Compound targeting EGR-1 and use thereof for treatment of atopic dermatitis

Abstract

The present invention relates to a compound targeting EGR-1 and a use thereof for treatment of atopic dermatitis. The compound targeting EGR-1, an isomer thereof, or a pharmaceutically acceptable salt thereof, and a composition comprising same, according to the present invention, inhibit the DNA binding capacity of the transcription factor EGR-1, thereby reducing inflammatory cytokines produced by the involvement of EGR-1, and thus may be useful for the prevention, alleviation, or treatment of atopic dermatitis.

Description

[0001] Description Title of the invention: Compound targeting EGR-1 and its use for treating atopic dermatitis Technical field The present invention relates to a compound targeting EGR-1, an isomer thereof or a pharmaceutically acceptable salt thereof, and a composition containing the same for preventing, improving or treating atopic dermatitis. Background art Atopic dermatitis is a chronic, relapsing skin inflammatory disease in which allergic symptoms due to immune hypersensitivity occur on the skin, weakening the skin barrier, drying the skin, and accompanied by severe itching. It is known that atopic dermatitis worsens inflammation and itching symptoms by overexpression of inflammatory cytokines in the lesion area. Cytokines are proteins secreted from cells in relation to microbial infection or immunity, and are factors that affect the interaction of cells related to the immune system. When the production and secretion of cytokines are excessive or not properly regulated, they can mediate or worsen various diseases related to the deficiency of immunoregulatory function and physiological state (e.g., inflammation). Thymic stromal lymphopoietin (TSLP), CD4, secreted by keratinocytes, are present in the lesion site of acute atopic dermatitis. +Interleukin-4 (IL-4), interleukin-13 (IL-13), and interleukin-31 (IL-31) secreted by helper type 2 T lymphocytes (Th2) are greatly increased, and in the lesion area of ​​chronic atopic dermatitis, cytokines secreted by Th1 lymphocytes, interferon-gamma (IFN y) and tumor necrosis factor-alpha (TNF a), are increased. In the past, topical steroid treatments were mainly used to treat atopic dermatitis. Steroid preparations are artificially synthesized from cortisol, a hormone secreted by the adrenal cortex, and can suppress hypersensitive immune responses, reduce cytokine production, and relieve itching of the skin. However, especially when infants and young children use steroid preparations for a long period of time, their immunity may be weakened and side effects such as skin atrophy or growth retardation may occur. For this reason, immunosuppressants such as non-steroidal calcineurin inhibitor cyclosporin have been developed and commercialized. However, these too can cause various side effects such as cancer development due to weakened immunity when used for a long period of time (J Invest Dermatol 2007; 127: 808-816). Therefore, various studies are being conducted on substances that alleviate atopic dermatitis symptoms in a way different from conventional steroid preparations.

[0002] EGR-1 (Early growth response-1) is a protein encoded by the EGR-1 gene and is a transcription factor important for cell growth, differentiation, survival, apoptosis, and immune response. EGR-1 has three zinc finger DNA-binding domains of the Cys2-His2 type, and transcription can only be initiated and gene expression can occur when EGR-1 binds to DNA. In other words, EGR-1 regulates the production of proteins, including cytokines.

[0003] EGR-1 regulates inflammatory responses in various tissues, and its expression is increased in dermal wounds and psoriatic tissues in the skin. In addition, EGR-1 mediates the production of thymic stromal lymphopoietic protein (TSLP) by IL-33 stimulation in human keratinocytes and increases the production of psoriasin (S100A7), a psoriasis-inducing factor produced by IL-17, and thus is thought to be an important factor in the skin inflammatory response (Exp Dermatol 2015; 24: 857— 63; Exp Dermatol 2014; 23: 890-5). The present inventors, through previous studies, discovered that when the skin is exposed to an inflammatory environment, EGR-1 expressed in keratinocytes increases the production of cytokines (e.g., TSLP, IL-1p, IL-6, IL-17, IL-23, etc.) that induce atopic dermatitis hypersensitivity reactions and chemokines (CXCL1 and CCL5) that attract inflammatory cells such as T lymphocytes and mast cells to the lesion site, and increases the expression of the P0MC gene, a precursor of beta-endorphin, a neurotransmitter that stimulates cutaneous sensory nerves and transmits itchiness to the brain (see Non-Patent Documents 1 and 2). Therefore, a substance that inhibits the DNA binding ability of EGR-1 can be an important strategy for the treatment of atopic dermatitis. Detailed Description of the Invention Technical Problem One object of the present invention is to provide a compound targeting the transcription factor EGR-1, an isomer thereof, or a pharmaceutically acceptable salt thereof. Another object of the present invention is to provide a composition for preventing, improving or treating atopic dermatitis, comprising a compound targeting EGR-1, an isomer thereof or a pharmaceutically acceptable salt thereof.Technical solution In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing, improving or treating atopic dermatitis, comprising a compound of the following chemical formula 1, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient:

[0004] [Chemical Formula 1] In the above formula,

[0005] ※ is hydrogen, C1-C6 alkyl, - CH2- C 6-10 Aryl or , and at this time, the C1-C6 alkyl and - CH2- C 6-10 Each aryl may be independently unsubstituted or substituted with 1 to 3 halogens;

[0006] R 1 is hydrogen or halogen;

[0007] R 2 is hydrogen, halogen, hydroxy, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each independently unsubstituted or substituted with 1 to 3 halogens;

[0008] R 3 , R 4 and each independently represents hydrogen, halogen, hydroxy, or C1-C6 alkoxy, wherein the C1-C6 alkoxy may be unsubstituted or substituted with 1 to 3 halogens;

[0009] R 6 is hydrogen, halogen, hydroxy, -NO2, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each independently unsubstituted or substituted with 1 to 3 halogens;

[0010] R 7is hydrogen, halogen, hydroxy, -NO2, -CN, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy may each independently be unsubstituted or substituted with 1 to 3 halogens. The present invention provides a pharmaceutical composition for preventing or improving atopic dermatitis, comprising a compound of the above chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. In addition, the present invention provides any one compound selected from the group consisting of the following, an isomer thereof, or a pharmaceutically acceptable salt thereof as a novel compound targeting EGR-1:

[0011] (Z)-N-(4-cyanophenyl)-2-(7-fluoro-2-oxoindolin-3-ylidene)hydrazinecarbothioamide;

[0012] (Z)-2-(7-fluoro-2-oxoindoline-3-ylidene)-N-(4-(trifluoromethyl)phenyl)hydrazinecarbotheramide;

[0013] (Z)-2-(6-methoxy-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide;

[0014] (Z)- 2-(6-methoxy-2-oxoindolin- 3-ylidene)- N-(3-nitrophenyl)hydrazine- 1-carbothioamide;

[0015] (Z)- 2-(6 -methoxy- 2 -oxoindolin- 3 -ylidene)- N-(2 -methoxyphenyl)hydrazine- 1-carbothioamide;

[0016] (Z)-N-(4-cyanophenyl)-2-(6-methoxy-2-oxoindoline-3-ylidene)hydrazinecarbotheramide;

[0017] (Z)-2-(6-methoxy-2-oxoindolin-3-ylidene)-N-(4-(trifluoromethyl)phenyl)hydrazinecarbotheramide;

[0018] (Z)-N-ethyl-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazinecarbotheramide;

[0019] (Z)-2-(5-methyl-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheroamide;

[0020] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(3 -nitrophenyl)hydrazinecarbotheramide;

[0021] (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheramide;

[0022] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(4 -nitrophenyl)hydrazinecarbotheramide;

[0023] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-phenylhydrazinecarbotheramide;

[0024] (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide;

[0025] (Z)-2-(7-bromo-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheramide;

[0026] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(3 -methoxyphenyl)hydrazinecarbotheramide;

[0027] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(4 -methoxyphenyl)hydrazinecarbotheramide;

[0028] (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-(4-nitrophenyl)hydrazinecarbotheramide;

[0029] (Z)-2-(4-chloro-2-oxoindolin-3-ylidene)-N-(2-methoxyphenyl)hydrazinecarbotheramide;

[0030] (Z)-2-(7-fluoro-2-oxoindolin-3-ylidene)-N-(4-nitrophenyl)hydrazinecarbothioamide;

[0031] (Z)- 2-(6-methoxy- 2-oxoindoline- 3-ylidene)- N-(3-(trifluoromethyl)phenyl)hydrazinecarbotheramide;

[0032] (Z)- N-(4-fluorophenyl)-2-(6-methoxy-2-oxoindoline-3-ylidene)hydrazine-1-carbotorimide;

[0033] (Z)- N-(4 -bromophenyl)- 2-(6 -methoxy-2 -oxoindolin- 3 -ylidene)hydrazine- 1-carbothioamide;

[0034] (Z)-N-Benzyl-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazine-1-carbothioamide;

[0035] (Z)- N-(4-cyanophenyl)-2-(5-methyl- 2-oxoindoline- 3-ylidene)hydrazinecarbotheroamide; and

[0036] (Z)-2-(5-methyl-2-oxoindoline-3-ylidene)-N-(m-tolyl)hydrazinecarbotheramide. In addition, the present invention provides a composition comprising any one compound selected from the group consisting of: an isomer thereof or a pharmaceutically acceptable salt thereof

[0037] (Z)-N-(4-cyanophenyl)-2-(7-fluoro-2-oxoindolin-3-ylidene)hydrazinecarbothioamide;

[0038] (Z)-2-(7-fluoro-2-oxoindoline-3-ylidene)-N-(4-(trifluoromethyl)phenyl)hydrazinecarbotheramide;

[0039] (Z)-2-(6-methoxy-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide

[0040] (Z)- 2-(6-methoxy-2-oxoindolin- 3-ylidene)- N-(3-nitrophenyl)hydrazine- 1-carbothioamide;

[0041] (Z)- 2-(6 -methoxy- 2 -oxoindolin- 3 -ylidene)- N-(2 -methoxyphenyl)hydrazine- 1-carbothioamide;

[0042] (Z)-N-(4-cyanophenyl)-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazinecarbotheramide;

[0043] (Z)- 2-(6-methoxy- 2-oxoindoline- 3-ylidene)- N-(4-(trifluoromethyl)phenyl)hydrazinecarbotheramide;

[0044] (Z)-N-ethyl-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazinecarbotheramide;

[0045] (Z)-2-(5-methyl-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheroamide;

[0046] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(3 -nitrophenyl)hydrazinecarbotheramide;

[0047] (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheramide;

[0048] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(4 -nitrophenyl)hydrazinecarbotheramide;

[0049] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-phenylhydrazinecarbotheramide;

[0050] (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide;

[0051] (Z)-2-(7-bromo-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheramide;

[0052] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(3 -methoxyphenyl)hydrazinecarbotheramide;

[0053] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(4 -methoxyphenyl)hydrazinecarbotheramide;

[0054] (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-(4-nitrophenyl)hydrazinecarbotheramide;

[0055] (Z)-2-(4-chloro-2-oxoindolin-3-ylidene)-N-(2-methoxyphenyl)hydrazinecarbotheramide;

[0056] (Z)-2-(7-fluoro-2-oxoindolin-3-ylidene)-N-(4-nitrophenyl)hydrazinecarbothioamide;

[0057] (Z)- 2-(6-methoxy- 2-oxoindoline- 3-ylidene)- N-(3-(trifluoromethyl)phenyl)hydrazinecarbotheramide;

[0058] (Z)- N-(4-fluorophenyl)-2-(6-methoxy-2-oxoindoline-3-ylidene)hydrazine-1-carbotorimide;

[0059] (Z)- N-(4 -bromophenyl)- 2-(6 -methoxy-2 -oxoindolin- 3 -ylidene)hydrazine- 1-carbothioamide;

[0060] (Z)-N-Benzyl-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazine-1-carbothioamide;

[0061] (Z)- N-(4-cyanophenyl)-2-(5-methyl- 2-oxoindoline- 3-ylidene)hydrazinecarbotheroamide; and

[0062] (Z)-2-(5-methyl-2-oxoindoline-3-ylidene)-N-(m-tolyl)hydrazinecarbotheramide; Effect of the invention The compound targeting EGR-1 according to the present invention, an isomer thereof or a pharmaceutically acceptable salt thereof, and a composition containing the same reduce the formation of cytokines that induce skin inflammation by binding to the DNA binding site of the transcription factor EGR-1, and thus can be usefully used for the prevention, improvement or treatment of atopic dermatitis. Brief description of the drawings Figure 1 briefly illustrates an EDBA (EGR1-DNA Binding Activity Assay) experimental method. Figure 2 is a graph showing the results of measuring the DNA binding inhibition rate of EGR-1 for a compound according to one embodiment of the present invention. Figure 3 is a graph showing the results of an in virto cytotoxicity test for a compound according to one embodiment of the present invention. Figure 4 shows the interaction between amino acid residues of compound 21 and EGR-1. Figure 5 is an image predicting the three-dimensional structure of the complex of compound 21 and EGR-1 using the PyMOL program. Figure 6 shows the interaction between amino acid residues of compound 23 and EGR-1. Figure 7 is an image predicting the three-dimensional structure of the complex of compound 23 and EGR-1 using the PyMOL program. Figure 8 shows the interaction between amino acid residues of compound 25 and EGR-1. Figure 9 is an image predicting the three-dimensional structure of the complex of compound 25 and EGR-1 using the PyMOL program. Figure 10 shows the results of a molecular docking experiment for compound 21. Figure 11 shows the results of a molecular docking experiment for compound 23. Figure 12 shows the results of a molecular docking experiment for compound 25. Figure 13 shows the results of electrophoretic mobility shift analysis (EMSA) performed after administering a compound according to one embodiment of the present invention to keratinocytes.FIG. 14 shows the results of reverse transcription polymerase chain reaction (RT-PCR) performed after administering a compound according to one embodiment of the present invention to keratinocytes. FIGS. 15 to 17 show the atopic dermatitis therapeutic effect of three compounds (Compounds 21, 23, and 25) in an atopic dermatitis animal model. Embodiment for carrying out the invention The present invention will be described in more detail below. As used herein, the term "halogen" means F, Cl, Br, or I unless otherwise specified. The term "hydroxy" means a -OH group. The term "cyano" means a -ON group. The term "alkyl" means a linear or branched saturated hydrocarbon 7] (functional group). For example, "C1-C6 alkyl" has 1 to 6 carbon atoms. Specifically, C1-C6 alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, 2-ethylbutyl, and the like. In one embodiment, the alkyl group can be independently substituted with one or more substituents, for example, with one to three halogen, hydroxy, C1-C6 alkyl, and other hydrocarbon groups. The term "alkoxy" means a group of formula - O-alkyl, wherein the alkoxy group can be independently substituted with one or more substituents. For example, C1-C6 alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, tert-pentoxy, sec-pentoxy, neopentoxy, hexyloxy, and the like. In one embodiment, the alkoxy group can be independently substituted with one or more substituents, for example, can be substituted with 1 to 3 halogen, hydroxy, C1-C6 alkyl, and other hydrocarbon groups.The term "aryl" refers to a hydrocarbon monocyclic or bicyclic aromatic ring. That is, as used herein, aryl may include phenyl, naphthyl, and the like, and biaryl, unless otherwise defined. In one embodiment of the present invention, C6-C. 10Aryl refers to an aromatic ring having 6 to 10 carbon atoms. In one embodiment, 0, 1, 2, 3, 4, 5 or 6 atoms of each ring of an aryl group may be substituted with a substituent. The term "substitution" refers to replacing a hydrogen atom in a molecular structure with a substituent so as to result in a chemically stable compound from such substitution without exceeding the valence on the designated atom. For example, "group A is substituted with a substituent" may mean that a hydrogen atom bonded to an atom such as carbon constituting the skeleton of group A is replaced by a substituent, so that group A and the substituent form a covalent bond. The term "substituent" is another group bonded to a group that serves as a parent nucleus, and there may be one or more substituents. When there are multiple substituents, each substituent may be the same or different from each other. When both the parent group and the substituent group are hydrocarbon groups, the number of carbon atoms in the parent group does not include the number of carbon atoms in the substituent group. For example, a butyl group (- C4H9) having a methoxy group (- O- CH3) as a substituent is classified as a C1 alkoxy group or a C4 alkyl group. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In this specification, the singular also includes the plural unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. No reference cited herein is admitted to be prior art to the claimed invention. In case of inconsistency, the present specification, including definitions, will control.In addition, the materials, methods and embodiments are for illustrative purposes only and are not intended to be limiting. The present invention provides a pharmaceutical composition for preventing, improving or treating atopic dermatitis, comprising a compound of the following chemical formula 1, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient:

[0063] [Chemical Formula 1] In the above formula,

[0064] ※ is hydrogen, C1-C6 alkyl, - CH2- C 6-10 Aryl or , and at this time, the C1-C6 alkyl and - CH2- C 6-10 Each aryl may be independently unsubstituted or substituted with 1 to 3 halogens;

[0065] R 1 is hydrogen or halogen;

[0066] R 2 is hydrogen, halogen, hydroxy, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each independently unsubstituted or substituted with 1 to 3 halogens;

[0067] R 3 , R 4 and each independently represents hydrogen, halogen, hydroxy, or C1-C6 alkoxy, wherein the C1-C6 alkoxy may be unsubstituted or substituted with 1 to 3 halogens;

[0068] R 6 is hydrogen, halogen, hydroxy, -NO2, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each independently unsubstituted or substituted with 1 to 3 halogens;

[0069] R 7is hydrogen, halogen, hydroxy, -NO2, -CN, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy may each independently be unsubstituted or substituted with 1 to 3 halogens. In addition, the present invention provides a pharmaceutical composition for preventing or improving atopic dermatitis, comprising a compound of the following chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient:

[0070] [Chemical Formula 1] In the above formula,

[0071] V is hydrogen, C1-C6 alkyl, - CH2- C 6-10 Aryl or , and at this time, the C1-C6 alkyl and - CH2- C 6-10 Each aryl may be independently unsubstituted or substituted with 1 to 3 halogens;

[0072] R 1 is hydrogen or halogen;

[0073] R 2 is hydrogen, halogen, hydroxy, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each independently unsubstituted or substituted with 1 to 3 halogens;

[0074] R 3 , R 4 and each independently represents hydrogen, halogen, hydroxy or C1-C6 alkoxy, wherein the C1-C6 alkoxy is unsubstituted or may be substituted with 1 to 3 halogens;

[0075] R 6 is hydrogen, halogen, hydroxy, -NO2, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each independently unsubstituted or substituted with 1 to 3 halogens;

