KR102101235B1 - Novel SIRT 1 activator and medical use thereof - Google Patents

Abstract

The present invention relates to a SIRT 1 activator and a medical use thereof, and in the present invention, a novel SIRT 1 activator compound based on a benzo [d] thiazole skeleton, a crystalline form thereof, a hydrate or a salt thereof was prepared. The effects of improving obesity, insulin resistance and dyslipidemia caused by the compound, fatty liver improvement effect, cell aging protection, oxidative stress protection, and prolonged lifespan of yeast were confirmed.
Therefore, the novel SIRT 1 activator compound having the above-described effect is for preventing metabolic diseases including obesity, diabetes, dyslipidemia, liver disease including alcoholic or non-alcoholic fatty liver, hepatitis, or the like. It can be usefully used as a therapeutic pharmaceutical composition, a health food composition for improving cell aging or prolonging life.

Description

New SIRT 1 activator and its medical use {Novel SIRT 1 activator and medical use thereof}

The present invention relates to a novel SIRT 1 (silent mating type information regulation 2 homolog; sirtuin 1) activator compound, a crystalline form thereof, a hydrate or salt thereof and a composition containing the same as an active ingredient.

SIRT 1 is a nicotinamide adenine dinucleotide (NAD) -dependent histone deacetylase that is distributed in the cell nucleus or cytoplasm, and is primarily a lysine of histone H3 (Lys9 or Lys14) or histone H4 of various transcription factors in the nucleus (Lys9 or Lys14). Lys16) deacetylation. In addition to histones, SIRT 1 in mammals affects the signal transduction system through deacetylation of transcription factors. As transcription factors that interact with SIRT 1, p53, forkhead transcription factor (FOXO), and peroxisome proliferation factor-active receptor Gamma coactivator 1-alpha (peroxisome proliferator-activated receptor γ coactivator 1-α; PGC1-α) and peroxisome proliferator-activated receptor-gamma (PPAR-γ) It is known to be related to aging, cell circulation regulation, apoptosis, metabolism, and inflammation.

 Resveratrol, a phytoalexin, is a type of polyphenol and is found in many plants, including grapes, peanuts, mulberries, raspberries, and berries such as raspberries. Resveratrol is known to have anti-cancer and potent antioxidant properties, as well as anti-viral, neuroprotective, anti-inflammatory, anti-aging and prolonging effects. Shows. In addition, resveratrol is a potent SIRT 1 activator and is known to enhance the survival rate of cells stressed by UV, as well as enhance SIRT 1 dependent cytoplasmic processes such as axonal protection, fat metabolism and NF-κB dependent transcriptional inhibition. have.

Recently, research to discover SIRT 1 activators stronger than resveratrol has attracted attention, and a compound called SRT1720 based on the skeleton of imdazo [2,1-b] thiazole is resveratrol. It has been reported to be a stronger SIRT 1 activator.

Accordingly, the present invention synthesizes several compounds based on a benzo [d] thiazole skeleton similar to the skeleton of imidazo [2,1-b] thiazole, the structure of SRT1720, and the compound By searching SIRT 1 activity against them, various effects in metabolic diseases (obesity, diabetes, dyslipidemia, etc.), fatty liver, inflammation, cell aging and prolongation of life are sought.

U.S. Patent No. 5118707 (1992.06.02)

It is an object of the present invention to provide a novel SIRT 1 activator compound, its crystalline form, its hydrate or salt thereof.

Another object of the present invention is a pharmaceutical composition for preventing or treating metabolic disease, pharmaceutical composition for preventing or treating liver disease, improving cell aging or prolonging life, containing the compound, its crystalline form, its hydrate or salt thereof as an active ingredient In providing a food composition.

In order to achieve the above object, the present invention provides a novel SIRT 1 activator compound, its crystalline form, its hydrate or salt thereof.

In addition, the present invention is a pharmaceutical composition for preventing or treating metabolic diseases, a pharmaceutical composition for preventing or treating liver disease, a health food composition for improving cell aging or prolonging life, containing the compound, a crystalline form thereof, a hydrate or a salt thereof as an active ingredient Gives

In the present invention, a novel SIRT 1 activator compound based on the benzo [d] thiazole skeleton, a crystalline form thereof, a hydrate or a salt thereof was prepared, and the effect of improving obesity, insulin resistance and dyslipidemia by the compound, fatty liver The improvement effect, cell aging protection, oxidative stress protection and yeast life extension effect were confirmed.

Therefore, the novel SIRT 1 activator compound having the above-described effect is for preventing metabolic diseases including obesity, diabetes, dyslipidemia, liver disease including alcoholic or non-alcoholic fatty liver, hepatitis, or the like. It may be useful as a therapeutic pharmaceutical composition, a health food composition for improving cell aging or prolonging life.

1A) and 1B) are results of confirming SIRT 1 activity of a candidate SIRT 1 activator compound (benzo [d] thiazole skeleton), and FIG. 1C) is a compound among candidate SIRT 1 activator compounds by performing a docking simulation. It is the result of confirming the binding power of SIRT 1 of 49h.
Figure 2 is an analysis of the effect of improving metabolic disease caused by compound 49h in a db / db mouse obese animal model lacking the appetite-regulating hormone leptin receptor, A) dietary intake, B) body weight, and C) resistance , D) fasting blood sugar and E) serum insulin changes.
Figure 3 analyzes the effect of improving fatty liver by compound 49h in the db / db mouse obese animal model, A) triglyceride, B) lipid synthesis related gene, C) lipid oxidation related gene and D) vesicle stress related marker expression It is the result of confirming the change.
Figure 4A) is a result confirming the effect of improving cell aging by compound 49h in skin fibroblasts with β-galactosidase staining, Figure 4B) is a result confirming the effect of prolonging life by compound 49h in yeast (Saccharomyces cerevisiae) model to be.

The inventors of the present invention synthesized a novel SIRT 1 compound based on the benzo [d] thiazole skeleton, a crystalline form thereof, a hydrate or a salt form thereof, and improved the obesity, insulin resistance and dyslipidemia of the compound , Fatty liver improvement effect, cell aging protection, oxidative stress protection and confirming the effect of extending the life of yeast, and completed the present invention.

The present invention provides a compound represented by Formula 1 below, a crystalline form thereof, a hydrate thereof or a salt thereof:

[Formula 1]

Wherein R is (C1 ~ C4) alkyl, (C1 ~ C4) alkoxy, halogen, nitro or phenyl with one or more substituents unsubstituted or substituted benzamide, nicotinamide, isonicotinamide, naphthamide, quinoline-2- Carboxamide, benzenesulfonamide, quinoxaline-2-carboxamide, cyclohexane-carboxamide, cinnamic amide, adamantane-1-carboxamide, phenylurea, naphthylurea, benzylurea and phenylcarbamate One selected from the group consisting of

Preferably, the compound represented by Chemical Formula 1, a crystalline form, a hydrate or a salt thereof may activate SIRT 1 (silent mating type information regulation 2 homolog; sirtuin 1).

The crystalline form means that at least 50% by weight, preferably at least 70%, 80% or 90% by weight of the compound is a crystalline form.

The hydrate means that the compounds or their salts are composed of water equivalently or non-equivalently.

The salt may be prepared by itself in the process of synthesis, separation or purification of the compound, or may be specially prepared. Examples of the salt prepared in this way are selected from the group consisting of sodium salt, potassium salt, calcium salt, lithium salt, magnesium salt, cesium salt, aluminum salt, ammonium salt, triethylaminium salt and pyridinium salt. It can be one or more basic salts, hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid, citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, oxalic acid, malonic acid, glutamic acid It may be one or more acidic salts selected from the group consisting of ric acid, acetic acid, trifluoroacetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid and aspartic acid , But is not limited to this.

Preferably, the compound may be a compound represented by Formula 1-1:

[Formula 1-1]

Wherein R is (C1 ~ C4) alkyl, (C1 ~ C4) alkoxy, halogen, nitro or phenyl with one or more substituents unsubstituted or substituted benzamide, nicotinamide, isonicotinamide, naphthamide, quinoline-2- Carboxamide, benzenesulfonamide, quinoxaline-2-carboxamide, cyclohexane-carboxamide, cinnamic amide, adamantane-1-carboxamide, phenylurea, naphthylurea, benzylurea and phenylcarbamate One selected from the group consisting of

Preferably, the compound represented by Formula 1-1 is N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [ N -(2- (4- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41a), 3-fluoro- N- (2- (4- (piperazin- 1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [3-Fluoro- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2- yl) phenyl) benzamide hydrochloride] (41b), 4-fluoro- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [4-Fluoro- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41c), 3-bromo- N- (2- ( 4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [3-Bromo- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d] thiazol-2-yl) phenyl) benzamide hydrochloride] (41d), 3- chloro - N - (2- (4- (piperazin- -1-ylmethyl) benzo [d] thiazol-2-yl) phenyl) benzamide hydrochloride [3-Chloro- N - (2- (4- (piperazin-1-ylmethyl) benzo [d] thiazol- 2-yl) phenyl) benzamide hydrochloride] (41e), 4-chloro- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride Chloride [4-Chloro- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41f), 3-nitro- N- (2- ( 4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [3-Nitro- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41g), 4-nitro- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl ) Benzamide hydrochloride [4-Nitro- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41h), 3,4,5- Trimethoxy- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydride Low Chloride [3,4,5-Trimethoxy- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41i), 2,4-dichloro - N - (2- (4- (piperazin-1-ylmethyl) benzo [d] thiazol-2-yl) phenyl) benzamide hydrochloride [2,4-Dichloro- N - (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41j), 3,4-dichloro- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [3,4-Dichloro- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41k), N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) nicotinamide hydrochloride [ N- (2- (4- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) nicotinamide hydrochloride] (41l), N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazole- 2-yl) phenyl) -1-naphthamide hydrochloride [ N- (2- (4- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) -1-naphthamide hydrochloride] (41m), N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) -2-naphthamide hydrochloride [ N- (2- (4- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) -2-naphthamide hydrochloride] (41n), N- (2- (4- (piperazin-1-yl Methyl) benzo [ d ] thiazol-2-yl) phenyl) quinoxaline-2-carboxamide hydrochloride [ N- (2- (4- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl ) phenyl) quinoxaline-2-carboxamide hydrochloride] (41o), N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl)-[1,1 ' -Biphenyl] -4-carboxamide hydrochloride [ N- (2- (4- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl)-[1,1'-biphenyl]- 4-carboxamide hydrochloride] (41p) and 4-methyl- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzenesulfonamide [4-Methyl - N - (2- (4- ( piperazin-1-ylmethyl) benzo [d] thiazol-2-yl) phenyl) can be selected from the group consisting of benzenesulfonamide] (41q), but , But is not limited to this.

Preferably, the compound may be a compound represented by Formula 1-2 below:

[Formula 1-2]

Wherein R is (C1 ~ C4) alkyl, (C1 ~ C4) alkoxy, halogen, nitro or phenyl with one or more substituents unsubstituted or substituted benzamide, nicotinamide, isonicotinamide, naphthamide, quinoline-2- Carboxamide, benzenesulfonamide, quinoxaline-2-carboxamide, cyclohexane-carboxamide, cinnamic amide, adamantane-1-carboxamide, phenylurea, naphthylurea, benzylurea and phenylcarbamate One selected from the group consisting of

Preferably, the compound represented by Chemical Formula 1-2 is N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide [ N- ( 2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide] (49a), N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] Thiazol-2-yl) phenyl) benzamide hydrochloride [ N- (2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49aa), 2 -Methyl- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [2-Methyl- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49bb), 3-methyl- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] Thiazol-2-yl) phenyl) benzamide hydrochloride [3-Methyl- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] ( 49cc), 4- methyl - N - (2- (6- (piperazin-1-ylmethyl) benzo [d] thiazol-2-yl) phenyl) benzamide high A chloride [4-Methyl- N - (2- (6- (piperazin-1-ylmethyl) benzo [d] thiazol-2-yl) phenyl) benzamide hydrochloride] (49dd), 3-fluoro - N - (2 -(6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [3-Fluoro- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49ee), 4-fluoro- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazole-2- 1) phenyl) benzamide hydrochloride [4-Fluoro- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49ff), 2-bro Mo- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [2-Bromo- N- (2- (6- ( piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49gg), 3-bromo- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] Thiazol-2-yl) phenyl) benzamide [3-Bromo- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide] (4 9h), 3-bromo- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [3-Bromo- N- ( 2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49hh), 3-bromo- N- (2- (6- (piperazin-1- Ilmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide 2,2,2-trifluoroacetate [3-Bromo- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide 2,2,2-trifluoroacetate] (49hhh), 4-bromo- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thia Zol-2-yl) phenyl) benzamide [4-Bromo- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide] (49i), 4- Bromo- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [4-Bromo- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49ii), 3-chloro- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] Thiazol-2-yl) phenyl) benzamide Jethro chloride [3-Chloro- N - (2- (6- (piperazin-1-ylmethyl) benzo [d] thiazol-2-yl) phenyl) benzamide hydrochloride] (49jj), 3- nitro - N - (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide [3-Nitro- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide] (49k), 4-nitro- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benz Amide [4-Nitro- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide] (49l), 4-nitro- N- (2- (6 -(Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [4-Nitro- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49ll), 3,4,5-trimethoxy- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazole- 2-yl) phenyl) benzamide [3,4,5-Trimethoxy- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide] (49m), 3,4,5-trimethoxy- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [3,4,5-Trimethoxy- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49mm), 2,4-dichloro- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [ 2,4-Dichloro- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49nn), 3,4-dichloro- N- (2 -(6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [3,4-Dichloro- N- (2- (6- (piperazin-1- ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49oo), N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl ) Nicotinamide [ N- (2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) nicotinamide] (49p), N- (2- (6- (piperazin-1 -ylmethyl) benzo [d] thiazol-2-yl) phenyl) - 1-naphtha amide [N - (2- (6- ( Piperazin-1-ylmethyl) benzo [d] thiazol-2-yl) phenyl) -1-naphthamide ] (49q), N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) -1-naphthamide hydrochloride [ N- (2- (6 -(Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) -1-naphthamide hydrochloride] (49qq), N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] Thiazol-2-yl) phenyl) -2-naphthamide [ N- (2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) -2-naphthamide] (49r ), N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) -2-naphthamide hydrochloride [ N- (2- (6- (Piperazin) -1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) -2-naphthamide hydrochloride] (49rr), N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazole -2-yl) phenyl) quinoxaline-2-carboxamide [ N- (2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) quinoxaline-2-carboxamide] ( 49s), N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) quinoxaline-2-carboxamide hydrochloride [ N- (2- ( 6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-y l) phenyl) quinoxaline-2-carboxamide hydrochloride] (49ss), N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl)-[1,1 '-Biphenyl] -4-carboxamide [ N- (2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl)-[1,1'-biphenyl] -4 -carboxamide] (49t), N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl)-[1,1'-biphenyl] -4- Carboxamide hydrochloride [ N- (2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl)-[1,1'-biphenyl] -4-carboxamide hydrochloride] (49tt ), N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) cyclohexanecarboxamide [ N- (2- (6- (Piperazin-1 -ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) cyclohexanecarboxamide] (49u), N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl ) Cinnamamide [ N- (2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) cinnamamide] (49v) and phenyl (2- (6- (piperazin-1- Monomethyl) benzo [ d ] thiazol-2-yl) phenyl) carbamate [Phenyl (2- (6- (piperazin-1-y) lmethyl) benzo [ d ] thiazol-2-yl) phenyl) carbamate] (49w), but is not limited thereto.

In addition, the present invention provides a pharmaceutical composition for preventing or treating metabolic diseases containing the compound according to the present invention, its crystalline form, its hydrate or salt thereof as an active ingredient.

Preferably, the metabolic disease may be selected from the group consisting of obesity, diabetes, hyperinsulinemia, hyperuricemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, metabolic syndrome and endothelial dysfunction. It is stated that it does not work.

In addition, the present invention provides a pharmaceutical composition for preventing or treating liver disease containing the compound according to the present invention, its crystalline form, its hydrate or salt thereof as an active ingredient.

Preferably, the liver disease may be selected from the group consisting of alcoholic fatty liver, non-alcoholic fatty liver and hepatitis, but is not limited thereto.

When the composition of the present invention is a pharmaceutical composition, it may be formulated as a cream, gel, patch, spray, ointment, warning agent, lotion agent, linen agent, pasta agent, and cataplasma. On the other hand, the pharmaceutical composition may include a pharmaceutically acceptable carrier in addition to the active ingredient, such a pharmaceutically acceptable carrier is commonly used in pharmaceutical preparations, lactose, dextrose, sucrose, sorbitol, Mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, Talc, magnesium stearate, mineral oil, and the like, but is not limited thereto. In addition, the pharmaceutical composition may further include a lubricant, wetting agent, sweetener, flavoring agent, emulsifying agent, suspending agent, preservative, etc. as additives.

The method of administration of the pharmaceutical composition is determined according to the severity of symptoms, and a topical administration method is usually preferred. In addition, the dosage of the active ingredient in the pharmaceutical composition may vary depending on the administration route, the degree of disease, the patient's age, gender, weight, etc., and may be administered once to several times a day.

In addition, the present invention provides a health food composition for improving cell aging or prolonging life, which contains a compound according to the present invention, a crystalline form thereof, a hydrate or a salt thereof as an active ingredient.

The health food composition may be provided in the form of a powder, granule, tablet, capsule, syrup, or beverage, and the health food composition is used together with other foods or food additives other than the active ingredient, and is suitably used according to a conventional method. You can. The mixing amount of the active ingredient may be appropriately determined according to its purpose of use, for example, prophylactic, health or therapeutic treatment.

The effective dose of the active ingredient contained in the health food composition may be used in accordance with the effective dose of the pharmaceutical composition, but in the case of long-term intake for health and hygiene purposes or for health control purposes, the effective dose may be less than or equal to the above range. It can be, it is clear that the active ingredient can be used in an amount above the range because there is no problem in terms of safety.

There are no particular restrictions on the type of the health food, for example, meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, drinks, tea, Drinks, alcoholic beverages, and vitamin complexes.

Hereinafter, the present invention will be described in more detail through examples. These examples are only intended to illustrate the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

Example  One : Benzothiazole ( benzothiazole ) Compound Synthesis

1-1. Synthesis of Compounds 33-41

Compounds 33 to 41 were synthesized as in Scheme 1 below.

[Scheme 1]

1) 4- Methyl benzo [ d ] Thiazole [4-Methylbenzo [ d ] thiazole ] (33)

Into 4-methyl-benzo [d] thiazol-2-amine phosphate (phosphoric acid, 2.0 mL) containing (4-Methylbenzo [d] thiazol -2-amine, 100 mg, 0.61 mmol) solution of NaNO ₂ (210 mg , 3.04 mmol) aqueous solution (0.4 mL) was slowly added at -8 ° C, and then H ₃ PO ₂ (hypophosphorous acid, 2.0 mL) was slowly added. At this time, it was adjusted so that the internal temperature did not rise above 0 ° C. After stirring for 2 hours, the pH was adjusted to 7 with 3N NaOH and extracted by adding methylene chloride and water. The organic layer was dried over MgSO ₄ and filtered, and the filtrate obtained was concentrated under reduced pressure to obtain Compound 33 (50 mg, 55%). It was used for the next reaction without further purification.

Brown liquid; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.94 (s, 1 H), 7.75 (d, 1 H, J = 8.0 Hz), 7.32-7.27 (m, 2 H), 2.78 (s, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 153.0, 152.8, 133.8, 133.7, 126.9, 125.7, 119.5, 18.7.

2) 2-amino-3- Methylbenzenethiol [2-Amino-3- methylbenzenethiol ] (34)

A solution of DMF ( N , N- dimethylformamide, 30 mL) containing compound 33 (8.0 g, 53.62 mmol) and hydrazine monohydrate (39 mL, 801.7 mmol) was stirred at 80 ° C. for 9 hours. After adding water and neutralizing with HCl, diethyl ether was added to separate the organic layer and the aqueous layer, and the aqueous layer was extracted several times with ether again, and all the organic layers were combined, dried over MgSO ₄ and filtered to reduce the filtrate obtained. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to give compound 34 (2.37 g, 32%) as a yellow solid.

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.06 (d, 1 H, J = 7.5 Hz), 7.04 (d, 1 H, J = 8.0 Hz), 6.52 (t, 1 H, J = 7.5 Hz), 4.33 (s, 2 H), 2.17 (s, 3 H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 147.0, 134.6, 132.6, 122.5, 118.5, 117.5, 18.1.

