Benzothiazole and benzimidazole derivatives, pharmaceutically acceptable salts, processes for their preparation and pharmaceutical compositions containing them as active ingredient

Abstract

The present application relates to a benzothiazole or benzimidazole derivative, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for preventing or treating a SIRTUIN 7 protein-related disease, which comprises the same as an active ingredient, and the SIRTUIN 7 protein has excellent inhibitory activity and can be used for preventing or treating a SIRTUIN 7 protein-related disease.

Description

Technical Field

[0001] This invention relates to a benzothiazole compound and a benzimidazole compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for the prevention or treatment of diseases related to the silent information regulator 7 (SIRTUIN 7) protein (hereinafter referred to as "SIRT7") containing the latter as an active ingredient. Background Technology

[0002] It has been reported that seven silencing information regulator (SIRTUIN) proteins, from SIRT1 to SIRT7 (hereinafter referred to as "SIRT"), have been identified to date, and SIRTs are involved in aging, metabolic diseases, and gene stability. Furthermore, SIRT7 has been reported to be present in the nucleolus and nucleoplasm (Kiran et al., FEBS J, 2013), playing an important role in cellular stress.

[0003] As an example, it has been reported that when SIRT7 is overexpressed, the expression of HIF-1α decreases independently of catalytic activity, while the expression of HIF-1α increases when treated with siRNA (Hubbi et al., J Biol Chem, 2013), thus SIRT7 intervenes in hypoxia.

[0004] Furthermore, SIRT7 is associated with hypoglycemic stress. For example, under hypoglycemic conditions or during AICAR treatment, which is an agonist of adenosine monophosphate kinase (AMPK), SIRT7 translocates from the nucleolus to the nucleoplasm. This can be seen as inhibiting rDNA transcription by reducing the binding between the nucleolus and PAF53, which can be explained as a system that responds to energy depletion (Chen et al., MolCell, 2013).

[0005] Furthermore, when the endoplasmic reticulum is stressed, SIRT7 messenger ribonucleic acid (mRNA) increases. This is because the activity of Myc is inhibited before the promoters of genes such as ribosomal protein (RPS20), which are endoplasmic reticulum stress response proteins, thus reducing the transcription of these genes. Therefore, it has been reported to inhibit endoplasmic reticulum stress (Shin et al., Cell Rep, 2013).

[0006] As another example, SIRT7 intervention in aging has been reported, including shortened lifespan (Vakhrusheva et al., Circ Res, 2008) and age-related hearing loss (Ryu et al., Cell Metabolism, 2014) in SIRT7 knockout mice, and reduced SIRT7 expression observed in aging mouse models (Lee et al., Proteomics, 2014) and in hepatocytes of aging mouse models (Ghiraldini et al., Mol Biol Cell, 2013). This suggests that SIRT7-based deacetylation of NPM1 helps inhibit aging (Lee et al., Proteomics, 2014).

[0007] Furthermore, SIRT7 interferes with DNA damage responses. For example, SIRT7 knockout mouse embryonic fibroblast (MEF) cells with higher ac-p53 knockout levels are more sensitive to adriamycin- or hydrogen peroxide-induced apoptosis (Vakhrusheva et al., J Physiol Pharmacol, 2008; Vakhrusheva et al., Cir Res, 2008). It was also observed that paraquat treatment increased homologous recombination efficiency when SIRT7 was overexpressed (Mao et al., Science, 2011). Moreover, it was found that doxorubicin-induced apoptosis or cellular senescence was reduced by inhibiting p38 and JNK activity when SIRT7 was overexpressed (Kiran et al., Exp Cell Res, 2014).

[0008] Furthermore, the association between SIRT7 and cancer has been reported. For example, SIRT7 has been reported to suppress the expression of tumor suppressor genes by mediating the deacetylation of H3K18 (Barber et al., Nature, 2012). Increased expression of SIRT7, regulated by mir-125a-5p and mir-125b, has led to increased growth of liver cancer cells (Kim et al., Hepatology, 2013). Moreover, increased SIRT7 expression has been observed in thyroid and breast cancer (de Nigris et al., Br J Cancer, 2002; Frye, Br J Cancer, 2002; Ashrafet et al., Br J Cancer, 2006).

[0009] Therefore, it is expected that compounds that inhibit SIRT7 activity or their pharmaceutically acceptable salts may be used for the treatment or prevention of SIRT7-related diseases. Summary of the Invention

[0010] Technical issues

[0011] The object of the present invention is to provide a benzothiazole derivative or a benzimidazole derivative or a pharmaceutically acceptable salt thereof that exhibits inhibitory activity against the silent information regulator 7 (SIRTUIN 7) protein (hereinafter referred to as "SIRT7").

[0012] Another object of the present invention is to provide a pharmaceutical composition comprising a benzothiazole derivative or a benzimidazole derivative or a pharmaceutically acceptable salt thereof exhibiting SIRT7 inhibitory activity for the prevention or treatment of SIRT7-related diseases.

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

[0014] Technical solution

[0015] The present invention provides a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0016] [Chemical Formula 1]

[0017]

[0018] Furthermore, in another aspect, the present invention provides a pharmaceutical composition for the prevention or treatment of SIRTUIN7 protein-related diseases comprising a compound represented by the aforementioned chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0019] Technical effect

[0020] The compounds according to the present invention have excellent inhibitory effects on SIRTUIN7 activity and have the effect of preventing or treating SIRTUIN7 protein-related diseases. Attached Figure Description

[0021] Figure 1a The results of the analysis of the inhibitory effect of COLO320DM and SW480 cells on cancer cell proliferation according to an embodiment of the present invention are shown.

[0022] Figure 1b The results of the analysis of the inhibitory effect of KRAS wild-type COLO320DM and HT29 cells on cancer cell proliferation according to an embodiment of the present invention are shown.

[0023] Figure 1c The results of the analysis of the inhibitory effect of SW480 and SW620 cells, which are KRAS mutants according to an embodiment of the present invention, on cancer cell proliferation are shown.

[0024] Figure 2 The results of an LDH cytotoxicity assay for a compound according to an embodiment of the present invention are shown. Figure 2 (a) shows the LDH assay of a cancer cell line. Figure 2 (b) shows the LDH assay in a normal lung fibroblast cell line.

[0025] Figure 3 These are photographs of mice used to evaluate the in vivo efficacy of a compound according to an embodiment of the present invention.

[0026] Figure 4 The results of in vivo efficacy evaluation (tumor size and body weight) of compounds 1-37 according to an embodiment of the present invention are shown.

[0027] Figure 5a Preliminary evaluation results of in vivo tumor size were shown for COLO320DM injected at concentrations of 1-37 according to an embodiment of the present invention.

[0028] Figure 5b These are photographs of mice showing preliminary evaluation results of in vivo tumor size in accordance with an embodiment of the present invention, after injection of compound 1-37 at concentrations of COLO320DM.

[0029] Figure 6a Preliminary evaluation results of in vivo tumor size at concentrations of compound 1-37 injected via SW480 according to an embodiment of the present invention are shown.

[0030] Figure 6b These are mouse photographs showing preliminary evaluation results of in vivo tumor size based on SW480 injection of compound 1-37 concentrations according to an embodiment of the present invention.

[0031] Figure 7 Preliminary evaluation results of in vivo body weight at concentrations of 1-37 of compound COLO320DM and SW480 injected according to an embodiment of the present invention are shown.

[0032] Figure 8a The results show secondary evaluation of in vivo tumor size at concentrations of 1-37 of compound COLO320DM injected according to an embodiment of the present invention.

[0033] Figure 8b These are photographs of mice showing secondary evaluation results of in vivo tumor size in accordance with an embodiment of the present invention, based on the injected concentrations of compound 1-37 of COLO320DM.

[0034] Figure 9a The results show secondary evaluation of in vivo tumor size at concentrations of compound 1-37 injected via SW480 according to an embodiment of the present invention.

[0035] Figure 9b These are photographs of mice showing secondary evaluation results of in vivo tumor size based on SW480 injection of compound 1-37 at concentrations according to an embodiment of the present invention.

[0036] Figure 10 The results of a secondary evaluation of in vivo body weight are shown, based on an embodiment of the present invention, using COLO320DM and SW480 injected at concentrations of compound 1-37.

[0037] Figure 11a The results of analysis on the inhibitory effect of COLO320DM injected compounds 1-105 and 1-106 on cancer cell proliferation according to an embodiment of the present invention are shown.

[0038] Figure 11bThe results show the evaluation of in vivo tumor size and weight of COLO320DM injected with compounds 1-105 and 1-106 according to an embodiment of the present invention.

[0039] Figure 11c These are photographs of mice showing the in vivo tumor size evaluation results of COLO320DM injected with compounds 1-105 and 1-106 according to an embodiment of the present invention.

[0040] Optimal Implementation

[0041] Hereinafter, a detailed description will be provided with reference to embodiments of the present invention. In describing the present invention, detailed descriptions of related well-known structures or functions will be omitted if it is determined that such specific descriptions may obscure the essence of the invention.

[0042] Unless otherwise stated, the following terms, as used in this specification and the appended claims, have the following meanings:

[0043] Unless otherwise stated, the term "halogen" as used in this invention refers to fluorine (F), bromine (Br), chlorine (Cl), or iodine (I).

[0044] The term "alkyl" or "alkyl group" as used in this invention refers to an aliphatic hydrocarbon group, and specifically to a free radical containing saturated aliphatic functional groups, including straight-chain alkyl, branched-chain alkyl, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. For example, C1-C6 alkyl groups, as aliphatic hydrocarbons having 1 to 6 carbon atoms, include all methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, etc.

[0045] The terms "alkenyl" or "alkynyl" as used in this invention refer to a group consisting of at least two carbon atoms forming at least one carbon-carbon double bond or at least two carbon atoms forming at least one carbon-carbon triple bond, and include, but are not limited to, straight-chain or branched chain groups.

[0046] Unless otherwise defined, the term "alkoxy" or "alkoxy group" as used in this invention refers to a free radical in which the hydrogen atom of the hydroxyl group is replaced by an alkyl group. For example, C1-C6 alkoxy groups include all of the following: methoxy, ethoxy, propoxy, n-butoxy, n-pentoxy, isopropoxy, sec-butoxy, tert-butoxy, neopentoxy, isopentoxy, etc.

[0047] Unless otherwise stated, the term "heterocycle" or "heterocyclic group" as used in this invention includes more than one heteroatom, including at least one of monocyclic and polycyclic rings, and including aliphatic heterocycles and heteroaromatic rings. It can also be formed by the combination of adjacent functional groups.

[0048] The term "aryl" or "arylene" as used in this invention refers to a monocyclic or polycyclic aromatic compound, including aromatic rings formed by the combination or reaction of adjacent substituents. For example, an aryl group can be phenyl, biphenyl, fluorenyl, or spirofluorenyl.

[0049] The term "aliphatic ring" as used in this invention refers to an aliphatic hydrocarbon ring.

[0050] The term "aromatic ring" as used in this invention refers to an aromatic system composed of hydrocarbons containing one or more rings, such as benzene and naphthalene.

[0051] Furthermore, the definitions described in this invention can be appended to form chemically related combinations (e.g., "arylalkyl", "alkylcarbonyl", "arylcarbonyl", etc.). When the term "alkyl" is used as a suffix in another term (such as "phenylalkyl" or "hydroxyalkyl"), it indicates an alkyl group substituted with a substituent selected from another explicitly named group. Thus, for example, "phenylalkyl" indicates an alkyl group having a phenyl substituent, and therefore includes benzyl, phenethyl, and biphenyl. "alkylaminoalkyl" indicates an alkyl group having an alkylamino substituent.

[0052] Hereinafter, compounds according to one aspect of the present invention and pharmaceutical compositions comprising the same will be described.

[0053] The present invention provides a compound, its stereoisomers, tautomers, derivatives, hydrates, solvates or pharmaceutically acceptable salts thereof, wherein the compound is represented by the following chemical formula 1.

[0054] Chemical Formula 1

[0055]

[0056]

[0057] {In the chemical formulas 1, 2-1, and 2-2,}

[0058] 1) X is S or N(R1),

[0059] 2) R1 is: hydrogen; a C1-C5 alkyl group; or a C7-C5 alkyl group substituted with fluorine. 20 arylalkyl,

[0060] 3) Y is either N or CH independently of each other.

[0061] 4)R 2 They are either identical or different, and independently exist as hydrogen; or halogens.

[0062] 5) L represents: a single bond; a C1-C6 alkylene group; a C2-C6 alkenylene group; a substituent represented by chemical formula 2-1; or a substituent represented by chemical formula 2-2.

[0063] 6) L' is selected from the group consisting of the following substituents: single bond; C1 to C2. 10 Alkylene; C2~C 10 The alkenyl group; and -(C n H 2n )-O-(C n H2 n )-,

[0064] 7) * indicates the binding site of L, *1 indicates the binding site of Ar.

[0065] 8)R 3 Each of the following substituents, selected independently and either identically or dissimilarly, consists of: hydrogen; halogens; and C1-C1 substituents, substituted or unsubstituted with fluorine. 10 alkyl groups,

[0066] 9) Ar is C6-C 20 arylene; or C2-C containing at least one heteroatom of N and O. 20 heterocyclic group,

[0067] 10)R 1 Choose from the group consisting of the following substituents: hydrogen; halogen; C1-C1 substituents, whether fluorine-substituted or unsubstituted. 10 Alkyl group; -SO2-R a ;-CO-NH-R b ; and -CO-R c ,

[0068] 11) The R a Choose from the following groups of substituents: C1 to C2 10 Alkyl groups; C3-C 20 Aliphatic cyclic groups; C6-C groups substituted with or unsubstituted with CF3. 20 aryl groups; and -N(R')(R”),

[0069] 12) R' and R" are independently C1 to C 10 alkyl groups,

[0070] 13) The R b Choose the group consisting of the following substituents: C6-C 20 aryl; C3~C20 Aliphatic cyclic group; C3-C 20 Aliphatic rings and C6-C 20 Fused ring group of aromatic ring; C1-C1 groups substituted with halogen or unsubstituted. 20 Alkyl groups; and -(C m H 2m )-CO-O-(C m H 2m+1 ),

[0071] 14) The R c Choose from the following groups of substituents: C1 to C2 10 Alkyl group; C6-C 20 aryl groups; and C1-C 10 alkoxy groups,

[0072] 15) a is 0 or 1, b is an integer from 0 to 3, c is an integer from 0 to 4, n is an integer from 0 to 2 independently, and m is an integer from 1 to 6 independently.

[0073] 16) In this case, the alkyl, alkenyl, alkoxy, aryl, arylalkyl, alkylene, alkenylene, arylene, aliphatic cyclic, heterocyclic, and fused-ring groups may be further substituted by one or more substituents selected from the group consisting of: halogen; C1-C1. 10 Alkyl groups; C2-C 10 alkenyl group; C2-C 10 alkynyl group; C1~C 10 alkoxy groups; C1~C 10 The carbonyl group; and the C1-C groups substituted with fluorine. 10 Alkyl groups.

[0074] Furthermore, the present invention provides a compound represented by the above-described chemical formula 1, its stereoisomers, tautomers, derivatives, hydrates, solvates, or pharmaceutically acceptable salts thereof, wherein the compound represented by chemical formula 1 is represented by the following chemical formula 3-1 or the following chemical formula 3-2:

[0075]

[0076] In the aforementioned chemical formulas 3-1 and 3-2, X, Y, and R 1 R 2 R 3 L', Ar, a, b, and c are the same as those defined above.

[0077] Furthermore, the present invention provides a compound represented by the stated chemical formula 1, its stereoisomers, tautomers, derivatives, hydrates, solvates, or pharmaceutically acceptable salts thereof, wherein the compound represented by the stated chemical formula 1 is represented by the following chemical formula 4.

[0078] Chemical Formula 4

[0079]

[0080] In the chemical formula 4,

[0081] 1)R 1 And 'a' is the same as the content defined above;

[0082] 2) Ar' is a C2~C group containing at least one N. 20 Heterocyclic groups}

[0083] Furthermore, the present invention provides a compound in which the Ar is represented by any one of the following chemical formulas Ar-1 to Ar-11, its stereoisomers, tautomers, derivatives, hydrates, solvates or pharmaceutically acceptable salts thereof.

[0084]

[0085]

[0086] {In the chemical formulas Ar-1 to Ar-11,

[0087] 1) * indicates the site where L binds.

[0088] 2)*2 represents the relationship with the R 1 The binding site.

[0089] Furthermore, the present invention provides a compound represented by the chemical formula 1, its stereoisomers, tautomers, derivatives, hydrates, solvates or pharmaceutically acceptable salts thereof, wherein the compound represented by the chemical formula 1 is represented by any one of the following compounds.

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098] Furthermore, the present invention provides a pharmaceutical composition for the prevention or treatment of diseases related to the Silent Information Regulation Factor (SIRTUIN) 7 protein (hereinafter referred to as "SIRT7"), comprising a compound represented by the present chemical formula 1, its stereoisomers, tautomers, derivatives, hydrates, solvates or pharmaceutically acceptable salts thereof as active ingredients.

[0099] The diseases associated with the Silent Information Regulation Factor 7 (SIRTUIN 7) protein are selected from, but are not limited to, obesity, metabolic disorders, glucose resistance, insulin resistance, weight gain, fatty liver, liver fibrosis, hepatitis, cirrhosis, mitochondrial myopathy, brain disorders, diabetes, neurodegenerative diseases, cardiovascular diseases, eye diseases, blood coagulation disorders, facial flushing, lactic acidosis, MELAS syndrome (mitochondrial ephalopathy, lactic acidosis, and stroke-like episodes), and cancer.

[0100] The cancers mentioned may include, but are not limited to, stomach cancer, breast cancer, uterine cancer, colon cancer, colorectal cancer, pancreatic cancer, liver cancer, or prostate cancer.

[0101] In addition, the pharmaceutical composition may also contain one or more pharmaceutically acceptable carriers.

[0102] The pharmaceutical composition has inhibitory activity against Silent Information Regulation Factor (SIRTUIN) 7.

[0103] The present invention will now be described in more detail through synthetic examples and embodiments. However, these embodiments are merely illustrative of the invention, and the scope of the invention is not limited to these embodiments.

