KR101916901B1 - Pharmaceutical composition comprising 2―arylcarbonylhydrazinecarbothioamide derivatives for preventing or treating endoplasmic reticulum stress-related diseases - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating an endocrine-stress related disease comprising a 2-arylcarbonylhydrazine carbothioamide derivative compound. Since the compound is structurally different from a known chemical stress-inhibiting compound, a chemical chaperone, it can be applied to the development of various chemical chaperone structures as a novel chemical chaperone. Using these compounds, new drug candidates for diseases known to be caused by endoplasmic reticulum stress, that is, unfolded protein accumulation, can be developed. Particularly, the compound is a scaffold which can find derivatives having very high physical properties including various heteroatoms and has a lower IC50 value than existing drugs, and thus can be used as a candidate drug for a new drug.

Description

[0001] The present invention relates to a pharmaceutical composition for preventing or treating an endocrine-stress-related disease comprising a 2-arylcarbonylhydrazine carbothioamide derivative compound, and a 2-arylcarbonylhydrazinecarbothioamide derivative for treating or preventing endo-

The present invention relates to a pharmaceutical composition for preventing or treating an endocrine-stress related disease comprising a 2-arylcarbonylhydrazine carbothioamide derivative compound.

The endoplasmic reticulum is a very important organelle that folds during protein biosynthesis. In the stress state of the endoplasmic reticulum, unfolded proteins accumulate in the endoplasmic reticulum, resulting in various pathological conditions. Various pathological states or diseases known to be caused by ER stress include, for example, diabetic complications such as degenerative brain diseases, arteriosclerosis, diabetes, diabetic eye disease and diabetic kidney disease, Alzheimer's disease, cystic fibrosis and the like.

On the other hand, chaperone is a substance that alleviates the stress of the endoplasmic reticulum, and endogenous chaperone is mostly protein. Thus, research continues to develop chemical chaperones of versions of compounds with chaperone efficacy.

As a chemical chaperone, 4-phenylbutyric acid (4-PBA) or its sodium salt (sodium butyrate), tauro-urosodesoxycholic acid (TUDCA), hydroxynaphthoic acid (HNA) and salicylate are well known. In particular, 4-PBA has been approved by the US FDA in 1996 for urea cycle anomalies and is currently in clinical use. TUDCA has not been approved by the US FDA as a clinical drug, but it has been known that many studies have been shown to inhibit the apoptotic pathway. In addition, it has been reported that obesity and type 2 diabetes mellitus are significantly improved by ER stress suppression (Ozcan et al, 2004, Ozcan et al, 2006). Hydroxynaphthoic acid has not been used clinically, but it is known to inhibit ER stress as a chemical chaperone (Jeong et al 2013).

However, 4-PBA, TUDCA, and HNA have chemical scaffolds with low drug-likeness, and IC50 values are relatively high. For example, TUDCA and salicylate showed IC50 values of 5.2 mM and 5.1 mM, respectively, and only HNA derivatives showed IC50 values of up to 183 μM.

Recently, researches are being conducted to develop compounds having superior efficacy than conventional chemical chaperones, but the number of such compounds is not so large. For example, 2- (4-methoxyphenoxy) acetic acid or the like has been developed as a compound having a greater effect of suppressing the stress of the endoplasmic reticulum than 4-PBA (Patent Document 1).

Accordingly, the present inventors have completed the present invention by developing a compound which is structurally different from the known chemical chaperone and has excellent activity of suppressing the stress of the endoplasmic reticulum.

Japanese Patent Application Laid-Open No. 2014-162741

It is an object of the present invention to provide a 2-arylcarbonylhydrazine carbothioamide derivative compound having an antifoaming activity.

Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of an endocrine-stress-related disease comprising the above compound.

The 2-arylcarbonylhydrazinecarbothioamide derivative compound according to one embodiment of the present invention is represented by the following formula (1).

[Chemical Formula 1]

Ar may be selected from the group consisting of a substituted or unsubstituted C ₆ -C ₂₄ aryl group and a substituted or unsubstituted C ₂ -C ₂₄ heteroaryl group; And

Wherein R is selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxy, substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted C ₅ -C _A substituted or unsubstituted C ₁ -C ₂₀ alkoxy group, a substituted or unsubstituted C ₇ -C ₂₄ benzyl group, a substituted or unsubstituted C ₆ -C ₂₄ aryl group, and a substituted Or an unsubstituted C ₂ to C ₂₄ heteroaryl group.

Specifically, Ar may be an aromatic substituent. More specifically, Ar may be a substituted or unsubstituted 2-pyridyl group, a substituted or unsubstituted 3-pyridyl group , A substituted or unsubstituted 4-pyridyl group, a substituted or unsubstituted phenyl group, and a substituted or unsubstituted thiophene group.

Specifically, R is a substituted or unsubstituted C ₂ to C ₁₀ alkyl group, a substituted or unsubstituted C ₃ to C ₁₀ cycloalkyl group, a substituted or unsubstituted C ₇ to C ₁₀ benzyl group, And an unsubstituted C ₆ to C ₁₀ aryl group.

The 2-arylcarbonylhydrazine carbothioamide derivative compound may be, but is not necessarily limited to, one of the following compounds according to one embodiment of the present invention:

N- (3,4-dichlorophenyl) -2-picolinoyl hydrazine carbothioamide;

N- (2- (trifluoromethyl) phenyl) -2-picolinoyl hydrazine carbothioamide;

N-phenyl-2-picolinoyl hydrazine carbothioamide;

N- (4-chlorobenzyl) -2-picolinoyl hydrazine carbothioamide;

N-butyl-2-picolinoyl hydrazine carbothioamide;

N-benzyl-2-picolinoyl hydrazine carbothioamide;

N- (4-methoxyphenyl) -2-picolinoyl hydrazine carbothioamide;

N- (4-chlorophenyl) -2-picolinoyl hydrazine carbothioamide;

N-cyclohexyl-2-picolinoyl hydrazine carbothioamide;

N- (4-chlorophenyl) -2-nicotinoylhydrazine carbothioamide;

N- (4-chlorophenyl) -2-isonicotinoylhydrazine carbothioamide;

N-phenyl-2-benzoylhydrazine carbothioamide;

N- (2-methoxy-5-methylphenyl) -2- (2-chlorobenzoyl) hydrazine carbothioamide;

N- (4-chlorophenyl) -2- (thiophene-2-carbonyl) hydrazinecarbothioamide;

N-phenyl-2- (thiophene-2-carbonyl) hydrazine carbothioamide;

N- (4-methoxyphenyl) -2- (thiophene-2-carbonyl) hydrazinecarbothioamide;

N- (4-isopropylphenyl) -2- (thiophene-2-carbonyl) hydrazine-1-carbothioamide;

N-cyclohexyl-2- (thiophene-2-carbonyl) hydrazine carbothioamide;

N-cyclohexyl-2- (5-chlorothiophene-2-carbonyl) hydrazine carbothioamide;

N-cyclohexyl-2- (4-ethyl-5-methylthiophene-3-carbonyl) hydrazinecarbothioamide;

N- (4-chlorophenyl) -2- (6-hydroxypicolinoyl) hydrazine-1-carbothioamide;

N- (4-chlorophenyl) -2- (6-fluoropicolinoyl) hydrazine-1-carbothioamide;

N- (4-chlorophenyl) -2- (5-hydroxypicolinoyl) hydrazine-1-carbothioamide;

N- (4-chlorophenyl) -2- (6-hydroxypicolinoyl) hydrazine-1-carbothioamide;

N- (4-chlorophenyl) -2- (quinoline-3-carbonyl) hydrazine-1-carbothioamide;

N- (4-chlorophenyl) -2- (5-fluoropicolinoyl) hydrazine-1-carbothioamide;

N- (4-chlorophenyl) -2- (3-ethoxy-7-hydroxy-2-naphthoyl) hydrazine-1-carbothioamide;

N- (4-chlorophenyl) -2- (3,5-dihydroxy-2-naphthoyl) hydrazine-1-carbothioamide;

N- (4-chlorophenyl) -2- (quinoline-2-carbonyl) hydrazine-1-carbothioamide;

N- (4-chlorophenyl) -2- (4-ethoxy-1-hydroxy-2-naphthoyl) hydrazine-1-carbothioamide; And

The 2-arylcarbonylhydrazinecarbothioamide derivative compound according to one embodiment of the present invention is a compound represented by the following formula (I): < EMI ID = It may be to suppress stress.

Another embodiment of the present invention provides a pharmaceutical composition for preventing or treating an endocardial stress related disease comprising the 2-arylcarbonylhydrazine carbothioamide derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.

As used herein, the term " endoplasmic reticulum " is a very important organelle where protein folding occurs during protein biosynthesis.

As used herein, the term " endoplasmic reticulum stress (ER stress) " refers to the accumulation of abnormal proteins in the endoplasmic reticulum. That is, proteins in the unfolded state accumulate in the endoplasmic reticulum in the state of the endoplasmic reticulum stress, resulting in various pathological conditions. Causative factors of ER stress include environmental changes in cells due to the addition of a disease or chemical reagent, decrease in glucose concentration, addition of an inhibitor of sugar chain hydrolase, accumulation of viral proteins due to viral infection, and the like.

