KR101849775B1 - N-aroylureas derivatives, preparation method thereof and pharmaceutical compositions for the prevention and treatment of cancer containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel N-aroylurea derivative having anticancer activity, a preparation method of the same, and a pharmaceutical composition comprising the same as an effective component. More specifically, the present invention relates to an N-aroylurea derivative formed as a product of consecutive reactions of C-H amidation and C-N bond formation using a rhodium (III) catalyst, a preparation method of the same, and a composition for preventing or treating cancer comprising the same as an effective component. The novel N-aroylurea derivative according to the present invention shows excellent anticancer activities in various human cancer cell lines, and thus can be beneficially used as a pharmaceutical composition for preventing and treating cancer. In addition, the preparation method of an N-aroylurea derivative using a rhodium (III) catalyst can be applied to and incorporated into a wide range of functional groups, and as a reaction with regioselectivity and chemoselectivity, may be extremely beneficial in the synthesis of new drugs or compounds having biological activities.

Description

[0001] The present invention relates to a N-aroylurea derivative, a method for preparing the same, and a composition for preventing and treating cancer, which comprises the same as an active ingredient.

The present invention relates to a novel N-aroyl urea derivative having an anticancer activity, a process for producing the same, and a pharmaceutical composition containing the same as an active ingredient.

Nitrogen containing heterocycles are one of the essential structural units found in natural products and pharmaceuticals with a wide range of medicinal applications. In particular, N-acylurea linked with N-heterocycles is attracting attention in the fields of medicine and phytochemistry, showing anti-inflammatory, analgesic, insect repellent, pesticide and antibacterial properties and biological activity. For example, carbergoline, a natural indole analog having an N-acylurea group, is known to exhibit potent inhibitory effects on prolonged pituitary prolactin cells. In addition, N-acylurea residues have been identified as core structures for pesticides and anticancer agents. Due to their unique structural features and their wide range of medicinal applications, research into efficient methods for synthesizing N-aroyl urea has been actively conducted in organic chemistry research. A conventional approach for the preparation of N-acyl or N-aroyl urea is to prepare by coupling reaction between a carboxylic acid derivative and a carbodiimide, and the condensation reaction of an amine with an acylisocyanate is also used to prepare an N- . Recently, it has also been known that an alternative protocol for the formation of N-aroylurea derivatives is via Pd (II) -catalyzon carbonylation of urea having an aryl halide in the presence of CO or Mo (CO) ₈ by microwave irradiation have.

Many studies have been made on CH functionalization by transition metal catalysts, since they provide an efficient approach to the formation of new CC bonds with various unsaturations such as alkenes, alkynes, allenes, and the like. Recent advances have also been made in the field of directly adding C (sp ² ) -H bonds to unsaturated C═O and C═N bonds under transition metal catalysts, in particular by directly inserting CH bonds into the polar π-bonds of isocyanates Is quite useful in providing synthetically useful amide residues. For example, it is known that a phthalimidine derivative can be obtained by reaction between an aromatic aldimine and an isocyanate Re (I) -catalyzed molecule, and the synthesis of N-acylanthranilamide and? -Enamine amide It is also known that an isocyanate is added to cause an amidation reaction of aryl and vinyl CH bonds with Rh (Ⅲ) -catalyst (Y. Kuninobu, Y. Tokunaga, A. Kawata, K. Takai, J. Am. Chem. Soc., 2006, 128, 202). In addition, various directing groups such as phenylpyridine, N-arylpyrazole, oxime and benzoic acid derivatives can be efficiently combined with isocyanate to give the corresponding ortho-amidation reaction or tandem cyclization product under catalysis such as Rh, Ru, Re and Co .

On the other hand, it is known that the C7 functionalizing group of indolin can be used as various structural motifs found in many biologically active natural products and medicines, and the demand for the C7-functionalization of the indolin is increasing. In particular, catalytic synthesis of C7-amidated indolines has attracted considerable interest due to the discovery of useful biological properties. In this connection it is also known to use organic azides, diazoles and anthranyls as sources for amidation under Ru (II), Ir (III) and Rh (III) catalysts.

In addition, recently, the present inventors have proposed C-H amidation reaction of azobenzene and indole and isocyanate with Rh (Ⅲ) -catalyzed site-selective. However, the content of N-aroyl urea formed using isocyanate has not been proposed at all.

Disclosure of the Invention The present invention has been conceived to solve the above-described problems in the prior art, and the present inventors have found that a novel N-aroyl urea derivative having anticancer activity is produced and treated, Prevention or treatment effect of the present invention, the present invention has been completed on the basis thereof.

Accordingly, an object of the present invention is to provide novel N-aroyl urea derivatives having an anticancer activity and pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a process for producing novel N-aroyl urea derivatives having anticancer activity.

It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating cancer, which comprises a novel N-arylaurea derivative having an anticancer activity and a pharmaceutically acceptable salt thereof as an active ingredient.

However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.

In order to achieve the object of the present invention, the present invention provides a N-aroylurea derivative represented by the general formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In this case, in Formula 1,

Wherein R ¹ is hydrogen, halogen, C ₁ -C ₆ alkyl, or CO ₂ Me;

R ² is hydrogen or C ₁ -C ₆ alkyl;

R ³ is C ₁ -C ₆ alkyl or C ₆ -C ₂₀ aryl; And

R ⁴ may be butyl, pentyl, hexyl, octyl, benzyl, phenethyl, cyclopentyl, phenyl, 4-methylphenyl, 4-fluorophenyl, or 4-chlorophenyl.

The present invention also provides a process for producing N-aroyl urea derivatives represented by the above formula (1), which comprises reacting a compound represented by the following formula (2) with an isocyanate represented by the following formula do:

(2)

In this case, in Formula 2,

Wherein R ¹ is hydrogen, halogen, C ₁ -C ₆ alkyl, or CO ₂ Me;

R ² is hydrogen or C ₁ -C ₆ alkyl;

Wherein R ³ is C ₁ -C ₆ alkyl or C ₆ -C ₂₀ aryl.

(3)

In this case, in Formula 3,

R ⁴ may be butyl, pentyl, hexyl, octyl, benzyl, phenethyl, cyclopentyl, phenyl, 4-methylphenyl, 4-fluorophenyl, or 4-chlorophenyl.

In another embodiment of the present invention, the rhodium catalyst may be cyclopentadienyl rhodium (III) complex catalyst substituted with C ₁ -C ₅ alkyl or more preferably pentamethyl (RhCp * Cl ₂ ) ₂ ) catalyst. The catalyst may be a catalyst such as tetramethylcyclopentadienylrhodium (III) chloride dimer.

In another embodiment of the present invention, the reaction may be carried out further comprising an additive.

As still another embodiment, the additive is methyl sulfonyl imide as silver trifluoroacetate (silver tri (fluoromethylsulfonyl) imide, AgNTf 2), copper acetate (Copper (Ⅱ) acetate; Cu (OAc) 2) , or their ≪ / RTI >

In another embodiment of the present invention, the process may be carried out in a dichloroethane (DCE) or toluene solvent.

In still another embodiment of the present invention, the above production method is characterized in that, after the reaction between the compound represented by the general formula (2) and the compound represented by the general formula (3), N-ethyl-1-pivaloylindoline- The compound represented by Formula 4 may be reacted with the compound represented by Formula 3 to form the N-aroyl urea derivative represented by Formula 1. Alternatively,

The present invention provides a pharmaceutical composition for preventing or treating cancer, which comprises an N-araoyl urea derivative represented by Formula 1, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

In one embodiment of the present invention, the cancer may be prostate cancer or breast cancer.

Further, the present invention provides a method for preventing or treating cancer, comprising the step of administering the pharmaceutical composition to a subject.

In addition, the present invention provides the use of the pharmaceutical composition for the prevention or treatment of cancer.

The novel N-aroyl urea derivatives according to the present invention exhibit excellent anticancer activity against various human cancer cells and are expected to be useful as pharmaceutical compositions for cancer prevention and treatment.

In addition, the production process according to the present invention is characterized in that N-aroyl urea is synthesized by a single step through two successive isocyanate-bonding reactions under a rhodium catalyst, and the decomposition of carbon- Which is the first synthesis of a compound into which N-aroylurea is introduced. This is because the conventional production method requires a multi-step synthesis process in which an amide compound is synthesized through various synthetic methods and then synthesized through bonding with isocyanate. In the prior art method in which an excess amount of base is needed in the coupling reaction of an amide compound and isocyanate Which has been overcome.

As described above, the process for preparing N-aroyl urea derivatives using the rhodium (III) catalyst of the present invention can be applied and introduced into a wide range of functional groups, and is a reaction having positional selectivity and chemical selectivity. It will be very useful.

1 shows a process for producing N-aroyl urea derivatives using the rhodium (III) catalyst of the present invention and a conventional process.
2 shows the N-arylaurea derivatives synthesized as a result of performing the CH amidation and the subsequent CN bond formation reaction (CH amidation and CN bond formation reaction) of the present invention using various indoline compounds and the yield will be.
FIG. 3 shows N-aroyl urea derivatives and yields obtained by performing CH-amidation and subsequent CN amidation and CN bond formation reaction according to the present invention using various isocyanate compounds .
4 shows the X-ray diffraction patterns of 3 g of 5-chloro-N-ethyl-N- (ethylcarbamoyl) -1-pivaloylindoline-7-carboxamide synthesized in the present invention The structure analyzed by crystallization analysis is shown.
Figure 5 shows the anticipated mechanism of the N-aroyl urea formation reaction through the CH amidation and subsequent CN bond formation reaction of the present invention.

The present invention provides a novel N-aroyl urea derivative having an anticancer activity, an isomer thereof, a pharmaceutically acceptable salt thereof and a composition for preventing or treating cancer comprising the same as an active ingredient. In addition, the compound according to the present invention inhibits the proliferation of cancer cells and has a prophylactic or therapeutic effect on cancer, and thus can be usefully used for prevention or treatment of cancer.

