Novel sulfoximide derivative or pharmaceutically acceptable salt thereof, and use thereof

Abstract

The present invention relates to a sulfinyl imide derivative or a pharmaceutically acceptable salt thereof, and a composition for preventing or treating cancer comprising the derivative as an active ingredient. The sulfoximide derivative or the pharmaceutically acceptable salt thereof according to the present invention has an excellent effect on activation of Nrf2, has high solubility and drug metabolism stability, has anti-inflammatory and antioxidant effects, and improves athletic performance and cognitive ability, and thus can be used in the prevention or treatment of diseases caused by a decrease in Nrf2 activity, such as diseases caused by a decrease in Nrf2 activity, as well as in the prevention or treatment of diseases caused by a decrease in Nrf2 activity. The compound is preferably used for treating liver diseases, kidney diseases, lung diseases, neurodegenerative diseases, mitochondrial myopathy, Friedel's ataxia, corneal endothelial cell loss, psoriasis and the like.

Description

Technical Field

[0001] The present invention relates to a novel sulfanone derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof, an Nrf2 activator comprising the sulfanone derivative as an active ingredient, and a pharmaceutical composition for preventing or treating diseases caused by decreased Nrf2 activity. Background Art

[0002] Nrf2 (nuclear factor erythroid-derived 2-related factor 2) is a Cap'n'Collar family basic region-leuzine zipper transcription factor that induces gene transcription by binding to ARE (antioxidant response element) sequences (involved in the expression of various genes that protect cells). Although not all antioxidant enzymes are induced by ARE inducers, studies using Nrf2-null mice (artificially knocked out this transcription factor) have shown that the expression of antioxidant enzymes is induced by ARE-mediated Nrf2 activation.

[0003] Nrf2 is negatively regulated by Keap1 (Kelch-like ECH associated protein 1). In the absence of oxidative stress, Nrf2 binds to Keap1, is ubiquitinated and degraded by the proteasome. However, under oxidative stress conditions, Nrf2 is released by binding to Keap1 and modifying the cysteine ​​residues of Keap1. Nrf2 enters the nucleus and binds to ARE to increase the transcription of various antioxidant genes in the promoter region.

[0004] Various structural compounds have been found to induce the transcription of protective genes through the Nrf2-Keap1 pathway in natural products, foods, metabolites, and organic synthetic compounds. All known compounds are either electrophilic compounds that react with the cysteine ​​of Keap1 or compounds that are converted into electrophilic compounds through intracellular metabolic processes. Such electrophilic compounds or reactive oxygen species react with the cysteine ​​residues of Keap1 to oxidize the thiol group or form a covalent bond, resulting in structural changes in Keap1. Nrf2 is released due to the changes in the cysteine ​​residues of Keap1, enters the cell nucleus and binds to the ARE, thereby inducing the expression of antioxidant enzymes. It has been reported that Nrf2 activators can prevent the development of degenerative brain diseases by pre-activating the Nrf2-Keap1 pathway using electrophilic compounds as a chemical defense mechanism against oxidative stress.

[0005] As a drug that can react with the cysteine ​​residue of Keap1, sulforaphane (1-isothiocyanato-4-methylsulfinylbutane) is mainly found in cruciferous vegetables such as broccoli and cabbage, and activates Nrf2 to protect dopaminergic neurons from oxidative stress. However, sulforaphane can non-selectively denature a variety of proteins containing thiol groups in cells, thereby causing cytotoxicity, and has the disadvantage of extremely low permeability of the vascular-brain barrier. In addition, since it disappears within 1 hour after in vivo administration, the Nrf2 activation induction effect does not last, so when it is administered at a high concentration to show a certain activity, it causes cytotoxicity.

[0006] Therefore, it is necessary to develop a new type of Nrf2 activator to overcome the problems of existing Nrf2 activators. In this context, the inventors of the present invention have completed the present invention by confirming that the new sulfonyl imine derivatives or pharmaceutically acceptable salts thereof have excellent Nrf2 activation effect, high solubility and drug metabolism stability, anti-inflammatory and antioxidant effects, and improve motor ability and cognitive ability. Summary of the invention

[0007] Technical issues to be solved

[0008] The technical problem to be solved by the present invention is to provide a sulfenyl imine derivative or a pharmaceutically acceptable salt thereof.

[0009] In addition, another object of the present invention is to provide a composition for preventing, improving or treating diseases caused by decreased Nrf2 activity, which comprises the sulfenyl imine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0010] The technical problem to be solved by the present invention is to provide a method for preparing the sulfenyl imine derivative or a pharmaceutically acceptable salt thereof.

[0011] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned will be clearly understood by ordinary technicians in this field through the following description.

[0012] Technical methods to solve problems

[0013] In order to solve the above problems, the present invention provides a sulfanone derivative represented by the following [Chemical Formula 1] or its racemate, isomer, solvate or pharmaceutically acceptable salt:

[0014] [Chemical formula 1]

[0015]

[0016] Wherein in the chemical formula 1,

[0017] A and B are each independently phenyl or pyridine;

[0018] R is hydrogen, cyano, trimethylsilyl (TMS) or methyl;

[0019] Each of A and B is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, cyano, nitro, C1-C7 alkyl and C1-C7 alkoxy;

[0020] One or more hydrogen atoms in the alkyl group or alkoxy group are unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, nitro and morpholino.

[0021] As an embodiment of the present invention, the sulfenyl imide derivative represented by [Chemical Formula 1] may be any one or more selected from the group consisting of the following compounds:

[0022] (1) (E)-(2-Fluorophenyl)(imino)(2-(pyridin-2-yl)vinyl)-λ 6 -sulfenyl imide ((E)-(2-fluorophenyl)(imino)(2-(pyridin-2-yl)vinyl)-λ 6 -sulfanone);

[0023] (2) (E)-Imino(4-methoxyphenyl)(2-(pyridin-2-yl)vinyl)-λ 6 -sulfenyl imide ((E)-imino(4-methoxyphenyl)(2-(pyridin-2-yl)vinyl)-λ 6 -sulfanone);

[0024] (3) (E)-(2-chlorophenyl)(2-(3-fluoropyridin-2-yl)vinyl)(imino)-λ 6 -sulfenyl imide ((E)-(2-chlorophenyl)(2-(3-fluoropyridin-2-yl)vinyl)(imino)-λ 6 -sulfanone);

[0025] (4) (E)-(2-chlorophenyl)(2-(3-chloropyridin-2-yl)vinyl)(imino)-λ 6-sulfenyl imide ((E)-(2-chlorophenyl)(2-(3-chloropyridin-2-yl)vinyl)(imino)-λ 6 -sulfanone);

[0026] (5) (E)-(2-fluorophenyl)(2-(3-fluoropyridin-2-yl)vinyl)(imino)-λ 6 -sulfenyl imide ((E)-(2-fluorophenyl)(2-(3-fluoropyridin-2-yl)vinyl)(imino)-λ 6 -sulfanone);

[0027] (6) (E)-(2-(3-chloropyridin-2-yl)vinyl)(2-fluorophenyl)(imino)-λ 6 -sulfenyl imide ((E)-(2-(3-chloropyridin-2-yl)vinyl)(2-fluorophenyl)(imino)-λ 6 -sulfanone);

[0028] (7) (E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(3-methoxyphenyl)-λ 6 -sulfenyl imide ((E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(3-methoxyphenyl)-λ 6 -sulfanone);

[0029] (8) (E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(2-methoxyphenyl)-λ 6 -sulfenyl imide ((E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(2-methoxyphenyl)-λ 6 -sulfanone);

[0030] (9) (E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(3-methoxyphenyl)-λ 6 -sulfenyl imide ((E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(3-methoxyphenyl)-λ 6 -sulfanone);

[0031] (10) (E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(4-methoxyphenyl)-λ 6 -sulfenyl imide ((E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(4-methoxyphenyl)-λ 6 -sulfanone);

[0032] (11) (E)-Imino(2-methoxyphenyl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6 -sulfenyl imide ((E)-imino(2-methoxyphenyl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6 -sulfanone);

[0033] (12) (E)-(2-chlorophenyl)(imino)(2-(pyridin-3-yl)vinyl)-λ 6 -sulfenyl imide ((E)-(2-chlorophenyl)(imino)(2-(pyridin-3-yl)vinyl)-λ 6 -sulfanone);

[0034] (13) (E)-(2-chlorophenyl)(2-(2-chloropyridin-3-yl)vinyl)(imino)-λ 6 -sulfenyl imide ((E)-(2-chlorophenyl)(2-(2-chloropyridin-3-yl)vinyl)(imino)-λ 6 -sulfanone);

[0035] (14) (E)-(2-chlorophenyl)(imino)(2-(2,4,6-trichloropyrimidin-5-yl)vinyl)-λ 6 -sulfenyl imide ((E)-(2-chlorophenyl)(imino)(2-(2,4,6-trichloropyrimidin-5-yl)vinyl)-λ 6 -sulfanone);

[0036] (15) (E)-(2-chlorophenylvinyl)(imino)(pyridin-2-yl)-λ 6 -sulfenyl imide ((E)-(2-chlorostyryl)(imino)(pyridin-2-yl)-λ 6 -sulfanone);

[0037] (16) (E)-(3-chlorophenylvinyl)(imino)(pyridin-2-yl)-λ 6 -sulfenyl imide ((E)-(3-chlorostyryl)(imino)(pyridin-2-yl)-λ 6 -sulfanone);

[0038] (17) (E)-Imino(pyridin-2-yl)(2-(trifluoromethyl)phenylvinyl)-λ 6 -sulfenyl imide ((E)-imino(pyridin-2-yl)(2-(trifluoromethyl)styryl)-λ 6 -sulfanone);

[0039] (18) (E)-Imino(pyridin-2-yl)(2-trifluoromethoxy)phenylvinyl)-λ 6 -sulfenyl imide ((E)-imino(pyridin-2-yl)(2-(trifluoromethoxy)styryl)-λ 6 -sulfanone);

[0040] (19) (E)-(2,6-dichlorophenylvinyl)(imino)(pyridin-2-yl)-λ 6 -sulfenyl imide ((E)-(2,6-dichlorostyryl)(imino)(pyridin-2-yl)-λ 6 -sulfanone);

[0041] (20) (E)-(4-chlorophenylvinyl)(imino)(pyridin-2-yl)-λ 6 -sulfenyl imide ((E)-(4-chlorostyryl)(imino)(pyridin-2-yl)-λ 6 -sulfanone);

[0042] (21) (E)-(5-chloropyridin-2-yl)(2-chlorophenylvinyl)(imino)-λ 6 -sulfenyl imide ((E)-(5-chloropyridin-2-yl)(2-chlorostyryl)(imino)-λ 6 -sulfanone);

[0043] (22) (E)-(2,6-difluorophenylvinyl)(imino)(pyridin-2-yl)-λ 6-sulfenyl imide ((E)-(2,6-difluorostyryl)(imino)(pyridin-2-yl)-λ 6 -sulfanone);

[0044] (23) (E)-Imino(pyridin-2-yl)(2,4,6-trifluorophenylvinyl)-λ 6 -sulfenyl imide ((E)-imino(pyridin-2-yl)(2,4,6-trifluorostyryl)-λ 6 -sulfanone);

[0045] (24) (E)-(2-Fluorophenylvinyl)(imino)(pyridin-2-yl)-λ 6 -sulfenyl imide ((E)-(2-fluorostyryl)(imino)(pyridin-2-yl)-λ 6 -sulfanone);

[0046] (25) (E)-Imino(3-methoxypyridin-2-yl)(2-(trifluoromethyl)phenylvinyl)-λ 6 -sulfenyl imide ((E)-imino(3-methoxypyridin-2-yl)(2-(trifluoromethyl)styryl)-λ 6 -sulfanone);

[0047] (26) (E)-Imino(4-methoxypyridin-2-yl)(2-(trifluoromethyl)phenylvinyl)-λ 6 -sulfenyl imide ((E)-imino (4-methoxypyridin-2-yl) (2- (trifluoromethyl) styryl) -λ 6 -sulfanone);

[0048] (27) (E)-Imino(4-methoxypyridin-2-yl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6 -sulfenyl imide ((E)-imino(4-methoxypyridin-2-yl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6 -sulfanone);

[0049] (28) (E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(4-methoxypyridin-2-yl)-λ6 -sulfenyl imide ((E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(4-methoxypyridin-2-yl)-λ 6 -sulfanone);

[0050] (29) (E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(4-methoxypyridin-2-yl)-λ 6 -sulfenyl imide ((E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(4-methoxypyridin-2-yl)-λ 6 -sulfanone);

[0051] (30) (E)-(2-Chlorostyryl)(Imino)(4-methoxypyridin-2-yl)-λ 6 -sulfenyl imide ((E)-(2-chlorostyryl)(imino)(4-methoxypyridin-2-yl)-λ 6 -sulfanone);

[0052] (31) (E)-(2-Fluorophenylvinyl)(imino)(4-methoxypyridin-2-yl)-λ 6 -sulfenyl imide ((E)-(2-fluorostyryl)(imino)(4-methoxypyridin-2-yl)-λ 6 -sulfanone);

[0053] (32) (E)-Imino(4-methoxypyridin-2-yl)(2-(3-methoxypyridin-2-yl)vinyl)-λ 6 -sulfenyl imide ((E)-imino(4-methoxypyridin-2-yl)(2-(3-methoxypyridin-2-yl)vinyl)-λ 6 -sulfanone);

[0054] (33) (E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(3-methoxypyridin-2-yl)-λ 6 -sulfenyl imide ((E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(3-methoxypyridin-2-yl)-λ 6 -sulfanone);

[0055] (34) (E)-Imino(3-methoxypyridin-2-yl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6 -sulfenyl imide ((E)-imino(3-methoxypyridin-2-yl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6 -sulfanone);

[0056] (35) (E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(5-methoxypyridin-2-yl)-λ 6 -sulfenyl imide ((E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(5-methoxypyridin-2-yl)-λ 6 -sulfanone);

[0057] (36) (E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(5-methoxypyridin-2-yl)-λ 6 -sulfenyl imide ((E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(5-methoxypyridin-2-yl)-λ 6 -sulfanone);

[0058] (37) (E)-Imino(5-methoxypyridin-2-yl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6 -sulfenyl imide ((E)-imino(5-methoxypyridin-2-yl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6 -sulfanone);

[0059] (38) (E)-(3-chloropyridin-2-yl)(2-chlorophenylvinyl)(imino)-λ 6 -sulfenyl imide ((E)-(3-chloropyridin-2-yl)(2-chlorostyryl)(imino)-λ 6 -sulfanone);

[0060] (39) (E)-(2-Chlorostyryl)(imino)(5-methoxypyridin-2-yl)-λ 6-sulfenyl imide ((E)-(2-chlorostyryl)(imino)(5-methoxypyridin-2-yl)-λ 6 -sulfanone);

[0061] (40) (E)-(2-chlorophenylvinyl)(3-fluoropyridin-2-yl)(imino)-λ 6 -sulfenyl imide ((E)-(2-chlorostyryl)(3-fluoropyridin-2-yl)(imino)-λ 6 -sulfanone);

[0062] (41) (E)-(3-chloropyridin-4-yl)(2-chlorophenylvinyl)(imino)-λ 6 -sulfenyl imide ((E)-(3-chloropyridin-4-yl)(2-chlorostyryl)(imino)-λ 6 -sulfanone);

[0063] (42) (E)-(5-chloropyridin-2-yl)(2-chlorophenylvinyl)(imino)-λ 6 -sulfenyl imide ((E)-(5-chloropyridin-2-yl)(2-chlorostyryl)(imino)-λ 6 -sulfanone);

[0064] (43) (E)-(2-Chlorostyryl)(imino)(3-methoxypyridin-2-yl)-λ 6 -sulfenyl imide ((E)-(2-chlorostyryl)(imino)(3-methoxypyridin-2-yl)-λ 6 -sulfanone);

[0065] (44) (E)-(2-Fluorophenylvinyl)(imino)(3-methoxypyridin-2-yl)-λ 6 -sulfenyl imide ((E)-(2-fluorostyryl)(imino)(3-methoxypyridin-2-yl)-λ 6 -sulfanone);

[0066] (45) (E)-(4-chloropyridin-2-yl)(2-chlorophenylvinyl)(imino)-λ 6-sulfenyl imide ((E)-(4-chloropyridin-2-yl)(2-chlorostyryl)(imino)-λ 6 -sulfanone);

[0067] (46) (E)-(2-chlorophenylvinyl)(3-fluoropyridin-4-yl)((trimethylsilyl)imino)-λ 6 -sulfenyl imide ((E)-(2-chlorostyryl)(3-fluoropyridin-4-yl)((trimethylsilyl)imino)-λ 6 -sulfanone);

[0068] (47) (E)-(2-Chlorostyryl)(3-fluoropyridin-4-yl)(imino)-λ 6 -sulfenyl imide ((E)-(2-chlorostyryl)(3-fluoropyridin-4-yl)(imino)-λ 6 -sulfanone);

[0069] (48) (E)-(4-chloropyridin-3-yl)(2-chlorophenylvinyl)(imino)-λ 6 -sulfenyl imide ((E)-(4-chloropyridin-3-yl)(2-chlorostyryl)(imino)-λ 6 -sulfanone);

[0070] (49) (E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(pyridin-2-yl)-λ 6 -sulfenyl imide ((E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(pyridin-2-yl)-λ 6 -sulfanone);

[0071] (50) (E)-Imino(2-(3-methoxypyridin-2-yl)vinyl)(pyridin-2-yl)-λ 6 -sulfenyl imide ((E)-imino(2-(3-methoxypyridin-2-yl)vinyl)(pyridin-2-yl)-λ 6 -sulfanone);

[0072] (51) (E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(pyridin-2-yl)-λ 6-sulfenyl imide ((E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(pyridin-2-yl)-λ 6 -sulfanone);

[0073] (52) (E)-Imino(pyridin-2-yl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6 -sulfenyl imide ((E)-imino(pyridin-2-yl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6 -sulfanone);

[0074] (53) (E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(5-(3-morpholinopropoxy)pyridin-2-yl)-λ 6 -sulfenyl imide ((E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(5-(3-morpholinopropoxy)pyridin-2-yl)-λ 6 -sulfanone);

[0075] (54) (E)-Imino(5-methoxypyridin-2-yl)(2-(trifluoromethyl)phenylvinyl)-λ 6 -sulfenyl imide ((E)-imino(5-methoxypyridin-2-yl)(2-(trifluoromethyl)styryl)-λ 6 -sulfanone);

[0076] (55) (E)-(2-Fluorophenylvinyl)(imino)(5-methoxypyridin-2-yl)-λ 6 -sulfenyl imide ((E)-(2-fluorostyryl)(imino)(5-methoxypyridin-2-yl)-λ 6 -sulfanone);

[0077] (56) (E)-(2-Fluorophenylvinyl)(5-methoxypyridin-2-yl)(methylimino)-λ 6 -sulfenyl imide ((E)-(2-fluorostyryl)(5-methoxypyridin-2-yl)(methylimino)-λ 6 -sulfanone);

[0078] (57) (E)-N-((2-chlorophenylvinyl)(2-methoxyphenyl)(oxo)-λ 6 -sulfonylimide)cyanamide((E)-N-((2-chlorostyryl)(2-methoxyphenyl)(oxo)-λ 6 -sulfanylidene)cyanamide); and

[0079] (58) (E)-N-((2-(3-chloropyridin-2-yl)vinyl)(2-methoxyphenyl)(oxo)-λ 6 -sulfonylimide)cyanamide((E)-N-((2-(3-chloropyridin-2-yl)vinyl)(2-methoxyphenyl)(oxo)-λ 6 -sulfaneylidene)cyanamide).

[0080] As another embodiment of the present invention, the sulfenyl imine derivative can activate Nrf2 (nuclear factor erythroid-derived 2-related factor 2).

[0081] As another embodiment of the present invention, the sulfenyl imide derivative or a pharmaceutically acceptable salt thereof can be any one or more selected from the group consisting of hydrochloride, bromate, sulfate, phosphate, nitrate, citrate, acetate, lactate, tartrate, maleate, gluconate, succinate, formate, trifluoroacetate, oxalate, fumarate, glutarate, adipate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, sodium salt, potassium salt, lithium salt, calcium salt and magnesium salt.

[0082] In addition, the present invention provides a pharmaceutical composition for preventing or treating a disease caused by decreased Nrf2 activity, comprising the sulfenyl imine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0083] As one embodiment of the present invention, the disease caused by decreased Nrf2 activity can be any one or more selected from the group consisting of liver diseases, kidney diseases, pulmonary diseases, neurodegenerative diseases, mitochondrial myopathy, Friedreich's ataxia, corneal endothelial cell loss and psoriasis, but is not limited thereto.

[0084] The liver disease may be alcoholic liver disease, non-alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), chronic liver injury, viral hepatitis, hepatocellular carcinoma, etc., but is not limited thereto.

[0085] The kidney disease may be diabetic nephropathy, focal segmental glomerulosclerosis, renal fibrosis, lupus-like autoimmune nephritis, chronic kidney disease (CKD) and hypertensive kidney disease, but is not limited thereto.

[0086] The pulmonary disease may be chronic obstructive pulmonary disease (COPD), emphysema, ventilation-associated lung injury, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), pulmonary artery hypertension (PAH), and right heart failure caused by the pulmonary artery hypertension, but is not limited thereto.

[0087] The neurodegenerative disease may be Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease, Lou Gehrig's disease, epilepsy, depression, insomnia, anxiety, multiple sclerosis (MS), etc., but is not limited thereto.

[0088] As another embodiment of the present invention, the pharmaceutical composition may further include: the sulfenyl imine derivative or a pharmaceutically acceptable salt thereof; and any one or more additional ingredients selected from the group consisting of pharmaceutically acceptable carriers, excipients, diluents, stabilizers and preservatives.

[0089] As another embodiment of the present invention, the pharmaceutical composition may have any one or more dosage forms selected from the group consisting of powder, granules, tablets, capsules and injections.

[0090] In addition, the present invention provides a method for preventing or treating a disease caused by decreased Nrf2 activity, comprising the step of administering the sulfenyl imide derivative or a pharmaceutically acceptable salt thereof to a subject.

[0091] In addition, the present invention provides a use of the sulfenyl imine derivative or a pharmaceutically acceptable salt thereof in preparing a pharmaceutical composition for preventing or treating a disease caused by decreased Nrf2 activity.

[0092] In addition, the present invention also provides a cosmetic composition for preventing or improving diseases caused by decreased Nrf2 activity, which comprises the sulfenyl imide derivative or a cosmetically acceptable salt thereof as an active ingredient.

[0093] In addition, the present invention also provides a food composition for preventing or improving diseases caused by decreased Nrf2 activity, which comprises the sulfenyl imine derivative or a food-acceptable salt thereof as an active ingredient.

[0094] In addition, the present invention also provides a feed composition for preventing or improving diseases caused by decreased Nrf2 activity, which comprises the sulfenyl imide derivative or a feed-acceptable salt thereof as an active ingredient.

[0095] In addition, the present invention provides a method for preparing the sulfenyl imine derivative or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0096] (1) a step of preparing a compound represented by [Chemical Formula 3] from a compound represented by [Chemical Formula 2];

[0097] (2) a step of preparing a compound represented by [Chemical Formula 4] from a compound represented by [Chemical Formula 3];

[0098] (3) a step of preparing a compound represented by [Chemical Formula 5] from a compound represented by [Chemical Formula 4]; and

[0099] (4) a step of adding a compound represented by [Chemical Formula 6] to a compound represented by [Chemical Formula 5] to prepare a compound represented by [Chemical Formula 1],

[0100] [Chemical formula 1]

[0101]

[0102] [Chemical formula 2]

[0103]

[0104] [Chemical formula 3]

[0105]

[0106] [Chemical formula 4]

[0107]

[0108] [Chemical formula 5]

[0109]

[0110] [Chemical formula 6]

[0111]

[0112] In the chemical formulas 1 to 6,

[0113] A and B are each independently phenyl or pyridine;

[0114] R is hydrogen, trimethylsilyl (TMS) or methyl;

[0115] Each of A and B is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, cyano, nitro, C1-C7 alkyl and C1-C7 alkoxy;

[0116] One or more hydrogen atoms in the alkyl group or alkoxy group are unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, nitro and morpholino.

[0117] As an embodiment of the present invention, the step (1) may be performed by dissolving the compound represented by [Chemical Formula 2] in methanol (MeOH), and sequentially adding ammonium carbonate ((NH4)2CO3) and diacetoxyiodobenzene (PhI(OAc)2).

[0118] As another embodiment of the present invention, in step (2), hexamethyldisilazane (HMDS) may be added to the compound represented by [Chemical Formula 3], followed by reflux stirring.

[0119] As another embodiment of the present invention, the step (3) may be performed by dissolving the compound represented by [Chemical Formula 4] in tetrahydrofuran (THF), and sequentially adding n-butyl lithium (n-BuLi) and diethylchlorophosphite.

[0120] Effects of the Invention

[0121] The present invention relates to a sulfenyl imine derivative or a pharmaceutically acceptable salt thereof, and a composition for preventing or treating cancer comprising the derivative as an active ingredient. The sulfenyl imine derivative or a pharmaceutically acceptable salt thereof of the present invention has an excellent effect on Nrf2 activation, has high solubility and drug metabolism stability, has anti-inflammatory and antioxidant effects, and improves athletic performance and cognitive ability, and can therefore be used to prevent or treat diseases caused by reduced Nrf2 activity, preferably for liver disease, kidney disease, lung disease, neurodegenerative disease, mitochondrial myopathy, Friedreich's ataxia, corneal endothelial cell loss, psoriasis, and the like.

[0122] The effects of the present invention are not limited to the effects mentioned above, and other effects not mentioned will be clearly understood by those skilled in the art through the following description. BRIEF DESCRIPTION OF THE DRAWINGS

[0123] Figure 1 The Nrf2 activation activity and cytotoxicity of compounds 1-4 according to the present invention and the positive control group DMF and Bardoxolone-methyl (CDDO-Me) are shown.

[0124] Figure 2 The inhibitory effects of the compounds 1-1 to 1-10, 1-12 to 1-20 of the present invention and the negative control group DMF (positive control) on NO are shown.

[0125] Figure 3 The expression patterns of antioxidant enzymes when the present compounds 1 to 4 were treated at different concentrations are shown.

[0126] Figure 4 The cell protection effect of MPTP mice, a Parkinson's disease model, when treated with compounds 1-4 of the present invention was shown. Figure 4 (a) shows the timeline of animal experiments; Figure 4 (b) is a schematic diagram showing a specific experimental method; Figure 4 (c) shows the vertical grid experimental results; Figure 4 (d) shows the results of a coat-hanger experiment.

[0127] Figure 5 The results of immunohistochemistry (IHC) analysis are shown to confirm the effects of the present compounds 1-4 on dopamine neurons in MPTP mice, a Parkinson's disease model, when treated.

[0128] Figures 6a to 6c The Morris water maze test results of Alzheimer's disease model APP / PS1 mice treated with compounds 1-4 of the present invention are shown. Figure 6a Shows acquisition / reversal test results; Figure 6b Shows the results of the reversal probe test; Figure 6c This is the result of the reversal probe test.

[0129] Figure 7a and Figure 7bThe results showed that the compounds 1-4 of the present invention had an effect on improving memory and cognitive function in APP / PS1 mice, which is an Alzheimer's disease model. Figure 7a The results of the Y-maze test are shown; Figure 7b Passive avoidance test results are shown. DETAILED DESCRIPTION

[0130] The present inventors have studied sulfonyl imine derivatives or pharmaceutically acceptable salts thereof and found that the derivatives or pharmaceutically acceptable salts thereof have excellent Nrf2 activation effect, high solubility and drug metabolism stability, anti-inflammatory and antioxidant effects, and can improve motor ability and cognitive ability.

[0131] According to the above results, the present invention can provide a sulfenyl imine derivative represented by the following [Chemical Formula 1] or a pharmaceutically acceptable salt thereof, wherein the sulfenyl imine derivative can include a racemate, isomer or solvate thereof.