[0076] R 7 is hydrogen, halogen, hydroxy, -NO2, -CN, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy may each independently be unsubstituted or substituted with 1 to 3 halogens. In one embodiment, hydrogen, methyl, ethyl, benzyl or from the compound of the above formula 1, wherein the methyl and benzyl are each independently unsubstituted, Or it can be substituted with 1 to 3 halogens. In addition, as an embodiment, in the compound of the above formula 1, R can be hydrogen or halogen. Specifically, R can be H, Br or C1, but is not limited thereto. In an embodiment, in the compound of the above formula 1, R 2 is hydrogen, halogen, hydroxy, methyl, or methoxy, wherein the methyl and methoxy may each be independently unsubstituted or substituted with 1 to 3 halogens. For example, R 2 is H, F, Br, CH3, -OCH3, or - 0CF3, but is not limited thereto. In one embodiment, in the compound of formula 1, R3 is hydrogen, halogen, hydroxy, or methoxy, wherein the methoxy groups are each independently unsubstituted or substituted with 1 to 3 halogens. For example, it may be H, Br, Cl, or - 0CH3, but is not limited thereto. In one embodiment, in the compound of formula 1, R 4 can be hydrogen, halogen or hydroxy. For example, R 4is H, F, or Br, but is not limited thereto. In one embodiment, in the compound of formula 1, R is hydrogen, hydroxy, or methoxy, wherein each of the methoxy groups may be independently unsubstituted or substituted with 1 to 3 halogens. For example, R may be H, or -0CH3, but is not limited thereto. In one embodiment, in the compound of formula 1, R6 is hydrogen, halogen, hydroxy, -N02, methyl, or methoxy, wherein each of the methyl and methoxy groups may be independently unsubstituted or substituted with 1 to 3 halogens. For example, R 6 may be, but is not limited to, H, -NO2, CH3, -0CH3, or CFs. In one embodiment, in the compound of formula 1, R 7 is hydrogen, halogen, hydroxy, -NO2, -CN, methyl, or methoxy, wherein the methyl and methoxy may each be independently unsubstituted or substituted with 1 to 3 halogens. For example, R 7 may be, but is not limited to, H, F, Br, -NO2, -CN, -OCH3, or CF3. In addition, specific examples of the compound of the above chemical formula 1 include, but are not limited to:

[0077] N-(3-(trifluoromethyl)phenyl)hydrazinecarbotheramide;

[0078] N-(4-fluorophenyl)hydrazinecarbotheramide;

[0079] N-(4-bromophenyl)hydrazinecarbotheramide;

[0080] N-(4-cyanophenyl)hydrazinecarbotheramide;

[0081] N-(4-(trifluoromethyl)phenyl)hydrazinecarbotheramide;

[0082] N-ethylhydrazinecarbotheramide;

[0083] N-isopropylhydrazinecarbotheramide;

[0084] N-isobutylhydrazine carbonate amide;

[0085] N-(hydrazinecarbonothioyl)benzamide;

[0086] N-Benzylhydrazinecarbotheramide;

[0087] N-(m-tolyl)hydrazinecarbotheramide;

[0088] (Z)-2-(5-fluoro-2-oxoindolin-3-ylidene)-N-phenylhydrazinecarbotheramide;

[0089] (Z)-2-(5-fluoro-2-oxoindolin-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbothioamide;

[0090] (Z)-2-(5-fluoro-2-oxoindoline-3-ylidene)-N-(4-fluorophenyl)hydrazinecarbothioamide;

[0091] (Z)-N-(4-bromophenyl)-2-(5-fluoro-2-oxoindolin-3-ylidene)hydrazinecarbothioamide;

[0092] (Z)-N-(4-cyanophenyl)-2-(5-fluoro-2-oxoindolin-3-ylidene)hydrazinecarbothioamide;

[0093] (Z)-2-(5-fluoro-2-oxoindoline-3-ylidene)-N-(4-(trifluoromethyl)phenyl)hydrazinecarbotheramide;

[0094] (Z)-2-(7-fluoro-2-oxoindoline-3-ylidene)-N-(4-fluorophenyl)hydrazinecarbothioamide; (Z)-N-(4-bromophenyl)-2-(7-fluoro-2-oxoindoline-3-ylidene)hydrazinecarbothioamide;

[0095] (Z)-N-(4-cyanophenyl)-2-(7-fluoro-2-oxoindolin-3-ylidene)hydrazinecarbothioamide;

[0096] (Z)-2-(7-fluoro-2-oxoindoline-3-ylidene)-N-(4-(trifluoromethyl)phenyl)hydrazinecarbotheramide;

[0097] (Z)-2-(6-methoxy-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide;

[0098] (Z)- 2-(6-methoxy-2-oxoindolin- 3-ylidene)- N-(3-nitrophenyl)hydrazine- 1-carbothioamide;

[0099] (Z)- 2-(6 -methoxy- 2 -oxoindolin- 3 -ylidene)- N-(2 -methoxyphenyl)hydrazine- 1-carbothioamide;

[0100] (Z)-N-(4-cyanophenyl)-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazinecarbotheramide;

[0101] (Z)- 2-(6-methoxy- 2-oxoindoline- 3-ylidene)- N-(4-(trifluoromethyl)phenyl)hydrazinecarbotheramide;

[0102] (Z)-N-ethyl-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazinecarbotheramide;

[0103] (Z)-2-(6-methoxy-2-oxoindolin-3-ylidene)-N-(m-tolyl)hydrazinecarbotheroamide;

[0104] (Z)-2-(5-methyl-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide;

[0105] (Z)-2-(5-methyl-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheroamide;

[0106] (Z)-N-(2-methoxyphenyl)-2-(5-methyl-2-oxoindolin-3-ylidene)hydrazinecarbotheroamide;

[0107] (Z)-2-(5-methyl-2-oxoindolin-3-ylidene)-N-(3-(trifluoromethyl)phenyl)hydrazinecarbotheramide;

[0108] (Z)- N-(4-fluorophenyl)-2-(5-methyl- 2-oxoindolin- 3-ylidene)hydrazinecarbotheramide;

[0109] (Z)-2-(5-bromo-2-oxoindoline-3-ylidene)hydrazinecarbotheramide;

[0110] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(3 -nitrophenyl)hydrazinecarbotheramide;

[0111] (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheramide;

[0112] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(4 -nitrophenyl)hydrazinecarbotheramide;

[0113] (Z)-2-(5-bromo-2-oxoindoline-3-ylidene)-N-(4-nitrophenyl)hydrazinecarbotheramide;

[0114] (Z)- N-(2 -methoxyphenyl)- 2-(2 -oxoindoline- 3 -ylidene)hydrazinecarbotheramide;

[0115] (Z)-2-(4-bromo-2-oxoindoline-3-ylidene)hydrazinecarbotheramide;

[0116] (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)hydrazinecarbotheramide;

[0117] (Z)-2-(7-bromo-2-oxoindoline-3-ylidene)hydrazinecarbotheramide;

[0118] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-phenylhydrazinecarbotheramide;

[0119] (Z)-2-(5-bromo-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide;

[0120] (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide;

[0121] (Z)-2-(7-bromo-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide;

[0122] (Z)- N-(3 -nitrophenyl)-2-(2 -oxoindoline-3 -ylidene)hydrazinecarbotheramide;

[0123] (Z)-2-(5-bromo-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheramide;

[0124] (Z)-2-(7-bromo-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheramide;

[0125] (Z)- N-(3 -methoxyphenyl)-2-(2 -oxoindoline-3 -ylidene)hydrazinecarbotheramide;

[0126] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(3 -methoxyphenyl)hydrazinecarbotheramide;

[0127] (Z)-2-(5-bromo-2-oxoindoline-3-ylidene)-N-(3-methoxyphenyl)hydrazinecarbotheramide;

[0128] (Z)- N-(4 -methoxyphenyl)-2-(2 -oxoindoline-3 -ylidene)hydrazinecarbotheramide;

[0129] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(4 -methoxyphenyl)hydrazinecarbotheramide;

[0130] (Z)-2-(5-bromo-2-oxoindoline-3-ylidene)-N-(4-methoxyphenyl)hydrazinecarbotheramide;

[0131] N-(3,4-dimethoxyphenyl)hydrazinecarbotheramide;

[0132] (Z)- N-(4-fluorophenyl)-2-(2-oxoindolin-3-ylidene)hydrazinecarbotheramide;

[0133] (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-(4-nitrophenyl)hydrazinecarbotheramide;

[0134] (Z)-2-(4-chloro-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide;

[0135] (Z)-2-(6-chloro-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide;

[0136] (Z)-2-(4-chloro-2-oxoindolin-3-ylidene)-N-(2-methoxyphenyl)hydrazinecarbotheramide;

[0137] (Z)-2-(5-fluoro-2-oxoindoline-3-ylidene)-N-(3-(trifluoromethyl)phenyl)hydrazinecarbotheramide;

[0138] (Z)-N-Benzyl-2-(5-fluoro-2-oxoindolin-3-ylidene)hydrazinecarbotheramide;

[0139] (Z)-2-(5-fluoro-2-oxoindolin-3-ylidene)-N-(m-tolyl)hydrazinecarbotheramide;

[0140] (Z)-2-(7-fluoro-2-oxoindolin-3-ylidene)-N-(4-nitrophenyl)hydrazinecarbothioamide;

[0141] (Z)- 2-(6-methoxy- 2-oxoindoline- 3-ylidene)- N-(3-(trifluoromethyl)phenyl)hydrazinecarbotheramide;

[0142] (Z)- N-(4-fluorophenyl)-2-(6-methoxy-2-oxoindoline-3-ylidene)hydrazine-1-carbotorimide;

[0143] (Z)- N-(4 -bromophenyl)- 2-(6 -methoxy-2 -oxoindolin- 3 -ylidene)hydrazine- 1-carbothioamide;

[0144] (Z)-N-Benzyl-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazine-1-carbothioamide;

[0145] (Z)- N-(4 -bromophenyl)-2-(5 -methyl- 2 -oxoindoline- 3 -ylidene)hydrazinecarbotheroamide;

[0146] (Z)- N-(4 -cyanophenyl)-2-(5 -methyl- 2 -oxoindoline- 3 -ylidene)hydrazinecarbotheroamide;

[0147] (Z)-2-(5-methyl-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide;

[0148] (Z)- N-Ethyl- 2-(5 -methyl- 2 -oxoindoline- 3 -ylidene)hydrazinecarbotheramide;

[0149] (Z)- N-Benzyl- 2-(5 -methyl- 2 -oxoindoline- 3 -ylidene)hydrazinecarbotheramide;

[0150] (Z)-2-(5-methyl-2-oxoindolin-3-ylidene)-N-(m-tolyl)hydrazinecarbotheramide;

[0151] (Z)-2-(2-oxo-5-(trifluoromethoxy)indolin-3-ylidene)-N-phenylhydrazinecarbotheramide;

[0152] (Z)-N-(3 -nitrophenyl)-2-(2 -oxo-5-(trifluoromethoxy)indolin-3 -ylidene)hydrazinecarbotheramide;

[0153] (Z)-N-(4-fluorophenyl)-2-(2-oxo-5-(trifluoromethoxy)indolin-3-ylidene)hydrazinecarbotheramide; and

[0154] (Z)-N-(4-bromophenyl)-2-(2-oxo-5-(trifluoromethoxy)indolin-3-ylidene)hydrazinecarbotheramide. The present invention includes "pharmaceutically acceptable salts" of the above-mentioned compounds. The pharmaceutically acceptable salts should have low toxicity to humans and should not have any adverse effects on the biological activity and physicochemical properties of the parent compound. For example, the pharmaceutically acceptable salts can be acid addition salts formed with a pharmaceutically acceptable free acid. The above-mentioned acid may be an inorganic acid or an organic acid, and the inorganic acid may be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, hydrobromic acid, etc., and the organic acid may be acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid, etc. The above-mentioned acid addition salt may be prepared by a conventional method, for example, by dissolving the compound of the above-mentioned chemical formula 1 in an excess amount of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent, for example, methanol, ethanol, acetone, or acetonitrile. In addition, the pharmaceutically acceptable salt may be an alkali metal salt (such as a sodium salt) or an alkaline earth metal salt (such as a potassium salt). The alkali metal salt or alkaline earth metal salt may be obtained, for example, by dissolving the compound of the above chemical formula 1 in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. In addition, the compound of the present invention may have a chiral carbon center, and thus may exist in the form of an R or S isomer, a racemic compound, an individual enantiomer or a mixture, an individual diastereomer or a mixture, and all such stereoisomers and mixtures thereof may fall within the scope of the present invention.In addition, the compound of the present invention may include a hydrate and a solvate of the compound of the above formula 1. The hydrate and solvate may be prepared using a known method, and are preferably non-toxic and water-soluble. In particular, preferably, the hydrate and solvate may be a combination of 1 to 5 molecules of water and an alcoholic solvent (particularly, ethanol, etc.). Since the compound according to an embodiment of the present invention, an isomer thereof, or a pharmaceutically acceptable salt thereof has an excellent effect of inhibiting the activity of EGR-1, the compound or a pharmaceutical composition containing the compound can be usefully used for the treatment of atopic dermatitis caused by an increase in inflammatory cytokines by EGR-1 and the development and worsening thereof. Specifically, the compound according to the present invention or the pharmaceutical composition comprising the same is a substance that targets the transcription factor EGR-1 involved in the immune system, such as the differentiation of immune cells and the production of cytokines, and can improve skin inflammation and itching caused by hypersensitive immune response by inhibiting the DNA binding ability of EGR-1, thereby reducing the production and secretion of inflammatory cytokines. By replacing the existing steroid preparations, the compounds can prevent the weakening of immunity and other side effects caused by the existing steroid-based treatment agents, and can be usefully used as a treatment for atopic dermatitis. The term "atopic dermatitis" used in the present invention may be used interchangeably with "atopy", "atopic disease", etc., and may mean a chronic allergic inflammatory disease occurring on the skin, and a disease accompanied by symptoms such as dry skin, scaly skin with a lot of keratin, skin inflammation, increased skin permeability, susceptibility to skin surface infection, seizures, and itching.The term "prevention" as used in the present invention means any action that inhibits or delays the occurrence, spread and recurrence of a disease by administering a compound or pharmaceutical composition according to the present invention, the term "improvement" means any action that reduces, at least, parameters related to the alleviation or treatment of a disease state, for example, the severity of symptoms, by administering a compound or pharmaceutical composition according to the present invention, and the term "treatment" means any action that improves or beneficially changes the symptoms of the disease by administering a compound or pharmaceutical composition according to the present invention, and includes inhibition, alleviation or elimination of the development of the disease. The present invention provides a use of a compound targeting EGR-1, an isomer thereof or a pharmaceutically acceptable salt thereof for preventing, improving or treating atopic dermatitis. The present invention provides a use of a compound targeting EGR-1, an isomer thereof or a pharmaceutically acceptable salt thereof for inhibiting the activity of transcription factor EGR-1. The present invention provides a use of a compound targeting EGR-1, an isomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing, improving, or treating atopic dermatitis. The present invention provides a use of a compound targeting EGR-1, an isomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting the activity of EGR-1. The present invention also provides a method for preventing, improving, or treating atopic dermatitis, comprising administering to a subject in need thereof a compound targeting EGR-1, an isomer thereof, or a pharmaceutically acceptable salt thereof. The present invention also provides a method for inhibiting the activity of EGR-1, comprising administering to a subject in need thereof a compound targeting EGR-1, an isomer thereof, or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of the present invention can inhibit the activity of EGR-1 and the production of cytokines resulting therefrom.The term "inhibition" used in the present invention means inhibition of any step of transcription, mRNA processing, translation, translocation and maturation of a gene, or inhibition of binding between proteins, activation of proteins or signal transduction through them. The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier in addition to the active ingredient. At this time, the pharmaceutically acceptable carrier is one that is commonly used in formulation, and includes, but is not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil. In addition to the above ingredients, lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc. may be additionally included. The pharmaceutical composition of the present invention may be administered orally or parenterally depending on the intended method, and parenteral administration may include, for example, intravenous, subcutaneous, intraperitoneal, or intramuscular injection, or topical application such as application to the skin. The dosage varies depending on the patient's condition and weight, the degree of the disease, the drug form, the administration route, and the time, but may be appropriately selected by a person skilled in the art. The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dosage level may be determined based on the type and severity of the patient's disease, the activity of the drug, the sensitivity to the drug, the administration time, the administration route, and the excretion rate, the treatment period, the concurrently used drugs, and other factors well known in the medical field.The pharmaceutical composition according to the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered singly or in multiple doses. Considering all of the above factors, it is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects, and this can be easily determined by those skilled in the art. In addition, the present invention provides a method for improving, controlling, or treating atopic dermatitis, comprising a step of administering the pharmaceutical composition to a subject. In the present invention, the “subject” means a subject in need of treatment for a disease, and more specifically, a mammal such as a human or a non-human primate, mouse, dog, cat, horse, or cow. In one embodiment, the pharmaceutical composition according to the present invention may be a composition for topical skin application. The topical skin application may be a cream, a gel, an ointment, a skin emulsifier, a skin suspension, a transdermal patch, a lotion, or a combination thereof. The above skin external preparation may be appropriately mixed with ingredients commonly used in skin external preparations such as cosmetics or medicines, such as aqueous ingredients, oily ingredients, powder ingredients, alcohols, moisturizers, thickeners, ultraviolet absorbers, whitening agents, preservatives, antioxidants, surfactants, fragrances, colorants, various skin nutrients, or combinations thereof, as needed. The above skin external preparation may also appropriately contain metal sequestrants such as sodium edetate, sodium trisodium edetate, sodium citrate, sodium polyphosphate, sodium metaphosphate, and gluconic acid; caffeine, tannin, bellapamil, licorice extract, glabridin, hot water extract of the fruit of Kalin, various herbal medicines, tocopheryl acetate, glycyrrhizic acid, tranexamic acid and derivatives or salts thereof; and sugars such as vitamin C, magnesium ascorbic acid phosphate, ascorbic acid glucoside, arbutin, kojic acid, glucose, fructose, and trehalose. The above skin includes all skin areas of the body including the face, hands, arms, legs, feet, chest, stomach, back, buttocks, and scalp.In this specification, the term "quasi-drug" means a product that is used for the purpose of diagnosing, treating, improving, alleviating, managing or preventing a disease of humans or animals, and has a milder effect than a drug. For example, according to the Pharmaceutical Affairs Act, a quasi-drug is a product excluding products used for the purpose of a drug, and includes fibers and rubber products used for the treatment or prevention of diseases of humans and animals, products that have a mild or no direct effect on the human body, and things that are not devices or machines or similar thereto, and sterilizing and insecticides for preventing infectious diseases. The type or formulation of the quasi-drug composition of the present invention is not particularly limited, but may be a bandage, gauze, cotton, adhesive plaster, disinfectant, shower foam, gargle, wet tissue, detergent soap, hand wash, humidifier filler, mask, or filter filler. The quasi-drug composition according to the present invention may have a preventive or improving effect on atopic dermatitis, but is not limited thereto. The quasi-drug composition of the present invention may further include a pharmaceutically acceptable carrier, excipient or diluent, in addition to the above components, as needed. The pharmaceutically acceptable carrier, excipient or diluent is not limited as long as it does not impair the effects of the present invention, and may include, for example, fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, sweeteners, fragrances, preservatives, etc. When the composition of the present invention is included in a quasi-drug for the purpose of preventing or improving atopic dermatitis, the composition may be used as is or may be used together with other quasi-drug ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient may be appropriately determined depending on the intended use. The present invention provides a method for preparing the above compounds. Specifically, the compound of the above chemical formula 1 may be prepared by the method shown in the following reaction schemes, but is not limited to being prepared by such a method.In particular, those skilled in the art will be able to fully understand that the compound of chemical formula 1 of the present invention can be prepared by various methods using well-known techniques in the relevant field. The following reaction schemes show the preparation method of representative compounds according to the present invention by preparation step, and various compounds of the present invention can be prepared by changing the reagents and solvents used in the following preparation steps or changing the reaction order.