3) 4- methyl -2- (2- Nitrophenyl ) -2,3- Dihydrobenzo [ d ] Thiazole [4-Methyl-2- (2-nitrophenyl) -2,3-dihydrobenzo [ d ] thiazole] (35)

DMF containing compound 34 (2.37 g, 17.02 mmol), 2-nitrobenzaldehyde, 2.57 g, 17.01 mmol) and Na ₂ S ₂ O ₅ (sodium metabisulfite, 3.89 g, 20.46 mmol) (30 mL) ) The solution was stirred at 80 ° C. for 18 hours, water and ether were added, the obtained solid was filtered, and the filtered solid was extracted with methylene chloride and water, and the filtrate was extracted with diethyl ether and water, and all organic layers (diethyl ether). The layers and methylene chloride layer) were combined, dried over anhydrous MgSO ₄ and filtered, and the filtrate obtained was concentrated under reduced pressure, and the obtained solid was recrystallized from diethyl ether and hexane to obtain the compound 35 (2.89g, 62.3%).

Yield, 62%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.05 (dd, 1 H, J = 8.5, 1.0 Hz), 7.95 (dd, 1 H, J = 8.0, 1.5 Hz), 7.61 (td, 1 H, J = 7.5, 1.5 Hz), 7.44 (td, 1 H, J = 7.5, 1.0 Hz), 6.92 (d, 1 H, J = 7.0 Hz), 6.86 (s, 1 H), 6.84 (d, 1 H, J = 7.5 Hz), 6.76 (t, 1 H, J = 7.5 Hz), 4.28 (brs, 1 H), 2.27 (s, 3 H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 146.1, 144.3, 139.5, 134.2, 128.7, 128.2, 126.9, 126.7, 125.1, 121.8, 121.3, 119.4, 63.9, 17.9.

4) 4- methyl -2- (2-nitrophenyl) benzo [ d ] Thiazole [4-Methyl-2- (2-nitrophenyl) benzo [ d ] thiazole] (36)

Slowly add DDQ (2,3-dichloro-5,6-dicyano- p- benzoquinone, 2.357 g, 10.36 mmol) into a methylene chloride (30 mL) solution containing compound 35 (2.82 g, 10.36 mmol) at 0 ° C Stir at room temperature for 3 hours. The reaction mixture was filtered, washed thoroughly with methylene chloride, and the filtrate was extracted with methylene chloride and sodium bicarbonate, and the organic layer was dried over MgSO ₄ and filtered, and the filtrate obtained was concentrated under reduced pressure to yield Compound 36 (2.74 g, 98%) as a bright solution. Obtained as a yellow solid.

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.86 (dd, 1 H, J = 8.0, 1.0 Hz), 7.80 (dd, 1 H, J = 7.5, 1.0 Hz), 7.75 (dd, 1 H, J = 7.5, 1.0 Hz), 7.67 (td, 1 H, J = 7.5, 1.0 Hz), 7.60 (td, 1 H, J = 7.5, 1.0 Hz), 7.33 (t, 1 H, J = 7.5 Hz), 7.31 (dd, 1 H, J = 7.5, 1.0 Hz), 2.74 (s, 3 H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 160.8, 153.1, 149.0, 135.6, 134.1, 132.2, 131.6, 130.8, 128.0, 127.1, 125.9, 124.3, 118.9, 18.3.

5) 4- ( Bromomethyl )-2- (2-nitrophenyl) benzo [ d ] Thiazole [4- ( Bromomethyl )-2- (2-nitrophenyl) benzo [ d ] thiazole] (37)

Compound 36 (2.74 g, 10.14 mmol) was dissolved in anhydrous chloroform (130 mL) and NBS ( N- bromosuccinimide, 2.455 g, 10.13 mmol) and benzoyl peroxide (180 mg, 1.01 mmol) were slowly added at room temperature, followed by 18 hours. It was stirred at reflux. After adding methylene chloride and water, the organic layer was separated, dried over MgSO ₄ , filtered, and the filtrate was concentrated under reduced pressure, and the solid obtained was washed with hexane mixed with a small amount of methylene chloride and filtered to obtain compound 37 (2.36 g, 67%). To a light yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (dd, 1 H, J = 7.6, 1.6 Hz), 7.89 (dd, 1 H, J = 8.0, 1.6 Hz), 7.84 (dd, 1 H, J = 7.6, 1.2 Hz), 7.71 (td, 1 H, J = 7.6, 1.6 Hz), 7.65 (td, 1 H, J = 8.0, 1.6 Hz), 7.58 (d, 1 H, J = 7.6 Hz), 7.43 (t, 1 H, J = 7.6 Hz), 5.02 (s, 2 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 162.5, 152.0, 149.3, 136.4, 133.4, 132.5, 131.9, 131.3, 127.9, 127.7, 126.3, 124.7, 122.1, 29.5.

6) Turt - Butyl  4-((2- (2-nitrophenyl) benzo [ d ] Thiazole -4-day) methyl ) Piperazine-1- Carboxylate [ tert -Butyl 4-((2- (2-nitrophenyl) benzo [ d ] thiazol -4-yl) methyl) piperazine-1-carboxylate] (38)

Compound 37 (2.36 g, 6.76 mmol) was dissolved in anhydrous THF (tetrahydrofuran, 40 mL) and triethylamine (0.7 mL, 5.02 mmol) and N- Bocpiperazine ( tert -butyl piperazine-1-carboxylate, 1.52 g, 8.16 mmol) ) Was sequentially added at room temperature and stirred for 21 hours. The reaction mixture was filtered and washed with sufficient diethyl ether, followed by extraction by adding water to the filtrate, and the organic layer was dried over MgSO ₄ , and the filtrate obtained by filtration was concentrated under reduced pressure to give the residue obtained by silica gel column chromatography (methylene Purification with chloride: methanol = 40: 1) gave compound 38 (1032 mg, 33.6%) as a light yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85 (dd, 1 H, J = 8.0, 1.2 Hz), 7.83 (dd, 1 H, J = 8.0, 1.2 Hz), 7.81 (dd, 1 H, J = 8.0, 1.6 Hz), 7.68 (td, 1 H, J = 7.6, 1.6 Hz), 7.62 (td, 1 H, J = 8.0, 1.6 Hz), 7.56 (d, 1 H, J = 7.2 Hz), 7.42 (t, 1 H, J = 7.6 Hz), 4.09 (s, 2 H), 3.45 (t, 4 H, J = 4.8 Hz), 2.51 (brt, 4 H, J = 4.8 Hz), 1.44 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 161.5, 155.0, 153.3, 149.4, 135.9, 133.4, 132.3, 131.7, 131.1, 127.8, 127.4, 126.1, 124.5, 120.6, 79.7, 58.4, 53.0, 43.5, 28.7.

7) Turt - Butyl  4-((2- (2-aminophenyl) benzo [ d ] Thiazole -4-day) methyl ) Piperazine-1- Carboxylate [ tert -Butyl 4-((2- (2-aminophenyl) benzo [ d ] thiazol -4-yl) methyl) piperazine-1-carboxylate] (39)

10 wt.% Pd / C (palladium on carbon, 300 mg) was added into a methylene chloride (50 mL) solution containing compound 38 (996 mg, 2.19 mmol) and the air in the reaction vessel was replaced with hydrogen gas, and then at room temperature. Stir for 1 hour. The reaction mixture was filtered using celite as a filter filler, and the filtrate was concentrated under reduced pressure to obtain Compound 39 (840 mg, 90.3%) as a solid.

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.80 (d, 1 H, J = 7.5 Hz), 7.70 (d, 1 H, J = 8.0 Hz), 7.49 (d, 1 H, J = 7.5 Hz), 7.34 (t, 1 H, J = 7.5 Hz), 7.23 (t, 1 H, J = 8.0 Hz), 6.80 (d, 1 H, J = 8.0 Hz), 6.75 (t, 1 H, J = 7.5 Hz) ), 6.44 (brs, 2 H), 4.08 (brs, 2 H), 3.45 (brs, 4 H), 2.53 (s, 4 H), 1.44 (s, 9 H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 168.7, 154.8, 152.8, 146.7, 133.4, 131.6, 130.2, 126.8, 124.8, 120.1, 117.0, 116.8, 115.4, 79.6, 59.0, 53.0, 43.4, 28.4.

8) Synthesis of Compound 40 (a to q)

A suitable acyl chloride (1.3 eq) or p -toluenesulfonyl chloride (1.3 eq) was added into a methylene chloride solution containing compound 39 (1.0 eq) and anhydrous pyridine (5.0 eq), followed by stirring at room temperature. Methylene chloride and sodium bicarbonate are added to the residue obtained by concentrating the reaction mixture under reduced pressure, the organic layer is dried over anhydrous MgSO ₄ , filtered, and the residue obtained by concentrating the filtrate under reduced pressure is subjected to silica gel column chromatography using methylene chloride and methanol. The compound was purified by chromatography (methylene chloride: methanol = 40: 1 to 80: 1) to obtain compound 40 (a to q) .

Turt - Butyl  4-((2- (2-benzamidophenyl) benzo [ d ] Thiazole -4-day) methyl ) Piperazine-1- Car Succinate [ tert -Butyl 4-((2- (2-benzamidophenyl) benzo [ d ] thiazol -4-yl) methyl) piperazine-1-carboxylate] (40a)

White solid; Reaction time, 3 hours; Yield, 69%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.55 (s, 1 H, NH), 8.90 (d, 1 H, J = 8.4 Hz), 7.98 (d, 2 H, J = 7.2 Hz), 7.91 (d , 1 H, J = 7.6 Hz), 7.83 (d, 1 H, J = 8.0 Hz), 7.60-7.51 (m, 5 H), 7.42 (t, 1 H, J = 7.6 Hz), 7.22 (t, 1 H, J = 8.0 Hz), 3.86 (s, 2 H), 3.35 (brs, 4 H), 2.18 (brs, 4 H), 1.45 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.7, 167.6, 154.9, 152.3, 138.1, 136.7, 133.7, 132.6, 132.2, 132.1, 130.5, 129.2, 128.2, 126.8, 126.0, 123.8, 121.6, 120.2, 79.8, 58.4 , 52.9, 43.5, 28.7.

Turt - Butyl  4-((2- (2- (3-fluorobenzamido) phenyl) benzo [ d ] Thiazole-4-) yl) methyl ) Piperazine-l-carboxylate [ tert -Butyl 4-((2- (2- (3- fluorobenzamido) phenyl) benzo [ d ] thiazol-4-yl) methyl) piperazine-1-carboxylate] (40b)

White solid; Reaction time, 3 hours; Yield, 85%; ¹ H NR (500 MHz, CDCl ₃ ) δ 12.58 s, 1 H, NH), 8.88 (d, 1 H, J = 8.5 Hz), 7.92 (d, 1 H, J = 8.0 Hz), 7.84 (brd, 1 H, J = 7.5 Hz), 7.79 (d, 1 H, J = 7.5 Hz), 7.67-7.61 (m, 2 H), 7.56 (t, 1 H, J = 8.0 Hz), 7.52 (m, 1 H), 7.43 (t, 1 H, J = 7.5 Hz), 7.29 (td, 1 H, J = 8.0, 2.0 Hz), 7.24 (t, 1 H, J = 7.5 Hz), 3.89 (s, 2 H ), 3.36 (s, 4 H), 2.22 (s, 4 H), 1.45 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.7, 166.1, 162.9 (d, J = 246.6 Hz), 154.9, 152.2, 138.8 (d, J = 6.8 Hz), 137.8, 133.7, 132.6, 132.2, 130.9 (d , J = 7.6 Hz), 130.5, 126.9, 126.1, 124.1, 124.0 (d, J = 2.3 Hz), 121.6, 120.3, 120.2, 119.1 (d, J = 21.3 Hz), 115.3 (d, J = 22.8 Hz) , 79.9, 58.2, 52.9, 43.4, 28.6.

Turt - Butyl  4-((2- (2- (4-fluorobenzamido) phenyl) benzo [ d ] Thiazol-4-yl) methyl ) Piperazine-1-carboxylate [ tert -Butyl 4-((2- (2- (4-fluorobenzamido) phenyl) benzo [ d ] thiazol-4-yl) methyl) piperazine-1-carboxylate] (40c)

White solid; Reaction time, 3 hours; Yield, 83%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 12.55 (s, 1 H, NH), 8.86 (d, 1 H, J = 8.0 Hz), 8.00 (dd, 2 H, J = 8.5, 5.0 Hz), 7.91 (d, 1 H, J = 8.0 Hz), 7.83 (d, 1 H, J = 8.0 Hz), 7.62 (brd, 1 H, J = 7.0 Hz), 7.55 (t, 1 H, J = 7.5 Hz) , 7.42 (t, 1 H, J = 8.0 Hz), 7.23 (t, 1 H, J = 7.5 Hz), 7.21 (t, 2 H, J = 8.5 Hz), 3.85 (s, 2 H), 3.36 ( s, 4 H), 2.22 (s, 4 H), 1.45 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.8, 166.5, 165.2 (d, J = 251.1 Hz), 154.9, 152.2, 138.0, 133.7, 132.9 (d, J = 3.1 Hz), 132.2, 130.6 (d, J = 8.4 Hz), 130.5, 130.5, 126.9, 126.1, 123.9, 121.5, 120.3, 120.2, 116.2 (d, J = 22.0 Hz), 79.9, 58.5, 53.0, 43.4, 28.6.

Turt - Butyl  4-((2- (2- (3-bromobenzamido) phenyl) benzo [ d ] Thiazol-4-yl) methyl) piperazin-1-carboxylate [ tert -Butyl 4-((2- (2- (3-bromobenzamido) phenyl) benzo [ d ] thiazol-4-yl) methyl) piperazine-1-carboxylate] (40d)

White solid; Reaction time, 3 hours; Yield, 78%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 12.64 (s, 1 H, NH), 8.87 (dd, 1 H, J = 8.5, 1.0 Hz), 8.06 (t, 1 H, J = 1.5 Hz), 7.92 (dt, 1 H, J = 8.5, 1.5 Hz), 7.90 (dt, 1 H, J = 8.5, 1.5 Hz), 7.84 (d, 1 H, J = 8.0 Hz), 7.72 (d, 1 H, J = 8.0 Hz), 7.60 (brd, 1 H, J = 7.0 Hz), 7.55 (td, 1 H, J = 8.0, 1.5 Hz), 7.42 (t, 1 H, J = 8.0 Hz), 7.42 (t, 1 H, J = 8.0 Hz), 7.24 (td, 1 H, J = 8.0, 1.0 Hz), 3.84 (s, 2 H), 3.33 (s, 4 H), 2.15 (s, 4 H), 1.44 ( s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.7, 166.2, 154.9, 152.2, 138.9, 137.9, 135.1, 133.6, 132.3, 131.2, 130.8, 130.4, 127.1, 126.9, 126.1, 124.1, 123.3, 121.5, 120.3, 120.2 , 79.8, 58.2, 52.9, 43.8, 28.7.

Turt - Butyl  4-((2- (2- (3-chlorobenzamido) phenyl) benzo [ d ] Thiazol-4-yl) methyl) piperazin-1-carboxylate [ tert -Butyl 4-((2- (2- (3-chlorobenzamido) phenyl) benzo [ d ] thiazol-4-yl) methyl) piperazine-1-carboxylate] (40e)

White solid; Reaction time, 3 hours; Yield, 84%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 12 . 63 (s, 1 H, NH), 8.88 (d, 1 H, J = 9.0 Hz), 7.92 (d, 1 H, J = 9.0 Hz), 7.91 (s, 1 H), 7.86 (dd, 1 H , J = 8.0, 1.0 Hz), 7.84 (brd, 1 H, J = 8.0 Hz), 7.61 (brd, 1 H, J = 7.0 Hz), 7.57 (d, 1 H, J = 8.0 Hz), 7.56 ( t, 1 H, J = 8.5 Hz), 7.49 (t, 1 H, J = 7.0 Hz), 7.43 (t, 1 H, J = 7.5 Hz), 7.24 (t, 1 H, J = 7.5 Hz), 3.85 (s, 2 H), 3.34 (s, 4 H), 2.16 (s, 4 H), 1.44 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.7, 166.2, 154.9, 152.2, 138.6, 137.9, 135.1, 133.6, 132.5, 132.2, 132.1, 130.5, 130.4, 128.3, 127.1, 126.4, 126.1, 124.1, 121.5, 120.2 , 79.8, 58.1, 52.9, 43.4, 28.7.

Turt - Butyl  4-((2- (2- (4-chlorobenzamido) phenyl) benzo [ d ] Thiazol-4-yl) methyl) piperazin-1-carboxylate [ tert -Butyl 4-((2- (2- (4-chlorobenzamido) phenyl) benzo [ d ] thiazol-4-yl) methyl) piperazine-1-carboxylate] (40f)

White solid; Reaction time, 3 hours; Yield, 86%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 12.60 (s, 1 H, NH), 8.85 (d, 1 H, J = 8.0 Hz), 7.91 (d, 2 H, J = 8.5 Hz), 7.91 (d , 1 H, J = 8.0 Hz), 7.83 (d, 1 H, J = 8.0 Hz), 7.62 (brd, 1 H, J = 7.0 Hz), 7.55 (td, 1 H, J = 8.0, 1.5 Hz) , 7.504 (d, 2 H, J = 8.5 Hz), 7.423 (t, 1 H, J = 8.0 Hz), 7.23 (t, 1 H, J = 8.0 Hz), 3.82 (s, 2 H), 3.38 ( s, 4 H), 2.21 (s, 4 H), 1.45 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.8, 166.6, 154.9, 152.1, 138.3, 138.0, 135.3, 133.6, 132.4, 132.3, 130.4, 129.6, 129.4, 126.7, 126.1, 124.0, 121.5, 120.1, 79.9, 58.4 , 53.1, 43.4, 28.7.

Turt - Butyl  4-((2- (2- (3-nitrobenzamido) phenyl) benzo [ d ] Thiazol-4-yl) methyl) piperazin-1-carboxylate [ tert -Butyl 4-((2- (2- (3-nitrobenzamido) phenyl) benzo [ d ] thiazol-4-yl) methyl) piperazine-1-carboxylate] (40g)

Yellow solid; Reaction time, 3 hours; Yield, 63%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 12.81 (s, 1 H, NH), 8.87 (d, 1 H, J = 9.0 Hz), 8.80 (s, 1 H), 8.46 (dt, 1 H, J = 8.5, 1.0 Hz), 8.33 (d, 1 H, J = 8.0 Hz), 7.94 (d, 1 H, J = 7.0 Hz), 7.84 (d, 1 H, J = 8.0 Hz), 7.76 (t, 1 H, J = 8.0 Hz), 7.58 (d, 1 H, J = 7.5 Hz), 7.58 (t, 1 H, J = 8.0 Hz), 7.43 (t, 1 H, J = 8.0 Hz), 7.28 ( t, 1 H, J = 7.5 Hz), 3.73 (s, 2 H), 3.30 (s, 4 H), 2.08 (s, 4 H), 1.44 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.7, 165.1, 154.9, 152.1, 148.6, 138.4, 137.5, 134.2, 133.6, 132.3, 132.2, 130.5, 130.5, 127.1, 126.6, 126.2, 124.5, 123.1, 121.6, 120.4 , 120.3, 79.9, 58.1, 52.8, 44.3, 28.6.

Turt - Butyl  4-((2- (2- (4-nitrobenzamido) phenyl) benzo [ d ] Thiazol-4-yl) methyl) piperazin-1-carboxylate [ tert -Butyl 4-((2- (2- (4-nitrobenzamido) phenyl) benzo [ d ] thiazol-4-yl) methyl) piperazine-1-carboxylate] (40h)

Yellow solid; Reaction time, 3 hours; Yield, 79%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 12.8 (s, 1 H, NH), 8.88 (d, 1 H, J = 8.5 Hz), 8.39 (d, 2 H, J = 8.0 Hz), 8.15 (d , 2 H, J = 8.0 Hz), 7.94 (d, 1 H, J = 8.0 Hz), 7.84 (d, 1 H, J = 8.0 Hz), 7.63 (brd, 1 H, J = 7.0 Hz), 7.57 (t, 1 H, J = 8.0 Hz), 7.44 (t, 1 H, J = 8.0 Hz), 7.28 (t, 1 H, J = 7.5 Hz), 3.81 (s, 2 H), 3.34 (s, 4 H), 2.17 (s, 4 H), 1.45 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.5, 165.1, 154.6, 151.8, 149.7, 142.0, 137.2, 133.4, 132.1, 130.3, 129.1, 126.7, 126.1, 124.4, 124.1, 121.3, 120.2, 120.1, 79.7, 58.3 , 52.9, 42.9, 28.4.

Turt - Butyl  4-((2- (2- (3,4,5-trimethoxybenzamido) phenyl) benzo [ d ] Thiazole -4-yl) methyl) piperazin-1-carboxylate [ tert -Butyl 4-((2- (2- (3,4,5-trimethoxybenzamido) phenyl) benzo [ d ] thiazol-4-yl) methyl) piperazine-1-carboxylate] (40i)

White solid; Reaction time, 3 hours; Yield, 84%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 12.69 (s, 1 H, NH), 8.88 (d, 1 H, J = 8.0 Hz), 7.94 (d, 1 H, J = 8.0 Hz), 7.58 (d , 1 H, J = 8.0 Hz), 7.56 (t, 1 H, J = 8.5 Hz), 7.56 (d, 1 H, J = 7.5 Hz), 7.43 (t, 1 H, J = 7.5 Hz), 7.24 (t, 1 H, J = 7.5 Hz), 7.18 (s, 2 H), 3.96 (s, 3 H), 3.87 (s, 6 H), 3.78 (s, 2 H), 3.29 (s, 4 H ), 2.10 (s, 4 H), 1.43 (s, 9 H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 168.6, 167.4, 154.6, 153.3, 152.0, 141.4, 138.2, 133.4, 132.1, 132.1, 130.1, 127.2, 125.8, 123.5, 121.0, 120.2, 119.6, 105.6, 79.5, 60.9 , 57.9, 56.4, 52.4, 43.1, 28.4.