Hereinafter, the present invention will be described in detail.

The present invention provides a N-aroylurea derivative represented by the general formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In this case, in Formula 1,

Wherein R ¹ is hydrogen, halogen, C ₁ -C ₆ alkyl, or CO ₂ Me;

R ² is hydrogen or C ₁ -C ₆ alkyl;

R ³ is C ₁ -C ₆ alkyl or C ₆ -C ₂₀ aryl;

R ⁴ may be butyl, pentyl, hexyl, octyl, benzyl, phenethyl, cyclopentyl, phenyl, 4-methylphenyl, 4-fluorophenyl, or 4-chlorophenyl.

More preferably, R 1 is hydrogen, methyl, chloro, bromo or CO ₂ Me, R ² is hydrogen or methyl, R ³ is methyl, phenyl or tert- Butyl.

The following describes the definitions of the various substituents for preparing the compounds according to the invention.

The term "C ₁ -C ₆ alkyl" as used herein means a monovalent alkyl group of 1 to 10 carbon atoms. The term is exemplified by functional groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-hexyl and the like.

The term "C ₆ -C ₂₀ aryl" as used herein refers to an unsaturated aromatic ring compound having from 6 to 20 carbon atoms and having a single ring (eg, phenyl) or multiple condensed rings (eg, naphthyl) . Aryl includes phenyl, naphthyl, and the like.

The alkyls described in the present invention, as well as the substituents comprising other alkyl moieties, include both straight chain and branched forms.

Preferred embodiments of the N-aroyl urea derivative represented by the formula (1) according to the present invention are as follows:

N-Ethyl-N-ethylcarbamoyl-1-pivaloyl-7-carboxamide (3a);

1-Benzoyl-N-ethyl-N- (ethylcarbamoyl) indolin-7-carboxamide (3c);

N-ethyl-N- (ethylcarbamoyl) -4-methyl-1-pivaloyl-7-carboxamide carboxamide) (3e);

N-ethyl-N- (ethylcarbamoyl) -5-methyl-1-pivaloylindoline-7- carboxamide carboxamide) (3f);

5-Chloro-N-ethyl-N- (ethylcarbamoyl) -1-pivaloylindoline-7- carboxamide) (3g);

N-ethyl-N- (ethylcarbamoyl) -1-pivaloylindoline-7-carboxamide -carboxamide) (3h);

(Ethyl (ethylcarbamoyl) carbamoyl) -1-pivaloylindoline-5-carboxylate (3 <);

N-ethyl-N- (ethylcarbamoyl) -6-methyl-1-pivaloyl-7-carboxamide carboxamide) (3j);

(6-Chloro-N-ethyl-N- (ethylcarbamoyl) -1-pivaloylindoline-7-carboxamide carboxamide (3k);

(Ethylcarbamoyl) -2-methyl-1-pivaloylindoline-7-carboxamide (N-ethyl-N-ethylcarbamoyl) carboxamide) (31);

(5-Chloro-N-ethyl-N- (ethylcarbamoyl) -2-methyl-1-pivaloyl) methyl-1-pivaloylindoline-7-carboxamide) (3m);

(Ethylcarbamoyl) -3-methyl-1-pivaloylindoline-7-carboxamide (N-ethyl-N-ethylcarbamoyl) carboxamide) (3n);

N-butyl-N- (butylcarbamoyl) -1-pivaloyl-7-carboxamide (4b);

N-Pentyl-N- (pentylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4c);

N-hexyl-N- (hexylcarbamoyl) -1-pivaloyl-N- (hexylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4d);

N-octyl-N- (octylcarbamoyl) -1-pivaloyl-N- (octylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4e);

N-phenethyl-N- (paratinylcarbamoyl) -1-pivaloyl-N- (phenethylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4f);

N-Benzyl-N- (benzylcarbamoyl) -1-pivaloyl-7-carboxamide (4 g);

N-cyclopentyl-N- (cyclopentylcarbamoyl) -1-pivaloyl-N- (cyclopentylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4h);

N-Phenyl-N- (phenylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4i);

1-pivaloyl-N- (p-tolyl) -N- (p-tolylcarbamoyl) indoline-7-carboxamide (1-Pivalyl- ) indoline-7-carboxamide) (4j);

N- (4-Fluorophenyl) -N - ((4-fluorophenyl) carbamoyl) -1-pivaloylindoline- -fluorophenyl) carbamoyl) -1-pivaloylindoline-7-carboxamide) (4k); And

N- (4-chlorophenyl) -N - ((4-chlorophenyl) carbamoyl) -1-pivaloylindoline- ) carbamoyl) -1-pivaloylindoline-7-carboxamide) (4l).

The compound of the present invention can be used in the form of a pharmaceutically acceptable salt. As the salt, acid addition salt formed by a pharmaceutically acceptable free acid is useful.

As used herein, the term "salt" is useful as an acid addition salt formed by a pharmaceutically acceptable free acid. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Dioleate, aromatic acid, aliphatic and aromatic sulfonic acids. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Propyl sulphonate, naphthalene-1-yne, xylenesulfonate, phenylsulfate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, Sulfonate, naphthalene-2-sulfonate or mandelate.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the above compound in an excess amount of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile . It may also be prepared by evaporating a solvent or excess acid in this mixture and then drying or by suction filtration of the precipitated salt.

In addition, the base may be used to make a pharmaceutically acceptable metal salt. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. The corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

In addition, the compounds of the present invention include not only pharmaceutically acceptable salts, but also all salts, isomers, hydrates and solvates which can be prepared by conventional methods.

In another aspect of the present invention, the present invention provides a process for producing N-aroyl urea represented by Formula 1, comprising reacting a compound represented by Formula 2 below with an isocyanate represented by Formula 3 in the presence of a rhodium catalyst A method for producing a derivative is provided.

(2)

(3)

Herein, R ¹ , R ² , R ³ , and R ⁴ in the general formulas (2) and (3) are as defined in the above formula (1).

The process for producing N-aroyl urea derivatives of the present invention is a process for synthesizing N-aroyl urea in a single step through two successive isocyanate-bonding reactions under a rhodium catalyst at room temperature, A compound in which N-aroylurea was introduced at the position 7 of indoline was first synthesized. This is because the conventional production method requires a multistage synthesis process in which an amide compound is synthesized through various synthesis methods and then synthesized through coupling with isocyanate and a problem that an excessive amount of base is needed in the coupling reaction of an amide compound and isocyanate It is overcome.

The above-mentioned production method of the present invention is produced by the above-mentioned Reaction Scheme 1.

[Reaction Scheme 1]

The rhodium catalyst of the present invention may be a C ₁ -C ₅ alkyl substituted or unsubstituted cyclopentadienyl rhodium (III) complex catalyst, more preferably pentamethylcyclopentadienylhodium (RhCp * Cl ₂ ) ₂ ) catalyst, and may be used in an amount of 1 to 4 mol%, preferably 2 to 3 mol, based on 1 mol of the compound of the formula (II) have.

In the production process of the present invention, it is preferable that the reaction is carried out by further comprising an additive. The additive is preferably silver tri (fluoromethylsulfonyl) imide, AgNTf ₂ , copper acetate (Cu (OAc) ₂ ), or a mixture thereof, , But is not limited thereto.

The reaction according to an embodiment of the present invention can be carried out in an organic solvent, and it is not necessary to limit the organic solvent as long as it can dissolve the reactant. Examples of the organic solvent include those selected from the group consisting of dichloroethane (DCE), tetrahydrofuran (THF), acetonitrile (MeCN), toluene, and mixtures thereof, Solubility and Ease of Removal It is preferable to use dichloroethane (DCE) or toluene, more preferably DCE, in view of the reaction efficiency.

In the present invention, the compound represented by Chemical Formula 2 and the compound represented by Chemical Formula 3 may be reacted to produce a compound represented by Chemical Formula 4, which is represented by Chemical Formula 4, N-ethyl-1-pivaloylindoline-7 - carboxamide compound. ≪ / RTI >

The compound represented by the following general formula (4) can be reacted with the compound represented by the general formula (3) to form the N-aroyl urea derivative represented by the general formula (1).

[Chemical Formula 4]

In one embodiment of the present invention, the N-aroyl urea derivative represented by Formula 1 was prepared, and its structure was analyzed and confirmed by NMR or Mass spectroscopy (see Examples 1 to 8).

In another aspect of the present invention, the present invention provides a pharmaceutical composition for preventing, ameliorating, or treating cancer comprising an N-araoyl urea derivative represented by the above formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient Lt; / RTI >

As used herein, the term "prophylactic " means any act that inhibits cancer or delays the onset of cancer by administration of the pharmaceutical composition according to the present invention.

As used herein, the term "treatment" refers to any action that improves or alters the symptoms of cancer by the administration of the pharmaceutical composition according to the present invention.

"Cancer" which is a preventive and therapeutic disease caused by the composition of the present invention is classified into diseases in which normal tissue cells proliferate unlimitedly for some reason and continue rapid development regardless of the life phenomenon of the living body or the surrounding tissue state. The cancer in the invention may preferably be prostate cancer, or breast cancer, but is not limited to this kind.

In one embodiment of the present invention, the anticancer activity against various human cancer cells was evaluated using the N-arylyl urea derivatives synthesized according to the production method of the present invention (see Example 9), and the compounds 4d and 4e Showed stronger anticancer activity than the known anticancer drug cisplatin.

Accordingly, the N-aroyl urea derivative represented by the formula (I) according to the present invention, an isomer thereof or a pharmaceutically acceptable salt thereof may be useful as a pharmaceutical composition for preventing, improving or treating cancer, .

