Benzothiazole and benzimidazole derivatives, pharmaceutically acceptable salts thereof, a method for producing the same, and a pharmaceutical composition containing the same as an active ingredient

Abstract

The present invention relates to a benzothiazole or benzimidazole derivative, a pharma- ceutical acceptable salt thereof, and a pharmaceutical composition for preventing or treating a SIRTUIN7 protein-related disease, which contains the same as an active ingredient, and has excellent inhibitory activity against SIRTUIN7 protein, and can be used for the prevention or treatment of a SIRTUIN7 protein-related disease.

Description

Technical Field

[0001] The present invention relates to a benzothiazole and benzimidazole compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for preventing or treating SIRTUIN7 protein (hereinafter referred to as 'SIRT7')-related diseases containing the same as an active ingredient.

Background Art

[0002] A total of seven SIRTUIN proteins (hereinafter referred to as 'SIRT') have been identified to date, from SIRT1 to SIRT7, and it has been reported that they are involved in aging, metabolic diseases, and gene stability. SIRT7 has been shown to be present in the nucleosome and nucleoplasm (Non-Patent Document 1), and it has been reported that it plays an important role in association with cellular stress.

[0003] As an example, it has been observed (Non-Patent Document 2) that the expression of HIF-1α decreases regardless of the catalytic activity during SIRT7 overexpression, and the expression of HIF-1α increases during siRNA treatment, and it has been reported that SIRT7 is involved in hypoxia.

[0004] In addition, SIRT7 is associated with hypoglycemic stress. As an example, during hypoglycemic conditions or treatment with AICAR, an AMPK activator, SIRT7 moves from the nucleosome to the nucleoplasm, which seems to reduce the binding to PAF53 in the nucleosome and suppress the rDNA transcription process, and thus it is interpreted that it has a system to cope with the energy depletion state (Non-Patent Document 3).

[0005] In addition, the mRNA of SIRT7 increases during the occurrence of endoplasmic reticulum stress. It has been reported that this suppresses Myc activity in front of the promoters of ribosomal protein genes (RPS20), which are endoplasmic reticulum stress response proteins, thereby reducing the transcription process of these genes and suppressing endoplasmic reticulum stress (Non-Patent Document 4).

[0006] As another example, SIRT7 is commonly associated with aging. For instance, in SIRT7 knockout mice, a shorter lifespan has been reported (Non-Patent Document 5), and age-related hearing loss has also been reported (Non-Patent Document 6). A decrease in SIRT7 expression has been observed in hepatocytes of an aging rat model (Non-Patent Document 7) and an aging mouse model (Non-Patent Document 8). Deacetylation of NPM1 by SIRT7 is thought to contribute to the suppression of aging (Non-Patent Document 9).

[0007] In addition, SIRT7 is involved in the DNA damage response. For example, SIRT7 knockout MEFs are more sensitive to apoptosis induced by adriamycin or hydrogen peroxide due to higher levels of ac-p53 compared to wild type (Non-Patent Documents 10 and 11). Overexpression of SIRT7 was observed to enhance the homologous recombination efficiency after paraquat treatment (Non-Patent Document 12). It was found that overexpression of SIRT7 reduces apoptosis and cellular senescence induced by doxorubicin by inhibiting the activities of p38 and JNK (Non-Patent Document 13).

[0008] Furthermore, the association between SIRT7 and cancer has been reported. As an example, SIRT7 suppresses the expression of tumor suppressor genes by mediating the deacetylation of H3K18 (Non-Patent Document 14), and it has been reported that increased SIRT7 expression regulated by mir-125a-5p and mir-125b enhances the growth of hepatocellular carcinoma cells (Non-Patent Document 15). In addition, an increase in the expression level of SIRT7 has been observed in thyroid cancer and breast cancer (Non-Patent Documents 16 and 17).

[0009] Therefore, it is expected that a compound that inhibits SIRT7 activity or a pharmaceutically acceptable salt thereof can be used for the treatment or prevention of diseases associated with SIRT7.

Prior Art Documents

Non-Patent Documents

[0010]

Non-Patent Document 1

Non-Patent Document 17

Summary of the Invention

Problems to be Solved by the Invention

[0011] An object of the present invention is to provide a benzothiazole derivative or a benzimidazole derivative having SIRTUIN7 protein (hereinafter referred to as 'SIRT7') inhibitory activity, or a pharmaceutically acceptable salt thereof.

[0012] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating SIRT7-related diseases, which contains a benzothiazole derivative or a benzimidazole derivative having SIRT7 inhibitory activity, or a pharmaceutically acceptable salt thereof.

[0013] Yet another object of the present invention is to provide a pharmaceutical composition comprising one or more selected from the group consisting of a benzothiazole derivative or a benzimidazole derivative according to the present invention, or a pharmaceutically acceptable salt thereof, a carrier, an excipient and a diluent.

Means for Solving the Problems

[0014] The present invention provides a compound represented by the following formula (1)

Chemical Formula

[0015] In another aspect, the present invention provides a pharmaceutical composition for preventing or treating SIRTUIN7 protein-related diseases, which contains the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

Effects of the Invention

[0016] The compounds according to the present invention have excellent SIRTUIN7 activity inhibitory effects and have preventive or therapeutic effects on SIRTUIN7 protein-related diseases.

Brief Description of Drawings

[0017]

Figure 1A

Figure 1B

Figure 1C

Figure 2

Figure 3

Figure 4

Figure 5A

Figure 5B

Figure 6A

Figure 6B

Figure 7

Figure 8A

Figure 8B

Figure 9A

Figure 9B

Figure 10

Figure 11A

Figure 11B

Figure 11C

Best Mode for Carrying Out the Invention

[0018] Hereinafter, it will be described in detail with reference to the embodiments of the present invention. In describing the present invention, when it is determined that a specific description of a related known configuration or function makes the gist of the present invention unclear, the detailed description thereof will be omitted.

[0019] As used in this specification and the appended claims, unless otherwise specified, the meanings of the following terms are as follows.

[0020] As used in the present invention, the term "halogen" means fluorine (F), bromine (Br), chlorine (Cl) or iodine (I), unless otherwise stated.

[0021] As used in the present invention, the term "alkyl" or "alkyl group" means an aliphatic hydrocarbon radical, and means a radical of a saturated aliphatic functional group including a straight-chain alkyl group, a branched-chain alkyl group, a cycloalkyl (alicyclic) group, an alkyl-substituted cycloalkyl group, and a cycloalkyl-substituted alkyl group. For example, C1-C6 alkyl is an aliphatic hydrocarbon having 1 to 6 carbon atoms, and includes methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and the like.

[0022] As used in the present invention, the term "alkenyl group" or "alkynyl group" means a group in which at least two carbon atoms consist of at least one carbon-carbon double bond or at least two carbon atoms consist of at least one carbon-carbon triple bond, and includes a straight-chain or branched-chain group, but is not limited thereto.

[0023] As used in the present invention, the term "alkoxyl group" or "alkoxy group" means a radical in which the hydrogen atom of the hydroxy group is substituted with an alkyl, unless otherwise defined. For example, C1-C6 alkoxy includes methoxy, ethoxy, propoxy, n-butoxy, n-pentyloxy, isopropoxy, sec-butoxy, tert-butoxy, neopentyloxy, isopentyloxy, and the like.

[0024] As used in the present invention, the term "heterocyclic ring" or "heterocyclic group" includes at least one of monocyclic and polycyclic rings, including heteroaliphatic rings and heteroaromatic rings, containing one or more heteroatoms, unless otherwise described. Adjacent functional groups may be bonded to form.

[0025] The term "aryl group" or "arylene group" used in the present invention means a monocyclic or polycyclic aromatic, and includes an aromatic ring formed by adjacent substituents participating in a bond or reaction. For example, the aryl group may be a phenyl group, a biphenyl group, a fluorene group, or a spirofluorene group.

[0026] The term "aliphatic ring" used in the present invention means an aliphatic hydrocarbon ring.

[0027] The term "aromatic ring" used in the present invention means an aromatic system composed of a hydrocarbon containing one or more rings. Examples include benzene and naphthalene.

[0028] In addition, the definitions described in the present invention can be added to form chemically related combinations, such as "arylalkyl", "alkylcarbonyl", "arylcarbonyl", etc. When the term "alkyl" is used as a suffix with another term, such as "phenylalkyl" or "hydroxyalkyl", this means an alkyl group substituted with a substituent selected from another clearly named group. Thus, for example, "phenylalkyl" means an alkyl group having a phenyl substituent, and thus includes benzyl, phenylethyl, and biphenyl. "Alkylaminoalkyl" means an alkyl group having an alkylamino substituent.

[0029] Hereinafter, a compound according to an aspect of the present invention and a pharmaceutical composition containing the same will be described.

[0030] The present invention provides the following formula (1)

Chemical formula

[0031] Further, in the present invention, the compound represented by the formula (1) is the following formula (3-1)

Chemical formula

[0032] Or the following formula (3-2)

Chemical formula

[0033] Further, in the present invention, the compound represented by the formula (1) is the following formula (4)

Chemical formula

[0034] Further, in the present invention, Ar is the following formula (Ar-1) to formula (Ar-11)

Chemical formula

[0035] Furthermore, the present invention provides a compound represented by any one of the following compounds, a stereoisomer, a tautomer, a derivative, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the said formula (1):

Chemical formula

[0036] In addition, the present invention provides a pharmaceutical composition for preventing or treating SIRTUIN7 protein-related diseases (hereinafter referred to as 'SIRT') containing the compound represented by the said formula (1), a stereoisomer, a tautomer, a derivative, a hydrate, a solvate or a pharmaceutically acceptable salt thereof as an active ingredient.

[0037] The SIRTUIN7 protein-related diseases may be selected from the group consisting of obesity, metabolic disorders, glucose resistance, insulin resistance, weight gain, fatty liver, liver fibrosis, hepatitis, liver cirrhosis, mitochondrial myopathy, brain disorders, diabetes, neurodegenerative diseases, cardiovascular diseases, eye diseases, blood coagulation disorders, flushing, lactic acidosis, MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) and cancer, but are not limited thereto.

[0038] The cancer can include, but is not limited to, gastric cancer, breast cancer, uterine cancer, colon cancer, colorectal cancer, pancreatic cancer, liver cancer, or prostate cancer.

[0039] Furthermore, the pharmaceutical composition can further include one or more pharmaceutically acceptable carriers.

[0040] The pharmaceutical composition has SIRTUIN7 inhibitory activity.

[0041] Hereinafter, the present invention will be described in more detail with reference to Synthesis Examples and Examples. However, these Examples are for illustrative purposes only, and the scope of the present invention is not limited by these Examples.

[0042] Synthesis Example 1: Synthesis of 4-((4-(tert-Butoxycarbonyl)piperazin-1-yl)methyl)benzoic acid (Compound 1) [Chemical formula] Step 1: Methyl 4-formylbenzoate (5.00 g, 30.46 mmol) and N-Boc-piperazine (5.11 g, 27.41 mmol) were dissolved in DCM (100 mL), sodium triacetoxyborohydride (9.68 g, 45.69 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction product was diluted with EtOAc, washed with purified water, and the organic layer was extracted. The separated organic layer was dehydrated with anhydrous Na2SO4, concentrated under reduced pressure, and separated by column chromatography to obtain 10.24 g of tert-butyl 4-(4-(methoxycarbonyl)benzyl)piperazine-1-carboxylate.

[0043] 11H NMR (300 MHz, CDCl3): δ 7.99 (d, 2H, J = 8.3 Hz), 7.40 (d, 2H, J = 8.2 Hz), 3.91 (s, 3H), 3.55 (s, 2H), 3.43 (t, 4H, J = 5.0 Hz), 2.39 (t, 4H, J = 5.0 Hz), 1.45 (s, 9H).

[0044] Step 2: tert-Butyl 4-(4-(methoxycarbonyl)benzyl)piperazine-1-carboxylate (10.00 g, 29.90 mmol) obtained in Step 1 and LiOH-H2O (1.88 g, 44.85 mmol) were added to 300 mL of THF / MeOH / H2O (ratio = 3:1:1), and the mixture was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction mixture, and ammonium chloride was added until the pH reached 4.0 - 5.0. The aqueous layer was extracted twice with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain 9.6 g of the title compound 4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)benzoic acid.

[0045] 1 1H NMR (300 MHz, CDCl3): δ 8.05 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 3.61 (s, 2H), 3.46 (t, J = 5.1 Hz, 4H), 2.44 (t, J = 4.8 Hz, 4H), 1.45 (s, 9H).

[0046] Synthesis Example 2: Synthesis of Compounds 2-1 to 2-6 Synthesis Example 2-1: Synthesis of 4-((6-methylpyridazin-3-yl)oxy)benzoic acid (Compound 2-1)

Chemical Structure

[0047] 1 1H NMR (500 MHz, DMSO): δ 8.24 (d, 2H, J = 8.61 Hz), 8.04 (d, 1H, J = 7.85 Hz), 7.80 (d, 1H, J = 8.10 Hz), 7.73 (d, 2H, J = 9.12 Hz), 3.98 (s, 3H), 2.59 (s, 3H).

[0048] Step 2: Methyl 4-((6-methylpyridazin-3-yl)oxy)benzoate (280 mg, 1.15 mmol) was dissolved in a THF / MeOH / H2O = 3:1:1 solution, and lithium hydroxide monohydrate (51 mg, 1.22 mmol) was added. The mixture was stirred at room temperature for 4 hours. After the reaction solution was concentrated under reduced pressure, it was diluted with purified water and adjusted to pH 2 - 3 using 1N HCl. The precipitated crystals were stirred for more than 10 minutes and then filtered to obtain 210 mg of the title compound.

[0049] 1 1H NMR (500 MHz, DMSO): δ 12.75 (bs, 1H), 8.27 (d, 2H, J = 8.61 Hz), 8.05 (d, 1H, J = 7.85 Hz), 7.89 (d, 1H, J = 8.10 Hz), 7.81 (d, 2H, J = 9.12 Hz), 2.59 (s, 3H).

[0050] Synthesis Example 2-2: Synthesis of 3-((6-methylpyridazin-3-yl)oxy)benzoic acid (Compound 2-2)

Chem.

[0051] 1 H NMR (300 MHz, DMSO): δ 12.72 (bs, 1H), 8.04 (d, 1H, J = 7.70 Hz), 7.92 (s, 1H), 7.71 (d, 1H, J = 9.05 Hz), 7.64 (d, 1H, J = 7.70 Hz), 7.16 (m, 2H), 2.59 (s, 3H).

[0052] Synthesis Example 2-3: Synthesis of 4-((5-ethylpyrimidin-2-yl)oxy)benzoic acid (Compound 2-3)

Chem.

[0053] 11H NMR (500 MHz, DMSO): δ 8.58 (s, 2H), 8.04 (d, 2H, J = 7.81 Hz), 7.80 (d, 2H, J = 7.81 Hz), 3.94 (s, 3H), 2.63 (q, 2H, J = 7.55 Hz), 1.22 (t, 3H, J = 7.55 Hz).

[0054] Step 2: Methyl 4 - ((5 - ethylpyrimidin - 2 - yl)oxy)benzoate (280 mg, 1.15 mmol) obtained in Step 1 was reacted in the same manner as in Step 2 of Synthesis Example 2 - 1 to obtain 200 mg of the title compound.

[0055] 1 1H NMR (500 MHz, DMSO): δ 12.75 (s, 1H), 8.58 (s, 2H), 8.07 (d, 2H, J = 7.81 Hz), 7.88 (d, 2H, J = 7.81 Hz), 2.64 (q, 2H, J = 7.55 Hz), 1.25 (t, 3H, J = 7.55 Hz).

[0056] Synthesis Example 2 - 4: Synthesis of 3 - ((5 - ethylpyrimidin - 2 - yl)oxy)benzoic acid (Compound 2 - 4)

Chemical Structure

[0057] 1 1H NMR (500 MHz, DMSO): δ 12.73 (s, 1H), 8.57 (s, 2H), 8.05 (t, 2H, J = 7.94 Hz), 7.97 (m, 1H), 7.99 (d, 1H, J = 7.94 Hz), 2.62 (q, 2H, J = 7.54 Hz), 1.21 (t, 3H, J = 7.94 Hz).

[0058] Synthesis Example 2-5: Synthesis of 4-((5-Fluoropyrimidin-2-yl)oxy)benzoic acid (Compound 2-5)

Chemical formula

[0059] 1 H NMR (500 MHz, DMSO): δ 12.76 (s, 1H), 8.79 (s, 2H), 8.24 (d, 2H, J = 8.45 Hz), 7.37 (d, 2H, J = 8.45 Hz).

[0060] Synthesis Example 2-6: Synthesis of 3-((5-Fluoropyrimidin-2-yl)oxy)benzoic acid (Compound 2-6)

Chemical formula

[0061] 1 H NMR (500 MHz, DMSO): δ 12.74 (s, 1H), 8.79 (s, 2H), 8.23 (d, 1H, J = 8.45 Hz), 8.07 (d, 1H, J = 8.45 Hz), 7.59 (s, 1H), 7.38 (m, 1H).

[0062] Synthesis Example 3: Synthesis of 4-(Benzyloxy)benzoic acid (Compound 3)

Chemical formula

[0063] 1 1H NMR (400 MHz, CDCl3): δ 8.07 - 7.79 (m, 2H), 7.46 - 7.31 (m, 5H), 7.04 - 6.95 (m, 2H), 5.12 (s, 2H), 3.88 (s, 3H).

[0064] Step 2: Methyl 4-(benzyloxy)benzoate (2.6 g, 10.73 mmol) obtained in Step 1 was dissolved in a THF / MeOH / H2O = 3:1:1 solution, lithium hydroxide monohydrate (1.35 g, 32.20 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After concentrating the reaction solution under reduced pressure, it was diluted with purified water and adjusted to pH 2 - 3 using 1N HCl. The precipitated crystals were stirred for 10 minutes or more and then filtered to obtain 2.4 g of the title compound.

[0065] 1 1H NMR (400 MHz, DMSO): δ 8.06 (d, J = 8.5 Hz, 2H), 7.51 - 7.29 (m, 5H), 7.02 (d, J = 8.5 Hz, 2H), 5.14 (s, 2H).

[0066] Synthesis Example 4: Synthesis of N-(benzo[d]thiazol-2-yl)-4-formylbenzamide (Compound 4)

Chemical formula

[0067] 1 1H NMR (300 MHz, DMSO): δ 13.16 (s, 1H), 10.14 (s, 1H), 8.32 (d, J = 8.1 Hz, 2H), 8.09 (d, J = 8.3 Hz, 2H), 8.05 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.53 - 7.44 (m, 1H), 7.41 - 7.32 (m, 1H).

[0068] Synthesis Example 5: Synthesis of N-(benzothiazol-2-yl)-4-bromobenzamide (Compound 5)

Chemical Structure

[0069] 11H NMR (500 MHz, DMSO): δ 13.00 (s, 1H), 8.10 - 8.07 (m, 2H), 8.03 (dd, J = 8.0, 1.3 Hz, 1H), 7.81 - 7.78 (m, 3H), 7.48 (ddd, J = 8.2, 7.2, 1.3 Hz, 1H), 7.36 (ddd, J = 8.2, 7.2, 1.1 Hz, 1H).