As used herein, the term " endoplasmic reticulum stress-related disease " means a disease caused by accumulation of unfolded proteins in the endoplasmic reticulum due to endoplasmic reticulum stress. Specifically, the endoplasmic reticulum stress- Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, Kreutzfeldt-Jakob disease (Kreutzfeldt-Jakob disease), glomerulonephritis ), Wolcott-Rallison syndrome, Wolfram syndrome, ischemic disease, cardiovascular disease, neurodegenerative disease, bipolar disorder, arteriosclerosis, inflammation, ischemia, heart disease, liver disease, pancreatic disease , Inflammatory bowel disease, Crohn's disease, ulcerative colitis, and cancer. It is not limited.

Since the compound according to the embodiment of the present invention is structurally different from the known chemical stress-inhibiting compound, chemical chaperone, it can be applied to the development of various chemical chaperone structures as a new chemical chaperone. Using these compounds, new drug candidates for diseases known to be caused by endoplasmic reticulum stress, that is, unfolded protein accumulation, can be developed. Particularly, the compound is a scaffold which can find derivatives having very high physical properties including various heteroatoms and has a lower IC50 value than existing drugs, and thus can be used as a candidate drug for a new drug.

FIG. 1 shows the results of Western blot analysis of HepG2 cells treated with 2-arylcarbonyl hydrazine carbothioamide derivative compound (compound 4h) and then assayed for expression of proteins (PERK phosphorylation, eIF2 alpha phosphorylation, CHOP) Blot test results.
2 is a schematic diagram of a process for obtaining N- (4-chlorophenyl) -2- (6-hydroxypicolinoyl) hydrazine-1-carbothioamide) (Compound 4u).
3 is a schematic diagram of a process for obtaining N- (4-chlorophenyl) -2- (6-fluoropicolinoyl) hydrazine-1-carbothioamide) (compound 4v).
4 is a schematic diagram of a process for obtaining N- (4-chlorophenyl) -2- (5-hydroxypicolinoyl) hydrazine-1-carbothioamide) (Compound 4w).
5 is a schematic diagram of a process for obtaining N- (4-chlorophenyl) -2- (6-hydroxypicolinoyl) hydrazine-1-carbothioamide (compound 4x).
6 is a schematic diagram of a process for obtaining N- (4-chlorophenyl) -2- (quinoline-3-carbonyl) hydrazine-1-carbothioamide (compound 4y).
7 is a schematic diagram of a process for obtaining N- (4-chlorophenyl) -2- (5-fluoropicolinoyl) hydrazine-1-carbothioamide (compound 4z).
8 is a schematic diagram for the process for obtaining N- (4-chlorophenyl) -2- (3-ethoxy-7-hydroxy-2-naphthoyl) hydrazine-1-carbothioamide (compound 4aa) .
9 is a schematic diagram of a process for obtaining N- (4-chlorophenyl) -2- (3,5-dihydroxy-2-naphthoyl) hydrazine-1-carbothioamide (compound 4ab).
10 is a schematic diagram of a process for obtaining N- (4-chlorophenyl) -2- (quinoline-2-carbonyl) hydrazine-1-carbothioamide (compound 4ac).
11 is a schematic diagram for the process for obtaining N- (4-chlorophenyl) -2- (4-ethoxy-1-hydroxy-2-naphthoyl) hydrazine-1-carbothioamide (compound 4ad) .
12 is a schematic diagram of a process for obtaining N- (4-chlorophenyl) -2- (6-fluoropicolinoyl) hydrazine-1-carbothioamide (Compound 4ae).

Hereinafter, the present invention will be described in more detail in the following Examples. It should be noted, however, that the following examples are illustrative only and do not limit or limit the scope of the present invention. It will be understood by those of ordinary skill in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

< Synthetic example > 2- Arylcarbonylhydrazine Carbothioamide  Synthesis of derivatives

2-Arylcarbonylhydrazinecarbothioamide derivatives were synthesized through the above reaction scheme. Specific synthesis examples are as follows.

Synthetic example  1. Synthesis of Compound 4a

1-1. Synthesis of intermediate compound 2a

Ethyl picolinate (Compound 1a) (13.5 mL, 100 mmol) was dissolved in EtOH (285 mL), hydrazine hydrate (25.1 mL, 400 mmol) was added dropwise, (reflux). Then, the solvent was removed by 1/2, and then poured into ice water to precipitate. The precipitated reaction product was filtered to obtain the residue picolinohydrazide (Compound 2a) as a white powder (10.8 g, yield 79%).

^{1 H NMR (400 MHz, DMSO} -d6) δ 9.88 (s, 1H), 8.64-8.57 (m, 1H), 8.03-7.94 (m, 2H), 7.56 (ddd, J = 6.1, 4.8, 2.9 Hz, 1H), &lt; / RTI &gt; 4.56 (s, 2H).

1-2. Synthesis of Compound 4a

Picolinohydrazide (Compound 2a) (137 mg, 1.0 mmol) was dissolved in EtOH (6 mL), 1,2-dichloro-4 -isothiocyanatobenzene) (165 μL, 1.1 mmol) were added, and the mixture was refluxed overnight. The reaction solution was cooled to room temperature, and the precipitated solid was filtered. The solid was washed with a small amount of cold EtOH to obtain the target compound N- (3,4-dichlorophenyl) -2-picolinoylhydrazinecarbothioamide (compound 4a) (309 mg, yield 91.1%).

mp (melting point): 209.7 DEG C; ^{1 H NMR (700 MHz, DMSO} -d6) δ 10.80 (s, 1H), 10.01 (s, 1H), 9.84 (s, 1H), 8.70 (d, J = 4.1 Hz, 1H), 8.08 (d, J = 7.7 Hz, 1H), 8.04 (t, J = 7.1 Hz, 1H), 7.85 (s, 1H), 7.66 (t, J = 7.1 Hz, 1H), 7.57-7.55 (m, 2H); ¹³ C NMR (176 MHz, DMSO-d6) δ 181.11, 164.30, 149.76, 148.99, 139.97, 138.19, 130.46, 130.21, 127.49, 127.01, 125.78, 125.66, 123.00; LRMS (ESI) m / z: 341.1 [M + H] &lt; + &gt;; HRMS (ESI) m / z calcd for C 13 H 10 C l2 N 4 OS [M + H] + 341.0025, found341.0022.

Synthetic example  2. Synthesis of Compound 4b

Picolinohydrazide (Compound 2a) was obtained in the same manner as in Synthesis Example 1-1. Picolinohydrazide (Compound 2a) (166 mg, 1.21 mmol) was dissolved in EtOH (6 mL), and then 1-isothiocyanato-2- (trifluoromethyl) 2- (trifluoromethyl) benzene) (200 μL, 1.33 mmol) was added thereto, and the mixture was refluxed overnight. The reaction solution was cooled to room temperature, and the precipitated solid was filtered. The solid was washed with a small amount of cold EtOH to obtain the target compound N- (2- (trifluoromethyl) phenyl) -2-picolinoyl hydrazinecarbothioamide (N- (2- (trifluoromethyl) -picolinoylhydrazinecarbothioamide (Compound 4b) (380 mg, yield 92.4%).

mp: 193.9 [deg.] C; ^{1 H NMR (700 MHz, DMSO} -d6) δ 10.79 (s, 1H), 9.90 (s, 1H), 9.49 (s, 1H), 8.70 (d, J = 4.3 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 8.04 (t, J = 7.2 Hz, 1H), 7.68-7.65 (m, 3H), 7.47 (t, J = 7.4 Hz, 1H); ¹³ C NMR (175 MHz, DMSO-d6) δ 183.17, 164.31, 149.86, 149.01, 138.19, 132.89, 127.56, 127.47, 126.54, 126.51, 124.74, 123.18, 122.95, 121.63; LRMS (ESI) m / z: 341.1 [M + H] &lt; + &gt;; HRMS (ESI) m / z: Calcd. for [M + H] + C 14 H 11 F 3 N 4 OS: 341.0678; found: 341.0676.

Synthetic example  3. Synthesis of Compound 4c

Picolinohydrazide (Compound 2a) was obtained in the same manner as in Synthesis Example 1-1. Picolinohydrazide (Compound 2a) (1.02 g, 7.5 mmol) was dissolved in EtOH (50 mL), isothiocyanatobenzene (977 μL, 8.25 mmol) was added thereto, Respectively. The reaction solution was cooled to room temperature, and the precipitated solid was filtered. The solid was washed with a small amount of cold EtOH to obtain the target compound N-phenyl-2-picolinoylhydrazinecarbothioamide (Compound 4c) (1.73 g, yield 85%).

^{1 H NMR (400 MHz, DMSO} -d6) δ 10.75 (s, 1H), 9.74 (s, 2H), 8.73-8.64 (m, 1H), 8.11-7.95 (m, 2H), 7.65 (ddd, J = 7.2, 4.8, 1.5 Hz, 1H), 7.46 (d, J = 6.2 Hz, 2H), 7.31 (t, J = 7.8 Hz, 2H), 7.18 7.09 (m, 1H).