Turt - Butyl  4-((2- (2- (2,4-dichlorobenzamido) phenyl) benzo [ d ] Thiazol-4-yl) Me Tyl) piperazin-1-carboxylate [ tert -Butyl 4-((2- (2- (2,4-dichlorobenzamido) phenyl) benzo [ d ] thiazol-4-yl) methyl) piperazine-1-carboxylate] (40j)

White solid; Reaction time, 3 hours; Yield, 80%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.81 (s, 1 H, NH), 8.961 (d, 1 H, J = 8.0 Hz), 7.92 (dd, 1 H, J = 8.0, 1.5 Hz), 7.79 (d, 1 H, J = 7.6 Hz), 7.61 (d, 1 H, J = 8.0 Hz), 7.60-7.53 (m, 2 H), 7.53 (d, 1 H, J = 1.5 Hz), 7.40 ( t, 1 H, J = 8.4 Hz), 7.38 (dd, 1 H, J = 8.4, 2.4 Hz), 7.24 (td, 1 H, J = 8.0, 1.2 Hz), 3.50 (s, 2 H), 3.39 (brs, 4 H), 2.13 (s, 4 H), 1.474 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.3, 165.1, 154.9, 151.8, 137.7, 137.2, 135.9, 133.3, 132.6, 132.4, 130.7, 130.6, 130.2, 127.9, 126.6, 126.2, 124.3, 121.3, 120.1, 119.8 , 79.8, 58.0, 53.2, 44.4, 28.7.

Turt - Butyl  4-((2- (2- (3,4-dichlorobenzamido) phenyl) benzo [ d ] Thiazol-4-yl) methyl ) Piperazine-1-carboxylate [ tert -Butyl 4-((2- (2- (3,4-dichlorobenzamido) phenyl) benzo [ d ] thiazol-4-yl) methyl) piperazine-1-carboxylate] (40k)

White solid; Reaction time, 6 hours; Yield, 68%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.70 (s, 1 H, NH), 8.83 (d, 1 H, J = 8.4 Hz), 8.01 (d, 1 H, J = 2.0 Hz), 7.92 (dd , 1 H, J = 7.6, 2.0 Hz), 7.84-7.79 (m, 2 H), 7.62 (d, 1 H, J = 8.4 Hz), 7.62 (brd, 1 H, J = 7.2 Hz), 7.55 ( t, 1 H, J = 7.6 Hz), 7.43 (t, 1 H, J = 7.6 Hz), 7.24 (t, 1 H, J = 8.0 Hz), 3.80 (s, 2 H), 3.35 (s, 4 H), 2.15 (s, 4 H), 1.44 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.7, 165.5, 154.9, 152.0, 137.8, 136.8, 136.6, 133.5, 132.5, 132.3, 131.3, 130.4, 130.2, 127.5, 127.0, 126.2, 124.2, 121.4, 120.2, 120.1 , 79.8, 58.1, 53.0, 43.1, 28.7.

Turt - Butyl  4-((2- (2- (nicotinamido) phenyl) benzo [ d ] Thiazole -4-day) methyl ) Piperazine-1-carboxylate [ tert -Butyl 4-((2- (2- (nicotinamido) phenyl) benzo [ d ] thiazol -4-yl) methyl) piperazine-1-carboxylate] (40l)

White solid; Reaction time, 3 hours; Yield, 80%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 12.79 (s, 1 H, NH), 9.24 (d, 1 H, J = 2.5 Hz), 8.90 (d, 1 H, J = 8.0 Hz), 8.82 (dd , 1 H, J = 5.0, 2.0 Hz), 8.30 (dt, 1 H, J = 7.5, 2.0 Hz), 7.93 (d, 1 H, J = 8.0 Hz), 7.83 (d, 1 H, J = 8.0 Hz), 7.65 (brd, 1 H, J = 7.0 Hz), 7.56 (t, 1 H, J = 7.5 Hz), 7.49 (dd, 1 H, J = 8.0, 5.0 Hz), 7.43 (t, 1 H , J = 7.5 Hz), 7.26 (t, 1 H, J = 7.5 Hz), 3.89 (s, 2 H), 3.37 (s, 4 H), 2.24 (s, 4 H), 1.45 (s, 9 H ); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.6, 165.4, 155.0, 152.9, 152.0, 148.9, 137.7, 136.3, 133.6, 132.8, 132.4, 132.3, 130.5, 126.7, 126.2, 124.3, 124.1, 121.5, 120.3, 120.1 , 79.8, 58.5, 53.1, 44.3, 28.7.

Turt - Butyl  4-((2- (2- (1-naphthaamido) phenyl) benzo [ d ] Thiazole -4-day) methyl ) Piperazine-1-carboxylate [ tert -Butyl 4-((2- (2- (1-naphthamido) phenyl) benzo [ d ] thiazol -4-yl) methyl) piperazine-1-carboxylate] (40m)

White solid; Reaction time, 3 hours; Yield, 63%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 12.86 (s, 1 H, NH), 9.12 (d, 1 H, J = 8.5 Hz), 8.41 (d, 1 H, J = 8.0 Hz), 8.01 (d , 1 H, J = 8.5 Hz), 7.95-7.92 (m, 2 H), 7.85 (d, 1 H, J = 7.0 Hz), 7.78 (d, 1 H, J = 7.5 Hz), 7.60 (t, 1 H, J = 8.0 Hz), 7.57-7.53 (m, 2 H), 7.51 (t, 1 H, J = 7.5 Hz), 7.41 (brt, 1 H, J = 7.5 Hz), 7.34 (t, 1 H, J = 7.5 Hz), 7.26 (t, 1 H, J = 7.5 Hz), 3.13 (s, 4 H), 3.11 (s, 2 H), 1.75 (s, 4 H), 1.47 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.8, 168.4, 154.8, 152.0, 138.4, 135.8, 134.1, 133.5, 132.5, 132.4, 131.4, 130.5, 130.3, 128.6, 127.6, 127.0, 126.0, 125.9, 125.7, 125.2 , 124.0, 121.4, 120.1, 119.8, 79.7, 57.6, 52.5, 43.5, 28.7.

Turt - Butyl  4-((2- (2- (2-naphthaamido) phenyl) benzo [ d ] Thiazole -4-day) methyl ) Piperazine-1-carboxylate [ tert -Butyl 4-((2- (2- (2-naphthamido) phenyl) benzo [ d ] thiazol -4-yl) methyl) piperazine-1-carboxylate] (40n)

White solid; Reaction time, 3 hours; Yield, 74%; ¹ H NMR (400 Hz, CDCl ₃ ) δ 12.83 (s, 1 H, NH), 8.94 (d, 1 H, J = 8.4 Hz), 8.42 (s, 1 H), 8.02 (dd, 1 H, J = 8.4, 1.6 Hz), 7.98 (d, 1 H, J = 8.8 Hz), 7.95-7.91 (m, 3 H), 7.81 (d, 1 H, J = 8.0 Hz), 7.63-7.55 (m, 3 H), 7.51 (brd, 1 H, J = 7.6 Hz), 7.38 (t, 1 H, J = 7.6 Hz), 7.23 (t, 1 H, J = 8.0 Hz), 3.56 (s, 2 H), 3.12 (s, 4 H), 1.63 (s, 4 H), 1.44 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.7, 168.1, 154.7, 152.1, 138.4, 135.3, 134.4, 133.5, 132.9, 132.6, 132.3, 130.4, 129.3, 129.1, 128.4, 128.2, 128.1, 127.2, 126.7, 126.0 , 124.9, 123.8, 121.5, 120.1, 112.0, 79.7, 57.9, 52.4, 42.9, 28.7.

Turt - Butyl  4-((2- (2- (quinoxaline-2-carboxamido) phenyl) benzo [ d ] Thiazol-4-yl) methyl ) Piperazine-1-carboxylate [ tert -Butyl 4-((2- (2- (quinoxaline-2-carboxamido) phenyl) benzo [ d ] thiazol-4-yl) methyl) piperazine-1-carboxylate] (40o)

Yellow solid; Reaction time, 3 hours; Yield, 46%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 12.96 (s, 1 H, NH), 9.76 (s, 1 H), 8.95 (d, 1 H, J = 8.5 Hz), 8.24 (d, 1 H, J = 8.5 Hz), 8.12 (d, 1 H, J = 8.0 Hz), 7.93-7,83 (m, 4 H), 7.59 (t, 1 H, J = 8.0 Hz), 7.52 (brd, 1 H, J = 7.0 Hz), 7.44 (t, 1 H, J = 7.5 Hz), 7.30 (t, 1 H, J = 7.5 Hz), 4.07 (s, 2 H), 3.21 (s, 4 H), 2.01 ( s, 4 H), 1.380 (s, 9 H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 167.5, 163.1, 154.5, 153.0, 145.2, 144.7, 143.9, 140.3, 136.6, 134.2, 131.8, 130.8, 130.6, 130.1, 129.8, 127.2, 125.6, 124.4, 121.9, 121.7 , 120.3, 79.5, 58.0, 52.1, 43.1, 28.4.

Turt - Butyl  4-((2- (2- ([1,1'- Biphenyl ]-4- Ilka Copy Mido ) Phenyl) Benzo [ d ] Thiazole -4-yl) methyl) piperazin-1-carboxylate [ tert -Butyl 4-((2- (2-([1,1'-biphenyl] -4-ylcarboxamido) phenyl) benzo [ d ] thiazol-4yl) methyl) piperazine-1-carboxylate] (40p)

White solid; Reaction time, 3 hours; Yield, 81%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 12.66 (s, 1 H, NH), 8.93 (d, 1 H, J = 9.0 Hz), 8.05 (d, 2 H, J = 8.5 Hz), 7.93 (d , 1 H, J = 8.0 Hz), 7.84 (d, 1 H, J = 8.0 Hz), 7.76 (d, 2 H, J = 7.5 Hz), 7.65 (d, 2 H, J = 8.5 Hz), 7.56 (t, 1 H, J = 8.0 Hz), 7.56 (t, 1 H, J = 8.0 Hz), 7.51 (t, 2 H, J = 8.0 Hz), 7.43 (d, 1 H, J = 7.5 Hz) , 7.42 (t, 1 H, J = 7.5 Hz), 7.23 (t, 1 H, J = 8.0 Hz), 3.87 (s, 2 H), 3.25 (s, 4 H), 2.10 (s, 4 H) , 1.43 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.8, 167.5, 154.9, 152.3, 145.0, 140.1, 138.3, 135.5, 133.6, 132.5, 132.3, 130.4, 129.3, 128.8, 128.4, 127.8, 127.4, 127.0, 126.0, 123.8 , 121.5, 120.3, 120.1, 79.8, 58.5, 53.0, 43.7, 28.6.

Turt - Butyl  4-((2- (2- (4-methylphenylsulfonamido) phenyl) benzo [ d ] Thiazol-4-yl) methyl ) Piperazine-1-carboxylate [ tert -Butyl 4-((2- (2- (4-methylphenylsulfonamido) phenyl) benzo [ d ] thiazol-4-yl) methyl) piperazine-1-carboxylate] (40q)

White solid; Reaction time, 3 hours; Yield, 82%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 12.57 (s, 1 H, NH), 7.83 (d, 1 H, J = 8.0 Hz), 7.76 (d, 1 H, J = 8.5 Hz), 7.74-7.71 (m, 3 H), 7.54 (brd, 1 H, J = 7.0 Hz), 7.43 (t, 1 H, J = 8.0 Hz), 7.36 (t, 1 H, J = 8.0 Hz), 7.11-7.08 ( m, 3 H), 4.15 (s, 2 H), 3.47 (s, 4 H), 2.62 (s, 4 H), 2.29 (s, 3 H), 1.44 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 167.9, 155.0, 152.0, 143.9, 137.5, 136.8, 133.5, 132.1, 130.1, 129.8, 128.3, 127.5, 126.0, 123.6, 120.6, 119.9, 119.6, 79.7, 59.4, 52.9 , 43,4, 28.7, 21.7.

9) Compound 41 (a to q) synthesis

Compound in the form of HCl salt: 1,4-dioxane and 8N-HCl (42.0 eq.) In a volume corresponding to 8N-HCl (42.0 eq.) Into Compound 40 (1.0 eq.) Were added in turn, and then the reaction mixture was mixed. Was stirred at room temperature. Concentrated under reduced pressure to remove the solvent, the remaining residue was added with diethyl ether in the presence of a small amount of methanol or in the absence of methanol to filter the resulting solid to obtain Compound 41 above.

Compound in free acid form: 15 equivalents of trifluoroacetic acid was added into a methylene chloride solution containing compound 40 (1.0 equivalent) and the reaction mixture was stirred at room temperature for 12 hours. The above compound was purified by silica gel column chromatography (methylene chloride: methanol = 5: 1) by adding methylene chloride and sodium bicarbonate, drying the organic layer over anhydrous MgSO ₄ and filtering, and distilling the filtrate under reduced pressure. 41 (a to q) was obtained.

N -(2- (4- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide hydrochloride [ N -(2- (4- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41a)

White solid; Reaction time, 5 hours; Yield, 85%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.43 (s, 1 H, CONH), 9.70 (brs, 2 H, H ₂ N ⁺ ), 8.26 -8.21 (m, 2 H), 8.16 (d, 1 H, J = 7.2 Hz), 8.03 (d, 2 H, J = 7.2 Hz), 7.90 (d, 1 H, J = 7.2 Hz), 7.66-7.61 (m, 4 H), 7.54 (td, 1 H, J = 7.6, 2.8 Hz), 7.42 (td, 1 H, J = 7.6, 2.8 Hz), 4.68 (s, 2 H), 3.54 (brs, 4 H), 3.22 (brs, 4 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 168.2, 167.0, 152.9, 137.5, 135.5, 135.3, 132.9, 132.6, 131.2, 130.9, 129.7, 128.5, 126.5, 126.3, 125.6, 125.3, 124.6, 123.4, 67.0 , 55.5, 48.2.

3- Fluoro - N -(2- (4- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide Hydrochloride [3- Fluoro - N -(2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol -2-yl) phenyl) benzamide hydrochloride] (41b)

White solid; Reaction time, 5 hours; Yield, 69%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.36 (brs, 1 H, CONH), 9.50 (brs, 2 H, H ₂ N ⁺ ), 8.24 (d, 1 H, J = 8.4 Hz), 8.24 (d, 1 H, J = 8.4 Hz), 8.06 (brd, 1 H, J = 7.2 Hz), 7.90 (d, 1 H, J = 7.6 Hz), 7.87 (d, 1 H, J = 7.6 Hz) , 7.80 (d, 1 H, J = 8.0 Hz), 7.71-7.63 (m, 2 H), 7.54 (t, 1 H, J = 8.0 Hz), 7.50 (t, 1 H, J = 8.4 Hz), 7.45 (t, 1 H, J = 8.0 Hz), 4.66 (s, 2 H), 3.43 (brs, 4 H), 3.35 (brs, 4 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 167.7, 165.7 (d, J = 2.2 Hz), 162.8 (d, J = 243.5 Hz), 152.9, 137.6 (d, J = 6.9 Hz), 137.0, 135.5 , 132.6, 131.9 (d, J = 7.6 Hz), 131.1, 130.9, 126.8, 126.4, 124.6, 123.5, 119.8 (d, J = 20.5 Hz), 115.4 (d, J = 22.8 Hz), 67.0, 55.4, 48.2 .

4- Fluoro - N -(2- (4- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide Hydrochloride [4- Fluoro - N -(2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol -2-yl) phenyl) benzamide hydrochloride] (41c)

White solid; Reaction time, 5 hours; Yield, 94%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.18 (s, 1 H, CONH), 9.66 (brs, 2 H, H ₂ N ⁺ ), 8.24 (t, 2 H, J = 7.2 Hz), 8.11 (t, 2 H, J = 7.2 Hz), 8.04 (d, 1 H, J = 8.0 Hz), 7.89 (d, 1 H, J = 7.2 Hz), 7.64 (t, 1 H, J = 7.6 Hz) , 7.55 (t, 1 H, J = 7.6 Hz), 7.47-7.42 (m, 3 H), 4.736 (s, 2 H), 3.39 (brs, 4 H), 3.37 (brs, 4 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 168.0, 166.5, 165.1 (d, J = 248.8 Hz), 152.7, 136.7, 135.5, 132.7, 131.6 (d, J = 2.3 Hz), 131.1 (d, J = 9.1 Hz), 131.1, 130.6, 127.0, 126.6, 126.2, 124.7, 123.3, 116.7 (d, J = 22.0 Hz), 56.2, 48.4, 40.9.

3- Bromo - N -(2- (4- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide hydrochloride [3-Bromo- N -(2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41d)

White solid; Reaction time, 5 hours; Yield, 88%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.31 (s, 1 H, CONH), 9.65 (brs, 2 H, H ₂ N ⁺ ), 8.25 (d, 1 H, J = 8.0 Hz), 8.25 (d, 1 H, J = 8.0 Hz), 8.16 (s, 1 H), 8.05 (d, 1 H, J = 7.6 Hz), 8.01 (brd, 1 H, J = 6.8 Hz), 7.89 (d, 1 H, J = 6.8 Hz) 7.84 (dd, 1 H, J = 8.4, 1.2 Hz), 7.64 (t, 1 H, J = 7.6, 1.2 Hz), 7.59 (t, 1 H, J = 7.6 Hz) , 7.54 (t, 1 H, J = 7.6 Hz), 7.45 (t, 1 H, J = 7.6 Hz), 4.70 (s, 2 H), 3.37 (brs, 4 H), 3.26 (brs, 4 H) ; ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 167.6, 165.6, 152.9, 137.5, 137.0, 135.6, 135.5, 132.6, 131.9, 131.2, 131.1, 130.8, 127.5, 126.8, 126.6, 126.4, 124.6, 122.8, 55.5 , 48.2, 40.8.

3- Chloro - N -(2- (4- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide hydrochloride [3-Chloro- N -(2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41e)

White solid; Reaction time, 3 hours; Yield, 84%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.32 (s, 1 H, CONH), 9.72 (s, 2 H, H ₂ N ⁺ ), 8.26-8.23 (m, 2 H), 8.04-7.98 ( m, 3 H), 7.90 (d, 1 H, J = 7.2 Hz), 7.71 (dt, 1 H, J = 8.4, 1.6 Hz), 7.66 (d, 1 H, J = 8.0 Hz), 7.64 (td , 1 H, J = 7.6, 1.2 Hz), 7.54 (t, 1 H, J = 8.0 Hz), 7.45 (td, 1 H, J = 7.6, 1.2 Hz), 4.72 (s, 2 H), 3.38 ( brs, 4 H), 3.29 (brs, 4 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 167.6, 165.7, 152.9, 137.3, 137.0, 135.5, 134.3, 132.7, 132.6, 131.7, 131.1, 130.8, 128.3, 127.2, 126.9, 126.5, 126.4, 124.6, 55.5 , 48.2, 40.8.

4- Chloro - N -(2- (4- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide hydrochloride [4-Chloro- N -(2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41f)

White solid; Reaction time, 5 hours; Yield, 86%; ¹ H NMR (400 MHz, DMSO- d ₆ + a few drops of D ₂ O) δ 8.15 (d, 1 H, J = 7.6 Hz), 8.10 (d, 1 H, J = 7.6 Hz), 7.97 (d , 1 H, J = 8.0 Hz), 7.92 (d, 2 H, J = 8.0 Hz), 7.64-7.58 (m, 4 H), 7.50 (t, 1 H, J = 7.6 Hz), 7.42 (t, 1 H, J = 7.6 Hz), 4.48 (s, 2 H), 3.21 (brs, 4 H), 3.08 (brs, 4 H); ¹³ C NMR (100 MHz, DMSO- d ₆ + a few drops of D ₂ O) δ 168.0, 166.8, 152.4, 138.1, 136.5, 135.3, 133.8, 132.8, 131.0, 130.2, 129.9, 129.7, 127.0, 126.7, 125.7 , 124.5, 124.2, 56.6, 48.6, 41.4.