[0070] Synthesis Example 6: Synthesis of N-(benzothiazol-2-yl)-4-bromo-2-(trifluoromethyl)benzamide (Compound 6)

Chemical Structure

[0071] 1 1H NMR (300 MHz, CDCl3) δ 11.90 (s, 1H), 7.89 - 7.81 (m, 1H), 7.79 (d, J = 1.9 Hz, 1H), 7.58 (dd, J = 8.3, 1.9 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.39 - 7.21 (m, 2H), 7.03 - 6.94 (m, 1H).

[0072] Synthesis Example 7: Synthesis of N-(benzothiazol-2-yl)-4-bromo-2-fluorobenzamide (Compound 7)

Chemical Structure

[0073] 1 H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 8.14 (t, J = 8.4 Hz, 1H), 7.89 (dt, J = 7.9, 1.0 Hz, 1H), 7.83 (dd, J = 8.1, 1.0 Hz, 1H), 7.56 (dd, J = 8.5, 1.8 Hz, 1H), 7.53 - 7.44 (m, 2H), 7.38 (ddd, J = 8.2, 7.2, 1.2 Hz, 1H).

[0074] Synthesis Example 8: Synthesis of N-(benzothiazol-2-yl)-4-bromo-3-chlorobenzamide (Compound 8)

Chemical formula

[0075] 1 H NMR (300 MHz, DMSO-d6) δ 13.11 (s, 1H), 8.37 (t, J = 1.2 Hz, 1H), 8.07 - 7.95 (m, 3H), 7.78 (d, J = 8.0 Hz, 1H), 7.54 - 7.42 (m, 1H), 7.41 - 7.29 (m, 1H).

[0076] Synthesis Example 9: Synthesis of N-(benzothiazol-2-yl)-4-bromo-2,6-difluorobenzamide (Compound 9)

Chemical formula

[0077] 1 H NMR (300 MHz, DMSO-d6) δ 13.29 (s, 1H), 8.11 - 8.01 (m, 1H), 7.87 - 7.77 (m, 1H), 7.79 - 7.68 (m, 2H), 7.56 - 7.44 (m, 1H), 7.44 - 7.32 (m, 1H).

[0078] Synthesis Example 10: Synthesis of N-(benzothiazol-2-yl)-4-bromo-2-chlorobenzamide (Compound 10)

Chemical formula

[0079] 1 H NMR (300 MHz, DMSO-d6) δ 13.02 (s, 1H), 8.05 (d, J = 7.9, 1.2 Hz, 1H), 7.94 (d, J = 1.7 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.76 - 7.64 (m, 2H), 7.54 - 7.43 (m, 1H), 7.41 - 7.31 (m, 1H).

[0080] Synthesis Example 11: Synthesis of N-(benzothiazol-2-yl)-5-bromothiophene-2-carboxamide (Compound 11)

Chemical formula

[0081] 1 H NMR (300 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.16 - 7.94 (m, 2H), 7.75 (d, J = 8.0 Hz, 1H), 7.53 - 7.40 (m, 2H), 7.40 - 7.28 (m, 1H).

[0082] Synthesis Example 12: Synthesis of N-(benzo[d]thiazol-2-yl)-2-bromothiazole-5-carboxamide (Compound 12)

Chemical Structure

[0083] 1 H NMR (300 MHz, DMSO-d6) δ 13.41 (s, 1H), 8.55 (s, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H).

[0084] Synthesis Example 13: Synthesis of N-(benzo[d]thiazol-2-yl)-4-bromo-2-methylbenzamide (Compound 13)

Chemical Structure

[0085] 1 H NMR (300 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.66 - 7.51 (m, 3H), 7.51 - 7.41 (m, 1H), 7.35 (t, J = 7.6 Hz, 1H), 2.44 (s, 3H).

[0086] Example 1: tert-Butyl 4-(4-((1H-benzo[d]imidazol-2-yl)carbamoyl)benzyl)piperazine-1-carboxylate (Compound 1-1) Compound 1 (500 mg, 1.56 mmol), 2-aminobenzimidazole (229 mg, 1.72 mmol), HBTU (888 mg, 2.34 mmol), HOBT (316 mg, 2.34 mmol) and NMM (316 mg, 3.12 mmol) were added to anhydrous DMF (3 mL) and stirred at room temperature overnight. The reaction product was diluted with EtOAc and washed with purified water. The separated organic layer was dehydrated over anhydrous Na2SO4, concentrated under reduced pressure, and separated by column chromatography to obtain 550 mg of the title compound.

[0087] 1 H NMR (300 MHz, CDCl3): δ 8.15 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.19 - 7.12 (m, 4H), 3.63 (s, 2H), 3.47 (t, J = 5.0 Hz, 4H), 2.45 (t, J = 5.0 Hz, 4H), 1.49 (s, 9H).

[0088] Example 2: tert-Butyl 4-(4-((1-methyl-1H-benzo[d]imidazol-2-yl)carbamoyl)benzyl)piperazine-1-carboxylate (Compound 1-2) tert-Butyl 4-(4-((1H-benzo[d]imidazol-2-yl)carbamoyl)benzyl)piperazine-1-carboxylate (50 mg, 0.11 mmol) obtained in Example 1 was dissolved in anhydrous dichloromethane, and NaH (5 mg, 0.23 mg) and iodomethane (17 mg, 0.13 mmol) were added at 0 °C, followed by stirring for 2 hours. The reaction product was diluted with EtOAc and washed with purified water. The separated organic layer was dehydrated with anhydrous Na2SO4, concentrated under reduced pressure, and separated by column chromatography to obtain 32 mg of the title compound.

[0089] 1 H NMR (300 MHz, CDCl3): δ 8.16 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.20 - 7.11 (m, 4H), 3.62 (s, 2H), 3.47 (t, J = 5.0 Hz, 4H), 3.44 (s, 3H), 2.44 (t, J = 5.0 Hz, 4H), 1.50 (s, 9H).

[0090] Example 3: N-(1H-benzo[d]imidazol-2-yl)-4-(piperazin-1-ylmethyl)benzamide (Compound 1-3) tert-Butyl 4-(4-((1H-benzo[d]imidazol-2-yl)carbamoyl)benzyl)piperazine-1-carboxylate (0.50 g, 1.15 mmol) obtained in Example 1 was dissolved in anhydrous DCM (5 mL), and TFA (2 mL) was added, followed by stirring at room temperature for 2 hours. After completion of the reaction, the solvent was concentrated under reduced pressure and washed twice with ether to obtain 500 mg of the title compound.

[0091] 11H NMR (300 MHz, Acetone-d6): δ 8.34 (d, J = 8.1 Hz, 2H), 7.86 - 7.74 (m, 4H), 7.56 - 7.53 (m, 2H), 4.24 (s, 2H), 3.70 (t, J = 5.2 Hz, 4H), 3.35 (t, J = 5.2 Hz, 4H).

[0092] Example 4: N-(1H-Benzimidazol-2-yl)-4-((6-methylpyridazin-3-yl)oxy)benzamide (Compound 1-4) Compound 2-1 (100 mg, 0.43 mmol), 1H-benzimidazol-2-amine (69 mg, 0.52 mmol), HBTU (189 mg, 0.50 mmol), N-methylmorpholine (50 mg, 0.50 mmol) and HOBt (62 mg, 0.46 mmol) were added to anhydrous DMF (3 mL) and stirred for 16 h. The reaction product was diluted with EtOAc and washed with purified water. The separated organic layer was dehydrated with anhydrous Na2SO4, concentrated under reduced pressure, and separated by column chromatography to obtain 86 mg of the title compound.

[0093] 1 1H NMR (500 MHz, DMSO): δ 12.29 (s, 2H), 8.23 (d, 2H, J = 8.94 Hz), 7.71 (d, 1H, J = 8.94 Hz), 7.48 (m, 3H), 7.33 (d, 2H, J = 8.47 Hz), 7.15 (dd, 2H, J = 3.29, 5.65 Hz), 2.59 (s, 3H).

[0094] Example 5: N-(1H-Benzimidazol-2-yl)-3-((6-methylpyridazin-3-yl)oxy)benzamide (Compound 1-5) Compound 2-2 (100 mg, 0.43 mmol) was reacted in the same manner as in Example 4 above to obtain 79 mg of the title compound.

[0095] 11H NMR (300 MHz, DMSO): δ 12.34 (s, 2H), 8.04 (d, 1H, J = 7.70 Hz), 7.92 (s, 1H), 7.71 (d, 1H, J = 9.05 Hz), 7.61 (t, 1H, J = 7.90 Hz), 7.47 (m, 4H), 7.16 (m, 2H), 2.59 (s, 3H).

[0096] Example 6: N-(5-Fluoro-1H-benzo[d]imidazol-2-yl)-4-((6-methylpyridazin-3-yl)oxy)benzamide (Compound 1-6) 5-Fluoro-1H-benzo[d]imidazol-2-amine (72 mg, 0.48 mmol) was reacted in the same manner as in Example 4 above to obtain 41 mg of the title compound.

[0097] 1 1H NMR (400 MHz, DMSO): δ 12.29 (s, 2H), 8.21 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 9.1 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.26 (dd, J = 9.5, 2.5 Hz, 1H), 7.03 - 6.92 (m, 1H), 2.59 (s, 3H).

[0098] Example 7: N-(5,6-Difluoro-1H-benzo[d]imidazol-2-yl)-4-((6-methylpyridazin-3-yl)oxy)benzamide (Compound 1-7) 5,6-Difluoro-1H-benzo[d]imidazol-2-amine (67 mg, 0.40 mmol) was reacted in the same manner as in Example 4 above to obtain 37 mg of the title compound.

[0099] 11H NMR (400 MHz, DMSO): δ 12.33 (s, 1H), 8.20 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 9.0 Hz, 1H), 7.55 - 7.43 (m, 3H), 7.35 (d, J = 8.5 Hz, 2H), 2.59 (s, 3H).

[0100] Example 8: N-(1H-Benzimidazol-2-yl)-3-((5-ethylpyrimidin-2-yl)oxy)benzamide (Compound 1-8) Compound 2-4 (105 mg, 0.43 mmol) was reacted in the same manner as in Example 4 to obtain 135 mg of the title compound.

[0101] 1 1H NMR (500 MHz, DMSO): δ 12.69 (s, 2H), 8.56 (s, 2H), 8.05 (d, 1H, J = 8.09 Hz), 7.93 (m, 1H), 7.59 (t, 1H, J = 8.09 Hz), 7.44 (m, 4H), 7.17 (m, 2H), 2.62 (q, 2H, J = 7.58 Hz), 1.21 (t, 3H, J = 7.58 Hz).

[0102] Example 9: N-(1H-Benzimidazol-2-yl)-4-((5-ethylpyrimidin-2-yl)oxy)benzamide (Compound 1-9) Compound 2-3 (105 mg, 0.43 mmol) was reacted in the same manner as in Example 4 to obtain 121 mg of the title compound.

[0103] 1 1H NMR (500 MHz, DMSO): δ 12.29 (s, 2H), 8.59 (s, 2H), 8.22 (d, 1H, J = 8.69 Hz), 7.47 (m, 1H), 7.34 (d, 2H, J = 8.72 Hz), 7.15 (m, 1H), 2.62 (q, 2H, J = 7.60 Hz), 1.21 (t, 3H, J = 7.46 Hz).

[0104] Example 10: N-(1H-Benzimidazol-2-yl)-4-((5-fluoropyrimidin-2-yl)oxy)benzamide (Compound 1-10) Compound 2-5 (100 mg, 0.42 mmol) was reacted in the same manner as in Example 4 to obtain 87 mg of the title compound.

[0105] 1 H NMR (500 MHz, DMSO): δ 12.29 (s, 1H), 8.79 (s, 2H), 8.24 (d, 2H, J = 8.45 Hz), 7.48 (m, 2H), 7.37 (d, 2H, J = 8.45 Hz), 7.16 (m, 2H).

[0106] Example 11: N-(1H-Benzimidazol-2-yl)-3-((5-fluoropyrimidin-2-yl)oxy)benzamide (Compound 1-11) Compound 2-6 (100 mg, 0.42 mmol) was reacted in the same manner as in Example 4 to obtain 75 mg of the title compound.

[0107] 1 H NMR (500 MHz, DMSO): δ 12.33 (s, 2H), 8.78 (s, 2H), 8.06 (d, 1H, J = 7.82 Hz), 7.95 (m, 1H), 7.61 (t, 1H, J = 7.82 Hz), 7.46 (m, 3H), 7.17 (m, 2H).

[0108] Example 12: N-(1H-Benzimidazol-2-yl)-4-(benzyloxy)benzamide (Compound 1-12) Compound 4 (1.89 g, 8.26 mmol) was reacted in the same manner as in Example 4 to obtain 675 mg of the title compound.

[0109] 11H NMR (400 MHz, DMSO): δ 12.12 (s, 2H), 8.13 (d, J = 8.6 Hz, 2H), 7.53 - 7.29 (m, 7H), 7.17 - 7.06 (m, 4H), 5.22 (s, 2H).

[0110] Example 13: N-(1H-Benzimidazol-2-yl)-4-((4-(trifluoromethyl)benzyl)oxy)benzamide (Compound 1-13) N-(1H-Benzimidazol-2-yl)-4-(benzyloxy)benzamide (50 mg, 0.20 mmol) obtained in Example 12 was dissolved in anhydrous acetonitrile (5 mL), 4-(trifluoromethyl)benzyl bromide (52 mg, 0.22 mmol) and potassium carbonate (82 mg, 0.59 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The reaction product was diluted with EtOAc and washed with purified water. The separated organic layer was dehydrated over anhydrous Na2SO4, concentrated under reduced pressure, and separated by column chromatography to obtain 21 mg of the title compound.

[0111] 1 1H NMR (400 MHz, CDCl3): δ 12.79 (s, 1H), 7.75 - 7.65 (m, 4H), 7.63 (d, J = 8.1 Hz, 2H), 7.58 - 7.50 (m, 1H), 7.45 - 7.38 (m, 1H), 7.26 - 7.13 (m, 2H), 7.08 (d, J = 8.4 Hz, 2H), 5.31 (s, 2H).

[0112] Example 14: N-(1-(4-(trifluoromethyl)benzyl)-1H-benzimidazol-2-yl)-4-((4-(trifluoromethyl)benzyl)oxy)benzamide (Compound 1-14) N-(1H-Benzimidazol-2-yl)-4-(benzyloxy)benzamide (50 mg, 0.20 mmol) obtained in Example 12 was dissolved in anhydrous acetonitrile (5 mL), 4-(trifluoromethyl)benzyl bromide (104 mg, 0.44 mmol) and potassium carbonate (82 mg, 0.59 mmol) were added, and the mixture was stirred at 60 °C for 12 hours. The reaction product was diluted with EtOAc and washed with purified water. The separated organic layer was dehydrated with anhydrous Na2SO4, concentrated under reduced pressure, and separated by column chromatography to obtain 31 mg of the title compound.

[0113] 1 H NMR (400 MHz, CDCl3): δ 12.79 (s, 1H), 8.20 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.75 - 7.65 (m, 4H), 7.63 (d, J = 8.1 Hz, 2H), 7.58 - 7.50 (m, 1H), 7.45 - 7.38 (m, 1H), 7.26 - 7.13 (m, 2H), 7.08 (d, J = 8.4 Hz, 2H), 5.61 (s, 2H), 5.31 (s, 2H).

[0114] Example 15: N-(Benzothiazol-2-yl)-4-((6-methylpyridazin-3-yl)oxy)benzamide (Compound 1-15) Compound 2-1 (100 mg, 0.43 mmol) and 2-aminobenzothiazole (71 mg, 0.47 mmol) were reacted in the same manner as in Example 4 to obtain 102 mg of the title compound.

[0115] 1 H NMR (500 MHz, DMSO): δ 12.95 (s, 1H), 8.24 (d, 2H, J= 8.61 Hz), 8.04 (d, 1H, J= 7.85 Hz), 7.80 (d, 1H, J= 8.10 Hz), 7.73 (d, 2H, J= 9.12 Hz), 7.50 (m, 3H), 7.37 (m, 3H), 2.59 (s, 3H).

[0116] Example 16: 4-((6-Methylpyridazin-3-yl)oxy)-N-(thiazolo[5,4-b]pyridin-2-yl)benzamide (Compound 1-16) Compound 2-1 (100 mg, 0.43 mmol) and thiazolo[5,4-b]pyridin-2-amine (71 mg, 0.47 mmol) were reacted in the same manner as in Example 4 to obtain 54 mg of the title compound.

[0117] 1 H NMR (400 MHz, DMSO): δ 13.04 (s, 1H), 8.51 (d, J = 4.6 Hz, 1H), 8.24 (d, J = 8.4 Hz, 2H), 8.16 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 8.9 Hz, 1H), 7.58 - 7.44 (m, 2H), 7.38 (d, J = 8.3 Hz, 2H), 2.60 (s, 3H).

[0118] Example 17: N-(Benzothiazol-2-yl)-3-((6-methylpyridazin-3-yl)oxy)benzamide (Compound 1-17) Compound 2-2 (100 mg, 0.43 mmol) and 2-aminobenzothiazole (71 mg, 0.47 mmol) were reacted in the same manner as in Example 4 to obtain 91 mg of the title compound.

[0119] 1 H NMR (500 MHz, DMSO): δ 12.97 (s, 1H), 8.05 (t, 2H, J = 6.33 Hz), 7.97 (s, 1H), 7.79 (d, 1H, J = 7.91 Hz), 7.72 (m, 2H), 7.53 (m, 3H), 7.36 (t, 1H, J = 7.72 Hz), 2.57 (s, 3H).

[0120] Example 18: N-(6-Bromobenzothiazol-2-yl)-4-((6-methylpyridazin-3-yl)oxy)benzamide (Compound 1-18) Compound 2-1 (100 mg, 0.43 mmol) and 2-amino-6-bromobenzothiazole (108 mg, 0.47 mmol) were reacted in the same manner as in Example 4 to obtain 121 mg of the title compound.

[0121] 1 H NMR (500 MHz, DMSO): δ 13.08 (s, 1H), 8.24 (d, 2H, J = 8.90 Hz), 8.03 (d, 1H, J = 8.39 Hz), 7.99 (d, 1H, J = 7.62 Hz), 7.73 (d, 1H, J = 8.90 Hz), 7.52 (m, 2H), 7.38 (d, 2H, J = 8.83 Hz), 2.59 (s, 3H).

[0122] Example 19: N-(Benzothiazol-2-yl)-4-((5-ethylpyrimidin-2-yl)oxy)benzamide (Compound 1-19) Compound 2-3 (100 mg, 0.41 mmol) was reacted in the same manner as in Example 4 to obtain 70 mg of the title compound.