Synthetic example  4. Synthesis of Compound 4d

Picolinohydrazide (Compound 2a) was obtained in the same manner as in Synthesis Example 1-1. After dissolving Picolinohydrazide (Compound 2a) (137 mg, 1.0 mmol) in EtOH (6 mL), 1-chloro-4- (isothiocyanatomethyl) benzene (isothiocyanatomethyl) benzene (201 mg, 1.1 mmol) were added thereto, and the mixture was refluxed overnight. The reaction solution was cooled to room temperature, and the precipitated solid was filtered. The solid was washed with a small amount of cold EtOH to obtain N- (4-chlorobenzyl) -2-picolinoylhydrazinecarbothioamide (compound 4d) as a target compound (300 mg, yield 93.5%).

mp: 194.2 [deg.] C; ^{1 H NMR (700 MHz, DMSO} -d6) δ 10.68 (s, 1H), 9.53 (s, 1H), 8.68 (d, J = 5.2 Hz, 1H), 8.58 (s, 1H), 8.06 (d, J = 7.8 Hz, 1H), 8.02 (td, J = 7.7, 1.7 Hz, 1H), 7.64 (ddd, J = 7.5, 4.7, 1.2 Hz, 1H), 7.35 (d, J = 6.0 Hz, 2H); ¹³ C NMR (176 MHz, DMSO-d6) δ 182.48, 164.14, 149.86, 148.92, 138.97, 138.12, 131.55, 129.44, 128.36, 127.39, 123.00, 46.58; LRMS (ESI) m / z: 321.1 [M + H] &lt; + &gt;; HRMS (ESI) m / z: Calcd. for [M + H] + C 14 H 13 ClN 4 OS: 321.0571; found: 321.0575.

Synthetic example  5. Synthesis of Compound 4e

Picolinohydrazide (Compound 2a) was obtained in the same manner as in Synthesis Example 1-1. Picolinohydrazide (Compound 2a) (350 mg, 2.55 mmol) was dissolved in EtOH (20 mL), and then 1-isothiocyanatobutane (340 μL, 2.81 mmol) And the mixture was refluxed overnight. The reaction solution was cooled to room temperature, and the precipitated solid was filtered. The solid was washed with a small amount of cold EtOH to obtain the target compound N-butyl-2-picolinoylhydrazinecarbothioamide (Compound 4e) (488 mg, yield 76%).

mp: 141.5-143.2 DEG C; ^{1 H NMR (400 MHz, DMSO} -d6) δ 10.51 (s, 1H), 9.28 (s, 1H), 8.70-8.62 (m, 1H), 8.08-7.98 (m, 2H), 7.97 (t, J = 2H), 1.52-1.39 (m, 2H), 1.25 (dd, J = 6.8 Hz, 1H), 7.64 (ddd, J = 6.8,4.8, 2.2 Hz, 1H) = 15.0, 7.4 Hz, 2H), 0.86 (t, J = 7.3 Hz, 3H); ¹³ C NMR (100 MHz, DMSO-d 6)? 181.2, 163.4, 149.4, 148.5, 137.7, 126.9, 122.5, 43.4, 30.9, 19.4, 13.8; LRMS (ESI) m / z 253 (M + H) &lt; + &gt;.

Synthetic example  6. Synthesis of Compound 4f

Picolinohydrazide (Compound 2a) was obtained in the same manner as in Synthesis Example 1-1. Picolinohydrazide (Compound 2a) (200 mg, 1.46 mmol) was dissolved in EtOH (10 mL), and then (isothiocyanatomethyl) benzene (213 μL, 1.61 mmol) And the mixture was stirred at reflux overnight. The reaction solution was cooled to room temperature, and the precipitated solid was filtered. The solid was washed with a small amount of cold EtOH to obtain the objective compound N-benzyl-2-picolinoylhydrazinecarbothioamide (Compound 4f) (275 mg, yield 66%).

^{1 H NMR (400 MHz, DMSO} -d6) δ 10.67 (s, 1H), 9.50 (s, 1H), 8.66 (ddd, J = 4.8, 1.6, 1.0 Hz, 1H), 8.56 (s, 1H), 8.10 J = 7.4, 4.8, 1.5 Hz, 1H), 7.34-7.25 (m, 4H), 7.21 (ddd, J = 8.5, 5.3, 2.4 Hz, 1H), 4.72 (d, J = 6.0 Hz, 2H).

Synthetic example  7. Synthesis of Compound 4g

Picolinohydrazide (Compound 2a) was obtained in the same manner as in Synthesis Example 1-1. After dissolving Picolinohydrazide (Compound 2a) (274 mg, 2.0 mmol) in EtOH (16 mL), 1-isothiocyanato-4-methoxybenzene (304 L, 2.2 mmol) were added, and the mixture was refluxed overnight. The reaction solution was cooled to room temperature, and the precipitated solid was filtered. The solid was washed with a small amount of cold EtOH to obtain the objective compound N- (4-methoxyphenyl) -2-picolinoylhydrazinecarbothioamide (compound 4g) (489 mg, yield 81%).

^{1 H NMR (400 MHz, DMSO} -d6) δ 10.70 (s, 1H), 9.65 (d, J = 25.1 Hz, 2H), 8.68 (ddd, J = 4.8, 1.5, 1.0 Hz, 1H), 8.10-7.95 (m, 2H), 7.64 (ddd, J = 7.3, 4.8,1.5 Hz, 1H), 7.30 (d, J = 8.3 Hz, 2H), 6.88 3H).

Synthetic example  8. Synthesis of Compound 4h

Picolinohydrazide (Compound 2a) was obtained in the same manner as in Synthesis Example 1-1. Picolinohydrazide (Compound 2a) (1.02 g, 7.5 mmol) was dissolved in EtOH (50 mL), and 1-chloro-4-isothiocyanatobenzene 1.27 g, 7.5 mmol), and the mixture was refluxed overnight. The reaction solution was cooled to room temperature, and the precipitated solid was filtered. The solid was washed with a small amount of cold EtOH to obtain N- (4-chlorophenyl) -2-picolinoylhydrazinecarbothioamide (compound 4h) (2.09 g, 91% yield).

¹ H NMR (400 MHz, DMSO-d 6)? 10.77 (s, IH), 9.86 (s, IH), 9.78 (D, J = 7.2, 4.8, 1.5 Hz, 1H), 7.50 (d, J = 6.6 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H).

Synthetic example  9. Synthesis of compound 4i

Picolinohydrazide (Compound 2a) was obtained in the same manner as in Synthesis Example 1-1. Picolinohydrazide (Compound 2a) (1.0 g, 7.3 mmol) was dissolved in EtOH (50 mL), isothiocyanatocyclohexane (1.06 mL, 7.5 mmol) was added thereto, Lt; / RTI &gt; The reaction solution was cooled to room temperature, and the precipitated solid was filtered. The solid was washed with a small amount of cold EtOH to obtain N-cyclohexyl-2-picolinoylhydrazinecarbothioamide (Compound 4i) as a target compound (1.66 g, yield 82%). .

^{1 H NMR (400 MHz, DMSO} -d6) δ 10.49 (s, 1H), 9.31 (s, 1H), 8.70-8.63 (m, 1H), 8.07-7.96 (m, 2H), 7.85-7.47 (m, 2H), 1.55 (d, J = 12.1 Hz, 1H), 1.32-1.15 (m, 4H) 1.06 (dd, J = 13.6, 6.6 Hz, 1H).

Synthetic example  10. Synthesis of Compound 4j

10-1. Synthesis of intermediate compound 2b

Ethyl nicotinate (Compound 1b) (13.6 mL, 100 mmol) was dissolved in EtOH (280 mL), hydrazine monohydrate (25.1 mL, 400 mmol) was added thereto, Lt; / RTI &gt; After the reaction solution was cooled to room temperature, half of the solvent was removed under reduced pressure, and the precipitated solid was filtered. The solid was washed with a small amount of cold EtOH to obtain the target compound nicotinohydrazide (compound 2b) (11.1 g, yield 81%). ^{1 H NMR (400 MHz, DMSO} -d6) δ 9.96 (s, 1H), 8.96 (dd, J = 2.3, 0.9 Hz, 1H), 8.69 (dd, J = 4.8, 1.7 Hz, 1H), 8.15 (ddd J = 7.9, 2.3, 1.7 Hz, 1H), 7.49 (ddd, J = 7.9,4.8, 0.9 Hz, 1H), 4.58 (s, 2H).

10-2. Synthesis of Compound 4j

Nicotinohydrazide (Compound 2b) (500 mg, 3.65 mmol) was dissolved in EtOH (25 mL), and 1-chloro-4-isothiocyanatobenzene 680 mg, 4.0 mmol), and the mixture was refluxed overnight. The reaction solution was cooled to room temperature, and the precipitated solid was filtered. The solid was washed with a small amount of cold EtOH to obtain the objective compound N- (4-chlorophenyl) -2-nicotinoylhydrazinecarbothioamide (compound 4j) (949 mg, 85% yield).

^{1 H NMR (400 MHz, DMSO} -d6) δ 10.79 (s, 1H), 9.91 (s, 2H), 9.10 (d, J = 1.7 Hz, 1H), 8.76 (dd, J = 4.8, 1.7 Hz, 1H ), 8.27 (dt, J = 8.0, 1.9 Hz, 1H), 7.56 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 7.46 (s, 2H), 7.42-7.34 (m, 2H).

