KR20210046424A - Novel lipoic acid-heterocycle thioacetal compounds and uses of the same - Google Patents

Abstract

The present invention relates to a novel lipoic acid-heterocycle thioacetal compound obtained by converting lipoic acid having an unstable disulfide structure into thioacetal and uses thereof. More specifically, the present invention relates to a pharmaceutical composition for preventing or treating degenerative diseases, and a health supplement composition for preventing or alleviating degenerative diseases containing a lipoic acid-heterocycle thioacetal compound.

Description

Novel lipoic acid-heterocycle thioacetal compound and its use TECHNICAL FIELD {NOVEL LIPOIC ACID-HETEROCYCLE THIOACETAL COMPOUNDS AND USES OF THE SAME}

The present invention relates to a thioacetal compound derived from lipoic acid and into which various substituents are introduced, and to a use thereof, and more particularly, to a lipoic acid synthesized through reduction of lipoic acid, reaction with an aldehyde compound, and reaction with an amine compound. It relates to a pharmaceutical composition for the prevention or treatment of degenerative diseases comprising the iksan-heterocycle thioacetal compound and the same as an active ingredient, and a health supplement composition for the prevention or improvement of degenerative diseases.

With the development of the medical industry and rapid economic growth, the quality of life is improving, and at the same time, various diseases and the elderly population are increasing. The life expectancy of humans has been extended, but the economic burden is increasing. One of them is senile dementia. More than 50% of them are Alzheimer's disease (Alzheimer type, AD) dementia. Alzheimer's disease (AD) is one of the irreversible and progressive cerebrovascular diseases. Age-related neurodegenerative disease accompanied by depression and gradual loss of cognitive abilities such as memory, speech, direction, and attention. to be. The exact cause of the invention of Alzheimer's disease (AD) has not been identified, and there is no cure for it. However, it is known that cholineacetyltransferase (ChAT), which synthesizes acetylcholine (ACh) in the brain of dementia patients indirectly, is reduced to 20-30%, and acetylcholine (ACh), a neuron transporter. It was confirmed that the concentration decreased by 16~30%.

In order to fundamentally treat Alzheimer's disease (AD), it is necessary to develop a substance that can prevent or inhibit the removal of major lesions found in the brain of AD patients and impairment of cognitive learning function. Methods for replenishing the cholinergic nervous system at synaptic intervals to improve cognitive function include: a) enhancing the synthesis of acetylcholine, b) enhancing the release of acetylcholine, c) inhibiting the degradation of acetylcholine. And d) a method of directly stimulating an acetylcholine receptor.

However, the method of injecting choline directly to increase the concentration of choline, a precursor to Alzheimer's disease (AD) patients, did not have much effect.

As a result, studies using inhibitors that inhibit cholinesterase (ChE), an enzyme that hydrolyzes acetylcholine, which is a neurotransmitter, has been conducted as an indirect treatment method. Cholinesterase has two forms: acetylcholinesterase (AChE) and butylcholinesterase (BuChE).

AChE is a membrane-bound enzyme and is present in brain, muscle and cholinergic neurons. In the mammalian brain, the majority of AChE exists in the form of membrane-bound G4 and decreases as neurons degenerate. In cholinergic synapses, the neurotransmitter acetylcholine is hydrolyzed by AChE. BChE is expressed in neuroglia and is present in the intestine, liver, kidney, heart, lung and serum. BChE is known to play an important role in the metabolism of compounds with ester groups. Like AChE, this enzyme can hydrolyze acetylcholine, and in AD patients, the concentration of this enzyme does not decrease even when a reaction occurs, which can worsen AD.

Previously, the synthesis or development of acetylcholinesterase inhibitors has been the main focus, but in recent studies, it is known that butylcholinesterase is increased in the AD brain, which is drawing high interest in the development of therapeutic agents. Alzheimer's disease (AD) treatments currently used in each country are mostly acetylcholine-degrading enzyme (AChE) inhibitors, tacrine (trade name: Cognex), and donepezil (trade name: Aricept). )) or Rivastigmine (trade name: exelon), more recently as Galanthamine (trade name: reminyl), and the cognitive function of Alzheimer's patients improved to some extent. These compounds still exhibit some undesirable side effects, such as tremors, dizziness, vomiting, hepatotoxicity and the like.

Most studies so far have also focused on selective acetylcholinesterase (AChE) inhibitors. Although it has been overlooked for many years, butyrylcholinesterase (BuChE) can also hydrolyze acetylcholine (ACh), and its activity in patients with Alzheimer's disease remains higher than that of acetylcholine degrading enzyme. It will play an important role. However, until today, very few compounds with selective BuChE inhibitory activity have been reported, for example, etopropazine (10-(2-diethylaminopropyl) phenothiazine hydrochloride), dansylarginine N-(3-ethyl-1, 5-pentanediyl)amide (DAPA), phenethylnorsimserine and the compounds disclosed in WO1999-002154 or EP 1251131.

On the other hand, lipoic acid is a powerful and effective antioxidant, and since alpha-lipoic acid (Alpha Lipoic Acid = ALA, hereinafter referred to as'lipoic acid') represented by the following formula is dissolved in lipids, ) Is named:

Lipoic acid can effectively prevent and cure most diseases associated with oxidative stress caused when the human body is overwhelmed by toxic compounds. Diseases that can be cured include cranial nerve diseases such as dementia (Parkinson's disease, Alzheimer's disease, etc.), diabetes, cardiovascular disease, heart disease, stroke, hyperlipidemia, cataracts, rheumatism, and cancer.

Meanwhile, in relation to the dementia, not only Alzheimer's dementia, but also cognitive decline in vascular dementia is associated with choline deficiency. The basal forebrain responsible for choline formation is supplied with blood by penetrating arterioles, which are easily affected by hypertension. Choline is produced in the diagonal band of Broca, the medial septal nuclei, and the nucleus basalis of Meynert in the basal forebrain, and passes through the cerebral white matter to the cerebral cortex. Delivered. The choline pathway to the cerebral cortex is blocked by hiatus cerebral infarction or white matter degeneration, which are commonly observed in the frontal lobe of vascular dementia patients, resulting in impaired executive function and attention. Biochemically, acetylcholine activity was decreased in the cerebral cortex, hippocampus, striatum, and cerebrospinal fluid of vascular dementia patients. This anatomical or biochemical evidence suggests the effectiveness of cholinesterase inhibitors in patients with vascular cognitive impairment. Currently, cholinesterase inhibitor therapy is being used for patients with vascular cognitive impairment regardless of the presence or absence of Alzheimer's dementia. That is, these cholinesterase inhibitors reduce the metabolism of acetylcholine and increase the action of acetylcholine at the cholinergic cranial nerve junction in the brain.

However, conventionally, only the conjugate compound of lipoic acid and polyphenol or 4-aminobenzylpiperidine derivative has been reported, and the thioacetal compound derived from lipoic acid and its use as an inhibitor against cholinesterase Has not yet been reported.

KR 10-2010-0121047 A KR 10-2015-0041278 A

As a result of conducting research to develop a therapeutic agent for Alzheimer's disease, the present inventors found that a novel lipoic acid-heterocycle thioacetal compound in which lipoic acid with an unstable disulfide structure was converted into thioacetal inhibited cholinesterase activity. It found that there was an effect and completed the present invention.

Accordingly, an object of the present invention is to provide a novel lipoic acid-heterocycle thioacetal compound having cholinesterase (ChEs) inhibitory activity.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating degenerative diseases containing the lipoic acid-heterocycle thioacetal compound as an active ingredient.

Another object of the present invention is to provide a dietary supplement for improving cognitive ability or improving degenerative diseases containing the lipoic acid-heterocycle thioacetal compound as an active ingredient.

Another object of the present invention is to provide a composition for the inhibitory activity of cholinesterase containing the lipoic acid-heterocycle thioacetal compound as an active ingredient.

One aspect of the present invention provides a lipoic acid-heterocycle thioacetal compound represented by the following Formula 1:

[Formula 1]

In Formula 1,

이고;R ₁ is C6-C20 aryl, C3-C20 heteroaryl or

ego;

R ₂ is C6-C20 aryl or C3-C20 heteroaryl,

The _{aryl or heteroaryl of R 1} and R ₂ is the group consisting of C1-C7 alkyl, halogen, C1-C7 alkoxy, halo C1-C7 alkyl, C6-C20 aryloxy, -NR'R'', cyano and nitro May be further substituted with one or more selected from;

R'and R'' are each independently hydrogen, C1-C7 alkyl or C6-C20 aryl;

R is hydrogen or C1-C7 alkyl;

L ^a is C1-C10 alkylene;

m is an integer of 2 to 7.

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating degenerative diseases containing the lipoic acid-heterocycle thioacetal compound or a pharmaceutically acceptable salt thereof as an active ingredient.

Another aspect of the present invention provides a dietary supplement for improving cognitive ability or improving degenerative diseases, containing the lipoic acid-heterocycle thioacetal compound or a pharmaceutically acceptable salt thereof as an active ingredient.

Another aspect of the present invention provides a composition for inhibiting cholinesterase activity containing the lipoic acid-heterocycle thioacetal compound or a pharmaceutically acceptable salt thereof as an active ingredient.

The lipoic acid-heterocycle thioacetal compound of the present invention is a compound of a novel structure synthesized through reduction of lipoic acid having antioxidant activity, reaction with an aldehyde compound, and reaction with an amine compound.

The lipoic acid-heterocycle thioacetal compound of the present invention is harmless to the human body and inhibits the activity of cholinesterases such as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE; butyrylcholinesterase). Therefore, it can be used not only for the prevention and treatment of degenerative diseases, specifically Parkinson's disease, Alzheimer's disease, etc., but also as a dietary supplement that improves degenerative diseases or improves learning ability and memory.

In particular, the lipoic acid-heterocycle thioacetal compound of the present invention not only has few side effects from AChE inhibitors, but also has high activity in the brain of Alzheimer's disease patients, selectively inhibiting only BuChE, which has recently attracted much interest among the forms of cholinesterase. At the same time, since it has a very strong inhibitory activity, it can be used as an active ingredient in a pharmaceutical composition for preventing and treating degenerative diseases and a health supplement for improving cognitive ability or for improving degenerative diseases.

Hereinafter, the present invention will be described in more detail. If there are no other definitions in the technical terms and scientific terms used at this time, they have the meanings commonly understood by those of ordinary skill in the technical field to which this invention belongs, and the following description will unnecessarily obscure the subject matter of the present invention. Description of possible known functions and configurations will be omitted.

Unless otherwise defined, all terms (including technical and scientific terms) used in the present specification may be used with meanings that can be commonly understood by those of ordinary skill in the art to which the present invention belongs. When a part of the specification "includes" a certain component, it means that other components may be further included rather than excluding other components unless specifically stated to the contrary. Also, the singular form includes the plural form unless specifically stated in the text.

The terms "substituent", "radical", "group", "moiety", and "fragment" can be used interchangeably.

The term "C _A -C _B " means "the number of carbons is greater than or equal to A and less than or equal to B", and the terms "A to B" mean "more than A and less than B".

The term "alkyl" refers to a monovalent straight chain or branched saturated hydrocarbon radical composed of only carbon and hydrogen atoms, and may have 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms. Examples of such alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like.

도 아릴에 포함된다. 구체적인 예로 페닐, 나프틸, 비페닐, 안트릴, 인데닐, 플루오레닐,

등을 포함하지만, 이에 한정되지는 않는다.The term "aryl" is an organic radical derived from an aromatic hydrocarbon by the removal of one hydrogen, and includes a single or fused ring system containing 4 to 7, preferably 5 or 6 ring atoms suitably in each ring. In this case, the fused ring may be aromatic or non-aromatic. In addition, aryl includes up to a form in which a plurality of aryls are connected by a single bond. Of the present invention

Also included in aryl. Specific examples of phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl,

And the like, but is not limited thereto.

