KR102458293B1 - Tetrahydroquinazoline derivatives and pharmaceutical composition for preventing or treating psoriasis comprising the same - Google Patents

Abstract

To a tetrahydroquinazoline derivative and a pharmaceutical composition for preventing or treating psoriasis containing the same as an active ingredient,
The compound provided in one aspect of the present invention has a proliferation inhibitory effect on a human keratinocyte-derived cell line and inhibits immune-related cytokines, so a pharmaceutical composition for the prevention or treatment of psoriasis and health It can be usefully used as a nutraceutical composition.

Description

Tetrahydroquinazoline derivatives and a pharmaceutical composition for preventing or treating psoriasis containing the same as an active ingredient

It relates to a tetrahydroquinazoline derivative and a pharmaceutical composition for preventing or treating psoriasis containing the same as an active ingredient.

Psoriasis is a chronic inflammatory disease characterized by hyperproliferation and abnormal differentiation of epithelial cells (Lowes, M.; M Bowcock, A.; G Krueger, J., Lowes MA, Bowcock AM, Krueger JGPathogenesis and therapy of psoriasis. Nature 445:866-873 (2007; Vol. 445, p 866-73). Although it is not judged to be a disease directly related to death, the risk of death due to complications of psoriasis is emerging in various studies.

Psoriasis treatment is limited to alleviating symptoms and managing complications, and a therapeutic approach that meets the needs of the patient is not well. Therefore, it is necessary to develop better therapeutic agents cost-effectively and to establish appropriate treatment guidelines for psoriasis patients.

Psoriasis affects 2-3% of the world's population. The most common symptom of psoriasis is reddish skin lesions of the skin. If proper treatment is not provided in the early stages, psoriasis can appear anywhere on the skin and nails, and various complications such as psoriatic arthritis, cardiovascular disease, and metabolic syndrome can be induced. 25-34% of psoriasis patients have psoriatic arthritis. Many studies are being conducted on the coexistence of cardiovascular disease and psoriasis. Psoriasis patients are also burdened with atherosclerosis and vascular problems, stiffness and impaired endothelial function. In addition, psoriasis is closely related to physical and emotional comorbidities such as suicide and depression, and is known to negatively affect the quality of life of patients.

Therefore, there is an urgent need to develop a drug that can completely treat the underlying cause of psoriasis.

An object of one aspect of the present invention is to provide a compound that can be used for treating psoriasis, or a pharmaceutically acceptable salt thereof, because it has a proliferation inhibitory effect of a human keratinocyte-derived cell line and suppresses immune-related cytokines.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating psoriasis containing the compound, or a pharmaceutically acceptable salt thereof, as an active ingredient.

Another object of the present invention is to provide a health functional food composition for preventing or improving psoriasis containing the compound, or a pharmaceutically acceptable salt thereof, as an active ingredient.

Another object of the present invention is to provide a method for treating psoriasis, comprising administering the compound, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

Another object of the present invention is to provide the compound, or a pharmaceutically acceptable salt thereof, for use in the treatment of psoriasis.

Another object of the present invention is to provide the use of the compound, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of psoriasis.

In order to achieve the above object,

One aspect of the present invention provides a compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof.

[Formula 1]

(In Formula 1,

R ¹ is hydrogen, or unsubstituted or substituted C _6-10 aryl,

The substituted C _6-10 aryl is selected from the group consisting of halogen, hydroxy, nitrile, nitro, C _1-10 straight or branched chain alkyl, and C _1-10 straight or branched chain alkoxy. C _6-10 aryl substituted with one or more substituents; and

이며,R ² is

is,

A ¹ is hydrogen, C _1-10 straight-chain or branched alkyl, C _1-10 straight-chain or branched alkoxy, unsubstituted or substituted C _6-10 aryl, unsubstituted or substituted C _6-10 Aryl C _1-10 straight or branched chain alkyl, unsubstituted or substituted C _5-10 cycloalkyl, or unsubstituted or substituted containing one or more heteroatoms selected from the group consisting of N, O and S 5 to 10 ring heteroaryl,

The substituted C _6-10 aryl, C _6-10 aryl C _1-10 straight or branched chain alkyl, C _5-10 cycloalkyl and 5 to 10 ring heteroaryl are independently halogen, hydroxy, At least one substituent selected from the group consisting of nitrile, nitro, unsubstituted or one or more halogen-substituted C _1-10 straight or branched chain alkyl, and C _1-10 straight or branched chain alkoxy is substituted C _6-10 aryl, C _6-10 aryl C _1-10 straight-chain or branched alkyl, C _5-10 cycloalkyl, and 5 to 10-membered heteroaryl).

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating psoriasis comprising the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof, as an active ingredient.

Another aspect of the present invention provides a health functional food composition for preventing or improving psoriasis containing the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof, as an active ingredient.

Another aspect of the present invention provides a method for treating psoriasis, comprising administering the compound, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

Another aspect of the present invention provides the compound, or a pharmaceutically acceptable salt thereof, for use in the treatment of psoriasis.

Another aspect of the present invention provides the use of the compound, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of psoriasis.

The compound provided in one aspect of the present invention has a proliferation inhibitory effect on a human keratinocyte-derived cell line and inhibits immune-related cytokines, so a pharmaceutical composition for the prevention or treatment of psoriasis and health It can be usefully used as a nutraceutical composition.

1 is a graph showing the results of cell migration analysis of the compound of Example.
2 is a graph showing the results of cell migration analysis of the compound of Example.
3 is a graph showing the results of cell migration analysis of the compound of Example.
4 is a diagram illustrating a psoriasis mechanism.
5 is a diagram showing the results of antiproliferative and migratory activity of test compounds (SD-592, 594, 604, 838, 851, 852, 854, 858, 911, 912, 1040, 1078) in HaCaT cells.
6 is a graph showing the antiproliferative and migratory activity results and confluence of the test compounds (SD-592, 594, 604, 838, 851, 852, 854, 858, 911, 912, 1040, 1078) in HaCaT cells.
7 is a diagram showing the structure of the SD1040 compound.

Hereinafter, the present invention will be described in detail.

On the other hand, the embodiment of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below. In addition, the embodiments of the present invention are provided in order to more completely explain the present invention to those of ordinary skill in the art. Furthermore, "including" a certain element throughout the specification means that other elements may be further included, rather than excluding other elements, unless otherwise stated.

The mechanism of psoriasis will be described.

A number of studies are being conducted in relation to the immune system of psoriasis. The onset of psoriasis is associated with T cells and dendritic cells. Various factors, environment, stress and drugs affect epithelial cells. Epithelial cells activate DCs through pattern recognition receptors (PRRs) or keratinocyte stress. Activated DCs can produce IL-23 to stimulate γδ T cells. Activated T cells secrete inflammatory factors such as IL-22, IL-17 and TNF-α that induce keratinocyte proliferation. Inducible IL-17, chemokines, are responsible for leukocyte recruitment. Persistent keratinocyte stress and the adaptive immune response widen the self-amplifying inflammatory loop. (Fig. 4)

A conventional method for treating psoriasis will be described.

There are three main types of psoriasis treatment methods: topical therapy, phototherapy, and systemic therapy.

Mild to moderate psoriasis can be treated with local or topical therapy, and moderate to severe psoriasis is managed with phototherapy or systemic therapy. Steroids are most commonly used to treat mild to moderate psoriasis. Vitamin D analogs and retinoids are also effective.

Phototherapy is recommended for patients with moderate to severe itching and for patients who have insufficient response to topical therapy.

Systemic therapy is most often prescribed for moderate to severe psoriasis. The first drugs include methotrexate, cyclosporine, and acitretin. However, long-term use as an immunosuppressive drug causes many side effects, such as hepatotoxicity and nephrotoxicity.

Biologics are usually used in combination with other drugs used for moderate to severe psoriasis. Recently, TNF-α, IL-23 and IL-17 have been accepted as major targets of psoriasis. Therefore, many modern biologics are being researched and developed.

However, newer biological therapies have the problem of being more expensive than systemic drug therapies and phototherapy.

In the present invention, phenotypic screening was first performed in order to develop a drug capable of completely treating the underlying cause of psoriasis. The specific experimental procedure is as follows:

cell culture

HaCaT cells, a human keratinocyte-derived cell line, were obtained from the Korean Cell Line Bank (Seoul, Korea). Cells were cultured in high-glucose Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS, Gibco, USA) and 1% penicillin/streptomycin (Lonza, USA) at 37°C under a 5% humidified CO ₂ atmosphere. , Hyclone, USA).

wound healing analysis

Thirteen compounds (SD-592, 594, 604, 838, 851, 852, 854, 858, 911, 912, 1040, 1078) preselected from the house library were screened by inhibition of proliferation and migration of HaCaT cells. HaCaT cells were seeded onto 96-well ImageLock plates (Essen Bioscience). Next, cells were cultured to form monolayers and scratch wounds were made using Wound Maker ^™ (Essen Bioscience, Arbor, MI). Cells were then washed with PBS and incubated in serum-free medium in the presence or absence of IL-22. Migrating cell images were measured every 2 hours using IncuCyte ^® ZOOM (Essen Biosience). The results are shown in FIGS. 5 and 6 .

As shown in FIG. 5 , SD1040 showed more wound area than other compounds. Looking at Fig. 6, which is a graph on wound consolidation, their strong effect can be confirmed statistically.

In conclusion, SD1040 was selected as a hit compound because it has an inhibitory effect on proliferation and migration by epithelial cells.

Taken together, one aspect of the present invention is

Provided is a compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof.

[Formula 1]

(In Formula 1,

R ¹ is hydrogen, or unsubstituted or substituted C _6-10 aryl,

The substituted C _6-10 aryl is selected from the group consisting of halogen, hydroxy, nitrile, nitro, C _1-10 straight or branched chain alkyl, and C _1-10 straight or branched chain alkoxy. C _6-10 aryl substituted with one or more substituents; and

이며,R ² is

is,

A ¹ is hydrogen, C _1-10 straight-chain or branched alkyl, C _1-10 straight-chain or branched alkoxy, unsubstituted or substituted C _6-10 aryl, unsubstituted or substituted C _6-10 Aryl C _1-10 straight or branched chain alkyl, unsubstituted or substituted C _5-10 cycloalkyl, or unsubstituted or substituted containing one or more heteroatoms selected from the group consisting of N, O and S 5 to 10 ring heteroaryl,

The substituted C _6-10 aryl, C _6-10 aryl C _1-10 straight or branched chain alkyl, C _5-10 cycloalkyl and 5 to 10 ring heteroaryl are independently halogen, hydroxy, At least one substituent selected from the group consisting of nitrile, nitro, unsubstituted or one or more halogen-substituted C _1-10 straight or branched chain alkyl, and C _1-10 straight or branched chain alkoxy is substituted C _6-10 aryl, C _6-10 aryl C _1-10 straight-chain or branched alkyl, C _5-10 cycloalkyl, and 5 to 10-membered heteroaryl).