Synthetic example  11. Synthesis of Compound 4k

11-1. Synthesis of intermediate compound 2c

Ethyl isonicotinate (Compound 1c) (15.1 mL, 100 mmol) was dissolved in EtOH (280 mL), hydrazine monohydrate (25.1 mL, 400 mmol) And the mixture was refluxed and stirred. After the reaction solution was cooled to room temperature, half of the solvent was removed under reduced pressure, and the precipitated solid was filtered. The solid was washed with a small amount of cold EtOH to obtain the desired compound, isonicotinohydrazide (Compound 2c) (12.1 g, yield 88%).

^{1 H NMR (400 MHz, DMSO} -d6) δ 9.88 (s, 1H), 8.64-8.57 (m, 1H), 8.01-7.93 (m, 2H), 7.56 (ddd, J = 6.1, 4.8, 2.9 Hz, 1H), &lt; / RTI &gt; 4.56 (s, 2H).

11-2. Synthesis of compound 4k

Isonicotinohydrazide (Compound 4c) (411 mg, 3.0 mmol) was dissolved in EtOH (20 mL), and 1-chloro-4-isothiocyanatobenzene (561 mg, 3.3 mmol), and the mixture was refluxed overnight. The reaction solution was cooled to room temperature, and the precipitated solid was filtered. The solid was washed with a small amount of cold EtOH to obtain the objective compound N- (4-chlorophenyl) -2-isonicotinoylhydrazinecarbothioamide (Compound 4k) (826 mg, 90% yield).

^{1 H NMR (400 MHz, DMSO} -d6) δ 10.88 (s, 1H), 9.93 (s, 2H), 8.78 (dd, J = 4.4, 1.6 Hz, 2H), 7.85 (d, J = 6.0 Hz, 2H ), 7.46 (s, 2H), 7.43-7. 31 (m, 2H).

Synthetic example  12. Synthesis of 4l Compound

12-1. Synthesis of intermediate compound 2d

Ethyl benzoate (Compound 1d) (14.4 mL, 100 mmol) was dissolved in EtOH (280 mL), hydrazine monohydrate (25.1 mL, 400 mmol) was added thereto and refluxed for 18 hours Respectively. After the reaction solution was cooled to room temperature, half of the solvent was removed under reduced pressure, and the precipitated solid was filtered. The solid was washed with a small amount of cold EtOH to obtain the target compound benzohydrazide (Compound 2d) (12.8 g, yield 94%).

^{1 H NMR (400 MHz, DMSO} -d6) δ 9.77 (s, 1H), 7.86-7.78 (m, 2H), 7.54-7.40 (m, 3H), 4.49 (s, 2H).

12-2. Synthesis of Compound 4

Benzohydrazide (Compound 2d) (408 mg, 3.0 mmol) was dissolved in EtOH (20 mL), and 1-chloro-4-isothiocyanatobenzene (561 mg, 3.3 mmol) were added thereto, and the mixture was refluxed overnight. The reaction solution was cooled to room temperature, and the precipitated solid was filtered. The solid was washed with a small amount of cold EtOH to obtain the desired compound N-phenyl-2-benzoylhydrazinecarbothioamide (Compound 4l) (869 mg, yield 95%).

^{1 H NMR (400 MHz, DMSO} -d6) δ 10.57 (s, 1H), 9.84 (s, 2H), 7.97 (s, 2H), 7.58 (d, J = 7.4 Hz, 1H), 7.50 (dd, J = 10.3, 4.6 Hz, 4H), 7.42-7.33 (m, 2H).

Synthetic example  13. Synthesis of compound 4m

Benzohydrazide (Compound 2d) was obtained in the same manner as in Synthesis Example 12-1. 2-chlorobenzohydrazide was synthesized from benzohydrazide (compound 2d). 2-Chlorobenzohydrazide (240 mg, 1.41 mmol) was dissolved in EtOH 2-isothiocyanato-1-methoxy-4-methylbenzene (277 mg, 1.55 mmol) was added to the reaction mixture, and the mixture was refluxed overnight . The reaction solution was cooled to room temperature, and the precipitated solid was filtered. The solid was washed with a small amount of cold EtOH to obtain the target compound N- (2-methoxy-5-methylphenyl) -2- (2-chlorobenzoyl) hydrazine carbothioamide -2- (2-chlorobenzoyl) hydrazinecarbothioamide (compound 4m) (404 mg, yield 82.1%).

mp: 157.5 [deg.] C; ^{1 H NMR (700 MHz, CDCl3} ) δ 10.10 (s, 1H), 8.73 (s, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.46-7.43 (m, 2H), 7.35 (t, J = 7.3 Hz, 1H), 7.29 (s, 1H), 6.98 (dd, J = 8.3, 1.1 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H) , 2H); ¹³ C NMR (175 MHz, CDCl 3) δ 149.31, 132.39, 131.67, 131.22, 130.72, 130.61, 130.25, 129.54, 128.53, 127.19, 125.85, 124.89, 123.61, 111.14, 55.76, 20.71; LRMS (ESI) m / z: 350.1 [M + H] &lt; + &gt;; HRMS (ESI) m / z: Calcd. for [M + H] + C16H16ClN3O2S: 350.0725; found: 350.0724.

Synthetic example  14. Synthesis of Compound 4n

14-1. Synthesis of intermediate compound 2e

Ethyl thiophene-2-carboylate (compound 1e) (15.6 mL, 100 mmol) was dissolved in EtOH (280 mL), hydrazine monohydrate (25.1 mL, 400 mmol) were added, and the mixture was refluxed with stirring for 18 hours. After the reaction solution was cooled to room temperature, half of the solvent was removed under reduced pressure, and the precipitated solid was filtered. The solid was washed with a small amount of cold EtOH to obtain the desired compound, thiophene-2-carbohydrazide (compound 2e) (11.5 g, yield 81%).

^{1 H NMR (400 MHz, DMSO} -d6) δ 9.75 (s, 1H), 7.74 (dd, J = 5.0, 1.1 Hz, 1H), 7.70 (dd, J = 3.7, 1.1 Hz, 1H), 7.12 (dd , J = 5.0, 3.7 Hz, 1 H), 4.45 (s, 2 H).

14-2. Synthesis of Compound 4n

Thiophene-2-carbohydrazide (Compound 2e) (200 mg, 1.41 mmol) was dissolved in EtOH (10 mL), and 1-chloro-4-isothiocyanatobenzene -chloro-4-isothiocyanatobenzene) (262 mg, 1.55 mmol) were added, and the mixture was refluxed overnight. The reaction solution was cooled to room temperature, and the precipitated solid was filtered. The solid was washed with a small amount of cold EtOH to obtain the target compound N- (4-chlorophenyl) -2- (thiophene-2-carbonyl) hydrazinecarbothioamide (N- -2-carbonyl) hydrazinecarbothioamide (Compound 4n) (412 mg, yield 94%).

mp: 193.3-193.6 [deg.] C; ^{1 H NMR (400 MHz, DMSO} -d6) δ 10.59 (s, 1H), 9.93 (s, 1H), 9.86 (s, 1H), 7.86 (d, J = 4.9 Hz, 2H), 7.48 (s, 2H ), 7.38 (d, J = 8.7 Hz, 2H), 7.25-7.16 (m, 1H); ¹³ C NMR (100 MHz, DMSO-d 6)? 181.2, 161.1, 138.2, 137.4, 131.8, 129.6, 129.1, 128.1, 127.9, 127.6; MS (ESI) m / z 311.9 (M + H) &lt; + &gt;.

Synthetic example  15. Synthesis of compound 4o

Thiophene-2-carbohydrazide (compound 2e) was obtained in the same manner as in Synthesis Example 14-1. Thiophene-2-carbohydrazide (Compound 2e) (200 mg, 1.41 mmol) was dissolved in EtOH (10 mL), and isothiocyanatobenzene (185 μL, 1.55 mmol) were added, and the mixture was refluxed overnight. The reaction solution was cooled to room temperature, and the precipitated solid was filtered. The solid was washed with a small amount of cold EtOH to obtain the objective compound N-phenyl-2- (thiophene-2-carbonyl) hydrazinecarbothioamide (compound 4o) (308 mg, yield 79%).

^{1 H NMR (400 MHz, DMSO} -d6) δ 10.56 (s, 1H), 9.88 (s, 1H), 9.74 (s, 1H), 7.86 (d, J = 4.9 Hz, 2H), 7.43 (s, 2H ), 7.32 (t, J = 7.8 Hz, 2H), 7.25-7.07 (m, 2H).

Synthetic example  16. Synthesis of Compound 4p

Thiophene-2-carbohydrazide (compound 2e) was obtained in the same manner as in Synthesis Example 14-1. Thiophene-2-carbohydrazide (Compound 2e) (200 mg, 1.41 mmol) was dissolved in EtOH (10 mL), and 1-methoxy-4-isothiocyanatobenzene 1-methoxy-4-isothiocyanatobenzene) (214 μL, 1.55 mmol), and the mixture was refluxed overnight. The reaction solution was cooled to room temperature, and the precipitated solid was filtered. The solid was washed with a small amount of cold EtOH to obtain the target compound N- (4-methoxyphenyl) -2- (thiophene-2-carbonyl) hydrazinecarbothioamide (N- thiophene-2-carbonyl) hydrazinecarbothioamide (Compound 4p) (363 mg, yield 87%).