[0123] 1 H NMR (500 MHz, DMSO): δ 12.93 (s, 1H), 8.58 (s, 2H), 8.23 (d, 2H, J = 8.74 Hz), 8.04 (d, 1H, J = 7.81 Hz), 7.80 (d, 1H, J = 7.81 Hz), 7.49 (t, 1H, J = 7.15 Hz), 7.39 (d, 2H, J = 8.74 Hz), 7.37 (t, 1H, J = 7.55 Hz), 2.63 (q, 2H, J = 7.55 Hz), 1.22 (t, 3H, J = 7.55 Hz).

[0124] Example 20: N-(Benzothiazol-2-yl)-3-((5-ethylpyrimidin-2-yl)oxy)benzamide (Compound 1-20) Compound 2-4 (100 mg, 0.41 mmol) was reacted in the same manner as in Example 4 to obtain 73 mg of the title compound.

[0125] 1 H NMR (500 MHz, DMSO): δ 12.95 (s, 1H), 8.57 (s, 2H), 8.05 (t, 2H, J = 7.94 Hz), 7.97 (m, 1H), 7.99 (d, 1H, J = 7.94 Hz), 7.52 (d, 1H, J = 7.94 Hz), 7.49 (t, 1H, J = 7.14 Hz), 7.36 (t, 1H, J = 7.14 Hz), 2.62 (q, 2H, J = 7.54 Hz), 1.21 (t, 3H, J = 7.94 Hz).

[0126] Example 21: N-(Benzothiazol-2-yl)-4-((5-fluoropyrimidin-2-yl)oxy)benzamide (Compound 1-21) Compound 2-5 (100 mg, 0.43 mmol) was reacted in the same manner as in Example 4 to obtain 53 mg of the title compound.

[0127] 1 H NMR (500 MHz, DMSO): δ 12.93 (s, 1H), 8.80 (s, 2H), 8.24 (d, 2H, J = 8.63 Hz), 8.04 (d, 1H, J = 7.61 Hz), 7.81 (d, 1H, J = 8.12 Hz), 7.50 (t, 1H, J = 7.03 Hz), 7.43 (d, 2H, J = 8.68 Hz), 7.37 (t, 1H, J = 8.63 Hz).

[0128] Example 22: tert-Butyl 4-(benzothiazol-2-yl)piperazine-1-carboxylate (Compound 1-22) 2-Chlorobenzothiazole (500 mg, 2.95 mmol), tert-butyl piperazine-1-carboxylate (576.47 mg, 3.09 mmol), and potassium carbonate (427.73 mg, 3.09 mmol) were added to anhydrous DMF (10 mL), and the mixture was stirred at 50 °C for 3 hours. The reaction product was diluted with EtOAc and washed with purified water. The separated organic layer was dehydrated with anhydrous Na2SO4, concentrated under reduced pressure, and separated by column chromatography to obtain 482 mg of the title compound.

[0129] 1 H NMR (300 MHz, CDCl3): δ 7.63 - 7.55 (m, 2H), 7.34 - 7.31 (m, 1H), 7.12 - 7.07 (m, 1H), 3.61 (m, 8H), 1.59 - 1.49 (s, 9H).

[0130] Example 23: 8-(Benzothiazol-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane (Compound 1-23) 4-Piperidine ethylene ketal (443.17 mg, 3.09 mmol) was reacted in the same manner as in Example 22 to obtain 709 mg of the title compound.

[0131] 1 H NMR (300 MHz, CDCl3): δ 7.59 - 7.52 (m, 2H), 7.30 - 7.25 (m, 1H), 7.08 - 7.03 (m, 1H), 4.00 (s, 4H), 3.75 (t, J = 6 Hz, 4H), 1.83 (t, J = 6 Hz, 4H).

[0132] Example 24: tert-Butyl 2-(benzothiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (Compound 1-24) 7-Boc-2,7-diazaspiro[3,5]nonane (700.45 mg, 3.09 mmol) was reacted in the same manner as in Example 22 to obtain 832 mg of the title compound.

[0133] 1 1H NMR (300 MHz, CDCl3): δ 7.62 - 7.58 (m, 2H), 7.33 - 7.30 (m, 1H), 7.11 - 7.06 (m, 1H), 3.93 (s, 4H), 3.43 - 3.39 (m, 4H), 1.84 - 1.80 (m, 4H), 1.46 (s, 1H).

[0134] Example 25: tert-Butyl (1S,4S)-5-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (Compound 1-25) Compound 4 (1.00 g, 3.54 mmol) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (632.03 mg, 3.19 mmol) were dissolved in 1,2-dichloroethane (20 mL), sodium triacetoxyborohydride (1.13 g, 5.31 mmol) was added, and the mixture was stirred at room temperature overnight. The pH was titrated to 8.0 - 9.0 with an aqueous sodium carbonate solution, diluted with EtOAc, and washed with purified water. The separated organic layer was dehydrated over anhydrous Na2SO4, concentrated under reduced pressure, and separated by column chromatography to obtain 1.32 g of the title compound.

[0135] 1 1H NMR (400 MHz, CDCl3): δ 11.07 (s, 1H), 7.99 - 7.93 (m, 2H), 7.88 - 7.82 (m, 1H), 7.47 - 7.40 (m, 3H), 7.33 - 7.28 (m, 2H), 4.39 - 4.26 (m, 1H), 3.78 (d, J = 4.4 Hz, 2H), 3.61 - 3.40 (m, 2H), 3.20 - 3.14 (m, 1H), 2.90 - 2.81 (m, 1H), 2.70 - 2.48 (m, 1H), 1.86 (d, J = 9.9 Hz, 1H), 1.68 (d, J = 9.6 Hz, 1H), 1.47 (s, 9H).

[0136] Example 26: tert-Butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)piperazine-1-carboxylate (Compound 1-26) N-Boc-piperazine (658 mg, 3.54 mmol) was reacted in the same manner as in Example 25 to obtain 1.35 g of the title compound.

[0137] 1 H NMR (500 MHz, CDCl3): δ 11.12 (s, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.88 - 7.82 (m, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.43 - 7.37 (m, 1H), 7.33 - 7.27 (m, 2H), 3.55 (s, 2H), 3.42 (t, J = 5.0 Hz, 4H), 2.36 (t, J = 5.0 Hz, 4H), 1.46 (s, 9H).

[0138] Example 27: tert-Butyl 7-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (Compound 1-27) tert-Butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (144 mg, 0.64 mmol) was reacted in the same manner as in Example 25 to obtain 220 mg of the title compound.

[0139] 1 H NMR (300 MHz, CDCl3): δ 7.95 (d, J = 7.9 Hz, 2H), 7.86 (d, J = 7.3 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.36 - 7.28 (m, 2H), 3.61 (s, 4H), 3.50 (s, 2H), 2.86 - 2.71 (m, 2H), 1.76-1.69 (m, 6H), 1.44 (s, 9H).

[0140] Example 28: tert-Butyl 9-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Compound 1-28) tert-Butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (162 mg, 0.64 mmol) was reacted in the same manner as in Example 25 to obtain 259 mg of the title compound.

[0141] 1 H NMR (300 MHz, CDCl3): δ 7.93 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 7.4 Hz, 1H), 7.56 (d, J = 7.3 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.34 (tt, J = 7.7, 6.1 Hz, 2H), 3.55 (s, 2H), 3.36 (t, J = 5.8 Hz, 4H), 2.39 (t, J = 5.6 Hz, 4H), 1.52 (t, J = 5.6 Hz, 4H), 1.45 (m, 13H).

[0142] Example 29: 4-((1,4-Dioxo-8-azaspiro[4.5]decane-8-yl)methyl)-N-(benzo[d]thiazol-2-yl)benzamide (Compound 1-29) 1,4-Dioxo-8-azaspiro[4.5]decane (91 mg, 0.64 mmol) was reacted in the same manner as in Example 25 to obtain 120 mg of the title compound.

[0143] 1 H NMR (300 MHz, CDCl3): δ 7.95 (d, J = 8.1 Hz, 2H), 7.89 - 7.82 (m, 1H), 7.46 - 7.41 (m, 3H), 7.32 - 7.28 (m, 2H), 3.96 (d, J = 2.3 Hz, 4H), 3.57 (s, 2H), 2.51 (t, J = 5.7 Hz, 4H), 1.74 (t, J = 5.7 Hz, 4H).

[0144] Example 30: 2-(7-Benzyl-2,7-diazaspiro[3.5]nonan-2-yl)benzo[d]thiazole (Compound 1-30) 2-(2,7-Diazaspiro[3.5]nonan-2-yl)benzo[d]thiazole (100 mg, 0.28 mmol) was dissolved in anhydrous acetonitrile (4 mL), potassium carbonate (124 mg, 0.90 mmol) and benzyl bromide (56 mg, 0.33 mmol) were added, and the reaction was carried out overnight. The reaction product was diluted with EtOAc and washed with purified water. The separated organic layer was dehydrated with anhydrous Na2SO4, concentrated under reduced pressure, and separated by column chromatography to obtain 24 mg of the title compound.

[0145] 1 H NMR (300 MHz, acetone): δ 7.70 (d, J = 9 Hz, 1H), 7.47 (d, J = 9 Hz, 1H), 7.36 - 7.20 (m, 6H), 7.08 - 7.03 (m, 1H), 3.87 (s, 4H), 3.47 (s, 2H), 2.39 (s, 2H), 1.87 (t, J = 6 Hz, 4H).

[0146] Example 31: N-(Benzo[d]thiazol-2-yl)-4-(piperazin-1-ylmethyl)benzamide (Compound 1-31) tert-Butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)piperazine-1-carboxylate (2.0 g, 4.42 mmol) obtained in Example 26 was reacted in the same manner as in Example 3 to obtain 2.2 g of the title compound.

[0147] 1 H NMR (300 MHz, Acetone-d6): δ 8.27 - 8.52 (m, 2H), 7.98 - 7.91 (m, 2H), 7.77 - 7.69 (m, 4H), 4.31 (s, 2H), 3.71 (s, 4H), 3.44 (s, 4H).

[0148] Example 32: N-(Benzothiazol-2-yl)-4-((4-(ethylsulfonyl)piperazin-1-yl)methyl)benzamide (Compound 1-32) N-(Benzothiazol-2-yl)-4-((4-(ethylsulfonyl)piperazin-1-yl)methyl)benzamide (100 mg, 0.28 mmol) obtained in Example 31 was dissolved in anhydrous dichloromethane (4 mL), ethanesulfonyl chloride (30 μL, 0.31 mmol) and trimethylamine (80 μL, 0.57 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction product was diluted with EtOAc and washed with purified water. The separated organic layer was dehydrated with anhydrous Na2SO4, concentrated under reduced pressure, and separated by column chromatography to obtain 88 mg of the title compound.

[0149] 1 H NMR (500 MHz, CDCl3): δ 10.56 (s, 1H), 7.90 (t, J = 8.1 Hz, 4H), 7.88 - 7.82 (m, 1H), 7.56 - 7.50 (m, 1H), 7.39 - 7.27 (m, 2H), 3.56 (s, 2H), 3.45 (qd, J = 7.1, 5.2 Hz, 2H), 3.07 (s, 4H), 2.54 (t, J = 5.0 Hz, 4H), 0.98 (t, J = 7.1 Hz, 3H).

[0150] Example 33: N-(Benzothiazol-2-yl)-4-((4-(N,N-dimethylsulfamoyl)piperazin-1-yl)methyl)benzamide (Compound 1-33) N,N-Dimethylsulfamoyl chloride (34 μL, 0.31 mmol) was reacted in the same manner as in Example 32 to obtain 79 mg of the title compound.

[0151] 11H NMR (500 MHz, CDCl3): δ 10.51 (s, 1H), 7.91 (t, J = 8.1 Hz, 4H), 7.88 - 7.80 (m, 1H), 7.56 - 7.54 (m, 1H), 7.39 - 7.29 (m, 2H), 3.56 (s, 2H), 3.07 (s, 4H), 2.66 (s, 6H), 2.54 (t, J = 5.0 Hz, 4H).

[0152] Example 34: N-(Benzothiazol-2-yl)-4-((4-(cyclopropylsulfonyl)piperazin-1-yl)methyl)benzamide (Compound 1-34) Cyclopropylsulfonyl chloride (48 mg, 0.31 mmol) was reacted in the same manner as in Example 32 to obtain 87 mg of the title compound.

[0153] 1 1H NMR (500 MHz, CDCl3): δ 10.83 (s, 1H), 7.96 (d, J = 8.3 Hz, 2H), 7.89 - 7.83 (m, 1H), 7.51 - 7.45 (m, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.35 - 7.29 (m, 2H), 3.60 (s, 2H), 3.33 (t, J = 4.9 Hz, 4H), 2.54 (t, J = 4.9 Hz, 4H), 2.32 - 2.22 (m, 1H), 1.20 - 1.15 (m, 2H), 1.03 - 0.97 (m, 3H).

[0154] Example 35: N-(Benzothiazol-2-yl)-4-((4-(phenylsulfonyl)piperazin-1-yl)methyl)benzamide (Compound 1-35) Benzenesulfonyl chloride (60 mg, 0.31 mmol) was reacted in the same manner as in Example 32 to obtain 85 mg of the title compound.

[0155] 11H NMR (500 MHz, CDCl3): δ 10.81 (s, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.86 - 7.83 (m, 1H), 7.79 - 7.75 (m, 2H), 7.65 - 7.60 (m, 1H), 7.57 - 7.54 (m, 2H), 7.50 - 7.46 (m, 1H), 7.36 (d, J = 8.3 Hz, 2H), 7.35 - 7.28 (m, 2H), 3.54 (s, 2H), 3.04 (s, 4H), 2.52 (t, J = 4.9 Hz, 4H).

[0156] Example 36: N-(Benzothiazol-2-yl)-4-((4-((4-(trifluoromethyl)phenyl)sulfonyl)piperazin-1-yl)methyl)benzamide (Compound 1-36) 4-(Trifluoromethyl)benzenesulfonyl chloride (76 mg, 0.31 mmol) was reacted in the same manner as in Example 32 to obtain 115 mg of the title compound.

[0157] 1 1H NMR (500 MHz, CDCl3): δ 10.56 (s, 1H), 7.90 (t, J = 8.1 Hz, 4H), 7.88 - 7.82 (m, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.56 - 7.50 (m, 1H), 7.38 (d, J = 8.3 Hz, 2H), 7.39 - 7.27 (m, 2H), 3.56 (s, 2H), 3.07 (s, 4H), 2.54 (t, J = 5.0 Hz, 4H).

[0158] Example 37: 4-(4-(Benzothiazol-2-ylcarbamoyl)benzyl)-N-ethylpiperazine-1-carboxamide (Compound 1-37) N-(Benzothiazol-2-yl)-4-((4-(ethylsulfonyl)piperazin-1-yl)methyl)benzamide (100 mg, 0.28 mmol) obtained in Example 31 was dissolved in anhydrous dichloromethane (4 mL), triethylamine (80 μL, 0.57 mmol) and ethyl isocyanate (24 μL, 0.31 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction product was diluted with EtOAc and washed with purified water. The separated organic layer was dehydrated over anhydrous Na2SO4, concentrated under reduced pressure, and separated by column chromatography to obtain 99 mg of the title compound.

[0159] 1 1H NMR (500 MHz, DMSO): δ 12.84 (s, 1H), 8.12 (d, J = 7.9 Hz, 2H), 8.02 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.51 - 7.45 (m, 3H), 7.38 - 7.30 (m, 1H), 3.57 (s, 2H), 3.28 (t, J = 4.9 Hz, 4H), 3.03 (qd, J = 7.1, 5.3 Hz, 2H), 2.33 (t, J = 5.0 Hz, 4H), 0.99 (t, J = 7.1 Hz, 3H).

[0160] Example 38: 4-(4-(Benzothiazol-2-ylcarbamoyl)benzyl)-N-phenylpiperazine-1-carboxamide (Compound 1-38) Phenyl isocyanate (34 μL, 0.31 mmol) was reacted in the same manner as in Example 37 to obtain 110 mg of the title compound.

[0161] 11H NMR (500 MHz, DMSO): δ 12.86 (s, 1H), 8.50 (s, 1H), 8.14 (d, J = 8.4 Hz, 2H), 8.03 (dd, J = 7.9, 1.1 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.3 Hz, 2H), 7.52 - 7.42 (m, 3H), 7.35 (td, J = 7.6, 1.1 Hz, 1H), 7.26 - 7.18 (m, 2H), 6.93 (tt, J = 7.4, 1.2 Hz, 1H), 3.63 (s, 2H), 3.48 (t, J = 4.9 Hz, 4H), 2.43 (t, J = 5.0 Hz, 4H).

[0162] Example 39: 4-(4-(Benzothiazol-2-ylcarbamoyl)benzyl)-N-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide (Compound 1-39) 4-(Trifluoromethyl)phenyl isocyanate (44 μL, 0.31 mmol) was reacted in the same manner as in Example 37 to obtain 107 mg of the title compound.

[0163] 1 1H NMR (500 MHz, DMSO): δ 12.98 - 12.71 (m, 1H), 8.14 (d, J = 8.1 Hz, 2H), 8.03 (d, J = 7.9 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 7.50 - 7.46 (m, 1H), 7.38 - 7.32 (m, 1H), 3.63 (s, 2H), 3.57 - 3.45 (m, 4H), 2.44 (t, J = 5.0 Hz, 4H).

[0164] Example 40: 4-(4-(Benzothiazol-2-ylcarbamoyl)benzyl)-N-isopropylpiperazine-1-carboxamide (Compound 1-40) Isopropyl isocyanate (21 mg, 0.25 mmol) was reacted in the same manner as in Example 37 to obtain 54 mg of the title compound.

[0165] 1 H NMR (300 MHz, CDCl3): δ 8.06 - 7.91 (m, 2H), 7.91 - 7.76 (m, 1H), 7.50 - 7.43 (m, 3H), 7.38 - 7.27 (m, 2H), 3.98 (h, J = 6.6 Hz, 1H), 3.57 (s, 2H), 3.35 (t, J = 5.0 Hz, 4H), 2.42 (t, J = 5.1 Hz, 4H), 1.16 (d, J = 6.5 Hz, 3H).

[0166] Example 41: N-(Adamantan-1-yl)-4-(4-benzothiazol-2-ylcarbamoyl)benzyl)piperazine-1-carboxamide (Compound 1-41) 1-Adamantyl isocyanate (44 mg, 0.25 mmol) was reacted in the same manner as in Example 37 to obtain 95 mg of the title compound.

[0167] 1 H NMR (300 MHz, CDCl3): δ 7.96 (d, J = 8.3 Hz, 2H), 7.91 - 7.78 (m, 1H), 7.58 - 7.48 (m, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.40 - 7.28 (m, 2H), 3.57 (s, 2H), 3.32 (t, J = 5.1 Hz, 4H), 2.42 (t, J = 5.1 Hz, 4H), 2.06 (d, J = 7.5 Hz, 3H), 2.01 - 1.87 (m, 6H), 1.68 - 1.66 (m, 6H).