3-Nitro- N -(2- (4- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide hydrochloride [3-Nitro- N -(2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41g)

Yellow solid; Reaction time, 5 hours; Yield, 93%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.47 (s, 1 H, CONH), 9.62 (brs, 2 H, H ₂ N ⁺ ), 8.77 (s, 1 H), 8.51 (d, 1 H , J = 7.6 Hz), 8.47 (d, 1 H, J = 8.4 Hz), 8.28 (d, 1 H, J = 7.6 Hz), 8.22 (d, 1 H, J = 8.0 Hz), 7.98 (brd, 1 H, J = 6.8 Hz), 7.93 (t, 1 H, J = 7.6 Hz), 7.88 (brd, 1 H, J = 7.2 Hz), 7.66 (t, 1 H, J = 8.0 Hz), 7.54 ( t, 1 H, J = 8.0 Hz), 7.48 (t, 1 H, J = 7.6 Hz), 4.69 (s, 2 H), 3.36 (brs, 4 H), 3.25 (brs, 4 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 167.4, 165.1, 152.9, 148.7, 136.7, 136.6, 135.5, 134.7, 132.6, 131.4, 131.1, 130.8, 127.4, 127.2, 127.0, 126.4, 124.5, 123.4, 55.5 , 48.2, 41.1.

4-nitro- N -(2- (4- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide hydrochloride [4-Nitro- N -(2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41h)

Yellow solid; Reaction time, 5 hours; Yield, 99%; ¹ H NMR (400 MHz, DMSO- d ₆ + a few drops of D ₂ O) δ 8.42-8.37 (m, 2 H), 8.23-8.21 (m, 4 H), 8.05 (d, 1 H, J = 7.6 Hz), 7.78 (d, 1 H, J = 8.0 Hz), 7.65 (t, 1 H, J = 8.0 Hz), 7.54 (t, 1 H, J = 8.0 Hz), 7.47 (t, 1 H, J = 7.6 Hz), 4.66 (s, 2 H), 3.54 (brs, 8 H); ¹³ C NMR (100 MHz, DMSO- d ₆ + a few drops of D ₂ O) δ 170.5, 170.2, 154.7, 152.6, 142.3, 138.3, 137.3, 135.2, 133.5, 132.8, 131.8, 130.6, 130.2, 129.3, 128.9 , 127.5, 127.0, 124.1, 59.4, 50.8, 43.2.

3,4,5- Trimethoxy - N -(2- (4- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide Hydrochloride [3,4,5- Trimethoxy - N -(2- (4- (piperazin-1- ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41i)

White solid; Reaction time, 5 hours; Yield, 82%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.02 (s, 1 H, CONH), 9.75 (brs, 2 H, H ₂ N ⁺ ), 8.34 (d, 1 H, J = 7.6 Hz), 8.24 (d, 1 H, J = 8.0 Hz), 7.86 (d, 1 H, J = 7.2 Hz), 7.81 (d, 1 H, J = 7.6 Hz), 7.63 (t, 1 H, J = 8.0 Hz) , 7.53 (t, 1 H, J = 7.6 Hz), 7.46 (t, 1 H, J = 7.6 Hz), 7.37 (s, 2 H), 4.73 (s, 2 H), 3.81 (s, 6 H) , 3.74 (s, 3 H), 3.38 (brs, 8 H).

2,4- Dichloro - N -(2- (4- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide Hydrochloride [2,4- Dichloro - N -(2- (4- ( piperazin -One- ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41j)

White solid; Reaction time, 3 hours; Yield, 99%; ¹ H NMR (400 MHz, DMSO- d ₆ + a few drops of D ₂ O) δ 8.23 (d, 1 H, J = 8.0 Hz), 8.18 (d, 1 H, J = 8.8 Hz), 8.13 (d , 1 H, J = 8.0 Hz), 7.80-7.75 (m, 3 H), 7.64-7.61 (m, 2 H), 7.55 (t, 1 H, J = 7.6 Hz), 7.42 (t, 1 H, J = 7.6 Hz), 4.49 (s, 2 H), 3.34 (brs, 4 H), 3.21 (brs, 4 H); ¹³ C NMR (100 MHz, DMSO- d ₆ + a few drops of D ₂ O) δ 168.0, 165.2, 152.7, 136.4, 136.4, 135.5, 135.3, 132.8, 132.0, 131.2, 131.2, 130.4, 130.4, 128.7, 126.7 , 126.6, 124.6, 124.6, 124.4, 124.2, 55.8, 48.4, 41.4.

3,4- Dichloro - N -(2- (4- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide Hydrochloride [3,4- Dichloro - N -(2- (4- ( piperazin -One- ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41k)

White solid; Reaction time, 3 hours; Yield, 89%; ¹ H NMR (400 MHz, DMSO- d ₆ + a few drops of D ₂ O) δ 8.21 (d, 1 H, J = 8.4 Hz), 8.17 (d, 1 H, J = 8.0 Hz), 8.15 (d , 1 H, J = 1.6 Hz), 7.94 (dd, 1 H, J = 8.4, 1.2 Hz), 7.89 (d, 1 H, J = 8.0 Hz), 7.84 (d, 1 H, J = 8.4 Hz) , 7.75 (d, 1 H, J = 6.8 Hz), 7.62 (t, 1 H, J = 8.0 Hz), 7.53 (t, 1 H, J = 7.6 Hz), 7.46 (t, 1 H, J = 8.0 Hz), 4.68 (s, 2 H), 3.31 (brs, 4 H), 3.28 (brs, 4 H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 167.5, 165.1, 152.7, 136.3, 135.8, 135.6, 135.3, 132.6, 132.5, 131.9, 131.1, 130.5, 130.3, 128.6, 127.3, 126.9, 126.7, 126.6, 124.6 , 123.9, 56.1, 48.4, 41.1.

N -(2- (4- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) nicotinamide hydrochloride [ N -(2- (4- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) nicotinamide hydrochloride] (41l)

White solid; Reaction time, 3 hours; Yield, 97%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.59 (s, 1 H, CONH), 9.84 (brs, 2 H, H ₂ N ⁺ ), 9.38 (s, 1 H), 8.98 (d, 1 H , J = 4.4 Hz), 8.79 (d, 1 H, J = 6.8 Hz), 8.29 (d, 1 H, J = 8.0 Hz), 8.23 (d, 1 H, J = 7.6 Hz), 7.99-7.92 ( m, 3 H), 7.66 (t, 1 H, J = 7.6 Hz), 7.55 (t, 1 H, J = 7.6 Hz), 7.49 (t, 1 H, J = 7.6 Hz), 4.76 (s, 2 H), 3.41 (brs, 4 H), 3.26 (brs, 4 H).

N -(2- (4- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) -1- Naphthaamide  Hydrochloride [ N -(2- (4- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) -1-naphthamide hydrochloride] (41m)

White solid; Reaction time, 5 hours; Yield, 92%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.77 (s, 1 H, CONH), 9.59 (brs, 2 H, H ₂ N ⁺ ), 8.45 (brd, 1 H, J = 8.0 Hz), 8.25 (d, 1 H, J = 8.8 Hz), 8.24 (d, 1 H, J = 7.6 Hz), 8.16 (d, 1 H, J = 7.6 Hz), 8.14 (d, 1 H, J = 7.6 Hz) , 8.02 (d, 1 H, J = 7.2 Hz), 8.04 (d, 1 H, J = 8.4 Hz), 7.79-7.74 (m, 2 H), 7.69 (t, 1 H, J = 8.0 Hz), 7.58 (t, 1 H, J = 8.0 Hz), 7.54-7.49 (m, 2 H), 7.43 (t, 1 H, J = 7.6 Hz), 4.26 (brs, 2 H), 3.23 (brs, 4 H ), 3.06 (brs, 4 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 168.6, 168.3, 152.8, 137.5, 135.0, 134.8, 134.0, 132.8, 131.9, 131.3, 130.3, 129.2, 127.9, 127.3, 126.7, 126.5, 126.1, 126.0, 125.9 , 124.4, 124.0, 55.4, 48.2, 40.7.

N -(2- (4- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) -2- Naphthaamide  Hydrochloride [ N -(2- (4- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) -2-naphthamide hydrochloride] (41n)

White solid; Reaction time, 5 hours; Yield, 92%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.48 (s, 1 H, CONH), 9.63 (brs, 2 H, H ₂ N ⁺ ), 8.68 (s, 1 H), 8.26 (d, 1 H , J = 7.6 Hz), 8.21 (d, 1 H, J = 8.4 Hz), 8.16-8.08 (m, 4 H), 8.04 (d, 1 H, J = 8.0 Hz), 7.85 (d, 1 H, J = 7.2 Hz), 7.69-7.61 (m, 3 H), 7.52 (t, 1 H, J = 8.0 Hz), 7.45 (t, 1 H, J = 7.6 Hz), 4.63 (s, 2 H), 3.30 (brs, 4 H), 3.13 (brs, 4 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 167.9, 167.1, 152.9, 137.5, 135.4, 135.2, 132.9, 132.7, 132.6, 131.1, 130.8, 129.8, 129.3, 129.1, 128.8, 128.5, 127.8, 126.5, 126.4 , 126.2, 125.0, 124.5, 55.4, 48.1, 40.8.

N -(2- (4- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) quinoxaline-2- Kaboksami De Hydrochloride [ N -(2- (4- (Piperazin-1-ylmethyl) benzo [ d ] thiazol -2-yl) phenyl) quinoxaline-2-carboxamide hydrochloride] (41o)

White solid; Reaction time, 5 hours; Yield, 99%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.68 (s, 1 H, CONH), 9.61 (s, 1 H), 9.56 (brs, 2 H, H ₂ N ⁺ ), 8.81 (d, 1 H , J = 8.0 Hz), 8.32 (d, 1 H, J = 8.0 Hz), 8.20 (dd, 1 H, J = 7.2, 2.0 Hz), 8.08 (d, 1 H, J = 8.0 Hz), 8.05- 7.94 (m, 4 H), 7.67 (d, 1 H, J = 7.6 Hz), 7.62 (t, 1 H, J = 7.6 Hz), 7.39 (t, 1 H, J = 7.6 Hz), 4.88 (s , 2 H), 3.67 (brs, 4 H), 2.89 (brs, 4 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 169.2, 163.3, 153.7, 145.3, 143.8, 139.9, 137.0, 134.8, 133.0, 133.0, 132.5, 131.7, 130.1, 130.0, 126.7, 125.7, 124.9, 122.4, 122.1 , 55.8, 47.7, 40.8.

N -(2- (4- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl)-(1,1'- Biphenyl ] -4-carboxamide Hydrochloride [ N -(2- (4- (Piperazin-1-ylmethyl) benzo [ d ] thiazol -2-yl) phenyl)-[1,1'-biphenyl] -4-carboxamide hydrochloride] (41p)

White solid; Reaction time, 5 hours; Yield, 94.7%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.49 (s, 1 H, CONH), 9.37 (brs, 2 H, H ₂ N ⁺ ), 8.25 (d, 1 H, J = 8.0 Hz), 8.21 (d, 1 H, J = 7.6 Hz), 8.11 (d, 2 H, J = 8.4 Hz), 7.92 (d, 2 H, J = 8.4 Hz), 7.84 (m, 2 H), 7.79 (d, 2 H, J = 7.6 Hz), 7.65 (t, 1 H, J = 7.6 Hz), 7.51-7.50 (m, 3 H), 7.45-7.41 (m, 2 H), 4.71 (s, 2 H), 3.31 (brs, 8 H).

4- methyl - N -(2- (4- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) Benzenesulfonamide [4-Methyl- N -(2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzenesulfonamide] (41q)

White solid; Reaction time, 12 hours; Yield, 84%; ¹ H NMR (400 MHz, DMSO- d ₆ + a few drops of D ₂ O) δ 8.26 (d, 1 H, J = 8.0 Hz), 7.96 (d, 1 H, J = 7.6 Hz), 7.64 (d , 2 H, J = 8.0 Hz), 7.42 (d, 1 H, J = 7.6 Hz), 7.39 (d, 1 H, J = 8.4 Hz), 7.32 (t, 1 H, J = 8.0 Hz), 7.12 (d, 2 H, J = 8.0 Hz), 7.11 (t, 1 H, J = 8.0 Hz), 6.72 (t, 1 H, J = 7.2 Hz), 4.14 (s, 2 H), 3.03 (s, 4 H), 2.65 (s, 4 H,), 2.22 (s, 3 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 166.1, 151.5, 147.2, 143.1, 140.6, 136.9, 131.2, 130.2, 129.4, 128.7, 127.1, 126.9, 124.3, 122.9, 121.1, 119.7, 118.1, 58.1, 50.5 , 44.2, 21.5.

1-2. Synthesis of Compounds 42 to 49

As shown in Scheme 2 below, compounds 42 to 49 were synthesized.

[Scheme 2]

10) 6- Methyl benzo [ d ] Thiazole -2- Amine [6- Methylbenzo [ d ] thiazol -2-amine] (42)

p - toluidine (p -toluidine, 10.0 g, 93.3 mmol) acetic acid (15 mL) added to acetic acid (15 mL) solution containing KSCN (36.3 g, 373.2 mmol) into the solution for 30 minutes while stirring at room temperature, including After that, it was adjusted to 0 ° C, and a solution of acetic acid (20 mL) containing Br ₂ (5.1 mL, 93.3 mmol) was slowly added. The reaction mixture was stirred at room temperature for 2 hours, and the resulting solid was filtered by adding ice water, and the organic layer obtained by extracting the filtrate with ethyl acetate was dried over anhydrous MgSO ₄ , filtered, and the filtrate was concentrated under reduced pressure. Compound 42 was liberated from the HBr salt of 6-methylbenzo [ d ] thiazol-2-amine by adding 28% ammonia water into the obtained residue. The resulting solid was filtered and washed with a solvent of hexane: methylene chloride = 1: 1 to obtain compound 42. The residue obtained by concentrating the filtrate under reduced pressure in the filtration process was silica gel column chromatography (methylene chloride: ethyl acetate) = 6: 1) to give additional compound 42 (total yield: 48%, 7.4 g, yellow solid).

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.40 (d, 1 H, J = 8.0 Hz), 7.36 (s, 1 H), 7.09 (d, 1 H, J = 8.0 Hz), 5.29 (brs, 2 H,), 2.38 (s, 3 H); ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.42 (s, 1 H), 7.30 (s, 2 H), 7.19 (d, 1 H, J = 8.0 Hz), 6.99 (d, 1 H, J = 8.0 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 166.0, 149.6, 132.3, 131.5, 127.4, 121.2, 118.7, 21.4.

11) 2-Amino-5- Methylbenzenethiol [2-Amino-5- methylbenzenethiol ] (43)

Solid KOH (82.7 g, 1.5 mol) was added into a 1: 1 mixed solution of 2-methoxyethanol and water containing compound 42 (11.9 g, 72.5 mmol) and stirred at reflux for 36 hours. After cooling, acetic acid was added slowly to adjust the pH between 7 and 8 and the resulting solid was filtered. Methylene chloride was added to the obtained solid and filtered again, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: methylene chloride) to obtain compound 43 (4.7 g, 47%) .

¹ H NMR (500 MHz, CDCl ₃ ) δ 6.98 (d, 1 H, J = 8.0 Hz), 6.96 (s, 1 H), 6.64 (d, 1 H, J = 8.5 Hz), 4.11 (brs, 2 H), 2.14 (s, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 148.0, 136.3, 132.6, 125.2, 117.3, 115.6, 20.3.

12) 6- methyl -2- (2-nitrophenyl) benzo [ d ] Thiazole [6-Methyl-2- (2-nitrophenyl) benzo [ d ] thiazole] (44)

Na ₂ S ₂ O ₅ (9.6) into a DMF ( N , N- dimethylformamide, 30 mL) solution containing compound 43 (4.7 g, 33.8 mmol) and 2-nitrobenzaldehyde (5.1 g, 33.8 mmol). g, 50.6 mmol) was added and stirred at 80 ° C. for 5 hours. Water and diethyl ether were added, the organic layer was dried over anhydrous MgSO ₄ , filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: methylene chloride = 10: 1) to obtain Compound 44 (4.5 g, 48%) as a yellow solid.

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.95 (d, 1 H, J = 8.5 Hz), 7.88 (d, 1 H, J = 7.5 Hz), 7.79 (d, 1 H, J = 7.5 Hz), 7.72 (s, 1 H), 7.68 (t, 1 H, J = 7.5 Hz), 7.62 (t, 1 H, J = 7.5 Hz), 7.33 (d, 1 H, J = 8.5 Hz), 2.51 (s , 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 161.4, 152.0, 149.2, 136.4, 136.2, 132.5, 132.0, 131.0, 128.5, 128.3, 124.7, 123.6, 121.5, 21.8.

13) 6- ( Bromomethyl )-2- (2-nitrophenyl) benzo [ d ] Thiazole [6- ( Bromomethyl )-2- (2-nitrophenyl) benzo [ d ] thiazole] (45)

N -bromosuccinimide (NBS, 3.5 g, 19.7 mmol) and benzoyl peroxide (0.5 g, 2.1 mmol) into an anhydrous carbon tetrachloride (50 mL) solution containing compound 44 (4.4 g, 16.2 mmol) ) Was added slowly at room temperature, followed by stirring at reflux for 22 hours. Methylene chloride and water were added, the organic layer was dried over anhydrous MgSO ₄ , filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: methylene chloride = 7: 1) to obtain compound 45 (4.5 g, 69%) as a white solid.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.04 (d, 1 H, J = 8.5 Hz), 7.97 (d, 1 H, J = 1.5 Hz), 7.93 (dd, 1 H, J = 7.5, 1.0 Hz ), 7.79 (dd, 1 H, J = 8.0, 1.0 Hz), 7.71 (td, 1 H, J = 7.5, 1.5 Hz), 7.65 (td, 1 H, J = 7.5, 1.5 Hz), 7.55 (dd , 1 H, J = 8.5, 1.5 Hz), 4.65 (s, 2 H).

14) Turt - Butyl  4-((2- (2-nitrophenyl) benzo [ d ] Thiazole -6-day) methyl ) Piperazine-1- Carboxylate [ tert -Butyl 4-((2- (2-nitrophenyl) benzo [ d ] thiazol -6-yl) methyl) piperazine-1-carboxylate] (46)

Tert -butyl piperazine-1-carboxylate ( tert -butyl) into an anhydrous THF (30 mL) solution containing Compound 45 (4.5 g, 12.9 mmol) and anhydrous triethylamine (Et ₃ N, 5.4 mL, 38.7 mmol). Anhydrous THF (15 mL) solution containing piperazine-1-carboxylate, 1-Boc-piperazine) (2.8 g, 15.5 mmol) was slowly added. After stirring at room temperature for 8 hours, methylene chloride and water were added, the organic layer was dried over anhydrous MgSO ₄ , filtered, and the residue obtained by distilling the filtrate under reduced pressure was silica gel column chromatography (hexane: ethyl acetate = 2: Purification with 1) gave compound 46 (2.9 g, 50%) as a brown, sticky liquid.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.00 (d, 1 H, J = 8.5 Hz), 7.90-7.92 (m, 2 H), 7.79 (d, 1 H, J = 8.0 Hz), 7.69 (t , 1 H, J = 8.0 Hz), 7.63 (t, 1 H, J = 8.0 Hz), 7.48 (d, 1 H, J = 8.0 Hz), 3.67 (s, 2 H), 3.46 (brs, 4 H ), 2.45 (brs, 4 H), 1.45 (s, 9 H).

15) Turt - Butyl  4-((2- (2-aminophenyl) benzo [ d ] Thiazole -6-day) methyl ) Piperazine-1- Carboxylate [ tert -Butyl 4-((2- (2-aminophenyl) benzo [ d ] thiazol -6-yl) methyl) piperazine-1-carboxylate] (47)

compound 10 wt.% Pd / C (palladium on carbon, 150 mg) was added into a methylene chloride (53 mL) solution containing 46 (0.7 g, 1.5 mmol) and the air in the reaction vessel was replaced with hydrogen gas, and then at room temperature. Stir for 40 minutes. The reaction mixture was filtered using celite as the filter filler, and the filtrate was concentrated under reduced pressure to give compound 47 (0.5 g, 77%) as a yellow solid.

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.90 (d, 1 H, J = 8.0 Hz), 7.86 (s, 1 H), 7.69 (dd, 1 H, J = 8.0, 1.5 Hz), 7.42 (d , 1 H, J = 8.5 Hz), 7.21 (td, 1 H, J = 8.0, 1.5 Hz), 6.78 (d, 1 H, J = 8.0 Hz), 6.74 (td, 1 H, J = 8.0, 1.0 Hz), 6.38 (brs, 2 H), 3.67 (s, 2 H), 3.48 (brs, 4 H), 2.47 (brs, 4 H), 1.45 (s, 9 H).

16) Compound 48 (a to w) synthesis

To the anhydrous pyridine solution containing compound 47 (1 eq.), Appropriate acyl chloride (2.0 eq.) Or phenyl chloroformate (2.0 eq.) Was added, followed by stirring at room temperature. To the residue obtained by concentrating the reaction mixture under reduced pressure, methylene chloride and sodium bicarbonate were added, and the organic layer was dried over anhydrous MgSO ₄ and filtered, and the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (methylene chloride: methanol = Purification from 40: 1 to 80: 1) gave compounds 48 (a-w) .