^{1 H NMR (400 MHz, DMSO} -d6) δ 10.53 (s, 1H), 9.76 (s, 1H), 9.64 (s, 1H), 7.86 (t, J = 3.3 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 7.20 (dd, J = 4.9,3.8 Hz, 1H), 6.89 (d, J = 8.9 Hz, 2H), 3.74 (s, 3H).

Synthetic example  17. Synthesis of compound 4q

Thiophene-2-carbohydrazide (compound 2e) was obtained in the same manner as in Synthesis Example 14-1. Thiophene-2-carbohydrazide (Compound 2e) (213 mg, 1.50 mmol) was dissolved in EtOH (12 mL), and 1-isopropyl-4-isothiocyanatobenzene 1-isopropyl-4-isothiocyanatobenzene) (292 mg, 1.65 mmol), and the mixture was refluxed overnight. The reaction solution was cooled to room temperature, and the precipitated solid was filtered. The solid was washed with a small amount of cold EtOH to give the title compound N- (4-isopropylphenyl) -2- (thiophene-2-carbonyl) hydrazine- 2- (thiophene-2-carbonyl) hydrazine-1-carbothioamide (compound 4q) (425 mg, 89%).

mp: 193.5 [deg.] C; ^{1 H NMR (700 MHz, DMSO} -d6) δ 10.54 (s, 1H), 9.80 (s, 1H), 9.68 (s, 1H), 7.88 (s, 1H), 7.86 (d, J = 4.9 Hz, 1H ), 7.35 (s, 2H), 7.20-7.21 (m, 3H), 2.88 (dt, J = 13.8, 6.9 Hz, 1H), 1.21 (d, J = 6.9 Hz, 6H); ¹³ C NMR (175 MHz, DMSO-d6) δ 181.75, 161.54, 145.62, 137.97, 137.37, 132.25, 132.09, 130.26, 130.04, 128.45, 126.63, 126.25, 33.43, 24.40, 24.29; LRMS (ESI) m / z: 320.1 [M + H] &lt; + &gt;; HRMS (ESI) m / z: Calcd. for [M + H] + C 15 H 17 N 3 OS 2: 320.0886; found: 320.0889.

Synthetic example  18. Synthesis of Compound 4r

Thiophene-2-carbohydrazide (compound 2e) was obtained in the same manner as in Synthesis Example 14-1. Thiophene-2-carbohydrazide (Compound 2e) (200 mg, 1.41 mmol) was dissolved in EtOH (10 mL), and isothiocyanatocyclohexane (219 μL, 1.55 mmol), and the mixture was refluxed overnight. The reaction solution was cooled to room temperature, and the precipitated solid was filtered. The solid was washed with a small amount of cold EtOH to obtain the target compound N-cyclohexyl-2- (thiophene-2-carbonyl) hydrazinecarbothioamide ( Compound 4r) (323 mg, yield 81%).

^{* 175 1 H NMR (400 MHz} , DMSO-d6) δ 10.29 (s, 1H), 9.23 (s, 1H), 7.84 (d, J = 4.6 Hz, 2H), 7.80 (d, J = 8.2 Hz, 1H J = 11.6 Hz, 2H), 1.57 (d, J = 12.4 Hz, 1H), 1.35 (s, -1.13 (m, 4H), 1.05 (d, J = 9.8 Hz, 1H).

Synthetic example  19. Synthesis of compound 4s

Thiophene-2-carbohydrazide (compound 2e) was obtained in the same manner as in Synthesis Example 14-1. 5-chlorothiophene-2-carbohydrazide was synthesized from thiophene-2-carbohydrazide (compound 2e). After 5-chlorothiophene-2-carbohydrazide (264 mg, 1.50 mmol) was dissolved in EtOH (12 mL), isothiocyanatocyclohexane (233 L , 1.65 mmol), and the mixture was refluxed overnight. The reaction solution was cooled to room temperature, and the precipitated solid was filtered. The solid was washed with a small amount of cold EtOH to obtain the target compound N-cyclohexyl-2- (5-chlorothiophene-2-carbonyl) hydrazinecarbothioamide (N- carbonyl) hydrazinecarbothioamide (Compound 4s) (437 mg, yield 92%).

mp: 183.7 [deg.] C; ^{1 H NMR (700 MHz, DMSO} -d6) δ 10.37 (s, 1H), 9.23 (s, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.70 (s, 1H), 7.24 (d, J = 4.0 Hz, 1H), 4.13 (s, 1H), 1.78 (s, 2H), 1.70 (d, J = 12.3 Hz, 2H), 1.58 , &Lt; / RTI &gt; 4H), 1.07-1.06 (m, 1H); ¹³ C NMR (175 MHz, DMSO-d6) δ 181.14, 160.47, 137.26, 134.20, 129.83, 128.60, 53.59, 32.29, 25.64, 25.42; LRMS (ESI) m / z: 318.1 [M + H] &lt; + &gt;; HRMS (ESI) m / z: Calcd. for [M + H] + C ₁₂ H ₁₆ ClN ₃ OS ₂ : 318.0496; found: 318.0499.

Synthetic example  20. Synthesis of compound 4t

Thiophene-2-carbohydrazide (compound 2e) was obtained in the same manner as in Synthesis Example 14-1. Thiophene-2-carbohydrazide (Compound 2e) Thiophene-2-carbohydrazide (Compound 2e) was prepared from 5-chlorothiophene-2-carbo 5-chlorothiophene-2-carbohydrazide was synthesized. 5-chlorothiophene-2-carbohydrazide (198 mg, 1.08 mmol) was dissolved in EtOH (12 mL), and isothiocyanatocyclohexane (167 L , 1.19 mmol), and the mixture was refluxed overnight. The reaction solution was cooled to room temperature, and the precipitated solid was filtered. The solid was washed with a small amount of cold EtOH to obtain the objective compound N-cyclohexyl-2- (4-ethyl-5-methylthiophene-3-carbonyl) hydrazinecarboxothiamide (N- ethyl-5-methylthiophene-3-carbonyl) hydrazinecarbothioamide (Compound 4t) (314 mg, yield 89.5%).

mp: 178.3 [deg.] C; ¹ H NMR (700 MHz, DMSO-d 6)? 9.90 (s, IH), 9.15 (s, IH), 7.84 2H, J = 7.4 Hz, 2H), 2.35 (s, 3H), 1.80-1.79 (m, 2H), 1.73-1.64 m, 4H), 1.03 (t, J = 7.4 Hz, 3H); ¹³ C NMR (175 MHz, DMSO-d6) δ 164.03, 140.07, 137.87, 137.55, 134.68, 133.87, 126.10, 53.20, 32.28, 25.62, 25.26, 20.16, 15.42, 12.89; LRMS (ESI) m / z: 326.1 [M + H] &lt; + &gt;; HRMS (ESI) m / z: Calcd. for [M + H] + C 15 H 24 N 3 OS 2: 326.1355; found: 326.1358.

Synthetic example  21. Synthesis of Compound 4u

21-1. Synthesis of intermediate compound 2f

Ethyl 6-hydroxypicolinate (167 mg, 1 mmol) was dissolved in methanol (20 ml), hydrazine hydrate (0.26 ml, 4 mmol) was added, and the mixture was refluxed for one day. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (2% MeOH in CH ₂ Cl ₂ ) to synthesize 6-hydroxypicolinohydrazide (compound 2f) (yield 80%) of the target compound 6-hydroxypicolinohydrazide.

^{1 H NMR (400 MHz, DMSO} ) δ 9.71 (s, 1H), 7.64 (dd, J = 8.7, 7.1 Hz, 1H), 7.06 (d, J = 6.5 Hz, 1H), 6.65 (d, J = 8.7 Hz, 1 H), 4.91 (s, 1 H).

21-2. Synthesis of compound 4u

6-hydroxypicolinohydrazide (Compound 2f) (77 mg, 0.5 mmol) was dissolved in EtOH (10 mL), 1-chloro-4-isothiocyanatobenzene -4-isothiocyanatobenzene) (94 mg, 0.55 mmol). The reaction solution was refluxed for 4 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with ether and filtered. The filtered solid was washed with ether and dried under reduced pressure to give the desired compound N- (4-chlorophenyl) -2- (6-hydroxypicolinoyl) hydrazine-1-carbothioamide) 2- (6-hydroxypicolinoyl) hydrazine-1-carbothioamide (Compound 4u) was obtained as a yellow solid (68 mg, 42% yield).

¹ H NMR (400 MHz, DMSO)? 11.25 (s, 1H), 10.53 (s, 1H), 10.01 = 8.0 Hz, 2H), 7.51 (d, J = 6.5 Hz, 1H), 7.41 (d, J = 8.8 Hz, 3H).