[0104] Synthetic Example 1: Synthesis of 4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)benzoic acid (Compound 1)

[0105] Compound 1

[0106]

[0107] Step 1: Methyl 4-formylbenzoate (5.00 g, 30.46 mmol) and N-Boc-piperazine (5.11 g, 27.41 mmol) were dissolved in dichloromethane (DCM) (100 mL), and sodium triacetoxyborohydride (9.68 g, 45.69 mmol) was added. The mixture was stirred at room temperature for 12 hours. The reaction product was diluted with ethyl acetate (EtOAc) and washed with purified water, and then 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 the compound tert-butyl 4-(4-(methoxycarbonyl)benzyl)piperazine-1-carboxylate.

[0108] 1 H NMR (300MHz, CDCl3): δ7.99 (d, 2H, J = 8.3Hz), 7.40 (d, 2H, J = 8.2Hz), 3.91 (s, 3H), 3.55 (s, 2H), 3.43 (t, 4H, J = 5.0Hz), 2.39 (t, 4H, J = 5.0Hz), 1.45 (s, 9H).

[0109] Step 2: 10.00 g (29.90 mmol) of 4-(4-(methoxycarbonyl)benzyl)piperazine-1-carboxylate obtained in Step 1 and 1.88 g (44.85 mmol) of LiOH-H2O were added to 300 mL of tetrahydrofuran (THF) / methanol (MeOH) / H2O (volume ratio: 3:1:1), and the mixture was stirred at room temperature for 4 hours. EtOAc was added to the reaction mixture, and ammonium chloride was added to adjust the pH to 4.0–5.0. The aqueous layer was extracted twice with ethyl acetate and then dried over anhydrous sodium sulfate. The solvent was concentrated to obtain the title compound 4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)benzoic acid, 9.6.

[0110] 1 H NMR (300MHz, 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).

[0111] Synthetic Example 2: Synthesis of Compounds 2-1 to 2-6

[0112] Synthetic Example 2-1: Synthesis of 4-((6-methylpyridazin-3-yl)oxy)benzoic acid (Compound 2-1)

[0113] Compound 2-1

[0114]

[0115] Step 1: Add 3-chloro-6-methylpyridazine (510 mg, 3.94 mmol) to methyl 4-hydroxybenzoate (500 mg, 3.28 mmol), followed by tripotassium phosphate (1.32 g, 6.27 mmol) and palladium acetate (96 mg, 0.32 mmol). Add Xphos (204 mg, 0.43 mmol) to the flask, then add toluene as the reaction solvent. Stir the reaction mixture at 100 °C for 24 hours, and confirm the reaction product by TLC. Dilute the reaction solution with ethyl acetate and wash with purified water. The organic layer was dehydrated with anhydrous Na2SO4 and concentrated under reduced pressure, then separated by column chromatography to obtain 480 mg of methyl 4-((6-methylpyridazin-3-yl)oxy)benzoate.

[0116] 1H NMR (500MHz, DMSO): δ 8.24 (d, 2H, J = 8.61Hz), 8.04 (d, 1H, J = 7.85Hz), 7.80 (d, 1H, J = 8.10Hz), 7.73 (d, 2H, J = 9.12Hz), 3.98 (s, 3H), 2.59 (s, 3H).

[0117] Step 2: Methyl 4-((6-methylpyridazin-3-yl)oxy)benzoate (280 mg, 1.15 mmol) was dissolved in a THF / MeOH / H2O solution (volume ratio) of 3:1:1. Lithium hydroxide monohydrate (51 mg, 1.22 mmol) was then added. The mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, diluted with purified water, and the pH was adjusted to 2–3 with 1N HCl. The precipitated crystals were stirred for at least 10 minutes and filtered to obtain 210 mg of the title compound.

[0118] 1 H NMR (500MHz, DMSO): δ 12.75 (bs, 1H), 8.27 (d, 2H, J = 8.61Hz), 8.05 (d, 1H, J = 7.85Hz), 7.89 (d, 1H, J = 8.10Hz), 7.81 (d, 2H, J = 9.12Hz), 2.59 (s, 3H).

[0119] Synthetic Example 2-2: Synthesis of 3-((6-methylpyridazin-3-yl)oxy)benzoic acid (Compound 2-2)

[0120] Compound 2-2

[0121]

[0122] The title compound was obtained by reacting methyl 3-hydroxybenzoate (500 mg, 3.28 mmol) and 3-chloro-6-methylpyridazine (510 mg, 3.94 mmol) in the same manner as in Synthetic Example 2-1 above.

[0123] 1H NMR (300MHz, DMSO): δ 12.72 (bs, 1H), 8.04 (d, 1H, J = 7.70Hz), 7.92 (s, 1H), 7.71 (d, 1H, J = 9.05Hz), 7.64 (d, 1H, J = 7.70Hz), 7.16 (m, 2H), 2.59 (s, 3H).

[0124] Synthetic Example 2-3: Synthesis of 4-((5-ethylpyrimidin-2-yl)oxy)benzoic acid (Compound 2-3)

[0125] Compounds 2-3

[0126]

[0127] Step 1: Methyl 4-hydroxybenzoate (500 mg, 3.28 mmol) and 2-chloro-5-ethylpyrimidine (516 mg, 3.61 mmol) were dissolved in anhydrous acetonitrile (40 mL), followed by the addition of potassium carbonate (543 mg, 3.94 mmol). The mixture was reacted overnight at 90 °C. After confirming the reaction product by TLC, the reaction solution was diluted with ethyl acetate and washed with purified water. The organic layer was dehydrated with anhydrous Na₂SO₄, concentrated under reduced pressure, and separated by column chromatography to obtain 510 mg of methyl 4-((5-ethylpyrimidin-2-yl)oxy)benzoate.

[0128] 1 H NMR (500MHz, DMSO): δ8.58 (s, 2H), 8.04 (d, 2H, J = 7.81Hz), 7.80 (d, 2H, J = 7.81Hz), 3.94 (s, 3H), 2.63 (q, 2H, J = 7.55Hz), 1.22 (t, 3H, J = 7.55Hz).

[0129] Step 2: The methyl 4-((5-ethylpyrimidin-2-yl)oxy)benzoate (280 mg, 1.15 mmol) obtained from Step 1 above was reacted in the same manner as in Step 2 of Synthetic Example 2-1 above to obtain 200 mg of the title compound.

[0130] 1 H NMR (500MHz, DMSO): δ12.75 (s, 1H), 8.58 (s, 2H), 8.07 (d, 2H, J = 7.81Hz), 7.88 (d, 2H, J = 7.81Hz), 2.64 (q, 2H, J = 7.55Hz), 1.25 (t, 3H, J = 7.55Hz).

[0131] Synthetic Example 2-4: Synthesis of 3-((5-ethylpyrimidin-2-yl)oxy)benzoic acid (Compound 2-4)

[0132] Compounds 2-4

[0133]

[0134] The title compound was obtained by reacting methyl 3-hydroxybenzoate (500 mg, 3.28 mmol) and 2-chloro-5-ethylpyrimidine (516 mg, 3.16 mmol) in the same manner as in Synthetic Examples 2-3 above.

[0135] 1 H NMR (500MHz, DMSO): δ12.73 (s, 1H), 8.57 (s, 2H), 8.05 (t, 2H, J = 7.94Hz), 7.97 (m,1H),7.99(d,1H,J=7.94Hz),2.62(q,2H,J=7.54Hz),1.21(t,3H,J=7.94Hz)

[0136] Synthetic Example 2-5: Synthesis of 4-((5-fluoropyrimidin-2-yl)oxy)benzoic acid (Compound 2-5)

[0137] Compounds 2-5

[0138]

[0139] The title compound was obtained by reacting methyl 4-hydroxybenzoate (1.00 g, 6.57 mmol) and 2-chloro-5-fluoropyrimidine (960 mg, 7.23 mmol) in the same manner as in Synthetic Examples 2-3 above.

[0140] 1 H NMR (500MHz, DMSO): δ12.76 (s, 1H), 8.79 (s, 2H), 8.24 (d, 2H, J = 8.45Hz), 7.37 (d, 2H, J = 8.45Hz).

[0141] Synthetic Examples 2-6: Synthesis of 3-((5-fluoropyrimidin-2-yl)oxy)benzoic acid (Compound 2-6)

[0142] Compounds 2-6

[0143]

[0144] The title compound was obtained by reacting methyl 3-hydroxybenzoate (1.00 g, 6.57 mmol) and 2-chloro-5-fluoropyrimidine (960 mg, 7.23 mmol) in the same manner as in Synthetic Examples 2-3 above.

[0145] 1 H NMR (500MHz, DMSO): δ12.74 (s, 1H), 8.79 (s, 2H), 8.23 ​​(d, 1H, J = 8.45Hz), 8.07 (d, 1H, J = 8.45Hz), 7.59 (s, 1H), 7.38 (m, 1H).

[0146] Synthetic Example 3: Synthesis of 4-(benzyloxy)benzoic acid (Compound 3)

[0147] Compound 3

[0148]

[0149] Step 1: Methyl 4-hydroxybenzoate (5.00 g, 32.86 mmol), benzyl bromide (6.18 g, 36.15 mmol), and potassium carbonate (9.08 g, 65.73 mmol) were added to anhydrous acetonitrile (60 mL), and stirred at 60 °C for 2 hours. After confirming the reaction product by TLC, the reaction solution was diluted with ethyl acetate and washed with purified water. The organic layer was dehydrated with anhydrous Na₂SO₄, concentrated under reduced pressure, and separated by column chromatography to obtain 7.93 g of methyl 4-(benzyloxy)benzoate.

[0150] 1 H NMR (400MHz, CDCl3): δ8.07-7.79(m,2H),7.46-7.31(m,5H),7.04-6.95(m,2H),5.12(s,2H),3.88(s,3H).

[0151] Step 2: Methyl 4-(benzyloxy)benzoate (2.6 g, 10.73 mmol) obtained in Step 1 was dissolved in a THF / MeOH / H2O solution of 3:1:1. Lithium hydroxide monohydrate (1.35 g, 32.20 mmol) was then added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, diluted with purified water, and the pH was adjusted to 2–3 with 1N HCl. The precipitated crystals were stirred for at least 10 minutes and then filtered to obtain 2.4 g of the title compound.

[0152] 1 H NMR (400MHz, DMSO): δ8.06 (d, J = 8.5 Hz, 2H), 7.51-7.29 (m, 5H), 7.02 (d, J = 8.5 Hz, 2H), 5.14 (s, 2H).

[0153] Synthetic Example 4: Synthesis of N-(benzo[d]thiazol-2-yl)-4-formylbenzamide (Compound 4)

[0154] Compound 4

[0155]

[0156] 2-aminobenzothiazole (2.00 g, 13.32 mmol), 4-carboxybenzaldehyde (2.20 g, 14.65 mmol), benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU) (7.58 g, 19.97 mmol), 1-hydroxybenzotriazole (HOBT) (2.70 g, 19.97 mmol), and N-methylmorpholine (NMM) (2.69 g, 26.63 mmol) were added to anhydrous dimethylformamide (DMF) (65 mL), and the mixture was stirred overnight at room temperature. Ethyl acetate and water were added to the reaction mixture, and the organic layer was dried over anhydrous sodium sulfate. After concentration, the mixture was recrystallized from ethyl acetate (EA) to give 2.5 g of the title compound.

[0157] 1 H NMR (300MHz, DMSO): δ13.16(s,1H),10.14(s,1H),8.32(d,J=8.1Hz,2H),8.09(d,J=8.3Hz ,2H),8.05(d,J=7.8Hz,1H),7.80(d,J=8.0Hz,1H),7.53-7.44(m,1H),7.41-7.32(m,1H).

[0158] Synthetic Example 5: Synthesis of N-(benzo[d]thiazol-2-yl)-4-bromobenzamide (Compound 5)

[0159] Compound 5

[0160]

[0161] 2-aminobenzothiazole (1.00 g, 6.66 mmol), 4-bromobenzoic acid (1.47 g, 7.32 mmol), HBTU (3.79 g, 9.99 mmol), and N,N-diisopropylethylamine (DIPEA) (2.32 mL, 13.32 mmol) were added to anhydrous DCM (30 mL), and the mixture was stirred overnight at room temperature. The reaction products were confirmed by TLC, and the reaction solution was diluted with ethyl acetate and washed with purified water. The organic layer was dehydrated with anhydrous Na₂SO₄, concentrated under reduced pressure, and separated by column chromatography to obtain 2.00 g of the title compound.

[0162] 1 H NMR (500MHz, DMSO): δ13.00 (s, 1H), 8.10-8.07 (m, 2H), 8.03 (dd, J = 8.0, 1.3Hz, 1H), 7. 81-7.78(m,3H),7.48(ddd,J=8.2,7.2,1.3Hz,1H),7.36(ddd,J=8.2,7.2,1.1Hz,1H).

[0163] Synthetic Example 6: Synthesis of N-(benzo[d]thiazol-2-yl)-4-bromo-2-(trifluoromethyl)benzamide (Compound 6)

[0164] Compound 6

[0165]

[0166] 2-aminobenzothiazole (2.80 g, 18.64 mmol), 4-bromo-2-(trifluoromethyl)benzoic acid (5.15 g, 20.51 mmol), HBTU (7.78 g, 20.51 mmol), and DIPEA (6.50 mL, 37.28 mmol) were added to anhydrous DCM (30 mL), and the mixture was stirred at room temperature for 4 hours. The reaction products were confirmed by TLC, and the reaction solution was diluted with ethyl acetate and washed with purified water. The organic layer was dehydrated with anhydrous Na₂SO₄, concentrated under reduced pressure, and separated by column chromatography to obtain 4.80 g of the title compound.

[0167] 1 H NMR (300MHz, CDCl3): δ11.90 (s, 1H), 7.89-7.81 (m, 1H), 7.79 (d, J = 1.9Hz, 1H), 7.58 (dd,J=8.3,1.9Hz,1H),7.42(d,J=8.2Hz,1H),7.39-7.21(m,2H),7.03-6.94(m,1H).

[0168] Synthetic Example 7: Synthesis of N-(benzo[d]thiazol-2-yl)-4-bromo-2-fluorobenzamide (Compound 7)

[0169] Compound 7

[0170]

[0171] The title compound was obtained by reacting 2-aminobenzothiazole (2.80 g, 18.64 mmol) and 4-bromo-2-fluorobenzoic acid (4.49 g, 20.51 mmol) in the same manner as in Synthetic Example 6 above.

[0172] 1 H NMR (400MHz, CDCl3): δ9.99(s,1H),8.14(t,J=8.4Hz,1H),7.89(dt,J=7.9,1.0Hz,1H),7.83(dd,J= 8.1, 1.0Hz, 1H), 7.56 (dd, J=8.5, 1.8Hz, 1H), 7.53-7.44 (m, 2H), 7.38 (ddd, J=8.2, 7.2, 1.2Hz, 1H).

[0173] Synthetic Example 8: Synthesis of N-(benzo[d]thiazol-2-yl)-4-bromo-3-chlorobenzamide (Compound 8)

[0174] Compound 8

[0175]

[0176] The title compound was obtained by reacting 2-aminobenzothiazole (3.00 g, 19.97 mmol) and 4-bromo-3-chlorobenzoic acid (5.17 g, 21.97 mmol) in the same manner as in Synthetic Example 6 above.

[0177] 1 H NMR (300MHz, DMSO-d6): δ13.11(s,1H),8.37(t,J=1.2Hz,1H),8.07-7.95(m,3H),7.78(d,J=8.0Hz,1H),7.54-7.42(m,1H),7.41-7.29(m,1H).

[0178] Synthetic Example 9: Synthesis of N-(benzo[d]thiazol-2-yl)-4-bromo-2,6-difluorobenzamide (Compound 9)

[0179] Compound 9

[0180]

[0181] The title compound was obtained by reacting 2-aminobenzothiazole (2.90 g, 19.31 mmol) and 4-bromo-2,6-difluorobenzoic acid (5.03 g, 21.24 mmol) in the same manner as in Synthetic Example 6 above.

[0182] 1 H NMR (300MHz, DMSO-d6): δ13.29(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).

[0183] Synthetic Example 10: Synthesis of N-(benzo[d]thiazol-2-yl)-4-bromo-2-chlorobenzamide (Compound 10)

[0184] Compound 10

[0185]

[0186] The title compound was obtained by reacting 2-aminobenzothiazole (1.50 g, 9.99 mmol) and 4-bromo-2-chlorobenzoic acid (2.59 g, 10.99 mmol) in the same manner as in Synthetic Example 6 above.

[0187] 1 H NMR (300MHz, DMSO-d6) δ13.02(s,1H),8.05(d,J=7.9,1.2Hz,1H),7.94(d,J=1.7Hz, 1H), 7.80 (d, J = 8.0Hz, 1H), 7.76-7.64 (m, 2H), 7.54-7.43 (m, 1H), 7.41-7.31 (m, 1H).

[0188] Synthetic Example 11: Synthesis of N-(benzo[d]thiazol-2-yl)-5-bromothiophene-2-carboxamide (Compound 11)

[0189] Compound 11

[0190]

[0191] The title compound was obtained by reacting 2-aminobenzothiazole (2.00 g, 13.32 mmol) and 5-bromothiophene-2-carboxylic acid (3.03 g, 14.65 mmol) in the same manner as in Synthetic Example 6 above.

[0192] 1 H NMR (300MHz, DMSO-d6): δ13.15 (s, 1H), 8.16-7.94 (m, 2H), 7.75 (d, J = 8.0Hz, 1H), 7.53-7.40 (m, 2H), 7.40-7.28 (m, 1H).

[0193] Synthetic Example 12: Synthesis of N-(benzo[d]thiazol-2-yl)-2-bromothiazole-5-carboxamide (Compound 12)

[0194] Compound 12

[0195]

[0196] The title compound was obtained by reacting 2-aminobenzothiazole (2.00 g, 13.32 mmol) and 2-bromothiazole-5-carboxylic acid (3.05 g, 14.65 mmol) in the same manner as in Synthetic Example 6 above.

[0197] 1 H NMR (300MHz, DMSO-d6): δ13.41(s,1H),8.55(s,1H),7.99(d,J=7.9Hz,1H),7.71(d,J=8.1Hz,1H),7.48(t,J=7.6Hz,1H),7.35(t,J=7.6Hz,1H).

