KR20210028379A - Pyrazinonindolone derivatives for treatment of triple-negative breast cancer with improved target selectivity and process of preparation thereof - Google Patents

Abstract

The present disclosure relates to a pyrazino indolone derivative with high target selectivity for triple-negative breast cancer and a method for manufacturing the same. More specifically, the present invention relates to: a pyrazino indolone derivative which improves a fact that the target selectivity for conventional triple-negative breast cancer is not high, and has a significantly higher proliferation inhibitory effect than gefitinib; and a method for manufacturing the same.

Description

Pharmaceutical composition of pyrazinonindolone derivatives for treatment of triple-negative breast cancer with improved target selectivity and process of preparation thereof

The present disclosure relates to a pharmaceutical composition of a pyrazinoindolone derivative for treatment of triple negative breast cancer and a method for preparing the same. More specifically, it relates to a pyrazinoindolone derivative having an effect of selectively inhibiting proliferation against MDA-MB-468 cells of triple-negative breast cancer and a method for producing the same.

Breast cancer is a cancer that mainly appears in women, and it has been known to be a complex disease composed of several subtypes as it exhibits various pathological patterns. Various subtypes of breast cancer are caused by different pathogenic factors, and therefore, it is important to use an appropriate target therapy according to the type of breast cancer for proper treatment.

Triple-negative breast cancer, one of the breast cancer subtypes, is a cancer that is negative for estrogen receptor, progesterone receptor and HER2 protein. General breast cancer is caused by overexpression of hormone receptors and HER2, and the prognosis has improved with the development of targeted treatments. However, triple-negative breast cancer accounts for about 20% of all breast cancers, but there is no specific target treatment for it, increasing the likelihood of recurrence and a very poor prognosis.

Various studies are underway to develop targeted treatments for triple negative breast cancer, and it is confirmed that epidermal growth factor receptor (EGFR) is overexpressed in common in patients with triple negative breast cancer, and by suppressing it, triple negative. A method of treating breast cancer is proposed, and a method of combination treatment with gefitinib and various candidate substances is being studied.

In the last study, the present inventors have presented a number of novel pyrazinoindolenic compounds having an effect on triple-negative breast cancer similar to gefitinib (Korean Patent Registration No. 10-1891657). However, the compounds with pyrazinoindolone skeletons that have already been presented showed weak inhibitory effects when target selectivity against MDA-MB-468 cells is strong, or target selectivity weakens when inhibitory effects are strong. Therefore, it was difficult to expect an effect as a target treatment for triple-negative breast cancer in that the selective inhibitory effect between normal breast cancer cells and triple-negative breast cancer cells overexpressing the epithelial cell growth factor receptor (EGFR) was not great.

The present disclosure is intended to provide a pyrazinoindolone derivative exhibiting higher anticancer activity and higher target selectivity than gefitinib (drug name: Iressa) and a method for preparing the same.

According to an embodiment of the present disclosure,

A pyrazinoindolone derivative of the following general formula 1, an isomer thereof, a solvate, or a pharmaceutically acceptable salt thereof is provided.

[General Formula 1]

R ¹ and R ² are each independently a substituted or unsubstituted C 1 to C 40 alkyl group; A substituted or unsubstituted alkenyl group having 2 to 40 carbon atoms; A substituted or unsubstituted alkynyl group having 2 to 40 carbon atoms; A substituted or unsubstituted aryl group having 6 to 40 carbon atoms; A substituted or unsubstituted heteroaryl group having 5 to 40 nuclear atoms; A substituted or unsubstituted aryloxy group having 6 to 40 carbon atoms; A substituted or unsubstituted C1-C40 alkyloxy group; A substituted or unsubstituted arylamine group having 6 to 40 carbon atoms; A substituted or unsubstituted C1-C40 alkylamine group; A substituted or unsubstituted C1-C40 alkyl group having 6 to 40 carbon atoms; A substituted or unsubstituted alkyl group having 1 to 40 carbon atoms having 1 to 6 alcohol groups; An alkyl group having 1 to 40 carbon atoms having a substituted or unsubstituted amine having 1 to 40 carbon atoms; A substituted or unsubstituted C3 to C40 cycloalkyl group; And a substituted or unsubstituted heterocycloalkyl group having 3 to 40 nuclear atoms.

According to another embodiment of the present disclosure,

There is provided a pharmaceutical composition for targeted treatment of triple negative breast cancer comprising a derivative of the general formula 1, an isomer thereof, a solvate, or a pharmaceutically acceptable salt. In addition, there is provided a pharmaceutical composition for treating triple negative breast cancer comprising a derivative of Formula 1, an isomer thereof, a solvate, or a pharmaceutically acceptable salt and gefitinib (drug name: Iressa).

The pyrazinoindolone derivative according to an embodiment of the present disclosure has an effect of strongly inhibiting MDA-MB-468 cells without showing inhibitory activity on MCF-7 cells. In addition, the pyrazinoindolone derivative has a higher inhibitory effect than gefitinib (drug name: Iressa) by inhibiting the expression of the proliferation signaling protein in MDA-MB-468 cells. Accordingly, the pyrazinoindolone derivative of the present disclosure can be suggested as a candidate material for a target therapeutic agent for triple negative breast cancer.

1 is a schematic diagram of a specific example of a method for preparing a pyrazinoindolone derivative according to the present disclosure.
Figure 2 is a schematic diagram of a comparison of the apoptosis values for MDA-MB-468 cells of compounds 2b, 2f and 2i according to the present disclosure with gefitinib (drug name: Iressa).
3 is a Western blot data showing the effect of the high activity 2b, 2f and 2i compounds on the subsignal of the MDA-MB-468 cell growth factor.
Figure 4 is a graph confirming the synergistic effect of the combination administration of the pyrazinoindolone derivative and gefitinib according to the present disclosure.

The present invention can all be achieved by the following description. The following description should be understood as describing specific embodiments of the present invention, and the present invention is not necessarily limited thereto. In addition, it should be understood that the accompanying drawings are provided to aid understanding, and the present invention is not limited thereto.

The embodiments of the present disclosure may be subjected to various changes and may be implemented in various forms. Accordingly, it is to be understood that the spirit and technical features of the present disclosure include all changes, equivalents, and substitutes within the recognized range.

Although not otherwise specified, all numbers used in this disclosure are to be understood as being modifiable by the term “about” in all instances. The modifier “about” is intended to have a generally recognized approximate meaning, which can be interpreted more accurately as a meaning within a certain percentage of the modified value, and more specifically ±20%, ±10%, ± It may mean 5%, ±2%, or ±1% or less.

Terms used in the present disclosure may be defined as follows. Terms that are not defined in the present disclosure may be defined in a range that can be commonly understood or acquired in the technical field to which the present invention belongs.

“Alkyl group” may mean a monovalent group derived from a linear or branched saturated hydrocarbon, and may be substituted or unsubstituted. Examples of such an alkyl group having 1 to 6 carbon atoms include methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), 1-propyl (n-Pr, n-propyl, -CH ₂ CH ₂ CH ₃ ) , 2-propyl (i-Pr, i-propyl, -CH(CH ₃ ) ₂ ), 1-butyl (n-Bu, n-butyl, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1 -Propyl (i-Bu, i-butyl, -CH ₂ CH(CH ₃ ) ₂ ), 2-butyl (s-Bu, s-butyl, -CH(CH ₃ )CH ₂ CH ₃ ), 2-methyl- 2-propyl (t-Bu, t-butyl, -C(CH ₃ ) ₃ ), 1-pentyl (n-pentyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl- 2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl(-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl(-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2 -Pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3- Pentyl(-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl(-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ) and 3,3-dimethyl-2-butyl(-CH(CH ₃ )C(CH ₃ ) ₃ , but these are only examples, and the alkyl group of the present disclosure Is not limited to 1 to 6 carbon atoms.

“Alkoxy group” is a monovalent group having an -O-alkyl group, and may be understood to include all of a linear, branched or cyclic structure. The alkyl group includes all of the alkyl groups defined above, and the alkyl group may or may not be substituted. Examples of such an alkoxy group include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and isobutoxy.

“Aryl group” may mean a monovalent group derived from a single ring or an aromatic hydrocarbon in which two or more rings are combined, may be substituted or unsubstituted, and may include a form in which two or more rings are simply attached or condensed with each other. I can. Examples of such aryl groups include phenyl, naphthyl, phenanthryl, and anthryl, but are not limited thereto.

“Heterocycle” may mean a structure in which at least one carbon of a saturated ring, an unsaturated ring, and an aromatic ring is substituted with a hetero atom (eg, N, O, or S) to form a ring skeleton. These heterocycles may be substituted or unsubstituted, examples of which are pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridyl, pyrazinyl, 6-membered monocyclic rings such as pyrimidinyl, pyridazinyl, and triazinyl; Polycyclics such as phenoxathienyl, indolizinyl, indolyl, purinyl, quinolyl, benzothiazole, and carbazolyl ring; And 2-furanyl, N-imidazolyl, 2-isoxazolyl, 2-pyridinyl, 2-pyrimidinyl, and the like, but are not limited thereto.

The “carbonyl group” may mean collectively a group having a double bond of carbon and oxygen, and may include a ketone group, an aldehyde group, a carboxyl group, and the like.