Synthetic example  22. Synthesis of Compound 4v

22-1. Synthesis of intermediate compound 2g

6-Fluoropicolinic acid (141 mg, 1 mmol) and tert-butyl hydrazinecarboxylate (159 mg, 1.2 mmol) were dissolved in DMF (3 ml) at 0 ^° C Dissolve, and sodium hydrogencarbonate (210 mg, 2.5 mmol), HOAt (272 mg, 2 mmol) and EDCI (310 mg, 2 mmol). The reaction solution was stirred at room temperature for 1 hour and then diluted with ethyl acetate. The organic layer was washed three times each with a 1N hydrochloric acid solution and a saturated aqueous solution of sodium hydrogencarbonate, and then washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give tert-butyl 2- (6-fluoropicolinoyl) Tert-butyl 2- (6-fluoropicolinoyl) hydrazine-1-carboxylate) as a white solid (246 mg, 96%). The resulting intermediate (130 mg, 0.5 mmol) was dissolved in DMF (1 mL), 4N HCl in dioxane (1 mL) was added to the mixture, the mixture was stirred at room temperature for 2 hours and the desired compound 6-fluoropicolino 6-fluoropicolinohydrazide &lt; / RTI &gt; (2 g).

^{1 H NMR (400 MHz, DMSO} ) δ 11.76 (s, 1H), 10.65 (s, 8H), 8.28 (dd, J = 15.7, 8.1 Hz, 1H), 8.06 (dd, J = 7.4, 1.8 Hz, 1H ), 7.57 (dd, J = 8.3, 1.8 Hz, 1 H).

22-2. Synthesis of compound 4v

6-fluoropicolinohydrazide (compound 2g) (78 mg, 0.5 mmol) was dissolved in EtOH (10 mL), and 1-chloro-4-isothiocyanatobenzene -4-isothiocyanatobenzene) (94 mg, 0.55 mmol). The reaction solution was refluxed for 6 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water and saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO ₂ , gradient, 4% to 6% MeOH in CH ₂ Cl ₂ ) to give the desired compound N- (4-chlorophenyl) -2- (6-fluoropicolinoyl) hydrazine (Compound 4v) was obtained as a white solid (142 mg, yield 87%). 1H NMR (400MHz, CDCl3)?

^{1 H NMR (400 MHz, DMSO} ) δ 10.60 (s, 1H), 10.01 - 9.70 (m, 2H), 7.90 (dd, J = 8.2, 7.4 Hz, 1H), 7.65 (dd, J = 7.3, 0.8 Hz , 1H), 7.54 (s, 2H), 7.39 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 7.9 Hz, 1H), 4.52 (q, J = 7.0 Hz, 2H), 1.35 (t , &Lt; / RTI &gt; J = 7.1 Hz, 3H).

Synthetic example  23. Synthesis of Compound 4w

23-1. Synthesis of intermediate compound 2h

Ethyl 5-hydroxypicolinate (167 mg, 1 mmol) was dissolved in methanol (20 ml), hydrazine hydrate (0.26 ml, 4 mmol) was added and the mixture was refluxed for one day. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (2% MeOH in CH ₂ Cl ₂ ) to obtain the target compound 5-hydroxypicolinohydrazide (Compound 2h) (yield: 27%).

^{1 H NMR (400 MHz, DMSO} ) δ 10.51 (s, 1H), 9.54 (s, 1H), 8.13 (d, J = 2.4 Hz, 1H), 7.88 - 7.82 (m, 1H), 7.29 (dd, J = 8.5, 2.8 Hz, 1 H), 4.52 (s, 2 H).

23-2. Synthesis of compound 4w

After 5-hydroxypicolinohydrazide (compound 2h) (39 mg, 0.25 mmol) was dissolved in EtOH (10 mL), 1-chloro-4-isothiocyanatobenzene -4-isothiocyanatobenzene) (48 mg, 0.28 mmol). The reaction solution was refluxed for 5 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue was purified by flash column chromatography (SiO ₂ , gradient, 3% MeOH in CH ₂ Cl ₂ ) to obtain the desired compound N- (4-chlorophenyl) -2- (5- hydroxypicolinoyl) hydrazine- 1-carbothioamide (Compound 4w) was obtained as a yellow solid (14 mg, yield: 17%). 1H-NMR (DMSO-d6)?

^{1 H NMR (400 MHz, MeOD} ) δ 8.09 (d, J = 2.5 Hz, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.9 Hz, 2H), 7.18 (m, 1H).

Synthetic example  24. Synthesis of compound 4x

6-hydroxypicolinohydrazide (Compound 2f) (92 mg, 0.6 mmol) was dissolved in EtOH (10 mL), and 1-chloro-4-isothiocyanatobenzene -4-isothiocyanatobenzene) (48 mg, 0.28 mmol). The reaction solution was refluxed for 6 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was washed with ether and filtered. After filtration, the solid was washed with ether and dried under reduced pressure to obtain the title compound N- (4-chlorophenyl) -2- (6-hydroxypicolinoyl) hydrazine-1-carbothioamide 2- (6-hydroxypicolinoyl) hydrazine-1-carbothioamide (compound 4x) as a white solid (173 mg, 89% yield).

^{1 H NMR (400 MHz, DMSO} ) δ 11.22 (s, 1H), 10.31 (s, 1H), 9.89 (s, 2H), 7.73 (s, 1H), 7.51 (d, J = 5.9 Hz, 2H), 7.41 (d, J = 8.7 Hz, 3H), 6.82 (s, 1H).

Synthetic example  25. Synthesis of compound 4y

25-1. Synthesis of intermediate compound 2i

Ethyl quinoline-2-carboxylate (201 mg, 1 mmol) was dissolved in methanol (20 ml), followed by addition of hydrazine hydrate (0.26 ml, 4 mmol) . The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (2% MeOH in CH ₂ Cl ₂ ) to synthesize the target compound quinolone-3-carbohydrazide (compound 2i) (yield: 43%).

25-2. Synthesis of Compound 4y

Quinoline-3-carbohydrazide (Compound 2i) (34 mg, 0.18 mmol) was dissolved in EtOH (4 mL), and then 1-chloro-4-isothiocyanatobenzene (1- chloro-4-isothiocyanatobenzene) (34 mg, 0.2 mmol). The reaction solution was refluxed for 4 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with ether and filtered. The resulting solid was washed with ether and dried under reduced pressure to obtain the title compound N- (4-chlorophenyl) -2- (quinoline-3-carbonyl) hydrazine- quinoline-3-carbonyl) hydrazine-1-carbothioamide (Compound 4y) as a brown solid (27 mg, 42% yield).

^{1 H NMR (400 MHz, MeOD} ) δ 9.36 (d, J = 2.2 Hz, 1H), 8.96 (d, J = 1.9 Hz, 1H), 8.14 (t, J = 8.7 Hz, 2H), 7.98 - 7.91 ( (m, 1H), 7.79-7.73 (m, 1H), 7.53 (d, J = 8.7 Hz, 2H), 7.41-7.34 (m, 2H).

Synthetic example  26. Synthesis of compound 4z

26-1. Synthesis of intermediate compound 2j

Tert-butyl hydrazinecarboxylate (159 mg, 1.2 mmol) and 5-fluoropicolinic acid (141 mg, 1 mmol) were dissolved in DMF (3 ml) at 0 ^° C Dissolve, and sodium hydrogencarbonate (210 mg, 2.5 mmol), HOAt (272 mg, 2 mmol) and EDCI (310 mg, 2 mmol). The reaction solution was stirred at room temperature for 1 hour and then diluted with ethyl acetate. The organic layer was washed three times each with a 1N hydrochloric acid solution and a saturated aqueous solution of sodium hydrogencarbonate, and then washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give tert-butyl 2- (5-fluoropicolinoyl) Tert-butyl 2- (5-fluoropicolinoyl) hydrazine-1-carboxylate) as a white solid (246 mg, 96%). The obtained intermediate (130 mg, 0.5 mmol) was dissolved in DMF (1 mL), and 4N HCl in dioxane (1 mL) was added thereto. The mixture was stirred at room temperature for 2 hours and then treated with nitrogen to obtain the target compound 5-fluoropicol 5-fluoropicolinohydrazide &lt; / RTI &gt; (Compound 2j) (yield: 68%).

^{1 H NMR (400 MHz, DMSO} ) δ 11.70 (s, 1H), 8.78 (d, J = 2.8 Hz, 1H), 8.26 - 8.13 (m, 1H), 8.05 - 7.98 (m, 1H), 4.77 (s , 3H).

26-2. Synthesis of compound 4z

5-fluoropicolinohydrazide (77 mg, 0.5 mmol) was dissolved in dioxane (8 mL), and then 1-chloro-4-isothiocyanatobenzene ) (93 mg, 0.5 mmol) and triethylamine (0.21 ml). The reaction solution was stirred at room temperature for 4 hours and then concentrated under reduced pressure. The residue was recrystallized from dichloromethane to obtain the target compound N- (4-chlorophenyl) -2- (5-fluoropicolinoyl) hydrazine-1-carbothioamide 5-fluoropicolinoyl) hydrazine-1-carbothioamide (Compound 4z) was obtained as a white solid (110 mg, yield 68%).

^{1 H NMR (400 MHz, DMSO} ) δ 10.78 (s, 1H), 9.83 (d, J = 45.9 Hz, 2H), 8.72 (d, J = 2.8 Hz, 1H), 8.21 - 8.11 (m, 1H), 8.02-7.91 (m, 1H), 7.51 (s, 2H), 7.39 (d, J = 8.8 Hz, 2H).

