid.

[0380] 1 H NMR (400MHz, CDCl3) δ9.31 (d, J=1.8Hz, 1H), 8.40 (dd, J=8.2, 2.2Hz, 1H), 7.51 (s, 1H), 7. 38(d,J=8.2Hz,1H),7.09(s,0.2H),6.96(s,0.5H),6.83(s,0.3H),5.74(s,2H),4.64(d,J =13.0Hz,1H),3.89(d,J=13.0Hz,1H),3.22(t,J=12.3Hz,1H),3.05(tt,J=11.4,3.8Hz,1H ),2.76(t,J=11.9Hz,1H),2.27-1.97(m,5H),1.66(dd,J=25.7,12.8Hz,2H); LRMS(ES)m / z 403.9(M + +1).

[0381] The compounds in Table 9 were synthesized according to substantially the same procedures described above for the synthesis of compound 3811, except using 2-(difluoromethyl)-5-(6-((4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reactants in Table 8.

[0382] [Table 8]

[0383] Example Compound number reactants Yield (%) 32 3812 Methanesulfonyl chloride 34 77 3891 Methyl chloroformate 56 78 3892 Ethyl chloroformate 46 79 3893 Trimethylacetyl chloride 45

[0384] [Table 9]

[0385]

[0386] Example 33: Synthesis of Compound 3813, 1-(4-(1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)-2-hydroxyethane-1-one

[0387]

[0388] 2-(Difluoromethyl)-5-(6-((4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.050 g, 0.138 mmol) prepared in Step 1 of Example 26, 2-hydroxyacetic acid (0.013 g, 0.166 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.043 g, 0.277 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (0.037 g, 0.277 mmol) were dissolved in dichloromethane (10 mL) at room temperature, followed by addition of N,N-diisopropylethylamine (0.048 mL, 0.277 mmol) to the resulting solution and stirring at the same temperature for 30 minutes. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified and concentrated via column chromatography (SiO2, 4g chromatographic column; methanol / dichloromethane = 0 to 5%) to give 1- (4- (1- ((5- (difluoromethyl) -1,3,4- oxadiazol-2-yl) pyridin-2-yl) methyl) -1H-1,2,3-triazol-4-yl) piperidin-1-yl) -2-hydroxyethane -1-one (0.021 g, 36.2%) as a white solid.

[0389] 1H NMR (400MHz, CDCl3) δ9.32 (d, J=1.7Hz, 1H), 8.41 (dd, J=8.2, 2.2Hz, 1H), 7.60-7. 47(m,2H),7.41(d,J=8.1Hz,1H),7.09(s,0.2H),6.96(s,0.5H),6.83(s,0.3H),5 .75(s,2H),4.61(d,J=13.6Hz,1H),4.19(s,2H),3.59(d,J=13.9Hz,1H),3.24-2. 99(m,2H),2.99-2.81(m,1H),2.24-2.07(m,2H),1.77-1.54(m,2H); LRMS(ES)m / z 420.3(M + +1).

[0390] The compounds of Table 11 were synthesized according to substantially the same procedures described above for the synthesis of compound 3813, except using 2-(difluoromethyl)-5-(6-((4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reactants of Table 10.

[0391] [Table 10]

[0392] Example Compound number reactants Yield (%) 80 3894 2-Fluoro-2-methylpropionic acid 47

[0393] [Table 11]

[0394]

[0395] Example 36: Synthesis of Compound 3824, 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylaniline

[0396] [Step 1] Synthesis of 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)aniline

[0397]

[0398] 2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.500 g, 1.983 mmol) prepared in Step 1 of Example 16 was dissolved in tert-butanol (4 mL) / water (4 mL) at room temperature. 3-Ethynylaniline (0.223 mL, 1.983 mmol) was then added to the resulting solution and stirred at the same temperature. Sodium ascorbate (1.00 M solution, 0.198 mL, 0.198 mmol) and copper (II) sulfate pentahydrate (0.50 M solution, 0.040 g, 0.020 mmol) were added to the reaction mixture and stirred at the same temperature for 18 hours. Saturated aqueous ammonium chloride was poured into the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; dichloromethane / methanol = 0 to 40%) and concentrated to give 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)aniline (0.650 g, 88.8%) as a beige solid.

[0399] [Step 2] Synthesis of compound 3824

[0400]

[0401] 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)aniline (0.030 g, 0.078 mmol) prepared in Step 1 and formaldehyde (37.00%, 0.063 g, 0.777 mmol) were dissolved in acetonitrile (1 mL) / acetic acid (0.01 mL). The resulting solution was then stirred at room temperature for 0.5 hours, and sodium cyanoborohydride (0.015 g, 0.233 mmol) was then added and stirred at the same temperature for a further hour. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 30%) and concentrated to give 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylaniline (0.012 g, 37.3%) as a pale yellow oil.

[0402] 1H NMR(400MHz,DMSO-d6)δ9.20(d,J=2.2Hz,1H),8.69(s,1H),8.49(dd,J=8.2,2.3Hz,1H),7.7 3-7.44(m,3H),7.28-7.20(m,2H),6.75-6.68(m,1H),5.92(s,2H),2.95(s,6H); LRMS(ES)m / z 398.2(M + +1).

[0403] The compounds of Table 13 were synthesized according to substantially the same procedures described above for the synthesis of compound 3824, except using 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)aniline and the reactants of Table 12.

[0404] [Table 12]

[0405] Example Compound number reactants Yield (%) 39 3827 Tetrahydro-4H-pyran-4-one 45 40 3828 Cyclohexanone 52 42 3830 1-Methylpiperidin-4-one 33

[0406] [Table 13]

[0407]

[0408]

[0409] Example 37: Synthesis of Compound 3825, N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)trimethylacetamide

[0410]

[0411] 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)aniline (0.050 g, 0.135 mmol) and triethylamine (0.028 mL, 0.203 mmol) prepared in Step 1 of Example 36 were dissolved in dichloromethane (1 mL) at room temperature. Trimethylacetyl chloride (0.020 mL, 0.162 mmol) was then added to the resulting solution, and the mixture was stirred at the same temperature for 1 hour. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 30%) and concentrated to give N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)trimethylacetamide (0.023 g, 37.5%) as a white solid.

[0412] 1 H NMR (400MHz, DMSO-d6) δ9.32(s,1H),9.21(dd,J=2.3,0.9Hz,1H),8.67(s,1H),8.50(dd,J=8.2,2.3Hz,1H),8.21(t,J=1.9Hz,1H),7.65(d dd,J=8.1,2.1,1.0Hz,1H),7.72-7.45(m,2H),7.52(dt,J=7.7,1.3Hz,1H),7.37(t,J=7.9Hz,1H),5.93(s,2H),1.25(s,9H); LRMS(ES)m / z 454.3(M + +1).

[0413] The compounds of Table 15 were synthesized according to substantially the same procedures described above for the synthesis of compound 3825, except using 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)aniline and the reactants of Table 14.

[0414] [Table 14]

[0415] Example Compound number reactants Yield (%) 38 3826 Ethyl chloroformate 50

[0416] [Table 15]

[0417]

[0418] Example 41: Synthesis of Compound 3829, (3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)(pyrrolidin-1-yl)methanone

[0419]

[0420] 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzoic acid (0.050 g, 0.126 mmol), pyrrolidine (0.012 g, 0.163 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium hexafluorophosphate 3-oxide (0.095 g, 0.251 mmol) were dissolved in dichloromethane (5 mL) at room temperature. Diisopropylethylamine (0.032 g, 0.251 mmol) was then added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; dichloromethane / methanol = 100% to 70%) and concentrated to give (3-(1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)(pyrrolidin-1-yl)methanone (0.032 g, 56.5%) as a pale yellow gum.

[0421] 1 H NMR(400MHz,CD3OD)δ9.28(dd,J=2.3,0.9Hz,1H),8.58(s,1H),8.53(dd,J=8.2,2.2Hz,1H), 8.02(t,J=1.6Hz,1H),7.98(dt,J=7.5,1.6Hz,1H),7.61(dd,J=8.2,0.8Hz,1H),7.59-7.54(m ,1H),7.52(dt,J=7.7,1.5Hz,1H),7.26(t,J=51.6Hz,1H),5.93(s,2H),3.64(t,J=7.0Hz,2H) ,3.52(t,J=6.6Hz,2H),2.02(dt,J=7.7,5.8Hz,2H),1.99-1.89(m,2H); LRMS(ES)m / z452.2(M + +1).

[0422] The compounds of Table 17 were synthesized according to substantially the same procedures described above for the synthesis of compound 3829, except using 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzoic acid and the reactants of Table 16.

[0423] [Table 16]

[0424] Example Compound number reactants Yield (%) 72 3885 Morpholine 42 73 3886 Azetidine 56 74 3887 1-Methylpiperazine 47 327 4448 1-Isopropylpiperazine 51 328 4449 N1,N1,N2-Trimethylethane-1,2-diamine 49 355 4480 1-Methylazetidin-3-amine 54 356 4482 1-Ethylpiperazine 46

[0425] [Table 17]

[0426]

[0427]

[0428] Example 47: Synthesis of Compound 3835, 2-(difluoromethyl)-5-(6-((4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0429] [Step 1] Synthesis of 3-ethynylpyridine

[0430]

[0431] Dimethyl (1-diazo-2-oxopropyl)phosphonate (0.771 mL, 5.135 mmol) and potassium carbonate (1.290 g, 9.336 mmol) were dissolved in methanol (20 mL) at room temperature, followed by the addition of nicotinaldehyde (0.439 mL, 4.668 mmol) and stirring at the same temperature for 4 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 30%) and concentrated to give 3-ethynylpyridine (0.204 g, 42.4%) as a white solid.

[0432] [Step 2] Synthesis of compound 3835

[0433]

[0434] 3-Ethynylpyridine (0.100 g, 0.970 mmol) prepared in Step 1, 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.245 g, 0.970 mmol) prepared in Step 1 of Example 16, sodium ascorbate (0.019 g, 0.097 mmol), and copper (II) sulfate pentahydrate (0.002 g, 0.010 mmol) were dissolved in tert-butyl alcohol (2 mL) / water (2 mL) at room temperature, and the resulting solution was stirred at the same temperature for 2 hours. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Hexane (20 mL) and dichloromethane (10 mL) were added to the obtained concentrate and stirred to filter out the precipitated solid, wash with hexane, and dry to give 2-(difluoromethyl)-5-(6-((4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.270 g, 78.4%) as a white solid.

[0435] 1 H NMR (400MHz, CD3OD) δ9.27(dd,J=2.2,0.9Hz,1H),9.08(s,1H),8.67(s,1H),8.54(d,J=2.2Hz,1H),8.52(d,J=2.2Hz,1H) ,8.36-8.29(m,1H),7.63(dd,J=8.2,0.9Hz,1H),7.56(t,J=6.5Hz,1H),7.26(t,J=51.6Hz,1H),5.96(s,2H); LRMS(ES)m / z 356.2(M + +1).

[0436] Example 75: Synthesis of Compound 3889, (N-(3-(1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-N-methyltrimethylacetamide

[0437] [Step 1] Synthesis of 3-ethynyl-N-methylaniline

[0438]

[0439] 3-Ethynylaniline (0.800 g, 6.829 mmol), potassium carbonate (3.775 g, 27.315 mmol) and iodomethane (1.063 mL, 17.072 mmol) were dissolved in dimethyl sulfoxide (8 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 30%) and concentrated to give 3-ethynyl-N-methylaniline (0.100 g, 11.2%) as a colorless oil.

[0440] [Step 2] Synthesis of 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N-methylaniline

[0441]

[0442] 2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.198 mmol) prepared in Step 1 of Example 16 and 3-ethynyl-N-methylaniline (0.026 g, 0.198 mmol) prepared in Step 1 were dissolved in tert-butanol (0.5 mL) / water (0.5 mL) at room temperature. Sodium ascorbate (1.00 M solution, 0.020 mL, 0.020 mmol) and copper (II) sulfate pentahydrate (0.50 M solution, 0.004 mL, 0.002 mmol) were then added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. Saturated aqueous ammonium chloride was poured into the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; dichloromethane / methanol = 0 to 40%) and concentrated to give 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N-methylaniline (0.040 g, 52.6%) as a pale yellow solid.

[0443] [Step 3] Synthesis of compound 3889

[0444]

[0445] 3-(1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N-methylaniline (0.010 g, 0.026 mmol), triethylamine (0.005 mL, 0.039 mmol), and pivaloyl chloride (0.004 mL, 0.031 mmol) prepared in Step 2 were dissolved in dichloromethane (0.5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous ammonium chloride was poured into the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; dichloromethane / methanol = 0 to 40%) and concentrated to give N-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-N-methyltrimethylacetamide (0.005 g, 41.0%) as a white solid.

[0446] 1 H NMR(400MHz, CDCl3)δ9.37(s,1H),8.54-8.45(m,1H),8.08(s,1H),7.87-7.76(m,2H),7.58-7.44(m,2H), 7.25-7.20(m,1H),6.97(t,J=51.6Hz,1H),5.88(s,2H),3.28(d,J=1.6Hz,3H),1.10(s,9H); LRMS(ES)m / z 468.3(M + +1).

[0447] The compounds of Table 19 were synthesized according to substantially the same procedures described above for the synthesis of compound 3889, except using 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N-methylaniline and the reactants of Table 18.

[0448] [Table 18]

[0449] Example Compound number reactants Yield (%) 76 3890 Ethyl chloroformate 50

[0450] [Table 19]

[0451]

[0452] Example 81: Synthesis of Compound 3895, 2-(difluoromethyl)-5-(6-((4-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0453] [Step 1] Synthesis of 6-(azidomethyl)nicotinate

[0454]

[0455] 6-(Bromomethyl)nicotinate (5.000 g, 21.733 mmol) and sodium azide (1.695 g, 26.080 mmol) were dissolved in N,N-dimethylformamide (120 mL) at 50 ° C., and the resulting solution was stirred at the same temperature for 12 hours, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified and concentrated by column chromatography (SiO2, 40 g column; ethyl acetate / hexane = 0 to 30%) to give 6-(azidomethyl)nicotinate (4.000 g, 95.8%) as a yellow solid.

[0456] [Step 2] Synthesis of methyl 6-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate

[0457]

[0458] Methyl 6-(azidomethyl)nicotinate (1.500 g, 7.805 mmol) prepared in Step 1, tert-butyl 4-ethynylpiperidine-1-carboxylate (1.797 g, 8.586 mmol), sodium ascorbate (1.00 M solution in H₂O, 0.781 mL, 0.781 mmol), and copper (II) sulfate pentahydrate (0.50 M solution in H₂O, 0.156 mL, 0.078 mmol) were dissolved in tert-butanol (10 mL) / water (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 24 g column; ethyl acetate / hexane = 0 to 70%) and concentrated to give methyl 6-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate (1.800 g, 57.4%) as a yellow solid.

[0459] [Step 3] Synthesis of 6-((4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate hydrochloride

[0460]

[0461] Methyl 6-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate (1.000 g, 2.491 mmol) prepared in Step 1 and hydrogen chloride (4.00 M solution in 1,4-dioxane, 1.868 mL, 7.473 mmol) were dissolved in dichloromethane (30 mL) at room temperature, and the resulting solution was stirred at the same temperature for 12 hours. The solvent was removed from the reaction mixture under reduced pressure, and the precipitated solid was filtered off, washed with dichloromethane, and dried to give methyl 6-((4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate hydrochloride (0.800 g, 95.1%) as a yellow solid.

[0462] [Step 4] Synthesis of 6-((4-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate

[0463]

[0464] Methyl 6-((4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate hydrochloride (0.200 g, 0.592 mmol), potassium carbonate (0.164 g, 1.184 mmol), and 2,2-dimethyloxirane (0.213 g, 2.960 mmol) prepared in step 2 were mixed in ethanol (12 mL) / water (3 mL), heated at 110° C. for 15 minutes using microwave irradiation, and the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Then, the obtained product (methyl 6-((4-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate, 0.160 g, 72.4%, yellow oil) was used without additional purification process.

[0465] [Step 5] Synthesis of methyl 6-((4-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate

[0466]

[0467] Methyl 6-((4-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate (0.100 g, 0.268 mmol) and diethylaminosulfur trifluoride (0.042 mL, 0.321 mmol) prepared in Step 3 were dissolved in dichloromethane (10 mL), and the resulting solution was stirred at the same temperature for 3 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product (methyl 6-((4-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate, 0.076 g, 75.6%, yellow solid) was used without additional purification.

[0468] [Step 6] Synthesis of 6-((4-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinic acid hydrazide

[0469]

[0470] Methyl 6-((4-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate (0.076 g, 0.202 mmol) and hydrazine monohydrate (0.098 mL, 2.024 mmol) prepared in Step 4 were dissolved in ethanol (30 mL) at 90° C., and the resulting solution was stirred at the same temperature for 12 hours, and then the temperature was lowered to room temperature to complete the reaction. The solvent was removed from the reaction mixture under reduced pressure, and the resulting product (6-((4-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate, 0.070 g, 92.1%, white solid) was used without additional purification.

[0471] [Step 7] Synthesis of compound 3895

[0472]

[0473] 6-((4-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinic acid hydrazide (0.070 g, 0.186 mmol), imidazole (0.038 g, 0.559 mmol), and 2,2-difluoroacetic anhydride (0.070 mL, 0.559 mmol) prepared in Step 5 were mixed in dichloromethane (30 mL) at room temperature. The resulting mixture was then heated under reflux for 12 hours and cooled to room temperature. Water was then poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 3%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.039 g, 48.0%) as a white solid.

[0474] 1 H NMR (400MHz, CDCl3) δ9.33 (d, J=1.5Hz, 1H), 8.40 (dd, J=8.2, 2.2Hz, 1H), 7. 49(s,1H),7.34(d,J=8.2Hz,1H),7.09(s,0.2H),6.96(s,0.5H),6.84(s,0.3 H),5.75(s,2H),3.05(s,2H),2.80(s,1H),2.51(d,J=23.0Hz,2H),2.32(s, 2H),2.02(s,2H),1.80(s,2H),1.42(t,J=21.6Hz,6H); LRMS(ES)m / z436.3(M + +1).

[0475] Example 82: Synthesis of Compound 3896, 2-(difluoromethyl)-5-(6-((4-(1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0476] [Step 1] Synthesis of 6-((4-(1-(2-ethyl-2-hydroxybutyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate

[0477]

[0478] Methyl 6-((4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate hydrochloride (0.200 g, 0.592 mmol), potassium carbonate (0.164 g, 1.184 mmol), and 2,2-dimethyloxirane (0.296 g, 2.960 mmol) prepared in Step 2 of Example 81 were mixed in ethanol (12 mL) / water (3 mL), heated at 110° C. for 15 minutes using microwave irradiation, and the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Then, the obtained product (methyl 6-((4-(1-(2-ethyl-2-hydroxybutyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate, 0.140 g, 58.9%, yellow oil) was used without additional purification process.

[0479] [Step 2] Synthesis of methyl 6-((4-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate

[0480]

[0481] Methyl 6-((4-(1-(2-ethyl-2-hydroxybutyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate (0.100 g, 0.249 mmol) and diethylaminosulfur trifluoride (0.039 mL, 0.299 mmol) prepared in Step 1 were dissolved in dichloromethane (10 mL), and the resulting solution was stirred at the same temperature for 3 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product (methyl 6-((4-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate, 0.066 g, 70.6%, yellow solid) was used without additional purification.

[0482] [Step 3] Synthesis of 6-((4-(1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinic acid hydrazide

[0483]

[0484] Methyl 6-((4-(1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate (0.066 g, 0.164 mmol) and hydrazine monohydrate (0.079 mL, 1.636 mmol) prepared in Step 2 were dissolved in ethanol (30 mL) at 90° C., and the resulting solution was stirred at the same temperature for 12 hours, and then the temperature was lowered to room temperature to complete the reaction. The solvent was removed from the reaction mixture under reduced pressure, and the resulting product (6-((4-(1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate, 0.060 g, 90.9%, white solid) was used without additional purification.

[0485] [Step 4] Synthesis of compound 3896

[0486]

[0487] 6-((4-(1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)nicotinic acid hydrazide (0.060 g, 0.149 mmol), imidazole (0.030 g, 0.446 mmol), and 2,2-difluoroacetic anhydride (0.055 mL, 0.446 mmol) prepared in Step 3 were mixed in dichloromethane (30 mL) at room temperature. The resulting mixture was then heated under reflux for 12 hours and cooled to room temperature. Water was then poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 3%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.039 g, 56.6%) as a white solid.

[0488] 1H NMR(400MHz, CDCl3) δ9.32(d,J=1.4Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.47(d,J=13.7H z,1H),7.33(d,J=8.2Hz,1H),7.09(s,0.2H),6.96(s,0.5H),6.83(s,0.3H),5.74(s,2H),3 .06(d,J=11.3Hz,2H),2.79(t,J=11.6Hz,1H),2.56(dd,J=25.7,15.4Hz,2H),2.30(t,J=1 1.2Hz,2H),2.01(s,2H),1.74(tt,J=15.0,9.6Hz,6H),0.89(t,J=7.5Hz,6H); LRMS(ES)m / z 464.10(M + +1).