[0155] <General procedure> In the present invention, the compound of chemical formula 1 can be prepared by a method as in Scheme 1. The compound is prepared by reacting various isothiocyanates having chain-like or cyclic substituents with hydrazine monohydrate to obtain hydrazine carbonate amides (A and B) (step 1), and then reacting the hydrazine thioamides (A and B) with isatin (C) to synthesize the compound of chemical formula D (step 2).

[0156] [Reaction Formula 1] The target compound produced in the above reaction scheme 1 can be separated and purified using conventional methods, such as column chromatography, recrystallization, etc. In another aspect, the present invention provides a novel compound that inhibits the activity of EGR-1, which is selected from the group consisting of: a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0157] (Z)-N-(4-cyanophenyl)-2-(7-fluoro-2-oxoindolin-3-ylidene)hydrazinecarbothioamide;

[0158] (Z)-2-(7-fluoro-2-oxoindoline-3-ylidene)-N-(4-(trifluoromethyl)phenyl)hydrazinecarbotheramide;

[0159] (Z)-2-(6-methoxy-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide;

[0160] (Z)- 2-(6-methoxy-2-oxoindolin- 3-ylidene)- N-(3-nitrophenyl)hydrazine- 1-carbothioamide;

[0161] (Z)- 2-(6 -methoxy- 2 -oxoindolin- 3 -ylidene)- N-(2 -methoxyphenyl)hydrazine- 1-carbothioamide;

[0162] (Z)-N-(4-cyanophenyl)-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazinecarbotheramide;

[0163] (Z)- 2-(6-methoxy- 2-oxoindoline- 3-ylidene)- N-(4-(trifluoromethyl)phenyl)hydrazinecarbotheramide;

[0164] (Z)-N-ethyl-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazinecarbotheramide;

[0165] (Z)-2-(5-methyl-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheroamide;

[0166] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(3 -nitrophenyl)hydrazinecarbotheramide;

[0167] (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheramide;

[0168] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(4 -nitrophenyl)hydrazinecarbotheramide;

[0169] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-phenylhydrazinecarbotheramide;

[0170] (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide;

[0171] (Z)-2-(7-bromo-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheramide;

[0172] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(3 -methoxyphenyl)hydrazinecarbotheramide;

[0173] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(4 -methoxyphenyl)hydrazinecarbotheramide; (Z)- 2-(6 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(4 -nitrophenyl)hydrazinecarbotheramide;

[0174] (Z)-2-(4-chloro-2-oxoindolin-3-ylidene)-N-(2-methoxyphenyl)hydrazinecarbotheramide;

[0175] (Z)-2-(7-fluoro-2-oxoindolin-3-ylidene)-N-(4-nitrophenyl)hydrazinecarbothioamide;

[0176] (Z)- 2-(6-methoxy- 2-oxoindoline- 3-ylidene)- N-(3-(trifluoromethyl)phenyl)hydrazinecarbotheramide;

[0177] (Z)- N-(4-fluorophenyl)-2-(6-methoxy-2-oxoindoline-3-ylidene)hydrazine-1-carbotorimide;

[0178] (Z)- N-(4 -bromophenyl)- 2-(6 -methoxy-2 -oxoindolin- 3 -ylidene)hydrazine- 1-carbothioamide;

[0179] (Z)-N-Benzyl-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazine-1-carbothioamide;

[0180] (Z)- N-(4-cyanophenyl)-2-(5-methyl- 2-oxoindoline- 3-ylidene)hydrazinecarbotheroamide; and

[0181] (Z)-2-(5-methyl-2-oxoindoline-3-ylidene)-N-(m-tolyl)hydrazinecarbotheramide; In the novel compound that inhibits the activity of EGR-1 according to the present invention, the isomer or pharmaceutically acceptable salt thereof is as described above. In addition, the present invention provides a composition comprising any one compound selected from the group consisting of the following, an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0182] (Z)-N-(4-cyanophenyl)-2-(7-fluoro-2-oxoindolin-3-ylidene)hydrazinecarbothioamide;

[0183] (Z)-2-(7-fluoro-2-oxoindoline-3-ylidene)-N-(4-(trifluoromethyl)phenyl)hydrazinecarbotheramide;

[0184] (Z)-2-(6-methoxy-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide

[0185] (Z)- 2-(6-methoxy-2-oxoindolin- 3-ylidene)- N-(3-nitrophenyl)hydrazine- 1-carbothioamide;

[0186] (Z)- 2-(6 -methoxy- 2 -oxoindolin- 3 -ylidene)- N-(2 -methoxyphenyl)hydrazine- 1-carbothioamide;

[0187] (Z)-N-(4-cyanophenyl)-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazinecarbotheramide;

[0188] (Z)-2-(6-methoxy-2-oxoindolin-3-ylidene)-N-(4-(trifluoromethyl)phenyl)hydrazinecarbotheramide;

[0189] (Z)-N-ethyl-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazinecarbotheramide;

[0190] (Z)-2-(5-methyl-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheroamide;

[0191] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(3 -nitrophenyl)hydrazinecarbotheramide;

[0192] (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheramide;

[0193] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(4 -nitrophenyl)hydrazinecarbotheramide;

[0194] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-phenylhydrazinecarbotheramide;

[0195] (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide;

[0196] (Z)-2-(7-bromo-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheramide;

[0197] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(3 -methoxyphenyl)hydrazinecarbotheramide;

[0198] (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(4 -methoxyphenyl)hydrazinecarbotheramide;

[0199] (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-(4-nitrophenyl)hydrazinecarbotheramide;

[0200] (Z)-2-(4-chloro-2-oxoindolin-3-ylidene)-N-(2-methoxyphenyl)hydrazinecarbotheramide;

[0201] (Z)-2-(7-fluoro-2-oxoindolin-3-ylidene)-N-(4-nitrophenyl)hydrazinecarbothioamide;

[0202] (Z)- 2-(6-methoxy- 2-oxoindoline- 3-ylidene)- N-(3-(trifluoromethyl)phenyl)hydrazinecarbotheramide;

[0203] (Z)- N-(4-fluorophenyl)-2-(6-methoxy-2-oxoindoline-3-ylidene)hydrazine-1-carbotorimide;

[0204] (Z)- N-(4 -bromophenyl)- 2-(6 -methoxy-2 -oxoindolin- 3 -ylidene)hydrazine- 1-carbothioamide;

[0205] (Z)-N-Benzyl-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazine-1-carbothioamide;

[0206] (Z)- N-(4-cyanophenyl)-2-(5-methyl- 2-oxoindoline- 3-ylidene)hydrazinecarbotheroamide; and

[0207] (Z)-2-(5-methyl-2-oxoindoline-3-ylidene)-N-(m-tolyl)hydrazinecarbotheramide. Hereinafter, the present invention will be described in more detail with reference to examples and experimental examples. However, the following examples and experimental examples are only illustrative of the present invention, and the scope of the present invention is not limited to the following examples and experimental examples. Therefore, the method for preparing the compound of the above chemical formula 1 is described using the synthetic processes of N-benzylhydrazinecarbotheramide (Compound 10), which is one of the compounds of the VI series, and (Z)-N-(4-cyanophenyl)-2-(6-methoxy-2-oxoindoline-3-ylidene)hydrazinecarbotheramide (Compound 25), which is one of the compounds of the VII series.

[0208] <Example> Example 1. Synthesis of N-benzylhydrazine carbonate amide (Compound 10) Benzyl isothiocyanate (1.49 g, 10 mmol) was placed in a round-bottom flask and dissolved in 40 mL of ethyl alcohol. Hydrazine monohydrate (0.6 g, 12 mmol) was added to the above solution at room temperature, and the reaction mixture was heated and stirred at 90 °C for 8 hours. The completion of the reaction was confirmed by thin-layer chromatography, and the reaction mixture was cooled. The solvent was removed under reduced pressure to obtain a solid product. This compound was recrystallized to obtain the title compound (1.37 g, 76%).

[0209] NMR (700 MHz, dmso) 5 8.74 (s, 1H) , 8.30 (s, 1H) , 7.35 — 7.26 (m, 4H) , 7.25 — 7.17 (m, 1H) , 4.71 (d, J = 6.0 Hz, 2H) , 4.51 (s, 2H) . 13 C NMR (175 MHz, dmso) 6 181.57, 139.78, 128.05, 127.30, 126.61, 46.16.

[0210] ESI-MS. Cal cd for C8HIIN3S (M + +H): m / z 182.0674. Found: m / z 182.0767. Example 2. Synthesis of (Z)-N-(4-cyanophenyl)-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazinecarbothioamide (Compound 25)

[0211]

[0212] 4-Cyanophenyl isothiocyanate and hydrazine monohydrate are reacted according to the method of Example 1 to obtain the synthetic intermediate N-(4-cyanophenyl)hydrazinecarbothioamide. N-(4-cyanophenyl)hydrazinecarbothioamide (135 mg, 0.7 mmol) is placed in a round-bottom flask and dissolved in 15 mL of ethyl alcohol. 6-Methoxyisotine (89 mg, 0.5 mmol) is added to the above solution and dissolved, followed by adding 2 mL of 3N hydrochloric acid solution and stirring at room temperature for 5 hours. As the reaction progresses, an orange solid is formed, and after the reaction is completed, the title compound (138 mg, 79%) is obtained by filtration under reduced pressure.

[0213] NMR (700 MHz, dmso) 5 12.83 (s, 1H), 11.26 (s, 1H) , 10.90 (s, 1H) , 7.97 (t, J = 9.6 Hz, 2H), 7.93 - 7.82 (m, 2H) , 7.68 (d, J = 8.4 Hz, 1H) , 6.79 - 6.63 (m, 1H) , 6.47 (dd, J = 32.7, 2.2 Hz, 1H) , 3.82 (d, J = 10.5 Hz, 3H). 13 C NMR (175 MHz, dmso) 6 175.80, 163.50, 162.86, 144.72, 142.99, 133.14, 132.64, 125.09, 123.29, 118.89, 112.15, 108.42, 107.62, 97.70, 55.76.

[0214] ESI-MS. Cal cd for C17H13N5O2S (M ++H): m / z 352.0790. Found: m / z 352.0877 Example 3. Synthesis of N-(3-(trifluoromethyl)phenyl)hydrazinecarbothioamide (compound 1) According to the synthetic method of Example 1, the title compound was synthesized using 3-(trifluoromethyl)phenylisothiocyanate and hydrazine as starting materials.

[0215] NMR (700 MHz, dmso) 6 9.36 (s, 1H), 8.25 (s, 1H), 7.87 (m, 2H), 7.51 (m, 1H), 7.42 (m, 1H), 4.90 (s, 2H). Example 4. Synthesis of N-(4-fluorophenyl)hydrazinecarbothermide (compound 2) The title compound was synthesized according to the synthetic method of Example 1 using 4-fluorophenylisothiocyanate and hydrazine as starting materials. 4l NMR (700 MHz, dmso) 6 9.69 (s, 1H), 9.14 (s, 1H), 7.60 (s, 2H), 7.12 (m, 2H), 4.76 (s, 2H). Example 5. Synthesis of N-(4-bromophenyl)hydrazinecarbothioamide (compound 3) According to the synthetic method of Example 1, the title compound was synthesized using 4-bromophenylisothiocyanate and hydrazine as starting materials.

[0216] NMR (700 MHz, dmso) 6 9.70 (s, 1H), 9.24 (s, 1H), 7.65 (d, J= 7.5 Hz, 2H), 7.46 (d, J = 7.5 Hz, 2H), 4.80 (s, 2H). Example 6. Synthesis of N-(4-cyanophenyl)hydrazinecarbothioamide (compound 4) According to the synthetic method of Example 1, the title compound was synthesized using 4-cyanophenylisothiocyanate and hydrazine as starting materials.

[0217] NMR (700 MHz, dmso) 6 9.50 (s, 1H) , 8.05 (d, J= 7.9 Hz, 2H) , 7.78 (d, J = 7.9 Hz, 2H), 7.64 (s, 1H) , 5.09 (s, 2H) . Example 7. Synthesis of N-(4-(trifluoromethyl)phenyl)hydrazinecarbothioamide (compound 5) According to the synthetic method of Example 1, the title compound was synthesized using 4-(trifluoromethyl)phenylisothiocyanate and hydrazine as starting materials.

[0218] NMR (700 MHz, dmso) 6 9.40 (s, 1H), 7.98 (s, 2H), 7.70 — 7.58 (m, 3H), 4.93 (s, 2H). Example 8. Synthesis of N-ethylhydrazinecarbothioamide (compound 6) The title compound was synthesized according to the synthetic method of Example 1, starting from ethyl isothiocyanate and hydrazine.

[0219] NMR (700 MHz, dmso) 6 8.49 (s, 1H), 7.81 (s, 1H), 4.42 (s, 2H), 3.45 (q, J = 7.1 Hz, 2H), 1.06 (t, J = 7.1 Hz, 3H). Example 9. Synthesis of N-isopropylhydrazinecarbothioamide (Compound 7) The title compound was synthesized according to the synthetic method of Example 1 using isopropylisothiocyanate and hydrazine as starting materials.

[0220] NMR (700 MHz, dmso) 6 8.52 (s, 1H), 7.48 (s, 1H), 4.42 (s, 2H), 4.35 (m, J = 6.6 Hz, 1H), 1.12 (d, J = 6.6 Hz, 6H). Example 10. Synthesis of N-isobutylhydrazine carbonate amide (compound 8) The title compound was synthesized according to the synthetic method of Example 1 using isobutyl isothiocyanate and hydrazine as starting materials.

[0221] 4l NMR (700 MHz, dmso) 6 8.56 (s, 1H), 7.80 (s, 1H), 4.46 (s, 2H), 3.27 (m, 2H), 1.92 - 1.80 (m, 1H), 0.85 (d, J = 6.7 Hz, 6H). Example 11. Synthesis of N-(hydrazinecarbonothioyl)benzamide (compound 9) The title compound was synthesized according to the synthetic method of Example 1, using benzoylisothiocyanate and hydrazine as starting materials.

[0222] NMR (700 MHz, dmso) 6 12.75 (s, 1H) , 12.10 - 9.22 (m, 3H) , 8.12 (d, J = 7.4 Hz, 2H), 7.67 (t, J= 7.4 Hz, 1H) , 7.57 (t, J = 7.4 Hz, 2H) . Example 12. Synthesis of N-(m-tolyl)hydrazinecarbotheroamide (Compound 11) The title compound was synthesized according to the synthetic method of Example 1, starting from m-tolyl isothiocyanate and hydrazine.

[0223] NMR (700 MHz, dmso) 6 9.62 (s, 1H), 9.10 (s, 1H), 7.45 (s, 2H), 7.21 (m, 1H), 6.92 (m, 1H), 4.77 (s, 2H), 2.28 (s, 3H). Example 13. Synthesis of (Z)-2-(5-fluoro-2-oxoindolin-3-ylidene)-N-phenylhydrazinecarbothioamide (Compound 12) The title compound was synthesized according to the synthetic method of Example 2 using phenylhydrazinecarbothioamide and 5-fluoroisatin as starting materials.

[0224] NMR (700 MHz, dmso) 6 12.67 (s, 1H), 11.26 (s, 1H), 10.86 (s, 1H),

[0225] 7.64 (dd, J = 8.0, 2.6 Hz, 1H) , 7.60 (d, J = 7.5 Hz, 2H) , 7.44 (t, J = 8.0 Hz, 2H), 7.29 (t, J = 7.5Hz, 1H) , 7.21 (m, 1H) , 6.94 (dd, J = 8.6, 4.1 Hz, 1H). Example 14. Synthesis of (Z)-2-(5-fluoro-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbothioamide (Compound 13) According to the synthetic method of Example 2, the title compound was synthesized using N-(3-nitrophenyl)hydrazinecarbothioamide and 5-fluoroisatin as starting materials.

[0226] NMR (700 MHz, dmso) 6 12.83 (s, 1H), 11.31 (s, 1H), 11.10 (s, 1H),

[0227] 8.65 (t, J = 2.2 Hz, 1H), 8.20 - 8.15 (m, 1H) , 8.13 (ddd, J = 8.3, 2.2, 0.9 Hz, 1H), 7.73 (t, J= 8.3 Hz, 1H) , 7.61 (dd, J= 8.0, 2.5 Hz, 1H) , 7.23 (td, J = 9.0, 2.7 Hz, 1H), 6.95 (dd, J = 8.8, 4.1 Hz, 1H) . Example 15. Synthesis of (Z)-2-(5-fluoro-2-oxoindoline-3-ylidene)-N-(4-fluorophenyl)hydrazinecarbotheramide (Compound 14) According to the synthetic method of Example 2, the title compound was synthesized using N-(4-fluorophenyl)hydrazinecarbotheramide and 5-fluoroisatin as starting materials.

[0228] NMR (700 MHz, dmso) 6 12.68 (s, 1H), 11.27 (s, 1H), 10.86 (s, 1H), 7.74 — 7.50 (m, 3H), 7.28 (t, J = 9.0 Hz, 2H), 7.21 (td, J = 9.0, 2.7 Hz, 1H), 6.94 (dd, J = 8.6, 4.1 Hz, 1H) Example 16. Synthesis of (Z)-N-(4-bromophenyl)-2-(5-fluoro-2-oxoindolin-3-ylidene)hydrazinecarbothioamide (Compound 15) According to the synthetic method of Example 2, N-(4 The title compound was synthesized using (bromophenyl)hydrazine carbonate amide and 5-fluoroisatin as starting materials.

[0229] NMR (700 MHz, dmso) 6 12.72 (s, 1H), 11.28 (s, 1H) , 10.87 (s, 1H) , 7.70 - 7.54 (m, 5H) , 7.22 (td, J = 9.2, 2.7 Hz, 1H) , 6.94 (dd, J = 8.6, 4.1 Hz, 1H). Example 17. Synthesis of (Z)-N-(4-cyanophenyl)-2-(5-fluoro-2-oxoindoline-3-ylidene)hydrazinecarbothioamide (Compound 16) According to the synthetic method of Example 2, the title compound was synthesized using N-(4-cyanophenyl)hydrazinecarbothioamide and 5-fluoroisatin as starting materials.