Preferably,

R ¹ is hydrogen, or unsubstituted or substituted C _6-10 aryl,

The substituted C _6-10 aryl is selected from the group consisting of halogen, hydroxy, nitrile, nitro, C _1-5 straight or branched chain alkyl, and C _1-5 straight or branched chain alkoxy. C _6-10 aryl substituted with one or more substituents; and

이며,R ² is

is,

A ¹ is hydrogen, C _1-5 straight-chain or branched alkyl, C _1-5 straight-chain or branched alkoxy, unsubstituted or substituted C _6-10 aryl, unsubstituted or substituted C _6-10 Unsubstituted or substituted aryl C _1-5 straight or branched chain alkyl, unsubstituted or substituted C _5-10 cycloalkyl, or at least one heteroatom selected from the group consisting of N, O and S 5 to 10 ring heteroaryl,

The substituted C _6-10 aryl, C _6-10 aryl C _1-5 straight or branched chain alkyl, C _5-10 cycloalkyl and 5 to 10 cyclic heteroaryl are independently halogen, hydroxy, At least one substituent selected from the group consisting of nitrile, nitro, unsubstituted or one or more halogen-substituted C _1-5 straight or branched chain alkyl, and C _1-5 straight or branched chain alkoxy is substituted C _6-10 aryl, C _6-10 aryl C _1-5 straight-chain or branched alkyl, C _5-10 cycloalkyl, and 5 to 10-membered heteroaryl.

More preferably,

R ¹ is hydrogen, or unsubstituted or substituted phenyl,

The substituted phenyl is halogen, hydroxy, nitrile, nitro, C _1-3 straight or branched chain alkyl, and C _1-3 At least one substituent selected from the group consisting of straight or branched alkoxy is substituted phenyl; and

이며,R ² is

is,

wherein A ¹ is hydrogen, C _1-3 straight-chain or branched alkyl, C _1-3 straight-chain or branched alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted cyclopentyl, or an unsubstituted or substituted 5- to 6-membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S;

The substituted phenyl, benzyl, cyclopentyl and 5- to 6-membered heteroaryl are independently halogen, hydroxy, nitrile, nitro, unsubstituted or C _1-3 straight-chain or branched alkyl substituted with one or more halogens. , and C _1-3 It may be phenyl, benzyl, cyclopentyl, and 5- to 6-membered heteroaryl substituted with one or more substituents selected from the group consisting of straight-chain or branched alkoxy.

Even more preferably,

R ¹ is hydrogen, unsubstituted phenyl, or phenyl substituted with one —Cl; and

이며,R ² is

is,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

, 또는

일 수 있다.The A ¹ is methyl, ethyl, iso-propyl,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

, or

can be

Most preferably,

The compound represented by Formula 1 may be any one compound selected from the following compound group.

(1) 2-(4-(furan-2-carbonyl)piperazin-1-yl)-7-(2-hydroxyphenyl)-7,8-dihydroquinazolin-5(6H)-one;

(2) 2-(4-(2-chlorobenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;

(3) 2-(4-(2-methylbenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;

(4) 2-(4-(2-fluorobenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;

(5) 2-(4-(4-methoxybenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;

(6) 2-(4-(3-chlorobenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;

(7) 2-(4-(4-fluorobenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;

(8) 2-(4-(4-chlorobenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;

(9) 7-phenyl-2-(4-(4-(trifluoromethyl)benzoyl)piperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one;

(10) 2-(4-(4-methylbenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;

(11) 2-(4-(2-fluorobenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;

(12) 2-(4-benzoylpiperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;

(13) 2-(4-(cyclopentanecarbonyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;

(14) 2-(4-acetylpiperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;

(15) 7-phenyl-2-(4-propionylpiperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one;

(16) 2-(4-isobutyrylpiperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;

(17) 2-(4-(furan-2-carbonyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;

(18) 2-(4-nicotinoylpiperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;

(19) 2-(4-(1H-pyrrole-2-carbonyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;

(20) 7-phenyl-2-(4-(thiophen-2-carbonyl)piperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one;

(21) 7-phenyl-2-(4-picolinoylpiperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one;

(22) 2-(4-(2-(4-fluorophenyl)acetyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;

(23) 2-(4-(2-(4-bromophenyl)acetyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;

(24) 7-phenyl-2-(4-(2-phenylacetyl)piperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one;

(25) 2-(4-(2-(3-fluorophenyl)acetyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;

(26) 7-(4-chlorophenyl)-2-(4-(furan-2-carbonyl)piperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one;

(27) 2-(4-acetylpiperazin-1-yl)-7-(4-chlorophenyl)-7,8-dihydroquinazolin-5(6H)-one;

(28) 7-(4-chlorophenyl)-2-(4-nicotinoylpiperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one;

(29) 2-(4-(1H-pyrrole-2-carbonyl)piperazin-1-yl)-7-(4-chlorophenyl)-7,8-dihydroquinazolin-5(6H)-one ; and

(30) 2-(4-(furan-2-carbonyl)piperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one.

The compound represented by Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc., organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. get it from Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube Late, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate formed by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic or inorganic acid It can be prepared by filtration and drying, or by distilling the solvent and excess acid under reduced pressure, followed by drying and crystallization in an organic solvent.

In addition, bases can be used to prepare pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. The corresponding salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg silver nitrate).

Furthermore, the present invention includes not only the compound represented by Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, optical isomers, hydrates, and the like, which may be prepared therefrom.

Another aspect of the present invention is

Provided is a pharmaceutical composition for preventing or treating psoriasis comprising the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof, as an active ingredient.

The compound may inhibit the proliferation of a human keratinocyte-derived cell line.

The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral formulations during clinical administration. In the case of formulation, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants that are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in one or more compounds, for example, starch, calcium carbonate, sucrose or lactose ( lactose), gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral administration include suspensions, internal solutions, emulsions, syrups, etc. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, and emulsions. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

A pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be administered parenterally, and parenteral administration is administered by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. depending on how

At this time, in order to formulate a formulation for parenteral administration, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or buffer to prepare a solution or suspension, which is an ampoule or vial unit dosage form. can be manufactured with The composition may be sterilized and/or contain adjuvants such as preservatives, stabilizers, wetting agents or emulsification accelerators, salts and/or buffers for regulating osmotic pressure, and other therapeutically useful substances, and mixing, granulation, in a conventional manner. It can be formulated according to the method of formulation or coating.

Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (eg silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine and the like, and optionally boron such as starch, agar, alginic acid or its sodium salt, etc. It may contain releasing or boiling mixtures and/or absorbents, colorants, flavoring agents, and sweetening agents.

Another aspect of the present invention is

It provides a health functional food composition for the prevention or improvement of psoriasis containing the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof, as an active ingredient.

The compound represented by Formula 1 according to the present invention may be added to food as it is or used together with other food or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient may be suitably determined according to the purpose of its use (for prevention or improvement). In general, the amount of the compound in the health food may be added in an amount of 0.1 to 90 parts by weight based on the total weight of the food. However, in the case of long-term ingestion for health and hygiene purposes or for health control, the above amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.

In addition, the health functional beverage composition of the present invention is not particularly limited in other ingredients except for containing the compound as an essential ingredient in the indicated ratio, and may contain various flavoring agents or natural carbohydrates as additional ingredients like a conventional beverage. have. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention.

Furthermore, in addition to the above, the compound represented by Formula 1 according to the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pects acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. In addition, the compound represented by Formula 1 of the present invention may contain natural fruit juice, fruit juice, and pulp for the production of fruit juice beverages and vegetable beverages.

Another aspect of the present invention provides a method for treating psoriasis, comprising administering the compound, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

Another aspect of the present invention provides the compound, or a pharmaceutically acceptable salt thereof, for use in the treatment of psoriasis.

Another aspect of the present invention provides the use of the compound, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of psoriasis.

The compound provided in one aspect of the present invention has a proliferation inhibitory effect of a human keratinocyte-derived cell line and inhibits immune-related cytokines, so a pharmaceutical composition for the prevention or treatment of psoriasis and health It can be usefully used as a nutraceutical composition, which is supported by the Examples and Experimental Examples to be described later.

Hereinafter, the present invention will be described in detail through Preparation Examples, Examples and Experimental Examples to be described later. However, Preparation Examples, Examples, and Experimental Examples to be described below are only partially exemplified by the present invention, and the present invention is not limited thereto.

Abbreviation:

Bu: Butyl

Boc: di-tert-butyl dicarbonate

Bn: benzyl

d: doublet

DC: dendritic cells

DCM: dichloromethane

dd: doublet of doublet

DMF: N,N-dimethylformamide

DMF-DMA: dimethylformamide dimethyl acetal

DIPEA: N,N-diisopropylethylamine

dt: doublet of triplet

Et: ethyl

HBA: hydrogen bond acceptor

HBD: hydrogen bond donor

I: interleukin

m: multiplet

Me: methyl

MPLC: medium pressure liquid chromatography

MS: mass spectrometry

NMR: nuclear magnetic resonance

Ph: phenyl

ppm: parts per million

s: singlet

t: triplet

TEA: triethylamine

TFA: trifluoroacetic acid

THF: tetrahydrofuran

TMS: tetramethylsilane

tt: triplet of triplet

SAR: Structure-Activity Relationship

Reagents were purchased from TCI or Alfa Aesar or other chemical companies, and the reaction solvent used for synthesis was dried through an appropriate desiccant, or purchased anhydrous or reagent grade. The reaction was carried out under N ₂ atmosphere or specified conditions. Purification of the product was performed using ZEOprep's flash column chromatography with silica gel (40-63 μm) or medium-performance liquid chromatography (Isolera ^™ by Biotage). Proton and carbon magnetic resonance spectra ( ¹ H NMR and ¹³ C NMR) were recorded on a Bruker 600 ( ¹ H NMR at 600 MHz and ¹³ C NMR at 150 MHz) spectrometer using solvent resonance as an internal standard ( ¹ H NMR: CDCl ₃ at 7.26 ppm, DMSO- d ₆ at 2.5 ppm; ¹³ C NMR: CDCl ₃ at 77.0 ppm, DMSO- d ₆ at 39.5 ppm). Mass spectra were obtained using an electrospray ionization calibrated Waters 3100 Mass Detector spectrometer with Waters Technologies, Accurate - Mass QTOF LCMS, 1200 series LC with dual spray ESI source. Optical rotation was measured with an optically active AA-10R automatic polarimeter in DCM. Melting points were measured with an Opti Melt-automated melting point system, Stanford Research Systems.

< production example 1> piperazinyl guanidine ( piperazinyl guanidine) manufacture, 10

The reaction was performed under the conditions of Entry 1 to 8 in the table below, and the results are also shown in the table below.

As shown in the above table, it was found that only in the case of Entry 8, piperazinyl guanidine was produced in high yield.

More specifically, in the case of Entry 2 and 3, piperazinyl guanidine was not produced even when the reaction was carried out at a high temperature, which is expected to be the reason why the boc protecting group is cleaved in the presence of water. In the case of Entry 6 and 7 using 2N NaOH as a base, piperazinyl guanidine was not prepared. In the case of Entry 4 and 5 using MeCN and MeOH as solvents, piperazinyl guanidine was not prepared. In case of Entry 8, in which DIPEA as a base and i-PrOH as a solvent and the reaction was performed under reflux conditions, piperazinyl guanidine was produced in the most ideal yield.