[0198] Synthetic Example 13: Synthesis of N-(benzo[d]thiazol-2-yl)-4-bromo-2-methylbenzamide (Compound 13)

[0199] Compound 13

[0200]

[0201] The title compound was obtained by reacting 2-aminobenzothiazole (0.70 g, 4.66 mmol) and 4-bromo-2-methylbenzoic acid (1.10 g, 5.13 mmol) in the same manner as in Synthetic Example 6 above.

[0202] 1 H NMR (300MHz, DMSO-d6): δ12.83(s,1H),8.03(d,J=7.9Hz,1H),7.79(d,J=8.0Hz ,1H),7.66-7.51(m,3H),7.51-7.41(m,1H),7.35(t,J=7.6Hz,1H),2.44(s,3H).

[0203] Example 1: 4-(4-((1H-benzo[d]imidazol-2-yl)carbamoyl)benzyl)piperazine-1-carboxylate (tert-butyl 4-(4-((1H-benzo[d]imidazol-2-yl)carbamoyl)benzyl)piperazine-1-carboxylate) (Compound 1-1)

[0204] 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 the mixture was stirred overnight at room temperature. 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 550 mg of the title compound.

[0205] 1 H NMR (300MHz, CDCl3): δ8.15(d,J=8.0Hz,2H),7.47(d,J=8.1Hz,2H),7.19-7.12 (m, 4H), 3.63 (s, 2H), 3.47 (t, J = 5.0Hz, 4H), 2.45 (t, J = 5.0Hz, 4H), 1.49 (s, 9H).

[0206] Example 2: 4-(4-((1-methyl-1H-benzo[d]imidazol-2-yl)carbamoyl)benzyl)piperazine-1-carboxylate (tert-butyl 4-(4-((1-methyl-1H-benzo[d]imidazol-2-yl)carbamoyl)benzyl)piperazine-1-carboxylate) (compounds 1-2)

[0207] 50 mg (0.11 mmol) of tert-butyl 4-(4-((1H-benzo[d]imidazol-2-yl)carbamoyl)benzyl)piperazine-1-carboxylate (tert-butyl 4-(4-((1H-benzo[d]imidazol-2-yl)carbamoyl)benzyl)piperazine-1-carboxylate (tert-butyl 4-(4-((1H-benzo[d]imidazol-2-yl)carbamoyl)benzyl) was dissolved in anhydrous dichloromethane. NaH (5 mg, 0.23 mg) and iodomethane (17 mg, 0.13 mmol) were added at 0 °C, and the mixture was stirred 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.

[0208] 1 H NMR (300MHz, CDCl3): δ8.16(d,J=8.0Hz,2H),7.45(d,J=8.1Hz,2H),7.20-7.11(m,4H) ,3.62(s,2H),3.47(t,J=5.0Hz,4H),3.44(s,3H),2.44(t,J=5.0Hz,4H),1.50(s,9H).

[0209] Example 3: N-(1H-benzo[d]imidazol-2-yl)-4-(piperazin-1-ylmethyl)benzamide (compounds 1-3)

[0210] 0.50 g (1.15 mmol) of tert-butyl 4-(4-((1H-benzo[d]imidazol-2-yl)carbamoyl)benzyl)piperazine-1-carboxylate (tert-butyl 4-(4-((1H-benzo[d]imidazol-2-yl)carbamoyl)benzyl)piperazine-1-carboxylate obtained in Example 1 above was dissolved in anhydrous DCM (5 mL), TFA (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was concentrated under reduced pressure, and the solution was washed twice with diethyl ether to obtain 500 mg of the title compound.

[0211] 1H NMR (300MHz, Acetone-d6): δ8.34(d,J=8.1Hz,2H),7.86-7.74(m,4H),7.56-7.53(m,2H),4.24(s,2H),3.70(t,J=5.2Hz,4H), 3.35(t,J=5.2Hz,4H).

[0212] Example 4: N-(1H-benzo[d]imidazol-2-yl)-4-((6-methylpyridazin-3-yl)oxy)benzamide (compounds 1-4)

[0213] Compound 2-1 (100 mg, 0.43 mmol), 1H-benzo[d]imidazol-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 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 then separated by column chromatography to obtain 86 mg of the title compound.

[0214] 1 H NMR (500MHz, DMSO): δ12.29 (s, 2H), 8.23 ​​(d, 2H, J = 8.94Hz), 7.71 (d, 1H, J = 8.94Hz) ,7.48(m,3H),7.33(d,2H,J=8.47Hz),7.15(dd,2H,J=3.29,5.65Hz),2.59(s,3H).

[0215] Example 5: N-(1H-benzo[d]imidazol-2-yl)-3-((6-methylpyridazin-3-yl)oxy)benzamide (compounds 1-5)

[0216] 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.

[0217] 1 H NMR (300MHz, DMSO): δ12.34(s,2H),8.04(d,1H,J=7.70Hz),7.92(s,1H),7.71(d ,1H,J=9.05Hz),7.61(t,1H,J=7.90Hz),7.47(m,4H),7.16(m,2H),2.59(s,3H).

[0218] Example 6: N-(5-fluoro-1H-benzo[d]imidazol-2-yl)-4-((6-methylpyridazin-3-yl)oxy)benzamide (compounds 1-6)

[0219] The title compound was obtained by reacting 5-fluoro-1H-benzo[d]imidazol-2-amine (72 mg, 0.48 mmol) in the same manner as in Example 4 above.

[0220] 1 H NMR (400MHz, DMSO): δ12.29(s,2H),8.21(d,J=8.4Hz,2H),7.71(d,J=9.1Hz,1H),7.48(d,J=8 .8Hz,2H),7.34(d,J=8.4Hz,2H),7.26(dd,J=9.5,2.5Hz,1H),7.03-6.92(m,1H),2.59(s,3H).

[0221] Example 7: N-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-4-((6-methylpyridazin-3-yl)oxy)benzamide (compounds 1-7)

[0222] The title compound was obtained by reacting 5,6-difluoro-1H-benzo[d]imidazol-2-amine (67 mg, 0.40 mmol) in the same manner as in Example 4 above.

[0223] 1H NMR (400MHz, DMSO): δ12.33 (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).

[0224] Example 8: N-(1H-benzo[d]imidazol-2-yl)-3-((5-ethylpyrimidin-2-yl)oxy)benzamide (compounds 1-8)

[0225] Compounds 2-4 (105 mg, 0.43 mmol) were reacted in the same manner as in Example 4 above to obtain 135 mg of the title compound.

[0226] 1 H NMR (500MHz, DMSO): δ12.69(s,2H),8.56(s,2H),8.05(d,1H,J=8.09Hz),7.93(m,1H),7.59( t, 1H, J = 8.09Hz), 7.44 (m, 4H), 7.17 (m, 2H), 2.62 (q, 2H, J = 7.58Hz), 1.21 (t, 3H, J = 7.58Hz).

[0227] Example 9: N-(1H-benzo[d]imidazol-2-yl)-4-((5-ethylpyrimidin-2-yl)oxy)benzamide (compounds 1-9)

[0228] Compounds 2-3 (105 mg, 0.43 mmol) were reacted in the same manner as in Example 4 above to obtain 121 mg of the title compound.

[0229] 1 H NMR (500MHz, DMSO): δ12.29(s,2H),8.59(s,2H),8.22(d,1H,J=8.69Hz),7.47(m,1H) ,7.34(d,2H,J=8.72Hz),7.15(m,1H),2.62(q,2H,J=7.60Hz),1.21(t,3H,J=7.46Hz).

[0230] Example 10: N-(1H-benzo[d]imidazol-2-yl)-4-((5-fluoropyrimidin-2-yl)oxy)benzamide (compounds 1-10)

[0231] Compounds 2-5 (100 mg, 0.42 mmol) were reacted in the same manner as in Example 4 above to obtain 87 mg of the title compound.

[0232] 1 H NMR (500MHz, DMSO): δ12.29 (s, 1H), 8.79 (s, 2H), 8.24 (d, 2H, J = 8.45Hz), 7.48 (m, 2H), 7.37 (d, 2H, J = 8.45Hz), 7.16 (m, 2H).

[0233] Example 11: N-(1H-benzo[d]imidazol-2-yl)-3-((5-fluoropyrimidin-2-yl)oxy)benzamide (Compound 1-11)

[0234] Compounds 2-6 (100 mg, 0.42 mmol) were reacted in the same manner as in Example 4 above to obtain 75 mg of the title compound.

[0235] 1 H NMR (500MHz, DMSO): δ12.33 (s, 2H), 8.78 (s, 2H), 8.06 (d, 1H, J = 7.82Hz), 7.95 (m, 1H), 7.61 (t, 1H, J = 7.82Hz), 7.46 (m, 3H), 7.17 (m, 2H).

[0236] Example 12: N-(1H-benzo[d]imidazol-2-yl)-4-(benzyloxy)benzamide (compounds 1-12)

[0237] Compound 4 (1.89 g, 8.26 mmol) was reacted using the same method as in Example 4 above to obtain 675 mg of the title compound.

[0238] 1H NMR (400MHz, DMSO): δ12.12 (s, 2H), 8.13 (d, J = 8.6Hz, 2H), 7.53-7.29 (m, 7H), 7.17-7.06 (m, 4H), 5.22 (s, 2H).

[0239] Example 13: N-(1H-benzo[d]imidazol-2-yl)-4-((4-(trifluoromethyl)benzyl)oxy)benzamide

[0240] (N-(1H-benzo[d]imidazol-2-yl)-4-((4-(trifluoromethyl)benzyl)oxy)benzamide)(Compound 1-13)

[0241] N-(1H-benzo[d]imidazol-2-yl)-4-(benzyloxy)benzamide (50 mg, 0.20 mmol) obtained in Example 12 above was dissolved in anhydrous acetonitrile (5 mL), and 4-(trifluoromethyl)benzylbromide (52 mg, 0.22 mmol) and potassium carbonate (82 mg, 0.59 mmol) were added. 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 with anhydrous Na2SO4, concentrated under reduced pressure, and then separated by column chromatography to obtain 21 mg of the title compound.

[0242] 1 H NMR (400MHz, CDCl3): δ12.79 (s, 1H), 7.75-7.65 (m, 4H), 7.63 (d, J = 8.1Hz, 2H), 7.58-7 .50(m,1H),7.45-7.38(m,1H),7.26-7.13(m,2H),7.08(d,J=8.4Hz,2H),5.31(s,2H).

[0243] Example 14: N-(1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-2-yl)-4-((4-(trifluoromethyl)benzyl)oxy)benzamide (N-(1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-2-yl)-4-((4-(trifluoromethyl)benzyl)oxy)benzamide)(Compound 1-14)

[0244] N-(1H-benzo[d]imidazol-2-yl)-4-(benzyloxy)benzamide (50 mg, 0.20 mmol) obtained in Example 12 above was dissolved in anhydrous acetonitrile (5 mL), and 4-(trifluoromethyl)benzylbromide (104 mg, 0.44 mmol) and potassium carbonate (82 mg, 0.59 mmol) were added. 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 then separated by column chromatography to obtain 31 mg of the title compound.

[0245] 1 H NMR (400MHz, CDCl3): δ12.79 (s, 1H), 8.20 (d, J = 8.4Hz, 2H), 7.78 (d, J = 8.0Hz, 2H), 7.75-7.65 (m, 4H), 7.63 (d, J = 8. 1Hz,2H),7.58-7.50(m,1H),7.45-7.38(m,1H),7.26-7.13(m,2H),7.08(d,J=8.4Hz,2H),5.61(s,2H),5.31(s,2H).

[0246] Example 15: N-(benzo[d]thiazol-2-yl)-4-((6-methylpyridazin-3-yl)oxy)benzamide (Compound 1-15)

[0247] 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 above to obtain 102 mg of the title compound.

[0248] 1 H NMR (500MHz, DMSO): δ12.95 (s, 1H), 8.24 (d, 2H, J = 8.61Hz), 8.04 (d, 1H, J = 7.85Hz), 7 .80(d,1H,J=8.10Hz),7.73(d,2H,J=9.12Hz),7.50(m,3H),7.37(m,3H),2.59(s,3H).

[0249] Example 16: 4-((6-methylpyridazin-3-yl)oxy)-N-(thiazolo[5,4-b]pyridin-2-yl)benzamide (compounds 1-16)

[0250] 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 above to obtain 54 mg of the title compound.

[0251] 1 H NMR (400MHz, DMSO): δ13.04(s,1H),8.51(d,J=4.6Hz,1H),8.24(d,J=8.4Hz,2H),8.16(d,J =8.2Hz, 1H), 7.72 (d, J = 8.9Hz, 1H), 7.58-7.44 (m, 2H), 7.38 (d, J = 8.3Hz, 2H), 2.60 (s, 3H).

[0252] Example 17: N-(benzo[d]thiazol-2-yl)-3-((6-methylpyridazin-3-yl)oxy)benzamide (compound 1-17)

[0253] 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 above to obtain 91 mg of the title compound.

[0254] 1 H NMR (500MHz, DMSO): δ12.97(s,1H),8.05(t,2H,J=6.33Hz),7.97(s,1H),7.79(d ,1H,J=7.91Hz),7.72(m,2H),7.53(m,3H),7.36(t,1H,J=7.72Hz),2.57(s,3H).

[0255] Example 18: N-(6-bromobenzo[d]thiazol-2-yl)-4-((6-methylpyridazin-3-yl)oxy)benzamide (Compound 1-18)

[0256] 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 above to obtain 121 mg of the title compound.

[0257] 1 H NMR (500MHz, DMSO): δ13.08 (s, 1H), 8.24 (d, 2H, J = 8.90Hz), 8.03 (d, 1H, J = 8.39Hz), 7.99 (d ,1H,J=7.62Hz),7.73(d,1H,J=8.90Hz),7.52(m,2H),7.38(d,2H,J=8.83Hz),2.59(s,3H).

[0258] Example 19: N-(benzo[d]thiazol-2-yl)-4-((5-ethylpyrimidin-2-yl)oxy)benzamide (compound 1-19)

[0259] Compounds 2-3 (100 mg, 0.41 mmol) were reacted in the same manner as in Example 4 above to obtain 70 mg of the title compound.

[0260] 1 H NMR (500MHz, DMSO): δ12.93 (s, 1H), 8.58 (s, 2H), 8.23 ​​(d, 2H, J = 8.74Hz), 8.04 (d, 1H, J = 7.81Hz), 7.80 (d, 1H, J = 7.81Hz) ,7.49(t,1H,J=7.15Hz), 7.39(d,2H,J=8.74Hz), 7.37(t,1H,J=7.55Hz), 2.63(q,2H,J=7.55Hz), 1.22(t,3H,J=7.55Hz).

[0261] Example 20: N-(benzo[d]thiazol-2-yl)-3-((5-ethylpyrimidin-2-yl)oxy)benzamide (N-(benzo[d]thiazol-2-yl)-3-((5-ethylpyrimidin-2-yl)oxy)benzamide) (Compounds 1-20)

[0262] Compounds 2-4 (100 mg, 0.41 mmol) were reacted in the same manner as in Example 4 above to obtain 73 mg of the title compound.

[0263] 1 H NMR (500MHz, DMSO): δ12.95(s,1H),8.57(s,2H),8.05(t,2H,J=7.94Hz),7.97(m,1H),7.99(d,1H,J=7.94Hz),7.52 (d, 1H, J = 7.94Hz), 7.49 (t, 1H, J = 7.14Hz), 7.36 (t, 1H, J = 7.14Hz), 2.62 (q, 2H, J = 7.54Hz), 1.21 (t, 3H, J = 7.94Hz).

[0264] Example 21: N-(benzo[d]thiazol-2-yl)-4-((5-fluoropyrimidin-2-yl)oxy)benzamide (Compound 1-21)

[0265] Compounds 2-5 (100 mg, 0.43 mmol) were reacted in the same manner as in Example 4 above to obtain 53 mg of the title compound.

[0266] 1 H NMR (500MHz, DMSO): δ12.93 (s, 1H), 8.80 (s, 2H), 8.24 (d, 2H, J = 8.63Hz), 8.04 (d, 1H, J = 7.61Hz) ,7.81(d,1H,J=8.12Hz), 7.50(t,1H,J=7.03Hz), 7.43(d,2H,J=8.68Hz), 7.37(t,1H,J=8.63Hz).

[0267] Example 22: tert-butyl 4-(benzo[d]thiazol-2-yl)piperazine-1-carboxylate (compound 1-22)

[0268] 2-Chlorobenzothiazole (500 mg, 2.95 mmol), tert-butylpiperazine-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 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 then separated by column chromatography to obtain 482 mg of the title compound.

[0269] 1 H NMR (300MHz, CDCl3): δ7.63-7.55(m,2H),7.34-7.31(m,1H),7.12-7.07(m,1H),3.61(m,8H),1.59-1.49(s,9H).

[0270] Example 23: 8-(benzo[d]thiazol-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane (compound 1-23)

[0271] 4-piperidine ethyleneketal (443.17 mg, 3.09 mmol) was reacted in the same manner as in Example 22 above to obtain 709 mg of the title compound.

[0272] 1 H NMR (300MHz, CDCl3): δ7.59-7.52(m,2H),7.30-7.25(m,1H),7.08-7.03(m,1H),4.00(s,4H),3.75(t,J=6Hz,4H),1.83(t,J=6Hz,4H).

[0273] Example 24: 2-(benzo[d]thiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (tert-butyl 2-(benzo[d]thiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate) (Compound 1-24)

[0274] The title compound was obtained by reacting tert-butyl 2,7-diazaspiro[3,5]nonane-7-carboxylate (7-Boc-2,7-diazaspiro[3,5]nonane) (700.45 mg, 3.09 mmol) in the same manner as in Example 22 above.

[0275] 1 H NMR (300MHz, CDCl3): δ7.62-7.58(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).

[0276] Example 25: (1S,4S)-5-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (tert-butyl (1S,4S)-5-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate) (Compound 1-25)

[0277] Compound 4 (1.00 g, 3.54 mmol) and (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), followed by the addition of sodium triacetoxyborohydride (1.13 g, 5.31 mmol), and stirred overnight at room temperature. 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 with anhydrous Na₂SO₄, concentrated under reduced pressure, and separated by column chromatography to obtain 1.32 g of the title compound.