[0230] NMR (700 MHz, dmso) 6 12.83 (s, 1H), 11.30 (s, 1H) , 11.01 (s, 1H) , 7.97 (d, J = 8.7 Hz, 2H) , 7.91 (d, J = 8.7 Hz, 2H) , 7.62 (dd, J = 8.0, 2.6 Hz, 1H), 7.23 (td, J = 9.4, 2.7 Hz, 1H), 6.95 (dd, J = 8.6, 4.1 Hz, 1H). Example 18. Synthesis of (Z)-2-(5-fluoro-2-oxoindoline-3-ylidene)-N-(4-(trifluoromethyl)phenyl)hydrazinecarbothioamide (Compound 17) According to the synthetic method of Example 2, the title compound was synthesized using N-(4-(trifluoromethyl)phenyl)hydrazinecarbothioamide and 5-fluoroisatin as starting materials.

[0231] NMR (700 MHz, dmso) 6 12.80 (s, 1H), 11.30 (s, 1H) , 11.02 (s, 1H) , 7.93 (d, J = 8.4 Hz, 2H) , 7.81 (d, J = 8.5 Hz, 2H) , 7.63 (dd, J = 8.6, 2.6 Hz, 1H), 7.23 (m, 1H), 6.95 (dd, J = 8.6, 4.1 Hz, 1H). Example 19. Synthesis of (Z)-2-(7-fluoro-2-oxoindoline-3-ylidene)-N-(4-fluorophenyl)hydrazinecarbothioamide (Compound 18) According to the synthetic method of Example 2, the title compound was synthesized using N-(4-fluorophenyl)hydrazinecarbothioamide and 7-fluoroisatin as starting materials.

[0232] NMR (700 MHz, dmso) 6 12.77 (s, 1H), 11.80 (s, 1H), 10.90 (s, 1H), 7.64 - 7.56 (m, 3H), 7.33 - 7.24 (m, 3H), 7.13 (m, 1H). Example 20. Synthesis of (Z)-N-(4-bromophenyl)-2-(7-fluoro-2-oxoindolin-3-ylidene)hydrazinecarbothioamide (Compound 19) The title compound was synthesized according to the synthetic method of Example 2, starting from N-(4-bromophenyl)hydrazinecarbothioamide and 7-fluoroisatin.

[0233] NMR (700 MHz, dmso) 6 12.80 (s, 1H), 11.81 (s, 1H) , 10.92 (s, 1H) , 7.61 (m, 5H), 7.30 (m, 1H) , 7.13 (m, 1H) Example 21. Synthesis of (Z)-N-(4-cyanophenyl)-2-(7-fluoro-2-oxoindolin-3-ylidene)hydrazinecarbothioamide (Compound 20) The title compound was synthesized according to the synthetic method of Example 2, starting from N-(4-cyanophenyl)hydrazinecarbothioamide and 7-fluoroisatin.

[0234] NMR (700 MHz, dmso) 6 12.91 (s, 1H), 11.83 (s, 1H) , 11.07 (s, 1H) , 7.98 - 7.94 (m, 2H) , 7.92 - 7.88 (m, 2H), 7.62 (m, 1H) , 7.32 (m, 1H) , 7.14 (m, 1H) . Example 22. Synthesis of (Z)-2-(7-fluoro-2-oxoindoline-3-ylidene)-N-(4-(trifluoromethyl)phenyl)hydrazinecarbothioamide (Compound 21) According to the synthetic method of Example 2, the title compound was synthesized using N-(4-(trifluoromethyl)phenyl)hydrazinecarbothioamide and 7-fluoroisatin as starting materials.

[0235] NMR (700 MHz, dmso) 6 12.88 (s, 1H), 11.83 (s, 1H) , 11.07 (s, 1H) , 7.92 (d, J= 8.4 Hz, 2H), 7.80 (d, J= 8.5 Hz, 2H) , 7.63 (d, J= 7.5 Hz, 1H) , 7.31 (m, 1H), 7.14 (m, 1H) . 13 C NMR (175 MHz, dmso) 6 176.48, 162.64, 147.71, 146.32, 142.21, 132.24 (d, J = 4.9 Hz), 129.51 (d, J = 13.3 Hz), 126.12 (d, J = 32.1 Hz), 125.72, 125.63 (q, J = 3.7 Hz), 125.05, 123.51, 123.42, 122.89 (d, J = 4.7 Hz), 118.33 (d, J = 17.5 Hz), 117.64.

[0236] ESI-MS. Cal cd for C17H13N5O2S (M + +H): m / z 383.0511. Found: m / z 383.0605. Example 23. Synthesis of (Z)-2-(6-methoxy-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide (Compound 22) According to the synthetic method of Example 2, the title compound was synthesized using phenylhydrazinecarbotheramide and 6-methoxyisatin as starting materials.

[0237] NMR (700 MHz, dmso) 6 12.67 (s, 1H), 11.22 (s, 1H) , 10.70 (s, 1H) , 7.68 (d, J= 8.4 Hz, 1H), 7.60 (d, J= 7.8 Hz, 2H) , 7.42 (t, J= 7.9 Hz, 2H) , 7.26 (m, 1H), 6.69 (dd, J = 8.4, 2.2 Hz, 1H) , 6.51 - 6.47 (m, 1H) , 3.81 (s, 3H). Example 24. Synthesis of (Z)-2-(6-methoxy-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazine-1-carbothioamide (Compound 23) According to the synthetic method of, the title compound was synthesized using N-(3-nitrophenyl)hydrazinecarbothioamide isatin as a starting material. 00 MHz, dmso) 6 12.83 (s, 1H) , 11.25 (s, 1H) , 10.95 (s 1H) , 8.67 (s, 1H), 8.18 (dd, J = 8.0, 2.0 Hz, 1H) , 8.13 - 8.06 (m, 1H), 7.69 (m, 2H), 6.71 (dd, J = 8.4, 2.0 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H), 3.82 (s, 3H). 13 C NMR (175 MHz, dmso) 6 176.13, 163.39, 162.74, 147.41, 144.60, 139.75, 133.01, 131.41, 129.55, 123.08, 120.25, 119.43, 112.08, 108.30, 97.60, 55.65.

[0238] ESI-MS. Cal cd for C16H13N5O4S (M ++H): m / z 372.0688. Found: m / z 372.0773. Example 25. Synthesis of (Z)-2-(6-methoxy-2-oxoindoline-3-ylidene)-N-(2-methoxyphenyl)hydrazine-1-carbothioamide (Compound 24) According to the synthetic method of Example 2, the title compound was synthesized using N-(2-methoxyphenyl)hydrazinecarbothioamide and 6-methoxyisatin as starting materials.

[0239] NMR (700 MHz, dmso) 6 12.67 (s, 1H), 11.23 (s, 1H), 10.33 (s, 1H),

[0240] 7.87 (d, J = 7.7 Hz, 1H) , 7.59 (d, J = 8.3 Hz, 1H) , 7.27 (td, J = 8.3, 1.5

[0241] Hz, 1H), 7.15 - 7.12 (m, 1H), 6.99 (td, J = 7.7, 1.0 Hz, 1H), 6.68 (dd, J =

[0242] 8.4, 2.2 Hz, 1H), 6.49 (d, J = 2.2 Hz, 1H), 3.86 (s, 3H), 3.81 (s, 3H). Example 26. Synthesis of (Z)-2-(6-methoxy-2-oxoindoline-3-ylidene)-N-(4-(trifluoromethyl)phenyl)hydrazinecarbothioamide (Compound 26) According to the synthetic method, the title compound was synthesized using N-(4-(trifluoromethyl)phenyl)hydrazinecarbothioamide 6-methoxyisatin as a starting material. 0 MHz, dmso) 6 12.80 (s, 1H), 11.25 (s, 1H) , 10.89 (s, 1H) , 7.93 (d, J= 8.4 Hz, 2H), 7.78 (d, J= 8.5 Hz, 2H) , 7.68 (d, J= 8.4 Hz, 1H) , 6.70 (dd, J = 8.5, 2.2 Hz, 1H) , 6.49 (d, J = 2.2 Hz, 1H) , 3.82 (s, 3H) . Example 27. Synthesis of (Z)-N-ethyl-2-(6-methoxy-2-oxoindoline-3-ylidene)hydrazinecarbothioamide (Compound 27) According to the synthetic method of Example 2, the title compound was synthesized using N-ethylhydrazinecarbothioamide and 6-methoxy isatin as starting materials.

[0243] NMR (700 MHz, dmso) 6 12.42 (s, 1H) , 11.16 (s, 1H) , 9.15 (m, 1H) , 7.56 (d, J = 8.4 Hz, 1H), 6.67 (dd, J = 8.4, 2.2 Hz, 1H) , 6.47 (d, J = 2.2 Hz, 1H), 3.80 (s, 3H), 3.65 - 3.59 (m, 2H), 1.18 (t, J = 7.2 Hz, 3H). Example 28. Synthesis of (Z)-2-(6-methoxy-2-oxoindoline-3-ylidene)-N-(m-tolyl)hydrazinecarbothioamide (Compound 28) According to the synthetic method of Example 2, the title compound was synthesized using N-(3-methylphenyl)hydrazinecarbothioamide and 6-methoxyisatin as starting materials.

[0244] NMR (700 MHz, dmso) 6 12.64 (s, 1H), 11.21 (s, 1H) , 10.64 (s, 1H) , 7.69 (d, J = 8.4 Hz, 1H) , 7.44 - 7.40 (m, 2H) , 7.29 (t, J = 7.7 Hz, 1H) , 7.08 (d, J = 7.5 Hz, 1H) , 6.69 (dd, J = 8.4, 2.1 Hz, 1H) , 6.49 (d, J = 2.2 Hz, 1H), 3.81 (s, 3H), 2.33 (s, 3H) . Example 29. Synthesis of (Z)-2-(5-methyl-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheroamide (Compound 29) According to the synthetic method of Example 2, the title compound was synthesized using phenylhydrazinecarbotheroamide and 5-methylisatin as starting materials.

[0245] NMR (700 MHz, dmso) 6 12.77 (s, 1H), 11.15 (s, 1H), 10.81 (s, 1H),

[0246] 7.64 - 7.58 (m, 3H), 7.43 (t, J = 7.9 Hz, 2H), 7.28 (m, 1H), 7.18 (dd, J = 8.0, 0.9 Hz, 1H), 6.83 (d, J = 7.9 Hz, 1H), 2.30 (s, 3H). Example 30. Synthesis of (Z)-2-(5-methyl-2-oxoindolin-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbothioamide (Compound 30) The title compound was synthesized according to the synthetic method of Example 2 using N-(3-nitrophenyl)hydrazinecarbothioamide and 5-methylisatin as starting materials.

[0247] NMR (700 MHz, dmso) 6 12.94 (s, 1H), 11.21 (s, 1H), 11.08 (s, 1H),

[0248] 8.65 (t, J = 2.1 Hz, 1H), 8.17 (m, 1H) , 8.12 (m, 1H) , 7.72 (t, J = 8.1 Hz, 1H), 7.60 (s, 1H), 7.20 (d, J = 7.9 Hz, 1H) , 6.84 (d, J = 7.9 Hz, 1H) , 2.31 (s, 3H). Example 31. Synthesis of (Z)-N-(2-methoxyphenyl)-2-(5-methyl-2-oxoindoline-3-ylidene)hydrazinecarbotheroamide (Compound 31) According to the synthetic method of Example 2, the title compound was synthesized using N-(2-methoxyphenyl)hydrazinecarbotheroamide and 5-methylisatin as starting materials.

[0249] NMR (700 MHz, dmso) 6 12.76 (s, 1H), 11.16 (s, 1H) , 10.44 (s, 1H) , 7.74 (d, J = 7.8 Hz, 1H) , 7.52 (s, 1H) , 7.29 (m, 1H) , 7.18 (d, J = 7.8 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H) , 7.00 (td, J = 8.0, 1.1 Hz, 1H) , 6.84 (d, J = 8.0 Hz, 1H), 3.85 (s, 3H) , 2.31 (s, 3H) . Example 32. Synthesis of (Z)-2-(5-methyl-2—oxoindoline-3-ylidene)-N-(3-(trifluoromethyl)phenyl)hydrazinecarbothioamide (Compound 32) According to the synthetic method of Example 2, the title compound was synthesized using N-(3-(trifluoromethyl)phenyl)hydrazinecarbothioamide and 5-methylisatin as starting materials.

[0250] NMR (700 MHz, dmso) 6 12.89 (s, 1H), 11.20 (s, 1H), 10.99 (s, 1H), 7.20-7.17 (m, 2H), 6.95 (m, 1H), 6.88-6.77 (m, 4H), 2.26 (s, 3H). Example 33. Synthesis of (Z)-N-(4-fluorophenyl)-2-(5-methyl-2-oxoindolin-3-ylidene)hydrazinecarbothioamide (Compound 33) The title compound was synthesized according to the synthetic method of Example 2, starting from N-(4-fluorophenyl)hydrazinecarbothioamide and 5-methylisatin.

[0251] NMR (700 MHz, dmso) 6 12.78 (s, 1H), 11.16 (s, 1H), 10.82 (s, 1H), 7.60-7.57 (m, 3H), 7.26 (m, 2H), 7.18 (dd, J = 7.9, 0.9 Hz, 1H) , 6.83 (d, J = 7.9 Hz, 1H), 2.30 (s, 3H) . Example 34. Synthesis of (Z)-2-(5-bromo-2-oxoindolin-3-ylidene)hydrazinecarbothioamide (Compound 34) According to the synthetic method of Example 2, the title compound was synthesized using thiosemicarbazide and 5-bromoisatin as starting materials.

[0252] NMR (500 MHz, dmso) 6 12.28 (s, 1H) , 11.28 (s, 1H) , 9.10 (s, 1H) , 8.81 (s, 1H), 7.88 (d, J= 2.1 Hz, 1H) , 7.51 - 7.48 (m, 1H) , 6.90 - 6.87 (m, 1H) . Example 35. Synthesis of (Z)-2-(4-bromo-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbothioamide (Compound 35) According to the synthetic method of Example 2, the title compound was synthesized using N-(3-nitrophenyl)hydrazinecarbothioamide and 4-bromoisatin as starting materials.

[0253] NMR (500 MHz, dmso) 6 13.23 (s, 1H), 11.54 (s, 1H) , 10.33 (s, 1H) , 8.86 (s, 1H), 8.19 - 7.98 (m, 2H) , 7.71 (t, J= 8.2 Hz, 1H) , 7.36 - 7.23 (m, 2H), 6.97 (m, 1H) . Example 36. Synthesis of (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbothioamide (Compound 36) According to the synthetic method of Example 2, the title compound was synthesized using N-(3-nitrophenyl)hydrazinecarbothioamide and 6-bromoisatin as starting materials.

[0254] NMR (500 MHz, dmso) 6 13.23 (s, 1H), 11.54 (s, 1H) , 10.33 (s, 1H) , 8.86 (t, J = 2.1 Hz, 1H), 8.19 - 7.98 (m, 2H) , 7.71 (t, J = 8.2 Hz, 1H) , 7.36 - 7.23 (m, 2H) , 6.97 (m, 1H) . Example 37. Synthesis of (Z)-2-(4-bromo-2-oxoindoline-3-ylidene)-N-(4-nitrophenyl)hydrazinecarbotheramide (Compound 37) According to the synthetic method of Example 2, N-(4-nitrophenyl)hydrazinecarbotheramide and

[0255] 4 - The title compound was synthesized using bromoisosatin as a starting material.

[0256] NMR (500 MHz, dmso) 6 13.22 (s, 1H), 11.55 (s, 1H), 10.47 (s, 1H), 8.31 - 8.26 (m, 2H), 8.17 - 8.12 (m, 2H), 7.34 - 7.27 (m, 2H), 6.98 (m, 1H). Example 38. Synthesis of (Z)-2-(5-bromo-2-oxoindoline-3-ylidene)-N-(4-nitrophenyl)hydrazinecarbotheramide (Compound 38) According to the synthetic method of Example 2, N-(4-nitrophenyl)hydrazinecarbotheramide and

[0257] 5 - The title compound was synthesized using bromoisosatin as a starting material.

[0258] NMR (500 MHz, dmso) 6 12.81 (s, 1H), 11.39 (s, 1H) , 11.11 (s, 1H) , 8.34 - 8.28 (m, 2H) , 8.10 - 8.06 (m, 2H) , 7.99 (d, J= 2.1 Hz, 1H) , 7.54 (m, 1H), 6.91 (m, 1H). Example 39. Synthesis of (Z)-N-(2-methoxyphenyl)-2-(2-oxoindoline-3-ylidene)hydrazinecarbothioamide (Compound 39) According to the synthetic method of Example 2, the title compound was synthesized using N-(2-methoxyphenyl)hydrazinecarbothioamide and isatin as starting materials.

[0259] NMR (500 MHz, dmso) 6 12.79 (s, 1H), 11.25 (s, 1H), 10.43 (s, 1H),

[0260] 7.86 (dd, J= 7.8, 1.2 Hz, 1H) , 7.68 (d, J= 7.5 Hz, 1H) , 7.38 (m, 1H) , 7.29 (ddd, J= 8.2, 7.5, 1.7 Hz, 1H) , 7.16 - 7.09 (m, 2H) , 7.00 (td, J= 7.7, 1.2 Hz, 1H), 6.95 (m, 1H), 3.87 (s, 3H). Example 40. Synthesis of (Z)-2-(4-bromo-2-oxoindolin-3-ylidene)hydrazinecarbothioamide (Compound 40) According to the synthetic method of Example 2, the title compound was synthesized using thiosemicarbazide and 4-bromoisatin as starting materials.

[0261] NMR (500 MHz, dmso) 6 12.77 (s, 1H), 11.43 (s, 1H), 9.30 (s, 1H), 7.71 (s, 1H), 7.29 - 7.23 (m, 2H), 6.94 (m, 1H). Example 41. Synthesis of (Z)-2-(6-bromo-2-oxoindolin-3-ylidene)hydrazinecarbotheramide (Compound 41) The title compound was synthesized according to the synthetic method of Example 2, starting from thiosemicarbazide and 6-bromoisatin.

[0262] NMR (500 MHz, dmso) 6 12.37 (s, 1H), 11.31 (s, 1H), 9.08 (s, 1H), 8.73 (s, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.30 (m, 1H), 7.08 (d, J = 1.7 Hz, 1H). Example 42. Synthesis of (Z)-2-(7-bromo-2-oxoindolin-3-ylidene)hydrazinecarbotheramide (Compound 42) The title compound was synthesized according to the synthetic method of Example 2 using thiosemicarbazide and 7-bromoisatin as starting materials.