[0489] Example 84: Synthesis of Compound 3914, 2-(difluoromethyl)-5-(6-((4-(1-methyl-1H-indol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0490] [Step 1] Synthesis of 1-methyl-1H-indole-6-carbaldehyde

[0491]

[0492] 1H-indole-6-carboxaldehyde (0.500 g, 3.444 mmol) and cesium carbonate (1.329 g, 6.889 mmol) were dissolved in acetonitrile (7 mL) at room temperature, and the resulting solution was heated under reflux for 2 hours, and iodomethane (0.236 mL, 3.789 mmol) was added and heated under reflux again for 1 hour, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified and concentrated by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 30%) to give 1-methyl-1H-indole-6-carboxaldehyde (0.200 g, 36.5%) as a colorless oil.

[0493] [Step 2] Synthesis of 6-ethynyl-1-methyl-1H-indole

[0494]

[0495] 1-Methyl-1H-indole-6-carbaldehyde (0.095 g, 0.597 mmol) prepared in Step 1 and dimethyl (1-diazo-2-oxopropyl)phosphonate (0.134 mL, 0.895 mmol) were dissolved in methanol (2 mL) at room temperature, followed by addition of potassium carbonate (0.165 g, 1.194 mmol) to the resulting solution and stirring at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, followed by pouring water into the resulting concentrate, and then extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified and concentrated via column chromatography (SiO 2 , 12 g column; ethyl acetate / hexane = 0 to 20%) to give 6-ethynyl-1-methyl-1H-indole (0.080 g, 86.4%) as a pale yellow solid.

[0496] [Step 3] Synthesis of compound 3914

[0497]

[0498] 2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.198 mmol) and 6-ethynyl-1-methyl-1H-indole (0.031 g, 0.198 mmol) prepared in Step 1 of Example 16 were dissolved in tert-butanol (1 mL) / water (1 mL) at room temperature. Sodium ascorbate (1.00 M solution, 0.020 mL, 0.020 mmol) and copper (II) sulfate pentahydrate (0.50 M solution, 0.004 mL, 0.002 mmol) were then added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; dichloromethane / methanol = 5% to 40%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(1-methyl-1H-indol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.050 g, 61.9%) as a white solid.

[0499] 1H NMR(400MHz,CD3OD)δ9.30(s,1H),8.71(s,1H),8.57-8.50(m,2H),7.79-7.71(m,2H),7.67(d,J=8.2Hz,1H),7.6 1(d,J=8.4Hz,1H),7.26(t,J=51.6Hz,1H),6.71(d,J=3.7Hz,1H),5.94(s,2H),4.10(s,3H); LRMS(ES)m / z408.3(M + +1).

[0500] Example 85: Synthesis of Compound 3915, 1-(3-(1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-N,N-dimethylmethanamine

[0501] [Step 1] Synthesis of 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzaldehyde

[0502]

[0503] 2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.250 g, 0.991 mmol) prepared in Step 1 of Example 16 and 3-ethynylbenzaldehyde (0.129 g, 0.991 mmol) were dissolved in tert-butanol (1 mL) / water (1 mL) at room temperature. Sodium ascorbate (1.00 M solution, 0.099 mL, 0.099 mmol) and copper (II) sulfate pentahydrate (0.50 M solution, 0.020 mL, 0.010 mmol) were then added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. A saturated aqueous ammonium solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 10% to 50%) and concentrated to give 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzaldehyde (0.300 g, 79.2%) as a pale yellow solid.

[0504] [Step 2] Synthesis of compound 3915

[0505]

[0506] 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzaldehyde (0.030 g, 0.078 mmol) prepared in Step 1 and dimethylamine (2.00 M solution, 0.039 mL, 0.078 mmol) were dissolved in dichloromethane (0.7 mL) at room temperature. Sodium triacetoxyborohydride (0.050 mL, 0.235 mmol) was then added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; dichloromethane / methanol = 100% to 70%) and concentrated to give 1-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-N,N-dimethylmethanamine (0.015 g, 46.5%) as a colorless oil.

[0507] 1 H NMR (400MHz, CD3OD) δ9.31-9.26(m,1H),8.53(dd,J=8.2,2.3Hz,1H),8.50(s,1H),7.85-7.78(m,2H),7.60(d,J=8.2Hz,1 LRMS(ES)m / z 412.3(M + +1).

[0508] The compounds of Table 21 were synthesized according to substantially the same procedures described above for the synthesis of compound 3915, except using 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)benzaldehyde and the reactants of Table 20.

[0509] [Table 20]

[0510] Example Compound number reactants Yield (%) 86 3916 Morpholine 61 87 3917 1-Methylpiperazine 51 88 3918 N1,N1,N2-Trimethylethane-1,2-diamine 49 89 3919 Methylamine 48 108 3963 Azetidine hydrochloride 60 109 3964 3-Fluoroazetidine hydrochloride 60 110 3965 2-Oxa-6-azaspiro[3.3]heptaneethanediol 49 111 3966 Pyrrolidine 64 284 4400 3,3-Difluoroazetidine 49 285 4401 4,4-Difluoropiperidine 55

[0511] [Table 21]

[0512]

[0513]

[0514]

[0515] Example 92: Synthesis of Compound 3944, 4-((6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indol-3-yl)methyl)morpholine

[0516] [Step 1] Synthesis of 3-((Morpholinylmethyl)-1H-indole-6-carbaldehyde

[0517]

[0518] Morpholine (0.238 mL, 2.755 mmol) and formaldehyde (37.00%, 0.224 g, 2.755 mmol) were dissolved in acetic acid (3 mL), and the resulting solution was stirred at 0° C. for 0.4 hours, and then 1H-indole-6-carbaldehyde (0.260 g, 1.791 mmol) was added and further stirred at room temperature for 18 hours. 1N-aqueous sodium hydroxide solution was poured into the resulting reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO 2 , 12 g column; dichloromethane / methanol = 0 to 60%) and concentrated to give 3-(morpholinomethyl)-1H-indole-6-carbaldehyde (0.180 g, 26.7%) as a pale yellow oil.

[0519] [Step 2] Synthesis of 4-((6-ethynyl-1H-indol-3-yl)methyl)morpholine

[0520]

[0521] 3-(Morpholinylmethyl)-1H-indole-6-carbaldehyde (0.100 g, 0.409 mmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (0.094 g, 0.491 mmol), and potassium carbonate (0.113 g, 0.819 mmol) prepared in Step 1 were dissolved in methanol (3 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, and water was poured into the resulting concentrate, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; dichloromethane / methanol = 90% to 40%) and concentrated to give 4-((6-ethynyl-1H-indol-3-yl)methyl)morpholine (0.050 g, 50.8%) as a white solid.

[0522] [Step 3] Synthesis of compound 3944

[0523]

[0524] 2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.030 g, 0.119 mmol) prepared in Step 1 of Example 16 and 4-((6-ethynyl-1H-indol-3-yl)methyl)morpholine (0.026 g, 0.107 mmol) prepared in Step 2 were dissolved in tert-butanol (1 mL) / water (1 mL) at room temperature. Sodium ascorbate (1.00 M solution, 0.012 mL, 0.012 mmol) and copper (II) sulfate pentahydrate (0.50 M solution, 0.002 mL, 0.001 mmol) were then added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; dichloromethane / methanol = 100% to 70%) and concentrated to give 4-((6-(1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indol-3-yl)methyl)morpholine (0.025 g, 42.7%) as a white solid.

[0525] 1H NMR (400MHz, CD3OD) δ9.30 (dd, J=2.2, 0.9Hz, 1H), 8.54 (dd, J=8.2, 2.3Hz, 1H) ,8.44(s,1H),7.90(dd,J=1.5,0.7Hz,1H),7.75(dd,J=8.3,0.8Hz,1H),7.60(d ,J=8.0Hz,1H),7.53(dd,J=8.3,1.5Hz,1H),7.30(s,1H),7.26(t,J=51.6Hz,1 H),5.93(s,2H),3.77(s,2H),3.71(t,J=4.7Hz,4H),2.58(s,4H); LRMS(ES)m / z 393.3(M + +1).

[0526] The compounds of Table 23 were synthesized according to essentially the same procedures described above for the synthesis of compound 3944, except using 4-((6-ethynyl-1H-indol-3-yl)methyl)morpholine and the reactants of Table 22.

[0527] [Table 22]

[0528] Example Compound number reactants Yield (%) 169 4112 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 36 174 4134 2-(4-(Azidomethyl)pyridinyl)-5-(difluoromethyl)-1,3,4-oxadiazole 42

[0529] [Table 23]

[0530]

[0531] Example 93: Synthesis of Compound 3945, 2-(difluoromethyl)-5-(6-((2-methyl-4-phenyl-1H-imidazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0532] [Step 1] Synthesis of 2-(6-((4-bromo-2-methyl-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0533]

[0534] 4-Bromo-2-methyl-1H-imidazole (0.200 g, 1.242 mmol), 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.360 g, 1.242 mmol), and potassium carbonate (0.343 g, 2.484 mmol) were dissolved in N,N-dimethylformamide (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. Water was poured into the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; ethyl acetate / hexane = 0 to 50%) and concentrated to give 2-(6-((4-bromo-2-methyl-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.308 g, 67.0%) as a yellow solid.

[0535] [Step 2] Synthesis of compound 3945

[0536]

[0537] 2-(6-((4-bromo-2-methyl-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.100 g, 0.270 mmol), phenyl Acid (0.033 g, 0.270 mmol), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl2, 0.018 g, 0.027 mmol) and cesium carbonate (0.156 g, 0.810 mmol) were mixed in 1,4-dioxane (3 mL) / water (1 mL), after which the resulting mixture was irradiated with microwaves, then heated at 100° C. for 20 minutes, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 10%) and concentrated to give 2-(difluoromethyl)-5-(6-((2-methyl-4-phenyl-1H-imidazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.032 g, 32.2%) as a brown solid.

[0538] 1H NMR (400MHz, CD3OD) δ9.28(d,J=2.2Hz,1H),8.50(dd,J=8.2,2.3Hz,1H),7.75-7.68(m,2H),7.51(s,1H),7.44(dd,J =8.3,3.0Hz,1H),7.40-7.33(m,2H),7.27-7.11(m,2H),5.43(d,J=23.7Hz,2H),2.41(d,J=29.3Hz,3H); LRMS(ES)m / z 368.2(M + +1).

[0539] Example 94: Synthesis of Compound 3949, 2-(6-((4-bromo-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0540]

[0541] 4-Bromo-1H-imidazole (0.200 g, 1.361 mmol), 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.395 g, 1.361 mmol), and potassium carbonate (0.376 g, 2.721 mmol) were dissolved in N,N-dimethylformamide (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. Water was poured into the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; ethyl acetate / hexane = 0 to 50%) and concentrated to give 2-(6-((4-bromo-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.344 g, 71.0%) as a yellow solid.

[0542] 1 H NMR (400MHz, CD3OD) δ9.26 (dd, J=2.3, 0.9Hz, 1H), 8.51 (dd, J=8.2, 2.2Hz, 1H), 7.81 (d, J=1.5Hz, 1H), 7.51(dd,J=8.2,0.9Hz,1H),7.30(d,J=1.5Hz,1H),7.26(t,J=51.6Hz,1H),5.47(s,2H); LRMS(ES)m / z 358.1(M + +1).

[0543] Example 95: Synthesis of Compound 3950, 2-(difluoromethyl)-5-(6-((4-phenyl-1H-imidazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0544]

[0545] 2-(6-((4-bromo-1H-imidazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.100 g, 0.281 mmol), phenyl Acid (0.034 g, 0.281 mmol), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl2, 0.018 g, 0.028 mmol) and cesium carbonate (0.163 g, 0.842 mmol) were mixed in 1,4-dioxane (3 mL) / water (1 mL), after which the resulting mixture was irradiated with microwaves, then heated at 100° C. for 20 minutes, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 10%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-phenyl-1H-imidazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.007 g, 7.1%) as a brown oil.

[0546] 1 H NMR (400MHz, CD3OD) δ9.27(ddd,J=7.2,2.2,0.8Hz,1H),8.50(dt,J=8.2,1.9Hz,1H),7.86(dd,J=44.8,1.4Hz,1H),7.76-7.69(m,1 H),7.60(d,J=1.4Hz,1H),7.51(dd,J=8.2,3.8Hz,1H),7.44-7.32(m,2H),7.31-7.11(m,2H),5.49(d,J=22.3Hz,2H); LRMS(ES)m / z 353.3(M + +1).

[0547] Example 96: Synthesis of Compound 3951, 2-(difluoromethyl)-5-(6-((4-(1-ethylazetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0548] [Step 1] Synthesis of 2-(6-((4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0549]

[0550] Tert-butyl 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)azetidine-1-carboxylate (0.625 g, 1.442 mmol) and trifluoroacetic acid (1.104 mL, 14.420 mmol) prepared in Example 91 were dissolved in dichloromethane (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 4 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting product (2-(6-((4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole, 0.480 g, 99.9%, yellow oil) was used without additional purification.

[0551] [Step 2] Synthesis of compound 3951

[0552]

[0553] 2-(6-((4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.040 g, 0.120 mmol) prepared in Step 1 and acetaldehyde (0.013 mL, 0.240 mmol) were dissolved in dichloromethane (1 mL), and the resulting solution was stirred at room temperature for 15 minutes. Subsequently, sodium triacetoxyborohydride (0.076 g, 0.360 mmol) was added and stirred at the same temperature for further 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 10%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(1-ethylpiperidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.013 g, 30.0%) as a white solid.

[0554] 1H NMR (400MHz, CD3OD) δ9.25(dd,J=2.2,0.9Hz,1H),8.51(dd,J=8.2,2.2Hz,1H),8.08(s,1H),7.56(dd,J=8.2,0.9Hz,1H),7.26(t ,J=51.6Hz,1H),5.86(s,2H),4.03-3.91(m,3H),3.60(s,2H),2.82(q,J=7.3Hz,2H),1.09(t,J=7.2Hz,3H); LRMS(ES)m / z362.3(M + +1).

[0555] The compounds of Table 25 were synthesized according to essentially the same procedures described above for the synthesis of compound 3951, except using 2-(6-((4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole and the reactants of Table 24.

[0556] [Table 24]

[0557] Example Compound number reactants Yield (%) 97 3952 acetone 76 98 3953 Butyraldehyde 77 99 3954 Cyclobutanone 60 100 3955 Oxetanes 62

[0558] [Table 25]

[0559]

[0560] Example 101: Synthesis of Compound 3956, 1-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)azetidin-1-yl)ethan-1-one

[0561]

[0562] 2-(6-((4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.040 g, 0.120 mmol) prepared in Step 1 of Example 96 and N,N-diisopropylethylamine (0.042 mL, 0.240 mmol) were dissolved in dichloromethane (1 mL) at room temperature, and acetyl chloride (0.010 mL, 0.144 mmol) was added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 5%) and concentrated to give 1-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)azetidin-1-yl)ethan-1-one (0.028 g, 62.2%) as a white solid.

[0563] 1 H NMR (400MHz, CD3OD) δ9.28-9.23(m,1H),8.51(dd,J=8.2,2.2Hz,1H),8.13(s,1H),7.56(d,J=8.0Hz,1H),7.26(t,J =51.6Hz,1H),5.87(s,2H),4.63(t,J=8.5Hz,1H),4.45-4.33(m,2H),4.15-4.00(m,2H),1.92(s,3H); LRMS(ES)m / z 376.2(M + +1).

[0564] The compounds of Table 27 were synthesized according to substantially the same procedures described above for the synthesis of compound 3956, except using 2-(6-((4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole and the reactants of Table 26.

[0565] [Table 26]

[0566] Example Compound number reactants Yield (%) 102 3957 Propionyl chloride 36 103 3958 Isobutyryl chloride 45 104 3959 Methyl chloroformate 60

[0567] [Table 27]

[0568]

[0569] Example 107: Synthesis of Compound 3962, 1-(6-(1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indol-3-yl)-N,N-dimethylmethanamine

[0570] [Step 1] Synthesis of 3-((dimethylamino)methyl)-1H-indole-6-carbaldehyde

[0571]

[0572] Dimethylamine (2.00 M solution in THF, 1.331 mL, 2.661 mmol) and formaldehyde (37.00%, 0.216 g, 2.661 mmol) were dissolved in acetic acid (3 mL). The resulting solution was stirred at 0°C for 0.4 hours, and then 1H-indole-6-carbaldehyde (0.251 g, 1.730 mmol) was added and stirred at room temperature for a further 18 hours. 1N-aqueous sodium hydroxide solution was poured into the resulting reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; dichloromethane / methanol = 0-60%) and concentrated to give 3-((dimethylamino)methyl)-1H-indole-6-carbaldehyde (0.070 g, 13.0%) as a pale yellow oil.

[0573] [Step 2] Synthesis of 1-(6-ethynyl-1H-indol-3-yl)-N,N-dimethylmethanamine

[0574]

[0575] 3-((Dimethylamino)methyl)-1H-indole-6-carbaldehyde (0.100 g, 0.494 mmol) prepared in Step 1, dimethyl (1-diazo-2-oxopropyl)phosphonate (0.114 g, 0.593 mmol), and potassium carbonate (0.137 g, 0.989 mmol) were dissolved in methanol (3 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, and water was poured into the resulting concentrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; dichloromethane / methanol = 90% to 40%) and concentrated to give 1-(6-ethynyl-1H-indol-3-yl)-N,N-dimethylmethanamine (0.020 g, 20.4%) as a colorless oil.

[0576] [Step 3] Synthesis of compound 3962

[0577]

[0578] 2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.050 g, 0.198 mmol) prepared in Step 1 of Example 16 and 1-(6-ethynyl-1H-indol-3-yl)-N,N-dimethylmethanamine (0.035 g, 0.178 mmol) prepared in Step 2 were dissolved in tert-butanol (1 mL) / water (1 mL) at room temperature. Sodium ascorbate (1.00 M solution, 0.020 mL, 0.020 mmol) and copper (II) sulfate pentahydrate (0.50 M solution, 0.004 mL, 0.002 mmol) were then added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. Saturated aqueous ammonium chloride was poured into the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (SiO2, 4 g column; dichloromethane / methanol = 100% to 70%) and concentrated, and then the obtained product was purified again by column chromatography (SiO2 plate, 20×20×1 mm; dichloromethane / methanol = 80%) and concentrated to give 1-(6-(1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indol-3-yl)-N,N-dimethylmethanamine (0.010 g, 11.2%) as a light yellow gum.

[0579] 1 H NMR(400MHz,CD3OD)δ9.29(s,1H),8.54(dd,J=8.2,2.3Hz,1H),8.50(s,1H),8.00(s,1H),7.82(d,J=8.3Hz,1H),7.70- 7.65(m,1H),7.65-7.59(m,2H),7.26(t,J=51.6Hz,1H),5.94(s,2H),3.59(d,J=10.8Hz,2H),2.90(s,6H); LRMS(ES)m / z 451.2(M + +1).

[0580] Example 112: Synthesis of Compound 3980, 2-(difluoromethyl)-5-(4-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole

[0581] [Step 1] Synthesis of methyl 4-(2-(2-benzoylhydrazide)-2-oxoethyl)benzoate

[0582]

[0583] Benzohydrazide (0.500 g, 3.672 mmol), 2-(4-(methoxycarbonyl)phenyl)acetic acid (0.927 g, 4.774 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium hexafluorophosphate 3-oxide (1.815 g, 4.774 mmol) were dissolved in N,N-dimethylformamide (50 mL). The resulting solution was then stirred at room temperature for 30 hours, and N,N-diisopropylethylamine (1.663 mL, 9.548 mmol) was then added and stirred at the same temperature for a further 12 hours. Water was poured into the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained product (methyl 4-(2-(2-benzohydrazino)-2-oxoethyl)benzoate, 1.000 g, 87.2%, white solid) was used without additional purification.

[0584] [Step 2] Synthesis of methyl 4-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)benzoate

[0585]

[0586] Methyl 4-(2-(2-benzoylhydrazino)-2-oxoethyl)benzoate (1.000 g, 3.202 mmol) prepared in step 1 and 1-methoxy-N-triethylammoniumsulfonyl-formimide ester (Burgess reagent, 2.289 g, 9.605 mmol) were mixed in tetrahydrofuran (20 mL) at room temperature, and the resulting mixture was heated under reflux for 12 hours and cooled to room temperature. Subsequently, water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified and concentrated by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 40%) to give methyl 4-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)benzoate (0.600 g, 63.7%) as a white solid.

[0587] [Step 3] Synthesis of methyl 4-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)benzoate

[0588]

[0589] Methyl 4-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)benzoate (0.600 g, 2.039 mmol) prepared in step 2 and hydrazine monohydrate (0.991 mL, 20.387 mmol) were dissolved in ethanol (50 mL) at 90 ° C., and the resulting solution was stirred at the same temperature for 12 hours, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting product (4-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)benzohydrazide, 0.380 g, 63.3%, white solid) was used without additional purification.