[0278] 1 H NMR (400MHz, CDCl3): δ11.07(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 .4Hz,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=9.9Hz,1H),1.68(d,J=9.6Hz,1H),1.47(s,9H).

[0279] Example 26: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)piperazine-1-carboxylate (tert-butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)piperazine-1-carboxylate) (Compound 1-26)

[0280] The title compound was obtained by reacting N-Boc-piperazine (658 mg, 3.54 mg) in the same manner as in Example 25 above.

[0281] 1H NMR (500MHz, CDCl3): δ11.12(s,1H),7.95(d,J=8.2Hz,2H),7.88-7.82(m,1H),7.42(d,J=8.0Hz,2H),7.4 3-7.37(m,1H),7.33-7.27(m,2H),3.55(s,2H),3.42(t,J=5.0Hz,4H),2.36(t,J=5.0Hz,4H),1.46(s,9H).

[0282] Example 27: 7-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (tert-butyl 7-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (compound 1-27)

[0283] The title compound was obtained by reacting 2,7-diazaspiro[3.5]nonane-2-carboxylate (144 mg, 0.64 mmol) in the same manner as in Example 25 above.

[0284] 1 H NMR (300MHz, CDCl3): δ7.95(d,J=7.9Hz,2H),7.86(d,J=7.3Hz,1H),7.50(d,J=7.5Hz,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).

[0285] Example 28: 9-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (tert-butyl 9-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate) (Compound 1-28)

[0286] The title compound was obtained by reacting tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (162 mg, 0.64 mmol) with the same method as in Example 25 above.

[0287] 1 H NMR (300MHz, CDCl3): δ7.93(d,J=8.0Hz,2H),7.86(d,J=7.4Hz,1H),7.56(d,J=7.3Hz,1H),7.45(d,J=8.0Hz,2H),7.34 (tt,J=7.7,6.1Hz,2H),3.55(s,2H),3.36(t,J=5.8Hz,4H),2.39(t,J=5.6Hz,4H),1.52(t,J=5.6Hz,4H),1.45(m,13H).

[0288] Example 29: 4-((1,4-dioxa-8-azaspiro[4.5]decan-8-yl)methyl)-N-(benzo[d]thiazol-2-yl)benzamide (4-((1,4-dioxa-8-azaspiro[4.5]decan-8-yl)methyl)-N-(benzo[d]thiazol-2-yl)benzamide) (Compound 1-29)

[0289] 1,4-dioxa-8-azaspiro[4.5]decane (91 mg, 0.64 mmol) was reacted with the same method as in Example 25 above to obtain 120 mg of the title compound.

[0290] 1 H NMR (300MHz, CDCl3): δ7.95 (d, J = 8.1Hz, 2H), 7.89-7.82 (m, 1H), 7.46-7.41 (m, 3H), 7.32-7. 28(m,2H),3.96(d,J=2.3Hz,4H),3.57(s,2H),2.51(t,J=5.7Hz,4H),1.74(t,J=5.7Hz,4H).

[0291] Example 30: 2-(7-benzyl-2,7-diazaspiro[3.5]nonan-2-yl)benzo[d]thiazole (compound 1-30)

[0292] 2-(2,7-Diazaspiro[3.5]nonan-2-yl)benzo[d]thiazole (100 mg, 0.28 mmol) was dissolved in anhydrous acetonitrile (4 mL), followed by the addition of potassium carbonate (124 mg, 0.90 mmol) and benzyl bromide (56 mg, 0.33 mmol) and reacted 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 then separated by column chromatography to obtain 24 mg of the title compound.

[0293] 1 H NMR (300MHz, acetone): δ7.70(d,J=9Hz,1H),7.47(d,J=9Hz,1H),7.36-7.20(m,6 H),7.08-7.03(m,1H),3.87(s,4H),3.47(s,2H),2.39(s,2H),1.87(t,J=6Hz,4H).

[0294] Example 31: N-(benzo[d]thiazol-2-yl)-4-(piperazin-1-ylmethyl)benzamide (Compound 1-31)

[0295] The title compound was obtained by reacting 2.2 g of 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)piperazine-1-carboxylate (2.0 g, 4.42 mmol) obtained in Example 26 with the same method as in Example 3 above.

[0296] 1H NMR (300MHz, Acetone-d6): δ8.27-8.52(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).

[0297] Example 32: N-(benzo[d]thiazol-2-yl)-4-((4-(ethylsulfonyl)piperazin-1-yl)methyl)benzamide (Compound 1-32)

[0298] N-(benzo[d]thiazol-2-yl)-4-(piperazin-1-ylmethyl)benzamide (100 mg, 0.28 mmol) obtained in Example 31 above was dissolved in anhydrous dichloromethane (4 mL), and ethanesulfonyl chloride (30 μL, 0.31 mmol) and trimethylamine (80 μL, 0.57 mmol) were added. 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 then separated by column chromatography to obtain 88 mg of the title compound.

[0299] 1 H NMR (500MHz, CDCl3): δ10.56 (s, 1H), 7.90 (t, J = 8.1Hz, 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=7.1,5.2Hz,2H),3.07(s,4H),2.54(t,J=5.0Hz,4H),0.98(t,J=7.1Hz,3H).

[0300] Example 33: N-(benzo[d]thiazol-2-yl)-4-((4-(N,N-dimethylaminosulfonyl)piperazin-1-yl)methyl)benzamide (N-(benzo[d]thiazol-2-yl)-4-((4-(N,N-dimethylsulfamoyl)piperazin-1-yl)methyl)benzamide)(Compound 1-33)

[0301] The title compound was obtained by reacting N,N-dimethylsulfamoylchloride (34 μL, 0.31 mmol) with the same method as in Example 32 above.

[0302] 1 H NMR (500MHz, CDCl3): δ10.51 (s, 1H), 7.91 (t, J = 8.1Hz, 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=5.0Hz,4H).

[0303] Example 34: N-(benzo[d]thiazol-2-yl)-4-((4-(cyclopropylsulfonyl)piperazin-1-yl)methyl)benzamide (Compound 1-34)

[0304] The title compound was obtained by reacting cyclopropylsulfonyl chloride (48 mg, 0.31 mmol) in the same manner as in Example 32 above.

[0305] 1 H NMR (500MHz, CDCl3): δ10.83(s,1H),7.96(d,J=8.3Hz,2H),7.89-7.83(m,1H),7.51-7.45(m,1H),7.45(d,J=8.2Hz,2H),7.35-7 .29(m,2H),3.60(s,2H),3.33(t,J=4.9Hz,4H),2.54(t,J=4.9Hz,4H),2.32-2.22(m,1H),1.20-1.15(m,2H),1.03-0.97(m,3H).

[0306] Example 35: N-(benzo[d]thiazol-2-yl)-4-((4-(phenylsulfonyl)piperazin-1-yl)methyl)benzamide (Compound 1-35)

[0307] The title compound was obtained by reacting benzenesulfonyl chloride (60 mg, 0.31 mmol) in the same manner as in Example 32.

[0308] 1 H NMR (500MHz, CDCl3): δ10.81 (s, 1H), 7.91 (d, J = 8.3Hz, 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=8.3Hz,2H),7.35-7.28(m,2H),3.54(s,2H),3.04(s,4H),2.52(t,J=4.9Hz,4H).

[0309] Example 36: N-(benzo[d]thiazol-2-yl)-4-((4-((4-(trifluoromethyl)phenyl)sulfonyl)piperazin-1-yl)methyl)benzamide (Compound 1-36)

[0310] The title compound was obtained by reacting 4-(trifluoromethyl)benzenesulfonyl chloride (76 mg, 0.31 mmol) in the same manner as in Example 32 above.

[0311] 1H NMR (500MHz, CDCl3): δ10.56(s,1H),7.90(t,J=8.1Hz,4H),7.88-7.82(m,1H),7.82(d,J=8.2Hz,2H),7.5 6-7.50(m,1H),7.38(d,J=8.3Hz,2H),7.39-7.27(m,2H),3.56(s,2H),3.07(s,4H),2.54(t,J=5.0Hz,4H).

[0312] Example 37: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-ethylpiperazine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-ethylpiperazine-1-carboxamide) (Compound 1-37)

[0313] N-(benzo[d]thiazol-2-yl)-4-((4-(ethylsulfonyl)piperazin-1-yl)methyl)benzamide (100 mg, 0.28 mmol) obtained in Example 32 above 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 with anhydrous Na2SO4, concentrated under reduced pressure, and then separated by column chromatography to obtain 99 mg of the title compound.

[0314] 1 H NMR (500MHz, DMSO): δ12.84(s,1H),8.12(d,J=7.9Hz,2H),8.02(d,J=7.8Hz,1H),7.78(d,J=8.1Hz,1H),7.51-7.45(m,3H),7. 38-7.30(m,1H),3.57(s,2H),3.28(t,J=4.9Hz,4H),3.03(qd,J=7.1,5.3Hz,2H),2.33(t,J=5.0Hz,4H),0.99(t,J=7.1Hz,3H).

[0315] Example 38: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-phenylpiperazine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-phenylpiperazine-1-carboxamide) (Compound 1-38)

[0316] 110 mg of the title compound was obtained by reacting phenyl isocyanate (34 μL, 0.31 mmol) with the same method as in Example 37 above.

[0317] 1 H NMR (500MHz, DMSO): δ12.86(s,1H),8.50(s,1H),8.14(d,J=8.4Hz,2H),8.03(dd,J=7.9,1.1Hz,1H),7.80(d,J=8.0Hz,1H),7.53(d,J=8.3Hz,2H),7.5 2-7.42(m,3H),7.35(td,J=7.6,1.1Hz,1H),7.26-7.18(m,2H),6.93(tt,J= 7.4, 1.2Hz, 1H), 3.63 (s, 2H), 3.48 (t, J = 4.9Hz, 4H), 2.43 (t, J = 5.0Hz, 4H).

[0318] Example 39: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide) (Compound 1-39)

[0319] The title compound was obtained by reacting 4-(trifluoromethyl)phenyl isocyanate (44 μL, 0.31 mmol) in the same manner as in Example 37 above.

[0320] 1H NMR (500MHz, DMSO): δ12.98-12.71(m,1H),8.14(d,J=8.1Hz,2H),8.03(d,J=7.9Hz,1H),7.80(d,J=8.0Hz,1H),7.69(d,J=8.5Hz,2H),7. 58(d,J=8.6Hz,2H),7.53(d,J=8.1Hz,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=5.0Hz,4H).

[0321] Example 40: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-isopropylpiperazine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-isopropylpiperazine-1-carboxamide) (Compound 1-40)

[0322] Isopropyl isocyanate (21 mg, 0.25 mmol) was reacted in the same manner as in Example 37 above to obtain 54 mg of the title compound.

[0323] 1 H NMR (300MHz, CDCl3): δ8.06-7.91(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).

[0324] Example 41: N-(adamantan-1-yl)-4-(4-benzo[d]thiazol-2-ylcarbamoyl)benzyl)piperazine-1-carboxamide (Compound 1-41)

[0325] 95 mg of the title compound was obtained by reacting 1-adamantylisocyanate (44 mg, 0.25 mmol) with the same method as in Example 37 above.

[0326] 1 H NMR (300MHz, CDCl3): δ7.96(d,J=8.3Hz,2H),7.91-7.78(m,1H),7.58-7.48(m,1H),7.46(d,J=8.1Hz,2H),7.40-7.28(m,2 H), 3.57 (s, 2H), 3.32 (t, J = 5.1Hz, 4H), 2.42 (t, J = 5.1Hz, 4H), 2.06 (d, J = 7.5Hz, 3H), 2.01-1.87 (m, 6H), 1.68-1.66 (m, 6H).

[0327] Example 42: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(4-methoxyphenyl)piperazine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(4-methoxyphenyl)piperazine-1-carboxamide) (Compound 1-42)

[0328] 4-methoxyphenylisocyanate (37 mg, 0.25 mmol) was reacted in the same manner as in Example 37 above to obtain 61 mg of the title compound.

[0329] 1 H NMR (300MHz, CDCl3): δ10.63(s,1H),7.97(d,J=7.8Hz,2H),7.86(d,J=7.6Hz,1H),7.57(d,J=7.8Hz,1H),7.48(d,J=7.9Hz,2H),7.35(p,J= 7.2Hz,2H),7.26-7.23(m,2H),6.84(d,J=8.3Hz,2H),6.27(s,1H),3.78(s,3H),3.61(s,2H),3.50(t,J=5.1Hz,4H),2.49(t,J=4.9Hz,4H).

[0330] Example 43: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(2-(trifluoromethyl)phenyl)piperazine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(2-(trifluoromethyl)phenyl)piperazine-1-carboxamide) (Compound 1-43)

[0331] 2-(trifluoromethyl)phenyl isocyanate (47 mg, 0.25 mmol) was reacted in the same manner as in Example 37 above to obtain 89 mg of the title compound.

[0332] 1 H NMR (300MHz, CDCl3): δ10.90(s,1H),8.10(d,J=8.3Hz,1H),7.97(d,J=8.2Hz,2H),7.91-7.70(m,1H),7.64-7.42(m,5 H),7.39-7.27(m,2H),7.14(t,J=7.7Hz,1H),6.79(s,1H),3.61(s,2H),3.52(t,J=5.1Hz,4H),2.50(t,J=5.1Hz,4H).

[0333] Example 44: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(4-fluorophenyl)piperazine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(4-fluorophenyl)piperazine-1-carboxamide) (Compound 1-44)

[0334] 4-fluorophenylisocyanate (43 mg, 0.31 mmol) was reacted in the same manner as in Example 37 above to obtain 106 mg of the title compound.

[0335] 1 H NMR (500MHz, CDCl3): δ10.74(s,1H),7.96(d,J=8.2Hz,2H),7.91-7.81(m,1H),7.54-7.49(m,1H),7.47(d,J=8.2Hz,2 H),7.37-7.27(m,4H),6.98(t,J=8.7Hz,2H),6.34(s,1H),3.60(s,2H),3.50(t,J=5.2Hz,4H),2.48(t,J=5.0Hz,4H).

[0336] Example 45: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(2-fluorophenyl)piperazine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(2-fluorophenyl)piperazine-1-carboxamide) (Compound 1-45)

[0337] 2-fluorophenylisocyanate (43 mg, 0.31 mmol) was reacted in the same manner as in Example 37 above to obtain 119 mg of the title compound.

[0338] 1 H NMR (500MHz, CDCl3): δ10.78(s,1H),8.09(td,J=8.2,1.6Hz,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=8.2,6.2,1.7Hz,1H),6.60(d,J=4.0Hz,1H),3.61(s,2H),3.53(t,J=5.0Hz,4H),2.50(t,J=5.0Hz,4H).

[0339] Example 46: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(2,3-dihydro-1H-inden-5-yl)piperazine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(2,3-dihydro-1H-inden-5-yl)piperazine-1-carboxamide) (Compound 1-46)

[0340] 5-indanyl isocyanate (50 mg, 0.31 mmol) was reacted in the same manner as in Example 37 above to obtain 115 mg of the title compound.

[0341] 1H NMR (500MHz, CDCl3): δ10.76 (s, 1H), 7.96 (d, J = 8.2Hz, 2H), 7.88-7.79 (m, 1H), 7 .52(dd,J=7.7,1.4Hz,1H),7.47(d,J=8.1Hz,2H),7.38-7.27(m,4H),7.11(d,J= 8.0Hz,1H),7.00(dd,J=8.0,1.6Hz,2H),6.33(s,1H),3.59(s,2H),3.53-3.34(m ,4H), 2.86(dt,J=13.9,7.4Hz,4H), 2.48(t,J=5.0Hz,4H), 2.05(p,J=7.4Hz,2H).

[0342] Example 47: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(3,5-dimethylphenyl)piperazine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(3,5-dimethyphenyl)piperazine-1-carboxamide) (Compound 1-47)

[0343] 3,5-dimethylphenylisocyanate (46 mg, 0.31 mmol) was reacted in the same manner as in Example 37 above to obtain 102 mg of the title compound.

[0344] 1 H NMR (300MHz, CDCl3): δ10.83(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=5.0Hz,4H),2.47(t,J=5.0Hz,4H),2.28(s,6H).

[0345] Example 48: Butyl-(4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)piperazine-1-carbonyl)glycine ester

[0346] (butyl-(4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)piperazine-1-carbonyl)glycinate)(compound 1-48)

[0347] The title compound was obtained by reacting butyl isocyanate (49 mg, 0.31 mmol) with the same method as in Example 37 above.

[0348] 1 H NMR (300MHz, CDCl3): δ10.65(s,1H),7.96(d,J=7.9Hz,2H),7.87-7.84(m,1H),7.57- 7.49(m,1H),7.45(d,J=8.0Hz,2H),7.40-7.27(m,2H),5.00(t,J=5.3Hz,1H),4.16(t, J=6.6Hz,2H),4.03(d,J=5.0Hz,2H),3.57(s,2H),3.41(t,J=5.0Hz,4H),2.42(t,J=5 .0Hz, 4H), 1.63 (dt, J = 14.5, 6.6Hz, 3H), 1.38 (h, J = 7.3Hz, 2H), 0.93 (t, J = 7.4Hz, 3H).

[0349] Example 49: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(4-chlorophenyl)piperazine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(4-chlorophenyl)piperazine-1-carboxamide) (Compound 1-49)

[0350] 4-chlorophenylisocyanate (48 mg, 0.31 mmol) was reacted in the same manner as in Example 37 above to obtain 59 mg of the title compound.

[0351] 1 H NMR (300MHz, CDCl3): δ7.96(d,J=8.2Hz,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 = 5.0Hz, 4H), 2.49 (t, J = 5.1Hz, 4H).

[0352] Example 50: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(2-ethylphenyl)piperazine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(2-ethylphenyl)piperazine-1-carboxamide) (Compounds 1-50)

[0353] 2-ethylphenylisocyanate (46 mg, 0.31 mmol) was reacted in the same manner as in Example 37 above to obtain 107 mg of the title compound.

[0354] 1 H NMR (300MHz, CDCl3): δ10.79 (s, 1H), 7.97 (d, J = 7.9Hz, 2H), 7.90-7.78 (m, 1 H),7.61(d,J=8.0Hz,1H),7.47(d,J=8.3Hz,3H),7.38-7.29(m,2H),7.18(d ,J=7.2Hz,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 = 7.6Hz, 2H), 2.49 (t, J = 5.0Hz, 4H), 1.24 (t, J = 7.6Hz, 3H).