Turt - Butyl  4-((2- (2-benzamidophenyl) benzo [ d ] Thiazole -6-day) methyl ) Piperazine-1- Car Succinate [ tert -Butyl 4-((2- (2-benzamidophenyl) benzo [ d ] thiazol -6-yl) methyl) piperazine-1-carboxylate] (48a)

White solid; Reaction time, 90 minutes; Yield, 81%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 13.33 (s, 1 H), 9.04 (d, 1 H, J = 8.0 Hz), 8.22-8.23 (m, 2 H), 7.89-7.94 (m, 3 H ), 7.57-7.61 (m, 3 H), 7.52-7.55 (m, 2 H), 7.20 (td, 1 H, J = 8.0, 1.0 Hz), 3.69 (brs, 2 H), 3.48 (brs, 4 H), 2.47 (brs, 4 H), 1.46 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.1, 166.5, 155.0, 152.3, 138.6, 136.6, 135.8, 133.8, 132.4, 132.1, 130.1, 128.9, 128.2, 128.0, 123.5, 122.1, 121.9, 121.1, 119.7, 79.9 , 63.0, 53.2, 43.7, 28.7.

Turt - Butyl  4-((2- (2- (2-methylbenzamido) phenyl) benzo [ d ] Thiazole -6-day) methyl ) Piperazine-1-carboxylate [ tert -Butyl 4-((2- (2- (2-methylbenzamido) phenyl) benzo [ d ] thiazol-6-yl) methyl) piperazine-1-carboxylate] (48b)

White solid; Reaction time, 4 hours; Yield, 77%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 13.00 (s, 1 H), 9.02 (d, 1 H, J = 8.5 Hz), 7.89 (dd, 1 H, J = 7.5, 1.0 Hz), 7.87 (s , 1 H), 7.81 (d, 1 H, J = 8.0 Hz), 7.68 (d, 1 H, J = 8.5 Hz), 7.53 (td, 1 H, J = 8.0, 1.5 Hz), 7.41-7.45 ( m, 2 H), 7.37 (t, 1 H, J = 8.0 Hz), 7.33 (d, 1 H, J = 8.0 Hz), 7.20 (td, 1 H, J = 7.5, 1.0 Hz), 3.63 (s , 2 H), 3.48 (brt, 4 H, J = 4.5 Hz), 2.42 (brt, 4 H, J = 4.5 Hz), 2.62 (s, 3 H), 1.45 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.9, 168.7, 155.0, 152.3, 138.6, 137.9, 136.9, 136.5, 133.7, 132.3, 131.8, 130.7, 130.0, 128.1, 127.8, 126.0, 123.5, 122.3, 121.7, 120.9 , 119.5, 79.9, 63.0, 53.2, 43.2, 28.7, 20.7.

Turt - Butyl  4-((2- (2- (3-methylbenzamido) phenyl) benzo [ d ] Thiazole -6-day) methyl ) Piperazine-1-carboxylate [ tert -Butyl 4-((2- (2- (3-methylbenzamido) phenyl) benzo [ d ] thiazol-6-yl) methyl) piperazine-1-carboxylate] (48c)

White solid; Reaction time, 4 hours; Yield, 95%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 13.27 (s, 1 H), 9.05 (d, 1 H, J = 9.0 Hz), 8.03 (d, 1 H, J = 8.0 Hz), 8.01 (s, 1 H), 7.95 (d, 1 H, J = 8.0 Hz), 7.89-7.92 (m, 2 H), 7.46-7.55 (m, 3 H), 7.42 (d, 1 H, J = 8.0 Hz), 7.20 (td, 1 H, J = 8.0, 1.5 Hz), 3.65 (s, 2 H), 3.46 (brs, 4 H), 2.42 (brs, 4 H), 2.53 (s, 3 H), 1.45 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.1, 166.7, 155.0, 152.4, 138.6, 138.6, 136.6, 135.8, 133.8, 132.9, 132.4, 130.1, 128.7, 128.7, 128.2, 125.1, 123.5, 122.1, 121.8, 121.1 , 119.7, 79.9, 63.1, 53.2, 43.6, 28.7, 21.8.

Turt - Butyl  4-((2- (2- (4-methylbenzamido) phenyl) benzo [ d ] Thiazole -6-day) methyl ) Piperazine-1-carboxylate [ tert -Butyl 4-((2- (2- (4-methylbenzamido) phenyl) benzo [ d ] thiazol-6-yl) methyl) piperazine-1-carboxylate] (48d)

White solid; Reaction time, 4 hours; Yield, 89%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 13.29 (s, 1 H), 9.04 (d, 1 H, J = 8.0 Hz), 8.13 (d, 2 H, J = 7.5 Hz), 7.95 (d, 1 H, J = 8.0 Hz), 7.90 (s, 1 H), 7.89 (d, 1 H, J = 8.0 Hz), 7.53 (t, 1 H, J = 8.0 Hz), 7.52 (d, 1 H, J = 8.0 Hz), 7.39 (d, 2 H, J = 8.5 Hz), 7.19 (t, 1 H, J = 8.0 Hz), 3.66 (s, 2 H), 3.46 (brt, 4 H, J = 4.5 Hz ), 2.48 (s, 3 H), 2.42 (brt, 4 H, J = 4.5 Hz), 1.46 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 166.5, 166.5, 155.0, 152.4, 142.6, 138.7, 133.8, 133.0, 132.4, 130.1, 129.6, 129.4, 128.3, 128.1, 123.4, 122.2, 121.9, 121.1, 119.6, 80.0 , 63.0, 53.1, 43.2, 28.7, 21.8.

Turt - Butyl  4-((2- (2- (3-fluorobenzamido) phenyl) benzo [ d ] Thiazole-6-day) methyl ) Piperazine-1-carboxylate [ tert -Butyl 4-((2- (2- (3-fluorobenzamido) phenyl) benzo [ d ] thiazol-6-yl) methyl) piperazine-1-carboxylate] (48e)

White solid; Reaction time, 2 hours; Yield, 91%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 13.40 (s, 1 H), 9.00 (dd, 1 H, J = 8.8, 0.8 Hz), 8.01 (td, 1 H, J = 7.6, 1.2 Hz), 7.95 -7.99 (m, 2 H), 7.88-7.91 (m, 2 H), 7.50-7.59 (m, 3 H), 7.31 (ddd, 1 H, J = 10.8, 8.0, 0.8 Hz), 7.20 (td, 1 H, J = 8.0, 1.2 Hz), 3.65 (s, 2 H), 3.45 (brt, 4 H, J = 4.4 Hz), 2.44 (brt, 4 H, J = 4.4 Hz), 1.45 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.0, 165.0, 163.1 (d, J = 245.8 Hz), 155.0, 152.2, 138.3, 138.0 (d, J = 6.8 Hz), 136.7, 133.7, 132.4, 130.5 (d , J = 7.6 Hz), 130.1, 128.4, 123.8 (d, J = 2.3 Hz), 123.8, 122.1, 121.8, 121.0, 119.7, 119.1 (d, J = 21.2 Hz), 115.0 (d, J = 23.5 Hz) , 79.9, 63.0, 53.2, 44.1, 28.7.

Turt - Butyl  4-((2- (2- (4-fluorobenzamido) phenyl) benzo [ d ] Thiazole-6-day) methyl ) Piperazine-1-carboxylate [ tert -Butyl 4-((2- (2- (4-fluorobenzamido) phenyl) benzo [ d ] thiazol-6-yl) methyl) piperazine-1-carboxylate] (48f)

White solid; Reaction time, 1.5 hours; Yield, 92%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 13.31 (s, 1 H), 9.00 (d, 1 H, J = 8.5 Hz), 8.21-8.25 (m, 2 H), 7.88-7.92 (m, 3 H ), 7.51-7.55 (m, 2 H), 7.24-7.29 (m, 2 H), 7.20 (brt, 1 H, J = 7.5 Hz), 3.67 (s, 2 H), 3.41 (brs, 4 H) , 2.45 (brs, 4 H), 1.45 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.2, 165.4, 165.3 (d, J = 250.3 Hz), 155.0, 152.3, 138.5, 133.8, 132.4, 132.0, 130.4 (d, J = 8.4 Hz), 130.1, 128.3 , 123.6, 122.0, 121.0, 119.6, 115.9 (d, J = 21.3 Hz), 80.0, 63.0, 53.2, 43.2, 28.7.

Tert - butyl 4-((2- (2- (2-bromobenzamido ) phenyl) benzo [ d ] thiazol-6-yl) methyl) piperazine-1-carboxylate [ tert -Butyl 4- ( (2- (2- (2-bromobenzamido) phenyl) benzo [ d ] thiazol-6-yl) methyl) piperazine-1-carboxylate] (48g)

White solid; Reaction time, 2 hours; Yield, 93%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 13.08 (s, 1 H), 8.99 (d, 1 H, J = 8.4 Hz), 7.88 (dd, 1 H, J = 8.0, 1.2 Hz), 7.86 (s , 1 H), 7.72-7.75 (m, 2 H), 7.60 (d, 1 H, J = 8.4 Hz), 7.54 (td, 1 H, J = 8.0, 1.2 Hz), 7.47 (dt, 1 H, J = 7.6, 1.2 Hz), 7.36-7.41 (m, 2 H), 7.22 (td, 1 H, J = 7.6, 1.2 Hz), 3.62 (s, 2 H), 3.43 (brt, 4 H, J = 4.8 Hz), 2.41 (brt, 4 H, J = 4.8 Hz), 1.45 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.5, 166.7, 155.0, 152.2, 138.8, 138.1, 136.5, 134.2, 133.7, 132.3, 131.7, 130.0, 129.6, 128.1, 127.6, 124.0, 122.4, 121.7, 121.2, 120.4 , 119.7, 79.9, 63.0, 53.2, 43.7, 28.7.

Turt - Butyl  4-((2- (2- (3-bromobenzamido) phenyl) benzo [ d ] Thiazole-6-yl) methyl) piperazin-1-carboxylate [ tert -Butyl 4-((2- (2- (3-bromobenzamido) phenyl) benzo [ d ] thiazol-6-yl) methyl) piperazine-1-carboxylate] (48h)

Yellow solid; Reaction time, 3 hours; Yield, 76%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 13.35 (s, 1 H), 9.01 (d, 1 H, J = 9.0 Hz), 8.38 (s, 1 H), 8.13-8.16 (m, 2 H), 7.90-7.92 (m, 2 H), 7.73 (dd, 1 H, J = 8.5, 2.0 Hz), 7.52-7.55 (m, 2 H), 7.46 (t, 1 H, J = 8.5 Hz), 7.21 ( t, 1 H, J = 8.0 Hz), 3.68 (brs, 2 H), 3.48 (brs, 4 H), 2.47 (brs, 4 H), 1.46 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.0, 164.8, 155.0, 152.3, 138.2, 137.7, 136.6, 135.0, 133.6, 132.4, 130.6, 130.6, 130.1, 128.3, 127.2, 123.8, 123.0, 122.6, 121.8, 121.1 , 119.7, 79.9, 63.0, 53.2, 43.4, 28.7.

Turt - Butyl  4-((2- (2- (4-bromobenzamido) phenyl) benzo [ d ] Thiazole-6-yl) methyl) piperazin-1-carboxylate [ tert -Butyl 4-((2- (2- (4-bromobenzamido) phenyl) benzo [ d ] thiazol-6-yl) methyl) piperazine-1-carboxylate] (48i)

White solid; Reaction time, 2 hours; Yield, 98%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 13.28 (s, 1 H), 8.93 (d, 1 H, J = 8.4 Hz), 8.02 (d, 2 H, J = 8.4 Hz), 7.81-7.85 (m , 3 H), 7.66 (d, 2 H, J = 8.4 Hz), 7.48 (d, 1 H, J = 7.6 Hz), 7.47 (t, 1 H, J = 7.6 Hz), 7.14 (t, 1 H , J = 7.6 Hz), 3.63 (brs, 2 H), 3.44 (brs, 4 H), 2.42 (brs, 4 H), 1.42 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.1, 165.4, 155.0, 152.2, 138.3, 136.8, 134.7, 133.7, 132.4, 132.1, 130.1, 129.6, 128.3, 126.9, 123.7, 122.0, 121.8, 121.0, 119.6, 79.9 , 63.0, 53.2, 43.7, 28.6.

Turt - Butyl  4-((2- (2- (3-chlorobenzamido) phenyl) benzo [ d ] Thiazole-6-yl) methyl) piperazin-1-carboxylate [ tert -Butyl 4-((2- (2- (3-chlorobenzamido) phenyl) benzo [ d ] thiazol-6-yl) methyl) piperazine-1-carboxylate] (48j)

White solid; Reaction time, 1.5 hours; Yield, 93%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 13.37 (s, 1 H), 9.01 (d, 1 H, J = 8.5 Hz), 8.24 (s, 1 H), 8.08-8.11 (m, 2 H), 7.90 (s, 1 H), 7.89 (d, 1 H, J = 7.5 Hz), 7.58 (d, 1 H, J = 8.0 Hz), 7.50-7.54 (m, 3 H), 7.20 (t, 1 H , J = 7.5 Hz), 3.67 (brs, 2 H), 3.47 (brs, 4 H), 2.46 (brs, 4 H), 1.46 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.9, 164.6, 154.7, 152.1, 138.1, 137.3, 136.1, 134.7, 133.4, 132.2, 131.8, 130.1, 129.8, 128.2, 127.5, 126.4, 123.6, 122.2, 121.6, 120.8 , 119.5, 79.7, 62.7, 52.9, 43.5, 28.4.

Turt - Butyl  4-((2- (2- (3-nitrobenzamido) phenyl) benzo [ d ] Thiazole-6-yl) methyl) piperazin-1-carboxylate [ tert -Butyl 4-((2- (2- (3-nitrobenzamido) phenyl) benzo [ d ] thiazol-6-yl) methyl) piperazine-1-carboxylate] (48k)

White solid; Reaction time, 40 minutes; Yield, 74%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 13.38 (s, 1 H), 8.97 (t, 1 H, J = 1.6 Hz), 8.93 (d, 1 H, J = 8.8 Hz), 8.50 (dt, 1 H, J = 8.0, 1.2 Hz), 8.41 (ddd, 1 H, J = 8.0, 1.6, 1.2 Hz), 8.00 (d, 1 H, J = 8.4 Hz), 7.82-7.84 (m, 2 H), 7.72 (t, 1 H, J = 8.0 Hz), 7.45-7.47 (m, 2 H), 7.16 (t, 1 H, J = 8.0 Hz), 3.62 (brs, 2 H), 3.43 (brs, 4 H ), 2.42 (brs, 4 H), 1.42 (s, 9 H).

Turt - Butyl  4-((2- (2- (4-nitrobenzamido) phenyl) benzo [ d ] Thiazole-6-yl) methyl) piperazin-1-carboxylate [ tert -Butyl 4-((2- (2- (4-nitrobenzamido) phenyl) benzo [ d ] thiazol-6-yl) methyl) piperazine-1-carboxylate] (48l)

Yellow solid; Reaction time, 3 hours; Yield, 80%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 13.54 (s, 1 H), 9.00 (d, 1 H, J = 8.0 Hz), 8.44 (dd, 2 H, J = 9.0, 2.0 Hz), 8.37 (dd , 2 H, J = 9.0, 2.0 Hz), 7.98 (brs, 1 H), 7.92 (d, 1 H, J = 8.0 Hz), 7.90 (d, 1 H, J = 8.0 Hz), 7.57 (d, 1 H, J = 8.0 Hz), 7.56 (t, 1 H, J = 7.5 Hz), 7.26 (t, 1 H, J = 8.0 Hz), 3.72 (brs, 2 H), 3.50 (brs, 4 H) , 2.49 (brs, 4 H), 1.46 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.1, 164.1, 155.0, 152.1, 150.0, 141.4, 137.9, 136.9, 132.5, 130.1, 129.1, 128.6, 124.3, 124.1, 122.0, 121.9, 121.1, 119.8, 80.0, 62.9 , 53.2, 43.7, 28.7.

Turt - Butyl  4-((2- (2- (3,4,5-trimethoxybenzamido) phenyl) benzo [ d ] Thiazole -6-yl) -methyl) piperazin-1-carboxylate [ tert -Butyl 4-((2- (2- (3,4,5-trimethoxybenzamido) phenyl) benzo [ d ] thiazol-6-yl) -methyl) piperazine-1-carboxylate] (48m)

White solid; Reaction time, 40 minutes; Yield, 74%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 13.12 (s, 1 H), 8.97 (d, 1 H, J = 8.0 Hz), 7.92 (brs, 1 H), 7.89 (d, 1 H, J = 7.5 Hz), 7.89 (d, 1 H, J = 8.0 Hz), 7.53 (td, 1 H, J = 7.5, 1.5 Hz), 7.47 (d, 1 H, J = 8.5 Hz), 7.39 (s, 2 H ), 7.19 (td, 1 H, J = 8.0, 1.0 Hz), 3.97 (s, 3 H), 3.96 (s, 6 H), 3.66 (brs, 2 H), 3.47 (brs, 4 H), 2.45 (brs, 4 H), 1.45 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.2, 166.6, 155.0, 153.6, 152.3, 142.0, 138.5, 136.7, 133.7, 132.4, 131.7, 130.1, 128.2, 123.6, 122.2, 121.8, 121.0, 119.6, 106.2, 79.9 , 63.0, 61.3, 57.1, 53.2, 43.4, 28.7.

Turt - Butyl  4-((2- (2- (2,4-dichlorobenzamido) phenyl) benzo [ d ] Thiazole-6-day) Me Tyl) piperazin-1-carboxylate [ tert -Butyl 4-((2- (2- (2,4-dichlorobenzamido) phenyl) benzo [ d ] thiazol-6-yl) methyl) piperazine-1-carboxylate] (48n)

White solid; Reaction time, 4 hours; Yield, 82%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 13.13 (s, 1 H), 8.95 (d, 1 H, J = 8.5 Hz), 7.89 (dd, 1 H, J = 7.5, 1.5 Hz), 7.88 (s , 1 H), 7.74 (d, 1 H, J = 8.5 Hz), 7.67 (d, 1 H, J = 8.0 Hz), 7.57 (d, 1 H, J = 1.5 Hz), 7.54 (td, 1 H , J = 8.0, 1.5 Hz), 7.45 (dd, 1 H, J = 8.5, 1.5 Hz), 7.41 (dd, 1 H, J = 8.5, 2.0 Hz), 7.24 (td, 1 H, J = 8.0, 1.5 Hz), 3.64 (brs, 2 H), 3.44 (brt, 4 H, J = 4.5 Hz), 2.42 (brt, 4 H, J = 4.5 Hz), 1.45 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.5, 164.8, 155.0, 152.2, 137.9, 137.1, 135.2, 133.7, 133.0, 132.3, 130.9, 130.8, 130.0, 128.2, 127.5, 124.1, 122.4, 121.7, 121.3, 119.8 , 79.9, 63.0, 53.2, 43.6, 28.7.

Tert - butyl 4-((2- (2- (3,4-dichlorobenzamido) phenyl) benzo [ d ] thiazol-6-yl) methyl ) piperazine-1-carboxylate [ tert- Butyl 4 -((2- (2- (3,4-dichlorobenzamido) phenyl) benzo [ d ] thiazol-6-yl) methyl) piperazine-1-carboxylate] (48o)

White solid; Reaction time, 4 hours; Yield, 68%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 13.41 (s, 1 H), 8.99 (d, 1 H, J = 8.5 Hz), 8.36 (d, 1 H, J = 2.0 Hz), 8.05-8.08 (m , 2 H), 7.92 (d, 1 H, J = 8.0 Hz), 7.91 (s, 1 H), 7.66 (d, 1 H, J = 8.0 Hz), 7.51-7.56 (m, 2 H), 7.23 (t, 1 H, J = 8.0 Hz), 3.66 (brs, 2 H), 3.46 (brt, 4 H, J = 4.5 Hz), 2.45 (brt, 4 H, J = 4.5 Hz), 1.46 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.9, 163.8, 154.8, 152.0, 137.9, 136.3, 135.3, 133.4, 133.0, 132.2, 130.8, 129.9, 129.4, 128.2, 127.4, 123.7, 122.1, 121.6, 120.8, 119.5 , 79.7, 62.8, 53.0, 43.7, 28.4.

Turt - Butyl  4-((2- (2- (nicotinamido) phenyl) benzo [ d ] Thiazole -6-day) methyl ) Piperazine-1-carboxylate [ tert -Butyl 4-((2- (2- (nicotinamido) phenyl) benzo [ d ] thiazol -6-yl) methyl) piperazine-1-carboxylate] (48p)

Yellow solid; Reaction time, 40 minutes; Yield, 61%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 13.51 (s, 1 H), 9.50 (s, 1 H), 9.00 (d, 1 H, J = 8.5 Hz), 8.84 (m, 1 H), 8.48 ( m, 1 H), 8.01 (d, 1 H, J = 8.5 Hz), 7.97 (brs, 1 H), 7.92 (d, 1 H, J = 8.0 Hz), 7.52-7.57 (m, 3 H), 7.23 (t, 1 H, J = 7.5 Hz), 3.73 (brs, 2 H), 3.51 (brs, 4 H), 2.50 (brs, 4 H), 1.46 (s, 9 H).