[0263] NMR (500 MHz, dmso) 6 12.40 (s, 1H), 11.50 (s, 1H), 9.11 (s, 1H), 8.76 (s, 1H), 7.66 (d, J = 7.3 Hz, 1H), 7.56 - 7.52 (m, 1H), 7.04 (dt, J = 7.0, 6.0 Hz, 1H). Example 43. Synthesis of (Z)-2-(4-bromo-2-oxoindolin-3-ylidene)-N-phenylhydrazinecarbothioamide (Compound 43) The title compound was synthesized according to the synthetic method of Example 2 using phenylhydrazinecarbothioamide and 4-bromoisatin as starting materials.

[0264] NMR (500 MHz, dmso) 6 13.04 (s, 1H) , 11.50 (s, 1H) , 9.98 (s, 1H) , 7.75-7.71 (m, 2H) , 7.45-7.40 (m, 2H) , 7.32 - 7.24 (m, 3H) , 6.97 (m, 1H) . Example 44. Synthesis of (Z)-2-(5-bromo-2-oxoindolin-3-ylidene)-N-phenylhydrazinecarbothioamide (Compound 44) ​​The title compound was synthesized according to the synthetic method of Example 2 using phenylhydrazinecarbothioamide and 5-bromoisatin as starting materials.

[0265] NMR (500 MHz, dmso) 6 12.61 (s, 1H), 11.34 (s, 1H) , 10.89 (s, 1H) , 8.01 (d, J = 2.1 Hz, 1H), 7.62 - 7.59 (m, 2H) , 7.54 - 7.51 (m, 1H) , 7.46 - 7.42 (m, 2H), 7.31 - 7.27 (m, 1H) , 6.90 (m, 1H) . Example 45. Synthesis of (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide (Compound 45) According to the synthetic method of Example 2, the title compound was synthesized using phenylhydrazinecarbotheramide and 6-bromoisatin as starting materials.

[0266] NMR (500 MHz, dmso) 6 12.69 (s, 1H) , 11.37 (s, 1H) , 10.86 (s, 1H) , 7.71 (d, J = 8.1 Hz, 1H), 7.62-7.60 (m, 2H) , 7.45 - 7.40 (m, 2H) , 7.33 (dd, J= 8.1, 2.1 Hz, 1H), 7.28 (ddt, J= 5.4, 4.3, 2.1 Hz, 1H) , 7.10 (d, J= 1.6 Hz, 1H). 46. ​​(Z)-2-(7-bromo-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbothide (compound 46) The title compound was synthesized according to the synthetic method 2 using phenylhydrazinecarbothioamide and 7-bromo as a starting material. (500 MHz, dmso) 6 12.73 (s, 1H) , 11.56 (s, 1H) , 10.89 (s, 1H) , 7.7(m, 1H), 7.62-7.58 (m, 2H) , 7.57 (m, 1H) , 7.46 - 7.41 (m, 2H) , 7.29 (m, 1H), 7.07(m, 1H). Example 47. Synthesis of (Z)-N-(3-nitrophenyl)-2-(2-oxoindoline-3-ylidene)hydrazinecarbothioamide (Compound 47) According to the synthetic method of Example 2, the title compound was synthesized using N-(3-nitrophenyl)hydrazinecarbothioamide and isatin as starting materials.

[0267] NMR (500 MHz, dmso) 6 12.95 (s, 1H) , 11.29 (s, 1H) , 11.09 (s, 1H) , 8.66 (t, J = 2.2 Hz, 1H), 8.18 (m, 1H) , 8.12 (m, 1H) , 7.77 (m, 1H) , 7.72 (dd, J = 10.8, 5.5 Hz, 1H) , 7.39 (m, 1H) , 7.13 (m, 1H) , 6.96 (m, 1H) . Example 48. Synthesis of (Z)-2-(5-bromo-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbothioamide (Compound 48) According to the synthetic method of Example 2, the title compound was synthesized using N-(3-nitrophenyl)hydrazinecarbothioamide and 5-bromoisatin as starting materials.

[0268] NMR (500 MHz, dmso) 6 12.76 (s, 1H), 11.39 (s, 1H) , 11.10 (s, 1H) , 8.65 (m, 1H), 8.17 (m, 1H) , 8.13 (m, 1H), 7.98 (d, J= 2.1 Hz, 1H) , 7.74 (m, 1H), 7.54 (m, 1H), 6.92 (m, 1H) . Example 49. Synthesis of (Z)-2-(7-bromo-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbothioamide (Compound 49) According to the synthetic method of Example 2, the title compound was synthesized using N-(3-nitrophenyl)hydrazinecarbothioamide and 7-bromoisatin as starting materials.

[0269] NMR (500 MHz, dmso) 6 12.88 (s, 1H) , 11.60 (s, 1H) , 11.15 (s, 1H) , 8.65 (t, J= 2.2 Hz, 1H), 8.18 (m, 1H) , 8.12 (m, 1H) , 7.79 (dd, J= 9.2, 4.9 Hz, 1H), 7.73 (dd, J = 10.9, 5.4 Hz, 1H), 7.59 (m, 1H), 7.10 (m, 1H). Example 50. Synthesis of (Z)-N-(3-methoxyphenyl)-2-(2-oxoindoline-3-ylidene)hydrazinecarbotheramide (Compound 50) According to the synthetic method of Example 2, the title compound was synthesized using N-(3-methoxyphenyl)hydrazinecarbotheramide and isatin as starting materials.

[0270] 4l NMR (500 MHz, dmso) 6 12.80 (s, 1H) , 11.25 (s, 1H) , 10.76 (s, 1H) , 7.79 (m, 1H), 7.37 (td, J = 7.7, 1.3 Hz, 1H) , 7.34 (s, 1H) , 7.30 (dd, J = 4.4, 2.2 Hz, 1H), 7.24 (m, 1H) , 7.11 (m, 1H) , 6.95 (m, 1H) , 6.85 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H) , 3.78 (s, 3H) . Example 51. Synthesis of (Z)-2-(4-bromo-2-oxoindoline-3-ylidene)-N-(3-methoxyphenyl)hydrazinecarbothioamide (Compound 51) According to the synthetic method of Example 2, N-(3-methoxyphenyl)hydrazinecarbothioamide and

[0271] 4 - The title compound was synthesized using bromoisosatin as a starting material.

[0272] NMR (500 MHz, dmso) 6 13.02 (s, 1H) , 11.50 (s, 1H) , 9.96 (s, 1H) , 7.54 (t, J = 2.2 Hz, 1H), 7.32 (m, 1H) , 7.30 - 7.25 (m, 2H) , 7.22 (m, 1H), 6.96 (m, 1H), 6.84 (ddd, J = 8.3, 2.5, 0.9 Hz, 1H), 3.78 (s, 3H). Example 52. Synthesis of (Z)-2-(5-bromo-2-oxoindoline-3-ylidene)-N-(3-methoxyphenyl)hydrazinecarbothioamide (Compound 52) According to the synthetic method of Example 2, N-(3-methoxyphenyl)hydrazinecarbothioamide and

[0273] 5 - The title compound was synthesized using bromoisosatin as a starting material.

[0274] NMR (500 MHz, dmso) 6 12.62 (s, 1H), 11.35 (s, 1H) , 10.84 (s, 1H) , 8.02 (d, J = 2.1 Hz, 1H), 7.52 (m, 1H) , 7.34 (m, 1H) , 7.28 (t, J = 2.2 Hz, 1H), 7.22 (m, 1H), 6.90 (m, 1H), 6.87 (m, 1H), 3.79 (s, 3H). Example 53. Synthesis of (Z)-N-(4-methoxyphenyl)-2-(2-oxoindoline-3-ylidene)hydrazinecarbothioamide (Compound 53) According to the synthetic method of Example 2, the title compound was synthesized using N-(4-methoxyphenyl)hydrazinecarbothioamide and isatin as starting materials.

[0275] NMR (500 MHz, dmso) 6 12.75 (s, 1H), 11.24 (s, 1H) , 10.72 (s, 1H) , 7.77 (d, J = 7.5 Hz, 1H) , 7.48 - 7.45 (m, 2H) , 7.37 (td, J = 7.7, 1.3 Hz, 1H), 7.11 (m, 1H), 7.00 - 6.96 (m, 2H), 6.94 (dt, J= 7.9, 0.8 Hz, 1H), 3.78 (s, 3H). Example 54. Synthesis of (Z)-2-(4-bromo-2-oxoindoline-3-ylidene)-N-(4-methoxyphenyl)hydrazinecarbothioamide (Compound 54) According to the synthetic method of Example 2, the title compound was synthesized using N-(4-methoxyphenyl)hydrazinecarbothioamide and 4-bromoisatin as starting materials.

[0276] NMR (500 MHz, dmso) 6 13.02 (s, 1H), 11.49 (s, 1H), 9.85 (s, 1H), 7.54 (m, 2H), 7.29 (m, 2H), 6.98 (m, 3H), 3.78 (s, 3H). Example 55. Synthesis of (Z)-2-(5-bromo-2-oxoindoline-3-ylidene)-N-(4-methoxyphenyl)hydrazinecarbothioamide (Compound 55) According to the synthetic method of Example 2, N-(4-methoxyphenyl)hydrazinecarbothioamide and

[0277] 5 - The title compound was synthesized using bromoisosatin as a starting material.

[0278] NMR (500 MHz, dmso) 6 12.56 (s, 1H), 11.33 (s, 1H) , 10.80 (s, 1H) , 8.00 (d, J= 1.9 Hz, 1H), 7.51 (m, 1H) , 7.48 - 7.43 (m, 2H) , 7.01 - 6.97 (m, 2H), 6.90 (m, 1H) , 3.79 (s, 3H) . Example 56. Synthesis of N-(3, 4-dimethoxyphenyl)hydrazinecarbotheroamide (Compound 56) The title compound was synthesized according to the synthetic method of Example 2 using 3, 4-dimethoxyphenyl isothiocyanate and hydrazine as a starting material.

[0279] NMR (700 MHz, dmso) 6 9.53 (s, 1H), 9.00 (s, 1H), 7.36 (s, 1H), 7.10 (s, 1H), 6.87 (d, J= 8.6 Hz, 1H), 4.73 (s, 2H), 3.72 (s, 3H), 3.71 (s, 3H). Example 57. Synthesis of (Z)-N-(4-fluorophenyl)-2-(2-oxoindolin-3-ylidene)hydrazinecarbothioamide (Compound 57) The title compound was synthesized according to the synthetic method of Example 2 using N-(4-fluorophenyl)hydrazinecarbothioamide and isatin as a starting material.

[0280] NMR (700 MHz, dmso) 6 12.80 (s, 1H), 11.27 (s, 1H) , 10.84 (s, 1H) , 7.75 (d, J = 7.5 Hz, 1H) , 7.62 - 7.57 (m, 2H) , 7.37 (td, J = 7.7, 1.2 Hz, 1H), 7.29 - 7.24 (m, 2H), 7.11 (td, J = 7.5, 0.7 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H). Example 58. Synthesis of (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-(4-nitrophenyl)hydrazinecarbotheramide (Compound 58) According to the synthetic method of Example 2, N-(4-nitrophenyl)hydrazinecarbotheramide and

[0281] 6 - The title compound was synthesized using bromoisosatin as a starting material.

[0282] NMR (700 MHz, dmso) 6 12.89 (s, 1H), 11.43 (s, 1H) , 11.15 (s, 1H) , 8.36 - 8.22 (m, 2H) , 8.15 - 8.00 (m, 2H) , 7.70 (d, J = 8.1 Hz, 1H) , 7.32 (ddd, J = 21.7, 11.6, 4.4 Hz, 1H) , 7.12 (d, J = 1.6 Hz, 1H) . Example 60. Synthesis of (Z)-2-(6-chloro-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide (Compound 60) According to the synthetic method of Example 2, the title compound was synthesized using phenylhydrazinecarbotheramide and 6-chloroisatin as starting materials.

[0283] NMR (700 MHz, dmso) 6 12.68 (s, 1H), 11.40 (s, 1H) , 10.87 (s, 1H) , 7.77 (d, J= 8.1 Hz, 1H), 7.60 (d, J= 7.7 Hz, 2H) , 7.43 (t, J= 7.9 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.19 (dd, J = 8.1, 1.8 Hz, 1H), 6.98 (d, J = 1.8 Hz, 1H). Example 61. Synthesis of (Z)-2-(4-chloro-2-oxoindoline-3-ylidene)-N-(2-methoxyphenyl)hydrazinecarbothioamide (Compound 61) According to the synthetic method of Example 2, N-(2-methoxyphenyl)hydrazinecarbothioamide and

[0284] 4 - The title compound was synthesized using chloroisatin as a starting material.

[0285] NMR (700 MHz, dmso) 6 12.96 (s, 1H), 11.53 (s, 1H) , 10.35 (s, 1H) , 8.83 (d, J = 7.7 Hz, 1H) , 7.37 (t, J = 8.0 Hz, 1H) , 7.20 (m, 1H) , 7.16 - 7.13 (m, 2H), 7.01 (m, 1H) , 6.92 (d, J = 7.8 Hz, 1H) , 3.88 (s, 3H) . Example 62. Synthesis of (Z)-2-(5-fluoro-2-oxoindoline-3-ylidene)-N-(3-(trifluoromethyl)phenyl)hydrazinecarbothioamide (Compound 62) According to the synthetic method, the title compound was synthesized using N-(3-(trifluoromethyl)phenyl)hydrazinecarbothioamide 5-fluoroisatin as a starting material. 0 MHz, dmso) 6 12.78 (s, 1H), 11.29 (s, 1H) , 11.00 (s, 1H) , 8.15 - 7.91 (m, 2H), 7.76 - 7.55 (m, 3H) , 7.23 (m, 1H) , 6.95 (dd, J = 8.6, 4.1 Hz, 1H). Example 63. Synthesis of (Z)-N-benzyl-2-(5-fluoro-2-oxoindolin-3-ylidene)hydrazinecarbothioamide (Compound 63) The title compound was synthesized according to the synthetic method of Example 2, starting from N-benzylhydrazinecarbothioamide and 5-fluoroisatin.

[0286] NMR (700 MHz, dmso) 6 12.52 (s, 1H) , 11.20 (s, 1H) , 9.85 (t, 7= 6.2 Hz, 1H), 7.45 (dd, J = 8.1, 2.6 Hz, 1H) , 7.36 - 7.30 (m, 4H), 7.24 (dd, J = 9.5, 4.3 Hz, 1H), 7.16 (td, J = 9.4, 2.7 Hz, 1H) , 6.90 (dd, J = 8.6, 4.1 Hz, 1H), 4.86 (d, J = 6.2 Hz, 2H) . Example 64. Synthesis of (Z)-2-(5-fluoro-2-oxoindoline-3-ylidene)-N-(m-tolyl)hydrazinecarbothioamide (Compound 64) According to the synthetic method of Example 2, N-(3-methylphenyl)hydrazinecarbothioamide and

[0287] 5 - The title compound was synthesized using fluoroisatin as a starting material. 4l NMR (700 MHz, dmso) 6 12.65 (s, 1H), 11.26 (s, 1H), 10.79 (s, 1H),

[0288] 7.65 (dd, J = 8.1, 2.5 Hz, 1H) , 7.46 - 7.36 (m, 2H) , 7.32 (t, J = 7.7 Hz, 1H), 7.21 (td, J = 9.3, 2.7 Hz, 1H) , 7.10 (d, J = 7.5 Hz, 1H) , 6.94 (dd, J = 8.6, 4.1 Hz, 1H), 2.34 (s, 3H) . Example 65. Synthesis of (Z)-2-(7-fluoro-2-oxoindoline-3-ylidene)-N-(4-nitrophenyl)hydrazinecarbotheramide (Compound 65) According to the synthetic method of Example 2, the title compound was synthesized using N-(4-nitrophenyl)hydrazinecarbotheramide and 7-fluoroisatin as starting materials.

[0289] NMR (700 MHz, dmso) 6 12.96 (s, 1H), 11.84 (s, 1H) , 11.17 (s, 1H) , 8.37 - 8.20 (d, J = 9.1 Hz, 2H) , 8.07 (d, J = 9.1 Hz, 2H) , 7.63 (d, J = 7.5 Hz, 1H), 7.32 (dd, J = 9.9, 8.9 Hz, 1H), 7.14 (m, 1H). Example 66. Synthesis of (Z)-2-(6-methoxy-2 —oxoindoline-3-ylidene)-N-(3-(trifluoromethyl)phenyl)hydrazinecarbothioamide (Compound 66) According to the synthetic method, the title compound was synthesized using N-(3-(trifluoromethyl)phenyl)hydrazinecarbothioamide 6-methoxyisatin as a starting material. 0 MHz, dmso) 6 12.77 (s, 1H), 11.25 (s, 1H) , 10.87 (s, 1H) , 8.06 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H) , 7.69 - 7.58 (m, 3H) , 6.68 (m, 1H), 6.47 (d, 2.2 Hz, 1H), 3.82 (s, 3H). 67. (Z)-N-(4-fluorophenyl)-2-(6-methoxy-2-oxoindoline-3-ylidene)hycarbothioamide (compound 67) The title compound was synthesized according to the synthetic method 2 using N-(4-fluorophenyl)hydrazinecarbothioamide cisatin as a starting material. (700 MHz, dmso) 6 12.68 (s, 1H), 11.23 (s, 1H) , 10.71 (s, 1H) ,

[0290] 7.66 (d, J = 8.4 Hz, 1H) , 7.62 - 7.55 (m, 2H) , 7.29 - 7.21 (m, 2H) , 6.67 (ddd, J = 34.4, 8.6, 2.3 Hz, 1H) , 6.46 (d, J = 2.3 Hz, 1H) , 3.81 (s, 3H) . Example 68. Synthesis of (Z)-N-(4-bromophenyl)-2-(6-methoxy-2-oxoindoline-3-ylidene)hydrazine-1-carbothioamide (Compound 68) According to the synthetic method of Example 2, the title compound was synthesized using N-(4-bromophenyl)hydrazinecarbothioamide and 6-methoxyisatin as starting materials.

[0291] NMR (700 MHz, dmso) 6 12.72 (s, 1H), 11.23 (s, 1H) , 10.72 (s, 1H) ,

[0292] 7.67 (d, J = 8.4 Hz, 1H), 7.60 (m, 4H), 6.68 (m, 1H), 6.46 (d, J = 2.3 Hz, 1H), 3.82 (s, 3H). Example 69. Synthesis of (Z)-N-benzyl-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazine-1-carbothioamide (Compound 69) The title compound was synthesized according to the synthetic method of Example 2 using N-benzylhydrazinecarbothioamide and 6-methoxy isatin as starting materials.