The term “heteroaryl” refers to an aryl group in which 1 to 4 heteroatoms are selected from N, O and S as an aromatic ring skeleton atom, and the remaining aromatic ring skeleton atoms are carbon, and 5 to 6 membered monocyclic heteroaryl , And polycyclic heteroaryl condensed with one or more benzene rings, and may be partially saturated. In addition, heteroaryl in the present specification includes a form in which one or more heteroaryls are linked by a single bond. Examples of the heteroaryl group include pyrrole, quinoline, isoquinoline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, benzoimidazole, isoxazole, benzoisooxazole, thiophene, Benzothiophene, furan, benzofuran, and the like, but are not limited thereto.

The term “halo” or “halogen” denotes a halogen element and includes, for example, fluoro, chloro, bromo and iodo.

The term "alkoxy" is an -O-alkyl radical and may have 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms. Here,'alkyl' is as defined above. Specific examples include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, and the like.

The term “haloalkyl” refers to an alkyl radical substituted with at least one halogen, wherein “alkyl” is as defined above. Examples of such haloalkyl radicals include, but are not limited to, fluoromethyl, trifluoromethyl, bromomethyl, perfluoroethyl, and the like.

The term "aryloxy" refers to an -O-aryl radical, wherein'aryl' is as defined above. Examples of such aryloxy radicals include, but are not limited to, phenoxy, naphthoxy, and the like.

The term "cyano" means -CN, and "nitro" means -NO ₂ .

The term "pharmaceutically acceptable salt" is any concentration of a compound of the present invention that is relatively non-toxic to the patient and has a harmless effective effect, and side effects due to this salt do not impair the beneficial efficacy of the compound of the present invention itself. It means any organic or inorganic addition salt.

The term “prevention” refers to any action that inhibits or delays the occurrence, spread and recurrence of a degenerative disease by administration of the composition of the present invention.

The term “improvement” refers to any action that at least reduces the severity of a parameter, such as a symptom, associated with the condition being treated by administration of the composition of the present invention.

The term "treatment" refers to any action in which symptoms of a degenerative disease are improved or beneficially altered by administration of the composition of the present invention.

The term “pharmaceutically acceptable” refers to a property that is not toxic to cells or individuals exposed to the composition, such as humans, and means suitable for use as a pharmaceutical preparation, and is generally regarded as safe for such use. And, for such use, it is officially approved by the national administrative agency or listed in the Korean Pharmacopoeia or the United States Pharmacopoeia.

The term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not cause side effects, and the effective dose level is the sex, age, weight, and weight of the patient. Health status, type of disease, severity, activity of the drug, sensitivity to the drug, method of administration, time of administration, route of administration, and rate of excretion, duration of treatment, factors including drugs used in combination or simultaneously, and other well-known in the medical field. Depending on the factor, it can be readily determined by a person skilled in the art.

The term "food" means meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, vitamin complexes , Health functional foods, health foods, etc., and all foods in the usual sense are included.

The term "health functional food" refers to a food manufactured and processed using raw materials or ingredients that have functions useful for the human body pursuant to the Health Functional Food Act No.6727, and the term "functional" refers to the structure and function of the human body. It refers to ingestion for the purpose of obtaining useful effects for health purposes such as controlling nutrients or physiological effects.

The lipoic acid-heterocycle thioacetal compound according to the present invention is a compound of a novel structure in which lipoic acid having an unstable disulfide structure is converted into thioacetal, and acetylcholinesterase (AChE) and butylcholinesterase ( BuChE) has inhibitory activity against cholinesterase (ChE), which has two forms, so it is useful as an active ingredient in pharmaceutical compositions for preventing or treating degenerative diseases, and also improving or learning degenerative diseases. It can also be used as an active ingredient in health supplements that improve ability and memory.

One aspect of the present invention provides a lipoic acid-heterocycle thioacetal compound represented by the following Formula 1:

[Formula 1]

In Formula 1,

이고;R ₁ is C6-C20 aryl, C3-C20 heteroaryl or

ego;

R ₂ is C6-C20 aryl or C3-C20 heteroaryl,

The _{aryl or heteroaryl of R 1} and R ₂ is the group consisting of C1-C7 alkyl, halogen, C1-C7 alkoxy, halo C1-C7 alkyl, C6-C20 aryloxy, -NR'R'', cyano and nitro May be further substituted with one or more selected from;

R'and R'' are each independently hydrogen, C1-C7 alkyl or C6-C20 aryl;

R is hydrogen or C1-C7 alkyl;

L ^a is C1-C10 alkylene;

m is an integer of 2 to 7.

In one embodiment, R may be hydrogen or C1-C4 alkyl, and m may be an integer of 4 to 6.

In one embodiment, the lipoic acid-heterocycle thioacetal compound may be represented by Formula 2 below.

[Formula 2]

In Formula 2, R ₁ and L ^a are the same as defined in Formula 1.

이고; R₂는 C6-C12아릴이고; 상기 R₁ 및 R₂의 아릴은 C1-C4알킬, 할로겐, C1-C4알콕시, 할로C1-C4알킬, -NR'R'' 및 니트로로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있고; R' 및 R''는 각각 독립적으로 수소 또는 C1-C4알킬이고; L^a는 C1-C5알킬렌일 수 있다.Specifically, R ₁ is C6-C12 aryl or

ego; R ₂ is C6-C12 aryl; The _{aryl of R 1} and R ₂ may be further substituted with one or more selected from the group consisting of C1-C4 alkyl, halogen, C1-C4 alkoxy, haloC1-C4 alkyl, -NR'R'' and nitro; R'and R'' are each independently hydrogen or C1-C4 alkyl; L ^a may be C1-C5 alkylene.

,

또는

이고; R^a 및 R^b는 각각 독립적으로 C1-C4알킬, 할로겐, C1-C4알콕시, 할로C1-C4알킬, -NR'R'' 또는 니트로이고; R' 및 R''는 각각 독립적으로 수소 또는 C1-C4알킬이고; x 및 y는 각각 독립적으로 0 내지 5의 정수이고; L^a는 C1-C3알킬렌일 수 있다. More specifically, R ₁ is

,

or

ego; R ^a and R ^b are each independently C1-C4 alkyl, halogen, C1-C4 alkoxy, haloC1-C4 alkyl, -NR'R'' or nitro; R'and R'' are each independently hydrogen or C1-C4 alkyl; x and y are each independently an integer of 0 to 5; L ^a may be C1-C3 alkylene.

,

,

또는

이고; R^a 및 R^b는 각각 독립적으로 C1-C4알킬, 할로겐, C1-C4알콕시, 할로C1-C4알킬, -NR'R'' 또는 니트로이고; R' 및 R''는 각각 독립적으로 C1-C4알킬이고; L^a는 C2-C3알킬렌일 수 있다.More preferably, R ₁ is

,

,

or

ego; R ^a and R ^b are each independently C1-C4 alkyl, halogen, C1-C4 alkoxy, haloC1-C4 alkyl, -NR'R'' or nitro; R'and R'' are each independently C1-C4 alkyl; L ^a may be C2-C3 alkylene.

Specifically, R ^a and R ^b are each independently methyl, ethyl, propyl, butyl, chloro, fluoro, methoxy, ethoxy, butoxy, trifluoromethyl, perfluoroethyl, dimethylamino or nitro; L ^a can be ethylene or propylene.

The lipoic acid-heterocycle thioacetal compound according to an embodiment has excellent inhibitory activity against two types of cholinesterase (ChE), acetylcholinesterase (AChE) and butylcholinesterase (BuChE). In particular, it has a more excellent inhibitory activity against butyrylcholinesterase (BuChE) selectively among cholinesterase (ChE) forms.

In one embodiment, the lipoic acid-heterocycle thioacetal compound may be selected from the following structures, but is not limited thereto.

The lipoic acid-heterocycle thioacetal compounds according to the present invention can be prepared by various methods based on known methods and/or techniques in the field of organic synthesis, as described later, and the following preparation method These are only some examples, and of course, other methods may exist.

The lipoic acid-heterocycle thioacetal compound according to an embodiment may be prepared by various methods based on known methods and/or techniques in the field of organic synthesis, as described later, and the following preparation methods are It is only a few examples, and of course, other methods may exist.

For example, the lipoic acid-heterocycle thioacetal compound of Formula 1 reduces lipoic acid (LA) to prepare dihydrolipoic acid (DHLA) as shown in Scheme 1 below. Then, by reacting with various aldehyde compounds (a1) to prepare a thioacetal intermediate compound (M), which can be prepared by reacting with various amine compounds (a2):

[Scheme 1]

In Reaction Scheme 1, R ₁ , R, L ^a and m are the same as defined in Formula 1.

In some cases, the reaction product may be separated and purified using a conventional method, for example, recrystallization and chromatography.

The lipoic acid-heterocycle thioacetal compound according to an embodiment can be used in the form of prodrugs, hydrates, solvates, and pharmaceutically acceptable salts to enhance absorption or increase solubility in vivo. Prodrugs, hydrates, solvates and pharmaceutically acceptable salts of are also within the scope of the present invention. In the case of salts and solvates, the additional ionic and solvent moieties should also be non-toxic. The lipoic acid-heterocycle thioacetal compound of the present invention may exist in different homogeneous forms, and the present invention is intended to include all of the above forms.

The lipoic acid-heterocycle thioacetal compound, prodrugs, hydrates, solvates, and pharmaceutically acceptable salts thereof according to an embodiment exhibit excellent cholinesterase inhibitory activity.

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating degenerative diseases containing the lipoic acid-heterocycle thioacetal compound or a pharmaceutically acceptable salt thereof as an active ingredient.

In one embodiment, the degenerative disease specifically includes a cranial nerve disease such as Parkinson's disease and Alzheimer's disease.

The pharmaceutically acceptable salt can be prepared by a conventional method in the art, for example, a salt with an inorganic acid such as hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, and formic acid. , Acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gastisic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin). Salts with organic acids, salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine and proline, methanesulfonic acid, ethanesulfonic acid, benzenesulfur And salts with sulfonic acids such as phonic acid and toluenesulfonic acid, metal salts obtained by reaction with alkali metals such as sodium and potassium, or salts with ammonium ions.

The pharmaceutical composition according to an embodiment is a pharmaceutical field by adding a conventional non-toxic pharmaceutically acceptable carrier, adjuvant, and excipient to the lipoic acid-heterocycle thioacetal compound or a pharmaceutically acceptable salt thereof. In conventional formulations, for example, tablets, capsules, troches, solutions, suspensions, etc. for oral administration or parenteral administration, it can be used for the treatment of the degenerative diseases.

Excipients that can be used in the pharmaceutical composition may include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, and the like. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, rubber tragacanth, alginic acid, sodium Alginate, methylcellulose, sodium carboxylmethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, and the like. The proportions and properties of these excipients can be determined by the solubility and chemical properties of the tablets chosen, the route of administration chosen and standard pharmaceutical practice.

The dosage of the lipoic acid-heterocycle thioacetal compound according to an embodiment to the human body may be in a total daily dosage range of 0.01 to 1000 mg/kg/day, but this is the patient's age, weight, It may vary according to sex, dosage form, health condition, and disease degree, and may be administered in divided doses from once a day to several times a day at regular time intervals according to the judgment of a doctor or pharmacist.

Another aspect of the present invention provides a dietary supplement for improving cognitive ability or improving Alzheimer's disease or degenerative diseases containing the lipoic acid-heterocycle thioacetal compound or a pharmaceutically acceptable salt thereof as an active ingredient. .