< production example 2> 7-phenyl-2-(piperazin-1-yl)-7,8- dihydroquinazoline -5(6H)-on preparation, 14

Step 1: Compound 11 → compound 12 synthesis

5-phenylcyclohexane-1,3-dione, 0.011 mol of compound 11 was dissolved in chloroform (53 ml), DMF-DMA (1.66 ml, 0.012 mmol) was added dropwise, and the reaction mixture was stirred at rt for 30 min. stirred. After stirring, the solution was extracted with DCM. After drying over MgSO4, the solvent was removed in vacuo. The residue is 12 compounds.

Step 2: Compound 12 → compound 13 synthesis

3.82 mmol of compound 12 and crude 10 compound were dissolved in MeOH (25 ml). NaOMe was added to the solution. The reaction mixture was refluxed for one day. After cooling to Rt, water was treated. The resulting mixture was extracted with DCM. After drying over MgSO ₄ , the solvent was removed in vacuo. The residue was purified via column chromatography to obtain tert-butyl 4-(5-oxo-7-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)piperazine-1-carboxylate, 13 The compound was prepared. (22%)

¹ H NMR (600 MHz, Chloroform- d ) δ 8.90 (s, 1H), 7.39 - 7.35 (m, 2H), 7.29 - 7.26 (m, 4H), 3.95 (d, J = 5.1 Hz, 4H), 3.51 (t, J = 5.2 Hz, 4H), 3.44 (s, 1H), 3.10 - 3.03 (m, 2H), 2.88 (ddd, J = 16.7, 4.0, 1.5 Hz, 1H), 2.78 (dd, J = 16.8) , 12.5 Hz, 1H), 1.49 (s, 9H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.8, 172.2, 161.7, 158.7, 154.7, 142.7, 128.9, 127.1, 126.7, 116.1, 80.3, 45.4, 43.8, 40.0, 39.2, 28.4.

Step 3: Compound 13 → compound 14 synthesis

13 Compound 1.2 mmol was dissolved in DCM (7 ml). TFA (2 ml, 26 mmol) was added to the solution at 0 °C. The reaction mixture was stirred at rt for one day. The solution was distilled and the resulting residue was placed under vacuum for several hours. The residue was purified via column chromatography. The residue is 7-phenyl-2-(piperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one, compound 14 .

¹ H NMR (600 MHz, Chloroform- d ) δ 8.92 (d, J = 13.0 Hz, 1H), 7.39 - 7.35 (m, 2H), 7.31 - 7.27 (m, 3H), 4.12 (d, J = 7.1 Hz) , 4H), 4.07 (td, J = 5.4, 2.4 Hz, 2H), 3.78 (dd, J = 6.5, 4.1 Hz, 1H), 3.70 (t, J = 5.3 Hz, 1H), 3.45 (d, J = 11.6 Hz, 1H), 3.10 (d, J = 10.7 Hz, 2H), 2.92 - 2.85 (m, 1H), 2.80 (dd, J = 16.6, 12.5 Hz, 1H).

< production example 3> 7-(4- chlorophenyl )-2-(piperazin-1-yl)-7,8- dihydroquinazoline -5(6H)-on preparation, 20

Step 1: Compound 15 → compound 16 synthesis

0.05 mol of 15 compound was dissolved in acetone (26 ml, 0.35 mol) and H ₂ O (4 ml). 10% NaOH (2 ml) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for one day. After stirring, the solution was extracted with DCM. After drying over MgSO ₄ , the solvent was removed in vacuo. The residue was purified by column chromatography to prepare (E)-4-(4-chlorophenyl)but-3-en-2-one, compound 16 . (57%)

¹ H NMR (600 MHz, Chloroform- d ) δ 7.49 - 7.47 (m, 2H), 7.45 (s, 1H), 7.38 (d, J = 8.6 Hz, 2H), 6.69 (d, J = 16.3 Hz, 1H) ), 2.38 (s, 3H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 198.1, 141.9, 136.4, 132.9, 129.4, 129.3, 127.5, 53.5, 27.7.

Step 2: Compound 16 → compound 17 synthesis

To a stirred solution of sodium methoxide (2.5 g, 0.046 mol) diluted with methanol (35 ml), dimethyl malonate (3.76 ml, 32.9 mmol) was added dropwise. The reaction mixture was heated to 60° C. and 0.023 mol of 16 compound dissolved in methanol (10 ml) was added dropwise. The reaction mixture was stirred under reflux conditions. After 1 hour, the reaction mixture was treated with 5N NaOH and heated to 100 °C. After one day, 5N HCl and the reaction mixture were refluxed for 2 h, and then allowed to cool to room temperature. The product was extracted with DCM. After drying over MgSO ₄ , the solvent was removed in vacuo. The residue was purified through column chromatography to prepare 5-(4-chlorophenyl)cyclohexane-1,3-dione, compound 17 . (90%)

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 7.37 (s, 4H), 5.28 (s, 1H), 3.32 (s, 1H), 2.57 (dd, J = 16.5, 11.8 Hz, 2H), 2.38 ( dd, J = 17.0, 4.5 Hz, 2H). ¹³ C NMR (151 MHz, DMSO) δ 143.0, 131.6, 129.4, 128.8, 104.0, 55.4, 38.5.

Step 3: Compound 17 → compound 18 synthesis

0.011 mol of 17 compound was dissolved in chloroform (53 ml), DMF-DMA (1.66 ml, 0.012 mmol) was added dropwise, and the reaction mixture was stirred at rt for 30 min. After stirring, the solution was extracted with DCM. After drying over MgSO ₄ , the solvent was removed in vacuo. The residue is 18 compound. (89%)

Step 4: Compound 18 → compound 19 synthesis

3.82 mmol of compound 18 and crude 10 compound were dissolved in MeOH (25 ml). NaOMe was added to the solution. The reaction mixture was refluxed for one day. After cooling to Rt, water was treated. The resulting mixture was extracted with DCM. After drying over MgSO ₄ , the solvent was removed in vacuo. The residue was purified by column chromatography to tert-butyl 4-(7-(4-chlorophenyl)-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)piperazine-1 -Carboxylate, 19 compounds were prepared. (17%)

¹ H NMR (600 MHz, Chloroform- d ) δ 8.88 (s, 1H), 7.32 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 3.94 (t, J = 5.1) Hz, 4H), 3.50 (t, J = 5.2 Hz, 4H), 3.46 - 3.38 (m, 1H), 3.06 - 2.99 (m, 2H), 2.84 (ddd, J = 16.7, 3.9, 1.7 Hz, 1H) , 2.73 (dd, J = 16.7, 12.4 Hz, 1H), 1.49 (s, 9H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.3, 171.8, 161.7, 158.7, 154.7, 146.7, 141.1, 132.8, 129.0, 128.1, 116.0, 85.2, 80.3, 45.2, 43.8, 39.8, 38.6, 28.4, 27.4.

Step 5: Compound 19 → compound 20 synthesis

1.2 mmol of compound 19 was dissolved in DCM (7 ml). TFA (2 ml, 26 mmol) was added to the solution at 0 °C. The reaction mixture was stirred at rt for one day. The solution was distilled and the resulting residue was placed under vacuum for several hours. The residue was purified via column chromatography. The residue is 7-(4-chlorophenyl)-2-(piperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one, 20 compound. (48%)

¹ H NMR (600 MHz, Chloroform- d ) δ 8.90 (s, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 4.25 (t, J = 4.6) Hz, 5H), 3.43 (s, 1H), 3.26 (s, 4H), 3.10 - 3.02 (m, 2H), 2.88 - 2.72 (m, 2H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.5, 172.2, 161.3, 158.9, 140.8, 133.0, 129.1, 128.0, 117.0, 45.1, 43.5, 40.6, 39.7, 38.5.

< production example 4> 2-(piperazin-1-yl)-7,8- dihydroquinazoline -5(6H)-on preparation, 24

Step 1: Compound 21 → compound 22 synthesis

0.011 mol of compound 21 was dissolved in chloroform (53 ml), DMF-DMA (1.66 ml, 0.012 mmol) was added dropwise, and the reaction mixture was stirred at rt for 30 min. After stirring, the solution was extracted with DCM. After drying over MgSO ₄ , the solvent was removed in vacuo. The residue is 22 compounds.

Step 2: Compound 22 → compound 23 synthesis

3.82 mmol of compound 22 and crude 10 compound were dissolved in MeOH (25 ml). NaOMe was added to the solution. The reaction mixture was refluxed for one day. After cooling to Rt, water was treated. The resulting mixture was extracted with DCM. After drying over MgSO ₄ , the solvent was removed in vacuo. The residue was purified by column chromatography to prepare tert-butyl 4-(5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)piperazine-1-carboxylate, compound 23 . (27%)

¹ H NMR (600 MHz, Chloroform- d ) δ 8.86 (d, J = 1.9 Hz, 1H), 3.94 (s, 4H), 3.51 (t, J = 5.3 Hz, 4H), 2.83 (d, J = 1.1) Hz, 2H), 2.57 (d, J = 7.2 Hz, 2H), 2.11 - 2.08 (m, 2H), 1.49 (s, 9H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 195.9, 195.7, 173.2, 172.9, 161.4, 158.7, 158.5, 154.7, 116.7, 43.7, 38.3, 38.3, 32.4, 32.4, 28.4, 21.4, 21.4.

Step 3: Compound 23 → compound 24 synthesis

23 Compound 1.2 mmol was dissolved in DCM (7 ml). TFA (2 ml, 26 mmol) was added to the solution at 0 °C. The reaction mixture was stirred at rt for one day. The solution was distilled and the resulting residue was placed under vacuum for several hours. The residue was purified via column chromatography. The residue is 2-(piperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one, 24 compound. (61%)

¹ H NMR (600 MHz, Chloroform- d ) δ 8.89 (s, 1H), 4.28 (t, J = 5.3 Hz, 4H), 3.25 (t, J = 5.3 Hz, 4H), 2.87 (s, 2H), 2.63 - 2.59 (m, 2H), 2.13 (s, 2H). ¹³ C NMR (151 MHz, DMSO) δ 195.5, 173.9, 161.1, 158.3, 117.2, 42.9, 40.8, 38.2, 32.2, 21.3.

< production example 5> 7-(4- methoxyphenyl )-2-(piperazin-1-yl)-7,8- dihydroquinazoline -5(6H)-on preparation, 30

Step 1: Compound 25 → compound 26 synthesis

0.05 mol of 25 compound was dissolved in acetone (26 ml, 0.35 mol) and H ₂ O (4 ml). 10% NaOH (2 ml) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for one day. After stirring, the solution was extracted with DCM. After drying over MgSO ₄ , the solvent was removed in vacuo. The residue was purified by column chromatography to prepare (E)-4-(4-methoxyphenyl)but-3-en-2-one, compound 26 . (78%)

¹ H NMR (600 MHz, Chloroform- d ) δ 7.89 (d, J = 16.5 Hz, 1H), 7.55 (dd, J = 7.7, 1.7 Hz, 1H), 7.40 - 7.35 (m, 1H), 6.98 (d) , J = 1.1 Hz, 1H), 6.93 (dd, J = 8.3, 1.1 Hz, 1H), 6.76 (d, J = 16.5 Hz, 1H), 3.90 (s, 3H), 2.39 (s, 3H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 199.2, 158.3, 138.7, 131.8, 128.4, 127.8, 123.4, 120.8, 111.1, 55.5, 27.2.