Turt - Butyl  4-((2- (2- (1-naphthaamido) phenyl) benzo [ d ] Thiazole -6-day) methyl ) Piperazine-1-carboxylate [ tert -Butyl 4-((2- (2- (1-naphthamido) phenyl) benzo [ d ] thiazol -6-yl) methyl) piperazine-1-carboxylate] (48q)

White solid; Reaction time, 1.5 hours; Yield, 93%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 13.28 (s, 1 H), 9.14 (d, 1 H, J = 9.0 Hz), 8.66 (m, 1 H), 8.03-8.06 (m, 2 H), 7.95 (m, 1 H), 7.90 (d, 1 H, J = 7.5 Hz), 7.85 (s, 1 H), 7.62 (t, 1 H, J = 8.5 Hz) 7.55-7.59 (m, 3 H) , 7.41 (d, 1 H, J = 8.5 Hz), 7.36 (d, 1 H, J = 8.5 Hz), 7.23 (t, 1 H, J = 8.0 Hz), 3.62 (brs, 2 H), 3.45 ( brs, 4 H), 2.43 (brs, 4 H), 1.45 (s, 9 H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 168.4, 168.2, 154.7, 152.0, 138.4, 136.2, 134.9, 134.0, 133.4, 132.1, 131.4, 130.6, 129.8, 128.3, 127.8, 127.2, 126.4, 126.1, 125.8, 124.6 , 123.4, 122.1, 121.4, 120.8, 119.4, 79.7, 62.8, 52.9, 43.1, 28.4.

Turt - Butyl  4-((2- (2- (2-naphthaamido) phenyl) benzo [ d ] Thiazole -6-day) methyl ) Piperazine-1-carboxylate [ tert -Butyl 4-((2- (2- (2-naphthamido) phenyl) benzo [ d ] thiazol -6-yl) methyl) piperazine-1-carboxylate] (48r)

White solid; Reaction time, 1.5 hours; Yield, 91%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 13.49 (s, 1 H), 9.10 (d, 1 H, J = 9.0 Hz), 8.71 (s, 1 H), 8.28 (d, 1 H, J = 9.0 Hz), 8.03-8.06 (m, 2 H), 7.98 (d, 1 H, J = 8.0 Hz), 7.90-7.96 (m, 3 H), 7.60-7.64 (m, 2 H), 7.53-7.57 ( m, 2 H), 7.21 (t, 1 H, J = 7.5 Hz), 3.68 (brs, 2 H), 3.48 (brs, 4 H), 2.47 (brs, 4 H), 1.46 (s, 9 H) ; ¹³ C NMR (100 MHz, CDCl ₃ ) δ 166.6, 155.0, 152.4, 143.5, 138.7, 136.5, 135.3, 133.8, 133.2, 133.1, 132.4, 130.1, 129.3, 128.7, 128.3, 128.1, 127.1, 124.5, 123.6, 122.2 , 121.9, 121.1, 119.7, 79.9, 63.0, 53.2, 43.2, 28.7.

Turt - Butyl  4-((2- (2- (quinoxaline-2-carboxamido) phenyl) benzo [ d ] Thiazole-6-day)- Me Tyl) piperazin-1-carboxylate [ tert -Butyl 4-((2- (2- (quinoxaline-2-carboxamido) phenyl) benzo [ d ] thiazol-6-yl) -methyl) piperazine-1-carboxylate] (48s)

White solid; Reaction time, 3 hours; Yield, 76%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 13.90 (s, 1 H), 9.78 (s, 1 H), 9.07 (d, 1 H, J = 8.5 Hz), 8.36 (d, 1 H, J = 7.5 Hz), 8.25 (d, 1 H, J = 8.5 Hz), 8.19 (d, 1 H, J = 8.5 Hz), 7.91-7.97 (m, 4 H), 7.56-7.61 (m, 2 H), 7.26 (t, 1 H, J = 8.0 Hz), 3.73 (brs, 2 H), 3.50 (brs, 4 H), 2.51 (brs, 4 H), 1.45 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.3, 163.3, 155.0, 153.0, 145.2, 144.7, 144.0, 140.8, 137.3, 136.3, 134.3, 132.1, 131.9, 131.2, 130.4, 130.0, 130.0, 128.1, 124.3, 122.8 , 122.0, 121.7, 121.1, 80.0, 63.1, 53.2, 44.1, 28.7.

Turt - Butyl  4-((2- (2- ([1,1'- Biphenyl ]-4- Ilka Copy Mido ) Phenyl) Benzo [ d ] Thiazole -6-yl) methyl) piperazin-1-carboxylate [ tert -Butyl 4-((2- (2-([1,1'-biphenyl] -4-ylcarboxamido) phenyl) benzo [ d ] thiazol-6-yl) methyl) piperazine-1-carboxylate] (48t)

White solid; Reaction time, 40 minutes; Yield, 72%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 13.37 (s, 1 H), 9.07 (d, 1 H, J = 8.5 Hz), 8.30 (d, 2 H, J = 8.0 Hz), 7.97 (d, 1 H, J = 8.5 Hz), 7.94 (brs, 1 H), 7.90 (d, 1 H, J = 7.5 Hz), 7.81 (d, 2 H, J = 8.0 Hz), 7.70 (d, 2 H, J = 7.5 Hz), 7.50-7.56 (m, 4 H), 7.43 (t, 1 H, J = 7.5 Hz), 7.20 (t, 1 H, J = 7.5 Hz), 3.71 (brs, 2 H), 3.50 (brs, 4 H), 2.50 (brs, 4 H), 1.45 (s, 9 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.2, 166.3, 155.0, 152.4, 144.9, 140.3, 138.6, 134.5, 133.8, 132.4, 130.1, 129.2, 128.6, 128.3, 127.6, 127.6, 123.5, 122.1, 121.9, 121.1 , 119.6, 80.0, 63.0, 53.1, 43.6, 28.7.

Tert - butyl 4-((2- (2- (cyclohexanecarboxamido) phenyl) benzo [ d ] thiazol-6-yl) methyl ) piperazine-1-carboxylate [ tert- Butyl 4-(( 2- (2- (cyclohexanecarboxamido) phenyl) benzo [ d ] thiazol-6-yl) methyl) piperazine-1-carboxylate] (48u)

White solid; Reaction time, 40 minutes; Yield, 76%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 12.39 (s, 1 H), 8.82 (d, 1 H, J = 8.0 Hz), 7.86-7.88 (m, 2 H), 7.80 (d, 1 H, J = 7.5 Hz), 7.48 (d, 1 H, J = 8.5 Hz), 7.43 (t, 1 H, J = 8.0 Hz), 7.11 (t, 1 H, J = 7.5 Hz), 3.66 (brs, 2 H ), 3.46 (brs, 4 H), 2.46 (brs, 4 H), 2.43 (m, 1 H), 2.15 (m, 2 H), 1.90 (m, 2 H), 1.76 (m, 1 H), 1.65 (m, 2 H), 1.45 (s, 9 H), 1.24-1.45 (m, 3 H).

(E) - Turt - Butyl  4-((2- (2-cinnamamidophenyl) benzo [ d ] Thiazole -6-day) methyl ) Piperazine-1-carboxylate [ (E) - tert -Butyl 4-((2- (2-cinnamamidophenyl) benzo [ d ] thiazol -6-yl) methyl) piperazine-1-carboxylate] (48v)

Yellow solid; Reaction time, 40 minutes; Yield, 91%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 12.75 (s, 1 H), 8.94 (d, 1 H, J = 8.5 Hz), 7.96 (d, 1 H, J = 8.5 Hz), 7.89 (s, 1 H), 7.85 (dd, 1 H, J = 8.0, 1.5 Hz), 7.79 (d, 1 H, J = 16.0 Hz), 7.61 (d, 2 H, J = 8.0 Hz), 7.39-7.52 (m, 5 H), 7.15 (t, 1 H, J = 8.5 Hz), 6.69 (d, 1 H, J = 16.0 Hz), 3.66 (brs, 2 H), 3.47 (brs, 4 H), 2.45 (brs, 4 H), 1.46 (s, 9 H).

Turt - Butyl  4-((2- (2- (phenoxycarbonylamino) phenyl) benzo [ d ] Thiazole-6-yl) methyl) piperazin-1-carboxylate [ tert -Butyl 4-((2- (2- (phenoxycarbonylamino) phenyl) benzo [ d ] thiazol-6-yl) methyl) piperazine-1-carboxylate] (48w)

White solid; Reaction time, 40 minutes; Yield, 42%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 12.33 (s, 1 H), 8.55 (d, 1 H, J = 8.0 Hz), 8.02 (d, 1 H, J = 8.5 Hz), 7.89 (s, 1 H), 7.86 (d, 1 H, J = 7.5 Hz), 7.41-7.49 (m, 5 H), 7.26 (d, 2 H, J = 8.0 Hz), 7.15 (t, 1 H, J = 7.5 Hz ), 3.66 (brs, 2 H), 3.47 (brs, 4 H), 2.45 (brs, 4 H), 1.46 (s, 9 H).

17) Synthesis of Compound 49 (a to w)

Method for synthesizing a non-salt compound (free acid compound): Compound 48 (1 eq.) Was dissolved in an appropriate amount of methylene chloride, and 1N-HCl acetic acid solution (using the same amount as methylene chloride) was added and stirred at room temperature. 2N-NaOH aqueous solution was added to adjust the pH to neutral, and then methylene chloride and water were added. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography using methylene chloride and methanol as a developing solvent to give Compound 49 (a to w) as a free acid form. Got into.

Compound in the form of HCl salt: 1,4-dioxane and 8N-HCl (42.0 eq.) In a volume corresponding to 8N-HCl (42.0 eq.) Are added sequentially into compound 48 (1 eq.), And then the reaction mixture. Was stirred at room temperature. It was concentrated under reduced pressure to remove the solvent, and the remaining residue was filtered by adding diethyl ether in the presence of a small amount of methanol or in the absence of methanol to obtain compound 49 as an HCl salt.

Compound in the form of a trifluoroacetic acid (TFA) salt: Compound 48h is reacted in a methylene chloride solution containing trifluoroacetic acid (30 equivalents), and the residue obtained by concentration under reduced pressure is recrystallized from diethyl ether and a small amount of methanol to give compound 49 Was obtained in the form of TFA salt.

N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide [ N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide] (49a)

White solid; Reaction time, 12 hours; Yield, 74%; ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 13.12 (brs, 1 H), 8.73 (d, 1 H, J = 8.0 Hz), 8.52 (d, 2 H, J = 8.5 Hz), 8.32 (d , 2 H, J = 8.5 Hz), 8.07-8.01 (m, 4 H), 7.60 (t, 1 H, J = 8.0 Hz), 7.54 (d, 1 H, J = 8.0 Hz), 7.33 (t, 1 H, J = 7.5 Hz), 3.57 (s, 2 H), 2.72 (brs, 4 H), 2.34 (brs, 4 H).

N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol -2-yl) phenyl) benzamide hydrochloride [ N- (2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] ( 49aa )

White solid; Reaction time, 4 hours; Yield, 80%; ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 12.82 (s, 1 H), 9.42 (brs, 2 H), 8.72 (d, 1 H, J = 7.5 Hz), 8.37 (s, 1 H), 8.07-8.13 (m, 4 H), 7.82 (d, 1 H, J = 8.5 Hz), 7.69-7.70 (m, 3 H), 7.64 (t, 1 H, J = 8.0 Hz), 7.34 (t, 1 H, J = 7.5 Hz), 4.44 (s, 2 H), 3.43 (brs, 8 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 169.9, 166.0, 152.8, 137.5, 134.7, 133.9, 133.0, 130.7, 130.3, 129.6, 127.7, 125.0, 122.6, 121.6, 120.4, 59.9, 48.2, 41.3.

2- methyl - N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide hydrochloride [2-Methyl- N -(2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] ( 49bb )

White solid; Reaction time, 6 hours; Yield, 100%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.77 (s, 1 H), 9.59 (brs, 2 H), 8.73 (d, 1 H, J = 7.6 Hz), 8.42 (brs, 1 H), 8.07 (d, 1 H, J = 8.0 Hz), 8.06 (d, 1 H, J = 8.4 Hz), 7.85-7.93 (m, 3 H), 7.63 (t, 1 H, J = 7.6 Hz), 7.58 (t, 1 H, J = 7.6 Hz), 7.50 (d, 1 H, J = 7.2 Hz), 7.33 (t, 1 H, J = 7.6 Hz), 4.46 (s, 2 H), 3.43 (brs, 8 H), 2.46 (s, 3 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 170.2, 166.1, 153.2, 139.1, 138.2, 135.3, 134.0, 133.6, 133.2, 131.1, 130.0, 128.5, 125.1, 124.9, 122.7, 121.8, 120.6, 59.3, 48.2 , 41.2, 21.8.

3- methyl - N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide hydrochloride [3-Methyl- N -(2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49cc)

White solid; Reaction time, 4 hours; Yield, 56%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.38 (s, 1 H), 9.57 (brs, 2 H), 8.65 (d, 1 H, J = 8.0 Hz), 8.39 (brs, 1 H), 8.04 (d, 1 H, J = 8.4 Hz), 7.76-7.79 (m, 3 H), 7.63 (t, 1 H, J = 8.0 Hz), 7.43-7.50 (m, 2 H), 7.37 (d, 1 H, J = 7.6 Hz), 7.34 (t, 1 H, J = 7.6 Hz), 4.46 (brs, 2 H), 3.39 (brs, 8 H), 2.44 (s, 3 H).

4- methyl - N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide hydrochloride [4-Methyl- N -(2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] ( 49dd )

White solid; Reaction time, 4 hours; Yield, 77%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.80 (s, 1 H), 9.56 (brs, 2 H), 8.74 (d, 1 H, J = 8.0 Hz), 8.41 (s, 1 H), 8.10 (d, 1 H, J = 8.0 Hz), 8.60 (d, 1 H, J = 7.6 Hz), 8.02 (d, 2 H, J = 7.2 Hz), 7.86 (d, 1 H, J = 8.4 Hz) ), 7.62 (t, 1 H, J = 7.6 Hz), 7.50 (d, 2 H, J = 7.6 Hz), 7.32 (t, 1 H, J = 7.6 Hz), 4.48 (brs, 2 H), 3.39 (brs, 8 H), 2.43 (s, 3 H).

3- Fluoro - N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide Hydrochloride [3- Fluoro - N -(2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol -2-yl) phenyl) benzamide hydrochloride] ( 49ee )

White solid; Reaction time, 6 hours; Yield, 83%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.78 (s, 1 H), 9.28 (brs, 2 H), 8.62 (d, 1 H, J = 8.0 Hz), 8.31 (brs, 1 H), 8.01-8.06 (m, 2 H), 7.93 (d, 1 H, J = 7.6 Hz), 7.82 (d, 1 H, J = 9.6 Hz), 7.70-7.77 (m, 2 H), 7.62 (t, 1 H, J = 8.0 Hz), 7.53 (td, 1 H, J = 8.4, 2.0 Hz), 7.34 (t, 1 H, J = 8.4 Hz), 4.41 (brs, 2 H), 3.35 (brs, 4 H), 3.32 (brs, 4 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 170.1, 164.6, 162.9 (d, J = 244.3 Hz), 137.6, 137.5 (d, J = 6.8 Hz), 134.1, 132.3, 132.1 (d, J = 9.7 Hz), 131.0, 130.7, 125.8, 125.4, 124.1 (d, J = 2.3 Hz), 122.6, 121.9, 120.9, 120.0 (d, J = 21.2 Hz), 114.9 (d, J = 22.3 Hz), 59.3, 48.3 , 41.2.

4- Fluoro - N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide Hydrochloride [4- Fluoro - N -(2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol -2-yl) phenyl) benzamide hydrochloride] ( 49ff )

White solid; Reaction time, 5 hours; Yield, 98%; ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 12.76 (s, 1 H), 9.60 (brs, 2 H), 8.69 (d, 1 H, J = 8.5 Hz), 8.41 (brs, 1 H), 8.18 (dd, 2 H, J = 9.0, 5.5 Hz), 8.15 (d, 1 H, J = 8.5 Hz), 8.08 (d, 1 H, J = 7.5 Hz), 7.83 (d, 1 H, J = 8.0 Hz), 7.63 (td, 1 H, J = 7.5, 1.5 Hz), 7.55 (t, 2 H, J = 9.0 Hz), 7.34 (t, 1 H, J = 7.5 Hz), 4.49 (brs, 2 H), 3.35 (brs, 8 H); ¹³ C NMR (125 MHz, DMSO- d ₆ ) δ 169.4, 164.5 (d, J = 248.8 Hz), 164.3, 152.5, 137.4, 133.3, 132.6, 131.1, 130.4, 130.1 (d, J = 8.4 Hz), 127.5 , 125.5, 125.0, 124.5, 122.5, 121.4, 120.3, 116.2 (d, J = 22.1 Hz), 58.9, 47.7, 41.2.

2- Bromo - N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide hydrochloride [2-Bromo- N -(2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] ( 49gg )

White solid; Reaction time, 4 hours; Yield, 84%; ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 12.32 (s, 1 H), 9.59 (brs, 2 H), 8.50 (d, 1 H, J = 8.0 Hz), 8.26 (s, 1 H), 8.03 (d, 1 H, J = 7.5 Hz), 7.77 (d, 1 H, J = 8.0 Hz), 7.73 (d, 1 H, J = 7.5 Hz), 7.70 (d, 1 H, J = 8.0 Hz) ), 7.61-7.65 (m, 2 H), 7.58 (t, 1 H, J = 7.5 Hz), 7.50 (t, 1 H, J = 8.0 Hz), 7.37 (t, 1 H, J = 8.0 Hz) , 4.34 (s, 2 H), 3.30 (brs, 4 H), 3.23 (brs, 4 H).

3- Bromo - N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide [3-Bromo- N -(2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide] (49h)

Yellow solid; Reaction time, 3 hours; Yield, 22%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.84 (brs, 1 H), 8.70 (d, 1 H, J = 8.4 Hz), 8.20 (s, 1 H), 8.07-8.02 (m, 3 H ), 7.98 (d, 1 H, J = 7.6 Hz), 7.85 (d, 1 H, J = 7.2 Hz), 7.61 (t, 1 H, J = 8.0 Hz), 7.55 (t, 1 H, J = 8.0 Hz), 7.49 (d, 1 H, J = 8.4 Hz), 7.27 (t, 1 H, J = 8.4 Hz), 3.52 (s, 2 H), 2.64 (brs, 4 H), 2.27 (brs, 4 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 168.6, 164.3, 151.9, 137.7, 137.4, 135.6, 133.7, 132.8, 132.0, 130.8, 130.5, 128.8, 127.3, 125.0, 122.9, 122.7, 122.4, 121.5, 120.7 , 63.2, 54.7, 46.2.

3- Bromo - N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide hydrochloride [3-Bromo- N -(2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] ( 49hh )

White solid; Reaction time, 6 hours; Yield, 74%; ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 12.76 (s, 1 H), 9.66 (brs, 2 H), 8.67 (d, 1 H, J = 8.0 Hz), 8.41 (s, 1 H), 8.21 (s, 1 H), 8.13 (dd, 1 H, J = 8.0, 2.0 Hz), 8.04-8.07 (m, 2 H), 7.85-7.89 (m, 2 H), 7.60-7.67 (m, 2 H), 7.33 (t, 1 H, J = 8.0 Hz), 4.48 (s, 2 H), 3.39 (brs, 8 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 170.1, 164.4, 153.1, 137.9, 137.4, 135.7, 133.9, 133.2, 132.1, 131.0, 130.8, 130.5, 128.6, 128.2, 127.3, 125.9, 125.3, 122.9, 122.0 , 120.9, 59.1, 48.2, 41.2.

3- Bromo - N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide 2,2,2-trifluoroacetate [3-Bromo- N -(2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide 2,2,2- trifluoroacetate ] (49hhh)

solid; Reaction time, 6 hours; Yield, 99%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.86 (s, 1 H), 8.84 (brs, 2 H), 8.70 (d, 1 H, J = 8.8 Hz), 8.24 (t, 1 H, J = 1.2 Hz), 8.20 (s, 1 H), 8.13 (d, 1 H, J = 8.4 Hz), 8.09 (d, 1 H, J = 7.6 Hz), 8.05 (dd, 1 H, J = 8.0, 1.2 Hz), 7.90 (dd, 1 H, J = 8.0, 1.2 Hz), 7.66-7.60 (m, 3 H), 7.33 (t, 1 H, J = 8.0 Hz), 4.00 (s, 2 H), 3.19 (brs, 4 H), 2.88 (brs, 4 H).