[0355] Example 51: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(p-tolyl)piperazine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(p-tolyl)piperazine-1-carboxamide) (Compound 1-51)

[0356] p-tolyl isocyanate (42 mg, 0.31 mmol) was reacted in the same manner as in Example 37 above to obtain 76 mg of the title compound.

[0357] 1H NMR (300MHz, CDCl3): δ10.59(s,1H),7.96(d,J=8.2Hz,2H),7.86(dd,J=7.5,1.7Hz,1H),7.56(dd,J=7.7,1.6Hz,1H),7.48(d,J=8.0Hz,2H),7.34(p d,J=7.3,1.5Hz,2H),7.26-7.20(m,2H),7.09(d,J=8.2Hz,2H),6.31(s,1H ), 3.60 (s, 2H), 3.49 (t, J = 5.0Hz, 4H), 2.48 (t, J = 5.0Hz, 4H), 2.30 (s, 3H).

[0358] Example 52: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(4-ethylphenyl)piperazine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(4-ethylphenyl)piperazine-1-carboxamide) (Compound 1-52)

[0359] The title compound was obtained by reacting 4-ethylphenylisocyanate (46 mg, 0.31 mmol) in the same manner as in Example 37 above.

[0360] 1 H NMR (300MHz, CDCl3): δ10.68 (s, 1H), 7.96 (d, J = 8.1Hz, 2H), 7.89-7.81 (m, 1 H),7.57-7.50(m,1H),7.47(d,J=8.0Hz,2H),7.41-7.28(m,2H),7.25(d,J= 8.2Hz,2H),7.12(d,J=8.3Hz,2H),6.32(s,1H),3.60(s,2H),3.50(t,J=5.0 Hz, 4H), 2.60 (q, J = 7.6Hz, 2H), 2.48 (t, J = 5.0Hz, 4H), 1.21 (t, J = 7.6Hz, 3H).

[0361] Example 53: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-cyclohexylpiperazine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-cyclohexylpiperazine-1-carboxamide) (Compound 1-53)

[0362] The title compound was obtained by reacting cyclohexyl isocyanate (39 mg, 0.31 mmol) in the same manner as in Example 37 above.

[0363] 1 H NMR (300MHz, CDCl3): δ10.93(s,1H),7.96(d,J=8.0Hz,2H),7.89-7.79(m,1H),7.49-7.39(m,3H),7.36-7.27(m,2H),4.25(d,J=7.6Hz,1H),3.71-3 .60(m,1H),3.56(s,1H),3.35(t,J=5.0Hz,4H),2.41(t,J=5.0Hz,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).

[0364] Example 54: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(chloromethyl)piperazine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(chloromethyl)piperazine-1-carboxamide) (Compound 1-54)

[0365] 2-chloroethylisocyanate (33 mg, 0.31 mmol) was reacted in the same manner as in Example 37 above to obtain 67 mg of the title compound.

[0366] 1 H NMR (300MHz, CDCl3): δ10.75 (s, 1H), 7.96 (d, J = 7.8Hz, 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=5.1Hz,4H),2.44(t,J=5.1Hz,4H).

[0367] Example 55: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-propylpiperazine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-propylpiperazine-1-carboxamide) (Compound 1-55)

[0368] Propyl isocyanate (27 mg, 0.31 mmol) was reacted in the same manner as in Example 37 above to obtain 64 mg of the title compound.

[0369] 1 H NMR (300MHz, CDCl3): δ10.89(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=5.6Hz,1H ), 3.56 (s, 2H), 3.37 (t, J = 5.0Hz, 4H), 3.21 (td, J = 7.1, 5.6Hz, 2H), 2.42 (t, J = 5.0Hz, 4H), 1.53 (h, J = 7.4Hz, 2H), 0.92 (t, J = 7.4Hz, 3H).

[0370] Example 56: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(2-ethoxyphenyl)piperazine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(2-ethoxyphenyl)piperazine-1-carboxamide) (Compound 1-56)

[0371] 2-Ethoxyphenylisocyanate (51 mg, 0.31 mmol) was reacted in the same manner as in Example 37 above to obtain 77 mg of the title compound.

[0372] 1H NMR (300MHz, CDCl3): δ10.71(s,1H),8.20-8.14(m,1H),7.99(d,J=8.2Hz,2H),7.93-7.84(m,1H),7.60-7.46(m,3H),7.43-7.30(m,2H),7.22(s,1 H),6.98-6.93(m,2H),6.88-6.84(m,1H),4.12(q,J=7.0Hz,2H),3.63(s, 2H), 3.55(t,J=5.0Hz,4H), 2.52(t,J=5.0Hz,4H), 1.45(t,J=7.0Hz,3H).

[0373] Example 57: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(2,4,4-trimethylpentan-2-yl)piperazine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(2,4,4-trimethylpentan-2-yl)piperazine-1-carboxamide) (Compound 1-57)

[0374] The title compound was obtained by reacting 1,1,3,3-tetramethylbutyl isocyanate (48 mg, 0.31 mmol) in the same manner as in Example 37 above.

[0375] 1 H NMR (300MHz, CDCl3): δ11.15(s,1H),7.96(d,J=8.0Hz,2H),7.89-7.82(m,1H),7.43-7.37(m,3H),7.34-7.27(m,2 H), 4.32 (s, 1H), 3.55 (s, 2H), 3.31 (t, J = 5.0Hz, 4H), 2.40 (t, J = 4.9Hz, 4H), 1.73 (s, 2H), 1.41 (s, 6H), 1.01 (s, 9H).

[0376] Example 58: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(2-bromophenyl)piperazine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-(2-bromophenyl)piperazine-1-carboxamide) (Compound 1-58)

[0377] 2-bromophenylisocyanate (62 mg, 0.31 mmol) was reacted in the same manner as in Example 37 above to obtain 94 mg of the title compound.

[0378] 1 H NMR (300MHz, CDCl3): δ10.66(s,1H),8.19(dd,J=8.3,1.6Hz,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=8.0,7.3,1.6Hz,1H),3.62(s,2H),3.56(t,J=5.0Hz,4H),2.52(t,J=5.0Hz,4H).

[0379] Example 59: N-(benzo[d]thiazol-2-yl)-4-((4-propionylpiperazin-1-yl)methyl)benzamide (Compound 1-59)

[0380] Acetyl chloride (22 μL, 0.31 mmol) was reacted using the same method as in Example 37 above to obtain 74 mg of the title compound.

[0381] 1 H NMR (500MHz, CDCl3): δ10.56 (s, 1H), 7.90 (t, J = 8.1Hz, 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=7.1,5.2Hz,2H),3.07(s,4H),2.51(t,J=5.0Hz,4H),0.99(t,J=7.1Hz,3H).

[0382] Example 60: N-(benzo[d]thiazol-2-yl)-4-((4-benzoylpiperazin-1-yl)methyl)benzamide (Compound 1-60)

[0383] The title compound was obtained by reacting benzoyl chloride (36 μL, 0.31 mmol) with the same method as in Example 37 above.

[0384] 1 H NMR (500MHz, DMSO): δ12.80(s,1H),8.50(s,1H),8.14(d,J=8.4Hz,2H),8.03(dd,J=7.9,1.1Hz,1H),7.80(d,J=8.0Hz,1H),7.53(d,J=8.3Hz,2H),7.5 2-7.42(m,3H),7.35(td,J=7.6,1.1Hz,1H),7.26-7.18(m,2H),6.93(tt,J= 7.4, 1.2Hz, 1H), 3.63 (s, 2H), 3.51 (t, J = 4.9Hz, 4H), 2.47 (t, J = 5.0Hz, 4H).

[0385] Example 61: N-(benzo[d]thiazol-2-yl)-4-((4-ethylpiperazin-1-yl)methyl)benzamide (Compound 1-61)

[0386] N-(benzo[d]thiazol-2-yl)-4-((4-(ethylsulfonyl)piperazin-1-yl)methyl)benzamide (100 mg, 0.28 mmol), obtained in Example 32, 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 then separated by column chromatography to obtain 54 mg of the title compound.

[0387] 1H NMR (500MHz, CDCl3): δ10.50 (s, 1H), 7.91 (t, J = 8.1Hz, 4H), 7.82 (m, 1H), 7.50 (m, 1H), 7.37 (m, 2H), 3.56(s,2H),3.45(qd,J=7.1,5.2Hz,2H),3.07(s,4H),2.50(t,J=5.0Hz,4H),0.94(t,J=7.1Hz,3H).

[0388] Example 62: N-(benzo[d]thiazol-2-yl)-4-((4-benzylpiperazin-1-yl)methyl)benzamide (Compound 1-62)

[0389] The title compound was obtained by reacting benzyl bromide (37 μL, 0.31 mmol) in the same manner as in Example 61 above.

[0390] 1 H NMR (500MHz, DMSO): δ12.80(s,1H),8.50(s,1H),8.14(d,J=8.4Hz,2H),8.03( dd,J=7.9,1.1Hz,1H),7.80(d,J=8.0Hz,1H),7.53(d,J=8.3Hz,2H),7.52-7.42 (m,3H),7.35(td,J=7.6,1.1Hz,1H),7.26-7.18(m,2H),6.93(tt,J=7.4,1.2H z, 1H), 3.66 (s, 2H), 3.63 (s, 2H), 3.50 (t, J = 4.9Hz, 4H), 2.46 (t, J = 5.0Hz, 4H).

[0391] Example 63: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzylidene)piperidine-1-carboxylate (tert-butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzylidene)piperidine-1-carboxylate (compound 1-63)

[0392] Compound 5 (247 mg, 0.74 mmol), 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), 1,4-dioxane (10 mL), and H2O (2 mL) were added to the reaction vessel. The reaction mixture was stirred at 95 °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 then separated by column chromatography to obtain 172 mg of the title compound.

[0393] 1 H NMR (400MHz, CDCl3): δ11.16(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=5.9Hz,3H),3.40(t,J=5.9Hz,3H),2.41-2.34(m,4H),1.49(s,9H).

[0394] Example 64: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)piperidine-1-carboxylate (tert-butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)piperidine-1-carboxylate) (Compound 1-64)

[0395] 160 mg (0.36 mmol) of tert-butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzylidene)piperidine-1-carboxylate (tert-butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzylidene) obtained in Example 63 above was dissolved in anhydrous MeOH (3 mL) and anhydrous THF (3 mL), and then 10 wt% Pd / C was added. The reaction mixture was reacted at room temperature under hydrogen atmosphere for 12 hours, and palladium was removed by passing it through a diatomaceous earth (Celite) filter. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain 147 mg of the title compound.

[0396] 1 H NMR (500MHz, CDCl3): δ11.01 (s, 1H), 7.93 (d, J = 8.0Hz, 2H), 7.86-7.85 (m, 1H), 7.47-7.45 (m, 1H), 7.33-7.29 (m, 2H),7.24(d,J=7.9Hz,2H),2.64-2.58(m,4H),1.70-1.66(m,3H),1.57(d,J=12.6Hz,2H),1.14(q,J=11.5Hz,2H).

[0397] Example 65: N-(benzo[d]thiazol-2-yl)-4-(piperidin-4-ylidenemethyl)benzamide (Compound 1-65)

[0398] 110 mg (0.25 mmol) of tert-butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzylidene)piperidine-1-carboxylate (tert-butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzylidene) obtained in Example 63 above was dissolved in anhydrous DCM (5 mL), and TFA (2 mL) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was concentrated under reduced pressure and then washed twice with diethyl ether to obtain 120 mg of the title compound.

[0399] 1H NMR (500MHz, DMSO): δ12.91(s,1H),8.71(s,2H),8.15(d,J=8.3Hz,2H),8.04(d,J=7.9Hz,1H),7.80(d,J=8.1Hz,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=6.1Hz,2H),2.57(t,J=6.1Hz,2H).

[0400] Example 66: N-(benzo[d]thiazol-2-yl)-4-(piperidin-4-ylmethyl)benzamide (Compound 1-66)

[0401] The title compound was obtained by reacting 112 mg of 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)piperidine-1-carboxylate (110 mg, 0.25 mmol) obtained in Example 64 with the same method as in Example 65 above.

[0402] 1 H NMR (500MHz, DMSO): δ12.85(s,1H),8.12(d,J=8.0Hz,2H),8.03(d,J=7.9Hz ,1H),7.80(d,J=8.2Hz,1H),7.48(t,J=7.7Hz,1H),7.41(d,J=8.0Hz,2H),7. 36(t,J=7.6Hz,1H),3.26(d,J=12.5Hz,2H),2.83(q,J=11.8Hz,2H),2.66(d, J=7.1Hz,2H),1.92-1.86(m,1H),1.73(d,J=13.9Hz,2H),1.39-1.30(m,2H).

[0403] Example 67: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzylidene)-N-ethylpiperidine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzylidene)-N-ethylpiperidine-1-carboxamide) (Compound 1-67)

[0404] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-4-(piperidin-4-ylidenemethyl)benzamide (75 mg, 0.17 mmol) and ethyl isocyanate (16 μL, 0.20 mmol) obtained in Example 65 with the same method as in Example 37 above.

[0405] 1 H NMR (400MHz, CDCl3): δ11.20(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,1 H), 4.44 (t, J = 5.4Hz, 1H), 3.48 (t, J = 5.8Hz, 2H), 3.38 (t, J = 5.8Hz, 2H), 3.30 (qd, J = 7.2, 5.3Hz, 2H), 2.46-2.39 (m, 4H), 1.16 (t, J = 7.2Hz, 3H).

[0406] Example 68: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzylidene)-N-phenylpiperidine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzylidene)-N-phenylpiperidine-1-carboxamide) (Compound 1-68)

[0407] The title compound was obtained by reacting phenyl isocyanate (22 μL, 0.20 mmol) in the same manner as in Example 67 above.

[0408] 1H NMR (400MHz, CDCl3): δ10.91(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= 7.0,1.3Hz,1H),6.52(s,1H),6.42(s,1H),3.61(t,J=5.9Hz,2H),3.52(t,J=5.9Hz,2H),2.56-2.53(m,2H),2.51-2.47(m,2H).

[0409] Example 69: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-ethylpiperidine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-ethylpiperidine-1-carboxamide) (Compound 1-69)

[0410] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-4-(piperidin-4-ylmethyl)benzamide (75 mg, 0.17 mmol) and ethyl isocyanate (16 μL, 0.20 mmol) obtained in Example 66 with the same method as in Example 37 above to obtain 40 mg of the title compound.

[0411] 1 H NMR (400MHz, CDCl3): δ11.03 (s, 1H), 7.93 (d, J = 8.3Hz, 2H), 7.87-7.83 (m, 1H), 7.4 8-7.44(m,1H),7.33-7.28(m,2H),7.23(d,J=8.2Hz,2H),4.38(t,J=5.4Hz,1H),3. 91(dt,J=13.0,2.9Hz,2H),3.27(qd,J=7.2,5.3Hz,2H),2.70(td,J=12.9,2.6Hz,2 H), 2.59 (d, J = 7.1Hz, 2H), 1.72-1.66 (m, 1H), 1.63-1.58 (m, 2H), 1.20-1.12 (m, 5H).

[0412] Example 70: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-ethylpiperidine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-ethylpiperidine-1-carboxamide) (Compound 1-70)

[0413] The title compound was obtained by reacting phenyl isocyanate (22 μL, 0.20 mmol) in the same manner as in Example 69 above.

[0414] 1 H NMR (400MHz, DMSO): δ12.80(s,1H),8.43(s,1H),8.10(d,J=8.0Hz,2H),8.02(d,J=7.9H z,1H),7.79(d,J=8.1Hz,1H),7.49-7.44(m,3H),7.40(d,J=7.9Hz,2H),7.34(t,J=7.6H z,1H),7.21(t,J=7.9Hz,2H),6.91(t,J=7.3Hz,1H),4.11(d,J=13.2Hz,2H),2.77-2.70 (m,2H),2.65(d,J=7.2Hz,2H),1.86-1.77(m,1H),1.62-1.58(m,2H),1.20-1.10(m,2H).

[0415] Example 71: 4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-N-(benzo[d]thiazol-2-yl)benzamide (4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-N-(benzo[d]thiazol-2-yl)benzamide)(Compound 1-71)

[0416] The title compound was obtained by reacting (1S,4S)-5-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (300 mg, 0.65 mmol) obtained in Example 25 with the same method as in Example 3 above.

[0417] 1 H NMR (400MHz, CDCl3): δ9.49(s,1H),9.27(s,1H),8.23(d,J=8.3Hz,2H),8.04(dd,J=8.0,1.2Hz,1H),7.80(d,J=8.0Hz ,1H),7.72(d,J=7.9Hz,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).

[0418] Example 72: (1S,4S)-5-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-ethyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide ((1S,4S)-5-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-ethyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide) (Compound 1-72)

[0419] The 4-(((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl)-N-(benzo[d]thiazolyl)benzamide obtained from Example 71 was processed using the same method as in Example 37 above.

[0420] The title compound was obtained by reacting (4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-N-(benzo[d]thiazol-2-yl)benzamide (200 mg, 0.43 mmol) and ethyl isocyanate (41 μL, 0.52 mmol).

[0421] 1 H NMR (400MHz, CDCl3): δ10.84(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=8.6,1.9Hz,1H),2.86(dt,J=9.6,1.9Hz ,1H),2.69(d,J=9.6Hz,1H),1.89(d,J=9.7Hz,1H),1.74-1.71(m,1H),1.18-1.14(m,3H).

[0422] Example 73: (1S,4S)-5-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-phenyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide ((1S,4S)-5-(4-(benzo[d]thiazol-2-ylcarbamoyl)benzyl)-N-phenyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide) (Compound 1-73)

[0423] 114 mg of the title compound was obtained by reacting phenyl isocyanate (56 μL, 0.52 mmol) with the same method as in Example 72 above.

[0424] 1 H NMR (400MHz, CDCl3): δ11.03(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=7.2,1.2Hz,1H),6.19(s,1H),4.57(s,1H ),3.80(s,2H),3.61(d,J=8.4Hz,1H),3.54(s,1H),3.33(dd,J=8.5,2.2Hz,1H),2. 88(dd,J=9.7,2.1Hz,1H),2.79-2.77(m,1H),1.97-1.94(m,1H),1.79-1.77(m,1H).