[0168] Example 42: 4-(4-(Benzothiazol-2-ylcarbamoyl)benzyl)-N-(4-methoxyphenyl)piperazine-1-carboxamide (Compound 1-42) 4-Methoxyphenyl isocyanate (37 mg, 0.25 mmol) was reacted in the same manner as in Example 37 to obtain 61 mg of the title compound.

[0169] 1 H NMR (300 MHz, CDCl3): δ 10.63 (s, 1H), 7.97 (d, J = 7.8 Hz, 2H), 7.86 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 7.9 Hz, 2H), 7.35 (p, J = 7.2 Hz, 2H), 7.26 - 7.23 (m, 2H), 6.84 (d, J = 8.3 Hz, 2H), 6.27 (s, 1H), 3.78 (s, 3H), 3.61 (s, 2H), 3.50 (t, J = 5.1 Hz, 4H), 2.49 (t, J = 4.9 Hz, 4H).

[0170] Example 43: 4-(4-(Benzothiazol-2-ylcarbamoyl)benzyl)-N-(2-(trifluoromethyl)phenyl)piperazine-1-carboxamide (Compound 1-43) 2-(Trifluoromethyl)phenyl isocyanate (47 mg, 0.25 mmol) was reacted in the same manner as in Example 37 to obtain 89 mg of the title compound.

[0171] 11H NMR (300 MHz, CDCl3): δ 10.90 (s, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.97 (d, J = 8.2 Hz, 2H), 7.91 - 7.70 (m, 1H), 7.64 - 7.42 (m, 5H), 7.39 - 7.27 (m, 2H), 7.14 (t, J = 7.7 Hz, 1H), 6.79 (s, 1H), 3.61 (s, 2H), 3.52 (t, J = 5.1 Hz, 4H), 2.50 (t, J = 5.1 Hz, 4H).

[0172] Example 44: 4-(4-(Benzothiazol-2-ylcarbamoyl)benzyl)-N-(4-fluorophenyl)piperazine-1-carboxamide (Compound 1-44) 4-Fluorophenyl isocyanate (43 mg, 0.31 mmol) was reacted in the same manner as in Example 37 to obtain 106 mg of the title compound.

[0173] 1 1H NMR (500 MHz, CDCl3): δ 10.74 (s, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.91 - 7.81 (m, 1H), 7.54 - 7.49 (m, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.37 - 7.27 (m, 4H), 6.98 (t, J = 8.7 Hz, 2H), 6.34 (s, 1H), 3.60 (s, 2H), 3.50 (t, J = 5.2 Hz, 4H), 2.48 (t, J = 5.0 Hz, 4H).

[0174] Example 45: 4-(4-(Benzothiazol-2-ylcarbamoyl)benzyl)-N-(2-fluorophenyl)piperazine-1-carboxamide (Compound 1-45) 2-Fluorophenyl isocyanate (43 mg, 0.31 mmol) was reacted in the same manner as in Example 37 to obtain 119 mg of the title compound.

[0175] 1 1H NMR (500 MHz, CDCl3): δ 10.78 (s, 1H), 8.09 (td, J = 8.2, 1.6 Hz, 1H), 8.01 - 7.92 (m, 2H), 7.89 - 7.79 (m, 1H), 7.53 - 7.43 (m, 3H), 7.33 (pd, J = 7.2, 1.4 Hz, 2H), 7.17 - 7.01 (m, 2H), 6.96 (tdd, J = 8.2, 6.2, 1.7 Hz, 1H), 6.60 (d, J = 4.0 Hz, 1H), 3.61 (s, 2H), 3.53 (t, J = 5.0 Hz, 4H), 2.50 (t, J = 5.0 Hz, 4H).

[0176] <{ Example 46: 4-(4-(Benzothiazol-2-ylcarbamoyl)benzyl)-N-(dihydro-1H-inden-5-yl)piperazine-1-carboxamide (Compound 1-46) 5-Indanyl isocyanate (50 mg, 0.31 mmol) was reacted in the same manner as in Example 37 to obtain 115 mg of the title compound.

[0177] 1 1H NMR (500 MHz, CDCl3): δ 10.76 (s, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.88 - 7.79 (m, 1H), 7.52 (dd, J = 7.7, 1.4 Hz, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.38 - 7.27 (m, 4H), 7.11 (d, J = 8.0 Hz, 1H), 7.00 (dd, J = 8.0, 1.6 Hz, 2H), 6.33 (s, 1H), 3.59 (s, 2H), 3.53 - 3.34 (m, 4H), 2.86 (dt, J = 13.9, 7.4 Hz, 4H), 2.48 (t, J = 5.0 Hz, 4H), 2.05 (p, J = 7.4 Hz, 2H).

[0178] Example 47: 4-(4-(Benzothiazol-2-ylcarbamoyl)benzyl)-N-(3,5-dimethylphenyl)piperazine-1-carboxamide (Compound 1-47) 3,5-Dimethylphenyl isocyanate (46 mg, 0.31 mmol) was reacted in the same manner as in Example 37 to obtain 102 mg of the title compound.

[0179] 1 H NMR (300 MHz, CDCl3): δ 10.83 (s, 1H), 8.03 - 7.93 (m, 2H), 7.90 - 7.80 (m, 1H), 7.53 - 7.42 (m, 3H), 7.39 - 7.28 (m, 2H), 6.98 (s, 2H), 6.69 (s, 1H), 6.30 (s, 1H), 3.59 (s, 2H), 3.49 (t, J = 5.0 Hz, 4H), 2.47 (t, J = 5.0 Hz, 4H), 2.28 (s, 6H).

[0180] Example 48: Butyl-(4-(4-(benzothiazol-2-ylcarbamoyl)benzyl)piperazine-1-carbonyl)glycinate (Compound 1-48) Butyl isocyanatoacetate (49 mg, 0.31 mmol) was reacted in the same manner as in Example 37 to obtain 80 mg of the title compound.

[0181] 11H NMR (300 MHz, CDCl3): δ 10.65 (s, 1H), 7.96 (d, J = 7.9 Hz, 2H), 7.87 - 7.84 (m, 1H), 7.57 - 7.49 (m, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.40 - 7.27 (m, 2H), 5.00 (t, J = 5.3 Hz, 1H), 4.16 (t, J = 6.6 Hz, 2H), 4.03 (d, J = 5.0 Hz, 2H), 3.57 (s, 2H), 3.41 (t, J = 5.0 Hz, 4H), 2.42 (t, J = 5.0 Hz, 4H), 1.63 (dt, J = 14.5, 6.6 Hz, 3H), 1.38 (h, J = 7.3 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H).

[0182] Example 49: 4-(4-(Benzothiazol-2-ylcarbamoyl)benzyl)-N-(4-chlorophenyl)piperazine-1-carboxamide (Compound 1-49) 4-Chlorophenyl isocyanate (48 mg, 0.31 mmol) was reacted in the same manner as in Example 37 to obtain 59 mg of the title compound.

[0183] 1 1H NMR (300 MHz, CDCl3): δ 7.96 (d, J = 8.2 Hz, 2H), 7.89 - 7.84 (m, 1H), 7.61 - 7.57 (m, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.42 - 7.22 (m, 6H), 6.35 (s, 1H), 3.61 (s, 2H), 3.51 (t, J = 5.0 Hz, 4H), 2.49 (t, J = 5.1 Hz, 4H).

[0184] Example 50: 4-(4-(Benzothiazol-2-ylcarbamoyl)benzyl)-N-(2-ethylphenyl)piperazine-1-carboxamide (Compound 1-50) 2-Ethylphenyl isocyanate (46 mg, 0.31 mmol) was reacted in the same manner as in Example 37 to obtain 107 mg of the title compound.

[0185] 1 H NMR (300 MHz, CDCl3): δ 10.79 (s, 1H), 7.97 (d, J = 7.9 Hz, 2H), 7.90 - 7.78 (m, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.3 Hz, 3H), 7.38 - 7.29 (m, 2H), 7.18 (d, J = 7.2 Hz, 2H), 7.09 - 7.04 (m, 1H), 6.23 (s, 1H), 3.60 (s, 2H), 3.50 (t, J = 4.9 Hz, 4H), 2.59 (q, J = 7.6 Hz, 2H), 2.49 (t, J = 5.0 Hz, 4H), 1.24 (t, J = 7.6 Hz, 3H).

[0186] Example 51: 4-(4-(Benzothiazol-2-ylcarbamoyl)benzyl)-N-(p-tolyl)piperazine-1-carboxamide (Compound 1-51) p-Tolyl isocyanate (42 mg, 0.31 mmol) was reacted in the same manner as in Example 37 to obtain 76 mg of the title compound.

[0187] 11H NMR (300 MHz, CDCl3): δ 10.59 (s, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.86 (dd, J = 7.5, 1.7 Hz, 1H), 7.56 (dd, J = 7.7, 1.6 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.34 (pd, J = 7.3, 1.5 Hz, 2H), 7.26 - 7.20 (m, 2H), 7.09 (d, J = 8.2 Hz, 2H), 6.31 (s, 1H), 3.60 (s, 2H), 3.49 (t, J = 5.0 Hz, 4H), 2.48 (t, J = 5.0 Hz, 4H), 2.30 (s, 3H).

[0188] Example 52: 4-(4-(Benzothiazol-2-ylcarbamoyl)benzyl)-N-(4-ethylphenyl)piperazine-1-carboxamide (Compound 1-52) 4-Ethylphenyl isocyanate (46 mg, 0.31 mmol) was reacted in the same manner as in Example 37 to obtain 46 mg of the title compound.

[0189] 1 1H NMR (300 MHz, CDCl3): δ 10.68 (s, 1H), 7.96 (d, J = 8.1 Hz, 2H), 7.89 - 7.81 (m, 1H), 7.57 - 7.50 (m, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.41 - 7.28 (m, 2H), 7.25 (d, J = 8.2 Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H), 6.32 (s, 1H), 3.60 (s, 2H), 3.50 (t, J = 5.0 Hz, 4H), 2.60 (q, J = 7.6 Hz, 2H), 2.48 (t, J = 5.0 Hz, 4H), 1.21 (t, J = 7.6 Hz, 3H).

[0190] Example 53: 4-(4-(Benzothiazol-2-ylcarbamoyl)benzyl)-N-cyclohexylpiperazine-1-carboxamide (Compound 1-53) Cyclohexyl isocyanate (39 mg, 0.31 mmol) was reacted in the same manner as in Example 37 to obtain 81 mg of the title compound.

[0191] 1 H NMR (300 MHz, CDCl3): δ 10.93 (s, 1H), 7.96 (d, J = 8.0 Hz, 2H), 7.89 - 7.79 (m, 1H), 7.49 - 7.39 (m, 3H), 7.36 - 7.27 (m, 2H), 4.25 (d, J = 7.6 Hz, 1H), 3.71 - 3.60 (m, 1H), 3.56 (s, 1H), 3.35 (t, J = 5.0 Hz, 4H), 2.41 (t, J = 5.0 Hz, 4H), 1.97 - 1.92 (m, 2H), 1.81 - 1.51 (m, 2H), 1.45 - 1.22 (m, 3H), 1.22 - 0.97 (m, 3H).

[0192] Example 54: 4-(4-(Benzothiazol-2-ylcarbamoyl)benzyl)-N-(chloromethyl)piperazine-1-carboxamide (Compound 1-54) 2-Chloroethyl isocyanate (33 mg, 0.31 mmol) was reacted in the same manner as in Example 37 to obtain 67 mg of the title compound.

[0193] 11H NMR (300 MHz, CDCl3): δ 10.75 (s, 1H), 7.96 (d, J = 7.8 Hz, 2H), 7.91 - 7.77 (m, 1H), 7.51 - 7.41 (m, 3H), 7.40 - 7.26 (m, 2H), 5.02 - 4.65 (m, 1H), 3.69 - 3.63 (m, 1H), 3.61 - 3.58 (m, 2H), 3.39 (t, J = 5.1 Hz, 4H), 2.44 (t, J = 5.1 Hz, 4H).

[0194] Example 55: 4-(4-(Benzothiazol-2-ylcarbamoyl)benzyl)-N-propylpiperazine-1-carboxamide (Compound 1-55) Propyl isocyanate (27 mg, 0.31 mmol) was reacted in the same manner as in Example 37 to obtain 64 mg of the title compound.

[0195] 1 1H NMR (300 MHz, CDCl3): δ 10.89 (s, 1H), 8.00 - 7.90 (m, 2H), 7.90 - 7.80 (m, 1H), 7.51 - 7.41 (m, 3H), 7.37 - 7.28 (m, 2H), 4.43 (t, J = 5.6 Hz, 1H), 3.56 (s, 2H), 3.37 (t, J = 5.0 Hz, 4H), 3.21 (td, J = 7.1, 5.6 Hz, 2H), 2.42 (t, J = 5.0 Hz, 4H), 1.53 (h, J = 7.4 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H).

[0196] Example 56: 4-(4-(Benzothiazol-2-ylcarbamoyl)benzyl)-N-(2-ethoxyphenyl)piperazine-1-carboxamide (Compound 1-56) 2-Ethoxyphenyl isocyanate (51 mg, 0.31 mmol) was reacted in the same manner as in Example 37 to obtain 77 mg of the title compound.

[0197] 1 1H NMR (300 MHz, CDCl3): δ 10.71 (s, 1H), 8.20 - 8.14 (m, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.93 - 7.84 (m, 1H), 7.60 - 7.46 (m, 3H), 7.43 - 7.30 (m, 2H), 7.22 (s, 1H), 6.98 - 6.93 (m, 2H), 6.88 - 6.84 (m, 1H), 4.12 (q, J = 7.0 Hz, 2H), 3.63 (s, 2H), 3.55 (t, J = 5.0 Hz, 4H), 2.52 (t, J = 5.0 Hz, 4H), 1.45 (t, J = 7.0 Hz, 3H).

[0198] Example 57: 4-(4-(Benzothiazol-2-ylcarbamoyl)benzyl)-N-(2,4,4-trimethylpentan-2-yl)piperazine-1-carboxamide (Compound 1-57) 1,1,3,3-Tetramethylbutyl isocyanate (48 mg, 0.31 mmol) was reacted in the same manner as in Example 37 to obtain 107 mg of the title compound.

[0199] 1 1H NMR (300 MHz, CDCl3): δ 11.15 (s, 1H), 7.96 (d, J = 8.0 Hz, 2H), 7.89 - 7.82 (m, 1H), 7.43 - 7.37 (m, 3H), 7.34 - 7.27 (m, 2H), 4.32 (s, 1H), 3.55 (s, 2H), 3.31 (t, J = 5.0 Hz, 4H), 2.40 (t, J = 4.9 Hz, 4H), 1.73 (s, 2H), 1.41 (s, 6H), 1.01 (s, 9H).

[0200] Example 58: 4-(4-(Benzothiazol-2-ylcarbamoyl)benzyl)-N-(2-bromophenyl)piperazine-1-carboxamide (Compound 1-58) 2-Bromophenyl isocyanate (62 mg, 0.31 mmol) was reacted in the same manner as in Example 37 to obtain 94 mg of the title compound.

[0201] 1 H NMR (300 MHz, CDCl3): δ 10.66 (s, 1H), 8.19 (dd, J = 8.3, 1.6 Hz, 1H), 8.01 - 7.93 (m, 2H), 7.91 - 7.82 (m, 1H), 7.54 - 7.47 (m, 4H), 7.40 - 7.27 (m, 3H), 7.03 (s, 1H), 6.89 (ddd, J = 8.0, 7.3, 1.6 Hz, 1H), 3.62 (s, 2H), 3.56 (t, J = 5.0 Hz, 4H), 2.52 (t, J = 5.0 Hz, 4H).

[0202] Example 59: N-(Benzothiazol-2-yl)-4-((4-propionylpiperazin-1-yl)methyl)benzamide (Compound 1-59) Acetyl chloride (22 μL, 0.31 mmol) was reacted in the same manner as in Example 37 to obtain 74 mg of the title compound.

[0203] 1 H NMR (500 MHz, CDCl3): δ 10.56 (s, 1H), 7.90 (t, J = 8.1 Hz, 4H), 7.88 - 7.82 (m, 1H), 7.56 - 7.50 (m, 1H), 7.39 - 7.27 (m, 2H), 3.56 (s, 2H), 3.45 (qd, J = 7.1, 5.2 Hz, 2H), 3.07 (s, 4H), 2.51 (t, J = 5.0 Hz, 4H), 0.99 (t, J = 7.1 Hz, 3H).

[0204] Example 60: N-(Benzothiazol-2-yl)-4-((4-benzoylpiperazin-1-yl)methyl)benzamide (Compound 1-60) Benzoyl chloride (36 μL, 0.31 mmol) was reacted in the same manner as in Example 37 to obtain 80 mg of the title compound.

[0205] 1 H NMR (500 MHz, DMSO): δ 12.80 (s, 1H), 8.50 (s, 1H), 8.14 (d, J = 8.4 Hz, 2H), 8.03 (dd, J = 7.9, 1.1 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.3 Hz, 2H), 7.52 - 7.42 (m, 3H), 7.35 (td, J = 7.6, 1.1 Hz, 1H), 7.26 - 7.18 (m, 2H), 6.93 (tt, J = 7.4, 1.2 Hz, 1H), 3.63 (s, 2H), 3.51 (t, J = 4.9 Hz, 4H), 2.47 (t, J = 5.0 Hz, 4H).

[0206] Example 61: N-(Benzothiazol-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)benzamide (Compound 1-61) N-(Benzothiazol-2-yl)-4-((4-(ethylsulfonyl)piperazin-1-yl)methyl)benzamide (100 mg, 0.28 mmol) obtained in Example 31 was dissolved in anhydrous DMF (3 mL), potassium carbonate (79 mg, 0.57 mmol) and bromoethane (23 μL, 0.31 mmol) were added, and the mixture was stirred at room temperature for 12 hours. The reaction product was diluted with EtOAc and washed with purified water. The separated organic layer was dehydrated with anhydrous Na2SO4, concentrated under reduced pressure, and separated by column chromatography to obtain 54 mg of the title compound.

[0207] 11H NMR (500 MHz, CDCl3): δ 10.50 (s, 1H), 7.91 (t, J = 8.1 Hz, 4H), 7.82 (m, 1H), 7.50 (m, 1H), 7.37 (m, 2H), 3.56 (s, 2H), 3.45 (qd, J = 7.1, 5.2 Hz, 2H), 3.07 (s, 4H), 2.50 (t, J = 5.0 Hz, 4H), 0.94 (t, J= 7.1 Hz, 3H).

[0208] Example 62: N-(Benzothiazol-2-yl)-4-((4-benzylpiperazin-1-yl)methyl)benzamide (Compound 1-62) Benzyl bromide (37 μL, 0.31 mmol) was reacted in the same manner as in Example 61 to obtain 79 mg of the title compound.

