Sulfoximine compounds as histone deacetylase 6 inhibitors and pharmaceutical compositions containing the same

Abstract

The present invention relates to a sulfoximine compound having a novel structure, its stereoisomer or a pharmaceutically acceptable salt thereof, and its use for preventing or treating histone deacetylase-mediated diseases. The sulfoximine compound having a novel structure according to the present invention is represented by the following formula (I): [Formula I] [Formula 1] TIFF2025533206000299.tif27170 It can be represented by:

Description

[Technical Field]

[0001] The present invention relates to a sulfoximine compound having histone deacetylase 6 (HDAC6) inhibitory activity, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and use thereof. [Background technology]

[0002] In cells, post-translational modifications such as acetylation serve as crucial regulatory modules at the heart of biological processes and are tightly controlled by numerous enzymes. As core proteins constituting chromatin, histones function as the axis around which DNA wraps, thus promoting DNA condensation. The balance between histone acetylation and deacetylation also plays a crucial role in gene expression.

[0003] Histone deacetylases (HDACs), enzymes that remove acetyl groups from lysine residues in histone proteins that make up chromatin, are known to be involved in gene silencing and induce cell cycle arrest, angiogenesis inhibition, immunomodulation, apoptosis, and other conditions (Hassig et al., Curr. Opin. Chem. Biol. 1997, 1, 300-308). It has also been reported that inhibition of HDAC enzyme function reduces the activity of cancer cell survival-related factors and activates cancer cell death-related factors, thereby inducing apoptosis in cancer cells (Warrell et al., J. Natl. Cancer Inst. 1998, 90, 1621-1625).

[0004] In humans, 18 HDACs are known and are classified into four classes according to their homology with yeast HDACs. The 11 HDACs that use zinc as a cofactor can be divided into three groups: class I (HDACs 1, 2, 3, and 8), class II (IIa: HDACs 4, 5, 7, and 9; IIb: HDACs 6 and 10), and class IV (HDAC 11). Seven HDACs in class III (SIRTs 1 to 7) use NAD+ instead of zinc as a cofactor (Bolden et al., Nat. Rev. Drug Discov. 2006, 5(9), 769-784).

[0005] Currently, various HDAC inhibitors are in preclinical or clinical development, but only nonselective HDAC inhibitors are known as anticancer drugs. Vorinostat (SAHA) and romidepsin (FK228) are approved for the treatment of cutaneous T-cell lymphoma, and panobinostat (LBH-589) is approved for the treatment of multiple myeloma. However, nonselective HDAC inhibitors are generally known to cause side effects such as fatigue and nausea at high doses (Piekarz et al., Pharmaceuticals 2010, 3, 2751-2767). These side effects have been reported to be caused by inhibition of class I HDACs. Due to side effects and other factors, the development of nonselective HDAC inhibitors in fields other than anticancer has been limited (Witt et al., Cancer Letters 277, (2009), 8-21).

[0006] On the other hand, selective inhibition of class II HDACs has been reported to avoid the toxicity caused by inhibition of class I HDACs. The development of selective HDAC inhibitors may potentially alleviate the side effects, such as toxicity, caused by non-selective inhibition of HDACs. Therefore, selective HDAC inhibitors may be developed as effective therapeutic agents for various diseases (Matthias et al., Mol. Cell. Biol. 2008, 28, 1688-1701).

[0007] HDAC6, a class IIb HDAC, is primarily found in the cytoplasm and is known to contain tubulin proteins. Therefore, it is involved in the deacetylation of numerous nonhistone substrates, such as HSP90 and cortactin (Yao et al., Mol. Cell 2005, 18, 601-607). HDAC6 possesses two catalytic domains, including a C-terminal zinc finger domain that can bind to ubiquitinated proteins. HDAC6 is known to target numerous nonhistone proteins as substrates, and plays an important role in various diseases, including cancer, inflammatory diseases, autoimmune diseases, neurological disorders, and neurodegenerative disorders (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 shared by various HDAC inhibitors are a capping group, a linker group, and a zinc-binding group (ZBG), as shown in the following structure of vorinostat. Many researchers have investigated the effects of structural modifications of the capping group and linker group on enzyme inhibitory activity and selectivity. Among these, the zinc-binding group is 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). [ka]

[0009] Most of these zinc-binding groups are composed of hydroxamic acid or benzamide, among which hydroxamic acid derivatives exhibit potent HDAC inhibitory effects but suffer from low bioavailability and serious off-target activity. Benzamides contain aniline, which may generate toxic metabolites in vivo (Woster et al., Med. Chem. Commun. 2015, published online).

[0010] Therefore, unlike non-selective inhibitors that have side effects, there is a need to develop selective HDAC6 inhibitors having a zinc-binding group with improved bioavailability that do not cause side effects for treating cancer, inflammatory diseases, autoimmune diseases, neurological diseases, neurodegenerative disorders, etc.

[0011] [Prior art document] [Patent Documents] International Publication No. 2011 / 091213 (Published July 28, 2011):ACY-1215 International Publication No. 2011 / 011186 (Published January 27, 2011): Tubastatin International Publication No. 2013 / 052110 (published April 11, 2013): Sloan-K International Publication No. 2013 / 041407 (Published March 28, 2013): Cellzome International Publication No. 2013 / 134467 (Published September 12, 2013): Kozi International Publication No. 2013 / 008162 (Published January 17, 2013): Novartis International Publication No. 2013 / 080120 (published June 6, 2013): Novartis International Publication No. 2013 / 066835 (published May 10, 2013): Tempero International Publication No. 2013 / 066838 (published May 10, 2013): Tempero International Publication No. 2013 / 066833 (published May 10, 2013): Tempero International Publication No. 2013 / 066839 (published May 10, 2013): Tempero Summary of the Invention [Problem to be solved by the invention]

[0012] An object of the present invention is to provide a novel sulfoximine compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which has HDAC6 inhibitory activity.

[0013] Another object of the present invention is to provide a pharmaceutical composition containing a novel sulfoximine compound having HDAC6 inhibitory activity, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0014] It is yet another object of the present invention to provide a process for preparing the novel sulfoximine compounds, their stereoisomers or their pharmaceutically acceptable salts.

[0015] Yet another object of the present invention is to provide a pharmaceutical composition for preventing or treating HDAC-mediated diseases, which comprises a novel sulfoximine compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0016] It is yet another object of the present invention to provide a method for preventing or treating HDAC-mediated diseases comprising administering to an individual a novel sulfoximine compound, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0017] It is yet another object of the present invention to provide the use of novel sulfoximine compounds, their stereoisomers or pharmaceutically acceptable salts thereof for the prevention or treatment of HDAC-mediated diseases.

[0018] Yet another object of the present invention is to provide the use of novel sulfoximine compounds, their stereoisomers or pharmaceutically acceptable salts thereof in the preparation of a medicament for preventing or treating HDAC-mediated diseases. [Means for solving the problem]

[0019] The present inventors have identified novel compounds having HDAC inhibitory activity and used them for the prevention and / or treatment of HDAC-mediated diseases, thereby completing the present invention.

[0020] This will be described in detail below. Any combination of the various elements disclosed in the present invention is included within the scope of the present invention. Furthermore, the scope of the present invention cannot be considered limited to the specific description set forth below.

[0021] compound The present invention provides a sulfoximine compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of the following (1) to (6).

[0022] (1) Formula I below: [Formula I] [ka] a sulfoximine compound represented by the formula I above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R1 is CF2H or CF3, L1 is -(C 1~3 alkylene)-, -C(=O)-, -S(=O)2-, -S(=O)2-(C 1~3 alkylene)-, -C(=O)N(R a )-, [ka] and R a is H or C 1~6 is alkyl, Q1 and Q2 are each independently CH or N; a, b, c, d, and k are each independently 1 or 2; [ka] is C 3~12 cycloalkyl, 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, C6-C 12 Aryl, -(C 1~3 Alkylene)C6~C 12 a 9- to 12-membered fused ring group containing a structure in which a 5- to 12-membered heteroaryl or aromatic ring group containing 1 to 3 heteroatoms independently selected from the group consisting of aryl, N, O, and S in the ring is fused with a non-aromatic ring group, The above [ka] At least one H in 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 3~12 Cycloalkenyl, C 1~6 alkoxy, 3-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from the group consisting of N, O and S in the ring (wherein at least one H of the heterocycloalkyl is -C(=O)(C 1~6 alkyl), a 5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of N, O and S in the ring, -CF3, -S(CF3), halogen or -S(=NH)(=O)R c and each independently may be substituted with R c is H or C 1~6 is alkyl, [ka] is C6~C 12aryl or 5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of N, O and S in the ring; The above [ka] At least one H in 1~6 each independently substituted with alkyl or halogen; [ka] teeth, [ka] and The above [ka] At least one H in 1~6 each independently substituted with alkyl or halogen; Z is CH or N; m and n are each independently 0, 1, or 2; p, q, r, s, and t are each independently 1 or 2; L2 is a single bond, -(C=O)-, -C(=O)O-, -C(=O)O-(C 1~3 alkylene)- or -S(=O)2-; R2 is H, C 1~6 Alkyl, C6-C 12 Aryl, CF3 or -(P=O)(OR b )2, R b is H or C 1~6 is alkyl, and R3 is C 1~6 A sulfoximine compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein

[0023] In the present invention, the functional group "C x", x may represent the number of carbons (C), x~y can mean an integer having at least x carbon atoms and at most y carbon atoms.

[0024] In the present invention, a "single bond" may mean that adjacent atoms or groups of atoms are directly bonded to each other.

[0025] In the present invention, unless otherwise specified, "alkyl" means a linear (or straight-chain) saturated hydrocarbon group or a branched (or side-chain) saturated hydrocarbon group, which may include at least one selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, etc., but is not limited thereto.

[0026] In the present invention, unless otherwise specified, "alkylene" may refer to a divalent functional group derived from the alkyl defined above. For example, C1 alkylene is methylene.

[0027] In the present invention, unless otherwise limited, "alkenyl" may refer to an unsaturated hydrocarbon group containing at least one double bond between carbon atoms.

[0028] In the present invention, unless otherwise limited, "alkynyl" may refer to an unsaturated hydrocarbon group containing at least one triple bond between carbon atoms.

[0029] In the present invention, "halogen" can mean F, Cl, Br or I, unless otherwise specified.

[0030] In the present invention, unless otherwise specified, "aryl" may include a monocyclic aromatic or a polycyclic aromatic, and the monocyclic aromatic may be phenyl, and the polycyclic aromatic may be at least one selected from biphenyl, naphthalenyl, etc., but is not limited thereto.

[0031] In the present invention, "benzyl" means [ka] It can mean:

[0032] In the present invention, "heteroaryl" may refer to a monocyclic or polycyclic heterocycle in which at least one carbon atom is replaced with nitrogen (N), oxygen (O), or sulfur (S) in an aryl. When a heteroaryl contains at least two heteroatoms, the two or more heteroatoms may be the same or different from each other. Heteroaryl may include, but is not limited to, at least one selected from pyridinyl, thiopenyl, triazolyl, tetrazolyl, benzothiazolyl, benzothiophenyl, quinolinyl, indolyl, isoindolyl, benzofuranyl, benzopyrrolyl, furanyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoquinolinyl, benzoxazolyl, benzimidazolyl, purinyl, indolizinyl, chromanyl, and the like.

[0033] In the present invention, "cycloalkyl" may refer to a saturated hydrocarbon ring having three or more specific carbon atoms comprising the ring, and the saturated hydrocarbon ring may include all monocyclic or polycyclic structures, and may further include bicyclic or polycyclic structures such as bridged rings or spiro structures. Examples of cycloalkyl may include at least one selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decahydronaphthalenyl, spiro[4.4]nonanyl, and bicyclo[2.2.1]heptanyl, etc., but are not limited thereto.

[0034] In the present invention, "heterocycloalkyl" may refer to a cyclic group in which at least one carbon atom forming the ring in the cycloalkyl is each independently replaced with a heteroatom selected from the group consisting of N, O, and S. Examples of heterocycloalkyl include oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, [ka] At least one selected from the following may be mentioned, but is not limited to these.

[0035] In the present invention, "cycloalkenyl" may refer to a functional group in which the defined cycloalkyl structure contains at least one double bond.

[0036] As used herein, "heterocycloalkenyl" can refer to a functional group in which at least one carbon atom in the defined cycloalkenyl structure is replaced with a heteroatom, each independently selected from the group consisting of N, O, and S.

[0037] In the present invention, a fused ring group may include a fused structure between an aromatic ring group and a non-aromatic ring group. The aromatic ring group may include the above-mentioned aryl group or heteroaryl group, and the non-aromatic ring group may include at least one of the above-mentioned cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl. Specifically, a fused ring group may be defined as a structure in which an aryl or heteroaryl is fused with one ring selected from the group consisting of the above-defined cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl. For example, the fused ring group may include a structure in which either an aryl or heteroaryl is fused to at least one ring selected from the group consisting of cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl (e.g., [ka] (wherein Y1 to Y7 may each independently be C, N, S, or O, hydrogen may be bonded according to the number of bonds of each atom, Y1-Y2-Y3 may all be single bonds or may include one double bond, and Y4-Y5-Y6-Y7 may all be connected by single bonds or may include at least one double bond) or a structure in which any one of cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl is fused with at least one ring of aryl and heteroaryl (for example, [ka] (wherein Y1 to Y7 are as defined above).

[0038] In the present invention, [ka] may represent a connection portion.

[0039] (2) The sulfoximine compound according to (1) above, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the formula I above: L1 is -C(=O)-, -S(=O)2-, -S(=O)2-(C 1~3 alkylene)-, -C(=O)N(R a )-, [ka] and [ka] is C6~C 12 Aryl, -(C 1~3 Alkylene)C6~C 12 a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of aryl, N, O, and S in the ring; or [ka] and Y1, Y2, and Y3 are each independently —CH2— or —O—; The above [ka] At least one H in 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 alkoxy, 3-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from the group consisting of N, O and S in the ring {wherein at least one H of the heterocycloalkyl is —C(═O)(C 1~6 alkyl), a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, -CF3, -S(CF3, halogen, or -S(=NH)(=O)R c and each independently may be substituted with [ka] is C6~C 12 aryl or 5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of N, O and S in the ring; The above [ka] wherein at least one H may be independently substituted with halogen; [ka] teeth, [ka] {In the formula, [ka] In [ka] At least one H in 1~6 each independently substituted with alkyl or halogen; [ka] and R1, R2, R3, R a , R b , R c , Q1, Q2, L2, Z, a, b, c, d, k, m, n, p, q, r, s and t may each be the same as defined in Formula I above, a sulfoximine compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0040] (3) The sulfoximine compound according to the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as described in (1) or (2) above, is represented by the following formula Ia: [Formula Ia] [ka] and in the above formula Ia, L1 is -C(=O)-, -S(=O)2-, -S(=O)2-(C 1~3 alkylene)-, -C(=O)N(R a )-, [ka] and [ka] is C6~C 12 Aryl, -(C 1~3 Alkylene)C6~C 12a 9- to 12-membered fused ring group containing a structure in which a 5- to 12-membered heteroaryl or aromatic ring group containing 1 to 3 heteroatoms independently selected from the group consisting of aryl, N, O, and S in the ring is fused with a non-aromatic ring group, The above [ka] At least one H in 1~6 Alkyl, C 1~6 alkoxy, 3-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from the group consisting of N, O and S in the ring {wherein at least one H of the heterocycloalkyl is —C(═O)(C 1~6 alkyl), a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, -CF3, -S(CF3, halogen, or -S(=NH)(=O)R c and each independently may be substituted with Z1, Z2, Z3, and Z4 are each independently CH, CX, or N, and at least one of Z1 to Z4 is CX or N; X is a halogen; [ka] teeth, [ka] and The above [ka] In [ka] At least one H in 1~6 may be substituted with alkyl, and R1, R2, R3, R a , Rc , Q1, Q2, L2, Z, k, m, n, p, q, r, s and t may each be the same as defined in Formula I above, a sulfoximine compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0041] of formula Ia above [ka] In the formula, Z can be bonded to L1 and N can be bonded to L2.

[0042] (4) The sulfoximine compound according to the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as described in (1), (2), or (3) above, is represented by the following formula Ib: [Formula Ib] [ka] and in formula Ib above, [ka] teeth, [ka] and Z5, Z6, Z7, and Z8 each independently represent CH, CX, or N, and at least one of Z5 to Z6 represents CX or N; Z9 is CH2, CHX, CX2, NR7, O or S; R7 is H or C 1~6 is alkyl, X is a halogen; [ka] wherein R1, R2, L2, Z, m and n may each be the same as defined in Formula I above, a sulfoximine compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0043] (5) The sulfoximine compound according to (1), (2), (3) or (4), its stereoisomer or pharmaceutically acceptable salt thereof, wherein in the above formula Ia: Z1 is CX or N; Z2 is CH, CX or N; Z3 and Z4 are each independently CH or N; X is a halogen; L1 is -C(=O)-, -S(=O)2-, -S(=O)2-(C 1~3 alkylene)-, -C(=O)NH-, [ka] and [ka] is C6~C 12 a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms in the ring independently selected from the group consisting of aryl, benzyl, N, O, and S; or [ka] and Y1, Y2, and Y3 are each independently —CH2— or —O—; The above [ka] At least one H in 1~6 Alkyl, C 1~6 alkoxy, 3-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from the group consisting of N, O and S in the ring {wherein at least one H of the heterocycloalkyl is —C(═O)(C1~6 alkyl), a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, -CF3, -S(CF3, halogen, or -S(=NH)(=O)R c and R c may be the same as defined in formula I above, a sulfoximine compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0044] (6) The sulfoximine compound according to (1), (2), (3), (4) or (5), its stereoisomer or its pharmaceutically acceptable salt, wherein in the above formula Ia: Z1 is CF or N; Z2 is CH, CF or N; Z3 and Z4 are each independently CH or N; L1 is -C(=O)-, -S(=O)2-, -S(=O)2-(C 1~3 alkylene)-, -C(=O)NH-, [ka] and R2 is H, C 1~6 Alkyl, C6-C 12 Aryl, CF3 or -(P=O)(OR b )2, R b is C 1~6 is alkyl, [ka] is C6~C 12 5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of aryl, benzyl, N, O and S in the ring; [ka] and The above [ka] In C6~C 12 At least one H of the aryl or 5-12 membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O and S in the ring is C 1~6 Alkyl, C 1~6 Alkoxy, 5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of N, O and S in the ring, -CF3, -S(CF3), halogen or -S(=NH)(=O)R c and R c is C 1~6 A sulfoximine compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which may be alkyl.

[0045] The sulfoximine compounds represented by Formula I above can include the group consisting of the compounds shown in Table 1 below.

[0046] (7) The sulfoximine compound, its stereoisomer, or its pharmaceutically acceptable salt according to (1), (2), (3), (4), (5), or (6) above, wherein the sulfoximine compound according to the present invention may be at least one compound selected from the group consisting of the compounds shown in Table 1 below.

[0047] [Table 1]

[0048] [Table 2]

[0049] [Table 3]

[0050]

Table 4

[0051]

Table 5

[0052]

Table 6

[0053]

Table 7

[0054]

Table 8

[0055]

Table 9

[0056] In the present invention, the term "pharmaceutically acceptable salt" refers to salts conventionally 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.; 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, gluconic acid, The term "salt" may refer to organic acid salts prepared from sucrose, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, etc.; sulfonate salts 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, picoline, etc., but the types of salts meant in the present invention are not limited to the listed salts.

[0057] In the present invention, the sulfoximine compounds represented by Formula I above may contain at least one asymmetric carbon and therefore may exist as racemates, racemic mixtures, single enantiomers, single diastereomers, and mixtures of diastereomers. Such isomers can be separated by resolution using conventional techniques, such as column chromatography, HPLC, etc. Alternatively, isomers can be stereospecifically synthesized using a known array of optically pure starting materials and / or reagents.

[0058] In the present invention, "stereoisomers" may include diastereomers and enantiomers, and stereoisomers may include not only enantiomers but also mixtures of enantiomers, as well as racemates.

[0059] Methods for preparing compounds The sulfoximine compound represented by Formula I according to the present invention, its stereoisomer, or its pharmaceutically acceptable salt can be prepared according to the following reaction schemes 1 to 13. Preparation methods obtained by modifying the above preparation methods to a level obvious to those skilled in the art are also included in the preparation methods of the present invention.

[0060] In the following reactions 1-13, [ka] may be the same as defined in Formula I.

[0061] In the following reaction schemes 1 to 13, "R" and [ka] can be null or of formula I [ka] R, and [ka] And, [ka] These may be expressed individually, but at least two of them are [ka] and R, or [ka] At least two of may be the same or different from each other.

[0062] In the following reaction schemes 1 to 13, "halo" represents a leaving group such as Br or Cl, K represents H or F, and "PG" can represent a protecting group.

[0063] The following reaction schemes 1 to 13 specifically show the reaction of Formula I [ka] but, [ka] wherein n and m each independently represent 1 or 2, [ka] is defined in formula I [ka] The same can be applied to the case where the compound has the structure (wherein n and m each independently represent 0 or 1).

[0064] [Reaction Scheme 1] [ka] Scheme 1 above may represent a method for the synthesis of 1,3,4-oxadiazole compounds bearing sulfoximine functional groups.

[0065] According to the first part of the method of Reaction Scheme 1, a compound of Formula 1-1 containing an isocyanate group can be reacted with a compound of Formula 1-2 containing a sulfide functional group to prepare a urea compound of Formula 1-3. Then, a compound of Formula 1-5 can be prepared by a substitution reaction with a compound of Formula 1-4, and a compound of Formula 1-6 containing a sulfoximine functional group can be prepared via a bisacetoxyiodobenzene medium and a nitrogen source.

[0066] Furthermore, according to the lower part of the method of Reaction Scheme 1 above, a compound of Formula 1-7, which is a sulfoximine compound having a protecting group contained in the imine functional group, can be reacted with a compound of Formula 1-1 to prepare a compound of Formula 1-8, which is a urea compound. For example, the protecting group can be benzyloxycarbonyl (Cbz). A compound of Formula 1-9 can then be prepared by a substitution reaction between a compound of Formula 1-8 and a compound of Formula 1-4, and then the protecting group of the compound of Formula 1-9 can be removed to prepare a compound of Formula 1-6.

[0067] In the present invention, compounds prepared according to Scheme 1 above can include compounds 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 20, 21, 22, 24, 25, 26, 27, 28, 31, 32, 33, 34, 41, 42, 45, 46, 49, 50, 51, 54, 55, 56, 57, 62, 63, 66, 79, 80, 81, 86, and the like.

[0068] [Reaction Scheme 2] [ka] Scheme 2 above may represent a method for the synthesis of 1,3,4-oxadiazole compounds containing a sulfoximine functionality.