[0590] [Step 4] Synthesis of compound 3980

[0591]

[0592] 4-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)benzohydrazide (0.380 g, 1.291 mmol), imidazole (0.264 g, 3.873 mmol), and 2,2-difluoroacetic anhydride (0.482 mL, 3.873 mmol) prepared in Step 3 were mixed in dichloromethane (20 mL) at room temperature. The resulting mixture was then heated under reflux for 12 hours and cooled to room temperature. Water was then poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; ethyl acetate / hexane = 0 to 60%) and concentrated to give 2-(difluoromethyl)-5-(4-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)phenyl)-1,3,4-oxadiazole (0.120 g, 26.2%) as a white solid.

[0593] 1 H NMR (400MHz, CDCl3) δ8.15 (d, J = 8.3Hz, 2H), 8.08-7.99 (m, 2H), 7.63-7.45 (m, 5H), 7.06 (s, 0.2H), 6.93 (s, 0.5H), 6.80 (s, 0.3H), 4.41 (s, 2H).

[0594] Example n3: Synthesis of Compound 3981, 2-(difluoromethyl)-5-(4-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-1,3,4-oxadiazole

[0595] [Step 1] Synthesis of methyl 4-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)methyl)benzoate

[0596]

[0597] Methyl 4-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)benzoate (0.210 g, 0.714 mmol) prepared in Step 2 of Example 112, acetic acid (0.163 mL, 2.854 mmol), and methylamine (2.00 M solution in THF, 8.919 mL, 17.838 mmol) were mixed at 150° C., and the reaction mixture was stirred at the same temperature for 12 hours, and then the temperature was lowered to room temperature to complete the reaction. Water was poured into the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 70%) and concentrated to give methyl 4-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)methyl)benzoate (0.100 g, 45.6%) as a white solid.

[0598] [Step 2] Synthesis of 4-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)methyl)benzohydrazide

[0599]

[0600] Methyl 4-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)methyl)benzoate (0.100 g, 0.325 mmol) prepared in Step 1 and hydrazine monohydrate (0.158 mL, 3.254 mmol) were dissolved in ethanol (15 mL) at 90° C., and the resulting solution was stirred at the same temperature for 12 hours, and then the temperature was lowered to room temperature to complete the reaction. The solvent was removed from the reaction mixture under reduced pressure, and the resulting product (4-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)methyl)benzohydrazide, 0.081 g, 81.0%, white solid) was used without additional purification.

[0601] [Step 3] Synthesis of compound 3981

[0602]

[0603] 4-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)methyl)benzohydrazide (0.080 g, 0.260 mmol), imidazole (0.053 g, 0.781 mmol), and 2,2-difluoroacetic anhydride (0.097 mL, 0.781 mmol) prepared in Step 2 were mixed in dichloromethane (30 mL) at room temperature. The resulting mixture was then heated under reflux for 12 hours and cooled to room temperature. Water was then poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 5%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-1,3,4-oxadiazole (0.061 g, 63.8%) as a white solid.

[0604] 1 H NMR(400MHz, CDCl3)δ8.12(d,J=8.3Hz,2H),7.69-7.58(m,2H),7.52(dd,J=7.6,4.7Hz,5 H),7.06(s,0.2H),6.93(s,0.5H),6.80(s,0.3H),4.39(s,2H),3.51(s,3H); LRMS(ES)m / z 368.4(M + +1).

[0605] Example 115: Synthesis of Compound 3986, 2-(difluoromethyl)-5-(6-((4-(3-((4-methylpiperazin-1-yl)methyl)-1H-indol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0606] [Step 1] Synthesis of 3-((4-methylpiperazin-1-yl)methyl)-1H-indole-6-carbaldehyde

[0607]

[0608] 1-Methylpiperazine (0.278 mL, 2.496 mmol) and formaldehyde (37.00%, 0.203 g, 2.496 mmol) were dissolved in acetic acid (3 mL), and the resulting solution was stirred at 0°C for 0.4 hours. 1H-indole-6-carbaldehyde (0.235 g, 1.622 mmol) was then added and stirred at room temperature for a further 18 hours. 1N-aqueous sodium hydroxide solution was poured into the resulting reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; dichloromethane / methanol = 0 to 60%) and concentrated to give 3-((4-methylpiperazin-1-yl)methyl)-1H-indole-6-carbaldehyde (0.100 g, 15.6%) as a pale yellow oil.

[0609] [Step 2] Synthesis of 6-ethynyl-3-((4-methylpiperazin-1-yl)methyl)-1H-indole

[0610]

[0611] 3-((4-Methylpiperazin-1-yl)methyl)-1H-indole-6-carbaldehyde (0.100 g, 0.389 mmol) prepared in Step 1, dimethyl (1-diazo-2-oxopropyl)phosphonate (0.090 g, 0.466 mmol), and potassium carbonate (0.107 g, 0.777 mmol) were dissolved in methanol (3 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, and water was poured into the resulting concentrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; dichloromethane / methanol = 90% to 40%) and concentrated to give 6-ethynyl-3-((4-methylpiperazin-1-yl)methyl)-1H-indole (0.030 g, 30.5%) as a white solid.

[0612] [Step 3] Synthesis of compound 3986

[0613]

[0614] 2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.020 g, 0.079 mmol) prepared in Step 1 of Example 16 and 6-ethynyl-3-((4-methylpiperazin-1-yl)methyl)-1H-indole (0.018 g, 0.071 mmol) prepared in Step 2 were dissolved in tert-butanol (1 mL) / water (1 mL) at room temperature. Sodium ascorbate (1.00 M solution, 0.008 mL, 0.008 mmol) and copper (II) sulfate pentahydrate (0.50 M solution, 0.002 mL, 0.001 mmol) were then added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; dichloromethane / methanol = 100% to 70%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(3-((4-methylpiperazin-1-yl)methyl)-1H-indol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.007 g, 17.5%) as a pale yellow gum.

[0615] 1 H NMR (400MHz, CD3OD) δ9.29(d,J=2.4Hz,1H),8.54(dd,J=8.2,2.3Hz,1H),8.47(s,1H),7.94(d,J=1.3Hz,1H),7.79(d,J=8.3Hz,1H), 7.61(t,J=9.6Hz,2H),7.44(s,1H),7.26(t,J=51.6Hz,1H),5.93(s,2H),4.17(s,2H),3.27-2.78(m,8H),2.62(s,3H); LRMS(ES)m / z 506.4(M + +1).

[0616] Example 116: Synthesis of Compound 3987, N-(3-(1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-fluoro-2-methylpropanamide

[0617]

[0618] 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)aniline (0.050 g, 0.135 mmol) and 2-fluoro-2-methylpropanoic acid (0.017 g, 0.162 mmol) prepared in Step 1 of Example 36 were dissolved in dichloromethane (2 mL) at room temperature. 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium hexafluorophosphate 3-oxide (0.103 g, 0.271 mmol) and N,N-diisopropylethylamine (0.047 mL, 0.271 mmol) were added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. A saturated aqueous sodium chloride solution was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified and concentrated via column chromatography (SiO 2 , 12 g column; ethyl acetate / hexane = 0 to 30%), followed by further purification and concentration via column chromatography (SiO 2 , 4 g column; ethyl acetate / hexane = 0 to 20%) to afford N-(3-(1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-fluoro-2-methylpropanamide (0.025 g, 40.4%) as a white solid.

[0619] 1 H NMR (400MHz, CDCl3) δ9.37(s,1H),8.45(dd,J=8.4,2.3Hz,1H),8.13(s,1H),8.06(s,1H),7.72(d,J=7.7Hz,1H ),7.59(d,J=8.6Hz,1H),7.45(t,J=8.0Hz,2H),6.97(t,J=51.7Hz,1H),5.85(s,2H),1.67(s,6H); LRMS(ES)m / z 358.3(M + +1).

[0620] The compounds of Table 29 were synthesized according to substantially the same procedures described above for the synthesis of compound 3987, except using 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)aniline and the reactants of Table 28.

[0621] [Table 28]

[0622]

[0623]

[0624] [Table 29]

[0625]

[0626] Example 117: Synthesis of Compound 3988, 2-(difluoromethyl)-5-(6-((4-(3-(4-ethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0627] [Step 1] Synthesis of tert-butyl 4-(3-ethynylphenyl)piperazine-1-carboxylate

[0628]

[0629] tert-Butyl 4-(3-formylphenyl)piperazine-1-carboxylate (0.500 g, 1.722 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (0.397 g, 2.066 mmol) were dissolved in methanol (7 mL) at room temperature, followed by addition of potassium carbonate (0.476 g, 3.444 mmol) and stirring at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, followed by pouring a saturated aqueous solution of ammonium chloride into the resulting concentrate, and then extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous solution, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO 2 , 12 g column; dichloromethane / methanol = 100% to 20%) and concentrated to give tert-butyl 4-(3-ethynylphenyl)piperazine-1-carboxylate (0.450 g, 91.3%) as a white solid.

[0630] [Step 2] Synthesis of tert-butyl 4-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)piperazine-1-carboxylate

[0631]

[0632] 2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.190 g, 0.753 mmol) prepared in Step 1 of Example 16 and tert-butyl 4-(3-ethynylphenyl)piperazine-1-carboxylate (0.216 g, 0.753 mmol) prepared in Step 1 were dissolved in tert-butanol (1 mL) / water (1 mL) at room temperature. Sodium ascorbate (1.00 M solution, 0.075 mL, 0.075 mmol) and copper (II) sulfate pentahydrate (0.50 M solution, 0.015 mL, 0.008 mmol) were then added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. A saturated aqueous solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 10% to 50%) and concentrated to give tert-butyl 4-(3-(1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)piperazine-1-carboxylate (0.300 g, 74.0%) as a white solid.

[0633] [Step 3] Synthesis of 2-(difluoromethyl)-5-(6-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0634]

[0635] Tert-butyl 4-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)piperazine-1-carboxylate (0.200 g, 0.371 mmol) prepared in Step 2 and trifluoroacetic acid (0.853 mL, 11.141 mmol) were dissolved in dichloromethane (3 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, and the resulting product (2-(difluoromethyl)-5-(6-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole, 0.190 g, 116.7%, light yellow oil) was used without additional purification.

[0636] [Step 4] Synthesis of compound 3988

[0637]

[0638] 2-(Difluoromethyl)-5-(6-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.020 g, 0.046 mmol) and acetaldehyde (0.006 g, 0.137 mmol) prepared in Step 3 were dissolved in dichloromethane (1 mL) at room temperature. Sodium triacetoxyborohydride (0.048 g, 0.228 mmol) was then added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. A saturated aqueous solution was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 10%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(3-(4-ethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.010 g, 47.0%) as a colorless oil.

[0639] 1 H NMR (400MHz, CD3OD) δ9.28 (dd, J=2.3, 0.9Hz, 1H), 8.53 (dd, J=8.2, 2.3Hz, 1H), 8.49(s,1H),7.60(dd,J=8.2,0.9Hz,1H),7.54-7.49(m,1H),7.37-7.31(m,2H), 7.26(t,J=51.6Hz,1H),7.01(dt,J=6.7,2.6Hz,1H),5.92(s,2H),3.34(t,7H),2 .83(t,J=5.1Hz,4H),2.67(q,J=7.3Hz,2H),1.22(t,J=7.3Hz,3H); LRMS(ES)m / z 367.3(M + +1).

[0640] The compounds of Table 31 were synthesized according to substantially the same procedures described above for the synthesis of compound 3988, except using 2-(difluoromethyl)-5-(6-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reactants of Table 30.

[0641] [Table 30]

[0642] Example Compound number reactants Yield (%) 118 3989 Oxetane-3-one 31 148 4070 N,N-Diisopropylethylamine 32

[0643] [Table 31]

[0644]

[0645] Example n9: Synthesis of Compound 3990, 1-(4-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)piperazin-1-yl)ethan-1-one

[0646]

[0647] 2-(Difluoromethyl)-5-(6-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.025 g, 0.057 mmol) and triethylamine (0.040 mL, 0.285 mmol) prepared in Step 3 of Example 117 were dissolved in dichloromethane (1 mL) at room temperature. Acetyl chloride (0.013 mL, 0.171 mmol) was then added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. A saturated aqueous solution was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 10%) and concentrated to give 1-(4-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)piperazin-1-yl)ethan-1-one (0.011 g, 40.2%) as a colorless oil.

[0648] 1 H NMR (400MHz, CD3OD) δ9.28(dd,J=2.3,0.9Hz,1H),8.53(dd,J=8.2,2.3Hz,1H),8.49(s,1H),7.60(d,J=8.2Hz,1H),7.52(t,J=1.7Hz,1H),7.37-7.31 (m,2H),7.26(t,J=51.6Hz,1H),7.06-6.99(m,1H),5.92(s,2H),3.76(dt, J=16.1,5.3Hz,4H),3.33-3.21(m,4H),2.17(s,3H); LRMS(ES)m / z481.3(M + +1).

[0649] The compounds of Table 33 were synthesized according to substantially the same procedures described above for the synthesis of compound 3990, except using 2-(difluoromethyl)-5-(6-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reactants of Table 32.

[0650] [Table 32]

[0651] Example Compound number reactants Yield (%) 120 3991 Propionyl chloride 35

[0652] [Table 33]

[0653]

[0654] Example 123: Synthesis of Compound 4001, tert-Butyl 4-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate

[0655] [Step 1] Synthesis of 6-((4-(3-bromophenyl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate

[0656]

[0657] Methyl 6-(azidomethyl)nicotinate (1.000 g, 5.203 mmol), 1-bromo-3-ethynylbenzene (1.130 g, 6.244 mmol), sodium ascorbate (1.00 M solution, 0.520 mL, 0.520 mmol), and copper (II) sulfate pentahydrate (0.50 M solution, 0.104 mL, 0.052 mmol) were dissolved in tert-butyl alcohol (20 mL) / water (20 mL) at room temperature, and the resulting solution was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 24 g column; ethyl acetate / hexane = 0 to 70%) and concentrated to give methyl 6-((4-(3-bromophenyl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate (1.500 g, 77.2%) as a white solid.

[0658] [Step 2] Synthesis of 6-((4-(3-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate

[0659]

[0660] Methyl 6-((4-(3-bromophenyl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate (1.000 g, 2.679 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) prepared in step 1 were added to the mixture at room temperature. tert-Butyl-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.911 g, 2.947 mmol), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (0.175 g, 0.268 mmol), and cesium carbonate (1.746 g, 5.359 mmol) were mixed in 1,4-dioxane (20 mL) / water (5 mL). The resulting mixture was then heated under reflux for 12 hours and cooled to room temperature. Water was then poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 60%) and concentrated to give methyl 6-((4-(3-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate (0.450 g, 35.3%) as a white solid.

[0661] [Step 3] Synthesis of 6-((4-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate

[0662]

[0663] Methyl 6-((4-(3-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate (0.450 g, 0.946 mmol) prepared in Step 2 was dissolved in methanol (20 mL) at room temperature, and then 10%-Pd / C (90 mg) was slowly added thereto, and stirred at the same temperature for 12 hours in the presence of a hydrogen balloon attached thereto. The reaction mixture was filtered through a pad of celite to remove solids therefrom, after which the solvent was removed from the obtained filtrate under reduced pressure, and then the obtained concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 70%) and concentrated to give methyl 6-((4-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate (0.420 g, 92.9%) as a yellow oil.

[0664] [Step 4] Synthesis of tert-butyl 4-(3-(1-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate

[0665]

[0666] Methyl 6-((4-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)nicotinate (0.420 g, 0.879 mmol) and hydrazine monohydrate (0.427 mL, 8.795 mmol) prepared in Step 3 were dissolved in ethanol (30 mL) at 90° C. The resulting solution was stirred at the same temperature for 12 hours, and then the temperature was lowered to room temperature to complete the reaction. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Subsequently, the obtained product (tert-butyl 4-(3-(1-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate, 0.350 g, 83.3%, white solid) was used without additional purification.

[0667] [Step 5] Synthesis of compound 4001

[0668]

[0669] tert-Butyl 4-(3-(1-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate (0.350 g, 0.733 mmol) prepared in Step 4, imidazole (0.150 g, 2.199 mmol), and 2,2-difluoroacetic anhydride (0.273 mL, 2.199 mmol) were mixed in dichloromethane (50 mL) at room temperature, and the resulting mixture was heated under reflux for 12 hours and cooled to room temperature. Water was then poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 60%) and concentrated to give tert-butyl 4-(3-(1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate (0.320 g, 81.2%) as a white solid.

[0670] 1H NMR(400MHz, CDCl3) δ9.35(d,J=1.6Hz,1H),8.42(dd,J=8.2,2.2Hz,1H),8.00(s,1H),7.76(d,J=1 .6Hz,1H),7.70-7.61(m,1H),7.47-7.35(m,2H),7.21(d,J=7.7Hz,1H),7.09(s,0.2H),6.96(s,0. 5H),6.83(s,0.3H),5.84(s,2H),4.27(s,2H),2.83(t,J=12.3Hz,2H),2.72(ddd,J=12.2,7.9,3.5 Hz,1H),1.87(d,J=13.6Hz,2H),1.69(qd,J=12.7,4.4Hz,2H),1.51(d,J=4.3Hz,9H); LRMS(ES)m / z 538.42(M + +1).

[0671] Example 124: Synthesis of Compound 4002, 2-(difluoromethyl)-5-(6-((4-(1-ethylpiperidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0672] [Step 1] Synthesis of 2-(difluoromethyl)-5-(6-((4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0673]

[0674] Tert-butyl 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate (0.446 g, 0.966 mmol) and trifluoroacetic acid (0.740 mL, 9.665 mmol) prepared in Example 106 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, and the resulting product (2-(difluoromethyl)-5-(6-((4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole, 0.350 g, 100.2%, orange oil) was used without additional purification.

[0675] [Step 2] Synthesis of compound 4002

[0676]

[0677] 2-(Difluoromethyl)-5-(6-((4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.070 g, 0.194 mmol) prepared in Step 1 and acetaldehyde (0.022 mL, 0.387 mmol) were dissolved in dichloromethane (1 mL), and the resulting solution was stirred at room temperature for 15 minutes. Subsequently, sodium triacetoxyborohydride (0.123 g, 0.581 mmol) was added thereto and further stirred at the same temperature for 18 hours. 1N-Sodium bicarbonate aqueous solution was poured into the resulting reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 10%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(1-ethylpiperidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.039 g, 51.7%) as a pale yellow oil.

[0678] 1 H NMR (400MHz, CD3OD) δ9.25(dd,J=2.3,0.9Hz,1H),8.51(dd,J=8.2,2.3Hz,1H),8.03(d,J=0.6Hz,1H ),7.55(dd,J=8.2,0.9Hz,1H),7.26(t,J=51.6Hz,1H),5.85(s,2H),3.44(d,J=12.0Hz,1H),3.28-3 .12(m,2H),2.81(q,J=7.3Hz,2H),2.49(dt,J=36.9,11.4Hz,2H),2.15(dd,J=13.4,3.5Hz,1H),1.9 7-1.91(m,1H),1.89-1.77(m,1H),1.64(qd,J=12.2,4.1Hz,1H),1.25(t,J=7.3Hz,3H); LRMS(ES)m / z 390.1(M + +1).

[0679] The compounds of Table 35 were synthesized according to substantially the same procedures described above for the synthesis of compound 4002, except using 2-(difluoromethyl)-5-(6-((4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reactants of Table 34.

[0680] [Table 34]

[0681] Example Compound number reactants Yield (%) 125 4003 Oxetanes 87

[0682] [Table 35]

[0683]

[0684] Example 126: Synthesis of Compound 4004, 1-(3-(1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)ethan-1-one

[0685]

[0686] 2-(Difluoromethyl)-5-(6-((4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.070 g, 0.194 mmol) prepared in Step 1 of Example 124 and N,N-diisopropylethylamine (0.067 mL, 0.387 mmol) were dissolved in dichloromethane (1 mL) at room temperature. Acetyl chloride (0.017 mL, 0.232 mmol) was then added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 5%) and concentrated to give 1-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)ethan-1-one (0.064 g, 81.9%) as a pale yellow oil.

[0687] 1 H NMR (400MHz, CD3OD) δ9.26 (dd, J=2.0, 1.0Hz, 1H), 8.51 (dt, J=8.2, 2.2Hz, 1H), 8. 05-7.98(m,1H),7.58-7.48(m,1H),7.26(td,J=51.6,0.7Hz,1H),5.85(d,J=4.3Hz ,2H),4.55-3.83(m,2H),3.27(ddd,J=14.0,10.7,2.9Hz,1H),3.10-2.86(m,2H),2 .23-2.14(m,1H),2.14(s,3H),1.93-1.76(m,2H),1.75-1.54(m,1H); LRMS(ES)m / z 404.2(M+ +1).

[0688] Example 127: Synthesis of Compound 4005, 2-(difluoromethyl)-5-(6-((4-(4-fluoro-1-methylpiperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0689] [Step 1] Synthesis of 2-(difluoromethyl)-5-(6-((4-(4-fluoropiperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0690]

[0691] Tert-butyl 4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-4-fluoropiperidine-1-carboxylate (0.650 g, 1.356 mmol) and trifluoroacetic acid (0.311 mL, 4.067 mmol) prepared in Example 121 were dissolved in dichloromethane (20 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting product (2-(difluoromethyl)-5-(6-((4-(4-fluoropiperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole, 0.500 g, 97.2%, yellow oil) was used without additional purification.