The health functional food composition may be provided in the form of powder, granules, tablets, capsules, syrup, or beverage, and the health functional food includes other foods or food additives in addition to the lipoic acid-heterocycle thioacetal compound as an active ingredient. They are used together, and can be appropriately used according to a conventional method. The mixing amount of the active ingredient may be appropriately determined according to the purpose of use, for example, prevention, health or therapeutic treatment.

The health functional food composition includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and heavy weight agents (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid and salts thereof. , Organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, and the like. In addition, it may contain flesh for the manufacture of natural fruit juice and fruit juice beverages and vegetable beverages. These components may be used independently or in combination.

In addition, the above health functional food may additionally contain food additives, and the suitability as a'food additive' shall be determined according to the General Regulations of the Food Additive Code approved by the Food and Drug Administration and general test methods, etc. It is judged according to the standards and standards.

Items listed in the above'Food Additives Code', for example, chemical synthetic products such as ketones, glycine, potassium citrate, nicotinic acid, cinnamic acid, natural additives such as red pigment, licorice extract, crystalline cellulose, guar gum, and sodium L-glutamate. Mixed preparations, such as a preparation, an alkali additive for noodles, a preservative preparation, and a tar color preparation, are mentioned.

There is no particular limitation on the type of the food. Examples of foods to which the above substances can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, tea, drinks, There are alcoholic beverages and vitamin complexes, and all health foods in the usual sense are included.

Another aspect of the present invention provides a composition for inhibiting cholinesterase activity containing the lipoic acid-heterocycle thioacetal compound or a pharmaceutically acceptable salt thereof as an active ingredient.

Hereinafter, the present invention will be described in detail through examples and experimental examples. However, this is presented as an example of the present invention, and the scope of the present invention is not limited thereto in any sense, and the scope of the present invention is only defined according to the claims to be described later.

[Production Example 1] Preparation of Dihydrolipoic acid (Compound DHLA)

Lipoic acid (LA, 4 g, 19.3 mmol) was dissolved in 0.25N Sodium bicarbonate (NaHCO ₃ , 130 mL), and sodium borohydride (NaBH ₄ , 1.86 g, 49.1 mmol) was added at 0°C. After 3 hours, the pH of the water layer was adjusted to 1 by adding 4N HCl. After work-up with dichloromethane (DCM), _{treatment with anhydrous MgSO 4} and filtration, the obtained filtrate was concentrated under reduced pressure with an evaporator to obtain a yellow oily compound DHLA (4.02 g, 99.5% yield).

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.31 (d, J = 7.6 Hz, 1H), 1.35 (t, J = 8 Hz, 1H), 1.62 (m, 7H), 1.91 (m, 1H), 2.38 (t, J = 7.6 Hz, 2H), 2.71 (m, 2H), 2.92 (m, 1H)

[Example 1] 5-(2-(4-(dimethylamino)phenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 1 ) Produce

(1) Preparation of 5-(2-(4-(dimethylamino)phenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-1)

After ar purge and drying tube was installed, 4-(dimethylamino)benzaldehyde (compound a1-1, 0.36 g, 2.4 mmol) was dissolved in DCM. Compound DHLA (0.6 g, 2.9 mmol) was added, and Para-toluene sulfonic acid (p-TsOH, 0.02 g, 0.1 mmol) was added. After refluxing at 50° C. for 8 hours, the reaction was terminated with Brine, followed by extraction with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (EA:Hex:Ether=3:7:0.2) to obtain a white solid compound M-1 (280 mg, 34% yield).

¹ H NMR (DMSO, 400 MHz) δ 1.46 (m, 8H), 2.19 (t, J = 7.2 Hz, 2H), 2.88 (s, 6H), 2.91 (m, 1H), 3.01 (m, 2H), 5.24 (S, 1H), 6.67 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 11.98 (s, 1H)

(2) Preparation of 5-(2-(4-(dimethylamino)phenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 1)

Ar purge was performed and compound M-1 (300 mg, 0.89 mmol) was dissolved in DCM. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 429 mg, 2.23 mmol) was added in portions under an ice bath, and after 20 minutes, N-Hydroxysuccinimide (NHS, 206 mg, 1.79 mmol) was added. After reacting overnight, the reaction was _{terminated with H 2} O and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (EA:HEX=1:1) and 2,5-dioxopyrrolidin-1-yl 5-(2-(4-(dimethylamino)phenyl)-1,3-dithian-4- yl)pentanoate was obtained, which was immediately used in the next reaction. 2,5-dioxopyrrolidin-1-yl 5-(2-(4-(dimethylamino)phenyl)-1,3-dithian-4-yl)pentanoate (180 mg, 0.43 mmol) was dissolved in DCM under an ice bath. 1-(2-aminoethyl)piperidine (Compound a2-1, 0.09 mL, 0.64 mmol) was added dropwise. After reacting overnight, it was concentrated under reduced pressure and separated by column chromatography (DCM:MeOH=9.2:0.8) to obtain oily compound 1 (10 mg, 5% yield).

TLC [DCM:MeOH=9:1 R _f =0.5]; ¹ H NMR (DMSO, 400 MHz) δ 1.41 (m, 14H), 2.03 (t, J = 7.2 Hz, 2H), 2.32 (s, 6H), 2.88 (m, 8H), 3.00 (m, 1H), 3.13 (m, 2H), 5.23 (S, 1H), 6.66 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.8 Hz, 2H), 7.71 (s, 1H).

[Example 2] (E)-5-(2-(4-(dimethylamino)styryl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide ( Preparation of compound 2 )

(1) Preparation of (E)-5-(2-(4-(dimethylamino)styryl)-1,3-dithian-4-yl)pentanoic acid (Compound M-2)

After ar purge was performed and a drying tube was installed, 4-(dimethylamino)cinnamaldehyde (compound a1-2, 0.42 g, 2.4 mmol) was dissolved in DCM. Compound DHLA (0.6 g, 2.9 mmol) was added, and P-TsOH (0.02 g, 0.1 mmol) was added. After refluxing at 50° C. for 10 hours, the reaction was terminated using Brine, followed by extraction with DCM. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (EA:Hex=1:1) to obtain a white solid compound M-2 (280 mg, 31% yield).

¹ H NMR (DMSO, 400 MHz) δ 1.44 (m, 8H), 2.20 (t, J = 7.2 Hz, 2H), 2.90 (m, 8H), 2.97 (m, 1H), 4.98 (d, J = 8.4 Hz, 1H), 5.98 (dd, J = 8.4 Hz, 15.6 Hz, 1H), 6.58 (d, J = 15.6 Hz, 1H), 6.66 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H), 11.96 (s, 1H)

(2) (E)-5-(2-(4-(dimethylamino)styryl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 2 ) Of the manufacture

Ar purge was performed and compound M-2 (100 mg, 0.27 mmol) was dissolved in DCM. EDC (130 mg, 0.68 mmol) was subdivided in an ice bath, and after 20 minutes, NHS (63 mg, 0.55 mmol) was added. After reacting overnight, the reaction was _{terminated with H 2} O and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (EA:HEX=6.4) to obtain (E)-2,5-dioxopyrrolidin-1-yl 5-(2-(4-(dimethylamino)styryl)-1,3-dithian- 4-yl)pentanoate was obtained, which was immediately used in the next reaction. (E)-2,5-dioxopyrrolidin-1-yl 5-(2-(4-(dimethylamino)styryl)-1,3-dithian-4-yl)pentanoate (89.4 mg, 0.19 mmol) in DCM under an ice bath Dissolved with. 1-(2-aminoethyl)piperidine (Compound a2-1, 0.04 mL, 0.29 mmol) was added dropwise. After reacting overnight, it was concentrated under reduced pressure and separated by column chromatography (DCM:MeOH=9.3:0.7) to obtain oily compound 2 (28 mg, 30% yield).

TLC [EA:Hex=1:1 R _f = 0.04 (bottom)]; ¹ H NMR (DMSO, 400 MHz) δ 1.43 (m, 12H), 2.05 (m, 4H), 2.31 (m, 4H), 2.95 (m, 9H), 3.14 (m, 2H), 4.98 (d, J = 8.4 Hz, 1H), 5.98 (dd, J = 8.4 Hz, 15.6 Hz, 1H), 6.59 (d, J = 15.6 Hz, 1H), 6.67 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H), 7.68 (m, 1H); ¹³ C NMR (DMSO, 100MHz) δ 24.2, 25.5, 25.6, 25.6, 25.7, 30.9, 32.8, 35.9, 36.4, 40.4, 44.5, 49.3, 54.4, 58.1, 58.2, 112.5, 112.6, 121.1, 123.9, 128.0, 133.3 , 150.7, 172.3.

[Example 3] Preparation of N-(2-(piperidin-1-yl)ethyl)-5-(2-(o-tolyl)-1,3-dithian-4-yl)pentanamide (Compound 3 )

(1) Preparation of 5-(2-(o-tolyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-3)

After ar purge was performed and a drying tube was installed, o-tolualdehyde (Compound a1-3, 0.29 g, 2.4 mmol) was dissolved in DCM. Compound DHLA (0.6 g, 2.9 mmol) was added, and P-TsOH (0.02 g, 0.14 mmol) was added. After refluxing at 45° C. for 12 hours, the reaction was terminated using Brine, followed by extraction with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (EA:Hex=7:3) to obtain a white solid compound M-3 (610 mg, 81% yield).

¹ H NMR (DMSO, 400 MHz) δ 1.46 (m, 8H), 2.20 (t, J = 6.8 Hz, 2H), 2.40 (s, 3H), 2.95 (m, 1H), 3.14 (m, 2H), 5.49 (s, 1H), 7.21 (m, 3H), 7.44 (m, 1H), 11.99 (s, 1H)

(2) Preparation of N-(2-(piperidin-1-yl)ethyl)-5-(2-(o-tolyl)-1,3-dithian-4-yl)pentanamide (Compound 3)

Ar purge was performed and compound M-3 (300 mg, 0.97 mmol) was dissolved in DCM. EDC (460 mg, 2.42 mmol) was subdivided in an ice bath, and after 20 minutes, NHS (220 mg, 1.93 mmol) was added. After reacting overnight, the reaction was _{terminated with H 2} O and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (EA:HEX=7:3) to obtain 2,5-dioxopyrrolidin-1-yl 2,5-dioxopyrrolidin-1-yl 5-(2-(o-tolyl)-1, 3-dithian-4-yl)pentanoate was obtained, which was immediately used in the next reaction. 2,5-dioxopyrrolidin-1-yl 2,5-dioxopyrrolidin-1-yl 5-(2-(o-tolyl)-1,3-dithian-4-yl)pentanoate (133 mg, 0.32 mmol) under an ice bath Was dissolved with DCM. 1-(2-aminoethyl)piperidine (Compound a2-1, 0.07 mL, 0.48 mmol) was added dropwise. After reacting overnight, it was concentrated under reduced pressure and separated by column chromatography (DCM:MeOH=9.2:0.8) to obtain a sticky solid compound 3 (99 mg, 72% yield).

TLC [DCM:MeOH=9:1 R _f =0.58]; ¹ H NMR (DMSO, 400 MHz) δ 1.44 (m, 14H), 2.04 (t, J = 7.2 Hz, 2H), 2.29 (m, 6H), 2.38 (s, 3H), 2.94 (m, 1H), 3.12 (m, 4H), 5.47 (s, 1H), 7.20 (m, 3H), 7.43 (m, 1H), 7.68 (s, 1H); ¹³ C NMR (DMSO, 100 MHz) δ 19.14 (2C), 24.3, 25.6 (2C), 25.8, 31.8, 32.9, 35.6, 35.9, 36.5, 45.5, 48.5, 54.4 (2C), 58.2, 126.8, 127.9, 128.4 , 130.8, 135.4, 137.7, 172.3.