[0069] According to the above reaction scheme 2, the compound of formula 1-6 prepared in reaction scheme 1 can be subjected to an alkylation reaction, an acetylation reaction, a phosphorylation reaction, etc. to prepare the compound of formula 2-1.

[0070] In the present invention, compounds prepared according to Reaction Scheme 2 above can include compounds 29, 30, 37, 38, 39, 40, 52, 53, and the like.

[0071] [Reaction Scheme 3] [ka] Scheme 3 above may represent a method for the synthesis of 1,3,4-oxadiazole compounds containing a sulfoximine functionality.

[0072] According to the above Reaction Scheme 3, the compound of formula 3-3 can be prepared by CC coupling (Suzuki reaction) between the compound of formula 3-1 and the compound of formula 3-2, which can be prepared according to substantially the same method as the preparation of the compound of formula 1-5 described in Reaction Scheme 1, and then the compound of formula 3-4, in which the sulfoximine functional group is introduced via a bisacetoxyiodobenzene medium and an N-source, can be prepared.

[0073] In the present invention, compounds prepared according to Reaction Scheme 3 above may include compounds 23, 43, 44, 47, and the like.

[0074] [Reaction Scheme 4] [ka] Scheme 4 above may represent a method for the synthesis of 1,3,4-oxadiazole sulfamide compounds containing a sulfoximine functionality.

[0075] According to the above reaction scheme 4, a compound of formula 4-1 can be reacted with methyl triflate (TfOCH3) to prepare a compound of formula 4-2. Subsequently, a compound of formula 4-2 can be reacted with a compound of formula 1-2 to prepare a compound of formula 4-3. The prepared compound of formula 4-3 can be reacted with methyl triflate to prepare a compound of formula 4-4, which can then be reacted with a compound of formula 4-5 containing an amine group to prepare a compound of formula 4-6 containing a sulfamide group. Subsequently, a compound of formula 4-7 can be prepared by a substitution reaction with a compound of formula 1-4, thereby preparing a compound of formula 4-8 containing a sulfoximine functional group via a bisacetoxyiodobenzene medium and a nitrogen source.

[0076] In the present invention, compounds prepared according to Reaction Scheme 4 above can include compounds 18, 19, 35, 36, 69, 70, 71, 72, 73, 76, 77, 78, and the like.

[0077] [Reaction Scheme 5] [ka] Scheme 5 above may represent a method for the synthesis of 1,3,4-oxadiazolecyclobutenedione compounds containing sulfoximine functional groups.

[0078] According to the above reaction scheme 5, a compound of formula 5-1 can be reacted with a compound of formula 1-2 containing a sulfide functional group to prepare a cyclobutenedione compound of formula 5-2. Subsequently, a compound of formula 5-3 can be prepared by a substitution reaction with a compound of formula 1-4, and then a compound of formula 5-4 containing a sulfoximine functional group can be prepared via a bisacetoxyiodobenzene medium and a nitrogen source.

[0079] In the present invention, compounds prepared according to the above reaction scheme may include compounds 60 and 61.

[0080] [Reaction Scheme 6] [ka] Scheme 6 above may represent a method for synthesizing compounds having a 1,3,4-oxadiazole amide structure containing a sulfoximine functional group.

[0081] According to the above Reaction Scheme 6, a compound of Formula 6-1 can be reacted with a compound of Formula 6-2 to prepare a compound of Formula 6-3, which is an amide compound containing a sulfide functional group. Subsequently, a compound of Formula 6-4, which has a sulfoximine functional group introduced therein, can be prepared via a bisacetoxyiodobenzene medium and an N source. Compounds prepared according to the above Reaction Scheme 6 can include Compound 8.

[0082] [Reaction Scheme 7] [ka] Scheme 7 above may represent a method for synthesizing compounds having a 1,3,4-oxadiazole urea structure containing a sulfoximine functionality.

[0083] According to the above Reaction Scheme 7, compounds of formula 7-1 can be prepared using compounds of formula 6-1 with triphosgene. This can then be reacted with compounds of formula 7-2, which are sulfoximine compounds bearing a protecting group on the S=N functional group, to prepare compounds of formula 7-3 and 7-4, from which the protecting group has been removed. Compounds prepared according to the above Reaction Scheme 7 can include compounds 58, 59, etc.

[0084] [Reaction Scheme 8] [ka] The above reaction scheme 8 may represent a method for synthesizing 1,3,4-oxadiazole compounds containing a sulfoximine functional group. [ka] teeth, [ka] wherein Q1 may represent CH or N, and k may represent 1 or 2.

[0085] According to the above-mentioned Reaction Scheme 8, a compound of Formula 8-1 can be subjected to a reductive amination reaction with a compound of Formula 8-2 to prepare a compound of Formula 8-3 containing a sulfide functional group. Then, a compound of Formula 8-4 containing a sulfoximine functional group can be prepared via a bisacetoxyiodobenzene medium and an N source. Compounds prepared according to the above-mentioned Reaction Scheme 8 can include compounds 48, 83, and 84.

[0086] [Reaction Scheme 9] [ka] The above reaction scheme 9 may represent a method for synthesizing 1,3,4-oxadiazolecyclobutenedione compounds containing sulfoximine functional groups. In the above reaction scheme 9, [ka] teeth, [ka] wherein Q1 may represent CH or N, and k may represent 1 or 2.

[0087] According to the above Reaction Scheme 9, a compound of Formula 9-1 can be subjected to a reductive amination reaction with a compound of Formula 8-2 to prepare a compound of Formula 9-2 containing a sulfide functional group. Subsequently, a compound of Formula 9-3 containing a sulfoximine functional group can be prepared via bisacetoxyiodobenzene as a medium and an N source. Compounds prepared according to the above Reaction Scheme 9 can include compounds 87, 88, and 89.

[0088] [Reaction Scheme 10] [ka] The above reaction scheme 10 may represent a method for synthesizing 1,3,4-oxadiazole compounds containing a sulfoximine functional group. [ka] teeth, [ka] Z may represent CH or N, k may represent 1 or 2, and L1 may represent [ka] R4 and R5 may each independently represent H, C 1~6 It may represent alkyl or F.

[0089] According to the above Reaction Scheme 10, compounds of formula 10-2 can be prepared using compounds of formula 10-1, and the sulfoximine functional group is introduced via a bisacetoxyiodobenzene medium and a N source. Compounds prepared according to the above Reaction Scheme 10 can include compounds 64, 65, 68, 82, 85, and 92.

[0090] [Reaction Scheme 11] [ka] Scheme 11 above may represent a method for the synthesis of 1,3,4-oxadiazole compounds bearing sulfoximine functional groups.

[0091] According to the above Reaction Scheme 11, compounds of formula 11-1 can be used to prepare compounds of formula 11-2, and the sulfoximine functional group is introduced via a bisacetoxyiodobenzene medium and a N source. Compounds prepared according to the above Reaction Scheme 11 can include compounds 75, 90, and 91.

[0092] [Reaction Scheme 12] [ka] Scheme 12 above may represent a method for the synthesis of 1,3,4-oxadiazole compounds bearing sulfoximine functional groups.

[0093] According to the above Reaction Scheme 12, a compound of formula 12-1 can be reacted with a compound of formula 12-2 to prepare a compound of formula 12-3. The resulting compound can then be subjected to a substitution reaction with a compound of formula 1-4 to prepare a compound of formula 12-4, which can then be reacted with a compound of formula 1-2 containing a sulfide functional group to prepare a compound of formula 12-5. Subsequently, a compound of formula 12-6 containing a sulfoximine functional group can be prepared via bisacetoxyiodobenzene medium and an N source. Compounds prepared according to the above Reaction Scheme 12 can include compound 74.

[0094] [Reaction Scheme 13] [ka] The above reaction scheme 13 may represent a method for synthesizing 1,3,4-oxadiazole compounds containing a sulfoximine functional group. In the above reaction scheme 13, R6 may represent an acetyl group.

[0095] According to the above Reaction Scheme 13, compounds of formula 13-2, which have a tetrahydropyridine structure containing a protecting group, can be prepared by CC coupling (Suzuki reaction) between compounds of formula 13-1 and compounds of formula 3-1, which can be prepared according to essentially the same method as the preparation of compounds of formula 1-5 described in Reaction Scheme 1. Subsequently, compounds of formula 13-3 can be prepared by converting the tetrahydropyridine of compounds of formula 13-2 to piperidine by reduction. Compounds of formula 13-4 can then be prepared by removing the protecting group, followed by acylation and alkylation reactions to prepare compounds of formula 13-5. Compounds of formula 13-6, which have a sulfoximine functional group introduced via bisacetoxyiodobenzene and an N source, can then be prepared. Compounds prepared according to the above Reaction Scheme 13 can include compound 67.

[0096] Pharmaceutical compositions and uses thereof The pharmaceutical composition of the present invention may contain the sulfoximine compound according to (1), (2), (3), (4), (5), (6), or (7) of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0097] The pharmaceutical composition of the present invention comprises, as an active ingredient, the sulfoximine compound of the present invention described above in (1), (2), (3), (4), (5), (6), or (7), its stereoisomer, or a pharmaceutically acceptable salt thereof, and can be used for the prevention or treatment of HDAC-mediated diseases.

[0098] The pharmaceutical composition of the present invention comprises a sulfoximine compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, and can be used for the prevention or treatment of HDAC-mediated diseases.

[0099] The HDAC-mediated diseases may include infectious diseases; neoplasms; endocrine, nutritional and metabolic disorders; mental and behavioral disorders; neurological disorders; diseases of the eye and ocular adnexa; cardiovascular diseases; respiratory diseases; dyspepsia; renal failure; skin and subcutaneous tissue diseases; musculoskeletal and connective tissue diseases; or malformations, deformities and chromosomal abnormalities.

[0100] In the present invention, the HDAC-mediated disease may be a disease associated with HDAC6 activity, ie, an HDAC6-mediated disease.

[0101] HDAC6-mediated diseases can include cancer, inflammatory diseases, autoimmune diseases, neurological or degenerative neurological diseases, specifically lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, brain cancer, ovarian cancer, gastric cancer, skin cancer, pancreatic cancer, glioma, glioblastoma cancer, leukemia, lymphoma, multiple myeloma, solid tumors, Wilson's disease, spinocerebellar ataxia, prion diseases, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, amyloidosis, Alzheimer's disease, alcoholic liver disease, spinal muscular atrophy, rheumatoid arthritis, osteoarthritis, Charcot-Marie-Tooth disease (CMT), heart failure (HF), pulmonary arterial hypertension (PAH), or idiopathic pulmonary fibrosis (IPF).

[0102] Endocrine, nutritional and metabolic disorders may include Wilson's disease, amyloidosis or diabetes; mental and behavioral disorders may include depression or Rett's syndrome; neurological disorders may include central nervous system atrophy, neurodegenerative diseases, movement disorders, neuropathy, motor neuron disease, central nervous system demyelinating disease or Charcot-Marie-Tooth disease (CMT); diseases of the eye and ocular adnexa may include uveitis; renal failure (RF) may include acute renal failure or chronic renal failure; skin and subcutaneous tissue disorders may include psoriasis; and connective tissue diseases may include rheumatoid arthritis, osteoarthritis or systemic lupus erythematosus; malformations, deformities and chromosomal abnormalities may include autosomal dominant polycystic kidney disease; infectious diseases may include prion diseases; neoplasms may include benign or malignant tumors; cardiovascular diseases may include atrial fibrillation (AF), heart failure (HF) or pulmonary arterial hypertension (PAH); respiratory diseases may include asthma or idiopathic pulmonary fibrosis (IPF); and gastrointestinal diseases may include alcoholic liver disease, inflammatory bowel disease, Crohn's disease or ulcerative colitis.

[0103] The pharmaceutical composition of the present invention may further contain at least one pharmaceutically acceptable carrier in addition to the sulfoximine compound, its optical isomer, or its pharmaceutically acceptable salt described in (1), (2), (3), (4), (5), (6), or (7) above. In this case, the pharmaceutically acceptable carrier may be one commonly used in pharmaceutical formulations, specifically, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, etc. Additionally, the pharmaceutical composition of the present invention may further contain, in addition to the above-mentioned components, a lubricant, a humectant, a sweetener, a flavoring, an emulsifier, a suspending agent, a preservative, etc.

[0104] Furthermore, the pharmaceutical composition of the present invention can be formulated into oral dosage forms such as tablets, powders, granules, pills, capsules, suspensions, emulsions, oral solutions, emulsions, and syrups, as well as into the form of external preparations, suppositories, and sterile injectable solutions, and therefore can be prepared in unit dosage forms or in multi-dose containers. The preparations can be prepared according to conventional methods used in the art for formulation or the methods disclosed in Remington's Pharmaceutical Science (19th ed., 1995), and various formulations are possible depending on the respective diseases or components.

[0105] The pharmaceutical composition of the present invention can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) according to the desired method, the dosage of which varies depending on the patient's condition and body weight, the severity of the disease, the dosage form, and the route and time of administration, and can be appropriately selected by those skilled in the art. Specifically, the daily dose of the compound of the present invention described in (1), (2), (3), (4), (5), (6), or (7) above can be about 0.1 to about 1000 mg / kg, preferably about 5 to about 100 mg / kg, and can be administered once a day or several times a day by dividing the daily dose of the compound.

[0106] The pharmaceutical composition of the present invention may further contain at least one component that can exhibit the same or similar medicinal effect or that can bring about a synergistic effect in combination with the sulfoximine compound, stereoisomer, or pharmaceutically acceptable salt thereof described in (1), (2), (3), (4), (5), (6), or (7) above of the present invention.

[0107] The present invention may provide a method for preventing or treating a histone deacetylase-mediated disease, comprising administering to an individual the sulfoximine compound according to (1), (2), (3), (4), (5), (6), or (7) of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0108] The sulfoximine compound, its stereoisomer or its pharmaceutically acceptable salt according to (1), (2), (3), (4), (5), (6) or (7) of the present invention can be administered in a therapeutically effective amount.

[0109] In the present invention, "therapeutically effective amount" can refer to an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical care, and the effective dose level can be determined according to factors including the type and severity of the patient's disease, the activity of the drug, sensitivity to the drug, administration time, administration route and excretion rate, treatment period and concurrently used drugs, and other factors well known in the medical field. Specifically, it can refer to an amount effective for preventing or treating HDAC6-mediated diseases.

[0110] In the present invention, the term "individual" may refer to a subject whose disease needs to be prevented or treated, more specifically, to mammals such as humans, monkeys, mice, dogs, cats, horses, cows, etc., but is not limited thereto.

[0111] In the present invention, the term "prevention" may refer to any action of inhibiting or delaying the onset of a disease by administering the sulfoximine compound of the present invention described above in (1), (2), (3), (4), (5), (6), or (7), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0112] In the present invention, the term "treatment" may refer to any action in which the symptoms of a disease are improved or taken in a beneficial direction by administering the sulfoximine compound of the present invention described above in (1), (2), (3), (4), (5), (6) or (7), its stereoisomer or a pharmaceutically acceptable salt thereof.

[0113] The present invention may provide use of the sulfoximine compound according to (1), (2), (3), (4), (5), (6), or (7) of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof, for preventing or treating an HDAC-mediated disease.

[0114] The present invention may provide use of the sulfoximine compound, its stereoisomer, or its pharmaceutically acceptable salt according to (1), (2), (3), (4), (5), (6), or (7) of the present invention in the preparation of a pharmaceutical for preventing or treating a histone deacetylase-mediated disease.

[0115] The references to the sulfoximine compounds, uses, compositions, and treatment methods of the present invention are equally applicable unless they contradict each other. Furthermore, terms and abbreviations used herein shall have their original meanings unless otherwise defined.

[0116] beneficial effects The sulfoximine compound, its stereoisomer, or pharmaceutically acceptable salt thereof of the present invention can selectively inhibit HDAC6 and therefore has extremely excellent effects in the prevention or treatment of HDAC-mediated diseases. Therefore, the sulfoximine compound, its stereoisomer, or pharmaceutically acceptable salt thereof of the present invention can be advantageously used in the prevention or treatment of HDAC-mediated diseases. DETAILED DESCRIPTION OF THE INVENTION

[0117] The present invention will be described in more detail below with reference to Preparations and Examples. However, the following Preparations and Examples are for the purpose of illustrating the present invention, and therefore the present invention is not limited to the Preparations and Examples.

[0118] <Preparation Example> The compounds according to the present invention were synthesized by the following methods, and those skilled in the art can use conventional methods derived from a combination of the following specific synthesis methods.

[0119] Each compound used in the synthesis was either purchased from an external supplier or synthesized using organic synthesis methods apparent to those skilled in the art, and was used without further purification. 1 The identity was determined by H-NMR (Agilent, 400-MR) and LC-Mass (Waters, SQD2) analysis.

[0120] Example 1: Synthesis of Compound 1, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-imino-N-phenylthiomorpholine-4-carboxamide 1-oxide [Step 1] Synthesis of N-phenylthiomorpholine-4-carboxamide [ka] Isocyanatobenzene (100.00%, 2.000 g, 16.790 mmol) and thiomorpholine (100.00%, 1.000 equivalents, 16.790 mmol) were dissolved in dichloromethane (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 4 hours. After the solvent was removed from the reaction mixture under reduced pressure, hexane (20 mL) and ethyl acetate (10 mL) were added to the resulting concentrate, and the resulting solid was stirred and filtered off. The solid was then washed with hexane and dried to give the title compound (3.000 g, 80.38%) in the form of a white solid.

[0121] [Step 2] Synthesis of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide [ka] N-Phenylthiomorpholine-4-carboxamide (100.00%, 2.270 g, 10.210 mmol) prepared in Step 1 was dissolved in N,N-dimethylformamide (10 mL) at 0 °C, and then sodium hydride (100.00%, 1.500 equivalents, 15.320 mmol) was added. The resulting solution was stirred at the same temperature for 30 minutes. 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.000 equivalents, 10.210 mmol) was added to the reaction mixture, which was then stirred at room temperature for 2 hours. The solvent was removed from the reaction mixture under reduced pressure, and then a saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 40 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (2.940 g, 64.19%) in the form of a colorless oil.

[0122] [Step 3] Synthesis of Compound 1 [ka] N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide (100.00%, 2.940 g, 6.555 mmol) prepared in Step 2, ammonium carbamate (100.00%, 2.000 equivalents, 13.110 mmol), and (diacetoxyiodo)benzene (100.00%, 2.500 equivalents, 16.390 mmol) were dissolved in methanol (50 mL) at room temperature, and the resulting solution was stirred at the same temperature overnight. The solvent was removed from the reaction mixture under reduced pressure, and then a saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 40 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (2.500 g, 79.54%) in the form of a colorless oil. 1 H NMR(400MHz,CDCl3)δ 7.86(dd,J=8.0,1.5Hz,1H),7.74(dd,J=10.1,1.5Hz,1H),7.67(t,J=7.6 Hz,1H),7.36(t,J=7.8Hz,2H),7.23-7.19(m,1H),7.13-7.11(m,2H),7.0 3(s,0.25H),6.90(s,0.5H),6.77(s,0.25H),4.92(s,2H),3.79-3.72(m, 2H),3.67-3.60(m,2H),2.80(t,J=5.2Hz,4H),2.46(s,1H);LRMS(ES)m / z 480.9(M + +1)

[0123] Example 2: Synthesis of Compound 2, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenyl-1-((2,2,2-trifluoroacetyl)imino)thiomorpholine-4-carboxamide 1-oxide [Step 1] Synthesis of N-phenyl-1-((2,2,2-trifluoroacetyl)imino)thiomorpholine-4-carboxamide 1-oxide [ka] Isocyanatobenzene (0.590 g, 4.953 mmol) and 2,2,2-trifluoro-N-(1-oxidothiomorpholin-1-ylidene)acetamide (1.140 g, 4.953 mmol) were dissolved in dichloromethane (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 5 h. The solvent was removed from the mixture under reduced pressure, and the concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0-30%) and concentrated to give the title compound (0.160 g, 9.2%) as a white solid.

[0124] [Step 2] Synthesis of Compound 2 [ka] N-phenyl-1-((2,2,2-trifluoroacetyl)imino)thiomorpholine-4-carboxamide 1-oxide (0.120 g, 0.344 mmol) prepared in Step 1 was dissolved in N,N-dimethylformamide (10 mL) at 0 °C, and then sodium hydride (60.00%, 0.014 g, 0.344 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.100 g, 0.344 mmol) was added to the reaction mixture and further stirred at room temperature for 3 hours. Water 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, 12 g cartridge; ethyl acetate / hexane = 0-50%) and concentrated to give the title compound (0.052 g, 27.1%) in the form of a colorless oil. 1H NMR(400MHz,CDCl3)δ 9.25(d,J=1.6Hz,1H),8.43(dd,J=8.0,2.0Hz,1H),7.54(d,J=8.0Hz,1H),7.39(t,J=7.8Hz,2H),7.25-7.19(m,3H),7.08(s, LRMS(ES)m / z 559.9(M + +1)

[0125] Example 3: Synthesis of Compound 3, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-imino-N-phenylthiomorpholine-4-carboxamide 1-oxide [ka] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenyl-1-((2,2,2-trifluoroacetyl)imino)thiomorpholine-4-carboxamide 1-oxide (0.052 g, 0.093 mmol) prepared in Step 2 of Example 2 and potassium carbonate (0.051 g, 0.372 mmol) were dissolved in methanol (5 mL) at room temperature, and the resulting solution was stirred at the same temperature for 1 hour. The solvent was removed from the resulting mixture under reduced pressure, and the resulting concentrate was purified by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0 to 10%) and concentrated to give the title compound (0.013 g, 30.2%) as a yellow oil. 1H NMR(400MHz,CDCl3)δ 9.26(d,J=1.6Hz,1H),8.38(dd,J=8.2,2.2Hz,1H),7.57(d,J=8.0Hz,1H),7.39-7.32(m,2H),7.21-7.17(m,3H),7.07(s, LRMS(ES)m / z 463.9(M + +1)

[0126] Example 4: Synthesis of Compound 4, Benzyl (4-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)(phenyl)carbamoyl)-1-oxidethiomorpholin-1-ylidene)carbamate [Step 1] Synthesis of benzyl (1-oxide-4-(phenylcarbamoyl)thiomorpholin-1-ylidene)carbamate [ka] Benzyl (1-oxidethiomorpholin-1-ylidene)carbamate (100.00%, 2.000 g, 7.454 mmol) and isocyanatobenzene (100.00%, 1.000 equivalents, 7.454 mmol) were dissolved in diethyl ether (50 mL) at room temperature, and the resulting solution was stirred at the same temperature for 5 hours. The precipitated solid was filtered, washed with hexane, and dried to give the title compound (2.65 g, 91.76%, yellow solid form).