“Carboxyl group” may mean a structure in which one oxygen atom is further bonded to a carbonyl group in which an oxygen atom is connected to a central carbon atom by a double bond, and various substituents may be present at the remaining bonding positions of carbon and oxygen.

“Halogen” may mean at least one halogen atom or a substituent, and examples thereof include fluorine, bromine, chlorine, or iodine. In addition, it can usually be represented by X in the general formula.

"Alkali" may mean at least one alkali metal atom or substituent, and examples thereof include lithium, sodium, potassium, cesium, rubidium, or francium.

Structure of pyrazinoindolone derivatives

According to an embodiment of the present disclosure, a pyrazinoindolone derivative represented by General Formula 1 is prepared.

[General Formula 1]

R ¹ and R ² are each independently a substituted or unsubstituted C 1 to C 40 alkyl group; A substituted or unsubstituted alkenyl group having 2 to 40 carbon atoms; A substituted or unsubstituted alkynyl group having 2 to 40 carbon atoms; A substituted or unsubstituted aryl group having 6 to 40 carbon atoms; A substituted or unsubstituted heteroaryl group having 5 to 40 nuclear atoms; A substituted or unsubstituted aryloxy group having 6 to 40 carbon atoms; A substituted or unsubstituted C1-C40 alkyloxy group; A substituted or unsubstituted arylamine group having 6 to 40 carbon atoms; A substituted or unsubstituted C1-C40 alkylamine group; A substituted or unsubstituted C1-C40 alkyl group having 6 to 40 carbon atoms; A substituted or unsubstituted alkyl group having 1 to 40 carbon atoms having 1 to 6 alcohol groups; An alkyl group having 1 to 40 carbon atoms having a substituted or unsubstituted amine having 1 to 40 carbon atoms; A substituted or unsubstituted C3 to C40 cycloalkyl group; And a substituted or unsubstituted heterocycloalkyl group having 3 to 40 nuclear atoms; but is not limited thereto.

According to a specific embodiment, R ¹ is a substituted or unsubstituted benzyl group; It may be a substituted or unsubstituted aryl group having 6 to 40 carbon atoms. More specifically, R ¹ is a nitro group (-NO ₂ ), a fluoride group (-F), a cyano group (-CN), a trifluoromethyl group (-CF ₃ ), a trifluoromethoxy group (-OCF ₃ ), a benzyl group in which a substituent selected from the group consisting of a methyl group (-CH ₃ ) and a phenyl group (-C ₆ H _{5 ) is substituted at the para position;, a nitro group (-NO 2} ), a fluoride group (- F), a benzyl group in which a substituent selected from the group consisting of a cyano group (-CN), a trifluoromethoxy group (-OCF ₃ ) and a methyl group (-CH _{3) is substituted at the meta position;} Or the naphthalenyl group may be a substituted methyl group, and R ² may be a substituted or unsubstituted benzyl group; or a substituted or unsubstituted furfuryl group.

Efficacy of pyrazinoindolone derivatives

The pyrazinoindolone derivatives of the present disclosure do not show inhibitory activity against MCF-7 cells, which are luminal A type breast cancer cells, and gefitinib against MDA-MB-468 of triple negative breast cancer (drug name: Iressa). It may exhibit a superior inhibitory response. Therefore, the pyrazinoindolone derivative may have high target selectivity for cells of triple negative breast cancer. The pyrazinoindolone derivative can inhibit the phosphorylation of Akt protein, a cell proliferation signaling protein, of MDA-MB-468 cells in triple negative breast cancer. The pyrazinoindolone derivative, its isomer, solvate, and a pharmaceutical composition containing a pharmaceutically acceptable salt may be a target therapeutic agent for triple negative breast cancer. The pyrazinoindolone derivative, its isomers, solvates, and pharmaceutical compositions comprising a pharmaceutically acceptable salt and gepinidip may be a therapeutic agent for triple negative breast cancer.

Method for preparing pyrazinoindolone derivatives

Stage 1

According to one embodiment of the present disclosure, the amine group of the general formula 2 ^{undergoes a nucleophilic attack on the carbonyl group of the general formula 3, and R 5} is eliminated to form an amide bond, thereby producing the reaction intermediate I represented by the general formula 4. do.

The reaction was carried out in anhydrous dichloride methane solvent in 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC), triethylamine and Reactive intermediate I material can be obtained by adding 1-hydroxybenzotriazole (HOBt) dropwise in order.

The reaction may be about -30 to 50°C, specifically about -10 to 20°C, and more specifically -5 to 10°C. The 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, triethylamine, and 1-hydroxybenzotriazole may be about 0.1 to 5 equivalents, specifically about 0.5 to 3 equivalents. And, more specifically, it may be 1.0 to 2.0 equivalents. The reaction may be performed for at least about 3 hours, specifically for at least about 10 hours, and more specifically for at least about 15 hours. The reaction catalyst, the number of equivalents, and the reaction medium may be equivalents or substitutes that can be selected by one of ordinary skill in the art to which the present invention belongs.

[General Formula 2]

[General Formula 3]

[General Formula 4]

Step 2

Reaction intermediate I of the general formula 4 can be produced by performing an intramolecular Mitsunobu reaction, and the reaction intermediate II represented by the general formula 5.

The reaction may be a condition that can be selected by a person skilled in the art to perform the Mitsonobu reaction. According to a specific embodiment, in the presence of diethyl azodicarboxylate (DEAD) and triphenylphosphine (PPh ₃ ) in anhydrous tetrahydrofuran (THF) solvent, the reaction intermediate I performs an intramolecular Mitsunobu reaction. Thus, reaction intermediate II can be obtained.

The reaction may be about 5 to 100°C, specifically about 10 to 50°C, and more specifically 155 to 30°C. The diethyl azodicarboxylate and triphenylphosphine may be about 0.1 to 5 equivalents, specifically about 0.5 to 3 equivalents, and more specifically 1.0 to 2.0 equivalents. The reaction may be performed for at least about 3 hours, specifically for at least about 10 hours, and more specifically for at least about 20 hours. The reaction catalyst, the number of equivalents, and the reaction medium may be equivalents or substitutes selectable by a person skilled in the art to which the present invention belongs. The reaction catalyst and reaction medium may be selected by a person skilled in the art to which the present invention belongs. There may be equivalents or substitutes.

[General Formula 5]

Step 3

Reaction Intermediate II of Formula 5 reacts with a halide represented by Formula 6 to produce Reactive Intermediate III represented by Formula 7.

The reaction can take place in the presence of alkali carbonate and tetrabutylammonium halide in anhydrous dichloride methane solvent. The alkali may be at least one selected from the group consisting of Li, Na, K, Cs, Rb and Fr, and the halide may be at least one selected from the group consisting of F, Cl, Br, and I. The reaction catalyst and reaction medium may be equivalents or substitutes that can be selected by a person skilled in the art to which the present invention belongs.

[General Formula 6]

[General Formula 7]

Step 4

Reaction Intermediate III of the general formula 7 may form a final product by amide bonds with various amines. The final product can be obtained by separating through a purification process that can be selected by a person skilled in the art. According to a specific embodiment, the amine may be R ² -NH ₂ , and may be a final product represented by General Formula 1. The reaction can take place in an alcoholic solvent having 1 to 4 carbon atoms. The reaction can be accelerated by adding an acid additive.

The reaction may occur at about 20 to 200°C, specifically at about 40 to 150°C, and more specifically at about 60 to 90°C. The reaction may be performed for at least about 3 hours, specifically for at least about 10 hours, and more specifically for at least about 20 hours. The reaction catalyst, the number of equivalents, and the reaction medium may be equivalents or substitutes that can be selected by one of ordinary skill in the art to which the present invention belongs.

[General Formula 1]

In the ^{second step, R 3} may be a substituent that causes ring closure and eliminates when the intramolecular Mitsunobu reaction occurs. If a similar substitution reaction other than Mitsonobu is used, R ³ can undergo a cyclization reaction by introducing various leaving groups such as a hydroxyl group, an alkyloxy group, and a halogen group.

The R ⁴ and R ⁵ may be a substituent which is released when an amine forms an amide bond by nucleophilic attack on a carbonyl group. Specifically, it may be selected from a group of substituents having weaker nucleophilicity than amines. More specifically, R ⁴ and R ⁵ are each independently a hydroxyl group (-OH), an alkyloxy group having 1 to 4 carbon atoms (-O-alkyl), a halogen group (-F, -Cl, -Br or -I), Nitro group (-NO ₂ ), sulfonyl group (-SO ₂ R ⁶ ), cyano group (-CN), ammonium group (-N(R ⁶ ) ₃ ⁺ ), carbonyl group (-COR ⁶ ) or trifluoromethyl group ( -CF ₃ ), wherein R ⁶ is hydrogen, a hydroxyl group, an alkyl group having 1 to 40 carbon atoms, an alkenyl group having 2 to 40 carbon atoms, an alkynyl group having 2 to 40 carbon atoms, an aryl group having 6 to 40 carbon atoms, and 5 to nuclear atoms Having a 40 heteroaryl group, a C 6 to C 40 aryloxy group, a C 1 to C 40 alkyloxy group, a C 6 to C 40 arylamine group, a C 1 to C 40 alkylamine group, a C 6 to C 40 aryl An alkyl group having 1 to 40 carbon atoms, an alkyl group having 1 to 40 carbon atoms having an alcohol group having 1 to 6 carbon atoms, an alkyl group having 1 to 40 carbon atoms having an amine having 1 to 40 carbon atoms, a cycloalkyl group having 3 to 40 carbon atoms, and 3 to 40 nuclear atoms It may be selected from the group consisting of a heterocycloalkyl group, but is not limited thereto.