Step 2: Compound 26 → compound 27 synthesis

To a stirred solution of sodium methoxide (2.5 g, 0.046 mol) diluted with methanol (35 ml), dimethyl malonate (3.76 ml, 32.9 mmol) was added dropwise. The reaction mixture was heated to 60° C. and 0.023 mol of 26 compound dissolved in methanol (10 ml) was added dropwise. The reaction mixture was stirred under reflux conditions. After 1 hour, the reaction mixture was treated with 5N NaOH and heated to 100 °C. After one day, 5N HCl and the reaction mixture were refluxed for 2 h, and then allowed to cool to room temperature. The product was extracted with DCM. After drying over MgSO ₄ , the solvent was removed in vacuo. The residue was purified through column chromatography to prepare 5-(4-methoxyphenyl)cyclohexane-1,3-dione, compound 27 . (60%)

¹ H NMR (600 MHz, Chloroform- d ) δ 7.28 - 7.23 (m, 1H), 7.14 (ddd, J = 31.8, 7.6, 1.6 Hz, 1H), 6.94 (dtd, J = 10.8, 7.5, 1.1 Hz, 1H), 6.88 (ddd, J = 8.3, 4.6, 1.1 Hz, 1H), 3.80 (d, J = 10.9 Hz, 3H), 3.68 (d, J = 53.7 Hz, 1H), 3.48 (s, 1H), 2.91 - 2.83 (m, 2H), 2.70 (d, J = 11.8 Hz, 1H), 2.63 (d, J = 4.6 Hz, 1H).

Step 3: Compound 27 → compound 28 synthesis

27 Compound 0.011 mol was dissolved in chloroform (53 ml), DMF-DMA (1.66 ml, 0.012 mmol) was added dropwise, and the reaction mixture was stirred at rt for 30 min. After stirring, the solution was extracted with DCM. After drying over MgSO ₄ , the solvent was removed in vacuo. The residue is 28 compounds. (99%)

Step 4: Compound 28 → compound 29 synthesis

3.82 mmol of compound 28 and crude 10 compound were dissolved in MeOH (25 ml). NaOMe was added to the solution. The reaction mixture was refluxed for one day. After cooling to Rt, water was treated. The resulting mixture was extracted with DCM. After drying over MgSO ₄ , the solvent was removed in vacuo. The residue was purified by column chromatography to tert-butyl 4-(7-(4-methoxyphenyl)-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)piperazine- Prepared 1-carboxylate, 29 compound. (30%)

¹ H NMR (600 MHz, Chloroform- d ) δ 8.89 (s, 1H), 7.27 - 7.23 (m, 1H), 7.17 (dd, J = 7.6, 1.7 Hz, 1H), 6.95 (td, J = 7.5, 1.1 Hz, 1H), 6.90 (dd, J = 8.3, 1.1 Hz, 1H), 3.94 (dd, J = 6.3, 4.0 Hz, 4H), 3.83 (s, 4H), 3.81 - 3.74 (m, 1H), 3.50 (t, J = 5.4 Hz, 4H), 3.14 - 3.02 (m, 2H), 2.82 (d, J = 10.2 Hz, 2H), 1.49 (s, 9H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 195.7, 173.0, 161.6, 158.6, 158.4, 157.0, 154.7, 130.7, 128.0, 127.9, 126.8, 120.7, 120.7, 116.2, 110.6, 110.6, 80.2, 55.3, 55.2, 43.9 , 43.7, 38.2, 33.5, 28.4.

Step 5: Compound 29 → compound 30 synthesis

1.2 mmol of 29 compound was dissolved in DCM (7 ml). TFA (2 ml, 26 mmol) was added to the solution at 0 °C. The reaction mixture was stirred at rt for one day. The solution was distilled and the resulting residue was placed under vacuum for several hours. The residue was purified via column chromatography. The residue is 7-(4-methoxyphenyl)-2-(piperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one, 30 compound. (70%)

¹ H NMR (600 MHz, Chloroform- d ) δ 9.96 (s, 1H), 8.92 (s, 1H), 7.27 (td, J = 7.7, 1.7 Hz, 1H), 7.17 (dd, J = 7.6, 1.6 Hz) , 1H), 6.96 (td, J = 7.5, 1.1 Hz, 1H), 6.91 (dd, J = 8.3, 1.1 Hz, 1H), 4.28 (t, J = 5.1 Hz, 4H), 3.84 (s, 3H) , 3.82 - 3.77 (m, 1H), 3.30 - 3.21 (m, 4H), 3.17 - 3.06 (m, 2H), 2.89 - 2.83 (m, 2H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 195.7, 173.3, 161.2, 158.8, 157.0, 130.4, 128.2, 126.8, 120.8, 117.2, 110.7, 55.3, 43.8, 43.3, 40.6, 38.1, 33.5.

< Example 1> 2-(4-( furan -2- carbonyl )piperazin-1-yl)-7-(2- hydroxyphenyl )-7,8-dihydroquinazolin-5(6H)-one preparation (SD 1040, 9)

Step 1: Compound One → compound 2 synthesis

Compound 1 (5.12 ml, 0.052 mol) and benzyl bromide (9.7 ml, 0.08 mol) were dissolved in MeOH (40 ml). K ₂ CO ₃ (14.3 g, 0.1 mol) was added to the solution. The reaction mixture was refluxed for one day. After cooling to room temperature, the solution was treated with water. The resulting mixture was extracted with DCM. After drying over MgSO ₄ , the solvent was removed under vacuum. The residue was purified by column chromatography to prepare 2-(benzyloxy)benzaldehyde, compound 2 . (10.79 g, 98%)

¹ H NMR (600 MHz, Chloroform- d ) δ 9.88 (s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 14.0 Hz, 4H), 7.36 (d, J = 7.1) Hz, 1H), 7.08 (d, J = 8.7 Hz, 2H), 5.15 (s, 2H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 190.8, 163.7, 135.9, 132.0, 130.1, 128.8, 128.4, 127.5, 115.2, 70.3.

Step 2: Compound 2 → compound 3 synthesis

Compound 2 (10.6 g, 0.05 mol) was dissolved in acetone (26 ml, 0.35 mol) and H ₂ O (4 ml). 10% NaOH (2 ml) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for one day. After stirring, the solution was extracted with DCM. After drying over MgSO ₄ , the solvent was removed in vacuo. The residue was purified by column chromatography to prepare (E)-4-(2-(benzyloxy)phenyl)but-3-en-2-one, compound 3 . (6.8 g, 54%)

¹ H NMR (600 MHz, Chloroform- d ) δ 7.95 (d, J = 16.5 Hz, 1H), 7.57 (dd, J = 7.7, 1.7 Hz, 1H), 7.45 - 7.38 (m, 4H), 7.36 - 7.32 (m, 2H), 7.00 - 6.96 (m, 2H), 6.77 (d, J = 16.5 Hz, 1H), 5.17 (s, 2H), 2.35 (s, 3H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 199.0, 157.4, 138.7, 136.6, 131.7, 128.7, 128.4, 128.1, 127.9, 127.2, 123.9, 121.2, 112.9, 70.5, 27.2.

Step 3: Compound 3 → compound 4 synthesis

To a stirred solution of sodium methoxide (2.5 g, 0.046 mol) diluted with methanol (35 ml), dimethyl malonate (3.76 ml, 32.9 mmol) was added dropwise. The reaction mixture was heated to 60° C. and compound 3 (5.72 g, 0.023 mol) dissolved in methanol (10 ml) was added dropwise. The reaction mixture was stirred under reflux conditions. After 1 hour, the reaction mixture was treated with 5N NaOH and heated to 100 °C. After one day, 5N HCl and the reaction mixture were refluxed for 2 h, and then allowed to cool to room temperature. The product was extracted with DCM. After drying over MgSO ₄ , the solvent was removed in vacuo. The residue was purified through column chromatography to prepare 5-(2-(benzyloxy)phenyl)cyclohexane-1,3-dione, compound 4 . (1.47 g, 22%)

¹ H NMR (600 MHz, Chloroform- d ) δ 7.45 - 7.42 (m, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.32 (d, J = 7.3 Hz, 1H), 7.19 - 7.15 (m) , 2H), 6.92 - 6.87 (m, 2H), 5.09 (s, 2H), 3.99 (t, J = 7.2 Hz, 1H), 2.85 (dd, J = 20.6, 7.1 Hz, 2H), 2.75 (dd, J = 9.9, 7.2 Hz, 2H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 207.7, 178.1, 156.2, 137.0, 130.7, 128.6, 128.0, 128.0, 127.3, 121.0, 112.2, 70.2, 47.7, 38.3, 32.5, 30.1.

Step 4: Compound 4 → compound 5 synthesis

Compound 4 (2 g, 0.011 mol) was dissolved in chloroform (53 ml), DMF-DMA (1.66 ml, 0.012 mmol) was added dropwise, and the reaction mixture was stirred at rt for 30 min. After stirring, the solution was extracted with DCM. After drying over MgSO ₄ , the solvent was removed in vacuo. The residue is 5 compounds. (2.3 g, 89%)

Step 5: Compound 5 → compound 6 synthesis

Compound 5 (1.33 g, 3.82 mmol) and crude 10 compound were dissolved in MeOH (25 ml). NaOMe was added to the solution. The reaction mixture was refluxed for one day. After cooling to Rt, water was treated. The resulting mixture was extracted with DCM. After drying over MgSO ₄ , the solvent was removed in vacuo. The residue was purified by column chromatography and tert-butyl 4-(7-(2-(benzyloxy)phenyl)-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)pipe Razine-1-carboxylate, 6 compounds were prepared. (616 mg, 31%)

¹ H NMR (600 MHz, Chloroform- d ) δ 8.89 (d, J = 2.1 Hz, 1H), 7.42 - 7.34 (m, 5H), 7.31 (dd, J = 6.5, 3.6 Hz, 1H), 7.23 - 7.20 (m, 1H), 6.96 (d, J = 7.9 Hz, 2H), 5.11 (s, 2H), 3.94 (t, J = 5.1 Hz, 4H), 3.86 (dd, J = 7.6, 3.5 Hz, 1H) , 3.54 - 3.46 (m, 4H), 3.17 - 3.06 (m, 2H), 2.88 - 2.81 (m, 2H), 1.49 (s, 9H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 195.6, 172.9, 161.6, 158.6, 158.4, 156.2, 154.7, 136.9, 131.1, 128.7, 128.0, 128.0, 127.9, 127.2, 127.1, 127.0, 121.1, 121.0, 116.2, 112.1 , 112.0, 80.2, 70.1, 70.1, 60.4, 44.0, 43.9, 43.8, 38.3, 38.3, 33.5, 33.5, 28.4, 21.1, 14.2.