[Example 4] 5-(2-(benzo[d][1,3]dioxol-5-yl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl) Preparation of ethyl)pentanamide (compound 4 )

(1) Preparation of 5-(2-(benzo[d][1,3]dioxol-5-yl)-1,3-dithian-4-yl)pentanoic acid (Compound M-4)

After ar purge and drying tube was installed, Piperonal (Compound a1-4, 0.69 g, 4.61 mmol) was dissolved in DCM. Compound DHLA (0.8 g, 3.84 mmol) was added, and P-TsOH (0.03 g, 0.19 mmol) was added. After overnight, the reaction was terminated using Brine and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (EA:Hex=2:3) to obtain a white solid compound M-4 (810 mg, 61% yield).

¹ H NMR (DMSO, 400 MHz) δ 1.45 (m, 8H), 2.19 (t, J = 7.2 Hz, 2H), 2.94 (m, 1H), 3.02 (m, 2H), 5.30 (s, 1H), 6.02 (s, 2H), 6.88 (m, 1H), 8.89 (m, 1H), 6.92 (m, 1H), 12.00 (s, 1H)

(2) 5-(2-(benzo[d][1,3]dioxol-5-yl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl) Preparation of pentanamide (compound 4)

Ar purge was performed and compound M-4 (500 mg, 1.47 mmol) was dissolved in DCM. EDC (700 mg, 3.67 mmol) was subdivided in an ice bath, and after 20 minutes, NHS (340 mg, 2.94 mmol) was added. After reacting overnight, the reaction was _{terminated with H 2} O and extracted with DCM. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (EA:HEX=7:3) and 2,5-dioxopyrrolidin-1-yl 5-(2-(benzo[d][1,3]dioxol-5-yl)- 1,3-dithian-4-yl)pentanoate was obtained, which was immediately used in the next reaction. Under Ice Bath 2,5-dioxopyrrolidin-1-yl 5-(2-(benzo[d][1,3]dioxol-5-yl)-1,3-dithian-4-yl)pentanoate (342 mg, 0.78 mmol) was dissolved with DCM. 1-(2-aminoethyl)piperidine (Compound a2-1, 0.17 mL, 1.17 mmol) was added dropwise. After reacting overnight, it was concentrated under reduced pressure and separated by column chromatography (DCM:MeOH=9.7:0.3) to obtain a sticky solid compound 4 (289 mg, 82% yield).

TLC [DCM:MeOH=9.5:0.5 R _f =0.43, 0.26]; ¹ H NMR (DMSO, 400 MHz) δ 1.43 (m, 14H), 2.03 (t, J = 7.2 Hz, 2H), 2.29 (m, 6H), 2.93 (m, 1H), 3.01 (t, J = 12.0 Hz, 2H), 3.12 (q, J = 6.4 Hz, 2H), 5.30 (s, 1H), 6.02 (s, 2H), 6.89 (m, 3H), 7.69 (s, 1H); ¹³ C NMR (DMSO, 100 MHz) δ 24.4, 25.5, 25.6, 25.9 (2C), 31.8, 32.7, 35.6, 35.8, 36.6, 45.6, 51.0, 54.5 (2C), 58.3, 101.6, 108.3, 108.8, 121.5, 133.5, 147.5, 147.7, 172.2.

[Example 5] Preparation of 5-(2-(4-chlorophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 5 )

(1) Preparation of 5-(2-(4-chlorophenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-5)

Ar purge was carried out, the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and 4-Chlorobenzaldehyde (Compound a1-5, 0.4 g, 2.8 mmol) was added dropwise. After 1 hour at room temperature, Boron trifluoride diethyl etherate (BF ₃ OEt ₂ , 0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O and extracted with DCM. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to give a colorless oily compound M-5 (660 mg, 83.1% yield).

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.58 (m, 7H), 2.17 (m, 1H), 2.35 (t, J = 7.2 Hz, 2H), 2.99 (m, 3H), 5.12 (s, 1H) , 7.30 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H)

(2) Preparation of 5-(2-(4-chlorophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 5)

Ar purge was performed and compound M-5 (200 mg, 0.60 mmol) was dissolved in DCM. N,N-dimethylaminopyridine (DMAP, 30 mg, 0.24 mmol) was added and 10 minutes later, EDC (170 mg, 0.88 mmol) was added in small portions and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1 , 0.10 mL, 0.70 mmol) was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a white solid compound 5 (70 mg, 26.2% yield).

TLC [DCM:MeOH=9:1 R _f =0.3]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.46 (m, 4H), 1.62 (m, 9H), 2.18 (t, J = 4.8 Hz, 3H), 2.41 (m, 6H), 2.99 (m, 3H) , 3.33 (d, J = 3.6 Hz, 2H), 5.11 (s, 1H), 7.30 (d, J = 5.6 Hz, 2H), 7.39 (d, J = 5.6 Hz, 2H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 24.1, 25.4, 25.7 (3C), 32.4, 32.5, 35.7, 35.8, 36.4, 46.0, 51.5, 54.2 (2C), 57.2, 128.9 (2C), 129.1 (2C) , 134.1, 137.3, 172.7.

[Example 6] Preparation of 5-(2-(2-chlorophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 6 )

(1) Preparation of 5-(2-(4-(dimethylamino)phenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-6)

Ar purge was carried out, the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and then 2-Chlorobenzaldehyde (Compound a1-6, 0.32 mL, 2.8 mmol) was added dropwise. After 1 hour at room temperature, BF ₃ OEt ₂ (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O and extracted with DCM. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to give a colorless oily compound M-6 (740 mg, 93.1% yield).

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.58 (m, 7H), 2.19 (m, 1H), 2.35 (t, J = 7.2 Hz, 2H), 3.04 (m, 3H), 5.62 (s, 1H) , 7.22 (t, J = 7.6 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H)

(2) Preparation of 5-(2-(2-chlorophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 6)

Ar purge was performed and compound M-6 (200 mg, 0.60 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and 10 minutes later, EDC (170 mg, 0.88 mmol) was subdivided, and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.10 mL, 0.70 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a colorless oily compound 6 (40 mg, 15.0% yield).

TLC [DCM:MeOH=9:1 R _f =0.3]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.46 (m, 4H), 1.63 (m, 9H), 2.19 (t, J = 4.8 Hz, 3H), 2.46 (m, 6H), 2.99 (m, 1H) , 3.06 (m, 2H), 3.34 (d, J = 2.0 Hz, 2H), 5.62 (s, 1H), 7.22 (t, J = 5.2 Hz, 1H), 7.27 (t, J = 4.8 Hz, 1H) , 7.36 (d, J = 4.8 Hz, 1H), 7.36 (dd, J = 4.8, 5.2 Hz, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 24.1, 25.4, 25.6 (2C), 25.7, 32.5, 32.7, 35.7, 35.8, 36.4, 46.1, 48.3, 54.2 (2C), 57.2, 127.4, 129.4, 129.6 (2C ), 132.4, 136.3, 172.7.

[Example 7] Preparation of N-(2-(piperidin-1-yl)ethyl)-5-(2-(p-tolyl)-1,3-dithian-4-yl)pentanamide (Compound 7 )

(1) Preparation of 5-(2-(p-tolyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-7)

Ar purge was performed and the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and then p-Tolualdehyde (Compound a1-7, 0.34 mL, 2.8 mmol) was added dropwise. After 1 hour at room temperature, BF ₃ OEt ₂ (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to obtain a white solid compound M-7 (589 mg, 79.0% yield).

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.53 (m, 3H), 1.66 (m, 4H), 2.17 (m, 1H), 2.32 (s, 3H), 2.34 (t, J = 7.2 Hz, 2H) , 2.99 (m, 3H), 5.12 (s, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H)

(2) Preparation of N-(2-(piperidin-1-yl)ethyl)-5-(2-(p-tolyl)-1,3-dithian-4-yl)pentanamide (Compound 7)

Ar purge was performed and compound M-7 (200 mg, 0.64 mmol) was dissolved in DCM. DMAP (40 mg, 0.32 mmol) was added and 10 minutes later, EDC (180 mg, 0.93 mmol) was subdivided, and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.09 mL, 0.69 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give an orange solid compound 7 (140 mg, 34.7% yield).

TLC [DCM:MeOH=9:1 R _f =0.3]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.46 (m, 4H), 1.58 (m, 9H), 2.17 (t, J = 4.8 Hz, 3H), 2.32 (s, 3H), 2.40 (m, 6H) , 2.99 (m, 3H), 3.32 (q, J = 3.6, 4.0 Hz, 2H), 5.12 (s, 1H), 7.13 (d, J = 5.2 Hz, 2H), 7.34 (d, J = 5.6 Hz, 2H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 21.2, 24.2, 25.5, 25.7, 25.8 (2C), 32.5, 32.7, 35.8, 35.9, 36.4, 46.0, 52.1, 54.2 (2C), 57.2, 127.5 (2C), 129.4 (2C), 135.8, 138.2, 172.7.

[Example 8] Preparation of 5-(2-(2-methoxyphenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 8 )

(1) Preparation of 5-(2-(2-methoxyphenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-8)

Ar purge was performed, and the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and then o-anisaldehyde (compound a1-8, 0.35 mL, 2.8 mmol) was added dropwise. After 1 hour at room temperature, BF ₃ OEt ₂ (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to give a yellow oily compound M-8 (784 mg, 100.0% yield).

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.58 (m, 7H), 2.17 (m, 1H), 2.34 (t, J = 7.2 Hz, 2H), 2.99 (m, 3H), 3.86 (s, 3H) , 5.69 (s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H)

(2) Preparation of 5-(2-(2-methoxyphenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 8)

Ar purge was performed and compound M-8 (400 mg, 1.23 mmol) was dissolved in DCM. DMAP (80 mg, 0.65 mmol) was added and 10 minutes later, EDC (350 mg, 1.82 mmol) was subdivided and 20 minutes later, 1-(2-aminoethyl)piperidine (compound a2-1, 0.2 mL, 1.48 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 8 (280 mg, 52.3% yield).

TLC [DCM:MeOH=9:1 R _f =0.3]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.46 (m, 4H), 1.62 (m, 9H), 2.17 (t, J = 5.2 Hz, 3H), 2.32 (s, 3H), 2.40 (m, 4H) , 2.44 (t, J = 3.6 Hz, 2H), 2.96 (m, 1H), 3.06 (m, 2H), 3.33 (q, J = 3.6, 4.0 Hz, 2H), 3.86, (s, 3H), 5.69 (s, 1H), 6.86 (d, J = 5.2 Hz, 1H), 6.95 (t, J = 5.2 Hz, 1H), 7.25 (t, J = 5.2 Hz, 1H), 7.57 (d, J = 5.2 Hz , 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 24.2, 25.5, 25.7 (2C), 25.8, 32.7, 32.9, 35.8, 35.9, 36.4, 44.3, 46.1, 54.2 (2C), 55.7, 57.2, 110.7, 121.0, 126.9 , 129.1, 129.4, 155.4, 172.8.

[Example 9] N-(2-(piperidin-1-yl)ethyl)-5-(2-(2-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (Compound 9 ) Produce

(1) Preparation of 5-(2-(2-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-9)

Ar purge was performed, and the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and then 2-(Trifluoromethyl)benzaldehyde (compound a1-9, 0.33 mL, 2.52 mmol) was added dropwise. After 1 hour at room temperature, BF ₃ OEt ₂ (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to give a colorless oily compound M-9 (870 mg, 99.4% yield).