[0209] 1 1H NMR (500 MHz, DMSO): δ 12.80 (s, 1H), 8.50 (s, 1H), 8.14 (d, J = 8.4 Hz, 2H), 8.03 (dd, J = 7.9, 1.1 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.3 Hz, 2H), 7.52 - 7.42 (m, 3H), 7.35 (td, J = 7.6, 1.1 Hz, 1H), 7.26 - 7.18 (m, 2H), 6.93 (tt, J = 7.4, 1.2 Hz, 1H), 3.66 (s, 2H), 3.63 (s, 2H), 3.50 (t, J = 4.9 Hz, 4H), 2.46 (t, J = 5.0 Hz, 4H).

[0210] Example 63: tert-Butyl 4-(4-(benzothiazol-2-ylcarbamoyl)benzylidene)piperidine-1-carboxylate (Compound 1-63) Compound 5 (247 mg, 0.74 mmol), tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)piperidine-1-carboxylate (200 mg, 0.62 mmol), Pd(PPh3)4 (71.50 mg, 0.06 mmol), potassium carbonate (213.79 mg, 1.55 mmol) and Pd(PPh3)4 (71.50 mg, 0.06 mmol) were placed in a reaction vessel, and 1,4-dioxane (10 mL) and H2O (2 mL) were added. The reaction mixture was stirred at 95 °C for 12 h, the reaction product was diluted with EtOAc and washed with purified water. The separated organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure, and separated by column chromatography to obtain 172 mg of the title compound.

[0211] 1 H NMR (400 MHz, CDCl3): δ 11.16 (s, 1H), 7.96 - 7.93 (m, 2H), 7.88 - 7.83 (m, 1H), 7.43 - 7.39 (m, 1H), 7.32 - 7.28 (m, 2H), 7.27 - 7.25 (m, 2H), 6.36 (s, 1H), 3.52 (t, J = 5.9 Hz, 3H), 3.40 (t, J = 5.9 Hz, 3H), 2.41 - 2.34 (m, 4H), 1.49 (s, 9H).

[0212] Example 64: tert-butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)piperidine-1-carboxylate (Compound 1-64) The tert-butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzylidene)piperidine-1-carboxylate (160 mg, 0.36 mmol) obtained in Example 63 was dissolved in anhydrous MeOH (3 mL) and anhydrous THF (3 mL), and 10 wt% Pd / C was added. The reaction mixture was reacted at room temperature for 12 h under hydrogen gas conditions, and palladium was removed through a celite filter. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain 147 mg of the title compound.

[0213] 1 1H NMR (500 MHz, CDCl3): δ 11.01 (s, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.86 - 7.85 (m, 1H), 7.47 - 7.45 (m, 1H), 7.33 - 7.29 (m, 2H), 7.24 (d, J = 7.9 Hz, 2H), 2.64 - 2.58 (m, 4H), 1.70 - 1.66 (m, 3H), 1.57 (d, J = 12.6 Hz, 2H), 1.14 (q, J = 11.5 Hz, 2H).

[0214] Example 65: N-(Benzothiazol-2-yl)-4-(piperidin-4-ylidenemethyl)benzamide (Compound 1-65) tert-Butyl 4-(4-(benzothiazol-2-ylcarbamoyl)benzylidene)piperidine-1-carboxylate (110 mg, 0.25 mmol) obtained in Example 63 was dissolved in anhydrous DCM (5 mL), TFA (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was concentrated under reduced pressure and then washed twice with ether to obtain 120 mg of the title compound.

[0215] 1 1H NMR (500 MHz, DMSO): δ 12.91 (s, 1H), 8.71 (s, 2H), 8.15 (d, J = 8.3 Hz, 2H), 8.04 (d, J = 7.9 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.50 - 7.45 (m, 3H), 7.38 - 7.34 (m, 1H), 6.57 (s, 1H), 3.21 - 3.20 (m, 2H), 3.15 - 3.14 (m, 2H), 2.67 (t, J = 6.1 Hz, 2H), 2.57 (t, J = 6.1 Hz, 2H).

[0216] Example 66: N-(Benzothiazol-2-yl)-4-(piperidin-4-ylmethyl)benzamide (Compound 1-66) tert-Butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)piperidine-1-carboxylate (110 mg, 0.25 mmol) obtained in Example 64 was reacted in the same manner as in Example 65 to obtain 112 mg of the title compound.

[0217] 1 H NMR (500 MHz, DMSO): δ 12.85 (s, 1H), 8.12 (d, J = 8.0 Hz, 2H), 8.03 (d, J = 7.9 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 7.6 Hz, 1H), 3.26 (d, J = 12.5 Hz, 2H), 2.83 (q, J = 11.8 Hz, 2H), 2.66 (d, J = 7.1 Hz, 2H), 1.92 - 1.86 (m, 1H), 1.73 (d, J = 13.9 Hz, 2H), 1.39 - 1.30 (m, 2H).

[0218] Example 67: 4-(4-(Benzo[d]thiazol-2-ylcarbamoyl)benzylidene)-N-ethylpiperidine-1-carboxamide (Compound 1-67) N-(Benzo[d]thiazol-2-yl)-4-(piperidin-4-ylidenemethyl)benzamide (75 mg, 0.17 mmol) obtained in Example 65 and ethyl isocyanate (16 μL, 0.20 mmol) were reacted in the same manner as in Example 37 to obtain 45 mg of the title compound.

[0219] 11H NMR (400 MHz, CDCl3): δ 11.20 (s, 1H), 7.97 - 7.95 (m, 2H), 7.88 - 7.83 (m, 1H), 7.43 - 7.39 (m, 1H), 7.32 - 7.28 (m, 2H), 7.27 - 7.25 (m, 2H), 6.37 (s, 1H), 4.44 (t, J = 5.4 Hz, 1H), 3.48 (t, J = 5.8 Hz, 2H), 3.38 (t, J = 5.8 Hz, 2H), 3.30 (qd, J = 7.2, 5.3 Hz, 2H), 2.46 - 2.39 (m, 4H), 1.16 (t, J = 7.2 Hz, 3H).

[0220] Example 68: 4-(4-(Benzothiazol-2-ylcarbamoyl)benzylidene)-N-phenylpiperidine-1-carboxamide (Compound 1-68) Phenyl isocyanate (22 μL, 0.20 mmol) was reacted in the same manner as in Example 67 to obtain 51 mg of the title compound.

[0221] 1 1H NMR (400 MHz, CDCl3): δ 10.91 (s, 1H), 7.98 - 7.96 (m, 2H), 7.87 - 7.85 (m, 1H), 7.53 - 7.41 (m, 1H), 7.38 - 7.27 (m, 8H), 7.05 (tt, J = 7.0, 1.3 Hz, 1H), 6.52 (s, 1H), 6.42 (s, 1H), 3.61 (t, J = 5.9 Hz, 2H), 3.52 (t, J = 5.9 Hz, 2H), 2.56 - 2.53 (m, 2H), 2.51 - 2.47 (m, 2H).

[0222] Example 69: 4-(4-(Benzothiazol-2-ylcarbamoyl)benzyl)-N-ethylpiperidine-1-carboxamide (Compound 1-69) N-(Benzothiazol-2-yl)-4-(piperidin-4-ylmethyl)benzamide (75 mg, 0.17 mmol) obtained in Example 66 and ethyl isocyanate (16 μL, 0.20 mmol) were reacted in the same manner as in Example 37 to obtain 40 mg of the title compound.

[0223] 1 H NMR (400 MHz, CDCl3): δ 11.03 (s, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.87 - 7.83 (m, 1H), 7.48 - 7.44 (m, 1H), 7.33 - 7.28 (m, 2H), 7.23 (d, J = 8.2 Hz, 2H), 4.38 (t, J = 5.4 Hz, 1H), 3.91 (dt, J = 13.0, 2.9 Hz, 2H), 3.27 (qd, J = 7.2, 5.3 Hz, 2H), 2.70 (td, J = 12.9, 2.6 Hz, 2H), 2.59 (d, J = 7.1 Hz, 2H), 1.72 - 1.66 (m, 1H), 1.63 - 1.58 (m, 2H), 1.20 - 1.12 (m, 5H).

[0224] Example 70: 4-(4-(Benzothiazol-2-ylcarbamoyl)benzyl)-N-ethylpiperidine-1-carboxamide (Compound 1-70) Phenyl isocyanate (22 μL, 0.20 mmol) was reacted in the same manner as in Example 69 to obtain 51 mg of the title compound.

[0225] 11H NMR (400 MHz, DMSO): δ 12.80 (s, 1H), 8.43 (s, 1H), 8.10 (d, J = 8.0 Hz, 2H), 8.02 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.49 - 7.44 (m, 3H), 7.40 (d, J = 7.9 Hz, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.21 (t, J = 7.9 Hz, 2H), 6.91 (t, J = 7.3 Hz, 1H), 4.11 (d, J = 13.2 Hz, 2H), 2.77 - 2.70 (m, 2H), 2.65 (d, J = 7.2 Hz, 2H), 1.86 - 1.77 (m, 1H), 1.62 - 1.58 (m, 2H), 1.20 - 1.10 (m, 2H).

[0226] Example 71: 4 - (((1S,4S)-2,5 - Diazabicyclo[2.2.1]heptan - 2 - yl)methyl)-N-(benzothiazol - 2 - yl)benzamide (Compound 1 - 71) The tert - butyl (1S,4S)-5-(4-(benzothiazol - 2 - ylcarbamoyl)benzyl)-2,5 - diazabicyclo[2.2.1]heptane - 2 - carboxylate (300 mg, 0.65 mmol) obtained in Example 25 was reacted in the same manner as in Example 3 to obtain 240 mg of the title compound.

[0227] 1H NMR (400 MHz, CDCl3): δ 9.49 (s, 1H), 9.27 (s, 1H), 8.23 (d, J = 8.3 Hz, 2H), 8.04 (dd, J = 8.0, 1.2 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.51 - 7.47 (m, 1H), 7.38 - 7.34 (m, 1H), 4.48 (s, 1H), 4.40 - 4.33 (m, 2H), 3.63 - 3.38 (m, 4H).

[0228] Example 72: (1S,4S)-5-(4-(Benzothiazol-2-ylcarbamoyl)benzyl)-N-ethyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (Compound 1-72) 4-(((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)methyl)-N-(benzothiazol-2-yl)benzamide (200 mg, 0.43 mmol) obtained in Example 71 and ethyl isocyanate (41 μL, 0.52 mmol) were reacted in the same manner as in Example 37 to obtain 118 mg of the title compound.

[0229] 1 H NMR (400 MHz, CDCl3): δ 10.84 (s, 1H), 7.96 - 7.94 (m, 2H), 7.87 - 7.84 (m, 1H), 7.52 - 7.49 (m, 1H), 7.46 - 7.44 (m, 2H), 7.37 - 7.28 (m, 2H), 4.44 (s, 1H), 4.12 - 4.09 (m, 1H), 3.78 (s, 2H), 3.48 - 3.45 (m, 2H), 3.33 - 3.26 (m, 2H), 3.18 (dt, J = 8.6, 1.9 Hz, 1H), 2.86 (dt, J = 9.6, 1.9 Hz, 1H), 2.69 (d, J = 9.6 Hz, 1H), 1.89 (d, J = 9.7 Hz, 1H), 1.74 - 1.71 (m, 1H), 1.18 - 1.14 (m, 3H).

[0230] Example 73: (1S,4S)-5-(4-(Benzothiazol-2-ylcarbamoyl)benzyl)-N-phenyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (Compound 1-73) Phenyl isocyanate (56 μL, 0.52 mmol) was reacted in the same manner as in Example 72 to obtain 114 mg of the title compound.

[0231] 11H NMR (400 MHz, CDCl3): δ 11.03 (s, 1H), 7.96 - 7.94 (m, 2H), 7.86 - 7.83 (m, 1H), 7.47 - 7.40 (m, 5H), 7.34 - 7.27 (m, 4H), 7.03 (tt, J = 7.2, 1.2 Hz, 1H), 6.19 (s, 1H), 4.57 (s, 1H), 3.80 (s, 2H), 3.61 (d, J = 8.4 Hz, 1H), 3.54 (s, 1H), 3.33 (dd, J = 8.5, 2.2 Hz, 1H), 2.88 (dd, J = 9.7, 2.1 Hz, 1H), 2.79 - 2.77 (m, 1H), 1.97 - 1.94 (m, 1H), 1.79 - 1.77 (m, 1H).

[0232] Example 74: tert-Butyl 4-(4-(benzothiazol-2-ylcarbamoyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (Compound 1-74) Compound 5 (1.00 g, 3.33 mmol) and (1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (1.00 g, 4.44 mmol) were reacted in the same manner as in Example 63 to obtain 950 mg of the title compound.

[0233] 1 1H NMR (500 MHz, CDCl3): δ 11.12 (s, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.88 - 7.82 (m, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.43 - 7.37 (m, 1H), 7.33 - 7.27 (m, 2H), 5.92 (1H, s), 3.83 (2H, m), 3.34 (2H, t, J = 5.6 Hz), 2.15 (2H, s), 1.43 (9H, s).

[0234] Example 75: N-(Benzothiazol-2-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (Compound 1-75) tert-Butyl 4-(4-(benzothiazol-2-ylcarbamoyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.46 mmol) obtained in Example 74 was reacted in the same manner as in Example 3 to obtain 189 mg of the title compound.

[0235] 1 H NMR (500 MHz, CDCl3): δ 11.14 (s, 1H), 7.97 (d, J = 8.2 Hz, 2H), 7.82 (m, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.43 (m, 1H), 7.37 (m, 2H), 5.90 (1H, s), 3.97 (2H, m), 3.34 (2H, t, J = 5.6 Hz), 2.45 (2H, s).

[0236] Example 76: 4-(4-(Benzothiazol-2-ylcarbamoyl)phenyl)-N-(4-(trifluoromethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (Compound 1-76) N-(Benzothiazol-2-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (150 mg, 0.45 mmol) obtained in Example 75 was reacted in the same manner as in Example 39 to obtain 198 mg of the title compound.

[0237] 11H NMR (500 MHz, CDCl3): δ 11.12 (s, 1H), 8.23 (d, J = 7.7 Hz, 2H), 8.03 (d, J= 7.7 Hz, 2H), 7.95 (d, J = 8.2 Hz, 2H), 7.82 (m, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.37 (m, 1H), 7.27 (m, 2H), 5.92 (1H, s), 3.83 (2H, m), 3.34 (2H, t, J = 5.6 Hz), 2.15 (2H, s).

[0238] Example 77: 4-(4-(Benzothiazol-2-ylcarbamoyl)phenyl)-N-(4-(trifluoromethyl)phenyl)piperidine-1-carboxamide (Compound 1-77) 4-(4-(Benzothiazol-2-ylcarbamoyl)phenyl)-N-(4-(trifluoromethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.19 mmol) obtained in Example 76 was reacted in the same manner as in Example 64 to obtain 69 mg of the title compound.

[0239] 1 1H NMR (500 MHz, CDCl3): δ 11.14 (s, 1H), 8.23 (d, J = 7.7 Hz, 2H), 8.03 (d, J= 7.7 Hz, 2H), 7.96 (d, J = 8.2 Hz, 2H), 7.91 - 7.81 (m, 1H), 7.54 - 7.49 (m, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.37 - 7.27 (m, 4H), 6.98 (t, J = 8.7 Hz, 2H), 6.34 (s, 1H), 2.73 (m, 1H), 1.89 (m, 2H), 1.64 (m, 2H).

[0240] Example 78: tert-Butyl 4-(4-(benzothiazol-2-ylcarbamoyl)-3-(trifluoromethyl)benzylidene)piperidine-1-carboxylate (Compound 1-78) Compound 6 (744 mg, 1.86 mmol) synthesized in Synthesis Example 6 and tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)piperidine-1-carboxylate (500 mg, 1.55 mmol) were reacted in the same manner as in Example 63 to obtain 300 mg of the title compound.

[0241] 1 H NMR (300 MHz, DMSO-d6) δ 13.02 (s, 1H), 8.09 - 7.99 (m, 1H), 7.80 (d, J = 8.2 Hz, 3H), 7.67 (d, J = 7.2 Hz, 2H), 7.54 - 7.42 (m, 2H), 7.42 - 7.30 (m, 2H), 6.53 (s, 1H), 3.46 (t, J = 5.9 Hz, 2H), 3.39 (t, J = 5.9 Hz, 3H), 2.44 (t, J = 5.9 Hz, 2H), 2.35 (t, J = 5.9 Hz, 2H), 1.43 (s, 9H).

[0242] Example 79: N-(benzothiazol-2-yl)-4-(piperidin-4-ylidenemethyl)-2-(trifluoromethyl)benzamide (Compound 1-79) tert-Butyl tert-butyl 4-(4-(benzothiazol-2-ylcarbamoyl)-3-(trifluoromethyl)benzylidene)piperidine-1-carboxylate (110 mg, 0.21 mmol) obtained in Example 78 was reacted in the same manner as in Example 3 to obtain 105 mg of the title compound.

[0243] 11H NMR (300 MHz, DMSO-d6) δ 13.05 (s, 1H), 8.82 (s, 2H), 8.04 (d, J = 7.8 Hz, 1H), 7.81 (t, J = 7.7 Hz, 2H), 7.70 (d, J = 6.4 Hz, 2H), 7.55 - 7.42 (m, 1H), 7.43 - 7.31 (m, 1H), 6.62 (s, 1H), 3.19 (dt, J = 17.0, 5.9 Hz, 4H), 2.61 (dt, J = 16.2, 5.9 Hz, 4H).

[0244] Example 80: 4-(4-(Benzothiazol-2-ylcarbamoyl)-3-(trifluoromethyl)benzylidene)-N-ethylpiperidine-1-carboxamide (Compound 1-80) N-(Benzothiazol-2-yl)-4-(piperidin-4-ylidenemethyl)-2-(trifluoromethyl)benzamide (45 mg, 0.09 mmol) obtained in Example 79 and ethyl isocyanate (6.83 mg, 0.10 mmol) were reacted in the same manner as in Example 37 to obtain 27 mg of the title compound.

[0245] 1 1H NMR (300 MHz, DMSO-d6) δ 13.00 (s, 1H), 8.09 - 7.99 (m, 1H), 7.80 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 7.1 Hz, 2H), 7.53 - 7.43 (m, 1H), 7.42 - 7.32 (m, 1H), 6.60 - 6.47 (m, 2H), 3.46 - 3.34 (m, 3H), 3.13 - 3.01 (m, 2H), 2.37 (dt, J = 24.5, 5.7 Hz, 4H), 1.03 (t, J = 7.1 Hz, 3H).

[0246] Example 81: 4-(4-(Benzothiazol-2-ylcarbamoyl)-3-(trifluoromethyl)benzylidene)-N-phenylpiperidine-1-carboxamide (Compound 1-81) N-(benzo[d]thiazol-2-yl)-4-(piperidin-4-ylidenemethyl)-2-(trifluoromethyl)benzamide (45 mg, 0.09 mmol) obtained in Example 79 and phenyl isocyanate (11.18 mg, 0.10 mmol) were reacted in the same manner as in Example 37 to obtain 33 mg of the title compound.