Step 6: Compound 6 → compound 7 synthesis

Compound 6 (614 mg, 1.2 mmol) was dissolved in DCM (7 ml). TFA (2 ml, 26 mmol) was added to the solution at 0 °C. The reaction mixture was stirred at rt for one day. The solution was distilled and the resulting residue was placed under vacuum for several hours. The residue was purified via column chromatography. The residue is 7-(2-(benzyloxy)phenyl)-2-(piperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one, 7 compound. (153 mg, 30%)

¹ H NMR (400 MHz, Chloroform- d ) δ 8.91 (s, 1H), 7.37 (d, J = 6.9 Hz, 4H), 7.32 (d, J = 6.5 Hz, 1H), 7.26 - 7.21 (m, 1H) ), 7.21 - 7.16 (m, 1H), 7.00 - 6.94 (m, 2H), 5.12 (s, 2H), 4.27 (s, 4H), 3.92 - 3.82 (m, 1H), 3.26 (s, 4H), 3.17 - 3.06 (m, 2H), 2.89 (d, J = 8.1 Hz, 2H).

Step 7: Compound 7 → compound 8 synthesis

Amine 7 compound (91 mg, 0.22 mmol), acid (30 mg, 0.263 mmol) and TEA (0.1 ml) were dissolved in DCM (1.1 ml). EDCI (70 mg, 0.45 mmol) and HOBt (60 mg, 0.45 mmol) were added to the solution at rt. The reaction mixture was stirred at rt for 12 h. The resulting mixture was extracted with DCM. After drying over MgSO ₄ , the solvent was removed under vacuum. The residue was purified by column chromatography to 7-(2-(benzyloxy)phenyl)-2-(4-(furan-2-carbonyl)piperazin-1-yl)-7,8-dihydroquina Zolin-5(6H)-one, 8 , was prepared. (73 mg, 65%)

¹ H NMR (600 MHz, Chloroform- d ) δ 8.91 (s, 1H), 7.52 (dd, J = 1.8, 0.8 Hz, 1H), 7.41 - 7.35 (m, 4H), 7.32 (d, J = 7.1 Hz) , 1H), 7.24 - 7.19 (m, 2H), 7.07 (dd, J = 3.5, 0.8 Hz, 1H), 6.97 (d, J = 7.9 Hz, 2H), 6.53 - 6.51 (m, 1H), 5.12 ( s, 2H), 4.06 (t, J = 5.3 Hz, 4H), 3.89 (dd, J = 7.8, 4.4 Hz, 4H), 3.87 - 3.85 (m, 1H), 3.17 - 3.08 (m, 2H), 2.87 (d, J = 8.3 Hz, 2H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 195.6, 161.6, 159.3, 158.6, 156.2, 143.9, 136.9, 131.0, 128.7, 128.1, 128.0, 127.2, 127.0, 121.1, 120.0, 117.0, 116.4, 112.1, 111.5, 70.1 , 60.4, 43.9, 38.3, 33.5.

Step 8: Compound 8 → compound 9 (SD 1040) synthesis

Compound 8 (73 mg, 0.14 mmol) was dissolved in MeOH (0.7 ml) and treated with 5% pd/C. The reaction mixture was stirred under H ₂ (1 atm, balloon) for 6 h. The catalyst was removed by filter through celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to 2-(4-(furan-2-carbonyl)piperazin-1-yl)-7-(2-hydroxyphenyl)-7,8-dihydroquinazoline- 5(6H)-one, 9 compounds were prepared. (30 mg, 50%)

¹ H NMR (600 MHz, Chloroform- d ) δ 8.93 (s, 1H), 7.52 (dd, J = 1.8, 0.9 Hz, 1H), 7.18 - 7.11 (m, 2H), 7.09 (d, J = 0.9 Hz) , 1H), 6.92 (dd, J = 7.5, 1.2 Hz, 1H), 6.81 (dd, J = 8.0, 1.2 Hz, 1H), 6.52 (dd, J = 3.5, 1.8 Hz, 1H), 6.10 (s, 1H), 4.07 (dd, J = 6.5, 4.1 Hz, 4H), 3.91 (s, 4H), 3.78 (s, 1H), 3.22 - 3.12 (m, 2H), 2.94 - 2.85 (m, 2H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 196.2, 173.2, 161.6, 159.4, 158.7, 153.6, 147.7, 144.0, 128.9, 128.0, 127.2, 120.8, 117.2, 116.4, 115.7, 111.6, 43.6, 37.9, 33.7, 29.7 .

< Example 2 to 30> tetrahydroquinazoline derivative preparation

With reference to the synthesis method of the compound of Example 1, Preparation Example 2 ( 14 compounds), Preparation Example 3 ( 20 compounds), Preparation Example 4 ( 24 compounds), Preparation Example 5 ( 30 compounds) A couple of the following reaction schemes using amines Examples 2 to 30 compounds were prepared through a ring reaction.

As an example, Preparation 2 (compound 14 ) corresponding to the amine (80 mg, 0.26 mmol), acid (36 mg, 0.29 mmol) and TEA (0.1 ml) were dissolved in DCM (1.2 ml). EDCI (48 mg, 0.3 mmol) and HOBt (41 mg, 0.3 mmol) were added to the solution at rt. The reaction mixture was stirred at rt for 12 h. The resulting mixture was extracted with DCM. After drying over MgSO ₄ , the solvent was removed in vacuo. The residue was purified through column chromatography to prepare the target compound. (20-60%)

The structures of the compounds of Examples 2 to 30, IUPAC Name and NMR Data are summarized and shown in Table 1 below.

Example rescue IUPAC Name NMR Data 2
(31a)

2-(4-(2-chlorobenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.90 (s, 1H), 7.45 - 7.41 (m, 1H), 7.37 (d, J = 5.2 Hz, 2H), 7.35 (d, J = 1.8 Hz, 2H) ), 7.35 - 7.31 (m, 1H), 7.30 - 7.26 (m, 3H), 4.17 - 4.05 (m, 2H), 4.02 - 3.93 (m, 3H), 3.88 - 3.80 (m, 1H), 3.44 (s) , 1H), 3.40 - 3.24 (m, 2H), 3.09 (s, 2H), 2.93 - 2.85 (m, 1H), 2.78 (dd, J = 16.8, 12.5 Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.9, 172.3, 167.2, 161.7, 158.8, 142.6, 135.4, 130.5, 130.3, 129.8, 128.9, 127.9, 127.4, 127.2, 126.7, 116.4, 46.5, 45.4, 44.1, 43.7 , 41.6, 39.9, 39.2. 3
(31b)

2-(4-(2-methylbenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.89 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.36 (dd, J = 8.3, 7.0 Hz, 2H), 7.27 (d, J ) = 1.6 Hz, 2H), 7.26 (d, J = 1.2 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 3.95 (s, 2H), 3.82 (s, 2H), 3.74 (s, 3H) ), 3.72 (d, J = 4.1 Hz, 2H), 3.52 (s, 2H), 3.44 (s, 1H), 3.07 (t, J = 7.8 Hz, 2H), 2.88 (ddd, J = 16.8, 4.0, 1.4 Hz, 1H), 2.78 (dd, J = 16.8, 12.5 Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.8, 172.3, 170.3, 161.7, 158.7, 142.6, 135.7, 134.2, 130.6, 129.2, 128.9, 127.1, 126.7, 126.1, 125.8, 116.4, 46.6, 45.3, 44.3, 43.8 , 41.4, 39.9, 39.2, 19.1. 4
(31c)

2-(4-(2-fluorobenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.91 (s, 1H), 7.43 (dd, J = 7.8, 6.4 Hz, 2H), 7.37 (dd, J = 8.7, 6.7 Hz, 2H), 7.28 (d) , J = 1.6 Hz, 2H), 7.25 (dd, J = 7.5, 1.0 Hz, 1H), 7.15 - 7.10 (m, 1H), 4.10 (d, J = 12.2 Hz, 2H), 3.97 (t, J = 5.2 Hz, 2H), 3.90 (s, 2H), 3.45 (d, J = 6.1 Hz, 2H), 3.42 (s, 1H), 3.14 - 3.03 (m, 2H), 2.91 - 2.87 (m, 1H), 2.78 (dd, J = 16.7, 12.5 Hz, 1H). ¹³ C NMR (151 MHz, Chloroform- d ) δ 194.8, 172.3, 165.5, 161.7, 158.7, 142.6, 131.7, 131.7, 129.4, 129.3, 128.9, 127.1, 126.7, 124.9, 124.9, 116.4, 115.9, 115.8, 46.8, 45.4, 44.2, 43.7, 42.0, 39.9, 39.2. 5
(31d)

2-(4-(4-methoxybenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.91 (s, 1H), 7.45 - 7.41 (m, 2H), 7.38 - 7.34 (m, 2H), 7.28 - 7.25 (m, 3H), 6.95 - 6.92 ( m, 2H), 4.01 (s, 4H), 3.85 (d, J = 1.1 Hz, 3H), 3.72 (d, J = 1.1 Hz, 4H), 3.44 (s, 1H), 3.09 (t, J = 7.8) Hz, 2H), 2.90 - 2.86 (m, 1H), 2.79 (d, J = 1.0 Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.8, 172.3, 170.6, 161.7, 161.0, 158.7, 142.6, 129.3, 128.9, 127.3, 127.1, 126.7, 116.3, 113.9, 55.4, 45.4, 39.9, 39.2. 6
(31e)

2-(4-(3-chlorobenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.91 (s, 1H), 7.46 - 7.42 (m, 2H), 7.41 - 7.34 (m, 3H), 7.34 - 7.30 (m, 1H), 7.29 - 7.25 ( m, 3H), 4.14 - 3.93 (m, 4H), 3.68 (d, J = 205.0 Hz, 4H), 3.48 - 3.42 (m, 1H), 3.08 (d, J = 11.3 Hz, 2H), 2.89 (ddd , J = 16.7, 4.0, 1.3 Hz, 1H), 2.79 (dd, J = 16.8, 12.5 Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.9, 172.3, 169.1, 161.6, 158.7, 142.6, 137.0, 134.8, 130.2, 130.1, 128.9, 127.4, 127.2, 126.7, 125.2, 116.5, 45.3, 39.9, 39.2. 7
(31f)

2-(4-(4-fluorobenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.91 (s, 1H), 7.47 (dd, J = 8.6, 5.3 Hz, 2H), 7.37 (dd, J = 8.7, 6.6 Hz, 2H), 7.28 (td) , J = 7.3, 6.5, 1.3 Hz, 3H), 7.13 (t, J = 8.6 Hz, 2H), 4.02 (s, 4H), 3.70 (d, J = 165.7 Hz, 4H), 3.45 (s, 1H) , 3.09 (t, J = 7.6 Hz, 2H), 2.89 (ddd, J = 16.8, 4.0, 1.4 Hz, 1H), 2.79 (dd, J = 16.8, 12.5 Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.8, 172.3, 169.8, 164.4, 162.8, 161.7, 158.7, 142.6, 131.3, 131.3, 129.6, 129.5, 128.9, 127.1, 126.7, 116.4, 115.9, 115.7, 45.4, 39.9 , 39.2. 8
(31 g)