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.60 (m, 7H), 2.19 (m, 1H), 2.34 (t, J = 7.2 Hz, 2H), 3.03 (m, 3H), 5.43 (s, 1H) , 7.38 (t, J = 7.6 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H)

(2) Preparation of N-(2-(piperidin-1-yl)ethyl)-5-(2-(2-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (Compound 9)

Ar purge was performed and compound M-9 (200 mg, 0.54 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and 10 minutes later, EDC (150 mg, 0.78 mmol) was subdivided, and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.09 mL, 0.62 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a pale yellow oily compound 9 (165 mg, 63.3% yield).

TLC [DCM:MeOH=9:1 R _f =0.3]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.46 (m, 4H), 1.62 (m, 9H), 2.17 (t, J = 5.2 Hz, 3H), 2.37 (m, 4H), 2.42 (t, J = 5.6 Hz, 2H), 3.02 (m, 3H), 3.32 (q, J = 4.0, 5.6 Hz, 2H), 5.43 (s, 1H), 6.12 (bs, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 24.2, 25.4, 25.7, 25.8 (2C), 32.6, 32.7, 35.8 (2C), 36.4, 46.3, 48.1, 54.2 (2C), 57.2, 125.8 (q, J = 5.5, 5.7 Hz), 128.2, 128.3, 130.7, 130.9, 132.4, 137.4, 172.7.

[Example 10] N-(2-(piperidin-1-yl)ethyl)-5-(2-(3-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (Compound 10 ) Produce

(1) Preparation of 5-(2-(3-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-10)

Ar purge was performed and the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and then 3-(Trifluoromethyl)benzaldehyde (compound a1-10, 0.3 mL, 2.5 mmol) was added dropwise. After 1 hour at room temperature, BF ₃ OEt ₂ (0.32 mL, 2.6 mmol) was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O and extracted with DCM. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to give a colorless oily compound M-10 (795 mg, 90.8% yield).

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.54 (m, 3H), 1.64 (m, 4H), 2.18 (m, 1H), 2.35 (t, J = 7.2 Hz, 2H), 3.01 (m, 3H) , 5.19 (s, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H)

(2) Preparation of N-(2-(piperidin-1-yl)ethyl)-5-(2-(3-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (Compound 10)

Ar purge was performed and compound M-10 (200 mg, 0.54 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and 10 minutes later, EDC (150 mg, 0.78 mmol) was subdivided, and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.09 mL, 0.62 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give an ivory solid compound 10 (157 mg, 60.2% yield).

TLC [DCM:MeOH=9:1 R _f =0.3]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.46 (m, 4H), 1.62 (m, 9H), 2.19 (t, J = 7.2 Hz, 3H), 2.45 (m, 4H), 2.50 (t, J = 6.0 Hz, 2H), 3.01 (m, 3H), 3.36 (q, J = 5.2, 6.0 Hz, 2H), 5.19 (s, 1H), 6.40 (bs, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.72 (s, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 24.0, 25.4, 25.5 (2C), 25.7, 32.4, 32.5, 35.6, 35.8, 36.3, 46.0, 51.7, 54.2 (2C), 57.2, 124.7 (q, J = 3.7 , 3.8 Hz), 125.2 (q, J = 3.6, 3.7 Hz), 129.2 (2C), 131.2 (2C), 139.8, 172.8.

[Example 11] N-(2-(piperidin-1-yl)ethyl)-5-(2-(4-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (Compound 11 ) Produce

(1) Preparation of 5-(2-(4-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-11)

After ar purge was performed, the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and 4-(Trifluoromethyl)benzaldehyde (compound a1-11, 0.4 mL, 2.8 mmol) was added dropwise. After 1 hour at room temperature, BF ₃ OEt ₂ (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O and extracted with DCM. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to obtain a white compound M-11 (500 mg, 57.1% yield).

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.53 (m, 3H), 1.66 (m, 4H), 2.19 (m, 1H), 2.36 (t, J = 7.2 Hz, 2H), 3.01 (m, 3H) , 5.19 (s, 1H), 7.59 (s, 4H)

(2) Preparation of N-(2-(piperidin-1-yl)ethyl)-5-(2-(4-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (Compound 11)

Ar purge was performed and compound M-11 (200 mg, 0.54 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and 10 minutes later, EDC (150 mg, 0.78 mmol) was subdivided, and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.09 mL, 0.62 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow solid compound 11 (249 mg, 95.5% yield).

TLC [DCM:MeOH=9:1 R _f =0.3]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.46 (m, 4H), 1.58 (m, 9H), 2.18 (t, J = 7.2 Hz, 3H), 2.40 (m, 4H), 2.43 (t, J = 5.6 Hz, 2H), 3.01 (m, 3H), 3.32 (q, J = 5.2, 5.6 Hz, 2H), 5.18 (s, 1H), 6.14 (bs, 1H), 7.58 (m, 4H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 24.2, 25.4, 25.7 (3C), 32.4, 32.5, 35.8 (2C), 36.4, 46.0, 51.8, 54.2, 57.2, 125.7 (q, J = 3.5, 3.8 Hz) , 128.4 (3C), 128.7, 130.5 (d, J = 32.3 Hz), 142.7, 172.7.

[Example 12] Preparation of 5-(2-(3-methoxyphenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 12 )

(1) Preparation of 5-(2-(3-methoxyphenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-12)

After ar purge was performed, the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and m-anisaldehyde (compound a1-12, 0.35 mL, 2.8 mmol) was added dropwise. After 1 hour at room temperature, BF ₃ OEt ₂ (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to give a yellow oily compound M-12 (781 mg, 100.0% yield).

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.58 (m, 7H), 2.16 (m, 1H), 2.34 (t, J = 7.2 Hz, 2H), 2.99 (m, 3H), 3.80 (s, 3H) , 5.12 (s, 1H), 6.84 (d, J = 7.6 Hz, 1H), 7.01 (s, 1H), 7.03 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H)

(2) Preparation of 5-(2-(3-methoxyphenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 12)

Ar purge was performed and compound M-12 (400 mg, 1.23 mmol) was dissolved in DCM. DMAP (80 mg, 0.65 mmol) was added and 10 minutes later, EDC (350 mg, 1.82 mmol) was subdivided and 20 minutes later, 1-(2-aminoethyl)piperidine (compound a2-1, 0.2 mL, 1.48 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 12 (308 mg, 57.5% yield).

TLC [DCM:MeOH=9:1 R _f =0.3]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.46 (m, 4H), 1.64 (m, 9H), 2.18 (t, J = 7.6 Hz, 3H), 2.46 (m, 4H), 2.50 (t, J = 6.0 Hz, 2H), 2.98 (m, 3H), 3.36 (q, J = 5.2, 6.0 Hz, 2H), 5.12 (s, 1H), 6.37 (bs, 1H), 6.83 (d, J = 7.6 Hz, 1H), 7.00 (s, 1H), 7.03 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 23.9, 25.3, 25.4 (2C), 25.7, 32.5, 32.7, 35.6, 35.9, 36.4, 46.1, 52.5, 54.2 (2C), 55.3, 57.3, 112.9, 114.5, 120.0 , 129.7, 140.2, 159.8, 172.9.

[Example 13] Preparation of 5-(2-(4-methoxyphenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 13 )

(1) Preparation of 5-(2-(4-methoxyphenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-13)

Ar purge was performed, and the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and then p-Anisaldehyde (compound a1-13, 0.25 mL, 2.8 mmol) was added dropwise. After 1 hour at room temperature, BF ₃ OEt ₂ (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O and extracted with DCM. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to give a white solid compound M-13 (510 mg, 43.0% yield).

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.58 (m, 7H), 2.15 (m, 1H), 2.35 (t, J = 7.2 Hz, 2H), 2.97 (m, 3H), 3.79 (s, 3H) , 5.12 (s, 1H), 6.86 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H)

(2) Preparation of 5-(2-(4-methoxyphenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 13)

Ar purge was performed and compound M-13 (200 mg, 0.61 mmol) was dissolved in DCM. DMAP (37 mg, 0.30 mmol) was added and 10 minutes later, EDC (170 mg, 0.88 mmol) was subdivided and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.1 mL, 0.70 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a white solid compound 13 (140 mg, 52.3% yield).

TLC [DCM:MeOH=9:1 R _f =0.3]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.45 (m, 4H), 1.60 (m, 9H), 2.17 (t, J = 7.2 Hz, 3H), 2.38 (m, 4H), 2.42 (t, J = 5.6 Hz, 2H), 2.97 (m, 3H), 3.36 (q, J = 5.2, 5.6 Hz, 2H), 3.79 (s, 3H), 5.11 (s, 1H), 6.11 (bs, 1H), 6.85 ( d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 24.2, 25.5, 25.7, 25.8 (2C), 32.5, 32.6, 35.8, 35.9, 36.4, 46.1, 51.6, 54.2 (2C), 55.3, 57.2, 114.1 (2C), 128.9 (2C), 131.0, 159.5, 172.7.

[Example 14] Preparation of N-(2-(piperidin-1-yl)ethyl)-5-(2-(m-tolyl)-1,3-dithian-4-yl)pentanamide (Compound 14 )

(1) Preparation of 5-(2-(m-tolyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-14)

After Ar purge was performed, the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and m-Tolualdehyde (Compound a1-14, 0.33 mL, 2.8 mmol) was added dropwise. After 1 hour at room temperature, BF ₃ OEt ₂ (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O and extracted with DCM. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to give a light green oily compound M-14 (597 mg, 80.1% yield).

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.53 (m, 3H), 1.66 (m, 4H), 2.19 (m, 1H), 2.41 (s, 3H), 2.35 (t, J = 7.2 Hz, 2H) , 3.00 (m, 3H), 5.12 (s, 1H), 7.10 (d, J = 6.8 Hz, 1H), 7.22 (t, J = 6.8 Hz, 2H), 7.28 (s, 1H)

(2) Preparation of N-(2-(piperidin-1-yl)ethyl)-5-(2-(m-tolyl)-1,3-dithian-4-yl)pentanamide (Compound 14)

Ar purge was performed and compound M-14 (200 mg, 0.64 mmol) was dissolved in DCM. DMAP (40 mg, 0.32 mmol) was added and 10 minutes later, EDC (180 mg, 0.93 mmol) was subdivided, and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.09 mL, 0.69 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give an orange oily compound 14 (140 mg, 51.6% yield).

TLC [DCM:MeOH=9:1 R _f =0.3]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.46 (m, 4H), 1.60 (m, 9H), 2.17 (t, J = 7.6 Hz, 3H), 2.23, (s, 3H), 2.40 (m, 4H) ), 2.43 (t, J = 5.6 Hz, 2H), 2.98 (m, 3H), 3.36 (q, J = 5.2, 5.6 Hz, 2H), 5.11 (s, 1H), 6.14 (bs, 1H), 6.83 (d, J = 7.6 Hz, 1H), 7.00 (s, 1H), 7.03 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 21.3, 24.1, 25.4, 25.7 (3C), 32.4, 32.7, 35.8 (2C), 36.4, 46.0, 52.4, 54.2 (2C), 57.2, 124.7, 128.2, 128.6, 129.2, 138.4, 138.6, 172.2.

[Example 15] Preparation of 5-(2-(3-chlorophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 15 )

(1) Preparation of 5-(2-(3-chlorophenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-15)

Ar purge was performed and the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and then 3-Chlorobenzaldehyde (Compound a1-15, 0.32 mL, 2.8 mmol) was added dropwise. After 1 hour at room temperature, BF ₃ OEt ₂ (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O and extracted with DCM. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to give a colorless oily compound M-15 (745 mg, 93.8% yield).

