Novel sulfanon derivatives or pharmaceutically acceptable salts thereof, and uses thereof

Abstract

The present invention relates to a sulfanon derivative or a pharmaceutically acceptable salt thereof, and a composition for cancer prevention or treatment containing the derivative as an active ingredient. The sulfanon derivative or a pharmaceutically acceptable salt thereof of the present invention has excellent Nrf2 activation effect, high solubility and drug metabolic stability, anti-inflammatory and antioxidant effects, and improves exercise ability and cognitive ability. Therefore, it is used for the prevention or treatment of diseases induced by the decrease of Nrf2 activity, preferably liver diseases, kidney diseases, lung diseases, neurodegenerative diseases, mitochondrial myopathy, Friedreich's ataxia, corneal endothelial cell reduction, and psoriasis.

Description

Technical Field

[0001] The present invention relates to a novel sulfanone derivative or a pharmaceutically acceptable salt thereof, a method for producing the same, an Nrf2 activator containing the same as an active ingredient, and a pharmaceutical composition for preventing or treating diseases induced by a decrease in Nrf2 activity, etc.

Background Art

[0002] Nrf2 (nuclear factor erythroid-derived 2-related factor 2) is a region involved in the expression of various genes that protect cells as a Cap’n’Collar family basic region-leuzine zipper transcription factor. It binds to the ARE (Antioxidant Response Element) sequence and induces gene transcription. Although the expression of all antioxidant enzymes is not induced by ARE inducers, it has been clarified through studies using Nrf2-null mice in which this transcription factor has been artificially knocked out that the expression of antioxidant enzymes is induced through the activation of Nrf2 mediated by ARE.

[0003] Nrf2 is negatively regulated by Keap1 (Kelch-like ECH associated protein 1). In the absence of oxidative stress, Nrf2 binds to Keap1 and is ubiquitinated and degraded by the proteasome. However, in the presence of oxidative stress, the binding to Nrf2 is separated through the modification of cysteine residues of Keap1, and Nrf2 moves into the nucleus, binds to ARE, and increases the transcription of various antioxidant genes present at the promoter site.

[0004] Compounds with various structures that can induce the transcription of protective genes through the Nrf2-Keap1 pathway have been discovered among natural products, foods, metabolites, organic synthetic compounds, etc. All of the previously known compounds are either electrophilic compounds that can react with the cysteine of Keap1 or compounds that can be converted into electrophilic compounds through intracellular metabolic processes. Compounds with such electrophilicity or reactive oxygen species react with the cysteine residues of Keap1 to oxidize or covalently bond to the thiol groups, thereby causing structural changes in Keap1. The separated Nrf2 due to the change in the cysteine residues of Keap1 moves into the nucleus and binds to ARE, thereby inducing the expression of antioxidant enzymes. It has been reported that by pre-activating the Nrf2-Keap1 pathway using electrophilic compounds, Nrf2 activators can prevent the development of degenerative brain diseases through a chemical defense mechanism against oxidative stress.

[0005] As a drug that reacts with the cysteine residues of Keap1, sulforaphane (1-isothiocyanato-4-methylsulfinylbutane) mainly exists in cruciferous plants such as broccoli and Chinese cabbage, activates Nrf2, and protects dopaminergic neurons from oxidative stress. However, sulforaphane may non-selectively denature various intracellular proteins having thiol groups and induce cytotoxicity, and has the demerit of a very low blood-brain barrier permeability. Also, when administered in the body, it disappears within 1 hour, so the Nrf2 activity induction effect cannot be sustained, and thus, when administered at a high concentration to show a certain activity, it causes cytotoxicity.

[0006] Therefore, the development of a novel Nrf2 activator that overcomes the problems of conventional Nrf2 activators is required. In such a context, the inventors of the present invention confirmed that a novel sulphanone derivative or a pharmaceutically acceptable salt thereof has excellent Nrf2 activation effects, high solubility and drug metabolism stability, anti-inflammatory and antioxidant effects, and improves motor ability and cognitive ability, and thus completed the present invention.

Summary of the Invention

Problems to be Solved by the Invention

[0007] The technical problem of the present invention is to provide a sulfanon derivative or a pharmaceutically acceptable salt thereof.

[0008] Another object of the present invention is to provide a composition for preventing, ameliorating, or treating a disease induced by a decrease in Nrf2 activity, which contains the sulfanon derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0009] The technical problem of the present invention is to provide a method for producing the sulfanon derivative or a pharmaceutically acceptable salt thereof.

[0010] However, the technical problems of the present invention are not limited to the problems mentioned above, and further other problems not mentioned will be clearly understood by those of ordinary skill in the art from the following description.

Means for Solving the Problems

[0011] To solve the above problems, the present invention provides a sulfanon derivative represented by the following Chemical Formula 1, or a racemate, isomer, solvate, or pharmaceutically acceptable salt thereof.

Chem.

[0012] As an embodiment of the present invention, the sulfanone derivative represented by Chemical Formula 1 may be any one selected from the group consisting of the following compounds. (1)(E)-(2-fluorophenyl)(imino)(2-(pyridin-2-yl)vinyl)-λ 6 -sulfanone; (2)(E)-imino(4-methoxyphenyl)(2-(pyridin-2-yl)vinyl)-λ 6 -sulfanone; (3)(E)-(2-chlorophenyl)(2-(3-fluoropyridin-2-yl)vinyl)(imino)-λ 6 -sulfanone; (4)(E)-(2-chlorophenyl)(2-(3-chloropyridin-2-yl)vinyl)(imino)-λ 6 -sulfanone; (5)(E)-(2-fluorophenyl)(2-(3-fluoropyridin-2-yl)vinyl)(imino)-λ 6 -sulfanone; (6)(E)-(2-(3-chloropyridin-2-yl)vinyl)(2-fluorophenyl)(imino)-λ 6 -sulfanone; (7)(E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(3-methoxyphenyl)-λ 6 -sulfanone; (8)(E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(2-methoxyphenyl)-λ 6 -sulfanone; (9)(E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(3-methoxyphenyl)-λ 6 -sulfanone; (10)(E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(4-methoxyphenyl)-λ 6 -sulfanone; (11)(E)-imino(2-methoxyphenyl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6 -sulfanone; (12)(E)-(2-chlorophenyl)(imino)(2-(pyridin-3-yl)vinyl)-λ 6 -sulfanone; (13)(E)-(2-chlorophenyl)(2-(2-chloropyridin-3-yl)vinyl)(imino)-λ 6 -sulfanone; (14)(E)-(2-chlorophenyl)(imino)(2-(2,4,6-trichloropyrimidin-5-yl)vinyl)-λ 6 -sulfanone; (15)(E)-(2-chlorostyryl)(imino)(pyridin-2-yl)-λ 6 -sulfanone; (16)(E)-(3-chlorostyryl)(imino)(pyridin-2-yl)-λ 6 -sulfanone; (17)(E)-imino(pyridin-2-yl)(2-(trifluoromethyl)styryl)-λ 6 -sulfanone; (18)(E)-imino(pyridin-2-yl)(2-(trifluoromethoxy)styryl)-λ 6 -sulfanone; (19)(E)-(2,6-dichlorostyryl)(imino)(pyridin-2-yl)-λ 6 -sulfanone; (20)(E)-(4-chlorostyryl)(imino)(pyridin-2-yl)-λ 6 -sulfanone; (21)(E)-(5-chloropyridin-2-yl)(2-chlorostyryl)(imino)-λ 6 -sulfanone; (22)(E)-(2,6-difluorostyryl)(imino)(pyridin-2-yl)-λ 6 -sulfanone; (23)(E)-imino(pyridin-2-yl)(2,4,6-trifluorostyryl)-λ 6 -sulfanone; (24)(E)-(2-fluorostyryl)(imino)(pyridin-2-yl)-λ 6 -sulfanone; (25)(E)-imino(3-methoxypyridin-2-yl)(2-(trifluoromethyl)styryl)-λ 6 -sulfanone; (26)(E)-imino(4-methoxypyridin-2-yl)(2-(trifluoromethyl)styryl)-λ 6 -sulfanone; (27)(E)-imino(4-methoxypyridin-2-yl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6 -sulfanone; (28)(E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(4-methoxypyridin-2-yl)-λ 6 -sulfanone; (29)(E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(4-methoxypyridin-2-yl)-λ 6 -sulfanone; (30)(E)-(2-chlorostyryl)(imino)(4-methoxypyridin-2-yl)-λ 6 -sulfanone; (31)(E)-(2-fluorostyryl)(imino)(4-methoxypyridin-2-yl)-λ 6 -sulfanone; (32)(E)-imino(4-methoxypyridin-2-yl)(2-(3-methoxypyridin-2-yl)vinyl)-λ 6 -sulfanone; (33)(E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(3-methoxypyridin-2-yl)-λ 6 -sulfanone; (34)(E)-imino(3-methoxypyridin-2-yl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6 -sulfanone; (35)(E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(5-methoxypyridin-2-yl)-λ 6 -sulfanone; (36)(E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(5-methoxypyridin-2-yl)-λ 6 -sulfanone; (37)(E)-imino(5-methoxypyridin-2-yl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6 -sulfanone; (38)(E)-(3-chloropyridin-2-yl)(2-chlorostyryl)(imino)-λ 6 -sulfanone; (39)(E)-(2-chlorostyryl)(imino)(5-methoxypyridin-2-yl)-λ 6 -sulfanone; (40)(E)-(2-chlorostyryl)(3-fluoropyridin-2-yl)(imino)-λ 6 -sulfanone; (41)(E)-(3-chloropyridin-4-yl)(2-chlorostyryl)(imino)-λ 6 -sulfanone; (42)(E)-(5-chloropyridin-2-yl)(2-chlorostyryl)(imino)-λ 6 -sulfanone; (43)(E)-(2-chlorostyryl)(imino)(3-methoxypyridin-2-yl)-λ 6 -sulfanone; (44)(E)-(2-fluorostyryl)(imino)(3-methoxypyridin-2-yl)-λ 6 -sulfanone; (45)(E)-(4-chloropyridin-2-yl)(2-chlorostyryl)(imino)-λ 6 -sulfanone; (46)(E)-(2-chlorostyryl)(3-fluoropyridin-4-yl)((trimethylsilyl)imino)-λ 6 -sulfanone; (47)(E)-(2-chlorostyryl)(3-fluoropyridin-4-yl)(imino)-λ 6 -sulfanone; (48)(E)-(4-chloropyridin-3-yl)(2-chlorostyryl)(imino)-λ6 -sulfanone; (49)(E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(pyridin-2-yl)-λ 6 -sulfanone; (50)(E)-imino(2-(3-methoxypyridin-2-yl)vinyl)(pyridin-2-yl)-λ 6 -sulfanone; (51)(E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(pyridin-2-yl)-λ 6 -sulfanone; (52)(E)-imino(pyridin-2-yl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6 -sulfanone; (53)(E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(5-(3-morpholinopropoxy)pyridin-2-yl)-λ 6 -sulfanone; (54)(E)-imino(5-methoxypyridin-2-yl)(2-(trifluoromethyl)styryl)-λ 6 -sulfanone; (55)(E)-(2-fluorostyryl)(imino)(5-methoxypyridin-2-yl)-λ 6 -sulfanone; (56)(E)-(2-fluorostyryl)(5-methoxypyridin-2-yl)(methylimino)-λ 6 -sulfanone; (57)(E)-N-((2-chlorostyryl)(2-methoxyphenyl)(oxo)-λ 6 -sulfanylidene)cyanamide; and (58)(E)-N-((2-(3-chloropyridin-2-yl)vinyl)(2-methoxyphenyl)(oxo)-λ 6 -sulfaneylidene)cyanamide。

[0013] As another embodiment of the present invention, the sulfanon derivative may activate Nrf2 (nuclear factor erythroid-derived 2-related factor 2).

[0014] As another embodiment of the present invention, the pharmaceutically acceptable salts of the sulfanon derivative may be any one or more selected from the group consisting of hydrochloride, bromate, sulfate, phosphate, nitrate, citrate, acetate, lactate, tartaric acid, maleate, gluconate, succinate, formate, trifluoroacetate, oxalate, fumarate, glutarate, adipate, methanesulfonate, benzenesulfonate, paratoluenesulfonate, camphorsulfonate, sodium salt, potassium salt, lithium salt, calcium salt, and magnesium salt.

[0015] The present invention also provides a pharmaceutical composition for preventing or treating diseases induced by a decrease in Nrf2 activity, which contains the sulfanon derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0016] As one embodiment of the present invention, the diseases induced by a decrease in Nrf2 activity may be any one or more selected from the group consisting of liver diseases, kidney diseases, pulmonary diseases, neurodegenerative diseases, Mitochondrial myopathy, Friedreich’s ataxia, Cornealendothelial cell loss, and Psoriasis, but are not limited thereto.

[0017] The liver diseases may include, but are not limited to, alcoholic liver disease, non-alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), chronic liver injury, viral hepatitis, hepatocellular carcinoma, etc.

[0018] The kidney diseases may include, but are not limited to, diabetic nephropathy, focal segmental glomerulosclerosis, renal fibrosis, lupus-like autoimmune nephritis, chronic kidney disease (CKD), hypertensive kidney disease, etc.

[0019] The lung diseases may include, but are not limited to, chronic obstructive pulmonary disease (COPD), pulmonary emphysema, ventilation-associated lung injury, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), pulmonary artery hypertension (PAH), right heart failure induced by the pulmonary artery hypertension, etc.

[0020] The neurodegenerative disease may be, but is not limited to, Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease, Lou Gehrig’s disease, epilepsy, depression, insomnia, anxiety, Multiple sclerosis (MS), etc.

[0021] As another embodiment of the present invention, the pharmaceutical composition may further include any one or more additional components selected from the group consisting of the sulfanone derivative or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, excipient, diluent, stabilizer, and preservative.

[0022] 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, granule, tablet, capsule, and injection.

[0023] In addition, the present invention provides a method for preventing or treating a disease induced by a decrease in Nrf2 activity, including the step of administering the sulfanone derivative or a pharmaceutically acceptable salt thereof to an individual.

[0024] In addition, the present invention provides the use of the sulfanone derivative or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing or treating a disease induced by a decrease in Nrf2 activity.

[0025] In addition, the present invention provides a cosmetic composition for preventing or improving a disease induced by a decrease in Nrf2 activity, having the sulfanone derivative or a cosmetically acceptable salt thereof as an active ingredient.

[0026] In addition, the present invention provides a food composition for preventing or improving a disease induced by a decrease in Nrf2 activity, having the sulfanone derivative or a food-acceptable salt thereof as an active ingredient.

[0027] The present invention also provides a feed composition for preventing or ameliorating a disease induced by a decrease in Nrf2 activity, which contains the sulfanon derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0028] The present invention also provides a method for producing the sulfanon derivative or a pharmaceutically acceptable salt thereof, which includes the following steps. (1) A step of producing a compound represented by Chemical Formula 3 from a compound represented by Chemical Formula 2, (2) A step of producing a compound represented by Chemical Formula 4 from a compound represented by Chemical Formula 3, (3) A step of producing a compound represented by Chemical Formula 5 from a compound represented by Chemical Formula 4, and (4) A step of adding a compound represented by Chemical Formula 6 to a compound represented by Chemical Formula 5 to produce a compound represented by Chemical Formula 1.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0029] As an embodiment of the present invention, the step (1) may be to dissolve the compound represented by Chemical Formula 2 in methanol (MeOH) and sequentially add ammonium carbonate ((NH4)2CO3) and diacetoxyiodobenzene (PhI(OAc)2).

[0030] As another embodiment of the present invention, the step (2) may be to add hexamethyldisilazane (HMDS) to the compound represented by Chemical Formula 3 and then reflux and stir.

[0031] As another embodiment of the present invention, the step (3) may be to dissolve the compound represented by Chemical Formula 4 in tetrahydrofuran (THF) and sequentially add n-butyllithium (n-BuLi) and diethyl chlorophosphite.

Advantages of the Invention

[0032] The present invention relates to a sulfanone derivative or a pharmaceutically acceptable salt thereof, and a composition for preventing or treating cancer containing the derivative as an active ingredient. The sulfanone derivative or a pharmaceutically acceptable salt thereof of the present invention has excellent Nrf2 activation effect, high solubility and drug metabolism stability, anti-inflammatory and antioxidant effects, and can improve exercise ability and cognitive ability. Therefore, it is used for the prevention or treatment of diseases induced by the decrease of Nrf2 activity, preferably liver diseases, kidney diseases, lung diseases, neurodegenerative diseases, mitochondrial myopathy, Friedreich's ataxia, corneal endothelial cell reduction, and psoriasis.

[0033] The effects of the present invention are not limited to those mentioned above, and other effects not mentioned will be clearly understood by those skilled in the art from the following description.

Brief Description of the Drawings

[0034]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

DETAILED DESCRIPTION OF THE INVENTION

[0035] As a result of intensive research on sulfanon derivatives or pharmaceutically acceptable salts thereof, the present inventors have confirmed that the derivatives or pharmaceutically acceptable salts thereof have excellent Nrf2 activation effects, high solubility and drug metabolic stability, anti-inflammatory and antioxidant effects, and improve motor and cognitive abilities.

[0036] Based on the above results, the present invention can provide a sulfanon derivative represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof. In this case, the sulfanon derivative may include its racemate, isomer, and solvate.

CHEMICAL

[0037] As used herein, the term "substitution" refers to a reaction in which an atom or atomic group contained in the molecule of a compound is replaced by another atom or atomic group.

[0038] As used herein, the term "alkyl group" means a residue of a monovalent linear, branched or cyclic saturated hydrocarbon consisting only of carbon and hydrogen atoms, 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 group, cyclopentyl group, cyclohexyl group, etc.

[0039] As used herein, the term "alkoxy group" means an alkyl group (-O-R) bonded to oxygen. Examples of such alkoxy groups include, but are not limited to, methoxy group, ethoxy group, propoxy group, butoxy group, etc.

[0040] The "halogen group" in the present invention may be, for example, fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0041] As used herein, the term "pharmaceutically acceptable salt" means a dosage form of a compound that does not cause serious irritation to the organism to which the compound is administered and does not damage the biological activity and physical properties of the compound.

[0042] The pharmaceutically acceptable salts can be obtained by reacting the compound of the present invention with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, and phosphoric acid, sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid, and organic carboxylic acids 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, and salicylic acid. Further, the compound of the present invention can be reacted with a base to form salts such as ammonium salts, alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, salts of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, and tris(hydroxymethyl)methylamine, and amino acid salts such as arginine and lysine.

[0043] In addition, the sulfanone derivative or its pharmaceutically acceptable salt can include not only pharmaceutically acceptable salts but also all salts, hydrates, and solvates that can be produced by conventional methods.

[0044] Since the sulfanone derivative or its pharmaceutically acceptable salt of the present invention has the effect of activating Nrf2, it can be used in a pharmaceutical composition for preventing or treating diseases induced by a decrease in Nrf2 activity containing the sulfanone derivative or its pharmaceutically acceptable salt as an active ingredient.

[0045] The term "Nrf2 (nuclear factor erythroid-derived 2-related factor 2)" of the present invention is a transcription factor encoded by the NFE2L2 gene in humans, and is a basic leucine zipper protein (bZIP) that regulates the expression of antioxidant proteins that protect against oxidative damage induced by injury and inflammation. Accordingly, drugs that activate the Nrf2 pathway have been studied for the treatment of diseases caused by oxidative stress.

[0046] As used herein, the term "prevention" means any act of suppressing or delaying the occurrence, spread or recurrence of a disease by administration of the composition of the present invention, and "treatment" means any act of improving or favorably changing the symptoms of the disease by administration of the composition of the present invention.

[0047] As described above, Nrf2 targeted by the compound of the present invention has been reported to be involved in the prevention and treatment of various diseases through its antioxidant defense mechanism via activation. For example, non-limiting examples of diseases induced by a decrease in Nrf2 activity that can be prevented or treated by administering the composition of the present invention 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; pulmonary diseases such as chronic obstructive pulmonary disease (COPD), pulmonary emphysema, ventilation-associated lung injury, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), pulmonary artery hypertension (PAH), and right heart failure induced by pulmonary artery hypertension; Parkinson's disease (PD), Alzheimer's disease;AD), neurodegenerative diseases such as 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.

[0048] The term "pharmaceutical composition" in the present invention means a composition manufactured for the purpose of preventing or treating diseases, and is formulated into various dosage forms by conventional methods and used accordingly. For example, it can be formulated into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, etc., and is formulated and used in the form of external preparations, suppositories, and sterile injection solutions.

[0049] "Containing as an active ingredient" in the present invention means that the component is contained in an amount necessary or sufficient for achieving the desired biological effect. In actual applications, the determination of the amount contained as an active ingredient is determined as the amount for treating the target disease, taking into account other factors that do not cause other toxicities, and can vary depending on various factors such as the disease or condition to be treated, the form of the administered composition, the size of the subject, or the severity of the disease or condition. A person skilled in the art with ordinary skills in the field to which the present invention pertains can empirically determine the effective amount of an individual composition without undue experimentation.

[0050] In addition, the pharmaceutical composition of the present invention may further contain one or more pharmaceutically acceptable carriers in addition to the aforementioned active ingredients according to each dosage form.

[0051] The pharmaceutically acceptable carrier may be saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and a mixture of one or more of these components, and may further contain other conventional additives such as antioxidants, buffers, bacteriostatic agents as necessary. Additionally, a diluent, dispersant, surfactant, binder, and lubricant may be further added to formulate into injection dosage forms such as aqueous solutions, suspensions, emulsions, pills, capsules, granules, or tablets. Furthermore, it can be preferably formulated according to each disease or component by an appropriate method in the art or using the method disclosed in Remington’s Pharmaceutical Science (Mack Publishing Company, Easton PA).

[0052] In addition, the present invention can provide a method for preventing, treating, and / or diagnosing a disease induced by a decrease in Nrf2 activity, which includes the step of administering the sulfanon derivative or its pharmaceutically acceptable salt to an individual.

[0053] The term "individual" in the present invention is not limited as long as it is a mammal such as a livestock or a human in which a disease induced by a decrease in Nrf2 activity has occurred or may occur and requires prevention or treatment of the disease, but 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 exhibits a therapeutic effect by activating Nrf2, a synergistic effect can be achieved by administering it in combination with a conventional therapeutic agent.

[0054] As used herein, the term "administer" means providing a predetermined substance to a patient by any suitable method, and the pharmaceutical composition of the present invention can be formulated in various forms for administration to an individual. Representative dosage forms for parenteral administration are dosage forms for injection, and isotonic aqueous solutions or suspensions are preferred. Dosage forms for injection can be produced according to techniques known in the art using compatible dispersing or wetting agents and suspending agents. For example, each component can be dissolved in saline or buffer solution and formulated into a dosage form for injection. In addition, dosage forms for oral administration include, for example, ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, and wafers. These dosage forms can contain, in addition to the active ingredient, diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine) and lubricants (e.g., silica, talc, stearic acid and its magnesium or calcium salts, and / or polyethylene glycol). The tablets can contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidine, and may further contain disintegrants, absorbents, colorants, flavoring agents, and / or sweetening agents such as starch, agar, alginic acid, or its sodium salt. The dosage forms can be produced by conventional mixing, granulating, or coating methods.

[0055] In addition, the pharmaceutical composition of the present invention can further contain adjuvants such as preservatives, hydrating agents, emulsification promoters, salts or buffers for adjusting osmotic pressure, and other therapeutically useful substances, and can be formulated by conventional methods.

[0056] The pharmaceutical composition according to the present invention can be administered via various routes including oral, transdermal, subcutaneous, intravenous, or intramuscular routes, and the dosage of the active ingredient is appropriately selected according to various factors such as the administration route, the age, sex, weight of the patient, and the severity of the patient. In addition, the composition of the present invention can be administered in combination with known compounds that enhance the desired effect.

[0057] As the administration route of the pharmaceutical composition according to the present invention, it can be administered orally, or parenterally to humans and animals, such as intravenously, subcutaneously, intranasally or intraperitoneally. Oral administration includes sublingual administration. Parenteral administration includes injection methods such as subcutaneous injection, intramuscular injection and intravenous injection, and infusion methods.

[0058] The composition of the present invention can be administered orally or parenterally in a pharmaceutically effective amount by the intended method. The term "pharmaceutically effective amount" as used in the present invention means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and that does not cause side effects. The level of the effective dose is determined by factors including the patient's health status, severity, drug activity, sensitivity to the drug, administration method, administration time, administration route and excretion rate, treatment period, ingredients including the formulation or co-administered drugs, and other factors known in the medical field.

[0059] That is, the total effective amount of the sulfanon derivative or its pharmaceutically acceptable salt according to the present invention is administered to the patient in a single dose, and multiple doses are administered by a fractionated treatment protocol administered over a long period. The pharmaceutical composition of the present invention can vary the content of the active ingredient according to the degree of the disease, and the effective dose for the patient is determined in consideration of various factors such as the administration route and number of treatments of the drug, as well as the patient's age, weight, health status, gender, disease severity, diet and excretion rate.