X may mean a halogen atom or a substituent, and more specifically, may be fluorine (F), bromine (Br), chlorine (Cl), or iodine (I).

Example 1. Preparation of pyrazinoindolone derivatives

Experiments were conducted as shown in FIG. 1.

More specifically, L-serine methyl ester ( 1 ) and 1H-indole- 2 -carboxylic acid (2) were mixed with 1-ethyl-3-(3-dimethylaminopropyl)- in anhydrous dichloride methane solvent at 0°C. 1.3 equivalents of carbodiimide (1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, EDC), 3 equivalents of triethylamine, and 1 equivalent of 1-hydroxybenzotriazole (HOBt) are added dropwise in order. Reaction Intermediate I (3 ) was synthesized after at least 18 hours reaction, and diethyl azodicarboxylate (DEAD) and triphenylphosyl were synthesized in anhydrous tetrahydrofuran (THF) solvent at room temperature (20-25 ℃). Reaction Intermediate II (4 ) was synthesized after reaction for 24 hours in the presence of 1.3 equivalents of pin (PPh _{3 ).} Reaction Intermediate II ( 4 ) and benzyl bromide having a substituent were _{synthesized in the presence of cesium carbonate (Cs 2} CO ₃ ) and tetrabutylammonium iodine (TBAI) in anhydrous dichloride methane solvent to synthesize reaction intermediate III (5 ). Reaction intermediate III (5 ) and 1.5 equivalents of perfurylamine were added to alcohol at 60 to 90° C., stirred for 12 to 24 hours, and then subjected to a series of purification processes to produce 1a-m compound. Alternatively, reaction intermediate III (5 ) and 1.5 equivalents of benzylamine were added to alcohol at 60 to 90° C., stirred for 12 to 24 hours, and then subjected to a series of purification processes to produce a 2a-m compound.

Example 2. Product yield and spectroscopic data

Example 2-1 (1a) (S)-N-Perfuryl-2-(3-nitrobenzyl)-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.07-8.04 (m, 1H), 7.98 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H ), 7.34-7.30 (m, 2H), 7.27-7.25 (m, 2H), 7.22-7.18 (m, 2H), 6.32 (t, J = 5.9 Hz, 1H, NH), 6.27 (dd, J = 3.2 , 1.9 Hz, 1H), 6.21 (d, J = 16.9 Hz, 1H), 6.08 (dd, J = 3.2, 0.8 Hz, 1H), 5.83 (d, J = 16.9 Hz, 1H), 4.85 (dd, J = 11.0, 8.6 Hz, 1H), 4.64 (dd, J = 11.0, 8.6 Hz, 1H), 4.53 (t, J = 8.6 Hz, 1H), 4.36 (dd, J = 15.5, 5.9 Hz, 1H), 4.15 (dd, J=15.6, 5.9 Hz, 1H); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 171.2, 160.4, 150.7, 148.6, 142.3, 140.8, 139.3, 131.9, 129.8, 126.7, 125.5, 125.2, 122.8, 122.4, 121.4, 121.1, 110.5, 110.2, 110.0, 107.6 , 69.5, 69.4, 47.6, 36.1; HRMS (ESI-QTOF) m/z calcd for C ₂₄ H ₂₁ N ₄ O ₅ ⁺ [M+H] ⁺ 445.1506, found 445.1507. Yield 41% Example 2-2 (1b) (S)-N-Perfuryl-2-(4-nitrobenzyl)-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.07 (d, J = 8.8 Hz, 2H), 7.74 (d, J = 7.9 Hz, 1H), 7.32 (ddd, J = 8.5, 6.8, 1.1 Hz, 1H ), 7.30 (d, J = 0.9 Hz, 1H), 7.29 (dd, J = 1.9, 0.9 Hz, 1H), 7.24 (dd, J = 8.5, 0.9 Hz, 1H), 7.21 (ddd, J = 7.9, 6.8, 1.1 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 6.27 (dd, J = 3.2, 1.9 Hz, 1H), 6.26 (d, J = 17.3 Hz, 1H), 6.23 (s, 1H, NH) 6.07 (dd, J = 3.2, 0.9 Hz, 1H), 5.79 (d, J = 17.3 Hz, 1H), 4.84 (dd, J = 11.0, 8.6 Hz, 1H), 4.63 (dd, J = 11.0, 8.6 Hz, 1H), 4.51 (t, J = 8.6 Hz, 1H), 4.31 (dd, J = 15.5, 5.9 Hz, 1H), 4.17 (dd, J = 15.5, 5.9 Hz, 1H); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 171.2, 160.4, 150.6, 147.2, 146.1, 142.4, 139.4, 126.7, 126.6, 125.5, 125.2, 124.1, 122.8, 121.4, 110.5, 110.2, 110.0, 107.6, 69.5, 69.4 , 47.8, 36.0; ; HRMS (ESI-QTOF) m/z calcd for C ₂₄ H ₂₁ N ₄ O ₅ ⁺ [M+H] ⁺ 445.1506, found 445.1510. Yield 55% Example 2-3 (1c) (S)-2-(3-Fluorobenzyl)-N-perfuryl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.73 (dt, J = 8.0, 1.0 Hz, 1H), 7.33-7.29 (m, 3H), 7.28 (s, 1H), 7.22-7.17 (m, 2H) , 6.87 (td, J = 8.4, 2.6 Hz, 1H), 6.75 (ddd, J = 7.7, 1.7, 0.9 Hz, 1H), 6.62 (dt, J = 9.7, 2.1 Hz, 1H), 6.35 (t, J = 5.9 Hz, 1H, NH), 6.29 (dd, J = 3.2, 1.8 Hz, 1H), 6.16 (d, J = 16.8 Hz, 1H), 6.09 (dd, J = 3.2, 0.9 Hz, 1H), 5.71 (d, J = 16.8 Hz, 1H), 4.85 (dd, J = 11.0, 8.4 Hz, 1H), 4.62 (dd, J = 11.0, 8.4 Hz, 1H), 4.50 (t, J = 8.4 Hz, 1H) , 4.35 (dd, J =15.6, 5.9 Hz, 1H), 4.11 (dd, J =15.6, 5.9 Hz, 1H); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 171.5, 163.3 ( J _FC = 247 Hz), 160.3, 151.0, 142.2, 141.4 ( J _FC = 6.9 Hz), 139.6, 130.4 ( J _FC = 8.2 Hz), 126.5, 125.3, 125.2, 122.6, 121.4 ( J _FC = 2.9 Hz), 121.1, 114.2 ( J _FC = 21.1 Hz), 112.9 ( J _FC = 22.2 Hz), 110.5, 110.3, 109.9, 107.4, 69.5, 69.4, 47.7 ( J _FC = 2.0 Hz), 36.1; HRMS (ESI-QTOF) m/z calcd for C ₂₄ H ₂₁ FN ₃ O ₃ ⁺ [M+H] ⁺ 418.1561, found 418.1566. Yield 54%