[0293] NMR (700 MHz, dmso) 6 12.53 (s, 1H) , 11.18 (s, 1H) , 9.69 (t, 7= 6.2 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H) , 7.37-7.32 (m, 4), 7.26 (t, J = 7.1 Hz, 1H), 6.63 (m, 1H), 6.45 (d, J = 2.3 Hz, 1H), 4.86 (d, J = 6.5 Hz, 2H), 3.81 (s, 3H). Example 70. Synthesis of (Z)-N-(4-bromophenyl)-2-(5-methyl-2-oxoindoline-3-ylidene)hydrazinecarbotheroamide (Compound 70) According to the synthetic method of Example 2, the title compound was synthesized using N-(4-bromophenyl)hydrazinecarbotheroamide and 5-methylisatin as starting materials.

[0294] NMR (700 MHz, dmso) 6 12.82 (s, 1H), 11.18 (s, 1H) , 10.84 (s, 1H) , 7.71 - 7.51 (m, 5H), 7.19 (dd, J = 8.0 Hz, 1H) , 6.82 (d, J = 8.0 Hz, 1H) , 2.28 (s, 3H). Example 71. Synthesis of (Z)-N-(4-cyanophenyl)-2-(5-methyl-2-oxoindoline-3-ylidene)hydrazinecarbothioamide (Compound 71) According to the synthetic method of Example 2, the title compound was synthesized using N-(4-cyanophenyl)hydrazinecarbothioamide and 5-methylisatin as starting materials.

[0295] NMR (700 MHz, dmso) 6 12.94 (s, 1H), 11.19 (s, 1H) , 10.96 (s, 1H) , 7.97 (d, J = 8.6 Hz, 2H) , 7.89 (m, J = 8.6 Hz, 2H) , 7.60 (s, 1H) , 7.20 (d, J = 7.9, 1H), 6.82 (d, J = 7.9 Hz, 1H), 2.28 (s, 3H) . Example 72. Synthesis of (Z)-2-(5-methyl-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbothioamide (Compound 72) According to the synthetic method of Example 2, the title compound was synthesized using phenylhydrazinecarbothioamide and 5-methylisatin as starting materials.

[0296] NMR (700 MHz, dmso) 6 12.91 (s, 1H), 11.19 (s, 1H) , 10.99 (s, 1H) , 7.93 (d, J= 8.4 Hz, 2H), 7.79 (d, J= 8.4 Hz, 2H) , 7.61 (s, 1H), 7.17 6.84 (d, J = 7.9 Hz, 1H), 2.31 (s, 3H) . Example 73. Synthesis of (Z)-N-ethyl-2-(5-methyl-2-oxoindoline-3-ylidene)hydrazinecarbotheroamide (Compound 73) According to the synthetic method of Example 2, the title compound was synthesized using N-ethylhydrazinecarbotheroamide and 5-methylisatin as a starting material.

[0297] NMR (700 MHz, dmso) 6 12.52 (s, 1H) , 11.10 (s, 1H) , 9.27 (t, 7= 5.8 Hz, 1H), 7.49 (s, 1H), 7.19 (m, 1H) , 6.81 (m, 1H) , 3.73 — 3.53 (m, 2H) , 2.31 (s, 3H), 1.19 (t, J= 7.2 Hz, 3H) . Example 74. Synthesis of (Z)-N-benzyl-2-(5-methyl-2-oxoindoline-3-ylidene)hydrazinecarbotheroamide (Compound 74) According to the synthetic method of Example 2, the title compound was synthesized using N-benzylhydrazinecarbotheroamide and 5-methylisatin as a starting material.

[0298] NMR (700 MHz, dmso) 6 12.64 (s, 1H) , 11.11 (s, 1H) , 9.81 (t, 7= 6.3 Hz, 1H), 7.48 (s, 1H), 7.35 (m, 4H) , 7.25 (dd, J = 12.6, 12.4 Hz, 1H), 7.16 (dd, J = 7.9, 0.9 Hz, 1H), 6.82 (d, J = 7.9 Hz, 1H), 4.87 (d, J = 8.7 Hz, 2H), 2.28 (s, 3H). Example 75. Synthesis of (Z)-2-(5-methyl-2-oxoindoline-3-ylidene)-N-(m-tolyl)hydrazinecarbothioamide (Compound 75) According to the synthetic method of Example 2, the title compound was synthesized using N-(3-methylphenyl)hydrazinecarbothioamide and 5-methylisatin as starting materials.

[0299] NMR (700 MHz, dmso) 6 12.75 (s, 1H), 11.15 (s, 1H) , 10.75 (s, 1H) , 7.62 (s, 1H), 7.48 - 7.38 (m, 2H) , 7.30 (t, J = 7.7 Hz, 1H) , 7.18 (dd, J = 7.9, 0.8 Hz, 1H), 7.09 (d, J = 7.5 Hz, 1H), 6.83 (d, J = 7.9 Hz, 1H), 2.34 (s, 3H), 2.30 (s, 3H). Example 76. Synthesis of (Z)-2-(2-oxo-5-(trifluoromethoxy)indolin-3-ylidene)-N-phenylhydrazinecarbothioamide (Compound 76) According to the synthetic method of Example 2, the title compound was synthesized using phenylhydrazinecarbothioamide and 5-(trifluoromethoxy)isatin as starting materials.

[0300] NMR (700 MHz, dmso) 6 12.65 (s, 1H), 11.42 (s, 1H) , 10.90 (s, 1H) , 7.80 (s, 1H), 7.59 (d, J = 7.7 Hz, 2H) , 7.44 (t, J = 7.7 Hz, 2H) , 7.37 (dd, J = 8.5, 1.9 Hz, 1H), 7.30 (t, J = 7.4 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H). Example 77. Synthesis of (Z)-N-(3-nitrophenyl)-2-(2-oxo-5-(trifluoromethoxy)indolin-3-ylidene)hydrazinecarbotheramide (Compound 77) According to the synthetic method of Example 2, the title compound was synthesized using N-(3-nitrophenyl)hydrazinecarbotheramide and 5-(trifluoromethoxy)isatin as starting materials. 4l NMR (700 MHz, dmso) 6 12.81 (s, 1H), 11.47 (s, 1H) , 11.14 (s, 1H) , 8.63 (t, J = 2.1 Hz, 1H), 8.15 (m, 2H) , 7.77 (s, 1H) , 7.73 (t, J = 8.2 Hz, 1H), 7.40 (dd, J = 8.5, 1.9 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H). Example 78. Synthesis of (Z)-N-(4-fluorophenyl)-2-(2-oxo-5-(trifluoromethoxy)indolin-3-ylidene)hydrazinecarbotheramide (Compound 78) According to the synthetic method of Example 2, the title compound was synthesized using N-(4-fluorophenyl)hydrazinecarbotheramide and 5-(trifluoromethoxy)isatin as starting materials.

[0301] NMR (700 MHz, dmso) 6 12.66 (s, 1H), 11.43 (s, 1H) , 10.90 (s, 1H) , 7.78 (s, 1H), 7.60-7.56 (m, 2H) , 7.38 (d, J = 10.1 Hz, 1H) , 7.30-7.26 (m, 2H), 7.04 (d, J = 8.5 Hz, 1H). Example 79. Synthesis of (Z)-N-(4-bromophenyl)-2-(2-oxo-5-(trifluoromethoxy)indolin-3-ylidene)hydrazinecarbothioamide (Compound 79) According to the synthetic method of Example 2, the title compound was synthesized using N-(4-bromophenyl)hydrazinecarbothioamide and 5-(trifluoromethoxy)isatin as starting materials.

[0302] NMR (700 MHz, dmso) 6 12.70 (s, 1H), 11.43 (s, 1H), 10.91 (s, 1H), 7.78 (s, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H), 7.38 (dd, J = 8.5, 1.8 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H). The compounds of the above chemical formula 1 are summarized in Table 1. [Table 1]

[0303]

[0304]

[0305]

[0306]

[0307] <Experimental Example> Experimental Example 1. Evaluation of DNA binding inhibitory effect of EGR-1 using EDBA In this experiment, the EGR-1 binding inhibitory effect of the compound according to the present invention was evaluated using EDBA (EGR-1-DNA Binding Activity Assay). The EDBA experimental method is briefly shown in Fig. 1.

[0308] (1) Production of biotin-labeled EGR1-binding sequence (biotin-EBS) oligonucleotides. Single-stranded sense and antisense oligonucleotides were produced from Bioneer Co. (Daejeon, Korea) based on the following EGR1-binding sequence (EGR1-binding sequence; EBS). The 5'-end of the sense nucleotide was labeled with biotin. The sense and antisense oligonucleotides were heated at 95 °C for 5 minutes and then left at room temperature overnight to bind the sense and antisense oligonucleotides. Hereinafter, the combined sense and antisense oligonucleotides are referred to as biotin-EBS. Sense sequence: Biotin- 5' -TCGCCCCCGCTCGCCCCCGCTGGATCC-3' Antisense sequence: 5' -GGATCCAGCGGGGGCGAGCGGGGGCGA-3'

[0309] (2) Preparation of biotin-EBS oligonucleotide-coated plates Biotin-EBS at a concentration of 0.5 pmol / 50 uL / well was added to a 96-we 11 plate (purchased from Thermo Fisher Scientific) coated with avidin protein and incubated at 37°C for 1 hour to allow the biotin-EBS oligonucleotide to attach to the plate. After washing three times with phosphate buffered saline containing 0.05% Tween 20 (PBS / Tween 20), unbound biotin-EBS oligonucleotide was removed, and 200 uL of PBS / Tween 20 solution containing 2% bovine serum albumin (BSA) was added to each well and incubated at 37°C for 1 hour to block the plate surface where the oligonucleotide was not attached.

[0310] (3) EGR1 binding inhibition assay 50 uL of the solution reacting the sample compound and EGR-1 protein was added to the biotin-EBS oligonucleotide-coated plate manufactured in (2) above. At this time, if the sample compound does not bind to the EGR-1 protein, a color reaction occurs due to the EGR-1 antibody reaction, but if the sample compound binds to the EGR-1 protein and inhibits the DNA binding ability of EGR1, the color reaction does not occur, and this principle was used to select the compound. 1 μL of the compound sample was reacted with the EGR-1 overexpression cell lysate containing 49 μL of 10 mM Tris, pH 7.5, 50 mM KC1, 2% BSA, and 8% glycerol at room temperature for 30 minutes, and then placed in a biotin-EBS-coated reaction well and reacted again at room temperature for 1 hour. After washing three times with 200 μL of PBS / Tween 20 solution, EGR-1 antibody was added to PBS solution containing 2% BSA and 5 mM NaCl, and 50 μL was added to each well. After incubation for 1 hour at room temperature, the cells were washed three times with PBS / Tween 20 solution, and horseradish peroxidase-conjugated secondary antibody (Goat anti-rabbit IgG antibody, Cell Signaling Technology, Danvers, MA, USA) was diluted 1:1000 and incubated for 1 hour at room temperature. After washing five times with PBS / Tween 20 solution, 50 μL of tetramethyl benzidine solution as a substrate was added to each well. After 5 minutes of reaction, the reaction was stopped by adding 100 μL of 2N sulfuric acid solution. The DNA binding inhibition ability of EGR-1 was measured using the absorbance at 450 nm using the following mathematical formula 1.

[0311] [Mathematical Formula 1]

[0312] EGR-1 DNA binding inhibition ability (%) = 100-{(As / Ap) X 100}

[0313] As: Absorbance of the sample reacted with EGR-1 overexpressing cell lysate and compound

[0314] Ap: Absorbance of a sample treated only with EGR-1 overexpressing cell lysate The results of measuring the DNA binding inhibition ability of EGR-1 using EDBA for the compounds prepared in the above example are shown in Table 2 below.

[0315] [Table 2] In addition, the results of measuring the DNA binding inhibition rate of EGR-1 for the compounds of chemical formula 1 (a total of 79 compounds) are shown graphically in Fig. 2. Among the 79 compounds of chemical formula 1, compounds 21, 23, and 25 had the best DNA binding ability to EGR-1. Experimental Example 2. In vitro cytotoxicity analysis of the compounds of the present invention In this experiment, the in vitro cytotoxicity of the compounds of chemical formula 1 was analyzed. Specifically, the cell viability of the compounds of chemical formula 1 (a total of 79 compounds) was measured using a CCK-8 kit (Cell Counting Kit-8; Sigma-Aldrich) in HaCaT keratinocytes, and compounds showing a cell viability of 80% or less compared to the control group treated with only the solvent were considered to be toxic. HaCaT keratinocytes were seeded 1x10 in a 96-well cell culture plate. 4 The cells were divided into groups and treated with each compound at a concentration of 100 μM, and cultured for 24 hours. Then, 10 M CCK-8 solution was added. After 2 hours, the absorbance of the cell culture medium was measured at 450 μM, and the cell viability was determined using the following mathematical formula 2.

[0316] [Mathematical Formula 2] Cell viability (%) = (As / Av) x 100

[0317] As: Absorbance of sample treated with compound

[0318] Av: As a result of the absorbance experiment of the sample treated with only the solvent, as shown in Fig. 3, when the cell viability of the control cell group treated with the solvent 0.1% dimethyl sulfoxide (DMSO) was considered 100%, all 79 compounds of the chemical formula 1 of the present invention were measured to have a cell viability of 90% or more. This result suggests that the compound of the chemical formula 1 of the present invention does not exhibit toxicity to human skin keratinocytes at a concentration of 100 iiM. Experimental Example 3. Prediction of EGR-1 binding site of the compound of the present invention In this experiment, the EGR-1 binding site of the compound of the present invention was predicted using molecular docking.

[0319] To determine whether there is binding between EGR-1 and the compound, in silico molecular docking experiments were performed using the Autodock vina program [J. Comp. Chem. 31: 455 (2010)] and the Sybyl program (Tripos, St. Louis, M0).

[0320] Several tertiary structures of EGR-1 are registered in the protein data bank (pdb). Among them, 5nl4.pdb is a structure determined by NMR spectroscopy and contains only 25 amino acid residues. 4x9 j.pdb and 4r2a.pdb are structures determined by X-ray crystallography. Since 4r2a.pdb contains slightly more amino acid residues than 4x9 j.pdb, 4r2a.pdb was used in this experiment [Genes Dev. 28:2304 (2014)]. The structure of the above 4r2a.pdb contains amino acid residues between E335 and D423, and thus contains ZnFl (338-362), ZnF2 (368-390), and ZnF3 (396-418) between E335 and D423. Since 4r2a.pdb does not contain a ligand, the binding site was determined using the MOLCAD module included in the Sybyl program (F377, S378, H382, T385, H386, T389, R407). The AutoDockTools program [J. Comp. Chem. Using the GRIDbox module of [31:455 (2010)], the size of the docking box was determined as 24, 24, 24 for x, y, and z, respectively, and the center of the docking box was determined as -8.194, -4.889, -6.333 for x, y, and z, respectively, and an in si 1 i co docking experiment was performed using the Autodock vina program.

[0321] Docking results were obtained using the LigPlot program provided by the European Bioinformatics Institute [Protein. 1999; 37: 228], and the 3D structure image was generated using the PyMOL program (The PyMOL Molecular Graphics System, Version l.Orl, SchrΦdinger, LLC). To obtain the apoprotein of EGR-1, the Sybyl program was used to remove the oligonucleotides included in 4r2a.pdb. The three compounds (Compounds 21, 23, and 25) with the highest EGR-1 DNA binding inhibition rate in Experimental Example 1 were selected and their binding state with EGR-1 was analyzed. The tertiary structures of compounds 21, 23, and 25 were obtained using the PyMOL program, using 1—[(7— f luoro— 2— hydroxy— 1H— indol— 3— yl ) imino]— 3—(4— f luorophenyl ) thiourea (PubChem CID = 136269038), whose tertiary structure is registered in PubChem (https: / / pubchem.ncbi .nlm.nih.gov / ), as a template. The tertiary structures obtained in this manner were subjected to energy minimization using the UCSF Chimera program, and the tertiary structure with the lowest energy was obtained [J Comput Chem. 2004 Oct;25(13): 1605] .