[0247] 1 H NMR (300 MHz, DMSO-d6) δ 12.99 (s, 1H), 8.59 (s, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.81 (dd, J = 8.1, 4.3 Hz, 2H), 7.69 (d, J = 7.2 Hz, 2H), 7.54 - 7.42 (m, 3H), 7.42 - 7.30 (m, 1H), 7.31 - 7.18 (m, 2H), 7.00 - 6.88 (m, 1H), 6.56 (s, 1H), 3.56 (dt, J = 22.4, 5.8 Hz, 4H), 2.43 (t, J = 5.7 Hz, 2H).

[0248] Example 82: tert-Butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-(trifluoromethyl)benzyl)piperidine-1-carboxylate (Compound 1-82) tert-Butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-(trifluoromethyl)benzylidene)piperidine-1-carboxylate (150 mg, 0.29 mmol) obtained in Example 78 was reacted in the same manner as in Example 64 to obtain 87 mg of the title compound.

[0249] 11H NMR (300 MHz, Chloroform-d) δ 11.79 (s, 1H), 7.84 - 7.77 (m, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.31 - 7.27 (m, 1H), 7.26 - 7.23 (m, 1H), 7.19 (td, J = 7.7, 7.2, 1.4 Hz, 1H), 7.08 (d, 1H), 4.07 (s, 2H), 2.69 - 2.51 (m, 4H), 1.70 - 1.43 (m, 13H), 1.20 - 1.02 (m, 2H).

[0250] Example 83: N-(Benzothiazol-2-yl)-4-(piperidin-4-ylmethyl)-2-(trifluoromethyl)benzamide (Compound 1-83) tert-Butyl 4-(4-(benzothiazol-2-ylcarbamoyl)-3-(trifluoromethyl)benzyl)piperidine-1-carboxylate (75 mg, 0.14 mmol) obtained in Example 82 was reacted in the same manner as in Example 79 to obtain 83 mg of the title compound.

[0251] 1 1H NMR (300 MHz, DMSO-d6) δ 13.02 (s, 1H), 8.58 (d, J = 11.6 Hz, 1H), 8.27 (d, J = 11.9 Hz, 1H), 8.04 (d, J = 7.9, 1.2 Hz, 1H), 7.84 - 7.70 (m, 3H), 7.71 - 7.59 (m, 1H), 7.53 - 7.42 (m, 1H), 7.42 - 7.31 (m, 1H), 3.27 (d, J = 12.3 Hz, 2H), 2.93 - 2.69 (m, 4H), 1.97 - 1.81 (m, 1H), 1.72 (d, J = 13.8 Hz, 2H), 1.45 - 1.26 (m, 2H).

[0252] Example 84: 4-(4-(Benzothiazol-2-ylcarbamoyl)-3-(trifluoromethyl)benzyl)-N-ethylpiperidine-1-carboxamide (Compound 1-84) N-(Benzothiazol-2-yl)-4-(piperidin-4-ylmethyl)-2-(trifluoromethyl)benzamide (41 mg, 0.10 mmol) obtained in Example 83 and ethyl isocyanate (7.6 mg, 0.11 mmol) were reacted in the same manner as in Example 37 to obtain 21 mg of the title compound.

[0253] 1 H NMR (300 MHz, DMSO-d6) δ 12.98 (s, 1H), 8.04 (d, 1H), 7.84 - 7.67 (m, 3H), 7.62 (d, J = 7.5 Hz, 1H), 7.52 - 7.42 (m, 1H), 7.41 - 7.31 (m, 1H), 6.40 (t, J = 5.4 Hz, 1H), 3.93 (d, J = 13.0 Hz, 2H), 3.10 - 2.95 (m, 2H), 2.69 (d, J = 7.0 Hz, 2H), 2.58 (t, J = 12.2 Hz, 2H), 1.82 - 1.65 (m, 1H), 1.51 (d, J = 12.7 Hz, 2H), 1.15 - 0.94 (m, 5H).

[0254] Example 85: 4-(4-(Benzothiazol-2-ylcarbamoyl)-3-(trifluoromethyl)benzyl)-N-phenylpiperidine-1-carboxamide (Compound 1-85) N-(Benzothiazol-2-yl)-4-(piperidin-4-ylmethyl)-2-(trifluoromethyl)benzamide (41 mg, 0.10 mmol) obtained in Example 83 and phenyl isocyanate (13 mg, 0.11 mmol) were reacted in the same manner as in Example 37 to obtain 25 mg of the title compound.

[0255] 11H NMR (300 MHz, DMSO-d6) δ 12.98 (s, 1H), 8.45 (s, 1H), 8.03 (d, J = 8.0, 1.2 Hz, 1H), 7.83 - 7.69 (m, 3H), 7.68 - 7.59 (m, 1H), 7.53 - 7.40 (m, 3H), 7.35 (td, J = 7.6, 1.2 Hz, 1H), 7.27 - 7.16 (m, 2H), 6.97 - 6.86 (m, 1H), 4.12 (d, J = 13.3 Hz, 2H), 2.86 - 2.64 (m, 4H), 1.89 - 1.72 (m, 1H), 1.59 (d, J = 12.6 Hz, 2H), 1.26 - 1.07 (m, 2H).

[0256] Example 86: tert-Butyl 4-(4-(benzothiazol-2-ylcarbamoyl)-3-fluorobenzylidene)piperidine-1-carboxylate (Compound 1-86) Compound 7 (2.99 g, 8.51 mmol) and tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)piperidine-1-carboxylate (2.5 g, 7.73 mmol) were reacted in the same manner as in Example 63 to obtain 1.18 g of the title compound.

[0257] 1 1H NMR (300 MHz, DMSO-d6) δ 12.75 (s, 1H), 8.09 - 7.99 (m, 1H), 7.85 - 7.72 (m, 2H), 7.54 - 7.42 (m, 1H), 7.42 - 7.30 (m, 1H), 7.30 - 7.18 (m, 2H), 6.44 (s, 1H), 3.42 (dt, J = 17.0, 6.0 Hz, 4H), 2.46 (t, J = 5.7 Hz, 4H), 2.33 (t, J = 5.5 Hz, 2H), 1.43 (s, 9H).

[0258] Example 87: N-(Benzothiazol-2-yl)-2-fluoro-4-(piperidin-4-ylidenemethyl)benzamide (Compound 1-87) tert-Butyl 4-(4-(benzothiazol-2-ylcarbamoyl)-3-fluorobenzylidene)piperidine-1-carboxylate (230 mg, 0.49 mmol) synthesized in Example 86 was reacted in the same manner as in Example 79 to obtain 321 mg of the title compound.

[0259] 1 H NMR (300 MHz, DMSO-d6) δ 8.81 (s, 2H), 8.09 - 7.99 (m, 1H), 7.87 - 7.74 (m, 2H), 7.54 - 7.42 (m, 1H), 7.42 - 7.20 (m, 3H), 6.53 (s, 1H), 3.30 - 3.10 (m, 4H), 2.66 (t, J = 6.0 Hz, 2H), 2.56 (t, J = 5.9 Hz, 3H).

[0260] Example 88: 4-(4-(Benzothiazol-2-ylcarbamoyl)-3-fluorobenzylidene)-N-ethylpiperidine-1-carboxamide (Compound 1-88) N-(Benzothiazol-2-yl)-2-fluoro-4-(piperidin-4-ylidenemethyl)benzamide (74 mg, 0.40 mmol) synthesized in Example 87 and ethyl isocyanate (31 mg, 0.44 mmol) were reacted in the same manner as in Example 63 to obtain 71 mg of the title compound.

[0261] 11H NMR (300 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.09 - 7.99 (m, 1H), 7.84 - 7.72 (m, 2H), 7.54 - 7.42 (m, 1H), 7.42 - 7.30 (m, 1H), 7.30 - 7.18 (m, 2H), 6.53 (t, J = 5.4 Hz, 1H), 6.42 (s, 1H), 3.47 - 3.34 (m, 4H), 3.15 - 2.99 (m, 2H), 2.43 (t, J = 5.8 Hz, 2H), 2.31 (t, J = 5.7 Hz, 2H), 1.03 (t, J = 7.1 Hz, 3H).

[0262] Example 89: 4-(4-(Benzothiazol-2-ylcarbamoyl)-3-fluorobenzylidene)-N-phenylpiperidine-1-carboxamide (Compound 1-89) N-(Benzothiazol-2-yl)-2-fluoro-4-(piperidin-4-ylidenemethyl)benzamide (146 mg, 0.40 mmol) synthesized in Example 87 and phenyl isocyanate (52 mg, 0.44 mmol) were reacted in the same manner as in Example 63 to obtain 71 mg of the title compound.

[0263] 1 1H NMR (300 MHz, DMSO-d6) δ 12.76 (s, 1H), 8.58 (s, 1H), 8.10 - 7.99 (m, 1H), 7.87 - 7.73 (m, 2H), 7.57 - 7.42 (m, 3H), 7.42 - 7.30 (m, 1H), 7.33 - 7.17 (m, 4H), 7.01 - 6.88 (m, 1H), 6.47 (s, 1H), 3.56 (dt, J = 19.5, 5.6 Hz, 4H), 3.18 (d, J = 5.2 Hz, 1H), 2.55 - 2.52 (m, 2H), 2.42 (t, J = 5.7 Hz, 2H).

[0264] Example 90: N-(Benzothiazol-2-yl)-2-fluoro-4-((1-(phenylsulfonyl)piperidin-4-ylidene)methyl)benzamide (Compound 1-90) N-(Benzothiazol-2-yl)-2-fluoro-4-(piperidin-4-ylidenemethyl)benzamide (120 mg, 0.33 mmol) synthesized in Example 87 and benzenesulfonyl chloride (63 mg, 0.36 mmol) were reacted in the same manner as in Example 63 to obtain 37 mg of the title compound.

[0265] 1 H NMR (300 MHz, DMSO-d6) δ 12.76 (s, 1H), 8.09 - 7.98 (m, 1H), 7.86 - 7.59 (m, 7H), 7.54 - 7.41 (m, 1H), 7.41 - 7.29 (m, 1H), 7.25 - 7.10 (m, 2H), 6.40 (s, 1H), 3.04 (dt, J = 16.4, 5.8 Hz, 4H), 2.59 - 2.52 (m, 2H), 2.49 - 2.38 (m, 2H).

[0266] Example 91: N-(Benzothiazol-2-yl)-4-((1-(ethylsulfonyl)piperidin-4-ylidene)methyl)-2-fluorobenzamide (Compound 1-91) N-(Benzothiazol-2-yl)-2-fluoro-4-(piperidin-4-ylidenemethyl)benzamide (120 mg, 0.33 mmol) synthesized in Example 87 and ethylsulfonyl chloride (46 mg, 0.36 mmol) were reacted in the same manner as in Example 63 to obtain 56 mg of the title compound.

[0267] 11H NMR (300 MHz, DMSO-d6) δ 12.77 (s, 1H), 8.09 - 7.99 (m, 1H), 7.79 (t, J = 7.6 Hz, 2H), 7.54 - 7.42 (m, 1H), 7.42 - 7.30 (m, 1H), 7.31 - 7.18 (m, 2H), 6.49 (s, 1H), 3.35 - 3.30 (m, 2H), 3.26 (t, J = 5.8 Hz, 2H), 3.08 (q, J = 7.4 Hz, 2H), 2.57 - 2.52 (m, 2H), 2.44 (t, J = 5.7 Hz, 2H), 1.22 (t, J = 7.4 Hz, 3H).

[0268] Example 92: N-(Benzothiazol-2-yl)-4-((1-benzoylpiperidin-4-ylidene)methyl)-2-fluorobenzamide (Compound 1-92) N-(Benzothiazol-2-yl)-2-fluoro-4-(piperidin-4-ylidenemethyl)benzamide (120 mg, 0.33 mmol) synthesized in Example 87 and benzoyl chloride (55 mg, 0.39 mmol) were reacted in the same manner as in Example 63 to obtain 55 mg of the title compound.

[0269] 1 1H NMR (300 MHz, DMSO-d6) δ 12.77 (s, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.79 (d, J = 8.1 Hz, 2H), 7.54 - 7.39 (m, 6H), 7.42 - 7.29 (m, 1H), 7.31 - 7.19 (m, 2H), 6.48 (s, 1H), 3.68 (s, 2H), 3.43 (s, 2H), 2.71 - 2.51 (m, 3H), 2.40 (s, 2H).

[0270] Example 93: 4-(4-(Benzothiazol-2-ylcarbamoyl)-3-fluorobenzylidene)-N-(4-(trifluoromethyl)phenyl)piperidine-1-carboxamide (Compound 1-93) N-(benzo[d]thiazol-2-yl)-2-fluoro-4-(piperidin-4-ylidenemethyl)benzamide (120 mg, 0.33 mmol) synthesized in Example 87 above and 4-(trifluoromethyl)phenyl isocyanate (67 mg, 0.36 mmol) were reacted in the same manner as in Example 63 above to obtain 75 mg of the title compound.

[0271] 1 H NMR (300 MHz, DMSO-d6) δ 12.77 (s, 1H), 8.99 (s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.85 - 7.67 (m, 4H), 7.60 (d, J = 8.7 Hz, 2H), 7.54 - 7.42 (m, 1H), 7.42 - 7.30 (m, 1H), 7.33 - 7.20 (m, 2H), 6.48 (s, 1H), 3.58 (dt, J = 19.2, 5.8 Hz, 4H), 2.60 - 2.53 (m, 2H), 2.48 - 2.37 (m, 2H).

[0272] Example 94: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-fluorobenzylidene)-N-isopropylpiperidine-1-carboxamide (Compound 1-94) N-(benzo[d]thiazol-2-yl)-2-fluoro-4-(piperidin-4-ylidenemethyl)benzamide (120 mg, 0.33 mmol) synthesized in Example 87 above and isopropyl isocyanate (31 mg, 0.36 mmol) were reacted in the same manner as in Example 63 above to obtain 75 mg of the title compound.

[0273] 11H NMR (300 MHz, DMSO-d6) δ 12.75 (s, 1H), 8.09 - 7.99 (m, 1H), 7.85 - 7.72 (m, 2H), 7.54 - 7.42 (m, 1H), 7.42 - 7.30 (m, 1H), 7.30 - 7.18 (m, 2H), 6.42 (s, 1H), 6.23 (d, J = 7.7 Hz, 1H), 3.87 - 3.70 (m, 1H), 3.39 (dt, J = 18.1, 5.8 Hz, 4H), 2.43 (t, J = 5.8 Hz, 2H), 2.31 (t, J = 5.7 Hz, 2H), 1.07 (d, J = 6.5 Hz, 6H).

[0274] Example 95: tert-Butyl 4-(4-(benzothiazol-2-ylcarbamoyl)-2-chlorobenzylidene)piperidine-1-carboxylate (Compound 1-95) Compound 8 (2.72 g, 7.40 mmol) and tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)piperidine-1-carboxylate (2.00 g, 6.20 mmol) were reacted in the same manner as in Example 63 to obtain 0.87 g of the title compound.

[0275] 1 1H NMR (300 MHz, DMSO-d6) δ 13.00 (s, 1H), 8.28 (d, J = 1.8 Hz, 1H), 8.13 - 7.98 (m, 2H), 7.80 (d, J = 8.1 Hz, 1H), 7.56 - 7.42 (m, 2H), 7.42 - 7.32 (m, 1H), 6.43 (s, 1H), 3.42 (dt, J = 23.6, 6.0 Hz, 6H), 2.34 (dt, J = 18.8, 5.9 Hz, 4H), 1.43 (s, 9H).

[0276] Example 96: N-(Benzothiazol-2-yl)-3-chloro-4-(piperidin-4-ylidenemethyl)benzamide (Compound 1-96) tert-Butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-2-chlorobenzylidene)piperidine-1-carboxylate (580 mg, 1.20 mmol) synthesized in Example 95 was reacted in the same manner as in Example 79 to obtain 480 mg of the title compound.

[0277] 1 H NMR (300 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.80 (d, J = 8.1 Hz, 2H), 7.51 - 7.34 (m, 6H), 7.40 - 7.19 (m, 1H), 7.31 - 7.19 (m, 2H), 6.41 (s, 1H), 3.61 (s, 2H), 3.40 (s, 2H), 2.70 - 2.41 (m, 3H), 2.40 (s, 2H).

[0278] Example 97: 4-(4-(Benzo[d]thiazol-2-ylcarbamoyl)-2-chlorobenzylidene)-N-ethylpiperidine-1-carboxamide (Compound 1-97) N-(Benzo[d]thiazol-2-yl)-3-chloro-4-(piperidin-4-ylidenemethyl)benzamide (65 mg, 0.18 mmol) synthesized in Example 96 and ethyl isocyanate (13 mg, 0.19 mmol) were reacted in the same manner as in Example 63 to obtain 36 mg of the title compound.

[0279] 11H NMR (300 MHz, DMSO-d6) δ 12.99 (s, 1H), 8.27 (d, J = 1.8 Hz, 1H), 8.13 - 7.99 (m, 2H), 7.80 (d, J = 8.1 Hz, 1H), 7.56 - 7.43 (m, 2H), 7.42 - 7.30 (m, 1H), 6.56 (t, J = 5.4 Hz, 1H), 6.41 (s, 1H), 3.48 - 3.40 (m, 2H), 3.15 - 2.99 (m, 2H), 2.40 - 2.23 (m, 4H), 1.02 (t, J = 7.1 Hz, 3H).

[0280] Example 98: tert-Butyl 4-(4-(benzothiazol-2-ylcarbamoyl)-3,5-difluorobenzylidene)piperidine-1-carboxylate (Compound 1-98) Compound 9 (1.37 g, 3.70 mmol) and tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)piperidine-1-carboxylate (1.00 g, 3.10 mmol) were reacted in the same manner as in Example 63 to obtain 400 mg of the title compound.

[0281] 1 1H NMR (300 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.06 (dd, J = 7.8, 1.2 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.56 - 7.43 (m, 2H), 7.44 - 7.32 (m, 1H), 7.16 (d, J = 9.2 Hz, 2H), 6.42 (s, 1H), 3.49 - 3.32 (m, 7H), 2.46 (t, J = 5.8 Hz, 8H), 2.33 (t, J = 5.8 Hz, 2H), 1.43 (s, 10H).

[0282] Example 99: N-(benzothiazol-2-yl)-2,6-difluoro-4-(piperidin-4-ylidenemethyl)benzamide (Compound 1-99) tert-Butyl 4-(4-(benzothiazol-2-ylcarbamoyl)-3,5-difluorobenzylidene)piperidine-1-carboxylate (58 mg, 0.12 mmol) synthesized in Example 98 was reacted in the same manner as in Example 79 to obtain 47 mg of the title compound.

[0283] 1 H NMR (300 MHz, DMSO-d6) δ 8.82 (s, 2H), 8.10 - 7.97 (m, 1H), 7.85 - 7.74 (m, 2H), 7.54 - 7.42 (m, 1H), 7.41 - 7.20 (m, 3H), 6.51 (s, 1H), 3.32 - 3.08 (m, 4H), 2.64 (t, J = 6.0 Hz, 2H), 2.51 (t, J = 5.9 Hz, 3H).