Example 2-4 (1d) (S)-2-(4-Fluorobenzyl)-N-perfuryl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.72 (d, J = 8.1 Hz, 1H), 7.33-7.29 (m, 3H), 7.26 (s, 1H), 7.18 (dt, J = 8.0, 4.0 Hz , 1H), 6.95-6.85 (m, 4H), 6.35 (t, J = 6.0 Hz, 1H, NH), 6.30 (dd, J = 3.3, 1.9 Hz, 1H), 6.18-6.06 (m, 2H), 5.66 (d, J = 16.5 Hz, 1H), 4.86 (dd, J = 11.0, 8.4 Hz, 1H), 4.62 (dd, J = 11.0, 8.4 Hz, 1H), 4.50 (t, J = 8.4 Hz, 1H ), 4.35 (dd, J =15.5, 6.0 Hz, 1H), 4.14 (dd, J =15.5, 6.0 Hz, 1H); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 171.5, 161.8 ( J _FC = 245 Hz), 160.4, 150.9, 142.4, 139.6, 134.3 ( J _FC = 3.1 Hz), 127.4 ( J _FC = 7.9 Hz), 126.6, 125.3, 125.2, 122.6, 121.1, 115.8 ( J _FC = 21.5 Hz), 110.5, 110.4, 109.8, 107.5, 69.5, 69.4, 47.5, 36.1; HRMS (ESI-QTOF) m/z calcd for C ₂₄ H ₂₁ FN ₃ O ₃ ⁺ [M+H] ⁺ 418.1561, found 418.1565. Yield 67% Example 2-5 (1e) (S)-2-(3-cyanobenzyl)-N-perfuryl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.74 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.35-7.32 (m, 2H), 7.32-7.28 (m , 2H), 7.26-7.23 (m, 2H), 7.23-7.17 (m, 2H), 6.34-6.29 (m, 1H), 6.28 (t, J = 5.9 Hz, 1H, NH), 6.12 (d, J = 16.9 Hz, 1H), 6.12 (dt, J = 3.2, 0.8 Hz, 2H), 5.80 (d, J = 16.9 Hz, 1H), 4.84 (dd, J = 11.0, 8.6 Hz, 1H), 4.63 (dd , J = 11.0, 8.6 Hz, 1H), 4.52 (t, J = 8.6 Hz, 1H), 4.37 (dd, J = 15.6, 5.9 Hz, 1H), 4.17 (dd, J = 15.6, 5.9 Hz, 1H) ; ¹³ C-NMR (100MHz, CDCl ₃ ) δ 171.3, 160.4, 150.8, 142.4, 140.3, 139.4, 131.1, 130.3, 129.6, 129.4, 126.7, 125.6, 125.2, 122.8, 121.4, 118.7, 113.1, 110.6, 110.2, 110.1 , 107.7, 69.5, 69.4, 47.6, 36.1; HRMS (ESI-QTOF) m/z calcd for C ₂₅ H ₂₁ N ₄ O ₃ ⁺ [M+H] ⁺ 425.1608, found 425.1610. Yield 44% Example 2-6 (1f) (S)-2-(4-cyanobenzyl)-N-perfuryl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.73 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.37-7.34 (m, 1H), 7.32 (ddd, J = 8.4, 6.9, 1.2 Hz, 1H), 7.29 (s, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.22-7.17 (m, 1H), 7.04 (d, J = 8.2 Hz, 2H) , 6.35 (dd, J = 3.1, 1.9 Hz, 1H), 6.26 (t, J = 5.8 Hz, 1H, NH), 6.21 (d, J = 17.2 Hz, 1H), 6.15 (d, J = 3.1 Hz, 1H), 5.75 (d, J = 17.2 Hz, 1H), 4.84 (dd, J = 11.0, 8.6 Hz, 1H), 4.63 (dd, J = 11.0, 8.6 Hz, 1H), 4.51 (t, J = 8.6 Hz, 1H), 4.35 (dd, J =15.5, 5.8 Hz, 1H), 4.17 (dd, J =15.5, 5.8 Hz, 1H); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 171.3, 160.4, 150.7, 144.2, 142.5, 139.4, 132.7, 126.7, 126.6, 125.5, 125.2, 122.8 121.4, 118.7, 111.3, 110.7, 110.12, 110.08, 107.8, 69.5, 69.4, 48.0, 36.1; HRMS (ESI-QTOF) m/z calcd for C ₂₅ H ₂₁ N ₄ O ₃ ⁺ [M+H] ⁺ 425.1608, found 425.1607. Yield 33%

Example 2-7 (1 g) (S)-N-Perfuryl-1-oxo-2-(4-trifluoromethylbenzyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxa Maid

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.74 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.34-7.29 (m, 3H), 7.28 (s, 1H) ), 7.23-7.16 (m, 1H), 7.07 (d, J = 8.0 Hz, 2H), 6.34 (t, J = 6.0 Hz, 1H, NH), 6.29 (dd, J = 3.2, 1.9 Hz, 1H) , 6.25 (d, J = 16.9 Hz, 1H), 6.10 (d, J = 3.2 Hz, 1H), 5.76 (d, J = 16.9 Hz, 1H), 4.85 (dd, J = 11.0, 8.5 Hz, 1H) , 4.62 (dd, J = 11.0, 8.5 Hz, 1H), 4.51 (t, J = 8.5 Hz, 1H), 4.35 (dd, J = 15.6, 6.4 Hz, 1H), 4.09 (dd, J = 15.6, 5.5 Hz, 1H); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 171.4, 160.4, 150.9, 142.8 ( J _FC = 1.4 Hz), 142.4, 139.5, 129.6 ( J _FC = 32.5 Hz), 126.7, 126.2, 125.9 ( J _FC = 3.8 Hz ), 125.4, 125.3, 124.1 ( J _FC = 272 Hz), 122.7, 121.3, 110.5, 110.2, 110.0, 107.5, 69.5, 69.4, 47.9, 36.0; HRMS (ESI-QTOF) m/z calcd for C ₂₅ H ₂₁ F ₃ N ₃ O ₃ ⁺ [M+H] ⁺ 468.1530, found 468.1537. Yield 77% Example 2-8 (1h) (S)-N-Perfuryl-1-oxo-2-(3-trifluoromethoxybenzyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxa Maid

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.73 (dt, J = 8.3, 0.9 Hz, 1H), 7.34-7.29 (m, 3H), 7.28 (s, 1H), 7.23-7.16 (m, 2H) , 7.08-7.02 (m, 1H), 6.88 (s, 1H), 6.83 (ddd, J = 7.7, 1.7, 0.9 Hz, 1H), 6.35 (t, J = 5.9 Hz, 1H, NH), 6.28 (dd , J = 3.2, 1.9 Hz, 1H), 6.13 (d, J = 16.9 Hz, 1H), 6.09 (dd, J = 3.2, 0.8 Hz, 1H), 5.76 (d, J = 16.9 Hz, 1H), 4.85 (dd, J = 11.0, 8.5 Hz, 1H), 4.62 (dd, J = 11.0, 8.5 Hz, 1H), 4.51 (t, J = 8.5 Hz, 1H), 4.35 (dd, J = 15.6, 5.9 Hz, 1H), 4.14 (dd, J =15.6, 5.9 Hz, 1H); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 171.4, 160.4, 151.0, 149.8 ( J _FC = 1.8 Hz), 142.3, 141.2, 139.5, 130.3, 126.6, 125.4, 125.3, 124.1, 122.6, 121.2, 120.5 ( J _FC = 258 Hz), 119.4, 118.5, 110.5, 110.3, 110.0, 107.4, 69.5, 69.4, 47.8, 36.1; HRMS (ESI-QTOF) m/z calcd for C ₂₅ H ₂₁ F ₃ N ₃ O ₄ ⁺ [M+H] ⁺ 484.1479, found 484.1494. Yield 62% Example 2-9 (1i) (S)-N-Perfuryl-1-oxo-2-(4-trifluoromethoxybenzyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxa Maid

¹ H-NMR (400MHz, CDCl ₃ ) δ 7.72 (d, J = 8.0 Hz, 1H), 7.35-7.29 (m, 3H), 7.28 (s, 1H), 7.19 (ddd, J = 8.0, 5.8, 2.0 Hz, 1H), 7.07 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 8.5 Hz, 2H), 6.41 (t, J = 5.8 Hz, 1H, NH), 6.30 (dd, J = 3.2 , 1.9 Hz, 1H), 6.17 (d, J = 16.7 Hz, 1H), 6.13 (d, J = 3.2 Hz, 1H), 5.72 (d, J = 16.7 Hz, 1H), 4.86 (dd, J = 11.0 , 8.5 Hz, 1H), 4.63 (dd, J = 11.0, 8.5 Hz, 1H), 4.52 (t, J = 8.5 Hz, 1H), 4.38 (dd, J = 15.6, 5.8 Hz, 1H), 4.13 (dd , J =15.6, 5.8 Hz, 1H); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 171.4, 160.4, 150.9, 149.7 ( J _FC = 1.4 Hz), 142.3, 141.2, 139.5, 130.2, 126.6, 125.4, 125.3, 124.0, 122.6, 121.2, 120.5 ( J _FC = 257 Hz), 119.4, 118.5, 110.5, 110.3, 109.9, 107.4, 69.5, 69.4, 47.8, 36.1; HRMS (ESI-QTOF) m/z calcd for C ₂₅ H ₂₁ F ₃ N ₃ O ₄ ⁺ [M+H] ⁺ 484.1479, found 484.1491. Yield 66%

Example 2-10 (1j) (S)-N-Perfuryl-2-(3-methylbenzyl)-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide

¹ H-NMR (400MHz, CDCl ₃ ) δ 7.73 (dd, J = 8.0, 1.0 Hz, 1H), 7.38-7.28 (m, 3H), 7.27 (s, 1H), 7.18 (ddd, J = 8.0, 6.4 , 1.4 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.77 (s, 1H), 6.71 (d, J = 7.6 Hz, 1H), 6.28 (dd, J = 3.2, 1.9 Hz, 1H), 6.26 (s, 1H, NH), 6.14 (d, J = 16.7 Hz, 1H), 6.06 (dd, J = 3.2, 0.9 Hz, 1H), 5.69 (d, J = 16.7 Hz, 1H), 4.84 (dd, J = 11.0, 8.3 Hz, 1H), 4.60 (dd, J = 11.0, 8.3 Hz, 1H), 4.50 (t, J = 8.3 Hz, 1H) , 4.28 (dd, J =15.6, 6.3 Hz, 1H), 4.02 (dd, J =15.7, 6.3 Hz, 1H), 2.22 (s, 3H); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 171.8, 160.4, 151.3, 142.0, 139.8, 138.8, 138.7, 128.7, 128.0, 126.5, 126.3, 125.4, 125.1, 122.7, 122.5, 120.9, 110.47, 110.46, 109.5, 107.1 , 69.5, 69.4, 48.2, 36.2, 21.6; HRMS (ESI-QTOF) m/z calcd for C ₂₅ H ₂₄ N ₃ O ₃ ⁺ [M+H] ⁺ 414.1812, found 414.1818. Yield 49% Example 2-11 (1k) (S)-N-Perfuryl-2-(4-methylbenzyl)-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.72 (dt, J = 8.0, 1.0 Hz, 1H), 7.38-7.28 (m, 3H), 7.26 (d, J = 0.8 Hz, 1H), 7.18 (ddd , J = 8.0, 6.7, 1.2 Hz, 1H), 7.01 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.0 Hz, 2H), 6.34 (t, J = 5.8 Hz, 1H, NH) , 6.29 (dd, J = 3.2, 1.8 Hz, 1H), 6.14 (d, J = 16.6 Hz, 1H), 6.06 (dd, J = 3.2, 0.9 Hz, 1H), 5.68 (d, J = 16.6 Hz, 1H), 4.84 (dd, J = 11.0, 8.0 Hz, 1H), 4.60 (dd, J = 11.0, 8.6 Hz, 1H), 4.49 (dd, J = 8.6, 8.0 Hz, 1H), 4.30 (dd, J = 15.7, 5.8 Hz, 1H), 4.02 (dd, J = 15.7, 5.8 Hz, 1H), 2.25 (s, 3H); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 171.8, 160.4, 151.3, 142.0, 139.8, 136.75, 135.72, 129.6, 126.5, 125.7, 125.3, 125.1, 122.5, 120.9, 110.48, 110.46, 109.5, 107.1, 69.5, 69.4 , 48.0, 36.1, 21.1; HRMS (ESI-QTOF) m/z calcd for C ₂₅ H ₂₄ N ₃ O ₃ ⁺ [M+H] ⁺ 414.1812, found 414.1817. Yield 45% Example 2-12 (1l) (S)-N-Perfuryl-2-(naphthalen-1-ylmethyl)-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.79-7.74 (m, 2H), 7.72 (d, J = 8.5 Hz, 1H), 7.65-7.60 (m, 1H), 7.45-7.35 (m, 3H) , 7.34-7.28 (m, 2H), 7.25 (s, 1H), 7.23-7.17 (m, 2H), 7.16 (dd, J = 1.9, 0.9 Hz, 1H), 6.36 (d, J = 16.9 Hz, 1H ), 6.16 (dd, J = 3.2, 1.9 Hz, 1H), 6.13 (d, J = 6.3 Hz, 1H, NH), 5.86 (d, J = 16.9 Hz, 1H), 5.81 (dd, J = 3.2, 0.9 Hz, 1H), 4.82 (dd, J = 10.9, 7.9 Hz, 1H), 4.59 (dd, J = 10.9, 8.7 Hz, 1H), 4.48 (dd, J = 8.7, 7.9 Hz, 1H), 3.98 ( dd, J =15.6, 6.3 Hz, 1H), 3.55 (dd, J =15.6, 6.3 Hz, 1H); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 171.6, 160.4, 151.0, 142.0, 139.8, 136.3, 133.4, 132.6, 128.8, 127.9, 127.8, 126.6, 126.5, 126.0, 125.5, 125.2, 124.1, 124.0, 122.6, 121.0 , 110.5, 110.3, 109.7, 106.9, 69.5, 69.4, 48.4, 35.8; HRMS (ESI-QTOF) m/z calcd for C ₂₈ H ₂₄ N ₃ O ₃ ⁺ [M+H] ⁺ 450.1812, found 450.1818. Yield 48%

Example 2-13 (1m) (S)-2-([1,1'-biphenyl]-4-ylmethyl)-N-furfuryl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a ]Indole-3-carboxamide

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.74 (dt, J = 8.0, 1.0 Hz, 1H), 7.50-7.47 (m, 2H), 7.47-7.43 (m, 2H), 7.43-7.39 (m, 2H), 7.38-7.36 (m, 1H), 7.35-7.30 (m, 2H), 7.29 (d, J = 0.8 Hz, 1H), 7.22 (dd, J = 1.9, 0.8 Hz, 1H), 7.24-7.14 (m, 1H), 7.02 (d, J = 8.5 Hz, 2H), 6.40 (t, J = 6.1 Hz, 1H, NH), 6.24 (d, J = 16.8 Hz, 1H), 6.19 (dd, J = 3.2, 1.9 Hz, 1H), 5.95 (dd, J = 3.2, 0.9 Hz, 1H), 5.76 (d, J = 16.8 Hz, 1H), 4.87 (dd, J = 11.0, 8.0 Hz, 1H), 4.62 ( dd, J = 11.0, 8.7 Hz, 1H), 4.51 (dd, J = 8.7, 8.0 Hz, 1H), 4.28 (dd, J = 15.6, 6.1 Hz, 1H), 3.97 (dd, J = 15.6, 6.1 Hz , 1H); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 171.7, 160.5, 142.1, 140.5, 140.0, 139.7, 129.0, 128.9, 127.6, 127.5, 127.1, 127.0, 126.6, 126.2, 125.4, 125.2, 122.5, 121.0, 110.5, 110.4 , 109.7, 107.2, 69.5, 69.4, 48.0, 36.1; HRMS (ESI-QTOF) m/z calcd for C ₃₀ H ₂₆ N ₃ O ₃ ⁺ [M+H] ⁺ 476.1969, found 476.1977. Yield 69% Example 2-14 (2a) (S)-N-Benzyl-2-(3-nitrobenzyl)-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.91 (s, 1H), 7.86 (dt, J = 7.1, 2.3 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.34-7.26 (m , 5H), 7.25-7.19 (m, 2H), 7.18-7.11 (m, 2H), 7.09-7.04 (m, 2H), 6.33 (t, J = 6.3 Hz, 1H, NH), 6.19, 5.79 (ABq , J = 16.9 Hz, 2H), 4.90 (dd, J = 11.0, 8.4 Hz, 1H), 4.68 (dd, J = 11.0, 8.8 Hz, 1H), 4.57 (t, J = 8.6 Hz, 1H), 4.38 (dd, J =15.0, 6.4 Hz, 1H), 4.20 (dd, J =15.0, 5.7 Hz, 1H); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 171.4, 160.5, 148.5, 140.8, 139.4, 137.7, 131.8, 129.7, 128.8, 127.7, 127.5, 126.8, 125.6, 125.3, 122.8, 122.4, 121.4, 121.0, 110.3, 110.1 , 69.59, 69.57, 47.7, 43.1; HRMS (ESI-QTOF) m/z calcd for C ₂₆ H ₂₃ N ₄ O ₄ ⁺ [M+H] ⁺ 455.1714, found 455.1719. Yield 73% Example 2-15 (2b) (S)-N-Perfuryl-2-(4-nitrobenzyl)-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.89 (d, J = 8.8 Hz, 2H), 7.76-7.72 (m, 1H), 7.33-7.26 (m, 5H), 7.23-7.18 (m, 2H) , 7.07-7.03 (m, 2H), 7.00 (d, J = 8.8 Hz, 2H), 6.30-6.23 (m, 2H), 5.75 (d, J = 17.3 Hz, 1H), 4.89 (dd, J = 11.0 , 8.4 Hz, 1H), 4.67 (dd, J = 11.0, 8.8 Hz, 1H), 4.56 (t, J = 8.6 Hz, 1H), 4.36 (dd, J = 15.0, 6.4 Hz, 1H), 4.16 (dd , J =15.0, 5.7 Hz, 1H); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 171.4, 160.4, 147.1, 146.0, 139.4, 137.6, 128.9, 127.8, 127.3, 126.7, 126.5, 125.6, 125.2, 124.1, 122.8, 121.5, 110.2, 110.1, 69.58, 69.54 , 47.8, 43.1; HRMS (ESI-QTOF) m/z calcd for C ₂₆ H ₂₃ N ₄ O ₄ ⁺ [M+H] ⁺ 455.1714, found 455.1717. Yield 52%