[0132] [Chemical formula 1]

[0133]

[0134] Wherein in the chemical formula 1,

[0135] A and B are each independently phenyl or pyridine;

[0136] R is hydrogen, cyano, trimethylsilane (TMS) or methyl;

[0137] Each of A and B is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, cyano, nitro, C1-C7 alkyl and C1-C7 alkoxy;

[0138] One or more hydrogen atoms in the alkyl group or alkoxy group are unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, nitro and morpholino.

[0139] In the present invention, the term "substitution" refers to a reaction in which an atom or an atomic group included in a molecule of a compound is substituted with another atom or an atomic group.

[0140] In the present invention, the term "alkyl" refers to a monovalent straight-chain, branched-chain or cyclic saturated hydrocarbon residue consisting only of carbon and hydrogen atoms and having 1 to 20 carbon atoms. Examples of such alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-butyl, 3-butyl, pentyl, n-hexyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0141] In the present invention, the term "alkoxy" refers to an alkyl group (-OR) bonded to oxygen. Examples of such alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.

[0142] In the present invention, the "halogen group" may be fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0143] In the present invention, "pharmaceutically acceptable salt" refers to a dosage form of a compound, wherein the compound does not cause severe irritation to an organism to which it is administered and does not impair the biological activity and physical properties of the compound.

[0144] The pharmaceutically acceptable salt can be obtained by reacting the compound of the present invention with an inorganic acid such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid and phosphoric acid; a sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid; an organic carboxylic acid such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, capric acid, isobutyric acid, malonic acid, succinic acid, phthalic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid. In addition, the compound of the present invention can also be obtained by reacting with a base to form an alkali metal salt such as an ammonium salt, a sodium salt or a potassium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; a salt of an organic base such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine; an amino acid salt such as arginine, lysine, etc.

[0145] Furthermore, the sulfenyl imine derivative or a pharmaceutically acceptable salt thereof includes not only pharmaceutically acceptable salts but also all salts, hydrates and solvates which can be prepared by conventional methods.

[0146] The sulfenyl imine derivative or its pharmaceutically acceptable salt of the present invention has the effect of activating Nrf2, and thus can be used in a pharmaceutical composition for preventing or treating a disease caused by decreased Nrf2 activity, wherein the sulfenyl imine derivative or its pharmaceutically acceptable salt is used as an active ingredient.

[0147] The term "Nrf2 (nuclear factor erythroid-derived 2-related factor 2)" in the present invention refers to a transcription factor encoded by the human NFE2L2 gene, which is a basicleucine zipper protein (bZIP) that regulates the expression of antioxidant proteins and prevents oxidative damage caused by injury or inflammation. Therefore, drugs that activate the Nrf2 pathway are being studied to treat diseases caused by oxidative stress.

[0148] In the present invention, the term "prevention" refers to any action to inhibit or delay the occurrence, spread or recurrence of a disease by administering the composition of the present invention; "treatment" refers to any action to improve or beneficially change the symptoms of the disease by administering the composition of the present invention.

[0149] As described above, it is reported that Nrf2 targeted by the compounds of the present invention is involved in the prevention and treatment of various diseases through the antioxidant defense mechanism through its activation. For example, non-limiting examples of diseases caused by decreased Nrf2 activity that can be prevented or treated by administering the composition of the present invention may include: liver diseases such as alcoholic liver disease, non-alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), chronic liver injury, viral hepatitis, and hepatocellular carcinoma; kidney diseases such as diabetic nephropathy, focal segmental glomerulosclerosis, renal fibrosis, lupus-like autoimmune nephritis, chronic kidney disease (CKD), and hypertensive kidney disease; chronic obstructive pulmonary disease (COPD), and other kidney diseases. The invention relates to pulmonary diseases such as pulmonary artery hypertension (PAH), right heart failure (right heart failure), pulmonary artery hypertension (PAH), pulmonary emphysema, ventilation-associated lung injury, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), pulmonary hypertension (PAH), and the like;Neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease, Lou Gehrig's disease, epilepsy, depression, insomnia, anxiety, and multiple sclerosis (MS); mitochondrial myopathy; Friedreich's ataxia; corneal endothelial cell loss and psoriasis, etc.;

[0150] In the present invention, the term "pharmaceutical composition" refers to a preparation for preventing or treating a disease, which can be prepared according to conventional methods and used in various forms. For example, it can be prepared into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, etc., and can also be prepared into external preparations, suppositories, sterile injections, etc.

[0151] In the present invention, "included as an active ingredient" means that the amount of the ingredient included is necessary or sufficient to achieve the desired biological effect. In practical applications, the amount of the active ingredient can be determined based on the amount of the target disease to be treated and not causing other toxicity, and may vary depending on the disease or condition to be treated, the form of the composition to be administered, the body shape of the subject, or the severity of the disease or condition. Those skilled in the art can determine the effective amount of a single composition based on experience without excessive experiments.

[0152] In addition, the pharmaceutical composition of the present invention may include one or more pharmaceutically acceptable carriers in addition to the above-mentioned active ingredients according to each dosage form.

[0153] The pharmaceutically acceptable carrier can be physiological saline, sterile water, Ringer's solution, buffered physiological saline, glucose solution, maltodextrin solution, glycerol, ethanol and a mixture of more than one of the above components, and other conventional additives such as antioxidants, buffers, antibacterial agents, etc. can also be added as needed. In addition, injection forms such as aqueous solutions, suspensions, emulsions, etc., as well as pills, capsules, granules or tablets can also be prepared by adding diluents, dispersants, surfactants, adhesives, lubricants, etc. In addition, it can be preferably formulated according to each disease or component using appropriate methods in the art or the methods disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA).

[0154] In addition, the present invention may also provide a method for preventing, treating and / or diagnosing a disease caused by decreased Nrf2 activity, comprising the step of administering the sulfenyl imide derivative or a pharmaceutically acceptable salt thereof to an individual.

[0155] In the present invention, the term "individual" refers to any mammal that has or may suffer from a disease caused by reduced Nrf2 activity and needs to prevent or treat the disease, such as livestock, humans, etc., but is not limited thereto, and is preferably a human. By administering the pharmaceutical composition of the present invention to an individual, the disease can be effectively prevented or treated. In addition, since the pharmaceutical composition of the present invention exerts a therapeutic effect through Nrf2 activation, it can exert a synergistic effect by being used in combination with an existing therapeutic agent.

[0156] The term "administration" in the present invention refers to providing a predetermined substance to a patient by any appropriate method. The pharmaceutical composition of the present invention can be formulated into various forms for application to an individual, and a typical formulation for parenteral administration is an injection form, preferably an isotonic aqueous solution or suspension. The injection form can be prepared according to techniques known in the art using a suitable dispersant or wetting agent and a suspending agent. For example, each component can be dissolved in physiological saline or a buffer solution and formulated into an injection form. In addition, oral dosage forms include, for example, ingestible tablets, oral tablets, lozenges, capsules, elixirs, suspensions, syrups and flakes, etc., which, in addition to active ingredients, may also include diluents (e.g., lactose, glucose, sucrose, mannitol, sorbitol, cellulose and / or glycine) and lubricants (e.g., silicon dioxide, talcum powder, stearic acid and its magnesium salt or calcium salt and / or polyethylene glycol). The tablet may include a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose and / or polyvinyl pyrrolidone, and may also include additional disintegrants such as starch, agar, alginic acid or its sodium salt as needed; absorbents; colorants; flavoring agents and / or sweeteners. The preparation may be prepared by conventional mixing, granulation or coating methods.

[0157] In addition, the pharmaceutical composition of the present invention may also include preservatives, moisturizers, emulsifiers, auxiliary agents such as salts or buffers for controlling osmotic pressure, and other substances with therapeutic effects, and can be prepared according to conventional methods.

[0158] The pharmaceutical composition of the present invention can be administered by various routes, including oral, transdermal, subcutaneous, intravenous or intramuscular injection, and the dosage of the active ingredient can be appropriately selected according to various factors, such as the route of administration, the age, sex, body weight or severity of the patient, etc. In addition, the composition of the present invention can be administered in combination with known compounds that can enhance the desired effect.

[0159] The pharmaceutical composition of the present invention can be administered to humans and animals orally or parenterally, such as intravenous injection, subcutaneous injection, intranasal injection or intraperitoneal injection. Oral administration also includes sublingual administration. Parenteral administration includes injection methods such as subcutaneous injection, intramuscular injection, intravenous injection and drip method.

[0160] The composition of the present invention can be administered orally or parenterally in a pharmaceutically effective amount according to the desired method. The term "pharmaceutically effective amount" of the present invention refers to a dose that is sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and does not cause side effects. The effective dosage level can be determined based on factors such as the patient's health status, severity, drug activity, sensitivity to the drug, administration method, administration time, administration route and excretion rate, treatment cycle, and other factors well known in the medical field (including combined or simultaneous medication).

[0161] That is, the total effective amount of the sulfenyl imide derivative or a pharmaceutically acceptable salt thereof of the present invention can be administered to a patient as a single dose, or can be administered to a patient in multiple doses over a longer period of time through a fractionated treatment protocol. The pharmaceutical composition of the present invention can change the content of the active ingredient according to the severity of the disease, and in addition to the route of administration and the number of treatments, the effective dose for the patient can also be determined by considering various factors, such as the patient's age, weight, health status, gender, severity of the disease, diet, excretion rate, etc.

[0162] The terms used in the embodiments are for descriptive purposes only and should not be considered as limiting. In the absence of special instructions in the content, singular expressions include plural meanings. In this specification, the terms "including" or "having" are used to express the presence of features, numbers, steps, operations, constituent elements, accessories or combinations thereof recorded in the specification, and do not exclude the presence of one or more other features, numbers, steps, operations, constituent elements, accessories or combinations thereof, or additional functions.

[0163] In the absence of other definitions, all terms used herein, including technical or scientific terms, have the common meanings understood by those of ordinary skill in the art. Commonly used terms that are the same as dictionary definitions should be understood to have meanings consistent with the common content of the relevant technology and should not be overly idealized or interpreted as formal meanings unless explicitly mentioned in this application.

[0164] Hereinafter, the embodiments will be described in detail with reference to the accompanying drawings. However, various changes can be made to the embodiments, and the scope of the present invention is not limited or defined by these embodiments. All variations, equivalents or substitutes of the embodiments are included in the scope of rights.

[0165] Furthermore, in the process of describing with reference to the accompanying drawings, the same components are given the same reference numerals regardless of the reference numerals, and repeated descriptions thereof are omitted. In the process of describing the embodiments, when it is determined that the detailed description of the related known technology will unnecessarily confuse the embodiments, the detailed description thereof is omitted.

[0166] Example 1. Synthesis of cyanosulfinyl imide derivatives

[0167] As an embodiment of the present invention, when R in Chemical Formula 1 is cyano, the synthesis process of the sulfenyl imide derivative is shown in the following Reaction Formula 1.

[0168] [Reaction formula 1]

[0169]

[0170] (1) Synthesis of substituted (methylsulfinyl)benzene by reaction with m-chloroperbenzoic acid

[0171]

[0172] The (methylsulfinyl)benzene substituted according to the above reaction formula was synthesized. Specifically, the substituted methyl (phenyl) sulfane (1.0 equivalent) was dissolved in dichloromethane (DCM), and m-chloroperbenzoic acid (mCPBA, 1.0 equivalent) was added at 0°C, and then stirred at the same temperature for 1 hour. After the reaction was completed, the reaction solution was diluted with ethyl acetate (EtOAc), washed with water and brine, and the organic layer was dried over anhydrous Na2SO4 and filtered. The residue obtained by distilling the solvent under reduced pressure was purified by column chromatography to obtain 2-, 3- or 4-substituted (methylsulfinyl)benzene.

[0173] (2) N-(methyl(oxy)(phenyl)-λ) substituted by reaction with cyanamide 6 -Synthesis of sulfaneylidene cyanamide

[0174]

[0175] The N-(methyl(oxo)(phenyl)-λ 6 -sulfonylimide)cyanamide(N-(methyl(oxo)(phenyl)-λ 6 -sulfaneylidene)cyanamide) was synthesized. Specifically, the compound synthesized by the above reaction (1) (1.0 equivalent) was dissolved in water, and cyanamide (Cyanamide, 2.0 equivalents), potassium tert-butoxide (KOtBu, Potassium tert-butoxide, 2.0 equivalents) and N-chlorosuccinimide (NCS, N-Chlorosuccinimide, 2.0 equivalents) were added, and then stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate (EtOAc, ethyl acetate), washed with water and brine, and the organic layer was dried over anhydrous Na2SO4 and filtered. The residue obtained by distilling the solvent under reduced pressure was purified by column chromatography to obtain 2-, 3- or 4-substituted N-(methyl(oxo)(phenyl)-λ 6 -sulfonylimide)cyanamide.

[0176] (3) Synthesis of substituted diethyl ((N-cyanophenylsulfonylimino)methyl)phosphonate by reaction with diethyl chlorophosphate

[0177]

[0178] The diethyl ((N-cyanophenylsulfonimidoyl)methyl)phosphonate substituted according to the above reaction formula was synthesized. Specifically, the compound (1.0 equivalent) synthesized by the above reaction (2) was dissolved in anhydrous tetrahydrofuran (THF, Tetrahydrofuran), and then cooled to -78°C using acetone and dry ice. Then, n-butyl lithium (2.2 equivalents, 2.0M cyclohexane solution) was added dropwise using acetone and dry ice at -78°C. After stirring at the same temperature for 30 minutes, diethyl chlorophosphate (1.5 equivalents) was added at the same temperature, and then stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate (EtOAc, ethyl acetate), washed with water and brine, and the organic layer was dried and filtered by anhydrous Na2SO4. The residue obtained by distilling off the solvent under reduced pressure is purified by column chromatography to obtain 2-, 3- or 4-substituted diethyl ((N-cyanophenylsulfonylimino)methyl)phosphonate.

[0179] (4) (E)-N-(oxy(phenyl)(2-(pyridin-2-yl)vinyl)-λ substituted by reaction with a pyridinecarboxaldehyde derivative 6 Synthesis of -sulfonylimide)cyanamide

[0180]

[0181] The (E)-N-(oxy(phenyl)(2-(pyridin-2-yl)vinyl)-λ 6 -sulfonylimide)cyanamide((E)-N-(oxo(phenyl)(2-(pyridin-2-yl)vinyl)-λ 6-sulfaneylidene)cyanamide) was synthesized. The compound synthesized by the above reaction (3) (1.0 equivalent) was dissolved in anhydrous THF and then cooled to -78°C using dry ice and acetone. n-Butyl lithium (n-BuLi) (1.2 equivalents, 2.0M cyclohexane solution) was slowly added dropwise to the above solution, stirred for 1 hour, a benzaldehyde derivative (1.2 equivalents) was added, and the reaction was continued for another hour. If the reaction is not completed when checking TLC, the reaction is continued for another 30 minutes at room temperature. After the reaction is completed by a small amount of water, it is extracted with water and 10% MeOH / MC, a small amount of water is removed by anhydrous Na2SO4, and the solvent is removed by reduced pressure distillation and vacuum dried. It is then purified by column chromatography to obtain 2-, 3- or 4-substituted (E)-N-(oxo(phenyl)(2-(pyridin-2-yl)vinyl)-λ 6 -sulfonylimide)cyanamide.

[0182] Example 1.1, (E)-N-((2-(3-chloropyridin-2-yl)vinyl)(2-methoxyphenyl)(oxo)-λ 6 -Synthesis of sulfonylimide)cyanamide (chemical formula 1-57)

[0183] 1.1.1 Synthesis of 1-methoxy-2-(methylsulfinyl)benzene

[0184]

[0185] Using the above reaction (1), (2-methoxyphenyl)(methyl)sulfane (1.00 g, 6.48 mmol) was fully dissolved in DCM and reacted with 70-75% mCPBA (1.60 g, 6.48 mmol) to synthesize 1-methoxy-2-(methylsulfinyl)benzene (0.99 g, 90%) as a pale yellow oil: R f =0.44(EtOAc100%); 1H NMR (400MHz, CDCl3) δ7.83 (dd, 1.6, 7.7Hz, ArH), 7.46 (td, 1.7, 7.9Hz, ArH), 7.20 (td, 0.8, 7.6Hz, ArH), 6.93 (d, 8.1Hz, ArH), 3.89 (s, OCH3), 2.78 (s, SCH3).

[0186] 1.1.2, N-((2-methoxyphenyl)(methyl)(oxo)-λ 6 -sulfonylimide)cyanamide(N-((2-methoxyphenyl)(methyl)(oxo)-λ 6 Synthesis of -sulfaneylidene)cyanamide

[0187]

[0188] Using the above reaction (1), 1-methoxy-2-(methylsulfinyl)benzene (0.99 g, 5.81 mmol) was fully dissolved in water, and then cyanamide (0.49 g, 11.63 mmol), KOtBu (1.31 g, 11.63 mmol) and NCS (1.55 g, 11.63 mmol) were added to synthesize a transparent oily N-((2-methoxyphenyl)(methyl)(oxo)-λ 6 -sulfonylimide)cyanamide (1.03 g, 84%): R f =0.30 (n-hexane 1: EtOAc); 1H NMR (400 MHz, DMSO-d6) δ7.90-7.84 (m, 2ArH), 7.44 (d, 8.4 Hz, ArH), 7.29 (t, 7.6 Hz, ArH), 4.00 (s, OCH3), 3.67 (s, OCH3).

[0189] 1.1.3 Synthesis of Diethyl((N-cyano-2-methoxyphenylsulfonimidoyl)methyl)phosphonate

[0190]

[0191] Using the above reaction (3), N-((2-methoxyphenyl)(methyl)(oxo)-λ 6N-((2-methoxyphenyl)(methyl)(oxo)-λ6-sulfaneylidene)cyanamide (1.03 g, 4.90 mmol) was fully dissolved in THF, and diethyl chlorophosphate (1.06 ml, 7.35 mmol) was reacted with 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (5.39 ml, 10.78 mmol) to synthesize yellow solid diethyl ((N-cyano-2-methoxyphenylsulfonimidoyl)methyl)phosphonate (0.91 g, 53%): R f =0.29(EtOAc100%); 1H NMR (400MHz, CDCl3) δ8.00 (dd, 1.5, 8.0Hz, ArH), 7.74 (td, 1.6, 8., 1Hz, ArH), 7.22 (t, 7.4Hz, ArH), 7.14 (d, 8 .3Hz, ArH), 4.37-4.21(m, SCH2P), 4.16-4.06(m, (POCH2CH3)2, OCH3), 1.27(dt, 7.2, 36.9Hz, (POCH2CH3)2).

[0192] 1.1.4, (E)-N-((2-chlorophenylvinyl)(2-methoxyphenyl)(oxy)-λ 6 -Synthesis of sulfonylimide)cyanamide (chemical formula 1-57)

[0193]

[0194] Using the above reaction (4), diethyl ((N-cyano-2-methoxyphenylsulfonylimino)methyl)phosphonate (0.20 g, 0.58 mmol), 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.32 mL, 0.64 mmol) and 3-chloropyridinecarboxaldehyde (0.07 ml, 0.64 mmol) were reacted to synthesize compound 1-57 (0.08 g, 39%) in the form of a white solid: R f=0.46 (n-hexane 1: EtOAc 3); 1H NMR (DMSO-d6, 400MHz) δ8.12-8.02 (m, (E)-isomer H, 2ArH), 7.92-7.86 (m, (E)-isomer H, ArH), 7.63 (d, J = 8.0 Hz, ArH), 7.56 (t, J = 7.5 Hz, ArH), 7.48-7.41 (m, 2ArH), 7.32 (t, J = 7.7 Hz, ArH), 4.00 (s, OCH3); 13C NMR (DMSO-d6, 100MHz) δ157.7, 142.0, 138.5, 135.0, 134.0, 130.7, 130.1, 130.0, 129.7, 128.5, 126.5, 122.7, 121.8, 114.6, 112.3, 57.4.

[0195] Example 1.2, (E)-N-((2-(3-chloropyridin-2-yl)vinyl)(2-methoxyphenyl)(oxo)-λ 6 -Synthesis of sulfonylimide)cyanamide (chemical formula 1-58)

[0196]

[0197] Diethyl ((N-cyano-2-methoxyphenylsulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 1.1.1 to 1.1.3.

[0198] Using the above reaction (4), diethyl ((N-cyano-2-methoxyphenylsulfonylimino)methyl)phosphonate (0.10 g, 0.29 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.17 mL, 0.35 mmol) to synthesize compound 1-58 (0.03 g, 30%) in the form of a white solid: R f=0.23 (n-hexane 1: EtOAc 2); 1H NMR (CDCl3, 400MHz) δ8.54 (dd, J = 1.3, 4.5Hz, ArH), 8.25 (d, J = 14.6Hz, (E)-isomer H), 8.06 (dd, J = 1.6, 8.0Hz, ArH), 7.85 (d, J = 14.6Hz, (E)-isomer H), 7.77 (dd, J = 1.4, 8.2Hz, ArH), 7.70 (td, J = 1.6, 8.0Hz, ArH), 7.32 (dd, J = 4.5, 8.2Hz, ArH), 7.19 (td, J = 0.7, 7.8Hz, ArH), 7.12 (td, J = 8.4Hz, ArH), 4.05 (s, OCH3); 13C NMR (CDCl3, 100MHz) δ157.5, 148.2, 147.4, 139.9, 138.1, 137.4, 133.6, 130.3, 129.9, 126.6, 123.2, 121.4, 113.1, 112.0, 56.9.

[0199] Example 2: Synthesis of sulfenyl imine derivatives wherein A is phenyl and B is pyridine

[0200] As an embodiment of the present invention, when A in Chemical Formula 1 is phenyl and B is pyridine, the synthesis process of the sulfenyl imide derivative is shown in the following Reaction Formula 2.

[0201] [Reaction 2]

[0202]

[0203] (1) Substitution of imino(methyl)(phenyl)-λ by reaction with ammonium carbonate and diacetoxyiodobenzene 6 -Synthesis of sulfenyl imine

[0204]

[0205] According to the above reaction formula, substituted imino(methyl)(phenyl)-λ 6 -sulfinyl imide (imino (methyl) (phenyl) -λ 6-sulfanone). Specifically, the compound synthesized in the above reaction (1) (1.0 equivalent) is dissolved in methanol (MeOH), and ammonium carbonate ((NH4)2CO3, 1.5 equivalent) is added. Then diacetoxyiodobenzene (PhI(OAc)2, 2.3 equivalent) is added in sequence and stirred at room temperature for 3 to 18 hours. After the reaction is completed, the reaction solution is decompressed to remove the solvent. The resulting residue is purified by column chromatography to obtain 2-, 3- or 4-substituted imino(methyl)(phenyl)-λ 6 -sulfenyl imide.

[0206] (2) Using HMDS-substituted methyl(phenyl)((trimethylsilyl)imino)-λ 6 -Synthesis of sulfenyl imine

[0207]

[0208] According to the above reaction formula, substituted methyl(phenyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide (methyl(phenyl)((trimethylsilyl)imino)-λ 6 -sulfanone). Specifically, hexamethyldisilazane (HMDS, 1.5 equivalents) was added to the compound (1.0 equivalents) synthesized in the above reaction (2), and refluxed and stirred at 80°C for 1 hour. After the reaction was completed, the pressure was reduced to remove HMDS to obtain 2-, 3- or 4-substituted methyl(phenyl)((trimethylsilyl)imino)-λ 6 -sulfenyl imide.

[0209] (3) Synthesis of diethyl (phenylsulfonyliminomethyl) phosphonate substituted by reaction with diethyl chlorophosphate

[0210]

[0211] Substituted diethyl (phenylsulfonimidoylmethyl) phosphonate was synthesized according to the above reaction formula. Specifically, the compound (1.0 equivalent) synthesized in the above reaction (3) was dissolved in anhydrous tetrahydrofuran (THF, Tetrahydrofuran), and then cooled to -78 ° C using acetone and dry ice. Then, n-butyl lithium (2.0 equivalents, 2.0M cyclohexane solution) was added dropwise using acetone and dry ice at -78 ° C. After stirring at the same temperature for 30 minutes, diethyl chlorophosphate (Diethyl chlorophosphate, 1.5 equivalents) was added at the same temperature, and then stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate (EtOAc, ethylacetate), washed with water and brine, and the organic layer was dried and filtered by anhydrous Na2SO4. The residue obtained by distilling off the solvent under reduced pressure is purified by column chromatography to obtain 2-, 3- or 4-substituted diethyl (phenylsulfonyliminomethyl)phosphonate.

[0212] (4) (E)-Imino(phenyl)(2-(pyridin-2-yl)vinyl)-λ substituted by reaction with a pyridinecarboxaldehyde derivative 6 -Synthesis of sulfenyl imine derivatives

[0213]

[0214] The substituted diethyl (phenylsulfonyliminomethyl) phosphonate (1.0 equivalent) synthesized in the above reaction (3) is dissolved in anhydrous THF and then cooled to -78°C using dry ice and acetone. After n-butyl lithium (1.2 equivalents, 2.0M cyclohexane solution) is slowly added dropwise to the above solution and stirred for 1 hour, picolinaldehyde derivatives (1.2 equivalents) are added and reacted for another hour. If the reaction is confirmed to be incomplete by TLC, react at room temperature for another 30 minutes. After the reaction is completed with a small amount of water, extract with water and 10% MeOH / MC, remove a small amount of water from the organic layer by anhydrous Na2SO4, and vacuum dry. Subsequently, it is separated and purified by column chromatography to obtain 2-, 3- or 4-substituted (E)-imino(phenyl)(2-(pyridin-2-yl)vinyl)-λ 6 -sulfenyl imine derivatives.

[0215] Example 2.1, (E)-(2-fluorophenyl)(imino)(2-(pyridin-2-yl)vinyl)-λ6 -Synthesis of sulfenyl imide (Chemical Formula 1-1)

[0216] 2.1.1. Imino(2-fluorophenyl)(methyl)-λ 6 -sulfinyl imide (Imino (2-fluorophenyl) (methyl) -λ 6 Synthesis of -sulfanone

[0217]

[0218] Using the above reaction (1), 1-fluoro-2-(methylsulfinyl)benzene (17.9 ml, 126.3 mmol) was fully dissolved in MeOH, and then diacetoxyiodobenzene (53.1 g, 189.4 mmol) was reacted with ammonium carbonate (14.0 g, 290.4 mmol) to synthesize pale yellow oily imino(2-fluorophenyl)(methyl)-λ 6 -sulfinyl imide (21.00 g, 96%): R f =0.40 (acetone / CH2Cl2 1 / 9); 1H NMR (300MHz, DMSO) δ7.88 (td, J=1.3, 7.6Hz, ArH), 7.39-7.74 (m, 3ArH), 4.71 (s, NH), 3.18 (s, CH3); 13C NMR (75MHz, DMSO) δ159.0 (d, J C-F =249.8Hz, ArC-F), 135.6(d,J C-F =8.4Hz,ArC),132.4(d,J C-F =15.6Hz, ArC), 129.8, 125.2 (d, J C-F =3.7Hz,ArC),117.5(d,J C-F =21.9Hz, 2ArC-CF), 45.3(d,J C-F =2.7 Hz, OCH3).

[0219] 2.1.2, (2-fluorophenyl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide ((2-Fluorophenyl)(methyl)((trimethylsilyl)imino)-λ 6 Synthesis of -sulfanone

[0220]

[0221] Using the above reaction (2), imino (2-fluorophenyl) (methyl) -λ6 -sulfenyl imide (5.00 g, 28.8 mmol) was added to hexamethyldisilazane (6.64 ml, 31.7 mmol) to synthesize (2-fluorophenyl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imine (7.0 g, 100%): R f =0.25 (acetone / CH2Cl2 1 / 9); 1H NMR (300MHz, DMSO) δ7.86 (td, J=1.6, 7.7Hz, ArH), 7.41-7.76 (m, 3ArH), 3.22 (s, NH), 0.00 (s, Si(CH3)3); 13C NMR (75MHz, DMSO) δ156.4 (d, J C-F =250.0Hz, ArC-F), 133.1(dd, J C-F =5.0, 8.3Hz, CSOCH3), 130.0(t, J C-F =14.9Hz, ArC), 127.2, 126.7, 122.7 (dd, J C-F =3.6, 14.4Hz, ArC), 115.0 (d, J C-F =4.8, 21.8Hz, ArC), 42.6(d, J C-F =2.8Hz, OCH3), 0.0(Si(CH3)3).

[0222] 2.1.3 Synthesis of Diethyl((2-fluoro-N-(trimethylsilyl)phenylsulfonimidoyl)methyl)phosphonate

[0223]

[0224] Using the above reaction (3), (2-fluorophenyl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide (1.00 g, 5.77 mmol) was fully dissolved in THF, and then diethyl chlorophosphate (0.99 ml, 6.93 mmol) was added and reacted with 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (3.43 ml, 6.93 mmol) to synthesize diethyl ((2-fluoro-N-(trimethylsilyl)phenylsulfonyl imide)methyl)phosphonate (0.75 g, 42%) as a white solid: R f =0.20 (n-hexane 1: EtOAc 1); 1H NMR (400MHz, DMSO-d6) δ7.37-7.90 (m, 4ArH), 4.16 (d, J=21.9Hz, SCH2P), 3.83-4.02 (m, P(OCH2CH3)2), 1.08-1.18 (m, P(OCH2CH3)2).

[0225] 2.1.4. (E)-(2-Fluorophenyl)(imino)(2-(pyridin-2-yl)vinyl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-1)

[0226]

[0227] Using the above reaction (4)-2, diethyl ((2-fluoro-N-(trimethylsilyl)phenylsulfonylimino)methyl)phosphonate, 2.0 M n-butyllithium (n-BuLi) in cyclohexane (0.68 mL, 2.19 mmol) and pyridinecarboxaldehyde (0.25 mL, 2.63 mmol) were reacted to synthesize a light yellow oily compound 1-1 (0.26 g, 45%): R f =0.30 (n-hexane 1: EtOAc 1); mp: 139.2-141.2°C; 1 H NMR (300 MHz, DMSO-d6) δ 8.64 (d, J = 4.6 Hz, ArH), 7.97 (td, J = 1.6, 8.0 Hz, ArH), 7.88 (td, J = 1.6, 7.6 Hz, ArH), 7.81 (d, J = 7.4 Hz, ArH), 7.63-7.74 (m, 2ArH, (E)-isomer H), 7.58 (d, J = 14.9 Hz, (E)-isomer 2H), 7.37-7.46 (m, 3ArH), 5.27 (s, NH); 13 C NMR (75MHz, DMSO-d6) δ158.6 (d, J C-F =251.8Hz), 151.0, 150.1, 140.6, 137.4, 135.5 (d, J C-F =8.3Hz), 133.1, 131.1 (d, J C-F =14.0Hz), 129.6, 125.1, 124.9 (d, J C-F =3.7Hz), 117.2(d, J C-F =21.5Hz).

[0228] Example 2.2, (E)-Imino(4-methoxyphenyl)(2-(pyridin-2-yl)vinyl)-λ 6 -Synthesis of sulfenyl imide (chemical formula 1-2)

[0229] 2.2.1. Imino (4-methoxyphenyl) (methyl) -λ 6 -sulfinyl imine (Imino (4-methoxyphenyl) (methyl) -λ 6 Synthesis of -sulfanone

[0230]

[0231] Using the above reaction (2), (4-methoxyphenyl)(methyl)sulfane (1.6 ml, 12.42 mmol) was fully dissolved in MeOH, and then diacetoxyiodobenzene (8.00 g, 28.53 mmol) was reacted with ammonium carbonate (1.20 g, 24.82 mmol) to synthesize pale yellow oily imino(4-methoxyphenyl)(methyl)-λ 6 -sulfinyl imide (2.96 g, 77%): R f =0.38 (acetone / CH2Cl2 1 / 9); 1 H NMR (300MHz, DMSO) δ7.84 (d, J = 8.7Hz, 2ArH), 7.11 (d, J = 8.7Hz, 2ArH), 4.05 (s, NH), 3.84 (s, OCH3), 3.02 (s, CH3).

[0232] 2.2.2, (4-methoxyphenyl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide ((4-Methoxyphenyl)(methyl)((trimethylsilyl)imino)-λ 6 Synthesis of -sulfanone

[0233]

[0234] Using the above reaction (3), hexamethyldisilazane (2.70 ml, 12.9 mmol) was added to imino(4-methoxyphenyl)(methyl)-λ 6 -sulfinyl imide (2.18 g, 11.7 mmol) was added to synthesize (4-methoxyphenyl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imine (3.40 g, 100%): R f =0.25 (acetone / CH2Cl2 1 / 9); 1H NMR (300MHz, DMSO) δ7.79 (d, J = 8.8 Hz, ArH), 7.09 (d, J = 6.9 Hz, ArH), 3.82 (s, OCH3), 3.01 (s, CH3), 0.00 (s, Si (CH3) 3).

[0235] 2.2.3 Synthesis of Diethyl((4-methoxyphenylsulfonimidoyl)methyl)phosphonate

[0236]

[0237] Using the above reaction (3), imino(4-methoxyphenyl)(methyl)((trimethylsilyl)imino)-λ6-sulfinyl imide (0.22 g, 0.72 mmol) was fully dissolved in THF, and then diethyl chlorophosphate (0.22 ml, 1.50 mmol) was reacted with 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (0.74 ml, 1.50 mmol) to synthesize diethyl ((4-methoxy-N-(trimethylsilyl)phenylsulfonyl imino)methyl)phosphonate (0.12 g, 52%) as a white solid: R f =0.29 (n-hexane 1: EtOAc 4); 1 H NMR(300MHz,DMSO-d6)δ7.90(d,J=8.9Hz,2ArH),7.11(d,J=8.9Hz,2ArH),4.37(s ,NH),3.95-4.08(m,P(OCH2CH3)2),3.85(s,OCH3),1.14-1.20(m,P(OCH2CH3)2).

[0238] 2.2.4. (E)-Imino(4-methoxyphenyl)(2-(pyridin-2-yl)vinyl)-λ 6 -Synthesis of sulfenyl imide (chemical formula 1-2)

[0239]

[0240] Using the above reaction (4)-2, diethyl ((4-methoxyphenylsulfonylimino)methyl)phosphonate (0.15 mL, 0.46 mmol), 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.30 mL, 0.55 mmol) and pyridinecarboxaldehyde (0.06 mL, 0.55 mmol) were reacted to synthesize compound 1-2 (0.14 g, 51%) as a light yellow oil: R f=0.30 (n-hexane 1: EtOAc 1); 1 H NMR (300 MHz, DMSO-d6) δ 8.59 (d, J = 4.7 Hz, ArH), 7.82-7.39 (m, 3ArH), 7.73 (d, J = 7.8, 8.2 Hz, ArH), 7.14-7.52 (m, ArH, (E)-isomer 2H), 7.12 (d, J = 7.3 Hz, 2ArH), 4.67 (s, NH), 3.83 (s, OCH3); 13 CNMR(75MHz,DMSO-d6)δ162.5,151.4,150.0,137.6,137.2,135.7,134.0,129.9,124.7,124.6,114.4,55.7(OCH3).

[0241] Example 2.3, (E)-(2-chlorophenyl)(2-(3-fluoropyridin-2-yl)vinyl)(imino)-λ 6 -Synthesis of sulfenyl imide (chemical formula 1-3)

[0242] 2.3.1. Imino(2-chlorophenyl)(methyl)-λ 6 -sulfinyl imide (Imino (2-chlorophenyl) (methyl) -λ 6 Synthesis of -sulfanone

[0243]

[0244] Using the above reaction (1), 1-chloro-2-(methylsulfinyl)benzene (6.45 ml, 50.43 mmol) was fully dissolved in MeOH, and then diacetoxyiodobenzene (37.36 g, 115.99 mmol) was reacted with ammonium carbonate (7.27 g, 75.64 mmol) to synthesize pale yellow oily imino(2-chlorophenyl)(methyl)-λ6-sulfinyl imide (5.0 g, 52%): R f =0.58 (EtOAc 100%); 1 H NMR (400MHz, DMSO-d6) δ8.08-8.10(m,ArH),7.62-7.68(m,2ArH),7.55-7.59(m,ArH),4.60(brs,NH),3.22(s,SCH3).

[0245] 2.3.2, (2-chlorophenyl)(methyl)((trimethylsilyl)imino)-λ 6-sulfinyl imide ((2-Chlorophenyl)(methyl)((trimethylsilyl)imino)-λ 6 Synthesis of -sulfanone

[0246]

[0247] Using the above reaction (2), hexamethyldisilazane (1.66 ml, 7.91 mmol) was added to imino(2-chlorophenyl)(methyl)-λ 6 -sulfinyl imide (1.00 g, 5.27 mmol) was added to synthesize (2-chlorophenyl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide (1.35 g, 98%): R f =0.81 (n-hexane 1: EtOAc 1); 1 H NMR (400MHz, DMSO-d6) δ8.08 (dd, J=1.5, 7.8Hz, ArH), 7.63-7.68 (m, 2ArH), 7.56-7.60 (m, ArH), 3.25 (s, SCH3), 0.00 (s, Si (CH3)3).

[0248] 2.3.3 Synthesis of Diethyl((2-chlorophenylsulfonimidoyl)methyl)phosphonate

[0249]

[0250] Using the above reaction (3), (2-chlorophenyl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide (1.35 g, 5.16 mmol) was fully dissolved in THF, and then diethyl chlorophosphate (0.89 ml, 6.19 mmol) was reacted with 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (3.09 ml, 6.19 mmol) to synthesize diethyl ((2-chlorophenylsulfonylimino)methyl)phosphonate (0.67 g, 40%) as a white solid: R f =0.18 (n-hexane 1: EtOAc 1); 1H NMR(400MHz,DMSO-d6)δ8.10(d,J=7.9Hz,ArH),7.66(d,J=3.7Hz,2ArH),7.56-7.60(m,ArH),4.9 3(s,NH),4.27(q,J=15.8Hz,SCH2P),3.87-4.01(m,P(OCH2CH3)2),1.11-1.16(m,P(OCH2CH3)2).

[0251] 2.3.4. (E)-(2-chlorophenyl)(2-(3-fluoropyridin-2-yl)vinyl)(imino)-λ 6 -Synthesis of sulfenyl imide (chemical formula 1-3)

[0252]

[0253] Using the above reaction (4)-2, diethyl ((2-chlorophenylsulfonylimino)methyl)phosphonate (0.20 mL, 0.62 mmol), 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.40 mL, 0.74 mmol) and 3-fluoropyridinecarboxaldehyde (0.10 g, 0.74 mmol) were reacted to synthesize compound 1-3 (0.11 g, 61%) in the form of a pale yellow powder: R f =0.51 (n-hexane 1: EtOAc 4); mp: 94.3-96.0°C 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 4.4 Hz, ArH), 8.21 (d, J = 7.4 Hz, ArH), 7.87 (t, J = 9.4 Hz, ArH), 7.75 (d, J = 14.8 Hz, (E)-isomer H), 7.52-7.69 (m, 4ArH, (E)-isomer H), 5.31 (s, NH); 13 C NMR(100MHz,DMSO-d6)δ157.8(d,J C-F =261.1Hz),146.4(d,J C-F =4.9Hz),139.9,138.8(d,J C-F =11.0Hz),134.4,133.5(d,J C-F =4.4Hz),132.8,131.8,131.3,130.6,127.8,127.5(d,J C-F =4.6Hz),124.7(d,J C-F =18.9Hz).

[0254] Example 2.4, (E)-(2-chlorophenyl)(2-(3-chloropyridin-2-yl)vinyl)(imino)-λ 6 -Synthesis of sulfenyl imide (chemical formula 1-4)

[0255]

[0256] Diethyl((2-chlorophenylsulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 2.3.1 to 2.3.3.

[0257] Using the above reaction (4)-2, diethyl ((2-chlorophenylsulfonylimino)methyl)phosphonate (1.00 g, 3.07 mmol), 2.0 M n-butyllithium (n-BuLi) solution in cyclohexane (1.84 mL, 3.68 mmol) and 3-chloropyridinecarboxaldehyde (0.44 g, 3.07 mmol) were reacted to synthesize compound 1-4 in the form of a white powder (0.48 g, 50%): R f =0.30 (n-hexane 1: EtOAc 2); mp: 144.8-146.5°C 1 H NMR (400 MHz, CDCl3) δ 8.61 (dd, J = 1.3, 4.5 Hz, ArH), 8.20-8.22 (m, ArH), 8.06 (dd, J = 1.4, 8.2 Hz, ArH), 7.97 (d, J = 14.6 Hz, (E)-isomer H), 7.59-7.68 (m, (E)-isomer H, 3ArH), 7.51 (dd, J = 4.5, 8.2 Hz, ArH), 7), 5.32 (brs, NH). 13 CNMR(75MHz,DMSO-d6)δ148.6,147.4,140.0,138.3,135.4,134.6,134.5,131.9,131.8,131.4,130.7,127.9,126.7.

[0258] Example 2.5, (E)-(2-fluorophenyl)(2-(3-fluoropyridin-2-yl)vinyl)(imino)-λ 6 -Synthesis of sulfenyl imide (chemical formula 1-5)

[0259]

[0260] Diethyl ((2-fluoro-N-(trimethylsilyl)phenylsulfonylimide)methyl)phosphonate was synthesized in the same manner as in Examples 2.1.1 to 2.1.3.

[0261] Using the above reaction (4)-2, diethyl ((2-fluorophenylsulfonylimino)methyl) phosphate (0.24 mL, 0.78 mmol), 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (0.50 mL, 0.94 mmol) and 3-fluoropyridine carboxaldehyde (0.12 g, 0.94 mmol) were reacted to synthesize compound 1-5 (0.11 g, 51%) as a light yellow oil: R f =0.30 (n-hexane 1: EtOAc 2); mp: 107.8-109.8°C 1 H NMR (300 MHz, DMSO-d6) δ 8.51 (d, J = 4.4 Hz, ArH), 7.98 (t, J = 7.8 Hz, ArH), 7.87 (t, J = 8.6 Hz, ArH), 7.38-7.76 (m, 4ArH, (E)-isomer 2H), 5.39 (s, NH); 13 C NMR(75MHz,DMSO-d6)δ158.6(d,J C-F =251.4Hz),157.8(d,J C-F =260.9Hz),146.4(d,J C-F =4.9Hz),138.8(d,J C-F =11.0Hz),135.8(d,J C-F =8.4Hz),134.7(d,J C-F =3.1Hz),132.3,130.6(d,J C-F =14.1Hz),129.7,127.6(d,J C-F =4.6Hz),125.0(d,J C-F =3.6Hz),124.7(d,J C-F =18.9Hz),117.2(d,J C-F =21.6Hz).

[0262] Example 2.6, (E)-(2-(3-chloropyridin-2-yl)vinyl)(2-fluorophenyl)(imino)-λ 6 -Synthesis of sulfenyl imine (chemical formula 1-6)

[0263]

[0264] Diethyl ((2-fluoro-N-(trimethylsilyl)phenylsulfonylimide)methyl)phosphonate was synthesized in the same manner as in Examples 2.1.1 to 2.1.3.

[0265] Using the above reaction (4)-2, diethyl ((2-fluoro-N-(trimethylsilyl)phenylsulfonylimino)methyl)phosphonate (0.24 mL, 0.78 mmol), 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.50 mL, 0.94 mmol) and 3-chloropyridinecarboxaldehyde (0.12 g, 0.94 mmol) were reacted to synthesize compound 1-6 (0.14 g, 59%) as a white powder: R f =0.30 (n-hexane 1: EtOAc 2); mp: 89.8-91.8°C 1 H NMR (300 MHz, DMSO-d6) δ 8.60 (d, J = 4.4 Hz, ArH), 8.06 (d, J = 8.2 Hz, ArH), 7.70-8.00 (m, 2ArH, (E)-isomer H), 7.61 (d, J = 14.9 Hz, (E)-isomer H), 7.29-7.54 (m, 3ArH) 5.41 (s, NH); 13 C NMR(75MHz,DMSO-d6)δ158.6(d,J C-F =251.4Hz),148.6,147.3,138.3,135.9,135.8,135.7,134.7,131.8,130.6(d,J C-F =14.0Hz),129.7,126.7,125.0(d,J C-F =3.6Hz),117.2(d,J C-F =21.5Hz).

[0266] Example 2.7, (E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(3-methoxyphenyl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-7)

[0267] 2.7.1. Imino(3-methoxyphenyl)methyl-λ 6 -sulfinyl imide (Imino (3-methoxyphenyl) methyl-λ 6 Synthesis of -sulfanone

[0268]

[0269] Using the above reaction (1), (3-methoxyphenyl)(methyl)sulfane (1.4 ml, 10.35 mmol) was fully dissolved in MeOH, and then diacetoxyiodobenzene (6.67 g, 23.78 mmol) was reacted with ammonium carbonate (1.00 g, 20.69 mmol) to synthesize pale yellow oily imino(3-methoxyphenyl)methyl-λ 6 -sulfinyl imide (2.96 g, 77%): R f =0.38 (acetone / CH2Cl2 1 / 9); 1 H NMR (300MHz, DMSO) δ7.19-7.54 (m, 4ArH), 4.19 (s, NH), 3.84 (s, OCH3), 3.06 (s, CH3).

[0270] 2.7.2, (3-methoxyphenyl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide ((3-Methoxyphenyl)(methyl)((trimethylsilyl)imino)-λ 6 Synthesis of -sulfanone

[0271]

[0272] Using the above reaction (2), hexamethyldisilazane (0.74 ml, 3.52 mmol) was added to imino(3-methoxyphenyl)methyl-λ 6 -sulfinyl imide (0.50 g, 2.93 mmol), thereby synthesizing transparent oily (3-methoxyphenyl)(methyl)((trimethylsilyl)imino)-λ6-sulfinyl imide (0.52 g, 70%): R f =0.25 (acetone / CH2Cl2 1 / 9); 1 H NMR (300MHz, DMSO) δ7.35-7.51 (m, 3ArH), 7.18 (d, J = 4.4Hz, ArH), 3.81 (s, OCH3), 3.05 (s, CH3), 0.00 (s, Si (CH3)3).

[0273] 2.7.3 Synthesis of Diethyl((3-methoxyphenylsulfonimidoyl)methyl)phosphonate

[0274]

[0275] Using the above reaction (3), imino(3-methoxyphenyl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide (0.34 g, 1.12 mmol) was fully dissolved in THF, and then diethyl chlorophosphate (0.25 ml, 1.68 mmol) was reacted with 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (0.83 ml, 1.68 mmol) to synthesize white solid diethyl ((3-methoxy-N-(trimethylsilyl)phenylsulfonyl imide)methyl)phosphonate (0.12 g, 51%): R f =0.27 (n-hexane 1: EtOAc 3); 1 H NMR (400MHz, DMSO-d6) δ7.48-7.55(m,4ArH),4.48(s,NH),3.95-4.06(m,P(OCH2CH3)2),3.84(s,OCH3),1.14-1.20(m,P(OCH2CH3)2).

[0276] 2.7.4. (E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(3-methoxyphenyl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-7)

[0277]

[0278] Using the above reaction (4)-2, diethyl ((3-methoxyphenylsulfonylimino)methyl)phosphonate (0.51 mL, 1.58 mmol), 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.95 mL, 1.89 mmol) and 3-fluoropyridinecarboxaldehyde (0.24 g, 1.89 mmol) were reacted to synthesize a transparent oily compound 1-7 (0.24 g, 52%): R f =0.34 (n-hexane 1: EtOAc 2); 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 4.4 Hz, ArH), 7.85 (t, J = 9.1 Hz, ArH), 7.62 (d, J = 14.9 Hz, (E)-isomer H), 7.48-7.58 (m, 4ArH, (E)-isomer H), 7.23 (d, J = 7.3 Hz, ArH), 4.95 (s, NH); 13 CNMR(75MHz,DMSO-d6)δ159.5,157.7(d,J C-F =261.8Hz),146.3(d,J C-F =4.8Hz),143.6,139.1(d,JC-F =11.1Hz),136.4(d,J C-F =4.3Hz),130.4(d,J C-F =11.4Hz),127.2(d,J C-F =2.4Hz),124.6(d,J C-F =18.9Hz),119.4(d,J C-F =83.1Hz),112.5,55.6(OCH3).

[0279] Example 2.8, (E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(2-methoxyphenyl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-8)

[0280] 2.8.1. Imino(2-methoxyphenyl)methyl-λ 6 -Sulfenimide (Imino(2-methoxyphenyl)methyl)-λ 6 Synthesis of -sulfanone

[0281]

[0282] Using the above reaction (1), (2-methoxyphenyl)(methyl)sulfane (2.8 ml, 20.70 mmol) was fully dissolved in MeOH, and then diacetoxyiodobenzene (15.33 g, 47.57 mmol) was reacted with ammonium carbonate (3.98 g, 41.39 mmol) to synthesize light yellow oily imino(2-methoxyphenyl)methyl)-λ 6 -sulfinyl imide (3.08 g, 80%): R f =0.30 (EtOAc 100%); 1 H NMR (400MHz, DMSO-d6) δ7.84(dd,1.7,7.8Hz,ArH),7.60(m,ArH),7.23(d,8.2Hz,ArH),7.11(m,ArH),4.23(brs,NH),3.92(s,OCH3),3.14(s,SCH3).

[0283] 2.8.2, (2-methoxyphenyl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide ((2-Methoxyphenyl)methyl((trimethylsilyl)imino)-λ 6 Synthesis of -sulfanone

[0284]

[0285] Using the above reaction (2), hexamethyldisilazane (5.1 ml, 24.30 mmol) was added to imino(2-methoxyphenyl)methyl)-λ 6 -sulfinyl imide (3.08 g, 16.63 mmol) was added to synthesize a transparent oily (2-methoxyphenyl)methyl((trimethylsilyl)imino)-λ 6 -sulfinyl imine (4.28 g, 100%): R f =0.81 (EtOAc 100%); 1 H NMR (400MHz, DMSO-d6) δ7.88(dd,1.7,7.8Hz,ArH),7.68(m,ArH),7.30(d,8.2Hz,ArH),7.18(m,ArH),3.99(s,OCH3),3.22(s,SCH3),0.00(s,Si(CH3)3).

[0286] 2.8.3 Synthesis of Diethyl((2-methoxyphenylsulfonimidoyl)methyl)phosphonate

[0287]

[0288] Using the above reaction (3), (2-methoxyphenyl)methyl((trimethylsilyl)imino)-λ 6 -sulfinyl imide (4.28 g, 16.63 mmol) was fully dissolved in THF, and then diethyl chlorophosphate (2.88 ml, 19.95 mmol) was reacted with 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (18.29 ml, 36.58 mmol) to synthesize diethyl ((2-methoxyphenylsulfonyl imide) methyl) phosphonate as a pale yellow solid: R f =0.28 (EtOAc 100%); 1 H NMR(400MHz,DMSO-d6)δ7.88(dd,7.8,29.7Hz,ArH),7.62(m,ArH),7.23(dd,4.3,8.2Hz,ArH),7.18(t,7 .5Hz,ArH),4.02-3.88(m,SCH2P,(POCH2CH3)2,OCH3),1.16-1.10(m,P(OCH2CH3)2),0.01(s,Si(CH3)3).

[0289] 2.8.4. (E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(2-methoxyphenyl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-8)

[0290]

[0291] Diethyl ((2-methoxyphenylsulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 1.1.1 to 1.1.3.

[0292] Using the above reaction (4)-2, diethyl ((2-methoxyphenylsulfonylimino)methyl)phosphonate (0.61 mL, 1.91 mmol), 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (1.20 mL, 2.29 mmol) and 3-chloropyridinecarboxaldehyde (0.33 g, 2.29 mmol) were reacted to synthesize compound 1-8 (0.40 g, 68%) in the form of a pale yellow powder: R f =0.35 (n-hexane 1: EtOAc 7), mp: 113.0-114.1°C 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 4.4 Hz, ArH), 8.04 (dd, J = 1.4, 8.2 Hz, ArH), 7.95 (dd, J = 1.6, 7.8 Hz, ArH), 7.90 (d, J = 14.7 Hz, (E)-isomer H), 7.67 (d, J = 14.6 Hz, (E)-isomer H), 7.48-7.64 (m, 2ArH), 7.22 (d, J = 8.2 Hz, ArH), 7.15 (t, J = 7.4 Hz, ArH), 4.84 (s, NH), 3.91 (OCH3); 13 C NMR (75MHz, DMSO-d6) δ156.7,148.6,147.7,138.2,136.4,134.9,133.7,131.6,130.2,128.8,126.4,120.4,113.3,56.2(OCH3).

[0293] Example 2.9, (E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(3-methoxyphenyl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-9)

[0294]

[0295] Diethyl ((3-methoxyphenylsulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 2.7.1 to 2.7.3.

[0296] Using the above reaction (4)-2, diethyl ((3-methoxyphenylsulfonylimino)methyl)phosphonate (0.62 mL, 1.93 mmol), 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (1.2 mL, 2.32 mmol) and 3-chloropyridinecarboxaldehyde (0.33 g, 2.32 mmol) were reacted to synthesize compound 1-9 (0.24 g, 44%) as a light yellow oil: R f =0.37 (n-hexane 1: EtOAc 2); 1 H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J = 4.5 Hz, ArH), 8.02-8.05 (m, ArH), 7.84 (d, J = 14.6 Hz, (E)-isomer H), 7.22-7.65 (m, 5ArH, (E)-isomer 2H), 4.98 (s, NH), 3.84 (OCH3); 13 C NMR (75MHz, DMSO-d6) δ160.1,148.5,147.9,143.1,137.8,136.7,134.4,130.8,125.5,120.8,119.7,113.0,55.7(OCH3).

[0297] Example 2.10, (E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(4-methoxyphenyl)-λ 6 -Synthesis of sulfenyl imide (chemical formula 1-10)

[0298]

[0299] Diethyl ((4-methoxyphenylsulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 2.2.1 to 2.2.3.

[0300] Using the above reaction (4)-2, diethyl ((4-methoxyphenylsulfonylimino)methyl)phosphonate (0.15 mL, 0.46 mmol), 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.30 mL, 0.55 mmol) and 3-chloropyridinecarboxaldehyde (0.07 mL, 0.55 mmol) were reacted to synthesize compound 1-10 (0.15 g, 53%) as a light yellow oil: R f =0.32 (n-hexane 1: EtOAc 2); mp: 103.6-105.6°C 1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 4.5 Hz, ArH), 7.11-7.89 (m, 7ArH, (E)-isomer 2H), 4.67 (s, NH), 3.83 (OCH3); 13 C NMR (75MHz, DMSO-d6) δ162.7,148.4,147.6,138.4,138.2,133.3,131.5,130.1,126.3,114.5,55.7(OCH3).

[0301] Example 2.11, (E)-Imino(2-methoxyphenyl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-11)

[0302]

[0303] Diethyl ((2-methoxyphenylsulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 2.8.1 to 2.8.3.

[0304] Using the above reaction (4)-2, diethyl ((2-methoxyphenylsulfonylimino)methyl)phosphonate (0.30 g, 0.76 mmol) was fully dissolved in THF, and then 3-(trifluoromethyl)picolinaldehyde (0.11 ml, 0.84 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.42 ml, 0.84 mmol) to synthesize 1-11 (0.07 g, 28%) in the form of a white solid: R f =0.22 (n-hexane 1: EtOAc 3); 1 H NMR (400 MHz, CDCl3) δ8.76 (d, 4.0 Hz, ArH), 8.09 (dd, 1.7, 7.9, ArH), 8.00-7.96 (m, 2ArH), 7.92 (d, J = 14.4 Hz, (E)-isomer H), 7.55 (td, J = 1.7, 7.6 Hz, ArH), 7.40 (dd, J = 4.7, 8.0 Hz, ArH), 7.10 (t, J = 7.3 Hz, ArH), 7.01 (d, J = 8.3 Hz, ArH), 3.95 (s, OCH3), 3.14 (brs, NH); 13 C NMR(100MHz,DMSO-d6)δ157.2,153.8,149.0,138.3,135.5(2ArC),133.9,130.4,129.5,125.3,124.0(q,J C-F =

[0305] 271.8Hz),124.4(q,J C-F =31.4Hz),120.9,113.7,56.7.

[0306] Example 2.12, (E)-(2-chlorophenyl)(imino)(2-(pyridin-3-yl)vinyl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-12)

[0307]

[0308] Diethyl((2-chlorophenylsulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 2.3.1 to 2.3.3.

[0309] Using the above reaction (4)-2, diethyl ((2-chlorophenylsulfonylimino)methyl)phosphonate (0.70 mL, 2.14 mmol), 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (1.20 mL, 2.14 mmol) and nicotinaldehyde (0.14 mL, 1.43 mmol) were reacted to synthesize compound 1-12 (0.43 g, 71%) as a light yellow oil: R f =0.52 (n-hexane 1: EtOAc 4); 1 H NMR (400 MHz, DMSO-d6) δ 8.90 (s, ArH), 8.60 (d, J = 4.6 Hz, ArH), 8.21 (t, J = 6.1 Hz, 2ArH), 7.44-7.70 (m, 4ArH, (E)-isomer 2H), 5.11 (s, NH).

[0310] Example 2.13, (E)-(2-chlorophenyl)(2-(2-chloropyridin-3-yl)vinyl)(imino)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-13)

[0311]

[0312] Diethyl((2-chlorophenylsulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 2.3.1 to 2.3.3.

[0313] Using the above reaction (4)-2, diethyl ((2-chlorophenylsulfonylimino)methyl)phosphonate (0.70 mL, 2.14 mmol), 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (1.20 mL, 2.14 mmol) and 2-chloronicotinaldehyde (0.21 g, 1.43 mmol) were reacted to synthesize compound 1-13 (0.48 g, 60%) in the form of a white powder: R f =0.50 (n-hexane 1: EtOAc 9); 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (dd, J = 1.8, 4.7 Hz, ArH), 8.37 (dd, J = 1.8, 7.8 Hz, ArH), 8.22 (dd, J = 1.5, 7.7 Hz, ArH), 7.86 (d, J = 15.2 Hz, (E)-isomer H), 7.49-7.69 (m, 4ArH, (E)-isomer H), 5.26 (s, NH); 13 C NMR (100MHz, DMSO-d6) δ151.8,150.6,140.6,138.4,136.8,134.9,133.9,132.4,131.9,131.2,128.3,127.9,124.3.

[0314] Example 2.14, (E)-(2-chlorophenyl)(imino)(2-(2,4,6-trichloropyrimidin-5-yl)vinyl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-14)

[0315]

[0316] Diethyl((2-chlorophenylsulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 2.3.1 to 2.3.3.

[0317] Using the above reaction (4)-2, diethyl ((2-chlorophenylsulfonylimino)methyl)phosphonate (0.60 mL, 1.84 mmol), 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (2.76 mL, 2.76 mmol) and 2,4,6-trichloropyrimidine-5-carboxaldehyde (0.39 g, 1.84 mmol) were reacted to synthesize white powdery compound 1-14 (0.46 g, 66%): R f =0.10 (n-hexane 3: EtOAc 1); 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, ArH), 8.60 (d, J = 4.6 Hz, ArH), 8.21 (t, J = 6.1 Hz, 2ArH), 7.44-7.70 (m, 4ArH, (E)-isomer 2H), 5.11 (s, NH).

[0318] Example 3: Synthesis of sulfenyl imine derivatives wherein A is pyridine and B is phenyl

[0319] As an embodiment of the present invention, when A in Chemical Formula 1 is pyridine and B is phenyl, the synthesis process of the sulfenyl imide derivative is shown in the following Reaction Formula 3.

[0320] [Reaction 3]

[0321]

[0322] (1) Synthesis of methylthiopyridine derivatives from halogenated pyridine derivatives

[0323]

[0324] According to the above reaction formula, 2-(methylthio)pyridine derivatives were synthesized. Specifically, a bromine or fluoropyridine starting material (1.0 equivalent) substituted by methoxy, fluorine or chlorine at the 3-, 4-, 5- or 6-position was dissolved in dimethylformamide (DMF), and then sodium methylthiolate (2.0 equivalent) was added, and then stirred at 60°C for 2 to 18 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate (EtOAc, ethyl acetate), washed with water and brine, and the organic layer was dried and filtered over anhydrous Na2SO4. The residue obtained by the reduced pressure distillation solvent was purified by column chromatography using a mixed developing solvent of ethyl acetate and n-hexane to obtain a 3-, 4-, 5- or 6-substituted 2-(methylthio)pyridine derivative.

[0325] (2) Imino(methyl)(pyridin-2-yl)-λ substituted by reaction with ammonium carbonate and diacetoxyiodobenzene 6 -Synthesis of sulfenyl imine derivatives

[0326]

[0327] According to the above reaction formula, substituted imino(methyl)(pyridin-2-yl)-λ 6-sulfinyl imide. Specifically, the compound synthesized from the above reaction (1) (1.0 equivalent) was dissolved in methanol (Methanol; MeOH), and then ammonium carbonate ((NH4)2CO3, 1.5 equivalent) was added. Then, diacetoxyiodobenzene (PhI(OAc)2, 2.3 equivalents) was added in sequence and stirred at room temperature for 3 to 18 hours. After the reaction was completed, the reaction solution was decompressed to remove the solvent. The resulting residue was purified by column chromatography to obtain 3-, 4-, 5- or 6-substituted imino(methyl)(pyridin-2-yl)-λ 6 -sulfenyl imide.

[0328] (3) Using HMDS-substituted methyl(pyridin-2-yl)((trimethylsilyl)imino)-λ 6 -Synthesis of sulfenyl imine

[0329]

[0330] Substituted methyl(pyridin-2-yl)((trimethylsilyl)imino)-λ 6 -sulfenyl imide. Specifically, hexamethyldisilazane (HMDS, 1.5 equivalents) was added to the compound (1.0 equivalents) synthesized from the above reaction (2), and refluxed at 80°C with stirring for 1 hour. After the reaction was completed, HMDS was removed under reduced pressure to obtain 3-, 4-, 5- or 6-substituted methyl(pyridin-2-yl)((trimethylsilyl)imino)-λ 6 -sulfenyl imide.

[0331] (4) Using HMDS-substituted methyl(pyridin-2-yl)((trimethylsilyl)imino)-λ 6 -Synthesis of sulfenyl imine

[0332]

[0333] Substituted diethyl ((pyridine-2-sulfonylimino)methyl)phosphonate was synthesized according to the above reaction formula. Specifically, the compound (1.0 equivalent) synthesized from the above reaction (3) was dissolved in anhydrous tetrahydrofuran (THF), and then cooled to -78°C using acetone and dry ice. Then, n-butyl lithium (2.0 equivalent, 2.0M cyclohexane solution) was added dropwise at -78°C using acetone and dry ice. After stirring at the same temperature for 30 minutes, diethyl chlorophosphate (1.5 equivalent) was added at the same temperature, and then stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate (EtOAc, ethyl acetate), washed with water and brine, and the organic layer was dried over anhydrous Na2SO4 and filtered. The residue obtained by distilling the solvent under reduced pressure was purified by column chromatography to obtain 3-, 4-, 5- or 6-substituted diethyl ((pyridine-2-sulfonylimino)methyl)phosphonate.

[0334] (5)-1. (E)-Imino(pyridin-2-yl)(styryl)-λ substituted by reaction with a benzaldehyde derivative 6 -Synthesis of sulfenyl imine derivatives

[0335]

[0336] Substituted (E)-imino(pyridin-2-yl)(phenylvinyl)-λ 6 -sulfinyl imine derivative. The compound synthesized in step 2-4 (1.0 equivalent) is dissolved in anhydrous THF and then cooled to -78°C using dry ice and acetone. n-Butyl lithium (n-BuLi) (1.2 equivalents, 2.0M cyclohexane solution) is slowly added dropwise to the above solution, stirred for 1 hour, and the benzaldehyde derivative (1.2 equivalents) is added and reacted for another 1 hour. If the reaction is not complete when confirmed by TLC, react for another 30 minutes at room temperature. After terminating the reaction with a small amount of water, extract with water and 10% MeOH / MC, remove a small amount of water from the organic layer by anhydrous Na2SO4, remove the solvent by reduced pressure distillation and vacuum dry. Subsequently, separate and purify by column chromatography to obtain 3-, 4-, 5- or 6-substituted (E)-imino(pyridin-2-yl)(styryl)-λ 6 -sulfenyl imine derivatives.

[0337] Example 3.1, (E)-(2-chlorophenylvinyl)(imino)(pyridin-2-yl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-15)

[0338] 3.1.1. Imino(methyl)(pyridin-2-yl)-λ 6 -sulfinyl imide (imino (methyl) (pyridin-2-yl) -λ 6 Synthesis of -sulfanone

[0339]

[0340] Using the above reaction (2), 2-(methylthio)pyridine (0.18 mL, 1.60 mmol) was fully dissolved in MeOH, and then diacetoxyiodobenzene (1.18 g, 3.67 mmol) was reacted with ammonium carbonate (0.23 g, 2.40 mmol) to synthesize white oily imino(methyl)(pyridin-2-yl)-λ 6 -sulfinyl imine (0.21 g, 83%): R f =0.18 (EtOAc 100%); 1 H NMR (400MHz, DMSO-d6) δ8.70-8.72(m,ArH),8.05-8.12(m,2ArH),7.63-7.66(m,ArH),4.41(s,NH),3.15(s,CH3).

[0341] 3.1.2, Methyl(pyridin-2-yl)((trimethylsilyl)imino)-λ 6 -sulfenyl imide (methyl (pyridin-2-yl) ((trimethylsilyl) imino) -λ 6 Synthesis of -sulfanone

[0342]

[0343] Using the above reaction (3), hexamethyldisilazane (0.46 mL, 2.18 mmol) was added to imino(methyl)(pyridin-2-yl)-λ 6 -sulfinyl imide (0.23 g, 1.45 mmol) was added to synthesize methyl(pyridin-2-yl)((trimethylsilyl)imino)-λ 6 -sulfinyl imine (0.35 g, 100%): R f =0.85 (EtOAc 100%); 1H NMR(400MHz,DMSO-d6)δ8.72-8.74(m,ArH),8.11(td,J=1.7,7.8Hz,ArH),8.01(d,J =7.8Hz, ArH), 7.66 (ddd, J = 1.2, 2.8, 7.7Hz, ArH), 3.16 (s, CH3), 0.00 (s, Si(CH3)3).

[0344] 3.1.3. Diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate

[0345]

[0346] Using the above reaction (4), methyl(pyridin-2-yl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide (0.24 g, 1.04 mmol) was fully dissolved in THF, and then diethyl chlorophosphate (0.18 mL, 1.25 mmol) was reacted with 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (1.14 mL, 2.28 mmol) to synthesize light yellow transparent oily diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.15 g, 48%): R f =0.43 (n-hexane 1: EtOAc 1); 1 H NMR (400MHz, DMSO-d6) δ8.71-8.73(m,ArH),8.11(td,J=1.7,7.8Hz,ArH),7.99(d,J=7.9Hz,ArH),7.66(ddd,J=1.1,2.9,7 .7Hz, ArH), 4.23 (d, J=16.0Hz, SCH2P), 3.89-4.05 (m, P(OCH2CH3)2), 1.13 (q, J=7.0Hz, P(OCH2CH3)2), 0.02 (s, Si(CH3)3).

[0347] 3.1.4. (E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(2-methoxyphenyl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-8)

[0348]

[0349] Using the above reaction (5)-1, diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.85 g, 2.91 mmol) was fully dissolved in THF, and then 2-chlorobenzaldehyde (0.41 g, 2.91 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (2.18 mL, 4.36 mmol) to synthesize white powdery compound 1-15 (0.55 g, 68%): R f =0.38 (EtOAc 100%); 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 4.4 Hz, ArH), 8.09-8.17 (m, 3ArH), 7.98 (d, J = 7.8 Hz, ArH), 7.90 (d, J = 15.3 Hz, (E)-isomer H), 7.56-7.67 (m, 2ArH, (E)-isomer H), 7.47 (t, J = 7.3 Hz, ArH), 7.39 (d, J = 7.6 Hz, ArH), 4.97 (s, NH); 13 C NMR (400MHz, DMSO-d6) δ160.8,150.3,139.2,137.0,134.3,132.7,132.5,130.8,130.6,129.4,128.3,127.3,121.8.

[0350] Example 3.2, (E)-(3-chlorophenylvinyl)(imino)(pyridin-2-yl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-16)

[0351]

[0352] Diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.1.1 to 3.1.3.

[0353] Using the above reaction (5)-1, diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.85 g, 2.91 mmol) was fully dissolved in THF, and then 3-chlorobenzaldehyde (0.50 g, 3.49 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (2.62 mL, 5.23 mmol) to synthesize white powdery compound 1-16 (0.68 g, 70%): R f =0.40 (EtOAc 100%); 1H NMR (400 MHz, DMSO-d6) δ 8.70-8.71 (m, ArH), 8.10-8.16 (m, 3ArH), 7.43-7.90 (m, 4ArH, (E)-isomer 2H), 4.86 (s, NH).

[0354] Example 3.3, (E)-Imino(pyridin-2-yl)(2-(trifluoromethyl)phenylvinyl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-17)

[0355]

[0356] Diethyl((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.1.1 to 3.1.3.

[0357] Using the above reaction (5)-1, diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.45 g, 1.54 mmol) was fully dissolved in THF, and then 3-(trifluoromethyl)benzaldehyde (0.25 g, 1.84 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (1.15 mL, 2.31 mmol) to synthesize white powdery compound 1-17 (0.24 g, 50%): R f =0.38 (EtOAc 4 / n-hexane 1); 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 4.5 Hz, ArH), 8.05-8.16 (m, 3ArH), 7.64-7.84 (m, 4ArH, (E)-isomer 2H), 4.50 (s, NH).

[0358] Example 3.4, (E)-Imino(pyridin-2-yl)(2-trifluoromethoxy)phenylvinyl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-18)

[0359]

[0360] Diethyl((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.1.1 to 3.1.3.

[0361] Using the above reaction (5)-1, diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.60 g, 2.05 mmol) was fully dissolved in THF, and then 2-(trifluoromethoxy)benzaldehyde (0.36 g, 2.46 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (1.60 mL, 3.07 mmol) to synthesize white powdery compound 1-18 (0.38 g, 57%): R f =0.28 (EtOAc 4 / n-hexane 1); 1 H NMR (400 MHz, DMSO-d6) δ 8.03-8.16 (m, 4ArH), 7.44-7.74 (m, 4ArH, (E)-isomer 2H), 4.97 (s, NH); 13 C NMR (400MHz, DMSO-d6) δ160.2,149.7,146.4,138.6,133.4,132.5,132.4,129.0,128.0,126.7,125.7,121.6,121.3.

[0362] Example 3.5, (E)-(2,6-dichlorophenylvinyl)(imino)(pyridin-2-yl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-19)

[0363]

[0364] Diethyl diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.1.1 to 3.1.3.

[0365] Using the above reaction (5)-1, diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.60 g, 2.05 mmol) was fully dissolved in THF, and then 2,6-dichlorobenzaldehyde (0.43 g, 2.46 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (1.60 mL, 3.07 mmol) to synthesize compound 1-19 (0.30 g, 47%) in the form of a white powder: R f =0.51 (EtOAc 4 / n-hexane 1); 1HNMR (400 MHz, DMSO-d6) δ8.73 (dd, J=0.9, 4.1 Hz, ArH), 8.11-8.16 (m, 2ArH), 7.64-7.70 (m, ArH, (E)-isomer H), 7.58 (d, J=8.0 Hz, ArH), 7.42-7.50 (m, ArH, (E)-isomer H), 5.01 (s, NH).

[0366] Example 3.6, (E)-(4-chlorophenylvinyl)(imino)(pyridin-2-yl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-20)

[0367]

[0368] Diethyl((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.1.1 to 3.1.3.

[0369] Using the above reaction (5)-1, diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.40 g, 1.37 mmol) was fully dissolved in THF, and then 4-chlorobenzaldehyde (0.23 g, 1.64 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (1.10 mL, 2.05 mmol) to synthesize white powdery compound 1-20 (0.22 g, 58%): R f =0.52 (EtOAc 4 / n-hexane 1); 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 3.9 Hz, ArH), 8.07-8.15 (m, 2ArH), 7.78 (d, J = 7.2 Hz, 2ArH), 7.48-7.65 (m, 3ArH, (E)-isomer 2H), 4.84 (s, NH).

[0370] Example 3.7, (E)-(5-chloropyridin-2-yl)(2-chlorophenylvinyl)(imino)-λ 6 -Synthesis of sulfenyl imine (Chemical Formula 1-21)

[0371] 3.7.1. Synthesis of 5-chloro-2-(methylthio)pyridine

[0372]

[0373] Using the above reaction (1), 5-chloro-2-fluoropyridine (0.20 g, 1.52 mmol) was fully dissolved in DMF, and then sodium thiomethoxide (0.11 g, 1.52 mmol) was reacted to synthesize transparent oily 5-chloro-2-(methylthio)pyridine (0.18 g, 75%): R f =0.67 (n-hexane 5: EtOAc 1); 1 H NMR (400MHz, DMSO-d6) δ8.39 (d, J = 2.4 Hz, ArH), 7.45 (dd, J = 2.5, 8.6 Hz, ArH), 7.12 (d, J = 8.6 Hz, ArH), 2.55 (s, CH3).

[0374] 3.7.2. (5-chloropyridin-2-yl)(imino)(methyl)-λ 6 -sulfinyl imide ((5-chloropyridin-2-yl)(imino)(methyl)-λ 6 Synthesis of -sulfanone

[0375]

[0376] Using the above reaction (2), 5-chloro-2-(methylthio)pyridine (0.18 g, 1.13 mmol) was fully dissolved in MeOH, and then diacetoxyiodobenzene (0.84 g, 2.61 mmol) was reacted with ammonium carbonate (0.16 g, 1.70 mmol) to synthesize white powder (5-chloropyridin-2-yl)(imino)(methyl)-λ 6 -sulfinyl imide (0.18 g, 83%): R f =0.41 (EtOAc 100%); 1 H NMR (400MHz, DMSO-d6) δ8.79(d,J=2.1Hz,ArH),8.24(dd,J=2.4,8.4Hz,ArH),8.08(d,J=8.3Hz,ArH),4.53(s,NH),3.17(s,CH3).

[0377] 3.7.3. (5-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide ((5-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone)

[0378]

[0379] Using the above reaction (3), hexamethyldisilazane (0.28 mL, 1.34 mmol) was added to (5-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide (0.17 g, 0.89 mmol) to synthesize transparent (5-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imine (0.24 g, 100%): R f =0.96 (EtOAc 100%); 1 H NMR (400MHz, DMSO-d6) δ 8.82 (d, J = 2.3 Hz, ArH), 8.24 (dd, J = 2.4, 8.4 Hz, ArH), 8.02 (d, J = 8.4 Hz), 3.17 (s, CH3), 0.00 (s, Si (OCH3) 3).

[0380] 3.7.4 Synthesis of diethyl((5-chloropyridine-2-sulfonimidoyl)methyl)phosphonate

[0381]

[0382] Using the above reaction (4), (5-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide (0.24 g, 0.92 mmol) was fully dissolved in THF, and then diethyl chlorophosphate (0.19 mL, 1.29 mmol) was reacted with 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (1.01 mL, 2.03 mmol) to synthesize yellow oily diethyl ((5-chloropyridine-2-sulfonylimino)methyl)phosphonate (0.067 g, 22%): R f =0.19 (EtOAc 100%); 1 H NMR(400MHz,DMSO-d6)δ8.81(d,J=2.0Hz,ArH),8.25(dd,J=2.4,8.5Hz,ArH),8.10(d,J=8.4Hz,ArH) ,4.86(s,NH),4.20-4.34(m,SCH2P),3.96-4.02(m,P(OCH2CH3)2),1.15(q,J=5.9Hz,P(OCH2CH3)2).

[0383] 3.7.5. (E)-(5-chloropyridin-2-yl)(2-chlorophenylvinyl)(imino)-λ 6 -Synthesis of sulfenyl imine (Chemical Formula 1-21)

[0384]

[0385] Using the above reaction (5)-1, diethyl ((5-chloropyridine-2-sulfonylimino)methyl)phosphonate (0.65 g, 1.99 mmol) was fully dissolved in THF, and then 2-chlorobenzaldehyde (0.34 g, 2.39 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (1.50 mL, 2.98 mmol) to synthesize compound 1-21 (0.45 g, 62%) in the form of a white powder: R f =0.56 (EtOAc 2 / n-hexane 1); 1 H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 1.8 Hz, ArH), 7.95-8.18 (m, 2ArH), 7.91 (d, J = 15.3 Hz, (E)-isomer H), 7.38-7.63 (m, 3ArH, (E)-isomer H), 5.10 (s, NH).

[0386] Example 3.8, (E)-(2,6-difluorophenylvinyl)(imino)(pyridin-2-yl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-22)

[0387]

[0388] Diethyl((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.1.1 to 3.1.3.

[0389] Using the above reaction (5)-1, diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.50 g, 1.71 mmol) was fully dissolved in THF, and then 2,6-difluorobenzaldehyde (0.23 g, 2.05 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (1.30 mL, 2.56 mmol) to synthesize compound 1-22 (0.47 g, 98%) in the form of a white powder: R f =0.34 (EtOAc 4 / n-hexane 1); 1HNMR (400 MHz, DMSO-d6) δ8.72-8.73 (m, ArH), 8.09-8.17 (m, 2ArH), 7.56-7.67 (m, 2ArH, (E)-isomer H), 7.42 (d, J=15.7 Hz, (E)-isomer H), 7.26 (t, J=9.0 Hz, 2ArH), 5.07 (s, NH).

[0390] Example 3.9, (E)-Imino(pyridin-2-yl)(2,4,6-trifluorophenylvinyl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-23)

[0391]

[0392] Diethyl((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.1.1 to 3.1.3.

[0393] Using the above reaction (5)-1, diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.50 g, 1.71 mmol) was fully dissolved in THF, and then 2,4,6-trifluorobenzaldehyde (0.33 g, 2.05 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (1.30 mL, 2.56 mmol) to synthesize white powdery compound 1-23 (0.44 g, 86%): R f =0.34 (EtOAc 4 / n-hexane 1); 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 4.7 Hz, ArH), 8.08-8.16 (m, 2ArH), 7.64-7.67 (m, ArH), 7.53 (d, J = 15.7 Hz, (E)-isomer H), 7.36-7.42 (m, 2ArH, (E)-isomer H), 5.06 (s, NH).

[0394] Example 3.10, (E)-(2-fluorophenylvinyl)(imino)(pyridin-2-yl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-24)

[0395]

[0396] Diethyl((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.1.1 to 3.1.3.

[0397] Using the above reaction (5)-1, diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.90 g, 3.08 mmol) was fully dissolved in THF, and then 2-fluorobenzaldehyde (0.39 g, 3.69 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (2.30 mL, 4.62 mmol) to synthesize white powdery compound 1-24 (0.47 g, 98%): R f =0.34 (EtOAc 4 / n-hexane 1); 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 4.6 Hz, ArH), 8.08-8.17 (m, 2ArH), 7.87-7.92 (m, ArH), 7.49-7.69 (m, 2ArH, (E)-isomer 2H), 7.25-7.35 (m, 2ArH), 4.94 (s, NH).

[0398] Example 3.11, (E)-Imino(3-methoxypyridin-2-yl)(2-(trifluoromethyl)phenylvinyl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-25)

[0399] 3.11.1 Synthesis of 3-methoxy-2-(methylthio)pyridine

[0400]

[0401] Using the above reaction (1), 2-bromo-3-methoxypyridine (0.20 g, 1.06 mmol) was fully dissolved in DMF, and then sodium thiomethoxide (0.15 g, 2.13 mmol) was reacted to synthesize transparent oily 3-methoxy-2-(methylthio)pyridine (0.096 g, 58%): R f =0.50 (n-hexane 9: EtOAc 1); 1 H NMR (400MHz, DMSO-d6) δ8.06 (dd, J = 1.2, 4.8 Hz, ArH), 7.26 (dd, J = 1.2, 8.1 Hz, ArH), 7.10 (dd, J = 4.8, 8.1 Hz, ArH), 3.84 (s, OCH3), 2.43 (s, CH3).

[0402] 3.11.2. Imino (3-methoxypyridin-2-yl)(methyl)-λ 6 -sulfinyl imide (imino (3-methoxypyridin-2-yl) (methyl) -λ6 Synthesis of -sulfanone

[0403]

[0404] Using the above reaction (2), 3-methoxy-2-(methylthio)pyridine (1.23 g, 7.92 mmol) was fully dissolved in MeOH, and then diacetoxyiodobenzene (5.87 g, 18.23 mmol) and ammonium carbonate (1.14 g, 11.89 mmol) were reacted to synthesize imino (3-methoxypyridin-2-yl) (methyl)-λ 6 -sulfinyl imine (0.97 g, 66%): R f =0.21 (DCM 4: acetone 1); 1 H NMR (400MHz, DMSO-d6) δ8.17(dd,J=1.1,4.5Hz,ArH),7.76(dd,J=1.0,8.5Hz,ArH),7.63(dd,J=4.5,8.5Hz,ArH),4.16(s,NH),3.96(s,OCH3),3.24(s,CH3).

[0405] 3.11.3. (3-methoxypyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide ((3-methoxypyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 Synthesis of -sulfanone

[0406]

[0407] Using the above reaction (3), hexamethyldisilazane (1.23 mL, 5.85 mmol) was added to imino(3-methoxypyridin-2-yl)(methyl)-λ 6 -sulfinyl imide (0.22 g, 1.17 mmol) was added to synthesize (3-methoxypyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide (0.25 g, 81%): R f =0.69 (DCM 4: acetone 1); 1H NMR (400MHz, DMSO-d6) δ8.18 (dd, J=1.2, 4.5Hz, ArH), 7.74 (dd, J=1.0, 8.4Hz, ArH) ,7.63(dd,J=4.4,8.4Hz,ArH),3.93(s,OCH3),3.19(s,CH3),0.00(s,Si(OCH3)3).

[0408] 3.11.4 Synthesis of diethyl ((3-methoxypyridine-2-sulfonimidoyl)methyl)phosphonate

[0409]

[0410] Using the above reaction (4), (3-methoxypyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide (0.24 g, 0.95 mmol) was fully dissolved in THF, and then diethyl chlorophosphate (0.19 mL, 1.33 mmol) was reacted with 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (1.04 mL, 2.09 mmol) to synthesize yellow transparent oily diethyl ((3-methoxypyridine-2-sulfonylimino)methyl)phosphonate (0.19 g, 60%): R f =0.20 (DCM 4: acetone 1); 1 H NMR(400MHz,DMSO-d6)δ8.17-8.21(m,ArH),7.76(d,J=8.4Hz,ArH),7.64(td,J=4.6,9.20Hz,ArH),4.60(s,NH ),4.24-4.40(m,SCH2P),3.97-4.06(m,P(OCH2CH3)2),3.96(s,OCH3),1.14(td,J=1.0,7.0Hz,P(OCH2CH3)2).

[0411] 3.11.5. (E)-Imino(3-methoxypyridin-2-yl)(2-(trifluoromethyl)phenylvinyl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-25)

[0412]

[0413] Using the above reaction (5)-1, diethyl ((3-methoxypyridine-2-sulfonylimino)methyl)phosphonate (0.13 g, 0.39 mmol) was fully dissolved in THF, and then 2-(trifluoromethyl)benzaldehyde (0.082 g, 0.47 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.24 mL, 1.2 mmol) to synthesize compound 1-25 (0.044 g, 33%) as a white powder: R f =0.69 (DCM 4: acetone 1); 1 H NMR (400 MHz, DMSO-d6) δ8.20 (dd, J=1.2, 4.5 Hz, ArH), 8.12 (d, J=7.8 Hz, ArH), 7.84-7.89 (m, ArH, (E)-isomer H), 7.74-7.78 (m, 2ArH), 7.62-7.69 (m, 2ArH, (E)-isomer H), 4.81 (s, NH), 3.92 (s, OCH3).

[0414] Example 3.12, (E)-Imino(4-methoxypyridin-2-yl)(2-(trifluoromethyl)phenylvinyl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-26)

[0415] 3.12.1 Synthesis of 4-methoxy-2-(methylthio)pyridine

[0416]

[0417] Using the above reaction (1), 2-bromo-4-methoxypyridine (1.00 g, 5.32 mmol) was fully dissolved in DMF, and then sodium thiomethoxide (0.75 g, 10.6 mmol) was reacted to synthesize transparent oily 4-methoxy-2-(methylthio)pyridine (0.36 g, 44%): R f =0.20 (n-hexane 9: EtOAc 1); 1 H NMR (400MHz, DMSO-d6) δ8.22 (d, J = 5.8 Hz, ArH), 6.83 (d, J = 2.2 Hz, ArH), 6.71 (dd, J = 2.2, 5.8, ArH), 3.81 (s, OCH3), 2.49 (s, CH3).

[0418] 3.12.2. Imino (4-methoxypyridin-2-yl)(methyl)-λ 6-sulfinyl imide (imino (4-methoxypyridin-2-yl) (methyl) -λ 6 Synthesis of -sulfanone

[0419]

[0420] Using the above reaction (2), 4-methoxy-2-(methylthio)pyridine (0.36 g, 2.33 mmol) was fully dissolved in MeOH, and then diacetoxyiodobenzene (1.72 g, 5.35 mmol) was reacted with ammonium carbonate (0.34 g, 3.49 mmol) to synthesize imino(4-methoxypyridin-2-yl)(methyl)-λ in the form of a white solid. 6 -sulfinyl imide (0.33 g, 75%): R f =0.32 (EtOAc 10:MeOH 1); 1 H NMR (400MHz, DMSO-d6) δ8.51 (d, J = 5.6 Hz, ArH), 7.59 (d, J = 2.4 Hz, ArH), 7.19 (dd, J = 2.5, 5.6 Hz, ArH), 4.41 (s, NH), 3.92 (s, OCH3), 3.14 (s, CH3).

[0421] 3.12.3. (4-methoxypyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfenyl imide ((4-methoxypyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 Synthesis of -sulfanone

[0422]

[0423] Using the above reaction (3), hexamethyldisilazane (0.66 mL, 3.14 mmol) was added to imino(4-methoxypyridin-2-yl)(methyl)-λ 6 -sulfinyl imide (0.33 g, 2.09 mmol) to synthesize pale yellow (4-methoxypyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imine (0.54 g, 100%): R f =0.70 (EtOAc 10:MeOH 1); 1H NMR (400MHz, DMSO-d6) δ 8.54 (d, J = 5.6 Hz, ArH), 7.47 (d, J = 2.4 Hz, ArH), 7.21 (dd, J = 2.5, 5.6 Hz, ArH), 3.93 (s, OCH3), 3.14 (s, CH3) 0.00 (s, Si (OCH3) 3).

[0424] 3.12.4 Synthesis of diethyl((4-methoxy-N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate

[0425]

[0426] Using the above reaction (4), (4-methoxypyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide (0.54 g, 2.10 mmol) was fully dissolved in THF, and then diethyl chlorophosphate (0.36 mL, 2.52 mmol) was reacted with 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (2.31 mL, 4.62 mmol) to synthesize transparent oily diethyl ((4-methoxy-N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.56 g, 67%): R f =0.42 (EtOAc 10:MeOH 1); 1 H NMR (400MHz, DMSO-d6) δ8.53-8.55(m,ArH),7.60(d,J=2.4Hz,ArH),7.45(d,J=2.4Hz,ArH),7.22(dd,J=2.5,5.6Hz,ArH ),4.16-4.29(m,SCH2P),3.94-4.04(m,P(OCH2CH3)2),3.93(s,OCH3),1.12-1.18(m,P(OCH2CH3)2),0.03(s,Si(CH3)3).

[0427] 3.12.5. (E)-Imino(4-methoxypyridin-2-yl)(2-(trifluoromethyl)phenylvinyl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-26)

[0428]

[0429] Using the above reaction (5)-1, diethyl ((4-methoxy-N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.38 g, 0.96 mmol) was fully dissolved in THF, and then 2-(trifluoromethyl)benzaldehyde (0.15 mL, 1.16 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.58 mL, 1.16 mmol) to synthesize compound 1-26 (0.17 g, 51%) as a white powder: R f =0.34 (EtOAc 100%); 1 HNMR (400MHz, DMSO-d6) δ8.51 (d, J = 5.6 Hz, ArH), 8.06 (d, J = 7.8 Hz, ArH), 7.80-7.84 (m, ArH, (E)-isomer H), 7.73 (t, J = 7.5 Hz, ArH), 7.62-7.67 (m, 2ArH, (E)-isomer H), 7.21 (dd, J = 2.5, 5.6 Hz, ArH), 4.99 (s, NH), 3.93 (s, OCH3); 13 CNMR(100MHz,DMSO-d6)δ167.2,162.5,151.6,136.5,133.8,133.6,131.2,129.5,127.7(q,J C-F =29.6Hz),126.7(q,J C-F =5.6Hz),124.5(q,J C-F =272.1Hz,113.1,107.8,56.6.

[0430] Example 3.13, (E)-(2-chlorophenylvinyl)(imino)(4-methoxypyridin-2-yl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-30)

[0431]

[0432] Diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.12.1 to 3.12.4.

[0433] Using the above reaction (5)-1, diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.091 g, 0.23 mmol) was fully dissolved in THF, and then 2-chlorobenzaldehyde (0.03 mL, 0.28 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.14 mL, 0.28 mmol) to synthesize compound 1-30 (0.030 g, 42%) as a white powder: R f =0.21 (EtOAc 100%); 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 5.6 Hz, ArH), 7.96 (dd, J = 1.5, 7.8 Hz, ArH), 7.89 (d, J = 15.8 Hz, (E)-isomer H), 7.67 (d, J = 2.4 Hz, ArH), 7.56-7.63 (m, ArH, (E)-isomer H), 7.47 (td, J = 1.6, 7.4 Hz, ArH), 7.39 (t, J = 7.5 Hz, ArH), 7.20 (dd, J = 2.5, 5.6 Hz, ArH), 4.96 (s, NH), 3.93 (s, OCH3); 13 C NMR (100MHz, DMSO-d6) δ167.3,162.3,151.7,149.1,147.9,138.9,135.8,134.9,132.2,127.2,113.3,107.8,56.6.

[0434] Example 3.14, (E)-(2-fluorophenylvinyl)(imino)(4-methoxypyridin-2-yl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-31)

[0435]

[0436] Diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.12.1 to 3.12.4.

[0437] Using the above reaction (5)-1, diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.31 g, 0.78 mmol) was fully dissolved in THF, and then 2-fluorobenzaldehyde (0.10 mL, 0.94 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.47 mL, 0.94 mmol) to synthesize 1-31 (0.057 g, 25%) as a white powder: R f=0.27 (EtOAc 100%); 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 5.6 Hz, ArH), 7.89 (t, J = 7.6 Hz, ArH), 7.64-7.68 (m, ArH, (E)-isomer H), 7.48-7.54 (m, ArH, (E)-isomer H), 7.25-7.34 (m, 2ArH), 7.19 (dd, J = 2.4, 5.6 Hz, ArH), 4.93 (s, NH), 3.93 (s, OCH3); 13 CNMR(100MHz,DMSO-d6)δ167.2,162.6,162.2,159.7,151.6,134.0(d,J C-F =3.9Hz),133.4(d,J C-F =8.8Hz),131.8(d,J C-F =5.4Hz),130.2(d,J C-F =1.9Hz),125.6(d,J C-F =3.4Hz),120.9(d,J C-F =11.1Hz),116.5(d,J C-F =21.4Hz),113.0,107.8,56.6.

[0438] Example 3.15, (E)-(3-chloropyridin-2-yl)(2-chlorophenylvinyl)(imino)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-38)

[0439] 3.15.1. Synthesis of 3-chloro-2-(methylthio)pyridine

[0440]

[0441] Using the above reaction (1), 3-chloro-2-fluoropyridine (1.00 g, 3.60 mmol) was fully dissolved in DMF, and then sodium thiomethoxide (0.53 g, 7.60 mmol) was reacted to synthesize transparent oily 3-chloro-2-(methylthio)pyridine (0.85 g, 70%): R f =0.69 (n-hexane 5: EtOAc 1); 1H NMR (400 MHz, DMSO-d6) δ 8.46 (dd, J = 1.3, 4.7 Hz, ArH), 7.84 (dd, J = 1.3, 7.9 Hz, ArH), 7.18 (dd, J = 4.7, 7.9 Hz, ArH), 2.52 (s, CH3).

[0442]

[0443] 3.15.2. (3-chloropyridin-2-yl)(imino)-λ 6 -sulfenyl imide ((3-chloropyridin-2-yl)(imino)(methyl)-λ 6 Synthesis of -sulfanone

[0444] Using the above reaction (2), 3-chloro-2-(methylthio)pyridine (0.20 g, 1.23 mmol) was fully dissolved in MeOH, and then diacetoxyiodobenzene (0.91 g, 2.82 mmol) was reacted with ammonium carbonate (0.18 g, 1.84 mmol) to synthesize white oily (3-chloropyridin-2-yl)(imino)(methyl)-λ 6 -sulfinyl imine (0.15 g, 63%): R f =0.37 (EtOAc 100%); 1 H NMR (400MHz, DMSO-d6) δ8.60 (dd, J = 1.2, 4.6 Hz, ArH), 8.19 (dd, J = 1.2, 8.1 Hz, ArH), 7.67 (dd, J = 4.5, 8.1 Hz, ArH), 4.64 (s, NH), 3.35 (s, CH3).

[0445] 3.15.3. (3-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide ((3-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 Synthesis of -sulfanone

[0446]

[0447] Using the above reaction (3), hexamethyldisilazane (0.24 mL, 1.16 mmol) was added to (3-chloropyridin-2-yl)(imino)(methyl)-λ 6-sulfinyl imide (0.15 g, 0.77 mmol) was added to synthesize (3-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide (0.19 g, 95%): R f =0.67 (n-hexane 1: EtOAc 1); 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (dd, J = 1.1, 4.5 Hz, ArH), 8.17 (dd, J = 1.2, 8.1 Hz, ArH), 7.67 (dd, J = 4.6, 8.1 Hz, ArH), 3.31 (s, CH3), 0.02 (s, Si (OCH3) 3).

[0448] 3.15.4. Synthesis of diethyl((3-chloropyridine-2-sulfonimidoyl)methyl)phosphonate

[0449]

[0450] Using the above reaction (4), (3-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide (0.20 g, 0.73 mmol) was fully dissolved in THF, and then diethyl chlorophosphate (0.15 mL, 1.02 mmol) was reacted with 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (0.80 mL, 1.61 mmol) to synthesize yellow oily diethyl ((3-chloropyridine-2-sulfonylimino)methyl)phosphonate (0.061 g, 26%): R f =0.35 (EtOAc 10:MeOH 1); 1 H NMR (400MHz, DMSO-d6) δ8.59 (dd, J=1.2, 4.6Hz, ArH), 8.18 (dd, J=1.2, 8.1Hz, ArH), 7.67 (dd, J=4.6, 8.1 Hz,ArH),4.62(s,NH),4.11-4.19(m,SCH2P),3.91-4.04(m,P(OCH2CH3)2),1.20-1.30(m,P(OCH2CH3)2).

[0451] 3.15.5. (E)-(3-chloropyridin-2-yl)(2-chlorophenylvinyl)(imino)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-38)

[0452]

[0453] Using the above reaction (5)-1, diethyl ((3-chloropyridine-2-sulfonylimino)methyl)phosphonate (0.16 g, 0.48 mmol) was fully dissolved in THF, and then 2-chlorobenzaldehyde (0.06 mL, 0.58 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.29 mL, 0.58 mmol) to synthesize compound 1-38 (0.017 g, 11%) as a white powder: R f =0.46 (EtOAc 100%); 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (dd, J = 1.3, 4.5 Hz, ArH), 8.19 (dd, J = 1.3, 8.1 Hz, ArH), 8.03 (dd, J = 1.6, 7, 7 Hz, ArH), 7.95 (d, J = 15.3 Hz, (E)-isomer H), 7.66-7.73 (m, ArH, (E)-isomer H), 7.59 (dd, J = 1.2, 8.0 Hz, ArH), 7.42-7.52 (m, 2ArH), 5.26 (s, NH); 13 C NMR (100MHz, DMSO-d6) δ157.0,147.4,141.5,137.8,134.4,132.8,131.2,130.9,130.6,129.5,128.6,128.4,128.3.

[0454] Example 3.16, (E)-(2-chlorophenylvinyl)(imino)(5-methoxypyridin-2-yl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-39)

[0455] 3.16.1. Synthesis of 5-methoxy-2-(methylthio)pyridine

[0456] Using the above reaction (1), 2-bromo-5-methoxypyridine (3.00 g, 15.9 mmol) was fully dissolved in DMF.

[0457]

[0458] Then sodium thiomethoxide (4.47 g, 63.8 mmol) was reacted to synthesize 5-methoxy-2-(methylthio)pyridine (0.84 g, 34%) as a transparent oil: R f =0.58 (n-hexane 3: EtOAc 1);1 H NMR (400MHz, DMSO-d6) δ8.19 (d, J = 3.0 Hz, ArH), 7.32 (dd, J = 3.0, 8.8 Hz, ArH), 7.23 (d, J = 8.8 Hz, ArH), 3.79 (s, OCH3), 2.47 (s, CH3).

[0459] 3.16.2. Imino(5-methoxypyridin-2-yl)(methyl)-λ 6 -sulfinyl imide (imino (5-methoxypyridin-2-yl) (methyl) -λ 6 Synthesis of -sulfanone

[0460]

[0461] Using the above reaction (2), 5-methoxy-2-(methylthio)pyridine (0.84 g, 5.41 mmol) was fully dissolved in MeOH, and then diacetoxyiodobenzene (4.00 g, 12.43 mmol) was reacted with ammonium carbonate (0.78 g, 8.11 mmol) to synthesize imino(5-methoxypyridin-2-yl)(methyl)-λ in the form of a white solid. 6 -sulfinyl imide (0.92 g, 91%): R f =0.32 (EtOAc 10:MeOH 1); 1 H NMR (400MHz, DMSO-d6) δ8.40 (d, J = 2.8Hz, ArH), 8.03 (d, J = 8.7Hz, ArH), 7.62 (dd, J = 2.9, 8.7Hz, ArH), 4.25 (s, NH), 3.91 (s, OCH3), 3.10 (s, CH3).

[0462] 3.16.3. (5-methoxypyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfenyl imide ((5-methoxypyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 Synthesis of -sulfanone

[0463]

[0464] Using the above reaction (3), hexamethyldisilazane (0.34 mL, 1.61 mmol) was added to imino(5-methoxypyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6-sulfinyl imide (0.20 g, 1.07 mmol) to synthesize yellow (5-methoxypyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imine (0.31 g, 100%): R f =0.90 (EtOAc 10:MeOH 1); 1 H NMR (400MHz, DMSO-d6) δ8.41(d,J=2.7Hz,ArH),7.96(d,J=8.7Hz,ArH),7.62(dd,J=2.8,8.7Hz,ArH),3.92(s,OCH3),3.10(s,CH3),0.00(s,Si(OCH3)3).

[0465] 3.16.4. Synthesis of diethyl((5-methoxypyridine-2-sulfonimidoyl)methyl)phosphonate

[0466]

[0467] Using the above reaction (4), (5-methoxypyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ6-sulfinyl imide (0.31 g, 1.21 mmol) was fully dissolved in THF, and then diethyl chlorophosphate (0.24 mL, 1.69 mmol) was reacted with 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (0.64 mL, 1.33 mmol) to synthesize transparent oily diethyl ((5-methoxypyridine-2-sulfonyl imino)methyl)phosphonate (0.17 g, 44%): R f =0.61 (EtOAc 10:MeOH 1); 1 H NMR (400MHz, DMSO-d6) δ8.40(t,J=3.0Hz,ArH),8.04(dd,J=8.8,12.1Hz,ArH),7.62(dd,J=1.9,5.8Hz,ArH),4. 56(s,NH),4.10-4.25(m,SCH2P),3.94-4.04(m,P(OCH2CH3)2),3.93(s,OCH3),1.15(q,J=7.2Hz,P(OCH2CH3)2).

[0468] 3.16.5. (E)-(2-Chlorostyryl)(Imino)(5-methoxypyridin-2-yl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-39)

[0469]

[0470] Using the above reaction (5)-1, diethyl ((5-methoxypyridine-2-sulfonylimino)methyl)phosphonate (0.19 g, 0.48 mmol) was fully dissolved in THF, and then 2-chlorobenzaldehyde (0.09 mL, 0.73 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.29 mL, 0.58 mmol) to synthesize compound 1-39 (0.030 g, 18%) as a white powder: R f =0.46 (EtOAc 100%); 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 2.8 Hz, ArH), 8.12 (d, J = 8.8 Hz, ArH), 7.94 (d, J = 7.8 Hz, ArH), 7.85 (d, J = 15.3 Hz, (E)-isomer H), 7.62 (dd, J = 2.8, 8.8 Hz, ArH), 7.53-7.57 (m, ArH, (E)-isomer H), 7.43-7.47 (m, ArH), 7.38 (t, J = 7.5 Hz, ArH), 4.80 (s, NH), 3.91 (s, OCH3); 13 C NMR (100MHz, DMSO-d6) δ157.9,152.0,138.4,136.1,134.2,133.2,132.6,130.9,130.6,129.3,128.3,123.9,121.9,56.7.

[0471] Example 3.17, (E)-(2-chlorophenylvinyl)(3-fluoropyridin-2-yl)(imino)-λ 6 -Synthesis of sulfenyl imide (chemical formula 1-40)

[0472] 3.17.1 Synthesis of 3-fluoro-2-(methylthio)pyridine

[0473]

[0474] Using the above reaction (1), 2,3-difluoropyridine (0.20 g, 1.74 mmol) was dissolved in DMF, and then sodium thiomethoxide (0.12 g, 1.74 mmol) was reacted to synthesize transparent oily 3-fluoro-2-(methylthio)pyridine (0.11 g, 45%): R f =0.64 (n-hexane 5: EtOAc 1);1 H NMR (400MHz, DMSO-d6) δ8.28 (d, J=4.8Hz, ArH), 7.20-7.26 (m, ArH), 6.98-7.02 (m, ArH), 2.59 (s, CH3).

[0475] 3.17.2. (3-fluoropyridin-2-yl)(imino)(methyl)-λ 6 -sulfenyl imide ((3-fluoropyridin-2-yl)(imino)(methyl)-λ 6 Synthesis of -sulfanone

[0476]

[0477] Using the above reaction (2), 3-fluoro-2-(methylthio)pyridine (0.32 g, 2.25 mmol) was fully dissolved in MeOH, and then diacetoxyiodobenzene (1.67 g, 5.17 mmol) was reacted with ammonium carbonate (0.32 g, 3.37 mmol) to synthesize (3-fluoropyridin-2-yl)(imino)(methyl)-λ in the form of a white solid. 6 -sulfinyl imine (0.25 g, 64%): R f =0.26 (EtOAc 100%); 1 H NMR (400MHz, DMSO-d6) δ8.51 (d, J = 4.5Hz, ArH), 8.01 (t, J = 9.0Hz, ArH), 7.74-7.78 (m, ArH), 4.75 (s, NH), 3.27 (s, CH3).

[0478] 3.17.3. (3-Fluoropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide ((3-fluoropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 Synthesis of -sulfanone

[0479]

[0480] Using the above reaction (3), hexamethyldisilazane (0.45 mL, 2.17 mmol) was added to (3-fluoropyridin-2-yl)(imino)(methyl)-λ 6 -sulfinyl imide (0.25 g, 1.45 mmol) was added to synthesize (3-fluoropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6-sulfinyl imide (0.33 g, 93%): R f =0.77 (EtOAc 100%); 1 H NMR (400MHz, DMSO-d6) δ8.52 (d, J = 4.4 Hz, ArH), 7.99 (t, J = 9.3 Hz, ArH), 7.74-7.78 (m, ArH), 3.26 (s, CH3), 0.02 (s, Si (OCH3) 3).

[0481] 3.17.4 Synthesis of diethyl((3-fluoro-N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate

[0482]

[0483] Using the above reaction (4), (3-fluoropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide (0.33 g, 1.35 mmol) was fully dissolved in THF, and then diethyl chlorophosphate (0.27 mL, 1.89 mmol) was reacted with 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (1.49 mL, 2.97 mmol) to synthesize translucent oily diethyl ((3-fluoro-N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.28 g, 54%): R f =0.44 (EtOAc 100%); 1 H NMR(400MHz,DMSO-d6)δ8.53(dt,J=1.3,4.4Hz,ArH),7.97-8.02(m,ArH),7.75-7.79(m,ArH),4.38(t,J=15.6Hz,SCH HP), 4.21 (t, J = 16.1Hz, SCHHP), 3.92-4.04 (m, P (OCH2CH3)2), 1.16 (t, J = 7.0Hz, P (OCH2CH3)2), 0.04 (s, Si (OCH3)3).

[0484] 3.17.5. (E)-(2-Chlorostyryl)(3-fluoropyridin-2-yl)(imino)-λ 6 -Synthesis of sulfenyl imide (chemical formula 1-40)

[0485]

[0486] Using the above reaction (5)-1, diethyl ((3-fluoro-N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.28 g, 0.73 mmol) was fully dissolved in THF, and then 2-chlorobenzaldehyde (0.14 mL, 1.10 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.44 mL, 0.88 mmol) to synthesize compound 1-40 (0.038 g, 18%) as a white powder: R f =0.54 (EtOAc 100%); 1 H NMR (400 MHz, DMSO-d6) δ8.53 (d, J=4.5 Hz, ArH), 7.96-8.02 (m, 2ArH, (E)-isomer H), 7.77-7.80 (m, ArH), 7.65 (d, J=15.3 Hz, (E)-isomer H), 7.58-7.60 (m, ArH), 7.49 (td, J=1.4, 7.4 Hz, ArH), 7.42 (t, J=7.2 Hz, ArH), 5.34 (s, NH).

[0487] Example 3.18, (E)-(3-chloropyridin-4-yl)(2-chlorophenylvinyl)(imino)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-41)

[0488] 3.18.1. Synthesis of 3-chloro-2-(methylthio)pyridine

[0489]

[0490] Using the above reaction (1), 4-bromo-3-chloropyridine (0.80 g, 4.16 mmol) was fully dissolved in DMF, and then sodium thiomethoxide (0.29 g, 4.16 mmol) was reacted to synthesize transparent oily 3-chloro-2-(methylthio)pyridine (0.53 g, 79%): R f =0.15 (n-hexane 5: EtOAc 1); 1 H NMR (400MHz, DMSO-d6) δ 8.46 (s, ArH), 8.40 (d, J = 5.3 Hz, ArH), 7.34 (d, J = 5.3 Hz, ArH), 2.55 (s, CH3).

[0491] 3.18.2. (3-chloropyridin-2-yl)(imino)(methyl)-λ 6-sulfenyl imide ((3-chloropyridin-2-yl)(imino)(methyl)-λ 6 Synthesis of -sulfanone

[0492]

[0493] Using the above reaction (2), 3-chloro-2-(methylthio)pyridine (0.53 g, 3.30 mmol) was fully dissolved in MeOH, and then diacetoxyiodobenzene (2.44 g, 7.58 mmol) was reacted with ammonium carbonate (0.48 g, 4.94 mmol) to synthesize (3-chloropyridin-2-yl)(imino)(methyl)-λ in the form of a white solid. 6 -sulfinyl imine (0.47 g, 100%): R f =0.24 (EtOAc 100%); 1 H NMR (400MHz, DMSO-d6) δ8.86 (s, ArH), 8.81 (d, J = 5.0 Hz, ArH), 7.97 (d, J = 5.0 Hz, ArH), 4.96 (s, NH), 3.27 (s, CH3).

[0494] 3.18.3. (3-Chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide ((3-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 Synthesis of -sulfanone

[0495]

[0496] Using the above reaction (3), hexamethyldisilazane (0.16 mL, 0.79 mmol) was added to (3-chloropyridin-2-yl)(imino)(methyl)-λ 6 -sulfinyl imide (0.10 g, 0.12 mmol) was added to synthesize (3-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imine (0.15 g, 100%): R f =0.73 (EtOAc 100%); 1 H NMR (400MHz, DMSO-d6) δ 8.88 (s, ArH), 8.82 (d, J = 5.0 Hz, ArH), 7.96 (d, J = 5.0 Hz, ArH), 3.30 (s, CH3), 0.00 (s, Si (CH3) 3).

[0497] 3.18.4 Synthesis of diethyl((3-chloro-N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate

[0498]

[0499] Using the above reaction (4), (3-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide (0.50 g, 1.91 mmol) was fully dissolved in THF, and then diethyl chlorophosphate (0.39 mL, 2.67 mmol) was reacted with 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (2.10 mL, 4.19 mmol) to synthesize yellow oily diethyl ((3-chloro-N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.62 g, 81%): R f =0.53 (EtOAc 100%); 1 H NMR(400MHz,DMSO-d6)δ8.87(s,ArH),8.82(d,J=5.0Hz,ArH),7.93(d,J=4.9Hz,ArH),4.27-4.4 3(m,SCH2P),3.95-4.04(m,P(OCH2CH3)2),1.22(t,J=7.0Hz,P(OCH2CH3)2),0.03(s,Si(CH3)3).

[0500] 3.18.5. (E)-(3-chloropyridin-4-yl)(2-chlorophenylvinyl)(imino)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-41)

[0501]

[0502] Using the above reaction (5)-1, the compound of reaction formula 3-4 (0.30 g, 0.74 mmol) was fully dissolved in THF, and then 2-chlorobenzaldehyde (0.11 mL, 1.11 mmol) was reacted with 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (0.44 mL, 0.89 mmol) to synthesize compound 1-41 (0.025 g, 11%) as a white powder: R f =0.54 (EtOAc 100%); 1H NMR (400 MHz, DMSO-d6) δ 8.82-8.83 (m, 2ArH), 8.08 (d, J = 5.0, ArH), 8.02 (d, J = 15.2, (E)-isomer H), 7.94 (d, J = 7.7 Hz, ArH), 7.59 (d, J = 8.0 Hz, ArH), 7.54 (d, J = 15.2 Hz, (E)-isomer H), 7.49 (t, J = 7.8 Hz, ArH), 7.41 (t, J = 7.6 Hz, ArH), 5.56 (s, NH).

[0503] Example 3.19, (E)-(5-chloropyridin-2-yl)(2-chlorophenylvinyl)(imino)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-42)

[0504]

[0505] Diethyl ((5-chloropyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.7.1 to 3.7.4.

[0506] Using the above reaction (5)-1, diethyl ((5-chloropyridine-2-sulfonylimino)methyl)phosphonate (0.16 g, 0.50 mmol) was fully dissolved in THF, and then 2-chlorobenzaldehyde (0.08 mL, 0.74 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.30 mL, 0.59 mmol) to synthesize compound 1-42 (0.070 g, 45%) as a white powder: R f =0.69 (EtOAc 100%); 1 H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 2.1 Hz, ArH), 8.24 (dd, J = 2.4, 8.4 Hz, ArH), 8.17 (d, J = 8.5 Hz, ArH), 7.96 (dd, J = 1.4, 7.8 Hz, ArH), 7.91 (d, J = 15.3 Hz, (E)-isomer H), 7.56-7.62 (m, ArH, (E)-isomer H), 7.47 (td, J = 1.4, 7.5 Hz, ArH), 7.39 (t, J = 7.2 Hz, ArH), 5.10 (s, NH); 13 C NMR (100MHz, DMSO-d6) δ159.2,148.9,138.8,137.5,134.6,134.3,132.8,132.1,130.7,130.6,129.4,128.3,123.5.

[0507] Example 3.20, (E)-(2-chlorophenylvinyl)(imino)(3-methoxypyridin-2-yl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-43)

[0508]

[0509] Diethyl ((3-methoxypyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.11.1 to 3.11.4.

[0510] Using the above reaction (5)-1, diethyl ((3-methoxypyridine-2-sulfonylimino)methyl)phosphonate (0.19 g, 0.57 mmol) was fully dissolved in THF, and then 2-chlorobenzaldehyde (0.10 mL, 0.86 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.34 mL, 0.69 mmol) to synthesize 1-43 (0.044 g, 25%) as a white powder: R f =0.35 (DCM 4: acetone 1); 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (dd, J = 1.0, 4.5 Hz, ArH), 8.01 (dd, J = 1.6, 7.7 Hz, ArH), 7.93 (d, J = 15.2 Hz, (E)-isomer H), 7.74-7.76 (m, ArH), 7.64 (dd, J = 4.5, 8.4 Hz, ArH), 7.56-7.60 (m, ArH, (E)-isomer H), 7.48 (td, J = 1.6, 7.4 Hz, ArH), 7.42 (t, J = 7.5, ArH), 4.77 (s, NH), 3.95 (s, OCH3); 13 C NMR (100MHz, DMSO-d6) δ153.0,148.5,140.1,137.7,134.3,132.6,131.4,131.1,130.6,129.4,128.9,128.4,122.7,56.8.

[0511] Example 3.21, (E)-(2-fluorophenylvinyl)(imino)(3-methoxypyridin-2-yl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-44)

[0512]

[0513] Diethyl ((3-methoxypyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.11.1 to 3.11.4.

[0514] Using the above reaction (5)-1, diethyl ((3-methoxypyridine-2-sulfonylimino)methyl)phosphonate (0.20 g, 0.61 mmol) was fully dissolved in THF, and then 2-fluorobenzaldehyde (0.10 mL, 0.92 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.37 mL, 0.74 mmol) to synthesize 1-44 (0.18 g, 65%) as a white powder: R f =0.56 (DCM 4: acetone 1); 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (dd, J = 1.1, 4.5 Hz, ArH), 7.93 (td, J = 1.5, 7.8 Hz, ArH), 7.75 (dd, J = 1.0, 8.5 Hz, ArH), 7.69 (d, J = 15.4 Hz, (E)-isomer H), 7.64 (dd, J = 4.5, 8.4 Hz, ArH), 7.50-7.55 (m, ArH, (E)-isomer H), 7.28-7.36 (m, 2ArH), 4.75 (s, NH), 3.94 (s, OCH3); 13 C NMR(100MHz,DMSO-d6)δ152.9,148.6,140.0,134.7(d,J C-F =3.3Hz),133.3(d,J C-F =8.8Hz),130.9(d,J C-F =5.7Hz),130.3,128.9,125.6(d,J C-F =3.4Hz),122.7,121.1(d,J C-F =10.9Hz),116.8,116.5,56.8.

[0515] Example 3.22, (E)-(4-chloropyridin-2-yl)(2-chlorophenylvinyl)(imino)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-45)

[0516] 3.22.1. (4-chloropyridin-2-yl)(imino)(methyl)-λ 6 -sulfenyl imide ((4-Chloropyridin-2-yl)(imino)(methyl)-λ 6 Synthesis of -sulfanone

[0517]

[0518] Using the above reaction (2), 4-chloro-2-(methylthio)pyridine (0.20 g, 1.25 mmol) was fully dissolved in MeOH, and then diacetoxyiodobenzene (0.93 g, 2.88 mmol) was reacted with ammonium carbonate (0.18 g, 1.88 mmol) to synthesize (4-chloropyridin-2-yl)(imino)(methyl)-λ in the form of a white solid. 6 -sulfinyl imide (0.18 g, 77%): R f =0.58 (EtOAc 10:MeOH 1); 1 H NMR (400MHz, DMSO-d6) δ8.59 (dd, J=1.0, 4.5Hz, ArH), 8.18 (dd, J=1.1, 8.1Hz, ArH), 7.65-7.68 (m, ArH), 4.62 (s, NH), 3.35 (s, CH3).

[0519] 3.22.2. (4-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide ((4-Chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 Synthesis of -sulfanone

[0520]

[0521] Using the above reaction (3), hexamethyldisilazane (0.30 mL, 1.44 mmol) was added to (4-chloropyridin-2-yl)(imino)(methyl)-λ 6 -sulfinyl imide (0.18 g, 0.96 mmol) was added to synthesize (4-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imine (0.29 g, 100%): R f =0.75 (EtOAc 100%); 1 H NMR (400MHz, DMSO-d6) δ 8.73 (d, J = 5.2 Hz, ArH), 8.02 (d, J = 2.0 Hz, ArH), 7.84 (dd, J = 2.0, 5.2 Hz, ArH), 3.19 (s, CH3), 0.01 (s, Si (OCH3) 3).

[0522] 3.22.3. Synthesis of Diethyl((4-chloro-N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate

[0523]

[0524] Using the above reaction (4), (4-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide (0.29 g, 1.10 mmol) was fully dissolved in THF, and then diethyl chlorophosphate (0.22 mL, 1.53 mmol) was reacted with 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (1.21 mL, 2.41 mmol) to synthesize yellow oily diethyl ((4-chloro-N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.28 g, 65%): R f =0.52 (EtOAc 100%); 1 H NMR (400MHz, DMSO-d6) δ8.73(d,J=5.2Hz,ArH),8.01(d,J=1.6Hz,ArH),7.84(dd,J=2.0,5.2Hz,ArH),4. 27(d,J=16.0Hz,SCH2P),3.93-4.01(m,P(OCH2CH3)2),1.12-1.17(m,P(OCH2CH3)2),0.04(s,Si(CH3)3).

[0525] 3.22.4. (E)-(4-chloropyridin-2-yl)(2-chlorophenylvinyl)(imino)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-45)

[0526]

[0527] Using the above reaction (5)-1, diethyl ((4-chloro-N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.28 g, 0.71 mmol) was fully dissolved in THF, and then 2-chlorobenzaldehyde (0.12 mL, 1.07 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.43 mL, 0.85 mmol) to synthesize compound 1-45 (0.15 g, 53%) as a white solid: R f =0.26 (n-hexane 1: EtOAc 1);1 H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 5.2 Hz, ArH), 8.21 (d, J = 1.9 Hz, ArH), 7.91-7.97 (m, ArH, (E)-isomer H), 7.82 (dd, J = 1.9, 5.2 Hz, ArH), 7.56-7.64 (m, ArH, (E)-isomer H), 7.47 (td, J = 1.4, 7.4 Hz, ArH), 7.40 (t, J = 7.4 Hz, ArH), 5.17 (s, NH); 13 C NMR (100MHz, DMSO-d6) δ162.5,151.8,145.4,137.9,134.4,132.9,131.6,130.7,130.6,129.4,128.3,127.3,121.9.

[0528] Example 3.23, (E)-(2-chlorophenylvinyl)(3-fluoropyridin-4-yl)((trimethylsilyl)imino)-λ 6 -Synthesis of sulfenyl imine (Chemical Formula 1-46)

[0529] 3.23.1. Synthesis of 3-fluoro-4-(methylthio)pyridine

[0530]

[0531] Using the above reaction (1), 4-bromo-3-fluoropyridine (1.00 g, 7.60 mmol) was fully dissolved in DMF, and then sodium thiomethoxide (0.53 g, 7.60 mmol) was reacted to synthesize transparent oily 3-fluoro-2-(methylthio)pyridine (0.72 g, 59%): R f =0.60 (n-hexane 1: EtOAc 1); 1 H NMR (400MHz, DMSO-d6) δ 8.39 (d, J=2.1Hz, ArH), 8.33 (dd, J=1.0, 5.2Hz, ArH), 7.39 (dd, J=5.2, 6.8Hz, ArH), 2.55 (s, CH3).

[0532] 3.23.2. (3-fluoropyridin-4-yl)(imino)(methyl)-λ 6 -sulfenyl imide ((3-fluoropyridin-4-yl)(imino)(methyl)-λ 6 Synthesis of -sulfanone

[0533]

[0534] Using the above reaction (2), 3-fluoro-4-(methylthio)pyridine (0.64 g, 4.43 mmol) was fully dissolved in MeOH, and then diacetoxyiodobenzene (3.29 g, 10.20 mmol) was reacted with ammonium carbonate (0.48 g, 4.94 mmol) to synthesize (3-fluoropyridin-2-yl)(imino)(methyl)-λ 6 -sulfinyl imide (0.47 g, 74%): R f =0.24 (EtOAc 100%); 1 H NMR (400MHz, DMSO-d6) δ 8.83 (d, J=1.7Hz, ArH), 8.70 (d, J=4.8Hz, ArH), 7.82 (dd, J=5.0, 5.9Hz, ArH), 5.11 (s, NH), 3.26 (s, CH3).

[0535] 3.23.3. (3-fluoropyridin-4-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide ((3-fluoropyridin-4-yl)(methyl)((trimethylsilyl)imino)-λ 6 Synthesis of -sulfanone

[0536]

[0537] Using the above reaction (3), hexamethyldisilazane (1.00 mL, 4.77 mmol) was added to (3-fluoropyridin-2-yl)(imino)(methyl)-λ 6 -sulfinyl imide (0.55 g, 3.18 mmol) was added to synthesize (3-fluoropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imine (0.76 g, 96%): R f =0.76 (EtOAc 100%); 1 H NMR (400MHz, DMSO-d6) δ 8.85-8.86 (m, ArH), 8.70-8.72 (m, ArH), 7.78-7.82 (m, ArH), 3.28 (s, CH3), 0.01 (s, Si(CH3)3).

[0538] 3.23.4. Synthesis of Diethyl((3-fluoro-N-(trimethylsilyl)pyridine-4-sulfonimidoyl)methyl)phosphonate

[0539]

[0540] Using the above reaction (4), (3-fluoropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide (0.76 g, 3.06 mmol) was fully dissolved in THF, and then diethyl chlorophosphate (0.62 mL, 4.29 mmol) was reacted with 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (3.37 mL, 6.74 mmol) to synthesize transparent oily diethyl (3-fluoro-N-(trimethylsilyl) pyridine-4-sulfonylimino)methyl)phosphonate (0.86 g, 73%): R f =0.52 (EtOAc 100%); 1 H NMR (400MHz, DMSO-d6) δ8.83 (d, J=1.7Hz, ArH), 8.70 (d, J=4.9Hz, ArH), 7.83 (dd, J=5.1, 6.0Hz, ArH), 5. 41 (s, NH), 4.30 (dd, J=1.6, 16.5Hz, SCH2P), 3.95-4.04 (m, P(OCH2CH3)2), 1.12-1.17 (m, P(OCH2CH3)2).

[0541] 3.23.5. (E)-(2-Chlorostyryl)(3-fluoropyridin-4-yl)((trimethylsilyl)imino)-λ 6 -Synthesis of sulfenyl imine (Chemical Formula 1-46)

[0542]

[0543] Using the above reaction (5)-1, the compound of reaction formula 3-4 (0.42 g, 1.09 mmol) was fully dissolved in THF, and then 2-chlorobenzaldehyde (0.18 mL, 1.63 mmol) was reacted with 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (0.65 mL, 1.31 mmol) to synthesize compound 1-46 (0.18 g, 45%) as a white powder: R f =0.80 (n-hexane 1: EtOAc 1); 1H NMR (DMSO-d6, 400 MHz) δ 8.81 (s, ArH), 8.72 (d, J = 4.6 Hz, ArH), 7.94-7.96 (m, ArH, (E)-isomer H), 7.88 (t, J = 5.2 Hz, ArH), 7.67 (d, J = 15.1 Hz, (E)-isomer H), 7.59 (d, J = 8.0 Hz, ArH), 7.49 (t, J = 7.5 Hz, ArH), 7.41 (t, J = 7.6 Hz, ArH), 0.11 (s, Si(CH3)3); 13 C NMR (100MHz, DMSO-d6) δ152.8, 151.0, 145.01 (d, J C-F =5.8Hz), 137.9(d, J C-F =24.2Hz), 136.7(d, J C-F =11.8Hz), 135.2, 131.9, 130.9, 130.4, 127.8 (d, J C-F =26.0Hz), 126.9, 125.6, 119.5.

[0544] Example 3.24, (E)-(2-chlorophenylvinyl)(3-fluoropyridin-4-yl)(imino)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-47)

[0545] 3.24.1. Synthesis of 3-chloro-4-(methylthio)pyridine

[0546]

[0547] Using the above reaction (1), 4-bromo-3-chloropyridine (0.80 g, 4.16 mmol) was fully dissolved in DMF, and then sodium thiomethoxide (0.29 g, 4.16 mmol) was reacted to synthesize transparent oily 3-chloro-4-(methylthio)pyridine (0.53 g, 79%): R f =0.15 (n-hexane 5: EtOAc 1); 1 H NMR (400MHz, DMSO-d6) δ 8.46 (s, ArH), 8.40 (d, J=5.3Hz, ArH), 7.34 (d, J=5.3Hz, ArH), 2.55 (s, CH3).

[0548] 3.24.2. (3-chloropyridin-4-yl)(imino)(methyl)-λ 6-sulfenyl imide ((3-chloropyridin-4-yl)(imino)(methyl)-λ 6 Synthesis of -sulfanone

[0549]

[0550] Using the above reaction (2), 3-chloro-4-(methylthio)pyridine (0.53 g, 3.30 mmol) was fully dissolved in MeOH, and then diacetoxyiodobenzene (2.44 g, 7.58 mmol) was reacted with ammonium carbonate (0.48 g, 4.94 mmol) to synthesize (3-chloropyridin-2-yl)(imino)(methyl)-λ6-sulfinyl imine (0.47 g, 74%) as a pale yellow oil: R f =0.24 (EtOAc 100%); 1 H NMR (400MHz, DMSO-d6) δ 8.86 (s, ArH), 8.81 (d, J=5.0Hz, ArH), 7.97 (d, J=5.0Hz, ArH), 4.96 (s, NH), 3.27 (s, CH3).

[0551] 3.24.3. (3-Chloropyridin-4-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide ((3-chloropyridin-4-yl)(methyl)((trimethylsilyl)imino)-λ 6 Synthesis of -sulfanone

[0552]

[0553] Using the above reaction (3), hexamethyldisilazane (0.16 mL, 0.79 mmol) was added to (3-chloropyridin-2-yl)(imino)(methyl)-λ 6 -sulfinyl imide (0.10 g, 0.12 mmol) was added to synthesize (3-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imine (0.15 g, 100%): R f =0.73 (EtOAc 100%); 1 H NMR (400MHz, DMSO-d6) δ 8.88 (s, ArH), 8.82 (d, J=5.0Hz, ArH), 7.96 (d, J=5.0Hz, ArH), 3.30 (s, CH3), 0.00 (s, Si(CH3)3).

[0554] 3.24.4. Diethyl ((3-chloro-N-(trimethylsilyl)pyridine-4-sulfonylimino)methyl)phosphonate

[0555]

[0556] Synthesis of (Diethyl((3-chloro-N-(trimethylsilyl)pyridine-4-sulfonimidoyl)methyl)phosphonate)

[0557] Using the above reaction (4), (3-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide (0.50 g, 1.91 mmol) was fully dissolved in THF, and then diethyl chlorophosphate (0.39 mL, 2.67 mmol) was reacted with 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (2.10 mL, 4.19 mmol) to synthesize light yellow oily diethyl ((3-chloro-N-(trimethylsilyl)pyridine-4-sulfonylimino)methyl)phosphonate (0.62 g, 81%): R f =0.53 (EtOAc 100%); 1 H NMR (400MHz, DMSO-d6) δ8.87 (s, ArH), 8.82 (d, J=5.0Hz, ArH), 7.93 (d, J=4.9Hz, ArH), 4.27-4.4 3(m, SCH2P), 3.95-4.04(m, P(OCH2CH3)2), 1.22(t, J=7.0Hz, P(OCH2CH3)2), 0.03(s, Si(CH3)3).

[0558] 3.24.5. (E)-(2-Chlorostyryl)(3-fluoropyridin-4-yl)(imino)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-47)

[0559]

[0560] Using the above reaction (5)-1, the compound of reaction formula 3-4 (0.42 g, 1.09 mmol) was fully dissolved in THF, and then 2-chlorobenzaldehyde (0.18 mL, 1.63 mmol) was reacted with 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (0.65 mL, 1.31 mmol) to synthesize white powder compound 1-47 (0.23 g, 58%): R f =0.29 (n-hexane 1: EtOAc 1);1 H NMR (DMSO-d6, 400 MHz) δ 8.79 (s, ArH), 8.71 (d, J = 3.2 Hz, ArH), 7.96-8.02 (m, ArH, (E)-isomer H); 7.91 (t, J = 3.6 Hz, ArH), 7.58-7.62 (m, ArH, (E)-isomer H), 7.49 (t, J = 4.9 Hz, ArH), 7.41 (t, J = 5.0 Hz, ArH), 5.69 (s, NH); 13 C NMR (100MHz, DMSO-d6) δ155.4, 153.6, 147.4 (d, J C-F =5.9Hz), 140.42(d, J C-F =24.3Hz), 139.1(d, J C-F =12.5Hz), 138.9, 134.5, 133.1, 131.5, 130.4 (d, J C-F =16.1Hz), 129.5, 128.2, 122.6 (d, J C-F =1.7Hz).

[0561] Example 3.25, (E)-(4-chloropyridin-3-yl)(2-chlorophenylvinyl)(imino)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-48)

[0562] 3.25.1. Synthesis of 4-chloro-3-(methylthio)pyridine

[0563]

[0564] Using the above reaction (1), 3-bromo-4-chloropyridine (1.00 g, 7.60 mmol) was fully dissolved in DMF, and then sodium thiomethoxide (0.53 g, 7.60 mmol) was reacted to synthesize transparent oily 4-chloro-3-(methylthio)pyridine (0.36 g, 30%): R f =0.60 (n-hexane 1: EtOAc 1); 1 H NMR (400MHz, DMSO-d6) δ 8.48 (s, ArH), 8.34 (d, J=5.2Hz, ArH), 7.53 (d, J=5.2Hz, ArH), 2.61 (s, CH3).

[0565] 3.25.2. (4-chloropyridin-3-yl)(imino)(methyl)-λ 6-sulfenyl imide ((4-chloropyridin-3-yl)(imino)(methyl)-λ 6 Synthesis of -sulfanone

[0566]

[0567] Using the above reaction (2), 4-chloro-3-(methylthio)pyridine (0.36 g, 2.28 mmol) was fully dissolved in MeOH, and then diacetoxyiodobenzene (1.69 g, 5.24 mmol) was reacted with ammonium carbonate (0.33 g, 3.42 mmol) to synthesize yellow oily (4-chloropyridin-3-yl)(imino)(methyl)-λ 6 -sulfinyl imine (0.20 g, 46%): R f =0.43 (EtOAc 10:MeOH 1); 1 H NMR (400MHz, DMSO-d6) δ9.09 (s, ArH), 8.76 (d, J=5.3Hz, ArH), 7.78 (d, J=5.2Hz, ArH), 4.89 (s, NH), 3.26 (s, CH3).

[0568] 3.25.3. (4-chloropyridin-3-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imide ((4-chloropyridin-3-yl)(methyl)((trimethylsilyl)imino)-λ 6 Synthesis of -sulfanone

[0569]

[0570] Using the above reaction (3), hexamethyldisilazane (0.33 mL, 1.59 mmol) was added to (4-chloropyridin-3-yl)(imino)(methyl)-λ 6 -sulfinyl imide (0.20 g, 1.06 mmol) was added to synthesize (4-chloropyridin-3-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfinyl imine (0.29 g, 100%): R f =0.87 (EtOAc 100%); 1 H NMR (400MHz, DMSO-d6) δ9.07 (s, ArH), 8.77 (d, J=5.3Hz, ArH), 7.80 (d, J=5.3Hz, ArH), 3.30 (s, CH3), 0.00 (s, Si(CH3)3).

[0571] 3.25.4. Synthesis of Diethyl((4-chloro-N-(trimethylsilyl)pyridine-3-sulfonimidoyl)methyl)phosphonate

[0572]

[0573] Using the above reaction (4), (4-chloropyridin-3-yl)(methyl)((trimethylsilyl)imino)-λ6-sulfinyl imide (0.50 g, 1.91 mmol) was fully dissolved in THF, and then diethyl chlorophosphate (0.39 mL, 2.67 mmol) was reacted with 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (2.10 mL, 4.19 mmol) to synthesize light yellow oily diethyl ((3-chloro-N-(trimethylsilyl)pyridine-4-sulfonyl imino)methyl)phosphonate (0.62 g, 81%): R f =0.53 (EtOAc 100%); 1 H NMR (400MHz, DMSO-d6) δ9.02 (s, ArH), 8.76 (d, J=5.3Hz, ArH), 7.79 (d, J=5.3Hz, ArH), 4.24-4 .39(m,SCH2P), 3.92-4.01(m,P(OCH2CH3)2), 1.13-1.17(m,P(OCH2CH3)2), 0.03(Si(CH3)3).

[0574] 3.25.5. (E)-(4-chloropyridin-3-yl)(2-chlorophenylvinyl)(imino)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-48)

[0575]

[0576] Using the above reaction (5)-1, the compound of reaction formula 4-4 (0.21 g, 0.52 mmol) was fully dissolved in THF, and then 2-chlorobenzaldehyde (0.09 mL, 0.77 mmol) was reacted with 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (0.31 mL, 0.62 mmol) to synthesize a white solid compound 1-48 (0.019 g, 12%): R f =0.59 (EtOAc 100%); 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, ArH), 8.76 (d, J = 5.2 Hz, ArH), 8.01 (d, J = 15.2 Hz, (E)-isomer H), 7.92 (dd, J = 1.6, 7.8 Hz, ArH), 7.75 (d, J = 5.2 Hz, ArH), 7.58 (dd, J = 1.1, 8.0 Hz, ArH), 7.54 (d, J = 15.2 Hz, (E)-isomer H), 7.48 (td, J = 1.5, 7.4 Hz, ArH), 7.38-7.42 (m, ArH), 5.48 (s, NH); 13 C NMR (DMSO-d6, 100MHz) δ154.9, 151.2, 142.4, 138.9, 136.9, 134.5, 132.9, 131.2, 130.7, 130.6, 129.5, 128.4, 127.0.

[0577] Example 3.26, (E)-Imino(5-methoxypyridin-2-yl)(2-(trifluoromethyl)phenylvinyl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-54)

[0578]

[0579] Diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.12.1 to 3.12.4.

[0580] Using the above reaction (5)-1, diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.35 g, 0.90 mmol) was fully dissolved in THF, and then 2-(trifluoromethyl)benzaldehyde (0.14 mL, 1.08 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.54 mL, 1.08 mmol) to synthesize compound 1-54 (0.13 g, 41%) as a white powder: R f =0.45 (EtOAc 100%); 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 2.9 Hz, ArH), 8.11 (d, J = 8.8 Hz, ArH), 8.03 (d, J = 7.8 Hz, ArH), 7.82 (d, J = 8.0 Hz, ArH), 7.69-7.77 (m, 2ArH), 7.60-7.65 (m, ArH, (E)-isomer H), 7.58 (d, J = 15.0 Hz, (E)-isomer H), 4.83 (s, NH), 3.91 (s, OCH3); 13 C NMR(100MHz,DMSO-d6)δ157.9,151.9,138.5,135.6,134.7,133.6,131.1,129.4,127.6(q,J C-F =29.5Hz),126.7(q,J C-F =5.5Hz),124.5(q,J C-F =272.1Hz),123.1,121.9,56.7.

[0581] Example 3.27, (E)-(2-fluorophenylvinyl)(imino)(5-methoxypyridin-2-yl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-55)

[0582]

[0583] Diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.12.1 to 3.12.4.

[0584] Using the above reaction (5)-1, diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.35 g, 1.08 mmol) was fully dissolved in THF, and then 2-fluorobenzaldehyde (0.14 mL, 1.29 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.65 mL, 1.29 mmol) to synthesize compound 1-55 (0.24 g, 76%) as a white solid: R f =0.78 (EtOAc 10:MeOH 1); 1H NMR (400 MHz, DMSO-d6) δ8.39 (d, J=2.8 Hz, ArH), 8.11 (d, J=8.8 Hz, ArH), 7.87 (t, J=7.3 Hz, ArH), 7.61-7.64 (m, ArH, (E)-isomer H), 7.46-7.50 (m, ArH, (E)-isomer H), 7.31 (t, J=10.7 Hz, ArH), 7.26 (t, J=7.6 Hz, ArH), 4.78 (s, NH), 3.91 (s, OCH3).

[0585] Example 3.28, (E)-(2-fluorophenylvinyl)(5-methoxypyridin-2-yl)(methylimino)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-56)

[0586]

[0587] (E)-(2-fluorophenylvinyl)(imino)(5-methoxypyridin-2-yl)-λ 6 -sulfenyl imide.

[0588] Sodium hydride (1.2 equivalents, 60% dispersion in mineral oil) was dissolved in anhydrous DMF and then cooled to 0°C with ice water. The synthesized (E)-(2-fluorostyryl)(imino)(5-methoxypyridin-2-yl)-λ6-sulfinyl imine (1.0 equivalent) was slowly added dropwise to the solution, then stirred for 30 minutes, and iodomethane (1.1 equivalents) was added and reacted at room temperature for 15 hours. After terminating the reaction with water, extraction was performed with water and EtOAc, a small amount of water in the organic layer was removed by anhydrous Na2SO4, the solvent was removed by reduced pressure distillation and vacuum drying was performed. Subsequently, the white solid compound 1-56 (0.02 g, 65%) was synthesized by separation and purification by column chromatography: R f =0.70 (EtOAc 10:MeOH 1); 1H NMR (400 MHz, DMSO-d6) δ8.44 (d, J=2.9 Hz, ArH), 8.09 (d, J=8.7 Hz, ArH), 7.90 (td, J=1.5, 7.9 Hz, ArH), 7.63 (dd, J=2.9, 8.8 Hz, ArH), 7.59 (d, J=15.6 Hz, (E)-isomer H), 7.48-7.54 (m, ArH), 7.39 (d, J=15.6 Hz, (E)-isomer H), 7.31-7.34 (m, ArH), 7.27 (t, J=7.6 Hz, ArH), 3.91 (s, OCH3), 2.62 (s, NCH3).

[0589] Example 4: Synthesis of sulfenyl imide derivatives of pyridine where both A and B are present

[0590] As an embodiment of the present invention, when A and B in Chemical Formula 1 are both pyridine, the synthesis process of the sulfenyl imine derivative is shown in the following Reaction Formula 4.

[0591] [Reaction 4]

[0592]

[0593] (5)-2. (E)-Imino(pyridin-2-yl)(2-(pyridin-2-yl)vinyl)-λ substituted by reaction with a pyridinecarboxaldehyde derivative 6 -Synthesis of sulfenyl imine derivatives

[0594]

[0595] In the same manner as reactions (1) to (4) of Example 3, substituted methyl(pyridin-2-yl)((trimethylsilyl)imino)-λ 6 -sulfenyl imide was synthesized according to the reaction formula to obtain (E)-imino(pyridin-2-yl)(2-(pyridin-2-yl)vinyl)-λ 6 -sulfenyl imine derivatives.

[0596] Specifically, the compound synthesized in the above steps 2-4 (1.0 equivalent) is dissolved in anhydrous THF and then cooled to -78°C using dry ice and acetone. n-Butyl lithium (n-BuLi) (1.2 equivalents, 2.0M cyclohexane solution) is slowly added dropwise to the solution and stirred for 1 hour, followed by addition of a pyridine carboxaldehyde derivative (1.2 equivalents) and the reaction is continued for another 1 hour. If the reaction is not complete when confirmed by TLC, react for another 30 minutes at room temperature. After terminating the reaction with a small amount of water, extract with water and 10% MeOH / MC, remove a small amount of water from the organic layer by anhydrous Na2SO4, remove the solvent by reduced pressure distillation and vacuum dry. Subsequently, separation and purification are performed by column chromatography to obtain 3-, 4-, 5- or 6-substituted (E)-imino(pyridin-2-yl)(2-(pyridin-2-yl)vinyl)-λ 6 -sulfenyl imine derivatives.

[0597] Example 4.1, (E)-Imino(4-methoxypyridin-2-yl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-27)

[0598]

[0599] Diethyl ((4-methoxy-N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.12.1 to 3.12.4.

[0600] Using reaction formula (5)-2, diethyl ((4-methoxy-N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.14 g, 0.34 mmol) was fully dissolved in THF, and then 3-(trifluoromethyl)pyridinecarboxaldehyde (0.050 mL, 0.41 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.21 mL, 0.41 mmol) to synthesize compound 1-27 (0.063 g, 54%) as a white powder: R f =0.35 (EtOAc 100%); 1HNMR (400 MHz, DMSO-d6) δ8.91 (d, J=4.4 Hz, ArH), 8.53 (d, J=5.6 Hz, ArH), 8.28-8.30 (m, ArH), 7.87 (d, J=14.5 Hz, (E)-isomer H), 7.73-7.77 (m, (E)-isomer H), 7.68-7.71 (m, 2ArH), 7.22 (dd, J=2.5, 5.6 Hz, ArH), 5.17 (s, NH), 3.94 (s, OCH3).

[0601] Example 4.2, (E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(4-methoxypyridin-2-yl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-28)

[0602]

[0603] Diethyl ((4-methoxy-N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.12.1 to 3.12.4.

[0604] Using reaction formula (5)-2, diethyl ((4-methoxy-N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.26 g, 0.65 mmol) was fully dissolved in THF, and then 3-chloropyridinecarboxaldehyde (0.10 mL, 0.78 mmol) and 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.39 mL, 0.78 mmol) were reacted to synthesize 1-28 (0.085 g, 42%) as a white powder: R f =0.33 (EtOAc 100%); 1 H NMR (400 MHz, DMSO-d6) δ 8.60-8.61 (m, ArH), 8.52 (d, J = 5.6 Hz, ArH), 8.05 (dd, J = 1.2, 8.2 Hz, ArH), 7.91 (d, J = 14.7 Hz, (E)-isomer H), 7.72 (d, J = 14.7 Hz, (E)-isomer H), 7.68 (d, J = 2.4 Hz, ArH), 7.51 (dd, J = 4.5, 8.2 Hz, ArH), 7.21 (dd, J = 2.4, 5.6 Hz, ArH), 5.11 (s, NH), 3.94 (s, OCH3); 13C NMR (100MHz, DMSO-d6) δ167.3,162.3,151.7,149.1,147.9,138.9,135.8,134.9,132.2,127.2,113.3,107.8,56.6.

[0605] Example 4.3, (E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(4-methoxypyridin-2-yl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-29)

[0606]

[0607] Diethyl ((4-methoxy-N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.12.1 to 3.12.4.

[0608] Using reaction formula (5)-2, diethyl ((4-methoxy-N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.28 g, 0.72 mmol) was fully dissolved in THF, and then 3-fluoropyridinecarboxaldehyde (0.11 g, 0.86 mmol) and 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.43 mL, 0.86 mmol) were reacted to synthesize 1-29 (0.10 g, 49%) of white powder: R f =0.40 (EtOAc 100%); 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 5.6 Hz, 2ArH), 7.84-7.89 (m, ArH), 7.64-7.73 (m, ArH, (E)-isomer 2H), 7.56-7.60 (m, ArH), 7.20 (dd, J = 2.5, 5.6 Hz, ArH), 5.09 (s, NH), 3.93 (s, OCH3); 13 C NMR(100MHz,DMSO-d6)δ167.3,162.3,159.6,157.0,151.7,146.9(d,J C-F =4.8Hz),139.5(d,J C-F =10.9Hz),132.7,127.9(d,J C-F =4.7Hz),125.2(d,J C-F =18.9Hz),113.3,107.8,56.6.

[0609] Example 4.4, (E)-Imino(4-methoxypyridin-2-yl)(2-(3-methoxypyridin-2-yl)vinyl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-32)

[0610]

[0611] Diethyl ((4-methoxy-N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.12.1 to 3.12.4.

[0612] Using reaction formula (5)-2, diethyl ((4-methoxy-N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.22 g, 0.68 mmol) was fully dissolved in THF, and then 3-methoxypyridinecarboxaldehyde (0.11 g, 0.82 mmol) and 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.41 mL, 0.82 mmol) were reacted to synthesize compound 1-32 (0.075 g, 36%) as a white solid: R f =0.27 (EtOAc 100%); 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 5.6 Hz, ArH), 8.22 (dd, J = 1.0, 4.5 Hz, ArH), 7.84 (d, J = 15.0 Hz, (E)-isomer H), 7.66 (d, J = 2.4 Hz, ArH), 7.59 (dd, J = 1.1, 8.5 Hz, ArH), 7.53 (d, J = 15.0 Hz, (E)-isomer H), 7.44-7.48 (m, ArH), 7.18 (dd, J = 2.5, 5.6 Hz, ArH), 4.90 (s, NH), 3.93 (s, OCH3), 3.91 (s, OCH3); 13 C NMR (100MHz, DMSO-d6) δ167.2,162.8,155.1,151.6,142.1,140.1,135.5,132.3,127.1,120.4,113.1,107.6,56.6,56.4.

[0613] Example 4.5, (E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(3-methoxypyridin-2-yl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-33)

[0614]

[0615] Diethyl ((3-methoxypyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.11.1 to 3.11.4.

[0616] Using the above reaction (5)-2, diethyl ((3-methoxypyridine-2-sulfonylimino)methyl)phosphonate (0.15 g, 0.45 mmol) was fully dissolved in THF, and then 3-chloropyridinecarboxaldehyde (0.076 g, 0.54 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.27 mL, 0.54 mmol) to synthesize compound 1-33 (0.056 g, 40%) as a white powder: R f =0.33 (DCM 4: acetone 1); 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 4.4 Hz, ArH), 8.19 (d, J = 4.4 Hz, ArH), 8.07 (d, J = 8.2 Hz, ArH), 7.97 (d, J = 14.7 Hz, (E)-isomer H), 7.74-7.79 (m, ArH, (E)-isomer H), 7.65 (dd, J = 4.5, 8.4 Hz, ArH), 7.53 (dd, J = 4.5, 8.2 Hz, ArH), 4.89 (s, NH), 3.96 (s, OCH3).

[0617] Example 4.6, (E)-Imino(3-methoxypyridin-2-yl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-34)

[0618]

[0619] Diethyl ((3-methoxypyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.11.1 to 3.11.4.

[0620] Using the above reaction (5)-2, diethyl ((3-methoxypyridine-2-sulfonylimino)methyl)phosphonate (0.15 g, 0.47 mmol) was fully dissolved in THF, and then 3-(trifluoromethyl)pyridinecarboxaldehyde (0.090 mL, 0.71 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.28 mL, 0.57 mmol) to synthesize compound 1-34 (0.091 g, 56%) as a white powder: R f =0.29 (DCM 4: acetone 1); 1H NMR (400 MHz, DMSO-d6) δ 8.95 (d, J = 4.4 Hz, ArH), 8.30 (d, J = 7.6 Hz, ArH), 8.19-8.21 (m, ArH), 7.91 (d, J = 14.4 Hz, (E)-isomer H), 7.83 (dd, J = 1.4, 14.4 Hz, (E)-isomer H), 7.78 (d, J = 7.9 Hz, ArH), 7.69-7.72 (m, ArH), 7.64-7.67 (m, ArH), 4.95 (s, NH), 3.95 (s, OCH3); 13 C NMR(100MHz,DMSO-d6)δ153.9,153.1,148.8,148.2,140.2,136.5,135.6(q,J C-F =5.1Hz),135.0,129.1,125.5,124.5(q,J C-F =31.3Hz),124.0(q,J C-F =271.1Hz),122.8,56.9.

[0621] Example 4.7, (E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(5-methoxypyridin-2-yl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-35)

[0622]

[0623] Diethyl ((5-methoxypyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.16.1 to 3.16.4.

[0624] Using the above reaction (5)-2, diethyl ((5-methoxypyridine-2-sulfonylimino)methyl)phosphonate (0.15 g, 0.47 mmol) was fully dissolved in THF, and then 3-chloropyridinecarboxaldehyde (0.080 g, 0.57 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.28 mL, 0.57 mmol) to synthesize compound 1-35 (0.067 g, 42%) as a white powder: R f =0.29 (EtOAc 100%); 1H NMR (400 MHz, DMSO-d6) δ 8.59 (dd, J = 1.2, 4.5 Hz, ArH), 8.41 (d, J = 2.8 Hz, ArH), 8.14 (d, J = 8.8 Hz, ArH), 8.05 (dd, J = 1.3, 8.2 Hz, ArH), 7.87 (d, J = 14.7 Hz, (E)-isomer H), 7.61-7.67 (m, ArH, (E)-isomer H), 7.49 (dd, J = 4.5, 8.2 Hz, ArH), 4.95 (s, NH), 3.91 (s, OCH3); 13 C NMR (100MHz, DMSO-d6) δ158.1,151.6,149.1,147.9,138.8,138.6,136.7,134.1,132.1,127.1,123.9,121.9,56.7.

[0625] Example 4.8, (E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(5-methoxypyridin-2-yl)-λ 6 -Synthesis of sulfenyl imine (Chemical Formula 1-36)

[0626]

[0627] Diethyl ((5-methoxypyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.16.1 to 3.16.4.

[0628] Using the above reaction (5)-2, diethyl ((5-methoxypyridine-2-sulfonylimino)methyl)phosphonate (0.13 g, 0.40 mmol) was fully dissolved in THF, and then 3-fluoropyridinecarboxaldehyde (0.060 g, 0.48 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.24 mL, 0.4 mmol) to synthesize compound 1-36 as a white powder: R f =0.43 (n-hexane 1: EtOAc 1); 1 H NMR (400MHz, DMSO-d6) δ8.50-8.51(m,ArH),8.41(d,J=2.8Hz,ArH),8.13(d,J=8.8Hz,ArH),7.83 -7.88(m,ArH),7.61-7.68(m,(E)-isomer 2H,ArH),7.55-7.59(m,ArH),4.94(s,NH),3.91(s,OCH3); 13 C NMR(100MHz,DMSO-d6)δ158.1,151.6,146.9(d,JC-F =4.8Hz),139.57(d,J C-F =10.7Hz),138.6,135.6(d,J C-F =4.6Hz),131.8,127.8(d,J C-F =4.9Hz),125.2(d,J C-F =18.9Hz),123.9,121.9,56.7.

[0629] Example 4.9, (E)-Imino(5-methoxypyridin-2-yl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-37)

[0630]

[0631] Diethyl ((5-methoxypyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.16.1 to 3.16.4.

[0632] Using the above reaction (5)-2, diethyl ((5-methoxypyridine-2-sulfonylimino)methyl)phosphonate (0.13 g, 0.40 mmol) was fully dissolved in THF, and then 3-(trifluoromethyl)pyridinecarboxaldehyde (0.08 mL, 0.60 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.24 mL, 0.48 mmol) to synthesize compound 1-37 as a white powder (0.089 g, 65%): R f =0.50 (n-hexane 1: EtOAc 1); 1 H NMR (400 MHz, DMSO-d6) δ8.89 (d, J=4.2 Hz, ArH), 8.42 (d, J=2.7 Hz, ArH), 8.28 (d, J=7.9 Hz, ArH), 8.14 (d, J=8.8 Hz, ArH), 7.79 (d, J=14.4 Hz, (E)-isomer H), 7.62-7.73 (m, 2ArH, (E)-isomer H), 5.01 (s, NH), 3.91 (s, OCH3).

[0633] Example 4.10, (E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(pyridin-2-yl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-49)

[0634]

[0635] Diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Example 3.1.1.

[0636] Using the above reaction (5)-2, diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.39 g, 1.06 mmol) was fully dissolved in THF, and then 3-chloropyridinecarboxaldehyde (0.18 mg, 1.27 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.64 ml, 1.59 mmol) to synthesize compound 1-49 (0.10 g, 35%) as a white solid: R f =0.32 (n-hexane 1: EtOAc 2); 1 H NMR(400MHz,DMSO-d6)δ8.73(d,4.3Hz,ArH),8.73(dd,1.0,4.5Hz,ArH),8.18(d,7.8Hz,ArH),8.12(td,1.6 7.6Hz, ArH), 8.06 (dd, 1.3, 8.2Hz, ArH), 7.93 (d, J=14.7Hz, (E)-isomeric H), 7.73 (d, J=14.7Hz, (E)-isomeric H),7.67(ddd,1.0,4.5,7.6Hz,ArH),7.52(dd,4.5,8.2Hz,ArH),5.13(brs,NH); 13 CNMR(100MHz,DMSO-d6)δ160.4,150.4,149.1,147.9,139.3,138.9,136.0,135.0,122.2,127.5,127.2,121.9.

[0637] Example 4.11, (E)-Imino(2-(3-methoxypyridin-2-yl)vinyl)(pyridin-2-yl)-λ 6 -Synthesis of sulfenyl imide (chemical formula 1-50)

[0638]

[0639] Diethyl((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.1.1 to 3.1.4.

[0640] Using the above reaction (5)-2, diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.35 g, 0.97 mmol) was fully dissolved in THF, and then 3-methoxypyridinecarboxaldehyde (0.16 g, 1.16 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.58 ml, 1.45 mmol) to synthesize compound 1-50 (0.09 g, 33%) as a white solid: R f =0.15 (n-hexane 1: EtOAc 3); 1 H NMR(400MHz,DMSO-d6)δ8.71(d,4.4Hz,ArH),8.23(d,4.4Hz,ArH),8.15(d,7.7Hz,ArH),8.10(t,7.5Hz,ArH),7.85(d,J=15.0Hz,(E)-isomeric H),7.66-7.53(m,2ArH,(E)-isomeric H),7.52(dd,4.5,8.4Hz,ArH),4.93(brs,NH),3.92(s,OCH3); 13 C NMR (100MHz, CD3OD) δ159.5,155.5,149.9,141.3,140.0,138.7,137.4,130.7,127.0,126.6,122.0,119.5,55.1.

[0641] Example 4.12, (E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(pyridin-2-yl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-51)

[0642]

[0643] Diethyl((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.1.1 to 3.1.4.

[0644] Using the above reaction (5)-2, diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.33 g, 0.91 mmol) was fully dissolved in THF, and then 3-fluoropyridinecarboxaldehyde (0.14 g, 1.09 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.54 ml, 1.09 mmol) to synthesize compound 1-51 (0.03 g, 14%) as a white solid: R f =0.55 (n-hexane 1: EtOAc 3);1 H NMR(400MHz,DMSO-d6)δ8.73(d,4.2Hz,ArH),8.53(d,4.4Hz,ArH),8.19(d,7.8Hz,ArH),8.12(td,1.6,6. 8Hz,ArH),7.87(t,9.0Hz,ArH),7.75-7.65(m,(E)-isomeric2H,ArH),7.61-7.57(m,ArH),5.13(brs,NH); 13 CNMR(100MHz,DMSO-d6)δ160.5,158.3(d,J C-F =260.9Hz),150.4,146.9(d,J C-F =4.9Hz),139.5(d,J C-F =11.0Hz),139.3,134.9(q,J C-F =4.3Hz),132.7,128.0(d,J C-F =4.6Hz),127.5,125.2(d,J C-F =18.9Hz),121.9.

[0645] Example 4.13, (E)-Imino(pyridin-2-yl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-52)

[0646]

[0647] Diethyl((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate was synthesized in the same manner as in Examples 3.1.1 to 3.1.4.

[0648] Using the above reaction (5)-2, diethyl ((N-(trimethylsilyl)pyridine-2-sulfonylimino)methyl)phosphonate (0.30 g, 0.82 mmol) was fully dissolved in THF, and then 3-(trifluoromethyl)pyridinecarboxaldehyde (0.12 ml, 0.91 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.45 ml, 0.91 mmol) to synthesize compound 1-52 (0.04 g, 17%) as a white solid: R f =0.21 (n-hexane 1: EtOAc 3); 1H NMR(400MHz,DMSO-d6)δ8.92(d,4.3Hz,ArH),8.75(d,4.3Hz,ArH),8.30(d,8.0Hz,ArH),8.20(d,7.7Hz,ArH),8.14(t,7.6Hz,ArH),7.89(d,J=14.4Hz,(E)-isomeric H),7.78(d,J=14.4Hz,(E)-isomeric H),7.72-7.67(m,2ArH),5.21(brs,NH); 13 C NMR(100MHz,DMSO-d6)δ160.3,153.8,150.4,148.6,139.4,137.5,135.6(q,J C-F =5.2Hz),134.6(q,J C-F =2.2Hz),127.6,125.6,124.5(q,J C-F =31.3Hz),124.0(q,J C-F =272.1Hz),122.0.

[0649] Example 4.14, (E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(5-(3-morpholinopropoxy)pyridin-2-yl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-53)

[0650] As an embodiment of the present invention, the synthesis process of compound 1-53 is shown in the following reaction formula 5.

[0651] [Reaction 5]

[0652]

[0653] 4.14.1 Introduction of morpholine groups via Mitsunobu reaction

[0654]

[0655] According to the above reaction formula, a 4-(3-((6-bromopyridin-3-yl)oxy)propyl)morpholine compound was synthesized. Specifically, the 3-bromopyridine starting material (whose position is substituted by a hydroxyl group) (1.0 equivalent) was dissolved in tetrahydrofuran (THF), and after fully dissolving 4-(3-hydroxypropyl)morpholine (1.3 equivalents) and triphenylphosphine (1.3 equivalents), diisopropyl azodicarboxylate (1.3 equivalents) was added dropwise at 0°C and stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate (EtOAc, ethylacetate), washed with water and brine, and the organic layer was dried and filtered over anhydrous Na2SO4. The residue obtained by distilling the solvent under reduced pressure was purified by column chromatography using a mixed solvent of ethyl acetate and methanol to obtain 4-(3-((6-bromopyridin-3-yl)oxy)propyl)morpholine.

[0656] 4.14.2 Synthesis of 4-(3-((6-Bromopyridin-3-yl)oxy)propyl)morpholine

[0657]

[0658] 6-Bromopyridin-3-ol (1.30 g, 7.47 mmol), 4-(3-hydroxypropyl)morpholine (1.34 ml, 9.71 mmol), triphenylphosphine (2.55 g, 9.71 mmol) and diisopropyl azodicarboxylate (1.91 ml, 9.71 mmol) were reacted to synthesize 4-(3-((6-bromopyridin-3-yl)oxy)propyl)morpholine (2.12 g, 95%) as a yellow oil: R f =0.20 (EtOAc 9: CH 3 OH 1); 1 H NMR (400MHz, CDCl3) δ8.06 (d, J=3.0Hz, ArH), 7.36 (d, J=8.7Hz, ArH), 7.10 (dd, J=3.1, 8.7Hz, ArH), 4.06 (t, J =6.2Hz, CH2), 3.72 (t, J = 4.5Hz, 2CH2), 2.51 (t, J = 7.1Hz, CH2), 2.46 (t, J = 4.4Hz, 2CH2), 2.01-1.94 (m, CH2).

[0659] 4.14.3 Synthesis of methylthiopyridine derivatives from bromopyridine derivatives

[0660]

[0661] According to the above reaction formula, 4-(3-((6-(methylthio)pyridin-3-yl)oxy)propyl)morpholine was synthesized. Specifically, 4-(3-((6-bromopyridin-3-yl)oxy)propyl)morpholine (1.0 equivalent) was dissolved in dimethyl sulfoxide (DMSO), and then cesium carbonate (4.0 equivalent) and S-methylisothiourea sulfate (1.0 equivalent) were added and stirred at 80°C for 18 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate (EtOAc, ethyl acetate), washed with water and brine, and the organic layer was dried and filtered through anhydrous Na2SO4. The residue obtained by decompression distillation of the solvent was purified by column chromatography using a mixed solvent of ethyl acetate and methanol to obtain 4-(3-((6-(methylthio)pyridin-3-yl)oxy)propyl)morpholine.

[0662] 4.14.4 Synthesis of 4-(3-((6-(Methylthio)pyridin-3-yl)oxy)propyl)morpholine

[0663]

[0664] 4-(3-((6-bromopyridin-3-yl)oxy)propyl)morpholine (2.12 g, 7.08 mmol), S-methylisothiourea sulfate (1.97 g, 7.08 mmol) and cesium carbonate (9.23 g, 28.34 mmol) were reacted to synthesize 4-(3-((6-(methylthio)pyridin-3-yl)oxy)propyl)morpholine (1.84 g, 97%) as a yellow oil: R f =0.21 (EtOAc 9:CH3OH1); 1 HNMR (400MHz, CDCl3) δ8.17 (t, J=1.8Hz, ArH), 7.11 (d, J=1.7Hz, ArH), 4.06 (t, J=6.2Hz, CH2), 3.72 (t , J=4.6Hz, 2CH2), 2.55 (s, SCH3) 2.51 (t, J=7.1Hz, CH2), 2.46 (t, J=4.4Hz, 2CH2), 2.00-1.93 (m, CH2).

[0665] 4.14.5. Imino(methyl)(5-(3-morpholinopropoxy)pyridin-2-yl)-λ 6 -sulfinyl imide (Imino (methyl) (5- (3-morpholinopropoxy) pyridin-2-yl) -λ 6Synthesis of -sulfanone

[0666]

[0667] Using the above reaction (2), 4-(3-((6-(methylthio)pyridin-3-yl)oxy)propyl)morpholine (1.00 g, 3.75 mmol) was fully dissolved in MeOH, and then diacetoxyiodobenzene (2.78 g, 8.63 mmol) was reacted with ammonium carbonate (0.54 g, 5.63 mmol) to synthesize yellow oily imino(methyl)(5-(3-morpholinopropyloxy)pyridin-2-yl)-λ 6 -sulfinyl imine (0.61 g, 55%): R f =0.24 (EtOAc 93:CH3OH7); 1 H NMR (400MHz, CDCl3) δ8.37 (d, J=2.7Hz, ArH), 8.08 (d, J=8.7Hz, ArH), 7.34 (dd, J=2.8, 8.7Hz, ArH), 4.16 (t, J=6.2Hz, CH2), 3.73 (t, J=4.4Hz, 2CH2), 3.49 (s, NH), 3.23 (s, SCH3), 2.56 (t, J=7.2Hz, CH2), 2.50 (t, J=4.4Hz, 2CH2), 2.07-2.00 (m, CH2).

[0668] 4.14.6, Methyl(5-(3-morpholinopropoxy)pyridin-2-yl)((trimethylsilyl)imino)-λ 6 -Methyl(5-(3-morpholinopropoxy)pyridin-2-yl)((trimethylsilyl)imino)-λ 6 Synthesis of -sulfanone

[0669]

[0670] Using the above reaction (3), hexamethyldisilazane (0.88 mL, 4.19 mmol) was added to methyl(5-(3-morpholinopropoxy)pyridin-2-yl)-λ 6 -sulfinyl imide (0.84 g, 2.79 mmol) was added to synthesize methyl (5-(3-morpholinopropoxy) pyridin-2-yl)((trimethylsilyl) imino)-λ 6 -sulfinyl imine (1.02 g, 100%): R f =0.61 (DCM 9:CH3OH1); 1H NMR (400MHz, DMSO-d6) δ8.41 (d, J=2.7Hz, ArH), 7.96 (d, J=8.7Hz, ArH), 7.63 (dd, J=2.8, 8.7Hz, ArH), 4.20 (t, J=6.4Hz, CH2), 3. 58 (t, J=4.6Hz, 2CH2), 3.11 (s, SCH3), 2.44 (t, J=7.2Hz, CH2), 2.38 (t, J=4.4Hz, 2CH2), 1.96-1.90 (m, CH2), 0.00 (s, Si(CH3)3).

[0671] 4.14.7. Synthesis of Diethyl((5-(3-morpholinopropoxy)pyridine-2-sulfonimidoyl)methyl)phosphonate

[0672]

[0673] Using the above reaction (4), methyl(5-(3-morpholinopropoxy)pyridin-2-yl)((trimethylsilyl)imino)-λ 6- Sulfinyl imide (2.70 g, 7.18 mmol) was fully dissolved in THF, and then when diethyl chlorophosphate (1.56 mL, 10.77 mmol) was reacted with 2.0 M n-butyl lithium (n-BuLi) cyclohexane solution (7.90 mL, 15.80 mmol), diethyl ((5-(3-morpholinopropoxy)pyridine-2-sulfonylimino)methyl)phosphonate (1.21 g, 39%) was synthesized as a yellow oil: R f =0.29 (EtOAc 4:CH3OH1); 1 H NMR (400MHz, DMSO-d6) δ8.39 (d, J=2.8Hz, ArH), 8.04 (d, J=8.8Hz, ArH), 7.63 (dd, J= 2.8, 8.8Hz, ArH), 4.58 (s, NH), 4.22-4.15 (m, CH2, SCH2P), 4.06-3.99 (m, 2CH3CH2O),

[0674] 3.58 (t, J=4.6Hz, 2CH2), 2.44 (t, J=7.2Hz, CH2), 2.37 (t, J=4.4Hz, 2CH2), 1.97-1.91 (m, CH2), 1.16 (t, J=7.1Hz, 2CH3CH2O).

[0675] 4.14.8. (E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(5-(3-morpholinopropoxy)pyridin-2-yl)-λ 6 -Synthesis of sulfenyl imide (Chemical Formula 1-53)

[0676]

[0677] Using the above reaction (5)-2, diethyl ((5-(3-morpholinopropoxy)pyridine-2-sulfonylimino)methyl)phosphonate (0.10 g, 0.23 mmol) was fully dissolved in THF, and then 3-fluoropyridinecarboxaldehyde (0.03 g, 0.25 mmol) was reacted with 2.0 M n-butyllithium (n-BuLi) cyclohexane solution (0.13 ml, 0.25 mmol) to synthesize bright yellow oily compound 1-53 (0.03 g, 31%): R f =0.11 (EtOAc 4:CH3OH 1); 1 H NMR (400MHz, DMSO-d6) δ8.51 (d, J=4.5Hz, ArH), 8.40 (d, J=2.8Hz, ArH), 8.12 (d, J=8.8Hz, ArH), 7.86 (t, J=9.5Hz, ArH), 7.68-7.55 (m, (E)-isomer 2H, 2ArH), 4.93 (s, NH), 4.18 (t, J=6.3Hz, CH2), 3.56 (t, J=4.4Hz, 2CH2), 2.42 (t, J=6.9Hz, CH2), 2.36 (t, J=4.4Hz, 2CH2), 1.94-1.87 (m, CH2).

[0678] Experimental Example 1: Evaluation of Nrf2 activation effect and cytotoxicity

[0679] In order to confirm the pharmacological activity of the compounds synthesized according to Examples 1 to 4 of the present invention, an Nrf2 functional cell based assay (DiscoveRx) was established to evaluate the Nrf2 activation effect of the synthesized derivatives, a major regulator of oxidative stress defense. Specifically, U2OS cells were used, and cell pellets were dissolved with CP 0 reagent and plated in 96-well plates at 1.5×10 4The density of cells / well was 80 μL, and cultured for 24 hours. The compounds synthesized according to Examples 1 to 4 were diluted 3 times in DMSO at 7 concentrations to prepare stock solutions, 10 μL of each compound solution was mixed with 90 μL of CP 0, and then 20 μL was added to each well of a 96-well plate, and each experiment was repeated 3 times. As a positive control group, 5 μM sulforaphane and DMF (Dimethyl fumarate) were treated, and the plate was wrapped with foil and cultured for 6 hours. After mixing substrate reagents 1 and 2 in cell assay buffer, 50 μL of substrate reagent per well was added to a 96-well plate, wrapped with foil and cultured for 1 hour. Then, the luminescence value at all wavelengths and 1000 milliseconds integration time was measured using a luminescence spectrophotometer (Molecular Devices). The effect of each compound was expressed as the concentration that activated 50% of the maximal effect at high concentration (Table 1).

[0680] [Table 1]

[0681]

[0682]

[0683] As shown in Table 1 above, the compounds of Examples 1 to 4 of the present invention (Compounds 1 to 55) can induce Nrf2 activity, especially Compounds 1-4, 1-6, 1-9, 1-19, 1-21, 1-25, 1-27, 1-28, 1-30, 1-33, 1-34, 1-35, 1-38, 1-40, 1-41, 1-42, 1-45, 1-46, 1-47, 1-49, 1-52, 1-54, 1-55 and 1-57 show better Nrf2 activation effect than Sulforaphane, a well-known Nrf2 activator.

[0684] Specifically, compound 1-41, which exhibited the best Nrf2 activation activity among the compounds of the present invention, exhibited an effect about 14 times higher than that of sulforaphane; compound 1-4 exhibited an Nrf2 activation activity about 30 times higher than that of DMF and about 4 times higher than that of sulforaphane, and its cytotoxicity was 250 times lower than that of bardoxolone-methyl (CDDO-methyl ester) ( Figure 1 ).