The pharmaceutical composition according to the present invention may contain, in addition to the active ingredient, a pharmaceutically acceptable carrier. Herein, pharmaceutically acceptable carriers are those conventionally used at the time of formulation, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose But are not limited to, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Further, in addition to the above components, a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like may be further included.

The pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dose may vary depending on the condition and weight of the patient, The mode of administration, the route of administration, and the time, but may be appropriately selected by those skilled in the art.

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will depend on the type of disease, severity, The sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, sequentially or concurrently with conventional therapeutic agents, and may be administered singly or in multiple doses. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.

Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the age, sex, condition, body weight, absorbency, inactivation rate and excretion rate of the active ingredient in the body, type of disease, 0.001 to 150 mg, preferably 0.01 to 100 mg, per kg of body weight may be administered daily or every other day, or one to three divided doses per day. However, the dosage may be varied depending on the route of administration, the severity of obesity, sex, weight, age, etc. Therefore, the dosage is not limited to the scope of the present invention by any means.

In another aspect of the present invention, the present invention provides a method of treating cancer comprising administering the pharmaceutical composition to a subject. The term " individual "as used herein refers to a subject in need of treatment for a disease, and more specifically refers to a mammal such as a human or non-human primate, mouse, dog, cat, horse and cattle .

As shown in FIG. 1, the novel N-aroyl urea derivatives produced as a result of the reaction using the rhodium (III) catalyst of the present invention showed excellent anticancer activity against various human cancer cells, It is expected that it can be usefully used as a composition. In addition, the process for preparing N-aroyl urea derivatives using the rhodium (III) catalyst of the present invention can be applied and introduced into a wide range of functional groups, and is a reaction having positional selectivity and chemical selectivity. As a reaction for synthesizing a new drug or a compound having biological activity It will be very useful for.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.

[ Example ]

In the examples of the present invention, commercially available reagents were used without further purification unless otherwise stated. Closed tubes (13 x 100 mm ² ) were purchased from Fischer Scientific, dried overnight in the oven and then cooled to room temperature prior to use and thin layer chromatography was performed using plates coated with Kieselgel 60F254 (Merck) And E. Merck Kieselgel 60 (230-400 mesh) for flash column chromatography.

Nuclear magnetic resonance spectra (1H and 13C NMR) were recorded using a CDCl ₃ solution in a Bruker Unity 400 and 500 spectrometer with chemical shifts reported in parts per million (ppm). The resonance pattern is represented by s (singlet), d (doublet), t (triplet), q (quartet), quint Is used. The coupling constant (J) is expressed in hertz (Hz).

IR spectra were recorded on a Varian 2000 infrared spectrophotometer and reported in cm ^-1 . High resolution mass spectra (HRMS) were analyzed using a JEOL JMS-600 spectrometer.

Example  1. N- Aroylurea  Search for Optimum Reaction Conditions for the Synthesis of Derivatives

In Example 1, in order to set reaction optimum conditions for the synthesis of enoylurea (N-aroylureas) derivatives through the coupling reaction of indoline and isocyanate, as shown in the following Reaction Scheme 2, The aim of this study was to investigate the coupling reaction between valonyl indoline (1a) and ethyl isocyanate (2a). As a result, as shown in Table 1, a cationic rhodium complex derived from [RhCp * Cl ₂ ] ₂ and AgSbF ₆ catalyzed the coupling reaction of 1a and 2a to form N-aroylurea 3a (36% To form amidated indoline 3aa (25%). Item 2 did not use [RhCp * Cl ₂ ] ₂ and no product was produced.

[Reaction Scheme 2]

Entry Additive (mol%) Solvent Yield (%) 3a 3aa One AgSbF ₆ (10) DCE 36 25 2 AgSbF ₆ (10) DCE N.R. N.R. 3 AgSbF ₆ (10), Cu (OAc) ₂ (100) DCE 75 5 4 Cu (OAc) ₂ (100) DCE N.R. N.R. 5 AgSbF ₆ (10), Cu (OAc) ₂ (30) DCE 70 8 6 _{AgNTf 2 (10), Cu (} OAc) 2 (30) DCE 92 4 7 AgPF ₆ (10), Cu (OAc) ₂ (30) DCE 45 14 8 _{AgNTf 2 (10), Cu (} OAc) 2 (10) DCE 72 10 9 _{AgNTf 2 (10), NaOAc (} 30) DCE 54 21 10 AgNTf ₂ (10), CuOAc (30) DCE 79 5 11 _{AgNTf 2 (10), AgOAc (} 30) DCE 78 11 12 _{AgNTf 2 (10), Cu (} OAc) 2 (30) THF 12 20 13 _{AgNTf 2 (10), Cu (} OAc) 2 (30) toluene 70 5 14 _{AgNTf 2 (10), Cu (} OAc) 2 (30) MeCN N.R. N.R. 15 _{AgNTf 2 (10), Cu (} OAc) 2 (30) MeOH N.R. N.R. 16 _{AgNTf 2 (10), Cu (} OAc) 2 (30) DCE 86 3 17 _{AgNTf 2 (10), Cu (} OAc) 2 (30) DCE 31 28 18 _{AgNTf 2 (10), Cu (} OAc) 2 (30) DCE 26 13 19 _{AgNTf 2 (10), Cu (} OAc) 2 (30) DCE N.R. N.R.

Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), [RhCp * Cl ₂ ] ₂ (2.5 mol%), additive (mol% Reaction in pressure tubes

Yield is derived by flash column chromatography

Addition of the Cu (OAc) ₂ additive also showed a significant improved formation of 3a at 75% yield (item 3), while the neutral Rh (III) catalyst did not provide any coupling products (item 4). Interestingly, it has been found that the amount of Cu (II) salt reduced to 30 mol% is comparable in conversion (item 5). Moreover, when the silver additive was changed from AgSbF ₆ to AgNTf ₂ , the formation of the desired N-aroylurea 3a was increased in 92% yield (item 6).

As can be seen in items 7 to 11, it has been found that the combination of different kinds of silver additive and acetate source is not effective in the coupling reaction of the present invention. After screening a range of solvents, it was found that the use of DCE as solvent showed the highest reactivity to the formation of 3a (items 12-15).

Further investigations have shown that using 5 equivalents of 2a (item 16) and 1.5 equivalents of 2a (item 17) and using 3 equivalents of 2a is the optimal amount of coupling product 3a to yield a high yield Respectively.

It is also possible to use a different type of cationic catalyst, Ru (II) catalyst ([Ru (p-cymene) Cl ₂ ] ₂ ) or a Co (III) catalyst ([CoCp * (CO) I ₂ ] (Item 19), it was confirmed that there was no effect on generation.

Example  2. Various Indolin  N- Aroylurea  Synthesis of derivatives

At the optimum conditions of the coupling reaction determined in Example 1 above, coupling reactions of various compounds were carried out. More specifically, as shown in the following Reaction Scheme 3, various indolines (1a to 1n) were reacted with ethyl isocyanate (2a). The resulting products 3a to 3n are shown in FIG.

[Reaction Scheme 3]

- Reaction conditions: 1a-1n (0.2 mmol) , 2a (0.6 mmol), [RhCp * Cl 2] 2 (2.5 mol%), AgNTf 2 (10 mol%), Cu (OAc) 2 (30 mol%), DCE (1 mL), reaction in a pressure tube for 20 hours at room temperature

As a result, N-acetylindoline 1b and N-carbamoylindoline 1d provide trace amounts of N-aroylureas 3b and 3d, whereas N-benzoylindoline 1c provides 3c 71% yield, confirming that it is a good substrate in the coupling reaction of the present invention. In the case of C4- and C5-substituted indolines 1e to 1i, the desired N-aroylurea adduct was obtained in high yield. In particular, the electron insufficiency substituents (Br, Cl and CO ₂ Me) at the C5- position are reduced by the use of 5 equivalents of isocyanate (2a) and / or an extended reaction time (40 hours) Lt; / RTI > It has also been found that C6-substituted indolines 1j and 1k, which have a sterically complex structure, provide C7-functionalized indolines 3j and 3k under slightly modified reaction conditions.

In the case of the indoline substituted with a methyl group, most of the starting compound 1j (68%) was recovered and no formation of C7-amidated indoline 3ja was observed. However, indoline 1k substituted with a C6-chloro group provided a mixture of N-aroylurea 3k (29%) and C7-amidated indoline 3ka (11%) along with the recovered starting material 1k (52% .

Surprisingly, the C6-substituted N-aroylurea products 3j and the diastereomeric E / Z mixture of 3k were observed in a 2.6: 1 ratio. In addition, it has been confirmed that C2- and C3-substituted indolines are compatible in the reaction and provide the desired products 3l-3n in high yield.

Example  3. Coupling of various isocyanates to N- Aroylurea  Synthesis of derivatives

In order to evaluate the range of isocyanate reactants, the ring forming reaction of various isocyanates (2b to 2l) and N-pivaloylindoline (1a) was carried out as shown in the following reaction scheme 4.

[Reaction Scheme 4]

- Reaction conditions: 1a (0.2 mmol), 2b -2l (0.6 mmol), [RhCp * Cl 2] 2 (2.5 mol%), AgNTf 2 (10 mol%), Cu (OAc) 2 (30 mol%), DCE (1 mL), reaction in a pressure tube for 20 hours at room temperature

As a result, it was confirmed that linear alkyl isocyanate 2b-2e was successfully coupled with 1a to give 4b-4e in high yield, as shown in Fig. However, phenethyl isocyanate (2f) and benzyl isocyanate (2g) were less reactive under optimum reaction conditions.

In addition, it was confirmed that an increase in the amount of added 2a (5 equiv.) And / or an extended reaction time (40 hours) formed the corresponding adducts 4f and 4g with increased yield. In contrast, the branched alkyl isocyanate 2h was found to provide a separable mixture of the N-araoyl urea product 4h (23%) and the C7-amidated indolin 4h (51%) under slightly modified reaction conditions.