[0060] The terms used in the examples are for illustrative purposes only and should not be construed as limiting. Singular expressions include plural expressions unless otherwise clearly indicated in the context. Terms such as "including" or "having" in this specification are used to specify the presence of the features, numbers, steps, operations, components, parts or combinations thereof described in the specification, and should be understood not to preclude the presence or addition possibility of one or more other features, numbers, steps, operations, components, parts or combinations thereof.

[0061] Unless otherwise defined, all terms used herein, including technical or scientific terms, shall have the same meaning as commonly understood by one of ordinary skill in the art to which the embodiments belong. Terms defined in commonly used dictionaries shall be interpreted to have a meaning consistent with the meaning in the context of the relevant art, and shall not be interpreted in an idealized or overly formal sense unless explicitly defined in this application.

[0062] Hereinafter, embodiments will be described in detail with reference to the accompanying drawings. However, various changes may be made to the embodiments, and the scope of the patent application shall not be limited or restricted by such embodiments. All changes, equivalents, or alternatives to the embodiments should be understood to be included within the scope of the rights.

[0063] Also, in the description with reference to the accompanying drawings, the same reference numerals are assigned to the same components regardless of the reference signs, and duplicate descriptions thereof are omitted. In the description of the embodiments, when it is determined that a specific description of related known technologies obscures the gist of the embodiments, the detailed description thereof is omitted. Modes for Carrying Out the Invention

[0064] Example 1. Synthesis of Cyanosulfonanone Derivatives As an example of the present invention, the synthesis process of the sulfonanone derivative when R in Chemical Formula 1 is cyano is shown in the following Reaction Formula 1.

Chemical Formula

[0065] (1) Synthesis of Substituted (Methylsulfinyl)benzene by Reaction with Meta-Chloroperoxybenzoic Acid

Chemical Formula

[0066] (Methylsulfinyl)benzene substituted by the above reaction formula was synthesized. Specifically, substituted methyl(phenyl)sulfane (1.0 eq) was dissolved in dichloromethane (DCM), and metachloroperbenzoic acid (mCPBA, 1.0 eq) was added at 0 °C, followed by stirring 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 then the organic layer was dried over anhydrous Na2SO4 and filtered. The residue obtained by distilling off the solvent under reduced pressure was purified by column chromatography to obtain 2-, 3- or 4-substituted (methylsulfinyl)benzene.

[0067] (2) Synthesis of substituted N-(methyl(oxo)(phenyl)-lambda 6 -sulfaneylidene)cyanamide using the reaction with cyanamide [Chemical formula]

[0068] Substituted N-(methyl(oxo)(phenyl)-lambda 6 -sulfaneylidene)cyanamide (N-(methyl(oxo)(phenyl)-λ 6 -sulfaneylidene)cyanamide) was synthesized. Specifically, the compound synthesized in the above reaction (1) (1.0 eq) was well dissolved in water, and cyanamide (2.0 eq), potassium tert-butoxide (KOtBu, 2.0 eq), and N-chlorosuccinimide (NCS, 2.0 eq) were added, followed by stirring at room temperature for 2 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate (EtOAc), washed with water and brine, and then the organic layer was dried over anhydrous Na2SO4 and filtered. The residue obtained by distilling off the solvent under reduced pressure was purified by column chromatography to obtain 2-, 3- or 4-substituted N-(methyl(oxo)(phenyl)-lambda6 -sulfanilidenecyanamide was obtained.

[0069] (3) Synthesis of substituted diethyl ((N-cyanophenylsulfonimidoyl)methyl)phosphonate by reaction with diethyl chlorophosphate

Chemical formula

[0070] Substituted diethyl ((N-cyanophenylsulfonimidoyl)methyl)phosphonate was synthesized according to the above reaction formula. Specifically, the compound synthesized in the above reaction (2) (1.0 eq) was dissolved in anhydrous tetrahydrofuran (THF), and then cooled to -78 °C using acetone and dry ice. Subsequently, n-butyllithium (2.2 eq, 2.0 M 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 eq) was added at the same temperature, and then the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate (EtOAc), washed with water and brine, and then the organic layer was dried over anhydrous Na2SO4 and filtered. The residue obtained by distilling off the solvent under reduced pressure was purified by column chromatography to obtain 2-, 3- or 4-substituted diethyl ((N-cyanophenylsulfonimidoyl)methyl)phosphonate.

[0071] (4) Synthesis of substituted (E)-N-(oxo(phenyl)(2-(pyridin-2-yl)vinyl)-lambda 6 -sulfanilidenecyanamide by reaction with picolinaldehyde derivative

Chemical formula

[0072] The (E)-N-(oxo(phenyl)(2-(pyridin-2-yl)vinyl)-lambda substituted 6 -sulfanilidene)cyanamide ((E)-N-(oxo(phenyl)(2-(pyridin-2-yl)vinyl)-λ 6 The compound (1.0 eq) synthesized in reaction (3) was dissolved in anhydrous THF and cooled to -78°C using dry ice and acetone. n-BuLi (1.2 eq, 2.0 M cyclohexane solution) was slowly added dropwise to the solution, stirred for 1 hour, and benzaldehyde derivatives (1.2 eq) were added and reacted for another 1 hour. If the reaction was not completed by checking TLC, the reaction was continued for another 30 minutes at room temperature. The reaction was terminated with a small amount of water, and then extracted with water and 10% MeOH / MC. The organic layer was removed with anhydrous Na2SO4 to remove a small amount of water, and the solvent was removed by distillation under reduced pressure and dried in vacuum. Then, the compound was separated and purified by column chromatography to obtain 2-, 3-, or 4-substituted (E)-imino(phenyl)(styryl)-lambda. 6 -sulfanone derivative was obtained.

[0073] Example 1.1.(E)-N-((2-(3-chloropyridin-2-yl)vinyl)(2-methoxyphenyl)(oxo)-λ 6 Synthesis of -sulfaneylidene)cyanamide (chemical formula 1-57)

[0074] Synthesis of 1.1.1.1-methoxy-2-(methylsulfinyl)benzene [ka]

[0075] Using the reaction (1), (2-methoxyphenyl)(methyl)sulfane (1.00 g, 6.48 mmol) was dissolved well in DCM, and then reacted with 70 - 75% mCPBA (1.60 g, 6.48 mmol) to synthesize pale yellow oily 1-methoxy-2-(methylsulfinyl)benzene (0.99 g, 90%); R f = 0.44 (EtOAc 100%); 1 1H NMR (400 MHz, CDCl3) δ 7.83 (dd, 1.6, 7.7 Hz, ArH), 7.46 (td, 1.7, 7.9 Hz, ArH), 7.20 (td, 0.8, 7.6 Hz, ArH), 6.93 (d, 8.1 Hz, ArH), 3.89 (s, OCH3), 2.78 (s, SCH3).

[0076] 1.1.2. Synthesis of N-((2-methoxyphenyl)(methyl)(oxo)-λ 6 -sulfaneylidene)cyanamide

Chemical Structure

[0077] Using the reaction (2), 1-methoxy-2-(methylsulfinyl)benzene (0.99 g, 5.81 mmol) was dissolved well 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 transparent oily N-((2-methoxyphenyl)(methyl)(oxo)-λ 6 -sulfaneylidene)cyanamide (1.03 g, 84%); R f = 0.30 (n-hexane 1:EtOAc 3); 1 1H NMR (400 MHz, DMSO-d6) δ 7.90 - 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, SCH3).

[0078] 1.1.3. Synthesis of Diethyl((N-cyano-2-methoxyphenylsulfonimidoyl)methyl)phosphonate [Chemical formula]

[0079] Using the above reaction (3), N-((2-methoxyphenyl)(methyl)(oxo)-λ 6 -sulfaneylidene)cyanamide (1.03 g, 4.90 mmol) was well dissolved in THF, and then reacted with diethyl chlorophosphate (1.06 ml, 7.35 mmol) and 2.0 M 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 (EtOAc 100%); 1 1H NMR (400 MHz, CDCl3) δ 8.00 (dd, 1.5, 8.0 Hz, ArH), 7.74 (td, 1.6, 8.1 Hz, ArH), 7.22 (t, 7.4 Hz, ArH), 7.14 (d, 8.3 Hz, ArH), 4.37 - 4.21 (m, SCH2P), 4.16 - 4.06 (m, (POCH2CH3)2, OCH3), 1.27 (dt, 7.2, 36.9 Hz, P(OCH2CH3)2).

[0080] 1.1.4. Synthesis of (E)-N-((2-chlorostyryl)(2-methoxyphenyl)(oxo)-λ 6 -sulfanylidene)cyanamide (Chemical formula 1-57) [Chemical formula]

[0081] Using the reaction (4), Diethyl((N-cyano-2-methoxyphenylsulfonimidoyl)methyl)phosphonate (0.20 g, 0.58 mmol), 2.0 M n-BuLi solution in cyclohexane (0.32 mL, 0.64 mmol), and 3-chloropicolinaldehyde (0.07 ml, 0.64 mmol) were reacted to synthesize a white solid compound 1-57 (0.08 g, 39%): R f = 0.46 (n-hexane 1:EtOAc 3); 1 1H NMR (DMSO-d6, 400 MHz) δ 8.12 - 8.02 (m, (E)-isomeric H, 2ArH), 7.92 - 7.86 (m, (E)-isomeric 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); 13 13C NMR (DMSO-d6, 100 MHz) δ 157.7, 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.

[0082] Example 1.2. Synthesis of (E)-N-((2-(3-chloropyridin-2-yl)vinyl)(2-methoxyphenyl)(oxo)-λ 6 -sulfaneylidene)cyanamide (Chemical Formula 1-58)

Chemical Structure

[0083] Diethyl((N-cyano-2-methoxyphenylsulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 1.1.1 to 1.1.3.

[0084] Using the reaction (4), Diethyl((N-cyano-2-methoxyphenylsulfonimidoyl)methyl)phosphonate (0.10 g, 0.29 mmol), 2.0 M n-BuLi solution in cyclohexane (0.17 mL, 0.35 mmol), and 3-chloropicolinaldehyde (0.05 g, 0.35 mmol) were reacted to synthesize a white solid compound 1-58 (0.03 g, 30%): R f = 0.23 (n-hexane 1:EtOAc 2); 1 H NMR (CDCl3, 400 MHz) δ 8.54 (dd, J = 1.3, 4.5 Hz, ArH), 8.25 (d, J = 14.6 Hz, (E)-isomeric H), 8.06 (dd, J = 1.6, 8.0 Hz, ArH), 7.85 (d, J = 14.6 Hz, (E)-isomeric H), 7.77 (dd, J = 1.4, 8.2 Hz, ArH) 7.70 (td, J = 1.6, 8.0 Hz, ArH), 7.32 (dd, J = 4.5, 8.2 Hz, ArH), 7.19 (td, J = 0.7, 7.8 Hz, ArH), 7.12 (td, J = 8.4 Hz, ArH), 4.05 (s, OCH3); 13 C NMR (CDCl3, 100 MHz) δ 157.5, 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.

[0085] Synthesis of sulfanone derivatives where A is phenyl and B is pyridine in Example 2.A As an example of the present invention, the synthesis process of the sulfanone derivative where A is phenyl and B is pyridine in Chemical Formula 1 is shown in the following Reaction Formula 2.

Chemical formula

[0086] (1) Synthesis of substituted imino(methyl)(phenyl)-lambda 6 -sulfanone by the reaction of ammonium carbonate and diacetoxyiodobenzene [Chemical formula]

[0087] The imino(methyl)(phenyl)-λ 6 -sulfanone substituted by the said reaction formula was synthesized. Specifically, the compound (1.0 eq) synthesized in the said reaction (1) was dissolved in methyl alcohol (Methanol; MeOH), and ammonium carbonate ((NH4)2CO3, 1.5 eq) was added. Next, after adding diacetoxyiodobenzene (PhI(OAc)2, 2.3 eq), it was stirred at room temperature for 3 to 18 hours. When the reaction was completed, the reaction solution was depressurized to remove the solvent. The obtained residue was purified by column chromatography to obtain 2-, 3- or 4-substituted imino(methyl)(phenyl)-λ 6 -sulfanone. 6

[0088] (2) Synthesis of substituted methyl(phenyl)((trimethylsilyl)imino)-λ 6 -sulfanone using HMDS [Chemical formula]

[0089] The methyl(phenyl)((trimethylsilyl)imino)-λ 6 -sulfanone substituted by the said reaction formula was synthesized. Specifically, hexamethyldisilazane (HMDS, 1.5 eq) was added to the compound (1.0 eq) synthesized in the said reaction (2), and then it was stirred with reflux at 80 °C for 1 hour. When the reaction was completed, it was depressurized to remove HMDS, and then 2-, 3- or 4-substituted methyl(phenyl)((trimethylsilyl)imino)-λ 6 -sulfanone was obtained. 6 ​​

[0090] (3) Synthesis of Substituted Diethyl (Phenylsulfonimidoylmethyl)phosphonate by Reaction with Diethyl Chlorophosphate

Chemical formula

[0091] Substituted diethyl (phenylsulfonimidoylmethyl)phosphonate was synthesized according to the above reaction formula. Specifically, the compound synthesized in the above reaction (3) (1.0 eq) was dissolved in anhydrous tetrahydrofuran (THF), and then cooled to -78 °C using acetone and dry ice. Thereafter, n-butyllithium (2.0 eq, 2.0 M 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 eq) 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), washed with water and brine, and then the organic layer was dried over anhydrous Na2SO4 and filtered. The residue obtained by distilling off the solvent under reduced pressure was purified by column chromatography to obtain 2-, 3- or 4-substituted diethyl (phenylsulfonimidoylmethyl)phosphonate.

[0092] (4) Synthesis of Substituted (E)-Imino(phenyl)(2-(pyridin-2-yl)vinyl)-lambda6-sulfanone Derivative by Reaction with Picoline Aldehyde Derivative

Chemical formula

[0093] The substituted diethyl (phenylsulfonimidoylmethyl)phosphonate (1.0 eq) synthesized in the reaction (3) was dissolved in anhydrous THF, and then cooled to -78 °C using dry ice and acetone. n-BuLi (1.2 eq, 2.0 M cyclohexane solution) was slowly added dropwise to the solution, and then stirred for 1 hour. A picolinaldehyde derivative (1.2 eq) was added and the reaction was further carried out for 1 hour. TLC was checked, and if the reaction was not complete, the reaction was further carried out at room temperature for 30 minutes. After terminating the reaction with a small amount of water, extraction was performed with water and 10% MeOH / MC. The organic layer was used with anhydrous Na2SO4 to remove a small amount of water, and the solvent was removed by distillation under reduced pressure and vacuum dried. Then, separation and purification were performed by column chromatography to obtain a 2-, 3- or 4-substituted (E)-imino(phenyl)(2-(pyridin-2-yl)vinyl)-λ6-sulfanone derivative.

[0094] Example 2.1. (E)-(2-fluorophenyl)(imino)(2-(pyridin-2-yl)vinyl)-λ 6 -sulfanone (Chemical Formula 1-1) Synthesis

[0095] 2.1.1. Imino(2-fluorophenyl)(methyl)-λ 6 -sulfanone Synthesis

Chem.

[0096] 1-Fluoro-2-(methylsulfinyl)benzene (17.9 ml, 126.3 mmol) was well dissolved in MeOH using the reaction (1), and then reacted with diacetoxyiodobenzene (53.1 g, 189.4 mmol) and ammonium carbonate (14.0 g, 290.4 mmol) to synthesize pale yellow oily Imino(2-fluorophenyl)(methyl)-λ 6 -sulfanone (21.00 g, 96%); R f= 0.40 (acetone / CH2Cl2 1 / 9); 1 1H NMR (300 MHz, DMSO) δ 7.88 (td, J = 1.3, 7.6 Hz, ArH), 7.39 - 7.74 (m, 3 ArH), 4.71 (s, NH), 3.18 (s, CH3); 13 13C NMR (75 MHz, DMSO) δ 159.0 (d, J C-F = 249.8 Hz, ArC-F), 135.6 (d, J C-F = 8.4 Hz, ArC), 132.4 (d, J C-F = 15.6 Hz, ArC), 129.8, 125.2 (d, J C-F = 3.7 Hz, ArC), 117.5 (d, J C-F = 21.9 Hz, 2 ArC-CF), 45.3 (d, J C-F = 2.7 Hz, OCH3).

[0097] 2.1.2. (2-Fluorophenyl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone synthesis

Chemical formula

[0098] Using the reaction (2), Imino(2-fluorophenyl)(methyl)-λ 6 -sulfanone (5.00 g, 28.8 mmol) was added with hexamethyldisilazane (6.64 ml, 31.7 mmol) to synthesize transparent oily (2-Fluorophenyl)(methyl)((trimethylsilyl)imino)-λ6-sulfanone (7.0 g, 100%); R f = 0.25 (acetone / CH2Cl2 1 / 9); 1 1H NMR (300 MHz, DMSO) δ 7.86 (td, J = 1.6, 7.7 Hz, ArH), 7.41 - 7.76 (m, 3 ArH), 3.22 (s, CH3), 0.00 (s, Si(CH3)3); 13 13C NMR (75 MHz, DMSO) δ 156.4 (d, J C-F= 250.0 Hz, ArC-F), 133.1 (dd, J C-F = 5.0, 8.3 Hz, CSOCH3), 130.0 (t, J C-F = 14.9 Hz, ArC), 127.2, 126.7, 122.7 (dd, J C-F = 3.6, 14.4 Hz, ArC), 115.0 (d, J C-F = 4.8, 21.8 Hz, ArC), 42.6 (d, J C-F = 2.8 Hz, OCH3), 0.0 (Si(CH3)3).

[0099] Synthesis of Diethyl((2-fluoro-N-(trimethylsilyl)phenylsulfonimidoyl)methyl)phosphonate

Chemical Structure

[0100] Using the above reaction (3), (2-Fluorophenyl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone (1.00 g, 5.77 mmol) was dissolved well in THF, then reacted with diethyl chlorophosphate (0.99 ml, 6.93 mmol) and 2.0 M n-BuLi cyclohexane solution (3.43 ml, 6.93 mmol) to synthesize white solid Diethyl((2-fluoro-N-(trimethylsilyl)phenylsulfonimidoyl)methyl)phosphonate (0.75 g, 42%); R f = 0.20 (n-hexane 1:EtOAc 1); 1 1H NMR (400 MHz, DMSO-d6) δ 7.37 - 7.90 (m, 4ArH), 4.16 (d, J = 21.9 Hz, SCH2P), 3.83 - 4.02 (m, P(OCH2CH3)2), 1.08 - 1.18 (m, P(OCH2CH3)2).

[0101] 2.1.4. (E)-(2-Fluorophenyl)(imino)(2-(pyridin-2-yl)vinyl)-λ 6 -sulfanone (Chemical Formula 1-1) Synthesis [Chem.]

[0102] Using the said reaction (4)-2, Diethyl((2-fluoro-N-(trimethylsilyl)phenylsulfonimidoyl)methyl)phosphonate (0.68 mL, 2.19 mmol), 2.0 M n-BuLi solution in cyclohexane (1.70 mL, 2.63 mmol), and picolinaldehyde (0.25 mL, 2.63 mmol) were reacted to synthesize a pale 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)-isomeric H), 7.58 (d, J = 14.9 Hz, (E)-isomeric 2H), 7.37 - 7.46 (m, 3ArH), 5.27 (s, NH); 13 C NMR (75 MHz, DMSO-d6) δ 158.6 (d, J C-F = 251.8 Hz), 151.0, 150.1, 140.6, 137.4, 135.5 (d, J C-F = 8.3 Hz), 133.1, 131.1 (d, J C-F = 14.0 Hz), 129.6, 125.1, 124.9 (d, J C-F = 3.7 Hz), 117.2 (d, J C-F = 21.5 Hz)

[0103] Example 2.2. Synthesis of (E)-imino(4-methoxyphenyl)(2-(pyridin-2-yl)vinyl)-λ 6 -sulfanone (Chemical Formula 1-2)

[0104] 2.2.1. Synthesis of Imino(4-methoxyphenyl)(methyl)-λ 6 -sulfanone

Chem.

[0105] Using the above reaction (2), (4-methoxyphenyl)(methyl)sulfane (1.6 ml, 12.42 mmol) was dissolved well in MeOH, and then reacted with diacetoxyiodobenzene (8.00 g, 28.53 mmol) and ammonium carbonate (1.20 g, 24.82 mmol) to synthesize pale yellow oily Imino(4-methoxyphenyl)(methyl)-λ 6 -sulfanone (2.96 g, 77%); R f = 0.38 (acetone / CH2Cl2 1 / 9); 1 1H NMR (300 MHz, DMSO) δ 7.84 (d, J = 8.7 Hz, 2 ArH), 7.11 (d, J = 8.7 Hz, 2 ArH), 4.05 (s, NH), 3.84 (s, OCH3), 3.02 (s, CH3).

[0106] 2.2.2. Synthesis of (4-Methoxyphenyl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone

Chem.

[0107] Using the above reaction (3), Imino(4-methoxyphenyl)(methyl)-λ 6-sulfanone (2.18 g, 11.7 mmol) was added to hexamethyldisilazane (2.70 ml, 12.9 mmol) to synthesize (4-Methoxyphenyl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone (3.40 g, 100%); R f = 0.25 (acetone / CH2Cl2 1 / 9); 1 1H NMR (300 MHz, DMSO) δ 7.79 (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).

[0108] 2.2.3. Synthesis of Diethyl((4-methoxyphenylsulfonimidoyl)methyl)phosphonate

Chemical formula

[0109] Using the above reaction (3), imino(4-methoxyphenyl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone (0.22 g, 0.72 mmol) was dissolved well in THF, and then reacted with diethyl chlorophosphate (0.22 ml, 1.50 mmol) and 2.0 M n-BuLi cyclohexane solution (0.74 ml, 1.50 mmol) to synthesize white solid Diethyl((4-methoxy-N-(trimethylsilyl)phenylsulfonimidoyl)methyl)phosphonate (0.12 g, 52%); R f = 0.29 (n-hexane 1:EtOAc 4); 11H NMR (300 MHz, DMSO-d6) δ 7.90 (d, J = 8.9 Hz, 2 ArH), 7.11 (d, J = 8.9 Hz, 2 ArH), 4.37 (s, NH), 3.95 - 4.08 (m, P(OCH2CH3)2), 3.85 (s, OCH3), 1.14 - 1.20 (m, P(OCH2CH3)2).

[0110] 2.2.4. (E)-Imino(4-methoxyphenyl)(2-(pyridin-2-yl)vinyl)-λ 6 -sulfanone (Chemical Formula 1-2) Synthesis

Chem.

[0111] Using the said reaction (4)-2, diethyl((4-methoxyphenylsulfonimidoyl)methyl)phosphonate (0.15 mL, 0.46 mmol), 2.0 M n-BuLi solution in cyclohexane (0.30 mL, 0.55 mmol), and picolinaldehyde (0.06 mL, 0.55 mmol) were reacted to synthesize a pale yellow oily compound 1-2 (0.14 g, 51%): R f = 0.30 (n-hexane 1:EtOAc 1); 1 1H NMR (300 MHz, DMSO-d6) δ 8.59 (d, J = 4.7 Hz, ArH), 7.82 - 7.39 (m, 3 ArH), 7.73 (d, J = 7.8, 8.2 Hz, ArH), 7.14 - 7.52 (m, ArH, (E)-isomeric 2H), 7.12 (d, J = 7.3 Hz, 2 ArH), 4.67 (s, NH), 3.83 (s, OCH3); 13 13C NMR (75 MHz, DMSO-d6) δ 162.5, 151.4, 150.0, 137.6, 137.2, 135.7, 134.0, 129.9, 124.7, 124.6, 114.4, 55.7 (OCH3).

[0112] Example 2.3. (E)-(2-chlorophenyl)(2-(3-fluoropyridin-2-yl)vinyl)(imino)-λ 6 -sulfanone (Chemical Formula 1-3) Synthesis

[0113] 2.3.1. Imino(2-chlorophenyl)(methyl)-λ 6 -sulfanone Synthesis

Chem.

[0114] Using the above reaction (1), 1-Chloro-2-(methylsulfinyl)benzene (6.45 ml, 50.43 mmol) was dissolved well in MeOH, then reacted with diacetoxyiodobenzene (37.36 g, 115.99 mmol) and ammonium carbonate (7.27 g, 75.64 mmol) to synthesize pale yellow oily Imino(2-chlorophenyl)(methyl)-λ 6 -sulfanone (5.0 g, 52%); R f = 0.58 (EtOAc 100%); 1 1H NMR (400 MHz, DMSO-d6) δ 8.08 - 8.10 (m, ArH), 7.62 - 7.68 (m, 2 ArH), 7.55 - 7.59 (m, ArH), 4.60 (brs, NH), 3.22 (s, SCH3).