[0127] [Step 2] Synthesis of Compound 4 [ka] Essentially the same reaction described in Step 2 of Example 1 was followed, except that benzyl (1-oxide-4-(phenylcarbamoyl)thiomorpholin-1-ylidene)carbamate (100.00%, 2.650 g, 6.840 mmol) prepared in Step 1 was used instead of N-phenylthiomorpholine-4-carboxamide to give the title compound (2.08 g, 49.56%, colorless oil). 1 H NMR(400MHz,CDCl3)δ 7.87(d,J=8.0Hz,1H),7.74(d,J=10.0Hz,1H),7.66(t,J=7.6Hz,1H),7.3 9-7.28(m,7H),7.25-7.21(m,1H),7.12(d,J=8.0Hz,2H),7.05(s,0.25H), 6.92(s,0.5H),6.79(s,0.25H),5.09(s,2H),4.93(s,2H),3.90-3.85(m,2 H),3.89-3.85(m,2H),3.56-3.50(m,2H),3.42-3.38(m,2H);LRMS(ES)m / z 614.9(M + +1)

[0128] Example 5: Synthesis of Compound 5, benzyl (4-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)(phenyl)carbamoyl)-1-oxidethiomorpholin-1-ylidene)carbamate [ka] Essentially the same reaction described in Step 2 of Example 2 was followed, except that benzyl (1-oxide-4-(phenylcarbamoyl)thiomorpholin-1-ylidene)carbamate was used instead of N-phenyl-1-((2,2,2-trifluoroacetyl)imino)thiomorpholin-4-carboxamide 1-oxide, to provide the title compound (0.12 g, 15.58%, white solid). 1H NMR(400MHz,CDCl3)δ 9.25(d,J=1.6Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.54(d,J=8.4Hz,1H),7.41-7.30(m,7H),7.22-7.18(m,3H),7.08(s,0.25H), 6.95(s,0.5H),6.82(s,0.25H),5.11(s,2H),5.10(s,2H),3.92-3.87(m,2H),3.57-3.50(m,4H),3.28-3.22(m,2H);LRMS(ES)m / z 597.9(M + +1)

[0129] Example 6: Synthesis of Compound 6, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3,4-difluorophenyl)-1-iminothiomorpholine-4-carboxamide 1-oxide [Step 1] Synthesis of N-(3,4-difluorophenyl)thiomorpholine-4-carboxamide [ka] Substantially the same reaction as described in Step 1 of Example 1 was followed, except that 1,2-difluoro-4-isocyanatobenzene was used instead of isocyanatobenzene, to give the title compound (1.500 g, 90.07%) in the form of a white solid.

[0130] [Step 2] Synthesis of N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3,4-difluorophenyl)thiomorpholine-4-carboxamide [ka] Following essentially the same reaction as described in Step 2 of Example 1, except that N-(3,4-difluorophenyl)thiomorpholine-4-carboxamide (100.00%, 0.300 g, 1.161 mmol) prepared in Step 1 was used instead of N-phenylthiomorpholine-4-carboxamide, the title compound (0.300 g, 53.32%) was obtained in the form of a white foam solid.

[0131] [Step 3] Synthesis of Compound 6 [ka] Following essentially the same reaction as described in Step 3 of Example 1, except that N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide prepared in Step 2 was used instead of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3,4-difluorophenyl)thiomorpholine-4-carboxamide, the title compound (0.22 g, 68.91%) was obtained in the form of a colorless oil. 1 H NMR(400MHz,CDCl3)δ 7.90(dd,J=8.0,1.6Hz,1H),7.78(dd,J=10.1,1.5Hz,1H),7.68(t,J=7.6Hz,1H),7.20-7.14(m,1H),7.06(s,0.25H),7.03-6.98(m,1H) ),6.93(s,0.5H),6.89-6.85(m,1H),6.80(s,0.25H),4.90(s,2H),3.79-3.62(m,4H),2.93-2.90(m,4H),2.50(brs,1H);LRMS(ES)m / z 516.9(M + +1)

[0132] Example 7: Synthesis of Compound 7, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(3,4-difluorophenyl)-1-iminothiomorpholine-4-carboxamide 1-oxide [Step 1] Synthesis of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(3,4-difluorophenyl)thiomorpholine-4-carboxamide [ka] The same reaction as described in Step 2 of Example 6 was followed, except that in Step 2 of Example 6, 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole was used instead of 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole, to obtain the title compound (0.220 g, 40.53%) in the form of a colorless oil.

[0133] [Step 2] Synthesis of Compound 7 [ka] Using N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(3,4-difluorophenyl)thiomorpholine-4-carboxamide obtained from Step 1, following essentially the same reaction as described in Step 3 of Example 6, the title compound (0.15 g, 64.82%) was obtained in the form of a colorless oil. 1 H NMR(400MHz,CDCl3)9.25(d,J=1.6Hz,1H),8.40(dd,J=8.2,2.2Hz,1H),7.54(d,J=8.2Hz,1H),7.18-7.08(m,2H),7.08(s,0.25H), 6.97-6.93(m,1H),6.96(s,0.5H),6.82(s,0.25H),5.06(s,2H),3.79-3.61(m,4H),3.07-2.98(m,4H),2.40(brs,1H);LRMS(ES)m / z 499.9(M + +1)

[0134] Example 8: Synthesis of Compound 8, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-imino-N-phenyltetrahydro-2H-thiopyran-4-carboxamide 1-oxide [Step 1] Synthesis of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenyltetrahydro-2H-thiopyran-4-carboxamide [ka] N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorophenyl)methyl)aniline (100.00%, 0.600 g, 1.879 mmol) was dissolved in N,N-dimethylformamide (10 mL) at 0° C., and then sodium hydride (60.00%, 1.500 equivalents, 2.819 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. Tetrahydrothiopyran-4-carbonyl chloride (100.00%, 1.000 equivalents, 1.879 mmol) was added to the reaction mixture and further stirred at room temperature for 2 hours. The solvent was removed from the reaction mixture under reduced pressure, and then a saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate and extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (0.510 g, 60.65%) in the form of a colorless oil.

[0135] [Step 2] Synthesis of Compound 8 [ka] Following essentially the same reaction as described in Step 3 of Example 1, except that N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide prepared in Step 1 was used instead of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenyltetrahydro-2H-thiopyran-4-carboxamide, the title compound (0.120 g, 22.01%) was obtained in the form of a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.87(d,J=8.0Hz,1H),7.73(dd,J=9.8,1.5Hz,1H),7.56-7.51(m,1H),7.41 -7.39(m,3H),7.05-7.03(m,2H),7.05(s,0.25H),6.92(s,0.5H),6.79(s,0. 25H),5.04(d,J=2.2Hz,2H),3.30-3.26(m,2H),2.82-2.79(m,2H),2.52-2.5 0(m,1H),2.41-2.36(m,2H),2.20(brs,1H),2.09-2.05(m,2H);LRMS(ES)m / z 479.9(M + +1)

[0136] Example 9: Synthesis of Compound 9, 1-imino-N-phenyl-N-((5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1-oxide [Step 1] Synthesis of N-phenyl-N-((5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide [ka] N-Phenylthiomorpholine-4-carboxamide (100.00%, 0.050 g, 0.225 mmol) was dissolved in N,N-dimethylformamide (10 mL) at 0 °C, and then sodium hydride (100.00%, 1.500 equivalents, 0.337 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. 2-(6-(bromomethyl)pyridin-3-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole (100.00%, 1.000 equivalents, 0.225 mmol) was added to the reaction mixture and further stirred at room temperature for 2 hours. The solvent was removed from the reaction mixture under reduced pressure, and then a saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate and extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 12 g cartridge; hexane / ethyl acetate = 0-30%) and concentrated to give the title compound (0.005 g, 4.95%) in the form of a colorless oil.

[0137] [Step 2] Synthesis of Compound 9 [ka] Following essentially the same reaction as described in Step 3 of Example 1, except that N-phenyl-N-((5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide prepared in Step 1 was used instead of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide, the title compound (0.010 g, 20.78%) was obtained in the form of a colorless oil. 1H NMR(400MHz,CDCl3)δ 9.26(d,J=1.6Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.39-7.35(m,2H),7.22-7.18(m,3H),5.12 (s,2H),3.82-3.76(m,2H),3.70-3.63(m,2H),2.98-2.94(m,4H),2.50(brs,1H);LRMS(ES)m / z 481.9(M + +1)

[0138] Examples 10 to 13: Synthesis of Compounds 10 to 13 Compounds 10 to 13 according to Examples 10 to 13 were prepared according to the same reactions as those described in Steps 1, 2, and 3 of Example 1, respectively, except that the reactants in Table 2 below were used instead of isocyanatobenzene in Step 1 of Example 1. Table 2 shows the properties and yields of the products prepared in Steps 1 to 3 of Examples 10 to 13, respectively.

[0139] [Table 10]

[0140] The names of compounds 10 to 13 prepared in Examples 10 to 13, respectively, and the results of their NMR and LC-Mass analysis are shown in Table 3 below.

[0141] [Table 11]

[0142] [Table 12]

[0143] Examples 14 to 17: Synthesis of Compounds 14 to 17 Compounds 14 to 17 according to Examples 14 to 17 were prepared according to the same reactions as described in Steps 1, 2, and 3 of Examples 10 to 13, respectively, except that in Step 2 of Examples 10 to 13, 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole was used instead of 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole. Table 4 shows the properties and yields of the products prepared in Steps 1 to 3 of Examples 14 to 17, respectively.

[0144] [Table 13]

[0145] The names of compounds 14 to 17 prepared in Examples 14 to 17, respectively, and the results of their NMR and LC-Mass analysis are shown in Table 5 below.

[0146] [Table 14]

[0147] [Table 15]

[0148] Example 18: Synthesis of Compound 18, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-imino-N-phenylthiomorpholine-4-sulfonamide 1-oxide [Step 1] Synthesis of 1-((1H-imidazol-1-yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate [ka] 1,1'-Sulfonylbis(1H-imidazole) (100.00%, 3.000 g, 15.136 mmol) and methyl trifluoromethanesulfonate (100.00% solution, 1.4903 mL, 13.623 mmol) were dissolved in dichloromethane (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 days. After the solvent was removed from the reaction mixture under reduced pressure, hexane (20 mL) and ethyl acetate (10 mL) were added to the resulting concentrate, stirred, and the precipitated solid was filtered off, which was then washed with hexane and dried to obtain the title compound (4.000 g, 72.94%) in the form of a white solid.

[0149] [Step 2] Synthesis of 4-((1H-imidazol-1-yl)sulfonyl)thiomorpholine [ka] 1-((1H-imidazol-1-yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (100.00%, 4.000 g, 11.040 mmol) prepared in Step 1 and thiomorpholine (100.00%, 1.100 equivalents, 12.140 mmol) were dissolved in acetonitrile (50 mL) at room temperature, and the resulting solution was stirred overnight at the same temperature. The solvent was removed from the reaction mixture under reduced pressure, and then a saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 40 g cartridge; hexane / ethyl acetate = 0 to 30%) and concentrated to give the title compound (0.500 g, 19.41%) in the form of a white solid.

[0150] [Step 3] Synthesis of 3-methyl-1-(thiomorpholinosulfonyl)-1H-imidazol-3-ium trifluoromethanesulfonate [ka] 4-((1H-imidazol-1-yl)sulfonyl)thiomorpholine (100.00%, 2.260 g, 9.687 mmol) prepared in step 2 and methyl triflate (100.00%, 1.100 equivalents, 10.660 mmol) were dissolved in dichloromethane (50 mL) at room temperature, and the resulting solution was stirred overnight at the same temperature. The solvent was removed from the reaction mixture under reduced pressure, and then dichloromethane (20 mL) and methanol (10 mL) were added to the resulting concentrate, stirred, and the precipitated solid was filtered off, which was then washed with hexane and dried to obtain the title compound (1.500 g, 38.96%) in the form of a white solid.

[0151] [Step 4] Synthesis of N-phenylthiomorpholine-4-sulfonamide [ka] 3-Methyl-1-(thiomorpholinosulfonyl)-1H-imidazol-3-ium trifluoromethanesulfonate (100.00%, 1.500 g, 3.775 mmol) prepared in Step 3 and aniline (100.00%, 1.000 equivalents, 3.775 mmol) were dissolved in acetonitrile (30 mL) at 80 °C. The resulting solution was stirred overnight at the same temperature and then cooled to room temperature to complete the reaction. The solvent was removed from the reaction mixture under reduced pressure, and then a saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 40 g cartridge; hexane / ethyl acetate = 0-50%) and concentrated to give the title compound (0.800 g, 82.02%) as a white solid.

[0152] [Step 5] Synthesis of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-sulfonamide [ka] Following essentially the same reaction as described in Step 2 of Example 1, except that N-phenylthiomorpholine-4-sulfonamide prepared in Step 4 was used instead of N-phenylthiomorpholine-4-carboxamide, the title compound (0.204 g, 47.93%) was obtained in the form of a colorless oil.

[0153] [Step 6] Synthesis of compound 18 [ka] Following essentially the same reaction as described in Step 3 of Example 1, except that N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-sulfonamide prepared in Step 5 was used instead of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide, the title compound (0.150 g, 69.11%) was obtained in the form of a colorless oil. 1 H NMR(400MHz,CDCl3)δ 7.81(dd,J=8.0,1.5Hz,1H),7.73(dd,J=9.9,1.5Hz,1H),7.47(t,J=7.6Hz,1H),7.36-7.26(m,5H),7.04(s,0.25H) ),6.91(s,0.5H),6.78(s,0.25H),4.92(s,2H),3.76-3.60(m,4H),3.10-3.04(m,4H),2.60(brs,1H);LRMS(ES)m / z 516.9(M + +1)

[0154] Example 19: Synthesis of Compound 19, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-imino-N-phenylthiomorpholine-4-sulfonamide 1-oxide [Step 1] Synthesis of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-sulfonamide [ka] By following essentially the same reaction as described in Step 5 of Example 18, except that in Step 5 of Example 18, 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole was used instead of 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole, the title compound (0.300 g, 78.96%) was obtained in the form of a colorless oil.

[0155] [Step 2] Synthesis of Compound 19 [ka] Essentially the same reaction as described in Step 3 of Example 1 was followed, except that N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-sulfonamide prepared in Step 1 was used, to provide the title compound (0.250 g, 78.15%) in the form of a colorless oil. 1 H NMR(400MHz,CDCl3)δ 9.25-9.24(m,1H),8.36(dd,J=8.2,2.2Hz,1H),7.57(d,J=8.2Hz,1H),7.42-7.28(m,5H),7.08(s,0.25H),6. 95(s,0.5H),6.82(s,0.25H),5.06(s,2H),3.84-3.68(m,4H),3.11-3.03(m,4H),2.50(brs,1H);LRMS(ES)m / z 499.9(M + +1)

[0156] Examples 20-22: Synthesis of Compounds 20-22 Compounds 20 to 22 according to Examples 20 to 22 were prepared according to the same reactions as those described in Steps 1, 2, and 3 of Example 1, respectively, except that the reactants in Table 6 below were used instead of isocyanatobenzene in Step 1 of Example 1. Table 6 shows the properties and yields of the products prepared in Steps 1 to 3 of Examples 20 to 22, respectively.

[0157] [Table 16]

[0158] The names of compounds 20 to 22 prepared in Examples 20 to 22, respectively, and the results of their NMR and LC-Mass analysis are shown in Table 7 below.

[0159] [Table 17]

[0160] Example 23: Synthesis of Compound 23, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(4-(furan-2-yl)phenyl)-1-iminothiomorpholine-4-carboxamide 1-oxide [Step 1] Synthesis of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(4-(furan-2-yl)phenyl)thiomorpholine-4-carboxamide [ka] N-(4-bromophenyl)-N-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluoro-benzyl)thiomorpholine-4-carboxamide (100.00%, 0.200 g, 0.379 mmol), 2-furylboronic acid (100.00%, 0.051 g, 0.456 mmol), (1,1'-bis(di-tert-butylphosphino)ferrocene)dichloropalladium(II) (Pd(dtbpf)Cl, 100.00%, 0.012 g, 0.018 mmol), and cesium carbonate (100.00%, 0.247 g, 0.758 mmol) were dissolved in 1,4-dioxane (2 ml). After mixing in a 100°C (0.5 mL) / water mixture at room temperature, the resulting mixture was irradiated with microwaves and then heated at 100°C for 30 minutes. The reaction was then stopped by cooling to room temperature. The solvent was removed from the reaction mixture under reduced pressure. The resulting concentrate was poured into saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and then filtered through a plastic filter to remove the solid residue and aqueous layer. The concentrate was then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 0-20%) and concentrated to give the title compound (0.110 g, 56.38%) as a pale yellow solid.

[0161] [Step 2] Synthesis of Compound 23 [ka] N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(4-(furan-2-yl)phenyl)thiomorpholine-4-carboxamide (100.00%, 0.100 g, 0.194 mmol) prepared in step 1, iodobenzene diacetate (100.00%, 0.153 g, 0.475 mmol) and ammonium carbamate (100.00%, 0.030 g, 0.384 mmol) were dissolved in methanol (3 mL) at room temperature, and the resulting solution was stirred at the same temperature. The solvent was removed from the resulting mixture under reduced pressure, and the resulting concentrate was then purified by column chromatography (SiO, 4 g cartridge; ethyl acetate = 100%) and concentrated to give the title compound (0.038 g, 35.84%) in the form of a yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.89(dd,J=8.0,1.6Hz,1H),7.76(d,J=8.5Hz,1H),7.72-7.65(m,3H),7.49(d,J=1.2Hz,1H),7.15(d,J=8.7Hz,2H),6.92(t,J=51.7H) z,1H),6.67-6.66(m,1H),6.50-6.49(m,1H),4.97(s,2H),3.82-3.77(m,2H),3.72-3.67(m,2H),2.88(t,J=5.2Hz,4H);LRMS(ES)m / z 546.8(M + +1).

[0162] Examples 24 to 28: Synthesis of Compounds 24 to 28 Compounds 24 to 28 according to Examples 24 to 28 were prepared according to the same reactions as those described in Steps 1, 2, and 3 of Example 1, respectively, except that the reactants in Table 8 below were used instead of isocyanatobenzene in Step 1 of Example 1. Table 8 shows the properties and yields of the products prepared in Steps 1 to 3 of Examples 24 to 28, respectively.

[0163] [Table 18]

[0164] The names of compounds 24 to 28 prepared in Examples 24 to 28, respectively, and the results of their NMR and LC-Mass analysis are shown in Table 9 below.

[0165] [Table 19]

[0166] [Table 20]

[0167] Example 29: Synthesis of Compound 29, diethyl (4-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)(3,4-difluorophenyl)carbamoyl)-1-oxidethiomorpholin-1-ylidene)sulforamidate [ka] N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3,4-difluorophenyl)-1-iminothiomorpholine-4-carboxamide 1-oxide (100.00%, 0.080 g, 0.155 mmol), 1-ethoxyphosphoryloxyethane (100.00%, 1.000 equivalents, 0.155 mmol), iodine (100.00%, 0.100 equivalents, 0.016 mmol), and hydrogen peroxide (100.00%, 1.000 equivalents, 0.155 mmol), obtained by essentially the same reaction as described in Example 6, were dissolved in dichloromethane (10 mL) at room temperature, and the resulting solution was stirred overnight at the same temperature. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (0.040 g, 39.56%) as a colorless oil. 1H NMR(400MHz,CDCl3)δ 7.90(dd,J=8.0,1.6Hz,1H),7.78(dd,J=10.4,1.6Hz,1H),7.69-7.65(m,1H),7.21-7. 14(m,1H),7.06(s,0.25H),7.03-6.97(m,1H),6.93(s,0.5H),6.89-6.86(m,1H),6.80 (s,0.25H),4.90(s,2H),4.29-4.25(m,2H),4.06-4.02(m,4H),3.91-3.87(m,2H),3.6 0-3.54(m,2H),3.40-3.35(m,2H),3.05-3.00(m,2H),1.33-1.30(m,6H);LRMS(ES)m / z 652.9(M + +1)

[0168] Example 30: Synthesis of Compound 30, 1-(acetylimino)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(3,4-difluorophenyl)thiomorpholine-4-carboxamide 1-oxide [ka] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(3,4-difluorophenyl)-1-iminothiomorpholine-4-carboxamide 1-oxide (100.00%, 0.034 g, 0.068 mmol), acetyl chloride (100.00%, 2.000 equivalents, 0.136 mmol), and triethylamine (100.00%, 1.500 equivalents, 0.102 mmol), obtained by essentially the same reaction as described in Example 7, were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred overnight at the same temperature. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (0.015 g, 40.68%) in the form of a colorless oil. 1 H NMR(400MHz,CDCl3)δ 9.27(dd,J=2.0,0.4Hz,1H),8.43(dd,J=8.2,2.2Hz,1H),7.54(dd,J=8.4,0.4Hz,1H),7.22-7.05(m,2H),7.09(s,0.25H),7.00-6.94(m ,1H),6.96(s,0.5H),6.83(s,0.25H),5.08(s,2H),3.90-3.80(m,2H),3.60-3.50(m,4H),3.30-3.20(m,2H),2.09(s,3H);LRMS(ES)m / z 541.9(M + +1)

[0169] Examples 31 to 34: Synthesis of Compounds 31 to 34 Compounds 31 to 34 according to Examples 31 to 34 were prepared according to the same reactions as those described in Steps 1, 2, and 3 of Example 1, respectively, except that the reactants in Table 10 below were used instead of isocyanatobenzene in Step 1 of Example 1. Table 10 shows the properties and yields of the products prepared in Steps 1 to 3 of Examples 31 to 34, respectively.

[0170] [Table 21]

[0171] The names of compounds 31 to 34 prepared in Examples 31 to 34, respectively, and the results of their NMR and LC-Mass analysis are shown in Table 11 below.

[0172] [Table 22]

[0173] [Table 23]

[0174] Example 35: Synthesis of Compound 35, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3-fluorophenyl)-1-iminothiomorpholine-4-sulfonamide 1-oxide [Step 1] Synthesis of N-(3-fluorophenyl)thiomorpholine-4-sulfonamide [ka] 3-Methyl-1-(thiomorpholinosulfonyl)-1H-imidazol-3-ium trifluoromethanesulfonate (100.00%, 0.580 g, 1.459 mmol) prepared in Step 3 of Example 18 and 3-fluoroaniline (100.00% solution, 0.14 mL, 1.462 mmol) were dissolved in acetonitrile (10 mL) at room temperature. The resulting solution was heated to reflux for 18 hours and then cooled to room temperature to terminate the reaction. The solvent was removed from the reaction mixture under reduced pressure. The resulting concentrate was poured into saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and then filtered through a plastic filter to remove the solid residue and aqueous layer. The concentrate was then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 5-20%) and concentrated to give the title compound (0.253 g, 62.72%) as a pale yellow solid.

[0175] [Step 2] Synthesis of N-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorobenzyl]-N-(3-fluorophenyl)thiomorpholine-4-sulfonamide [ka] Substantially the same reaction as described in Step 2 of Example 1 was followed, except that N-(3-fluorophenyl)thiomorpholine-4-sulfonamide prepared in Step 1 was used, to give the title compound (0.153 g, 70.13%) in the form of a white solid.

[0176] [Step 3] Synthesis of Compound 35 [ka] By following essentially the same reaction as described in Step 3 of Example 1, except that N-[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorobenzyl]-N-(3-fluorophenyl)thiomorpholine-4-sulfonamide prepared in Step 2 was used, the title compound (0.151 g, 92.96%) was obtained in the form of a white solid. 1 H NMR(400MHz,CDCl3)δ 7.86(dd,J=8.0,1.5Hz,1H),7.79(dd,J=9.9,1.5Hz,1H),7.49(t,J=7.6Hz,1H),7.37-7.31(m,1H),7 .09-6.80(m,4H),.94(s,2H),3.82-3.76(m,2H),3.73-3.67(m,2H),3.19-3.09(m,4H);LRMS(ES)m / z 534.7(M + +1).

[0177] Example 36: Synthesis of Compound 36, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(3-fluorophenyl)-1-iminothiomorpholine-4-sulfonamide 1-oxide [Step 1] Synthesis of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]-N-(3-fluorophenyl)thiomorpholine-4-sulfonamide [ka] By following essentially the same reaction as described in Step 2 of Example 35, except that 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole was used instead of 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole, the title compound (0.208 g, 98.68%) was obtained in the form of a colorless oil.

[0178] [Step 2] Synthesis of compound 36 [ka] The title compound (0.105 g, 47.5%) was obtained in the form of a white solid by a reaction similar to that described in Step 3 of Example 1, except that N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]-N-(3-fluorophenyl)thiomorpholine-4-sulfonamide obtained in Step 1 was used. 1 H NMR(400MHz,CDCl3)δ 9.29(d,J=1.6Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.55(d,J=8.0Hz,1H),7.38-7.32(m,1H),7.23 -7.20(m,2H),7.08-6.83(m,2H),5.06(s,2H),3.86-3.82(m,2H),3.78-3.74(m,2H);LRMS(ES)m / z 517.7(M + +1).

[0179] Example 37: Synthesis of Compound 37, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-((methylsulfonyl)imino)-N-phenylthiomorpholine-4-carboxamide 1-oxide [ka] N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-imino-N-phenylthiomorpholine-4-carboxamide 1-oxide (100.00%, 0.200 g, 0.417 mmol), methanesulfonyl chloride (100.00%, 1.500 equivalents, 0.626 mmol), and triethylamine (100.00%, 2.000 equivalents, 0.834 mmol), obtained by essentially the same reaction as described in Example 1, were dissolved in dichloromethane (10 mL) at room temperature, and the resulting solution was stirred overnight at the same temperature. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (0.180 g, 77.39%) in the form of a colorless oil. 1 H NMR(400MHz,CDCl3)δ 7.87(dd,J=8.0,1.6Hz,1H),7.75(dd,J=10.0,1.6Hz,1H),7.65(t,J=7.6Hz,1H),7.38(t,J=7.8Hz,2H),7.28-7.24(m,1H),7.13-7.11(m,2H),7 .05(s,0.25H),6.92(s,0.5H),6.79(s,0.25H),4.94(s,2H),4.00-3.96 (m,2H),3.57-3.44(m,4H),3.08(s,3H),3.06-3.01(m,2H);LRMS(ES)m / z 558.9(M + +1)

[0180] Example 38: Synthesis of Compound 38, methyl (4-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)(phenyl)carbamoyl)-1-oxidethiomorpholin-1-ylidene)carbamate [ka] N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-imino-N-phenylthiomorpholine-4-carboxamide 1-oxide (100.00%, 0.200 g, 0.417 mmol), methyl carbonochloridate (100.00%, 1.500 equivalents, 0.626 mmol), and triethylamine (100.00%, 2.000 equivalents, 0.834 mmol), obtained by essentially the same reaction as described in Example 1, were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred overnight at the same temperature. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (0.150 g, 66.91%) in the form of a colorless oil. 1 H NMR(400MHz,CDCl3)δ 7.88(dd,J=8.0,1.6Hz,1H),7.76(dd,J=10.0,1.6Hz,1H),7.67(t,J=7.6Hz ,1H),7.40-7.36(m,2H),7.26-7.23(m,1H),7.14-7.12(m,2H),7.05(s,0.25 H),6.92(s,0.5H),6.79(s,0.25H),4.94(s,2H),3.93-3.92(m,2H),3.58(s ,3H),3.56-3.52(m,2H),3.43-3.38(m,2H),3.05-2.99(m,2H);LRMS(ES)m / z 538.9(M + +1)

[0181] Example 39: Synthesis of Compound 39, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-(methylimino)-N-phenylthiomorpholine-4-carboxamide 1-oxide [ka] N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-imino-N-phenylthiomorpholine-4-carboxamide 1-oxide (100.00%, 0.200 g, 0.417 mmol), sodium carbonate (100.00%, 5.000 equivalents, 2.086 mmol), and trimethyloxonium tetrafluoroborate (100.00%, 1.000 equivalents, 0.417 mmol), obtained by essentially the same reaction as described in Example 1, were dissolved in dichloromethane (5 mL) at room temperature, and the resulting solution was stirred overnight at the same temperature. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (0.015 g, 7.29%) in the form of a colorless oil. 1 H NMR(400MHz,CDCl3)δ 7.88(dd,J=8.0,1.2Hz,1H),7.75(dd,J=10.0,1.6Hz,1H),7.68(t,J=7.6Hz,1H),7.39-7.35(m,2H),7.24-7.20(m,1H),7.14-7.12(m,2H),7.0 5(s,0.25H),6.92(s,0.5H),6.79(s,0.25H),4.94(s,2H),3.82-3.76( m,2H),3.58-3.51(m,2H),2.87-2.78(m,4H),2.74(s,3H);LRMS(ES)m / z 494.9(M + +1)

[0182] Example 40: Synthesis of Compound 40, 1-(acetylimino)-N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide 1-oxide [ka] Substantially the same reaction as described in Example 30 was followed, except that N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-imino-N-phenylthiomorpholine-4-carboxamide 1-oxide obtained in substantially the same manner as in Example 1 was used instead of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(3,4-difluorophenyl)-1-iminothiomorpholine-4-carboxamide 1-oxide, to give the title compound (0.020 g, 36.78%) in the form of a colorless oil. 1 H NMR(400MHz,CDCl3)δ 7.88(dd,J=8.0,1.6Hz,1H),7.76(dd,J=10.0,1.6Hz,1H),7.68(t,J=7.6Hz ,1H),7.41-7.37(m,2H),7.27-7.23(m,1H),7.15-7.12(m,2H),7.05(s,0.25 H),6.92(s,0.5H),6.79(s,0.25H),4.95(s,2H),3.88-3.81(m,2H),3.60-3 .55(m,2H),3.49-3.39(m,2H),3.01-2.97(m,2H),2.05(s,3H);LRMS(ES)m / z 522.9(M + +1)

[0183] Examples 41 and 42: Synthesis of Compounds 41 and 42 Compounds 41 and 42 according to Examples 41 and 42 were prepared according to the same reactions as those described in Steps 1, 2, and 3 of Example 1, respectively, except that the reactants in Table 12 below were used instead of isocyanatobenzene in Step 1 of Example 1. Table 12 shows the properties and yields of the products prepared in Steps 1 to 3 of Examples 41 and 42, respectively.

[0184] [Table 24]

[0185] The names of compounds 41 and 42 prepared in Examples 41 and 42, respectively, and their NMR and LC-Mass analysis results are shown in Table 13 below.

[0186] [Table 25]

[0187] Example 43: Synthesis of Compound 43, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-imino-N-(3-(thiazol-5-yl)phenyl)thiomorpholine-4-carboxamide 1-oxide [Step 1] Synthesis of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3-(thiazol-5-yl)phenyl)thiomorpholine-4-carboxamide [ka] N-(3-bromophenyl)-N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)thiomorpholine-4-carboxamide (100.00%, 0.200 g, 0.379 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (100.00%, 1.500 equiv., 0.569 mmol), (1,1'- Bis(di-tert-butylphosphino)ferrocene)palladium(II) dichloride (100.00%, 0.100 equiv., 0.038 mmol) and cesium carbonate (100.00%, 2.500 equiv., 0.948 mmol) were mixed in 1,4-dioxane (10 mL) and water (3 mL). The resulting mixture was irradiated with microwaves and then heated at 100°C for 30 minutes. The reaction was then cooled to room temperature to complete the reaction. The solvent was removed from the reaction mixture under reduced pressure, and then a saturated aqueous solution of sodium bicarbonate was poured into the concentrate, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0-30%) and concentrated to give the title compound (0.013 g, 6.45%) in the form of a colorless oil.

[0188] [Step 2] Synthesis of compound 43 [ka] Following essentially the same reaction as described in Step 3 of Example 1, except that N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide prepared in Step 1 was used instead of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3-(thiazol-5-yl)phenyl)thiomorpholine-4-carboxamide, the title compound (0.004 g, 29.07%) was obtained in the form of a colorless oil. 1H NMR(400MHz,CDCl3)δ 8.81(s,1H),8.07(s,1H),7.91(dd,J=8.0,1.6Hz,1H),7.79(dd,J=10.2,1.4Hz,1H),7.72(t,J=7.8Hz,1H),7.43-7.39(m,2H),7.35(s,1H),7.1 1-7.09(m,1H),7.05(s,0.25H),6.93(s,0.5H),6.80(s,0.25H),5.00(s ,2H),3.83-3.50(m,4H),2.91-2.88(m,4H),2.50(brs,1H);LRMS(ES)m / z 563.9(M + +1)

[0189] Example 44: Synthesis of Compound 44, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3-(furan-2-yl)phenyl)-1-iminothiomorpholine-4-carboxamide 1-oxide [Step 1] Synthesis of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3-(furan-2-yl)phenyl)thiomorpholine-4-carboxamide [ka] Following essentially the same reaction as described in Step 1 of Example 43, except that 2-furylboronic acid was used instead of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole, the title compound (0.030 g, 15.38%) was obtained in the form of a colorless oil.

[0190] [Step 2] Synthesis of compound 44 [ka] By following essentially the same reaction as described in Step 2 of Example 43, except that N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3-(furan-2-yl)phenyl)thiomorpholine-4-carboxamide obtained in Step 1 was used, the title compound (0.010 g, 36.28%) was obtained in the form of a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.89(dd,J=8.0,1.6Hz,1H),7.78(dd,J=10.0,1.6Hz,1H),7.70(t,J=7.6Hz, 1H),7.51-7.48(m,3H),7.37(t,J=7.8Hz,1H),7.05(s,0.25H),7.01-6.99(m, 1H),6.92(s,0.5H),6.79(s,0.25H),6.68-6.67(m,1H),6.51-6.50(m,1H),4. 98(s,2H),3.85-3.66(m,4H),2.90-2.86(m,4H),2.55(brs,1H);LRMS(ES)m / z 546.9(M + +1)

[0191] Example 45: Synthesis of Compound 45, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(2,5-difluorophenyl)-1-iminothiomorpholine-4-carboxamide 1-oxide [Step 1] Synthesis of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]-N-(2,5-difluorophenyl)thiomorpholine-4-carboxamide [ka] Substantially the same reaction as described in Step 1 of Example 7 was followed, except that in Step 1 of Example 7, N-(2,5-difluorophenyl)thiomorpholine-4-carboxamide was used instead of N-(3,4-difluorophenyl)thiomorpholine-4-carboxamide, to give the title compound (0.074 g, 40.89%) in the form of a white solid.

[0192] [Step 2] Synthesis of compound 45 [ka] By following essentially the same reaction as described in step 2 of example 7, except that N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl]methyl]-N-(2,5-difluorophenyl)thiomorpholine-4-carboxamide obtained in step 1 was used, the title compound (0.047 g, 59.56%) was obtained in the form of a white solid. 1 H NMR(400MHz,CDCl3)δ 9.24(d,J=1.6Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.61(d,J=8.2Hz,1H),7.16-6.83(m, 4H),5.02(s,2H),3.82-3.76(m,2H),3.71-3.65(m,2H),2.97-2.93(m,4H);LRMS(ES)m / z 499.9(M + +1).

[0193] Example 46: Synthesis of Compound 46, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)-N-(2,5-difluorophenyl)-1-iminothiomorpholine-4-carboxamide 1-oxide [Step 1] Synthesis of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]-N-(2,5-difluorophenyl)thiomorpholine-4-carboxamide [ka] The same reaction as described in step 1 of Example 45 was carried out, except that in step 1 of Example 45, 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole was used instead of 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole, to obtain the title compound (0.057 g, 30.33%) in the form of a white solid.

[0194] [Step 2] Synthesis of compound 46 [ka] By following essentially the same reaction as described in Step 2 of Example 7, except that N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]-N-(2,5-difluorophenyl)thiomorpholine-4-carboxamide obtained in Step 1 was used, the title compound (0.048 g, 79.16%) was obtained in the form of a pale yellow solid. 1 H NMR(400MHz,CDCl3)δ 9.10(s,1H),8.12(dd,J=9.3,1.7Hz,1H),7.17-6.84(m,4H),5.09(s,2H),3.82-3 .76(m,2H),3.70-3.64(m,2H),3.11-3.00(m,4H),3.11-3.00(m,4H);LRMS(ES)m / z 517.8(M + +1).

[0195] Example 47: Synthesis of Compound 47, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-1-imino-N-(3-(pyridin-3-yl)phenyl)thiomorpholine-4-carboxamide 1-oxide [Step 1] Synthesis of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3-(pyridin-3-yl)phenyl)thiomorpholine-4-carboxamide [ka] Following essentially the same reaction as described in Step 1 of Example 44, except using 3-pyridylboronic acid instead of 2-furylboronic acid, the title compound (0.113 g, 28.35%) was obtained in the form of a colorless oil.

[0196] [Step 2] Synthesis of compound 47 [ka] Following essentially the same reaction as described in Step 2 of Example 44, except that N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3-(pyridin-3-yl)phenyl)thiomorpholine-4-carboxamide prepared from Step 1 was used, yielding the title compound (0.080 g, 66.84%) in the form of a colorless oil. 1 H NMR(400MHz,CDCl3)δ 8.78(d,J=1.6Hz,1H),8.63(dd,J=4.8,1.6Hz,1H),7.89(dd,J=8.0,1.6Hz,1H),7.82-7.70(m,3H),7.49-7.36(m,4H),7.16-7.13(m, 1H),7.05(s,0.25H),6.92(s,0.5H),6.79(s,0.25H),5.01(s,2H),3.83-3.64(m,4H),2.92-2.85(m,4H),2.50(brs,1H);LRMS(ES)m / z 557.9(M + +1)

[0197] Example 48 Synthesis of Compound 48, (1S,4S)—N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(2-fluorophenyl)-5-(1-imino-1-oxidetetrahydro-2H-thiopyran-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide [Step 1] Synthesis of (1S,4S)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-pyridyl)methyl)-N-(2-fluorophenyl)-5-(tetrahydro-2H-thiopyran-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide [ka] (1S,4S)—N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(2-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (100.00%, 0.300 g, 0.675 mmol), tetrahydrothiopyran-4-one (100.00%, 1.000 equivalents, 0.675 mmol), and sodium triacetoxyborohydride (100.00%, 2.000 equivalents, 1.350 mmol) were dissolved in dichloromethane (10 mL) at room temperature, and the resulting solution was stirred overnight at the same temperature. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (0.284 g, 77.25%) as a colorless oil.

[0198] [Step 2] Synthesis of compound 48 [ka] The title compound (0.200 g, 66.63%) was obtained in the form of a colorless oil by substantially the same reaction as described in step 3 of example 1, except that (1S,4S)—N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-pyridyl)methyl)-N-(2-fluorophenyl)-5-(tetrahydro-2H-thiopyran-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide prepared in step 1 was used instead of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide. 1 H NMR(400MHz,CDCl3)δ 9.16(d,J=1.6Hz,1H),8.35(dd,J=8.2,2.2Hz,1H),7.73(d,J=8.0Hz,1H),7.26-7.17(m,2H),7.1 1-7.07(m,2H),7.07(s,0.25H),6.94(s,0.5H),6.81(s,0.25H),5.09-4.95(m,2H),4.34(s,1H), 3.40(s,1H),3.37-3.27(m,2H),3.05-2.90(m,2H),2.88-2.82(m,2H),2.65-2.64(m,1H),2.58-2 .52(m,2H),2.50(brs,1H),2.22-2.12(m,2H),2.06-1.85(m,2H),1.78-1.60(m,2H);LRMS(ES)m / z 576.9(M + +1)

[0199] Examples 49-51: Synthesis of Compounds 49-51 Compounds 49 to 51 according to Examples 49 to 51 were prepared according to the same reactions as those described in Steps 1, 2, and 3 of Example 1, respectively, except that 2,4-dichloro-1-isocyanato-benzene was used instead of isocyanatobenzene in Step 1 of Example 1, and the reactants in Table 14 below were used instead of 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole in Step 2. Table 14 shows the properties and yields of the products prepared in Steps 1 to 3 of Examples 49 to 51, respectively.

[0200] [Table 26]

[0201] The names of compounds 49 to 51 prepared in Examples 49 to 51, respectively, and the results of their NMR and LC-Mass analysis are shown in Table 15 below.

[0202] [Table 27]

[0203] Example 52: Synthesis of Compound 52, 1-(acetylimino)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1-oxide [ka] The title compound (0.100 g, 57.30%) was obtained in the form of a colorless oil by substantially the same reaction as described in Example 30, except that N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3,4-difluorophenyl)-1-iminothiomorpholine-4-carboxamide 1-oxide obtained by substantially the same reaction as described in Example 3 was used instead of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3,4-difluorophenyl)-1-iminothiomorpholine-4-carboxamide 1-oxide. 1H NMR(400MHz,CDCl3)δ 9.26(d,J=1.6Hz,1H),8.41(dd,J=8.2,2.2Hz,1H),7.55(d,J=8.0Hz,1H),7.40-7.36(m,2H),7.23-7.19(m,3H),7.08(s,0.25H), 6.95(s,0.5H),6.82(s,0.25H),5.12(s,2H),3.87-3.83(m,2H),3.60-3.55(m,4H),3.23-3.17(m,2H),2.10(s,3H);LRMS(ES)m / z 505.9(M + +1)

[0204] Example 53: Synthesis of Compound 53, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-1-((methylsulfonyl)imino)-N-phenylthiomorpholine-4-carboxamide 1-oxide [ka] The title compound (0.110 g, 47.05%) was obtained in the form of a colorless oil by substantially the same reaction as described in Example 37, except that N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3,4-difluorophenyl)-1-iminothiomorpholine-4-carboxamide 1-oxide obtained by substantially the same reaction as described in Example 3 was used instead of N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(3,4-difluorophenyl)-1-iminothiomorpholine-4-carboxamide 1-oxide. 1H NMR(400MHz,CDCl3)δ 9.26(d,J=1.6Hz,1H),8.41(dd,J=8.2,2.2Hz,1H),7.54(d,J=8.2Hz,1H),7.39-7.35(m,2H),7.23-7.17(m,2H),7.08(s,0.25H), 6.96(s,0.5H),6.83(s,0.25H),5.13(s,2H),4.04-3.98(m,2H),3.62-3.51(m,4H),3.33-3.28(m,2H),3.11(s,3H);LRMS(ES)m / z 541.9(M + +1)

[0205] Examples 54 to 57: Synthesis of Compounds 54 to 57 Compounds 54 to 57 according to Examples 54 to 57 were prepared according to the same reactions as those described in Steps 1, 2, and 3 of Example 1, respectively, except that 1-fluoro-2-isocyanatobenzene was used instead of isocyanatobenzene in Step 1 of Example 1, and the reactants in Table 16 below were used instead of 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole in Step 2. Table 16 shows the properties and yields of the products prepared in Steps 1 to 3 of Examples 54 to 57, respectively.

[0206] [Table 28]

[0207] The names of compounds 54 to 57 prepared in Examples 54 to 57, respectively, and the results of their NMR and LC-Mass analysis are shown in Table 17 below.

[0208] [Table 29]

[0209] [Table 30]

[0210] Example 58: Synthesis of Compound 58, N-(4-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-3-phenylureido)-1-oxidetetrahydro-2H-thiopyran-1-ylidene)-2,2,2-trifluoroacetamide

[0211] Example 59: Synthesis of Compound 59, 1-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-3-(1-imino-1-oxidetetrahydro-2H-thiopyran-4-yl)-1-phenylurea [Step 1] Synthesis of (4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)(phenyl)carbamic acid chloride [ka] N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)aniline (1.380 g, 4.322 mmol) and N,N-diisopropylethylamine (0.753 mL, 4.322 mmol) were dissolved in dichloromethane (20 mL). Then, triphosgene (0.898 g, 3.025 mmol) was added to the resulting solution at 0 °C. The mixture was stirred at the same temperature for 30 minutes and then at room temperature for 18 hours. Water was poured into the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0 to 30%) and concentrated to give the title compound (0.880 g, 53.3%) in the form of a white solid.