[0284] Example 100: 4-(4-(Benzothiazol-2-ylcarbamoyl)-3,5-difluorobenzylidene)-N-ethylpiperidine-1-carboxamide (Compound 1-100) N-(Benzothiazol-2-yl)-2,6-difluoro-4-(piperidin-4-ylidenemethyl)benzamide (69 mg) synthesized in Example 99 and ethyl isocyanate (14 mg, 0.20 mmol) were reacted in the same manner as in Example 63 to obtain 34 mg of the title compound.

[0285] 11H NMR (300 MHz, DMSO-d6) δ 13.16 (s, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.55 - 7.43 (m, 1H), 7.44 - 7.32 (m, 1H), 7.16 (d, J = 9.2 Hz, 2H), 6.55 (t, J = 5.4 Hz, 1H), 6.40 (s, 1H), 3.46 - 3.33 (m, 4H), 3.15 - 2.99 (m, 2H), 2.43 (t, J = 5.8 Hz, 2H), 2.30 (t, J = 5.8 Hz, 2H), 1.03 (t, J = 7.1 Hz, 3H).

[0286] Example 101: 4-(4-(Benzothiazol-2-ylcarbamoyl)-3,5-difluorobenzylidene)-N-phenylpiperidine-1-carboxamide (Compound 1-101) N-(Benzothiazol-2-yl)-2,6-difluoro-4-(piperidin-4-ylidenemethyl)benzamide (69 mg) synthesized in Example 99 and phenyl isocyanate (19 mg, 0.16 mmol) were reacted in the same manner as in Example 63 to obtain 29 mg of the title compound.

[0287] 1 1H NMR (300 MHz, DMSO-d6) δ 13.18 (s, 1H), 8.60 (s, 1H), 8.11 - 8.01 (m, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.56 - 7.43 (m, 3H), 7.44 - 7.32 (m, 1H), 7.30 - 7.13 (m, 4H), 7.00 - 6.88 (m, 1H), 6.45 (s, 1H), 3.56 (dt, J = 17.1, 5.9 Hz, 4H), 2.41 (t, J = 5.8 Hz, 2H).

[0288] Example 102: 4-(4-(Benzothiazol-2-ylcarbamoyl)-3,5-difluorobenzylidene)-N-(4-(trifluoromethyl)phenyl)piperidine-1-carboxamide (Compound 1-102) N-(Benzothiazol-2-yl)-2,6-difluoro-4-(piperidin-4-ylidenemethyl)benzamide (69 mg) synthesized in Example 99 and 4-(trifluoromethyl)phenyl isocyanate (30 mg, 0.16 mmol) were reacted in the same manner as in Example 63 to obtain 40 mg of the title compound.

[0289] 1 H NMR (300 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.00 (s, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 8.7 Hz, 2H), 7.55 - 7.43 (m, 1H), 7.44 - 7.32 (m, 1H), 7.19 (d, J = 9.2 Hz, 2H), 6.45 (s, 1H), 3.58 (dt, J = 16.6, 5.9 Hz, 4H), 2.54 (s, 4H), 2.44 (d, J = 5.8 Hz, 2H).

[0290] Example 103: tert-Butyl 4-(4-(benzothiazol-2-ylcarbamoyl)-3-chlorobenzylidene)piperidine-1-carboxylate (Compound 1-103) Compound 10 (525 mg, 1.43 mmol) and tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)piperidine-1-carboxylate (692 mg, 2.14 mmol) were reacted in the same manner as in Example 63 to obtain 330 mg of the title compound.

[0291] 1H NMR (300 MHz, DMSO-d6) δ 12.92 (s, 1H), 8.09 - 7.99 (m, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.54 - 7.40 (m, 2H), 7.42 - 7.29 (m, 2H), 6.43 (s, 1H), 3.41 (dt, J = 18.4, 5.9 Hz, 7H), 2.44 (t, J = 6.0 Hz, 2H), 2.33 (t, J = 5.7 Hz, 2H), 1.43 (s, 9H).

[0292] Example 104: N-(benzo[d]thiazol-2-yl)-2-chloro-4-(piperidin-4-ylidenemethyl)benzamide (Compound 1-104) tert-Butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-chlorobenzylidene)piperidine-1-carboxylate (320 mg, 0.66 mmol) synthesized in Example 103 was reacted in the same manner as in Example 79 to obtain 300 mg of the title compound.

[0293] 1 H NMR (300 MHz, DMSO-d6) δ 12.72 (s, 1H), 8.07 - 7.87 (m, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.54 - 7.40 (m, 2H), 7.42 - 7.29 (m, 2H), 6.45 (s, 1H), 3.44 (dt, J = 18.4, 5.9 Hz, 7H), 2.48 (t, J = 6.0 Hz, 2H), 2.37 (t, J = 5.7 Hz, 2H).

[0294] Example 105: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-chlorobenzylidene)-N-ethylpiperidine-1-carboxamide (Compound 1-105) N-(benzothiazol-2-yl)-2-chloro-4-(piperidin-4-ylidenemethyl)benzamide (100 mg, 0.26 mmol) synthesized in Example 104 and ethyl isocyanate (20 mg, 0.27 mmol) were reacted in the same manner as in Example 63 to obtain 45 mg of the title compound.

[0295] 1 H NMR (300 MHz, DMSO-d6) δ 12.91 (s, 1H), 8.04 (d, J = 8.0, 1.2 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.54 - 7.40 (m, 2H), 7.42 - 7.28 (m, 2H), 6.54 (t, J = 5.4 Hz, 1H), 6.41 (s, 1H), 3.42 (t, J = 5.7 Hz, 3H), 3.07 (qd, J = 7.1, 5.2 Hz, 2H), 2.35 (dt, J = 30.4, 5.7 Hz, 4H), 1.03 (t, J = 7.1 Hz, 3H).

[0296] Example 106: 4-(4-(benzothiazol-2-ylcarbamoyl)-3-chlorobenzylidene)-N-phenylpiperidine-1-carboxamide (Compound 1-106) N-(benzothiazol-2-yl)-2-chloro-4-(piperidin-4-ylidenemethyl)benzamide (100 mg, 0.26 mmol) synthesized in Example 104 and phenyl isocyanate (34 mg, 0.29 mmol) were reacted in the same manner as in Example 63 to obtain 54 mg of the title compound.

[0297] 11H NMR (300 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.59 (s, 1H), 8.09 - 8.00 (m, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.54 - 7.42 (m, 4H), 7.42 - 7.31 (m, 2H), 7.24 (t, J = 7.9 Hz, 2H), 7.00 - 6.89 (m, 1H), 6.46 (s, 1H), 3.56 (dt, J = 21.1, 5.8 Hz, 4H), 2.47 - 2.35 (m, 2H).

[0298] Example 107: 4-(4-(Benzothiazol-2-ylcarbamoyl)-3-chlorobenzylidene)-N-(4-(trifluoromethyl)phenyl)piperidine-1-carboxamide (Compound 1-107) N-(Benzothiazol-2-yl)-2-chloro-4-(piperidin-4-ylidenemethyl)benzamide (100 mg, 0.26 mmol) synthesized in Example 104 and 4-(trifluoromethyl)phenyl isocyanate (51 mg, 0.29 mmol) were reacted in the same manner as in Example 63 to obtain 57 mg of the title compound.

[0299] 1 1H NMR (300 MHz, DMSO-d6) δ 12.92 (s, 1H), 8.99 (s, 1H), 8.08 - 8.00 (m, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.76 - 7.65 (m, 3H), 7.60 (d, J = 8.7 Hz, 2H), 7.52 - 7.42 (m, 2H), 7.41 - 7.32 (m, 2H), 6.47 (s, 1H), 3.58 (dt, J = 20.6, 6.0 Hz, 4H), 2.43 (t, J = 5.7 Hz, 2H).

[0300] Example 108: 4-(4-(Benzothiazol-2-ylcarbamoyl)-3-chlorobenzylidene)-N-(4-fluorophenyl)piperidine-1-carboxamide (Compound 1-108) N-(Benzothiazol-2-yl)-2-chloro-4-(piperidin-4-ylidenemethyl)benzamide (200 mg, 0.52) synthesized in Example 104 and 4-fluorophenyl isocyanate (78 mg, 0.57 mmol) were reacted in the same manner as in Example 63 to obtain 117 mg of the title compound.

[0301] 1 H NMR (300 MHz, DMSO-d6) δ 12.92 (s, 1H), 8.63 (s, 1H), 8.04 (dd, J = 8.0, 1.2 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.54 - 7.43 (m, 4H), 7.41 - 7.31 (m, 2H), 7.14 - 7.02 (m, 2H), 6.46 (s, 1H), 3.55 (dt, J = 20.9, 5.7 Hz, 4H), 2.50 - 2.35 (m, 4H).

[0302] Example 109: tert-Butyl 4-((5-(benzothiazol-2-ylcarbamoyl)thiophen-2-yl)methylene)piperidine-1-carboxylate (Compound 1-109) Compound 11 (1.26 g, 3.71 mmol) and tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)piperidine-1-carboxylate (1.00 g, 3.09 mmol) were reacted in the same manner as in Example 63 to obtain 285 mg of the title compound.

[0303] 11H NMR (400 MHz, DMSO-d6) δ 13.23 (s, 1H), 8.79 (s, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.75 (s, 1H), 7.48 (ddd, J = 8.3, 7.3, 1.3 Hz, 1H), 7.34 (td, J = 7.7, 1.1 Hz, 1H), 6.68 (s, 1H), 3.46 (t, J = 5.9 Hz, 4H), 2.96 (t, J = 5.9 Hz, 2H), 2.39 (t, J = 5.9 Hz, 2H), 1.43 (s, 9H).

[0304] Example 110: N-(Benzothiazol-2-yl)-5-(piperidin-4-ylidenemethyl)thiophene-2-carboxamide (Compound 1-110) tert-Butyl 4-((5-(benzothiazol-2-ylcarbamoyl)thiophen-2-yl)methylene)piperidine-1-carboxylate (250 mg, 0.55 mmol) synthesized in Example 109 was reacted in the same manner as in Example 79 to obtain 377 mg of the title compound.

[0305] MS (ESI) m / z calcd for C 18 H 17 N3OS2[M] + , 355.1; found, 356.3 [M + H] + .

[0306] Example 111: 4-((5-(Benzothiazol-2-ylcarbamoyl)thiophen-2-yl)methylene)-N-ethylpiperidine-1-carboxamide (Compound 1-111) N-(Benzothiazol-2-yl)-5-(piperidin-4-ylidenemethyl)thiophene-2-carboxamide (100 mg, 0.28 mmol) synthesized in Example 109 and ethyl isocyanate (22 mg, 0.31 mmol) were reacted in the same manner as in Example 63 to obtain 47 mg of the title compound.

[0307] 1 1H NMR (300 MHz, DMSO-d6) δ 12.98 (s, 1H), 8.20 (s, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.47 (ddd, J = 8.3, 7.3, 1.3 Hz, 1H), 7.33 (td, J = 7.6, 1.2 Hz, 1H), 7.15 (d, J = 4.0 Hz, 1H), 6.55 (d, J = 7.0 Hz, 2H), 3.47 - 3.39 (m, 4H), 3.07 (qd, J = 7.1, 5.2 Hz, 2H), 2.63 - 2.54 (m, 2H), 2.34 (t, J = 5.7 Hz, 2H), 1.03 (t, J = 7.1 Hz, 3H).

[0308] Example 112: 4-((5-(Benzothiazol-2-ylcarbamoyl)thiophen-2-yl)methylene)-N-phenylpiperidine-1-carboxamide (Compound 1-112) N-(Benzothiazol-2-yl)-5-(piperidin-4-ylidenemethyl)thiophene-2-carboxamide (100 mg, 0.28 mmol) synthesized in Example 109 and phenyl isocyanate (37 mg, 0.31 mmol) were reacted in the same manner as in Example 63 to obtain 54 mg of the title compound.

[0309] 1 1H NMR (300 MHz, DMSO-d6) δ 12.99 (s, 1H), 8.58 (s, 1H), 8.22 (s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.55 - 7.43 (m, 3H), 7.39 - 7.28 (m, 1H), 7.29 - 7.15 (m, 3H), 7.00 - 6.90 (m, 1H), 6.61 (s, 1H), 3.65 - 3.54 (m, 4H), 2.69 (d, J = 5.7 Hz, 2H), 2.46 (d, J = 5.8 Hz, 2H).

[0310] Example 113: 4-((5-(Benzothiazol-2-ylcarbamoyl)thiophen-2-yl)methylene)-N-(4-fluorophenyl)piperidine-1-carboxamide (Compound 1-113) N-(Benzothiazol-2-yl)-5-(piperidin-4-ylidenemethyl)thiophene-2-carboxamide (100 mg, 0.28 mmol) synthesized in Example 109 and 4-(trifluoromethyl)phenyl isocyanate (42 mg, 0.31 mmol) were reacted in the same manner as in Example 63 to obtain 58 mg of the title compound.

[0311] 1 H NMR (300 MHz, DMSO-d6) δ 12.98 (s, 1H), 8.62 (s, 1H), 8.22 (s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.48 (dddd, J = 8.4, 6.4, 4.3, 2.5 Hz, 3H), 7.34 (td, J = 7.6, 1.2 Hz, 1H), 7.18 (d, J = 4.0 Hz, 1H), 7.15 - 7.00 (m, 2H), 6.61 (s, 1H), 3.58 (q, J = 5.4 Hz, 4H), 2.68 (t, J = 5.8 Hz, 2H), 2.44 (t, J = 5.8 Hz, 2H).

[0312] Example 114: tert-Butyl 4-((5-(benzothiazol-2-ylcarbamoyl)thiazol-2-yl)methylene)piperidine-1-carboxylate (Compound 1-114) Compound 12 (1.26 g, 3.71 mmol) and tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)piperidine-1-carboxylate (1.00 g, 3.09 mmol) were reacted in the same manner as in Example 63 to obtain 350 mg of the title compound.

[0313] 1 1H NMR (400 MHz, DMSO-d6) δ 13.23 (s, 1H), 8.79 (s, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.75 (s, 1H), 7.48 (ddd, J = 8.3, 7.3, 1.3 Hz, 1H), 7.34 (td, J = 7.7, 1.1 Hz, 1H), 6.68 (s, 1H), 3.46 (t, J = 5.9 Hz, 4H), 2.96 (t, J = 5.9 Hz, 2H), 2.39 (t, J = 5.9 Hz, 2H), 1.43 (s, 9H).

[0314] Example 115: N-(Benzothiazol-2-yl)-2-(piperidin-4-ylidenemethyl)thiazole-5-carboxamide (Compound 1-115) tert-Butyl 4-((5-(benzothiazol-2-ylcarbamoyl)thiazol-2-yl)methylene)piperidine-1-carboxylate (250 mg, 0.55 mmol) synthesized in Example 114 was reacted in the same manner as in Example 79 to obtain 374 mg of the title compound.

[0315] MS (ESI) m / z calcd for C 17 H 16 N4OS2 [M] + , 356.1; found, 357.1 [M + H] +

[0316] Example 116: N-(Benzothiazol-2-yl)-2-((1-(ethylcarbamoyl)piperidin-4-ylidene)methyl)thiazole-5-carboxamide (Compound 1-116) N-(Benzothiazol-2-yl)-2-(piperidin-4-ylidenemethyl)thiazole-5-carboxamide (120 mg, 0.34 mmol) synthesized in Example 115 and ethyl isocyanate (26 mg, 0.31 mmol) were reacted in the same manner as in Example 63 to obtain 47 mg of the title compound.

[0317] 1 1H NMR (400 MHz, DMSO-d6) δ 13.22 (s, 1H), 8.79 (s, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.54 - 7.42 (m, 1H), 7.41 - 7.30 (m, 1H), 6.67 (s, 1H), 6.55 (t, J = 5.4 Hz, 1H), 3.44 (t, J = 5.7 Hz, 4H), 3.08 (qd, J = 7.1, 5.1 Hz, 2H), 2.91 (t, J = 5.7 Hz, 2H), 2.37 (t, J = 5.7 Hz, 2H), 1.03 (t, J = 7.1 Hz, 3H).

[0318] Example 117: N-(Benzothiazol-2-yl)-2-((1-(phenylcarbamoyl)piperidin-4-ylidene)methyl)thiazole-5-carboxamide (Compound 1-117) N-(Benzothiazol-2-yl)-2-(piperidin-4-ylidenemethyl)thiazole-5-carboxamide (120 mg, 0.34 mmol) synthesized in Example 115 and phenyl isocyanate (44 mg, 0.37 mmol) were reacted in the same manner as in Example 63 to obtain 48 mg of the title compound.

[0319] 1 1H NMR (400 MHz, DMSO-d6) δ 13.22 (s, 1H), 8.81 (s, 1H), 8.59 (s, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.76 (s, 1H), 7.53 - 7.44 (m, 3H), 7.39 - 7.31 (m, 1H), 7.28 - 7.20 (m, 2H), 6.98 - 6.91 (m, 1H), 6.72 (s, 1H), 3.61 (dq, J = 6.5, 3.9 Hz, 4H), 3.02 (t, J = 5.8 Hz, 2H), 2.47 (d, J = 6.0 Hz, 2H).

[0320] Example 118: N-(Benzothiazol-2-yl)-2-((1-((4-fluorophenyl)carbamoyl)piperidin-4-ylidene)methyl)thiazole-5-carboxamide (Compound 1-118) N-(Benzothiazol-2-yl)-2-(piperidin-4-ylidenemethyl)thiazole-5-carboxamide (120 mg, 0.34 mmol) synthesized in Example 115 and 4-(trifluoromethyl)phenyl isocyanate (51 mg, 0.37 mmol) were reacted in the same manner as in Example 63 to obtain 56 mg of the title compound.

[0321] 1 H NMR (400 MHz, DMSO-d6) δ 13.23 (s, 1H), 8.80 (s, 1H), 8.63 (s, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.83 - 7.69 (m, 1H), 7.55 - 7.43 (m, 3H), 7.40 - 7.30 (m, 1H), 7.15 - 7.04 (m, 2H), 6.71 (s, 1H), 3.65 - 3.56 (m, 4H), 3.01 (t, J = 5.8 Hz, 2H), 2.47 (d, J = 6.0 Hz, 4H).

[0322] Example 119: tert-Butyl 4-(4-(benzothiazol-2-ylcarbamoyl)-3-methylbenzylidene)piperidine-1-carboxylate (Compound 1-119) Compound 13 (700 mg, 2.02 mmol) and tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)piperidine-1-carboxylate (977 mg, 3.02 mmol) were reacted in the same manner as in Example 63 to obtain 552 mg of the title compound.

[0323] 11H NMR (300 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.07 - 7.97 (m, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.53 - 7.41 (m, 1H), 7.40 - 7.28 (m, 1H), 7.19 (d, J = 8.3 Hz, 2H), 6.41 (s, 1H), 3.41 (dt, J = 20.9, 5.9 Hz, 7H), 2.45 (s, 5H), 2.32 (t, J = 5.9 Hz, 2H), 1.43 (s, 9H).