It has also been confirmed that the aryl isocyanate 2i-2l is also produced under the reaction conditions determined above or slightly modified reaction conditions. The electron enriched isocyanate 2j was found to be relatively less responsive to the formation of 4j, with trace amounts of C7-amidated indolin 4ja and starting compound 1a (30%) being detected. It was confirmed that the anilide group on the N-acylurea formed did not assist further C (sp ² ) -H amidation reaction. Finally, for high yield products (Figures 2 and 3), a mixture of minor amounts of C7-amidated indoline and starting materials as well as mixtures of uncharacterized impurities were observed. However, for 3k, 4c and 4h, a 10-51% yield of C7-amidated indoline was obtained.

Example  4. N- Aroylurea  Identification of derivatives structure

In order to confirm the structure of the resulting N-aroyl urea derivative, its structure was analyzed by X-ray crystallography.

As a result, it was confirmed that 5-Chloro-N-ethyl-N- (ethylcarbamoyl) -1-pivaloylindoline-7-carboxamide compound was produced through the coupling reaction of 1 g of indoline and isocyanate 2a as shown in FIG. .

Example  5. C7- Amidated  (N-ethyl-1-pivaloylindoline-7-carboxamide) Aroylurea  Synthesis of derivatives

In order to obtain a mechanistic insight into the production of the N-aroyl urea derivatives of the present invention, the reaction of 3aa with isocyanate 2a (3 eq.) Was carried out first under the optimum reaction conditions as shown in the following Reaction Scheme 5. N-Aroylurea 3a was produced in high yield (81%) and starting material 3aa was formed together at 7% yield.

[Reaction Scheme 5]

To understand the reaction of N-aroylurea 3a from C7-amidated indoline 3aa, two control experiments were performed. First, as shown in Scheme 6, Cu (OAc) ₂ without the use of, a cationic Rh (Ⅲ) reaction of the amidated C7- indoline 3aa using the composite, N- aroyl urea 3a (70% ) And starting material 3aa (14%).

[Reaction Scheme 6]

The reaction of 3aa with Cu (OAc) ₂ was then carried out as shown in Scheme 7 to give 3a (56%) and the starting material 3aa (42%) was recovered. Based on these results, it can be seen that the formation of urea can be initiated by a cationic Rh (III) complex. It is also noted that the process of the present invention requires Cu (OAc) ₂ , which acts as a source of acetate and base, to provide the N-aroylurea product 3a from indolin-1a and / or C7-amidated indolin- Respectively.

[Reaction Scheme 7]

As shown in the following Reaction Scheme 8, the temperature was changed to 120 deg. C under the above reaction conditions and the reaction of 3a was carried out without adding isocyanate. As a result, it was confirmed that C7-amidated Indoleine 3aa (45%). These results indicate that the formation of N-aroyl derivatives may be reversible.

[Reaction Scheme 8]

Example  6. N- Aroylurea  Identify the mechanism of production reaction

From the above Examples 1 to 5, the production mechanism of the N-aroyl urea derivative of the present invention is shown in Fig. As shown in FIG. 5, when [RhCp * Cl ₂ ] ₂ is treated with AgNTf ₂ and Cu (OAc) ₂ , [RhCp * (OAc)] [NTf ₂ ], which is a cationic Rh To produce an annular porous composite A. The coordination of the subsequent mobile additive of isocyanate 2a can then transfer the rhodacycle intermediate C, which protonates to AcOH and provides C7-amidated indoline 3aa. Formation of N-aroylurea 3a can be derived from intermediate C via a nucleophilic addition to isocyanate (2a) and then a protonation step (path a).

Alternatively, product 3a may also be formed via a metal-mediated and / or base-mediated coupling reaction between amide 3aa and isocyanate 2a (path b). This reaction path is supported by the results of Example 5.

Example  7. N- Aroylurea  Confirm conversion response

In this Example 7, conversion of N-aroylurea functional groups to C7-functionalized indoline was performed as shown in Scheme 9 below. 3a was reacted by addition of NaOEt at 100 < 0 > C and EtOH to give C7-amidated indoline 3aa in 70% yield. Further, the pivaloyl and carbamoyl groups of 3a were all removed with NaOH in EtOH solvent to give C7-amidated pre- (NH) -indolin (6a) in 86% yield.

[Reaction Scheme 9]

Next, sequential C6-functionalization of C7-amidated indoline 3aa was investigated, as shown in Scheme 10 below. First, an allylation reaction was performed using allylmethyl carbonate (7a) under the reaction conditions determined in Example 1 to obtain C6-allylated product 8a in a yield of 63%. In addition, the production of isoquinolone 8b derived from 3a and the alpha -diazo ester (7b) was achieved by C6-alkylation between the amido and acetyl groups and intermolecular condensation.

[Reaction Scheme 10]

The method of synthesizing such N-arylaurea derivatives is applicable to compounds having various functional groups and is very useful in the synthesis of new drugs and compounds having biological activity.

Example 8. Structural Analysis of New Compounds by NMR Analysis

8-1. N-Ethyl-N- (ethylcarbamoyl) -1-pivaloylindoline-7-carboxamide (3a)

Turned feet yl N- blood (1a) (40.7 mg, 0.2 mmol, 100 mol%), [RhCp * Cl 2] 2 (3.1 mg, 0.005 mmol, 2.5 mol%), Cu (OAc) 2 (10.9 mg, 0.06 Ethyl isocyanate (2a) (42.6 mg, 0.6 mmol, 300 mol%) and DCE (1 ml) were added to a solution containing AgNTf ₂ (7.8 mg, 0.02 mmol, 10 mol% . The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with EtOAc (3 mL) and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexane / EtOAc = 3: 1) to give 92.2 mg of 3a in 65.2% yield, which was analyzed by NMR. The production of 3a to 31 and 4b to 4l was also produced according to the above conditions.

[Chemical Formula 3]

63.5 mg (92%); white solid; mp = 119.3-120.9 ^o C; ^{1 H NMR (400 MHz, CDCl} 3) δ 7.79 (br s, 1H), 7.25 (d, J = 6.2 Hz, 2H), 7.14 (d, J = 7.6 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 4.36 (br s, 1H), 4.11 (br s, 1H), 3.82 (br s, 1H), 3.31-2.91 (m, 4H), 1.34 (s, 9H), 1.22 (t, J = 7.0 Hz, 3H), 0.61 (br s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 179.2, 178.4, 156.1, 134.1, 134.1, 127.4, 125.9, 125.1, 124.2, 50.5, 39.8, 35.4, 35.2, 30.3, 27.8, 15.3, 13.6; IR (KBr) υ 3293, 3055 , 2971, 2933, 2874, 2362, 1699, 1650, 1632, 1550, 1446, 1400, 1371, 1359, 1315, 1247, 1163, 1078, 1042, 902, 848, 751 cm - ¹ ; HRMS (orbitrap, ESI) calcd for C 19 H 28 N 3 O 3 [M + H] + 346.2130, found 346.2126.

8-2. 1-Benzoyl-N-ethyl-N- (ethylcarbamoyl) indoline-7-carboxamide (3c)

[Chemical Formula 3c]

51.8 mg (71%); yellow sticky solid; ^{1 H NMR (400 MHz, CDCl} 3) δ 7.78 (br s, 1H), 7.67 (d, J = 7.2 Hz, 2H), 7.50 (d, J = 7.3 Hz, 1H), 7.45-7.41 (m, 2H ), 7.29 (d, J = 7.4 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H) , 3.80 (br s, 2H), 3.11-3.01 (m, 4H), 1.24-1.21 (m, 6H); ¹³ C NMR (100 MHz, CDCl 3)? 170.8, 168.5, 156.4, 139.4, 135.3, 135.2, 131.8, 128.7, 128.4, 127.8, 126.6, 125.4, 125.2, 53.3, 35.5, 29.8, 29.7, 14.0, 13.9; IR (KBr) v 3286, 3058, 2924, 2853, 2304, 1697, 1634, 1549, 1448, 1390, 1330, 1249, 1191, 1077, 1025, 970, 883, 736 cm ^-1 ; HRMS (quadrupole, EI) calcd for C 21 H 23 N 3 O 3 [M] + 365.1739, found 365.1737.

8-3. N-Ethyl-N- ( ethylcarbamoyl ) -4-methyl-1- 피발oylindoline -7-carboxamide (3e) and its structural analysis

[Formula 3e]

68.4 mg (95%); white solid; mp = 130.1-133.7 ^o C; ^{1 H NMR (500 MHz, CDCl} 3) δ 7.88 (br s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 4.34 (br s, 1H) J = 7.0 Hz, 3H (m, IH), 4.08 (br s, IH) ), 0.70 (br s, 3H); ¹³ C NMR (125 MHz, CDCl ₃ )? 179.0, 165.0, 156.2, 140.6, 135.8, 132.7, 132.6, 125.6, 125.1, 50.2, 39.8, 35.2, 29.0, 27.7, 18.7, 13.7 (two carbon overlap); IR (KBr) 3297, 3054, 2970, 2933, 2874, 2359, 2341, 1698, 1627, 1542, 1477, 1447, 1400, 1355, 1316, 1244, 1190, 1172, 1078, 1056, 1026, 813, 735 cm < ^{-1 &} gt ;; HRMS (quadrupole, EI) calcd for C 20 H 29 N 3 O 3 [M] + 359.2209, found 359.2211.