[0115] 2.3.2. (2-Chlorophenyl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone Synthesis

Chem.

[0116] Using the above reaction (2), Imino(2-chlorophenyl)(methyl)-λ 6-Sulfanone (1.00 g, 5.27 mmol) was added to hexamethyldisilazane (1.66 ml, 7.91 mmol) to synthesize (2-Chlorophenyl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone as a pale yellow oil (1.35 g, 98%); R f = 0.81 (n-hexane 1:EtOAc 1); 1 1H NMR (400 MHz, DMSO-d6) δ 8.08 (dd, J = 1.5, 7.8 Hz, ArH), 7.63 - 7.68 (m, 2 ArH), 7.56 - 7.60 (m, ArH), 3.25 (s, SCH3), 0.00 (s, Si(CH3)3).

[0117] Synthesis of Diethyl((2-chlorophenylsulfonimidoyl)methyl)phosphonate [Chemical formula]

[0118] Using the above reaction (3), (2-Chlorophenyl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone (1.35 g, 5.16 mmol) was dissolved well in THF, and then reacted with diethyl chlorophosphate (0.89 ml, 6.19 mmol) and 2.0 M n-BuLi cyclohexane solution (3.09 ml, 6.19 mmol) to synthesize white solid diethyl((2-chlorophenylsulfonimidoyl)methyl)phosphonate (0.67 g, 40%); R f = 0.18 (n-hexane 1:EtOAc 1); 11H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J = 7.9 Hz, ArH), 7.66 (d, J = 3.7 Hz, 2 ArH), 7.56 - 7.60 (m, ArH), 4.93 (s, NH), 4.27 (q, J = 15.8 Hz, SCH2P), 3.87 - 4.01 (m, P(OCH2CH3)2), 1.11 - 1.16 (m, P(OCH2CH3)2).

[0119] 2.3.4. (E)-(2-Chlorophenyl)(2-(3-fluoropyridin-2-yl)vinyl)(imino)-λ 6 -sulfanone (Chemical Formula 1-3) Synthesis

Chem.

[0120] Using the above reaction (4)-2, diethyl ((2-chlorophenylsulfonimidoyl)methyl)phosphonate (0.20 mL, 0.62 mmol), 2.0 M n-BuLi solution in cyclohexane (0.40 mL, 0.74 mmol), and 3-fluoropicolinaldehyde (0.10 g, 0.74 mmol) were reacted to synthesize a pale yellow powdery compound 1-3 (0.11 g, 61%); R f = 0.51 (n-hexane 1:EtOAc 4); mp: 94.3 - 96.0 °C 1 1H 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)-isomeric H), 7.52 - 7.69 (m, 4 ArH, (E)-isomeric H), 5.31 (s, NH); 13 13C NMR (100 MHz, DMSO-d6) δ 157.8 (d, J C-F = 261.1 Hz), 146.4 (d, J C-F = 4.9 Hz), 139.9, 138.8 (d, J C-F = 11.0 Hz), 134.4, 133.5 (d, JC-F = 4.4 Hz), 132.8, 131.8, 131.3, 130.6, 127.8, 127.5 (d, J C-F = 4.6 Hz), 124.7 (d, J C-F = 18.9 Hz).

[0121] Example 2.4. Synthesis of (E)-(2-chlorophenyl)(2-(3-chloropyridin-2-yl)vinyl)(imino)-λ 6 -sulfanone (Chemical Formula 1-4)

Chemical Structure

[0122] Diethyl ((2-chlorophenylsulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 2.3.1 to 2.3.3.

[0123] Using the above reaction (4)-2, diethyl ((2-chlorophenylsulfonimidoyl)methyl)phosphonate (1.00 g, 3.07 mmol), 2.0 M n-BuLi solution in cyclohexane (1.84 mL, 3.68 mmol), and 3-chloropicolinaldehyde (0.44 g, 3.07 mmol) were reacted to synthesize a white powdery compound 1-4 (0.48 g, 50%); R f = 0.30 (n-hexane 1:EtOAc 2); mp: 144.8 - 146.5 °C 1 1H 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)-isomeric H), 7.59 - 7.68 (m, (E)-isomeric H, 3 ArH), 7.51 (dd, J = 4.5, 8.2 Hz, ArH), 7), 5.32 (brs, NH). 1313C NMR (75 MHz, DMSO-d6) δ 148.6, 147.4, 140.0, 138.3, 135.4, 134.6, 134.5, 131.9, 131.8, 131.4, 130.7, 127.9, 126.7.

[0124] Example 2.5. Synthesis of (E)-(2-fluorophenyl)(2-(3-fluoropyridin-2-yl)vinyl)(imino)-λ 6 -sulfanone (Chemical Formula 1-5) [Chem.]

[0125] Diethyl ((2-fluoro-N-(trimethylsilyl)phenylsulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 2.1.1 to 2.1.3.

[0126] Using the above reaction (4)-2, diethyl ((2-fluorophenylsulfonimidoyl)methyl)phosphate (0.24 mL, 0.78 mmol), 2.0 M n-BuLi solution in cyclohexane (0.50 mL, 0.94 mmol), and 3-fluoropicolinaldehyde (0.12 g, 0.94 mmol) were reacted to synthesize a pale yellow oily compound 1-5 (0.11 g, 51%): R f = 0.30 (n-hexane 1:EtOAc 2); mp: 107.8 - 109.8 °C 1 1H 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)-isomeric 2H), 5.39 (s, NH); 13 13C NMR (75 MHz, DMSO-d6) δ 158.6 (d, J C-F = 251.4 Hz), 157.8 (d, J C-F = 260.9 Hz), 146.4 (d, J C-F=4.9 Hz), 138.8 (d, J C-F =11.0 Hz), 135.8 (d, J C-F =8.4 Hz), 134.7 (d, J C-F =3.1 Hz), 132.3, 130.6 (d, J C-F =14.1 Hz), 129.7, 127.6 (d, J C-F =4.6 Hz), 125.0 (d, J C-F =3.6 Hz), 124.7 (d, J C-F =18.9 Hz), 117.2 (d, J C-F =21.6 Hz).

[0127] Example 2.6. Synthesis of (E)-(2-(3-chloropyridin-2-yl)vinyl)(2-fluorophenyl)(imino)-λ 6 -sulfanone (Chemical Formula 1-6)

Chemical Structure

[0128] Diethyl((2-fluoro-N-(trimethylsilyl)phenylsulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 2.1.1 to 2.1.3.

[0129] Using the above reaction (4)-2, diethyl((2-fluoro-N-(trimethylsilyl)phenylsulfonimidoyl)methyl)phosphonate (0.24 mL, 0.78 mmol), 2.0 M n-BuLi solution in cyclohexane (0.50 mL, 0.94 mmol), and 3-chloropicolinaldehyde (0.12 g, 0.94 mmol) were reacted to synthesize a white powdery compound 1-6 (0.14 g, 59%): R f =0.30 (n-hexane 1:EtOAc 2); mp: 89.8 - 91.8 °C 11H 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, 2 ArH, (E)-isomeric H), 7.61 (d, J = 14.9 Hz, (E)-isomeric H), 7.29 - 7.54 (m, 3 ArH) 5.41 (s, NH); 13 13C NMR (75 MHz, DMSO-d6) δ 158.6 (d, J C-F = 251.4 Hz), 148.6, 147.3, 138.3, 135.9, 135.8, 135.7, 134.7, 131.8, 130.6 (d, J C-F = 14.0 Hz), 129.7, 126.7, 125.0 (d, J C-F = 3.6 Hz), 117.2 (d, J C-F = 21.5 Hz).

[0130] Example 2.7. Synthesis of (E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(3-methoxyphenyl)-λ 6 -sulfanone (Chemical Formula 1-7)

[0131] 2.7.1. Synthesis of Imino(3-methoxyphenyl)methyl-λ 6 -sulfanone

Chem.

[0132] Using the above reaction (1), (3-methoxyphenyl)(methyl)sulfane (1.4 ml, 10.35 mmol) was well dissolved in MeOH, then reacted with diacetoxyiodobenzene (6.67 g, 23.78 mmol) and ammonium carbonate (1.00 g, 20.69 mmol) to synthesize pale yellow oily Imino(3-methoxyphenyl)methyl-λ 6 -sulfanone (2.96 g, 77%); R f = 0.38 (acetone / CH2Cl2 1 / 9); 11H NMR (300 MHz, DMSO) δ 7.19 - 7.54 (m, 4 ArH), 4.19 (s, NH), 3.84 (s, OCH3), 3.06 (s, CH3).

[0133] 2.7.2. (3 - Methoxyphenyl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone Synthesis

Chem.

[0134] Using the reaction (2), Imino(3 - methoxyphenyl)methyl-λ 6 -sulfanone (0.50 g, 2.93 mmol) was added with hexamethyldisilazane (0.74 ml, 3.52 mmol) to synthesize transparent oily (3 - Methoxyphenyl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone (0.52 g, 70%); R f = 0.25 (acetone / CH2Cl2 1 / 9); 1 1H NMR (300 MHz, DMSO) δ 7.35 - 7.51 (m, 3 ArH), 7.18 (d, J = 4.4 Hz, ArH), 3.81 (s, OCH3), 3.05 (s, CH3), 0.00 (s, Si(CH3)3).

[0135] 2.7.3. Synthesis of Diethyl((3 - methoxyphenylsulfonimidoyl)methyl)phosphonate

Chem.

[0136] Using the reaction (3), imino(3 - methoxyphenyl)(methyl)((trimethylsilyl)imino)-λ 6-Sulfanone (0.34 g, 1.12 mmol) was dissolved well in THF, and then reacted with diethyl chlorophosphate (0.25 ml, 1.68 mmol) and 2.0 M n-BuLi cyclohexane solution (0.83 ml, 1.68 mmol) to synthesize white solid Diethyl((3-methoxy-N-(trimethylsilyl)phenylsulfonimidoyl)methyl)phosphonate (0.12 g, 51%); R f = 0.27 (n-hexane 1:EtOAc 3); 1 1H NMR (400 MHz, DMSO-d6) δ 7.48 - 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).

[0137] Synthesis of (E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(3-methoxyphenyl)-λ6-sulfanone (Chemical Formula 1-7) [Chemical formula]

[0138] Using the above reaction (4)-2, diethyl((3-methoxyphenylsulfonimidoyl)methyl)phosphonate (0.51 mL, 1.58 mmol), 2.0 M n-BuLi solution in cyclohexane (0.95 mL, 1.89 mmol), and 3-fluoropicolinaldehyde (0.24 g, 1.89 mmol) were reacted to synthesize transparent oily compound 1-7 (0.24 g, 52%): R f = 0.34 (n-hexane 1:EtOAc 2); 11H 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)-isomeric H), 7.48 - 7.58 (m, 4 ArH, (E)-isomeric H), 7.23 (d, J = 7.3 Hz, ArH), 4.95 (s, NH); 13 13C NMR (75 MHz, DMSO-d6) δ 159.5, 157.7 (d, J C-F = 261.8 Hz), 146.3 (d, J C-F = 4.8 Hz), 143.6, 139.1 (d, J C-F = 11.1 Hz), 136.4 (d, J C-F = 4.3 Hz), 130.4 (d, J C-F = 11.4 Hz), 127.2 (d, J C-F = 2.4 Hz), 124.6 (d, J C-F = 18.9 Hz), 119.4 (d, J C-F = 83.1 Hz), 112.5, 55.6 (OCH3).

[0139] Example 2.8. Synthesis of (E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(2-methoxyphenyl)-λ 6 -sulfanone (Chemical Formula 1-8)

[0140] 2.8.1. Synthesis of Imino(2-methoxyphenyl)methyl)-λ 6 -sulfanone

Chem.

[0141] Using the above reaction (1), (2-methoxyphenyl)(methyl)sulfane (2.8 ml, 20.70 mmol) was dissolved well in MeOH, and then reacted with diacetoxyiodobenzene (15.33 g, 47.57 mmol) and ammonium carbonate (3.98 g, 41.39 mmol) to obtain pale yellow oily Imino(2-methoxyphenyl)methyl)-λ6 -sulfanone was synthesized (3.08 g, 80%); R f = 0.30 (EtOAc 100%); 1 1H NMR (400 MHz, DMSO-d6) δ 7.84 (dd, 1.7, 7.8 Hz, ArH), 7.60 (m, ArH), 7.23 (d, 8.2 Hz, ArH), 7.11 (m, ArH), 4.23 (brs, NH), 3.92 (s, OCH3), 3.14 (s, SCH3).

[0142] 2.8.2. (2-Methoxyphenyl)methyl((trimethylsilyl)imino)-λ 6 Synthesis of -sulfanone

Chemical formula

[0143] Using the above reaction (2), imino(2-methoxyphenyl)methyl)-λ 6 -sulfanone (3.08 g, 16.63 mmol) was added with hexamethyldisilazane (5.1 ml, 24.30 mmol) to synthesize transparent oily (2-methoxyphenyl)methyl((trimethylsilyl)imino)-λ 6 -sulfanone (4.28 g, 100%); R f = 0.81 (EtOAc 100%); 1 1H NMR (400 MHz, DMSO-d6) δ 7.88 (dd, 1.7, 7.8 Hz, ArH), 7.68 (m, ArH), 7.30 (d, 8.2 Hz, ArH), 7.18 (m, ArH), 3.99 (s, OCH3), 3.22 (s, SCH3), 0.00 (s, Si(CH3)3).

[0144] 2.8.3. Synthesis of Diethyl((2-methoxyphenylsulfonimidoyl)methyl)phosphonate

Chemical formula

[0145] Using the reaction (3), (2-methoxyphenyl)methyl((trimethylsilyl)imino)-λ 6 -sulfanone (4.28 g, 16.63 mmol) was dissolved well in THF, and then reacted with diethyl chlorophosphate (2.88 ml, 19.95 mmol) and 2.0 M n-BuLi cyclohexane solution (18.29 ml, 36.58 mmol) to synthesize Diethyl((2-methoxyphenylsulfonimidoyl)methyl)phosphonate as a pale yellow solid (3.48 g, 53%); R f = 0.28 (EtOAc 100%); 1 1H NMR (400 MHz, DMSO-d6) δ 7.88 (dd, 7.8, 29.7 Hz, ArH), 7.62 (m, ArH), 7.23 (dd, 4.3, 8.2 Hz, ArH), 7.18 (t, 7.5 Hz, ArH), 4.02 - 3.88 (m, SCH2P, (POCH2CH3)2, OCH3), 1.16 - 1.10 (m, P(OCH2CH3)2), 0.01 (s, Si(CH3)3).

[0146] Synthesis of (E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(2-methoxyphenyl)-λsulfanone (Chemical Formula 1-8)

Chemical Structure

[0147] Diethyl((2-methoxyphenylsulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 1.1.1 to 1.1.3.

[0148] Using the reaction (4)-2, diethyl((2-methoxyphenylsulfonimidoyl)methyl)phosphonate (0.61 mL, 1.91 mmol), 2.0 M n-BuLi solution in cyclohexane (1.20 mL, 2.29 mmol), and 3-chloropicolinaldehyde (0.33 g, 2.29 mmol) were reacted to synthesize a pale yellow powdery compound 1-8 (0.40 g, 68%): R f = 0.35 (n-hexane 1:EtOAc 7), mp: 113.0 - 114.1 °C 1 1H 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)-isomeric H), 7.67 (d, J = 14.6 Hz, (E)-isomeric 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 13C NMR (75 MHz, DMSO-d6) δ 156.7, 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).

[0149] Example 2.9. Synthesis of (E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(3-methoxyphenyl)-λ 6 -sulfanone (Chemical Formula 1-9)

Chem.

[0150] In the same manner as in Examples 2.7.1 to 2.7.3, diethyl((3-methoxyphenylsulfonimidoyl)methyl)phosphonate was synthesized.

[0151] Using the reaction (4)-2, diethyl((3-methoxyphenylsulfonimidoyl)methyl)phosphonate (0.62 mL, 1.93 mmol), 2.0 M n-BuLi solution in cyclohexane (1.2 mL, 2.32 mmol), and 3-chloropicolinaldehyde (0.33 g, 2.32 mmol) were reacted to synthesize a pale yellow oily compound 1-9 (0.24 g, 44%): R f = 0.37 (n-hexane 1:EtOAc 2); 1 1H 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)-isomeric H), 7.22 - 7.65 (m, 5ArH, (E)-isomeric 2H), 4.98 (s, NH), 3.84 (OCH3); 13 13C NMR (75 MHz, DMSO-d6) δ 160.1, 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).

[0152] Example 2.10. Synthesis of (E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(4-methoxyphenyl)-λ 6 -sulfanone (Chemical Formula 1-10)

Chem.

[0153] In the same manner as in Examples 2.2.1 to 2.2.3, diethyl((4-methoxyphenylsulfonimidoyl)methyl)phosphonate was synthesized.

[0154] Using the reaction (4)-2, diethyl((4-methoxyphenylsulfonimidoyl)methyl)phosphonate (0.15 mL, 0.46 mmol), 2.0 M n-BuLi solution in cyclohexane (0.30 mL, 0.55 mmol), and 3-chloropicolinaldehyde (0.07 mL, 0.55 mmol) were reacted to synthesize a pale yellow oily compound 1-10 (0.15 g, 53%): R f = 0.32 (n-hexane 1:EtOAc 2); mp: 103.6 - 105.6 °C 1 H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J = 4.5 Hz, ArH), 7.11 - 7.89 (m, 7ArH, (E)-isomeric 2H), 4.67 (s, NH), 3.83 (OCH3); 13 C NMR (75 MHz, DMSO-d6) δ 162.7, 148.4, 147.6, 138.4, 138.2, 133.3, 131.5, 130.1, 126.3, 114.5, 55.7 (OCH3).

[0155] Example 2.11. Synthesis of (E)-imino(2-methoxyphenyl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6 -sulfanone (Chemical Formula 1-11)

Chemical Structure

[0156] In the same manner as in Examples 2.8.1 to 2.8.3, diethyl((2-methoxyphenylsulfonimidoyl)methyl)phosphonate was synthesized.

[0157] Using the reaction (4)-2, diethyl((2-methoxyphenylsulfonimidoyl)methyl)phosphonate (0.30 g, 0.76 mmol) in THF After dissolving well, 3-(trifluoromethyl)picolinaldehyde (0.11 ml, 0.84 mmol) and 2.0 M n-BuLi cyclohexane solution (0.42 ml, 0.84 mmol) were reacted to synthesize white solid 1-11 (0.07 g, 28%): R f = 0.22 (n-hexane 1:EtOAc 3); 1 H NMR (400 MHz, CDCl3) δ 8.76 (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)-isomeric 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 (100 MHz, DMSO-d6) δ 157.2, 153.8, 149.0, 138.3, 135.5 (2ArC), 133.9, 130.4, 129.5, 125.3, 124.0 (q, J C-F = 271.8 Hz), 124.4 (q, J C-F = 31.4 Hz), 120.9, 113.7, 56.7。

[0158] Example 2.12. Synthesis of (E)-(2-chlorophenyl)(imino)(2-(pyridin-3-yl)vinyl)-λ 6 -sulfanone (Chemical Formula 1-12)

Chem.

[0159] Diethyl ((2-chlorophenylsulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 2.3.1 to 2.3.3.

[0160] Using the above reaction (4)-2, diethyl((2-chlorophenylsulfonimidoyl)methyl)phosphonate (0.70 mL, 2.14 mmol), 2.0 M n-BuLi solution in cyclohexane (1.20 mL, 2.14 mmol), and nicotinaldehyde (0.14 mL, 1.43 mmol) were reacted to synthesize a pale yellow oily compound 1-12 (0.43 g, 71%); R f = 0.52 (n-hexane 1:EtOAc 4); 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)-isomeric 2H), 5.11 (s, NH).

[0161] Example 2.13. Synthesis of (E)-(2-chlorophenyl)(2-(2-chloropyridin-3-yl)vinyl)(imino)-λ 6 -sulfanone (Chemical Formula 1-13)

Chemical Structure

[0162] In the same manner as in Examples 2.3.1 to 2.3.3, diethyl((2-chlorophenylsulfonimidoyl)methyl)phosphonate was synthesized.

[0163] Using the above reaction (4)-2, diethyl((2-chlorophenylsulfonimidoyl)methyl)phosphonate (0.70 mL, 2.14 mmol), 2.0 M n-BuLi solution in cyclohexane (1.20 mL, 2.14 mmol), and 2-chloronicotinaldehyde (0.21 g, 1.43 mmol) were reacted to synthesize a white powdery compound 1-13 (0.48 g, 60%); R f= 0.50 (n - hexane 1:EtOAc 9); 1 1H 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)-isomeric H), 7.49 - 7.69 (m, 4 ArH, (E)-isomeric H), 5.26 (s, NH); 13 13C NMR (100 MHz, DMSO - d6) δ 151.8, 150.6, 140.6, 138.4, 136.8, 134.9, 133.9, 132.4, 131.9, 131.2, 128.3, 127.9, 124.3。

[0164] Example 2.14. Synthesis of (E)-(2 - chlorophenyl)(imino)(2-(2,4,6 - trichloropyrimidin - 5 - yl)vinyl)-λ 6 -sulfanone (Chemical formula 1 - 14)

Chemical formula

[0165] In the same manner as in Examples 2.3.1 to 2.3.3, diethyl((2 - chlorophenylsulfonimidoyl)methyl)phosphonate was synthesized.

[0166] Using the above reaction (4)-2, diethyl((2 - chlorophenylsulfonimidoyl)methyl)phosphonate (0.60 mL, 1.84 mmol), 2.0 M n - BuLi solution in cyclohexane (2.76 mL, 2.76 mmol), and 2,4,6 - trichloropyrimidine - 5 - carbaldehyde (0.39 g, 1.84 mmol) were reacted to synthesize a white powdery compound 1 - 14 (0.46 g, 66%); R f = 0.10 (n - hexane 3:EtOAc 1); 11H 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)-isomeric 2H), 5.11 (s, NH).

[0167] Synthesis of sulfanone derivative where A is pyridine and B is phenyl in Example 3.A As an example of the present invention, the synthesis process of the sulfanone derivative where A is pyridine and B is phenyl in Chemical Formula 1 is shown in the following Reaction Formula 3. [Chemical Formula]

[0168] (1) Synthesis of methylthiopyridine derivative from halogenopyridine derivative [Chemical Formula]

[0169] According to the above reaction formula, 2-(methylthio)pyridine derivatives were synthesized. Specifically, a bromo or fluoropyridine starting material (1.0 eq) substituted with a methoxy group, fluorine, or chlorine at the 3-, 4-, 5-, or 6-position was dissolved in dimethyl formamide (DMF), sodium thiomethoxide (2.0 eq) was added, and the mixture was stirred at 60 °C for 2 to 18 hours. 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 off the solvent under reduced pressure was purified by column chromatography using a mixed developing solvent of ethyl acetate and n-hexane to obtain 3-, 4-, 5-, or 6-substituted 2-(methylthio)pyridine derivatives.

[0170] (2) Synthesis of Substituted Imino(methyl)(pyridine-2-yl)-λ6-sulfanone by the Reaction of Ammonium Carbonate and Diacetoxyiodobenzene

Chem.

[0171] Substituted imino(methyl)(pyridine-2-yl)-λ6-sulfanone was synthesized according to the above reaction formula. Specifically, the compound synthesized in the above reaction (1) (1.0 eq) was dissolved in methyl alcohol (Methanol; MeOH), and ammonium carbonate ((NH4)2CO3, 1.5 eq) was added. Next, diacetoxyiodobenzene (PhI(OAc)2, 2.3 eq) was added, and the mixture was stirred at room temperature for 3 to 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The obtained residue was purified by column chromatography to obtain 3-, 4-, 5- or 6-substituted imino(methyl)(pyridine-2-yl)-λ6-sulfanone.

[0172] (3) Synthesis of Substituted Methyl(pyridine-2-yl)((trimethylsilyl)imino)-λ6-sulfanone Using HMDS

Chem.

[0173] Methyl(pyridine-2-yl)((trimethylsilyl)imino)-λ6-sulfanone substituted by the said reaction formula was synthesized. Specifically, hexamethyldisilazane (HMDS, 1.5 eq) was added to the compound (1.0 eq) synthesized in the said reaction (2), and then the mixture was stirred with reflux at 80°C over 1 hour. After the reaction ended, HMDS was removed under reduced pressure, and 3-, 4-, 5- or 6-substituted methyl(pyridine-2-yl)((trimethylsilyl)imino)-λ6-sulfanone was obtained.

[0174] (4) Synthesis of Substituted Methyl(pyridine-2-yl)((trimethylsilyl)imino)-λ6-sulfanone Using HMDS

Chemical formula

[0175] Diethyl((pyridine-2-sulfonimidoyl)methyl)phosphonate substituted by the above reaction formula was synthesized. Specifically, the compound (1.0 eq) synthesized in the above reaction (3) was dissolved in anhydrous tetrahydrofuran (THF), and then cooled to -78 °C using acetone and dry ice. Then, n-butyllithium (2.0 eq, 2.0 M 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 eq) was added at the same temperature, and then stirred at room temperature for 2 hours. When the reaction was completed, the reaction solution was diluted with ethyl acetate (EtOAc), washed with water and brine, and then the organic layer was dried over anhydrous Na2SO4 and filtered. The residue obtained by distilling off the solvent under reduced pressure was purified by column chromatography to obtain 3-, 4-, 5- or 6-substituted diethyl((pyridine-2-sulfonimidoyl)methyl)phosphonate.

[0176] (5)-1. Synthesis of Substituted (E)-Imino(pyridin-2-yl)(styryl)-λ6-sulfanone Derivatives by Reaction with Benzaldehyde Derivatives [Chemical formula]

[0177] (E)-imino(pyridin-2-yl)(styryl)-λ6-sulfanone derivative substituted by the above reaction formula was synthesized. After dissolving the compound synthesized in Step 2-4 (1.0 eq) in anhydrous THF, it was cooled to -78 °C using dry ice and acetone. n-BuLi (1.2 eq, 2.0 M cyclohexane solution) was slowly added dropwise to the solution, and then stirred for 1 hour. Benzaldehyde derivatives (1.2 eq) were added and reacted for another 1 hour. TLC was checked. If the reaction was not complete, the reaction was continued at room temperature for another 30 minutes. After terminating the reaction with a small amount of water, extraction was performed with water and 10% MeOH / MC. The organic layer was used with anhydrous Na2SO4 to remove a small amount of water, and the solvent was removed by distillation under reduced pressure and then vacuum dried. Then, separation and purification were performed by column chromatography to obtain 3-, 4-, 5- or 6-substituted (E)-imino(pyridin-2-yl)(styryl)-λ6-sulfanone derivative.

[0178] Example 3.1. (E)-(2-chlorostyryl)(imino)(pyridin-2-yl)-λ 6 -sulfanone (Chemical formula 1-15) synthesis

[0179] 3.1.1. imino(methyl)(pyridin-2-yl)-λ 6 -sulfanone synthesis [Chemical formula]

[0180] Using the above reaction (2), 2-(methylthio)pyridine (0.18 mL, 1.60 mmol) was well dissolved in MeOH, and then reacted with diacetoxyiodobenzene (1.18 g, 3.67 mmol) and ammonium carbonate (0.23 g, 2.40 mmol) to obtain white oily imino(methyl)(pyridin-2-yl)-λ 6-sulfanone was synthesized (0.21 g, 83%): R f = 0.18 (EtOAc 100%); 1 1H NMR (400 MHz, DMSO-d6) δ 8.70 - 8.72 (m, ArH), 8.05 - 8.12 (m, 2 ArH), 7.63 - 7.66 (m, ArH), 4.41 (s, NH), 3.15 (s, CH3).

[0181] 3.1.2. methyl(pyridin-2-yl)((trimethylsilyl)imino)-λ 6 -sulfanone synthesis

Chemical Structure

[0182] Using the above reaction (3), hexamethyldisilazane (0.46 mL, 2.18 mmol) was added to imino(methyl)(pyridin-2-yl)-λ 6 -sulfanone (0.23 g, 1.45 mmol) to synthesize transparent oily methyl(pyridin-2-yl)((trimethylsilyl)imino)-λ 6 -sulfanone (0.35 g, 100%): R f = 0.85 (EtOAc 100%); 1 1H NMR (400 MHz, DMSO-d6) δ 8.72 - 8.74 (m, ArH), 8.11 (td, J = 1.7, 7.8 Hz, ArH), 8.01 (d, J = 7.8 Hz, ArH), 7.66 (ddd, J = 1.2, 2.8, 7.7 Hz, ArH), 3.16 (s, CH3), 0.00 (s, Si(CH3)3).

[0183] 3.1.3. diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate

Chemical Structure

[0184] Using the reaction (4), methyl(pyridin-2-yl)((trimethylsilyl)imino)-λ 6 -sulfanone (0.24 g, 1.04 mmol) was dissolved well in THF, and then reacted with diethyl chlorophosphate (0.18 mL, 1.25 mmol) and 2.0 M n-BuLi cyclohexane solution (1.14 mL, 2.28 mmol) to synthesize diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate as a pale yellow transparent oily substance (0.15 g, 48%): R f = 0.43 (n-hexane 1:EtOAc 1); 1 1H NMR (400 MHz, DMSO-d6) δ 8.71 - 8.73 (m, ArH), 8.11 (td, J = 1.7, 7.8 Hz, ArH), 7.99 (d, J = 7.9 Hz, ArH), 7.66 (ddd, J = 1.1, 2.9, 7.7 Hz, ArH), 4.23 (d, J = 16.0 Hz, SCH2P), 3.89 - 4.05 (m, P(OCH2CH3)2), 1.13 (q, J = 7.0 Hz, P(OCH2CH3)2), 0.02 (s, Si(CH3)3).

[0185] 3.1.4. Synthesis of (E)-(2-chlorostyryl)(imino)(pyridin-2-yl)-λ 6 -sulfanone (Chemical Formula 1-15)

Chemical Structure

[0186] Using the reaction (5)-1, diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.85 g, 2.91 mmol) was dissolved well in THF, and then reacted with 2-chlorobenzaldehyde (0.41 g, 2.91 mmol) and 2.0 M n-BuLi cyclohexane solution (2.18 mL, 4.36 mmol) to synthesize a 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, 3 ArH), 7.98 (d, J = 7.8 Hz, ArH), 7.90 (d, J = 15.3 Hz, (E)-isomeric H), 7.56 - 7.67 (m, 2 ArH, (E)-isomeric H), 7.47 (t, J = 7.3 Hz, ArH), 7.39 (d, J = 7.6 Hz, ArH), 4.97 (s, NH); 13 C NMR (400 MHz, DMSO-d6) δ 160.8, 150.3, 139.2, 137.0, 134.3, 132.7, 132.5, 130.8, 130.6, 129.4, 128.3, 127.3, 121.8。

[0187] Example 3.2. Synthesis of (E)-(3-chlorostyryl)(imino)(pyridin-2-yl)-λ 6 -sulfanone (Chemical Formula 1-16)

Chemical Structure

[0188] Diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 3.1.1 to 3.1.3.

[0189] After diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.85 g, 2.91 mmol) was well dissolved in THF using the reaction (5)-1, 3-chlorobenzaldehyde (0.50 g, 3.49 mmol) and 2.0 M n-BuLi cyclohexane solution (2.62 mL, 5.23 mmol) were reacted to synthesize a white powdery compound 1-16 (0.68 g, 70%): R f = 0.40 (EtOAc 100%); 1 1H NMR (400 MHz, DMSO-d6) δ 8.70 - 8.71 (m, ArH), 8.10 - 8.16 (m, 3 ArH), 7.43 - 7.90 (m, 4ArH, (E)-isomeric 2H), 4.86 (s, NH).

[0190] Example 3.3. Synthesis of (E)-imino(pyridin-2-yl)(2-(trifluoromethyl)styryl)-λ 6 -sulfanone (Chemical Formula 1-17) [Chemical Structure Diagram]

[0191] Diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 3.1.1 to 3.1.3.

[0192] After diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.45 g, 1.54 mmol) was well dissolved in THF using the reaction (5)-1, 3-(trifluoromethyl)benzaldehyde (0.25 g, 1.84 mmol) and 2.0 M n-BuLi cyclohexane solution (1.15 mL, 2.31 mmol) were reacted to synthesize a white powdery compound 1-17 (0.24 g, 50%): R f = 0.38 (EtOAc 4 / n-hexane 1); 1 1H 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)-isomeric 2H), 4.50 (s, NH).

[0193] Example 3.4. Synthesis of (E)-imino(pyridin-2-yl)(2-(trifluoromethoxy)styryl)-λ 6 -sulfanone (Chemical formula 1-18)

Chemical formula

[0194] Diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 3.1.1 to 3.1.3.

[0195] Using the reaction (5)-1, diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.60 g, 2.05 mmol) was dissolved well in THF, and then reacted with 2-(trifluoromethoxy)benzaldehyde (0.36 g, 2.46 mmol) and 2.0 M n-BuLi cyclohexane solution (1.60 mL, 3.07 mmol) to synthesize a white powdery compound 1-18 (0.38 g, 57%): R f = 0.28 (EtOAc 4 / n-hexane 1); 1 1H NMR (400 MHz, DMSO-d6) δ8.03 - 8.16 (m, 4ArH), 7.44 - 7.74 (m, 4ArH, (E)-isomeric 2H), 4.97 (s, NH); 13 13C NMR (400 MHz, 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.

[0196] Example 3.5. Synthesis of (E)-(2,6-dichlorostyryl)(imino)(pyridin-2-yl)-λ 6 -sulfanone (Chemical formula 1-19)

Chem.

[0197] Diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 3.1.1 to 3.1.3.

[0198] After diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.60 g, 2.05 mmol) was well dissolved in THF using the reaction (5)-1, 2,6-dichlorobenzaldehyde (0.43 g, 2.46 mmol) and 2.0 M n-BuLi cyclohexane solution (1.60 mL, 3.07 mmol) were reacted to synthesize a white powdery compound 1-19 (0.30 g, 47%): R f = 0.51 (EtOAc 4 / n-hexane 1); 1 1H NMR (400 MHz, DMSO-d6) δ 8.73 (dd, J = 0.9, 4.1 Hz, ArH), 8.11 - 8.16 (m, 2ArH), 7.64 - 7.70 (m, ArH, (E)-isomeric H), 7.58 (d, J = 8.0 Hz, ArH), 7.42 - 7.50 (m, ArH, (E)-isomeric H), 5.01 (s, NH).

[0199] Example 3.6. Synthesis of (E)-(4-chlorostyryl)(imino)(pyridin-2-yl)-λ 6 -sulfanone (Chemical Formula 1-20)

Chemical Structure

[0200] Diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 3.1.1 to 3.1.3.

[0201] Using the reaction (5)-1, diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.40 g, 1.37 mmol) was dissolved well in THF, and then reacted with 4-chlorobenzaldehyde (0.23 g, 1.64 mmol) and 2.0 M n-BuLi cyclohexane solution (1.10 mL, 2.05 mmol) to synthesize a 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)-isomeric 2H), 4.84 (s, NH).

[0202] Example 3.7. Synthesis of (E)-(5-chloropyridin-2-yl)(2-chlorostyryl)(imino)-λ 6 -sulfanone (Chemical formula 1-21)

[0203] 3.7.1. Synthesis of 5-chloro-2-(methylthio)pyridine

Chemical formula

[0204] Using the reaction (1), 5-chloro-2-fluoropyridine (0.20 g, 1.52 mmol) was dissolved well in DMF, and then reacted with sodium thiomethoxide (0.11 g, 1.52 mmol) to synthesize a transparent oily 5-chloro-2-(methylthio)pyridine (0.18 g, 75%): R f = 0.67 (n-hexane 5:EtOAc 1); 11H NMR (400 MHz, DMSO-d6) δ 8.39 (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).

[0205] 3.7.2. (5-chloropyridin-2-yl)(imino)(methyl)-λ 6 -sulfanone synthesis

Chem.

[0206] Using the said reaction (2), 5-chloro-2-(methylthio)pyridine (0.18 g, 1.13 mmol) was dissolved well in MeOH, then reacted with diacetoxyiodobenzene (0.84 g, 2.61 mmol) and ammonium carbonate (0.16 g, 1.70 mmol) to synthesize white powdery (5-chloropyridin-2-yl)(imino)(methyl)-λ 6 -sulfanone (0.18 g, 83%): R f = 0.41 (EtOAc 100%); 1 1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 2.1 Hz, ArH), 8.24 (dd, J = 2.4, 8.4 Hz, ArH), 8.08 (d, J = 8.3 Hz, ArH), 4.53 (s, NH), 3.17 (s, CH3).

[0207] 3.7.3. (5-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone

Chem.

[0208] Using the said reaction (3), (5-chloropyridin-2-yl)(imino)(methyl)-λ 6Hexamethyldisilazane (0.28 mL, 1.34 mmol) was added to -sulfanone (0.17 g, 0.89 mmol) to synthesize transparent (5-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone (0.24 g, 100%): R f = 0.96 (EtOAc 100%); 1 1H NMR (400 MHz, 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).

[0209] Synthesis of diethyl ((5-chloropyridine-2-sulfonimidoyl)methyl)phosphonate

Chemical formula

[0210] Using the above reaction (4), (5-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone (0.24 g, 0.92 mmol) was dissolved well in THF, then reacted with diethyl chlorophosphate (0.19 mL, 1.29 mmol) and 2.0 M n-BuLi cyclohexane solution (1.01 mL, 2.03 mmol) to synthesize yellow oily diethyl ((5-chloropyridine-2-sulfonimidoyl)methyl)phosphonate (0.067 g, 22%): R f = 0.19 (EtOAc 100%); 11H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 2.0 Hz, ArH), 8.25 (dd, J = 2.4, 8.5 Hz, ArH), 8.10 (d, J = 8.4 Hz, ArH), 4.86 (s, NH), 4.20 - 4.34 (m, SCH2P), 3.96 - 4.02 (m, P(OCH2CH3)2), 1.15 (q, J = 5.9 Hz, P(OCH2CH3)2).

[0211] 3.7.5. (E)-(5-chloropyridin-2-yl)(2-chlorostyryl)(imino)-λ 6 -sulfanone (Chemical Formula 1-21) synthesis

Chem.

[0212] Using the above reaction (5)-1, diethyl ((5-chloropyridine-2-sulfonimidoyl)methyl)phosphonate (0.65 g, 1.99 mmol) was well dissolved in THF, then reacted with 2-chlorobenzaldehyde (0.34 g, 2.39 mmol) and 2.0 M n-BuLi cyclohexane solution (1.50 mL, 2.98 mmol) to synthesize the white powdery compound 1-21 (0.45 g, 62%): R f = 0.56 (EtOAc 2 / n-hexane 1); 1 1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 1.8 Hz, ArH), 7.95 - 8.18 (m, 2 ArH), 7.91 (d, J = 15.3 Hz, (E)-isomeric H), 7.38 - 7.63 (m, 3 ArH, (E)-isomeric H), 5.10 (s, NH).

[0213] Example 3.8. (E)-(2,6-difluorostyryl)(imino)(pyridin-2-yl)-λ 6 -sulfanone (Chemical Formula 1-22) synthesis

Chem.

[0214] In the same manner as in Examples 3.1.1 to 3.1.3, diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized.

[0215] After diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.50 g, 1.71 mmol) was well dissolved in THF using the reaction (5)-1, 2,6-difluorobenzaldehyde (0.23 g, 2.05 mmol) and 2.0 M n-BuLi cyclohexane solution (1.30 mL, 2.56 mmol) were reacted to synthesize a white powdery compound 1-22 (0.47 g, 98%): R f = 0.34 (EtOAc 4 / n-hexane 1); 1 1H NMR (400 MHz, DMSO-d6) δ 8.72-8.73 (m, ArH), 8.09-8.17 (m, 2ArH), 7.56-7.67 (m, 2ArH, (E)-isomeric H), 7.42 (d, J = 15.7 Hz, (E)-isomeric H), 7.26 (t, J = 9.0 Hz, 2ArH), 5.07 (s, NH).

[0216] Example 3.9. Synthesis of (E)-imino(pyridin-2-yl)(2,4,6-trifluorostyryl)-λ 6 -sulfanone (Chemical formula 1-23) [Chemical formula]

[0217] In the same manner as in Examples 3.1.1 to 3.1.3, diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized.

[0218] After diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.50 g, 1.71 mmol) was well dissolved in THF using the reaction (5)-1, it was reacted with 2,4,6-trifluorobenzaldehyde (0.33 g, 2.05 mmol) and 2.0 M n-BuLi cyclohexane solution (1.30 mL, 2.56 mmol) to synthesize a white powdery compound 1-23 (0.44 g, 86%): R f = 0.34 (EtOAc 4 / n-hexane 1); 1 1H 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)-isomeric H), 7.36 - 7.42 (m, 2ArH, (E)-isomeric H), 5.06 (s, NH).

[0219] Example 3.10. Synthesis of (E)-(2-fluorostyryl)(imino)(pyridin-2-yl)-λ 6 -sulfanone (Chemical formula 1-24)

Chemical formula

[0220] Diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 3.1.1 to 3.1.3.

[0221] Using the reaction (5)-1, diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.90 g, 3.08 mmol) was dissolved well in THF, and then reacted with 2-fluorobenzaldehyde (0.39 g, 3.69 mmol) and 2.0 M n-BuLi cyclohexane solution (2.30 mL, 4.62 mmol) to synthesize a white powdery compound 1-24 (0.47 g, 98%): R f = 0.34 (EtOAc 4 / n-hexane 1); 1 1H 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)-isomeric 2H), 7.25 - 7.35 (m, 2ArH), 4.94 (s, NH).

[0222] Example 3.11. Synthesis of (E)-imino(3-methoxypyridin-2-yl)(2-(trifluoromethyl)styryl)-λ 6 -sulfanone (Chemical Formula 1-25)

[0223] 3.11.1. Synthesis of 3-methoxy-2-(methylthio)pyridine

Chemical Structure

[0224] Using the reaction (1), 2-bromo-3-methoxypyridine (0.20 g, 1.06 mmol) was dissolved well in DMF, and then reacted with sodium thiomethoxide (0.15 g, 2.13 mmol) to synthesize a transparent oily 3-methoxy-2-(methylthio)pyridine (0.096 g, 58%): R f = 0.50 (n-hexane 9:EtOAc 1); 11H NMR (400 MHz, DMSO-d6) δ 8.06 (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).

[0225] 3.11.2. imino(3-methoxypyridin-2-yl)(methyl)-λ 6 -sulfanone synthesis

Chem.

[0226] Using the reaction (2), 3-methoxy-2-(methylthio)pyridine (1.23 g, 7.92 mmol) was well dissolved in MeOH, and then reacted with diacetoxyiodobenzene (5.87 g, 18.23 mmol) and ammonium carbonate (1.14 g, 11.89 mmol) to synthesize transparent oily imino(3-methoxypyridin-2-yl)(methyl)-λ 6 -sulfanone (0.97 g, 66%): R f = 0.21 (DCM 4:Acetone 1); 1 1H NMR (400 MHz, DMSO-d6) δ 8.17 (dd, J = 1.1, 4.5 Hz, ArH), 7.76 (dd, J = 1.0, 8.5 Hz, ArH), 7.63 (dd, J = 4.5, 8.5 Hz, ArH), 4.16 (s, NH), 3.96 (s, OCH3), 3.24 (s, CH3).

[0227] 3.11.3. (3-methoxypyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone synthesis

Chem.

[0228] Using the above reaction (3), imino(3-methoxypyridin-2-yl)(methyl)-λ 6 -sulfanone (0.22 g, 1.17 mmol) was added with hexamethyldisilazane (1.23 mL, 5.85 mmol) to synthesize yellow oily (3-methoxypyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone (0.25 g, 81%): R f = 0.69 (DCM 4:Acetone 1); 1 H NMR (400 MHz, DMSO-d6) δ8.18 (dd, J = 1.2, 4.5 Hz, ArH), 7.74 (dd, J = 1.0, 8.4 Hz, ArH), 7.63 (dd, J = 4.4, 8.4 Hz, ArH), 3.93 (s, OCH3), 3.19 (s, CH3), 0.00 (s, Si(OCH3)3).

[0229] Synthesis of diethyl((3-methoxypyridine-2-sulfonimidoyl)methyl)phosphonate

Chemical formula

[0230] Using the above reaction (4), (3-methoxypyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone (0.24 g, 0.95 mmol) was well dissolved in THF, then reacted with diethyl chlorophosphate (0.19 mL, 1.33 mmol) and 2.0 M n-BuLi cyclohexane solution (1.04 mL, 2.09 mmol) to synthesize yellow transparent oily diethyl((3-methoxypyridine-2-sulfonimidoyl)methyl)phosphonate (0.19 g, 60%): R f = 0.20 (DCM 4:Acetone 1); 11H NMR (400 MHz, DMSO-d6) δ 8.17 - 8.21 (m, ArH), 7.76 (d, J = 8.4 Hz, ArH), 7.64 (td, J = 4.6, 9.20 Hz, 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, 7.0 Hz, P(OCH2CH3)2).

[0231] 3.11.5. (E)-imino(3-methoxypyridin-2-yl)(2-(trifluoromethyl)styryl)-λ 6 -sulfanone (Chemical Formula 1-25) Synthesis

Chem.

[0232] Using the above reaction (5)-1, diethyl ((3-methoxypyridine-2-sulfonimidoyl)methyl)phosphonate (0.13 g, 0.39 mmol) was dissolved well in THF, then reacted with 2-(trifluoromethyl)benzaldehyde (0.082 g, 0.47 mmol) and 2.0 M n-BuLi cyclohexane solution (0.24 mL, 1.2 mmol) to synthesize a white powdery compound 1-25 (0.044 g, 33%): R f = 0.69 (DCM 4:Acetone 1); 1 1H NMR (400 MHz, DMSO-d6) δ 8.20 (dd, J = 1.2, 4.5 Hz, ArH), 8.12 (d, J = 7.8 Hz, ArH), 7.84 - 7.89 (m, ArH, (E)-isomeric H), 7.74 - 7.78 (m, 2 ArH), 7.62 - 7.69 (m, 2 ArH, (E)-isomeric H), 4.81 (s, NH), 3.92 (s, OCH3).

[0233] Example 3.12. (E)-imino(4-methoxypyridin-2-yl)(2-(trifluoromethyl)styryl)-λ6 Synthesis of -sulfanone (Chemical Formula 1-26)

[0234] Synthesis of 3.12.1.4-methoxy-2-(methylthio)pyridine

Chem.

[0235] After dissolving 2-bromo-4-methoxypyridine (1.00 g, 5.32 mmol) well in DMF using the above reaction (1), 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 1H NMR (400 MHz, DMSO-d6) δ 8.22 (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).

[0236] 3.12.2. imino(4-methoxypyridin-2-yl)(methyl)-λ 6 Synthesis of -sulfanone

Chem.

[0237] After dissolving 4-methoxy-2-(methylthio)pyridine (0.36 g, 2.33 mmol) well in MeOH using the above reaction (2), diacetoxyiodobenzene (1.72 g, 5.35 mmol) and ammonium carbonate (0.34 g, 3.49 mmol) were reacted to synthesize white solid imino(4-methoxypyridin-2-yl)(methyl)-λ 6 -sulfanone (0.33 g, 75%): R f= 0.32 (EtOAc 10:MeOH 1); 1 1H NMR (400 MHz, DMSO-d6) δ 8.51 (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).

[0238] 3.12.3. (4 - methoxypyridin - 2 - yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone synthesis

Chemical formula

[0239] Using the reaction (3), hexamethyldisilazane (0.66 mL, 3.14 mmol) was added to imino(4 - methoxypyridin - 2 - yl)(methyl)-λ 6 -sulfanone (0.33 g, 2.09 mmol) to synthesize pale yellow (4 - methoxypyridin - 2 - yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone (0.54 g, 100%): R f = 0.70 (EtOAc 10:MeOH 1); 1 1H NMR (400 MHz, 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).

[0240] 3.12.4. Synthesis of diethyl((4 - methoxy - N-(trimethylsilyl)pyridine - 2 - sulfonimidoyl)methyl)phosphonate

Chemical formula

[0241] Using the reaction (4), (4-methoxypyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone (0.54 g, 2.10 mmol) was dissolved well in THF, and then reacted with diethyl chlorophosphate (0.36 mL, 2.52 mmol) and 2.0 M n-BuLi cyclohexane solution (2.31 mL, 4.62 mmol) to synthesize transparent oily diethyl((4-methoxy-N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.56 g, 67%): R f = 0.42 (EtOAc 10:MeOH 1); 1 1H NMR (400 MHz, DMSO-d6) δ 8.53 - 8.55 (m, ArH), 7.60 (d, J = 2.4 Hz, ArH), 7.45 (d, J = 2.4 Hz, ArH), 7.22 (dd, J = 2.5, 5.6 Hz, 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).