[0324] Example 120: N-(Benzothiazol-2-yl)-2-methyl-4-(piperidin-4-ylidenemethyl)benzamide (Compound 1-120) tert-Butyl 4-(4-(benzothiazol-2-ylcarbamoyl)-3-methylbenzylidene)piperidine-1-carboxylate (420 mg, 0.91 mmol) synthesized in Example 119 was reacted in the same manner as in Example 79 to obtain 700 mg of the title compound.

[0325] 1 1H NMR (400 MHz, DMSO-d6) δ 8.02 (dd, J = 7.9, 1.2 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.47 (td, J = 8.2, 7.7, 1.3 Hz, 1H), 7.35 (td, J = 7.6, 1.1 Hz, 1H), 7.22 (d, J = 7.6 Hz, 2H), 6.50 (s, 1H), 3.25 - 3.07 (m, 4H), 2.60 (dt, J = 39.0, 6.0 Hz, 4H), 2.46 (s, 3H).

[0326] Example 121: 4-(4-(Benzothiazol-2-ylcarbamoyl)-3-methylbenzylidene)-N-ethylpiperidine-1-carboxamide (Compound 1-121) N-(benzothiazol-2-yl)-2-methyl-4-(piperidin-4-ylidenemethyl)benzamide (150 mg, 0.41 mmol) synthesized in Example 120 and ethyl isocyanate (32 mg, 0.45 mmol) were reacted in the same manner as in Example 63 to obtain 70 mg of the title compound.

[0327] 1 H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.02 (dd, J = 7.9, 1.1 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.51 - 7.42 (m, 1H), 7.39 - 7.30 (m, 1H), 7.19 (d, J = 8.1 Hz, 2H), 6.52 (t, J = 5.4 Hz, 1H), 6.39 (s, 1H), 3.45 - 3.37 (m, 2H), 3.35 (s, 4H), 3.12 - 3.03 (m, 2H), 2.45 (s, 3H), 2.41 (t, J = 5.9 Hz, 5H), 2.30 (t, J = 5.7 Hz, 2H), 1.03 (t, J = 7.1 Hz, 3H).

[0328] Example 122: 4-(4-(benzothiazol-2-ylcarbamoyl)-3-methylbenzylidene)-N-phenylpiperidine-1-carboxamide (Compound 1-122) N-(benzothiazol-2-yl)-2-methyl-4-(piperidin-4-ylidenemethyl)benzamide (150 mg, 0.41 mmol) synthesized in Example 120 and ethyl isocyanate (54 mg, 0.45 mmol) were reacted in the same manner as in Example 63 to obtain 85 mg of the title compound.

[0329] 11H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.02 (dd, J = 7.9, 1.1 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.51 - 7.42 (m, 1H), 7.39 - 7.30 (m, 1H), 7.19 (d, J = 8.1 Hz, 2H), 6.52 (t, J = 5.4 Hz, 1H), 6.39 (s, 1H), 3.45 - 3.37 (m, 2H), 3.35 (s, 4H), 3.12 - 3.03 (m, 2H), 2.45 (s, 3H), 2.41 (t, J = 5.9 Hz, 5H), 2.30 (t, J = 5.7 Hz, 2H), 1.03 (t, J = 7.1 Hz, 3H).

[0330] Example 123: 4-(4-(Benzothiazol-2-ylcarbamoyl)-3-methylbenzylidene)-N-(4-fluorophenyl)piperidine-1-carboxamide (Compound 1-123) N-(Benzothiazol-2-yl)-2-methyl-4-(piperidin-4-ylidenemethyl)benzamide (150 mg, 0.41 mmol) synthesized in Example 120 and 4-(trifluoromethyl)phenyl isocyanate (62 mg, 0.45 mmol) were reacted in the same manner as in Example 63 to obtain 88 mg of the title compound.

[0331] 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.61 (s, 1H), 8.02 (dd, J = 8.1, 1.1 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.53 - 7.42 (m, 3H), 7.34 (td, J = 7.7, 1.2 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.12 - 7.04 (m, 2H), 6.43 (s, 1H), 3.63 - 3.54 (m, 2H), 3.50 (t, J = 5.7 Hz, 2H), 2.54 - 2.51 (m, 2H), 2.46 (s, 3H), 2.40 (t, J = 5.8 Hz, 2H).

[0332] Experimental Example 1: Measurement of Sirt7 Inhibitory Activity The Cat.No.6450 SIRT Glo assay kit manufactured by Promega was used, and the Cat.No.S41-30H protein manufactured by SignalChem was used as the target SIRT7 protein. The compound was prepared by diluting it in advance to a concentration twice the final concentration in SIRT Glo buffer. 5 μL of sirt7 protein diluted in SIRT Glo buffer so that 20 ng per well was dispensed into the positive control group and the compound group in a white 384-well plate (Greiner Bio-one, white, small volume, Cat.No.874075). 10 μL of SIRT Glo buffer was dispensed into the background target group.

[0333] 5 μL of SIRT Glo buffer was added to the positive control group, and 5 μL of the diluted compound was added to the compound group, and the reaction was carried out for 30 minutes. The substrate provided in the SIRT Glo assay was prepared, 10 μL was added each, and after reacting for 1 hour, the luciferase activity was measured with a microplate reader (manufactured by Molecular Devices, spectramax i3).

[0334] The background control group luciferase values of all wells were subtracted. The sirt7 activity inhibition rate of the compound was determined by the formula % inhibition activity of the compound = 100 - (compound group / positive control group) × 100. The results are shown in Table 1 below.

Table 1

[0335] Experimental Example 2: Cancer cell growth inhibitory effect of Sirt7 inhibitor compounds KRAS is part of the RAS / MAPK pathway, and this signal promotes cell growth and proliferation and contributes to the carcinogenesis process. Mutations in KRAS are found in about 20% of solid cancers, and are commonly seen in the pancreas, colon, and lung cancers. There is a report that Sirt7 increases MAPK activity through upregulation of p-ERK and p-MEK, and increases colon cancer. Therefore, in this experiment, the cancer cell growth inhibitory activity of the compound of the present invention was evaluated using human colon cancer cells COLO320DM (KRAS wild type) and SW480 (KRAS mutant) cells.

[0336] Cell growth was measured by measuring cytotoxicity using CCK-8 (Cell counting kit: Cat. No. CK04 manufactured by Dojindo), and the presence or absence of orange color formation due to the activity of dehydrogenase enzyme of living cells was measured at an absorbance of 450 nm. COLO320DM and SW480 cells were seeded at 3,000 cells per well in a 96-well plate (manufactured by BD Falcon, Cat. No. 353072), and after 24 hours, each selected inhibitor compound was treated. The medium was changed at 2-day intervals, and the treatment was carried out for a total of 4 days in a method of treating the inhibitor compounds together. For cell growth, 10 μL of CCK-8 was treated per well, reacted at 37 °C for 30 minutes, and then measured with a microplate reader (Molecular Devices, spectramax i3) at a wavelength of 450 nm.

[0337] As a comparative compound, the Sirt7 inhibitor reported in Biochem Biophys Res Commun. 2019;508:451-457 was synthesized and used. Hereinafter, 97491 represents the comparative compound.

[0338] As a result, referring to Figure 1A, in COLO320DM cells, the comparative compound (97491) showed an LD50 of 22.5 μM, the compound 1-37 of the present invention showed an LD50 of 12.7 μM, and the compound 1-38 of the present invention showed an LD50 of 16.2 μM. In SW480 cells, it was observed that the comparative compound (97491) showed an LD50 of 23.3 μM, the compound 1-37 of the present invention showed an LD50 of 3976 μM, and the compound 1-38 of the present invention showed an LD50 of 1137 μM.

[0339] Also, referring to Figure 1B, in COLO320DM cells, the comparative compound (97491) showed an LD50 of 19.2 μM, the compound 1-37 of the present invention showed an LD50 of 23.6 μM, and the compound 1-38 of the present invention showed an LD50 of 24.2 μM. In HT29 cells, it was observed that the comparative compound (97491) showed an LD50 of 16.4 μM, the compound 1-37 of the present invention showed an LD50 of 19.7 μM, and the compound 1-38 of the present invention showed an LD50 of 6.7 μM.

[0340] Also, referring to Figure 1C, in SW480 cells, the comparative compound (97491) showed an LD50 of 18 μM, the compound 1-37 of the present invention showed an LD50 of 68.4 μM, and the compound 1-38 of the present invention showed an LD50 of 28 μM. In SW620 cells, it was confirmed that the comparative compound (97491) showed an LD50 of 18.1 μM, the compound 1-37 of the present invention showed an LD50 of 48 μM, and the compound 1-38 of the present invention showed an LD50 of 24.8 μM.

[0341] Experimental Example 3: Lactate dehydrogenase (LDH) cytotoxicity experiment LDH (lactate dehydrogenase) is an enzyme present in the cytoplasm and usually does not pass through the cell membrane. However, when the cell membrane is damaged, it is released outside the cell, that is, into the culture medium. The released LDH was measured to determine the toxicity of the compound. The comparative compound (97491) and the compound 1-37 of the present invention were treated at high concentrations of 100 μM and 500 μM in COLO320DM and SW480 cells.

[0342] The Thermo Cat. No. 88953 LDHC cytotoxicity assay kit was used. 20,000 cells were seeded in a 96-well plate. After culturing for 24 hours, the cells were treated with 100 μM and 500 μM of the compound. After 48 hours, 50 μL of the culture supernatant treated with the compound was transferred to a new 96-well plate, 50 μL of the substrate mixed buffer provided in the kit was added, the light was blocked, and the reaction was carried out at room temperature for 30 minutes. Further, after adding 50 μL of the stop solution, the absorbance was measured at 490 nm using a microplate reader (Molecular Devices, spectramax i3).

[0343] As a result, referring to Fig. 2(a), in COLO320DM cells, compared with the positive control that completely damaged the cell membrane, the cytotoxicities of the comparative compound (97491) at 100 μM was 51.9%, the comparative compound (97491) at 500 μM was 59.2%, the compound 1-37 of the present invention at 100 μM was 62.1%, and the compound 1-37 of the present invention at 500 μM was 62.0%. In SW480 cells, compared with the positive control that completely damaged the cell membrane, the cytotoxicities of the comparative compound (97491) at 100 μM was 13.4%, the comparative compound (97491) at 500 μM was 46.7%, the compound 1-37 of the present invention at 100 μM was 14.8%, and the compound 1-37 of the present invention at 500 μM was 45.1% were confirmed.

[0344] Referring to Fig. 2(b), WI38 cells were treated with the comparative compound (97491) and the compound 1-37 of the present invention at high concentrations of 100 μM and 500 μM. In WI38 cells, compared with the positive control that completely damaged the cell membrane, the cytotoxicities of the comparative compound (97491) at 100 μM was 30.2%, the comparative compound (97491) at 500 μM was 54.7%, the compound 1-37 of the present invention at 100 μM was 29.9%, and the compound 1-37 of the present invention at 500 μM was 41.6%.

[0345] Experimental Example 4: Evaluation of in vivo efficacy The invention compound was administered to xenograft tumor mice to measure the in vivo efficacy of tumor inhibition. Five-week-old female BALB / C-nu mice were introduced. Human colon cancer cells, COLO320DM and SW480 cells, were separated from the culture flask using trypsin and prepared at a concentration of 1×10 8 cells / mL. They were mixed at a ratio of 1:1 with Matrigel (manufactured by Gibco, Cat. No. A14133-02) and 100 μL was subcutaneously injected into the dorsal surface of 5-week-old mice. Two weeks later, when the volume of the mouse tumor reached 100 mm 3 , oral administration of the compound was started 5 times a week. It was carried out for 3 weeks after (Day0).

[0346] The compound was dissolved in 0.1% carboxymethyl cellulose (CMC), 0.2% tween80 solution at concentrations of 2 mg / mL, 4 mg / mL, and 8 mg / mL, and 100 μL was orally administered to make the concentrations 10 mpk, 20 mpk, and 40 mpk. In the negative control group, 0.1% carboxymethyl cellulose, 0.2% tween80 solution was administered instead of the compound according to the same administration route and number of administrations. Six mice were used for each experimental group (Figure 3). The tumor size was measured once every 3 days for the major axis (L) and minor axis (W), and the volume of the tumor (mm 3 ) was calculated as (L×W×W) / 2, and the average of each group was calculated. Statistical processing was performed using the GraphPad Prism6 program, and a p-value of less than 0.05 was considered significant.

[0347] Five-week-old nude mice with thymus removed, reduced T cells, and suppressed immune systems were introduced, and human colorectal cancer cell lines COLO320DM and SW480 were subcutaneously injected. The compounds 1-37 (10 mpk, 20 mpk, 40 mpk), 1-105 (100 mpk), and 1-106 (100 mpk) of the present invention, which are Sirt7 inhibitors, were orally administered for 3 weeks. As a result, referring to FIGS. 4 to 11, the tumor size of both cell lines decreased compared to the control group given only the solution in which the reagent was dissolved. The results of the primary and secondary in vivo experiments showed the same results. When the compound 1-37 of the present invention was orally administered at 40 mpk to the mouse group injected with COLO320DM, the most significant tumor growth inhibitory effect was observed, showing a concentration-dependent tumor growth inhibitory effect.

[0348] The above description is only an illustrative explanation of the present invention. Those with ordinary knowledge in the technical field to which the present invention pertains can make various modifications without departing from the essential characteristics of the present invention. Therefore, the examples disclosed in this specification do not limit the present invention but are for the purpose of explanation, and the idea and scope of the present invention are not limited by these examples. The protection scope of the present invention should be interpreted by the following claims, and all technologies within the equivalent scope should be interpreted as being included in the scope of rights of the present invention.

Industrial Applicability

[0349] It has excellent inhibitory activity against SIRTUIN7 protein and can be used for the prevention or treatment of SIRTUIN7 protein-related diseases.

Claims

1. The following formula (1): [Wherein, X is N(R 1 )(wherein, R 1 is hydrogen, a C 1 -C 5 alkyl group, or a C 7 -C 20 arylalkyl group substituted with fluorine.) and Y is independently N or CH, R 1 is an alkyl group of C 1 to C 10 substituted or unsubstituted with hydrogen, halogen, fluorine, -SO 2 -R a {wherein R a is an alkyl group of C 1 to C 10 ; an aliphatic ring group of C 3 to C 20 ; an aryl group of C 3 substituted or unsubstituted with CF 6 to C 20 ; and -N(R')(R'') (wherein R' and R'' are each independently an alkyl group of C 1 to C 10 ).} is selected from the group consisting of. -CO-NH-R b {wherein R b is an aryl group of C 6 to C 20 , an aliphatic ring group of C 3 to C 20 , a condensed ring group of an aliphatic ring of C 3 to C 20 and an aromatic ring of C 6 to C 20 , a C 1 to C 20 alkyl group substituted or unsubstituted with halogen; and -(C m H 2m )-CO-O-(C m H 2m+1 )(wherein m is, independently of each other, an integer of 1 to 6).} and -CO-R c (where R c is C 1 ~C 10 alkyl group of C 6 ~C 20 and C 1 ~C 10 and an alkoxy group selected from the group consisting of: R 2 which are each the same or different and independent of one another and are hydrogen or halogen, a is 0 or 1, b is an integer from 0 to 3, Ar is a group represented by any one of the following formula Ar-2, formula Ar-5, formula Ar-7 to formula Ar-11, (In the formula, * represents the position of bonding to L, and *2 represents the position of bonding to the said R 1 .) L is the following formula (2-1): (Wherein L' is a single bond; C 1 ~C 10 an alkylene group represented by C 2 ~C 10 an alkenylene group represented by the formula -(C n H 2n )—O—(C n H 2n )-(wherein n is, independently of each other, an integer from 0 to 2); * represents the position where it binds to the above L, *1 represents the position where it binds to the above Ar, R 3 is each, independently of one another, the same or different and is selected from the group consisting of hydrogen, halogen, and an alkyl group of C 1 to C 10 which is substituted or unsubstituted with fluorine, c is an integer from 1 to 4.) A substituent represented by or formula (2-2): (wherein, L' is a single bond; C 1 ~C 10 alkylene group; C 2 ~C 10 alkenylene group; and -(C n H 2n )-O-(C n H 2n )-(wherein, n is independently an integer of 0 to 2 from the group consisting of.) is selected from the group consisting of, * represents the position where it binds to L, *1 represents the position where it binds to Ar.) It is a substituent represented by.] A compound represented by, its stereoisomer, tautomer, hydrate, solvate or its pharmaceutically acceptable salt.

2. The above formula (1) is the following formula (3-1): (In the formula, X, Y, R 1 , R 2 , R 3 , L', Ar, a, b, and c are defined as in claim 1. Or the following formula (3-2): (In the formula, X, Y, R 1 , R 2 , L', Ar, a and b are as defined in claim 1. The compound according to claim 1, its stereoisomer, tautomer, hydrate, solvate or pharmaceutically acceptable salt thereof, characterized in that

3. A pharmaceutical composition containing, as an active ingredient, the compound according to any one of Claims 1 to 2, its stereoisomer, tautomer, hydrate, solvate or its pharmaceutically acceptable salt.

4. A pharmaceutical composition for preventing or treating SIRTUIN7 protein-related diseases, containing, as an active ingredient, the compound according to any one of Claims 1 to 2, its stereoisomer, tautomer, hydrate, solvate or its pharmaceutically acceptable salt, wherein the SIRTUIN7 protein-related disease is any one selected from the group consisting of obesity, metabolic disorder, glucose resistance, insulin resistance, weight gain, fatty liver, liver fibrosis, hepatitis, liver cirrhosis, mitochondrial myopathy, brain disorder, diabetes, neurodegenerative disease, cardiovascular disease, eye disease, blood coagulation disorder, facial flushing, lactic acidosis, MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) and cancer. A pharmaceutical composition characterized by being.

5. The pharmaceutical composition according to Claim 4, wherein the cancer includes gastric cancer, breast cancer, uterine cancer, colon cancer, colorectal cancer, pancreatic cancer, liver cancer or prostate cancer.

6. The pharmaceutical composition according to any one of Claims 3 to 5, further comprising one or more pharmaceutically acceptable carriers.

7. The pharmaceutical composition according to any one of Claims 3 to 6, wherein the pharmaceutical composition has SIRTUIN7 inhibitory activity.

8. Use in the manufacture of a medicament for preventing or treating a SIRTUIN7 protein-related disease in a subject in need thereof, said disease being a compound according to any one of claims 1 to 2, a stereoisomer, a tautomer, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, wherein the SIRTUIN7 protein-related disease is any one selected from the group consisting of obesity, metabolic disorder, glucose resistance, insulin resistance, weight gain, fatty liver, liver fibrosis, hepatitis, liver cirrhosis, mitochondrial myopathy, brain disorder, diabetes, neurodegenerative disease, cardiovascular disease, eye disease, blood coagulation disorder, facial flushing, lactic acidosis, MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes), and cancer.

9. The use according to claim 8, wherein the cancer includes gastric cancer, breast cancer, uterine cancer, colon cancer, colorectal cancer, pancreatic cancer, liver cancer or prostate cancer.

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