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.58 (m, 7H), 2.17 (m, 1H), 2.35 (t, J = 7.2 Hz, 2H), 3.00 (m, 3H), 5.11 (s, 1H) , 7.27 (m, 2H), 7.33 (m, 1H), 7.46 (s, 1H)

(2) Preparation of 5-(2-(3-chlorophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 15)

Ar purge was performed and compound M-15 (200 mg, 0.60 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and 10 minutes later, EDC (170 mg, 0.88 mmol) was subdivided, and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.10 mL, 0.70 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 15 (160 mg, 77.6% yield).

TLC [DCM:MeOH=9:1 R _f =0.3]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.46 (m, 4H), 1.66 (m, 9H), 2.18 (t, J = 7.6 Hz, 3H), 2.45 (m, 4H), 2.47 (t, J = 5.6 Hz, 2H), 3.00 (m, 3H), 3.35 (q, J = 5.2, 5.6 Hz, 2H), 5.01 (s, 1H), 6.31 (bs, 1H), 7.27 (m, 2H), 7.33 ( m, 1H), 7.46 (s, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 24.2, 25.4, 25.7 (3C), 32.4, 32.6, 35.8 (2C), 36.4, 46.0, 51.7, 54.2 (2C), 57.2, 125.9, 128.0, 128.6, 130.0, 134.5, 140.7, 172.7.

[Example 16] Preparation of 5-(2-(2-nitrophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 16 )

(1) Preparation of 5-(2-(2-nitrophenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-16)

After Ar purge was performed, the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and 2-Nitrobenzaldehyde (compound a1-16, 0.43 g, 2.8 mmol) was added dropwise. After 1 hour at room temperature, BF ₃ OEt ₂ (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O and extracted with DCM. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to give a colorless oily compound M-16 (800 mg, 97.6% yield).

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.58 (m, 7H), 2.19 (m, 1H), 2.35 (t, J = 7.2 Hz, 2H), 3.04 (m, 3H), 5.87 (s, 1H) , 7.44 (t, J = 7.2 Hz, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H)

(2) Preparation of 5-(2-(2-nitrophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 16)

Ar purge was performed and compound M-16 (200 mg, 0.58 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and 10 minutes later, EDC (170 mg, 0.88 mmol) was subdivided, and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.10 mL, 0.70 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 16 (100 mg, 37.8% yield).

TLC [DCM:MeOH=9:1 R _f =0.3]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.56 (m, 9H), 1.83 (bs, 4H), 2.22 (t, J = 7.6 Hz, 3H), 2.78 (bs, 6H), 3.05 (m, 3H) , 3.51 (q, J = 5.2 Hz, 2H), 5.86 (s, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 22.9 23.9 (2C), 25.3 25.6, 32.5, 32.6, 34.7, 35.7, 36.1, 46.4, 36.7, 54.2 (2C), 57.5, 124.6, 129.0, 130.7, 133.2, 133.4 , 147.6, 173.4.

[Example 17] Preparation of 5-(2-(3-nitrophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 17 )

(1) Preparation of 5-(2-(3-nitrophenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-17)

Ar purge was performed and the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and then 3-Nitrobenzaldehyde (Compound a1-17, 0.43 g, 2.8 mmol) was added dropwise. After 1 hour at room temperature, BF ₃ OEt ₂ (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O and extracted with DCM. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to obtain an ivory solid compound M-17 (688 mg, 83.9% yield).

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.58 (m, 7H), 2.19 (m, 1H), 2.36 (t, J = 7.2 Hz, 2H), 3.04 (m, 3H), 5.23 (s, 1H) , 7.52 (t, J = 8.0 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.34 (s, 1H)

(2) Preparation of 5-(2-(3-nitrophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 17)

Ar purge was performed and compound M-17 (200 mg, 0.58 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and 10 minutes later, EDC (170 mg, 0.88 mmol) was subdivided, and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.10 mL, 0.70 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 17 (160 mg, 60.4% yield).

TLC [DCM:MeOH=9:1 R _f =0.3]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.46 (m, 4H), 1.66 (m, 9H), 2.19 (t, J = 7.6 Hz, 3H), 2.44 (m, 4H), 2.47 (t, J = 5.6 Hz, 2H), 3.04 (m, 3H), 3.35 (q, J = 5.2, 5.6 Hz, 2H), 5.23 (s, 1H), 6.30 (bs, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.34 (s, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 23.9, 25.3 (2C), 25.4, 25.6, 32.3 (2C), 35.5, 35.7, 36.3, 46.0, 51.3, 54.2 (2C), 57.2, 123.0, 123.4, 129.7, 133.9, 140.9, 148.3, 172.8.

[Example 18] Preparation of 5-(2-(4-nitrophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 18 )

(1) Preparation of 5-(2-(4-nitrophenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-18)

After Ar purge was performed, the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and 4-Nitrobenzaldehyde (Compound a1-18, 0.4 g, 2.8 mmol) was added dropwise. After 1 hour at room temperature, BF ₃ OEt ₂ (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to obtain a white solid compound M-18 (745 mg, 90.9% yield).

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.58 (m, 7H), 2.19 (m, 1H), 2.36 (t, J = 7.2 Hz, 2H), 3.04 (m, 3H), 5.22 (s, 1H) , 7.63 (d, J = 8.8 Hz, 2H), 8.20 (d, J = 8.8 Hz, 2H)

(2) Preparation of 5-(2-(4-nitrophenyl)-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 18)

Ar purge was performed and compound M-18 (300 mg, 0.87 mmol) was dissolved in DCM. DMAP (50 mg, 0.40 mmol) was added and 10 minutes later, EDC (250 mg, 1.30 mmol) was added in small portions and after 20 minutes, 1-(2-aminoethyl)piperidine (compound a2-1, 0.15 mL, 1.01 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow solid compound 18 (293 mg, 73.8% yield).

TLC [DCM:MeOH=9:1 R _f =0.3]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.58 (m, 9H), 1.90 (bs, 4H), 2.27 (t, J = 7.6 Hz, 3H), 2.85 (bs, 6H), 3.03 (m, 3H) , 3.54 (bs, 2H), 5.23 (s, 1H), 7.63 (d, J = 8.8 Hz, 2H), 8.19 (d, J = 8.8 Hz, 2H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 22.7, 23.6 (2C), 25.2, 25.6, 32.3, 32.4, 34.4, 35.7, 36.1, 45.9, 51.5, 54.2 (2C), 57.6, 123.9 (2C), 128.9 ( 2C), 146.0, 147.6, 173.4.

[Example 19] Preparation of 5-(2-phenyl-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 19 )

(1) Preparation of 5-(2-phenyl-1,3-dithian-4-yl)pentanoic acid (Compound M-19)

Ar purge was performed and the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and Benzaldehyde (Compound a1-19, 0.3 mL, 2.8 mmol) was added dropwise. After 1 hour at room temperature, BF ₃ OEt ₂ (0.35 mL, 2.8 mmol) was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to obtain a white solid compound M-19 (555 mg, 78.0% yield).

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.53 (m, 3H), 1.67 (m, 4H), 2.19 (m, 1H), 2.35 (t, J = 7.2 Hz, 2H), 3.00 (m, 3H) , 5.15 (s, 1H), 7.31 (m, 3H), 7.45 (d, J = 8.4 Hz, 2H)

(2) Preparation of 5-(2-phenyl-1,3-dithian-4-yl)-N-(2-(piperidin-1-yl)ethyl)pentanamide (Compound 19)

Ar purge was performed and compound M-19 (200 mg, 0.67 mmol) was dissolved in DCM. DMAP (40 mg, 0.32 mmol) was added and 10 minutes later, EDC (200 mg, 1.04 mmol) was subdivided and 20 minutes later, 1-(2-aminoethyl)piperidine (compound a2-1, 0.11 mL, 0.77 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 19 (100 mg, 36.4% yield).

TLC [DCM:MeOH=9:1 R _f =0.3]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.57 (m, 9H), 1.68 (bs, 4H), 2.18 (m, 1H), 2.26 (t, J = 7.6 Hz, 2H), 2.87 (bs, 6H) , 3.00 (m, 3H), 3.55 (q, J = 5.2, 5.6 Hz, 2H), 5.15 (s, 1H), 7.32 (m, 3H), 7.45 (d, J = 6.8 Hz, 2H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 22.5, 23.4 (2C), 25.3, 25.6, 32.4, 32.7, 34.3, 35.8, 36.1, 46.0, 52.3, 54.1 (2C), 57.5, 127.7 (2C), 128.4, 128.7 (2C), 138.9, 173.7.

[Example 20] Preparation of 5-(2-phenyl-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (Compound 20 )

Ar purge was performed and compound M-19 (200 mg, 0.67 mmol) was dissolved in DCM. DMAP (40 mg, 0.32 mmol) was added and 10 minutes later, EDC (200 mg, 1.04 mmol) was added in small portions and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.11 mL, 0.77 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 20 (222 mg, 78.2% yield).

TLC [DCM:MeOH=9:1 R _f =0.4]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.58 (m, 8H), 1.95 (bs, 4H), 2.02 (q, J = 6.4, 6.8 Hz, 3H), 2.18 (m, 1H), 2.23 (t, J = 7.6 Hz, 2H), 2.90 (m, 9H), 3.35 (q, J = 5.6, 6.4 Hz, 2H), 5.15 (s, 1H), 7.31 (m, 3H), 7.45 (d, J = 6.8 Hz, 2H), 7.54 (t, J = 5.6 Hz, 2H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 22.2, 22.9 (2C), 23.6, 25.4, 25.7, 32.4, 32.7, 35.8, 36.2, 36.3, 46.0, 52.3, 53.4 (2C), 54.8, 127.7 (2C), 128.4, 128.7 (2C), 138.9, 173.9.

[Example 21] N-(3-(piperidin-1-yl)propyl)-5-(2-(2-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (Compound 21 ) Produce

Ar purge was performed and compound M-9 (200 mg, 0.54 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and 10 minutes later, EDC (150 mg, 0.78 mmol) was subdivided and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.10 mL, 0.63 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a colorless oily compound 21 (116 mg, 43.2% yield).

TLC [DCM:MeOH=9:1 R _f =0.4]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.58 (m, 8H), 1.97 (m, 7H), 2.21 (t, J = 7.6 Hz, 3H), 3.30 (m, 9H), 3.36 (q, J = 5.6, 6.4 Hz, 2H), 5.41 (s, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 5.2 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H) , 7.62 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 22.4, 23.2 (2C), 23.6, 25.4, 25.7, 32.5, 32.7, 35.8, 36.2, 36.6, 46.3, 48.0, 53.5 (2C), 55.1, 125.7 (q, J = 5.6 Hz), 127.1 (d, J = 30.0 Hz), 128.2, 130.7 (2C), 132.4, 137.4, 173.7.

[Example 22] N-(3-(piperidin-1-yl)propyl)-5-(2-(3-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (Compound 22 ) Produce

Ar purge was performed and compound M-10 (200 mg, 0.54 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and 10 minutes later, EDC (150 mg, 0.78 mmol) was subdivided and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.10 mL, 0.63 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 22 (197 mg, 73.4% yield).

TLC [DCM:MeOH=9:1 R _f =0.4]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.58 (m, 8H), 1.98 (m, 7H), 2.28 (t, J = 7.6 Hz, 3H), 3.02 (m, 9H), 3.37 (q, J = 5.6, 6.0 Hz, 2H), 5.21 (s, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 5.2 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H) , 7.65 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 22.3, 23.0 (2C), 23.6, 25.4, 25.6, 32.4, 32.5, 35.7, 36.2, 36.4, 46.0, 51.7, 53.5 (2C), 54.9, 124.7 (q, J = 3.6, 3.9 Hz), 125.2 (q, J = 3.6, 3.9 Hz), 129.2 (2C), 131.2 (2C), 139.9, 173.8.