4- Bromo - N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide [4-Bromo- N -(2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide] (49i)

White solid; Reaction time, 12 hours; Yield, 62%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.99 (s, 1 H), 8.71 (d, 1 H, J = 8.4 Hz), 8.03-7.98 (m, 5 H), 7.89 (d, 2 H , J = 7.2 Hz), 7.56 (t, 1 H, J = 8.4 Hz), 7.52 (d, 1 H, J = 7.6 Hz), 7.28 (t, 1 H, J = 7.2 Hz), 3.54 (s, 2 H), 2.65 (brs, 4 H), 2.29 (brs, 4 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 168.5, 164.9, 151.9, 137.9, 137.7, 134.4, 133.6, 132.8, 130.8, 130.0, 129.7, 129.3, 129.0, 126.9, 125.0, 122.6, 121.5, 120.6, 63.2 , 54.6, 46.2.

4- Bromo - N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide hydrochloride [4-Bromo- N -(2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49ii)

White solid; Reaction time, 6 hours; Yield, 82%; ¹ H NMR (400 MHz, D ₂ O + DMSO- d ₆ ) δ 8.62 (d, 1 H, J = 8.0 Hz), 8.23 (s, 1 H), 8.11 (dd, 1 H, J = 8.0, 1.2 Hz), 8.05 (d, 1 H, J = 8.4 Hz), 8.01 (d, 2 H, J = 7.6 Hz), 7.89 (d, 2 H, J = 7.6 Hz), 7.74 (d, 1 H, J = 8.4 Hz), 7.61 (t, 1 H, J = 8.0 Hz), 7.34 (t, 1 H, J = 7.6 Hz), 4.36 (s, 2 H), 3.34 (brs, 4 H), 3.28 (brs , 4 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 169.7, 164.9, 152.8, 137.3, 133.9, 133.8, 133.0, 132.5, 130.7, 130.4, 129.7, 126.7, 125.2, 125.1, 122.8, 121.8, 120.6, 110.0, 59.7 , 48.2, 41.2.

3- Chloro - N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide hydrochloride [3-Chloro- N -(2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] ( 49jj )

White solid; Reaction time, 4 hours; Yield, 64%; ¹ H NMR (500 MHz, D ₂ O + DMSO- d ₆ ) δ 8.64 (d, 1 H, J = 8.5 Hz), 8.30 (s, 1 H), 8.08-8.11 (m, 2 H), 8.05 ( d, 1 H, J = 8.0 Hz), 8.03 (d, 1 H, J = 7.5 Hz), 7.75 (d, 1 H, J = 8.5 Hz), 7.75 (d, 1 H, J = 8.5 Hz), 7.70 (t, 1 H, J = 8.0 Hz), 7.62 (t, 1 H, J = 8.0 Hz), 7.34 (t, 1 H, J = 8.0 Hz), 4.38 (s, 2 H), 3.34 (brs , 4 H), 3.26 (brs, 4 H); ¹³ C NMR (100 MHz, D ₂ O + DMSO- d ₆ ) δ 169.2, 164.2, 152.8, 137.6, 137.0, 134.2, 133.7, 132.9, 132.5, 131.6, 130.8, 127.4, 126.7, 125.1, 122.4, 121.7, 120.7 , 59.6, 48.3, 41.3.

3-Nitro- N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide [3-Nitro- N -(2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide] (49k)

Yellow solid; Reaction time, 3 hours; Yield, 89%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.97 (brs, 1 H, CONH), 8.74 (s, 1 H), 8.66 (d, 1 H, J = 8.0 Hz), 8.46 (d, 1 H , J = 7.2 Hz), 8.46 (d, 1 H, J = 7.2 Hz), 7.90-7.99 (m, 4 H), 7.54 (t, 1 H, J = 8.0 Hz), 7.44 (d, 1 H, J = 8.0 Hz), 7.27 (d, 1 H, J = 8.4 Hz), 3.51 (s, 2 H), 2.66 (brs, 4 H), 2.28 (s, 4 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 168.4, 163.7, 151.9, 148.8, 137.6, 137.6, 136.7, 134.4, 133.7, 132.7, 131.5, 130.8, 128.8, 127.5, 125.3, 122.6, 122.6, 122.5, 121.8 , 121.0, 63.5, 54.3, 45.9.

4-nitro- N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide [4-Nitro- N -(2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide] (49l)

White solid; Reaction time, 12 hours; Yield, 83%; ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 13.09 (brs, 1 H), 8.71 (d, 1 H, J = 8.0 Hz), 8.53 (d, 2 H, J = 8.5 Hz), 8.32 (d , 2 H, J = 8.5 Hz), 8.07-8.02 (m, 3 H), 7.61 (t, 1 H, J = 8.0 Hz), 7.54 (d, 1 H, J = 8.5 Hz), 7.34 (t, 1 H, J = 7.5 Hz), 3.57 (s, 2 H), 2.71 (brs, 4 H), 2.34 (brs, 4 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 168.4, 164.1, 151.9, 150.2, 140.8, 137.6, 133.6, 132.8, 130.7, 129.5, 129.0, 125.4, 124.9, 122.8, 122.6, 121.7, 120.9, 63.5, 54.1 , 45.9.

4-nitro- N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide Hydrochloride [4-Nitro- N -(2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] ( 49ll )

White solid; Reaction time, 6 hours; Yield, 97%; ¹ H NMR (500 MHz, D ₂ O + DMSO- d ₆ ) δ 8.49 (d, 1 H, J = 8.0 Hz), 8.38 (d, 2 H, J = 8.5 Hz), 8.19 (d, 2 H, J = 8.5 Hz), 8.03 (s, 1 H), 7.99 (d, 1 H, J = 8.0 Hz), 7.97 (d, 1 H, J = 8.5 Hz), 7.60 (d, 1 H, J = 8.0 Hz), 7.56 (t, 1 H, J = 8.0 Hz), 7.31 (t, 1 H, J = 7.5 Hz), 7.24 (s, 2 H), 3.27 (s, 4 H), 3.17 (s, 4 H); ¹³ C NMR (150 MHz, D ₂ O + DMSO- d ₆ ) δ 169.3, 164.3, 152.5, 150.0, 140.3, 136.7, 133.8, 132.9, 130.7, 129.8, 129.1, 125.7, 124.5, 124.2, 122.8, 122.0, 121.1 , 60.5, 48.5, 41.9.

3,4,5 -trimethoxy - N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol -2-yl) phenyl) benzamide [ 3,4,5-Trimethoxy - N - (2- (6- ( piperazin-1-ylmethyl) benzo [d] thiazol-2-yl) phenyl) benzamide] (49m)

White solid; Reaction time, 3 hours; Yield, 94%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.43 (brs, 1 H), 8.56 (d, 1 H, J = 8.4 Hz), 8.03 (s, 1 H), 8.00 (d, 1 H, J = 8.8 Hz), 7.81 (d, 1 H, J = 8.8 Hz), 7.56 (t, 1 H, J = 8.4 Hz), 7.48 (d, 1 H, J = 8.4 Hz), 7.30-7.26 (m, 3 H), 3.82 (s, 6 H), 3.74 (s, 3 H), 3.52 (s, 2 H), 2.66 (brs, 4 H), 2.28 (brs, 4 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 168.2, 165.9, 153.7, 152.0, 141.8, 137.9, 137.4, 133.9, 132.6, 131.1, 130.9, 128.7, 124.9, 122.7, 122.1, 122.0, 121.5, 106.3, 63.4 , 60.9, 57.1, 54.3, 45.9.

3,4,5- Trimethoxy - N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide Hydrochloride [3,4,5- Trimethoxy - N -(2- (6- (piperazin-1- ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49mm)

Yellow solid; Reaction time, 5 hours; Yield, 71%; ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 12.19 (s, 1 H), 9.70 (brs, 2 H), 8.49 (d, 1 H, J = 8.0 Hz), 8.45 (s, 1 H), 8.11 (d, 1 H, J = 8.0 Hz), 7.98 (d, 1 H, J = 8.0 Hz), 7.85 (d, 1 H, J = 8.0 Hz), 7.64 (t, 1 H, J = 8.0 Hz) ), 7.37 (t, 1 H, J = 8.0 Hz), 7.34 (s, 2 H), 4.53 (s, 2 H), 3.86 (s, 6 H), 3.78 (s, 3 H), 3.45 (brs , 8 H); ¹³ C NMR (125 MHz, DMSO- d ₆ ) δ 169.1, 165.4, 153.1, 152.8, 141.3, 137.3, 133.8, 132.4, 130.4, 130.3, 130.3, 127.2, 125.6, 124.9, 122.6, 122.1, 121.8, 105.8, 60.4 , 58.4, 56.5, 47.4, 41.2.

2,4- Dichloro - N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide Hydrochloride [2,4- Dichloro - N -(2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] ( 49nn )

White solid; Reaction time, 6 hours; Yield, 68%; ¹ H NMR (400 MHz, D ₂ O + DMSO- d ₆ ) δ 8.44 (d, 1 H, J = 8.4 Hz), 8.30 (s, 1 H), 8.02 (d, 1 H, J = 8.0 Hz) , 7.79-7.82 (m, 3 H), 7.69 (d, 1 H, J = 8.4 Hz), 7.64 (d, 1 H, J = 8.4 Hz), 7.63 (t, 1 H, J = 7.6 Hz), 7.37 (t, 1 H, J = 7.6 Hz), 4.43 (s, 2 H), 3.34 (brs, 8 H); ¹³ C NMR (100 MHz, D ₂ O + DMSO- d ₆ ) δ 169.5, 164.7, 153.3, 136.9, 136.6, 135.2, 134.3, 133.1, 132.0, 131.3, 131.1, 130.7, 130.6, 128.6, 128.2, 126.0, 125.8 , 123.1, 122.7, 121.9, 59.5, 48.1, 41.0.

3,4- Dichloro - N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) benzamide Hydrochloride [3,4- Dichloro - N -(2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] ( 49oo )

White solid; Reaction time, 6 hours; Yield, 89%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.77 (s, 1 H), 9.57 (brs, 2 H), 8.63 (d, 1 H, J = 8.0 Hz), 8.39 (s, 1 H), 8.25 (s, 1 H), 8.13 (d, 1 H, J = 8.0 Hz), 8.03-8.08 (m, 2 H), 7.99 (d, 1 H, J = 8.0 Hz), 7.83 (d, 1 H , J = 8.0 Hz), 7.63 (t, 1 H, J = 8.0 Hz), 7.35 (t, 1 H, J = 7.6 Hz), 4.38 (brs, 2 H), 3.37 (brs, 8 H); ¹³ C NMR (100 MHz, D ₂ O + DMSO- d ₆ ) δ 170.0, 163.5, 152.8, 137.2, 136.0, 135.0, 133.9, 133.1, 132.5, 131.9, 130.8, 130.2, 129.9, 129.3, 128.2, 125.4, 125.0 , 122.7, 121.5, 120.3, 60.2, 48.5, 41.6.

N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) nicotinamide [ N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) nicotinamide] (49p)

White solid; Reaction time, 3 hours; Yield, 91%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.92 (s, 1 H), 9.24 (s, 1 H), 8.80 (m, 1 H), 8.65 (d, 1 H, J = 7.6 Hz), 8.39 (d, 1 H, J = 5.6 Hz), 8.03 (s, 1 H), 7.98 (d, 1 H, J = 7.6 Hz), 7.89 (d, 1 H, J = 8.4 Hz), 7.67 (m , 1 H), 7.56 (t, 1 H, J = 8.4 Hz), 7.49 (d, 1 H, J = 8.4 Hz), 7.28 (t, 1 H, J = 7.6 Hz), 3.52 (s, 2 H ), 2.66 (s, 4 H), 2.29 (s, 4 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 168.3, 164.5, 153.4, 151.9, 149.2, 137.7, 135.9, 133.8, 132.8, 131.2, 130.7, 128.9, 125.2, 124.7, 122.8, 122.3, 121.9, 121.1, 63.4 , 54.7, 46.2.

N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) -1- Naphthaamide [ N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) -1-naphthamide] (49q)

White solid; Reaction time, 12 hours; Yield, 66%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.80 (brs, 1H), 8.77 (d, 1 H, J = 8.8 Hz), 8.44 (d, 1 H, J = 8.4 Hz), 8.15 (d, 1 H, J = 8.4 Hz), 8.05-7.97 (m 3 H), 7.70 (t, 1 H, J = 7.6 Hz), 7.65-7.53 (m, 4 H), 7.45 (d, 1 H, J = 8.4 Hz), 7.38 (d, 1 H, J = 8.4 Hz), 7.31 (t, 1 H, J = 7.6 Hz), 3.48 (s, 2 H), 2.63 (brs, 4 H), 2.25 (brs, 4 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 168.2, 167.8, 151.8, 138.1, 137.5, 134.6, 134.2, 133.7, 132.7, 132.1, 130.8, 130.4, 129.2, 128.7, 127.9, 127.2, 126.7, 125.9, 125.8 , 125.0, 122.6, 122.1, 121.7, 120.9, 63.1, 54.5, 46.0.

N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) -1- Naphthaamide  Hydrochloride [ N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) -1-naphthamide hydrochloride] ( 49qq )

White solid; Reaction time, 4 hours; Yield, 90%; ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 12.56 (s, 1 H), 9.44 (brs, 2 H, ⁺ NH ₂ ), 8.71 (d, 1 H, J = 8.0 Hz), 8.44 (d, 1 H, J = 7.5 Hz), 8.34 (s, 1 H), 8.18 (d, 1 H, J = 8.5 Hz), 8.04-8.07 (m, 3 H), 7.67-7.74 (m, 3 H), 7.57-7.62 (m, 3 H), 7.38 (t, 1 H, J = 8.0 Hz), 4.41 (s, 2 H), 3.37 (brs, 4 H), 3.29 (brs, 4 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 169.5, 167.6, 152.9, 137.7, 137.5, 134.2, 133.9, 132.9, 131.9, 130.8, 130.2, 130.1, 129.0, 127.8, 127.1, 126.4, 125.6, 125.2, 122.5 , 122.1, 122.0, 121.1, 59.4, 48.0, 41.0.

N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) -2- Naphthaamide [ N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) -2-naphthamide] (49r)

Yellow solid; Reaction time, 12 hours; Yield, 84%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.12 (s, 1 H), 8.80 (d, 1 H, J = 8.4 Hz), 8.65 (s, 1 H), 8.48-8.11 (m, 3 H ), 8.03-8.01 (m, 2 H), 7.98 (d, 1 H, J = 8.0 Hz), 7.93 (d, 1 H, J = 8.0 Hz), 7.66-7.62 (m, 2 H), 7.58 ( t, 1 H, J = 8.0 Hz), 7.50 (d, 1 H, J = 8.4 Hz), 7.27 (t, 1 H, J = 7.6 Hz), 3.52 (s, 2 H), 2.68 (brs, 4 H), 2.30 (brs, 4 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 168.7, 165.9, 152.0, 138.2, 137.6, 135.2, 133.7, 133.0, 132.8, 132.7, 130.8, 129.8, 129.4, 128.9, 128.8, 128.5, 128.0, 124.8, 124.3 , 122.8, 122.2, 121.4, 120.4, 63.0, 54.1, 45.8.

N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) -2- Naphthaamide  Hydrochloride [ N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) -2-naphthamide hydrochloride] ( 49rr )

White solid; Reaction time, 4 hours; Yield, 92%; ¹ H NMR (500 MHz, D ₂ O + DMSO- d ₆ ) δ 8.70 (d, 1 H, J = 8.5 Hz), 8.63 (s, 1 H), 8.30 (s, 1 H), 8.17 (d, 1 H, J = 8.5 Hz), 8.12 (d, 1 H, J = 8.0 Hz), 8.12 (d, 1 H, J = 8.0 Hz), 8.02-8.04 (m, 3 H), 7.75 (d, 1 H, J = 8.5 Hz), 7.64-7.70 (m, 2 H), 7.62 (t, 1 H, J = 8.5 Hz), 7.32 (t, 1 H, J = 8.0 Hz), 4.41 (s, 2 H ), 3.36 (s, 4 H), 3.31 (s, 4 H).

N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) quinoxaline-2- Carboxamide [ N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) quinoxaline-2-carboxamide] (49s)

White solid; Reaction time, 12 hours; Yield, 86%; ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 13.70 (brs, 1 H), 9.59 (s, 1 H), 8.91 (d, 1 H, J = 8.5 Hz), 8.34 (d, 1 H, J = 8.5 Hz), 8.23 (d, 1 H, J = 8.5 Hz), 8.16 (d, 1 H, J = 8.0 Hz), 8.11-8.03 (m, 3 H), 7.99 (d, 1 H, J = 7.5 Hz), 7.64-7.59 (m, 2 H), 7.34 (t, 1 H, J = 7.5 Hz), 3.58 (s, 2 H), 2.70 (brs, 4 H), 2.34 (brs, 4 H) .

N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) quinoxaline-2- Kaboksami De Hydrochloride [ N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol -2-yl) phenyl) quinoxaline-2-carboxamide hydrochloride] ( 49ss )

Yellow solid; Reaction time, 6 hours; Yield, 97%; ¹ H NMR (500 MHz, D ₂ O + DMSO- d ₆ ) δ 9.41 (s, 1 H), 8.70 (d, 1 H, J = 8.0 Hz), 8.18-8.21 (m, 2 H), 8.11- 8.15 (m, 2 H), 7.97-7.99 (m, 2 H), 7.90 (d, 1 H, J = 7.5 Hz), 7.70 (d, 1 H, J = 8.5 Hz), 7.53 (t, 1 H , J = 8.0 Hz), 7.27 (t, 1 H, J = 8.0 Hz), 4.42 (s, 2 H), 3.51 (brs, 8 H); ¹³ C NMR (100 MHz, D ₂ O + DMSO- d ₆ ) δ 169.9, 162.8, 153.8, 144.5, 144.3, 143.5, 140.2, 136.6, 134.3, 133.2, 132.5, 131.1, 130.5, 129.8, 129.7, 127.8, 127.6 , 125.7, 125.5, 123.1, 121.4, 120.5, 59.9, 48.2, 41.0.

N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl)-(1,1'- Biphenyl ] -4-carboxamide [ N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl)-[1,1'-biphenyl] -4-carboxamide] (49t)

White solid; Reaction time, 12 hours; Yield, 56%; ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 13.13 (s, 1 H), 8.84 (d, 1 H, J = 8.0 Hz), 8.22 (d, 2 H, J = 8.0 Hz), 8.09 (d , 1 H, J = 8.5 Hz), 8.07 (s, 1 H), 8.03-7.97 (m, 3 H), 7.82 (d, 2 H, J = 7.0 Hz), 7.60 (t, 1 H, J = 7.0 Hz), 7.57 (d, 1 H, J = 8.5 Hz), 7.53 (t, 2 H, J = 7.0 Hz), 7.44 (t, 1 H, J = 7.0 Hz), 7.30 (t, 1 H, J = 7.0 Hz), 3.57 (s, 2 H), 2.71 (brs, 4 H), 2.34 (brs, 4 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 168.7, 165.5, 152.0, 144.5, 139.6, 138.2, 137.6, 134.0, 133.6, 132.8, 129.8, 129.2, 128.7, 128.0, 127.8, 122.7, 122.0, 121.3, 120.3 , 63.0, 54.2, 45.9.

N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl)-(1,1'- Biphenyl ] -4-carboxamide Hydrochloride [ N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol -2-yl) phenyl)-[1,1'-biphenyl] -4-carboxamide hydrochloride] ( 49tt )

White solid; Reaction time, 6 hours; Yield, 97%; ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 12.90 (s, 1 H), 9.54 (brs, 2 H, ⁺ NH ₂ ), 8.78 (d, 1 H, J = 8.0 Hz), 8.41 (s, 1 H), 8.20-8.24 (m, 3 H), 8.09 (d, 1 H, J = 8.0 Hz), 8.02 (d, 2 H, J = 8.0 Hz), 7.80-7.88 (m, 3 H), 7.64 (t, 1 H, J = 8.0 Hz), 7.54 (t, 2 H, J = 8.0 Hz), 7.45 (t, 1 H, J = 8.0 Hz), 7.34 (t, 1 H, J = 8.0 Hz) ), 4.47 (s, 2 H), 3.38 (brs, 8 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 170.0, 165.7, 152.7, 144.4, 139.0, 137.2, 133.8, 133.2, 132.9, 130.5, 130.0, 129.6, 128.9, 128.8, 128.3, 127.4, 127.3, 124.9, 124.8 , 122.5, 121.3, 119.9, 60.1, 48.2, 41.3.

N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] Thiazole -2-yl) phenyl) Cyclohexanecarboxamide [ N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) cyclohexanecarboxamide] (49u)

White solid; Reaction time, 12 hours; Yield, 27%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.02 (s, 1 H), 8.53 (d, 1 H, J = 8.0 Hz), 8.03 (s, 1 H), 7.89-7.91 (m, 2 H ), 7.45-7.50 (m, 2 H), 7.19 (t, 1 H, J = 7.6 Hz), 3.53 (s, 2 H), 2.68 (brs, 4 H), 2.39 (m, 1 H), 2.30 (brs, 4 H), 1.97 (m, 2 H), 1.74 (m, 2 H), 1.64 (m, 1 H), 1.18-1.51 (m, 5 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 175.2, 168.3, 152.1, 138.2, 137.4, 133.8, 132.6, 130.7, 128.9, 124.3, 122.7, 122.4, 121.5, 120.2, 63.1, 54.1, 46.8, 45.9, 29.9 , 26.2, 25.9.