[0692] [Step 2] Synthesis of compound 4005

[0693]

[0694] 2-(Difluoromethyl)-5-(6-((4-(4-fluoropiperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.080 g, 0.211 mmol) prepared in Step 1, N,N-diisopropylethylamine (0.073 mL, 0.422 mmol), formaldehyde (37.00%, 0.034 g, 0.422 mmol), and sodium triacetoxyborohydride (0.089 g, 0.422 mmol) were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 5%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(4-fluoro-1-methylpiperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.021 g, 25.3%) as a white solid.

[0695] 1 H NMR (400MHz, CDCl3) δ9.33(d,J=1.6Hz,1H),8.47-8.37(m,1H),7.78(d,J=0.6Hz,1H),7.40(t,J=11.6Hz,1H),7.09(s,0.2H),6.96(s, 0.5H),6.83(s,0.3H),5.77(s,2H),2.78(d,J=11.5Hz,2H),2.50(t,J=10.9Hz,2H),2.45-2.32(m,4H),2.31-2.19(m,3H); LRMS(ES)m / z 494.26(M + +1).

[0696] The compounds of Table 37 were synthesized according to substantially the same procedures described above for the synthesis of compound 4005, except using 2-(difluoromethyl)-5-(6-((4-(4-fluoropiperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reactants of Table 36.

[0697] [Table 36]

[0698] Example Compound number reactants Yield (%) 128 4006 acetaldehyde 14 129 4007 Propan-2-one 24 130 4008 Oxetane-3-one 33

[0699] [Table 37]

[0700]

[0701] Example 131: Synthesis of Compound 4009, 1-(4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-4-fluoropiperidin-1-yl)ethan-1-one

[0702]

[0703] 2-(Difluoromethyl)-5-(6-((4-(4-fluoropiperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.080 g, 0.211 mmol), triethylamine (0.059 mL, 0.422 mmol), and acetic anhydride (0.060 mL, 0.633 mmol) prepared in Step 1 of Example 127 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 5%) and concentrated to give 1-(4-(1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-4-fluoropiperidin-1-yl)ethan-1-one (0.021 g, 23.6%) as a white solid.

[0704] 1 H NMR (400MHz, CDCl3) δ9.34(d,J=1.7Hz,1H),8.43(dd,J=8.2,2.2Hz,1H),7.82(s,1H),7.45(d,J=8.2Hz,1H),7.09(s,0.2H),6.96(s,0.5H),6.8 3(s,0.3H),5.78(s,2H),4.48(d,J=13.2Hz,1H),3.79(d,J=13.6Hz,1H),3.63-3.51(m,1H),3.24-3.10(m,1H),2.38-2.11(m,7H); LRMS(ES)m / z 422.24(M + +1).

[0705] Example 132: Synthesis of Compound 4010, 2-(difluoromethyl)-5-(6-((4-(3-(1-methylpiperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0706] [Step 1] Synthesis of 2-(difluoromethyl)-5-(6-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0707]

[0708] Tert-butyl 4-(3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate (0.320 g, 0.595 mmol) prepared in Step 5 of Example 123 and trifluoroacetic acid (0.137 mL, 1.786 mmol) were dissolved in dichloromethane (20 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting product (2-(difluoromethyl)-5-(6-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole, 0.250 g, 96.0%, yellow oil) was used without additional purification.

[0709] [Step 2] Synthesis of compound 4010

[0710]

[0711] 2-(Difluoromethyl)-5-(6-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.080 g, 0.183 mmol) prepared in Step 1, N,N-diisopropylethylamine (0.064 mL, 0.366 mmol), and formaldehyde (37.00%, 0.030 g, 0.366 mmol) were dissolved in dichloromethane (5 mL), and the resulting solution was stirred at room temperature for 30 minutes. Subsequently, sodium triacetoxyborohydride (0.078 g, 0.366 mmol) was added thereto and stirred at the same temperature for further 12 hours. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 5%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(3-(1-methylpiperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.032 g, 38.8%) as a white solid.

[0712] 1 H NMR (400MHz, CDCl3) δ9.35 (d, J=1.7Hz, 1H), 8.41 (dd, J=8.2, 2.2Hz, 1H), 7.97 (s, 1 H),7.75(s,1H),7.68(d,J=7.7Hz,1H),7.44-7.33(m,2H),7.24(d,J=7.7Hz,1H),7 .09(s,0.2H),6.96(s,0.5H),6.83(s,0.3H),5.83(s,2H),3.04(d,J=11.7Hz,2H), 2.62-2.48(m,1H),2.37(s,3H),2.18-2.07(m,2H),1.94-1.85(m,4H); LRMS(ES)m / z 452.13(M + +1).

[0713] The compounds of Table 39 were synthesized according to substantially the same procedures described above for the synthesis of compound 4010, except using 2-(difluoromethyl)-5-(6-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reactants of Table 38.

[0714] [Table 38]

[0715] Example Compound number reactants Yield (%) 133 4011 acetaldehyde 24 134 4012 Propan-2-one 12 135 4013 Oxetane-3-one 16

[0716] [Table 39]

[0717]

[0718] Example 136: Synthesis of Compound 4014, 2-(difluoromethyl)-5-(6-((4-((1-methylpiperidin-4-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0719] [Step 1] Synthesis of 2-(difluoromethyl)-5-(6-((4-(piperidin-4-ylmethyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0720]

[0721] Tert-butyl 4-((1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)piperidine-1-carboxylate (0.700 g, 1.472 mmol) and trifluoroacetic acid (0.338 mL, 4.416 mmol) prepared in Example 122 were dissolved in dichloromethane (20 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting product (2-(difluoromethyl)-5-(6-((4-(piperidin-4-ylmethyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole, 0.550 g, 99.5%, yellow oil) was used without additional purification.

[0722] [Step 2] Synthesis of compound 4014

[0723]

[0724] 2-(Difluoromethyl)-5-(6-((4-(piperidin-4-ylmethyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.080 g, 0.213 mmol) prepared in Step 1, N,N-diisopropylethylamine (0.074 mL, 0.426 mmol), and formaldehyde (37.00%, 0.035 g, 0.426 mmol) were dissolved in dichloromethane (5 mL). The resulting solution was then stirred at room temperature for 30 minutes, and sodium triacetoxyborohydride (0.090 g, 0.426 mmol) was then added thereto and stirred at the same temperature for further 12 hours. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 5%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-((1-methylpiperidin-4-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.021 g, 25.3%) as a white solid.

[0725] 1H NMR(400MHz, CDCl3) δ9.33(d,J=1.6Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.48(d,J =12.2Hz,1H),7.34(d,J=8.2Hz,1H),7.09(s,0.2H),6.96(s,0.5H),6.83(s,0.3H) ,5.74(s,2H),2.87(d,J=11.5Hz,2H),2.69(d,J=6.4Hz,2H),2.29(s,3H),1.94(t, J=11.0Hz,2H),1.69(t,J=10.1Hz,3H),1.35(dt,J=32.6,18.4Hz,2H); LRMS(ES)m / z 390.5(M + +1).

[0726] Example 137: Synthesis of Compound 4015, 1-(4-((1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)piperidin-1-yl)ethan-1-one

[0727]

[0728] 2-(Difluoromethyl)-5-(6-((4-(piperidin-4-ylmethyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.080 g, 0.213 mmol), triethylamine (0.036 mL, 0.256 mmol), and acetic anhydride (0.022 mL, 0.234 mmol) prepared in Step 1 of Example 136 were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 5%) and concentrated to give 1-(4-((1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)piperidin-1-yl)ethan-1-one (0.023 g, 25.9%) as a white solid.

[0729] 1H NMR (400MHz, CDCl3) δ9.30(d,J=1.7Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.51(s,1H),7.36(d,J =8.2Hz,1H),7.08(s,0.2H),6.96(s,0.5H),6.83(s,0.3H),5.73(s,2H),4.58(d,J=13.3Hz,1H) ,3.79(d,J=13.6Hz,1H),3.09-2.92(m,1H),2.68(d,J=6.9Hz,2H),2.50(dd,J=18.2,7.5Hz,1H) ,2.06(s,3H),2.00-1.88(m,1H),1.74(dd,J=29.3,13.0Hz,2H),1.30-1.05(m,2H); LRMS(ES)m / z 418.2(M + +1).

[0730] Example 138: Synthesis of Compound 4023, 4-((4-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indol-3-yl)methyl)morpholine

[0731] [Step 1] Synthesis of 4-ethynyl-1H-indole

[0732]

[0733] 1H-Indole-4-carbaldehyde (0.500 g, 3.444 mmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (0.794 g, 4.133 mmol), and potassium carbonate (0.952 g, 6.889 mmol) were dissolved in methanol (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture, which was then extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; ethyl acetate / hexane = 0-30%) and concentrated to give 4-ethynyl-1H-indole (0.300 g, 61.7%) as a yellow solid.

[0734] [Step 2] 2-(6-((4-(1H-indol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0735]

[0736] 4-Ethynyl-1H-indole (0.280 g, 1.983 mmol) prepared in Step 1, 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.500 g, 1.983 mmol) prepared in Step 1 of Example 16, copper (II) sulfate pentahydrate (0.005 g, 0.020 mmol), and sodium ascorbate (0.039 g, 0.198 mmol) were dissolved in tert-butyl alcohol (5 mL) / water (5 mL) at room temperature. The resulting solution was then stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 60%) and concentrated to give 2-(6-((4-(1H-indol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.400 g, 51.3%) as a white solid.

[0737] [Step 3] Synthesis of compound 4023

[0738]

[0739] Morpholine (10.00 M aqueous solution, 0.023 mL, 0.230 mmol), formaldehyde (37.00%, 0.020 g, 0.253 mmol) and acetic acid (0.013 mL, 0.230 mmol) were dissolved in methanol (5 mL) at room temperature, and 2-(6-((4-(1H-indol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (1.00 M solution in MeOH, 0.230 mL, 0.230 mmol) prepared in Step 3 was added to the resulting solution and stirred at the same temperature for 12 hours. 1N-aqueous sodium bicarbonate solution was poured into the reaction mixture, which was then extracted with dichloromethane and filtered through a plastic filter to remove the solid residue and aqueous layer, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; dichloromethane / methanol = 0 to 10%) and concentrated to give 4-((4-(1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indol-3-yl)methyl)morpholine (0.020 g, 17.7%) as a white solid.

[0740] 1H NMR (400MHz, CDCl3) δ9.29(d,J=2.3Hz,1H),9.08(s,1H),8.42(s,1H),8.37(dd,J=8.1,2.3Hz,1H),7.46(d,J=8.2Hz,1H),7.37(d,J=8.0 Hz,1H),7.28-7.20(m,1H),7.20-7.10(m,1H),7.09-6.78(m,2H),5.79(s,2H),3.47(d,J=4.1Hz,6H),2.21(t,J=4.7Hz,4H); LRMS(ES)m / z 493.4(M + +1).

[0741] Example 139: Synthesis of Compound 4026, (S)-2-(difluoromethyl)-5-(6-((4-(1-(oxetane-3-yl)pyrrolidin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0742] [Step 1] Synthesis of (S)-tert-butyl 2-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrrolidine-1-carboxylate

[0743]

[0744] (S)-tert-Butyl 2-ethynylpyrrolidine-1-carboxylate (0.400 g, 2.049 mmol), 2-(6-(azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.517 g, 2.049 mmol) prepared in Step 1 of Example 16, sodium ascorbate (0.036 g, 0.205 mmol), and copper (II) sulfate pentahydrate (0.005 g, 0.020 mmol) were dissolved in water (3 mL) / tert-butanol (3 mL) at room temperature. The resulting solution was then stirred at the same temperature for 18 hours. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Subsequently, the obtained product ((S)-tert-butyl 2-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrrolidine-1-carboxylate, 0.850 g, 92.7%, in the form of a brown solid) was used without additional purification.

[0745] [Step 2] Synthesis of (S)-2-(difluoromethyl)-5-(6-((4-(pyrrolidin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0746]

[0747] (S)-tert-Butyl 2-(1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrrolidine-1-carboxylate (0.850 g, 1.900 mmol) prepared in Step 1 and trifluoroacetic acid (2.909 mL, 37.993 mmol) were dissolved in dichloromethane (10 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, and the resulting concentrate was purified by column chromatography (SiO2, 40 g column; methanol / dichloromethane = 10%) and concentrated to give (S)-2-(difluoromethyl)-5-(6-((4-(pyrrolidin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.775 g, 117.5%) as a colorless gel.

[0748] [Step 3] Synthesis of compound 4026

[0749]

[0750] (S)-2-(Difluoromethyl)-5-(6-((4-(pyrrolidin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.070 g, 0.202 mmol), oxetan-3-one (0.029 g, 0.403 mmol), and sodium triacetoxyborohydride (0.128 g, 0.605 mmol) prepared in Step 2 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by chromatography (SiO2 plate, 20×20×1 mm; methanol / dichloromethane = 10%) and concentrated to give (S)-2-(difluoromethyl)-5-(6-((4-(1-(oxetane-3-yl)pyrrolidin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.012 g, 14.8%) as a pale yellow solid.

[0751] 1 H NMR (400MHz, CDCl3) δ9.32(dd,J=2.2,0.9Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.59(s,1H),7.37(d,J=8.2Hz,1H),6.94(t,J=51.6Hz,1H),5.73(s,2H), 4.71(dd,J=12.7,6.8Hz,4H),3.84(s,1H),3.71-3.60(m,1H),3.16(s,1H),2 .88(s,1H),2.76(s,2H),2.07(dt,J=13.2,6.9Hz,1H); LRMS(ES)m / z404.3(M + +1).

[0752] The compounds of Table 41 were synthesized according to substantially the same procedures described above for the synthesis of compound 4026, except using (S)-2-(difluoromethyl)-5-(6-((4-(pyrrolidin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reactants of Table 40.

[0753] [Table 40]

[0754] Example Compound number reactants Yield (%) 140 4027 2-Oxaspiro[3.3]heptan-6-one 29

[0755] [Table 41]

[0756]

[0757] Example 141: Synthesis of Compound 4028, (S)-methyl 2-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrrolidine-1-carboxylate

[0758]

[0759] (S)-2-(Difluoromethyl)-5-(6-((4-(pyrrolidin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.070 g, 0.202 mmol), (chlorocarbonyl)oxy)methyl (0.023 g, 0.242 mmol), and triethylamine (0.034 g, 0.242 mmol) prepared in Step 2 of Example 139 were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by chromatography (SiO2 plate, 20×20×1 mm; methanol / dichloromethane = 10%) and concentrated to give (S)-methyl 2-(1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrrolidine-1-carboxylate (0.035 g, 42.8%) as a white solid.

[0760] 1 H NMR (400 MHz, CDCl3; two rotamers in a 6:4 ratio) δ 9.31 (d, J = 2.2 Hz, 1H), 8.38 (d, J = 8.0 Hz, 1H), 7.71 (s, 0.6H), 7.52 (s, 0.4H), 7.31 (d, J = 8.8 Hz, 1H), 6.94 (t, J = 51.6 Hz, 1H), 5.72 (d, J = 6.7 Hz, 2H), 5.09 (dd, J = 7.5, 2.7 Hz, 1H), 3.68 (s, 2H), 3.63 (s, 1H), 3.59-3.40 (m, 2H), 2.48 (s, 0.5H), 2.38-2.08 (m, 2H), 1.98 (s, 1.5H); LRMS (ES) m / z 406.3 (M + +1).

[0761] The compounds of Table 43 were synthesized according to substantially the same procedures described above for the synthesis of compound 4028, except using (S)-2-(difluoromethyl)-5-(6-((4-(pyrrolidin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reactants of Table 42.

[0762] [Table 42]

[0763] Example Compound number reactants Yield (%) 142 4029 Acetic anhydride 53

[0764] [Table 43]

[0765]

[0766] Example 143: Synthesis of Compound 4051, 2-(difluoromethyl)-5-(6-((4-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0767] [Step 1] Synthesis of tert-butyl 6-ethynyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0768]

[0769] tert-Butyl 6-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.500 g, 1.913 mmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (0.345 mL, 2.296 mmol), and potassium carbonate (0.529 g, 3.827 mmol) were dissolved in methanol (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product (tert-butyl 6-ethynyl-3,4-dihydroisoquinoline-2(1H)-carboxylate, 0.490 g, 99.5%, yellow solid) was used without further purification.

[0770] [Step 2] Synthesis of tert-butyl 6-(1-((5-(methoxycarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0771]

[0772] Tert-butyl 6-ethynyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.500 g, 1.943 mmol) prepared in Step 1, methyl 6-(azidomethyl)nicotinate (0.373 g, 1.943 mmol) prepared in Step 1 of Example 81, sodium ascorbate (0.038 g, 0.194 mmol) and copper (II) sulfate pentahydrate (0.005 g, 0.019 mmol) were dissolved in ethanol (150 mL) at room temperature, and the resulting solution was stirred at 80° C. for 18 hours, and the reaction was then completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, after which the resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 80%) and concentrated to give tert-butyl 6-(1-((5-(methoxycarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.853 g, 97.7%) as a yellow solid.

[0773] [Step 3] Synthesis of tert-butyl 6-(1-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0774]

[0775] tert-Butyl 6-(1-((5-(methoxycarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.100 g, 2.447 mmol) and hydrazine monohydrate (1.287 mL, 36.707 mmol) prepared in Step 2 were mixed in ethanol (50 mL) at room temperature, and the resulting mixture was then heated under reflux and cooled to room temperature. Subsequently, the solvent was removed from the reaction mixture under reduced pressure, and the resulting product (tert-butyl 6-(1-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate, 1.100 g, 100.0%, yellow solid) was used without additional purification.

[0776] [Step 4] Synthesis of tert-butyl 6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0777]

[0778] tert-Butyl 6-(1-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.490 g, 1.090 mmol) prepared in Step 3 and triethylamine (0.456 mL, 3.270 mmol) were dissolved in tetrahydrofuran (15 mL) at room temperature. Difluoroacetic anhydride (0.678 mL, 5.450 mmol) was then added to the resulting solution, and the mixture was stirred at the same temperature for 5 hours. Water was poured into the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 24 g column; ethyl acetate / hexane = 0 to 80%) and concentrated to give tert-butyl 6-(1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.471 g, 84.8%) as a white solid.

[0779] [Step 5] Synthesis of 2-(difluoromethyl)-5-(6-((4-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole trifluoroacetic acid

[0780]

[0781] Tert-butyl 6-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.471 g, 0.924 mmol) prepared in Step 4 was dissolved in dichloromethane (15 mL) at room temperature, followed by addition of trifluoroacetic acid (TFA, 0.212 mL, 2.773 mmol) and stirring at the same temperature for 5 hours. The solvent was removed from the reaction mixture under reduced pressure, after which the precipitated solid was filtered off, washed with dichloromethane, and dried to give 2-(difluoromethyl)-5-(6-((4-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazoletrifluoroacetic acid (0.450 g, 96.1%) as a white solid.

[0782] [Step 6] Synthesis of compound 4051

[0783]

[0784] 2-(Difluoromethyl)-5-(6-((4-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazoletrifluoroacetic acid (0.050 g, 0.099 mmol), formaldehyde (37.00% solution in H2O, 0.020 mL, 0.197 mmol), and N,N-diisopropylethylamine (0.034 mL, 0.197 mmol) prepared in Step 5 were dissolved in dichloromethane (5 mL) at room temperature. Sodium triacetoxyborohydride (0.052 g, 0.246 mmol) was then added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 15%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.007 g, 16.8%) as a yellow solid.

[0785] 1 H NMR (400MHz, CDCl3) δ9.32 (dd, J=2.3, 0.9Hz, 1H), 8.38 (dd, J=8.2, 2.3Hz, 1H) ,7.93(s,1H),7.63(d,J=1.8Hz,1H),7.56(dd,J=7.9,1.8Hz,1H),7.39(dd,J= 8.2,0.9Hz,1H),7.08(d,J=8.2Hz,1H),7.06-6.94(m,1H),5.80(s,2H),3.62( s,2H),2.98(t,J=6.0Hz,2H),2.73(t,J=6.0Hz,2H),2.48(s,3H); LRMS(ES)m / z 424.1(M + +1).

[0786] The compounds of Table 45 were synthesized according to substantially the same procedures described above for the synthesis of compound 4051, except using 2-(difluoromethyl)-5-(6-((4-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reactants of Table 44.

[0787] [Table 44]

[0788] Example Compound number reactants Yield (%) 144 4052 acetaldehyde 16 145 4053 Propan-2-one 11 146 4054 Cyclobutanone 24 147 4055 Oxetane-3-one 21

[0789] [Table 45]

[0790]

[0791] Example 165: Synthesis of Compound 4108, 2-(difluoromethyl)-5-(4-((4-(3-(pyrrolidin-1-ylmethyl)-1H-indol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[0792] [Step 1] Synthesis of 3-(pyrrolidin-1-ylmethyl)-1H-indole-6-carbaldehyde

[0793]

[0794] Pyrrolidine (0.300 g, 4.218 mmol) and formaldehyde (37.00%, 0.377 g, 4.640 mmol) were dissolved in acetic acid (3 mL), and the resulting solution was stirred at 0° C. for 0.4 hours, and then 1H-indole-6-carbaldehyde (0.490 g, 3.375 mmol) was added and further stirred at room temperature for 18 hours. 2N-aqueous sodium hydroxide solution was poured into the resulting reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO 2 , 12 g column; methanol / dichloromethane = 0 to 5%) and concentrated to give 3-(pyrrolidin-1-ylmethyl)-1H-indole-6-carbaldehyde (0.300 g, 31.2%) as a yellow gum.