2-(4-(4-chlorobenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.91 (s, 1H), 7.44 - 7.41 (m, 2H), 7.41 - 7.38 (m, 2H), 7.36 (dd, J = 8.7, 6.7 Hz, 2H) , 7.30 - 7.27 (m, 3H), 4.01 (d, J = 57.1 Hz, 4H), 3.84 (s, 2H), 3.52 (s, 2H), 3.48 - 3.40 (m, 1H), 3.09 (t, J ) = 7.8 Hz, 2H), 2.88 (ddd, J = 16.8, 4.0, 1.4 Hz, 1H), 2.78 (dd, J = 16.7, 12.5 Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.8, 172.3, 169.6, 161.6, 158.7, 142.6, 136.2, 133.6, 129.0, 128.9, 128.7, 127.1, 126.7, 116.4, 45.3, 39.9, 39.2. 9
(31h)

7-phenyl-2-(4-(4-(trifluoromethyl)benzoyl)piperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.91 (s, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.57 (d, J = 7.8 Hz, 2H), 7.36 (d, J = 7.4) Hz, 2H), 7.27 (d, J = 8.8 Hz, 3H), 4.10 (s, 2H), 3.91 (d, J = 39.3 Hz, 4H), 3.54 - 3.46 (m, 2H), 3.45 (s, 1H) ), 3.09 (d, J = 11.2 Hz, 2H), 2.89 (dd, J = 16.9, 3.9 Hz, 1H), 2.79 (dd, J = 16.7, 12.6 Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.8, 172.3, 169.2, 161.6, 158.8, 142.6, 138.9, 128.9, 127.5, 127.2, 126.7, 125.8, 125.8, 116.5, 45.3, 39.9, 39.2, 29.7. 10
(31i)

2-(4-(4-methylbenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.90 (s, 1H), 7.39 - 7.33 (m, 4H), 7.29 - 7.27 (m, 2H), 7.24 (d, J = 7.8 Hz, 2H), 3.98 (s, 4H), 3.83 (s, 2H), 3.56 (s, 2H), 3.44 (ddd, J = 11.7, 8.0, 5.4 Hz, 1H), 3.08 (t, J = 8.0 Hz, 2H), 2.88 ( ddd, J = 16.7, 4.0, 1.4 Hz, 1H), 2.78 (dd, J = 16.8, 12.5 Hz, 1H), 2.39 (s, 3H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.8, 172.3, 170.9, 161.7, 158.7, 142.6, 140.3, 132.3, 129.2, 128.9, 127.3, 127.1, 126.7, 116.3, 45.4, 39.9, 39.2, 21.5. 11
(31j)

2-(4-(2-fluorobenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.90 (s, 1H), 7.47 - 7.41 (m, 2H), 7.36 (dd, J = 8.6, 6.8 Hz, 2H), 7.30 - 7.24 (m, 4H) , 7.15 - 7.09 (m, 1H), 4.15 - 4.04 (m, 2H), 3.97 (t, J = 5.2 Hz, 2H), 3.89 (s, 2H), 3.50 - 3.44 (m, 1H), 3.42 (t) , J = 5.2 Hz, 2H), 3.08 (d, J = 11.0 Hz, 2H), 2.91 - 2.83 (m, 1H), 2.78 (dd, J = 16.7, 12.5 Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.8, 172.3, 165.5, 161.6, 158.9, 158.7, 157.3, 142.6, 131.7, 131.7, 129.4, 129.3, 128.9, 127.1, 126.7, 124.9, 124.9, 123.7, 123.6, 116.4 , 115.9, 115.8, 46.8, 45.3, 44.2, 43.7, 42.0, 39.9, 39.2. 12
(31k)

2-(4-benzoylpiperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.90 (s, 1H), 7.46 - 7.43 (m, 5H), 7.36 (dd, J = 8.6, 6.8 Hz, 2H), 7.29 - 7.26 (m, 3H) , 4.01 (d, J = 77.3 Hz, 4H), 3.86 (s, 2H), 3.53 (s, 2H), 3.44 (td, J = 7.9, 6.9, 3.7 Hz, 1H), 3.08 (d, J = 11.4) Hz, 2H), 2.88 (ddd, J = 16.7, 4.0, 1.3 Hz, 1H), 2.78 (dd, J = 16.8, 12.5 Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.8, 172.2, 170.6, 161.6, 158.7, 142.6, 135.3, 130.0, 128.8, 128.8, 128.6, 127.1, 126.6, 116.3, 45.3, 39.9, 39.1. 13
(31l)

2-(4-(cyclopentanecarbonyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.91 (d, J = 0.8 Hz, 1H), 7.39 - 7.34 (m, 2H), 7.28 (q, J = 2.6, 1.9 Hz, 3H), 4.01 - 3.94 (m, 4H), 3.73 (d, J = 5.3 Hz, 2H), 3.62 (d, J = 5.2 Hz, 2H), 3.45 (s, 1H), 3.13 - 3.04 (m, 2H), 2.96 - 2.92 ( m, 1H), 2.90 - 2.86 (m, 1H), 2.78 (dd, J = 16.7, 12.5 Hz, 1H), 1.85 (tt, J = 6.1, 3.3 Hz, 4H), 1.79 - 1.72 (m, 2H) , 1.64 - 1.56 (m, 2H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.8, 174.86, 172.26, 161.64, 158.69, 142.65, 128.87, 127.11, 126.67, 116.26, 45.34, 45.25, 44.12, 43.83, 41.65, 41.14, 39.93, 39.19, 30.95, 30.16 , 26.08. 14
(31m)

2-(4-Acetylpiperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.91 (s, 1H), 7.39 - 7.34 (m, 2H), 7.30 - 7.27 (m, 3H), 4.03 - 3.99 (m, 2H), 3.99 - 3.94 ( m, 2H), 3.73 - 3.69 (m, 2H), 3.57 - 3.54 (m, 2H), 3.44 (d, J = 11.4 Hz, 1H), 3.09 (d, J = 11.0 Hz, 2H), 2.87 (dd , J = 3.9, 1.6 Hz, 1H), 2.78 (dd, J = 16.7, 12.5 Hz, 1H), 2.16 (s, 3H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.8, 172.3, 169.2, 161.6, 158.7, 142.6, 128.9, 127.1, 126.7, 116.3, 46.0, 45.3, 43.9, 43.7, 41.2, 39.9, 39.2, 21.5. 15
(31n)

7-phenyl-2-(4-propionylpiperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.91 (s, 1H), 7.36 (dd, J = 8.2, 7.2 Hz, 2H), 7.30 - 7.27 (m, 3H), 3.98 (dt, J = 22.4, 5.3 Hz, 4H), 3.72 (dd, J = 6.5, 4.1 Hz, 2H), 3.56 (dd, J = 6.4, 4.0 Hz, 2H), 3.44 (ddd, J = 11.5, 7.5, 5.5 Hz, 1H), 3.15 - 3.03 (m, 2H), 2.88 (ddd, J = 16.7, 4.0, 1.5 Hz, 1H), 2.78 (dd, J = 16.7, 12.5 Hz, 1H), 2.41 (q, J = 7.4 Hz, 2H) , 1.19 (t, J = 7.4 Hz, 3H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.8, 172.5, 172.3, 161.6, 158.7, 142.6, 128.9, 127.1, 126.7, 116.3, 45.3, 45.1, 43.9, 43.8, 41.3, 39.9, 39.2, 26.6, 9.4. 16
(31o)

2-(4-isobutyrylpiperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.90 (s, 1H), 7.36 (dd, J = 8.6, 6.7 Hz, 2H), 7.28 (d, J = 6.5 Hz, 3H), 3.98 (dt, J ) = 25.2, 5.3 Hz, 4H), 3.71 (t, J = 5.2 Hz, 2H), 3.63 - 3.58 (m, 2H), 3.47 - 3.40 (m, 1H), 3.13 - 3.04 (m, 2H), 2.87 ( ddd, J = 16.6, 3.9, 1.4 Hz, 1H), 2.85 - 2.81 (m, 1H), 2.80 - 2.74 (m, 1H), 1.16 (d, J = 6.8 Hz, 6H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.8, 175.7, 172.3, 161.6, 158.7, 142.6, 128.9, 127.1, 126.7, 116.3, 45.3, 45.2, 44.1, 43.8, 41.5, 39.9, 39.2, 30.2, 19.4. 17
(31p)

2-(4-(furan-2-carbonyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.92 (s, 1H), 7.52 (dd, J = 1.8, 0.8 Hz, 1H), 7.39 - 7.34 (m, 2H), 7.30 - 7.27 (m, 3H) , 7.08 (dd, J = 3.5, 0.8 Hz, 1H), 6.52 (dd, J = 3.5, 1.8 Hz, 1H), 4.08 - 4.04 (m, 4H), 3.91 (s, 4H), 3.49 - 3.42 (m , 1H), 3.15 - 3.05 (m, 2H), 2.89 (ddd, J = 16.7, 3.9, 1.5 Hz, 1H), 2.79 (dd, J = 16.7, 12.5 Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.8, 172.3, 161.6, 159.3, 158.7, 147.8, 143.9, 142.6, 128.9, 127.1, 126.7, 117.0, 116.3, 111.5, 45.4, 39.9, 39.2. 18
(31q)

2-(4-nicotinoylpiperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.89 (s, 1H), 8.71 - 8.67 (m, 2H), 7.79 (dt, J = 7.8, 2.0 Hz, 1H), 7.39 (dd, J = 7.8, 4.9 Hz, 1H), 7.34 (dd, J = 8.6, 6.7 Hz, 2H), 7.28 - 7.25 (m, 3H), 4.13 - 3.95 (m, 4H), 3.86 (s, 2H), 3.53 (s, 2H) ), 3.47 - 3.38 (m, 1H), 3.07 (d, J = 10.9 Hz, 2H), 2.86 (ddd, J = 16.7, 4.0, 1.4 Hz, 1H), 2.77 (dd, J = 16.8, 12.5 Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.8, 172.3, 168.0, 161.6, 158.7, 151.1, 148.0, 142.6, 135.2, 131.2, 128.9, 127.1, 126.7, 123.6, 116.5, 45.3, 39.9, 39.2. 19
(31r)

2-(4-(1H-pyrrole-2-carbonyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 10.01 (s, 1H), 8.92 (s, 1H), 7.37 (dd, J = 8.2, 7.0 Hz, 2H), 7.30 - 7.25 (m, 4H), 6.95 (td, J = 2.7, 1.2 Hz, 1H), 6.56 (ddd, J = 3.8, 2.4, 1.3 Hz, 1H), 6.27 (dt, J = 3.8, 2.6 Hz, 1H), 4.08 - 4.04 (m, 5H) ), 3.96 (t, J = 5.4 Hz, 4H), 3.48 - 3.41 (m, 1H), 3.15 - 3.05 (m, 2H), 2.89 (ddd, J = 16.7, 4.0, 1.6 Hz, 1H), 2.79 ( dd, J = 16.8, 12.5 Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.9, 172.3, 162.1, 161.6, 158.7, 142.7, 128.9, 127.1, 126.7, 124.3, 121.5, 116.3, 112.4, 109.7, 45.4, 43.8, 39.9, 39.2. 20
(31s)