[0425] Example 74: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)phenyl)-3,6-dihydropyridine-1-(2H)-carboxylate (tert-butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)phenyl)-3,6-dihydropyridine-1-(2H)-carboxylate (compound 1-74)

[0426] 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 above to obtain 950 mg of the title compound.

[0427] 1 H NMR (500MHz, CDCl3): δ11.12(s,1H),7.95(d,J=8.2Hz,2H),7.88-7.82(m,1H),7.42(d,J=8.0Hz,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=5.6Hz),2.15(2H,s),1.43(9H,s).

[0428] Example 75: N-(benzo[d]thiazol-2-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (Compound 1-75)

[0429] The title compound was obtained by reacting 200 mg of tert-butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)phenyl)-3,6-dihydropyridine-1-(2H)-carboxylate (200 mg, 0.46 mmol) obtained in Example 74 with the same method as in Example 3 above.

[0430] 1H NMR (500MHz, CDCl3): δ11.14(s,1H),7.97(d,J=8.2Hz,2H),7.82(m,1H),7.42(d,J=8.0Hz,2 H),7.43(m,1H),7.37(m,2H),5.90(1H,s),3.97(2H,m),3.34(2H,t,J=5.6Hz),2.45(2H,s).

[0431] Example 76: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)phenyl)-N-(4-trifluoromethyl)phenyl)-3,6-dihydropyridine-1-(2H)-carboxylate (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)phenyl)-N-(4-trifluoromethyl)phenyl)-3,6-dihydropyridine-1-(2H)-carboxylate (Compound 1-76)

[0432] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (150 mg, 0.45 mmol) obtained in Example 75 with the same method as in Example 39 above, to give 198 mg of the title compound.

[0433] 1 H NMR (500MHz, CDCl3): δ11.12(s,1H),8.23(d,J=7.7Hz,2H),8.03(d,J=7.7Hz,2H),7.95(d,J=8.2Hz,2H),7.82(m,1 H),7.42(d,J=8.0Hz,2H),7.37(m,1H),7.27(m,2H),5.92(1H,s),3.83(2H,m),3.34(2H,t,J=5.6Hz),2.15(2H,s).

[0434] Example 77: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)phenyl)-N-(4-trifluoromethyl)phenyl)piperidine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)phenyl)-N-(4-trifluoromethyl)phenyl)piperidine-1-carboxamide (Compound 1-77)

[0435] The 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)phenyl)-N-(4-trifluoromethyl)phenyl)-3,6-dihydropyridine-1-(2H)-carboxylic acid ester obtained from Example 76 was processed in the same manner as in Example 64 above.

[0436] The title compound was obtained by reacting (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)phenyl)-N-(4-trifluoromethyl)phenyl)-3,6-dihydropyridine-1-(2H)-carboxylate (100 mg, 0.19 mmol) with 0.19 mmol.

[0437] 1 H NMR (500MHz, CDCl3): δ11.14(s,1H),8.23(d,J=7.7Hz,2H),8.03(d,J=7.7Hz,2H),7.96(d,J=8.2Hz,2H),7.91-7.81(m,1H),7.54- 7.49(m,1H),7.47(d,J=8.2Hz,2H),7.37-7.27(m,4H),6.98(t,J=8.7Hz,2H),6.34(s,1H),2.73(m,1H),1.89(m,2H),1.64(m,2H).

[0438] Example 78: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-(trifluoromethyl)benzylidene)piperidine-1-carboxylate (tert-butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-(trifluoromethyl)benzylidene)piperidine-1-carboxylate (Compound 1-78)

[0439] The title compound was obtained by reacting compound 6 (744 mg, 1.86 mmol) synthesized in Synthesis Example 6 above with 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)piperidine-1-carboxylate (tert-butyl4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)piperidine-1-carboxylate (500 mg, 1.55 mmol) in the same manner as in Example 63 above.

[0440] 1 H NMR (300MHz, DMSO-d6) δ13.02(s,1H),8.09-7.99(m,1H),7.80(d,J=8.2Hz,3H),7.67(d,J=7.2Hz,2H),7.54-7.42(m,2H),7.42-7 .30(m,2H),6.53(s,1H),3.46(t,J=5.9Hz,2H),3.39(t,J=5.9Hz,3H),2.44(t,J=5.9Hz,2H),2.35(t,J=5.9Hz,2H),1.43(s,9H).

[0441] Example 79: N-(benzo[d]thiazol-2-yl)-4-(piperidin-4-ylidenemethyl)-2-(trifluoromethyl)benzamide (Compound 1-79)

[0442] The title compound was obtained by reacting 110 mg of tert-butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-(trifluoromethyl)benzylidene)piperidine-1-carboxylate (110 mg, 0.21 mmol) obtained in Example 78 with the same method as in Example 3 above.

[0443] 1 H NMR (300MHz, DMSO-d6) δ13.05(s,1H),8.82(s,2H),8.04(d,J=7.8Hz,1H),7.81(t,J=7.7Hz,2H),7.70(d,J=6.4Hz, 2H),7.55-7.42(m,1H),7.43-7.31(m,1H),6.62(s,1H),3.19(dt,J=17.0,5.9Hz,4H),2.61(dt,J=16.2,5.9Hz,4H).

[0444] Example 80: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-(trifluoromethyl)benzylidene)-N-ethylpiperidine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-(trifluoromethyl)benzylidene)-N-ethylpiperidine-1-carboxamide) (Compound 1-80)

[0445] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-4-(piperidin-4-ylidenemethyl)-2-(trifluoromethyl)benzamide (45 mg, 0.09 mmol) and ethyl isocyanate (6.83 mg, 0.10 mmol) obtained in Example 79 with the same method as in Example 37 above to obtain 27 mg of the title compound.

[0446] 1 H NMR (300MHz, DMSO-d6) δ13.00(s,1H),8.09-7.99(m,1H),7.80(d,J=8.1Hz,2H),7.67(d,J=7.1Hz,2H),7.53-7.43(m,1H),7.4 2-7.32(m,1H),6.60-6.47(m,2H),3.46-3.34(m,3H),3.13-3.01(m,2H),2.37(dt,J=24.5,5.7Hz,4H),1.03(t,J=7.1Hz,3H).

[0447] Example 81: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-(trifluoromethyl)benzylidene)-N-phenylpiperidine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-(trifluoromethyl)benzylidene)-N-phenylpiperidine-1-carboxamide) (Compound 1-81)

[0448] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-4-(piperidin-4-ylidenemethyl)-2-(trifluoromethyl)benzamide (45 mg, 0.09 mmol) and phenyl isocyanate (11.18 mg, 0.10 mmol) obtained in Example 79 above with the same method as in Example 37 above, to obtain 33 mg of the title compound.

[0449] 1 H NMR (300MHz, DMSO-d6) δ12.99(s,1H),8.59(s,1H),8.04(d,J=7.9Hz,1H),7.81(dd,J=8.1,4.3Hz,2H),7.69(d,J=7.2Hz,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=22.4,5.8Hz,4H),2.43(t,J=5.7Hz,2H).

[0450] Example 82: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-(trifluoromethyl)benzyl)piperidine-1-carboxylate (tert-butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-(trifluoromethyl)benzyl)piperidine-1-carboxylate (Compound 1-82)

[0451] The title compound was obtained by reacting 150 mg of tert-butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-(trifluoromethyl)benzylidene)piperidine-1-carboxylate (150 mg, 0.29 mmol) obtained in Example 78 with the same method as in Example 64 above.

[0452] 1H NMR(300MHz,Chloroform-d)δ11.79(s,1H),7.84-7.77(m,1H),7.56(d,J=7.8Hz,1H),7.49(s,1H),7.31-7.27(m,1H),7.26-7.2 3(m,1H),7.19(td,J=7.7,7.2,1.4Hz,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).

[0453] Example 83: N-(benzo[d]thiazol-2-yl)-4-(piperidin-4-ylmethyl)-2-(trifluoromethyl)benzamide (Compound 1-83)

[0454] The title compound was obtained by reacting 75 mg of tert-butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-(trifluoromethyl)benzyl)piperidine-1-carboxylic acid tert-butyl (75 mg, 0.14 mmol) obtained in Example 82 with the same method as in Example 79 above.

[0455] 1 H NMR (300MHz, DMSO-d6): δ13.02(s,1H),8.58(d,J=11.6Hz,1H),8.27(d,J=11.9Hz,1H),8.04(d,J=7.9,1.2Hz,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=12.3Hz,2H),2.93-2 .69(m,4H),1.97-1.81(m,1H),1.72(d,J=13.8Hz,2H),1.45-1.26(m,2H).

[0456] Example 84: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-(trifluoromethyl)benzyl)-N-ethylpiperidine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-(trifluoromethyl)benzyl)-N-ethylpiperidine-1-carboxamide) (Compound 1-84)

[0457] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-4-(piperidin-4-ylmethyl)-2-(trifluoromethyl)benzamide (41 mg, 0.10 mmol) and ethyl isocyanate (7.6 mg, 0.11 mmol) obtained from Example 83 above with the same method as in Example 37 above, to obtain 21 mg of the title compound.

[0458] 1 H NMR (300MHz, DMSO-d6): δ12.98(s,1H),8.04(d,1H),7.84-7.67(m,3H),7.62 (d,J=7.5Hz,1H),7.52-7.42(m,1H),7.41-7.31(m,1H),6.40(t,J=5.4Hz,1H ),3.93(d,J=13.0Hz,2H),3.10-2.95(m,2H),2.69(d,J=7.0Hz,2H),2.58(t, J=12.2Hz,2H),1.82-1.65(m,1H),1.51(d,J=12.7Hz,2H),1.15-0.94(m,5H).

[0459] Example 85: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-(trifluoromethyl)benzyl)-N-phenylpiperidine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-(trifluoromethyl)benzyl)-N-phenylpiperidine-1-carboxamide) (Compound 1-85)

[0460] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-4-(piperidin-4-ylmethyl)-2-(trifluoromethyl)benzamide (41 mg, 0.10 mmol) and phenyl isocyanate (13 mg, 0.11 mmol) obtained from Example 83 above with the same method as in Example 37 above, to obtain 25 mg of the title compound.

[0461] 1 H NMR(300MHz,DMSO-d6)δ12.98(s,1H),8.45(s,1H),8.03(d,J=8.0,1.2Hz,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 .2Hz,1H),7.27-7.16(m,2H),6.97-6.86(m,1H),4.12(d,J=13.3Hz,2H),2.8 6-2.64(m,4H),1.89-1.72(m,1H),1.59(d,J=12.6Hz,2H),1.26-1.07(m,2H).

[0462] Example 86: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-fluorobenzylidene)piperidine-1-carboxylate (tert-butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-fluorobenzylidene)piperidine-1-carboxylate (Compound 1-86)

[0463] Compound 7 (2.99 g, 8.51 mmol) and 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 above to obtain 1.18 g of the title compound.

[0464] 1H NMR(300MHz,DMSO-d6)δ12.75(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=17.0,6.0Hz,4H),2.46(t,J=5.7Hz,4H),2.33(t,J=5.5Hz,2H),1.43(s,9H).

[0465] Example 87: N-(benzo[d]thiazol-2-yl)-2-fluoro-4-(piperidin-4-ylidenemethyl)benzamide (Compound 1-87)

[0466] The tert-butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-fluorobenzylidene)piperidine-1-carboxylate (230 mg, 0.49 mmol) synthesized in Example 86 above was reacted in the same manner as in Example 79 above to obtain 321 mg of the title compound.

[0467] 1 H NMR(300MHz,DMSO-d6)δ8.81(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=6.0Hz,2H),2.56(t,J=5.9Hz,3H).

[0468] Example 88: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-fluorobenzylidene)-N-ethylpiperidine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-fluorobenzylidene)-N-ethylpiperidine-1-carboxamide) (Compound 1-88)

[0469] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-2-fluoro-4-(piperidin-4-ylidenemethyl)benzamide (74 mg, 0.40 mmol) synthesized in Example 87 with ethylisocyanate (31 mg, 0.44 mmol) in the same manner as in Example 63 above.

[0470] 1 H NMR(300MHz,DMSO-d6)δ12.74(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),6.5 3(t,J=5.4Hz,1H),6.42(s,1H),3.47-3.34(m,4H),3.15-2.99(m,2H),2.43(t,J=5.8Hz,2H),2.31(t,J=5.7Hz,2H),1.03(t,J=7.1Hz,3H).

[0471] Example 89: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-fluorobenzylidene)-N-phenylpiperidine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-fluorobenzylidene)-N-phenylpiperidine-1-carboxamide) (Compound 1-89)

[0472] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-2-fluoro-4-(piperidin-4-ylidenemethyl)benzamide (146 mg, 0.40 mmol) synthesized in Example 87 with phenylisocyanate (52 mg, 0.44 mmol) in the same manner as in Example 63 above.

[0473] 1H NMR (300MHz, DMSO-d6) δ12.76(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=19.5,5.6Hz,4H),3.18(d,J=5.2Hz,1H),2.55-2.52(m,2H),2.42(t,J=5.7Hz,2H).

[0474] Example 90: N-(benzo[d]thiazol-2-yl)-2-fluoro-4-((1-(phenylsulfonyl)piperidin-4-ylidene)methyl)benzamide (Compound 1-90)

[0475] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-2-fluoro-4-(piperidin-4-ylidenemethyl)benzamide (120 mg, 0.33 mmol) synthesized in Example 87 with benzenesulfonyl chloride (63 mg, 0.36 mmol) in the same manner as in Example 63 above.

[0476] 1 H NMR(300MHz,DMSO-d6)δ12.76(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=16.4,5.8Hz,4H),2.59-2.52(m,2H),2.49-2.38(m,2H).

[0477] Example 91: N-(benzo[d]thiazol-2-yl)-4-((1-(ethylsulfonyl)piperidin-4-ylidene)methyl)-2-fluorobenzamide (Compound 1-91)

[0478] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-2-fluoro-4-(piperidin-4-ylidenemethyl)benzamide (120 mg, 0.33 mmol) synthesized in Example 87 with ethylsulfonyl chloride (46 mg, 0.36 mmol) in the same manner as in Example 63 above.

[0479] 1 H NMR (300MHz, DMSO-d6) δ12.77(s,1H),8.09-7.99(m,1H),7.79(t,J=7.6Hz,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=5.8Hz,2H),3.08(q,J=7.4Hz,2H),2.57-2.52(m,2H),2.44(t,J=5.7Hz,2H),1.22(t,J=7.4Hz,3H).

[0480] Example 92: N-(benzo[d]thiazol-2-yl)-4-((1-benzoylpiperidin-4-ylidene)methyl)-2-fluorobenzamide (Compound 1-92)

[0481] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-2-fluoro-4-(piperidin-4-ylidenemethyl)benzamide (120 mg, 0.33 mmol) synthesized in Example 87 with benzoyl chloride (55 mg, 0.39 mmol) in the same manner as in Example 63 above.

[0482] 1 H NMR (300MHz, DMSO-d6) δ12.77(s,1H),8.04(d,J=7.7Hz,1H),7.79(d,J=8.1Hz,2H),7.54-7.39(m,6H),7.4 2-7.29(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).

[0483] Example 93: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-fluorobenzylidene)-N-(4-(trifluoromethyl)phenyl)piperidine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-fluorobenzylidene)-N-(4-(trifluoromethyl)phenyl)piperidine-1-carboxamide) (Compound 1-93)

[0484] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-2-fluoro-4-(piperidin-4-ylidenemethyl)benzamide (120 mg, 0.33 mmol) and 4-(trifluoromethyl)phenyl isocyanate (67 mg, 0.36 mmol) synthesized in Example 87 above with the same method as in Example 63 above.

[0485] 1H NMR (300MHz, DMSO-d6) δ12.77(s,1H),8.99(s,1H),8.04(d,J=7.8Hz,1H),7.85-7.67(m,4H),7.60(d,J=8.7Hz,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=19.2,5.8Hz,4H),2.60-2.53(m,2H),2.48-2.37(m,2H).

[0486] Example 94: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-fluorobenzylidene)-N-isopropylpiperidine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-fluorobenzylidene)-N-isopropylpiperidine-1-carboxamide)(Compound 1-94)

[0487] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-2-fluoro-4-(piperidin-4-ylidenemethyl)benzamide (120 mg, 0.33 mmol) synthesized in Example 87 with isopropyl isocyanate (31 mg, 0.36 mmol) in the same manner as in Example 63 above.

[0488] 1 H NMR(300MHz,DMSO-d6)δ12.75(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,1 H), 6.23 (d, J = 7.7Hz, 1H), 3.87-3.70 (m, 1H), 3.39 (dt, J = 18.1, 5.8Hz, 4H), 2.43 (t, J = 5.8Hz, 2H), 2.31 (t, J = 5.7Hz, 2H), 1.07 (d, J = 6.5Hz, 6H).

[0489] Example 95: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-2-chlorobenzylidene)piperidine-1-carboxylate (tert-butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-2-chlorobenzylidene)piperidine-1-carboxylate (Compound 1-95)

[0490] Compound 8 (2.72 g, 7.40 mmol) and 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 above to obtain 0.87 g of the title compound.

[0491] 1 H NMR (300MHz, DMSO-d6): δ13.00(s,1H),8.28(d,J=1.8Hz,1H),8.13-7.98(m,2H),7.80(d,J=8.1Hz,1H),7.56-7.4 2(m,2H),7.42-7.32(m,1H),6.43(s,1H),3.42(dt,J=23.6,6.0Hz,6H),2.34(dt,J=18.8,5.9Hz,4H),1.43(s,9H).

[0492] Example 96: N-(benzo[d]thiazol-2-yl)-3-chloro-4-(piperidin-4-ylidenemethyl)benzamide (Compound 1-96)

[0493] The title compound was obtained by reacting 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-2-chlorobenzylidene)piperidine-1-carboxylate (580 mg, 1.20 mmol) synthesized in Example 95 with the same method as in Example 79 above.

[0494] 1 H NMR (300MHz, DMSO-d6): δ12.71(s,1H),8.02(d,J=7.7Hz,1H),7.80(d,J=8.1Hz,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).