[0795] [Step 2] Synthesis of 6-ethynyl-3-(pyrrolidin-1-ylmethyl)-1H-indole

[0796]

[0797] 3-(Pyrrolidin-1-ylmethyl)-1H-indole-6-carbaldehyde (0.100 g, 0.438 mmol) prepared in Step 1 and dimethyl (1-diazo-2-oxopropyl)phosphonate (0.101 mL, 0.526 mmol) were dissolved in methanol (2 mL) at room temperature, followed by addition of potassium carbonate (0.121 g, 0.876 mmol) and stirring at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, followed by pouring water into the resulting concentrate and subsequent extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO 2 , 12 g column; methanol / dichloromethane = 0 to 5%) and concentrated to give 6-ethynyl-3-(pyrrolidin-1-ylmethyl)-1H-indole (0.065 g, 66.2%) as a yellow oil.

[0798] [Step 3] Synthesis of compound 4108

[0799]

[0800] 2-(4-(Azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.030 g, 0.104 mmol) prepared in Step 1 of Example 1 and 6-ethynyl-3-(pyrrolidin-1-ylmethyl)-1H-indole (0.023 g, 0.104 mmol) prepared in Step 2 were dissolved in tert-butanol (1 mL) / water (1 mL) at room temperature. Sodium ascorbate (1.00 M solution, 0.010 mL, 0.010 mmol) and copper (II) sulfate pentahydrate (0.50 M solution, 0.002 mL, 0.001 mmol) were then added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 5%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(3-(pyrrolidin-1-ylmethyl)-1H-indol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.012 g, 24.3%) as a pale yellow oil.

[0801] 1H NMR (400MHz, CD3OD) δ8.43(s,1H),8.21-8.14(m,2H),7.97(d,J=1.6Hz,1H),7.82(d,J=8.4Hz,1H),7.67-7.61(m,3H),7 .59(s,1H),7.23(t,J=51.6Hz,1H),5.81(s,2H),4.59(d,J=7.9Hz,2H),3.38(d,J=7.1Hz,4H),2.09(s,4H); LRMS(ES)m / z 476.3(M + +1).

[0802] The compounds of Table 47 were synthesized according to essentially the same procedures described above for the synthesis of compound 4108, except using 6-ethynyl-3-(pyrrolidin-1-ylmethyl)-1H-indole and the reactants of Table 46.

[0803] [Table 46]

[0804] Example Compound number reactants Yield (%) 166 4109 2-(4-(Azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 27 367 4493 2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 20

[0805] [Table 47]

[0806]

[0807] Example 167: Synthesis of Compound 4110, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-((4-methylpiperidin-1-yl)methyl)-1H-indol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[0808] [Step 1] Synthesis of 3-((4-methylpiperidin-1-yl)methyl)-1H-indole-6-carbaldehyde

[0809]

[0810] 4-Methylpiperidine (0.300 g, 3.025 mmol) and formaldehyde (37.00%, 0.270 g, 3.327 mmol) were dissolved in acetic acid (3 mL), and the resulting solution was stirred at 0° C. for 0.4 hours, and then 1H-indole-6-carbaldehyde (0.351 g, 2.420 mmol) was added and further stirred at room temperature for 18 hours. 2N-Sodium hydroxide aqueous solution was poured into the resulting reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO 2 , 12 g column; methanol / dichloromethane = 0 to 5%) and concentrated to give 3-((4-methylpiperidin-1-yl)methyl)-1H-indole-6-carbaldehyde (0.150 g, 19.3%) as a yellow gum.

[0811] [Step 2] Synthesis of 6-ethynyl-3-((4-methylpiperidin-1-yl)methyl)-1H-indole

[0812]

[0813] 3-((4-methylpiperidin-1-yl)methyl)-1H-indole-6-carbaldehyde (0.100 g, 0.390 mmol) prepared in Step 1 and dimethyl (1-diazo-2-oxopropyl)phosphonate (0.090 mL, 0.468 mmol) were dissolved in methanol (2 mL) at room temperature, followed by addition of potassium carbonate (0.108 g, 0.780 mmol) and stirring at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, followed by pouring water into the resulting concentrate and subsequent extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; methanol / dichloromethane = 0 to 5%) and concentrated to give 6-ethynyl-3-((4-methylpiperidin-1-yl)methyl)-1H-indole (0.055 g, 55.9%) as a yellow oil.

[0814] [Step 3] Synthesis of compound 4110

[0815]

[0816] 2-(4-(Azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.030 g, 0.111 mmol) prepared in Step 1 of Example 2 and 6-ethynyl-3-((4-methylpiperidin-1-yl)methyl)-1H-indole (0.028 g, 0.111 mmol) prepared in Step 2 were dissolved in tert-butanol (1 mL) / water (1 mL) at room temperature. Sodium ascorbate (1.00 M solution, 0.011 mL, 0.011 mmol) and copper (II) sulfate pentahydrate (0.50 M solution, 0.002 mL, 0.001 mmol) were then added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; dichloromethane / methanol = 100% to 50%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-((4-methylpiperidin-1-yl)methyl)-1H-indol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.011 g, 18.9%) as a pale yellow oil.

[0817] 1 H NMR (400MHz, CD3OD) δ8.43(s,1H),8.02-7.93(m,3H),7.80(d,J=8.5Hz,1H),7.68-7.60(m,2H),7.59(s,1H),7.24(t,J=51.6Hz,1H),5.87(s,2H),4 .49(s,2H),3.57-3.46(m,2H),3.10-2.96(m,2H),1.93(d,J=14.3Hz,2H), 1.75-1.64(m,1H),1.51-1.34(2,3H),1.02(d,J=6.5Hz,3H); LRMS(ES)m / z 522.5(M + +1).

[0818] The compounds of Table 49 were synthesized according to essentially the same procedures described above for the synthesis of compound 4110, except using 6-ethynyl-3-((4-methylpiperidin-1-yl)methyl)-1H-indole and the reactants of Table 48.

[0819] [Table 48]

[0820] Example Compound number reactants Yield (%) 168 4111 2-(6-(Bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole 17 366 4492 2-(4-(Azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 15

[0821] [Table 49]

[0822]

[0823] Example 170: Synthesis of Compound 4133, 2-(difluoromethyl)-5-(6-((4-phenyl-1H-pyrazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0824] [Step 1] Synthesis of 2-(6-((4-bromo-1H-pyrazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0825]

[0826] 4-Bromo-1H-pyrazole (0.200 g, 1.361 mmol), 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.395 g, 1.361 mmol), and potassium carbonate (0.376 g, 2.721 mmol) were dissolved in N,N-dimethylformamide (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, and extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; ethyl acetate / hexane = 0 to 50%) and concentrated to give 2-(6-((4-bromo-1H-pyrazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.395 g, 81.5%) as a yellow oil.

[0827] [Step 2] Synthesis of compound 4133

[0828]

[0829] Phenylboronic acid (0.040 g, 0.328 mmol), 2-(6-((4-bromo-1H-pyrazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.117 g, 0.328 mmol) prepared in Step 1, [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl 2 , 0.021 g, 0.033 mmol) and cesium carbonate (0.190 g, 0.984 mmol) were mixed in 1,4-dioxane (3 mL) / water (1 mL) at room temperature. The resulting mixture was then irradiated with microwaves and heated at 100° C. for 20 minutes, and the reaction was then completed by lowering the temperature to room temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO 2 , 4 g column; methanol / dichloromethane = 0 to 10%) and concentrated. The resulting product was then purified again by chromatography (SiO 2 , 4 g column; methanol / dichloromethane = 0 to 5%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-phenyl-1H-pyrazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.014 g, 12.1%) as a brown solid.

[0830] 1 H NMR (400MHz, CDCl3) δ9.33(dd,J=2.3,0.9Hz,1H),8.38(dd,J=8.2,2.2Hz,1H),7.92(d,J=0.8Hz,1H),7.85(d,J=0.8 Hz,1H),7.56-7.48(m,2H),7.45-7.37(m,2H),7.28-7.23(m,2H),6.96(t,J=51.6Hz,1H),5.61(s,2H); LRMS(ES)m / z 354.2(M + +1).

[0831] The compounds of Table 51 were synthesized according to essentially the same procedures described above for the synthesis of compound 4133, except using 2-(6-((4-bromo-1H-pyrazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole and the reactants of Table 50.

[0832] [Table 50]

[0833] Example Compound number reactants Yield (%) 184 4208 (1H-Indol-6-yl)boronic acid 15

[0834] [Table 51]

[0835]

[0836]

[0837] Example 173: Synthesis of Compound 4136, 2-(difluoromethyl)-5-(6-((4-(1-ethyl-1H-indol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0838] [Step 1] Synthesis of 1-ethyl-1H-indole-6-carbaldehyde

[0839]

[0840] 1H-indole-6-carboxaldehyde (0.500 g, 3.444 mmol) and cesium carbonate (1.329 g, 6.889 mmol) were dissolved in acetonitrile (7 mL) at room temperature, and the resulting solution was heated under reflux for 2 hours. Iodoethane (0.305 mL, 3.789 mmol) was added and heated under reflux again for 1 hour, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified and concentrated by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 30%) to give 1-ethyl-1H-indole-6-carboxaldehyde (0.180 g, 30.2%) as a colorless oil.

[0841] [Step 2] Synthesis of 6-ethynyl-1-methyl-1H-indole

[0842]

[0843] 1-Methyl-1H-indole-6-carbaldehyde (0.095 g, 0.597 mmol) prepared in Step 1 and dimethyl (1-diazo-2-oxopropyl)phosphonate (0.134 mL, 0.895 mmol) were dissolved in methanol (2 mL) at room temperature, followed by addition of potassium carbonate (0.165 g, 1.194 mmol) to the resulting solution and stirring at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, followed by pouring water into the resulting concentrate, and then extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified and concentrated via column chromatography (SiO 2 , 12 g column; ethyl acetate / hexane = 0 to 20%) to give 6-ethynyl-1-methyl-1H-indole (0.080 g, 86.4%) as a pale yellow solid.

[0844] [Step 3] Synthesis of compound 4136

[0845]

[0846] 2-(6-(Azidomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.040 g, 0.159 mmol) prepared in Step 1 of Example 16 and 1-ethyl-6-ethynyl-1H-indole (0.027 g, 0.159 mmol) prepared in Step 2 were dissolved in tert-butanol (1 mL) / water (1 mL) at room temperature. Sodium ascorbate (1.00 M solution, 0.016 mL, 0.016 mmol) and copper (II) sulfate pentahydrate (0.50 M solution, 0.003 mL, 0.002 mmol) were then added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. Saturated aqueous ammonium chloride was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; dichloromethane / methanol = 5% to 40%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(1-ethyl-1H-indol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.050 g, 74.8%) as a pale yellow solid.

[0847] 1 H NMR (400MHz, CDCl3) δ9.40-9.35 (m, 1H), 8.47 (dd, J = 8.2, 2.2Hz, 1H), 8.29 (d, J = 32 .0Hz,1H),8.14(d,J=7.3Hz,1H),7.70-7.66(m,1H),7.55(d,J=8.0Hz,1H),7.43(d d,J=8.2,1.5Hz,1H),7.23(d,J=3.1Hz,1H),6.97(t,J=51.6Hz,1H),6.53(dd,J=3. 2,0.9Hz,1H),5.89(s,2H),4.30(q,J=7.3Hz,2H),1.58-1.51(m,3H); LRMS(ES)m / z 422.3(M + +1).

[0848] Example 182: Synthesis of Compound 4186, 4-((5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-1H-indol-3-yl)methyl)morpholine

[0849]

[0850] Morpholine (0.010 mL, 0.115 mmol) and formaldehyde (37.00%, 0.010 g, 0.126 mmol) were dissolved in acetic acid (0.5 mL) / methanol (0.5 mL). The resulting solution was stirred at 0°C for 0.4 hours, and then 2-(4-((4-(1H-indol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.027 g, 0.069 mmol) prepared in Example 158 was added and stirred at room temperature for 18 hours. 2N-Aqueous sodium hydroxide solution was poured into the resulting reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 5%) and concentrated to give 4-((5-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-1H-indol-3-yl)methyl)morpholine (0.003 g, 5.3%) as a yellow gum.

[0851] 1 H NMR(400MHz,CD3OD)δ8.41(s,1H),8.27-8.20(m,1H),8.21-8.15(m,3H),7.70-7.61(m,4H),7.54(dd,J=8.6,0.7Hz,1H),7.24 (t,J=51.6Hz,1H),5.81(d,J=8.1Hz,2H),4.61(s,2H),4.12-3.97(m,2H),3.80-3.60(m,4H),3.54-3.40(m,2H); LRMS(ES)m / z 492.2(M + +1).

[0852] Example 183: Synthesis of Compound 4187, 4-((5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indol-3-yl)methyl)morpholine

[0853]

[0854] Morpholine (0.010 mL, 0.115 mmol) and formaldehyde (37.00%, 0.010 g, 0.126 mmol) were dissolved in acetic acid (0.5 mL) / methanol (0.5 mL). The resulting solution was stirred at 0°C for 0.4 hours, and then 2-(6-((4-(1H-indol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.027 g, 0.069 mmol) prepared in Step 2 of Example 150 was added and stirred at room temperature for 18 hours. 2N-Aqueous sodium hydroxide solution was poured into the resulting reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 5%) and concentrated to give 4-((5-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indol-3-yl)methyl)morpholine (0.005 g, 8.8%) as a colorless oil.

[0855] 1 H NMR (400MHz, CD3OD) δ9.30 (d, J=1.7Hz, 1H), 8.54 (dd, J=8.2, 2.2Hz, 1H), 8.46 (d, J=8.5 Hz,1H),8.23(d,J=10.5Hz,1H),7.73-7.63(m,1H),7.62(d,J=7.7Hz,1H),7.56-7.49(m ,1H),7.45(d,J=25.6Hz,1H),7.26(t,J=51.6Hz,1H),5.93(s,2H),4.14-4.07(m,2H),3 .84-3.76(m,3H),3.67-3.54(m,2H),3.08(d,J=12.0Hz,1H),2.89(s,2H); LRMS(ES)m / z 493.5(M + +1).

[0856] Example 185: Synthesis of Compound 4209, 2-(difluoromethyl)-5-(6-((4-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0857] [Step 1] Synthesis of tert-butyl 7-ethynyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0858]

[0859] Tert-butyl 7-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.000 g, 3.827 mmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (0.882 g, 4.592 mmol), and potassium carbonate (1.058 g, 7.653 mmol) were dissolved in methanol (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 12 hours. The solvent was removed from the reaction mixture under reduced pressure, and water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO 2 , 4 g column; ethyl acetate / hexane=0 to 20%) and concentrated to give tert-butyl 7-ethynyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.200 g, 87.8%) as a yellow oil.

[0860] [Step 2] Synthesis of tert-butyl 7-(1-((5-(methoxycarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0861]

[0862] tert-Butyl 7-ethynyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.170 g, 4.547 mmol) prepared in Step 1, methyl 6-(azidomethyl)nicotinate (0.874 g, 4.547 mmol) prepared in Step 1 of Example 81, copper (II) sulfate pentahydrate (0.114 g, 0.455 mmol), and sodium ascorbate (0.009 g, 0.045 mmol) were dissolved in tert-butanol (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 2 hours. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 80%) and concentrated to give tert-butyl 7-(1-((5-(methoxycarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.100 g, 102.8%) as a yellow solid.

[0863] [Step 3] Synthesis of tert-butyl 7-(1-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0864]

[0865] Tert-butyl 7-(1-((5-(methoxycarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.100 g, 4.672 mmol) and hydrazine monohydrate (2.271 mL, 46.718 mmol) prepared in Step 2 were dissolved in ethanol (50 mL) at room temperature, and the resulting solution was heated under reflux for 12 hours, and then the reaction was completed by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, and the resulting product (tert-butyl 7-(1-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate, 2.000 g, 95.2%, yellow solid) was used without additional purification.

[0866] [Step 4] Synthesis of tert-butyl 7-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0867]

[0868] Tert-butyl 7-(1-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.000 g, 4.449 mmol), difluoroacetic anhydride (2.323 g, 13.348 mmol), and triethylamine (1.850 mL, 13.348 mmol) prepared in Step 3 were dissolved in dichloromethane (100 mL) at room temperature. The resulting solution was then heated under reflux for 12 hours, and the reaction was then completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 100%) and concentrated to give tert-butyl 7-(1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.000 g, 44.1%) as a white solid.

[0869] [Step 5] Synthesis of 2-(difluoromethyl)-5-(6-((4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0870]

[0871] Tert-butyl 7-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.000 g, 1.963 mmol) prepared in Step 4 and trifluoroacetic acid (1.503 mL, 19.626 mmol) were dissolved in dichloromethane (50 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, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; dichloromethane / methanol = 0 to 10%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.600 g, 74.7%) as a white solid.

[0872] [Step 6] Synthesis of compound 4209

[0873]

[0874] 2-(Difluoromethyl)-5-(6-((4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.060 g, 0.147 mmol) prepared in Step 5, formaldehyde (0.009 g, 0.293 mmol) and acetic acid (0.009 mL, 0.161 mmol) were dissolved in methanol (5 mL) at room temperature, and then sodium triacetoxyborohydride (0.062 g, 0.293 mmol) was added to the resulting solution and stirred at the same temperature for 12 hours. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, which was then extracted with dichloromethane and then filtered through a plastic filter to remove the solid residue and the aqueous solution layer, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; dichloromethane / methanol = 0 to 10%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.025 g, 40.3%) as a yellow solid.

[0875] 1 H NMR (400MHz, CDCl3) δ9.32-9.26(m,1H),8.36(dd,J=8.2,2.3Hz,1H),7.93(s,1H),7.60-7.50(m,2H),7.38(d,J=8.2Hz,1H),7.14(d,J =7.9Hz,1H),6.93(t,J=51.6Hz,1H),5.78(s,2H),3.73(s,2H),2.97(t,J=6.0Hz,2H),2.84(t,J=6.0Hz,2H),2.51(s,3H); LRMS(ES)m / z 493.4(M + +1).

[0876] The compounds of Table 53 were synthesized according to substantially the same procedures described above for the synthesis of compound 4209, except using 2-(difluoromethyl)-5-(6-((4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole and the reactants of Table 52.

[0877] [Table 52]

[0878] Example Compound number reactants Yield (%) 186 4210 Propan-2-one 45 187 4211 acetaldehyde 15 188 4212 Cyclobutanone 51 189 4213 Oxetane-3-one 51

[0879] [Table 53]

[0880]

[0881]

[0882] Example 193: Synthesis of Compound 4232, 2-(difluoromethyl)-5-(6-((5-(thiophen-2-yl)-2H-tetrazol-2-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0883] [Step 1] Synthesis of 5-(thiophen-2-yl)-2H-tetrazolyl

[0884]

[0885] Thiophene-2-carbonitrile (0.500 g, 4.581 mmol), sodium azide (0.655 g, 10.078 mmol), and ammonium chloride (0.539 g, 10.078 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature, and the resulting solution was stirred at 120° C. for 18 hours, and then the temperature was lowered to complete the reaction. After adding 10 ml of water, 1N hydrogen chloride was added to filter out the precipitated solid, which was then washed with hexane and dried to obtain 5-(thiophen-2-yl)-2H-tetrazole (0.620 g, 88.9%) as a white solid.

[0886] [Step 2] Synthesis of methyl 6-((5-(thiophen-2-yl)-2H-tetrazol-2-yl)methyl)nicotinate

[0887]

[0888] 5-(Thiophen-2-yl)-2H-tetrazole (0.200 g, 1.314 mmol) prepared in Step 1 and potassium carbonate (0.182 g, 1.314 mmol) were dissolved in acetonitrile (5 mL) at room temperature. Methyl 6-(bromomethyl)nicotinate (0.333 g, 1.446 mmol) was then added to the resulting solution and stirred at 100° C. for 18 hours. The reaction was then completed by lowering the temperature to room temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO 2 , 12 g column; ethyl acetate / hexane = 0 to 30%) and concentrated to give methyl 6-((5-(thiophen-2-yl)-2H-tetrazole-2-yl)methyl)nicotinate (0.320 g, 80.8%) as a white solid.

[0889] [Step 3] 6-((5-(Thien-2-yl)-2H-tetrazol-2-yl)methyl)nicotinic acid hydrazide

[0890]

[0891] Methyl 6-((5-(thiophen-2-yl)-2H-tetrazol-2-yl)methyl)nicotinate (0.150 g, 0.499 mmol) prepared in Step 2 and hydrazine monohydrate (0.485 mL, 9.989 mmol) were dissolved in ethanol (3 mL), and the resulting solution was stirred at 80° C. for 18 hours and at room temperature for a further 18 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting product (6-((5-(thiophen-2-yl)-2H-tetrazol-2-yl)methyl)nicotinate, 0.150 g, 100.0%, white solid) was used without additional purification.