8-4. N-Ethyl-N- ( ethylcarbamoyl ) -5-methyl-1- 피발oylindoline -7- carboxamide  (3f) and analysis of structure

(3f)

50.4 mg (70%); light yellow solid; mp = 125.8-127.0 ^o C; ¹ H NMR (400 MHz, CDCl ₃ )? 7.83 (br s, IH), 7.05 (s, IH), 6.92 (s, 3H), 1.32 (s, 9H), 1.20 (t, J = 6.7 Hz, 3H), 0.57 (br s, 2H) (br s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 179.1, 168.3, 156.4, 138.7, 134.4, 127.3, 126.7, 125.5, 125.4, 50.8, 40.0, 39.5, 35.4, 30.5, 28.0, 21.0, 15.6, 13.8; IR (KBr) v 3294, 3055, 2974, 2932, 2874, 2361, 1698, 1651, 1632, 1556, 1475, 1398, 1357, 1328, 1268, 1240, 1193, 1166, 1090, 1045, 910, 866, 741 cm ^-1 ; HRMS (quadrupole, EI) calcd for C 20 H 29 N 3 O 3 [M] + 359.2209, found 359.2209.

8-5. 5- Chloro -N-ethyl-N- ( ethylcarbamoyl )-One- 피발oylindoline -7- carboxamide  (3g) < / RTI >

[Formula 3g]

50.0 mg (66%); yellow solid; mp = 128.2-128.7 ^o C; ¹ H NMR (400 MHz, CDCl 3)? 7.70 (br s, IH), 7.21 (s, IH), 7.11 2H), 3.21 (br s, 2H), 2.98 (br s, 2H), 1.31 (s, 9H), 1.19 (t, J = 7.0 Hz, 3H), 0.66 (br s, 3H); ^{13 C NMR (100 MHz, CDCl} 3) δ 179.5, 166.7, 155.8, 139.9, 136.3, 129.6, 128.4, 126.1, 125.0, 50.7, 40.0, 39.6, 35.5, 30.3, 29.9, 27.9, 13.8; IR (KBr) υ 3299, 3070, 2971, 2932, 2874, 2344, 1700, 1652, 1634, 1588, 1544, 1457, 1417, 1370, 1353, 1322, 1246, 1213, 1175, 1079, 905, 809, 737 cm ^-1 ; HRMS (quadrupole, EI) calcd for C 19 H 26 ClN 3 O 3 [M] + 379.1663, found 379.1665.

8-6. 5- Bromo -N-ethyl-N- ( ethylcarbamoyl )-One- 피발oylindoline -7- carboxamide  (3h) and analysis of structure

[Chemical Formula 3h]

58.6 mg (69%); light yellow solid; mp = 124.9-125.7 ^o C; ¹ H NMR (400 MHz, CDCl ₃ )? 7.67 (br s, IH), 7.36 (s, IH), 7.25 2H), 3.23 (br s, 2H), 2.99 (br s, 2H), 1.31 (s, 9H), 1.19 (t, J = 7.0 Hz, 3H), 0.67 (br s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 179.4, 166.4, 155.8, 140.4, 136.6, 129.0, 128.8, 127.7, 116.9, 50.7, 40.0, 39.7, 35.5, 30.2, 29.9, 27.9, 13.8; IR (KBr) υ 3296, 3068, 2973, 2932, 2875, 2368, 1701, 1651, 1634, 1581, 1547, 1456, 1414, 1371, 1353, 1321, 1246, 1213, 1162, 1078, 1043, 906, 870 , 808, 733 cm < ^{-1 &} gt ;; HRMS (quadrupole, EI) calcd for C 19 H 26 BrN 3 O 3 [M] + 423.1158, found 423.1160.

8-7. Methyl 7- ( ethyl (ethylcarbamoyl) carbamoyl )-One- 피발oylindoline -5- carboxylate  (3i) and its structural analysis

[Formula 3i]

72.6 mg (90%); yellow solid; mp = 124.4-125.7 ^o C; ¹ H NMR (400 MHz, CDCl ₃ )? 7.91 (s, IH), 7.80 (s, IH), 7.56 (br s, (s, 3H), 3.82 (br s, 2H), 3.27-2.92 (m, 4H), 1.32 (s, 9H), 1.20 (t, J = 7.0 Hz, 3H), 0.58 (br s, 3H); ^{13 C NMR (100 MHz, CDCl} 3) δ 179.9, 167.3, 166.2, 155.8, 145.2, 134.6, 134.5, 127.2, 126.9, 126.0, 52.4, 50.9, 40.2, 39.6, 35.4, 30.0, 29.8, 27.8, 13.9; IR (KBr) υ 3298, 3057, 2965, 2927, 2873, 2364, 1701, 1650, 1540, 1437, 1417, 1355, 1326, 1288, 1242, 1207, 1176, 1120, 1082, 1044, 905, 816, 770 , 733 cm < ^{-1 &} gt ;; HRMS (quadrupole, EI) calcd for C 21 H 29 N 3 O 5 [M] + 403.2107, found 403.2109.

8-8. N-Ethyl-N- ( ethylcarbamoyl ) -6-methyl-1- 피발oylindoline -7- carboxamide  (3j) and analysis of structure

[Chemical formula 3j]

14.4 mg (20%, E: Z = 2.6: 1); white solid; mp = 135.7-137.2 ^o C; ^{1 H NMR (400 MHz, CDCl} 3) δ 7.79 (br s, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 4.35 (t, J = 9.0 2H), 2.26 (s, 3H), 1.33 (m, 2H) s, 9H), 1.24 (t, J = 7.0 Hz, 3H), 0.59 (t, J = 7.2 Hz, 3H); ¹³ C NMR (100 MHz, CDCl 3) δ 179.6, 167.8, 156.2, 141.6, 134.1, 131.9, 127.1, 127.0, 125.1, 51.2, 40.0, 39.1, 35.3, 30.5, 28.0, 20.0, 13.8, 13.7; IR (KBr) ν 3284, 3059, 2973, 2928, 2370, 1699, 1645, 1540, 1456, 1402, 1372, 1316, 1245, 1166, 1079, 897, 808, 743 cm ^-1 ; HRMS (quadrupole, EI) calcd for C 20 H 29 N 3 O 3 [M] + 359.2209, found 359.2209.

8-9. 6- Chloro -N-ethyl-N- ( ethylcarbamoyl )-One- 피발oylindoline -7- carboxamide  (3k) generation and structural analysis

[Chemical Formula 3k]

13.7 mg (18%, E: Z = 2.6: 1); white solid; mp = 152.8-153.5 ^o C; ^{1 H NMR (400 MHz, CDCl} 3) δ 7.43 (br s, 1H), 7.12 (d, J = 8.1 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 4.37 (t, J = 9.2 (M, 2H), 2.97-2.87 (m, 1H), 3.85-3.76 (m, 2H), 1.33 (s, 9H), 1.23 (t, J = 6.9 Hz, 3H), 0.68 (t, J = 7.2 Hz, 3H); ^{13 C NMR (100 MHz, CDCl} 3) δ 179.8, 165.2, 155.5, 143.1, 133.1, 130.0, 127.0, 125.8, 125.7, 51.2, 42.2, 39.3, 35.4, 30.4, 27.9, 13.9, 13.6; IR (KBr) v 3307, 3055, 2965, 2924, 2361, 2342, 1701, 1645, 1540, 1445, 1401, 1373, 1313, 1267, 1244, 1161, 1099, 816, 742 cm ^-1 ; HRMS (orbitrap, ESI) calcd for C ₁₉ H ₂₇ ClN ₃ O ₃ [M + H] ⁺ 380.1735, found 380.1740.

8-10. Production and structural analysis of 6-Chloro-N-ethyl-1-pivaloylindoline-7-carboxamide (3ka)

[Formula 3ka]

6.8 mg (11%); light brown solid; mp = 174.2-178.9 ^o C; ^{1 H NMR (400 MHz, CDCl} 3) δ 7.08 (t, J = 8.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.16 (br s, 1H), 4.14 (t, J = 8.0 Hz, 2H), 3.41-3.34 (m, 2H), 2.98 (t, J = 7.6 Hz, 2H), 1.29 (s, 9H), 1.21 (t, J = 7.2 Hz, 3H); ^{13 C NMR (100 MHz, CDCl} 3) δ 178.6, 165.4, 143.2, 133.1, 129.4, 126.8, 125.6, 125.3, 50.9, 39.8, 34.8, 30.1, 27.9, 14.4; IR (KBr)? 3333, 3055, 2970, 2932, 2876, 2361, 1644, 1589, 1540, 1443, 1421, 1401, 1355, 1267, 1187, 1158, 1097, 1056, 956, 917, 872, 806, 738 cm ^-1 ; HRMS (quadrupole, EI) calcd for C 16 H 21 ClN 2 O 2 [M] + 308.1292, found 308.1294.

8-11. N-Ethyl-N- ( ethylcarbamoyl ) -2-methyl-1- 피발oylindoline -7- carboxamide  (3l) < / RTI >

≪ EMI ID =

44.4 mg (62%); yellow sticky solid; ^{1 H NMR (400 MHz, CDCl} 3) δ 7.92 (br s, 1H), 7.29 (d, J = 7.3 Hz, 1H), 7.18 (d, J = 7.3 Hz, 1H), 7.05 (t, J = 7.5 (Br s, 2H), 3.32 (q, J = 7.1 Hz, 1H), 3.09 (br s, 1H), 2.99 2.58 (d, J = 15.0 Hz, 1H), 1.34 (s, 9H), 1.30 (d, J = 6.3 Hz, 3H), 1.20 (br s, 3H), 0.64 (br s, 3H); ^{13 C NMR (100 MHz, CDCl} 3) δ 177.7, 168.1, 156.1, 139.9, 133.9, 129.3, 126.5, 124.9, 124.6, 57.2, 40.0, 39.5, 37.7, 35.2, 28.4, 20.6, 13.6, 13.7; IR (KBr) υ 3291, 3070 , 2963, 2923, 2853, 2366, 1700, 1653, 1629, 1589, 1551, 1442, 1400, 1373, 1358, 1324, 1247, 1189, 994, 831, 785, 749 cm - ¹ ; HRMS (orbitrap, ESI) calcd for C 20 H 30 N 3 O 3 [M + H] + 360.2282, found 360.2284.