7-phenyl-2-(4-(thiophen-2-carbonyl)piperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.91 (s, 1H), 7.49 - 7.44 (m, 2H), 7.39 - 7.34 (m, 2H), 7.30 - 7.27 (m, 2H), 7.13 (t, J = 8.6 Hz, 2H), 4.01 (s, 4H), 3.70 (d, J = 165.5 Hz, 4H), 3.45 (s, 1H), 3.09 (t, J = 7.7 Hz, 2H), 2.89 (ddd, J = 16.8, 4.0, 1.4 Hz, 1H), 2.79 (dd, J = 16.8, 12.5 Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.9, 172.3, 163.9, 161.7, 158.7, 142.6, 136.7, 129.2, 129.1, 128.9, 127.1, 126.9, 126.7, 116.4, 45.4, 43.9, 39.9, 39.2. 21
(31t)

7-phenyl-2-(4-picolinoylpiperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.91 (s, 1H), 8.61 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 7.83 (td, J = 7.7, 1.8 Hz, 1H), 7.73 (dt, J = 7.9, 1.1 Hz, 1H), 7.39 - 7.35 (m, 3H), 7.29 - 7.27 (m, 2H), 4.13 - 4.10 (m, 2H), 4.06 - 4.01 (m, 2H), 3.92 - 3.87 (m, 2H), 3.76 - 3.71 (m, 2H), 3.45 (d, J = 3.3 Hz, 1H), 3.08 (d, J = 11.2 Hz, 2H), 2.88 (ddd, J = 16.7, 4.0 , 1.3 Hz, 1H), 2.78 (dd, J = 16.7, 12.5 Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.8, 172.3, 167.7, 161.7, 158.7, 153.6, 148.3, 142.7, 137.2, 128.9, 127.1, 126.7, 124.8, 124.3, 116.3, 47.0, 45.4, 44.3, 43.7, 42.4 , 39.9, 39.2. 22
(31u)

2-(4-(2-(4-fluorophenyl)acetyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.89 (s, 1H), 7.38 - 7.34 (m, 2H), 7.27 (dd, J = 4.6, 3.1 Hz, 3H), 7.24 (dd, J = 8.6, 5.3 Hz, 2H), 7.03 (t, J = 8.6 Hz, 2H), 3.95 (s, 2H), 3.82 (s, 2H), 3.76 (s, 2H), 3.75 - 3.71 (m, 2H), 3.56 - 3.51 (m, 2H), 3.47 - 3.39 (m, 1H), 3.07 (t, J = 7.9 Hz, 2H), 2.88 (ddd, J = 16.8, 4.0, 1.4 Hz, 1H), 2.77 (dd, J = 16.7, 12.5 Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.8, 172.3, 169.6, 162.7, 161.6, 161.0, 158.7, 142.6, 130.4, 130.4, 130.2, 130.2, 128.9, 127.1, 126.7, 116.4, 115.8, 115.7, 45.8, 45.3 , 43.7, 43.6, 41.7, 40.2, 39.9, 39.2. 23
(31v)

2-(4-(2-(4-bromophenyl)acetyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.89 (s, 1H), 7.47 - 7.44 (m, 2H), 7.36 (dd, J = 8.2, 7.0 Hz, 2H), 7.30 - 7.26 (m, 3H) , 7.16 - 7.13 (m, 2H), 3.95 (t, J = 5.4 Hz, 2H), 3.82 (t, J = 5.1 Hz, 2H), 3.74 (s, 2H), 3.73 (t, J = 3.7 Hz, 2H), 3.52 (dd, J = 6.3, 4.1 Hz, 2H), 3.44 (s, 1H), 3.07 (t, J = 7.8 Hz, 2H), 2.88 (ddd, J = 16.7, 3.9, 1.4 Hz, 1H) ), 2.80 - 2.74 (m, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.9, 172.3, 169.2, 161.6, 158.7, 142.6, 133.7, 132.0, 131.7, 131.1, 130.4, 128.9, 127.1, 126.7, 121.0, 116.4, 45.8, 45.3, 43.7, 43.6 , 41.7, 40.4, 39.9, 39.2. 24
(31w)

7-phenyl-2-(4-(2-phenylacetyl)piperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.87 (s, 1H), 7.34 (ddd, J = 15.4, 8.5, 7.3 Hz, 5H), 7.29 - 7.26 (m, 5H), 3.93 (d, J = 5.5 Hz, 2H), 3.80 (s, 2H), 3.77 - 3.72 (m, 4H), 3.56 - 3.49 (m, 2H), 3.42 (s, 1H), 3.06 (t, J = 7.9 Hz, 2H), 2.87 (ddd, J = 16.7, 4.0, 1.4 Hz, 1H), 2.76 (dd, J = 16.8, 12.5 Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.8, 172.2, 169.8, 161.6, 158.7, 142.6, 134.8, 128.9, 128.9, 128.5, 127.1, 127.0, 126.7, 116.3, 45.9, 45.3, 43.7, 43.6, 41.6, 41.3 , 39.9, 39.2. 25
(31x)

2-(4-(2-(3-fluorophenyl)acetyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.88 (s, 1H), 7.36 (dd, J = 8.3, 6.9 Hz, 2H), 7.32 - 7.26 (m, 4H), 7.05 (dt, J = 7.6, 1.2 Hz, 1H), 7.00 (d, J = 9.8 Hz, 1H), 6.95 (dd, J = 2.6, 0.9 Hz, 1H), 3.95 (s, 2H), 3.83 (s, 2H), 3.78 (s, 2H), 3.76 - 3.71 (m, 2H), 3.55 - 3.51 (m, 2H), 3.42 (td, J = 7.8, 6.7, 3.3 Hz, 1H), 3.07 (t, J = 8.0 Hz, 2H), 2.85 (dd, J = 4.0, 1.4 Hz, 1H), 2.77 (dd, J = 16.7, 12.5 Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.8, 172.3, 169.1, 163.8, 162.2, 161.6, 158.7, 142.6, 137.2, 137.1, 130.4, 130.3, 128.9, 127.1, 126.7, 124.4, 124.4, 116.4, 115.8, 115.6 , 114.1, 114.0, 45.8, 45.3, 43.7, 43.6, 41.7, 40.7, 40.7, 39.9, 39.2. 26
(32a)

7-(4-chlorophenyl)-2-(4-(furan-2-carbonyl)piperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.91 (s, 1H), 7.52 (dd, J = 1.8, 0.8 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.20 (d, J ) = 8.5 Hz, 2H), 7.08 (dd, J = 3.4, 0.9 Hz, 1H), 6.51 (dd, J = 3.5, 1.8 Hz, 1H), 4.07 - 4.04 (m, 4H), 3.90 (s, 4H) , 3.43 (s, 1H), 3.12 - 3.06 (m, 1H), 3.05 (d, J = 11.2 Hz, 1H), 2.86 (ddd, J = 16.7, 3.9, 1.7 Hz, 1H), 2.75 (dd, J ) = 16.7, 12.4 Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.4, 171.9, 161.6, 159.3, 158.8, 147.7, 144.0, 141.1, 132.9, 129.0, 128.1, 117.1, 116.2, 111.5, 45.2, 44.0, 39.8, 38.1. 27
(32b)

2-(4-acetylpiperazin-1-yl)-7-(4-chlorophenyl)-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.90 (s, 1H), 7.33 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 4.02 - 3.93 (m, 4H) ), 3.72 - 3.68 (m, 2H), 3.57 - 3.52 (m, 2H), 3.41 (d, J = 11.8 Hz, 1H), 3.04 (d, J = 11.2 Hz, 2H), 2.84 (d, J = 2.2 Hz, 1H), 2.74 (dd, J = 16.7, 12.4 Hz, 1H), 2.16 (s, 3H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.4, 171.9, 169.2, 161.6, 158.8, 141.1, 132.9, 129.0, 128.0, 116.2, 46.0, 45.2, 43.9, 43.7, 41.2, 39.8, 38.6, 21.5. 28
(32c)

7-(4-Chlorophenyl)-2-(4-nicotinoylpiperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.91 (s, 1H), 8.73 - 8.70 (m, 2H), 7.83 - 7.80 (m, 1H), 7.43 - 7.39 (m, 1H), 7.35 - 7.31 ( m, 2H), 7.23 - 7.18 (m, 2H), 4.15 - 3.97 (m, 4H), 3.88 (s, 2H), 3.55 (s, 2H), 3.43 (s, 1H), 3.05 (d, J = 11.3 Hz, 2H), 2.86 (ddd, J = 16.8, 4.0, 1.6 Hz, 1H), 2.75 (dd, J = 16.7, 12.4 Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.3, 171.9, 168.0, 161.6, 158.8, 151.1, 148.0, 141.0, 135.2, 132.9, 131.2, 129.0, 129.0, 128.0, 123.6, 116.4, 45.1, 39.7, 38.6. 29
(32d)

2-(4-(1H-pyrrole-2-carbonyl)piperazin-1-yl)-7-(4-chlorophenyl)-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 9.81 (s, 1H), 8.92 (s, 1H), 7.33 (d, J = 7.9 Hz, 2H), 7.21 (d, J = 8.1 Hz, 2H), 6.95 (s, 1H), 6.57 (d, J = 3.7 Hz, 1H), 6.28 (t, J = 3.3 Hz, 1H), 4.06 (t, J = 5.3 Hz, 4H), 3.96 (s, 4H), 3.43 (dq, J = 11.2, 6.1, 4.1 Hz, 1H), 3.12 - 3.02 (m, 2H), 2.89 - 2.84 (m, 1H), 2.75 (dd, J = 16.6, 12.4 Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 194.4, 171.9, 162.0, 161.6, 158.8, 141.1, 132.9, 129.0, 128.1, 124.3, 121.5, 116.2, 112.4, 109.8, 45.2, 43.8, 39.8, 38.6. 30
(32e)

2-(4-(furan-2-carbonyl)piperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one ¹ H NMR (600 MHz, Chloroform- d ) δ 8.85 (s, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.05 (d, J = 3.4 Hz, 1H), 6.50 (dd, J = 3.4) , 1.8 Hz, 1H), 4.06 - 4.00 (m, 5H), 3.88 (s, 4H), 2.83 (t, J = 6.2 Hz, 2H), 2.56 (t, J = 6.5 Hz, 2H), 2.09 (p , J = 6.3 Hz, 2H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 195.7, 173.2, 161.4, 159.2, 158.7, 147.7, 143.9, 117.0, 116.9, 111.5, 43.9, 38.3, 32.4, 21.4.

< Example 31, 32> Preparation of a compound modified with a ketone moiety, (34a, 34b)

Through a reaction similar to the above 31p → 33 → 34a-b reaction scheme,

Example 31 compound (34a) and Example 32 compound (34b) were prepared.