[0322] Since the AutoDock vina program performed the docking experiment nine times, nine complexes of compound 21 bound to EGR-1 were obtained. The binding energies of these nine complexes ranged from -6.9 kcal / mol to -5.7 kcal / mol, and were therefore judged to be stably bound. Among these nine complexes, the complex with the lowest binding energy showed a pose in which compound 21 was stably bound to EGR-1, and thus this was determined to be the result of compound 21 binding to EGR-1. These results were analyzed for interactions between amino acid residues of compound 21 and EGR-1 using the LigPlot program. Figure 4 shows the interactions between amino acid residues of compound 21 and EGR-1. Referring to Figure 4, compound 21 shows hydrophobic interactions with 1361, F377, and H382, and forms hydrogen bonds with R357, S378, and R379. The distances that form hydrogen bonds with R357, S378, and R379 are 3.25 A, 2.83 A, and 3.11 A, respectively. These residues are included in the binding site determined using the MOLCAD module included in the Sybyl program mentioned above, and it was determined that compound 21 binds well to EGR-1. In addition, Figure 5 is an image of the three-dimensional structure of the complex of compound 21 and EGR-1 predicted using the PyMOL program. Looking at Figure 5, it was confirmed that compound 21, shown in white, binds well to EGR-1, which is composed of green amino acids. The results of forming hydrogen bonds with S378 and R379 are shown as distances of 2.83 A and 3.11 A, respectively, in the 3D image. The same docking experiment as above was performed with compound 23.A total of nine complexes of compound 23 bound to EGR-1 were obtained. The binding energies of these nine complexes ranged from -6.7 kcal / mol to -5.8 kcal / mol, and were therefore judged to be stably bound. Among these nine complexes, the complex with the lowest binding energy showed a pose in which compound 23 was stably bound to EGR-1, and thus this was determined to be the result of compound 23 binding to EGR-1. The results were analyzed for interactions between residues of compound 23 and EGR-1 using the LigPlot program. Figure 6 shows the interactions between amino acid residues of compound 23 and EGR-1. Referring to Figure 6, compound 23 shows hydrophobic interactions with eight residues, H358, R379, F377, H382, R375, K366, 1361, and R360, and forms a total of four hydrogen bonds with residues R357 and S378 at two locations each. The distances for forming hydrogen bonds with R357 are 2.90A and 3.95A, respectively, and the distances for forming hydrogen bonds with S378 are 2.85A and 2.96A, respectively. These residues are included in the binding site determined using the MOLCAD module included in the Sybyl program mentioned above, and it was determined that compound 23 binds well to EGR-1. Also, Figure 7 is an image predicting the three-dimensional structure of the complex of compound 23 and EGR-1 using the PyMOL program. Looking at Figure 7, it was confirmed that compound 23, shown in white, was well bound to EGR-1, which is composed of green amino acids. The same docking experiment as above was performed with compound 25. A total of 9 compound 25 complexes bound to EGR-1 were obtained. The binding energy of these 9 complexes was -6.Since it showed a value between 4 kcal / mol and -5.3 kcal. / mol, it was judged to be stably bound. Since the complex with the lowest binding energy among these 9 complexes showed a pose in which compound 25 was stably bound to EGR-1, it was determined that this was the result of compound 25 binding to EGR-1. This result was analyzed for the interaction between residues of compound 25 and EGR-1 using the LigPlot program. Figure 8 shows the interaction between amino acid residues of compound 25 and EGR-1. Referring to Figure 8, compound 25 shows hydrophobic interactions with 8 residues, F377, K366, R407, H382, 1361, R379, R357, and H358, and forms one hydrogen bond with residue S378. The distance that forms a hydrogen bond with S378 is 3.06 A. These residues are included in the binding site determined using the M0LCAD module included in the Sybyl program mentioned above, and it was determined that compound 25 bound well to EGR-1. In addition, Fig. 9 is an image of the three-dimensional structure of the complex of compound 25 and EGR-1 predicted using the PyMOL program. Looking at Fig. 9, it was confirmed that compound 25, shown in white, was well bound to EGR-1 composed of green amino acids. In addition, the result of forming a hydrogen bond with S378 shows a distance of 3.06 A in the three-dimensional image. Experimental Example 4. In silico ADME analysis of the compound of the present invention In this experiment, we attempted to predict absorption-distribution-to-human{}-excretion} (ADME; Absorption, Distribution, Metabolism, Excretion) in silico. ADME is SwissADME [Sci. Rep.7, 42717(2017)] was used. Compound 21 is moderately soluble in water, well absorbed in the gastrointestinal tract, and has an inhibitory effect on CYP1A2, CYP2C9, and CYP3A4 among cytochrome P450 isozymes, so it is possible that it may interact with other drugs that use these as substrates. However, it is judged that it is unlikely to interact with other drugs that use these as substrates because it does not inhibit CYP2C19 and CYP2D6. The saturation value, which requires that the ratio of sp3 carbons to the total carbon number contained in compound 21 be at least 0.25, is outside the standard value, which may result in poor bioavailability. However, other factors such as molecular size, molecular polarity, solubility, flexibility, and lipophilicity all meet the standard values, so the bioavailability of compound 21 was judged to be good. Compound 23 is highly soluble in water, poorly absorbed in the gastrointestinal tract, and has an inhibitory effect on CYP1A2, CYP2C9, and CYP3A4 among cytochrome P450 enzymes, so there is a possibility of interaction with other drugs that use them as substrates. However, since it does not inhibit CYP2C19 and CYP2D6, it was judged that there is no possibility of interaction with other drugs that use them as substrates. The bioavailability of compound 23 was judged to be good because, although the saturation and molecular polarity values ​​were beyond the standard, other factors such as molecular size, solubility, flexibility, and lipophilicity all satisfied the standard.Compound 25 is highly soluble in water, well absorbed in the gastrointestinal tract, and has an inhibitory effect on CYP1A2, CYP2C9, and CYP3A4 among cytochrome P450 isozymes. Therefore, it is possible that it may interact with other drugs that use them as substrates. However, since it does not inhibit CYP2C19 and CYP2D6, it is judged that it is unlikely to interact with other drugs that use them as substrates. Compound 25 was judged to have good bioavailability because all factors except for saturation, such as molecular size, molecular polarity, solubility, flexibility, and lipophilicity, satisfied the standards. Experimental Example 5. In silico toxicity analysis of the compound of the present invention In this experiment, the toxicity was predicted in silico. Toxicity was evaluated using the method provided by Pro-Tox-II [Nucleic Acids Res 46(W1), W257 (2018)]. Compound 21 had an LD50 of 2100 mg / Kg and was toxic in all regions except hepatotoxicity, carcinogenicity, aryl hydrocarbon receptor, and mitochondrial membrane potential pathway. Compound 23 had an LD50°] of 2100 mg / Kg and was toxic in all regions except immunotoxicity, mutagenicity, aryl hydrocarbon receptor, and mitochondrial membrane potential pathway. Compound 23 had an LD50 of 2100 mg / Kg and was toxic in all regions except hepatotoxicity, carcinogenicity, mutagenicity, and mitochondrial membrane potential pathway. Experimental Example 6. Off-target effect of the compound of the present invention In this experiment, in addition to the effect of inhibiting DNA binding of EGR-1 in silico, the target protein was predicted to avoid targeting other proteins.The target protein example was obtained using the method provided by SwissTarget [Nucleic Acids Research 47(W1), W357 (2019)]. The top 10 target proteins predicted as non-specific targets of compound 21 were identified, and the target with the highest probability was 0.109, suggesting no non-specific target effect. The top 10 target proteins predicted as non-specific targets of compound 23 were identified, and the target with the highest probability was 0.109, suggesting no non-specific target effect. The top 10 target proteins predicted as non-specific targets of compound 25 were identified, and the target with the highest probability was 0.097, suggesting no non-specific target effect. Experimental Example 7. Inhibitory effect of EGR-1 binding ability of the compound of the present invention using EMSA technique When nucleic acid and protein bind, the complex of nucleic acid and protein migrates more slowly than the nucleic acid that moves alone. Therefore, in the electrophoretic mobility shift assay (EMSA), the band of the nucleic acid bound to the protein appears higher than the band of the nucleic acid alone. Using this experimental principle, the compounds (compounds 21, 23, 25) that had the highest EGR-1 DNA binding inhibition rate in Experimental Example 1 were selected, and the EGR-1 binding inhibition effect of the compound of the present invention was evaluated by analyzing the electrophoretic mobility shift. Specifically, protein-DNA binding was analyzed using a LightShift Chemi luminescence EMSA kit (ThermoFisher Scientific, Waltham, MA, USA). The EGR-1 probe sequence was synthesized by requesting the synthesis of a biotin-labeled deoxyoligonucleotide containing the EGR-1 binding sequence (5'-biotin- AGA GTG TGT CTC CTT CGC ACA CAT C- 3') from Macrogen (Seoul, Korea).The EGR-1 protein for use in the experiment was a cell extract obtained by overexpressing human EGR-1 protein in Sf21 insect cells as described in the paper by Yeo et al. [Journal of Investigative Dermatology 2021: 141: 1851-1855]. Wild-type Sf21 cell extract was used as a negative control. EGR-1 overexpressing Sf21 cell extract (3 μg) and 1 u 1 of the present invention compound at a concentration of 20 mM, 50 fmol of biotin-labeled EGR-1-binding deoxyoligonucleotide probe, 1 11 g poly (dI-dC) (Amersham Pharmacia Biotech Inc) were reacted for 20 minutes, and then electrophoresed on a 6% non-denaturing polyacrylamide gel. The electrophoretically separated samples were attached to a nylon membrane (Immobi km-Ny+ Transfer membrane, Millioore) and soaked in a 5% skim milk solution for 30 minutes. Afterwards, streptavidin conjugated with horseradish peroxidase was added and reacted for 15 minutes. After washing away proteins not bound to the membrane, the EGR-1-DNA complex was detected on X-ray film using an enhanced chemiluminescence (ECL) detection system (ThermoFisher Scientific). The intensity of the EGR-1-DNA complex band was analyzed using the ImageJ program (National Institute of Health, USA), and the relative intensity was measured with the intensity of the sample without the compound added set as 100%. The experimental results are shown in Fig. 13. Figure 13 shows the results of electrophoretic mobility shift analysis (EMSA) performed after administering compounds (compounds 21, 23, 25) according to the present invention to keratinocytes.As shown in Fig. 13, all three selected compounds (compounds 21, 23, and 25) inhibited the DNA binding of EGR-1 in a concentration-dependent manner. Experimental Example 8. Inhibitory effect on EGR-1 target TSLP gene mRNA expression In order to confirm whether the compounds of the present invention (compounds 21, 23, and 25) inhibit the expression of TSLP, IL-1P, and IL-6 genes, which are EGR-1 target genes that play a key role in atopic dermatitis aggravation, the inhibitory effect of the compounds on EGR-1 target TSLP gene mRNA expression was evaluated using reverse transcription polymerase chain reaction (RT-PCR) in HaCaT keratinocytes. Specifically, HaCaT keratinocytes (purchased from Cel 1 Lines Service (Eppelheim, Germany)) were cultured in Dulbecco's modified Eagle's medium (Invitrogen Life Technologies) containing 10% fetal bovine serum (Invitrogen Life Technologics) and an antibacterial-antimycotic mixture (Invitrogen Life Technologics) at 1xlO in 100 mm cell culture dishes every other day. 6 The cultures were cultured in a 37 °C, 5% CO2 incubator with seed density of 10.

[0323] HaCaT cells were treated with compounds of the present invention (compounds 21, 23, and 25) at concentrations of 0, 5, 10, and 20 yM, respectively, and 30 minutes later, 10 ng / ml of the inflammatory cytokine TNF a was treated, and 12 hours later, the cells were harvested. To measure the amount of gene mRNA, total RNA was extracted using TRIzol RNA Isolation Reagents (TRIzol purchased from Life Technologies Korea). 0.5 ug of total RNA was used to synthesize complementary DNA (cDNA) using reverse transcription according to the method recommended by the manufacturer using the iScript cDNA synthesis kit (iScript cDNA synthesis kit; Bio-Rad, Hercules, CA, USA). PCR experiments were performed with 0.0125 ug of double-stranded cDNA. Primer bases for gene amplification were synthesized by Macrogen (Seoul, Korea), and the primer sequences are shown in Table 3 below.

[0324] [Table 3] As a control, GAPDH (g lyceraldehyde-3-phosphate dehydrogenase), a housekeeping gene, was used. Double-stranded cDNA was denatured at 95°C for 5 minutes, followed by 30 cycles of 94°C for 1 minute, 65°C for 2 minutes, and 70°C for 1 minute. The final PCR product was confirmed by electrophoresis on a 1% agarose gel and staining with EtBr (ethidium bromide). The experimental results are shown in Fig. 14. Fig. 14 shows the results of reverse transcription polymerase chain reaction (RT-PCR) performed after administering three compounds (compounds 21, 23, and 25) according to the present invention to keratinocytes. As shown in Fig. 14, the expression of TSLP, IL-1P, and IL-6 mRNA, which are EGR-1 target genes produced by TNFQ stimulation, was dose-dependently reduced by the compounds of the present invention (compounds 21, 23, and 25). Experimental Example 9. Effect of atopic dermatitis treatment in an animal model of atopic dermatitis induced by DNCB.

[0325] (1) Production of atopic dermatitis animal model Male BALB / c mice aged 6-8 weeks were acclimated for 1 week in an animal laboratory maintained at a temperature of 20°C, a humidity of 10%, and a 12-hour light / dark cycle. For the atopic dermatitis control group, 4% sodium dodecyl sulfate (SDS) was applied to the ear area of ​​the mice to increase skin sensitivity, and then 1% 2,4-dinitrochlorobenzene (DNCB; Sigma Chemical Co., St. Louis, MO, USA) was prepared as a mixture of acetone and olive oil (3:1, v / v) and applied to the ear area of ​​the mice once a day for 3 days. After a 4-day rest period, atopic dermatitis was induced by applying 100 μL of 4% SDS and 0.5% DNCB to the same area once a day, 5 times a week for 2 weeks. Approximately 2 to 3 hours later, (i) drug solvent (atopic positive control), (ii) 0.1% tofacitinib (Tofacitinib, JAK kinase inhibitor; drug positive control), (iii) 0.1% compound 21, (iv) 0.1% compound 23, and (v) 0.1% compound 25 were applied to the same area and the symptom relief effect was observed (see Figure 15A).

[0326] (2) Treatment effect of atopic dermatitis by skin application of the compound of this invention

[0327] (2-1) On the final day of the experiment (day 22) for improvement of macroscopic skin inflammation, all experimental mice were sacrificed and macroscopic skin clinical symptoms were observed. In mice treated with only DNCB, skin rash due to skin inflammatory reaction was significantly improved in mice treated with compounds 21, 23, and 25, similar to the positive control drug, tofacitinib (see Figure 15B).

[0328] (2-2) Histopathological improvement effect In atopic dermatitis, due to repeated inflammatory reactions, the proliferation of keratinocytes increases, and an imbalance occurs in the differentiation process into keratin, resulting in an increase in the thickness of the skin. It is known that major immune cells infiltrate a lot into the tissue, promoting the inflammatory reaction. Therefore, the histopathological treatment effect of the compound (Compound 21, 23, 25) of the present invention was analyzed. (a) H&E (Hematoxylin and Eosin) staining experiment The ear skin of the mouse was excised, fixed in a 100% acetone solution for 24 hours, and then a paraffin block was prepared. After the paraffin block was thinly sliced to a thickness of 5 μm, hematoxylin / eosin staining was performed using an H&E staining kit (H&E Staining Kit; Abeam, Cambridge, UK). As a result, it was observed that the thicknesses of the epidermis and dermis in the skin tissue of the experimental group induced with atopic dermatitis by treating DNCB were significantly increased compared to the normal control group (see Fig. 15C). When the change in the thickness of the skin was quantitatively measured using the stained skin tissue, the epidermis thickness was 24.47 ± 2.353 μm and the dermis thickness was 143.2 ± 19.61 μm in the normal skin tissue. In the tissue treated with only DNCB, the epidermis was 37.27 ± 4.393 μm and the dermis was 197.5 ± 17.83 μm. In the mouse treated with the control drug tacitinib, the epidermis was 27.09 ± 1.719 μm and the dermis was 154.5 ± 11.32 μm. In the skin tissue injected with the compound (Compound 21, 23, 25) of the present invention, the epidermis thicknesses were 25.22 ± 2.993, 22.92 ± 3.617, and 23.46 ± 1.530 μm, respectively. The dermis thicknesses were 163.4 ± 7.905, 147.5 ± 8.302, and 157.8 ± 17.05 μm, respectively (see Fig. 15D).Through the above experimental results, it was confirmed that the compounds of the present invention (compounds 21, 23, 25) can alleviate skin inflammation symptoms and inhibit the proliferation of skin keratinocytes similarly to the positive control drug, tofacitinib.

[0329] (b) Inhibitory effect on inflammatory cell infiltration During an inflammatory response, when inflammatory cells such as mast cells, neutrophils, and macrophages infiltrate into the inflamed area of ​​the skin, various inflammatory substances are secreted, which aggravates the inflammatory response. Therefore, the inhibitory effect of the compounds according to the present invention (compounds 21, 23, and 25) on inflammatory cell infiltration was evaluated. In order to measure the number of mast cells infiltrating into the inflamed area, 0.5% toluidine blue (TB) staining was performed on the paraffin tissue prepared in (a) above. As a result, it was observed that mast cell infiltration was significantly increased in the atopic dermatitis tissue induced by DNCB compared to the normal group, and in the experimental group tissues to which the control drug tofacitinib and the compounds according to the present invention (compounds 21, 23, and 25) were applied, mast cell infiltration was significantly reduced compared to the positive control group (see Fig. 16A). As a result of quantitatively measuring the number of infiltrated mast cells, the number of mast cells infiltrated into the normal skin tissue was 2.5 cm 2In the skin tissues where the compounds of the present invention (compounds 21, 23, and 25) were applied, the number of mast cells was 18:3, 19:5, and 15:5, respectively (see Figure 16B). Neutrophils and phagocytes were analyzed by immunohistochemistry using myeloperoxidase (MP0) antibody and F4 / 80 antibody, respectively. Paraffin tissues prepared in the above (a) were deparaffinized with xylene and hydrated with ethanol. The tissue sections were then reacted in ImM EDTA (pH 8.0) at 70°C for 20 minutes and incubated in a blocking solution containing 7% goat serum at room temperature for 1 hour. Subsequently, antibodies to the phagocytic cell marker F4 / 80 (Cell signaling Biotechnology, Beverly, USA) and antibodies to the neutrophil marker MP0 (DAK0, Glostrup, Denmark) were added to each tissue section and incubated overnight at 4°C. After washing the tissue slides with phosphate buffer, secondary antibodies conjugated with horseradish peroxidase (HRP0) were added and incubated at room temperature for 1 hour. After washing the tissue slides with phosphate buffer, they were reacted with 3,3-diaminobenzidine tetrahydrochloride substrate for 5 minutes, and then counterstained with H&E dye. As a result, it was observed that the expression of MP0, a neutrophil marker (see Figure 16C), and F4 / 80, a phagocyte marker (see Figure 16D), was significantly increased in the atopic dermatitis tissues induced by DNCB compared to the normal group, and in the experimental group tissues treated with the control drug tofacitinib and the compounds according to the present invention (compounds 21, 23, and 25), a decrease in expression was observed similar to that in the normal tissues.Through the above experimental results, it was confirmed that the compounds of the present invention (compounds 21, 23, 25) have the effect of reducing the infiltration of mast cells, neutrophils, and phagocytes into the inflamed area, which worsens the symptoms of atopic skin inflammation, similarly to the control drug tofacitinib.

[0330] (c) TSLP inhibition and filaggrin recovery effect Thymic stromal lymphopoietin (TSLP) is an IL-7 family cytokine secreted by various non-immune cells such as epithelial cells, smooth muscle cells, fibroblasts, and epidermal keratinocytes. TSLP is a major inflammatory cytokine that is produced in large quantities in keratinocytes by skin inflammatory reactions, promotes the differentiation of T lymphocytes, activates various inflammatory cells, and stimulates skin sensory nerves to cause itching, thereby aggravating atopic dermatitis. Filaggrin is a protein that binds to keratin in the stratum corneum of skin tissue to create a skin barrier that is important for skin hydration and plays a role in creating a natural moisturizing factor. As skin inflammation worsens, filaggrin production decreases, causing damage to the skin barrier, which in turn worsens dry skin and itching, facilitating the invasion of various microorganisms, fine dust, and allergens, thereby worsening atopic dermatitis symptoms. Therefore, the effects of the compounds of the present invention (compounds 21, 23, and 25) on suppressing TSLP production and restoring filaggrin production were analyzed. Specifically, after removing paraffin from the tissue sections as described in (b) above, they were reacted in a blocking solution containing 1% bovine serum albumin for 1 hour. Afterwards, TSLP antibody (Novus Biologicals, Centennial, USA) and FLG antibody (Santa Cruz Biotechnology, Dallas, USA) were added to each tissue section and reacted overnight at 4°C. After washing the sections with phosphate buffer, they were reacted with secondary antibody conjugated with rhodamine red-X (Jackson ImmunoResearch Laboratories, West Grove, USA; 1:300 dilution) for 1 hour at 25°C.For contrast staining, nuclear staining was performed with Hoechst 33258 solution, and after adding a fluorescent mounting medium (ProLong Gold ant i fade reagent, Invitrogen, Carlsbad, CA, USA) to the coverslip, the fluorescent images were analyzed using an EVOS FL fluorescence microscope (Advanced Microscopy Group; Bothel 1, WA, USA). As a result, it was observed that TSLP expression was significantly increased in the atopic dermatitis tissues induced by DNCB compared to the normal group, and in the experimental group tissues to which the control drug tofacitinib and the compounds according to the present invention (compounds 21, 23, 25) were applied, TSLP expression was significantly decreased compared to the positive control group (see Fig. 17A). In addition, it was observed that filaggrin was significantly reduced in atopic dermatitis tissues, but in the experimental group tissues to which the control drug tofacitinib and the compounds according to the present invention (compounds 21, 23, 25) were applied, it was observed that filaggrin expression was restored to a similar degree as in normal tissues (see Figure 17B). Through the above experimental results, it was confirmed that the compounds of the present invention (compounds 21, 23, 25) have the effect of restoring the production of filaggrin protein, which is essential for skin barrier repair, while reducing the expression of TSLP, which worsens atopic skin inflammation symptoms, similar to the positive control drug tofacitinib. The above description of the present invention is for the purpose of illustration, and those skilled in the art to which the present invention pertains will understand that the present invention can be easily modified into other specific forms without changing the technical spirit or essential characteristics of the present invention. Therefore, it should be understood that the embodiments described above are exemplary in all aspects and not limiting.