[0212] [Step 2] Synthesis of compounds 58 and 59 [ka] N-(4-amino-1-oxidetetrahydro-2H-thiopyran-1-ylidene)-2,2,2-trifluoroacetamide 2,2,2-trifluoroacetate (0.500 g, 1.396 mmol) was dissolved in N,N-dimethylformamide (10 mL) at 0 °C, and then sodium hydride (60.00%, 0.140 g, 3.489 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. (4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)(phenyl)carbamic acid chloride (0.586 g, 1.535 mmol) prepared in Step 1 was added to the reaction mixture, and the mixture was further stirred at room temperature for 3 hours. Water 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 (SiO, 12 g cartridge; ethyl acetate / hexane = 0 to 100%) and concentrated to give compound 58 (0.110 g, 13.4%) and compound 59 (0.160 g, 23.2%), respectively, in the form of a white solid. <Compound 58> 1 H NMR (400 MHz, CDCl3) δ 7.86(dd,J=8.0,1.2Hz,1H),7.72(dd,J=9.8,1.4Hz,1H),7.58(t,J=7.6Hz,1H ),7.43-7.34(m,3H),7.13-7.12(m,2H),7.05(s,0.25H),6.92(s,0.5H),6.79 (s,0.25H),5.02(s,2H),4.39(d,J=7.2Hz,1H),4.11-4.02(m,1H),3.89-3.85 (m,2H),3.35-3.28(m,2H),2.38-2.33(m,2H),1.92-1.83(m,2H);LRMS(ES)m / z 590.9(M + +1) <Compound 59> 1H NMR(400MHz,CDCl3)δ 7.84(d,J=7.6Hz,1H),7.68(d,J=9.6Hz,1H),7.58(t,J=7.6Hz,1H),7.39- 7.30(m,3H),7.11-7.08(m,2H),7.04(s,0.25H),6.90(s,0.5H),6.78(s,0 .25H),4.97(s,2H),4.34(d,J=7.6Hz,1H),3.90-3.93(m,1H),3.18-3.00( m,4H),2.80(brs,1H),2.18-2.14(m,2H),1.93-1.87(m,2H);LRMS(ES)m / z 494.9(M + +1)

[0213] Example 60: Synthesis of Compound 60, 3-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)(phenyl)amino)-4-(1-imino-1-oxidethiomorpholino)cyclobut-3-ene-1,2-dione [Step 1] Synthesis of 3-(phenylamino)-4-thiomorpholinocyclobut-3-ene-1,2-dione [ka] 3-Methoxy-4-(phenylamino)cyclobut-3-ene-1,2-dione (100.00%, 2.000 g, 9.843 mmol), thiomorpholine (100.00%, 1.200 equivalents, 11.812 mmol), and N,N-diisopropylethylamine (100.00%, 3.000 equivalents, 29.529 mmol) were dissolved in methanol (30 mL) at room temperature, and the resulting solution was stirred at the same temperature for 3 days. The precipitated solid was filtered, washed with hexane, and dried to give the title compound (2.000 g, 74.08%) in the form of a white solid.

[0214] [Step 2] Synthesis of 3-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)(phenyl)amino)-4-thiomorpholinocyclobut-3-ene-1,2-dione [ka] 3-(Phenylamino)-4-thiomorpholinocyclobut-3-ene-1,2-dione (100.00%, 0.300 g, 1.094 mmol) prepared in Step 1 was dissolved in N,N-dimethylformamide (10 mL) at 0 °C. Sodium hydride (100.00%, 1.500 equivalents, 1.641 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. 2-(4-(Bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.000 equivalents, 1.094 mmol) was added to the reaction mixture and stirred at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 12 g cartridge; hexane / ethyl acetate=0-50%) and concentrated to give the title compound (0.300 g, 54.81%) in the form of a white solid.

[0215] [Step 3] Synthesis of Compound 60 [ka] 3-((4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)(phenyl)amino)-4-thiomorpholinocyclobut-3-ene-1,2-dione (100.00%, 0.150 g, 0.300 mmol) prepared in step 2, iodobenzene diacetate (100.00%, 2.500 equivalents, 0.749 mmol) and ammonium carbamate (100.00%, 2.000 equivalents, 0.599 mmol) were dissolved in methanol (10 mL) at room temperature, and the resulting solution was stirred overnight at the same temperature. The precipitated solid was filtered, washed with hexane and dried to give the title compound (0.080 g, 50.22%) in the form of a white solid. 1H NMR(400MHz,CDCl3)δ 7.86-7.81(m,2H),7.67-7.63(m,1H),7.66(s,0.25H),7.53(s,0.5H),7.42-7.38(m,2H),7.40(s,0.2 5H),7.25-7.18(m,3H),5.57(s,2H),3.80(s,1H),3.56-3.36(m,4H),3.02-2.93(m,4H);LRMS(ES)m / z 532.9(M + +1)

[0216] Example 61: Synthesis of Compound 61, 3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)(phenyl)amino)-4-(1-imino-1-oxidethiomorpholino)cyclobut-3-ene-1,2-dione [Step 1] Synthesis of 3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)(phenyl)amino)-4-thiomorpholinocyclobut-3-ene-1,2-dione [ka] By following essentially the same reaction as described in Step 2 of Example 60, except that 2-(6-(bromomethyl)-5-fluoro-3-pyridyl)-5-(difluoromethyl)-1,3,4-oxadiazole was used instead of 2-(4-(bromomethyl)-3-fluorophenyl)-5-(difluoromethyl)-1,3,4-oxadiazole, the title compound (0.128 g, 35.01%) was obtained in the form of a colorless oil.

[0217] [Step 2] Synthesis of Compound 61 [ka] Following essentially the same reaction as described in Step 3 of Example 60, except that 3-(((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-3-fluoropyridin-2-yl)methyl)(phenyl)amino)-4-thiomorpholinocyclobut-3-ene-1,2-dione was used, the title compound (0.05 g, 51.09%) was obtained in the form of a colorless oil. 1 H NMR(400MHz,CDCl3)δ 8.99(s,1H),8.40(dd,J=10.0,1.6Hz,1H),7.70(s,0.25H),7.57(s,0.5H),7.45(s,0.25H),7.40(t,J=8. 0Hz,2H),7.19-7.17(m,3H),5.68(s,2H),3.66(s,1H),3.60-3.40(m,4H),3.05-2.97(m,4H);LRMS(ES)m / z 533.9(M + +1)

[0218] Example 62: Synthesis of Compound 62, N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(4-fluorophenyl)-1-imino-1-oxo-1,4-thiazinane-4-carboxamide [Step 1] Synthesis of N-(4-fluorophenyl)thiomorpholine-4-carboxamide [ka] 1-Fluoro-4-isocyanatobenzene (100.00%, 0.500 g, 3.647 mmol) and thiomorpholine (100.00%, 0.376 g, 3.644 mmol) were dissolved in diethyl ether (20 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The precipitated solid was filtered, washed with diethyl ether, and dried to give the title compound (0.667 g, 76.12%) in the form of a white solid.

[0219] [Step 2] Synthesis of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(4-fluorophenyl)thiomorpholine-4-carboxamide [ka] N-(4-Fluorophenyl)thiomorpholine-4-carboxamide (100.00%, 0.100 g, 0.416 mmol) and sodium hydride (60.00%, 0.018 g, 0.450 mmol) were dissolved in N,N-dimethylformamide (2 mL) at 0 °C. 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.121 g, 0.417 mmol) was added to the resulting solution and stirred at room temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into water, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane=5-40%) and concentrated to give the title compound (0.040 g, 21.39%) in the form of a pale yellow oil.

[0220] [Step 3] Synthesis of Compound 62 [ka] N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(4-fluorophenyl)thiomorpholine-4-carboxamide (100.00%, 0.040 g, 0.089 mmol), iodobenzene diacetate (100.00%, 0.072 g, 0.224 mmol), and ammonium carbamate (100.00%, 0.014 g, 0.179 mmol) were dissolved in methanol (3 mL) at room temperature, and the resulting solution was stirred at 50°C for 18 hours. The temperature was then lowered to room temperature to complete the reaction. The solvent was removed from the resulting mixture under reduced pressure, and the resulting concentrate was then purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0-5%) and concentrated to give the title compound (0.010 g, 23.38%) in the form of a pale yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.89(d,J=8.0Hz,1H),7.77(d,J=8.6Hz,1H),7.68(t,J=7.7Hz,1H),7.49(d,J=8.7Hz,2H),7.06- 6.80(m,3H),5.32(s,2H),3.79-3.73(m,2H),3.69-3.63(m,2H),2.91-2.88(m,4H);LRMS(ES)m / z 481.8(M + +1).

[0221] Example 63: Synthesis of Compound 63, N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(4-fluorophenyl)-1-imino-1-oxo-1,4-thiazinane-4-carboxamide [Step 1] Synthesis of N-(4-fluorophenyl)thiomorpholine-4-carboxamide [ka] N-(4-fluorophenyl)thiomorpholine-4-carboxamide (100.00%, 0.100 g, 0.416 mmol) and sodium hydride (60.00%, 0.018 g, 0.450 mmol) were dissolved in N,N-dimethylformamide (2 mL) at 0 °C, and 2-[4-(bromomethyl)-3-fluorophenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.128 g, 0.417 mmol) was added to the resulting solution and stirred at room temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into water, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 5-40%) and concentrated to give the title compound (0.033 g, 17.00%) in the form of a white solid.

[0222] [Step 3] Synthesis of compound 63 [ka] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]-N-(4-fluorophenyl)thiomorpholine-4-carboxamide (100.00%, 0.033 g, 0.071 mmol), iodobenzene diacetate (100.00%, 0.057 g, 0.177 mmol), and ammonium carbamate (100.00%, 0.011 g, 0.141 mmol) were dissolved in methanol (3 mL) at room temperature, and the resulting solution was stirred at 50°C for 18 hours. The temperature was then lowered to room temperature to complete the reaction. The solvent was removed from the resulting mixture under reduced pressure, and the resulting concentrate was then purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0-5%) and concentrated to give the title compound (0.025 g, 71.02%) in the form of a pale yellow solid. 1H NMR(400MHz,CDCl3)δ 7.90(d,J=7.92Hz,1H),7.77(dd,J=10.1,1.3Hz,1H),7.13-6.80(m,5H),4.91 (s,2H),3.79-3.75(m,2H),3.67-3.63(m,2H),2.88-2.87(m,4H);LRMS(ES)m / z 498.8(M + +1)

[0223] Example 64: Synthesis of Compound 64, N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(4-fluorophenyl)-1-imino-2,6-dimethyl-1-oxo-1,4-thiazinane-4-carboxamide [Step 1] Synthesis of N-(4-fluorophenyl)-2,6-dimethyl-thiomorpholine-4-carboxamide [ka] 1-Fluoro-4-isocyanatobenzene (100.00% solution, 0.4098 mL, 3.647 mmol) and 2,6-dimethylthiomorpholine (100.00%, 0.376 g, 2.865 mmol) were dissolved in diethyl ether (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The resulting precipitated solid was filtered, washed with diethyl ether, and dried to give the title compound (0.568 g, 58.03%) in the form of a pale orange solid.

[0224] [Step 2] Synthesis of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(4-fluorophenyl)-2,6-dimethyl-thiomorpholine-4-carboxamide [ka] N-(4-Fluorophenyl)-2,6-dimethyl-thiomorpholine-4-carboxamide (100.00%, 0.100 g, 0.373 mmol) and sodium hydride (60.00%, 0.016 g, 0.400 mmol) were dissolved in N,N-dimethylformamide (2 mL) at 0 °C. 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.108 g, 0.372 mmol) was added to the resulting solution and stirred at room temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into water, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 5-40%) and concentrated to give the title compound (0.050 g, 28.10%) in the form of a pale yellow oil.

[0225] [Step 3] Synthesis of compound 64 [ka] N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(4-fluorophenyl)-2,6-dimethyl-thiomorpholine-4-carboxamide (100.00%, 0.050 g, 0.105 mmol), iodobenzene diacetate (100.00%, 0.084 g, 0.261 mmol), and ammonium carbamate (100.00%, 0.016 g, 0.205 mmol) were dissolved in methanol (3 mL) at room temperature, and the resulting solution was stirred at 50°C for 18 hours. The mixture was then cooled to room temperature to complete the reaction. The solvent was removed from the resulting mixture under reduced pressure, and the resulting concentrate was then purified by column chromatography (SiO, 4 g cartridge; ethyl acetate / hexane = 50-100%) and concentrated to give the title compound (0.033 g, 61.98%) in the form of a pale yellow solid. 1H NMR(400MHz,CDCl3)δ 9.25(d,J=1.8Hz,1H),8.36(dd,J=8.1,2.3Hz,1H),7.60(d,J=8.12Hz,1H),7.28 -7.21(m,2H),7.09-7.06(m,2H),7.05-6.83(m,1H),5.18-4.86(m,2H),3.97-3. 92(m,0.6H),3.79-3.74(m,0.6H),3.69(dd,J=14.2,2.8Hz,0.6H),3.52-3.47(m ,0.6H),3.31-3.25(m,0.6H),3.03-2.93(m,3H),1.25-1.21(m,6H);LRMS(ES)m / z 509.9(M + +1)

[0226] Example 65: Synthesis of Compound 65, N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(4-fluorophenyl)-1-imino-2,6-dimethyl-1-oxo-1,4-thiazinane-4-carboxamide [Step 1] Synthesis of N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(4-fluorophenyl)-2,6-dimethyl-thiomorpholine-4-carboxamide [ka] N-(4-Fluorophenyl)-2,6-dimethyl-thiomorpholine-4-carboxamide (100.00%, 0.100 g, 0.373 mmol) and sodium hydride (60.00%, 0.016 g, 0.400 mmol) were dissolved in N,N-dimethylformamide (2 mL) at 0 ° C., and then 2-[4-(bromomethyl)-3-fluoro-phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.114 g, 0.371 mmol) was added to the resulting solution and stirred at room temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into water, extracted with dichloromethane, filtered through a plastic filter to remove solid residues and the aqueous layer, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 5-40%) and concentrated to give the title compound (0.146 g, 79.24%) in the form of a colorless oil.

[0227] [Step 2] Synthesis of compound 65 [ka] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]-N-(4-fluorophenyl)-2,6-dimethyl-thiomorpholine-4-carboxamide (100.00%, 0.146 g, 0.295 mmol), iodobenzene diacetate (100.00%, 0.238 g, 0.739 mmol), and ammonium carbamate (100.00%, 0.046 g, 0.589 mmol) were dissolved in methanol (3 mL) at room temperature, and the resulting solution was stirred at 50°C for 18 hours. The mixture was then cooled to room temperature to complete the reaction. The solvent was removed from the resulting mixture under reduced pressure, and the resulting concentrate was then purified via column chromatography (SiO, 4 g cartridge; ethyl acetate / hexane = 50-100%) and concentrated to give the title compound (0.126 g, 81.21%) in the form of a white solid. 1H NMR(400MHz,CDCl3)δ 7.88(d,J=8.0Hz,1H),7.78-7.69(m,2H),7.13-7.06(m,4H),7.05-6.80( m,1H),5.00-4.73(m,2H),3.98(d,J=15.0Hz,0.6H),3.76(d,J=14.2Hz,0 .6H),3.68(d,J=14.0Hz,0.6H),3.31-3.26(m,0.6H),2.99-2.93(m,1H), 2.81-2.77(m,2H),2.14-2.04(m,0.6H),1.24-1.18(m,6H);LRMS(ES)m / z 526.9(M + +1)

[0228] Example 66: Synthesis of Compound 66, N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-1-imino-1-oxo-N-(3-pyridyl)-1,4-thiazinane-4-carboxamide [Step 1] Synthesis of benzyl N-[1-oxo-4-(3-pyridylcarbamoyl)-1,4-thiazinan-1-ylidene]carbamate [ka] Pyridin-3-amine (100.00%, 0.200 g, 2.125 mmol) and di(imidazol-1-yl)methanone (100.00%, 0.448 g, 2.763 mmol) were dissolved in tetrahydrofuran (5 mL). The resulting solution was stirred at room temperature for 1 h, and then benzyl N-(1-oxo-1,4-thiazinan-1-ylidene)carbamate (100.00%, 0.684 g, 2.549 mmol) was added thereto and stirred at the same temperature for another 18 h. The solvent was removed from the resulting mixture under reduced pressure, and the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 50-100%) and concentrated to give the title compound (0.112 g, 13.57%) as a pale yellow solid.

[0229] [Step 2] Synthesis of benzyl N-[4-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl-(3-pyridyl)carbamoyl]-1-oxo-1,4-thiazinan-1-ylidene]carbamate [ka] Benzyl N-[1-oxo-4-(3-pyridylcarbamoyl)-1,4-thiazinan-1-ylidene]carbamate (100.00%, 0.100 g, 0.258 mmol) and sodium hydride (60.00%, 0.011 g, 0.275 mmol) were dissolved in N,N-dimethylformamide (3 mL) at 0 ° C., and then 2-[4-(bromomethyl)-3-fluorophenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.079 g, 0.257 mmol) was added to the resulting solution and stirred at room temperature for 3 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into an aqueous N-dichloromethane solution, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 50-100%) and concentrated to give the title compound (0.030 g, 18.96%) in the form of a pale yellow oil.

[0230] [Step 3] Synthesis of compound 66 [ka] Benzyl N-[4-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl-(3-pyridyl)carbamoyl]-1-oxo-1,4-thiazinan-1-ylidene]carbamate (100.00%, 0.030 g, 0.049 mmol) was dissolved in methanol (5 mL) and stirred at room temperature. 10% Pd / C (5 mg) was slowly added at the same temperature, and the mixture was stirred for 3 hours under a hydrogen balloon at the same temperature. The reaction mixture was filtered through a Celite pad to remove solids. The solvent was then removed from the resulting filtrate under reduced pressure without solids, and the resulting product was used without further purification (0.022 g, 93.80%, pale yellow solid). 1 H NMR(400MHz,CDCl3)δ 78.50-8.47(m,1H),7.91(dd,J=8.0,1.6Hz,1H),7.79(dd,J=10.2,1.5Hz,1H),7.71(t,J=7.6Hz,1H),7.51-7.48(m,1H),7. 36-7.33(m,1H),7.06-6.80(m,1H),4.97(s,2H),3.77-3.72(m,2H),3.68-3.63(m,2H),2.90(t,J=5.2Hz,4H);LRMS(ES)m / z 481.7(M + +1)

[0231] Example 67: Synthesis of Compound 67, N-(4-(1-acetylpiperidin-4-yl)phenyl)-N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)thiomorpholine-4-carboxamide [Step 1] Synthesis of tert-butyl 4-[4-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl-(thiomorpholine-4-carbonyl)amino]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka] N-(4-bromophenyl)-N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]thiomorpholine-4-carboxamide (100.00%, 1.710 g, 3.242 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (100.00%, 1.200 g, 3.881

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088] [0089 ...90]

[0089]

[0090]

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[0090]

[0089]

[0090]

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[0089]

[0090]

[0089] [ The concentrate obtained was purified by column chromatography (SiO2, 40 g cartridge; ethyl acetate / hexane=10-40%) and concentrated to give the title compound (0.950 g, 46.53%) in the form of a brown solid.

[0232] [Step 2] Tert-butyl 4-[4-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl-(thiomorpholine-4-carbonyl)amino]phenyl]piperidine-1-carboxylate [ka] tert-Butyl 4-[4-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl-(thiomorpholine-4-carbonyl)amino]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (100.00%, 0.950 g, 1.509 mmol) was dissolved in methanol (50 mL) and stirred at room temperature. 10% Pd / C (100 mg) was slowly added to the resulting solution at the same temperature. A hydrogen balloon was attached and the mixture was stirred at 50°C for 18 hours. The temperature was then lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a Celite pad to remove solids, and the resulting filtrate was then stripped of the solvent under reduced pressure without solids. The concentrate obtained was then purified via column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 10-40%) and concentrated to give the title compound (0.341 g, 35.78%) in the form of a white solid.

[0233] [Step 3] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-[4-(4-piperidyl)phenyl]thiomorpholine-4-carboxamide [ka] Tert-butyl 4-[4-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl-(thiomorpholine-4-carbonyl)amino]phenyl]piperidine-1-carboxylate (100.00%, 0.341 g, 0.540 mmol) and trifluoroacetic acid (100.00% solution, 0.3 mL, 3.920 mmol) were dissolved in dichloromethane (3 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting product was used without further purification (0.287 g, 100.00%, pale orange solid).

[0234] [Step 4] N-[4-(1-acetyl-4-piperidyl)phenyl]-N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]thiomorpholine-4-carboxamide [ka] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]-N-[4-(4-piperidyl)phenyl]thiomorpholine-4-carboxamide (100.00%, 0.100 g, 0.188 mmol), acetyl chloride (100.00% solution, 0.02 mL, 0.281 mmol), and triethylamine (100.00% solution, 0.05 mL, 0.359 mmol) were dissolved in dichloromethane (3 mL) at 0 °C, and the resulting solution was stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 50-100%) and concentrated to give the title compound (0.092 g, 85.26%) in the form of a pale yellow oil.

[0235] [Step 5] Synthesis of compound 67 [ka] N-[4-(1-acetyl-4-piperidyl)phenyl]-N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]thiomorpholine-4-carboxamide (100.00%, 0.092 g, 0.160 mmol), iodobenzene diacetate (100.00%, 0.129 g, 0.401 mmol), and ammonium carbamate (100.00%, 0.025 g, 0.320 mmol) were dissolved in methanol (3 mL) at room temperature, and the resulting solution was stirred at 50°C for 6 hours. The temperature was then lowered to room temperature to complete the reaction. The solvent was removed from the resulting mixture under reduced pressure, and the resulting concentrate was then purified via column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0-5%) and concentrated to give the title compound (0.062 g, 63.94%) in the form of a white solid. 1 H NMR(400MHz,CDCl3)δ 7.85(d,J=7.88Hz,1H),7.73(d,J=10.0Hz,1H),7.65(t,J=7.6Hz,1H),7.17(d,J=8.16H z,2H),7.06-6.80(m,3H),4.90(s,2H),4.79-4.76(m,1H),3.95-3.92(m,1H),3.74-3.7 3(m,2H),3.62-3.61(m,2H),3.16(t,J=12.9Hz,1H),2.88-2.79(m,4H),2.75-2.69(m,1 LRMS(ES)m / z 605.9(M + +1)

[0236] Example 68: Synthesis of Compound 68, (1S,4S)—N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-2-imino-2-oxo-N-phenyl-2lambda 6-thia-5-azabicyclo[2.2.1]heptane-5-carboxamide [Step 1] Synthesis of (1S,4S)-N-phenyl-2-thia-5-azabicyclo[2.2.1]heptane-5-carboxamide [ka] Isocyanatobenzene (100.00%, 0.500 g, 4.197 mmol), (1S,4S)-2-thia-5-azabicyclo[2.2.1]heptane hydrochloride (100.00%, 1.000 equiv., 4.197 mmol), and N,N-diisopropylethylamine (100.00%, 2.000 equiv., 8.395 mmol) were dissolved in dichloromethane (20 mL) at room temperature, and the resulting solution was stirred overnight at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, dichloromethane (20 mL) and methanol (10 mL) were added to the concentrate, and the resulting mixture was stirred. The precipitated solid was filtered off, washed with hexane, and dried to give the title compound (0.700 g, 71.18%) as a white solid.

[0237] [Step 2] Synthesis of (1S,4S)-N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-phenyl-2-thia-5-azabicyclo[2.2.1]heptane-5-carboxamide [ka] (1S,4S)-N-phenyl-2-thia-5-azabicyclo[2.2.1]heptane-5-carboxamide (100.00%, 0.210 g, 0.896 mmol) prepared in Step 1 was dissolved in N,N-dimethylformamide (10 mL) at 0 °C. Sodium hydride (100.00%, 1.500 equivalents, 1.344 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. 2-[4-(bromomethyl)-3-fluorophenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.000 equivalents, 0.896 mmol) was added to the reaction mixture and stirred at room temperature for another 2 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (0.021 g, 5.09%) as a colorless oil.