N - (2- (6- (piperazin-1-ylmethyl) benzo [ d ] Thiazol-2-yl) phenyl) Shinnamamide [ N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) cinnamamide] (49v)

White solid; Reaction time, 12 hours; Yield, 43%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.11 (s, 1 H), 8.55 (d, 1 H, J = 8.4 Hz), 8.17 (d, 1 H, J = 8.4 Hz), 8.06 (s , 1 H), 7.96 (d, 1 H, J = 8.0 Hz), 7.74 (d, 2 H, J = 7.6 Hz), 7.64 (d, 1 H, J = 16.0 Hz), 7.49-7.53 (m, 2 H), 7.41-7.43 (m, 3 H), 7.26 (t, 1 H, J = 8.0 Hz), 6.92 (d, 1 H, J = 16.0 Hz), 3.63 (s, 2 H), 2.95 ( s, 4 H), 2.52 (s, 4 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 168.0, 164.9, 152.3, 142.0, 137.8, 136.6, 135.0, 134.0, 132.5, 130.8, 129.7, 128.9, 128.6, 124.9, 123.3, 123.0, 122.6, 122.4, 121.2 , 63.4, 50.5, 43.9.

Phenyl (2- (6- (piperazin-1-ylmethyl) benzo [ d ] Thiazol-2-yl) phenyl) Carbamate [Phenyl (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) carbamate] (49w)

Yellow solid; Reaction time, 12 hours; Yield, 40%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.85 (s, 1 H), 8.58 (d, 1 H, J = 7.6 Hz), 7.87 (s, 1 H), 7.77 (d, 1 H, J = 7.6 Hz), 7.66-7.71 (m, 2 H), 7.41 (d, 2 H, J = 6.8 Hz), 7.18 (d, 1 H, J = 7.6 Hz), 7.02 (t, 2 H, J = 7.6 Hz ), 6.87 (t, 1 H, J = 7.6 Hz), 6.80 (d, 1 H, J = 8.4 Hz), 3.76 (s, 4 H), 3.67 (s, 2 H), 2.60 (s, 4 H) ).

Example  2 : Benzo [ d ] Thiazole  Of derivatives synthesized based on the skeleton SIRT  1 active navigation and SIRT  1 Excavator (Compound 49h) excavation

2-1. Compound 49h SIRT1  Active check

SIRT 1 activity was measured using a SIRT 1 fluorometric drug discovery kit (AK-555, Biomol) for a candidate SIRT 1 activator compound synthesized based on the skeleton of benzo [d] thiazole. Briefly, the substrate for analysis was 0.2 U / L as a mixture of Fluor de Lys-SIRT 1 substrate developer, which means amino acid 379382 of human p53 (Arg-His-Lys-Lys AC) and human SIRT 1 and auxiliary substrate NAD + are incubated. Fluor de Lys-Sirt1 In the 25 μM and NAD ⁺ 25 μM environment, the initial deacetylation degree of SIRT 1 for 100 μM candidate was measured using 100 μM resveratrol as a positive control. After the reaction was stopped using Fluor de Lys ^TM Developer II / 2 mM nicotinamide, fluorescence (Excitation: 360 nm, Emission: 460 nm) was measured.

As a result, referring to FIGS. 1A and 1B, it was confirmed that compound 49h exhibits a higher SIRT 1 activity effect than resveratrol, which is known as a strong SIRT 1 activator. Compounds with a value of 0 had too high a fluorescence value of their own, and it was impossible to measure with a SIRT 1 fluorometric kit (AK-555, Biomol) measured by fluorescence.

In addition, docking simulation was performed using the AutoDock4 and DOCK6 programs to confirm the binding force of SIRT 1 to compound 49h.

As a result, referring to FIG. 1C, it was confirmed that compound 49h has a higher binding capacity to SIRT 1 than resveratrol and SRT1720, which are known as strong SIRT 1 activators.

2-2. Confirmation of improvement of insulin resistance of compound 49h

Using a db / db mouse lacking the appetite-regulating hormone leptin receptor as an obese animal model, the ability to control metabolic disease of compound 49h was analyzed. Compound 49h was administered orally to db / db mice (9 weeks old) at a concentration of 5 mg / kg daily for 4 weeks.

As a result, referring to FIGS. 2A and 2B, it was confirmed that the dietary intake and body weight were significantly increased in the db / m mice that are homozygous compared to the db / m mice that are heterozygous that do not exhibit the obesity phenotype. It means that the animal model was well derived. When the compound 49h was orally administered to the db / db mouse, it was confirmed that there was no difference in dietary intake and body weight when compared with the db / db mouse group.

Compound 49h was administered orally and a glucose tolerance test was performed 3 weeks later. The mice were kept on an empty stomach for at least 12 hours, and glucose (2 g / kg) was intraperitoneally injected, and then blood glucose collected from the tail of the mouse was used to measure sugar in the blood every hour with a glucometer (ACCU-CHECK). .

As a result, referring to FIG. 2C, the db / db mouse group exhibited glucose resistance in which high levels of blood glucose were maintained due to poor insulin signaling, whereas this glucose resistance was recovered in the group administered orally with compound 49h. It was confirmed that the blood sugar level decreased. In addition, referring to Figure 2D, when compared to the db / db mouse group, it was confirmed that the fasting blood sugar decreases in the compound 49h oral administration group.

Next, the insulin concentration in the blood was measured using an enzyme-linked immunosorbent assay (ELISA). Mouse insulin ELISA (TMB) kit (AKRIN-011T, SHIBAYAGI, Japan) was used, and serum isolated from animal blood was added to a 96 well plate coated with insulin primary antibody and reacted. , The secondary antibody and the substrate were added and reacted to measure the changed color with an absorbance meter.

As a result, referring to Figure 2E, when compared to the db / db mouse group, it was confirmed that the serum insulin concentration was decreased in the compound 49h oral administration group.

2-3. Confirmation of improvement of fatty liver of compound 49h

Since obesity and insulin resistance are typical diseases directly related to the occurrence of non-alcoholic fatty liver, the effect of improving the fatty liver of compound 49h was analyzed. Compound 49h was administered orally to db / db mice (9 weeks old) at a concentration of 5 mg / kg daily for 4 weeks. First, fat accumulation in the liver, the most representative phenotype, was measured. Briefly, the liver was quantified to about 50 mg, crushed in cold phosphate buffered saline (PBS) or 0.9% sodium chloride (NaCl), and then crushed, followed by a 2: 1 volume ratio of chloroform and methanol (MeOH). The mixed solvent was treated and reacted for 2 hours. Thereafter, the sample was filtered using a paper filter, and the filtered liquid was removed in a dry-oven at 60 ° C. Then, the amount of triglyceride was measured by absorbance using a triglyceride measurement kit (Stanbio laboratory, TX USA).

As a result, referring to FIG. 3A, it was confirmed that triglyceride was accumulated in the liver of the obese animal model db / db mouse group, which means that non-alcoholic fatty liver is induced. On the other hand, it was confirmed that the triglyceride was decreased in the group to which the compound 49h was orally administered, which means that the non-alcoholic fatty liver was alleviated.

In order to confirm the mechanism corresponding to this, mRNA expression of genes related to fat synthesis and degradation was analyzed. Briefly, about 25 mg of liver was quantified, RNA was isolated using RiboEx Total RNA (GeneAll Biotechnology), and then synthesized by cDNA using HyperscriptTM One-Step RT-PCR Master mix (GeneAll Biotechnology). The synthesized cDNA was subjected to a real-time polymerase chain reaction (quatative real-time PCR) capable of targeting a desired gene as a primer and quantifying in real time.

As a result, referring to Figure 3B, it was confirmed that the expression of fat synthesis-related genes (FASN, ACC, SREBP-1a, SREBP-1c, and SREBP-2) increased in the db / db mouse group, while Compound 49h was observed. In the oral administration group, it was confirmed that the genes related to fat synthesis were significantly reduced. In comparison, referring to FIG. 3C, the expression of the fat oxidation-related genes (CPT1 and ACOX1) was not significantly different in the two groups. Through the above results, it is thought that the decrease in the expression of genes related to fat synthesis by compound 49h contributed to the improvement of non-alcoholic fatty liver by reducing triglycerides.

 Although the cause of non-alcoholic liver disease (NAFLD) is unclear, recent studies report that ER stress may be related to the development of fatty liver and progression to non-alcoholic liver disease. have. Thus, in order to analyze the effect of compound 49h on endoplasmic reticulum stress, vesicular stress-related markers (p-IRE) were identified by Western blot. Briefly, about 50 mg of liver was quantified, and the protein was extracted by homogenizing and lysis. After quantifying the extracted protein and loading the same amount on the polyacrylamide gel, the protein was separated according to molecular weight through SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis). Proteins separated according to molecular weight were transferred to a membrane by applying an electric field, and desired proteins were detected using specific antibodies. After reacting the primary antibody specifically binding to the protein to be detected for 12 hours or more, react the secondary antibody specifically binding to the primary antibody for 1 hour, and HRP (horse radish peroxidase) present in the secondary antibody ), The expression of the protein can be analyzed by treating the developer containing the substrate.

As a result, referring to FIG. 3D, it was confirmed that the protein expression of the vesicle stress-related marker (p-IRE) increased in the db / db mouse group, which is an obese animal model, was significantly reduced in the group treated with orally compound 49h. α-tubulin (α-tubulin) is a housekeeping gene, and it can be confirmed that the protein was quantitatively loaded. Through this, it is thought that compound 49h reduced the vesicle stress induced by obesity, which contributed to the relief of fatty liver.

2-4. Cell aging of compound 49h Protection  Confirm

Β-galactosidase (β), which induces cell aging of the fibroblast, the main cell of the skin epithelial layer, using UVB, which is known as the most important environmental factor in skin aging, and is used as the most common marker for cell aging. -galactosidase) staining to analyze the cellular aging protective capacity of compound 49h.

As a result, referring to FIG. 4A, it was confirmed that cells stained with β-galactosidase were increased by UVB at 12 mJ / cm ² , and β in the group pretreated with compound 49h at a concentration of 1 μM for 24 hours. -It was confirmed that the galactosidase staining decreased. This means that compound 49h has a protective effect in cell aging.

The effect of prolonging life was analyzed in a rapidly dividing yeast (Saccharomyces cerevisiae) model targeting compound 49h, which has been shown to inhibit cell aging.

As a result, referring to FIG. 4B, when compared with the control group, it was confirmed that the life span was significantly extended in the yeast group treated with compound 49h. Through these results, it was confirmed that the compound 49h has a protective effect on cell aging and an extended life.

The specific parts of the present invention have been described in detail above, and it is obvious that for those skilled in the art, these specific techniques are only preferred embodiments, and the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

The scope of the present invention is indicated by the following claims, and all modifications or variations derived from the meaning and scope of the claims and their equivalent concepts should be interpreted to be included in the scope of the present invention.

Claims (11)

A compound represented by Formula 1, a hydrate or a salt thereof:
[Formula 1]

Wherein R is (C1 ~ C4) alkyl, (C1 ~ C4) alkoxy, halogen, nitro or phenyl with one or more substituents unsubstituted or substituted benzamide, nicotinamide, isonicotinamide, naphthamide, quinoline-2- Carboxamide, benzenesulfonamide, quinoxaline-2-carboxamide, cyclohexane-carboxamide, cinnamic amide, adamantane-1-carboxamide, phenylurea, naphthylurea, benzylurea and phenylcarbamate One selected from the group consisting of The compound according to claim 1, wherein the compound is a compound represented by the following Chemical Formula 1-1, a hydrate or a salt thereof:
[Formula 1-1]

Wherein R is (C1 ~ C4) alkyl, (C1 ~ C4) alkoxy, halogen, nitro or phenyl with one or more substituents unsubstituted or substituted benzamide, nicotinamide, isonicotinamide, naphthamide, quinoline-2- Carboxamide, benzenesulfonamide, quinoxaline-2-carboxamide, cyclohexane-carboxamide, cinnamic amide, adamantane-1-carboxamide, phenylurea, naphthylurea, benzylurea and phenylcarbamate One selected from the group consisting of The compound represented by Formula 1-1 is N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [ N- (2- (4- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41a), 3-fluoro- N- (2- (4- (pipe 1-ylmethyl) benzo [d] thiazol-2-yl) phenyl) benzamide hydrochloride [3-Fluoro- N - (2- (4- (piperazin-1-ylmethyl) benzo [d] thiazol- 2-yl) phenyl) benzamide hydrochloride] (41b), 4-fluoro- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide Hydrochloride [4-Fluoro- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41c), 3-bromo- N- (2 -(4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [3-Bromo- N- (2- (4- (piperazin-1-ylmethyl) benzo [d] thiazol-2- yl) phenyl) benzamide hydrochloride] (41d), 3- chloro - N - (2- (4- (P 1-ylmethyl) benzo [d] thiazol-2-yl) phenyl) benzamide hydrochloride [3-Chloro- N - (2- (4- (piperazin-1-ylmethyl) benzo [d] thiazol- 2-yl) phenyl) benzamide hydrochloride] (41e), 4-chloro- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride Chloride [4-Chloro- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41f), 3-nitro- N- (2- ( 4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [3-Nitro- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41g), 4-nitro- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl ) Benzamide hydrochloride [4-Nitro- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41h), 3,4,5- Trimethoxy- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide high Drochloride [3,4,5-Trimethoxy- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41i), 2,4-dichloro - N - (2- (4- (piperazin-1-ylmethyl) benzo [d] thiazol-2-yl) phenyl) benzamide hydrochloride [2,4-Dichloro- N - (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41j), 3,4-dichloro- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [3,4-Dichloro- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (41k), N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) nicotinamide hydrochloride [ N- (2- (4- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) nicotinamide hydrochloride] (41l), N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazole- 2-yl) phenyl) -1-naphthamide hydrochloride [ N- (2- (4- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phen yl) -1-naphthamide hydrochloride] (41m), N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) -2-naphthamide hydrochloride [ N- (2- (4- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) -2-naphthamide hydrochloride] (41n), N- (2- (4- (piperazin-1 -ylmethyl) benzo [d] thiazol-2-yl) phenyl) quinoxaline-2-carboxamide hydrochloride [N - (2- (4- ( Piperazin-1-ylmethyl) benzo [d] thiazol-2 -yl) phenyl) quinoxaline-2-carboxamide hydrochloride] (41o), N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl)-[1, 1'-biphenyl] -4-carboxamide hydrochloride [ N- (2- (4- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl)-[1,1'-biphenyl ] -4-carboxamide hydrochloride] (41p) and 4-methyl- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzenesulfonamide [4 -Methyl- N- (2- (4- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzenesulfonamide] (41q) A compound as a gong, a hydrate or salt thereof. According to claim 1, wherein the compound is a compound, a hydrate or a salt thereof, characterized in that the compound represented by Formula 1-2:
[Formula 1-2]

Wherein R is (C1 ~ C4) alkyl, (C1 ~ C4) alkoxy, halogen, nitro or phenyl with one or more substituents unsubstituted or substituted benzamide, nicotinamide, isonicotinamide, naphthamide, quinoline-2- Carboxamide, benzenesulfonamide, quinoxaline-2-carboxamide, cyclohexane-carboxamide, cinnamic amide, adamantane-1-carboxamide, phenylurea, naphthylurea, benzylurea and phenylcarbamate One selected from the group consisting of The compound according to claim 4, wherein the compound represented by Chemical Formula 1-2 is N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide [ N -(2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide] (49a), N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [ N- (2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49aa) , 2-methyl- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [2-Methyl- N- (2- ( 6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49bb), 3-methyl- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [3-Methyl- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride ] (49cc), 4- methyl - N - (2- (6- (piperazin-1-ylmethyl) benzo [d] thiazol-2-yl) phenyl) benzamide and Draw chloride [4-Methyl- N - (2- (6- (piperazin-1-ylmethyl) benzo [d] thiazol-2-yl) phenyl) benzamide hydrochloride] (49dd), 3-fluoro - N - (2 -(6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [3-Fluoro- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49ee), 4-fluoro- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazole-2- 1) phenyl) benzamide hydrochloride [4-Fluoro- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49ff), 2-bro Mo- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [2-Bromo- N- (2- (6- ( piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49gg), 3-bromo- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] Thiazol-2-yl) phenyl) benzamide [3-Bromo- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide] (49h), 3-Bromo- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [3-Bromo- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49hh), 3-bromo- N- (2- (6- (piperazin-1 -Ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide 2,2,2-trifluoroacetate [3-Bromo- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide 2,2,2-trifluoroacetate] (49hhh), 4-bromo- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] Thiazol-2-yl) phenyl) benzamide [4-Bromo- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide] (49i), 4 -Bromo- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [4-Bromo- N- (2- (6 -(piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49ii), 3-chloro- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide Hydrochloride [3-Chloro- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49jj), 3-nitro- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide [3-Nitro- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide] (49k), 4-nitro- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benz Amide [4-Nitro- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide] (49l), 4-nitro- N- (2- (6 -(Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [4-Nitro- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49ll), 3,4,5-trimethoxy- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazole- 2-yl) phenyl) benzamide [3,4,5-Trimethoxy- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide] (49m), 3,4,5-trimethoxy- N- (2- (6- (piperazin-1-ylmethyl) bene Crude [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [3,4,5-Trimethoxy- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl ) phenyl) benzamide hydrochloride] (49mm), 2,4-dichloro- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [2,4-Dichloro- N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49nn), 3,4-dichloro- N- ( 2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride [3,4-Dichloro- N- (2- (6- (piperazin-1 -ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) benzamide hydrochloride] (49oo), N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) Phenyl) nicotinamide [ N- (2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) nicotinamide] (49p), N- (2- (6- (piperazin- 1- ylmethyl) benzo [d] thiazol-2-yl) phenyl) - 1-naphtha amide [N - (2- (6- ( Piperazin-1-ylmethyl) benzo [d] thiazol-2-yl) phenyl ) -1-naphtham ide] (49q), N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) -1-naphthamide hydrochloride [ N- (2- ( 6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) -1-naphthamide hydrochloride] (49qq), N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) -2-naphthamide [ N- (2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) -2-naphthamide] ( 49r), N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) -2-naphthamide hydrochloride [ N- (2- (6- ( Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) -2-naphthamide hydrochloride] (49rr), N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thia Zol-2-yl) phenyl) quinoxaline-2-carboxamide [ N- (2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) quinoxaline-2-carboxamide] (49s), N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) quinoxaline-2-carboxamide hydrochloride [ N- (2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol- 2-yl) phenyl) quinoxaline-2-carboxamide hydrochloride] (49ss), N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl)-[1 , 1'-biphenyl] -4-carboxamide [ N- (2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl)-[1,1'-biphenyl] -4-carboxamide] (49t), N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl)-[1,1'-biphenyl]- 4-carboxamide hydrochloride [ N- (2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl)-[1,1'-biphenyl] -4-carboxamide hydrochloride] (49tt), N- (2- (6- (piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) cyclohexanecarboxamide [ N- (2- (6- (Piperazin -1-ylmethyl) benzo [d] thiazol-2-yl) phenyl) cyclohexanecarboxamide] (49u), N - (2- (6- ( piperazin-1-ylmethyl) benzo [d] thiazol-2-yl ) Phenyl) cinnamamide [ N- (2- (6- (Piperazin-1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) cinnamamide] (49v) and phenyl (2- (6- (piperazin- 1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) carbamate [Phenyl (2- (6- (piperazin- 1-ylmethyl) benzo [ d ] thiazol-2-yl) phenyl) carbamate] (49w), a compound, a hydrate or a salt thereof. The compound, its hydrate or its hydrate, or a hydrate thereof, according to any one of claims 1 to 5, wherein the compound, its hydrate or salt thereof activates SIRT 1 (silent mating type information regulation 2 homolog; sirtuin 1). salt. A pharmaceutical composition for the prevention or treatment of metabolic diseases comprising the compound according to any one of claims 1 to 5, a hydrate or a salt thereof as an active ingredient. The method of claim 7, wherein the metabolic disease is characterized in that it is selected from the group consisting of obesity, diabetes, hyperinsulinemia, hyperuricemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, metabolic syndrome and endothelial dysfunction. Pharmaceutical composition for preventing or treating metabolic disease. A pharmaceutical composition for preventing or treating liver disease, comprising the compound according to any one of claims 1 to 5, a hydrate or a salt thereof as an active ingredient. The pharmaceutical composition for preventing or treating liver disease according to claim 9, wherein the liver disease is selected from the group consisting of alcoholic fatty liver, non-alcoholic fatty liver and hepatitis. delete

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