8-12. 5- Chloro -N-ethyl-N- ( ethylcarbamoyl ) -2-methyl-1- 피발oylindoline -7- carboxamide  (3m) and analysis of structure

[Formula 3m]

49.6 mg (63%); brown solid; mp = 121.0-122.1 ^o C; ^{1 H NMR (400 MHz, CDCl} 3) δ 7.80 (br s, 1H), 7.26 (s, 1H), 7.16 (s, 1H), 4.88-4.82 (m, 1H), 3.80 (br s, 2H), (D, J = 15.2 Hz, 1H), 1.33 (s, 9H), 1.30 (br s, 1H) , J = 6.3 Hz, 3H), 1.18 (br s, 3H), 0.68 (br s, 3H); ^{13 C NMR (100 MHz, CDCl} 3) δ δ 177.9, 166.3, 155.6, 138.6, 135.9, 130.1, 129.9, 126.6, 124.9, 57.4, 40.1, 39.5, 37.6, 35.3, 28.3, 20.6, 13.6 (two carbon overlap) ; IR (KBr) ν 3296, 3071, 2969, 2931, 2873, 2361, 1700, 1654, 1629, 1587, 1546, 1454, 1415, 1372, 1350, 1322, 1296, 1246, 1203, 1189, 1105, 1069, 995 , 894, 848, 809, 728 cm < ^{-1 &} gt ;; HRMS (orbitrap, ESI) calcd for C ₂₀ H ₂₉ ClN ₃ O ₃ [M + H] + 394.1892, found 394.1895.

8-13. N-Ethyl-N- ( ethylcarbamoyl ) -3-methyl-1- 피발oylindoline -7- carboxamide  (3n) and analysis of structure

(3n)

64.9 mg (90%); light yellow sticky solid; ^{1 H NMR (500 MHz, CDCl} 3) δ 7.81 (br s, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.02 (t, J = 7.5 2H), 1.33 (s, 9H), 1.21 (t, J = 7.0 Hz, 6H) , 0.60 (br s, 3H); ^{13 C NMR (125 MHz, CDCl} 3) δ 178.7, 167.9, 155.9, 140.7, 139.8, 138.9, 127.3, 124.9, 124.4, 58.1, 39.6, 39.4, 36.8, 35.1, 27.6, 20.6, 16.5, 13.5; IR (KBr) ν 3286, 3057, 2969, 2933, 2874, 2362, 1700, 1633, 1589, 1550, 1439, 1401, 1359, 1315, 1246, 1078, 1048, 957, 901, 849, 732 cm ^-1 ; HRMS (quadrupole, EI) calcd for C 20 H 29 N 3 O 3 [M] + 359.2209, found 359.2208.

8-14. N-Butyl-N- (butylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4b)

(4b)

70.6 mg (88%); brown sticky solid; ^{1 H NMR (400 MHz, CDCl} 3) δ 7.86 (br s, 1H), 7.22 (d, J = 7.3 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 6.98 (t, J = 7.5 (M, 2H), 1.45-1.31 (m, 2H), 3.60 (s, 3H) (m, 15 H), 0.89 (br s, 6 H); ^{13 C NMR (100 MHz, CDCl} 3) δ 179.2, 168.4, 156.9, 141.1, 134.4, 127.9, 126.0, 125.1, 124.6, 50.7, 44.5, 40.4, 39.9, 30.9, 30.7, 30.5, 27.9, 20.2, 19.9, 14.1 , 13.8; IR (KBr) ν 3288, 3057, 2958, 2930, 2872, 2372, 1700, 1651, 1633, 1590, 1552, 1446, 1401, 1361, 1327, 1266, 1227, 1208, 1161, 1095, 746 cm ^-1 ; HRMS (quadrupole, EI) calcd for C ₂₃ H ₃₅ N ₃ O ₃ [M] ⁺ 401.2678, found 401.2676.

8-15. N-Pentyl-N- (pentylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4c)

[Chemical Formula 4c]

63.5 mg (74%); brown sticky solid; ^{1 H NMR (400 MHz, CDCl} 3) δ 7.84 (br s, 1H), 7.22 (d, J = 7.3 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.98 (t, J = 7.5 (M, 3H), 1.66 (m, IH), 4.37 (br s, IH), 4.09-4.02 1.59 (m, 2H), 1.32 (s, 13H), 1.04 (br s, 3H), 0.85-0.71 (m, 9H); ^{13 C NMR (100 MHz, CDCl} 3) δ 179.0, 168.2, 156.8, 141.1, 134.3, 127.9, 126.1, 125.1, 124.6, 50.7, 44.7, 40.6, 39.9, 30.4, 29.1, 28.9, 28.8, 28.4, 27.9, 22.7 , 22.4, 14.1, 14.0; IR (KBr) ν 3289, 3070, 2956, 2929, 2870, 2370, 1700, 1651, 1633, 1551, 1446, 1401, 1361, 1329, 1231, 1097, 902, 747 cm ^-1 ; HRMS (orbitrap, ESI) calcd for C 25 H 40 N 3 O 3 [M + H] + 430.3064, found 430.3066.

8-16. Synthesis and structural analysis of N-Pentyl-1-pivaloylindoline-7-carboxamide (4ca)

[Chemical Formula 4ca]

6.5 mg (10%); white solid; mp = 186.0-188.3 ^o C; ^{1 H NMR (500 MHz, CDCl} 3) δ 7.26 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 5.86 (br J = 8.0 Hz, 2H), 3.64 (q, J = 7.0 Hz, 2H), 3.05 (t, 1.35 (br s, 1H), 1.25 (s, 2H), 0.90 (t, J = 7.0 Hz, 3H); ^{13 C NMR (125 MHz, CDCl} 3) δ 178.1, 168.7, 141.3, 134.4, 128.3, 125.8, 125.7, 124.0, 50.3, 39.9, 39.7, 30.4, 29.3, 29.2, 27.9, 22.4, 13.9; IR (KBr) ν 3239, 3075, 2953, 2927, 2857, 2360, 2341, 1657, 1588, 1557, 1431, 1396, 1355, 1326, 1266, 1233, 1209, 1163, 1100, 1013, 899, 861, 799 , 737 cm < ^{-1 &} gt ;; HRMS (quadrupole, EI) calcd for C 19 H 28 N 2 O 2 [M] + 316.2151, found 316.2148.

8-17. N-Hexyl-N- (hexylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4d)

[Chemical formula 4d]

74.1 mg (81%); brown sticky solid; ^{1 H NMR (400 MHz, CDCl} 3) δ 7.84 (br s, 1H), 7.23 (d, J = 7.3 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.99 (t, J = 7.5 1H), 4.38 (br s, 1H), 4.10-4.04 (m, 1H), 3.75 (br s, 2H), 3.25-3.16 1.59 (m, 2H), 1.33-1.27 (m, 15H), 1.14-1.02 (m, 6H), 0.85-0.78 (m, 8H); ^{13 C NMR (100 MHz, CDCl} 3) δ 179.1, 168.2, 156.8, 141.2, 134.4, 127.9, 126.1, 125.1, 124.6, 50.7, 44.8, 40.7, 39.9, 31.9, 31.6, 30.5, 28.7, 27.9, 26.6, 26.5 , 22.7, 14.3, 14.2; IR (KBr) υ 3296, 3069 , 2955, 2928, 2857, 2346, 1702, 1651, 1633, 1590, 1550, 1446, 1401, 1361, 1328, 1248, 1228, 1162, 1098, 1029, 901, 749 cm - ¹ ; HRMS (quadrupole, EI) calcd for C ₂₇ H ₄₃ N ₃ O ₃ [M] ⁺ 457.3304, found 457.3302.

8-18. N-Octyl-N- (octylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4e)

[Chemical Formula 4e]

84.2 mg (82%); brown sticky solid; ^{1 H NMR (400 MHz, CDCl} 3) δ 7.84 (br s, 1H), 7.21 (d, J = 7.3 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.98 (t, J = 7.5 (M, 3H), 1.67 (m, IH), 4.37 (br s, IH), 4.09-4.02 1.59 (m, 2H), 1.32 (s, 9H), 1.23-1.03 (m, 22H), 0.84 (t, J = 6.9 Hz, 6H); ^{13 C NMR (100 MHz, CDCl} 3) δ 179.1, 168.2, 156.8, 141.2, 134.3, 127.9, 126.0, 125.1, 124.5, 50.7, 44.8, 40.7, 40.0, 32.0, 31.9, 30.5, 29.9, 29.6, 29.4, 29.3 , 28.9, 28.7, 28.6, 27.9, 26.9, 26.8, 22.8, 14.3, 14.2; IR (KBr) ν 3294, 3073, 2954, 2923, 2854, 2361, 1703, 1651, 1634, 1590, 1550, 1446, 1401, 1360, 1325, 1236, 1162, 1099, 901, 749 cm ^-1 ; HRMS (quadrupole, EI) calcd for C ₃₁ H ₅₁ N ₃ O ₃ [M] ⁺ 513.3930, found 513.3931.