[0238] [Step 3] Synthesis of compound 68 [ka] (1S,4S)—N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]-N-phenyl-2-thia-5-azabicyclo[2.2.1]heptane-5-carboxamide (100.00%, 0.076 g, 0.165 mmol), (diacetoxyiodo)benzene (100.00%, 2.500 equivalents, 0.413 mmol), and ammonium carbamate (100.00%, 2.000 equivalents, 0.330 mmol) were dissolved in methanol (10 mL) at room temperature. The resulting solution was stirred overnight at the same temperature. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (0.030 g, 36.98%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.91-7.88(m,1H),7.80-7.71(m,2H),7.35-7.31(m,2H),7.23-7.19(m,1H),7 .14-7.12(m,2H),7.05(s,0.25H),6.92(s,0.5H),6.79(s,0.25H),5.21-5.15( m,1H),4.87-4.81(m,1H),4.69(s,1H),3.68-3.65(m,1H),3.56-3.51(m,1H), 3.44(s,1H),2.69-2.63(m,1H),2.60-2.55(m,1H),2.25-2.20(m,1H),1.90(br s, 1H); LRMS (ES) m / z 492.9 (M + +1)

[0239] Example 69: Synthesis of Compound 69, N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(2,5-difluorophenyl)-1-imino-1-oxo-1,4-thiazinane-4-sulfonamide [Step 1] Synthesis of N-(2,5-difluorophenyl)thiomorpholine-4-sulfonamide [ka] 4-(3-Methylimidazol-3-ium-1-yl)sulfonylthiomorpholine; trifluoromethanesulfonate (100.00%, 1.000 g, 2.516 mmol) and 2,5-difluoroaniline (100.00%, 1.100 equiv., 2.768 mmol) were dissolved in acetonitrile (30 mL) at 80 °C. The resulting solution was stirred overnight at the same temperature and then cooled to room temperature to complete the reaction. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; hexane / ethyl acetate = 0-50%) and concentrated to give the title compound (0.500 g, 67.52%) as a white solid.

[0240] [Step 2] Synthesis of N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(2,5-difluorophenyl)thiomorpholine-4-sulfonamide [ka] N-(2,5-difluorophenyl)thiomorpholine-4-sulfonamide (100.00%, 0.080 g, 0.272 mmol) prepared in Step 1 was dissolved in N,N-dimethylformamide (10 mL) at 0 °C. Sodium hydride (100.00%, 1.500 equivalents, 0.408 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. 2-[4-(bromomethyl)-3-fluorophenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.100 equivalents, 0.299 mmol) was added to the reaction mixture and stirred at room temperature for another 2 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, which was then extracted 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 obtained concentrate was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (0.100 g, 70.68%) in the form of a colorless oil.

[0241] [Step 3] Synthesis of compound 69 [ka] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]-N-(2,5-difluorophenyl)thiomorpholine-4-sulfonamide (100.00%, 0.100 g, 0.192 mmol) prepared in Step 2, ammonium carbamate (100.00%, 2.000 equivalents, 0.384 mmol), and (diacetoxyiodo)benzene (100.00%, 2.500 equivalents, 0.480 mmol) were dissolved in methanol (10 mL) at room temperature, and the resulting solution was stirred overnight at the same temperature. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (0.050 g, 47.19%) in the form of a colorless oil. 1 H NMR(400MHz,CDCl3)δ 7.87(dd,J=8.0,1.6Hz,1H),7.78(dd,J=9.6,1.6Hz,1H),7.52(t,J=7.6Hz,1H),7.14-7.03(m,3H),7.02 (s,0.25H),7.69(s,0.5H),6.80(s,0.25H),4.90(s,2H),3.92-3.73(m,4H),3.22-3.10(m,4H),2.14(br s,1H);LRMS(ES)m / z 552.9(M + +1).

[0242] Example 70: Synthesis of Compound 70, N-(3-chlorophenyl)-N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-1-imino-1-oxo-1,4-thiazinane-4-sulfonamide [Step 1] Synthesis of N-(3-chlorophenyl)thiomorpholine-4-sulfonamide [ka] 4-(3-Methylimidazol-3-ium-1-yl)sulfonylthiomorpholine; trifluoromethanesulfonate (100.00%, 0.991 g, 2.494 mmol) and 3-chloroaniline (100.00%, 1.100 equiv., 2.743 mmol) were dissolved in acetonitrile (20 mL) at 80 °C. The resulting solution was stirred overnight at the same temperature and then cooled to room temperature to complete the reaction. The solvent was removed from the resulting mixture under reduced pressure, and the concentrate was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (0.560 g, 76.70%) as a white solid.

[0243] [Step 2] Synthesis of N-(3-chlorophenyl)-N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]thiomorpholine-4-sulfonamide [ka] N-(3-chlorophenyl)thiomorpholine-4-sulfonamide (100.00%, 0.260 g, 0.888 mmol) prepared in Step 1, 2-[4-(bromomethyl)-3-fluorophenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.100 equiv., 0.977 mmol), potassium carbonate (100.00%, 1.500 equiv., 1.332 mmol), and potassium iodide (100.00%, 0.100 equiv., 0.089 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature. The resulting solution was stirred overnight at the same temperature. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (0.260 g, 56.42%) in the form of a colorless oil.

[0244] [Step 3] Synthesis of Compound 70 [ka] N-(3-chlorophenyl)-N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]thiomorpholine-4-sulfonamide (100.00%, 0.260 g, 0.501 mmol), ammonium carbamate (100.00%, 2.000 equivalents, 1.002 mmol), and (diacetoxyiodo)benzene (100.00%, 2.500 equivalents, 1.252 mmol) were dissolved in methanol (10 mL) at room temperature, and the resulting solution was stirred overnight at the same temperature. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (0.200 g, 72.59%) in the form of a colorless oil. 1 H NMR(400MHz,CDCl3)δ 7.86(dd,J=8.0,1.2Hz,1H),7.78(dd,J=10.0,1.6Hz,1H),7.47(t,J=7.6Hz,1H),7.34-7.27(m,3H),7.18-7.15(m ,1H),7.06(s,0.25H),6.93(s,0.5H),6.80(s,0.25H),4.92(s,2H),3.82-3.66(m,4H),3.20-3.09(m,4H),2.10(br s,1H);LRMS(ES)m / z 550.9(M + +1).

[0245] Example 71: Synthesis of Compound 71, N-(3-chlorophenyl)-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-1-imino-1-oxo-1,4-thiazinane-4-sulfonamide [Step 1] Synthesis of N-(3-chlorophenyl)-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]thiomorpholine-4-sulfonamide [ka] N-(3-chlorophenyl)thiomorpholine-4-sulfonamide (100.00%, 0.240 g, 0.820 mmol), 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.100 equiv., 0.902 mmol), potassium carbonate (100.00%, 1.500 equiv., 1.230 mmol), and potassium iodide (100.00%, 0.100 equiv., 0.082 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature. The resulting solution was stirred overnight at the same temperature. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (0.219 g, 53.22%) in the form of a colorless oil.

[0246] [Step 2] Synthesis of Compound 71 [ka] N-(3-chlorophenyl)-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]thiomorpholine-4-sulfonamide (100.00%, 0.219 g, 0.436 mmol), ammonium carbamate (100.00%, 2.000 equivalents, 0.873 mmol), and (diacetoxyiodo)benzene (100.00%, 2.500 equivalents, 1.091 mmol) were dissolved in methanol (10 mL) at room temperature, and the resulting solution was stirred overnight at the same temperature. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (0.150 g, 64.51%) in the form of a colorless oil. 1 H NMR(400MHz,CDCl3)δ 9.29(t,J=1.0Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.55(d,J=8.4Hz,1H),7.48-7.47(m,1H),7.32-7.29(m,3H) ),7.09(s,0.25H),6.96(s,0.5H),6.83(s,0.25H),5.04(s,2H),3.87-3.74(m,4H),3.15-3.11(m,4H),2.20(br s,1H);LRMS(ES)m / z 533.9(M + +1).

[0247] Example 72: Synthesis of Compound 72, N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-1-imino-N-(3-methoxyphenyl)-1-oxo-1,4-thiazinane-4-sulfonamide [Step 1] Synthesis of N-(3-methoxyphenyl)thiomorpholine-4-sulfonamide [ka] 4-(3-Methylimidazol-3-ium-1-yl)sulfonylthiomorpholine trifluoromethanesulfonate (100.00%, 0.580 g, 1.459 mmol) and 3-methoxyaniline (100.00% solution, 0.14 mL, 1.246 mmol) were dissolved in acetonitrile (10 mL) at room temperature. The resulting solution was heated to reflux for 18 hours and then cooled to room temperature to complete the reaction. The solvent was removed from the reaction mixture under reduced pressure. The concentrate was then poured into saturated aqueous sodium bicarbonate, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 5-20%) and concentrated to give the title compound (0.151 g, 35.87%) as a brown oil.

[0248] [Step 2] Synthesis of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(3-methoxyphenyl)thiomorpholine-4-sulfonamide [ka] N-(3-Methoxyphenyl)thiomorpholine-4-sulfonamide (100.00%, 0.075 g, 0.260 mmol) and sodium hydride (60.00%, 0.013 g, 0.325 mmol) were dissolved in N,N-dimethylformamide (3 mL) at 0° C., and then 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.086 g, 0.296 mmol) was added to the resulting solution and stirred at room temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, and then saturated aqueous sodium bicarbonate solution was poured into the resulting concentrate, which was extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane=10-50%) and concentrated to give the title compound (0.106 g, 81.93%) in the form of a pale yellow oil.

[0249] [Step 3] Synthesis of Compound 72 [ka] N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(3-methoxyphenyl)thiomorpholine-4-sulfonamide (100.00%, 0.106 g, 0.213 mmol), iodobenzene diacetate (100.00%, 0.172 g, 0.534 mmol), and ammonium carbamate (100.00%, 0.033 g, 0.423 mmol) were dissolved in methanol (3 mL) at room temperature, and the resulting solution was stirred at 50°C for 6 hours. The temperature was then lowered to room temperature to complete the reaction. The solvent was removed from the resulting mixture under reduced pressure, and the resulting concentrate was then purified by column chromatography (SiO, 4 g cartridge; methanol / dichloromethane=0-5%) and concentrated to give the title compound (0.057 g, 50.61%) in the form of a pale orange solid. 1 H NMR(400MHz,CDCl3)δ 9.25(d,J=1.60Hz,1H),8.36(dd,J=8.2,2.2Hz,1H),7.58(d,J=8.00Hz,1H),7.26-7.24(m,1H),7.0 8-6.82(m,4H),5.05(s,2H),3.85-3.79(m,5H),3.75-3.71(m,2H),3.12-3.07(m,4H);LRMS(ES)m / z 529.8(M + +1).

[0250] Example 73: Synthesis of Compound 73, N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-1-imino-N-(3-methoxyphenyl)-1-oxo-1,4-thiazinane-4-sulfonamide [Step 1] Synthesis of N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(3-methoxyphenyl)thiomorpholine-4-sulfonamide [ka] N-(3-Methoxyphenyl)thiomorpholine-4-sulfonamide (100.00%, 0.075 g, 0.260 mmol) and sodium hydride (60.00%, 0.013 g, 0.325 mmol) were dissolved in N,N-dimethylformamide (3 mL) at 0 ° C., and then 2-[4-(bromomethyl)-3-fluorophenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.091 g, 0.296 mmol) was added to the resulting solution and stirred at room temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, saturated aqueous sodium bicarbonate solution was poured into the resulting concentrate, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane=10-50%) and concentrated to give the title compound (0.085 g, 63.53%) in the form of a pale yellow oil.

[0251] [Step 2] Synthesis of Compound 73 [ka] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]-N-(3-methoxyphenyl)thiomorpholine-4-sulfonamide (100.00%, 0.085 g, 0.165 mmol), iodobenzene diacetate (100.00%, 0.143 g, 0.444 mmol), and ammonium carbamate (100.00%, 0.028 g, 0.359 mmol) were dissolved in methanol (3 mL) at room temperature. The resulting solution was stirred at 50 °C for 6 h and then cooled to room temperature to complete the reaction. The solvent was removed from the resulting mixture under reduced pressure, and the concentrate was purified via column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0-5%) and concentrated to give the title compound (0.051 g, 56.58%) as a white solid. 1 H NMR(400MHz,CDCl3)δ 7.85(dd,J=8.0,1.5Hz,1H),7.77(dd,J=9.9,1.5Hz,1H),7.51(t,J=7.64Hz,1H),7.26-7.24(m,1H),7 .05-6.79(m,4H),4.94(s,2H),3.78-3.75(m,5H),3.72-3.65(m,2H),3.13-3.09(m,4H);LRMS(ES)m / z 546.5(M + +1).

[0252] Example 74: Synthesis of Compound 74, N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-2-(1-imino-1-oxo-1,4-thiazinan-4-yl)-N-phenyl-ethanesulfonamide [Step 1] Synthesis of N-phenylethanesulfonamide [ka] Aniline (100.00%, 1.000 g, 10.740 mmol), 2-chloroethanesulfonyl chloride (100.00%, 1.000 equiv., 10.740 mmol), and triethylamine (100.00%, 2.000 equiv., 21.480 mmol) were dissolved in dichloromethane (50 mL) at room temperature, and the resulting solution was stirred overnight at the same temperature. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 40 g cartridge; hexane / ethyl acetate = 0-30%) and concentrated to give the title compound (0.738 g, 37.51%) as a colorless oil.

[0253] [Step 2] Synthesis of N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-phenyl-ethanesulfonamide [ka] N-Phenylethenesulfonamide (100.00%, 0.738 g, 4.028 mmol), 2-[4-(bromomethyl)-3-fluorophenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.000 equiv., 4.028 mmol), potassium carbonate (100.00%, 1.500 equiv., 6.042 mmol), and potassium iodide (100.00%, 0.100 equiv., 0.403 mmol) were dissolved in N,N-dimethylformamide (30 mL) at room temperature. The resulting solution was stirred overnight at the same temperature. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (SiO2, 40 g cartridge; hexane / ethyl acetate = 0-50%) and concentrated to give the title compound (1.530 g, 92.79%) in the form of a colorless oil.

[0254] [Step 3] Synthesis of N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-phenyl-2-thiomorpholino-ethanesulfonamide [ka] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]-N-phenyl-ethenesulfonamide (100.00%, 1.530 g, 3.737 mmol) prepared in Step 2, thiomorpholine (100.00%, 1.300 equivalents, 4.858 mmol), and N,N-diisopropylethylamine (100.00%, 2.000 equivalents, 7.474 mmol) were dissolved in dichloromethane (30 mL) at room temperature, and the resulting solution was stirred overnight at the same temperature. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 40 g cartridge; hexane / ethyl acetate = 0-100%) and concentrated to give the title compound (0.917 g, 47.87%) in the form of a colorless oil.

[0255] [Step 4] Synthesis of N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-2-(1-oxo-1,4-thiazinan-4-yl)-N-phenyl-ethanesulfonamide [ka] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]-N-phenyl-2-thiomorpholinoethanesulfonamide (100.00%, 0.900 g, 1.756 mmol), (diacetoxyiodo)benzene (100.00%, 2.500 equivalents, 4.389 mmol), and ammonium carbamate (100.00%, 2.000 equivalents, 3.512 mmol) were dissolved in methanol (10 mL) at room temperature, and the resulting solution was stirred overnight at the same temperature. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (0.239 g, 25.75%) in the form of a colorless oil.

[0256] [Step 5] Synthesis of compound 74 [ka] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]-2-(1-oxo-1,4-thiazinan-4-yl)-N-phenyl-ethanesulfonamide (100.00%, 0.239 g, 0.452 mmol), ammonium carbamate (100.00%, 2.000 equivalents, 0.904 mmol), and (diacetoxyiodo)benzene (100.00%, 2.500 equivalents, 1.130 mmol) prepared in Step 4 were dissolved in methanol (10 mL) at room temperature. The resulting solution was stirred overnight at the same temperature. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (0.030 g, 12.21%) in the form of a colorless oil. 1 H NMR(400MHz,CDCl3)δ 7.87(dd,J=8.0,1.4Hz,1H),7.75(dd,J=9.9,1.5Hz,1H),7.63(t,J=7.7Hz,1H),7.40-7.31(m,5H),7.05(s,0.25H) ),6.92(s,0.5H),6.79(s,0.25H),5.05(s,2H),3.31-3.27(m,2H),3.17-3.03(m,10H),2.52(s,1H);LRMS(ES)m / z 444.3(M + +1).

[0257] Example 75: Synthesis of Compound 75, N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-4-(methylsulfonimidoyl)-N-phenyl-piperidine-1-carboxamide [Step 1] Synthesis of 4-methylsulfyl-N-phenyl-piperidine-1-carboxamide [ka] 4-Methylsulfylpiperidine hydrochloride (100.00%, 0.500 g, 2.982 mmol), isocyanatobenzene (100.00%, 1.000 equiv., 2.982 mmol), and N,N-diisopropylethylamine (100.00%, 1.000 equiv., 2.982 mmol) were dissolved in dichloromethane (10 mL) at room temperature, and the resulting solution was stirred overnight at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, dichloromethane (20 mL) and methanol (10 mL) were added to the concentrate, and the resulting mixture was stirred. The precipitated solid was filtered off, washed with hexane, and dried to give the title compound (0.400 g, 53.58%) as a white solid.

[0258] [Step 2] Synthesis of N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-4-methylsulfyl-N-phenyl-piperidine-1-carboxamide [ka] 4-Methylsulfonyl-N-phenyl-piperidine-1-carboxamide (100.00%, 0.240 g, 0.959 mmol) prepared in Step 1 was dissolved in N,N-dimethylformamide (10 mL) at 0 °C. Sodium hydride (100.00%, 1.500 equivalents, 1.438 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. 2-[4-(bromomethyl)-3-fluoro-phenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.100 equivalents, 1.054 mmol) was added to the reaction mixture and stirred at room temperature for an additional 2 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (0.025 g, 5.47%) in the form of a colorless oil.

[0259] [Step 3] Synthesis of compound 75 [ka] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]-4-methylsulfonyl-N-phenyl-piperidine-1-carboxamide (100.00%, 0.025 g, 0.052 mmol) prepared in Step 2, ammonium carbamate (100.00%, 2.000 equivalents, 0.105 mmol), and (diacetoxyiodo)benzene (100.00%, 2.500 equivalents, 0.131 mmol) were dissolved in methanol (10 mL) at room temperature, and the resulting solution was stirred overnight at the same temperature. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (0.005 g, 18.78%) in the form of a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.87(dd,J=8.0,1.5Hz,1H),7.75(dd,J=10.1,1.5Hz,1H),7.70(t,J=7.6Hz,1H ),7.36-7.32(m,2H),7.19-7.17(m,3H),7.05(s,0.25H),6.92(s,0.5H),6.79( s,0.25H),4.96(s,2H),4.10-4.07(m,2H),2.94-2.88(m,2H),2.84(s,3H),2.6 8-2.60(m,2H),2.45(s,1H),2.01-1.97(m,2H),1.51-1.44(m,2H);LRMS(ES)m / z 508.9(M + +1).

[0260] Example 76: Synthesis of Compound 76, N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(4-fluorophenyl)-1-imino-1-oxo-1,4-thiazinane-4-sulfonamide [Step 1] Synthesis of N-(4-fluorophenyl)thiomorpholine-4-sulfonamide [ka] 4-(3-Methylimidazol-3-ium-1-yl)sulfonylthiomorpholine; trifluoromethanesulfonate (100.00%, 1.000 g, 2.516 mmol) and 4-fluoroaniline (100.00% solution, 0.238 mL, 2.512 mmol) were dissolved in acetonitrile (10 mL) at room temperature. The resulting solution was heated to reflux for 18 hours and then cooled to room temperature to complete the reaction. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was poured into saturated aqueous sodium bicarbonate, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 5-20%) and concentrated to give the title compound (0.305 g, 43.85%) as a brown solid.

[0261] [Step 2] Synthesis of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(4-fluorophenyl)thiomorpholine-4-sulfonamide [ka] N-(4-Fluorophenyl)thiomorpholine-4-sulfonamide (100.00%, 0.100 g, 0.362 mmol) and sodium hydride (60.00%, 0.016 g, 0.400 mmol) were dissolved in N,N-dimethylformamide (3 mL) at 0 °C, and then 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.105 g, 0.362 mmol) was added to the resulting solution and stirred at room temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into an N-dichloromethane aqueous solution, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane=10-50%) and concentrated to give the title compound (0.080 g, 45.54%) in the form of a pale yellow oil.

[0262] [Step 3] Synthesis of Compound 76 [ka] N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(4-fluorophenyl)thiomorpholine-4-sulfonamide (100.00%, 0.080 g, 0.165 mmol), iodobenzene diacetate (100.00%, 0.143 g, 0.444 mmol), and ammonium carbamate (100.00%, 0.028 g, 0.359 mmol) were dissolved in methanol (3 mL) at room temperature, and the resulting solution was stirred at 50°C for 6 hours. The temperature was then lowered to room temperature to complete the reaction. The solvent was removed from the resulting mixture under reduced pressure, and the resulting concentrate was then purified by column chromatography (SiO, 4 g cartridge; methanol / dichloromethane=0-5%) and concentrated to give the title compound (0.068 g, 79.90%) in the form of a pale orange solid. 1H NMR(400MHz,CDCl3)δ 9.27(d,J=1.52Hz,1H),8.37(dd,J=8.2,2.2Hz,1H),7.54(d,J=8.20Hz,1H),7.40-7.37(m,2H),7.0 8-6.83(m,3H),5.01(s,2H),3.86-3.80(m,2H),3.76-3.70(m,2H),3.19-3.09(m,4H);LRMS(ES)m / z 517.8(M + +1).

[0263] Example 77: Synthesis of Compound 77, N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]-N-(4-fluorophenyl)-1-imino-1-oxo-1,4-thiazinane-4-sulfonamide [Step 1] Synthesis of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]-N-(4-fluorophenyl)thiomorpholine-4-sulfonamide [ka] N-(4-fluorophenyl)thiomorpholine-4-sulfonamide (100.00%, 0.100 g, 0.362 mmol) and sodium hydride (60.00%, 0.016 g, 0.400 mmol) were dissolved in N,N-dimethylformamide (3 mL) at 0 °C, and 2-[6-(bromomethyl)-5-fluoro-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.111 g, 0.360 mmol) was added to the resulting solution and stirred at room temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into an N-dichloromethane aqueous solution, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane=10-50%) and concentrated to give the title compound (0.126 g, 69.17%) in the form of a pale yellow oil.