Step 1: Compound 31p → compound 33 synthesis

31p compound (384 mg, 0.95 mmol) was dissolved in methanol (5 ml). At room temperature, NaBH ₄ (26.4 mg, 0.95 mmol) was added to the solution. The reaction mixture was stirred for 5 minutes. After the reaction, 5% HCl was added to the mixture, and the solution was extracted with EA. The organic layer was dried and concentrated. The residue was purified by column chromatography and furan-2-yl (4- (5-hydroxy-7-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl) piperazine-1- 1) Methanone, 33 compound was prepared. (280 mg, 73%)

¹ H NMR (600 MHz, Chloroform- d ) δ 8.54 (s, 1H), 7.50 (dd, J = 1.9, 0.9 Hz, 1H), 7.35 (d, J = 7.7 Hz, 2H), 7.28 - 7.24 (m) , 3H), 7.04 (dd, J = 3.4, 0.9 Hz, 1H), 6.50 (d, J = 1.7 Hz, 1H), 4.95 - 4.90 (m, 1H), 3.90 (t, J = 3.7 Hz, 4H) , 3.85 (s, 4H), 3.09 - 3.03 (m, 1H), 2.98 - 2.92 (m, 1H), 2.86 - 2.80 (m, 1H), 2.49 - 2.44 (m, 1H), 1.88 (d, J = 10.2 Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 165.5, 160.7, 159.3, 157.3, 147.8, 144.3, 143.9, 128.8, 126.7, 126.7, 121.4, 116.7, 111.4, 77.3, 77.1, 76.8, 67.5, 40.7, 40.4, 38.1 .

Step 2: Compound 33 → compound 34' synthesis

Acetyl chloride (21 mg, 0.15 mmol) and TEA (0.6 ml) were added to 33 compound (51 mg, 0.126 mmol) dissolved in DCM (0.6 ml) at 0°C. The reaction mixture was then stirred at rt for 3 h. After the reaction, the solution was extracted with DCM. The organic layer was dried and concentrated.

34a ( Example 31): 7-(4 -chlorophenyl )-2-(4-( furan -2 - carbonyl )piperazin-1-yl)-5,6,7,8-tetrahydroquinazoline- 5-Day Butyrate (49 mg, 76%)

¹ H NMR (600 MHz, Chloroform- d ) δ 8.24 (d, J = 0.8 Hz, 1H), 7.51 (dd, J = 1.8, 0.9 Hz, 1H), 7.35 (dd, J = 8.3, 6.8 Hz, 2H) ), 7.28 - 7.26 (m, 3H), 7.05 (dd, J = 3.4, 0.9 Hz, 1H), 6.50 (dd, J = 3.5, 1.8 Hz, 1H), 6.10 (dd, J = 9.8, 6.2 Hz, 1H), 3.94 - 3.92 (m, 4H), 3.87 (s, 4H), 3.12 (dd, J = 5.2, 2.5 Hz, 1H), 2.97 (dd, J = 5.1, 1.9 Hz, 1H), 2.92 (dd) , J = 11.8, 1.2 Hz, 1H), 2.56 (dd, J = 12.3, 6.2 Hz, 1H), 2.33 (td, J = 7.4, 2.4 Hz, 2H), 1.92 (td, J = 12.6, 9.9 Hz, 1H), 1.69 (q, J = 7.4 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 173.6, 166.3, 160.7, 159.3, 157.1, 147.9, 143.8, 143.8, 128.7, 126.8, 126.7, 117.5, 116.7, 111.4, 69.1, 40.0, 37.9, 36.5, 36.4, 18.6 , 13.7.

34b ( Example 32): 2- (4- acetylpiperazin -1-yl)-7- (4 -chlorophenyl )-5,6,7,8 -tetrahydroquinazolin- 5- yl benzoate (28%)

¹ H NMR (600 MHz, Chloroform- d ) δ 8.36 (s, 1H), 8.02 - 7.98 (m, 2H), 7.59 - 7.54 (m, 1H), 7.52 - 7.49 (m, 1H), 7.45 - 7.40 ( m, 2H), 7.38 - 7.31 (m, 2H), 7.29 - 7.24 (m, 2H), 7.05 (dd, J = 3.4, 0.9 Hz, 1H), 6.50 (dd, J = 3.5, 1.8 Hz, 1H) , 6.33 (dd, J = 9.5, 6.2 Hz, 1H), 3.99 - 3.92 (m, 5H), 3.88 (s, 4H), 3.24 - 3.18 (m, 1H), 3.06 - 2.94 (m, 2H), 2.74 - 2.68 (m, 1H), 2.09 (td, J = 12.5, 9.6 Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 166.5, 166.4, 160.8, 159.3, 157.4, 147.9, 143.8, 133.2, 130.0, 129.7, 128.8, 128.4, 126.8, 117.5, 116.7, 111.4, 69.9, 39.9, 37.8, 36.3 .

< Experimental example 1> HaCaT Evaluation of inhibitory activity against cells 1

First, to evaluate the effect on HaCaT cells, compounds (9, 31f, 31j, 31k, 31l, 31m, 31n, 31o, 31p, 31q, 31r, 31w, 31x) were screened in vitro by cell migration assay. . All compounds were treated with cells at two concentrations of 0.1 μm and 1 μm. The results are shown in FIG. 1 .

1 is a graph showing the results of cell migration analysis of the compound of Example according to the present invention.

As shown in Figure 1,

Among the compound groups subjected to the experiment, the compound of Example 17 (31p) exhibited the highest inhibitory effect at a concentration of 1 μm.

< Experimental example 2> HaCaT Evaluation of inhibitory activity against cells 2

The inhibitory activity of the example compounds on the proliferation and migration of HaCaT cells was evaluated. All compounds were treated with cells at a fixed concentration of 1 μm. The results are shown in FIG. 2 .

2 is a graph showing the results of cell migration analysis of the compound of Example according to the present invention. As in FIG. 1 , among the compound groups subjected to the experiment, the compound of Example 17 (31p) exhibited the highest inhibitory effect at a concentration of 1 μm.

< Experimental example 3> HaCaT Evaluation of inhibitory activity against cells 3

The inhibitory activity on HaCaT cells was evaluated by selecting five example compounds.

9: Example 1 (SD 1040)

31p: Example 17

31i: Example 10

32a: Example 26

Treatment concentrations were set at 0.05 μm, 0.1 μm, and 1 μm.

The results are shown in FIG. 3 .

3 is a graph showing the results of cell migration analysis of the compound of Example according to the present invention. As in FIGS. 1 and 2 , among the compound groups subjected to the experiment, the compound of Example 17 (31p) exhibited the highest inhibitory effect.

Summarizing the results of the above experimental example, the introduction of the furan ring into the piperazine ring is very important for the activity by hydrogen bonding interaction. On the other hand, the alteration of the ketone position did not significantly affect the activity. The presence of the phenyl ring was essential for activity.

Claims (8)

A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Formula 1]

(In Formula 1,
R ¹ is hydrogen,
R ² is

is,
A ¹ is an unsubstituted 5- to 6-membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S; or
R ¹ is unsubstituted or substituted phenyl,
the substituted phenyl is phenyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C _1-3 straight-chain or branched alkyl, and C _1-3 straight-chain or branched alkoxy; and
R ² is

is,
wherein A ¹ is C _1-3 straight or branched chain alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted cyclopentyl, or 1 selected from the group consisting of N, O and S It is an unsubstituted or substituted 5- to 6-membered heteroaryl containing more than one heteroatom,
The substituted phenyl, benzyl, cyclopentyl and 5- to 6-membered heteroaryl are independently halogen, hydroxy, unsubstituted or C _1-3 straight-chain or branched alkyl substituted with one or more halogens, and C _1-3 phenyl, benzyl, cyclopentyl and 5- to 6-membered heteroaryl with at least one substituent selected from the group consisting of straight-chain or branched alkoxy of
delete delete According to claim 1,
R ¹ is hydrogen,
R ² is

is,
A ¹ is

; or
R ¹ is unsubstituted phenyl or phenyl substituted with hydroxy or —Cl; and
R ² is

is,
The A ¹ is methyl, ethyl, iso-propyl,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

, or

A compound or a pharmaceutically acceptable salt thereof, characterized in that
According to claim 1,
The compound represented by Formula 1 is a compound or a pharmaceutically acceptable salt thereof, characterized in that any one compound selected from the following compound group:
(1) 2-(4-(furan-2-carbonyl)piperazin-1-yl)-7-(2-hydroxyphenyl)-7,8-dihydroquinazolin-5(6H)-one;
(2) 2-(4-(2-chlorobenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;
(3) 2-(4-(2-methylbenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;
(4) 2-(4-(2-fluorobenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;
(5) 2-(4-(4-methoxybenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;
(6) 2-(4-(3-chlorobenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;
(7) 2-(4-(4-fluorobenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;
(8) 2-(4-(4-chlorobenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;
(9) 7-phenyl-2-(4-(4-(trifluoromethyl)benzoyl)piperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one;
(10) 2-(4-(4-methylbenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;
(11) 2-(4-(2-fluorobenzoyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;
(12) 2-(4-benzoylpiperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;
(13) 2-(4-(cyclopentanecarbonyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;
(14) 2-(4-acetylpiperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;
(15) 7-phenyl-2-(4-propionylpiperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one;
(16) 2-(4-isobutyrylpiperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;
(17) 2-(4-(furan-2-carbonyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;
(18) 2-(4-nicotinoylpiperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;
(19) 2-(4-(1H-pyrrole-2-carbonyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;
(20) 7-phenyl-2-(4-(thiophen-2-carbonyl)piperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one;
(21) 7-phenyl-2-(4-picolinoylpiperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one;
(22) 2-(4-(2-(4-fluorophenyl)acetyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;
(23) 2-(4-(2-(4-bromophenyl)acetyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;
(24) 7-phenyl-2-(4-(2-phenylacetyl)piperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one;
(25) 2-(4-(2-(3-fluorophenyl)acetyl)piperazin-1-yl)-7-phenyl-7,8-dihydroquinazolin-5(6H)-one;
(26) 7-(4-chlorophenyl)-2-(4-(furan-2-carbonyl)piperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one;
(27) 2-(4-acetylpiperazin-1-yl)-7-(4-chlorophenyl)-7,8-dihydroquinazolin-5(6H)-one;
(28) 7-(4-chlorophenyl)-2-(4-nicotinoylpiperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one;
(29) 2-(4-(1H-pyrrole-2-carbonyl)piperazin-1-yl)-7-(4-chlorophenyl)-7,8-dihydroquinazolin-5(6H)-one ; and
(30) 2-(4-(furan-2-carbonyl)piperazin-1-yl)-7,8-dihydroquinazolin-5(6H)-one.
A pharmaceutical composition for the prevention or treatment of psoriasis comprising the compound represented by Formula 1 of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
7. The method of claim 6,
The compound is a pharmaceutical composition, characterized in that inhibiting the proliferation of a human keratinocyte-derived cell line (human keratinocyte-derived cell line).
A health functional food composition for preventing or improving psoriasis, comprising the compound represented by Formula 1 of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

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