Example 2-16 (2c) (S)-N-Benzyl-2-(3-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72 (d, J = 8.0 Hz, 1H), 7.32-7.24 (m, 6H), 7.18 (ddd, J = 7.9, 5.6, 2.3 Hz, 1H), 7.12- 7.08 (m, 2H), 7.00 (td, J = 7.9, 5.8 Hz, 1H), 6.74 (td, J = 8.2, 2.3 Hz, 1H), 6.69 (d, J = 7.7 Hz, 1H), 6.59 (d , J = 9.2 Hz, 1H), 6.41 (t, J = 6.4 Hz, 1H, NH), 6.15, 5.69 (ABq, J = 16.8 Hz, 2H), 4.88 (dd, J = 10.9, 8.1 Hz, 1H) , 4.64 (dd, J = 10.9, 8.7 Hz, 1H), 4.52 (dd, J = 8.7, 8.1 Hz, 1H), 4.37 (dd, J = 15.0, 6.7 Hz, 1H), 4.12 (dd, J = 15.0 , 5.8 Hz, 1H); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 171.7, 163.2 ( J _FC = 247 Hz), 160.3, 141.5 ( J _FC = 6.9 Hz), 139.5, 137.9, 130.3 ( J _FC = 8.2 Hz), 128.7, 127.5, 127.4, 126.6, 125.3 ( J _FC = 2.4 Hz), 122.6, 121.2 ( J _FC = 2.6 Hz), 121.1, 114.1 ( J _FC = 21.1 Hz), 112.8 ( J _FC = 22.1 Hz), 110.2, 109.8, 69.5, 69.5, 47.7, 42.9; HRMS (ESI-QTOF) m/z calcd for C ₂₆ H ₂₃ FN ₃ O ₂ ⁺ [M+H] ⁺ 428.1769, found 428.1775. Yield 44% Example 2-17 (2d) (S)-N-Benzyl-2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.72 (dt, J = 8.0, 1.0 Hz, 1H), 7.33-7.26 (m, 6H), 7.17 (ddd, J = 8.0, 5.2, 2.8 Hz, 1H) , 7.14-7.10 (m, 2H), 6.87-6.81 (m, 2H), 6.77-6.69 (m, 2H), 6.33 (d, J = 6.5 Hz, 1H, NH), 6.13, 5.62 (ABq, J = 16.6 Hz, 2H), 4.89 (dd, J = 10.9, 8.1 Hz, 1H), 4.64 (dd, J = 10.9, 8.7 Hz, 1H), 4.53 (dd, J = 8.7, 8.1 Hz, 1H), 4.38 ( dd, J =15.0, 6.7 Hz, 1H), 4.11 (dd, J =15.0, 5.7 Hz, 1H); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 171.7, 161.8 ( J _FC = 245 Hz), 160.4, 139.6, 137.9 134.3 ( J _FC = 3.1 Hz), 128.8, 127.6, 127.5, 127.3 ( J _FC = 7.9 Hz) , 126.6, 125.3, 125.2, 122.6, 121.1, 115.7 ( J _FC = 21.5 Hz), 110.3, 109.8, 69.6, 69.5, 47.5, 43.0; HRMS (ESI-QTOF) m/z calcd for C ₂₆ H ₂₃ FN ₃ O ₂ ⁺ [M+H] ⁺ 428.1769, found 428.1778. Yield 67% Example 2-18(2e) (S)-N-Benzyl-2-(3-cyanobenzyl)-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.74 (d, J = 7.9 Hz, 1H), 7.35-7.26 (m, 6H), 7.24-7.17 (m, 3H), 7.13-7.06 (m, 4H) , 6.29 (t, J = 5.8 Hz, 1H, NH), 6.10, 5.75 (ABq, J = 16.9 Hz, 2H), 4.89 (dd, J = 11.0, 8.4 Hz, 1H), 4.66 (dd, J = 11.0 , 8.7 Hz, 1H), 4.56 (t, J = 8.5 Hz, 1H), 4.41 (dd, J = 15.1, 6.4 Hz, 1H), 4.20 (dd, J = 15.0, 5.7 Hz, 1H); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 171.4, 160.4, 140.2, 139.3, 137.7, 130.9, 130.1, 129.5, 129.2, 128.9, 127.7, 127.5, 126.7, 125.5, 125.1, 122.8, 121.4, 118.6, 112.9, 110.2 , 110.0, 69.52, 69.50, 47.5, 43.1; HRMS (ESI-QTOF) m/z calcd for C ₂₇ H ₂₃ N ₄ O ₂ ⁺ [M+H] ⁺ 435.1816, found 435.1823. Yield 67%

Example 2-19 (2f) (S)-N-Benzyl-2-(4-cyanobenzyl)-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.73 (d, J = 7.9 Hz, 1H), 7.37-7.27 (m, 5H), 7.24 (d, J = 8.6 Hz, 2H), 7.22-7.17 (m , 2H), 7.13 (dd, J = 7.7, 1.8 Hz, 2H), 6.93 (d, J = 8.3 Hz, 2H), 6.25 (t, J = 6.1 Hz, 1H, NH), 6.20, 5.69 (ABq, J = 17.2 Hz, 2H), 4.88 (dd, J = 10.9, 8.3 Hz, 1H), 4.65 (dd, J = 11.0, 8.8 Hz, 1H), 4.55 (t, J = 8.5 Hz, 1H), 4.39 ( dd, J =15.0, 6.4 Hz, 1H), 4.15 (dd, J =15.0, 5.6 Hz, 1H); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 171.4, 160.4, 144.1, 139.4, 137.7, 132.6, 129.0, 127.8, 127.5, 126.6, 126.4, 125.5, 125.2, 122.7, 121.4, 118.6, 111.1, 110.1, 110.0, 69.52 , 69.49, 47.9, 43.1; HRMS (ESI-QTOF) m/z calcd for C ₂₇ H ₂₃ N ₄ O ₂ ⁺ [M+H] ⁺ 435.1816, found 435.1821. Yield 70% Example 2-20 (2g) (S)-N-Benzyl-1-oxo-2-(4-fluoromethylbenzyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.74 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.33-7.26 (m, 5H), 7.26-7.23 (m , 1H), 7.19 (ddd, J = 7.9, 6.7, 1.1 Hz, 1H), 7.14-7.10 (m, 2H), 7.00 (d, J = 8.0 Hz, 2H), 6.38 (t, J = 6.3 Hz, 1H, NH), 6.24, 5.73 (ABq, J = 16.9 Hz, 2H), 4.89 (dd, J = 11.0, 8.3 Hz, 1H), 4.65 (dd, J = 11.0, 8.7 Hz, 1H), 4.55 (t , J = 8.5 Hz, 1H), 4.40 (dd, J = 15.1, 6.8 Hz, 1H), 4.07 (dd, J = 15.1, 5.6 Hz, 1H); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 171.5, 160.4, 142.8 ( J _FC = 1.3 Hz), 139.5, 137.9, 129.5 ( J _FC = 32.5 Hz), 128.8, 127.6, 127.4, 126.7, 126.2, 125.90 ( J _FC = 3.8 Hz), 125.4, 125.3, 124.1 ( J _FC = 272 Hz), 122.7, 121.3, 110.2, 110.0, 69.6, 69.5, 47.9, 42.9; HRMS (ESI-QTOF) m/z calcd for C ₂₇ H ₂₃ F ₃ N ₃ O ₂ ⁺ [M+H] ⁺ 478.1737, found 478.1746. Yield 72% Example 2-21 (2h) (S)-N-Benzyl-1-oxo-2-(3-trifluoromethoxybenzyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.73 (d, J = 8.0 Hz, 1H), 7.34-7.26 (m, 6H), 7.19 (ddd, J = 8.0, 6.5, 1.4 Hz, 1H), 7.12 -7.08 (m, 2H), 7.01 (t, J = 7.9 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.84 (s, 1H), 6.76 (d, J = 7.6 Hz, 1H) , 6.36 (t, J = 5.7 Hz, 1H, NH), 6.13, 5.72 (ABq, J = 16.8 Hz, 2H), 4.88 (dd, J = 11.0, 8.3 Hz, 1H), 4.65 (dd, J = 11.0 , 8.7 Hz, 1H), 4.54 (t, J = 8.5 Hz, 1H), 4.37 (dd, J = 15.1, 6.6 Hz, 1H), 4.15 (dd, J = 15.1, 5.8 Hz, 1H); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 171.6, 160.4, 149.7 ( J _FC = 1.7 Hz), 141.2, 139.5, 137.9, 130.2, 128.8 127.6, 127.5, 126.6, 125.4, 125.3, 123.9, 122.6, 121.2, 120.5 ( J _FC = 258 Hz), 119.3 ( J _FC = 0.8 Hz), 118.4 ( J _FC = 0.8 Hz), 110.2, 109.9, 69.6, 69.5, 47.8, 43.0; HRMS (ESI-QTOF) m/z calcd for C ₂₇ H ₂₃ F ₃ N ₃ O ₃ ⁺ [M+H] ⁺ 494.1686, found 494.1699. Yield 85%

Example 2-22 (2i) (S)-N-Benzyl-1-oxo-2-(4-trifluoromethoxybenzyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.72 (d, J = 8.0 Hz, 1H), 7.34-7.25 (m, 6H), 7.18 (t, J = 7.0 Hz, 1H), 7.14 (d, J = 6.9 Hz, 2H), 6.91 (m, 4H), 6.42 (t, J = 6.5 Hz, 1H, NH), 6.15, 5.68 (ABq, J = 16.7 Hz, 2H), 4.90 (dd, J = 10.9, 8.2 Hz, 1H), 4.65 (dd, J = 10.9, 8.7 Hz, 1H), 4.54 (t, J = 8.5 Hz, 1H), 4.41 (dd, J = 15.0, 6.7 Hz, 1H), 4.10 (dd, J = 15.0, 5.6 Hz, 1H); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 171.6, 160.4, 148.2 ( J _FC = 1.8 Hz), 139.5, 137.9, 137.3, 128.8, 127.6, 127.5, 127.2, 126.6, 125.3, 125.2, 122.61,, 121.3 ( J _FC = 1.0 Hz), 121.2, 120.5 ( J _FC = 257 Hz), 110.3, 109.9, 69.6, 69.2, 47.5, 43.0; HRMS (ESI-QTOF) m/z calcd for C ₂₇ H ₂₃ F ₃ N ₃ O ₃ ⁺ [M+H] ⁺ 494.1686, found 494.1695. Yield 70% Example 2-23 (2j) (S)-N-Benzyl-2-(3-methylbenzyl)-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.73 (dt, J = 8.0, 1.0 Hz, 1H), 7.33-7.23 (m, 6H), 7.18 (ddd, J = 8.0, 6.2, 1.8 Hz, 1H) , 7.09-7.04 (m, 2H), 6.97 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 6.73 (s, 1H), 6.66 (d, J = 7.6 Hz, 1H), 6.29 (t, J = 6.3 Hz, 1H, NH), 6.16, 5.65 (ABq, J = 16.7 Hz, 2H), 4.87 (dd, J = 10.9, 7.8 Hz, 1H), 4.62 (dd, J = 10.9, 8.7 Hz, 1H), 4.52 (dd, J = 8.7, 7.8 Hz, 1H), 4.30 (dd, J = 15.1, 6.9 Hz, 1H), 4.03 (dd, J = 15.1, 5.9 Hz, 1H) , 2.11 (s, 3H); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 172.0, 160.4, 139.8, 138.8, 138.6, 138.2, 128.68, 128.65, 127.9, 127.33, 127.26, 126.5, 126.2, 125.4, 125.1, 122.6, 122.5, 120.9, 110.4, 109.5 , 69.6, 69.5, 48.2, 42.9, 21.5; HRMS (ESI-QTOF) m/z calcd for C ₂₇ H ₂₆ N ₃ O ₂ ⁺ [M+H] ⁺ 424.2020, found 424.2026. Yield 28% Example 2-24 (2k) (S)-N-Benzyl-2-(4-methylbenzyl)-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide

¹ H-NMR (400MHz, CDCl ₃ ) δ 7.72 (d, J = 8.1 Hz, 1H), 7.35-7.24 (m, 6H), 7.17 (ddd, J = 7.9, 6.5, 1.3 Hz, 1H), 7.09- 7.06 (m, 2H), 6.89 (d, J = 7.7 Hz, 2H), 6.79 (d, J = 7.9 Hz, 2H), 6.39 (t, J = 6.4 Hz, 1H, NH), 6.17 (d, J = 16.5 Hz, 1H), 5.64 (d, J = 16.5 Hz, 1H), 4.88 (dd, J = 11.0, 7.9 Hz, 1H), 4.62 (dd, J = 11.0, 8.7 Hz, 1H), 4.51 (dd , J = 8.7, 7.9 Hz, 1H), 4.33 (dd, J = 15.2, 6.8 Hz, 1H), 4.04 (dd, J = 15.2, 5.9 Hz, 1H), 2.16 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 171.9, 160.4, 139.7, 138.1, 136.7, 135.7, 129.6, 128.7, 127.4, 127.2, 126.5, 125.6, 125.4, 125.1, 122.5, 120.9, 110.5, 109.5, 69.55, 69.56, 47.9, 42.8, 21.1; HRMS (ESI-QTOF) m/z calcd for C ₂₇ H ₂₆ N ₃ O ₂ ⁺ [M+H] ⁺ 424.2020, found 424.2021. Yield 45%

Example 2-25 (2l) (S)-N-Benzyl-2-(naphthalen-1-ylmethyl)-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.77 (d, J = 8.0 Hz, 1H), 7.70 (dd, J = 6.3, 2.8 Hz, 1H), 7.60 (d, J = 6.7 Hz, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.42-7.38 (m, 2H), 7.38-7.35 (m, 1H), 7.33 (s, 1H), 7.31 (ddd, J = 8.4, 6.9, 1.2 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.21-7.13 (m, 5H), 6.83-6.79 (m, 2H), 6.38 (d, J = 16.8 Hz, 1H), 6.16 (t, J = 6.2 Hz, 1H, NH), 5.82 (d, J = 16.8 Hz, 1H), 4.85 (dd, J = 10.9, 7.9 Hz, 1H), 4.61 (dd, J = 10.9, 8.6 Hz, 1H), 4.51 (dd, J = 8.6, 7.9 Hz, 1H), 4.00 (dd, J = 15.0, 7.0 Hz, 1H), 3.50 (dd, J = 15.0, 5.7 Hz, 1H); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 171.8, 160.4, 139.8, 137.9, 136.3, 133.4, 132.5, 128.7, 128.5, 127.8, 127.3, 127.21, 128.20, 126.60, 126.55, 126.0, 125.4, 125.2, 124.0, 123.9 , 122.6, 121.0, 110.4, 109.6, 69.52, 69.49, 48.4, 42.6; HRMS (ESI-QTOF) m/z calcd for C ₃₀ H ₂₆ N ₃ O ₂ ⁺ [M+H] ⁺ 460.2020, found 460.2022. Yield 88% Example 2-26 (2m) (S)-2-([1,1'-biphenyl]-4-ylmethyl)-N-benzyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a] Indole-3-carboxamide

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.75 (d, J = 8.2 Hz, 1H), 7.39 (d, J = 4.4 Hz, 4H), 7.37-7.33 (m, 2H), 7.33-7.30 (m , 4H), 7.23-7.16 (m, 4H), 6.97 (d, J = 7.9 Hz, 2H), 6.96-6.93 (m, 2H), 6.39 (t, J = 6.4 Hz, 1H, NH), 6.26 ( d, J = 16.7 Hz, 1H), 5.71 (d, J = 16.7 Hz, 1H), 4.91 (dd, J = 10.9, 8.0 Hz, 1H), 4.64 (dd, J = 10.9, 8.8 Hz, 1H), 4.54 (t, J = 8.4 Hz, 1H), 4.29 (dd, J = 15.2, 6.9 Hz, 1H), 3.94 (dd, J = 15.2, 5.7 Hz, 1H); ¹³ C-NMR (100MHz, CDCl ₃ ) δ 171.9, 160.4, 140.3, 140.0, 139.7, 138.0, 137.8, 128.9, 128.6, 127.54, 127.49, 127.3, 127.1, 127.0, 126.6, 126.2, 125.4, 125.2, 122.6, 121.0 , 110.4, 109.7, 69.56, 69.57, 48.0, 42.8; HRMS (ESI-QTOF) m/z calcd for C ₃₂ H ₂₈ N ₃ O ₂ ⁺ [M+H] ⁺ 486.2176, found 486.2179. Yield 50%

Experimental Example 1. Target selectivity of pyrazinoindolone derivatives to MDA-MB-468 cells

Compound GI ₅₀ (μM) Compound GI ₅₀ (μM) MCF-7 MDA-MB-468 MCF-7 MDA-MB-468 1a >30 19.8 2a >30 7.6 1b >30 17.3 2b >30 4.0 1c >30 8.0 2c 12.4 7.8 1d >30 8.8 2d >30 8.8 1e >30 19.9 2e >30 8.4 1f >30 19.1 2f >30 2.9 1g >30 8.2 2g >30 5.9 1h >30 7.9 2h >30 7.0 1i >30 8.3 2i >30 3.0 1j 12.2 6.6 2j 8.8 8.2 1k >30 9.3 2k 21.4 23.1 1 l >30 9.5 2l 9.5 10.4 1m >30 >30 2m >30 >30 - Gefitinib >30 13.0

_{For each of the synthesized compounds, GI 50} values for MCF-7 and MDA-MB-468 were measured. Among the resulting compounds, compounds excluding 1j, 2c, 2j, 2k and 2l compounds did not show inhibitory activity against MCF-7, a luminal A type breast cancer cell. In addition, it was confirmed that compounds excluding 1m and 2m compounds among the produced compounds inhibit the proliferation of MDA-MB-468 cells. Therefore, it was confirmed that a number of compounds inhibit proliferation with high selectivity only for MDA-MB-468. In particular, 1c, 1d, 1g- l, 2a -j and l 2 compounds showed inhibitory effect superior than the error correcting capability of the nip. Therefore, it was confirmed that the compound has the potential as a target therapeutic agent with high selectivity for MDA-MB-468 cells in triple negative breast cancer.

Experimental Example 2. Measurement of MDA-MB-468 Apoptosis Activity of Compounds 2b, 2f, and 2i

According to the results of Experimental Example 1, Annexin V-FITC assay was performed to confirm the cytotoxic activity of the 2b, 2f and 2i compounds inhibiting the survival and proliferation of MDA-MB-468 cells. As can be seen in Figure 2, the apoptosis value was evaluated when the 2b, 2f, and 2i compounds and 10 μM of gefitinib were injected into MDA-MB-468 cells, and 2b and 2i were similar to gefitinib. The values were recorded, and 2f showed a superior cell death value than gefitinib, and it was confirmed that there is a remarkable effect.

Experimental Example 3. Measurement of proliferation signaling protein activation of MDA-MB-468 cells

Akt protein is a protein involved in cell growth, and when activated, it plays a role of transmitting growth signals outside the cell into the cell, thereby regulating cell proliferation and survival. Therefore, inhibiting the activated form of Akt protein in cancer cells is one of the mechanisms that prevent cancer cell proliferation. As can be seen in Figure 3, it was confirmed that the expression of p-Akt was inhibited when the Akt protein of MDA-MB-468 cells was treated with 2b and 2f compounds, and this was confirmed that the 2b and 2f compounds inhibited the proliferation of MDA-MB-468. It was confirmed that it is one of the mechanisms to do so.