[0242] 3.12.5. Synthesis of (E)-imino(4-methoxypyridin-2-yl)(2-(trifluoromethyl)styryl)-λ 6 -sulfanone (Chemical Formula 1-26) [Chemical Structure Diagram]

[0243] After diethyl((4-methoxy-N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.38 g, 0.96 mmol) was well dissolved in THF using the reaction (5)-1, 2-(trifluoromethyl)benzaldehyde (0.15 mL, 1.16 mmol) and 2.0 M n-BuLi cyclohexane solution (0.58 mL, 1.16 mmol) were reacted to synthesize a white powdery compound 1-26 (0.17 g, 51%): R f = 0.34 (EtOAc 100%); 1 H NMR (400 MHz, 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)-isomeric H), 7.73 (t, J = 7.5 Hz, ArH), 7.62 - 7.67 (m, 2 ArH, (E)-isomeric H), 7.21 (dd, J = 2.5, 5.6 Hz, ArH), 4.99 (s, NH), 3.93 (s, OCH3); 13 C NMR (100 MHz, DMSO-d6) δ167.2, 162.5, 151.6, 136.5, 133.8, 133.6, 131.2, 129.5, 127.7 (q, J C-F = 29.6 Hz), 126.7 (q, J C-F = 5.6 Hz), 124.5 (q, J C-F = 272.1 Hz, 113.1, 107.8, 56.6。

[0244] Example 3.13. Synthesis of (E)-(2-chlorostyryl)(imino)(4-methoxypyridin-2-yl)-λ 6 -sulfanone (Chemical formula 1-30)

Chem.

[0245] Diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 3.12.1 to 3.12.4.

[0246] Using the above reaction (5)-1, diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.091 g, 0.23 mmol) was dissolved well in THF, and then reacted with 2-chlorobenzaldehyde (0.03 mL, 0.28 mmol) and 2.0 M n-BuLi cyclohexane solution (0.14 mL, 0.28 mmol) to synthesize a white powdery compound 1-30 (0.030 g, 42%): 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)-isomeric H), 7.67 (d, J = 2.4 Hz, ArH), 7.56 - 7.63 (m, ArH, (E)-isomeric 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 (100 MHz, DMSO-d6) δ 167.3, 162.3, 151.7, 149.1, 147.9, 138.9, 135.8, 134.9, 132.2, 127.2, 113.3, 107.8, 56.6.

[0247] Example 3.14. Synthesis of (E)-(2-fluorostyryl)(imino)(4-methoxypyridin-2-yl)-λ 6 -sulfanone (Chemical Formula 1-31)

Chemical Structure

[0248] Diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 3.12.1 to 3.12.4.

[0249] After diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.31 g, 0.78 mmol) was well dissolved in THF using the reaction (5)-1, 2-fluorobenzaldehyde (0.10 mL, 0.94 mmol) and 2.0 M n-BuLi cyclohexane solution (0.47 mL, 0.94 mmol) were reacted to synthesize white powdery 1-31 (0.057 g, 25%): R f = 0.27 (EtOAc 100%); 1 1H 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)-isomeric H), 7.48 - 7.54 (m, ArH, (E)-isomeric H), 7.25 - 7.34 (m, 2 ArH), 7.19 (dd, J = 2.4, 5.6 Hz, ArH), 4.93 (s, NH), 3.93 (s, OCH3); 13 13C NMR (100 MHz, DMSO-d6) δ 167.2, 162.6, 162.2, 159.7, 151.6, 134.0 (d, J C-F = 3.9 Hz), 133.4 (d, J C-F = 8.8 Hz), 131.8 (d, J C-F = 5.4 Hz), 130.2 (d, J C-F = 1.9 Hz), 125.6 (d, J C-F = 3.4 Hz), 120.9 (d, J C-F = 11.1 Hz), 116.5 (d, J C-F = 21.4 Hz), 113.0, 107.8, 56.6.

[0250] Example 3.15. (E)-(3-chloropyridin-2-yl)(2-chlorostyryl)(imino)-λ 6 -sulfanone (Chemical Formula 1-38) Synthesis

[0251] 3.15.1. Synthesis of 3-chloro-2-(methylthio)pyridine

Chem.

[0252] Using the above reaction (1), 3-chloro-2-fluoropyridine (1.00 g, 3.60 mmol) was well 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); 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).

[0253] 3.15.2. Synthesis of (3-chloropyridin-2-yl)(imino)(methyl)-λ 6 -sulfanone

Chem.

[0254] Using the above reaction (2), 3-chloro-2-(methylthio)pyridine (0.20 g, 1.23 mmol) was well dissolved in MeOH, and then diacetoxyiodobenzene (0.91 g, 2.82 mmol) and ammonium carbonate (0.18 g, 1.84 mmol) were reacted to obtain white oily (3-chloropyridin-2-yl)(imino)(methyl)-λ6 -sulfanone was synthesized (0.15 g, 63%): R f = 0.37 (EtOAc 100%); 1 1H NMR (400 MHz, DMSO-d6) δ 8.60 (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).

[0255] 3.15.3. (3-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 Synthesis of -sulfanone

Chemical formula

[0256] Using the above reaction (3), (3-chloropyridin-2-yl)(imino)(methyl)-λ 6 -sulfanone (0.15 g, 0.77 mmol) was added with hexamethyldisilazane (0.24 mL, 1.16 mmol) to synthesize transparent oily (3-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone (0.19 g, 95%): R f = 0.67 (n-hexane 1:EtOAc 1); 1 1H 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).

[0257] 3.15.4. Synthesis of diethyl((3-chloropyridine-2-sulfonimidoyl)methyl)phosphonate

Chemical formula

[0258] Using the reaction (4), (3-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone (0.20 g, 0.73 mmol) was dissolved well in THF, and then reacted with diethyl chlorophosphate (0.15 mL, 1.02 mmol) and 2.0 M n-BuLi cyclohexane solution (0.80 mL, 1.61 mmol) to synthesize yellow oily diethyl((3-chloropyridine-2-sulfonimidoyl)methyl)phosphonate (0.061 g, 26%): R f = 0.35 (EtOAc 10:MeOH 1); 1 1H NMR (400 MHz, DMSO-d6) δ 8.59 (dd, J = 1.2, 4.6 Hz, ArH), 8.18 (dd, J = 1.2, 8.1 Hz, 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).

[0259] 3.15.5. Synthesis of (E)-(3-chloropyridin-2-yl)(2-chlorostyryl)(imino)-λ 6 -sulfanone (Chemical Formula 1-38)

Chemical Structure

[0260] Using the reaction (5)-1, diethyl((3-chloropyridine-2-sulfonimidoyl)methyl)phosphonate (0.16 g, 0.48 mmol) was dissolved well in THF, and then reacted with 2-chlorobenzaldehyde (0.06 mL, 0.58 mmol) and 2.0 M n-BuLi cyclohexane solution (0.29 mL, 0.58 mmol) to synthesize a white powdery compound 1-38 (0.017 g, 11%): 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)-isomeric H), 7.66 - 7.73 (m, ArH, (E)-isomeric H), 7.59 (dd, J = 1.2, 8.0 Hz, ArH), 7.42 - 7.52 (m, 2 ArH), 5.26 (s, NH); 13 C NMR (100 MHz, DMSO-d6) δ 157.0, 147.4, 141.5, 137.8, 134.4, 132.8, 131.2, 130.9, 130.6, 129.5, 128.6, 128.4, 128.3。

[0261] Example 3.16. Synthesis of (E)-(2-chlorostyryl)(imino)(5-methoxypyridin-2-yl)-λ 6 -sulfanone (Chemical formula 1-39)

[0262] 3.16.1. Synthesis of 5-methoxy-2-(methylthio)pyridine

Chem.

[0263] Using the reaction (1), 2-bromo-5-methoxypyridine (3.00 g, 15.9 mmol) was dissolved well in DMF, and then sodium thiomethoxide (4.47 g, 63.8 mmol) was reacted to synthesize transparent oily 5-methoxy-2-(methylthio)pyridine (0.84 g, 34%): R f = 0.58 (n-hexane 3:EtOAc 1); 1 1H NMR (400 MHz, DMSO-d6) δ 8.19 (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).

[0264] 3.16.2. imino(5-methoxypyridin-2-yl)(methyl)-λ 6 -sulfanone synthesis

Chemical Structure

[0265] Using the reaction (2), 5-methoxy-2-(methylthio)pyridine (0.84 g, 5.41 mmol) was dissolved well in MeOH0, and then diacetoxyiodobenzene (4.00 g, 12.43 mmol) and ammonium carbonate (0.78 g, 8.11 mmol) were reacted to synthesize white solid imino(5-methoxypyridin-2-yl)(methyl)-λ 6 -sulfanone (0.92 g, 91%): R f = 0.32 (EtOAc 10:MeOH 1); 1 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 2.8 Hz, ArH), 8.03 (d, J = 8.7 Hz, ArH), 7.62 (dd, J = 2.9, 8.7 Hz, ArH), 4.25 (s, NH), 3.91 (s, OCH3), 3.10 (s, CH3).

[0266] 3.16.3. Synthesis of (5-methoxypyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone

Chemical formula

[0267] Using the above reaction (3), hexamethyldisilazane (0.34 mL, 1.61 mmol) was added to imino(5-methoxypyridin-2-yl)(methyl)-λ 6 -sulfanone (0.20 g, 1.07 mmol) to synthesize yellow (5-methoxypyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone (0.31 g, 100%): R f = 0.90 (EtOAc 10:MeOH 1); 1 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 2.7 Hz, ArH), 7.96 (d, J = 8.7 Hz, ArH), 7.62 (dd, J = 2.8, 8.7 Hz, ArH), 3.92 (s, OCH3), 3.10 (s, CH3), 0.00 (s, Si(OCH3)3).

[0268] 3.16.4. Synthesis of diethyl((5-methoxypyridine-2-sulfonimidoyl)methyl)phosphonate

Chemical formula

[0269] Using the above reaction (4), (5-methoxypyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6-Sulfanone (0.31 g, 1.21 mmol) was dissolved well in THF, then reacted with diethyl chlorophosphate (0.24 mL, 1.69 mmol) and 2.0 M n-BuLi cyclohexane solution (0.64 mL, 1.33 mmol) to synthesize transparent oily diethyl ((5-methoxypyridine-2-sulfonimidoyl)methyl)phosphonate (0.17 g, 44%): R f = 0.61 (EtOAc 10:MeOH 1); 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (t, J = 3.0 Hz, ArH), 8.04 (dd, J = 8.8, 12.1 Hz, ArH), 7.62 (dd, J = 1.9, 5.8 Hz, 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 = 7.2 Hz, P(OCH2CH3)2).

[0270] 3.16.5. (E)-(2-Chlorostyryl)(imino)(5-methoxypyridin-2-yl)-λ 6 -Sulfanone (Chemical Formula 1-39) Synthesis

Chem.

[0271] Using the above reaction (5)-1, diethyl ((5-methoxypyridine-2-sulfonimidoyl)methyl)phosphonate (0.19 g, 0.48 mmol) was dissolved well in THF, then reacted with 2-chlorobenzaldehyde (0.09 mL, 0.73 mmol) and 2.0 M n-BuLi cyclohexane solution (0.29 mL, 0.58 mmol) to synthesize white powdery Compound 1-39 (0.030 g, 18%): R f = 0.46 (EtOAc 100%); 11H 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)-isomeric H), 7.62 (dd, J = 2.8, 8.8 Hz, ArH), 7.53 - 7.57 (m, ArH, (E)-isomeric H), 7.43 - 7.47 (m, ArH), 7.38 (t, J = 7.5 Hz, ArH), 4.80 (s, NH), 3.91 (s, OCH3); 13 13C NMR (100 MHz, DMSO-d6) δ 157.9, 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。

[0272] Example 3.17. Synthesis of (E)-(2-chlorostyryl)(3-fluoropyridin-2-yl)(imino)-λ 6 -sulfanone (Chemical Formula 1-40)

[0273] 3.17.1. Synthesis of 3-fluoro-2-(methylthio)pyridine

Chemical Structure

[0274] Using the above reaction (1), 2,3-difluoropyridine (0.20 g, 1.74 mmol) was well dissolved in DMF, and then reacted with sodium thiomethoxide (0.12 g, 1.74 mmol) to synthesize transparent oily 3-fluoro-2-(methylthio)pyridine (0.11 g, 45%): R f = 0.64 (n-hexane 5:EtOAc 1); 1 1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 4.8 Hz, ArH), 7.20 - 7.26 (m, ArH), 6.98 - 7.02 (m, ArH), 2.59 (s, CH3).

[0275] 3.17.2. Synthesis of (3-fluoropyridin-2-yl)(imino)(methyl)-λ 6 -sulfanone

Chemical formula

[0276] After dissolving 3-fluoro-2-(methylthio)pyridine (0.32 g, 2.25 mmol) well in MeOH using the said reaction (2), react with diacetoxyiodobenzene (1.67 g, 5.17 mmol) and ammonium carbonate (0.32 g, 3.37 mmol) to synthesize white solid (3-fluoropyridin-2-yl)(imino)(methyl)-λ 6 -sulfanone (0.25 g, 64%): R f = 0.26 (EtOAc 100%); 1 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 4.5 Hz, ArH), 8.01 (t, J = 9.0 Hz, ArH), 7.74 - 7.78 (m, ArH), 4.75 (s, NH), 3.27 (s, CH3).

[0277] 3.17.3. Synthesis of (3-fluoropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone

Chemical formula

[0278] Using the said reaction (3), add hexamethyldisilazane (0.45 mL, 2.17 mmol) to (3-fluoropyridin-2-yl)(imino)(methyl)-λ 6 -sulfanone (0.25 g, 1.45 mmol) to obtain yellow oily (3-fluoropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6-sulfanone was synthesized (0.33 g, 93%): R f = 0.77 (EtOAc 100%); 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (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).

[0279] Synthesis of diethyl ((3-fluoro-N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate

Chem.

[0280] Using the above reaction (4), (3-fluoropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone (0.33 g, 1.35 mmol) was dissolved well in THF, then reacted with diethyl chlorophosphate (0.27 mL, 1.89 mmol) and 2.0 M n-BuLi cyclohexane solution (1.49 mL, 2.97 mmol) to synthesize semi-transparent oily diethyl ((3-fluoro-N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.28 g, 54%): R f = 0.44 (EtOAc 100%); 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (dt, J = 1.3, 4.4 Hz, ArH), 7.97 - 8.02 (m, ArH), 7.75 - 7.79 (m, ArH), 4.38 (t, J = 15.6 Hz, SCHHP), 4.21 (t, J = 16.1 Hz, SCHHP), 3.92 - 4.04 (m, P(OCH2CH3)2), 1.16 (t, J = 7.0 Hz, P(OCH2CH3)2), 0.04 (s, Si(OCH3)3).

[0281] 3.17.5. (E)-(2-chlorostyryl)(3-fluoropyridin-2-yl)(imino)-λ 6 -sulfanone (Chemical Formula 1-40) Synthesis

Chem.

[0282] Using the above reaction (5)-1, diethyl((3-fluoro-N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.28 g, 0.73 mmol) was dissolved well in THF, then reacted with 2-chlorobenzaldehyde (0.14 mL, 1.10 mmol) and 2.0 M n-BuLi cyclohexane solution (0.44 mL, 0.88 mmol) to synthesize a white powdery compound 1-40 (0.038 g, 18%): R f = 0.54 (EtOAc 100%); 1 1H NMR (400 MHz, DMSO-d6) δ8.53 (d, J = 4.5 Hz, ArH), 7.96 - 8.02 (m, 2 ArH, (E)-isomeric H), 7.77 - 7.80 (m, ArH), 7.65 (d, J = 15.3 Hz, (E)-isomeric 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).

[0283] Example 3.18. (E)-(3-chloropyridin-4-yl)(2-chlorostyryl)(imino)-λ 6 -sulfanone (Chemical Formula 1-41) Synthesis

[0284] 3.18.1. Synthesis of 3-chloro-2-(methylthio)pyridine

Chem.

[0285] After dissolving 4-bromo-3-chloropyridine (0.80 g, 4.16 mmol) well in DMF using the reaction (1), 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 1H NMR (400 MHz, 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).

[0286] 3.18.2. Synthesis of (3-chloropyridin-2-yl)(imino)(methyl)-λ 6 -sulfanone

Chemical formula

[0287] After dissolving 3-chloro-2-(methylthio)pyridine (0.53 g, 3.30 mmol) well in MeOH using the reaction (2), diacetoxyiodobenzene (2.44 g, 7.58 mmol) and ammonium carbonate (0.48 g, 4.94 mmol) were reacted to synthesize white solid (3-chloropyridin-2-yl)(imino)(methyl)-λ 6 -sulfanone (0.47 g, 100%): R f = 0.24 (EtOAc 100%); 1 1H NMR (400 MHz, DMSO-d6) δ 8.86 (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).

[0288] 3.18.3. (3-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6Synthesis of -sulfanone

Chem.

[0289] Using the said reaction (3), (3-chloropyridin-2-yl)(imino)(methyl)-λ 6 To (3-chloropyridin-2-yl)(imino)(methyl)-λ-sulfanone (0.10 g, 0.12 mmol), hexamethyldisilazane (0.16 mL, 0.79 mmol) was added to synthesize transparent oily (3-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone (0.15 g, 100%): R f = 0.73 (EtOAc 100%); 1 1H NMR (400 MHz, 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).

[0290] Synthesis of 3.18.4.diethyl((3-chloro-N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate

Chem.

[0291] Using the said reaction (4), (3-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6-Sulfanone (0.50 g, 1.91 mmol) was dissolved well in THF, then reacted with diethyl chlorophosphate (0.39 mL, 2.67 mmol) and 2.0 M n-BuLi cyclohexane solution (2.10 mL, 4.19 mmol) to synthesize yellow oily diethyl ((3-chloro-N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.62 g, 81%): R f = 0.53 (EtOAc 100%); 1 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, ArH), 8.82 (d, J = 5.0 Hz, ArH), 7.93 (d, J = 4.9 Hz, ArH), 4.27 - 4.43 (m, SCH2P), 3.95 - 4.04 (m, P(OCH2CH3)2), 1.22 (t, J = 7.0 Hz, P(OCH2CH3)2), 0.03 (s, Si(CH3)3).

[0292] 3.18.5. Synthesis of (E)-(3-chloropyridin-4-yl)(2-chlorostyryl)(imino)-λ 6 -sulfanone (Chemical Formula 1-41)

Chem.

[0293] Using the above reaction (5)-1, the compound of Reaction Formula 3-4 (0.30 g, 0.74 mmol) was dissolved well in THF, then reacted with 2-chlorobenzaldehyde (0.11 mL, 1.11 mmol) and 2.0 M n-BuLi cyclohexane solution (0.44 mL, 0.89 mmol) to synthesize white powdery Compound 1-41 (0.025 g, 11%): R f = 0.54 (EtOAc 100%); 11H NMR (400 MHz, DMSO-d6) δ 8.82 - 8.83 (m, 2 ArH), 8.08 (d, J = 5.0, ArH), 8.02 (d, J = 15.2, (E)-isomeric 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)-isomeric H), 7.49 (t, J = 7.8 Hz, ArH), 7.41 (t, J = 7.6 Hz, ArH), 5.56 (s, NH).

[0294] Example 3.19. Synthesis of (E)-(5-chloropyridin-2-yl)(2-chlorostyryl)(imino)-λ 6 -sulfanone (Chemical formula 1-42) [Chemical formula]

[0295] Diethyl ((5-chloropyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 3.7.1 to 3.7.4.

[0296] After diethyl ((5-chloropyridine-2-sulfonimidoyl)methyl)phosphonate (0.16 g, 0.50 mmol) was well dissolved in THF using the above reaction (5)-1, 2-chlorobenzaldehyde (0.08 mL, 0.74 mmol) and 2.0 M n-BuLi cyclohexane solution (0.30 mL, 0.59 mmol) were reacted to synthesize a white powdery compound 1-42 (0.070 g, 45%): R f = 0.69 (EtOAc 100%); 11H 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)-isomeric H), 7.56 - 7.62 (m, ArH, (E)-isomeric H), 7.47 (td, J = 1.4, 7.5 Hz, ArH), 7.39 (t, J = 7.2 Hz, ArH), 5.10 (s, NH); 13 13C NMR (100 MHz, DMSO-d6) δ 159.2, 148.9, 138.8, 137.5, 134.6, 134.3, 132.8, 132.1, 130.7, 130.6, 129.4, 128.3, 123.5。

[0297] Example 3.20. Synthesis of (E)-(2-chlorostyryl)(imino)(3-methoxypyridin-2-yl)-λ 6 -sulfanone (Chemical Formula 1-43) [Chemical Structure]

[0298] Diethyl ((3-methoxypyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 3.11.1 to 3.11.4.

[0299] After diethyl ((3-methoxypyridine-2-sulfonimidoyl)methyl)phosphonate (0.19 g, 0.57 mmol) was well dissolved in THF using the above reaction (5)-1, 2-chlorobenzaldehyde (0.10 mL, 0.86 mmol) and 2.0 M n-BuLi cyclohexane solution (0.34 mL, 0.69 mmol) were reacted to synthesize white powdery 1-43 (0.044 g, 25%): R f = 0.35 (DCM 4:Acetone 1); 11H 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)-isomeric H), 7.74 - 7.76 (m, ArH), 7.64 (dd, J = 4.5, 8.4 Hz, ArH), 7.56 - 7.60 (m, ArH, (E)-isomeric 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 13C NMR (100 MHz, DMSO-d6) δ 153.0, 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。

[0300] Example 3.21. Synthesis of (E)-(2-fluorostyryl)(imino)(3-methoxypyridin-2-yl)-λ 6 -sulfanone (Chemical Formula 1-44)

Chem.

[0301] Diethyl ((3-methoxypyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 3.11.1 to 3.11.4.

[0302] After diethyl ((3-methoxypyridine-2-sulfonimidoyl)methyl)phosphonate (0.20 g, 0.61 mmol) was well dissolved in THF using the above reaction (5)-1, 2-fluorobenzaldehyde (0.10 mL, 0.92 mmol) and 2.0 M n-BuLi cyclohexane solution (0.37 mL, 0.74 mmol) were reacted to synthesize white powdery 1-44 (0.18 g, 65%): R f = 0.56 (DCM 4:Acetone 1); 11H 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)-isomeric H), 7.64 (dd, J = 4.5, 8.4 Hz, ArH), 7.50 - 7.55 (m, ArH, (E)-isomeric H), 7.28 - 7.36 (m, 2 ArH), 4.75 (s, NH), 3.94 (s, OCH3); 13 13C NMR (100 MHz, DMSO-d6) δ 152.9, 148.6, 140.0, 134.7 (d, J C-F = 3.3 Hz), 133.3 (d, J C-F = 8.8 Hz), 130.9 (d, J C-F = 5.7 Hz), 130.3, 128.9, 125.6 (d, J C-F = 3.4 Hz), 122.7, 121.1 (d, J C-F = 10.9 Hz), 116.8, 116.5, 56.8。

[0303] Example 3.22. Synthesis of (E)-(4-chloropyridin-2-yl)(2-chlorostyryl)(imino)-λ 6 -sulfanone (Chemical Formula 1-45)

[0304] 3.22.1. Synthesis of (4-Chloropyridin-2-yl)(imino)(methyl)-λ 6 -sulfanone

Chem.

[0305] Using the above reaction (2), 4-Chloro-2-(methylthio)pyridine (0.20 g, 1.25 mmol) was dissolved well in MeOH, then reacted with diacetoxyiodobenzene (0.93 g, 2.88 mmol) and ammonium carbonate (0.18 g, 1.88 mmol) to obtain white solid (4-Chloropyridin-2-yl)(imino)(methyl)-λ6 -sulfanone was synthesized (0.18 g, 77%): R f = 0.58 (EtOAc 10:MeOH 1); 1 1H NMR (400 MHz, DMSO-d6) δ 8.59 (dd, J = 1.0, 4.5 Hz, ArH), 8.18 (dd, J = 1.1, 8.1 Hz, ArH), 7.65 - 7.68 (m, ArH), 4.62 (s, NH), 3.35 (s, CH3).

[0306] 3.22.2. (4-Chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 Synthesis of -sulfanone

Chemical formula

[0307] Using the reaction (3), hexamethyldisilazane (0.30 mL, 1.44 mmol) was added to (4-Chloropyridin-2-yl)(imino)(methyl)-λ 6 -sulfanone (0.18 g, 0.96 mmol) to synthesize transparent oily (4-Chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone (0.29 g, 100%): R f = 0.75 (EtOAc 100%); 1 1H NMR (400 MHz, 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).

[0308] 3.22.3. Synthesis of Diethyl((4-chloro-N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate

Chemical formula

[0309] Using the reaction (4), (4-Chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone (0.29 g, 1.10 mmol) was dissolved well in THF, and then reacted with diethyl chlorophosphate (0.22 mL, 1.53 mmol) and 2.0 M n-BuLi cyclohexane solution (1.21 mL, 2.41 mmol) to synthesize yellow oily Diethyl((4-chloro-N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.28 g, 65%): R f = 0.52 (EtOAc 100%); 1 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 5.2 Hz, ArH), 8.01 (d, J = 1.6 Hz, ArH), 7.84 (dd, J = 2.0, 5.2 Hz, ArH), 4.27 (d, J = 16.0 Hz, SCH2P), 3.93 - 4.01 (m, P(OCH2CH3)2), 1.12 - 1.17 (m, P(OCH2CH3)2), 0.04 (s, Si(CH3)3).