[0892] [Step 4] Synthesis of compound 4232

[0893]

[0894] 6-((5-(thiophen-2-yl)-2H-tetrazol-2-yl)methyl)nicotinic acid hydrazide (0.070 g, 0.233 mmol), triethylamine (0.195 mL, 1.398 mmol), and 2,2-difluoroacetic anhydride (0.116 mL, 0.932 mmol) prepared in Step 3 were dissolved in tetrahydrofuran (3 mL) at room temperature. The resulting solution was then stirred with heating at 80° C. for 4 hours, and the reaction was then completed by lowering the temperature to room temperature. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 30%) and concentrated to give 2-(difluoromethyl)-5-(6-((5-(thiophen-2-yl)-2H-tetrazol-2-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.055 g, 65.3%) as a white solid.

[0895] 1 H NMR (400MHz, CDCl3) δ9.36(dd,J=2.3,0.8Hz,1H),8.45(dd,J=8.2,2.2Hz,1H),7.86(dd,J=3.7,1.2Hz,1H),7.50(dd,J =5.0,1.2Hz,1H),7.39(d,J=8.2Hz,1H),7.19(dd,J=5.0,3.7Hz,1H),6.96(t,J=51.6Hz,1H),6.10(s,2H); LRMS(ES)m / z 362.1(M + +1).

[0896] The compounds of Table 55 were synthesized according to essentially the same procedures described above for the synthesis of compound 4232, except using 6-((5-(thiophen-2-yl)-2H-tetrazol-2-yl)methyl)nicotinic acid hydrazide and the reactants of Table 54.

[0897] [Table 54]

[0898] Example Compound number reactants Yield (%) 194 4233 Trifluoroacetic anhydride 69

[0899] [Table 55]

[0900]

[0901] Example 195: Synthesis of Compound 4234, 2-(difluoromethyl)-5-(6-((5-phenyl-2H-tetrazol-2-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0902] [Step 1] Synthesis of 5-phenyl-2H-tetrazole

[0903]

[0904] Benzonitrile (0.500 g, 4.128 mmol), sodium azide (0.590 g, 9.083 mmol), and ammonium chloride (0.486 g, 9.083 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature, and the resulting solution was stirred at 120° C. for 18 hours, and then the temperature was lowered to room temperature to complete the reaction. After adding 10 ml of water, 1N hydrogen chloride was added to filter out the precipitated solid, which was then washed with hexane and dried to obtain 5-phenyl-2H-tetrazole (0.600 g, 99.4%) as a white solid.

[0905] [Step 2] Synthesis of 6-((5-phenyl-2H-tetrazol-2-yl)methyl)nicotinate

[0906]

[0907] 5-Phenyl-2H-tetrazole (0.200 g, 1.368 mmol) prepared in Step 1 and potassium carbonate (0.189 g, 1.368 mmol) were dissolved in acetonitrile (5 mL) at room temperature. 6-(bromomethyl)nicotinate (0.346 g, 1.505 mmol) was then added to the resulting solution and stirred at 100° C. for 18 hours. The reaction was then completed by lowering the temperature to room temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO 2 , 12 g column; ethyl acetate / hexane = 0 to 30%) and concentrated to give 6-((5-phenyl-2H-tetrazol-2-yl)methyl)nicotinate (0.300 g, 74.2%) as a white solid.

[0908] [Step 3] Synthesis of (6-((5-phenyl-2H-tetrazol-2-yl)methyl)nicotinic acid hydrazide

[0909]

[0910] Methyl 6-((5-phenyl-2H-tetrazol-2-yl)methyl)nicotinate (0.150 g, 0.508 mmol) prepared in Step 2 and hydrazine monohydrate (0.494 mL, 10.159 mmol) were dissolved in ethanol (3 mL), and the resulting solution was stirred at 80° C. for 18 hours and further stirred at room temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting product (6-((5-phenyl-2H-tetrazol-2-yl)methyl)nicotinate hydrazide, 0.150 g, 100.3%, white solid) was used without additional purification.

[0911] [Step 4] Synthesis of compound 4234

[0912]

[0913] 6-((5-phenyl-2H-tetrazol-2-yl)methyl)nicotinic acid hydrazide (0.070 g, 0.237 mmol), triethylamine (0.198 mL, 1.422 mmol), and 2,2-difluoroacetic anhydride (0.118 mL, 0.948 mmol) prepared in Step 3 were dissolved in tetrahydrofuran (3 mL) at room temperature. The resulting solution was then stirred at 80° C. for 4 hours, and the reaction was then completed by lowering the temperature to room temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 30%) and concentrated to give 2-(difluoromethyl)-5-(6-((5-phenyl-2H-tetrazol-2-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.056 g, 66.5%) as a white solid.

[0914] 1 H NMR (400MHz, CDCl3) δ9.36 (dd, J=2.1, 0.9Hz, 1H), 8.44 (dd, J=8.2, 2.2Hz, 1H), 8.23-8.16 (m, 2H), 7 .52(dd,J=5.1,2.0Hz,3H),7.39(d,J=8.2Hz,1H),6.96(t,J=51.6Hz,1H),6.12(s,2H); LRMS(ES)m / z 356.3(M + +1).

[0915] The compounds of Table 57 were synthesized according to essentially the same procedures described above for the synthesis of compound 4234, except using 6-((5-phenyl-2H-tetrazol-2-yl)methyl)nicotinic acid hydrazide and the reactants of Table 56.

[0916] [Table 56]

[0917] Example Compound number reactants Yield (%) 196 4235 Trifluoroacetic anhydride 64

[0918] [Table 57]

[0919]

[0920] Example 201: Synthesis of Compound 4280, 2-(difluoromethyl)-5-(6-((4-(3-fluorooxetane-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0921]

[0922] 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)oxetane-3-ol (0.020 g, 0.057 mmol) prepared in Example 197 and diethylaminosulfur trifluoride (0.009 mL, 0.069 mmol) were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 1 hour. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; ethyl acetate / hexane = 0 to 50%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(3-fluorooxetane-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.011 g, 54.7%) as a white solid.

[0923] 1 H NMR (400MHz, CDCl3) δ9.34(s,1H),8.44(dd,J=8.2,2.2Hz,1H),7.86(s,1H),7.47(d,J=8.2Hz,1H),7.09(s,0.2H),6.96(s,0.5H),6. 84(s,0.3H),5.80(s,2H),5.19(dd,J=7.9,1.1Hz,1H),5.11(ddd,J=17.2,8.0,1.1Hz,2H),5.04(dd,J=7.9,1.1Hz,1H); LRMS(ES)m / z 353.25(M + +1).

[0924] Example 202: Synthesis of Compound 4281, 2-(difluoromethyl)-5-(6-((4-(3-fluorotetrahydrofuran-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0925]

[0926] 3-(1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)tetrahydrofuran-3-ol (0.020 g, 0.057 mmol) prepared in Example 198 and diethylaminosulfur trifluoride (DAST, 0.009 mL, 0.069 mmol) were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 1 hour. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; ethyl acetate / hexane = 0 to 50%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(3-fluorotetrahydrofuran-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.008 g, 39.8%) as a white solid.

[0927] 1 H NMR (400MHz, CDCl3) δ9.35(d,J=1.5Hz,1H),8.44(dd,J=8.2,2.2Hz,1H),7.86(s,1H),7.45(d,J=8.2Hz ,1H),7.09(s,0.2H),6.97(s,0.5H),6.84(s,0.3H),5.79(s,2H),4.35-4.06(m,4H),2.81-2.46(m,2H).

[0928] Example 203: Synthesis of Compound 4282, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-fluorooxetane-3-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[0929]

[0930] 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)oxetane-3-ol (0.020 g, 0.054 mmol) prepared in Example 199 and diethylaminosulfur trifluoride (0.009 mL, 0.065 mmol) were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 1 hour. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; ethyl acetate / hexane = 0 to 50%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-fluorooxetane-3-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.013 g, 64.6%) as a white solid.

[0931] 1 H NMR (400MHz, CDCl3) δ7.99-7.90(m,2H),7.70(s,1H),7.50(t,J=7.6Hz,1H),7.07(s,0.2H),6.94(s,0.51H),6.82(s,0.3H ),5.72(s,2H),5.18(dd,J=8.0,1.2Hz,1H),5.10(ddd,J=17.9,8.0,1.2Hz,2H),5.02(dd,J=8.0,1.1Hz,1H); LRMS(ES)m / z 370.29(M + +1).

[0932] Example 204: Synthesis of Compound 4283, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-fluorotetrahydrofuran-3-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[0933]

[0934] 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)tetrahydrofuran-3-ol (0.020 g, 0.052 mmol) prepared in Example 200 and diethylaminosulfur trifluoride (DAST, 0.008 mL, 0.063 mmol) were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 1 hour. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; ethyl acetate / hexane = 0 to 50%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-fluorotetrahydrofuran-3-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.016 g, 79.6%) as a white solid.

[0935] 1 H NMR (400MHz, CDCl3) δ7.99-7.89 (m, 2H), 7.71 (s, 1H), 7.50 (t, J = 7.6Hz, 1H), 7.07 (s, 0.2H), 6 .94(s,0.5H),6.82(s,0.3H),5.70(s,2H),4.32-4.03(m,4H),2.83-2.43(m,2H); LRMS(ES)m / z 384.33(M + +1).

[0936] Example 208: Synthesis of Compound 4287, 2-(difluoromethyl)-5-(6-((4-(2-methyl-1H-indol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole

[0937] [Step 1] Synthesis of methyl 2-methyl-1H-indole-6-carboxylate

[0938]

[0939] Methyl 3-aminobenzoate (3.000 g, 19.845 mmol), copper acetate monohydrate (11.886 g, 59.536 mmol), acetone (34.578 g, 595.356 mmol) and palladium (II) acetate (0.089 g, 0.397 mmol) were dissolved in dimethyl sulfoxide (15 mL) at room temperature, and the resulting solution was then stirred at the same temperature for 48 hours. The reaction mixture was filtered through a celite pad to remove solids therefrom, and the solvent was then removed from the resulting filtrate under reduced pressure without solids. The resulting concentrate was then purified by column chromatography (SiO 2 , 24 g column; ethyl acetate / hexane = 0 to 30%) and concentrated to give methyl 2-methyl-1H-indole-6-carboxylate (0.150 g, 4.0%) as a pale yellow solid.

[0940] [Step 2] Synthesis of (2-methyl-1H-indol-6-yl)methanol

[0941]

[0942] 2-Methyl-1H-indole-6-carboxylic acid methyl ester (0.130 g, 0.687 mmol) prepared in step 1 was dissolved in tetrahydrofuran (2 mL), and the resulting solution was stirred at 0° C. for 0.1 hour, and then lithium aluminum hydride (1.00 M solution, 1.718 mL, 1.718 mmol) was added to the resulting solution and further stirred at room temperature for 2 hours. The reaction mixture was filtered through a celite pad to remove solids therefrom, and the solvent was then removed from the solid-free filtrate under reduced pressure, and the obtained product ((2-methyl-1H-indol-6-yl)methanol, 0.113 g, 102.0%, colorless oil) was then used without an additional purification process.

[0943] [Step 3] Synthesis of 2-methyl-1H-indole-6-carbaldehyde

[0944]

[0945] (2-Methyl-1H-indol-6-yl)methanol (0.130 g, 0.806 mmol) prepared in Step 2 and MANGAS (ip) oxide (0.491 g, 5.645 mmol) were dissolved in dichloromethane (3 mL) at room temperature, and the resulting solution was then stirred at the same temperature for 18 hours. The reaction mixture was filtered through a Celite pad to remove solids therefrom, and the solvent was then removed from the solid-free filtrate under reduced pressure, and the resulting product (2-methyl-1H-indole-6-carbaldehyde, 0.110 g, 85.7%, yellow solid) was then used without additional purification.

[0946] [Step 4] Synthesis of 6-ethynyl-2-methyl-1H-indole

[0947]

[0948] 2-Methyl-1H-indole-6-carbaldehyde (0.100 g, 0.628 mmol) prepared in step 3 and dimethyl (1-diazo-2-oxopropyl)phosphonate (0.189 mL, 1.256 mmol) were dissolved in methanol (2 mL) at room temperature, followed by addition of potassium carbonate (0.243 g, 1.759 mmol) to the resulting solution and stirring at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, followed by pouring water into the resulting concentrate, and then extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO 2 , 4 g column; dichloromethane / methanol = 100% to 40%) and concentrated to give 6-ethynyl-2-methyl-1H-indole (0.040 g, 41.0%) as a pale yellow solid.

[0949] [Step 5] Synthesis of compound 4287

[0950]

[0951] 2-(4-(Azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.028 g, 0.111 mmol) prepared in Step 1 of Example 18 and 6-ethynyl-2-methyl-1H-indole (0.017 g, 0.111 mmol) prepared in Step 4 were dissolved in tert-butanol (1 mL) / water (1 mL) at room temperature. Sodium ascorbate (1.00 M solution, 0.011 mL, 0.011 mmol) and copper (II) sulfate pentahydrate (0.50 M solution, 0.002 mL, 0.001 mmol) were then added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. Saturated aqueous ammonium chloride was poured into the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; dichloromethane / methanol = 100% to 80%) and concentrated to give 2-(difluoromethyl)-5-(6-((4-(2-methyl-1H-indol-6-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-3-yl)-1,3,4-oxadiazole (0.032 g, 70.8%) as a pale yellow solid.

[0952] 1H NMR (400MHz, DMSO-d6) δ11.02(s,1H),9.21(dd,J=2.3,0.9Hz,1H),8.61(s,1H),8.49(dd,J=8.2,2.3Hz,1H),7.79(q,J=1.0Hz,1H),7. 58(t,J=51.2Hz,1H),7.55(d,J=8.1Hz,1H),7.43(d,J=1.5Hz,1H),6.16-6.11(m,1H),5.91(s,2H),2.40(d,J=1.0Hz,3H); LRMS(ES)m / z 408.1(M + +1).

[0953] The compounds of Table 59 were synthesized according to essentially the same procedures described above in the synthesis of compound 4287, except using 6-ethynyl-2-methyl-1H-indole and the reactants of Table 58.

[0954] [Table 58]

[0955] Example Compound number reactants Yield (%) 209 4288 2-(4-(Azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole 77

[0956] [Table 59]

[0957]

[0958] Example 211: Synthesis of Compound 4290, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(1-methylpiperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[0959] [Step 1] Synthesis of methyl 4-(azidomethyl)-3-fluorobenzoate

[0960]

[0961] Methyl 4-(bromomethyl)-3-fluorobenzoate (2.000 g, 8.095 mmol) and sodium azide (0.632 g, 9.714 mmol) were dissolved in N,N-dimethylformamide (50 mL) at 50 ° C., and the resulting solution was stirred at the same temperature for 5 hours, and then the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified and concentrated by column chromatography (SiO2, 24 g column; ethyl acetate / hexane = 0 to 20%) to give methyl 4-(azidomethyl)-3-fluorobenzoate (1.500 g, 88.6%) as a yellow oil.

[0962] [Step 2] Synthesis of methyl 4-((4-(3-bromophenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorobenzoate

[0963]

[0964] Methyl 4-(azidomethyl)-3-fluorobenzoate (0.900 g, 4.303 mmol) prepared in Step 1, 1-bromo-4-ethynylbenzene (0.935 g, 5.163 mmol), sodium ascorbate (1.00 M solution in H2O, 0.430 mL, 0.430 mmol), and copper (II) sulfate pentahydrate (0.50 M solution in H2O, 0.086 mL, 0.043 mmol) were dissolved in tert-butanol (15 mL) / water (15 mL) at room temperature, and the resulting solution was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 30%) and concentrated to give methyl 4-((4-(3-bromophenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorobenzoate (1.300 g, 77.4%) as a white solid.

[0965] [Step 3] Synthesis of methyl 4-((4-(3-bromophenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorobenzoate

[0966]

[0967] Methyl 4-((4-(3-bromophenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorobenzoate (1.300 g, 3.332 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) prepared in step 2 were added at 60°C. tert-Butyl (-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.236 g, 3.998 mmol), bis(triphenylphosphine)palladium(I) dichloride (0.117 g, 0.167 mmol), and sodium carbonate (1.059 g, 9.995 mmol) were mixed in N,N-dimethylformamide (20 mL) / water (10 mL). The resulting mixture was then stirred at the same temperature for 5 hours, and the reaction was then completed by lowering the temperature to room temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 24 g column; ethyl acetate / hexane = 0 to 40%) and concentrated to give tert-butyl 4-(3-(1-(2-fluoro-4-(methoxycarbonyl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.400 g, 85.3%) as a white solid.

[0968] [Step 4] Synthesis of tert-butyl 4-(3-(1-(2-fluoro-4-(methoxycarbonyl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate

[0969]

[0970] Tert-butyl 4-(3-(1-(2-fluoro-4-(methoxycarbonyl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.000 g, 2.030 mmol) prepared in Step 3 was dissolved in methanol (50 mL) at room temperature, and then 10%-Pd / C (150 mg) was slowly added thereto, and stirred at the same temperature for 12 hours in the presence of a hydrogen balloon attached thereto. The reaction mixture was filtered through a pad of celite to remove solids therefrom, after which the solvent was removed from the obtained filtrate under reduced pressure, and then the obtained concentrate was purified by column chromatography (SiO2, 24 g column; ethyl acetate / hexane = 0 to 30%) and concentrated to give tert-butyl 4-(3-(1-(2-fluoro-4-(methoxycarbonyl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate (0.900 g, 89.6%) as a yellow oil.

[0971] [Step 5] Synthesis of tert-butyl 4-(3-(1-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate

[0972]

[0973] tert-Butyl 4-(3-(1-(2-fluoro-4-(methoxycarbonyl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate (0.900 g, 1.820 mmol) prepared in Step 4 and hydrazine monohydrate (0.884 mL, 18.198 mmol) were dissolved in ethanol (50 mL) at 90° C., and the resulting solution was stirred at the same temperature for 12 hours, and then the temperature was lowered to room temperature to complete the reaction. The solvent was removed from the reaction mixture under reduced pressure, and water was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Then, the obtained product (tert-butyl 4-(3-(1-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate, 0.820 g, 91.1%, white solid) was used without additional purification.

[0974] [Step 6] Synthesis of tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate

[0975]

[0976] tert-Butyl 4-(3-(1-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate (0.820 g, 1.658 mmol) prepared in Step 5, imidazole (0.339 g, 4.974 mmol), and 2,2-difluoroacetic anhydride (0.618 mL, 4.974 mmol) were mixed in dichloromethane (50 mL) at room temperature. The resulting mixture was then heated under reflux for 12 hours and cooled to room temperature. Water was then poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 50%) and concentrated to give tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate (0.770 g, 83.7%) as a white solid.

[0977] [Step 7] Synthesis of 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[0978]

[0979] Tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate (0.770 g, 1.388 mmol) and trifluoroacetic acid (0.319 mL, 4.165 mmol) prepared in Step 6 were dissolved in dichloromethane (20 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting product (2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole, 0.510 g, 80.8%, yellow oil) was used without additional purification.

[0980] [Step 8] Synthesis of compound 4290

[0981]

[0982] 2-(Difluoromethyl)-5-(3-fluoro-4-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.070 g, 0.154 mmol) prepared in Step 7, formaldehyde (36.00%, 0.026 g, 0.308 mmol), acetic acid (0.011 mL, 0.185 mmol), and sodium triacetoxyborohydride (0.065 g, 0.308 mmol) were dissolved in dichloromethane (5 mL), and the resulting solution was stirred at room temperature for 30 minutes and further stirred at the same temperature for 12 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 5%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(1-methylpiperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.029 g, 40.2%) as a white solid.

[0983] 1H NMR (400MHz, CDCl3) δ7.97-7.91 (m, 2H), 7.89 (s, 1H), 7.73 (d, J = 9.0Hz, 2H) ,7.47(t,J=7.7Hz,1H),7.40(t,J=7.6Hz,1H),7.26(d,J=7.5Hz,1H),7.07( s,0.2H),6.94(s,0.5H),6.81(s,0.3H),5.75(s,2H),3.37(s,2H),2.77-2. 47(m,5H),2.30-2.28(m,3H),2.01(d,J=12.0Hz,2H); LRMS(ES)m / z469.5(M + +1).

[0984] The compounds of Table 61 were synthesized according to substantially the same procedures described above for the synthesis of compound 4290, except using 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole and the reactants of Table 60.

[0985] [Table 60]

[0986] Example Compound number reactants Yield (%) 212 4291 acetaldehyde 40 213 4292 Propan-2-one 40 214 4293 Oxetane-3-one 36

[0987] [Table 61]

[0988]

[0989]

[0990] Example 215: Synthesis of Compound 4294, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(1-(1-methylazetidin-3-yl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[0991] [Step 1] Synthesis of tert-butyl 3-(4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidin-1-yl)azetidine-1-carboxylate

[0992]

[0993] 2-(Difluoromethyl)-5-(3-fluoro-4-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.400 g, 0.880 mmol), tert-butyl 3-oxoazetidine-1-carboxylate (0.301 g, 1.760 mmol), acetic acid (0.060 mL, 1.056 mmol), and sodium triacetoxyborohydride (0.373 g, 1.760 mmol) prepared in Step 7 of Example 211 were dissolved in dichloromethane (5 mL), and the resulting solution was stirred at room temperature for 30 minutes and further stirred at the same temperature for 12 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 5%) and concentrated to give tert-butyl 3-(4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidin-1-yl)azetidine-1-carboxylate (0.300 g, 55.9%) as a white solid.

[0994] [Step 2] Synthesis of 2-(4-((4-(3-(1-(azetidin-3-yl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole

[0995]

[0996] Tert-butyl 3-(4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidin-1-yl)azetidine-1-carboxylate (0.300 g, 0.492 mmol) prepared in Step 1 and trifluoroacetic acid (0.113 mL, 1.476 mmol) were dissolved in dichloromethane (20 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Subsequently, the obtained product (2-(4-((4-(3-(1-(azetidin-3-yl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole, 0.200 g, 79.8%, yellow oil) was used without additional purification process.

[0997] [Step 3] Synthesis of compound 4294

[0998]

[0999] 2-(4-((4-(3-(1-(azetidin-3-yl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.070 g, 0.137 mmol) prepared in Step 2, formaldehyde (0.008 g, 0.275 mmol) and acetic acid (0.009 mL, 0.165 mmol) were dissolved in dichloromethane (5 mL), and the resulting solution was stirred at room temperature for 30 minutes. Then, sodium triacetoxyborohydride (0.058 g, 0.275 mmol) was added thereto and further stirred at the same temperature for 12 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 5%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(1-(1-methylazetidin-3-yl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.036 g, 50.1%) as a white solid.

[1000] 1 H NMR (400MHz, CDCl3) δ7.94(d,J=8.8Hz,2H),7.81(s,1H),7.76(d,J=9.6Hz,1H),7.66( d,J=7.6Hz,1H),7.48(t,J=7.6Hz,1H),7.37(t,J=7.7Hz,1H),7.22(d,J=7.7Hz,1H),7 .07(s,0.2H),6.94(s,0.5H),6.81(s,0.3H),5.74(s,2H),3.71(s,2H),3.05(s,3H),2 .89(d,J=11.0Hz,2H),2.64-2.52(m,1H),2.47(s,3H),2.02-1.73(m,6H); LRMS(ES)m / z 524.2(M + +1).

[1001] The compounds of Table 63 were synthesized according to substantially the same procedures described above for the synthesis of compound 4294, except using 2-(4-((4-(3-(1-(azetidin-3-yl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole and the reactants of Table 62.

[1002] [Table 62]

[1003] Example Compound number reactants Yield (%) 216 4295 acetaldehyde 39 217 4296 Propan-2-one 40

[1004] [Table 63]

[1005]

[1006] Example 218: Synthesis of Compound 4316, 2-(4-((4-(3-((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole

[1007] [Step 1] Synthesis of 2-(3-bromophenyl)-1,3-dioxolane

[1008]

[1009] 3-Bromobenzaldehyde (3.145 mL, 27.024 mmol), p-toluenesulfonic acid monohydrate (0.051 g, 0.270 mmol), and ethylene glycol (1.813 mL, 32.429 mmol) were dissolved in toluene (20 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product (2-(3-bromophenyl)-1,3-dioxolane, 5.500 g, 88.8%, brown oil) was used without additional purification.

[1010] [Step 2] Synthesis of tert-butyl (1S,4S)-5-(3-(1,3-dioxolan-2-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[1011]

[1012] Tert-butyl (1S,4S)-5-(3-(1,3-dioxolan-2-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.900 g, 2.598 mmol) prepared in Step 1 and hydrochloric acid (1.00 M solution, 12.990 mL, 12.990 mmol) were dissolved in water (50 mL) at room temperature, and the resulting solution was stirred at the same temperature for 6 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; ethyl acetate / hexane = 0 to 50%) and concentrated to give tert-butyl (1S,4S)-5-(3-(1,3-dioxolan-2-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.550 g, 70.0%) as a yellow solid.

[1013] [Step 3] Synthesis of tert-butyl (1S,4S)-5-(3-formylphenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[1014]

[1015] Tert-butyl (1S,4S)-5-(3-(1,3-dioxolan-2-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.900 g, 2.598 mmol) prepared in Step 2 and hydrochloric acid (1.00 M solution, 12.990 mL, 12.990 mmol) were dissolved in water (50 mL) at room temperature, and the resulting solution was stirred at the same temperature for 6 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; ethyl acetate / hexane = 0 to 50%) and concentrated to give tert-butyl (1S,4S)-5-(3-formylphenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.550 g, 70.0%) as a yellow solid.

[1016] [Step 4] Synthesis of tert-butyl (1S,4S)-5-(3-(2,2-dibromovinyl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[1017]

[1018] Tert-butyl (1S,4S)-5-(3-formylphenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (2.300 g, 7.607 mmol), carbon tetrabromide (5.045 g, 15.213 mmol), and triphenylphosphine (5.985 g, 22.820 mmol) prepared in Step 3 were dissolved in dichloromethane (50 mL) at room temperature, and the resulting solution was stirred at the same temperature for two hours. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 50%) and concentrated to give tert-butyl (1S,4S)-5-(3-(2,2-dibromovinyl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3.450 g, 99.0%) as a yellow oil.

[1019] [Step 5] Synthesis of tert-butyl (1S,4S)-5-(3-ethynylphenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[1020]

[1021] Tert-butyl (1S,4S)-5-(3-(2,2-dibromovinyl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3.450 g, 7.530 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (4.504 mL, 30.119 mmol) prepared in Step 4 were dissolved in acetonitrile (50 mL) at room temperature, and the resulting solution was stirred at the same temperature for 16 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 50%) and concentrated to give tert-butyl (1S,4S)-5-(3-ethynylphenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.100 g, 49.0%) as a white solid.

[1022] [Step 6] Synthesis of tert-butyl (1S,4S)-5-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[1023]

[1024] Tert-butyl (1S,4S)-5-(3-ethynylphenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.500 g, 1.676 mmol) prepared in Step 5, 2-(4-(azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.451 g, 1.676 mmol) prepared in Step 1 of Example 2, copper (II) sulfate pentahydrate (0.004 g, 0.017 mmol), and sodium ascorbate (0.033 g, 0.168 mmol) were dissolved in tert-butyl alcohol (5 mL) at room temperature. The resulting solution was then stirred at the same temperature for 2 hours. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 50%) and concentrated to give tert-butyl (1S,4S)-5-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.400 g, 42.1%) as a yellow solid.

[1025] [Step 7] Synthesis of compound 4316

[1026]

[1027] Tert-butyl (1S,4S)-5-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.420 g, 0.740 mmol) and trifluoroacetic acid (0.567 mL, 7.400 mmol) prepared in Step 6 were dissolved in dichloromethane (50 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, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; dichloromethane / methanol = 0 to 10%) and concentrated to give 2-(4-((4-(3-((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.200 g, 57.8%) as a white solid.

[1028] 1 H NMR (400MHz, CDCl3) δ7.94-7.85 (m, 2H), 7.82 (s, 1H), 7.42 (t, J = 7.6Hz, 1H), 7.22 (q,J=6.8,5.7Hz,1H),7.12(t,J=1.9Hz,1H),7.05-6.76(m,2H),6.55-6.48(m,1H ),5.70(s,2H),4.41(s,1H),3.95(s,1H),3.65(dd,J=9.4,2.2Hz,1H),3.22-3.07 (m,3H),2.67(s,1H),2.00(d,J=10.0Hz,1H),1.92(d,J=9.9Hz,1H); LRMS(ES)m / z 468.2(M + +1).

[1029] Example 219: Synthesis of Compound 4317, 2-(4-((4-(3-((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole

[1030] [Step 1] Synthesis of tert-butyl (1S,4S)-5-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[1031]

[1032] Tert-butyl (1S,4S)-5-(3-ethynylphenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.400 g, 1.341 mmol) prepared in Step 5 of Example 218, 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.337 g, 1.341 mmol) prepared in Step 1 of Example 2, copper (II) sulfate pentahydrate (0.003 g, 0.013 mmol), and sodium ascorbate (0.027 g, 0.134 mmol) were dissolved in tert-butanol (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 2 hours. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 50%) and concentrated to give tert-butyl (1S,4S)-5-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.560 g, 76.0%) as a yellow solid.

[1033] [Step 2] Synthesis of compound 4317

[1034]

[1035] Tert-butyl (1S,4S)-5-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.560 g, 1.019 mmol) and trifluoroacetic acid (0.780 mL, 10.190 mmol) prepared in Step 1 were dissolved in dichloromethane (50 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, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; dichloromethane / methanol = 0 to 10%) and concentrated to give 2-(4-((4-(3-((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.360 g, 78.6%) as a brown solid.

[1036] 1H NMR (400MHz, CDCl3) δ7.92(d,J=8.0Hz,2H),7.86(s,1H),7.32(d,J=8.1Hz,2H ),7.10(t,J=8.0Hz,1H),7.03-6.73(m,3H),6.51(s,1H),6.37(d,J=8.2Hz,1H ),5.52(s,2H),4.27(s,1H),3.92(s,1H),3.48(d,J=9.0Hz,1H),3.08(dd,J=1 5.5,10.0Hz,2H),3.00(d,J=10.1Hz,1H),1.88(d,J=9.6Hz,1H); LRMS(ES)m / z 450.9(M + +1).

[1037] Example 220: Synthesis of Compound 4318, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[1038]

[1039] 2-(4-((4-(3-((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.060 g, 0.128 mmol), paraformaldehyde (0.008 g, 0.257 mmol) and acetic acid (0.008 mL, 0.141 mmol) prepared in Step 8 of Example 218 were dissolved in dichloromethane (5 mL) at room temperature, and sodium triacetoxyborohydride (0.054 g, 0.257 mmol) was added to the resulting solution and stirred at the same temperature for 12 hours. Water was poured into the reaction mixture, which was then extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and the aqueous solution layer, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; dichloromethane / methanol = 0 to 10%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.025 g, 40.5%) as a white solid.

[1040] 1H NMR(400MHz, CDCl3)δ7.88(dt,J=9.8,1.7Hz,2H),7.81(s,1H),7.46-7.37(m,1H),7.22(t,J =7.9Hz,1H),7.18-7.12(m,1H),7.05-6.77(m,2H),6.52(dd,J=8.0,2.5Hz,1H),5.70(s,2H), 4.33(s,1H),3.69(s,1H),3.46(d,J=1.5Hz,2H),3.10(dd,J=10.0,2.0Hz,1H),2.77(dd,J=1 0.0,1.6Hz,1H),2.45(s,3H),2.13-2.06(m,1H),1.98(d,J=9.2Hz,1H); LRMS(ES)m / z482.1(M + +1).

[1041] The compounds of Table 65 were synthesized according to substantially the same procedures described above for the synthesis of compound 4318, except using 2-(4-((4-(3-((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole and the reactants of Table 64.

[1042] [Table 64]

[1043] Example Compound number reactants Yield (%) 221 4319 Cyclobutanone 52

[1044] [Table 65]

[1045]

[1046] Example 222: Synthesis of Compound 4320, 2-(difluoromethyl)-5-(4-((4-(3-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[1047]

[1048] 2-(4-((4-(3-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.060 g, 0.128 mmol), cyclobutanone (0.018 g, 0.257 mmol) and acetic acid (0.008 mL, 0.141 mmol) prepared in Step 2 of Example 219 were dissolved in dichloromethane (5 mL) at room temperature, and sodium triacetoxyborohydride (0.054 g, 0.257 mmol) was added to the resulting solution and stirred at the same temperature for 12 hours. Water was poured into the reaction mixture, which was then extracted with dichloromethane, then filtered through a plastic filter to remove the solid residue and the aqueous solution layer, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; dichloromethane / methanol = 0 to 10%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(3-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.036 g, 53.8%) as a white solid.

[1049] 1 H NMR (400MHz, CDCl3) δ8.15-8.07(m,2H),7.73(s,1H),7.44(d,J=8.3Hz,2H),7.23(dd,J =16.6,8.7Hz,1H),7.17-7.12(m,1H),7.06-6.76(m,2H),6.52(dd,J=8.1,2.5Hz,1H),5. 65(s,2H),4.32(s,1H),3.69(s,1H),3.45(s,2H),3.10(dd,J=9.9,2.0Hz,1H),2.75(dd, J=9.9,1.6Hz,1H),2.44(s,3H),2.08(dt,J=10.0,1.6Hz,1H),1.96(s,1H); LRMS(ES)m / z 464.1(M + +1).

[1050] The compounds of Table 67 were synthesized according to substantially the same procedures described above for the synthesis of compound 4320, except using 2-(4-((4-(3-((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole and the reactants from Table 66.

[1051] [Table 66]

[1052] Example Compound number reactants Yield (%) 223 4321 Propan-2-one 54 224 4322 Cyclobutanone 51

[1053] [Table 67]

[1054]

[1055] Example 225: Synthesis of Compound 4323, 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylaniline

[1056] [Step 1] Synthesis of 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)aniline

[1057]

[1058] 3-Ethynylaniline (0.289 mL, 2.089 mmol), 2-(4-(azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.525 g, 2.089 mmol) prepared in Step 1 of Example 1, sodium ascorbate (0.50 M aqueous solution, 0.418 mL, 0.209 mmol), and copper (II) sulfate pentahydrate (1.00 M aqueous solution, 0.042 mL, 0.042 mmol) were dissolved in tert-butanol (5 mL) / water (5 mL) at room temperature. The resulting solution was then stirred at the same temperature for 2 hours. Saturated aqueous ammonium chloride was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The precipitated solid was filtered, washed with hexanes and dried to give 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)aniline (0.193 g, 25.1%) as a brown solid.

[1059] [Step 2] Synthesis of compound 4323

[1060]

[1061] 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)aniline (0.040 g, 0.109 mmol) prepared in Step 1 and formaldehyde (37.00% aqueous solution, 0.016 mL, 0.217 mmol) were dissolved in dichloromethane (1 mL). The resulting solution was stirred at room temperature for 15 minutes, and then sodium triacetoxyborohydride (0.069 g, 0.326 mmol) was added and stirred at the same temperature for further 18 hours. 1N aqueous sodium bicarbonate solution was poured into the resulting reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 10%) and concentrated to give 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylaniline (0.004 g, 9.3%) as a yellow solid.

[1062] 1 H NMR (400MHz, CD3OD) δ8.40 (s, 1H), 8.18-8.14 (m, 2H), 7.61 (d, J = 8.4Hz, 2H), 7.36-7.1 0(m,4H),6.83-6.75(m,1H),5.79(d,J=4.3Hz,2H),3.00(s,6H); LRMS(ES)m / z397.4(M + +1).

[1063] The compounds of Table 69 were synthesized according to substantially the same procedures described above for the synthesis of compound 4323, except using 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)aniline and the reactants of Table 68.

[1064] [Table 68]

[1065] Example Compound number reactants Yield (%) 226 4324 Cyclohexanone 35 227 4325 Tetrahydro-4H-pyran-4-one 55 228 4326 Oxetane-3-one 61

[1066] [Table 69]

[1067]

[1068]

[1069] Example 229: Synthesis of Compound 4327, N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)trimethylacetamide

[1070]

[1071] 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)aniline (0.040 g, 0.109 mmol) and N,N-diisopropylethylamine (0.038 mL, 0.217 mmol) prepared in Step 1 of Example 225 were dissolved in dichloromethane (1 mL) at room temperature. Trimethylacetyl chloride (0.016 mL, 0.130 mmol) was then added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 10%) and concentrated to give N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)trimethylacetamide (0.031 g, 63.1%) as a brown solid.

[1072] 1 H NMR (400MHz, CD3OD) δ8.40(s,1H),8.20-8.12(m,2H),8.02(t,J=1.9Hz,1H),7.65-7.58(m,3H),7.54(ddd,J=8.1 ,2.2,1.1Hz,1H),7.40(t,J=7.9Hz,1H),7.23(t,J=51.7Hz,1H),5.80(s,2H),1.33(s,9H); LRMS(ES)m / z453.5(M + +1).

[1073] Example 230: Synthesis of Compound 4328, N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-fluoro-2-methylpropanamide

[1074]

[1075] 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)aniline (0.040 g, 0.109 mmol), 2-fluoro-2-methylpropanoic acid (0.014 g, 0.130 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium hexafluorophosphate 3-oxide (0.124 g, 0.326 mmol), and N,N-diisopropylethylamine (0.038 mL, 0.217 mmol) were dissolved in N,N-dimethylformamide (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 10%) and concentrated to give N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-fluoro-2-methylpropanamide (0.022 g, 44.4%) as a brown solid.

[1076] 1 H NMR (400MHz, CD3OD) δ8.42(s,1H),8.20-8.13(m,2H),8.08(t,J=1.9Hz,1H),7.63(dddd,J=7.9,6.5,2.4,1.2Hz ,4H),7.43(t,J=8.0Hz,1H),7.23(t,J=51.7Hz,1H),5.80(s,2H),1.65(d,J=21.7Hz,6H); LRMS(ES)m / z457.4(M + +1).

[1077] The compounds of Table 71 were synthesized according to substantially the same procedures described above for the synthesis of compound 4328, except using 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)aniline and the reactants of Table 70.

[1078] [Table 70]

[1079] Example Compound number reactants Yield (%) 231 4329 dimethylglycine 24 253 4351 2-(Dimethylamino)-2-methylpropionic acid 4

[1080] [Table 71]

[1081]

[1082] Example 236: Synthesis of Compound 4334, N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-fluoro-2-methylpropanamide

[1083]

[1084] 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)aniline (0.080 g, 0.207 mmol), 2-fluoro-2-methylpropanoic acid (0.026 g, 0.248 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium hexafluorophosphate 3-oxide (0.236 g, 0.621 mmol), and N,N-diisopropylethylamine (0.072 mL, 0.414 mmol) were dissolved in N,N-dimethylformamide (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 10%) and concentrated to afford N-(4-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-fluoro-2-methylpropanamide (0.038 g, 38.7%) as a white solid.

[1085] 1 H NMR(400MHz,CD3OD)δ8.43(s,1H),8.09(t,J=1.9Hz,1H),8.03-7.92(m,2H),7.68-7.57(m,3H),7 .43(t,J=7.9Hz,1H),7.24(t,J=51.6Hz,1H),5.86(s,2H),1.68(s,3H),1.63(s,3H); LRMS(ES)m / z 475.4(M + +1).

[1086] The compounds of Table 73 were synthesized according to substantially the same procedures described above for the synthesis of compound 4334, except using 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)aniline and the reactants of Table 72.

[1087] [Table 72]

[1088] Example Compound number reactants Yield (%) 237 4335 3-(Dimethylamino)propionic acid 49

[1089] [Table 73]

[1090]

[1091] Example 251: Synthesis of Compound 4349, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[1092] [Step 1] Synthesis of methyl 3-fluoro-4-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)benzoate hydrochloride

[1093]

[1094] Tert-butyl 4-(3-(1-(2-fluoro-4-(methoxycarbonyl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-1-carboxylate (0.500 g, 0.841 mmol) prepared in Step 4 of Example 211 and hydrogen chloride (4.00 M solution in 1,4-dioxane, 0.841 mL, 3.364 mmol) were dissolved in dichloromethane (50 mL) at room temperature, and the resulting solution was stirred at the same temperature for 12 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting product (methyl 3-fluoro-4-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)benzoate hydrochloride, 0.420 g, 94.1%, white solid) was used without additional purification.

[1095] [Step 2] Synthesis of methyl 3-fluoro-4-((4-(3-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)benzoate

[1096]

[1097] Methyl 3-fluoro-4-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)benzoate hydrochloride (0.200 g, 0.464 mmol) prepared in Step 1, 2,2-dimethyloxirane (0.335 g, 4.641 mmol) and potassium carbonate (0.128 g, 0.928 mmol) were mixed in ethanol (10 mL), heated at 110° C. for 20 hours under microwave irradiation, and the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Then, the obtained product (methyl 3-fluoro-4-((4-(3-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)benzoate, 0.100 g, 46.2%, yellow oil) was used without additional purification process.

[1098] [Step 3] Synthesis of methyl 3-fluoro-4-((4-(3-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)benzoate

[1099]

[1100] Methyl 3-fluoro-4-((4-(3-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)benzoate (0.100 g, 0.214 mmol) prepared in Step 2 and diethylaminosulfur trifluoride (0.031 mL, 0.236 mmol) were dissolved in dichloromethane (20 mL) at room temperature, and the resulting solution was stirred at the same temperature for 1 hour. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; ethyl acetate / hexane = 0 to 50%) and concentrated to give methyl 3-fluoro-4-((4-(3-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)benzoate (0.090 g, 89.6%) as a white solid.

[1101] [Step 4] Synthesis of 3-fluoro-4-((4-(3-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)benzohydrazide

[1102]

[1103] Methyl 3-fluoro-4-((4-(3-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)benzoate (0.090 g, 0.192 mmol) prepared in Step 3 and hydrazine monohydrate (0.093 mL, 1.921 mmol) were dissolved in ethanol (10 mL) at 90° C. The resulting solution was stirred at the same temperature for 12 hours, and then the temperature was lowered to room temperature to complete the reaction. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Then, the obtained product (3-fluoro-4-((4-(3-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)benzohydrazide, 0.081 g, 90.0%, white solid) was used without additional purification process.