[0495] Example 97: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-2-chlorobenzylidene)-N-ethylpiperidine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-2-chlorobenzylidene)-N-ethylpiperidine-1-carboxamide) (Compound 1-97)

[0496] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-3-chloro-4-(piperidin-4-ylidenemethyl)benzamide (65 mg, 0.18 mmol) synthesized in Example 96 with ethylisocyanate (13 mg, 0.19 mmol) in the same manner as in Example 63 above.

[0497] 1 H NMR (300MHz, DMSO-d6): δ12.99(s,1H),8.27(d,J=1.8Hz,1H),8.13-7.99(m,2H),7.80(d,J=8.1Hz,1H),7.56-7.43(m,2H),7.42- 7.30(m,1H),6.56(t,J=5.4Hz,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=7.1Hz,3H).

[0498] Example 98: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3,5-difluorobenzylidene)piperidine-1-carboxylate (tert-butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3,5-difluorobenzylidene)piperidine-1-carboxylate (Compound 1-98)

[0499] Compound 9 (1.37 g, 3.70 mmol) and 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 above to obtain 400 mg of the title compound.

[0500] 1 H NMR (300MHz, DMSO-d6): δ13.17(s,1H),8.06(dd,J=7.8,1.2Hz,1H),7.82(d,J=8.1Hz,1H),7.56-7.43(m,2H),7.44-7.32( m, 1H), 7.16 (d, J = 9.2Hz, 2H), 6.42 (s, 1H), 3.49-3.32 (m, 7H), 2.46 (t, J = 5.8Hz, 8H), 2.33 (t, J = 5.8Hz, 2H), 1.43 (s, 10H).

[0501] Example 99: N-(benzo[d]thiazol-2-yl)-2,6-difluoro-4-(piperidin-4-ylidenemethyl)benzamide (Compound 1-99)

[0502] The title compound was obtained by reacting 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3,5-difluorobenzylidene)piperidine-1-carboxylic acid tert-butyl ester (58 mg, 0.12 mmol) synthesized in Example 98 with the same method as in Example 79 above.

[0503] 1 H NMR (300MHz, DMSO-d6): δ8.82(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=6.0Hz,2H),2.51(t,J=5.9Hz,3H).

[0504] Example 100: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3,5-difluorobenzylidene)-N-ethylpiperidine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3,5-difluorobenzylidene)-N-ethylpiperidine-1-carboxamide) (Compound 1-100)

[0505] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-2,6-difluoro-4-(piperidin-4-ylidenemethyl)benzamide (69 mg) synthesized in Example 99 with ethylisocyanate (14 mg, 0.20 mmol) in the same manner as in Example 63 above.

[0506] 1H NMR (300MHz, DMSO-d6): δ13.16(s,1H),8.06(d,J=7.8Hz,1H),7.82(d,J=8.0Hz,1H),7.55-7.43(m,1H),7.44-7.32(m,1H),7.16(d,J=9.2Hz,2H ),6.55(t,J=5.4Hz,1H),6.40(s,1H),3.46-3.33(m,4H),3.15-2.99(m, 2H), 2.43(t,J=5.8Hz,2H), 2.30(t,J=5.8Hz,2H), 1.03(t,J=7.1Hz,3H).

[0507] Example 101: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3,5-difluorobenzylidene)-N-phenylpiperidine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3,5-difluorobenzylidene)-N-phenylpiperidine-1-carboxamide) (Compound 1-101)

[0508] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-2,6-difluoro-4-(piperidin-4-ylidenemethyl)benzamide (69 mg) synthesized in Example 99 with phenylisocyanate (19 mg, 0.16 mmol) in the same manner as in Example 63 above.

[0509] 1 H NMR (300MHz, DMSO-d6): δ13.18(s,1H),8.60(s,1H),8.11-8.01(m,1H),7.82(d,J=8.0Hz,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=17.1,5.9Hz,4H),2.41(t,J=5.8Hz,2H).

[0510] Example 102: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3,5-difluorobenzylidene)-N-(4-(trifluoromethyl)phenyl)piperidine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3,5-difluorobenzylidene)-N-(4-(trifluo romethyl)phenyl)piperidine-1-carboxamide) (Compound 1-102)

[0511] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-2,6-difluoro-4-(piperidin-4-ylidenemethyl)benzamide (69 mg) and 4-(trifluoromethyl)phenyl isocyanate (30 mg, 0.16 mmol) synthesized in Example 99 in the same manner as in Example 63 above.

[0512] 1 H NMR (300MHz, DMSO-d6): δ13.18(s,1H),9.00(s,1H),8.06(d,J=7.9Hz,1H),7.81(d,J=8.0Hz,1H),7.72(d,J=8.6Hz,2H),7.60(d,J=8.7Hz,2H ),7.55-7.43(m,1H),7.44-7.32(m,1H),7.19(d,J=9.2Hz,2H),6.45(s,1H),3.58(dt,J=16.6,5.9Hz,4H),2.54(s,4H),2.44(d,J=5.8Hz,2H).

[0513] Example 103: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-chlorobenzylidene)piperidine-1-carboxylate (tert-butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-chlorobenzylidene)piperidine-1-carboxylate (Compound 1-103)

[0514] Compound 10 (525 mg, 1.43 mmol) and 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 above to obtain 330 mg of the title compound.

[0515] 1 H NMR (300MHz, DMSO-d6): δ12.92(s,1H),8.09-7.99(m,1H),7.80(d,J=8.0Hz,1H),7.68(d,J=7.9Hz,1H),7.54-7.40(m,2H) ,7.42-7.29(m,2H),6.43(s,1H),3.41(dt,J=18.4,5.9Hz,7H),2.44(t,J=6.0Hz,2H),2.33(t,J=5.7Hz,2H),1.43(s,9H).

[0516] Example 104: N-(benzo[d]thiazol-2-yl)-2-chloro-4-(piperidin-4-ylidenemethyl)benzamide (Compound 1-104)

[0517] The title compound was obtained by reacting 320 mg of tert-butyl 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-chlorobenzylidene)piperidine-1-carboxylate (320 mg, 0.66 mmol) synthesized in Example 103 with the same method as in Example 79 above.

[0518] 1H NMR (300MHz, DMSO-d6): δ12.72(s,1H),8.07-7.87(m,1H),7.79(d,J=8.0Hz,1H),7.70(d,J=7.9Hz,1H),7.54-7.40 (m,2H),7.42-7.29(m,2H),6.45(s,1H),3.44(dt,J=18.4,5.9Hz,7H),2.48(t,J=6.0Hz,2H),2.37(t,J=5.7Hz,2H).

[0519] Example 105: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-chlorobenzylidene)-N-ethylpiperidine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-chlorobenzylidene)-N-ethylpiperidine-1-carboxamide) (Compound 1-105)

[0520] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-2-chloro-4-(piperidin-4-ylidenemethyl)benzamide (100 mg, 0.26 mmol) synthesized in Example 104 with ethylisocyanate (20 mg, 0.27 mmol) in the same manner as in Example 63 above.

[0521] 1 H NMR (300MHz, DMSO-d6): δ12.91(s,1H),8.04(d,J=8.0,1.2Hz,1H),7.80(d,J=8.0Hz,1H),7.68(d,J=7.9Hz,1H),7.54-7.40(m,2H),7.42-7.28(m ,2H),6.54(t,J=5.4Hz,1H),6.41(s,1H),3.42(t,J=5.7Hz,3H),3.07(qd ,J=7.1,5.2Hz,2H),2.35(dt,J=30.4,5.7Hz,4H),1.03(t,J=7.1Hz,3H).

[0522] Example 106: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-chlorobenzylidene)-N-phenylpiperidine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-chlorobenzylidene)-N-phenylpiperidine-1-carboxamide) (Compound 1-106)

[0523] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-2-chloro-4-(piperidin-4-ylidenemethyl)benzamide (100 mg, 0.26 mmol) synthesized in Example 104 with phenylisocyanate (34 mg, 0.29 mmol) in the same manner as in Example 63 above.

[0524] 1 H NMR (300MHz, DMSO-d6): δ12.93(s,1H),8.59(s,1H),8.09-8.00(m,1H),7.80(d,J=8.0Hz,1H),7.69(d,J=7.9Hz,1H),7.54-7.42( m,4H),7.42-7.31(m,2H),7.24(t,J=7.9Hz,2H),7.00-6.89(m,1H),6.46(s,1H),3.56(dt,J=21.1,5.8Hz,4H),2.47-2.35(m,2H).

[0525] Example 107: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-chlorobenzylidene)-N-(4-(trifluoromethyl)phenyl)piperidine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-chlorobenzylidene)-N-(4-(trifluoromethyl)phenyl)piperidine-1-carboxamide) (Compound 1-107)

[0526] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-2-chloro-4-(piperidin-4-ylidenemethyl)benzamide (100 mg, 0.26 mmol) and 4-(trifluoromethyl)phenyl isocyanate (51 mg, 0.29 mmol) synthesized in Example 104 above with the same method as in Example 63 above.

[0527] 1 H NMR (300MHz, DMSO-d6): δ12.92(s,1H),8.99(s,1H),8.08-8.00(m,1H),7.80(d,J=8.0Hz,1H),7.76-7.65(m,3H),7.60( d,J=8.7Hz,2H),7.52-7.42(m,2H),7.41-7.32(m,2H),6.47(s,1H),3.58(dt,J=20.6,6.0Hz,4H),2.43(t,J=5.7Hz,2H).

[0528] Example 108: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-chlorobenzylidene)-N-(4-fluorophenyl)piperidine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-chlorobenzylidene)-N-(4-fluorophenyl)piperidine-1-carboxamide) (Compound 1-108)

[0529] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-2-chloro-4-(piperidin-4-ylidenemethyl)benzamide (200 mg, 0.5 mmol) synthesized in Example 104 with 4-fluorophenyl isocyanate (78 mg, 0.57 mmol) in the same manner as in Example 63 above.

[0530] 1H NMR (300MHz, DMSO-d6): δ12.92(s,1H),8.63(s,1H),8.04(dd,J=8.0,1.2Hz,1H),7.80(d,J=8.0Hz,1H),7.69(d,J=7.9Hz,1 H),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=20.9,5.7Hz,4H),2.50-2.35(m,4H).

[0531] Example 109: 4-((5-(benzo[d]thiazol-2-ylcarbamoyl)thiophen-2-yl)methylene)piperidine-1-carboxylate (tert-butyl 4-((5-(benzo[d]thiazol-2-ylcarbamoyl)thiophen-2-yl)methylene)piperidine-1-carboxylate)(Compound 1-109)

[0532] Compound 11 (1.26 g, 3.71 mmol) and 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 above to obtain 285 mg of the title compound.

[0533] 1 H NMR (400MHz, DMSO-d6): δ13.23(s,1H),8.79(s,1H),8.01(d,J=7.9Hz,1H),7.75(s,1H),7.48(ddd,J=8.3,7.3,1.3Hz,1H), 7.34(td,J=7.7,1.1Hz,1H), 6.68(s,1H), 3.46(t,J=5.9Hz,4H), 2.96(t,J=5.9Hz,2H), 2.39(t,J=5.9Hz,2H), 1.43(s,9H).

[0534] Example 110: N-(benzo[d]thiazol-2-yl)-5-(piperidin-4-ylidenemethyl)thiophene-2-carboxamide (Compound 1-110)

[0535] The title compound was obtained by reacting 250 mg of tert-butyl 4-((5-(benzo[d]thiazol-2-ylcarbamoyl)thiophen-2-yl)methylene)piperidine-1-carboxylate (250 mg, 0.55 mmol) synthesized in Example 109 with the same method as in Example 79 above.

[0536] C 18 H 17 N3OS2[M] + Calculated MS(ESI) m / z value: 355.1; Measured value: 356.3 [M+H] + .

[0537] Example 111: 4-((5-(benzo[d]thiazol-2-ylcarbamoyl)thiophen-2-yl)methylene)-N-ethylpiperidine-1-carboxamide (4-((5-(benzo[d]thiazol-2-ylcarbamoyl)thiophen-2-yl)methylene)-N-ethylpiperidine-1-carboxamide)(Compound 1-111)

[0538] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-5-(piperidin-4-ylidenemethyl)thiophene-2-carboxamide (100 mg, 0.28 mmol) synthesized in Example 110 with ethyl isocyanate (22 mg, 0.31 mmol) in the same manner as in Example 63 above.

[0539] 1H NMR (300MHz, DMSO-d6): δ12.98(s,1H),8.20(s,1H),8.01(d,J=7.7Hz,1H),7.7 6(d,J=8.0Hz,1H),7.47(ddd,J=8.3,7.3,1.3Hz,1H),7.33(td,J=7.6,1.2Hz,1H ),7.15(d,J=4.0Hz,1H),6.55(d,J=7.0Hz,2H),3.47-3.39(m,4H),3.07(qd,J=7 .1,5.2Hz,2H),2.63-2.54(m,2H),2.34(t,J=5.7Hz,2H),1.03(t,J=7.1Hz,3H).

[0540] Example 112: 4-((5-(benzo[d]thiazol-2-ylcarbamoyl)thiophen-2-yl)methylene)-N-phenylpiperidine-1-carboxamide (4-((5-(benzo[d]thiazol-2-ylcarbamoyl)thiophen-2-yl)methylene)-N-phenylpiperidine-1-carboxamide)(Compound 1-112)

[0541] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-5-(piperidin-4-ylidenemethyl)thiophene-2-carboxamide (100 mg, 0.28 mmol) synthesized in Example 110 with phenylisocyanate (37 mg, 0.31 mmol) in the same manner as in Example 63 above.

[0542] 1 H NMR (300MHz, DMSO-d6): δ12.99(s,1H),8.58(s,1H),8.22(s,1H),8.01(d,J=7.8Hz,1H),7.76(d,J=8.0Hz,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=5.7Hz,2H),2.46(d,J=5.8Hz,2H).

[0543] Example 113: 4-((5-(benzo[d]thiazol-2-ylcarbamoyl)thiophen-2-yl)methylene)-N-(4-fluorophenyl)piperidine-1-carboxamide (4-((5-(benzo[d]thiazol-2-ylcarbamoyl)thiophen-2-yl)methylene)-N-(4-fluorophenyl)piperidine-1-carboxamide) (Compound 1-113)

[0544] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-5-(piperidin-4-ylidenemethyl)thiophene-2-carboxamide (100 mg, 0.28 mmol) and 4-(trifluoromethyl)phenyl isocyanate (42 mg, 0.31 mmol) synthesized in Example 110 with the same method as in Example 63 above.

[0545] 1 H NMR (300MHz, DMSO-d6): δ12.98(s,1H),8.62(s,1H),8.22(s,1H),8.01(d,J =7.8Hz,1H),7.76(d,J=8.0Hz,1H),7.48(dddd,J=8.4,6.4,4.3,2.5Hz,3H), 7.34(td,J=7.6,1.2Hz,1H),7.18(d,J=4.0Hz,1H),7.15-7.00(m,2H),6.61 (s, 1H), 3.58 (q, J = 5.4Hz, 4H), 2.68 (t, J = 5.8Hz, 2H), 2.44 (t, J = 5.8Hz, 2H).

[0546] Example 114: 4-((5-(benzo[d]thiazol-2-ylcarbamoyl)thiazol-2-yl)methylene)piperidine-1-carboxylate (tert-butyl 4-((5-(benzo[d]thiazol-2-ylcarbamoyl)thiazol-2-yl)methylene)piperidine-1-carboxylate)(compound 1-114)

[0547] Compound 12 (1.26 g, 3.71 mmol) and 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 above to obtain 350 mg of the title compound.

[0548] 1 H NMR (400MHz, DMSO-d6): δ13.23(s,1H),8.79(s,1H),8.01(d,J=7.9Hz,1H),7.75(s,1H),7.48(ddd,J=8.3,7.3,1.3Hz,1H), 7.34(td,J=7.7,1.1Hz,1H), 6.68(s,1H), 3.46(t,J=5.9Hz,4H), 2.96(t,J=5.9Hz,2H), 2.39(t,J=5.9Hz,2H), 1.43(s,9H).

[0549] Example 115: N-(benzo[d]thiazol-2-yl)-2-(piperidin-4-ylidenemethyl)thiazole-5-carboxamide (Compound 1-115)

[0550] The title compound was obtained by reacting 250 mg of 4-((5-(benzo[d]thiazol-2-ylcarbamoyl)thiazol-2-yl)methylene)piperidine-1-carboxylate (tert-butyl ...methylene)piperidine-1-carboxylate) synthesized in Example 114 with the same method as in Example 79 above.

[0551] C 17 H 16 N4OS2[M] + Calculated MS(ESI) m / z value: 356.1; Measured value: 357.1 [M+H] +

[0552] Example 116: N-(benzo[d]thiazol-2-yl)-2-((1-(ethylcarbamoyl)piperidin-4-ylidene)methyl)thiazole-5-carboxamide (Compound 1-116)

[0553] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-2-(piperidin-4-ylidenemethyl)thiazole-5-carboxamide (120 mg, 0.34 mmol) synthesized in Example 115 with ethylisocyanate (26 mg, 0.31 mmol) in the same manner as in Example 63 above.

[0554] 1 H NMR (400MHz, DMSO-d6): δ13.22(s,1H),8.79(s,1H),8.01(d,J=7.9Hz,1H),7.75(d,J=7.7Hz,1H),7.54-7.42(m,1H),7.41-7.30(m,1H),6.67(s,1 H), 6.55 (t, J = 5.4Hz, 1H), 3.44 (t, J = 5.7Hz, 4H), 3.08 (qd, J = 7.1, 5.1Hz, 2H), 2.91 (t, J = 5.7Hz, 2H), 2.37 (t, J = 5.7Hz, 2H), 1.03 (t, J = 7.1Hz, 3H).

[0555] Example 117: N-(benzo[d]thiazol-2-yl)-2-((1-(phenylcarbamoyl)piperidin-4-ylidene)methyl)thiazole-5-carboxamide (N-(benzo[d]thiazol-2-yl)-2-((1-(phenylcarbamoyl)piperidin-4-ylidene)methyl)thiazole-5-carboxamide) (Compound 1-117)

[0556] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-2-(piperidin-4-ylidenemethyl)thiazole-5-carboxamide (120 mg, 0.34 mmol) synthesized in Example 115 with phenylisocyanate (44 mg, 0.37 mmol) in the same manner as in Example 63 above.