[0310] 3.22.4. Synthesis of (E)-(4-chloropyridin-2-yl)(2-chlorostyryl)(imino)-λ 6 -sulfanone (Chemical Formula 1-45)

Chemical Structure

[0311] After dissolving Diethyl((4-chloro-N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate(0.28 g, 0.71 mmol) well in THF using the reaction (5)-1, 2-chlorobenzaldehyde(0.12 mL, 1.07 mmol) and 2.0 M n-BuLi cyclohexane solution(0.43 mL, 0.85 mmol) were reacted to synthesize a white solid compound 1-45(0.15 g, 53%): R f =0.26(n-hexane 1:EtOAc 1); 1 H NMR(400 MHz, DMSO-d6)δ8.70(d, J = 5.2 Hz, ArH), 8.21(d, J = 1.9 Hz, ArH), 7.91 - 7.97(m, ArH, (E)-isomeric H), 7.82(dd, J = 1.9, 5.2 Hz, ArH), 7.56 - 7.64(m, ArH, (E)-isomeric 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(100 MHz, 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。

[0312] Example 3.23. Synthesis of (E)-(2-chlorostyryl)(3-fluoropyridin-4-yl)((trimethylsilyl)imino)-λ 6 -sulfanone (Chemical formula 1-46)

[0313] 3.23.1. 3-fluoro-4-(methylthio)pyridine

Chemical formula

[0314] Using the reaction (1), 4-bromo-3-fluoropyridine(1.00 g, 7.60 mmol) was dissolved in DMF After dissolving well, 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 1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 2.1 Hz, ArH), 8.33 (dd, J = 1.0, 5.2 Hz, ArH), 7.39 (dd, J = 5.2, 6.8 Hz, ArH), 2.55 (s, CH3).

[0315] 3.23.2. Synthesis of (3-fluoropyridin-4-yl)(imino)(methyl)-λ 6 -sulfanone

Chemical formula

[0316] Using the above reaction (2), after dissolving 3-fluoro-4-(methylthio)pyridine (0.64 g, 4.43 mmol) well in MeOH, diacetoxyiodobenzene (3.29 g, 10.20 mmol) and ammonium carbonate (0.48 g, 4.94 mmol) were reacted to synthesize pale yellow oily (3-fluoropyridin-2-yl)(imino)(methyl)-λ 6 -sulfanone (0.47 g, 74%): R f = 0.24 (EtOAc 100%); 1 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 1.7 Hz, ArH), 8.70 (d, J = 4.8 Hz, ArH), 7.82 (dd, J = 5.0, 5.9 Hz, ArH), 5.11 (s, NH), 3.26 (s, CH3).

[0317] 3.23.3. Synthesis of (3-fluoropyridin-4-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone [Chemistry]

[0318] Using the said reaction (3), (3-fluoropyridin-2-yl)(imino)(methyl)-λ 6 -sulfanone (0.55 g, 3.18 mmol) was added with hexamethyldisilazane (1.00 mL, 4.77 mmol) to synthesize yellow oily (3-fluoropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone (0.76 g, 96%): R f = 0.76 (EtOAc 100%); 1 1H NMR (400 MHz, 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).

[0319] Synthesis of Diethyl ((3-fluoro-N-(trimethylsilyl)pyridine-4-sulfonimidoyl)methyl)phosphonate [Chemistry]

[0320] Using the said reaction (4), (3-fluoropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6-Sulfanone (0.76 g, 3.06 mmol) was dissolved well in THF, and then reacted with diethyl chlorophosphate (0.62 mL, 4.29 mmol) and 2.0 M n-BuLi cyclohexane solution (3.37 mL, 6.74 mmol) to synthesize transparent oily Diethyl((3-fluoro-N-(trimethylsilyl)pyridine-4-sulfonimidoyl)methyl)phosphonate (0.86 g, 73%): R f = 0.52 (EtOAc 100%); 1 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 1.7 Hz, ArH), 8.70 (d, J = 4.9 Hz, ArH), 7.83 (dd, J = 5.1, 6.0 Hz, ArH), 5.41 (s, NH), 4.30 (dd, J = 1.6, 16.5 Hz, SCH2P), 3.95 - 4.04 (m, P(OCH2CH3)2), 1.12 - 1.17 (m, P(OCH2CH3)2).

[0321] 3.23.5. (E)-(2-chlorostyryl)(3-fluoropyridin-4-yl)((trimethylsilyl)imino)-λ 6 -Sulfanone (Chemical Formula 1-46) synthesis

Chemical Structure

[0322] Using the above reaction (5)-1, the compound of Reaction Formula 3-4 (0.42 g, 1.09 mmol) was dissolved well in THF, and then reacted with 2-chlorobenzaldehyde (0.18 mL, 1.63 mmol) and 2.0 M n-BuLi cyclohexane solution (0.65 mL, 1.31 mmol) to synthesize white powdery Compound 1-46 (0.18 g, 45%): R f = 0.80 (n-hexane 1:EtOAc 1); 11H 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)-isomeric H), 7.88 (t, J = 5.2 Hz, ArH), 7.67 (d, J = 15.1 Hz, (E)-isomeric 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 13C NMR (100 MHz, DMSO-d6) δ 152.8, 151.0, 145.01 (d, J C-F = 5.8 Hz), 137.9 (d, J C-F = 24.2 Hz), 136.7 (d, J C-F = 11.8 Hz), 135.2, 131.9, 130.9, 130.4, 127.8 (d, J C-F = 26.0 Hz), 126.9, 125.6, 119.5。

[0323] Example 3.24. Synthesis of (E)-(2-chlorostyryl)(3-fluoropyridin-4-yl)(imino)-λ 6 -sulfanone (Chemical Formula 1-47)

[0324] 3.24.1. Synthesis of 3-chloro-4-(methylthio)pyridine

Chem.

[0325] Using the above reaction (1), 4-bromo-3-chloropyridine (0.80 g, 4.16 mmol) was dissolved well in DMF, and then reacted with sodium thiomethoxide (0.29 g, 4.16 mmol) to synthesize transparent oily 3-chloro-4-(methylthio)pyridine (0.53 g, 79%): R f = 0.15 (n-hexane 5:EtOAc 1); 11H NMR (400 MHz, 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).

[0326] 3.24.2. Synthesis of (3-chloropyridin-4-yl)(imino)(methyl)-λ 6 -sulfanone

Chem.

[0327] Using the reaction (2), 3-chloro-4-(methylthio)pyridine (0.53 g, 3.30 mmol) was well dissolved in MeOH, then reacted with diacetoxyiodobenzene (2.44 g, 7.58 mmol) and ammonium carbonate (0.48 g, 4.94 mmol) to synthesize pale yellow oily (3-chloropyridin-2-yl)(imino)(methyl)-λ 6 -sulfanone (0.47 g, 74%): R f = 0.24 (EtOAc 100%); 1 1H NMR (400 MHz, DMSO-d6) δ 8.86 (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).

[0328] 3.24.3. Synthesis of (3-chloropyridin-4-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone

Chem.

[0329] Using the reaction (3), (3-chloropyridin-2-yl)(imino)(methyl)-λ 6-Sulfanone (0.10 g, 0.12 mmol) was added to hexamethyldisilazane (0.16 mL, 0.79 mmol) to synthesize transparent oily (3-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone (0.15 g, 100%): R f = 0.73 (EtOAc 100%); 1 1H NMR (400 MHz, 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).

[0330] 3.24.4. Synthesis of Diethyl((3-chloro-N-(trimethylsilyl)pyridine-4-sulfonimidoyl)methyl)phosphonate

Chemical formula

[0331] Using the above reaction (4), (3-chloropyridin-2-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone (0.50 g, 1.91 mmol) was dissolved well in THF, and then reacted with diethyl chlorophosphate (0.39 mL, 2.67 mmol) and 2.0 M n-BuLi cyclohexane solution (2.10 mL, 4.19 mmol) to synthesize pale yellow oily Diethyl((3-chloro-N-(trimethylsilyl)pyridine-4-sulfonimidoyl)methyl)phosphonate (0.62 g, 81%): R f = 0.53 (EtOAc 100%); 11H NMR (400 MHz, DMSO-d6) δ 8.87 (s, ArH), 8.82 (d, J = 5.0 Hz, ArH), 7.93 (d, J = 4.9 Hz, ArH), 4.27 - 4.43 (m, SCH2P), 3.95 - 4.04 (m, P(OCH2CH3)2), 1.22 (t, J = 7.0 Hz, P(OCH2CH3)2), 0.03 (s, Si(CH3)3).

[0332] 3.24.5.(E)-(2-chlorostyryl)(3-fluoropyridin-4-yl)(imino)-λ 6 -sulfanone (Chemical Formula 1-47) synthesis

Chem.

[0333] Using the above reaction (5)-1, the compound of Reaction Formula 3-4 (0.42 g, 1.09 mmol) was well dissolved in THF, and then reacted with 2-chlorobenzaldehyde (0.18 mL, 1.63 mmol) and 2.0 M n-BuLi cyclohexane solution (0.65 mL, 1.31 mmol) to synthesize white powdery Compound 1-47 (0.23 g, 58%): R f = 0.29 (n-hexane 1:EtOAc 1); 1 1H 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)-isomeric H), 7.91 (t, J = 3.6 Hz, ArH), 7.58 - 7.62 (m, ArH, (E)-isomeric H), 7.49 (t, J = 4.9 Hz, ArH), 7.41 (t, J = 5.0 Hz, ArH), 5.69 (s, NH); 13 13C NMR (100 MHz, DMSO-d6) δ 155.4, 153.6, 147.4 (d, J C-F = 5.9 Hz), 140.42 (d, J C-F = 24.3 Hz), 139.1 (d, J C-F = 12.5 Hz), 138.9, 134.5, 133.1, 131.5, 130.4 (d, J C-F= 16.1 Hz), 129.5, 128.2, 122.6 (d, J C-F = 1.7 Hz).

[0334] Example 3.25. Synthesis of (E)-(4-chloropyridin-3-yl)(2-chlorostyryl)(imino)-λ 6 -sulfanone (Chemical Formula 1-48)

[0335] 3.25.1. Synthesis of 4-chloro-3-(methylthio)pyridine

Chemical Structure

[0336] Using the above reaction (1), 3-bromo-4-chloropyridine (1.00 g, 7.60 mmol) was well dissolved in DMF, and then reacted with sodium thiomethoxide (0.53 g, 7.60 mmol) to synthesize transparent oily 4-chloro-3-(methylthio)pyridine (0.36 g, 30%): R f = 0.60 (n-hexane 1:EtOAc 1); 1 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, ArH), 8.34 (d, J = 5.2 Hz, ArH), 7.53 (d, J = 5.2 Hz, ArH), 2.61 (s, CH3).

[0337] 3.25.2. Synthesis of (4-chloropyridin-3-yl)(imino)(methyl)-λ 6 -sulfanone

Chemical Structure

[0338] Using the reaction (2), 4-chloro-3-(methylthio)pyridine (0.36 g, 2.28 mmol) was dissolved well in MeOH, and then reacted with diacetoxyiodobenzene (1.69 g, 5.24 mmol) and ammonium carbonate (0.33 g, 3.42 mmol) to synthesize yellow oily (4-chloropyridin-3-yl)(imino)(methyl)-λ 6 -sulfanone (0.20 g, 46%): R f = 0.43 (EtOAc 10:MeOH 1); 1 1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, ArH), 8.76 (d, J = 5.3 Hz, ArH), 7.78 (d, J = 5.2 Hz, ArH), 4.89 (s, NH), 3.26 (s, CH3).

[0339] 3.25.3. Synthesis of (4-chloropyridin-3-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone

Chemical formula

[0340] Using the reaction (3), hexamethyldisilazane (0.33 mL, 1.59 mmol) was added to (4-chloropyridin-3-yl)(imino)(methyl)-λ 6 -sulfanone (0.20 g, 1.06 mmol) to synthesize yellow oily (4-chloropyridin-3-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone (0.29 g, 100%): R f = 0.87 (EtOAc 100%); 1 1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, ArH), 8.77 (d, J = 5.3 Hz, ArH), 7.80 (d, J = 5.3 Hz, ArH), 3.30 (s, CH3), 0.00 (s, Si(CH3)3).

[0341] Synthesis of Diethyl((4-chloro-N-(trimethylsilyl)pyridine-3-sulfonimidoyl)methyl)phosphonate [Chemical formula]

[0342] Using the above reaction (4), (4-chloropyridin-3-yl)(methyl)((trimethylsilyl)imino)-λ 6 -sulfanone (0.50 g, 1.91 mmol) was dissolved well in THF and then reacted with diethyl chlorophosphate (0.39 mL, 2.67 mmol) and 2.0 M n-BuLi cyclohexane solution (2.10 mL, 4.19 mmol) to synthesize pale yellow oily Diethyl((3-chloro-N-(trimethylsilyl)pyridine-4-sulfonimidoyl)methyl)phosphonate (0.62 g, 81%): R f = 0.53 (EtOAc 100%); 1 1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, ArH), 8.76 (d, J = 5.3 Hz, ArH), 7.79 (d, J = 5.3 Hz, 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).

[0343] Synthesis of (E)-(4-chloropyridin-3-yl)(2-chlorostyryl)(imino)-λ 6 -sulfanone (Chemical formula 1-48) [Chemical formula]

[0344] After dissolving the compound of Reaction Formula 4-4 (0.21 g, 0.52 mmol) well in THF% using the reaction (5)-1, 2-chlorobenzaldehyde (0.09 mL, 0.77 mmol) and 2.0 M n-BuLi cyclohexane solution (0.31 mL, 0.62 mmol) were reacted to synthesize a white solid compound 1-48 (0.019 g, 12%): R f = 0.59 (EtOAc 100%); 1 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)-isomeric 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)-isomeric H), 7.48 (td, J = 1.5, 7.4 Hz, ArH), 7.38 - 7.42 (m, ArH), 5.48 (s, NH); 13 13C NMR (DMSO-d6, 100 MHz) δ 154.9, 151.2, 142.4, 138.9, 136.9, 134.5, 132.9, 131.2, 130.7, 130.6, 129.5, 128.4, 127.0.

[0345] Example 3.26. Synthesis of (E)-imino(5-methoxypyridin-2-yl)(2-(trifluoromethyl)styryl)-λ 6 -sulfanone (Chemical Formula 1-54)

Chemical Structure

[0346] Diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 3.12.1 to 3.12.4.

[0347] Using the reaction (5)-1, diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.35 g, 0.90 mmol) was dissolved well in THF, and then reacted with 2-(trifluoromethyl)benzaldehyde (0.14 mL, 1.08 mmol) and 2.0 M n-BuLi cyclohexane solution (0.54 mL, 1.08 mmol) to synthesize a white powdery compound 1-54 (0.13 g, 41%): R f = 0.45 (EtOAc 100%); 1 H 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, 2 ArH), 7.60 - 7.65 (m, ArH, (E)-isomeric H), 7.58 (d, J = 15.0 Hz, (E)-isomeric H), 4.83 (s, NH), 3.91 (s, OCH3); 13 C NMR (100 MHz, DMSO-d6) δ 157.9, 151.9, 138.5, 135.6, 134.7, 133.6, 131.1, 129.4, 127.6 (q, J C-F = 29.5 Hz), 126.7 (q, J C-F = 5.5 Hz), 124.5 (q, J C-F = 272.1 Hz), 123.1, 121.9, 56.7。

[0348] Example 3.27. Synthesis of (E)-(2-fluorostyryl)(imino)(5-methoxypyridin-2-yl)-λ 6 -sulfanone (Chemical formula 1-55)

Chem.

[0349] Diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 3.12.1 to 3.12.4.

[0350] After diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.35 g, 1.08 mmol) was well dissolved in THF using the above reaction (5)-1, 2-fluorobenzaldehyde (0.14 mL, 1.29 mmol) and 2.0 M n-BuLi cyclohexane solution (0.65 mL, 1.29 mmol) were reacted to synthesize a white solid compound 1-55 (0.24 g, 76%): R f = 0.78 (EtOAc 10:MeOH 1); 1 1H NMR (400 MHz, DMSO-d6) δ 8.39 (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)-isomeric H), 7.46 - 7.50 (m, ArH, (E)-isomeric 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).

[0351] Synthesis of (E)-(2-fluorostyryl)(5-methoxypyridin-2-yl)(methylimino)-λ6-sulfanone (Chemical Formula 1-56) in Example 3.28

Chemical Structure

[0352] (E)-(2-fluorostyryl)(imino)(5-methoxypyridin-2-yl)-λ 6 -sulfanone was synthesized in the same manner as in Example 3.27.

[0353] Sodium hydride (1.2 eq, 60% dispersion in mineral oil) was dissolved in anhydrous DMF and then cooled to 0 °C using ice water. To the said solution, the synthesized (E)-(2-fluorostyryl)(imino)(5-methoxypyridin-2-yl)-λ 6 -sulfanone (1.0 eq) was slowly added dropwise, followed by stirring for 30 minutes. Iodomethane (1.1 eq) was added and the reaction was carried out at room temperature for 15 hours. After quenching the reaction with water, extraction was performed with water and EtOAc. The organic layer was dried over anhydrous Na2SO4 to remove a small amount of water, and the solvent was removed by distillation under reduced pressure and then dried under vacuum. Subsequently, purification by column chromatography was carried out to synthesize white solid compound 1-56 (0.02 g, 65%): R f = 0.70 (EtOAc 10:MeOH 1); 1 1H NMR (400 MHz, DMSO-d6) δ 8.44 (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)-isomeric H), 7.48 - 7.54 (m, ArH), 7.39 (d, J = 15.6 Hz, (E)-isomeric H), 7.31 - 7.34 (m, ArH), 7.27 (t, J = 7.6 Hz, ArH), 3.91 (s, OCH3), 2.62 (s, NCH3).

[0354] Synthesis of sulfanone derivatives where both Example 4.A and B are pyridine As an example of the present invention, the synthesis process of sulfanone derivatives when both A and B in Chemical Formula 1 are pyridine is shown in the following Reaction Formula 4.

Chemical formula

[0355] (5)-2. Synthesis of substituted (E)-imino(pyridin-2-yl)(2-(pyridin-2-yl)vinyl)-lambda6-sulfanone derivatives by reaction with 2-picolinaldehyde derivatives

Chem.

[0356] In the same manner as the reactions (1) to (4) of Example 3, from substituted methyl(pyridin-2-yl)((trimethylsilyl)imino)-λ6-sulfanone, the substituted (E)-imino(pyridine-2-yl)(2-(pyridin-2-yl)vinyl)-λ6-sulfanone derivative ((E)-imino(pyridine-2-yl)(2-(pyridin-2-yl)vinyl)-λ6-sulfanone) was synthesized according to the above reaction formula.

[0357] Specifically, after dissolving the compound synthesized in Step 2-4 (1.0 eq) in anhydrous THF, it was cooled to -78 °C using dry ice and acetone. n-BuLi (1.2 eq, 2.0 M cyclohexane solution) was slowly added dropwise to the solution, and then stirred for 1 hour. A picolinaldehyde derivative (1.2 eq) was added and the reaction was continued for another 1 hour. TLC was checked, and if the reaction was not complete, the reaction was continued at room temperature for an additional 30 minutes. After quenching the reaction with a small amount of water, extraction was performed with water and 10% MeOH / MC. The organic layer was dried over anhydrous Na2SO4 to remove a small amount of water, and the solvent was removed by distillation under reduced pressure and dried in vacuo. Then, separation and purification by column chromatography gave the 3-, 4-, 5- or 6-substituted (E)-imino(pyridine-2-yl)(2-(pyridin-2-yl)vinyl)-λ6-sulfanone derivative.

[0358] Example 4.1. Synthesis of (E)-imino(4-methoxypyridin-2-yl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6 -sulfanone (Chemical Formula 1-27)

Chem.

[0359] Diethyl((4-methoxy-N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 3.12.1 to 3.12.4.

[0360] Using Reaction Scheme (5)-2, diethyl((4-methoxy-N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.14 g, 0.34 mmol) was dissolved well in THF and then reacted with 3-(trifluoromethyl)picolinaldehyde (0.050 mL, 0.41 mmol) and 2.0 M n-BuLi cyclohexane solution (0.21 mL, 0.41 mmol) to synthesize a white powdery compound 1-27 (0.063 g, 54%): R f = 0.35 (EtOAc 100%); 1 1H NMR (400 MHz, DMSO-d6) δ 8.91 (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)-isomeric H), 7.73 - 7.77 (m, (E)-isomeric H), 7.68 - 7.71 (m, 2 ArH), 7.22 (dd, J = 2.5, 5.6 Hz, ArH), 5.17 (s, NH), 3.94 (s, OCH3).

[0361] Example 4.2. Synthesis of (E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(4-methoxypyridin-2-yl)-λ 6 -sulfanone (Chemical Formula 1-28)

Chemical Structure

[0362] In the same manner as in Examples 3.12.1 to 3.12.4, diethyl((4-methoxy-N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized.

[0363] Using Reaction Scheme (5)-2, diethyl((4-methoxy-N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.26 g, 0.65 mmol) was dissolved well in THF, and then reacted with 3-chloropicolinaldehyde (0.10 mL, 0.78 mmol) and 2.0 M n-BuLi cyclohexane solution (0.39 mL, 0.78 mmol) to synthesize white powdery 1-28 (0.085 g, 42%): R f = 0.33 (EtOAc 100%); 1 1H 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)-isomeric H), 7.72 (d, J = 14.7 Hz, (E)-isomeric 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); 13 13C NMR (100 MHz, DMSO-d6) δ 167.3, 162.3, 151.7, 149.1, 147.9, 138.9, 135.8, 134.9, 132.2, 127.2, 113.3, 107.8, 56.6.

[0364] Example 4.3. Synthesis of (E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(4-methoxypyridin-2-yl)-λ 6 -sulfanone (Chemical Formula 1-29)

Chemical Structure

[0365] In the same manner as in Examples 3.12.1 to 3.12.4, diethyl((4-methoxy-N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized.

[0366] Using Reaction Scheme (5)-2, diethyl((4-methoxy-N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.28 g, 0.72 mmol) was dissolved well in THF, and then reacted with 3-fluoropicolinaldehyde (0.11 g, 0.86 mmol) and 2.0 M n-BuLi cyclohexane solution (0.43 mL, 0.86 mmol) to synthesize white powdery 1-29 (0.10 g, 49%): R f = 0.40 (EtOAc 100%); 1 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 5.6 Hz, 2 ArH), 7.84 - 7.89 (m, ArH), 7.64 - 7.73 (m, ArH, (E)-isomeric 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 13C NMR (100 MHz, DMSO-d6) δ 167.3, 162.3, 159.6, 157.0, 151.7, 146.9 (d, J C-F = 4.8 Hz), 139.5 (d, J C-F = 10.9 Hz), 132.7, 127.9 (d, J C-F = 4.7 Hz), 125.2 (d, J C-F = 18.9 Hz), 113.3, 107.8, 56.6.

[0367] Example 4.4. (E)-imino(4-methoxypyridin-2-yl)(2-(3-methoxypyridin-2-yl)vinyl)-λ 6Synthesis of -sulfanone (Chemical Formula 1-32) [Chem.]

[0368] Diethyl((4-methoxy-N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 3.12.1 to 3.12.4.

[0369] After diethyl((4-methoxy-N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.22 g, 0.68 mmol) was well dissolved in THF using Reaction Scheme (5)-2, 3-methoxypicolinaldehyde (0.11 g, 0.82 mmol) and 2.0 M n-BuLi cyclohexane solution (0.41 mL, 0.82 mmol) were reacted to synthesize white solid Compound 1-32 (0.075 g, 36%): R f = 0.27 (EtOAc 100%); 1 1H 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)-isomeric 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)-isomeric 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 13C NMR (100 MHz, DMSO-d6) δ 167.2, 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.

[0370] Example 4.5. Synthesis of (E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(3-methoxypyridin-2-yl)-λ 6 -sulfanone (Chemical Formula 1-33)

Chem.

[0371] Diethyl((3-methoxypyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 3.11.1 to 3.11.4.

[0372] After diethyl((3-methoxypyridine-2-sulfonimidoyl)methyl)phosphonate (0.15 g, 0.45 mmol) was well dissolved in THF using the said reaction (5)-2, 3-chloropicolinaldehyde (0.076 g, 0.54 mmol) and 2.0 M n-BuLi cyclohexane solution (0.27 mL, 0.54 mmol) were reacted to synthesize a white powdery compound 1-33 (0.056 g, 40%): R f = 0.33 (DCM 4:Acetone 1); 1 1H NMR (400 MHz, DMSO-d6) δ8.65 (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)-isomeric H), 7.74 - 7.79 (m, ArH, (E)-isomeric 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).