Experimental Example 4. Synergistic effect of co-administration with Gefitinib

When co-administration of a pyrazinoindolone derivative and gefitinib, it was confirmed that it exhibited a synergistic effect on the inhibition of MDA-MB-468 cell proliferation in triple negative breast cancer. For MDA-MB-468 cells, the x-axis _{is the relative concentration of the GI 50} value of gefitinib, and the y-axis is the relative concentration of the GI ₅₀ value of each derivative. When co-administration with gefitinib, it was confirmed that the _{GI 50 value was lower even when treated with a small concentration.} Through this, it was confirmed that gefitinib and pyrazinoindolo derivatives 2b, 2f and 2i showed higher inhibitory effects than when administered alone. Therefore, it was confirmed that the inhibitory effect on MDA-MB-468 cells was increased when administered in combination, resulting in improved anticancer activity.

Claims (9)

A pyrazinoindolone derivative of the following general formula 1, an isomer, solvate, or pharmaceutically acceptable salt thereof:
[General Formula 1]

R ¹ and R ² are each independently a substituted or unsubstituted C 1 to C 40 alkyl group; A substituted or unsubstituted alkenyl group having 2 to 40 carbon atoms; A substituted or unsubstituted alkynyl group having 2 to 40 carbon atoms; A substituted or unsubstituted aryl group having 6 to 40 carbon atoms; A substituted or unsubstituted heteroaryl group having 5 to 40 nuclear atoms; A substituted or unsubstituted aryloxy group having 6 to 40 carbon atoms; A substituted or unsubstituted C1-C40 alkyloxy group; A substituted or unsubstituted arylamine group having 6 to 40 carbon atoms; A substituted or unsubstituted C1-C40 alkylamine group; A substituted or unsubstituted C1-C40 alkyl group having 6 to 40 carbon atoms; A substituted or unsubstituted alkyl group having 1 to 40 carbon atoms having 1 to 6 alcohol groups; An alkyl group having 1 to 40 carbon atoms having a substituted or unsubstituted amine having 1 to 40 carbon atoms; A substituted or unsubstituted C3 to C40 cycloalkyl group; And a substituted or unsubstituted heterocycloalkyl group having 3 to 40 nuclear atoms. The method of claim 1,
The R ¹ is a substituent selected from the group consisting of a fluoride group (-F), a trifluoromethyl group (-CF ₃ ), a trifluoromethoxy group (-OCF ₃ ), and a methyl group (-CH _{3 ).} A benzyl group substituted at the) position,
A benzyl group in which a substituent selected from the group consisting of a fluoride group (-F) and a trifluoromethoxy group (-OCF _{3) is substituted at the meta position, or}
Naphthalenyl group is a substituted methyl group,
R ² is a pyrazinoindolone derivative, an isomer, solvate, or a pharmaceutically acceptable salt thereof, which is an unsubstituted furfuryl group;
The R ¹ is a group consisting of a nitro group (-NO ₂ ), a fluoride group (-F), a cyano group (-CN), a trifluoromethyl group (-CF ₃ ), and a trifluoromethoxy group (-OCF ₃ ) The substituent selected from is a benzyl group substituted at the para position, or
A substituent selected from the group consisting of a nitro group (-NO ₂ ), a cyano group (-CN) and a trifluoromethoxy group (-OCF ₃ ) is a benzyl group substituted at the meta position,
The R ² is an unsubstituted benzyl group, a pyrazinoindolone derivative, an isomer thereof, a solvate, or a pharmaceutically acceptable salt. The method of claim 1,
The R ¹ is a benzyl group in which a substituent selected from the group consisting of a nitro group (-NO ₂ ), a cyano group (-CN) and a trifluoromethoxy group (-OCF _{3) is substituted at the para position,}
The R ² is an unsubstituted benzyl group, a pyrazinoindolone derivative, an isomer thereof, a solvate, or a pharmaceutically acceptable salt. In the anhydrous dichloride methane solvent, in the presence of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, trialkylamine, and 1-hydroxybenzotriazole, the amine group of the general formula 2 is 1 step of synthesizing reaction intermediate I represented by the general formula 4 by nucleophilic attack on the carbonyl group;
[General Formula 2]

[General Formula 3]

[General Formula 4]

The second step of synthesizing reaction intermediate II represented by general formula 5 by carrying out an intramolecular Mitsunobu reaction in the presence of diethyl azodicarboxylate and triphenylphosphine in anhydrous tetrahydrofuran solvent of reaction intermediate I of formula 4 ;
[General Formula 5]

A third step of synthesizing reaction intermediate III represented by general formula 7 by reacting reaction intermediate II of general formula 5 with a halide represented by general formula 6 in the presence of alkali carbonate and tetrabutylammonium halide in anhydrous dichloride methane solvent; And
[General Formula 6]

[General Formula 7]

Reaction Intermediate III of Formula 7 is a fourth step of bonding with ^{R 2} -NH _{2 in an alcohol solvent;}
A method of preparing a pyrazinoindolone derivative represented by General Formula 1, including:
[General Formula 1]

R ¹ and R ² are each independently a substituted or unsubstituted C 1 to C 40 alkyl group; A substituted or unsubstituted alkenyl group having 2 to 40 carbon atoms; A substituted or unsubstituted alkynyl group having 2 to 40 carbon atoms; A substituted or unsubstituted aryl group having 6 to 40 carbon atoms; A substituted or unsubstituted heteroaryl group having 5 to 40 nuclear atoms; A substituted or unsubstituted aryloxy group having 6 to 40 carbon atoms; A substituted or unsubstituted C1-C40 alkyloxy group; A substituted or unsubstituted arylamine group having 6 to 40 carbon atoms; A substituted or unsubstituted C1-C40 alkylamine group; A substituted or unsubstituted C1-C40 alkyl group having 6 to 40 carbon atoms; A substituted or unsubstituted alkyl group having 1 to 40 carbon atoms having 1 to 6 alcohol groups; An alkyl group having 1 to 40 carbon atoms having a substituted or unsubstituted amine having 1 to 40 carbon atoms; A substituted or unsubstituted C3 to C40 cycloalkyl group; And a substituted or unsubstituted heterocycloalkyl group having 3 to 40 nuclear atoms; is selected from the group consisting of,
The R ³ is selected from the group consisting of a hydroxyl group, an alkyloxy group, and a halogen group,
R ⁴ and R ⁵ are each independently a hydroxyl group (-OH), an alkyloxy group having 1 to 4 carbon atoms (-O-alkyl), is -I), a nitro group (-NO ₂ ), a sulfonyl group (-SO ₂ R ⁶ ), cyano group (-CN), ammonium group (-N(R ⁶ ) ₃ ⁺ ), carbonyl group (-COR ⁶ ) or trifluoromethyl group (-CF ₃ ), where R ⁶ is hydrogen, hydroxyl group, Alkyl group having 1 to 40 carbon atoms, alkenyl group having 2 to 40 carbon atoms, alkynyl group having 2 to 40 carbon atoms, aryl group having 6 to 40 carbon atoms, heteroaryl group having 5 to 40 nuclear atoms, aryloxy group having 6 to 40 carbon atoms , A C1-C40 alkyloxy group, a C6-C40 arylamine group, a C1-C40 alkylamine group, a C1-C40 alkyl group having a C6-C40 aryl, and a 1-6 alcohol group Selected from the group consisting of an alkyl group having 1 to 40 carbon atoms, an alkyl group having 1 to 40 carbon atoms having an amine having 1 to 40 carbon atoms, a cycloalkyl group having 3 to 40 carbon atoms, and a heterocycloalkyl group having 3 to 40 nuclear atoms. The method of claim 4,
The R ¹ is a substituent selected from the group consisting of a fluoride group (-F), a trifluoromethyl group (-CF ₃ ), a trifluoromethoxy group (-OCF ₃ ), and a methyl group (-CH _{3 ).} A benzyl group substituted at the) position,
A benzyl group in which a substituent selected from the group consisting of a fluoride group (-F) and a trifluoromethoxy group (-OCF _{3) is substituted at the meta position, or}
Naphthalenyl group is a substituted methyl group,
R ² is an unsubstituted furfuryl group;
The R ¹ is a group consisting of a nitro group (-NO ₂ ), a fluoride group (-F), a cyano group (-CN), a trifluoromethyl group (-CF ₃ ), and a trifluoromethoxy group (-OCF ₃ ) The substituent selected from is a benzyl group substituted at the para position, or
A substituent selected from the group consisting of a nitro group (-NO ₂ ), a cyano group (-CN) and a trifluoromethoxy group (-OCF ₃ ) is a benzyl group substituted at the meta position,
The R ² is an unsubstituted benzyl group, a method of producing a pyrazinoindolone derivative. The method of claim 4,
The R ¹ is a benzyl group in which a substituent selected from the group consisting of a nitro group (-NO ₂ ), a cyano group (-CN) and a trifluoromethoxy group (-OCF _{3) is substituted at the para position,}
The R ² is an unsubstituted benzyl group, a method of producing a pyrazinoindolone derivative. A pharmaceutical composition for targeted treatment of triple-negative breast cancer comprising a derivative of any one of claims 1 to 3, an isomer thereof, a solvate, or a pharmaceutically acceptable salt. A pharmaceutical composition for specific inhibition of MDA-MB-468 cells comprising a derivative of any one of claims 1 to 3, an isomer thereof, a solvate, or a pharmaceutically acceptable salt. A pharmaceutical composition for the treatment of triple negative breast cancer comprising a derivative of any one of claims 1 to 3, an isomer thereof, a solvate, or a pharmaceutically acceptable salt and gefitinib.

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