Synthetic example  27. Compound 4aa  synthesis

27-1. Synthesis of intermediate compound 2k

Ethyl 3-ethoxy-7-hydroxy-2-naphthoate (260 mg, 1 mmol) was dissolved in methanol (20 ml) and hydrazine hydrate 0.26 ml, 4 mmol), and the mixture was refluxed for one day. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (2% MeOH in CH ₂ Cl ₂ ) to obtain the target compound 3-ethoxy-7-hydroxy-2-naphthohydrazide ) (Compound 2k) (yield: 90%).

¹ H NMR (400 MHz, DMSO)? 11.60 (s, IH), 10.11 (s, IH), 8.33 (s, IH), 7.67 (d, J = 8.9 Hz, IH), 7.30-7. ), 4.74 (s, 2H), 4.12 (q, J = 7.0 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H).

27-2. Synthesis of compound 4z

3-ethoxy-7-hydroxy-2-naphthohydrazide (110 mg, 0.45 mmol) was dissolved in EtOH (15 mL) 4-isothiocyanatobenzene (48 mg, 0.28 mmol) was added thereto. The reaction solution was stirred at room temperature for 4 hours and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (Si02, 1% MeOH in CH2Cl2) to obtain the desired compound N- (4-chlorophenyl) -2- (3-ethoxy- (3-ethoxy-2-naphthoyl) hydrazine-1-carbothioamide (Compound 4aa) was obtained as a yellow solid (75 mg, yield 40%).

^{1 H NMR (400 MHz, DMSO} ) δ 11.27 (s, 1H), 10.79 (s, 1H), 9.94 (d, J = 43.6 Hz, 2H), 8.41 (s, 1H), 7.70 (d, J = 9.1 Hz, 1H), 7.58 (s , 2H), 7.41 (d, J = 8.8 Hz, 2H), 7.28 (s, 2H), 7.20 (dd, J = 9.0, 2.5 Hz, 1H), 4.13 (q, J = 6.9 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H).

Synthetic example  28. Compound Of 4ab  synthesis

28-1. Synthesis of 2l of intermediate compound

Ethyl 3,5-dihydroxy-2-naphthoate (232 mg, 1 mmol) was dissolved in methanol (20 ml) and hydrazine hydrate (0.26 ml, mmol) were added, and the mixture was refluxed and stirred for one day. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (2% MeOH in CH ₂ Cl ₂ ) to obtain the target compound 3,5-dihydroxy-2-naphthohydrazide (compound 21 ) (Yield: 86%).

^{1 H NMR (400 MHz, DMSO} ) δ 11.31 (s, 1H), 10.02 (s, 2H), 8.35 (s, 1H), 7.43 (s, 1H), 7.27 (d, J = 8.4 Hz, 1H), (Dd, J = 8.1, 7.6 Hz, 1H), 6.83 (dd, J = 7.4, 0.8 Hz, 1H), 4.73 (s, 2H).

28-2. compound Of 4ab  synthesis

3,5-dihydroxy-2-naphthohydrazide (175 mg, 0.8 mmol) was dissolved in EtOH (30 mL), and 1-chloro-4-isothiou 1-chloro-4-isothiocyanatobenzene (204 mg, 1.2 mmol) and triethylamine (0.12 ml) were added. The reaction solution was stirred at room temperature for 4 hours and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (Si02, 10% MeOH in CH2Cl2) to obtain the desired compound N- (4-chlorophenyl) -2- (3,5- dihydroxy-2-naphthoyl) hydrazine- (4-chlorophenyl) -2- (3,5-dihydroxy-2-naphthoyl) hydrazine-1-carbothioamide (compound 4ab) was obtained as a yellow solid (131 mg, yield 42%).

^{1 H NMR (400 MHz, DMSO} ) δ 11.40 (s, 1H), 10.76 (s, 1H), 10.10 (s, 1H), 9.96 (d, J = 44.7 Hz, 2H), 8.45 (s, 1H), 7.60 (s, 2H), 7.53 (s, 1H), 7.41 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 7.6 Hz, 1H), 7.17 (t, 1H), 6.88 (d, J = 6.9 Hz, 1H).

Synthetic example  29. Compound 4ac  synthesis

29-1. Synthesis of intermediate compound 2m

Ethyl quinoline-2-carboxylate (201 mg, 1 mmol) was dissolved in methanol (20 ml), followed by addition of hydrazine hydrate (0.26 ml, 4 mmol) . The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (2% MeOH in CH ₂ Cl ₂ ) to obtain the target compound quinolone-2-carbohydrazide (compound 2m) as a yellow solid (120 mg, 64 %).

^{1 H NMR (400 MHz, DMSO} ) δ 10.04 (s, 1H), 8.57 (d, J = 8.1 Hz, 1H), 8.12 (d, J = 8.5 Hz, 2H), 8.09 (dd, J = 8.3, 1.1 (Ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.73 (ddd, J = 8.1, 6.9,1.2 Hz, 1H), 4.66 (s, 2H).

29-2. compound 4ac  synthesis

Quinoline-2-carbohydrazide (compound 2m) (55 mg, 0.29 mmol) was dissolved in EtOH (10 mL), 1-chloro-4-isothiocyanatobenzene -4-isothiocyanatobenzene) (56 mg, 0.33 mmol). The reaction solution was stirred at room temperature for 4 hours and then concentrated under reduced pressure. The residue was diluted with ether and filtered to give a solid. The resulting solid was washed again with ether and dried to obtain the objective compound N- (4-chlorophenyl) -2- (quinoline-2-carbonyl) hydrazine-1-carbothioamide quinoline-2-carboyl) hydrazine-1-carbothioamide (Compound 4ac) as a red solid (50 mg, 48% yield).

^{1 H NMR (400 MHz, DMSO} ) δ 10.96 (s, 1H), 9.91 (d, J = 40.4 Hz, 2H), 8.61 (d, J = 8.5 Hz, 1H), 8.18 (dd, J = 8.5, 3.7 Hz, 2H), 8.13 (d , J = 7.5 Hz, 1H), 7.95 - 7.88 (m, 1H), 7.80 - 7.73 (m, 1H), 7.52 (d, J = 9.9 Hz, 2H), 7.38 (d , J = 8.7 Hz, 2H).

Synthetic example  30. Compound 4ad  synthesis

30-1. Synthesis of intermediate compound 2n

Ethyl 4-ethoxy-1-hydroxy-2-naphthoate (260 mg, 1 mmol) was dissolved in methanol (20 ml) and hydrazine hydrate 0.26 ml, 4 mmol), and the mixture was refluxed for one day. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (2% MeOH in CH ₂ Cl ₂ ) to obtain the target compound 4-ethoxy-1-hydroxy-2-naphthohydrazide ) (Compound 2n) (yield 40%).

^{1 H NMR (400 MHz, DMSO} ) δ 13.95 (s, 1H), 10.28 (s, 1H), 8.29 - 8.21 (m, 1H), 8.12 (dd, J = 8.2, 0.7 Hz, 1H), 7.69 - 7.56 (m, 2H), 7.27 (s, 1H), 4.74 (s, 2H), 4.18 (q, J = 7.0 Hz, 2H), 1.47 (t, J = 7.0 Hz, 3H).

30-2. compound 4ad  synthesis

After 4-ethoxy-1-hydroxy-2-naphthohydrazide (50 mg, 0.2 mmol) was dissolved in EtOH (10 mL), 1-chloro-4- -Ithothiocyanatobenzene (51 mg, 0.3 mmol) and triethylamine (0.03 ml) were added to the reaction mixture, and the reaction solution was stirred at room temperature for 4 hours and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 25% EtOAc in Hexanes) to obtain the desired compound N- (4-chlorophenyl) -l, 2- (4-ethoxy-1-hydroxy-2-naphthoyl) hydrazine-1-carbothioamide hydrazine-1-carbothioamide (compound 4ad) as a yellow solid (31 mg, yield 37%).

^{1 H NMR (400 MHz, DMSO} ) δ 13.33 (s, 1H), 11.00 (s, 1H), 10.01 (d, J = 16.9 Hz, 2H), 8.29 (d, J = 8.1 Hz, 1H), 8.16 ( d, J = 8.1 Hz, 1H ), 7.73 - 7.68 (m, 1H), 7.67 - 7.61 (m, 1H), 7.51 (s, 2H), 7.41 (d, J = 8.7 Hz, 2H), 7.35 (s , 1H), 4.22 (q, J = 6.9 Hz, 2H), 1.50 (t, J = 7.0 Hz, 3H).

Synthetic example  31. Compound Of 4ae  synthesis

6-fluoropicolinohydrazide (compound 2g) was obtained by following the same procedure as Synthesis Example 22-1.

6-Fluoropicolinohydrazide (compound 2g) (77 mg, 0.5 mmol) was dissolved in dioxane (8 mL), and 1-chloro-4-isothiocyanatobenzene -4-isothiocyanatobenzene) (93 mg, 0.55 mmol) and triethylamine (0.21 ml). The reaction solution was stirred at room temperature for 4 hours and concentrated under reduced pressure. The residue was diluted with ether and filtered to give a solid. The solid was washed with ether and then dried to give the title compound N- (4-chlorophenyl) -2- (6-fluoropicolinoyl) hydrazine-1-carbothioamide -fluoropicolinoyl) hydrazine-1-carbothioamide (compound 4ae) as a black solid (57 mg, 35%).