[Example 23] N-(3-(piperidin-1-yl)propyl)-5-(2-(4-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanamide (Compound 23 ) Produce

Ar purge was performed and compound M-11 (200 mg, 0.54 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and 10 minutes later, EDC (150 mg, 0.78 mmol) was subdivided and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.10 mL, 0.63 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a white solid compound 23 (202 mg, 75.3% yield).

TLC [DCM:MeOH=9:1 R _f =0.4]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.59 (m, 8H), 1.97 (m, 7H), 2.23 (t, J = 7.6 Hz, 3H), 3.01 (m, 9H), 3.32 (q, J = 5.6, 6.0 Hz, 2H), 5.20 (s, 1H), 7.47 (bs, 1H), 7.59 (s, 4H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 22.3, 23.0 (2C), 23.6, 25.4, 25.7, 32.4, 32.5, 35.7, 36.2, 36.4, 46.0, 51.7, 53.5 (2C), 54.9, 125.7 (q, J = 3.7, 3.9 Hz), 128.2 (3C), 130.4 (d, J = 32.4 Hz), 142.8 (2C), 173.8.

[Example 24] Preparation of N-(3-(piperidin-1-yl)propyl)-5-(2-(o-tolyl)-1,3-dithian-4-yl)pentanamide (Compound 24 )

Ar purge was performed and compound M-3 (200 mg, 0.64 mmol) was dissolved in DCM. DMAP (40 mg, 0.32 mmol) was added and 10 minutes later, EDC (180 mg, 0.93 mmol) was subdivided and 20 minutes later, 1-(3-aminopropyl)piperidine (compound a2-2, 0.12 mL, 0.70 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 24 (204 mg, 72.8% yield).

TLC [DCM:MeOH=9:1 R _f =0.4]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.58 (m, 8H), 1.97 (m, 4H), 2.21 (q, J = 6.0, 6.4 Hz, 3H), 2.18 (m, 1H), 2.23 (t, J = 7.6 Hz, 2H), 2.43 (s, 3H), 3.00 (m, 9H), 3.36 (q, J = 6.0 Hz, 2H), 5.29 (s, 1H), 7.18 (m, 3H), 7.47 ( t, J = 5.2 Hz, 1H), 7.56 (t, J = 6.4 Hz, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 19.1, 22.2, 22.9 (2C), 23.6, 25.4, 25.7, 32.6, 32.8, 35.9, 36.2, 36.3, 46.2, 48.9, 53.4 (2C), 54.8, 126.5, 127.8 , 128.1, 130.4, 135.1, 137.0, 173.9.

[Example 25] Preparation of N-(3-(piperidin-1-yl)propyl)-5-(2-(m-tolyl)-1,3-dithian-4-yl)pentanamide (Compound 25 )

Ar purge was performed and compound M-14 (200 mg, 0.64 mmol) was dissolved in DCM. DMAP (40 mg, 0.32 mmol) was added and 10 minutes later, EDC (180 mg, 0.93 mmol) was subdivided and 20 minutes later, 1-(3-aminopropyl)piperidine (compound a2-2, 0.12 mL, 0.70 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 25 (216 mg, 77.1% yield).

TLC [DCM:MeOH=9:1 R _f =0.4]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.58 (m, 8H), 2.00 (m, 7H), 2.28 (t, J = 7.6 Hz, 3H), 2.33 (s, 3H), 2.97 (m, 9H) , 3.38 (q, J = 5.6, 6.4 Hz, 2H), 5.11 (s, 1H), 7.10 (d, J = 6.8 Hz, 1H), 7.23 (m, 2H), 7.27 (s, 1H), 7.50 ( t, J = 5.2 Hz, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 21.3, 22.2, 22.9 (2C), 23.6, 25.4, 25.7, 32.5, 32.8, 35.9, 36.2, 36.3, 46.1, 52.3, 53.4 (2C), 54.8, 124.8, 128.3 , 128.6, 129.2, 138.5, 138.8, 173.9.

[Example 26] Preparation of N-(3-(piperidin-1-yl)propyl)-5-(2-(p-tolyl)-1,3-dithian-4-yl)pentanamide (Compound 26 )

Ar purge was performed and compound M-7 (200 mg, 0.64 mmol) was dissolved in DCM. DMAP (40 mg, 0.32 mmol) was added and 10 minutes later, EDC (180 mg, 0.93 mmol) was subdivided and 20 minutes later, 1-(3-aminopropyl)piperidine (compound a2-2, 0.12 mL, 0.70 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 26 (213 mg, 76.0% yield).

TLC [DCM:MeOH=9:1 R _f =0.4]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.59 (m, 8H), 2.01 (m, 7H), 2.18 (m, 1H), 2.22 (t, J = 7.6 Hz, 2H), 2.32 (s, 3H) , 2.97 (m, 9H), 3.36 (q, J = 6.0 Hz, 2H), 5.12 (s, 1H), 7.13 (d, J = 7.6 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H) , 7.47 (t, J = 5.2 Hz, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 21.2, 22.2, 22.9 (2C), 23.6, 25.4, 25.7, 32.5, 32.7, 35.9, 36.3 (2C), 46.1, 52.0, 53.4 (2C), 54.8, 127.6 ( 2C), 129.4 (2C), 136.0, 138.2, 173.9.

[Example 27] Preparation of 5-(2-(2-nitrophenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (Compound 27 )

Ar purge was performed and compound M-16 (265 mg, 0.77 mmol) was dissolved in DCM. DMAP (47 mg, 0.38 mmol) was added and 10 minutes later, EDC (220 mg, 1.14 mmol) was subdivided and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.14 mL, 0.91 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 27 (123 mg, 34.0% yield).

TLC [DCM:MeOH=9:1 R _f =0.4]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.58 (m, 8H), 2.00 (m, 7H), 2.23 (t, J = 7.6 Hz, 3H), 3.00 (m, 9H), 3.37 (q, J = 5.6, 6.0 Hz, 2H), 5.85 (s, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H) ; ¹³ C NMR (CDCl ₃ , 100 MHz) δ 22.2, 22.8 (2C), 23.6, 25.4, 25.7, 32.5, 32.6, 35.7, 36.2 (2C), 46.4, 46.7, 53.4 (2C), 54.7, 124.6, 129.0, 130.7, 133.2, 133.5, 147.7, 173.9.

[Example 28] Preparation of 5-(2-(3-nitrophenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (Compound 28 )

Ar purge was performed and M-17 (200 mg, 0.58 mmol) was dissolved in DCM. DMAP (35 mg, 0.28 mmol) was added and 10 minutes later, EDC (160 mg, 0.83 mmol) was subdivided and 20 minutes later, 1-(3-aminopropyl)piperidine (Compound a2-2, 0.11 mL, 0.69 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 28 (157 mg, 57.5% yield).

TLC [DCM:MeOH=9:1 R _f =0.4]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.58 (m, 8H), 2.00 (m, 7H), 2.23 (m, 3H), 3.02 (m, 9H), 3.37 (m, 2H), 5.26 (s, 1H), 6.40 (bs, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.56 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 8.34 (s, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 22.3, 23.0 (2C), 23.6, 25.3, 25.6, 32.3 (2C), 35.7, 36.2, 36.4, 46.0, 51.2, 53.5 (2C), 54.9, 123.0, 123.3, 129.7, 134.0, 141.0, 148.3, 173.8; ESI-MS: m/z [M]+ 465.9 (calcd. 465.21)

[Example 29] Preparation of 5-(2-(4-nitrophenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (Compound 29 )

Ar purge was performed and M-18 (137 mg, 0.40 mmol) was dissolved in DCM. DMAP (20 mg, 0.16 mmol) was added and 10 minutes later, EDC (110 mg, 0.57 mmol) was subdivided and after 20 minutes, 1-(3-aminopropyl)piperidine (Compound a2-2, 0.076 mL, 0.47 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give an orange oily compound 29 (131 mg, 70.1% yield).

TLC [DCM:MeOH=9:1 R _f =0.4]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.58 (m, 8H), 1.99 (m, 7H), 2.23 (t, J = 7.2 Hz, 3H), 3.02 (m, 9H), 3.37 (q, J = 5.2, 5.6 Hz, 2H), 5.24 (s, 1H), 7.51 (bs, 1H), 7.64 (t, J = 8.0 Hz, 2H), 8.19 (d, J = 8.0 Hz, 2H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 22.3, 23.0 (2C), 23.6, 25.3, 25.6, 32.3, 32.4, 35.7, 36.2, 36.4, 45.9, 51.4, 53.5 (2C), 54.9, 123.9 (2C), 128.9 (2C), 146.0, 147.6, 173.8; ESI-MS: m/z [M]+ 465.9 (calcd. 465.21)

[Example 30] Preparation of 5-(2-(2-chlorophenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (Compound 30 )

Ar purge was performed and compound M-6 (200 mg, 0.60 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and 10 minutes later, EDC (170 mg, 0.88 mmol) was subdivided, and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.12 mL, 0.70 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 30 (214 mg, 77.7% yield).

TLC [DCM:MeOH=9:1 R _f =0.4]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.58 (m, 8H), 2.00 (m, 7H), 2.23 (t, J = 7.6 Hz, 3H), 3.00 (m, 9H), 3.37 (q, J = 5.6, 6.4 Hz, 2H), 5.61 (s, 1H), 7.25 (m, 2H), 7.35 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 5.2 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 22.3, 22.9 (2C), 23.5, 25.4, 25.7, 32.5, 32.6, 35.8, 36.2, 36.3, 46.2, 48.3, 53.4 (2C), 54.8, 127.4, 129.4, 129.5 , 129.7, 132.4, 136.3, 173.8.

[Example 31] Preparation of 5-(2-(3-chlorophenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (Compound 31 )

Ar purge was performed and compound M-15 (200 mg, 0.60 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and 10 minutes later, EDC (170 mg, 0.88 mmol) was subdivided, and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.12 mL, 0.70 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 31 (192 mg, 69.7% yield).

TLC [DCM:MeOH=9:1 R _f =0.4]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.58 (m, 8H), 2.00 (m, 7H), 2.17 (m, 1H), 2.23 (t, J = 7.6 Hz, 2H), 3.00 (m, 9H) , 3.36 (q, J = 5.6, 6.0 Hz, 2H), 5.12 (s, 1H), 7.26 (m, 2H), 7.34 (m, 1H), 7.46 (s, 1H), 7.54 (t, J = 5.2 Hz, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 22.2, 22.8 (2C), 23.6, 25.4, 25.7, 32.4, 32.6, 35.8, 36.2 (2C), 46.0, 51.6, 53.4 (2C), 54.7, 126.0, 128.0, 128.5, 130.0, 134.4, 140.8, 173.9.

[Example 32] Preparation of 5-(2-(4-chlorophenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (Compound 32 )

Ar purge was performed and compound M-5 (200 mg, 0.60 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and 10 minutes later, EDC (170 mg, 0.88 mmol) was subdivided, and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.12 mL, 0.70 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a white solid compound 32 (137 mg, 49.8% yield).

TLC [DCM:MeOH=9:1 R _f =0.4]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.58 (m, 8H), 1.99 (m, 7H), 2.23 (t, J = 7.6 Hz, 3H), 2.90 (t, J = 6.8 Hz, 2H), 3.02 (m, 3H), 3.37 (q, J = 5.6, 6.0 Hz, 2H), 5.12 (s, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H) , 7.43 (t, J = 4.8 Hz, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 22.3, 22.9 (2C), 23.6, 25.4, 25.7, 32.4, 32.5, 35.8, 36.2, 36.3, 46.0, 51.5, 53.4 (2C), 54.8, 128.8 (2C), 129.1 (2C), 134.0, 137.4, 173.8

[Example 33] Preparation of 5-(2-(2-methoxyphenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (Compound 33 )

Ar purge was performed and compound M-8 (200 mg, 0.61 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and 10 minutes later, EDC (170 mg, 0.88 mmol) was subdivided and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.11 mL, 0.70 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 33 (176 mg, 63.7% yield).