[0264] [Step 2] Synthesis of compound 77 [ka] N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]-N-(4-fluorophenyl)thiomorpholine-4-sulfonamide (100.00%, 0.126 g, 0.250 mmol), iodobenzene diacetate (100.00%, 0.217 g, 0.674 mmol), and ammonium carbamate (100.00%, 0.042 g, 0.538 mmol) were dissolved in methanol (3 mL) at room temperature, and the resulting solution was stirred at 50°C for 6 hours. The temperature was then lowered to room temperature to complete the reaction. The solvent was removed from the resulting mixture under reduced pressure, and the resulting concentrate was then purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0-5%) and concentrated to give the title compound (0.027 g, 20.19%) in the form of a pale yellow solid. 1 H NMR(400MHz,CDCl3)δ 9.14(d,J=0.72Hz,1H),8.07(dd,J=9.2,1.7Hz,1H),7.43-7.39(m,2H),7.09-6.83(m,3 H),5.06(s,2H),3.88-3.83(m,2H),3.79-3.73(m,2H),3.16-3.11(m,4H);LRMS(ES)m / z 535.8(M + +1).

[0265] Example 78: Synthesis of Compound 78, N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(4-fluorophenyl)-1-imino-1-oxo-1,4-thiazinane-4-sulfonamide [Step 1] Synthesis of N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(4-fluorophenyl)thiomorpholine-4-sulfonamide [ka] N-(4-fluorophenyl)thiomorpholine-4-sulfonamide (100.00%, 0.100 g, 0.362 mmol) and sodium hydride (60.00%, 0.016 g, 0.400 mmol) were dissolved in N,N-dimethylformamide (3 mL) at 0 °C, and 2-[4-(bromomethyl)-3-fluorophenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.111 g, 0.361 mmol) was added to the resulting solution and stirred at room temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into an N-dichloromethane aqueous solution, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 10-50%) and concentrated to give the title compound (0.090 g, 49.50%) in the form of a pale yellow oil.

[0266] [Step 2] Synthesis of compound 78 [ka] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]-N-(4-fluorophenyl)thiomorpholine-4-sulfonamide (100.00%, 0.090 g, 0.179 mmol), iodobenzene diacetate (100.00%, 0.155 g, 0.481 mmol), and ammonium carbamate (100.00%, 0.030 g, 0.384 mmol) were dissolved in methanol (3 mL) at room temperature. The resulting solution was stirred at 50 °C for 6 h and then cooled to room temperature to complete the reaction. The solvent was removed from the resulting mixture under reduced pressure, and the concentrate was purified via column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0-5%) and concentrated to give the title compound (0.080 g, 83.72%) as a white solid. 1H NMR(400MHz,CDCl3)δ 7.85(dd,J=8.0,1.5Hz,1H),7.77(dd,J=9.9,1.5Hz,1H),7.50(t,J=7.60Hz,1H),7.27-7.23(m,2H),7 .07-6.80(m,3H),4.89(s,2H),3.79-3.73(m,2H),3.70-3.64(m,2H),3.18-3.10(m,4H);LRMS(ES)m / z 534.8(M + +1).

[0267] Example 79: Synthesis of Compound 79, benzyl N-[4-[[6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl]methyl-(3-fluorophenyl)carbamoyl]-1-oxo-1,4-thiazinan-1-ylidene]carbamate [Step 1] Synthesis of benzyl N-[4-[(3-fluorophenyl)carbamoyl]-1-oxo-1,4-thiazinan-1-ylidene]carbamate [ka] 1-Fluoro-3-isocyanatobenzene (100.00% solution, 0.41 mL, 3.591 mmol) and benzyl N-(1-oxo-1,4-thiazinan-1-ylidene)carbamate (100.00%, 0.978 g, 3.645 mmol) were dissolved in diethyl ether (40 mL) at room temperature, and the resulting solution was stirred at the same temperature for 2 hours. The precipitated solid was filtered, washed with diethyl ether, and dried to give the title compound (1.390 g, 95.47%) in the form of a white solid.

[0268] [Step 2] Synthesis of compound 79 [ka] Benzyl N-[4-[(3-fluorophenyl)carbamoyl]-1-oxo-1,4-thiazinan-1-ylidene]carbamate (100.00%, 0.270 g, 0.666 mmol), 2-[6-(bromomethyl)pyridazin-3-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.194 g, 0.667 mmol), and cesium carbonate (100.00%, 0.434 g, 1.332 mmol) were dissolved in acetonitrile (5 mL). The resulting solution was stirred at room temperature for 10 minutes and then at the same temperature for 3 hours. The solvent was removed from the reaction mixture under reduced pressure. Water was then poured into the concentrate, which was then extracted with dichloromethane. The solid residue and aqueous layer were removed by filtration through a plastic filter, and the mixture was concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane=20-80%) and concentrated to give the title compound (0.105 g, 25.61%) in the form of a yellow solid. 1 H NMR(400MHz,CDCl3)δ 8.44(d,J=8.7Hz,1H),7.83(d,J=8.7Hz,1H),7.39-7.31(m,6H),5.29(s,2 H),3.93-3.89(m,2H),3.58-3.53(m,4H),3.27-3.21(m,2H);LRMS(ES)m / z 616.9(M + +1).

[0269] Example 80: Synthesis of Compound 80, N-[[6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl]methyl]-N-(3-fluorophenyl)-1-imino-1-oxo-1,4-thiazinane-4-carboxamide [Step 1] Synthesis of Compound 80 [ka] Benzyl N-[4-[[6-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl]methyl-(3-fluorophenyl)carbamoyl]-1-oxo-1,4-thiazinan-1-ylidene]carbamate (100.00%, 0.100 g, 0.162 mmol) was dissolved in methanol (2 mL) / tetrahydrofuran (2 mL) and stirred at room temperature. 10% Pd / C (10 mg) was slowly added at the same temperature, and the mixture was stirred for 3 hours under a hydrogen balloon at the same temperature. The reaction mixture was filtered through a Celite pad to remove solids, and the resulting filtrate was then stripped of the solvent under reduced pressure without solids. The concentrate obtained was then purified via column chromatography (SiO2, 12 g cartridge; ethyl acetate = 100%, methanol / dichloromethane = 0-5%) and concentrated to give the title compound (0.054 g, 69.05%) in the form of a pale yellow solid. 1 H NMR(400MHz,CDCl3)δ 8.42(d,J=8.7Hz,1H),7.87(d,J=8.7Hz,1H),7.38-7.32(m,1H),7.12-6.87(m,4H), 5.29(s,2H),3.82-3.76(m,2H),3.71-3.65(m,2H),2.98-2.97(m,4H);LRMS(ES)m / z 482.5(M + +1).

[0270] Example 81: Synthesis of Compound 81, N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]methyl]-N-(3-fluorophenyl)-1-imino-1-oxo-1,4-thiazinane-4-carboxamide [Step 1] Synthesis of benzyl N-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]methyl-(3-fluorophenyl)carbamoyl]-1-oxo-1,4-thiazinan-1-ylidene]carbamate [ka] Benzyl N-[4-[(3-fluorophenyl)carbamoyl]-1-oxo-1,4-thiazinan-1-ylidene]carbamate (100.00%, 0.300 g, 0.740 mmol), 2-[5-(bromomethyl)pyrazin-2-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.214 g, 0.735 mmol), and cesium carbonate (100.00%, 0.482 g, 1.479 mmol) were dissolved in acetonitrile (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 concentrate was poured into water, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 20 to 80%) and concentrated to give the product, which was then purified again by chromatography (SiO2 plate, 20 x 20 x 1 mm; ethyl acetate / hexane = 50%) and concentrated to give the title compound (0.040 g, 8.78%) in the form of a yellow solid.

[0271] [Step 2] Synthesis of Compound 81 [ka] Benzyl N-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]methyl-(3-fluorophenyl)carbamoyl]-1-oxo-1,4-thiazinan-1-ylidene]carbamate (100.00%, 0.040 g, 0.065 mmol) was dissolved in methanol (2 mL) / tetrahydrofuran (1 mL) and stirred at room temperature. 10% Pd / C (5 mg) was slowly added at the same temperature, and the mixture was stirred for 20 minutes under a hydrogen balloon at the same temperature. The reaction mixture was filtered through a Celite pad to remove solids, and the resulting filtrate was then stripped of solvent under reduced pressure without solids. The concentrate obtained was then purified via chromatography (SiO2 plate, 20x20x1 mm; ethyl acetate / =100%) and concentrated to give the title compound (0.005 g, 15.98%) in the form of a pale yellow solid. 1 H NMR(400MHz,CDCl3)δ 9.43(d,J=1.2Hz,1H),8.86(d,J=1.0Hz,1H),7.40-7.34(m,1H),7.11-6.86(m,4H), 5.15(s,2H),3.81-3.76(m,2H),3.71-3.65(m,2H),2.99-2.98(m,4H);LRMS(ES)m / z 482.8(M + +1).

[0272] Example 82: Synthesis of Compound 82, N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-1-imino-2-methyl-1-oxo-N-phenyl-1,4-thiazinane-4-carboxamide [Step 1] Synthesis of 2-methyl-N-phenyl-thiomorpholine-4-carboxamide [ka] 2-Methylthiomorpholine (100.00%, 0.500 g, 4.266 mmol) and isocyanatobenzene (100.00%, 1.000 equivalents, 4.266 mmol) were dissolved in dichloromethane (10 mL) at room temperature, and the resulting solution was stirred overnight at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, dichloromethane (5 mL) and hexane (30 mL) were added to the resulting concentrate, and the mixture was stirred to precipitate a solid, which was filtered off, washed with hexane, and dried to give the title compound (0.600 g, 59.52%) in the form of a white solid.

[0273] [Step 2] Synthesis of N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-2-methyl-N-phenyl-thiomorpholine-4-carboxamide [ka] 2-Methyl-N-phenyl-thiomorpholine-4-carboxamide (100.00%, 0.200 g, 0.846 mmol) prepared in Step 1 was dissolved in N,N-dimethylformamide (10 mL) at 0 °C. Sodium hydride (100.00%, 1.500 equivalents, 1.270 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. 2-[4-(bromomethyl)-3-fluorophenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.100 equivalents, 0.931 mmol) was added to the reaction mixture and stirred at room temperature for an additional 2 hours. Saturated aqueous sodium bicarbonate was poured into the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 12 g cartridge; hexane / ethyl acetate = 0-50%) and concentrated to give the title compound (0.161 g, 41.13%) in the form of a colorless oil.

[0274] [Step 3] Synthesis of Compound 82 [ka] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]-2-methyl-N-phenyl-thiomorpholine-4-carboxamide (100.00%, 0.160 g, 0.346 mmol), (diacetoxyiodo)benzene (100.00%, 2.500 equivalents, 0.865 mmol), and ammonium carbamate (100.00%, 3.000 equivalents, 1.038 mmol) were dissolved in methanol (10 mL) at room temperature, and the resulting solution was stirred overnight at the same temperature. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (0.110 g, 64.43%) in the form of a colorless oil. 1 H NMR(400MHz,CDCl3)δ 7.89(dd,J=8.0,1.6Hz,1H),7.76(dd,J=10.2,1.4Hz,1H),7.70(t,J=7.6Hz,1H),7.40-7.37(m,2H),7.26-7.22(m,1H),7.15-7.11(m,2H) ),7.02(s,0.25H),6.93(s,0.5H),6.80(s,0.25H),5.00-4.89(m,2H),4.08-3.92(m,2H),3.45-3.34(m,1H),3.10-2.73(m,4H),1.70(br s,1H),1.19-1.14(m,3H);LRMS(ES)m / z 494.9(M + +1).

[0275] Example 83: Synthesis of Compound 83, N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-6-(1-imino-1-oxo-thietan-3-yl)-N-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxamide [Step 1] Synthesis of N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-phenyl-6-(thietan-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxamide [ka] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]-N-phenyl-2,6-diazaspiro[3.3]heptane-2-carboxamide (100.00%, 0.200 g, 0.451 mmol) and thietan-3-one (100.00%, 0.060 g, 0.681 mmol) were dissolved in dichloromethane (4 mL) at room temperature. Sodium triacetoxyborohydride (100.00%, 0.190 g, 0.901 mmol) was added, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate was poured into the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane=0-2.5%) and concentrated to give the title compound (0.155 g, 66.65%) in the form of a colorless oil.

[0276] [Step 2] Synthesis of Compound 83 [ka] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]-N-phenyl-6-(thietan-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxamide (100.00%, 0.155 g, 0.301 mmol), iodobenzene diacetate (100.00%, 0.242 g, 0.751 mmol), ammonium carbamate (100.00%, 0.047 g, 0.602 mmol) were dissolved in methanol (3 mL) at room temperature, and the resulting solution was stirred at 50 ° C for 6 hours. The temperature was then lowered to room temperature to complete the reaction. The solvent was removed from the resulting mixture under reduced pressure, and the resulting concentrate was then purified via column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0-5%) and concentrated to give the title compound (0.023 g, 14.00%) in the form of a white solid. 1 H NMR(400MHz,CDCl3)δ 7.87(dd,J=8.0,1.5Hz,1H),7.73-7.68(m,2H),7.35-7.32(m,2H),7.27-7.24(m,1H),7.13(dd,J=5.3,3.2Hz,2H),7.05-6.7 9(m,1H),5.00(s,2H),4.09-4.04(m,2H),3.75-3.71(m,2H),3.64(s,4H),3.30-3.26(m,1H),3.23-3.16(m,4H);LRMS(ES)m / z 547.8(M + +1).

[0277] Example 84: Synthesis of Compound 84, (1S,4S)—N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(1-imino-1-oxo-thietan-3-yl)-N-phenyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide [Step 1] Synthesis of (1S,4S)-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-phenyl-5-(thietan-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide [ka] (1S,4S)-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-phenyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (100.00%, 0.110 g, 0.258 mmol) and thietan-3-one (100.00%, 0.034 g, 0.386 mmol) were dissolved in dichloromethane (4 mL) at room temperature. Sodium triacetoxyborohydride (100.00%, 0.109 g, 0.517 mmol) was added, and the resulting solution was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate was poured into the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane=0-2.5%) and concentrated to give the title compound (0.066 g, 51.31%) in the form of a colorless oil.

[0278] [Step 2] Synthesis of compound 84 [ka] (1S,4S)-N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-phenyl-5-(thietan-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (100.00%, 0.066 g, 0.132 mmol), iodobenzene diacetate (100.00%, 0.107 g, 0.332 mmol), and ammonium carbamate (100.00%, 0.021 g, 0.269 mmol) were dissolved in methanol (3 mL) at room temperature, and the resulting solution was stirred at 50 °C for 6 hours, after which the temperature was lowered to room temperature to quench the reaction. The solvent was removed from the resulting mixture under reduced pressure, and the resulting concentrate was then purified via column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0-5%) and concentrated to give the title compound (0.007 g, 9.99%) in the form of a white solid. 1 H NMR(400MHz,CDCl3)δ 9.25(d,J=1.9Hz,1H),8.37(dd,J=8.2,2.2Hz,1H),7.64(d,J=8.2Hz,1H),7.34-7.31(m,2H),7.23-7. 22(m,2H),7.18-7.14(m,1H),7.08-6.82(m,1H),5.20(d,J=16.3Hz,1H),5.05(d,J=16.3Hz,1H),4.40( s,1H),4.10-4.01(m,2H),3.92-3.87(m,2H),3.56-3.50(m,1H),3.26(s,1H),3.04(d,J=10.1Hz,1H),2 .79(q,J=6.5Hz,2H),2.57(d,J=8.6Hz,1H),1.77(d,J=9.8Hz,1H),1.62(d,J=9.9Hz,1H);LRMS(ES)m / z 530.9(M + +1).

[0279] Example 85: Synthesis of Compound 85, N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-1-imino-2-methyl-1-oxo-N-phenyl-1,4-thiazinane-4-carboxamide [Step 1] Synthesis of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-2-methyl-N-phenyl-thiomorpholine-4-carboxamide [ka] 2-Methyl-N-phenyl-thiomorpholine-4-carboxamide (100.00%, 0.150 g, 0.635 mmol) was dissolved in N,N-dimethylformamide (10 mL) at 0 °C. Sodium hydride (100.00%, 1.500 equiv., 0.952 mmol) was added to the resulting solution and stirred at the same temperature for 30 minutes. 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.100 equiv., 0.698 mmol) was added to the reaction mixture and stirred at room temperature for 2 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (SiO2, 12 g cartridge; hexane / ethyl acetate = 0-50%) and concentrated to give the title compound (0.100 g, 35.36%) in the form of a colorless oil.

[0280] [Step 2] Synthesis of Compound 85 [ka] N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-2-methyl-N-phenyl-thiomorpholine-4-carboxamide (100.00%, 0.030 g, 0.067 mmol), (diacetoxyiodo)benzene (100.00%, 2.500 equivalents, 0.168 mmol), and ammonium carbamate (100.00%, 2.000 equivalents, 0.135 mmol) were dissolved in methanol (10 mL) at room temperature, and the resulting solution was stirred overnight at the same temperature. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (0.015 g, 46.75%) in the form of a colorless oil. 1 H NMR(400MHz,CDCl3)δ 9.25(d,J=2.0Hz,1H),8.38(dt,J=8.4,2.1Hz,1H),7.58(d,J=8.0Hz,1H),7.37(td,J=6.8,1.7Hz,2H),7.22-7.18(m,3H),7.08(s,0.25H) ,6.95(s,0.5H),6.82(s,0.25H),5.17-5.03(m,2H),4.09-4.03(m,1H),3.97-3.93(m,1H),3.42-3.32(m,1H),3.11-2.89(m,4H),1.70(br s,1H),1.20-1.17(m,3H);LRMS(ES)m / z 477.9(M + +1).

[0281] Example 86: Synthesis of Compound 86, N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-1-imino-1-oxo-N-phenyl-1,4-thiazinane-4-sulfonamide [Step 1] Synthesis of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-phenyl-thiomorpholine-4-sulfonamide [ka] N-Phenylthiomorpholine-4-sulfonamide (100.00%, 0.200 g, 0.774 mmol), 2-[2-(bromomethyl)thiazol-5-yl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.100 equiv., 0.851 mmol), potassium carbonate (100.00%, 1.500 equiv., 1.161 mmol), and potassium iodide (100.00%, 0.100 equiv., 0.077 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature, and the resulting solution was stirred overnight at the same temperature. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol = 0-10%) and concentrated to give the title compound (0.033 g, 9.00%) in the form of a colorless oil.

[0282] [Step 2] Synthesis of Compound 86 [ka] N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]thiazol-2-yl]methyl]-N-phenyl-thiomorpholine-4-sulfonamide (100.00%, 0.033 g, 0.070 mmol), (diacetoxyiodo)benzene (100.00%, 2.500 equivalents, 0.174 mmol), and ammonium carbamate (100.00%, 2.000 equivalents, 0.139 mmol) were dissolved in methanol (10 mL) at room temperature, and the resulting solution was stirred overnight at the same temperature. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 12 g cartridge; dichloromethane / methanol=0-10%) and concentrated to give the title compound (0.005 g, 14.22%) in the form of a yellow solid. 1 H NMR(400MHz,CDCl3)δ 8.39(s,1H),7.49-7.36(m,5H),7.05(s,0.25H),6.93(s,0.5H),6.80(s,0.25H),5.20(s,2H),3.80-3.63(m,4H),3.15-3.03(m,4H),2.57(br s,1H);LRMS(ES)m / z 505.8(M + +1).

[0283] Example 87: Synthesis of compound 87, 3-[N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]anilino]-4-[(1S,4S)-5-(1-imino-1-oxo-thietan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobut-3-ene-1,2-dione [Step 1] Synthesis of 3-[N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]anilino]-4-[(1S,4S)-5-(thietan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobut-3-ene-1,2-dione [ka] 3-[(1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl]-4-[N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]anilino]cyclobut-3-ene-1,2-dione (100.00%, 0.200 g, 0.418 mmol) and thietan-3-one (100.00%, 0.055 g, 0.624 mmol) were dissolved in dichloromethane (4 mL) at room temperature, and sodium triacetoxyborohydride (100.00%, 0.176 g, 0.834 mmol) was added. The resulting solution was stirred at the same temperature for 18 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 60-90%) and concentrated to give the title compound (0.156 g, 67.77%) as a yellow solid.

[0284] [Step 2] Synthesis of Compound 87 [ka] 3-[N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]anilino]-4-[(1S,4S)-5-(thietan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobut-3-ene-1,2-dione (100.00%, 0.156 g, 0.283 mmol), iodobenzene diacetate (100.00%, 0.228 g, 0.708 mmol), ammonium carbamate (100.00%, 0.044 g, 0.564 mmol) were dissolved in methanol (3 mL) at room temperature, and the resulting solution was stirred at 50 °C for 18 hours, after which the temperature was lowered to room temperature to complete the reaction. The solvent was removed from the reaction mixture under reduced pressure, and the concentrate was then poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0-5%) and concentrated to give the product, which was then purified again by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 5%) and concentrated to give the title compound (0.030 g, 18.21%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 9.27(d,J=1.8Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.63(d,J=8.2Hz,1H),7.40-7.36 (m,2H),7.27-7.25(m,1H),7.22-7.20(m,2H),7.08-6.82(m,1H),5.64-5.52(m,2H),4 .13-4.07(m,1H),4.01-3.96(m,1H),3.89-3.80(m,2H),3.45-3.41(m,1H),3.26(s,1H) ),3.20(s,1H),2.73-2.70(m,3H),1.88-1.83(m,2H),1.63-1.60(m,1H);LRMS(ES)m / z 582.4(M + +1).

[0285] Example 88: Synthesis of Compound 88, 3-[N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]anilino]-4-[(1S,4S)-5-(1-imino-1-oxo-thietan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobut-3-ene-1,2-dione [Step 1] Synthesis of 3-[N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]anilino]-4-[(1S,4S)-5-(thietan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobut-3-ene-1,2-dione [ka] 3-[(1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl]-4-[N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]anilino]cyclobut-3-ene-1,2-dione (100.00%, 0.200 g, 0.403 mmol) and thietan-3-one (100.00%, 0.053 g, 0.601 mmol) were dissolved in dichloromethane (4 mL) at room temperature, and sodium triacetoxyborohydride (100.00%, 0.170 g, 0.806 mmol) was added. The resulting solution was stirred at the same temperature for 18 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 60-80%) and concentrated to give the title compound (0.120 g, 52.38%) as a yellow solid.

[0286] [Step 2] Synthesis of Compound 88 [ka] 3-[N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]anilino]-4-[(1S,4S)-5-(thietan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobut-3-ene-1,2-dione (100.00%, 0.120 g, 0.211 mmol), iodobenzene diacetate (100.00%, 0.170 g, 0.528 mmol), ammonium carbamate (100.00%, 0.033 g, 0.423 mmol) were dissolved in methanol (3 mL) at room temperature, and the resulting solution was stirred at 50 ° C. for 18 hours, after which the temperature was lowered to room temperature to complete the reaction. The solvent was removed from the reaction mixture under reduced pressure, and the concentrate was then poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0-5%) and concentrated to give the product, which was then purified again by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 5%) and concentrated to give the title compound (0.041 g, 32.40%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 79.10(s,1H),8.08(dd,J=9.3,1.7Hz,1H),7.39-7.35(m,2H),7.28-7.25(m ,1H),7.19-7.16(m,2H),7.09-6.83(m,1H),5.73-5.64(m,2H),4.16-4.15(m ,2H),4.13-4.09(m,1H),4.02-3.97(m,2H),3.48-3.44(m,1H),3.21-3.20(m ,1H),2.76-2.72(m,3H),1.87-1.84(m,1H),1.65-1.63(m,1H);LRMS(ES)m / z 600.8(M + +1).

[0287] Example 89: Synthesis of compound 89, 3-[N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]anilino]-4-[(1S,4S)-5-(1-imino-1-oxo-thietan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobut-3-ene-1,2-dione [Step 1] Synthesis of 3-[N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]anilino]-4-[(1S,4S)-5-(thietan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobut-3-ene-1,2-dione [ka] 3-[(1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl]-4-[N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]anilino]cyclobut-3-ene-1,2-dione (100.00%, 0.150 g, 0.303 mmol) and thietan-3-one (100.00%, 0.040 g, 0.454 mmol) were dissolved in dichloromethane (4 mL) at room temperature, and sodium triacetoxyborohydride (100.00%, 0.128 g, 0.607 mmol) was added. The resulting solution was stirred at the same temperature for 18 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 5 to 70%) and concentrated to give the title compound (0.053 g, 30.84%) in the form of a white solid.

[0288] [Step 1] Synthesis of Compound 89 [ka] 3-[N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]anilino]-4-[(1S,4S)-5-(thietan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]cyclobut-3-ene-1,2-dione (100.00%, 0.053 g, 0.093 mmol), iodobenzene diacetate (100.00%, 0.075 g, 0.233 mmol), ammonium carbamate (100.00%, 0.015 g, 0.192 mmol) were dissolved in methanol (3 mL) at room temperature, and the resulting solution was stirred at 50 °C for 18 hours, after which 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 concentrate was then poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0-5%) and concentrated to give the product, which was then purified again by chromatography (SiO2 plate, 20 x 20 x 1 mm; methanol / dichloromethane = 5%) and concentrated to give the title compound (0.008 g, 14.31%) as a white solid. 1 H NMR(400MHz,CDCl3)δ 7.89(dd,J=8.0,1.4Hz,1H),7.74-7.67(m,2H),7.39-7.35(m,2H),7.31-7.28(m,1H),7 .09-7.07(m,2H),7.05-6.79(m,1H),5.60(d,J=15.4Hz,1H),5.47(d,J=15.4Hz,1H),4. 13-4.07(m,1H),4.01-3.95(m,1H),3.86-3.80(m,2H),3.43-3.41(m,1H),3.28(s,1H), 3.17(s,1H),2.71(brs,3H),1.83(d,J=9.9Hz,1H),1.59(d,J=10.1Hz,1H);LRMS(ES)m / z 599.8(M + +1).

[0289] Example 90: Synthesis of Compound 90, N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(3-fluorophenyl)-3-(methylsulfonimidoyl)azetidine-1-carboxamide [Step 1] Synthesis of N-(3-fluorophenyl)-3-methylsulfil-azetidine-1-carboxamide [ka] 3-Methylsulfazetidine hydrochloride (100.00%, 0.452 g, 3.237 mmol) and N,N-diisopropylethylamine (100.00% solution, 1.15 mL, 6.585 mmol) were dissolved in dichloromethane (20 mL) at room temperature, and 1-fluoro-3-isocyanatobenzene (100.00% solution, 0.5 mL, 4.380 mmol) was added to the resulting solution and stirred at the same temperature for 2 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 24 g cartridge; ethyl acetate / hexane = 10 to 40%) and concentrated to give the title compound (0.815 g, 77.44%) in the form of a white solid.

[0290] [Step 2] Synthesis of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(3-fluorophenyl)-3-methylsulfil-azetidine-1-carboxamide [ka] N-(3-Fluorophenyl)-3-methylsulfonyl-azetidine-1-carboxamide (100.00%, 0.200 g, 0.832 mmol) and sodium hydride (60.00%, 0.037 g, 0.925 mmol) were dissolved in N,N-dimethylformamide (4 mL) at 0° C., and 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.266 g, 0.917 mmol) was added to the resulting solution and stirred for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, saturated aqueous sodium bicarbonate solution was poured into the resulting concentrate, which was extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The obtained concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane=10-40%) and concentrated to give the title compound (0.207 g, 55.34%) in the form of a pale yellow oil.

[0291] [Step 3] Synthesis of Compound 90 [ka] N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(3-fluorophenyl)-3-methylsulfonyl-azetidine-1-carboxamide (100.00%, 0.207 g, 0.461 mmol), iodobenzene diacetate (100.00%, 0.371 g, 1.152 mmol), and ammonium carbamate (100.00%, 0.072 g, 0.922 mmol) were dissolved in methanol (5 mL) at room temperature. The resulting solution was stirred at 50 °C for 18 hours and then cooled to room temperature to quench the reaction. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into saturated aqueous sodium bicarbonate solution. The extract was then extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0 to 5%), and the product obtained after concentration was purified again by chromatography (SiO2 plate, 20 × 20 × 1 mm; methanol / dichloromethane = 5%) and concentrated to give the title compound (0.042 g, 18.98%) in the form of a white solid. 1 H NMR(400MHz,CDCl3)δ 9.26(d,J=2.0Hz,1H),8.39(dd,J=8.2,2.2Hz,1H),7.61(d,J=8.2Hz,1H),7.36-7.31(m,1H),7.11-6.83 (m,4H),5.13-5.04(m,2H),4.00-3.93(m,4H),3.88-3.83(m,1H),2.88(s,3H),2.66(s,1H);LRMS(ES)m / z 481.7(M + +1).

[0292] Example 91: Synthesis of Compound 91, N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(3-fluorophenyl)-3-(methylsulfonimidoyl)azetidine-1-carboxamide [Step 1] Synthesis of N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-N-(3-fluorophenyl)-3-methylsulfil-azetidine-1-carboxamide [ka] N-(3-fluorophenyl)-3-methylsulfonyl-azetidine-1-carboxamide (100.00%, 0.200 g, 0.832 mmol) and sodium hydride (60.00%, 0.037 g, 0.925 mmol) were dissolved in N,N-dimethylformamide (4 mL) at 0 ° C., and 2-(100.00%, 0.281 g, 0.915 mmol)-5-(difluoromethyl)-1,3,4-oxadiazole (4-(bromomethyl)-3-fluorophenyl) was added to the resulting solution and stirred at room temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, and then saturated aqueous sodium bicarbonate solution was poured into the resulting concentrate, which was extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 5 to 40%) and concentrated to give the title compound (0.194 g, 49.98%) in the form of a white solid.

[0293] [Step 2] Synthesis of Compound 91 [ka] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]-N-(3-fluorophenyl)-3-methylsulfonyl-azetidine-1-carboxamide (100.00%, 0.197 g, 0.422 mmol), iodobenzene diacetate (100.00%, 0.340 g, 1.056 mmol), and ammonium carbamate (100.00%, 0.066 g, 0.845 mmol) were dissolved in methanol (5 mL) at room temperature. The resulting solution was stirred at 50 °C for 18 hours and then cooled to room temperature to quench the reaction. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into saturated aqueous sodium bicarbonate solution. The extract was then extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane=0-5%) and concentrated to give the title compound (0.064 g, 30.46%) in the form of a white solid. 1 H NMR(400MHz,CDCl3)δ 7.90(dd,J=8.0,1.5Hz,1H),7.75-7.69(m,2H),7.36-7.30(m,1H),7.06-6.80(m, 4H),5.01(s,2H),3.96-3.91(m,4H),3.87-3.84(m,1H),2.87(s,3H);LRMS(ES)m / z 498.7(M + +1).

[0294] Example 92: Synthesis of Compound 92, N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]methyl]-2-imino-2-oxo-N-phenyl-2lambda 6-thia-6-azaspiro[3.3]heptane-6-carboxamide [Step 1] Synthesis of N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(4-fluorophenyl)thiomorpholine-4-carboxamide [ka] N-[[4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-fluorophenyl]methyl]aniline (100.00%, 0.200 g, 0.626 mmol) and N,N-diisopropylethylamine (100.00% solution, 0.55 mL, 3.149 mmol) were dissolved in dichloromethane (5 mL) at 0 °C. Triphosgene (100.00%, 0.074 g, 0.249 mmol) was added to the resulting solution and stirred at the same temperature. Oxalic acid and 2-thia-6-azaspiro[3.3]heptane (100.00%, 0.120 g, 0.375 mmol) were added to the reaction mixture and further stirred at room temperature for 18 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The concentrate obtained was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 10 to 50%) and concentrated to give the title compound (0.119 g, 41.26%) as a white solid.

[0295] [Step 2] Synthesis of Compound 92 [ka] N-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-N-(4-fluorophenyl)thiomorpholine-4-carboxamide (100.00%, 0.040 g, 0.089 mmol), iodobenzene diacetate (100.00%, 0.072 g, 0.224 mmol), and ammonium carbamate (100.00%, 0.014 g, 0.179 mmol) were dissolved in methanol (3 mL) at room temperature, and the resulting solution was stirred at 50°C for 18 hours. The temperature was then lowered to room temperature to complete the reaction. The solvent was removed from the resulting mixture under reduced pressure, and the resulting concentrate was then purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0-5%) and concentrated to give the title compound (0.010 g, 23.38%) in the form of a pale yellow solid. 1H NMR(400MHz,CDCl3)δ 7.86(dd,J=8.0,1.4Hz,1H),7.70-7.66(m,2H),7.35-7.32(m,2H),7.28-7.24(m,1H),7.13-7.12(m,2H),7 .05-6.79(m,1H),4.99(s,2H),4.09(q,J=11.8Hz,4H),3.77(d,J=7.0Hz,4H),3.08(brs,1H);LRMS(ES)m / z 492.5(M + +1).

[0296] <Experimental Example> Activity measurement and analysis protocol for the compound of the present invention Experimental Example 1: Identification of HDAC enzyme activity inhibitors (in vitro) Since the selectivity of HDAC1 inhibition, which is the cause of side effects, is important for selective HDAC6 inhibitors, experiments were conducted to identify the HDAC1 / 6 enzyme selectivity and cell selectivity (HDAC1: histone acetylation / HDAC6: tubulin acetylation) of the compounds of the present invention.

[0297] 1. Experimental Method The HDAC enzyme inhibitory activity of test substances was measured using the HDAC1 Fluorimetric Drug Discovery Assay Kit (enzyme: BML-AK511) and HDAC6 human recombinant (Calbiochem: 382180). For the HDAC1 assay, samples were treated at concentrations of 100 nM, 1000 nM, and 10,000 nM. For the HDAC6 assay, samples were treated at concentrations of 0.1, 1, 10, 100, and 1000 nM.

[0298] To test HDAC1 enzyme activity, human recombinant HDAC1 (BML-SE456) was used as the zymogen and Fluor de Lys®-SIRT1 (BNL-KI177) was used as the substrate. A 5-fold dilution of the compound was divided into 96-well plates, and 0.3 μg of enzyme and 10 μM of substrate were added to each well. The reaction was allowed to proceed at 37°C for 60 minutes. Fluor de Lys® Developer II (BML-KI176) was then added and the reaction was terminated for 30 minutes. The fluorescence value (Example 360, Em 460) was then measured using a multiplate reader (FlexStation 3, Molecular Devices). Human recombinant HDAC6 (382180) from Calbiochem Inc. was used in the HDAC6 enzyme experiment, following the same protocol as the HDAC1 enzyme activity test. The final results were calculated using the GraphPad Prism 4.0 program, with each IC 50 The value was calculated.

[0299] 2. Experimental Results The results of the search for HDAC enzyme activity inhibition obtained according to the above experimental method are shown in Table 18 below.

[0300] [Table 31]

[0301] [Table 32]

[0302] [Table 33]

[0303] As can be seen from Table 18 above, the results of the activity inhibition test against HDAC1 and HDAC6 show that the sulfoximine compounds of the present invention have an IC 50 It was confirmed that the inhibitory activity of HDAC6 was excellent and selective, with a value of approximately 7 to 500 times that of HDAC1.

[0304] Although the present invention has been described with reference to one exemplary embodiment thereof, it will be understood by those skilled in the art that the present invention can be variously changed and modified without departing from the spirit and scope of the invention, as set forth in the following claims.

Claims

1. A sulfoximine compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the sulfoximine compound has the following formula I: Formula I 【Chemical 1】 and in formula I above, R １ is CF ２ H or CF ３ and L １ is -(C １～３ alkylene)-, -C(=O)-, -S(=O) ２ -, -S(=O) ２ -(C １～３ alkylene)-, -C(=O)N(R ａ ) -, 【Chemistry 2】 and R ａ is H or C １～６ is alkyl, Q １ and Q ２ are each independently CH or N; a, b, c, d, and k are each independently 1 or 2; 【Chemistry 3】 is C ３～１２ cycloalkyl, 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; C ６ ~C １２ Aryl, -(C １～３ Alkylene) C ６ ~C １２ a 9- to 12-membered fused ring group containing a structure in which a 5- to 12-membered heteroaryl or aromatic ring group containing 1 to 3 heteroatoms independently selected from the group consisting of aryl, N, O, and S in the ring is fused with a non-aromatic ring group, The above 【Chemistry 4】 At least one H in １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～１０ Cycloalkyl, C ３～１２ Cycloalkenyl, C １～６ alkoxy, 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, wherein at least one H of the heterocycloalkyl is —C(═O)(C １～６ alkyl), a 5-12 membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O and S in the ring; ３ , -S(CF ３ ), halogen or —S(═NH)(═O)R ｃ and each independently may be substituted with R ｃ is H or C １～６ is alkyl, 【Chemistry 5】 is C ６ ~C １２ aryl or a 5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of N, O and S; The above 【Chemistry 6】 At least one H in １～６ each independently substituted with alkyl or halogen; 【Chemistry 7】 teeth, 【Chemistry 8】 and The above 【Chemistry 9】 At least one H in １～６ each independently substituted with alkyl or halogen; Z is CH or N; m and n are each independently 0, 1, or 2; p, q, r, s, and t are each independently 1 or 2; L ２ represents a single bond, -(C=O)-, -C(=O)O-, -C(=O)O-(C １～３ alkylene)- or -S(=O) ２ - and R ２ is H, C １～６ Alkyl, C ６ ~C １２ Aryl, CF ３ or -(P=O)(OR ｂ ) ２ and R ｂ is H or C １～６ is alkyl, and R ３ is C １～６ A sulfoximine compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein

2. L １ is -C(=O)-, -S(=O) ２ -, -S(=O) ２ -(C １～３ alkylene)-, -C(=O)N(R ａ ) -, 【Chemistry 10】 and 【Chemistry 11】 is C ６ ~C １２ Aryl, -(C １～３ Alkylene) C ６ ~C １２ a 5-12 membered heteroaryl containing 1-3 heteroatoms in the ring independently selected from the group consisting of aryl, N, O and S; or 【Chemistry 12】 and Y １ , Y ２ and Y ３ are each independently —CH ２ - or -O-, The above 【Chemistry 13】 At least one H in １～６ Alkyl, C ３～１０ Cycloalkyl, C １～６ alkoxy, 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring {wherein at least one H of the heterocycloalkyl is —C(═O)(C １～６ alkyl), a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, —CF ３ , -S(CF ３ ), halogen or —S(═NH)(═O)R ｃ and each independently may be substituted with 【Chemistry 14】 is C ６ ~C １２ aryl or a 5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of N, O and S; The above 【Chemistry 15】 wherein at least one H may be independently substituted with halogen; 【Chemistry 16】 teeth, 【Chemistry 17】 {During the ceremony, 【Chemistry 18】 In 【Chemistry 19】 At least one H in １～６ each independently substituted with alkyl or halogen; 【Chemistry 20】 and R １ , R ２ , R ３ , R ａ , R ｂ , R ｃ , Q １ , Q ２ , L ２ 2. The sulfoximine compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein Z, a, b, c, d, k, m, n, p, q, r, s and t are each the same as defined in claim 1.

3. The sulfoximine compound has the following formula Ia: Formula Ia 【Chemical 21】 and in formula Ia above, L １ is -C(=O)-, -S(=O) ２ -, -S(=O) ２ -(C １～３ alkylene)-, -C(=O)N(R ａ ) -, 【Chemical 22】 and 【Chemical 23】 is C ６ ~C １２ Aryl, -(C １～３ Alkylene) C ６ ~C １２ a 9- to 12-membered fused ring group containing a structure in which a 5- to 12-membered heteroaryl or aromatic ring group containing 1 to 3 heteroatoms independently selected from the group consisting of aryl, N, O, and S in the ring is fused with a non-aromatic ring group, The above 【Chemistry 24】 At least one H in １～６ Alkyl, C １～６ alkoxy, 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring {wherein at least one H of the heterocycloalkyl is —C(═O)(C １～６ alkyl), a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, —CF ３ , -S(CF ３ ), halogen or —S(═NH)(═O)R ｃ and Z １ , Z ２ , Z ３ and Z ４ are each independently CH, CX or N, and Z １ ~Z ４ at least one of is CX or N; X is a halogen; 【Chemistry 25】 teeth, 【Chemical 26】 and The above 【Chemical 27】 In 【Chemical Formula 28】 At least one H in １～６ may be substituted with alkyl, and R １ , R ２ , R ３ , R ａ , R ｃ , Q １ , Q ２ , L ２ 2. The sulfoximine compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein Z, k, m, n, p, q, r, s and t are each the same as defined in claim 1.

4. In the above formula Ia, Z １ is CX or N, Z ２ is CH, CX or N, Z ３ and Z ４ are each independently CH or N; X is a halogen; L １ is -C(=O)-, -S(=O) ２ -, -S(=O) ２ -(C １～３ alkylene)-, —C(═O)NH—, 【Chemical Formula 29】 and 【Chemistry 30】 is C ６ ~C １２ a 5-12 membered heteroaryl containing 1-3 heteroatoms in the ring independently selected from the group consisting of aryl, benzyl, N, O and S; or 【Chemical 31】 and Y １ , Y ２ and Y ３ are each independently —CH ２ - or -O-, The above 【Chemical 32】 At least one H in １～６ Alkyl, C １～６ alkoxy, 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring {wherein at least one H of the heterocycloalkyl is —C(═O)(C １～６ alkyl), a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, —CF ３ , -S(CF ３ ), halogen or —S(═NH)(═O)R ｃ and R ｃ The sulfoximine compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 3, wherein is the same as defined in claim 3.

5. In the above formula Ia, Z １ is CF or N, Z ２ is CH, CF or N, Z ３ and Z ４ are each independently CH or N; L １ is -C(=O)-, -S(=O) ２ -, -S(=O) ２ -(C １～３ alkylene)-, —C(═O)NH—, 【Chemical 33】 and R ２ is H, C １～６ Alkyl, C ６ ~C １２ Aryl, CF ３ or -(P=O)(OR ｂ ) ２ and R ｂ is C １～６ is alkyl, 【Chemical Formula 34】 is C ６ ~C １２ a 5-12 membered heteroaryl containing 1 to 3 heteroatoms in the ring independently selected from the group consisting of aryl, benzyl, N, O and S; 【Chemical 35】 and The above 【Chemical 36】 In C ６ ~C １２ At least one H of the aryl or 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring is C １～６ Alkyl, C １～６ alkoxy, a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; —CF ３ , -S(CF ３ ), halogen or —S(═NH)(═O)R ｃ and R ｃ is C １～６ The sulfoximine compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 3, wherein R is alkyl.

6. The sulfoximine compound has the following formula Ib: [Formula Ib] 【Chemical 37】 and in formula Ib above, 【Chemical 38】 teeth, 【Chemical 39】 and Z ５ , Z ６ , Z ７ and Z ８ are each independently CH, CX or N, and Z ５ ~Z ６ at least one of is CX or N; Z ９ is CH ２ , CHX, CX ２ , N.R. ７ , O or S; R ７ is H or C １～６ is alkyl, X is a halogen; 【Chemistry 40】 , R １ , R ２ , L ２ 2. The sulfoximine compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein Z, m and n are each the same as defined in claim 1.

7. A sulfoximine compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is any one selected from the group consisting of the compounds shown in the table below. 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 【Table 7】 【Table 8】

8. A pharmaceutical composition comprising the sulfoximine compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 as an active ingredient.

9. The pharmaceutical composition according to claim 8, which is for preventing or treating a histone deacetylase-mediated disease.

10. The pharmaceutical composition of claim 9, wherein the histone deacetylase-mediated disease includes infectious diseases; neoplasms; endocrine, nutritional and metabolic disorders; mental and behavioral disorders; neurological disorders; diseases of the eye and ocular appendages; cardiovascular diseases; respiratory diseases; digestive disorders; renal failure; skin and subcutaneous tissue diseases; musculoskeletal and connective tissue diseases; or malformations, deformities and chromosomal abnormalities.

11. the endocrine, nutritional and metabolic disorders include Wilson's disease, amyloidosis or diabetes; the mental and behavioral disorder comprises depression or Rett syndrome; the neurological disease comprises a central nervous system atrophy, a neurodegenerative disease, a movement disorder, a neuropathy, a motor neuron disease, a central nervous system demyelinating disease, or Charcot-Marie-Tooth (CMT) disease; said eye and ocular adnexal diseases including uveitis; said skin and subcutaneous tissue disorders include psoriasis; the musculoskeletal and connective tissue disease comprises rheumatoid arthritis, osteoarthritis or systemic lupus erythematosus; the malformations, deformities and chromosomal abnormalities include autosomal dominant polycystic kidney disease; the infectious disease comprises a prion disease; the neoplasm comprises a benign or malignant tumor; the cardiovascular disease includes atrial fibrillation, stroke, heart failure or pulmonary hypertension; The respiratory disease comprises asthma or idiopathic pulmonary fibrosis, and The indigestion includes alcoholic liver disease, inflammatory bowel disease, Crohn's disease or ulcerative bowel disease, and The pharmaceutical composition of claim 10, wherein the renal failure includes acute renal failure and chronic renal failure.

12. 10. A method for preventing or treating an HDAC-mediated disease, comprising administering to an individual the sulfoximine compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7.

13. Use of the sulfoximine compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 7 for the prevention or treatment of histone deacetylase.

14. Use of the sulfoximine compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 7 in the preparation of a medicament for preventing or treating an HDAC-mediated disease.

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