8-19. N- Phenethyl -N- ( 폴리ethylcarbamoyl )-One- 피발oylindoline -7- carboxamide  (4f) and analysis of structure

[Formula 4f]

67.6 mg (68%); yellow sticky solid; ^{1 H NMR (400 MHz, CDCl} 3) δ 7.78 (br s, 1H), 7.33-6.93 (m, 13H), 4.34 (br s, 1H), 4.08-3.99 (m, 3H), 3.22 (br s, 2H), 3.05-2.89 (m, 4H), 2.40 (br s, 1H), 2.15 (br s, 1H), 1.34 (s, 9H); ^{13 C NMR (100 MHz, CDCl} 3) δ 178.9, 168.1, 156.6, 139.3, 138.9, 134.3, 129.4, 129.0, 128.8, 128.6, 128.5, 128.4, 128.3, 126.3, 126.2, 125.0, 124.4, 50.5, 46.1, 41.6 , 40.0, 35.1, 30.4, 29.9, 27.9; IR (KBr) v 3295, 3059, 2955, 2923, 2853, 2364, 1698, 1650, 1633, 1590, 1538, 1447, 1400, 1359, 1328, 1261, 1225, 1194, 1163, 1132, 1100, 1028, 902 , 782, 734 cm < ^{-1 &} gt ;; HRMS (quadrupole, EI) calcd for C 31 H 35 N 3 O 3 [M] + 497.2678, found 497.2676.

8-20. N-Benzyl-N- (benzylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4g)

[Chemical Formula 4g]

68.5 mg (73%); white solid; mp = 138.2-139.8 ^o C; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.21 (br s, 1H), 7.55 (br s, 1H), 7.31-7.04 (m, 10H), 6.95 (t, J = 7.2 Hz, 1H), 6.59 ( (m, 2H), 1.32 (s, 9H), 4.32 (d, J = 5.8 Hz, 2H), 4.19-4.87 ); ^{13 C NMR (100 MHz, CDCl} 3) δ 178.8, 168.9, 156.2, 141.0, 139.5, 137.9, 134.5, 128.9, 128.4, 128.3, 127.6, 127.4, 127.1, 126.9, 126.3, 125.2, 124.9, 50.6, 44.9, 44.7 , 39.9, 30.4, 27.9; IR (KBr) ν 3287, 2967, 2932, 2360, 2341, 1712, 1655, 1630, 1588, 1549, 1446, 1433, 1402, 1362, 1223, 1145, 1100, 1028, 905, 794, 745 cm ^-1 ; HRMS (quadrupole, EI) calcd for C ₂₉ H ₃₁ N ₃ O ₃ [M] ⁺ 469.2365, found 469.2368.

8-21. N- Cyclopentyl -N- ( cyclopentylcarbamoyl )-One- 피발oylindoline -7- carboxamide  (4h) and analysis of structure

[Chemical Formula 4h]

17.1 mg (20%); brown solid; mp = 124.9-125.3 ^o C; ^{1 H NMR (400 MHz, CDCl} 3) δ 8.12 (br s, 1H), 7.23-7.18 (m, 2H), 7.01 (t, J = 7.5 Hz, 1H), 4.70-4.62 (m, 1H), 4.37 (t, J = 9.4 Hz, IH), 4.04 (q, J = 9.9 Hz, IH), 3.84 (br s, IH), 3.24-3.15 (m, IH), 2.99-2.93 -2.13 (m, 1H), 1.97-1.67 (m, 9H), 1.39-1.24 (m, 15H); ^{13 C NMR (100 MHz, CDCl} 3) δ 178.9, 167.8, 155.7, 141.0, 134.2, 128.4, 125.9, 125.2, 124.6, 52.4, 50.8, 40.1, 32.6, 31.3, 30.8, 30.5, 29.8, 28.8, 28.0, 24.8 , 24.6, 23.4, 23.0; IR (KBr) ν 3272, 2959, 2870, 2360, 2341, 1715, 1653, 1634, 1557, 1446, 1362, 1222, 1158, 1095, 899, 759 cm ^-1 ; HRMS (quadrupole, EI) calcd for C 25 H 35 N 3 O 3 [M] + 425.2678, found 425.2675.

8-22. Production and structural analysis of N-Cyclopentyl-1-pivaloylindoline-7-carboxamide (4ha)

[Chemical Formula 4 ha]

32.1 mg (51%); white solid; mp = 186.2-189.8 ^o C; _{1H NMR (400 MHz, CDCl 3} ) δ 7.27-7.22 (m, 2H), 7.02 (t, J = 7.6 Hz, 1H), 5.75 (d, J = 7.2 Hz, 1H), 4.32-4.28 (m, 1H 2H), 1.73-1.62 (m, 2H), 1.60-1.54 (m, 2H), 4.23 (t, J = 7.6 Hz, 2H) 4H), 1.35 (s, 9H); ^{13 C NMR (100 MHz, CDCl} 3) δ 178.0, 168.4, 141.2, 134.2, 128.3, 125.8, 124.1 (two carbon overlap), 51.5, 50.4, 39.6, 33.0, 30.4, 27.9, 23.8; IR (KBr) υ 3225, 3055, 2991, 2953, 2923, 2867, 2362, 2341, 1658, 1619, 1586, 1549, 1473, 1450, 1432, 1394, 1351, 1324, 1305, 1267, 1237, 1207, 1162 , 1102, 1029, 975, 954, 935, 907, 892, 871, 853, 777 cm < ^{-1 &} gt ;; HRMS (quadrupole, EI) calcd for C 19 H 26 N 2 O 2 [M] + 314.1994, found 314.1992.

8-23. N-Phenyl-N- (phenylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4i)

[Formula 4i]

62.7 mg (71%); brown solid; mp = 126.9-128.0 ^o C; ^{1 H NMR (400 MHz, CDCl} 3) δ 10.90 (br s, 1H), 7.41 (d, J = 7.1 Hz, 2H), 7.33-7.23 (m, 8H), 7.15 (d, J = 7.4 Hz, 1H ), 7.05 (t, J = 7.4 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 4.05 (br s, 2H), 3.02-2.98 (m, 2H), 1.39 (s, 9H); ^{13 C NMR (100 MHz, CDCl3} ) δ 178.0, 170.5, 152.9, 140.3, 138.4, 138.2, 133.8, 129.5, 128.9, 128.6, 127.9, 126.9, 126.4, 126.3, 124.5, 124.1, 119.9, 50.4, 40.0, 30.1, 28.1; IR (KBr) υ 3205, 3065, 2967, 2925, 2358, 2339, 1716, 1672, 1623, 1597, 1542, 1490, 1445, 1361, 1222, 1140, 1101, 1028, 901, 753 cm ^-1 ; HRMS (quadrupole, EI) calcd for C ₂₇ H ₂₇ N ₃ O ₃ [M] + 441.2052, found 441.2051.

8-24. One- Pivaloyl -N- (p- tolyl ) -N- (p- tolylcarbamoyl ) indoline -7- carboxamide  (4j) and analysis of structure

[Chemical formula 4j]

44.1 mg (47%); brown solid; mp = 146.0-147.9 ^o C; ^{1 H NMR (400 MHz, CDCl} 3) δ 10.81 (br s, 1H), 7.28-7.26 (m, 3H), 7.21 (d, J = 7.1Hz, 2H), 7.15 (d, J = 7.3 Hz, 1H ), 7.09 (d, J = 7.4 Hz, 2H), 7.05 (d, J = 8.1 Hz, 2H), 6.96 (t, J = 7.6 Hz, 1H) , 2H), 2.30 (s, 3H), 2.27 (s, 3H), 1.38 (s, 9H); ^{13 C NMR (100 MHz, CDCl} 3) δ 178.1, 166.7, 152.9, 140.3, 137.7, 135.7, 135.6, 133.8, 133.6, 129.4, 129.3, 129.1, 127.0, 126.3, 126.1, 124.5, 119.9, 50.4, 39.9, 30.1 , 28.0, 21.3, 21.0; IR (KBr) υ 3258, 3029, 2966, 2920, 2360, 1713, 1670, 1626, 1588, 1538, 1500, 1474, 1444, 1402, 1359, 1313, 1268, 1238, 1205, 1169, 1140, 1101, 1064 , 901, 813, 754 cm < ^{-1 &} gt ;; HRMS (quadrupole, EI) calcd for C ₂₉ H ₃₁ N ₃ O ₃ [M] ⁺ 469.2365, found 469.2363.

8-25. N- (4- Fluorophenyl ) -N - ((4- fluorophenyl ) carbamoyl )-One- 피발oylindoline -7- carboxamide  (4k) generation and structural analysis

[Chemical Formula 4k]

66.8 mg (70%); brown sticky solid; ^{1 H NMR (400 MHz, CDCl} 3) δ 10.91 (br s, 1H), 7.36-7.27 (m, 4H), 7.20-7.19 (m, 2H), 7.07-6.90 (m, 5H), 4.13 (br s , 2H), 3.07 (br s, 2H), 1.40 (s, 9H); ^{13 C NMR (100 MHz, CDCl} 3) δ 178.4, 169.7, 162.0 (d, J CF = 246.0 Hz), 159.5 (d, J CF = 241.5 Hz), 140.5, 134.2 (d, J CF = 31.5 Hz), _{134.0 (d, J CF = 25.2} Hz), 131.4 (d, J CF = 79.1 Hz), 131.3, 126.6, 126.5, 126.1, 124.5, 121.7 (d, J CF = 76.7 Hz), 115.7 (d, J CF = 37.8 Hz), 115.5 (d, J _CF = 42.4 Hz), 50.5, 40.1, 30.2, 28.1; IR (KBr) v 3221, 3072, 2965, 2923, 2379, 1714, 1672, 1611, 1549, 1505, 1475, 1402, 1505, 1475, 1402, 1360, 1334, 1271, 1216, 1153, 1140, 1101, 1064 , 902, 833 cm < ^{-1 &} gt ;; HRMS (orbitrap, ESI) calcd for C ₂₇ H ₂₆ F ₂ N ₃ O ₃ [M + H] ⁺ 478.1937, found 478.1941.