[0557] 1 H NMR (400MHz, DMSO-d6): δ13.22(s,1H),8.81(s,1H),8.59(s,1H),8.01(d,J=7.9Hz,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=6.5,3.9Hz,4H),3.02(t,J=5.8Hz,2H),2.47(d,J=6.0Hz,2H).

[0558] Example 118: N-(benzo[d]thiazol-2-yl)-2-((1-((4-fluorophenyl)carbamoyl)piperidin-4-ylidene)methyl)thiazole-5-carboxamide (N-(benzo[d]thiazol-2-yl)-2-((1-((4-fluorophenyl)carbamoyl)piperidin-4-ylidene)methyl)thiazole-5-carboxamide) (Compound 1-118)

[0559] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-2-(piperidin-4-ylidenemethyl)thiazole-5-carboxamide (120 mg, 0.34 mmol) and 4-(trifluoromethyl)phenyl isocyanate (51 mg, 0.37 mmol) synthesized in Example 115 with the same method as in Example 63 above.

[0560] 1H NMR (400MHz, DMSO-d6): δ13.23(s,1H),8.80(s,1H),8.63(s,1H),8.01(d,J=7.9Hz,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=5.8Hz,2H),2.47(d,J=6.0Hz,4H).

[0561] Example 119: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-methylbenzylidene)piperidine-1-carboxylic acid tert-butyl ester (compound 1-119)

[0562] Compound 13 (700 mg, 2.02 mmol) and 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 above to obtain 552 mg of the title compound.

[0563] 1 H NMR (300MHz, DMSO-d6): δ12.71(s,1H),8.07-7.97(m,1H),7.78(d,J=7.9Hz,1H),7.61(d,J=7.8Hz,1H),7.53-7.41(m,1H),7.40 -7.28(m,1H),7.19(d,J=8.3Hz,2H),6.41(s,1H),3.41(dt,J=20.9,5.9Hz,7H),2.45(s,5H),2.32(t,J=5.9Hz,2H),1.43(s,9H).

[0564] Example 120: N-(benzo[d]thiazol-2-yl)-2-methyl-4-(piperidin-4-ylidenemethyl)benzamide (Compound 1-120)

[0565] The title compound was obtained by reacting 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-methylbenzylidene)piperidine-1-carboxylate (420 mg, 0.91 mmol) synthesized in Example 119 with the same method as in Example 79 above.

[0566] 1 H NMR (400MHz, DMSO-d6): δ8.02(dd,J=7.9,1.2Hz,1H),7.78(d,J=8.0Hz,1H),7.64(d,J=7.8Hz,1H),7.47(td,J=8.2,7.7,1.3Hz,1 H),7.35(td,J=7.6,1.1Hz,1H),7.22(d,J=7.6Hz,2H),6.50(s,1H),3.25-3.07(m,4H),2.60(dt,J=39.0,6.0Hz,4H),2.46(s,3H).

[0567] Example 121: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-methylbenzylidene)-N-ethylpiperidine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-methylbenzylidene)-N-ethylpiperidine-1-carboxamide) (Compound 1-121)

[0568] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-2-methyl-4-(piperidin-4-ylidenemethyl)benzamide (150 mg, 0.41 mmol) synthesized in Example 120 with ethylisocyanate (32 mg, 0.45 mmol) in the same manner as in Example 63 above.

[0569] 1 H NMR (400MHz, DMSO-d6): δ12.70(s,1H),8.02(dd,J=7.9,1.1Hz,1H),7.78(d,J=7.9Hz ,1H),7.61(d,J=7.7Hz,1H),7.51-7.42(m,1H),7.39-7.30(m,1H),7.19(d,J=8.1Hz,2 H),6.52(t,J=5.4Hz,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 = 5.9Hz, 5H), 2.30 (t, J = 5.7Hz, 2H), 1.03 (t, J = 7.1Hz, 3H).

[0570] Example 122: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-methylbenzylidene)-N-phenylpiperidine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-methylbenzylidene)-N-phenylpiperidine-1-carboxamide) (Compound 1-122)

[0571] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-2-methyl-4-(piperidin-4-ylidenemethyl)benzamide (150 mg, 0.41 mmol) synthesized in Example 120 with ethylisocyanate (54 mg, 0.45 mmol) in the same manner as in Example 63 above.

[0572] 1H NMR (400MHz, DMSO-d6): δ12.71(s,1H),8.57(s,1H),8.02(dd,J=8.0,1.2Hz,1H),7.78(d ,J=8.0Hz,1H),7.63(d,J=7.7Hz,1H),7.53-7.43(m,3H),7.34(td,J=7.6,1.2Hz,1H),7. 23(td,J=8.3,6.3Hz,4H),6.94(tt,J=7.3,1.2Hz,1H),6.43(s,1H),3.59(dd,J=6.9,4.5 Hz, 2H), 3.51 (t, J = 5.7Hz, 2H), 2.52 (d, J = 5.9Hz, 2H), 2.46 (s, 3H), 2.40 (t, J = 5.7Hz, 2H).

[0573] Example 123: 4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-methylbenzylidene)-N-(4-fluorophenyl)piperidine-1-carboxamide (4-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3-methylbenzylidene)-N-(4-fluorophenyl)piperidine-1-carboxamide) (Compound 1-123)

[0574] The title compound was obtained by reacting N-(benzo[d]thiazol-2-yl)-2-methyl-4-(piperidin-4-ylidenemethyl)benzamide (150 mg, 0.41 mmol) and 4-(trifluoromethyl)phenyl isocyanate (62 mg, 0.45 mmol) synthesized in Example 120 with the same method as in Example 63 above.

[0575] 1H NMR (400MHz, DMSO-d6): δ12.71(s,1H),8.61(s,1H),8.02(dd,J=8.1,1.1Hz,1H), 7.78(d,J=8.0Hz,1H),7.63(d,J=7.7Hz,1H),7.53-7.42(m,3H),7.34(td,J=7.7, 1.2Hz,1H),7.21(d,J=8.0Hz,2H),7.12-7.04(m,2H),6.43(s,1H),3.63-3.54(m, 2H), 3.50 (t, J = 5.7Hz, 2H), 2.54-2.51 (m, 2H), 2.46 (s, 3H), 2.40 (t, J = 5.8Hz, 2H).

[0576] Experimental Example 1: Measurement of Sirt7 Inhibitory Activity

[0577] The SIRT7 protein was prepared using the Promega Cat. No. 6450 SIRT Glo assay kit and the SignalChem Cat. No. S41-30H protein as the target. The compound was prepared by diluting it twice its final concentration in SIRT Glo buffer. In the positive control and compound groups of white 384-well plates (Greiner Bioone, white, small volume, Cat. No. 874075), 5 μL of SIRT7 protein was diluted in SIRT Glo buffer and dispensed as 20 ng per well. In the background control, 10 μL of SIRT Glo buffer was dispensed.

[0578] Add 5 μL of SIRT Glo buffer to the positive control group and 5 μL of diluted compound to the compound group, and react for 30 minutes. Prepare the substrate provided in the SIRT Glo assay by adding 10 μL each time. After reacting for 1 hour, measure luciferase activity using a microplate reader (Molecular Device, Spectramax i3).

[0579] The luciferase values ​​of the background control group were removed from all wells. The sirt7 activity inhibition rate of the compound was calculated using the following formula: Inhibition rate (% inhibition) = 100 - (compound group / positive control group) × 100. The results are shown in Table 1 below.

[0580] [Table 1]

[0581]

[0582]

[0583]

[0584]

[0585] Experimental Example 2: The inhibitory effect of Sirt7 inhibitor compounds on cancer cell proliferation

[0586] KRAS, as part of the RAS / MAPK pathway, promotes carcinogenesis by boosting cell growth and proliferation. Mutations in KRAS are found in approximately 20% of solid tumors, primarily pancreatic, colon, and lung cancers. Sirt7 has been reported to increase MAPK activity through upregulation of p-ERK and p-MEK, thereby increasing the incidence of colon cancer. Therefore, in this study, the cancer cell proliferation inhibitory activity of the compounds of this invention was evaluated using COLO320DM (KRAS wild-type) and SW480 (KRAS mutant) cells, which are human colon cancer cells.

[0587] For cell proliferation, cytotoxicity was determined using CCK-8 (Cell counting kit: Dojindo, Cat. No. CK04). Absorbance at 450 nm was measured based on the presence or absence of orange light, indicating the activity of dehydrogenases in live cells. COLO320DM and SW480 cells were seeded at 3,000 cells per well in 96-well plates (BD Falcon, Cat. No. 353072). After 24 hours, each screened inhibitor was applied, with treatment occurring at 2-day intervals during medium replacement, for a total of 4 days. For cell proliferation, 10 μL of CCK-8 was added to each well, and after incubation at 37°C for 30 minutes, absorbance was measured at 450 nm using a microplate reader (Molecular Device, Spectramax i3).

[0588] As a comparative compound, a Sirt7 inhibitor reported in Biochem Biophys Res Commun. 2019; 508: 451-457 was synthesized and used. Hereinafter, 97491 denotes the above comparative compound.

[0589] The result, refer to Figure 1a In COLO320DM cells, it was observed that the comparative compound 97491 exhibited an LD50 of 22.5 μM, compounds 1-37 of the present invention exhibited an LD50 of 12.7 μM, and compounds 1-38 of the present invention exhibited an LD50 of 16.2 μM. In SW480 cells, the comparative compound 97491 exhibited an LD50 of 23.3 μM, compounds 1-37 of the present invention exhibited an LD50 of 3976 μM, and compounds 1-38 of the present invention exhibited an LD50 of 1137 μM.

[0590] Furthermore, referring to Figure 1b In COLO320DM cells, the comparative compound 97491 exhibited an LD50 of 19.2 μM, compounds 1-37 of the present invention exhibited an LD50 of 23.6 μM, and compounds 1-38 of the present invention exhibited an LD50 of 24.2 μM. In HT29 cells, the comparative compound 97491 exhibited an LD50 of 16.4 μM, compounds 1-37 of the present invention exhibited an LD50 of 19.7 μM, and compounds 1-38 of the present invention exhibited an LD50 of 6.7 μM.

[0591] Furthermore, referring to Figure 1c In SW480 cells, it was observed that the comparative compound 97491 exhibited an LD50 of 18 μM, compound 1-37 of the present invention exhibited an LD50 of 68.4 μM, and compound 1-38 of the present invention exhibited an LD50 of 28 μM. In SW620 cells, the comparative compound 97491 exhibited an LD50 of 18.1 μM, compound 1-37 of the present invention exhibited an LD50 of 48 μM, and compound 1-38 of the present invention exhibited an LD50 of 24.8 μM.

[0592] Experiment Example 3: Lactate dehydrogenase (LDH) cytotoxicity experiment

[0593] Lactate dehydrogenase (LDH), an enzyme present in the cytoplasm, normally does not cross the cell membrane, but if the cell membrane is damaged, it is released into the extracellular space (i.e., into the culture medium). The released LDH is measured to determine the toxicity of the compounds. Compound 97491 and compounds 1-37 of this invention were compared by treating COLO320DM and SW480 cells at high concentrations of 100 μM and 500 μM.

[0594] The Thermo Fisher Scientific Cat. No. 88953LDH Cytotoxicity Assay Kit was used. 20,000 cells were seeded in 96-well plates and cultured for 24 hours, followed by treatment with 100 μM and 500 μM compounds. Forty-eight hours later, 50 μL of the compound-treated culture supernatant was transferred to a new 96-well plate, and 50 μL of the substrate mix buffer provided in the kit was added. The mixture was incubated at room temperature for 30 minutes in the dark. Then, 50 μL of stop solution was added, and the absorbance was measured at 490 nm using a microplate reader (Molecular Device, Spectramaxi3).

[0595] The result, refer to Figure 2(a) Confirmed that in COLO320DM cells, the cytotoxicity compared to the positive control group that caused complete cell membrane damage was as follows: 51.9% for 100 μM comparative compound 97491, 59.2% for 500 μM comparative compound 97491, 62.1% for 100 μM compound 1-37 of the present invention, and 62.0% for 500 μM compound 1-37 of the present invention. In SW480 cells, the cytotoxicity compared to the positive control group that caused complete cell membrane damage was as follows: 13.4% for 100 μM comparative compound 97491, 46.7% for 500 μM comparative compound 97491, 14.8% for 100 μM compound 1-37 of the present invention, and 45.1% for 500 μM compound 1-37 of the present invention.

[0596] Reference Figure 2 (b) WI38 cells were treated with high concentrations of comparative compound 97491 (100 μM) and compound 1-37 of the present invention (500 μM). In WI38 cells, the cytotoxicity compared to the positive control group (which caused complete cell membrane damage) was: 30.2% with 100 μM comparative compound 97491, 54.7% with 500 μM comparative compound 97491, 29.9% with 100 μM compound 1-37 of the present invention, and 41.6% with 500 μM compound 1-37 of the present invention.

[0597] Experimental Example 4: In vivo activity evaluation

[0598] The compounds of this invention were administered to xenograft tumor-bearing mice, and their in vivo tumor-suppressive activity was measured. Five-week-old BALB / c nu-female laboratory mice were introduced. COLO320DM and SW480 cells, which are human colorectal cancer cells, were isolated from culture flasks using trypsin and administered at 1×10⁻⁶. 8 Cells / ml concentrations were prepared. Mixed 100 μL with basement membrane matrix (Matrigel) (Gibco, Cat. No. A14133-02) at a 1:1 ratio, the mixture was subcutaneously injected into the dorsal side of 5-week-old mice. Two weeks later, when the tumor volume in the mice reached 100 mmHg... 3 At that time, the compound was administered orally 5 times a week. (Day 0) This was followed for 3 weeks.

[0599] The compound was dissolved in 0.1% carboxymethyl cellulose (CMC) and 0.2% Tween 80 solutions at concentrations of 2 mg / ml, 4 mg / ml, and 8 mg / ml, and administered orally at 100 μL to achieve concentrations of 10 MPa, 20 MPa, and 40 MPa, respectively. For the negative control group, the same route of administration and frequency of administration were used instead of the compound, with the same 0.1% carboxymethyl cellulose and 0.2% Tween 80 solutions administered. Six mice were used in each experimental group. Figure 3 The tumor size was measured every three days by measuring its major axis (length, L) and minor axis (width, W), and the tumor volume (mm²) was calculated as (L×W×W) / 2. 3 This allowed for the calculation of the mean for each group. Statistical processing was performed using the Graph Pad Prism6 program, with p-values ​​less than 0.05 considered significant.

[0600] Five-week-old nude mice with suppressed immune systems due to T-cell reduction caused by thymus ablation were introduced and subcutaneously injected with COLO320DM and SW480, human colorectal cancer cell lines. Results of oral administration for 3 weeks of the present invention compounds 1-37 (10 mpk, 20 mpk, 40 mpk), 1-105 (100 mpk), and 1-106 (100 mpk), as Sirt7 inhibitors, were compared with those of the present invention. Figure 4 As shown in Figure 11, compared to the control group that was only fed a solution containing the reagent, the tumor size of both cell lines was reduced, and the results of the first and second in vivo experiments were consistent. In the group of mice injected with COLO320DM, the most significant tumor generation inhibition effect was observed when the compound of the present invention was administered orally at 40 mpk, and this inhibition effect was concentration-dependent.

[0601] The above description is merely illustrative of the invention. Those skilled in the art can make various modifications without departing from the essential characteristics of the invention. Therefore, the embodiments disclosed in this specification are not intended to limit the invention, but rather to illustrate it. The concept and scope of the invention are not limited to such embodiments. The scope of protection of this invention should be interpreted according to the scope of the claims, and all technologies within the equivalent scope should be interpreted as included within the scope of the claims of this invention.

[0602] Industrial availability

[0603] Due to its excellent inhibitory activity against the silencing information regulator 7 (SIRTUIN 7) protein, it can be used to prevent or treat diseases related to the SIRTUIN 7 protein.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein, The compound is represented by the following chemical formula 1: Chemical Formula 1 Chemical formula 2-1 ， In the aforementioned chemical formulas 1 and 2-1, 1) X is N(R1), 2) R1 is: hydrogen; a C1-C5 alkyl group; or a C7-C group substituted with fluorine. 20 arylalkyl, 3) Y is either N or CH independently of each other. 4) R 2 They are either identical or different, and independently exist as hydrogen; or halogens. 5) L represents the substituent indicated by the chemical formula 2-1. 6) L' is selected from the group consisting of the following substituents: single bond; C1~C 10 Alkylene; C2~C 10 The alkenyl group; and -(C n H 2n )-O-(C n H 2n )-, 7) Indicates that it is related to the chemical formula 1. binding site, 1 indicates the site where Ar binds. 8) R 3 Each of the following substituents, either identical or dissimilar, is independently selected from the group consisting of: hydrogen; halogens; and C1-C atoms substituted or unsubstituted with fluorine. 10 alkyl groups, 9) Ar is represented by one of the following chemical formulas: Ar-2, Ar-5, Ar-7 to Ar-11: Among the chemical formulas Ar-2, Ar-5, Ar-7 to Ar-11, This indicates the site where L binds. 2 indicates that it is related to the R 1 binding site, 10) R 1 Choose from the group consisting of the following substituents: hydrogen; halogen; C1-C atoms substituted with or unsubstituted with fluorine. 10 Alkyl group; -SO2-R a ;-CO-NH-R b ; and -CO-R c , 11) The R a Choose the group consisting of the following substituents: C1~C 10 Alkyl groups; C3~C 20 Aliphatic cyclic groups; C6-C groups substituted with or unsubstituted with CF3. 20 aryl groups; and -N(R')(R''), 12) R' and R" are independently C1~C 10 alkyl groups, 13) The R b Choose from the group consisting of the following substituents: C6-C 20 aryl; C3~C 20 Aliphatic cyclic groups; C1~C substituted or unsubstituted halogenated groups 20 Alkyl groups; and -(C m H 2m )-CO-O-(C m H 2m+1 ), 14) The R c Choose the group consisting of the following substituents: C1~C 10 Alkyl group; C6-C 20 aryl groups; and C1~C 10 alkoxy groups, 15) a is 0 or 1, b is an integer from 0 to 3, c is an integer from 0 to 4, n is an integer from 0 to 2 independently, and m is an integer from 1 to 6 independently.

2. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The compound is represented by any one of the following compounds: 。

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