[0373] Example 4.6. (E)-imino(3-methoxypyridin-2-yl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6Synthesis of -sulfanone (Chemical Formula 1-34) [Chem.]

[0374] Diethyl((3-methoxypyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 3.11.1 to 3.11.4.

[0375] After diethyl((3-methoxypyridine-2-sulfonimidoyl)methyl)phosphonate (0.15 g, 0.47 mmol) was well dissolved in THF using the reaction (5)-2, 3-(trifluoromethyl)picolinaldehyde (0.090 mL, 0.71 mmol) and 2.0 M n-BuLi cyclohexane solution (0.28 mL, 0.57 mmol) were reacted to synthesize a white powdery compound 1-34 (0.091 g, 56%): R f = 0.29 (DCM 4:Acetone 1); 1 H NMR (400 MHz, DMSO-d6) δ8.95 (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)-isomeric H), 7.83 (dd, J = 1.4, 14.4 Hz, (E)-isomeric 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 (100 MHz, DMSO-d6) δ153.9, 153.1, 148.8, 148.2, 140.2, 136.5, 135.6 (q, J C-F = 5.1 Hz), 135.0, 129.1, 125.5, 124.5 (q, J C-F = 31.3 Hz), 124.0 (q, J C-F = 271.1 Hz), 122.8, 56.9.

[0376] Example 4.7. Synthesis of (E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(5-methoxypyridin-2-yl)-λ 6 -sulfanone (Chemical Formula 1-35)

Chem.

[0377] Diethyl((5-methoxypyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 3.16.1 to 3.16.4.

[0378] After diethyl((5-methoxypyridine-2-sulfonimidoyl)methyl)phosphonate (0.15 g, 0.47 mmol) was well dissolved in THF using the reaction (5)-2, 3-chloropicolinaldehyde (0.080 g, 0.57 mmol) and 2.0 M n-BuLi cyclohexane solution (0.28 mL, 0.57 mmol) were reacted to synthesize a white powdery compound 1-35 (0.067 g, 42%): R f = 0.29 (EtOAc 100%); 1 1H NMR (400 MHz, DMSO-d6) δ8.59 (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)-isomeric H), 7.61 - 7.67 (m, ArH, (E)-isomeric H), 7.49 (dd, J = 4.5, 8.2 Hz, ArH), 4.95 (s, NH), 3.91 (s, OCH3); 13 13C NMR (100 MHz, 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.

[0379] Example 4.8. Synthesis of (E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(5-methoxypyridin-2-yl)-λ 6 -sulfanone (Chemical Formula 1-36)

Chemical Structure

[0380] Diethyl((5-methoxypyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 3.16.1 to 3.16.4.

[0381] After diethyl((5-methoxypyridine-2-sulfonimidoyl)methyl)phosphonate (0.13 g, 0.40 mmol) was well dissolved in THF using the reaction (5)-2, 3-fluoropicolinaldehyde (0.060 g, 0.48 mmol) and 2.0 M n-BuLi cyclohexane solution (0.24 mL, 0.48 mmol) were reacted to synthesize a white powdery compound 1-36 (0.029 g, 25%): R f = 0.43 (n-hexane 1:EtOAc 1); 1 1H NMR (400 MHz, DMSO-d6) δ8.50 - 8.51 (m, ArH), 8.41 (d, J = 2.8 Hz, ArH), 8.13 (d, J = 8.8 Hz, ArH), 7.83 - 7.88 (m, ArH), 7.61 - 7.68 (m, (E)-isomeric 2H, ArH), 7.55 - 7.59 (m, ArH), 4.94 (s, NH), 3.91 (s, OCH3); 13 13C NMR (100 MHz, DMSO-d6) δ158.1, 151.6, 146.9 (d, J C-F = 4.8 Hz), 139.57 (d, J C-F = 10.7 Hz), 138.6, 135.6 (d, J C-F = 4.6 Hz), 131.8, 127.8 (d, J C-F= 4.9 Hz), 125.2 (d, J C-F = 18.9 Hz), 123.9, 121.9, 56.7。

[0382] Example 4.9. Synthesis of (E)-imino(5-methoxypyridin-2-yl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6 -sulfanone (Chemical Formula 1-37)

Chem.

[0383] Diethyl((5-methoxypyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 3.16.1 to 3.16.4.

[0384] After dissolving diethyl((5-methoxypyridine-2-sulfonimidoyl)methyl)phosphonate (0.13 g, 0.40 mmol) well in THF using the said reaction (5)-2, 3-(trifluoromethyl)picolinaldehyde (0.08 mL, 0.60 mmol) and 2.0 M n-BuLi cyclohexane solution (0.24 mL, 0.48 mmol) were reacted to synthesize a white powdery compound 1-37 (0.089 g, 65%): R f = 0.50 (n-hexane 1:EtOAc 1); 1 1H NMR (400 MHz, DMSO-d6) δ 8.89 (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)-isomeric H), 7.62 - 7.73 (m, 2 ArH, (E)-isomeric H), 5.01 (s, NH), 3.91 (s, OCH3).

[0385] Example 4.10. Synthesis of (E)-(2-(3-chloropyridin-2-yl)vinyl)(imino)(pyridin-2-yl)-λ 6 -sulfanone (Chemical Formula 1-49) [Chemical Formula]

[0386] Diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 3.1.1 to 3.1.4.

[0387] After diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.39 g, 1.06 mmol) was well dissolved in THF using the reaction (5)-2, 3-chloropicolinaldehyde (0.18 mg, 1.27 mmol) and 2.0 M n-BuLi cyclohexane solution (0.64 ml, 1.59 mmol) were reacted to synthesize a white solid compound 1-49 (0.10 g, 35%): R f = 0.32 (n-hexane 1:EtOAc 2); 1 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, 4.3 Hz, ArH), 8.73 (dd, 1.0, 4.5 Hz, ArH), 8.18 (d, 7.8 Hz, ArH), 8.12 (td, 1.6 7.6 Hz, ArH), 8.06 (dd, 1.3, 8.2 Hz, ArH), 7.93 (d, J = 14.7 Hz, (E)-isomeric H), 7.73 (d, J = 14.7 Hz, (E)-isomeric H), 7.67 (ddd, 1.0, 4.5, 7.6 Hz, ArH), 7.52 (dd, 4.5, 8.2 Hz, ArH), 5.13 (brs, NH); 1313C NMR (100 MHz, DMSO-d6) δ 160.4, 150.4, 149.1, 147.9, 139.3, 138.9, 136.0, 135.0, 122.2, 127.5, 127.2, 121.9

[0388] Example 4.11. Synthesis of (E)-imino(2-(3-methoxypyridin-2-yl)vinyl)(pyridin-2-yl)-λ 6 -sulfanone (Chemical Formula 1-50) [Chem.]

[0389] Diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 3.1.1 to 3.1.4.

[0390] After diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.35 g, 0.97 mmol) was well dissolved in THF using the reaction (5)-2, 3-methoxypicolinaldehyde (0.16 g, 1.16 mmol) and 2.0 M n-BuLi cyclohexane solution (0.58 ml, 1.45 mmol) were reacted to synthesize a white solid compound 1-50 (0.09 g, 33%): R f = 0.15 (n-hexane 1:EtOAc 3); 1 1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, 4.4 Hz, ArH), 8.23 (d, 4.4 Hz, ArH), 8.15 (d, 7.7 Hz, ArH), 8.10 (t, 7.5 Hz, ArH), 7.85 (d, J = 15.0 Hz, (E)-isomeric H), 7.66 - 7.53 (m, 2ArH, (E)-isomeric H), 7.52 (dd, 4.5, 8.4 Hz, ArH), 4.93 (brs, NH), 3.92 (s, OCH3); 1313C NMR (100 MHz, CD3OD) δ 159.5, 155.5, 149.9, 141.3, 140.0, 138.7, 137.4, 130.7, 127.0, 126.6, 122.0, 119.5, 55.1

[0391] Example 4.12. Synthesis of (E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(pyridin-2-yl)-λ 6 -sulfanone (Chemical Formula 1-51) [Chem.]

[0392] Diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 3.1.1 to 3.1.4.

[0393] After diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.33 g, 0.91 mmol) was well dissolved in THF using the reaction (5)-2, 3-fluoropicolinaldehyde (0.14 g, 1.09 mmol) and 2.0 M n-BuLi cyclohexane solution (0.54 ml, 1.09 mmol) were reacted to synthesize a white solid compound 1-51 (0.03 g, 14%): R f = 0.55 (n-hexane 1:EtOAc 3); 1 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, 4.2 Hz, ArH), 8.53 (d, 4.4 Hz, ArH), 8.19 (d, 7.8 Hz, ArH), 8.12 (td, 1.6, 6.8 Hz, ArH), 7.87 (t, 9.0 Hz, ArH), 7.75 - 7.65 (m, (E)-isomeric 2H, ArH), 7.61 - 7.57 (m, ArH), 5.13 (brs, NH); 1313C NMR (100 MHz, DMSO-d6) δ 160.5, 158.3 (d, J C-F = 260.9 Hz), 150.4, 146.9 (d, J C-F = 4.9 Hz), 139.5 (d, J C-F = 11.0 Hz), 139.3, 134.9 (q, J C-F = 4.3 Hz), 132.7, 128.0 (d, J C-F = 4.6 Hz), 127.5, 125.2 (d, J C-F = 18.9 Hz), 121.9

[0394] Example 4.13. Synthesis of (E)-imino(pyridin-2-yl)(2-(3-(trifluoromethyl)pyridin-2-yl)vinyl)-λ 6 -sulfanone (Chemical Formula 1-52)

Chem.

[0395] Diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate was synthesized in the same manner as in Examples 3.1.1 to 3.1.4.

[0396] After diethyl((N-(trimethylsilyl)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.30 g, 0.82 mmol) was well dissolved in THF using the reaction (5)-2, 3-(trifluoromethyl)picolinaldehyde (0.12 ml, 0.91 mmol) and 2.0 M n-BuLi cyclohexane solution (0.45 ml, 0.91 mmol) were reacted to synthesize a white solid compound 1-52 (0.04 g, 17%): R f = 0.21 (n-hexane 1:EtOAc 3); 11H NMR (400 MHz, DMSO-d6) δ 8.92 (d, 4.3 Hz, ArH), 8.75 (d, 4.3 Hz, ArH), 8.30 (d, 8.0 Hz, ArH), 8.20 (d, 7.7 Hz, ArH), 8.14 (t, 7.6 Hz, ArH), 7.89 (d, J = 14.4 Hz, (E)-isomeric H), 7.78 (d, J = 14.4 Hz, (E)-isomeric H), 7.72 - 7.67 (m, 2 ArH), 5.21 (brs, NH); 13 13C NMR (100 MHz, DMSO-d6) δ 160.3, 153.8, 150.4, 148.6, 139.4, 137.5, 135.6 (q, J C-F = 5.2 Hz), 134.6 (q, J C-F = 2.2 Hz), 127.6, 125.6, 124.5 (q, J C-F = 31.3 Hz), 124.0 (q, J C-F = 272.1 Hz), 122.0

[0397] Example 4.14. Synthesis of (E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(5-(3-morpholinopropoxy)pyridin-2-yl)-λ 6 -sulfanone (Chemical Formula 1-53)

[0398] As an example of the present invention, the synthesis process of Compound 1-53 is shown in the following Reaction Scheme 5.

Chemical Structure

[0399] 4.14.1. Introduction of the morpholine group by Mitsunobu reaction

Chemical Structure

[0400] The compound 4-(3-((6-Bromopyridin-3-yl)oxy)propyl)morpholine was synthesized according to the above reaction formula. Specifically, a bromopyridine starting material (1.0 eq) with a hydroxy group substituted at the 3-position was dissolved in tetrahydrofuran (THF), and 4-(3-Hydroxypropyl)morpholine (1.3 eq) and triphenylphosphine (1.3 eq) were dissolved well. Then, diisopropylazodicarboxylate (1.3 eq) 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), 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 using a mixed developing solvent of ethyl acetate and methanol to obtain 4-(3-((6-Bromopyridin-3-yl)oxy)propyl)morpholine.

[0401] 4.14.2. Synthesis of 4-(3-((6-Bromopyridin-3-yl)oxy)propyl)morpholine

Chemical formula

[0402] 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 diisopropylazodicarboxylate (1.91 ml, 9.71 mmol) were reacted to synthesize yellow oily 4-(3-((6-Bromopyridin-3-yl)oxy)propyl)morpholine (2.12 g, 95%); R f = 0.20 (EtOAc 9:CH3OH 1); 11H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 3.0 Hz, ArH), 7.36 (d, J = 8.7 Hz, ArH), 7.10 (dd, J = 3.1, 8.7 Hz, ArH), 4.06 (t, J = 6.2 Hz, CH2), 3.72 (t, J = 4.5 Hz, 2CH2), 2.51 (t, J = 7.1 Hz, CH2), 2.46 (t, J = 4.4 Hz, 2CH2), 2.01 - 1.94 (m, CH2).

[0403] 4.14.3. Synthesis of methylthiopyridine derivatives from bromopyridine derivatives

Chemical formula

[0404] 4-(3-((6-(Methylthio)pyridin-3-yl)oxy)propyl)morpholine was synthesized according to the above reaction formula. Specifically, 4-(3-((6-bromopyridin-3-yl)oxy)propyl)morpholine (1.0 eq) was dissolved in dimethyl sulfoxide (DMSO), cesium carbonate (4.0 eq) and S-methylisothiourea sulfate (1.0 eq) were added, and the mixture was stirred at 80 °C for 18 hours. 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 off the solvent under reduced pressure was purified by column chromatography using a mixed developing solvent of ethyl acetate and methanol to obtain 4-(3-((6-(methylthio)pyridin-3-yl)oxy)propyl)morpholine.

[0405] 4.14.4. Synthesis of 4-(3-((6-(Methylthio)pyridin-3-yl)oxy)propyl)morpholine

Chemical formula

[0406] 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 yellow oily 4-(3-((6-(methylthio)pyridin-3-yl)oxy)propyl)morpholine (1.84 g, 97%); R f = 0.21 (EtOAc 9:CH3OH1); 1 1H NMR (400 MHz, CDCl3) δ 8.17 (t, J = 1.8 Hz, ArH), 7.11 (d, J = 1.7 Hz, ArH), 4.06 (t, J = 6.2 Hz, CH2), 3.72 (t, J = 4.6 Hz, 2CH2), 2.55 (s, SCH3) 2.51 (t, J = 7.1 Hz, CH2), 2.46 (t, J = 4.4 Hz, 2CH2), 2.00 - 1.93 (m, CH2).

[0407] 4.14.5. Imino(methyl)(5-(3-morpholinopropoxy)pyridin-2-yl)-λ 6 -sulfanone synthesis

Chemical formula

[0408] Using the above reaction (2), 4-(3-((6-(methylthio)pyridin-3-yl)oxy)propyl)morpholine (1.00 g, 3.75 mmol) was dissolved well in MeOH, and then reacted with diacetoxyiodobenzene (2.78 g, 8.63 mmol) and ammonium carbonate (0.54 g, 5.63 mmol) to synthesize yellow oily imino(methyl)(5-(3-morpholinopropoxy)pyridin-2-yl)-lambda 6 -sulfanone (0.61 g, 55%): R f = 0.24 (EtOAc 93:CH3OH7); 11H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 2.7 Hz, ArH), 8.08 (d, J = 8.7 Hz, ArH), 7.34 (dd, J = 2.8, 8.7 Hz, ArH), 4.16 (t, J = 6.2 Hz, CH2), 3.73 (t, J = 4.4 Hz, 2CH2), 3.49 (s, NH), 3.23 (s, SCH3), 2.56 (t, J = 7.2 Hz, CH2), 2.50 (t, J = 4.4 Hz, 2CH2), 2.07 - 2.00 (m, CH2).

[0409] 4.14.6. Methyl (5-(3-morpholinopropoxy)pyridin-2-yl)((trimethylsilyl)imino)-λ 6 -sulfanone synthesis

Chemical formula

[0410] Using the reaction (3), imino(methyl)(5-(3-morpholinopropoxy)pyridin-2-yl)-lambda 6 -sulfanone (0.84 g, 2.79 mmol) was added with hexamethyldisilazane (0.88 mL, 4.19 mmol) to synthesize methyl (5-(3-morpholinopropoxy)pyridin-2-yl)((trimethylsilyl)imino)-lambda 6 -sulfanone (1.02 g, 100%): R f = 0.61 (DCM 9:CH3OH 1); 1 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 2.7 Hz, ArH), 7.96 (d, J = 8.7 Hz, ArH), 7.63 (dd, J = 2.8, 8.7 Hz, ArH), 4.20 (t, J = 6.4 Hz, CH2), 3.58 (t, J = 4.6 Hz, 2CH2), 3.11 (s, SCH3), 2.44 (t, J = 7.2 Hz, CH2), 2.38 (t, J = 4.4 Hz, 2CH2), 1.96 - 1.90 (m, CH2), 0.00 (s, Si(CH3)3).

[0411] Synthesis of Diethyl((5-(3-morpholinopropoxy)pyridine-2-sulfonimidoyl)methyl)phosphonate

Chem.

[0412] Using the above reaction (4), methyl (5-(3-morpholinopropoxy)pyridin-2-yl)((trimethylsilyl)imino)-lambda 6 -sulfanone (2.70 g, 7.18 mmol) was dissolved well in THF, then reacted with diethyl chlorophosphate (1.56 mL, 10.77 mmol) and 2.0 M n-BuLi cyclohexane solution (7.90 mL, 15.80 mmol) to synthesize yellow oily diethyl((5-(3-morpholinopropoxy)pyridine-2-sulfonimidoyl)methyl)phosphonate (1.21 g, 39%): R f = 0.29 (EtOAc 4:CH3OH1); 1 1H NMR (400 MHz, DMSO-d6) δ8.39 (d, J = 2.8 Hz, ArH), 8.04 (d, J = 8.8 Hz, ArH), 7.63 (dd, J = 2.8, 8.8 Hz, ArH), 4.58 (s, NH), 4.22 - 4.15 (m, CH2, SCH2P), 4.06 - 3.99 (m, 2CH3CH2O), 3.58 (t, J = 4.6 Hz, 2CH2), 2.44 (t, J = 7.2 Hz, CH2), 2.37 (t, J = 4.4 Hz, 2CH2), 1.97 - 1.91 (m, CH2), 1.16 (t, J = 7.1 Hz, 2CH3CH2O).

[0413] (E)-(2-(3-fluoropyridin-2-yl)vinyl)(imino)(5-(3-morpholinopropoxy)pyridin-2-yl)-lambda 6 -sulfanone (Chemical formula 1-53) synthesis

Chem.

[0414] Using the reaction formula (5)-2, diethyl ((5-(3-morpholinopropoxy)pyridine-2-sulfonimidoyl)methyl)phosphonate (0.10 g, 0.23 mmol) was well dissolved in THF, and then reacted with 3-fluoropicolinaldehyde (0.03 g, 0.25 mmol) and 2.0 M n-BuLi cyclohexane solution (0.13 ml, 0.25 mmol) to synthesize a pale yellow oily compound 1-53 (0.03 g, 31%): R f = 0.11 (EtOAc 4:CH3OH1); 1 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 4.5 Hz, ArH), 8.40 (d, J = 2.8 Hz, ArH), 8.12 (d, J = 8.8 Hz, ArH), 7.86 (t, J = 9.5 Hz, ArH), 7.68 - 7.55 (m, (E)-isomeric 2H, 2ArH), 4.93 (s, NH), 4.18 (t, J = 6.3 Hz, CH2), 3.56 (t, J = 4.4 Hz, 2CH2), 2.42 (t, J = 6.9 Hz, CH2), 2.36 (t, J = 4.4 Hz, 2CH2), 1.94 - 1.87 (m, CH2).

[0415] Experimental Example 1. Evaluation of Nrf2 activation effect and cytotoxicity To confirm the pharmacological activities of the compounds synthesized according to Examples 1 to 4 of the present invention, an Nrf2 functional cell based assay (DiscoveRx) was constructed to evaluate the Nrf2 activity induction effect of the synthesized derivatives, which is a major regulator of oxidative stress defense. Specifically, U2OS cells were used. After suspending the cell pellet with CP 0 reagent, 1.5×10 4Dispensed 80 μL each at a cell / well density and cultured for 24 hours. The compounds synthesized according to Examples 1 to 4 were serially diluted 3-fold at seven concentrations in DMSO to prepare a stock solution. 10 μL of each compound solution was mixed with 90 μL of CP 0 and added 20 μL per well of the 96-well plate, and each experiment was repeated 3 times. As a positive control group, 5 μM sulforaphane and DMF (dimethyl fumarate) were treated, the plate was wrapped with foil, and cultured for 6 hours. Substrate reagents 1 and 2 were placed in a cell assay buffer and mixed thoroughly. Then, 50 μL of the substrate reagent was added per well of the 96-well plate, wrapped with foil, and cultured for 1 hour. After that, the luminescence value was measured using a luminescence spectrophotometer (Molecular Devices) at all wavelengths and an integration time of 1000 ms. The effect of each compound was shown as the concentration that activates 50% relative to the maximum effect at a high concentration (Table 1).

[0416]

Table 1

[0417] As shown in Table 1 above, the compounds (Compounds 1 to 55) of Examples 1 to 4 of the present invention were found to induce Nrf2 activity. In particular, 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 showed a more excellent Nrf2 activation effect compared to sulforaphane, which is known as an Nrf2 activator.

[0418] Specifically, in the case of Compound 1-41, which exhibits the most excellent Nrf2 activation activity among the compounds of the present invention, it shows an effect approximately 14 times superior to that of sulforaphane. In the case of Compounds 1-4, it shows an Nrf2 activation activity approximately 30 times superior to that of DMF and approximately 4 times superior to that of sulforaphane, and shows a cytotoxicity 250 times lower than that of Bardoxolone-methyl (CDDO-Me) (Figure 1).

[0419] Sulforaphane contains an isothiocyanate group (NCS) and is known to exhibit high toxicity at concentrations of 5 μM or higher due to its non-selective strong reactivity despite its high activity. However, the results from the experimental examples of the present invention suggest that the compounds of the present invention, which do not show cytotoxicity even at 10 μM and are confirmed to induce Nrf2 activity, can be used as Nrf2 activators instead of sulforaphane.

[0420] Experimental Example 2. Evaluation of CYP Activity Inhibitory Ability To confirm the potential of the compounds according to the examples of the present invention as drugs for actual administration in vivo, the CYP activity inhibitory ability, which is involved in approximately 75% of drug metabolism, was confirmed. Specifically, compared with compounds containing a sulfone group as the core and having similar functional groups, Compounds 1-1, 1-2, 1-6, 1-8, 1-9, 1-10, 1-12, and 1-13 of the present invention containing sulfanone were evaluated for their activity inhibition against five isoenzymes, namely 2C19, 2D6, 2C9, 1A2, and 3A4, which are reported to account for more than 90% of the metabolism by all CYPs.

[0421] Human liver microsomes (0.25 mg / mL), 0.1 M phosphate buffer (pH 7.4), the substrate drug cocktail of the five drug-metabolizing enzymes (Phenacetin 50 μM, Diclofenac 10 μM, S-mephenytoin 100 μM, Dextromethorphan 5 μM, and Midazolam 2.5 μM), and 1-1, 1-2, 1-6, 1-8, 1-9, 1-10, 1-12, and 1-13 were added at concentrations of 0 or 10 μM, respectively, and pre-cultured at 37°C for 5 minutes. Then, an NADPH generation system solution was added and cultured at 37°C for 15 minutes. Thereafter, an acetonitrile solution containing the internal standard substance (Terfenadine) was added to terminate the reaction, and after centrifugation for 5 minutes (14,000 rpm, 4°C), the supernatant was injected into an LC-MS / MS system to simultaneously analyze the metabolites of the substrate drugs, and the drug-metabolizing enzyme inhibitory ability of these compounds was evaluated. The metabolites of each CYP isoenzyme index drug generated through the above reaction were analyzed using a Shimadzu Nexera XR system and TSQ vantage (Thermo). 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 phase. The generated metabolites were quantified using the multiple reaction monitoring (MRM) quantification mode, and the data were analyzed using Xcalibur (version 1.6.1). The activity inhibitory ability against each CYP isoenzyme was converted to the % activity relative to the negative control group without the addition of the above compounds (Table 2).

[0422] [Table 2] TIFF2025519227000160.tif106165

[0423] As shown in Table 2 above, as a result of evaluating the possibility of drug interaction of drug-metabolizing enzymes with respect to each compound, the compounds of the present invention did not show inhibitory activity against the five CYP isoenzymes, suggesting that there is little possibility of drug interaction compared to the comparative examples.