[0685] Sulforaphane is known to have high activity due to its presence of an isothiocyanate group (NCS), but it has strong non-selective reactivity and exhibits high toxicity at concentrations above 5 μM. The results of the experimental examples of the present invention show that the compound of the present invention does not exhibit cytotoxicity even at a concentration of 10 μM and can induce Nrf2 activity, so it can be used as an Nrf2 activator instead of sulforaphane.

[0686] Experimental Example 2: Evaluation of CYP Activity Inhibition Ability

[0687] In order to confirm the possibility of the compounds according to the embodiments of the present invention as actual drugs for in vivo administration, the ability to inhibit the activity of CYP involved in about 75% of drug metabolism was confirmed. Specifically, compared with compounds including sulfonic acid groups as cores and other similar functional groups, the inhibitory activity of the compounds of the present invention 1-1, 1-2, 1-6, 1-8, 1-9, 1-10, 1-12 and 1-13 including sulfenyl imines was evaluated against 5 isozymes 2C19, 2D6, 2C9, 1A2, 3A4, which are reported to account for more than 90% of the total CYP metabolism.

[0688] Human liver microsomes (0.25 mg / mL) and 0.1 M phosphate buffer (pH 7.4), a substrate drug mixture of the five drug-metabolizing enzymes (50 μM phenacetin, 10 μM diclofenac, 100 μM S-mephenytoin, 5 μM dextromethorphan and 2.5 μM midazolam), and 1-1, 1-2, 1-6, 1-8, 1-9, 1-10, 1-12, 1-13 were added at a concentration of 0 or 10 μM, respectively, and pre-incubated at 37° C. for 5 minutes, then an NADPH generation system solution was added and incubated at 37° C. for 15 minutes. The reaction was then terminated by adding an acetonitrile solution containing an internal standard substance (Terfenadine), and after centrifugation for 5 minutes (14,000 rpm, 4°C), the supernatant was injected into the LC-MS / MS system, and the metabolites of the substrate drug were analyzed simultaneously to evaluate the inhibitory ability of these compounds against drug-metabolizing enzymes. The metabolites of each CYP isoenzyme indicator drug generated by the above reaction were analyzed using the Shimadzu Nexera XR system and TSQ vantage (Thermo). The Kinetex C18 column was used as the HPLC column, and distilled water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid were used as the mobile phase. The generated metabolites were quantified using the multiple reaction monitoring (MRM) quantitative mode, and the data were analyzed using Xcalibur (version 1.6.1). The activity inhibition ability of each CYP isoenzyme was converted into the percentage of activity of the negative control group to which the compound was not added (Table 2).

[0689] [Table 2]

[0690]

[0691]

[0692] As shown in Table 2 above, by evaluating the possibility of drug interaction between each compound and drug metabolizing enzymes, compared with the comparative examples, the compounds of the present invention did not show inhibitory activity on the five CYP isozymes, which indicates that the possibility of drug interaction is almost non-existent compared with the comparative examples.

[0693] Experimental Example 3: Evaluation of metabolic stability

[0694] Metabolic stability is a factor that can affect pharmacokinetic parameters (PK parameters, pharmacokinetic parameter) such as drug clearance, half-life, oral bioavailability, etc., and is one of the characteristics that candidate drugs must possess. Therefore, in order to predict the degree of drug metabolism in the liver, the main organ of drug metabolism, through in vitro experiments, the metabolic stability of drugs was evaluated using liver microsomes.

[0695] Specifically, a stability test (microsomal stability) was performed using microsomes: Compounds 1-2, 1-4 and 1-6 of the present invention including sulfonyl imine and compounds including sulfonic acid groups as core and other identical functional groups were treated in microsomes and incubated for a certain period of time to determine the amount of remaining drug. Specifically, the compound was added to human liver microsomes (0.5 mg / mL) and 0.1 M phosphate buffer (pH 6.4) at a concentration of 1 μM, and pre-cultured at 37°C for 5 minutes, and then NADPH regeneration system solution was added and cultured at 37°C for 30 minutes. The reaction was then terminated by adding an acetonitrile solution containing an internal standard substance (chloropropamide), and after centrifugation for 5 minutes (14,000 rpm, 4°C), the supernatant was injected into the LC-MS / MS system, thereby analyzing the substrate drug, thereby evaluating the metabolic stability of these compounds. The amount of substrate remaining after the reaction was analyzed using the Shimadzu Nexera XR system and TSQ vantage. A Kinetex C18 column was used as the HPLC column, and distilled water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid were used as the mobile phases. The data were analyzed using Xcalibur (version 1.6.1) (Table 3).

[0696] [Table 3]

[0697]

[0698] As shown in Table 3 above, each compound was incubated with microsomes for 30 minutes and the amount of remaining drug was measured. The results confirmed that compounds 1-2, 1-4 and 1-6 of the present invention did not undergo metabolic decomposition after 30 minutes, and the concentration was maintained at a high level. This shows that the stability of the compounds according to the examples of the present invention to human liver microsomes is significantly improved compared with the comparative examples.

[0699] Experimental Example 4: Evaluation of Solubility

[0700] In the development of new drugs, drug solubility is one of the most important factors related to bioabsorption. For example, compounds with low solubility in aqueous solution may show lower bioabsorption overall. In addition, since drugs with low solubility may crystallize in tissues or cause severe toxicity, the FDA requires additional research results for oral drugs with low solubility. In addition, low solubility is also the biggest reason for the failure of candidate substance development. Therefore, the solubility of compounds 1-4 of the present invention in 1% DMSO was measured.

[0701] Specifically, compounds 1-4 showed high solubility of more than 0.5 mg / mL, while compounds including sulfonic acid groups as cores and other identical functional groups (comparative examples) showed very low solubility of less than 0.01 mg / mL. That is, this indicates that the compounds of the present invention have a solubility that is increased by more than 50 times by using sulfenyl imide as a core.

[0702] Experimental Example 5: Anti-inflammatory Effect

[0703] Nrf2 is an anti-inflammatory factor, and the activation effect of the compounds of the present invention on Nrf2 was confirmed by the above Experimental Example 1. Therefore, in order to confirm the anti-inflammatory effect of the compounds of the present invention, the anti-inflammatory effect of activated Nrf2 was confirmed by evaluating NO (nitric oxide) inhibitory activity (Table 4).

[0704] BV-2 mouse microglia were cultured at 1.5 × 10 5 The density of cells / well was distributed in 12-well plates and cultured for 24 hours. All cell culture medium was then removed, and the compound stock solution dissolved in DMSO was diluted with serum-free medium (DMEM / high glucose + 100U / mL penicillin / streptomycin) to a final concentration of 0.1μM, 1μM, 10μM, and 0.1% DMSO, 900μl was treated per well, and cultured for 4 hours. To induce an inflammatory response in microglia, 100μl was treated per well to give a final concentration of 1μg / ml of lipopolysaccharide (LPS) and cultured for another 24 hours. The cell culture medium was centrifuged at 2356g for 3 minutes to remove dead cell debris, and the supernatant was added to a transparent 96-well plate (50μl per well). 50 μl of sulfonamide solution (1% sulfonamide in 5% phosphoric acid) was added to each well and reacted at room temperature for 5 minutes, and then 50 μl of NED solution (0.1% N-1-naphthylethylenediamine dihydrochloride aqueous solution) was added and reacted at room temperature for 5 minutes. The microplate was read using a microplate reader ( Microplate reader (Molecular Devices) measured the absorbance at 540 nm and compared it with a standard curve using sodium nitrite to determine the NO concentration in each cell culture medium. When each compound was treated, the NO concentration was converted to the percentage of activity of the positive control group treated with LPS.

[0705] [Table 4]

[0706]

[0707]

[0708] As shown in Table 4 above, the compounds of the present invention have an inhibitory effect on NO and have a better anti-inflammatory effect than the known Nrf2 activators sulforaphane and DMF. In particular, even at a low concentration of 1 μM, compound 1-4 inhibited the production of NO by about 70% compared with the negative control group treated with LPS alone. Figure 2 ).

[0709] This suggests that the compounds of the present invention can exhibit their anti-inflammatory effects through concentration-dependent NO inhibition.

[0710] Experimental Example 6: Antioxidant Effect

[0711] Nrf2 is a transcription factor that protects cells by increasing antioxidant enzymes in the nucleus. The above-mentioned Experimental Example 1 confirmed the activation of Nrf2 by the compounds of the present invention. Therefore, by measuring the amount of antioxidant enzymes using Western blot, it was confirmed whether activated Nrf2 increased antioxidant enzymes. As the antioxidant enzymes to be detected, we selected GCLC, GCLM and HO-1, whose expression is known to increase due to Nrf2. Specifically, BV2 cells were plated in 6-well plates at 5×10 5 The density of cells / well was divided into 1.5 mL and cultured in RPM1640 medium for 24 hours. The next day, compounds 1-4 were mixed into each culture medium at 0.1% DMSO to a final concentration of 0 to 10 μM, and then added to the cells and cultured for 24 hours. The cultured cells were harvested, lysed and total protein was extracted, and then subjected to 10% SDS-PAGE electrophoresis. The entire extract after electrophoresis was transferred to a PVDF membrane and blocked with bovine serum albumin. Afterwards, the amount of antioxidant enzymes expressed in the cells was measured using antibodies corresponding to each antioxidant enzyme, and the results were as follows Figure 3 shown.

[0712] Specifically, compounds 1-4 can visually confirm the significant increase of antioxidant enzymes when untreated and treated with low concentrations of 0.1 μM to high concentrations of 10 μM, and all show the highest expression at 10 μM. This shows that the compounds of the present invention, such as compounds 1-4, can increase the expression of antioxidant enzymes through concentration-dependent Nrf2 activation, thereby protecting cells.

[0713] Experimental Example 7: Cytoprotective Effect of MPTP Mice Model of Parkinson's Disease

[0714] The above experimental examples 1 and 6 directly show that compounds 1-4 of the present invention can activate Nrf2 in cells and increase the expression of antioxidant enzymes. Therefore, in order to confirm whether the compounds of the present invention also show cytoprotective effects in animal models, we used a mouse animal model of Parkinson's disease induced by administering the neurotoxic substance MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to kill only dopaminergic neurons. The specifically designed animal experiment schedule is as follows: Figure 4 As shown in (a). Using 10-week-old C57 / BL6 mice as the animal model, the animal experimental model was prepared by dividing the animal experimental model into three groups: a negative control group, which was intraperitoneally injected with normal saline and orally administered with a solution without compound 1-4; a positive control group, which was intraperitoneally injected with MPTP and orally administered with a solution without compound 1-4; and an experimental group, which was intraperitoneally injected with MPTP and orally administered with a solution containing compound 1-4. The MPTP-induced Parkinson's disease model was prepared by intraperitoneal injection of 20 mg / kg MPTP, once every 2 hours, for a total of four injections per day. For the negative control group, normal saline without MPTP was injected at the same time point. In order to confirm whether Parkinson's disease is induced, the vertical grid test and the hanger test were used to confirm movement disorders caused by the death of dopaminergic neurons (which is the main symptom of Parkinson's disease). Compound 1-4 was orally administered once a day at a dose of 20 mg / mL for 3 consecutive days starting from the day before MPTP injection, and behavioral tests were performed 6 days after the MPTP injection date. The results are shown as follows: Figure 4 shown.

[0715] The vertical grid test is used to evaluate the time required for an experimental animal model to turn around and get down from a vertical ladder. In the present invention, the time it takes for a mouse to turn to the floor when placed on a ladder (time to turn) and the total time required to get down from the ladder (total time) were measured. Figure 4 (c) shows that in the positive control group injected with MPTP only, the turning time and the total time were increased compared with the negative control group of normal mice, which shows that the motor ability in the Parkinson's disease model induced by MPTP is reduced. In addition, in the experimental group using the compounds of this invention 1-4, the turning time and the total time were reduced to a level similar to the negative control group again, and showed significant differences with the above-mentioned positive control group.

[0716] Another behavioral test to assess motor ability is the coat hanger test. Figure 4 As shown in (b), the mouse is placed in the middle of a hanger 30 cm above the ground. The mouse will climb to the safe position on the top of the hanger while hanging, and a score will be given based on the position at that time. The time limit is 3 minutes. Figure 4As shown in the graph of (d), most of the mice in the negative control group moved to the top of the hanger, which is equivalent to 5 points, while most of the mice in the positive control group stopped at both ends of the bottom of the hanger, with scores of 2 to 3. However, in the experimental groups administered with compounds 1 to 4 of the present invention, a considerable number of mice moved to the top, which is equivalent to 4 or 5 points, and the average score was as high as 4 points or more.

[0717] Based on the results of the above two motor ability experiments, it is confirmed that the compound of the present invention can restore the motor ability reduced by MPTP to a level similar to that of normal mice.

[0718] Experimental Example 8: Role of dopamine neurons in MPTP mice, a Parkinson's disease model

[0719] The effect of the compound of the present invention on the recovery of motor ability can be confirmed from the results of the above-mentioned Experimental Example 7. In order to confirm whether the recovery of motor ability is due to the neuroprotective effect of the compound of the present invention, the brain was removed from the mouse and immunohistochemistry (IHC) analysis was performed using tyrosine hydroxylase (as a marker of dopaminergic neurons). The striatum and substantia nigra, where dopaminergic neurons are densely distributed, were selected as the analysis area.

[0720] Specifically, after anesthetizing the negative control group, positive control group and experimental group mice with avertin, physiological saline and 4% formaldehyde were perfused into the heart, and the brain was taken out and placed in 4% formaldehyde and 30% sucrose respectively, and stored in the refrigerator for one day. Then, a freezing microtome was used to obtain striatum and substantia nigra tissue slices from the above-mentioned preserved brains. Using tyrosine hydroxylase antibodies specifically expressed in dopaminergic neurons, brain tissue slices were stained with DAB by immunohistochemical staining and observed under a microscope. The results are shown in Figure 2. Figure 5 shown.

[0721] By the above immunohistochemical staining, the area containing tyrosine hydroxylase was stained brown, indicating the presence of live dopaminergic neurons. Figure 5 As shown on the right, the stained striatum and substantia nigra of the negative control group (normal mice) are dark brown, but in the positive control group induced by MPTP, the staining becomes significantly lighter, which may be due to the death of a large number of dopaminergic neurons caused by MPTP treatment. In addition, in the experimental group treated with compounds 1-4 of the present invention, the staining becomes darker again, which is believed to be due to the antioxidant effect of compounds 1-4 inhibiting the death of dopaminergic neurons caused by MPTP, thereby playing a cytoprotective role, which indicates that the compounds of the present invention have a preventive or therapeutic effect on neurodegenerative diseases such as Parkinson's disease caused by the death of dopaminergic neurons.

[0722] Experimental Example 9: Memory enhancement and cognitive function improvement in APP / PS1 mice, an Alzheimer's disease model

[0723] In order to confirm whether the compounds of the present invention show cognitive function improvement efficacy in animal models, we used the APP / PS1 (APPswe / PSEN1dE9, stock number 004462) mouse animal model that has been genetically modified to induce Alzheimer's disease. Compounds 1-4 were dissolved in an excipient mixed with 12.5% ​​DMSO, 5% solute HS15 and 82.5% triple distilled water, and were orally administered once a day at a dose of 20 mg / kg, 250 μl from the time the mice reached 10 months of age for 2 months, and behavioral tests to evaluate cognitive function were performed at 12 months of age (the time point when cognitive impairment was observed).

[0724] Experimental Example 9.1: Morris water maze experiment

[0725] The Morris water maze test was used to evaluate the spatial learning and memory ability of mice. A white circular water tank (150 cm in diameter and 58 cm in height) was filled with water at 22 ± 2 °C, and a 20 cm diameter white circular escape platform with a base was placed 1.5 cm below the water surface. The water maze was divided into four quadrants: northeast, northwest, southeast, and southwest. The escape platform was placed in the northwest quadrant, and the mice were released from the northeast, east, south, and southwest directions. Spatial cues (cues) of different shapes were posted on the walls facing north, east, and south to help mice identify the directions, and white water-based non-toxic paint was dissolved in the water so that the mice could not visually identify the location of the escape platform. The mice were trained to find the escape platform in each direction for eight days, four times a day for 60 seconds each time, every two hours (acquisition test), and the escape platform was removed on the ninth day and the mice were allowed to swim freely for 90 seconds (probe test). Afterwards, the escape platform was placed in the opposite southeast quadrant, and the mice were trained for four days from the tenth to the thirteenth day (reversal test), and then the escape platform was removed again on the fourteenth day, and the mice were allowed to swim freely for 90 seconds (reversal probe test). All experimental processes were recorded with a camera, and the Ethovision XT 11.5 (Noldus) program was used to analyze the time taken by the mice to climb onto the escape platform during the training process (acquisition test, reversal test), the time spent by the mice in the target quadrant where the escape platform was located during the free swimming process (probe test, reversal probe test) (time spent in target zone), the number of times the mice crossed the escape platform position (platform crossover), and the time to first reach the escape platform position (latency to platform).

[0726] During the swimming training of mice (acquisition test), wild type normal mice will remember the location of the escape platform as the number of training increases, and quickly reach the escape platform, but APP / PS1 Alzheimer's disease mice arrive at the escape platform relatively late, and the escape latency is maintained at 40 seconds. In APP / PS1 mice administered with compound 1-4, the time to reach the escape platform is shortened to a level similar to that of normal mice over time. Even if the escape platform is moved to a new position (reversal test), the time for mice administered with compound 1-4 to reach the escape platform is also significantly reduced, which confirms that compound 1-4 improves the spatial learning ability of mice. During the free swimming process (probe test, reversal probe test) in which the escape platform is removed after the training process, APP / PS1 mice cannot remember the location of the escape platform, so the time spent in the target quadrant where the escape platform is located is reduced compared to normal mice. When compound 1-4 was administered to APP / PS1 mice, the time the mice stayed in the target area, the number of times the mice crossed the platform, and the time they first reached the platform all returned to the levels of normal mice, which confirmed the efficacy of compound 1-4 in improving spatial learning and memory abilities ( Figures 6a to 6c ).

[0727] Experimental Example 9.2: Y-maze test

[0728] The spatial learning and memory ability of mice was evaluated by the Y-maze test. The Y-maze is made of 5mm thick black acrylic matte material, using three identical arms (length 41cm, width 7cm, height 15cm), which are 120° angles to each other. The mouse is placed at one end of the maze arm, and its movement is recorded for 10 minutes. The spontaneous alternation rate (alternation rate % = number of alternations / (total number of times entering the arm-2)) as a measure of cognitive ability is calculated and recorded. When the center point of the mouse passes through two-thirds of the arm, it is considered that the mouse has entered the arm, and the alternation behavior ability (alternation) is defined as the mouse entering all three arms at once without overlapping.

[0729] Normal mice showed a high alternation ability of about 77% by remembering the order of entering the arms in the maze, but the spatial learning and memory ability of APP / PS1 Alzheimer's mice to the maze was statistically significantly reduced compared with wild-type normal mice. When compounds 1-4 were applied to APP / PS1 mice, a statistically significant increase in alternation ability was observed, indicating that spatial learning and memory abilities had been restored to the level of wild-type normal mice. In addition, the average total number of entries into the arms of all mouse groups during the test did not show mutual significance, confirming that the mobility of mice between the dosing groups was the same and did not affect alternation ability ( Figure 7a ).

[0730] Experimental Example 9.3: Passive avoidance test

[0731] The hippocampus-dependent contextual learning and memory of mice were evaluated by the passive avoidance test. The passive avoidance test apparatus used the GEMINI avoidance system equipment from San Diego Instruments, which separated a dark room and a light room by an automatic door. On the first day of the test (habituation), the mice were placed in the test apparatus and allowed to move freely for 3 minutes to adapt to the environment of the apparatus. On the second day of the test (acquisition), the mice were placed in the light room using the natural preference of mice for dark places. After 30 seconds, the automatic door opened. When the mice spontaneously crossed the automatic door into the dark room, a 0.4 mA electric shock was applied for 1 second. After 24 hours (retention), the mice were placed back in the same light room, and the time required for the mice to enter the dark room after the automatic door opened for 15 seconds (step-through latency) was measured to measure the learning and memory ability related to electrical stimulation and the environment of the apparatus.

[0732] The results of the passive avoidance test showed that APP / PS1 Alzheimer's disease mice were unable to remember the electrical stimulation in the acquisition trial, resulting in a significant reduction in the time to enter the dark chamber (step-through latency). When compound 1-4 was administered to APP / PS1 mice, the time to enter the dark chamber (step-through latency) increased to a level similar to that of normal mice, indicating that hippocampal-dependent learning and memory abilities were restored by administering compound 1-4 ( Figure 7b ).

[0733] In summary, the embodiments are described through limited drawings, and a person skilled in the art can make various changes and modifications based on the description. For example, the described techniques are performed in a different order from the described method, and / or the described systems, structures, devices, circuits and other components are combined or combined in a different form from the described method, or replaced or substituted by other components or equivalents, and appropriate results can also be obtained.

[0734] Therefore, other embodiments, other examples and equivalents of the claims are all within the scope of the claims of the present invention.

Claims

1. A sulfanone derivative represented by the following [Chemical Formula 1] or a pharmaceutically acceptable salt thereof: [Chemical formula 1] Wherein in the chemical formula 1, A and B are each independently phenyl or pyridine; R is hydrogen, cyano, trimethylsilyl (TMS) or methyl (except when A and B are both phenyl and R is hydrogen); Each of A and B is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, cyano, nitro, C1-C7 alkyl and C1-C7 alkoxy (except when both A and B are unsubstituted); One or more hydrogen atoms in the alkyl group or alkoxy group are unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, nitro and morpholino.

2. The sulfenyl imine derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The sulfenyl imide derivative represented by [Chemical Formula 1] is any one or more selected from the group consisting of compounds represented by the following chemical formulas: [Chemical formula 1-1] [Chemical formula 1-2] [Chemical formula 1-3] [Chemical formula 1-4] [Chemical formula 1-5] [Chemical formula 1-6] [Chemical formula 1-7] [Chemical formula 1-8] [Chemical formula 1-9] [Chemical formula 1-10] [Chemical formula 1-11] [Chemical formula 1-12] [Chemical formula 1-13] [Chemical formula 1-14] [Chemical formula 1-15] [Chemical formula 1-16] [Chemical formula 1-17] [Chemical formula 1-18] [Chemical formula 1-19] [Chemical formula 1-20] [Chemical formula 1-21] [Chemical formula 1-22] [Chemical formula 1-23] [Chemical formula 1-24] [Chemical formula 1-25] [Chemical formula 1-26] [Chemical formula 1-27] [Chemical formula 1-28] [Chemical formula 1-29] [Chemical formula 1-30] [Chemical formula 1-31] [Chemical formula 1-32] [Chemical formula 1-33] [Chemical formula 1-34] [Chemical formula 1-35] [Chemical formula 1-36] [Chemical formula 1-37] [Chemical formula 1-38] [Chemical formula 1-39] [Chemical formula 1-40] [Chemical formula 1-41] [Chemical formula 1-42] [Chemical formula 1-43] [Chemical formula 1-44] [Chemical formula 1-45] [Chemical formula 1-46] [Chemical formula 1-47] [Chemical formula 1-48] [Chemical formula 1-49] [Chemical formula 1-50] [Chemical formula 1-51] [Chemical formula 1-52] [Chemical formula 1-53] [Chemical formula 1-54] [Chemical formula 1-55] [Chemical formula 1-56] [Chemical formula 1-57] as well as [Chemical formula 1-58] 3. An Nrf2 (nuclear factor erythroid-derived 2-related factor 2) activating composition comprising a sulfenyl imine derivative represented by the following [Chemical Formula 1] or a pharmaceutically acceptable salt thereof as an active ingredient: [Chemical formula 1] Wherein in the chemical formula 1, A and B are each independently phenyl or pyridine; R is hydrogen, cyano, trimethylsilyl (TMS) or methyl (except when A and B are both phenyl and R is hydrogen); Each of A and B is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, cyano, nitro, C1-C7 alkyl and C1-C7 alkoxy (except when both A and B are unsubstituted); One or more hydrogen atoms in the alkyl group or alkoxy group are unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, nitro and morpholino.

4. A pharmaceutical composition for preventing or treating any one or more selected from the group consisting of liver disease, kidney disease, lung disease, neurodegenerative disease, mitochondrial myopathy, Friedreich's ataxia, corneal endothelial cell loss and psoriasis, comprising a sulfenyl imine derivative represented by the following [Chemical Formula 1] or a pharmaceutically acceptable salt thereof as an active ingredient: [Chemical formula 1] Wherein in the chemical formula 1, A and B are each independently phenyl or pyridine; R is hydrogen, cyano, trimethylsilyl (TMS) or methyl (except when A and B are both phenyl and R is hydrogen); Each of A and B is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, cyano, nitro, C1-C7 alkyl and C1-C7 alkoxy (except when both A and B are unsubstituted); One or more hydrogen atoms in the alkyl group or alkoxy group are unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, nitro and morpholino.

5. The pharmaceutical composition according to claim 4, characterized in that The disease is a disease caused by decreased Nrf2 activity.

6. The pharmaceutical composition according to claim 4, characterized in that The liver disease is any one or more selected from the group consisting of alcoholic liver disease, non-alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), chronic liver damage, viral hepatitis and hepatocellular carcinoma.

7. The pharmaceutical composition according to claim 4, characterized in that The renal disease is any one or more selected from the group consisting of diabetic nephropathy, focal segmental glomerulosclerosis, renal fibrosis, lupus-like autoimmune nephritis, chronic kidney disease (CKD) and hypertensive nephropathy.

8. The pharmaceutical composition according to claim 4, characterized in that The pulmonary disease is any one or more selected from the group consisting of chronic obstructive pulmonary disease (COPD), emphysema, ventilation-related lung injury, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), pulmonary arterial hypertension (PAH) and right heart failure caused by the pulmonary arterial hypertension.

9. The pharmaceutical composition according to claim 4, characterized in that The neurodegenerative disease is any one or more selected from the group consisting of Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease, Lou Gehrig's disease, epilepsy, depression, insomnia, anxiety, and multiple sclerosis (MS).

10. The pharmaceutical composition according to claim 4, characterized in that The pharmaceutical composition further comprises: A sulfenyl imine derivative or a pharmaceutically acceptable salt thereof; and Any one or more additional ingredients selected from the group consisting of pharmaceutically acceptable carriers, excipients, diluents, stabilizers and preservatives.

11. The pharmaceutical composition according to claim 10, characterized in that The pharmaceutical composition has any one or more dosage forms selected from the group consisting of powder, granules, tablets, capsules and injections.

12. A method for preparing a sulfenyl imine derivative or a pharmaceutically acceptable salt thereof, comprising the following steps: (1) a step of preparing a compound represented by [Chemical Formula 3] from a compound represented by [Chemical Formula 2]; (2) a step of preparing a compound represented by [Chemical Formula 4] from a compound represented by [Chemical Formula 3]; (3) a step of preparing a compound represented by [Chemical Formula 5] from a compound represented by [Chemical Formula 4]; as well as (4) a step of adding a compound represented by [Chemical Formula 6] to a compound represented by [Chemical Formula 5] to prepare a compound represented by [Chemical Formula 1], [Chemical formula 1] [Chemical formula 2] [Chemical formula 3] [Chemical formula 4] [Chemical formula 5] [Chemical formula 6] In the chemical formulas 1 to 6, A and B are each independently phenyl or pyridine (except when both A and B are phenyl); R is hydrogen, trimethylsilyl (TMS) or methyl; Each of A and B is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, cyano, nitro, C1-C7 alkyl and C1-C7 alkoxy (except when both A and B are unsubstituted); One or more hydrogen atoms in the alkyl group or alkoxy group are unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, nitro and morpholino.

13. The preparation method according to claim 12, characterized in that: In the step (1), the compound represented by [Chemical Formula 2] is dissolved in methanol (MeOH), and ammonium carbonate ((NH4)2CO3) and diacetoxyiodobenzene (PhI(OAc)2) are added in sequence.

14. The preparation method according to claim 12, characterized in that: In the step (2), hexamethyldisilazane (HMDS) is added to the compound represented by [Chemical Formula 3], followed by reflux stirring.

15. The preparation method according to claim 12, characterized in that: In the step (3), the compound represented by [Chemical Formula 4] is dissolved in tetrahydrofuran (THF), and n-butyl lithium (n-BuLi) and diethyl chlorophosphate are added in sequence.

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