^{1 H NMR (400 MHz, DMSO} ) δ 10.79 (s, 1H), 9.85 (d, J = 39.9 Hz, 2H), 8.23 (d, J = 6.8 Hz, 1H), 8.03 (d, J = 5.9 Hz, 1H), 7.49 (d, J = 7.2 Hz, 3H), 7.39 (d, J = 8.2 Hz, 2H).

< Example > Measuring the activity of the endoplasmic reticulum stress inhibitor

Experiments were conducted to measure the endogenous stress inhibitory activity of the compounds synthesized in Synthesis Examples 1 to 20.

Example  1. Reporter Assay  Measurement of endoplasmic reticulum stress inhibitory activity using system

1.1 Cell culture

Human embryonic kidney cells (HEK293 cells) and human hepatocarcinoma cells (HepG2) were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS), penicillin and streptomycin , And incubated at 37 ° C in a 5% CO ₂ atmosphere saturated with water vapor.

1.2 Reporter Assay  system

The effect of 2-arylcarbonylhydrazine carbothioamide derivatives on the expression of GRP78, one of the typical genes as a marker of ER stress, was confirmed by GRP78 reporter gene assay (Jeong et al., 2013).

A reporter assay system was used in the literature (Jeong et al, 2013) for measuring IC50 values in ER stress. Briefly, 293 cells were transfected with a human GRP78 promoter (human GRP78 promoter) repeatedly containing ER stress response elements (ERSE) to express the GRP78 promoter responsive to luciferase activity. 5,000 cells were plated on 384-well microplates and the ER stress was induced by administration of tunicamycin. Screening for inhibitors of the luciferase signal increased by induced ER stress. The ER stress inhibitory activity was expressed as a percentage of the relative value based on the luciferase activity induced by only tunicamycin. Activity at various concentrations was treated with Prism 5 software (Graphpad Software Inc.) to calculate IC 50 values.

1.3 Results of measurement of endoplasmic reticulum stress inhibitory activity

The IC ₅₀ values of 2-arylcarbonylhydrazine carbothioamide derivative compounds 4a to 4t synthesized according to Synthesis Examples 1 to 20 and 1-HNA (hydroxynaphthoic acid) of the conventional endoplasmic reticulum stress inhibitor were measured. Each IC ₅₀ value is the mean value of three independent experiments.

<Table 1>

As a result, 2-arylcarbonylhydrazine carbothioamide derivative compounds showed IC ₅₀ values of 0.63 to 50 μM. this is 10 times or more than the base chemical chaperone salicylate good IC ₅₀ illustrating a flow HNA (Jeong et al, 2013) have shown an IC ₅₀ = 183 μM of all, an IC ₅₀ improvement over up to 200 times the value (Table 1).

Example 2. Measurement of changes in the endoplasmic reticulum markers using the Western blot test

HepG2 cells were treated with a 2-arylcarbonylhydrazine carbothioamide derivative compound, and then the expression level of the protein reflecting the stress of the endoplasmic reticulum was measured using a Western blotting method.

The 2-arylcarbonyl hydrazinecarbothioamide derivative compound was used in a concentration of 1, 3, 5, and 10 μM, respectively, using Compound 4h prepared according to Synthesis Example 8.

Specifically, the Western blot test was performed as follows. HepG2 cells were plated on a 6-well plate in a number of 500,000 cells / well. Twenty-four hours later, tunicamycin was added to a final concentration of 1 mg / mL to induce endoplasmic reticulum stress and further cultured for 22 hours. Cells were harvested and lysed in a lysis buffer (50 mM N- (2-hydroxyethyl) pierazine-N'-2-ethanesulfonic acid (HEPES), pH 7.4, 100 mM NaF, 50 mM NaCl, (10 mM sodium pyrophosphate, 10 mM glycerol-2-phosphate, 5 mM ethylenediamine tetraacetic acid (EDTA), 5 mM ethylene glycol bis (2-aminoethylether) -N, N, N ', N'-tetraacetic acid % Triton X-100) was added thereto to destroy the cells. After incubation for 20 min on ice, 6x sodium dodecyl sulfate (SDS) sample buffer was added for 5 min to clarify and heated, followed by SDS-PAGE gel electrophoresis. Proteins were transferred to a nitrocellulose membrane and analyzed by Western blot. Western blotting was performed using anti-phosphorylated PERK (Thr980) antibody, anti-phosphorylated eIF2a antibody, and anti-CHOP antibody.

As a result, it was confirmed that when compound 4h was administered, the expression of the protein related to the stress of the endoplasmic reticulum was decreased. Specifically, phosphorylation of PERK, phosphorylation of eIF2a, and expression of CHOP decreased significantly (Fig. 1). Thus, it was found that the 2-arylcarbonylhydrazine carbothioamide derivative compound had an effect of suppressing the stress of the endoplasmic reticulum.

Claims (6)

Claims 1. A pharmaceutical composition comprising a 2-arylcarbonylhydrazine carbothioamide derivative compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient,
Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, Kreutzfeldt-Jakob disease (Alzheimer's disease), schizophrenia, -Jakob disease, Wolcott-Rallison syndrome, Wolfram syndrome, ischemic disease, cardiovascular disease, neurodegenerative disease, bipolar disorder, arteriosclerosis, inflammation, ischemia, heart disease, liver disease , Pancreatic disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and cancer.
[Chemical Formula 1]

Ar is phenyl, phenyl unsubstituted or substituted with chloro, pyridine unsubstituted or substituted with fluoro or hydroxy, thiophen unsubstituted or substituted with chloro, methyl or ethyl, quinoline and unsubstituted or ethoxy, &Lt; / RTI &gt; substituted naphthyl; And
Wherein R is selected from the group consisting of phenyl, butyl, phenylmethyl and cyclohexyl unsubstituted or substituted by chloro, trifluoromethyl, methoxy, methyl or isopropyl. delete delete The pharmaceutical composition according to claim 1, wherein said compound is one of the following compounds:
N- (3,4-dichlorophenyl) -2-picolinoyl hydrazine carbothioamide;
N- (2- (trifluoromethyl) phenyl) -2-picolinoyl hydrazine carbothioamide;
N-phenyl-2-picolinoyl hydrazine carbothioamide;
N- (4-chlorobenzyl) -2-picolinoyl hydrazine carbothioamide;
N-butyl-2-picolinoyl hydrazine carbothioamide;
N-benzyl-2-picolinoyl hydrazine carbothioamide;
N- (4-methoxyphenyl) -2-picolinoyl hydrazine carbothioamide;
N- (4-chlorophenyl) -2-picolinoyl hydrazine carbothioamide;
N-cyclohexyl-2-picolinoyl hydrazine carbothioamide;
N- (4-chlorophenyl) -2-nicotinoylhydrazine carbothioamide;
N- (4-chlorophenyl) -2-isonicotinoylhydrazine carbothioamide;
N-phenyl-2-benzoylhydrazine carbothioamide;
N- (2-methoxy-5-methylphenyl) -2- (2-chlorobenzoyl) hydrazine carbothioamide;
N- (4-chlorophenyl) -2- (thiophene-2-carbonyl) hydrazinecarbothioamide;
N-phenyl-2- (thiophene-2-carbonyl) hydrazine carbothioamide;
N- (4-methoxyphenyl) -2- (thiophene-2-carbonyl) hydrazinecarbothioamide;
N- (4-isopropylphenyl) -2- (thiophene-2-carbonyl) hydrazine-1-carbothioamide;
N-cyclohexyl-2- (thiophene-2-carbonyl) hydrazine carbothioamide;
N-cyclohexyl-2- (5-chlorothiophene-2-carbonyl) hydrazine carbothioamide;
N-cyclohexyl-2- (4-ethyl-5-methylthiophene-3-carbonyl) hydrazinecarbothioamide;
N- (4-chlorophenyl) -2- (6-hydroxypicolinoyl) hydrazine-1-carbothioamide;
N- (4-chlorophenyl) -2- (6-fluoropicolinoyl) hydrazine-1-carbothioamide;
N- (4-chlorophenyl) -2- (5-hydroxypicolinoyl) hydrazine-1-carbothioamide;
N- (4-chlorophenyl) -2- (6-hydroxypicolinoyl) hydrazine-1-carbothioamide;
N- (4-chlorophenyl) -2- (quinoline-3-carbonyl) hydrazine-1-carbothioamide;
N- (4-chlorophenyl) -2- (5-fluoropicolinoyl) hydrazine-1-carbothioamide;
N- (4-chlorophenyl) -2- (3-ethoxy-7-hydroxy-2-naphthoyl) hydrazine-1-carbothioamide;
N- (4-chlorophenyl) -2- (3,5-dihydroxy-2-naphthoyl) hydrazine-1-carbothioamide;
N- (4-chlorophenyl) -2- (quinoline-2-carbonyl) hydrazine-1-carbothioamide;
N- (4-chlorophenyl) -2- (4-ethoxy-1-hydroxy-2-naphthoyl) hydrazine-1-carbothioamide; And
N- (4-chlorophenyl) -2- (6-fluoropicolinoyl) hydrazine-1-carbothioamide. The pharmaceutical composition according to claim 1, wherein the compound inhibits the stress of the endoplasmic reticulum. delete

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