Claims

Scope of the claim

1. A pharmaceutical composition for preventing, improving or treating atopic dermatitis, comprising a compound of the following chemical formula 1, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient: In the above formula, ※ is hydrogen, C1-C6 alkyl, - CH2- C 6-10 Aryl or , and at this time, the C1-C6 alkyl and - CH2- C 6-10 Each aryl may be independently unsubstituted or substituted with 1 to 3 halogens; R 1 is hydrogen or halogen; R 2 is hydrogen, halogen, hydroxy, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each independently unsubstituted or substituted with 1 to 3 halogens; R 3 , R 4 and each independently represents hydrogen, halogen, hydroxy or C1-C6 alkoxy, wherein the C1-C6 alkoxy may be unsubstituted or substituted with 1 to 3 halogens; R 6 is hydrogen, halogen, hydroxy, -NO2, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each independently unsubstituted or substituted with 1 to 3 halogens; R 7 is hydrogen, halogen, hydroxy, -NO2, -CN, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy may each independently be unsubstituted or substituted with 1 to 3 halogens.

2. A pharmaceutical composition according to claim 1, wherein the compound comprises any one compound selected from the group consisting of: an isomer thereof or a pharmaceutically acceptable salt thereof: N-(3-(trifluoromethyl)phenyl)hydrazinecarbotheramide; N-(4-fluorophenyl)hydrazinecarbotheramide; N-(4-bromophenyl)hydrazinecarbotheramide; N-(4-cyanophenyl)hydrazinecarbotheramide; N-(4-(trifluoromethyl)phenyl)hydrazinecarbotheramide; N-ethylhydrazinecarbotheramide; N-isopropylhydrazinecarbotheramide; N-isobutylhydrazine carbonate amide; N-(hydrazinecarbonothioyl)benzamide; N-Benzylhydrazinecarbotheramide; N-(m-tolyl)hydrazinecarbotheramide; (Z)-2-(5-fluoro-2-oxoindolin-3-ylidene)-N-phenylhydrazinecarbotheramide; (Z)-2-(5-fluoro-2-oxoindolin-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbothioamide; (Z)-2-(5-fluoro-2-oxoindoline-3-ylidene)-N-(4-fluorophenyl)hydrazinecarbothioamide; (Z)-N-(4-bromophenyl)-2-(5-fluoro-2-oxoindolin-3-ylidene)hydrazinecarbothioamide; (Z)-N-(4-cyanophenyl)-2-(5-fluoro-2-oxoindolin-3-ylidene)hydrazinecarbothioamide; (Z)-2-(5-fluoro-2-oxoindoline-3-ylidene)-N-(4-(trifluoromethyl)phenyl)hydrazinecarbotheramide; (Z)-2-(7-fluoro-2-oxoindolin-3-ylidene)-N-(4-fluorophenyl)hydrazinecarbotheramide; (Z)-N-(4-bromophenyl)-2-(7-fluoro-2-oxoindolin-3-ylidene)hydrazinecarbothioamide; (Z)-N-(4-cyanophenyl)-2-(7-fluoro-2-oxoindolin-3-ylidene)hydrazinecarbothioamide; (Z)-2-(7-fluoro-2-oxoindoline-3-ylidene)-N-(4-(trifluoromethyl)phenyl)hydrazinecarbotheramide; (Z)-2-(6-methoxy-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide; (Z)- 2-(6-methoxy-2-oxoindolin- 3-ylidene)- N-(3-nitrophenyl)hydrazine- 1-carbothioamide; (Z)- 2-(6 -methoxy- 2 -oxoindolin- 3 -ylidene)- N-(2 -methoxyphenyl)hydrazine- 1-carbothioamide; (Z)-N-(4-cyanophenyl)-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazinecarbotheramide; (Z)- 2-(6-methoxy- 2-oxoindolin- 3-ylidene)- N-(4-(trifluoromethyl)phenyl)hy Drazinecarboteoamide; (Z)-N-ethyl-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazinecarbotheramide; (Z)-2-(6-methoxy-2-oxoindolin-3-ylidene)-N-(m-tolyl)hydrazinecarbotheroamide; (Z)-2-(5-methyl-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide; (Z)-2-(5-methyl-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheroamide; (Z)-N-(2-methoxyphenyl)-2-(5-methyl-2-oxoindolin-3-ylidene)hydrazinecarbotheroamide; (Z)-2-(5-methyl-2-oxoindolin-3-ylidene)-N-(3-(trifluoromethyl)phenyl)hydrazinecarbotheramide; (Z)- N-(4-fluorophenyl)-2-(5-methyl- 2-oxoindolin- 3-ylidene)hydrazinecarbotheramide; (Z)-2-(5-bromo-2-oxoindoline-3-ylidene)hydrazinecarbotheramide; (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(3 -nitrophenyl)hydrazinecarbotheramide; (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheramide; (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(4 -nitrophenyl)hydrazinecarbotheramide; (Z)-2-(5-bromo-2-oxoindoline-3-ylidene)-N-(4-nitrophenyl)hydrazinecarbotheramide; (Z)- N-(2 -methoxyphenyl)- 2-(2 -oxoindoline- 3 -ylidene)hydrazinecarbotheramide; (Z)-2-(4-bromo-2-oxoindoline-3-ylidene)hydrazinecarbotheramide; (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)hydrazinecarbotheramide; (Z)-2-(7-bromo-2-oxoindoline-3-ylidene)hydrazinecarbotheramide; (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-phenylhydrazinecarbotheramide; (Z)- 2-(5 -bromo- 2 -oxoindoline- 3 -ylidene)- N-phenylhydrazine carboteramide; (Z)- 2-(6 -bromo- 2 -oxoindoline- 3 -ylidene)- N-phenylhydrazine carboteramide; (Z)- 2-(7 -bromo- 2 -oxoindoline- 3 -ylidene)- N-phenylhydrazine carboteramide; (Z)- N-(3 -nitrophenyl)- 2-(2 -oxoindoline- 3 -ylidene)hydrazine carboteramide; (Z)- 2-(5 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(3 -nitrophenyl)hydrazine carboteramide ; (Z)-2-(7-bromo-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheramide; (Z)- N-(3 -methoxyphenyl)-2-(2 -oxoindoline-3 -ylidene)hydrazinecarbotheramide; (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(3 -methoxyphenyl)hydrazinecarbotheramide; (Z)-2-(5-bromo-2-oxoindoline-3-ylidene)-N-(3-methoxyphenyl)hydrazinecarbotheramide; (Z)- N-(4 -methoxyphenyl)-2-(2 -oxoindoline-3 -ylidene)hydrazinecarbotheramide; (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(4 -methoxyphenyl)hydrazinecarbotheramide; (Z)-2-(5-bromo-2-oxoindoline-3-ylidene)-N-(4-methoxyphenyl)hydrazinecarbotheramide; N-(3,4-dimethoxyphenyl)hydrazinecarbotheramide; (Z)- N-(4-fluorophenyl)-2-(2-oxoindolin-3-ylidene)hydrazinecarbotheramide; (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-(4-nitrophenyl)hydrazinecarbotheramide; (Z)-2-(4-chloro-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide; (Z)-2-(6-chloro-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide; (Z)-2-(4-chloro-2-oxoindolin-3-ylidene)-N-(2-methoxyphenyl)hydrazinecarbotheramide; (Z)-2-(5-fluoro-2-oxoindoline-3-ylidene)-N-(3-(trifluoromethyl)phenyl)hydrazinecarbotheramide; (Z)-N-Benzyl-2-(5-fluoro-2-oxoindolin-3-ylidene)hydrazinecarbotheramide; (Z)-2-(5-fluoro-2-oxoindolin-3-ylidene)-N-(m-tolyl)hydrazinecarbotheramide; (Z)-2-(7-fluoro-2-oxoindolin-3-ylidene)-N-(4-nitrophenyl)hydrazinecarbothioamide; (Z)- 2-(6-methoxy- 2-oxoindoline- 3-ylidene)- N-(3-(trifluoromethyl)phenyl)hydrazinecarbotheramide; (Z)- N-(4-fluorophenyl)-2-(6-methoxy-2-oxoindoline-3-ylidene)hydrazine-1-carbotorimide; (Z)- N-(4 -bromophenyl)- 2-(6 -methoxy-2 -oxoindolin- 3 -ylidene)hydrazine- 1-carbothioamide; (Z)-N-Benzyl-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazine-1-carbothioamide; (Z)- N-(4 -bromophenyl)-2-(5 -methyl- 2 -oxoindoline- 3 -ylidene)hydrazinecarbotheroamide; (Z)- N-(4 -cyanophenyl)-2-(5 -methyl- 2 -oxoindoline- 3 -ylidene)hydrazinecarbotheroamide; (Z)-2-(5-methyl-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide; (Z)- N-Ethyl- 2-(5 -methyl- 2 -oxoindoline- 3 -ylidene)hydrazinecarbotheramide; (Z)- N-Benzyl- 2-(5 -methyl- 2 -oxoindoline- 3 -ylidene)hydrazinecarbotheramide; (Z)-2-(5-methyl-2-oxoindolin-3-ylidene)-N-(m-tolyl)hydrazinecarbotheramide; (Z)-2-(2-oxo-5-(trifluoromethoxy)indolin-3-ylidene)-N-phenylhydrazinecarbotheramide; (Z)-N-(3 -nitrophenyl)-2-(2 -oxo-5-(trifluoromethoxy)indolin-3 -ylidene)hydrazinecarbotheramide; (Z)-N-(4-fluorophenyl)-2-(2-oxo-5-(trifluoromethoxy)indolin-3-ylidene)hydrazinecarbotheramide; and (Z)- N-(4-bromophenyl)-2-(2-oxo-5-(trifluoromethoxy)indolin-3-ylidene)hydrazinecarbotheramide. [

3. A pharmaceutical composition according to claim 1 or 2, which can be administered orally, parenterally, or through the skin. [

4. A pharmaceutical composition for preventing or improving atopic dermatitis, comprising a compound of the following chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient: [Chemical Formula 1] ※ is hydrogen, C1-C6 alkyl, - CH2- C 6-10 Aryl or , wherein the C1-C6 alkyl and - CH2-C 6-10 Each aryl may be independently unsubstituted or substituted with 1 to 3 halogens; R 1 is hydrogen or halogen; R 2 is hydrogen, halogen, hydroxy, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each independently unsubstituted or substituted with 1 to Can be substituted with three halogens; R 3 , R 4 and each independently represents hydrogen, halogen, hydroxy or C1-C6 alkoxy, wherein the C1-C6 alkoxy is unsubstituted or may be substituted with 1 to 3 halogens; R 6 is hydrogen, halogen, hydroxy, -NO2, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each independently unsubstituted or substituted with 1 to 3 halogens; R 7 is hydrogen, halogen, hydroxy, -NO2, -CN, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy may each independently be unsubstituted or substituted with 1 to 3 halogens.

5. A method for preventing or treating atopic dermatitis, comprising administering to a subject a compound of the following chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above formula, hydrogen, C1-C6 alkyl, - CH2- C 6-10 Aryl or At this time, the above C1-C6 alkyl and - CH2- C 6-10 Each aryl may be independently unsubstituted or substituted with 1 to 3 halogens; R 1 is hydrogen or halogen; R 2 is hydrogen, halogen, hydroxy, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each independently unsubstituted or substituted with 1 to 3 halogens; R 3 , R 4 and each independently represents hydrogen, halogen, hydroxy or C1-C6 alkoxy, wherein the C1-C6 alkoxy is unsubstituted or may be substituted with 1 to 3 halogens; R 6 is hydrogen, halogen, hydroxy, -NO2, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each independently unsubstituted or substituted with 1 to 3 halogens; R 7 is hydrogen, halogen, hydroxy, -NO2, -CN, C1-C6 alkyl, or C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are each independently unsubstituted, or It can be substituted with 1 to 3 halogens.

6. Any one compound selected from the group consisting of: an isomer thereof or a pharmaceutically acceptable salt thereof; (Z)-N-(4-cyanophenyl)-2-(7-fluoro-2-oxoindolin-3-ylidene)hydrazinecarbothioamide; (Z)-2-(7-fluoro-2-oxoindoline-3-ylidene)-N-(4-(trifluoromethyl)phenyl)hydrazinecarbotheramide; (Z)-2-(6-methoxy-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide (Z)- 2-(6-methoxy-2-oxoindolin- 3-ylidene)- N-(3-nitrophenyl)hydrazine- 1-carbothioamide; (Z)- 2-(6 -methoxy- 2 -oxoindolin- 3 -ylidene)- N-(2 -methoxyphenyl)hydrazine- 1-carbothioamide; (Z)-N-(4-cyanophenyl)-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazinecarbotheramide; (Z)- 2-(6-methoxy- 2-oxoindoline- 3-ylidene)- N-(4-(trifluoromethyl)phenyl)hydrazinecarbotheramide; (Z)-N-ethyl-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazinecarbotheramide; (Z)-2-(5-methyl-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheroamide; (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(3 -nitrophenyl)hydrazinecarbotheramide; (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheramide; (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(4 -nitrophenyl)hydrazinecarbotheramide; (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-phenylhydrazinecarbotheramide; (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide; (Z)-2-(7-bromo-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheramide; (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(3 -methoxyphenyl)hydrazinecarbotheramide; (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(4 -methoxyphenyl)hydrazinecarbotheramide; (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-(4-nitrophenyl)hydrazinecarbotheramide; (Z)-2-(4-chloro-2-oxoindolin-3-ylidene)-N-(2-methoxyphenyl)hydrazinecarbotheramide; (Z)-2-(7-fluoro-2-oxoindolin-3-ylidene)-N-(4-nitrophenyl)hydrazinecarbothioamide; (Z)- 2-(6-methoxy- 2-oxoindoline- 3-ylidene)- N-(3-(trifluoromethyl)phenyl)hydrazinecarbotheramide; (Z)- N-(4-fluorophenyl)-2-(6-methoxy-2-oxoindoline-3-ylidene)hydrazine-1-carbotorimide; (Z)- N-(4 -bromophenyl)- 2-(6 -methoxy-2 -oxoindolin- 3 -ylidene)hydrazine- 1-carbothioamide; (Z)-N-Benzyl-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazine-1-carbothioamide; (Z)- N-(4-cyanophenyl)-2-(5-methyl- 2-oxoindoline- 3-ylidene)hydrazinecarbotheroamide; and (Z)-2-(5-methyl-2-oxoindolin-3-ylidene)-N-(m-tolyl)hydrazinecarbotheramide;

7. A composition comprising any one compound selected from the group consisting of: an isomer thereof or a pharmaceutically acceptable salt thereof; (Z)-N-(4-cyanophenyl)-2-(7-fluoro-2-oxoindolin-3-ylidene)hydrazinecarbothioamide; (Z)-2-(7-fluoro-2-oxoindoline-3-ylidene)-N-(4-(trifluoromethyl)phenyl)hydrazinecarbotheramide; (Z)-2-(6-methoxy-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide (Z)- 2-(6-methoxy-2-oxoindolin- 3-ylidene)- N-(3-nitrophenyl)hydrazine- 1-carbothioamide; (Z)- 2-(6 -methoxy- 2 -oxoindolin- 3 -ylidene)- N-(2 -methoxyphenyl)hydrazine- 1-carbothioamide; (Z)-N-(4-cyanophenyl)-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazinecarbotheramide; (Z)- 2-(6-methoxy- 2-oxoindoline- 3-ylidene)- N-(4-(trifluoromethyl)phenyl)hydrazinecarbotheramide; (Z)-N-ethyl-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazinecarbotheramide; (Z)-2-(5-methyl-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheroamide; (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(3 -nitrophenyl)hydrazinecarbotherm Oamide; (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheramide; (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(4 -nitrophenyl)hydrazinecarbotheramide; (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-phenylhydrazinecarbotheramide; (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-phenylhydrazinecarbotheramide; (Z)-2-(7-bromo-2-oxoindoline-3-ylidene)-N-(3-nitrophenyl)hydrazinecarbotheramide; (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(3 -methoxyphenyl)hydrazinecarbotheramide; (Z)- 2-(4 -bromo- 2 -oxoindoline- 3 -ylidene)- N-(4 -methoxyphenyl)hydrazinecarbotheramide; (Z)-2-(6-bromo-2-oxoindoline-3-ylidene)-N-(4-nitrophenyl)hydrazinecarbotheramide; (Z)-2-(4-chloro-2-oxoindolin-3-ylidene)-N-(2-methoxyphenyl)hydrazinecarbotheramide; (Z)-2-(7-fluoro-2-oxoindolin-3-ylidene)-N-(4-nitrophenyl)hydrazinecarbothioamide; (Z)- 2-(6-methoxy- 2-oxoindoline- 3-ylidene)- N-(3-(trifluoromethyl)phenyl)hydrazinecarbotheramide; (Z)- N-(4-fluorophenyl)-2-(6-methoxy-2-oxoindoline-3-ylidene)hydrazine-1-carbotorimide; (Z)- N-(4 -bromophenyl)- 2-(6 -methoxy-2 -oxoindolin- 3 -ylidene)hydrazine- 1-carbothioamide; (Z)-N-Benzyl-2-(6-methoxy-2-oxoindolin-3-ylidene)hydrazine-1-carbothioamide; (Z)- N-(4-cyanophenyl)-2-(5-methyl- 2-oxoindoline- 3-ylidene)hydrazinecarbotheroamide; and (Z)-2-(5-methyl-2-oxoindolin-3-ylidene)-N-(m-tolyl)hydrazinecarbotheramide;

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