[1104] [Step 5] Synthesis of compound 4349

[1105]

[1106] 3-Fluoro-4-((4-(3-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)benzohydrazide (0.081 g, 0.173 mmol), imidazole (0.035 g, 0.519 mmol), and 2,2-difluoroacetic anhydride (0.064 mL, 0.519 mmol) prepared in Step 4 were mixed in dichloromethane (20 mL) at room temperature, and the resulting mixture was heated under reflux for 12 hours and cooled to room temperature. Water was then poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; ethyl acetate / hexane = 0 to 70%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.055 g, 60.2%) as a white solid.

[1107] 1H NMR(400MHz, CDCl3) δ7.94(d,J=8.7Hz,2H),7.85(s,1H),7.76(s,1H),7.66(dd,J=4.8, 2.7Hz,1H),7.47(ddd,J=17.0,8.1,2.0Hz,1H),7.37(t,J=7.7Hz,1H),7.24(d,J=7.8Hz ,1H),7.07(s,0.2H),6.94(s,0.5H),6.81(s,0.3H),5.75(s,2H),3.11(s,2H),2.56(s, 3H),2.33-2.30(m,2H),1.84(d,J=10.3Hz,4H),1.69(s,3H),1.64(s,3H); LRMS(ES)m / z 529.6(M + +1).

[1108] Example 252: Synthesis of Compound 4350, 2-(difluoromethyl)-5-(4-((4-(3-(1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-1,3,4-oxadiazole

[1109] [Step 1] Synthesis of methyl 4-((4-(3-(1-(2-ethyl-2-hydroxybutyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorobenzoate

[1110]

[1111] Methyl 3-fluoro-4-((4-(3-(piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)benzoate hydrochloride (0.200 g, 0.464 mmol), 2,2-diethyloxirane (0.465 g, 4.641 mmol), and potassium carbonate (0.128 g, 0.928 mmol) prepared in Step 1 of Example 251 were mixed in ethanol (10 mL), heated at 110° C. for 20 hours under microwave irradiation, and the reaction was completed by lowering the temperature to room temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Then, the obtained product (methyl 4-((4-(3-(1-(2-ethyl-2-hydroxybutyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorobenzoate, 0.110 g, 47.9%, yellow oil) was used without additional purification process.

[1112] [Step 2] Synthesis of methyl 4-((4-(3-(1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorobenzoate

[1113]

[1114] Methyl 4-((4-(3-(1-(2-ethyl-2-hydroxybutyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorobenzoate (0.110 g, 0.222 mmol) prepared in Step 1 and diethylaminosulfur trifluoride (0.032 mL, 0.245 mmol) were dissolved in dichloromethane (20 mL) at room temperature, and the resulting solution was stirred at the same temperature for 1 hour. Water was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; ethyl acetate / hexane = 0 to 50%) and concentrated to give methyl 4-((4-(3-(1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorobenzoate (0.080 g, 72.4%) as a white solid.

[1115] [Step 3] Synthesis of 4-((4-(3-(1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorobenzohydrazide

[1116]

[1117] Methyl 4-((4-(3-(1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorobenzoate (0.080 g, 0.161 mmol) prepared in Step 2 and hydrazine monohydrate (0.078 mL, 1.611 mmol) were dissolved in ethanol (10 mL) at 90° C. The resulting solution was stirred at the same temperature for 12 hours, and then the temperature was lowered to room temperature to complete the reaction. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Subsequently, the obtained product (4-((4-(3-(1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorobenzohydrazide, 0.070 g, 87.5%, white solid) was used without additional purification process.

[1118] [Step 4] Synthesis of compound 4350

[1119]

[1120] 4-((4-(3-(1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorobenzohydrazide (0.081 g, 0.163 mmol) prepared in Step 3, imidazole (0.033 g, 0.489 mmol), and 2,2-difluoroacetic anhydride (0.061 mL, 0.489 mmol) were mixed in dichloromethane (20 mL) at room temperature, and the resulting mixture was heated under reflux for 12 hours and cooled to room temperature. Water was then poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; ethyl acetate / hexane = 0 to 70%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(3-(1-(2-ethyl-2-fluorobutyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-1,3,4-oxadiazole (0.060 g, 66.1%) as a white solid.

[1121] 1 H NMR (400MHz, CDCl3) δ7.94(d,J=8.6Hz,2H),7.85(s,1H),7.76(s,1H),7.66(d,J=6.8Hz,1H ),7.46(t,J=7.6Hz,1H),7.37(t,J=7.7Hz,1H),7.24(d,J=7.7Hz,1H),7.07(s,0.2H),6.94( s,0.5H),6.81(s,0.3H),5.75(s,2H),3.08(s,1H),2.50(d,J=24.2Hz,2H),2.23(s,1H),1.8 0(d,J=32.7Hz,6H),1.60(s,3H),1.28(t,J=7.1Hz,2H),0.94(t,J=7.3Hz,6H); LRMS(ES)m / z 557.6(M + +1).

[1122] Example 254: Synthesis of Compound 4352, N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(dimethylamino)acetamide

[1123]

[1124] 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)aniline (0.080 g, 0.207 mmol), dimethylglycine (0.026 g, 0.248 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium hexafluorophosphate 3-oxide (0.236 g, 0.621 mmol), and N,N-diisopropylethylamine (0.072 mL, 0.414 mmol) were dissolved in N,N-dimethylformamide (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 10%) and concentrated to afford N-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-2-(dimethylamino)acetamide (0.015 g, 15.4%) as a yellow solid.

[1125] 1 H NMR (400MHz, CD3OD) δ8.43(s,1H),8.09(t,J=1.9Hz,1H),8.02-7.92(m,2H),7.61(dddd,J=8.3,4.5,2.4,1.1Hz, 3H),7.42(t,J=7.9Hz,1H),7.24(t,J=51.6Hz,1H),5.86(s,2H),3.25(s,2H),2.45(s,6H); LRMS(ES)m / z472.5(M + +1).

[1126] The compounds of Table 75 were synthesized according to substantially the same procedures described above for the synthesis of compound 4352, except using 3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)aniline and the reactants of Table 74.

[1127] [Table 74]

[1128] Example Compound number reactants Yield (%) 255 4353 2-(Dimethylamino)-2-methylpropionic acid 5

[1129] [Table 75]

[1130]

[1131] Example 256: Synthesis of Compound 4358, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[1132] [Step 1] Synthesis of tert-butyl 6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[1133]

[1134] 2-(4-(Azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.300 g, 1.114 mmol) prepared in Step 1 of Example 2, tert-butyl 6-ethynyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.344 g, 1.337 mmol) prepared in Step 1 of Example 150, sodium ascorbate (1.00 M solution in H2O, 0.111 mL, 0.111 mmol), and copper (II) sulfate pentahydrate (0.50 M solution in H2O, 0.022 mL, 0.011 mmol) were dissolved in tert-butanol (10 mL) / water (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO 2 , 12 g column; ethyl acetate / hexane = 0 to 70%) and concentrated to afford tert-butyl 6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.450 g, 76.7%) as a white solid.

[1135] [Step 2] Synthesis of 2-(difluoromethyl)-5-(3-fluoro-4-((4-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[1136]

[1137] Tert-butyl 6-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.450 g, 0.855 mmol) prepared in Step 1 and trifluoroacetic acid (0.196 mL, 2.564 mmol) were dissolved in dichloromethane (50 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting product (2-(difluoromethyl)-5-(3-fluoro-4-((4-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole, 0.350 g, 96.0%, yellow oil) was used without additional purification.

[1138] [Step 3] Synthesis of compound 4358

[1139]

[1140] 2-(Difluoromethyl)-5-(3-fluoro-4-((4-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.070 g, 0.164 mmol) prepared in Step 2, formaldehyde (0.010 g, 0.328 mmol), acetic acid (0.010 mL, 0.181 mmol), and sodium triacetoxyborohydride (0.070 g, 0.328 mmol) were dissolved in dichloromethane (5 mL), and the resulting solution was stirred at room temperature for 30 minutes and further stirred at the same temperature for 12 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 5%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.033 g, 45.6%) as a white solid.

[1141] 1H NMR (400MHz, CDCl3) δ7.92(dd,J=6.2,4.7Hz,2H),7.81(s,1H),7.63(s,1H),7.56(dd,J=7.9,1.7Hz,1H),7.46(t,J=7.7Hz,1H),7.09(d,J=8.0Hz,1 H),7.07(s,0.2H),6.94(s,0.5H),6.81(s,0.3H),5.73(s,2H),3.65(s,2H ),3.00(t,J=5.9Hz,2H),2.76(t,J=6.0Hz,2H),2.51(s,3H); LRMS(ES)m / z 441.5(M + +1).

[1142] The compounds of Table 77 were synthesized according to substantially the same procedures described above for the synthesis of compound 4358, except using 2-(difluoromethyl)-5-(3-fluoro-4-((4-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole and the reactants of Table 76.

[1143] [Table 76]

[1144] Example Compound number reactants Yield (%) 257 4359 acetaldehyde 38 258 4360 Propan-2-one 50 259 4361 Cyclobutanone 49 260 4362 Oxetane-3-one 51

[1145] [Table 77]

[1146]

[1147]

[1148] Example 261: Synthesis of Compound 4363, 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[1149] [Step 1] Synthesis of tert-butyl 7-ethynyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

[1150]

[1151] tert-Butyl 7-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.500 g, 1.913 mmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (0.441 g, 2.296 mmol), and potassium carbonate (0.529 g, 3.827 mmol) were dissolved in methanol (20 mL) at room temperature, and the resulting solution was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product (tert-butyl 7-ethynyl-3,4-dihydroisoquinoline-2(1H)-carboxylate, 0.450 g, 91.4%, white solid) was used without further purification.

[1152] [Step 2] Synthesis of tert-butyl 7-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[1153]

[1154] 2-(4-(Azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.500 g, 1.857 mmol) prepared in Step 1 of Example 2, tert-butyl 7-ethynyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.574 g, 2.229 mmol) prepared in Step 1, sodium ascorbate (1.00 M solution in H₂O, 0.186 mL, 0.186 mmol), and copper (II) sulfate pentahydrate (0.50 M solution in H₂O, 0.037 mL, 0.019 mmol) were dissolved in tert-butanol (10 mL) / water (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 12 hours. Water was poured into the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0 to 60%) and concentrated to give tert-butyl 7-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.580 g, 59.3%) as a white solid.

[1155] [Step 3] Synthesis of 2-(difluoromethyl)-5-(3-fluoro-4-((4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[1156]

[1157] Tert-butyl 7-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.400 g, 0.760 mmol) prepared in Step 2 and trifluoroacetic acid (0.175 mL, 2.279 mmol) were dissolved in dichloromethane (30 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting product (2-(difluoromethyl)-5-(3-fluoro-4-((4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole, 0.320 g, 98.8%, yellow oil) was used without additional purification.

[1158] [Step 4] Synthesis of compound 4363

[1159]

[1160] 2-(Difluoromethyl)-5-(3-fluoro-4-((4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.070 g, 0.164 mmol) prepared in Step 3, formaldehyde (0.006 g, 0.197 mmol), acetic acid (0.010 mL, 0.181 mmol), and sodium triacetoxyborohydride (0.070 g, 0.328 mmol) were dissolved in dichloromethane (5 mL), and the resulting solution was stirred at room temperature for 30 minutes and further stirred at the same temperature for 12 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0 to 5%) and concentrated to give 2-(difluoromethyl)-5-(3-fluoro-4-((4-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.026 g, 36.0%) as a white solid.

[1161] 1H NMR (400MHz, CDCl3) δ7.91(dd,J=6.6,4.6Hz,2H),7.81(d,J=2.4Hz,1H),7.55(d,J=6.4Hz,2H),7.45(t,J=7.7Hz,1H),7.17(d,J=8.5Hz,1H),7.07( s,0.2H),6.94(s,0.5H),6.81(s,0.3H),5.72(s,2H),3.63(d,J=6.2Hz,2H ),2.96(t,J=5.8Hz,2H),2.74(t,J=6.0Hz,2H),2.49(s,3H); LRMS(ES)m / z 441.5(M + +1).

[1162] The compounds of Table 79 were synthesized according to substantially the same procedures described above for the synthesis of compound 4363, except using 2-(difluoromethyl)-5-(3-fluoro-4-((4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole and the reactants of Table 78.

[1163] [Table 78]

[1164] Example Compound number reactants Yield (%) 262 4364 acetaldehyde 50 263 4365 Propan-2-one 50 264 4366 Cyclobutanone 52 265 4367 Oxetane-3-one 61

[1165] [Table 79]

[1166]

[1167] Example 266: Synthesis of Compound 4368, 2-(difluoromethyl)-5-(4-((4-(3-(4-ethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[1168] [Step 1] Synthesis of tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperazine-1-carboxylate

[1169]

[1170] 2-(4-(Azidomethyl)phenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.300 g, 1.194 mmol) prepared in Step 1 of Example 1 and tert-butyl 4-(3-ethynylphenyl)piperazine-1-carboxylate (0.342 g, 1.194 mmol) prepared in Step 1 of Example 117 were dissolved in tert-butanol (1 mL) / water (1 mL) at room temperature. Sodium ascorbate (1.00 M solution, 0.119 mL, 0.119 mmol) and copper (II) sulfate pentahydrate (0.50 M solution, 0.024 mL, 0.012 mmol) were then added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (SiO2, 12 g column; dichloromethane / methanol = 100% to 70%) and concentrated to give tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperazine-1-carboxylate (0.430 g, 67.0%) as a white solid.

[1171] [Step 2] Synthesis of (2-(difluoromethyl)-5-(4-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[1172]

[1173] Tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperazine-1-carboxylate (0.300 g, 0.558 mmol) and trifluoroacetic acid (1.282 mL, 16.742 mmol) prepared in Step 1 were dissolved in dichloromethane (3.5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting product (2-(difluoromethyl)-5-(4-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole, 0.310 g, 100.7%, pale yellow oil) was used without additional purification.

[1174] [Step 3] Synthesis of compound 4368

[1175]

[1176] 2-(Difluoromethyl)-5-(4-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.050 g, 0.114 mmol) and acetaldehyde (0.015 g, 0.342 mmol) prepared in Step 2 were dissolved in dichloromethane (1 mL) at room temperature. Sodium triacetoxyborohydride (0.121 g, 0.570 mmol) was then added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; dichloromethane / methanol = 100% to 70%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(3-(4-ethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.035 g, 65.9%) as a pale yellow oil.

[1177] 1 H NMR (400MHz, CD3OD) δ8.42(s,1H),8.20-8.13(m,2H),7.62(d,J=8.4Hz,2H),7.48(d,J=2.1Hz,1H),7.35-7.28(m,2H),7.23(t,J=51.6Hz,1H),6.9 9(dt,J=7.5,2.2Hz,1H),5.79(s,2H),3.30(d,J=5.4Hz,4H),2.73-2.66( m,4H),2.54(q,J=7.3Hz,2H),1.18(t,J=7.2Hz,3H); LRMS(ES)m / z466.3(M + +1).

[1178] The compounds of Table 81 were synthesized according to essentially the same procedures described above for the synthesis of compound 4368, except using 2-(difluoromethyl)-5-(4-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole and the reactants of Table 80.

[1179] [Table 80]

[1180] Example Compound number reactants Yield (%) 267 4369 Propionaldehyde 67 268 4370 Oxetane-3-one 67 269 4371 Cyclobutanone 69

[1181] [Table 81]

[1182]

[1183] Example 270: Synthesis of Compound 4372, 1-(4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperazin-1-yl)propan-1-one

[1184]

[1185] 2-(Difluoromethyl)-5-(4-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.050 g, 0.114 mmol) and propionyl chloride (0.032 g, 0.342 mmol) prepared in Step 2 of Example 266 were dissolved in dichloromethane (1 mL) at room temperature, and triethylamine (0.079 g, 0.570 mmol) was added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; dichloromethane / methanol = 100% to 70%) and concentrated to give 1-(4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperazin-1-yl)propan-1-one (0.034 g, 60.4%) as a pale yellow oil.

[1186] 1 H NMR (400MHz, CD3OD) δ8.43(s,1H),8.20-8.13(m,2H),7.65-7.58(m,2H),7.52-7.47(m,1H),7.35-7.29(m,2H),7.23(t,J=51.6Hz,1H),7.01(d t,J=6.9,2.6Hz,1H),5.80(s,2H),3.75(dt,J=17.5,5.3Hz,4H),3.30-3.20(m,4H),2.49(q,J=7.5Hz,2H),1.16(t,J=7.5Hz,3H); LRMS(ES)m / z 494.3(M + +1).

[1187] Example 271: Synthesis of Compound 4373, 2-(difluoromethyl)-5-(4-((4-(3-(4-ethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-1,3,4-oxadiazole

[1188] [Step 1] Synthesis of tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperazine-1-carboxylate

[1189]

[1190] 2-(4-(Azidomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.300 g, 1.114 mmol) prepared in Step 1 of Example 2 and tert-butyl 4-(3-ethynylphenyl)piperazine-1-carboxylate (0.319 g, 1.114 mmol) prepared in Step 1 of Example 117 were dissolved in tert-butanol (1 mL) / water (1 mL) at room temperature. Sodium ascorbate (1.00 M solution, 0.111 mL, 0.111 mmol) and copper (II) sulfate pentahydrate (0.50 M solution, 0.022 mL, 0.011 mmol) were then added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (SiO2, 12 g column; dichloromethane / methanol = 100% to 70%) and concentrated to give tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperazine-1-carboxylate (0.470 g, 75.9%) as a white solid.

[1191] [Step 2] Synthesis of (2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole

[1192]

[1193] Tert-butyl 4-(3-(1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)piperazine-1-carboxylate (0.300 g, 0.540 mmol) and trifluoroacetic acid (1.241 mL, 16.200 mmol) prepared in Step 1 were dissolved in dichloromethane (3.5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting product (2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole, 0.310 g, 100.8%, pale yellow oil) was used without additional purification.

[1194] [Step 3] Synthesis of compound 4373

[1195]

[1196] 2-(Difluoromethyl)-5-(3-fluoro-4-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole (0.050 g, 0.110 mmol) and acetaldehyde (0.015 g, 0.329 mmol) prepared in Step 2 were dissolved in dichloromethane (1 mL) at room temperature. Sodium triacetoxyborohydride (0.116 g, 0.549 mmol) was then added to the resulting solution, and the mixture was stirred at the same temperature for 18 hours. A saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g column; dichloromethane / methanol = 100% to 70%) and concentrated to give 2-(difluoromethyl)-5-(4-((4-(3-(4-ethylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-3-fluorophenyl)-1,3,4-oxadiazole (0.036 g, 67.8%) as a pale yellow oil.

[1197] 1H NMR (400MHz, CD3OD) δ8.43(s,1H),8.03-7.93(m,2H),7.61(t,J=7.7Hz,1H),7.50(d,J=2.8Hz,1H),7.37-7.28(m,2H),7.24(t,J=51.6Hz,1H),7 .00(dt,J=7.3,2.4Hz,1H),5.85(s,2H),3.35(d,J=3.8Hz,4H),2.81(t,J=5.1Hz,4H),2.66(q,J=7.3Hz,2H),1.22(t,J=7.3Hz,3H); LRMS(ES)m / z 484.3(M + +1).

[1198] The compounds of Table 83 were synthesized according to substantially the same procedures described above for the synthesis of compound 4373, except using 2-(difluoromethyl)-5-(3-fluoro-4-((4-(3-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,3,4-oxadiazole and the reactants of Table 82.

[1199] [Table 82]

[1200] ...

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is any one selected from the following compounds:

2. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 3 . Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease mediated by histone deacetylase-6 (HDAC6).

4. The method of claim 3, wherein the histone deacetylase-6 (HDAC6)-mediated disease is an infectious disease; a tumor; an endocrine disease; a nutritional and metabolic disease; a mental and behavioral disorder; a neurological disease; a disease of the eye and ocular adnexa; a respiratory disease; a digestive problem; a skin and subcutaneous tissue disease; a musculoskeletal system and connective tissue disease; or a deformity, a deformation, and a chromosomal aberration.

5. The use according to claim 4, wherein the endocrine disease, nutritional and metabolic disease is Wilson's disease, amyloidosis or diabetes; the mental and behavioral disorder is depression or Rett syndrome; the neurological disease is central nervous system atrophy, neurodegenerative disease, movement disorder, neuropathy, motor neuron disease or central nervous system demyelinating disease; the eye and eye adnexal disease is uveitis; the skin and subcutaneous tissue disease is psoriasis; the musculoskeletal system and connective tissue disease is rheumatoid arthritis, osteoarthritis or systemic lupus erythematosus; the deformity, deformation and chromosomal aberration is autosomal dominant polycystic kidney disease; the infectious disease is prion disease; the tumor is benign or malignant; the respiratory disease is asthma; and the digestive problem is alcoholic liver disease or inflammatory bowel disease.

6. The use according to claim 4, wherein the digestive problem is Crohn's disease or ulcerative bowel disease.

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