8-26. N- (4- Chlorophenyl ) -N - ((4- klorophenyl ) carbamoyl )-One- 피발oylindoline -7- carboxamide  (4l) < / RTI >

(4l)

71.3 mg (70%); light yellow solid; mp = 158.7-159.6 ^o C; ¹ H NMR (400 MHz, CDCl ₃ )? 10.96 (br s, 1 H), 7.34-7.28 (m, 6H), 7.22-7.16 (br s, 2H), 3.05 (t, J = 7.5 Hz, 2H), 1.38 (s, 9H); ^{13 C NMR (100 MHz, CDCl} 3) δ 178.3, 165.4, 152.7, 140.5, 136.8, 136.7, 134.0, 133.9, 130.9, 129.2, 129.0, 128.9, 126.7, 126.3, 126.0, 124.6, 121.1, 50.5, 40.1, 30.2 , 28.1; IR (KBr) ν 3246, 3057, 2964, 2924, 2853, 2358, 2341, 1715, 1676, 1645, 1588, 1538, 1489, 1432, 1401, 1360, 1334, 1304, 1267, 1207, 1172, 1140, 1089 , 1012, 827, 754 cm < ^{-1 &} gt ;; HRMS (orbitrap, ESI) calcd for C 27 H 26 C l2 N 3 O 3 [M + H] + 510.1346, found 510.1351.

Example 9. Evaluation of antitumor activity of N-aroylurea derivatives

In order to evaluate the anticancer activity of the N-aroyl urea derivatives prepared and analyzed in Examples 1 to 8, MTT assay was performed to confirm the growth inhibitory effect on cancer cells. More specifically, human prostate adenocarcinoma cell line (DU145), human breast cancer cell line (MCF-7) and triple negative human breast cancer cell line (MDA-MB-231) were cultured in the presence of 1% penicillin / streptomycin and 10% fetal bovine serum Technologies, Grand Island, NY). Cells were seeded in 96-well plates (3 x 10 ³ cells / well) containing 100 μL of growth medium for 24 hours. After removing the medium, 100 .mu.L of each analogue compound (dissolved in DMSO in an amount of 0.025% or less) was added to each well and cultured at 37.degree. C. for 48 hours. After 48 hours of incubation, 100 占 퐇 of MTT reagent was added to each well. After incubation at 37 ° C for 4 hours, the supernatant was aspirated and the formazan crystals were dissolved in 100 μL of DMSO at 37 ° C for 10 minutes with gentle stirring. Absorbance per well was measured at 540 nm using a VERSA max microplate reader (Molecular Devices Corp.). IC ₅₀ values were defined as concentrations of compounds that inhibited cell proliferation by 50% compared to cells treated with the highest amount of DMSO (0.025%) and were considered to be 100% viability.

As a result, N-aroyl derivative derivatives having linear alkyl side chains showed promising inhibitory activity on DU145 and MCF-7 cell lines, as shown in Table 2 below. In particular, and it showed the compound 4d and 4e have the strongest activity in the treatment of DU145 cancer cell lines _{(4d: IC 50 = 10.9μM,} 4e: IC 50 = 9.8μM). Cytotoxicity of 4d and 4e was about 3 times stronger than that of cisplatin (IC ₅₀ = 30.1 μM), a chemotherapeutic agent known as a positive control.

These results imply that the N-arylaurea derivatives prepared by the method of the present invention can be used as a novel inhibitor for prostate cancer or breast cancer cells.

compounds DU145 ([mu] M) MCF-7 ([mu] M) MDA-MB-231 ([mu] M) 3a > 50 > 50 > 50 3aa > 50 > 50 > 50 3c > 50 > 50 > 50 3e > 50 > 50 > 50 3f > 50 > 50 > 50 3g > 50 > 50 > 50 3h > 50 > 50 > 50 3i > 50 > 50 > 50 3j > 50 > 50 > 50 3k > 50 > 50 > 50 3ka > 50 > 50 > 50 3l > 50 > 50 > 50 3m > 50 > 50 > 50 3n > 50 > 50 > 50 4b > 50 > 50 > 50 4c 28.6 34.4 > 50 4ca > 50 > 50 > 50 4d 10.9 15.7 25.5 4e 9.8 13.6 15.1 4f 11.9 16.2 17.4 4g 30.4 35.8 > 50 4h > 50 > 50 > 50 4ha > 50 > 50 > 50 4i > 50 > 50 > 50 4j > 50 > 50 > 50 4k > 50 > 50 > 50 4l > 50 > 50 > 50 doxorubicin 3.3 5.6 9.2 cisplatin 30.1 35.2 > 50

It will be understood by those skilled in the art that the foregoing description of the present invention is for illustrative purposes only and that those of ordinary skill in the art can readily understand that various changes and modifications may be made without departing from the spirit or essential characteristics of the present invention. will be. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive.

Claims (10)

A N-aroylurea derivative represented by the formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

In Formula 1,
Wherein R ¹ is hydrogen, halogen, C ₁ -C ₆ alkyl, or CO ₂ Me;
R ² is hydrogen or C ₁ -C ₆ alkyl;
R ³ is C ₁ -C ₆ alkyl or C ₆ -C ₂₀ aryl;
R ⁴ may be butyl, pentyl, hexyl, octyl, benzyl, phenethyl, cyclopentyl, phenyl, 4-methylphenyl, 4-fluorophenyl, or 4-chlorophenyl.
The method according to claim 1,
Wherein said N-arylaurea derivative is any one selected from the group consisting of the following compounds: an N-aroylurea derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof;
N-ethyl-N-ethylcarbamoyl-1-pivaloylindoline-7-carboxamide (3a); 1-Benzoyl-N-ethyl-N- (ethylcarbamoyl) indolin-7-carboxamide (3c); N-ethyl-N- (ethylcarbamoyl) -4-methyl-1-pivaloylindoline-7-carboxamide (3e); N-ethyl-N- (ethylcarbamoyl) -5-methyl-1-pivaloylindoline-7-carboxamide (3f); 5-Chloro-N-ethyl-N- (ethylcarbamoyl) -1-pivaloylindoline-7-carboxamide (3g); 5-Bromo-N-ethyl-N- (ethylcarbamoyl) -1-pivaloylindoline-7-carboxamide (3h); Methyl-7- (ethyl (ethylcarbamoyl) carbamoyl) -1-pivaloylindoline-5-carboxylate (3i); N-ethyl-N- (ethylcarbamoyl) -6-methyl-1-pivaloylindene-7-carboxamide (3j); 6-Chloro-N-ethyl-N- (ethylcarbamoyl) -1-pivaloylindoline-7-carboxamide (3k); N-ethyl-N- (ethylcarbamoyl) -2-methyl-1-pivaloylindoline-7-carboxamide (3l); 5-Chloro-N-ethyl-N- (ethylcarbamoyl) -2-methyl-1-pivaloylindoline-7-carboxamide (3m); N-ethyl-N- (ethylcarbamoyl) -3-methyl-1-pivaloylindoline-7-carboxamide (3n); N-butyl-N- (butylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4b); N-pentyl-N- (pentylcarbamoyl) -1-pivaloylindene-7-carboxamide (4c); N-hexyl-N- (hexylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4d); N-octyl-N- (octylcarbamoyl) -1-pivaloylindene-7-carboxamide (4e); N-phenethyl-N- (paratinylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4f); N-Benzyl-N- (benzylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4 g); N-cyclopentyl-N- (cyclopentylcarbamoyl) -1-pivaloylindene-7-carboxamide (4h); N-phenyl-N- (phenylcarbamoyl) -1-pivaloylindoline-7-carboxamide (4i); 1-pivaloyl-N- (p-tolyl) -N- (p-tolylcarbamoyl) indolin-7-carboxamide (4j); N- (4-fluorophenyl) -N - ((4-fluorophenyl) carbamoyl) -1-pivaloylindoline-7-carboxamide (4k); And N- (4-chlorophenyl) -N - ((4-chlorophenyl) carbamoyl) -1-pivaloylindoline-7-carboxamide (4l).
A method for producing N-aroyl urea derivatives represented by the following formula (1), comprising reacting a compound represented by the following formula (2) with an isocyanate represented by the formula (3) in the presence of a rhodium catalyst:
[Chemical Formula 1]

(2)

(3)

In the formulas of any one of formulas (1) to (3)
Wherein R ¹ is hydrogen, halogen, C ₁ -C ₆ alkyl, or CO ₂ Me;
R ² is hydrogen or C ₁ -C ₆ alkyl;
R ³ is C ₁ -C ₆ alkyl or C ₆ -C ₂₀ aryl; And
R ⁴ may be butyl, pentyl, hexyl, octyl, benzyl, phenethyl, cyclopentyl, phenyl, 4-methylphenyl, 4-fluorophenyl, or 4-chlorophenyl.
The method of claim 3,
Wherein the rhodium catalyst is cyclopentadienyl rhodium (III) complex catalyst substituted with C ₁ -C ₅ alkyl or unsubstituted cyclopentadienyl rhodium (III) complex catalyst.
5. The method of claim 4,
Wherein the rhodium catalyst is a pentamethylcyclopentadienylrhodium (III) chloride dimer; [RhCp * Cl ₂ ] ₂ ) catalyst. The method for producing a N-aroylurea derivative .
The method of claim 3,
Wherein the reaction is carried out further comprising an additive.
The method according to claim 6,
Wherein the additive is silver tri (fluoromethylsulfonyl) imide, AgNTf ₂ , copper (II) acetate, Cu (OAc) ₂ ) A method for producing an N-aroylurea derivative.
The method of claim 3,
Wherein the production method is carried out in a solvent of dichloroethane (DCE) or toluene.
A pharmaceutical composition for preventing or treating cancer, which comprises the N-aroyl urea derivative of claim 1 or 2, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
The pharmaceutical composition according to claim 9, wherein the cancer is prostate cancer or breast cancer.

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