[0424] Experimental Example 3. Evaluation of Metabolic Stability Metabolic stability is a factor that can affect pharmacokinetic parameters (PK parameters) such as drug clearance, half-life, and oral bioavailability, and thus is one of the characteristics that a group of drug candidates should possess. Therefore, in order to predict the degree of drug metabolism by the liver, which is the main organ of drug metabolism, through in vitro experiments, the metabolic stability of the drug was evaluated using liver microsomes.

[0425] Specifically, compounds 1-2, 1-4, and 1-6 of the present invention containing sulfanone and a compound containing a sulfone group as a core and having a similar functional group were treated with microsomes and incubated for a certain period of time to confirm the amount of the remaining drug, and a microsomal stability test was performed. Specifically, the compound was added at a concentration of 1 μM to human liver microsomes (0.5 mg / mL) and 0.1 M phosphate buffer solution (pH 6.4) and pre-cultured at 37°C for 5 minutes, and then an NADPH regeneration system solution was added and cultured at 37°C for 30 minutes. Thereafter, an acetonitrile solution containing an internal standard substance (chloropropamide) was added to terminate the reaction, and after centrifugation (14,000 rpm, 4°C) for 5 minutes, the supernatant was injected into an LC-MS / MS system to analyze the substrate drug, thereby evaluating the metabolic stability of these compounds. The amount of the remaining substrate through the above reaction was analyzed using a Shimadzu Nexera XR system and a TSQ vantage. As the HPLC column, a Kinetex C18 column was used, and as the mobile phase, distilled water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid were used. The data was analyzed with Xcalibur (version 1.6.1) (Table 3).

[0426]

Table 3

[0427] As shown in Table 3 above, as a result of measuring the amount of the drug remaining after incubating each compound with microsomes for 30 minutes, it was confirmed that compounds 1-2, 1-4, and 1-6 of the present invention were not decomposed by metabolism after 30 minutes and high concentrations were maintained. This suggests that the compounds according to the examples of the present invention have significantly improved stability against human liver microsomes compared to the comparative examples.

[0428] Experimental Example 4. Evaluation of Solubility In new drug development, the solubility of a drug is one of the extremely important factors related to the bioabsorption rate. For example, a compound with low solubility in an aqueous solution may generally exhibit a low bioabsorption rate. In addition, drugs with low solubility may crystallize in tissues or induce serious toxicity. Therefore, the FDA is demanding further research results for oral drugs with low solubility. Furthermore, low solubility can be the biggest cause of failure in the development of candidate substances. Thus, the solubility of Compounds 1-4 of the present invention in 1% DMSO was measured.

[0429] Specifically, Compounds 1-4 showed a high solubility of 0.5 mg / mL or more. On the other hand, in the case of a compound (comparative example) containing a sulfone group as the core and having a similar functional group, it showed an extremely low solubility of 0.01 mg / ml or less. That is, it is suggested that the solubility of the compound of the present invention was improved by more than 50 times by adopting sulfanone as the core.

[0430] Experimental Example 5. Anti-inflammatory effect Nrf2 is an anti-inflammatory factor, and the activation of Nrf2 by the compound of the present invention was confirmed through the above Experimental Example 1. Therefore, in order to confirm the anti-inflammatory effect of the compound of the present invention, the anti-inflammatory effect of the activated Nrf2 was confirmed by evaluating the NO (nitric oxide) inhibitory activity (Table 4).

[0431] BV-2 mouse microglia were placed in a 12-well plate at 1.5×10 5Cells / wells were dispensed according to density and cultured for 24 hours. Subsequently, after removing all the cell culture medium, the stock solution of the compound dissolved in DMSO was diluted with serum-free medium (DMEM / High glucose + 100 U / mL penicillin / streptomycin) to final concentrations of 0.1 μM, 1 μM, and 10 μM and 0.1% DMSO, and 900 μl was treated per well and cultured for 4 hours. To induce an inflammatory response in microglia, lipopolysaccharide (LPS) was treated at a final concentration of 1 μg / ml, 100 μl per well, and further cultured for 24 hours. The cell culture medium was centrifuged at 2356 g for 3 minutes to remove dead cell debris, and 50 μl of the supernatant was added to each well of a transparent 96-well plate. 50 μl of sulfanilamide solution (1% sulfanilamide in 5% phosphoric acid) was added per well and reacted at room temperature for 5 minutes, and then 50 μl of NED solution (0.1% N-1-napthylethylene diaminedihydrochloride in water) was added and reacted at room temperature for 5 minutes. The NO concentration in each cell culture medium was determined by measuring the absorbance at a wavelength of 540 nm using a microplate reader (SpectraMax(R) i3 microplate reader, Molecular Devices) and comparing it with a standard curve using sodium nitrite. The NO concentration at the time of each compound treatment was converted to the % activity relative to the positive control group treated with LPS.

[0432]

Table 4

[0433] As shown in Table 4 above, it was found that the compounds of the present invention suppress NO and showed a more excellent anti-inflammatory effect than sulforaphane and DMF, which are known as Nrf2 activators. In particular, Compounds 1-4 suppressed NO by about 70% compared to the negative control group treated with only LPS even at a low concentration of 1 μM (Figure 2).

[0434] This suggests that the compound of the present invention can exhibit an anti-inflammatory effect through concentration-dependent NO suppression.

[0435] Experimental Example 6. Antioxidant effect Nrf2 plays a role in protecting cells by increasing antioxidant enzymes in the nucleus as a transcription factor. The activation of Nrf2 by the compound of the present invention was confirmed through the above Experimental Example 1. Therefore, by measuring the amount of antioxidant enzymes using Western blot, it was confirmed whether the activated Nrf2 increases antioxidant enzymes. As the antioxidant enzymes to be detected, GCLC, GCLM, and HO-1, which are known to have increased expression by Nrf2, were selected. Specifically, BV2 cells were dispensed at a density of 5×10 5 cells / well at 1.5 mL each into a 6-well plate and cultured in RPM1640 medium for 24 hours. The next day, Compounds 1-4 were mixed into each medium at a final concentration of 0 to 10 μM under 0.1% DMSO conditions and then the cells were added and cultured for 24 hours. The cultured cells were collected and lysed to extract total protein, which was electrophoresed on 10% SDS-PAGE. After transferring the electrophoresed total extract to a PVDF membrane, it was blocked with bovine serum albumin. Then, the amount of antioxidant enzymes expressed in the cells was measured using antibodies corresponding to each antioxidant enzyme, and the results are shown in Figure 3.

[0436] Specifically, when treating with non-treatment and low concentrations of 0.1 μM to high concentrations of 10 μM of Compounds 1-4, a significant increase in antioxidant enzymes was visually confirmed, and all showed the highest expression at 10 μM. This suggests that the compounds of the present invention, for example, Compounds 1-4, can increase the expression of antioxidant enzymes through concentration-dependent Nrf2 activation, thereby showing the effect of protecting cells.

[0437] Experimental Example 7. Cell protection effect in MPTP mice of Parkinson's disease model In Experimental Examples 1 and 6 above, it was directly demonstrated that Compounds 1-4 of the present invention activate intracellular Nrf2 and increase the expression of antioxidant enzymes. Therefore, in order to confirm whether the compounds of the present invention also exhibit a cytoprotective effect in an animal model, a mouse animal model was used in which a neurotoxic substance, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), was administered to induce Parkinson's disease by killing only dopaminergic neurons. The specifically devised animal experiment schedule is shown in Fig. 4(a). As the animal model, 10-week-old C57 / BL6 mice were used, and a negative control group in which physiological saline was intraperitoneally injected and a solution not containing Compounds 1-4 was orally administered; a positive control group in which MPTP was intraperitoneally injected and a solution not containing Compounds 1-4 was orally administered; and an experimental group in which MPTP was intraperitoneally injected and a solution containing Compounds 1-4 was orally administered were prepared to form three groups for the animal experiment model. The MPTP-induced Parkinson's disease model was prepared by intraperitoneally injecting 20 mg / kg of MPTP four times in total at 2-hour intervals per day. The negative control group was injected with physiological saline not containing MPTP at the same time points. In order to confirm the presence or absence of induction of Parkinson's disease, the motor disorder due to the death of dopaminergic neurons, which is known as a major symptom of Parkinson's disease, was confirmed by a vertical grid test and a coat-hanger test. Compounds 1-4 were orally administered at a dose of 20 mg / mL once a day for 3 days starting from the day before MPTP injection, and after 6 days had passed since MPTP injection, behavioral experiments were conducted and the results are shown in Fig. 4 respectively.

[0438] The vertical grid test is to place an experimental animal model on a vertical ladder and evaluate the time taken to climb up and down. In the present invention, when a mouse was placed on the ladder, the time to turn in the floor direction and the total time required to get off the ladder were measured. As shown in the graph shown in Fig. 4(c), in the positive control group injected with only MPTP, both the rotation time and the total time required were increased compared to the negative control group of normal mice, indicating that the motor ability was decreased in the MPTP-induced Parkinson's disease model. On the other hand, in the case of the experimental group administered with Compound 1-4 of the present invention, both the rotation time and the total time required decreased again to a level similar to that of the negative control group, showing a significant difference from the above-mentioned positive control group.

[0439] Another behavioral experiment for evaluating motor ability, the hanger test, as shown in Fig. 4(b), when a mouse was placed in the middle of a hanger 30 cm away from the floor, the mouse would hang and climb towards the safest position at the top of the hanger. At this time, it was conducted in a way of giving points to the position at that time with a 3-minute time limit. As shown in the graph of Fig. 4(d), most of the negative control group moved to the top end of the hanger corresponding to 5 points, while in the case of the positive control group, it mainly stopped at both lower end parts of the hanger and recorded 2-3 points. However, in the experimental group administered with Compound 1-4 of the present invention, a considerable number of mice moved to the upper end corresponding to 4 or 5 points and recorded a high score of more than 4 points on average.

[0440] As a result of summarizing the above two kinds of motor ability experiment results, it was confirmed that the compound of the present invention restored the motor ability decreased by MPTP to a level similar to that of normal mice.

[0441] Experimental Example 8. Effect on Dopaminergic Neurons in MPTP Mice of Parkinson's Disease Model From the results of Experimental Example 7, the effect of the compound of the present invention on the recovery of motor ability was confirmed. To confirm whether such 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 analyzed by immunohistochemistry (IHC) using tyrosine hydroxylase, which is used as a marker for dopaminergic neurons. As the sites for analysis, the striatum and substantia nigra where dopaminergic neurons are concentrated were selected.

[0442] Specifically, after anesthetizing the negative control group, positive control group, and experimental group mice with tribromoethanol (Avertin), physiological saline and 4% formaldehyde were perfused through the heart, the brain was removed, and immersed in 4% formaldehyde and 30% sucrose, and stored refrigerated for one day each in turn. Then, tissue sections of the striatum and substantia nigra sites were obtained from the stored brain using a cryostat. The brain tissue sections were stained by DAB staining using an antibody against tyrosine hydroxylase that is specifically expressed in dopaminergic neurons by immunohistochemistry, and the results were observed under a microscope and shown in Fig. 5.

[0443] By the above-described immunohistochemistry, the site containing tyrosine hydroxylase was stained brown, which indicates the presence of living dopaminergic neurons. As shown on the right side of Fig. 5, the stained striatum and substantia nigra of the negative control group, which are normal mice, showed dark brown, but in the positive control group induced with disease by MPTP, the staining became considerably lighter, which may be due to the death of a large number of dopaminergic neurons by MPTP treatment. On the other hand, in the experimental group treated with Compounds 1-4 of the present invention, the staining became even darker, which is considered to be due to the cell protection effect that inhibits the death of dopaminergic neurons by MPTP due to the antioxidant effect by the administration of Compounds 1-4, indicating that the compound of the present invention has a preventive or therapeutic effect on neurodegenerative diseases such as Parkinson's disease induced by the death of dopaminergic neurons.

[0444] Experimental Example 9. Effect of enhancing memory and improving cognitive function in APP / PS1 mice, an Alzheimer's disease model To confirm whether the compound of the present invention exhibits an effect of improving cognitive function in an animal model, an APP / PS1 (APPswe / PSEN1dE9, stock number 004462) mouse animal model genetically modified to induce Alzheimer's dementia was used. Compounds 1-4 were dissolved in an excipient prepared by mixing 12.5% DMSO, 5% Solutol HS15, and 82.5% triple-distilled water, and orally administered once a day at a dose of 20 mg / kg, 250 μl for 2 months starting from the time the mice reached 10 months of age. A cognitive function evaluation behavioral experiment was conducted at 12 months of age when cognitive impairment was shown.

[0445] Example 9.1. Morris water maze test

[0446] The Morris water maze test was used to evaluate the spatial learning and memory abilities of mice. A white circular water tank (diameter 150 cm, height 58 cm) was filled with water at a temperature of 22 ± 2 °C, and a supported white circular platform with a diameter of 20 cm was positioned 1.5 cm below the water surface. In the hand maze, it was divided into quadrants of northeast, northwest, southeast, and southwest, the platform was placed in the northwest quadrant, and the mice were released and started in the northeast, east, south, and southwest directions. Different patterned spatial cues were attached to the walls in the north, east, and south directions so that the mice could recognize each direction, and a water-soluble non-toxic white paint was dissolved in the water so that the mice could not visually confirm the position of the platform. The mice were trained to reach the platform four times a day at two-hour intervals for 60 seconds in each direction for 8 days (acquisition test), and on the 9th day, the platform was removed and the mice were allowed to swim freely for 90 seconds (probe test). Then, the platform was placed in the southeast quadrant, and the mice were trained for 4 days from the 10th day to the 13th day (reversal test), and on the 14th day, the platform was removed again and the mice were allowed to swim freely for 90 seconds (reversal probe test). All experimental procedures were recorded with a video camera, and the Ethovision XT 11.5 (Noldus) program was used to analyze the time it took for the mice to climb onto the platform during the training process (acquisition test, reversal test), the time spent in the target zone where the platform was located during the free swimming process (probe test, reversal probe test), the number of times the mice passed through the position of the platform (platform crossover), and the latency to reach the position of the platform for the first time (latency to platform).

[0447] In the swimming training process (acquisition test) of mice, wild-type normal mice remembered the position of the platform with increasing training times and reached the platform within a short time. However, APP / PS1 Alzheimer's disease mice reached the platform relatively late and the escape latency was maintained at 40 seconds. In the case of APP / PS1 mice administered with Compounds 1-4, the time to reach the platform decreased over time at a level similar to that of normal mice. When the platform was moved to a new position (reversal test), the time to reach the platform significantly decreased in the group administered with Compounds 1-4, confirming that Compounds 1-4 improved the spatial learning ability of mice. After the training process, in the free swimming process (probe test, reversal probe test) with the platform removed, APP / PS1 mice were unable to remember the position of the platform and showed a decrease in the time spent in the target quadrant where the platform had been compared to normal mice. When Compounds 1-4 were administered to APP / PS1 mice, the time spent in the target zone, the number of times passing through the platform position, and the latency to the platform position all recovered to the level of normal mice, confirming the efficacy of Compounds 1-4 in improving spatial learning and memory ability (Figures 6a - 6c).

[0448] Example 9.2. Y-maze Test

[0449] The spatial learning and memory abilities of mice were evaluated by the Y-maze test. The Y-shaped maze was self-made and used, with three identical arms (length 41 cm, width 7 cm, height 15 cm) made of black acrylic matte material with a thickness of 5 mm, arranged at an angle of 120° to each other. The mouse was placed at the end of one arm of the maze, and its movements were recorded for 10 minutes. The spontaneous alternation% (alternation% = number of alternations / (total number of entries into the arms - 2)), which is a measure of cognitive ability, was calculated and recorded. The mouse was considered to have entered an arm when its center point passed through the two-thirds point of the arm. The alternation behavior was defined as the mouse entering each of the three arms once without repetition.

[0450] Normal mice remembered the order of entering the arms of the maze and showed a high alternation behavior of about 77%. However, in APP / PS1 Alzheimer's disease mice, the spatial learning and memory abilities for the maze were statistically significantly decreased compared to wild-type normal mice. When compounds 1-4 were administered to APP / PS1 mice, a statistically significant increase in alternation behavior was observed, suggesting that the spatial learning and memory abilities were restored to the level of wild-type normal mice. Also, during the experiment, there was no significant difference in the average total number of entries into the arms among all mouse groups, confirming that the motility of the mice among the administered groups was equal and did not affect the alternation behavior (Figure 7a).

[0451] Example 9.3. Passive avoidance test

[0452] The hippocampus-dependent contextual learning and memory of mice was evaluated by the passive avoidance test. The passive avoidance test device used was the GEMINI Avoidance System equipped by San Diego Instruments, in which the dark area and the bright area were separated by an automatic opening and closing door. On the first day of the experiment (habituation), the mice were placed in the test device and allowed to move freely for 3 minutes to get used to and adapt to the device environment. On the second day of the experiment (acquisition), taking advantage of the mice's habit of preferring the dark area, the mice were placed in the bright area. After 30 seconds, when the automatic opening and closing door opened and the mice spontaneously moved to the dark area, an electric shock of 0.4 mA was applied for 1 second. After 24 hours (retention), the mice were placed in the same bright area again. After 15 seconds, when the automatic opening and closing door opened, the time (step-through latency) for the mice to move to the dark area was measured to measure the learning and memory ability with respect to the electric stimulation and the device environment.

[0453] As a result of the passive avoidance test, the APP / PS1 Alzheimer's disease mice could not remember the electric stimulation during the acquisition trial, and the step-through latency decreased significantly. When compounds 1-4 were administered to the APP / PS1 mice, the step-through latency increased to a level similar to that of the normal mice, indicating that the administration of compounds 1-4 restored the hippocampus-dependent learning and memory ability (Figure 7b).

[0454] As described above, although the embodiments have been described with the limited drawings, those with ordinary knowledge in the technical field can apply various technical modifications and deformations based on the above. For example, the described technology is carried out in a procedure different from the described method, and / or the components such as the described system, structure, device, circuit, etc. are combined or assembled in a form different from the described method, and are opposed or replaced by other components or equivalents, and appropriate results can still be achieved.

[0455] Therefore, other embodiments, other examples, and equivalents to the claims also fall within the scope of the claims described below.

Claims

1. A sulfanone derivative represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof. 【Chemical 1】 In the Chemical Formula 1, A and B are each independently phenyl or pyridine, R is hydrogen, a cyano group, a trimethylsilyl group (Tetramethylsilane, TMS), or a methyl group (provided that when both A and B are phenyl, R is not hydrogen), Each of A and B is unsubstituted or substituted with one or more substituents selected from the group consisting of a hydroxy group, a halogen group, a cyano group, a nitro group, an alkyl group of C １ -C ７ , an alkyl group of C １ -C ７ and an alkoxy group of C (except when both A and B are unsubstituted). One or more hydrogens of the alkyl group or alkoxy group are unsubstituted or substituted with any one or more substituents selected from the group consisting of a hydroxy group, a cyano group, a nitro group, and a morpholine group.

2. The sulfanone derivative according to Claim 1, or a pharmaceutically acceptable salt thereof, wherein the sulfanone derivative represented by the Chemical Formula 1 is any one or more selected from the group consisting of compounds represented by the following chemical formulas. [Chemical 2] [Chemical 3] 【Chemical 4】 【Chemical Formula 5】 【Chemical Formula 6】 【Chemical Formula 7】 [Chemical 8] 【Chemical Formula 9】 【Chemical Formula 10】 【Chemical 11】 【Chemical 12】 【Chemical 13】 【Chemical Formula 14】 【Chemical Formula 15】 【Chemical Formula 16】 【Chemical 17】 【Chemical Formula 18】 【Chemical 19】 【Chemical 20】 【Chemical 21】 【Chemical 22】 【Chemical 23】 【Chemical 24】 【Chemical Formula 25】 【Chemical 26】 【Chemical 27】 ​ 【Chemical 29】 【Chemical 30】 【Chemical 31】 【Chemical 32】 【Chemical 33】 【Chemical 34】 【Chemical 35】 【Chemical 36】 【Chemical 37】 【Chemical Formula 38】 【Chemical 39】 【Chemical 40】 【Chemical 41】 【Chemical Formula 42】 【Chemical 43】 【Chemical 44】 【Chemical 45】 【Chemical 46】 【Chemical 47】 【Chemical 48】 【Chemical Formula 49】 【Chemical Formula 50】 【Chemical Formula 51】 【Chemical 52】 【Chemical Formula 53】 【Chemical 54】 【Chemical Formula 55】 【Chemical 56】 【Chemical 57】 【Chemical Formula 58】 【Chemical Formula 59】

3. A composition for activating Nrf2 (nuclear factor erythroid-derived 2-related factor 2) containing, as an active ingredient, a sulfanone derivative represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof. 【Chemical Formula 60】 In the Chemical Formula 1, A and B are each independently phenyl or pyridine, R is hydrogen, a cyano group, a trimethylsilyl group (Tetramethylsilane, TMS), or a methyl group (provided that when both A and B are phenyl, R is not hydrogen), The A and B are each unsubstituted or substituted with any one or more substituents selected from the group consisting of a hydroxy group, a halogen group, a cyano group, a nitro group, an alkyl group of C １ -C ７ and an alkoxy group of C １ -C ７ (except when both A and B are unsubstituted). One or more hydrogens of the alkyl group or alkoxy group are unsubstituted or substituted with any one or more substituents selected from the group consisting of a hydroxy group, a cyano group, a nitro group, and a morpholine group.

4. A pharmaceutical composition for preventing or treating any one or more diseases 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, comprising a sulfanon derivative represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 【Chemical Formula 61】 In the above chemical formula 1, A and B are each independently phenyl or pyridine, R is hydrogen, a cyano group, a trimethylsilyl group (Tetramethylsilane, TMS), or a methyl group (provided that when both A and B are phenyl, R is not hydrogen), The above A and B are each unsubstituted or substituted with any one or more substituents selected from the group consisting of a hydroxy group, a halogen group, a cyano group, a nitro group, an alkyl group of C １ -C ７ , and an alkoxy group of C １ -C ７ (provided that this does not apply when both A and B are unsubstituted). One or more hydrogens of the alkyl group or alkoxy group are unsubstituted or substituted with any one or more substituents selected from the group consisting of a hydroxy group, a cyano group, a nitro group, and a morpholine group.

5. The pharmaceutical composition according to claim 4, wherein the disease is a disease induced by a decrease in Nrf2 activity.

6. The pharmaceutical composition according to claim 4, wherein 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 injury, viral hepatitis, and hepatocellular carcinoma.

7. The kidney 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 kidney disease, and is characterized by the above, the pharmaceutical composition according to claim 4.

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

9. 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), and is characterized by the above, the pharmaceutical composition according to claim 4.

10. The pharmaceutical composition comprises the sulfanon derivative or a pharmaceutically acceptable salt thereof; and The pharmaceutical composition according to claim 4, further comprising any one or more additional components 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 powders, granules, tablets, capsules, and injections.

12. A method for producing a sulfanon derivative or a pharmaceutically acceptable salt thereof, comprising the following steps. (1) A step of producing a compound represented by Chemical Formula 3 from a compound represented by Chemical Formula 2, (2) A step of producing a compound represented by Chemical Formula 4 from a compound represented by Chemical Formula 3, (3) A step of producing a compound represented by Chemical Formula 5 from a compound represented by Chemical Formula 4, and (4) A step of adding a compound represented by Chemical Formula 6 to a compound represented by Chemical Formula 5 to produce a compound represented by Chemical Formula 1. 【Chemical 62】 【Chemical Formula 63】 【Chemical Formula 64】 【Chemical Formula 65】 【Chemical Formula 66】 【Chemical Formula 67】 In the above Chemical Formulas 1 to 6, A and B are each independently phenyl or pyridine (provided that the case where both A and B are phenyl is excluded), R is hydrogen, a trimethylsilyl group (Tetramethylsilane, TMS), or a methyl group, Said A and B are each unsubstituted or substituted with any one or more substituents selected from the group consisting of a hydroxy group, a halogen group, a cyano group, a nitro group, an alkyl group of C １ -C ７ , and an alkoxy group of C １ -C ７ (however, excluded when both A and B are unsubstituted), One or more hydrogens of the alkyl group or alkoxy group are unsubstituted or substituted with any one or more substituents selected from the group consisting of a hydroxy group, a cyano group, a nitro group, and a morpholine group.

13. The step (1) is characterized in that the compound represented by Chemical Formula 2 is dissolved in methanol (MeOH), and ammonium carbonate ((NH ４ )) ２ CO ３ ), and diacetoxyiodobenzene (PhI(OAc) ２ ) are added in sequence, and the production method according to claim 12

14. The production method according to claim 12, characterized in that in the step (2), hexamethyldisilazane (HMDS) is added to the compound represented by Chemical Formula 3, and then reflux stirring is performed.

15. The production 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-butyllithium (n-BuLi) and diethyl chlorophosphate are added in sequence.

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