TLC [DCM:MeOH=9:1 R _f =0.4]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.58 (m, 8H), 2.00 (m, 7H), 2.22 (t, J = 7.6 Hz, 3H), 3.00 (m, 9H), 3.36 (q, J = 5.6, 6.4 Hz, 2H), 3.88 (s, 3H), 5.67 (s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 7.25 (td, J = 1.6, 8.4 Hz, 1H), 7.56 (dd, J = 1.6, 7.6 Hz, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 22.3, 22.9 (2C), 23.6, 25.5, 25.8, 32.6, 32.9, 35.9, 36.3, 36.4, 44.3, 46.2, 53.5 (2C), 54.9, 55.7, 110.7, 121.0 , 127.0, 129.1, 129.3, 155.4, 173.8.

[Example 34] Preparation of 5-(2-(3-methoxyphenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (Compound 34 )

Ar purge was performed and compound M-12 (200 mg, 0.61 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and 10 minutes later, EDC (170 mg, 0.88 mmol) was subdivided and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.11 mL, 0.70 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 34 (200 mg, 72.4% yield).

TLC [DCM:MeOH=9:1 R _f =0.4]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.58 (m, 8H), 2.00 (m, 7H), 2.17 (m, 1H), 2.22 (t, J = 7.6 Hz, 2H), 3.00 (m, 9H) , 3.36 (q, J = 6.0 Hz, 2H), 3.81 (s, 3H), 5.12 (s, 1H), 6.83 (d, J = 8.0 Hz, 1H), 7.00 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 5.2 Hz, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 22.3, 22.9 (2C), 23.6, 25.4, 25.7, 32.5, 32.7, 35.8, 36.2, 36.3, 46.1, 52.4, 53.4 (2C), 54.9, 55.3, 113.0, 114.4 , 120.0, 129.7, 140.3, 159.8, 173.9.

[Example 35] Preparation of 5-(2-(4-methoxyphenyl)-1,3-dithian-4-yl)-N-(3-(piperidin-1-yl)propyl)pentanamide (Compound 35 )

Ar purge was performed and compound M-13 (200 mg, 0.61 mmol) was dissolved in DCM. DMAP (30 mg, 0.24 mmol) was added and 10 minutes later, EDC (170 mg, 0.88 mmol) was subdivided and after 20 minutes, 1-(3-aminopropyl)piperidine (compound a2-2, 0.11 mL, 0.70 mmol) ) Was added dropwise. After reacting overnight, the reaction was _{terminated with H 2} O, adjusted to pH=2 with 1N HCl, and extracted with DCM. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. The crude residue was separated by column chromatography (DCM:MeOH=19:1 → DCM:MeOH=9:1) to give a yellow oily compound 35 (143 mg, 51.7% yield).

TLC [DCM:MeOH=9:1 R _f =0.4]; ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.58 (m, 8H), 1.99 (m, 7H), 2.17 (m, 1H), 2.22 (t, J = 7.6 Hz, 2H), 2.98 (m, 9H) , 3.37 (q, J = 5.6, 6.4 Hz, 2H), 3.79 (s, 3H), 5.11 (s, 1H), 6.85 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 7.43 (t, J = 4.8 Hz, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 22.2, 22.8 (2C), 23.6, 25.4, 25.7, 32.5, 32.6, 35.8, 36.2 (2C), 46.1, 51.6, 53.4 (2C), 54.8, 55.3, 114.0 ( 2C), 128.9 (2C), 131.1, 159.5, 173.9.

[Experimental Example 1] Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition test ( In vitro assay)

For the lipoic acid-heterocycle thioacetal compound prepared in the above example, the AChE and BuChE inhibitory activities were described in [Ellman, G.L.; Courtney, K.D.; Andres, B.; Featherstone, R.M. Biochem. Pharmacol. 1961, 7, 88-95] was evaluated at 30 ℃ by the colorimetric measurement method reported.

Analytical solutions for AChE inhibitory activity include 0.1M phosphate buffer (pH 8), 0.3mM 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB, Elman's reagent), and 0.02 units of AChE (Sigma Chemical Co., Ltd., From bovine red blood cells), and 0.5 mM acetylthiocholine iodide as a substrate for the enzymatic reaction. The test compound was added to the assay solution and preincubated with the enzyme at 30° C. for 5 minutes. After this period, the substrate was added. The change in absorbance at 412 nm was recorded for 5 minutes using a microplate reader Digiscan 340T, the reaction rates were compared, and the percent inhibition due to the presence of the test compound was calculated. The reaction rate was calculated using at least three measurements, and the percent inhibition due to the presence of the test compound was calculated for the control without the compound. The concentration of the compound that produced 50% AChE inhibition (IC ₅₀ ) was determined. The results are shown in Table 1 below.

Assay solution for BuChE inhibitory activity is 0.01 units of butyrylcholinesterase from human serum, 0.1M sodium phosphate buffer (pH 8), 0.3mM 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB, Ellman's reagent), and 0.5mM butyrylthiocholine iodide as a substrate for the enzymatic reaction. Enzyme activity was measured by measuring the absorbance at 412 nm for 5 minutes using a microplate reader Digiscan 340T. Test compounds were pre-incubated with the enzyme at 30° C. for 10 minutes. The reaction rate was calculated using at least three measurements. IC ₅₀ is defined as the concentration of each compound that reduces the enzyme activity by 50% relative to the absence of an inhibitor. The results are shown in Tables 1 and 2 below.

Table 1 below shows the results analyzed in DMSO, and Table 2 shows the results analyzed in methanol.

Real compound AChE inhibition IC ₅₀ (μM) BuChE inhibition IC ₅₀ (μM) Compound 2 (Example 2) 7.17±0.22 0.53±0.29 Compound 3 (Example 3) 6.67±0.69 0.24±0.13 Compound 4 (Example 4) 3.88±0.23 0.46±0.28 Control galantamine 12.09±12.74 12.74±0.86

Real compound BuChE inhibition IC ₅₀ (μM) Real compound BuChE inhibition IC ₅₀ (μM) Compound 5 (Example 5) 0.89±0.48 Compound 22 (Example 22) 0.031±0.032 Compound 6 (Example 6) 0.16±0.05 Compound 23 (Example 23) 1.67±0.26 Compound 7 (Example 7) 0.63±0.30 Compound 24 (Example 24) 0.47±0.09 Compound 8 (Example 8) 0.13±0.08 Compound 25 (Example 25) 0.057±0.06 Compound 9 (Example 9) 0.02±0.04 Compound 26 (Example 26) 0.29±0.22 Compound 10 (Example 10) 0.02±0.05 Compound 27 (Example 27) 0.14±0.05 Compound 11 (Example 11) 1.00±0.27 Compound 28 (Example 28) 0.14±0.004 Compound 12 (Example 12) 0.19±0.06 Compound 29 (Example 29) 0.15±0.008 Compound 13 (Example 13) 1.08±0.44 Compound 30 (Example 30) 0.35±0.15 Compound 14 (Example 14) 0.20±0.12 Compound 31 (Example 31) 0.051±0.056 Compound 15 (Example 15) 0.02±0.06 Compound 32 (Example 32) 0.80±0.06 Compound 16 (Example 16) 0.28±0.15 Compound 33 (Example 33) 0.08±0.004 Compound 17 (Example 17) 0.05±0.05 Compound 34 (Example 34) 0.058±0.053 Compound 18 (Example 18) 0.66±0.23 Compound 35 (Example 35) 0.17±0.14 Compound 19 (Example 19) 0.14±0.10 Control galantamine 9.4±2.50 Compound 20 (Example 20) 0.22±0.14 Lipoic acid >1900 Compound 21 (Example 21) 0.054±0.14

As shown in Tables 1 and 2, the lipoic acid-heterocycle thioacetal compounds prepared in the above Example exhibited cholinesterase (ChEs) inhibitory activity.

In particular, the lipoic acid-heterocycle thioacetal compounds of the present invention more selectively inhibit butyrylcholinesterase (BuChE) among cholinesterases and at the same time significantly improved butyrylcholinesterase compared to the control galantamine. Showed inhibitory activity. As a result, it is possible to solve the problem of side effects that an acetylcholinesterase (AChE) inhibitor may have, and to target butyrylcholinesterase (BuChE), which is highly active in the brain of Alzheimer's disease patients.

Therefore, the lipoic acid-heterocycle thioacetal compound of the present invention has inhibitory activity against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and thus Parkinson's disease, Alzheimer's disease, etc. It can be very usefully used as an active ingredient of a pharmaceutical composition or a dietary supplement composition capable of preventing, improving or treating degenerative diseases such as cranial nerve diseases.

Those of ordinary skill in the art that the present invention is not limited by the above-described embodiments, and that various substitutions, modifications and changes are possible within the scope of the technical spirit of the present invention. Will be clear to you.

Claims (9)

Lipoic acid-heterocycle thioacetal compound represented by the following formula (1).
[Formula 1]

In Formula 1,
R ₁ is C6-C20 aryl, C3-C20 heteroaryl or

ego;
R ₂ is C6-C20 aryl or C3-C20 heteroaryl,
The _{aryl or heteroaryl of R 1} and R ₂ is the group consisting of C1-C7 alkyl, halogen, C1-C7 alkoxy, halo C1-C7 alkyl, C6-C20 aryloxy, -NR'R'', cyano and nitro May be further substituted with one or more selected from;
R'and R'' are each independently hydrogen, C1-C7 alkyl or C6-C20 aryl;
R is hydrogen or C1-C7 alkyl;
L ^a is C1-C10 alkylene;
m is an integer of 2 to 7. The method of claim 1,
The lipoic acid-heterocycle thioacetal compound is represented by the following formula (2), a lipoic acid-heterocycle thioacetal compound.
[Formula 2]

In Formula 2, R ₁ and L ^a are the same as defined in Formula 1 of claim 1. The method of claim 2,
Wherein R ₁ is C6-C12 aryl or

ego; R ₂ is C6-C12 aryl; The _{aryl of R 1} and R ₂ may be further substituted with one or more selected from the group consisting of C1-C4 alkyl, halogen, C1-C4 alkoxy, haloC1-C4 alkyl, -NR'R'' and nitro; R'and R'' are each independently hydrogen or C1-C4 alkyl; L ^a is a C1-C5 alkylene, a lipoic acid-heterocycle thioacetal compound. The method of claim 2,
R ₁ is

,

or

ego; R ^a and R ^b are each independently C1-C4 alkyl, halogen, C1-C4 alkoxy, haloC1-C4 alkyl, -NR'R'' or nitro; R'and R'' are each independently hydrogen or C1-C4 alkyl; x and y are each independently an integer of 0 to 5; L ^a is a C1-C3 alkylene, a lipoic acid-heterocycle thioacetal compound. The method of claim 1,
The lipoic acid-heterocycle thioacetal compound is a lipoic acid-heterocycle thioacetal compound selected from the following structures.

A pharmaceutical composition for the prevention or treatment of degenerative diseases comprising the lipoic acid-heterocycle thioacetal compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient. The method of claim 6,
The pharmaceutical composition of the degenerative disease is Parkinson's disease or Alzheimer's disease. A health aid for improving cognitive ability or improving degenerative diseases containing the lipoic acid-heterocycle thioacetal compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient food. A composition for the inhibitory activity of cholinesterase comprising the lipoic acid-heterocycle thioacetal compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient.