KR102161674B1 - Isatin derivatives and method for preparation thereof - Google Patents

Abstract

상기 식에서, R₁ 내지 R₄의 정의는 명세서에서 정의한 바와 같다. The present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition comprising the same, which can be usefully used in the prevention or treatment of peptic ulcer, gastritis or reflux esophagitis For.
[Formula 1]

In the above formula, the definition of R ₁ to R ₄ is as defined in the specification.

Description

Isatin derivatives and method for preparation thereof

The present invention relates to an isatin derivative, a preparation method thereof, and a pharmaceutical composition comprising the same, which can be usefully used in the prevention or treatment of peptic ulcer, gastritis or reflux esophagitis.

The development of therapeutic agents for peptic ulcer has been largely developed in two ways (control of attack factors and strengthening of defense factors), and a representative treatment method among them is control of attack factors. Development of flow thereof is gradually anticholinergic drugs (anticholinergic drug) development and H ₂ receptor antagonists (H ₂ receptor antagonist) led to a development, the drug present, proton pump inhibitors (proton pump inhibitor, PPI) in the past, antacids (antacid) Development Leading the market.

Since Prout discovered that high concentrations of hydrochloric acid are secreted from the gastric mucosa in 1884, research on the mechanism of acid secretion has been actively conducted for nearly 100 years. Since Belladonna was used as the first anti-ulcer drug, anticholinergic drugs have been mainly used. In 1920, it was discovered that gastric acid secretion was stimulated by histamine, and in 1977, strong gastric acid secretion. histamine is responsible for hormone antagonizing a number of the first histamine H ₂ receptor antagonists of the acid secretion stimulated material after the development of _{Cimetidine (Tagamet®) (histamine H 2} -receptor antagonist) that inhibit action of the H ₂ receptor Drugs of the histamine H ₂ receptor antagonist, represented by Ranitidine (Zantac®) developed in 1981 and Famotidine (Gaster®/Pepcid®) developed in 1985, have become the mainstream of the global anti-ulcer drug market. come. Since Helicobacter pylori was first isolated as the causative agent of gastritis and ulcers in 1983, it has developed into a multi-drug combination therapy consisting of a proton pump inhibitor or an H ₂ antagonist and chemotherapy to eradicate it.

Recently, among proton pump inhibitors, the need for drugs with a reversible inhibitory mechanism is increasing, and research is being actively conducted mainly by global pharmaceutical companies. In order to distinguish it from the conventional PPI drug represented by omeprazole, the reversible proton pump inhibitor is called potassium competitive acid blocker (P-CAB) or acid pump antagonist (APA). Thus, the present invention relates to a reversible proton pump inhibitor (P-CAB).

On the other hand, the secretion process of H ⁺ in gastric parietal cells has not been identified for a long time, but recently, H ⁺ /K ⁺ -ATPase enzyme in the microsomal fraction of gastric parietal cells acts on the secretion of H ^{+ in the} gastrointestinal tract to exchange H ⁺ and K ^+. It turns out, these H ⁺ /K ⁺ -ATPAse were named "proton pumps". In vivo, H ⁺ /K ⁺ -ATPAse secretes H ⁺ into the gastric cavity by decomposing energy obtained by decomposing ATP, which is abundantly contained in mitochondria, into H ₂ O. At this time, the conversion of K ⁺ and H ⁺ is made 1:1, and the presence of H ⁺ /K ⁺ -ATPase has been confirmed in many animals that secrete H ⁺ including humans.

In other words, a series of gastric acid secretion reactions are triggered by the binding of various acid secretion stimulants (histamine, acetylcholine, gastrin) in the receptors on the cell membrane of gastric parietal cells. In the final process of this reaction, H ⁺ is released and K H ⁺ /K ⁺ -ATPAse, called a proton pump that absorbs ⁺ , works. Compounds that inhibit gastric acid secretion by inhibiting the proton pump, which is the final process of gastric acid secretion, have no anticholinergic action or antagonistic action of H ₂ receptors, and when absorbed into the body, they are absorbed as an inactive form of a prodrug. After being intensively distributed in the secretory tubules of each gastric mucosa, the only acidic compartment in the human body, it is activated and blocks the proton pump, the final stage of gastric acid production, and inhibits gastric acid secretion with a unique and selective mode of action.

Representative drugs developed to control such a proton pump include Omeprazole, Lansoprazole, Pantoprazole, and Esomepraole, and these drugs have a stronger and more continuous inhibitory effect on the secretion of gastric acid than conventional drugs, and are therefore widely used as drugs for treating peptic ulcer. In addition, omeprazole-based compounds strongly inhibit gastric acid secretion and at the same time have gastric mucosa protective action (cytoprotective activity), showing the characteristics of both aggressive and defensive types, and are stronger than H ₂ receptor antagonists at night as well as during the day. It is known that it inhibits acid secretion and has a low recurrence rate.

However, proton pump inhibitors having an irreversible mechanism of action result in a state of suppression of gastric acid secretion in the stomach for a long period of time, and the possibility of tumor cell formation due to the proliferation of bacteria in the stomach, promotion of proton pump expression, and increase in gastrin concentration has been raised. Through the development of phosphorus proton pump inhibitors, the development of substances that inhibit gastric acid secretion for a certain period of time only when drug is administered is emerging as a research subject. Yuhan Corporation's revaprazan (Revanex®), which was released in January 2007, is the only drug related to this, and the direction of research and development of anti-ulcer drugs by major pharmaceutical companies around the world is also focused on reversible proton pump inhibitors. I am looking forward to this.

As a representative example of a reversible proton pump inhibitor, a pyrrole derivative is described in International Patent Publication WO 2007/026916 (Takeda Pharmaceutical Co. Ltd.), and a pyrrolo [2,3-c] pyridine derivative is described in International Patent Publication WO 2006/025716 (Yuhan Corp.), and benzimidazole derivatives are described in International Patent Publication WO 2007/072146 (Pfizer Inc., Japan; Raqualia Pharma Inc.).

Accordingly, the inventors of the present invention confirmed that while researching a novel compound having a proton pump inhibitory effect, isatin derivatives have a proton pump inhibitory effect and thus can be usefully used for the prevention or treatment of peptic ulcer, gastritis or reflux esophagitis. The present invention has been completed.

The present invention is to provide an isatin derivative, a preparation method thereof, and a pharmaceutical composition comprising the same, which can be usefully used in the prevention or treatment of peptic ulcer, gastritis or reflux esophagitis.

In order to solve the above problems, the present invention provides a compound represented by the following formula 1 which is an isatin derivative, or a pharmaceutically acceptable salt thereof:

[Formula 1]

In the above formula,

R ₁ is hydrogen or halogen,

R ₂ is hydrogen or NHR ₅ ,

Wherein, R ₅ is phenyl substituted by any of the substituents selected from the group consisting of a C _{1 -4} alkyl and halogen,

R ₃ is hydrogen or XR ₆ ,

Where X is a bond or NH,

R ₆ is phenyl or pyridinyl,

Here, one in which the phenyl or pyridinyl is C _{1 -4} alkyl, C _{1 -4} alkoxy, C _{1 -4} haloalkyl, C _{1 -4} haloalkoxy, each independently selected from halogen, and morpholino group consisting of furnace Or substituted with two substituents,

R ₄ is a C _{1 -4} alkyl, morpholinophenyl or YR _7,

Here, Y is NH, NH (CH ₂₎ or N (C _{1 -4} alkyl),

R ₇ is C _{1 -4} alkyl, phenyl or pyridinyl,

Wherein said phenyl or pyridinyl is substituted with one or two substituents each independently selected from the group consisting of unsubstituted or substituted C _{1 -4} alkyl, C _{1 -4} haloalkyl, and halogen,

However, one of R ₂ and R ₃ is hydrogen, and the other is not hydrogen.

Preferably, R ₁ is hydrogen or fluoro.

Preferably, R ₅ is phenyl substituted with any one substituent selected from the group consisting of methyl, fluoro, chloro and bromo.

Preferably, R ₆ is phenyl or pyridinyl, wherein the phenyl or pyridinyl is methyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, fluoro, chloro, bromo and morpholino. It is substituted with 1 or 2 substituents each independently selected from the group consisting of. More preferably, the phenyl or pyridinyl is substituted with a substituent selected from the group consisting of methyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, fluoro, chloro, bromo, and morpholino. Become; Or two methyls.

Preferably, R ₄ is tert-butyl, morpholino or YR ₇ , wherein Y is NH, NH(CH ₂ ), N(CH ₃ ) or N(isopropyl), and R ₇ is isopropyl, Phenyl or pyridinyl, wherein the phenyl or pyridinyl is unsubstituted or substituted with one or two substituents each independently selected from the group consisting of tert-butyl, trifluoromethyl, fluoro and chloro. More preferably, the phenyl or pyridinyl is substituted with a substituent selected from the group consisting of tert-butyl, trifluoromethyl, fluoro and chloro; Or by two fluoros.

Preferably, R ₁ is hydrogen, R ₂ is NHR _5, wherein, R ₅ is phenyl substituted by any of the substituents selected from the group consisting of a C _{1 -4} alkyl and halogen, R ₃ is hydrogen and, R ₄ is a C _{1 -4} alkyl.

Preferably, R ₁ is hydrogen or halogen, R ₂ is hydrogen and R ₃ is XR ₆ . More preferably, X is a bond, R ₆ is phenyl or pyridinyl, wherein said phenyl or pyridinyl is optionally substituted by C _{1 -4} alkyl or halogen, R ₄ is morpholinophenyl or YR _7, wherein Y is NH, NH (CH ₂₎ or N (C _{1 -4} alkyl), R ₇ is C _{1 -4} alkyl, phenyl or pyridinyl, wherein said phenyl or pyridinyl is unsubstituted or C _{1 -4} alkyl It is substituted with one or two substituents each independently selected from the group consisting of C _{1 -4} haloalkyl, and halogen. In addition, more preferably, X is NH, R ₆ is phenyl or pyridinyl, wherein said phenyl or pyridinyl is C _{1 -4} alkyl, C _{1 -4} alkoxy, C _{1 -4} haloalkyl, C _{1- 4} haloalkoxy, halogen, and morpholino group consisting of the furnace is substituted with one or two substituents each independently selected, R ₄ is a C _{1 -4} alkyl.

Representative examples of the compound represented by Formula 1 are as follows:

1) 1-(4-(tert-butyl)benzyl)-7-((2-chlorophenyl)amino)indolein-2,3-dione,

2) 1-(4-(tert-butyl)benzyl)-7-((3-chlorophenyl)amino)indolein-2,3-dione,

3) 1-(4-(tert-butyl)benzyl)-7-(p-tolylamino)indolein-2,3-dione,

4) 1-(4-(tert-butyl)benzyl)-7-((4-fluorophenyl)amino)indolein-2,3-dione,

5) 1-(4-(tert-butyl)benzyl)-7-((4-chlorophenyl)amino)indolein-2,3-dione,

6) 7-((4-bromophenyl)amino)-1-(4-(tert-butyl)benzyl)indolein-2,3-dione,

7) 1-(4-(tert-butyl)benzyl)-7-((4-(tert-butyl)phenyl)amino)indolein-2,3-dione,

8) 1-(4-(tert-butyl)benzyl)-7-((4-(trifluoromethyl)phenyl)amino)indolein-2,3-dione,

9) 1-(4-(tert-butyl)benzyl)-7-((4-methoxyphenyl)amino)indolein-2,3-dione,

10) 1-(4-(tert-butyl)benzyl)-7-((4-(trifluoromethoxy)phenyl)amino)indolein-2,3-dione,

11) 1-(4-(tert-butyl)benzyl)-7-((2,4-dimethylphenyl)amino)indolein-2,3-dione,

12) 1-(4-(tert-butyl)benzyl)-6-(p-tolylamino)indolein-2,3-dione,

13) 1-(4-(tert-butyl)benzyl)-6-((4-fluorophenyl)amino)indolein-2,3-dione,

14) 1-(4-(tert-butyl)benzyl)-6-((4-chlorophenyl)amino)indolein-2,3-dione,

15) 6-((4-bromophenyl)amino)-1-(4-(tert-butyl)benzyl)indolein-2,3-dione,

16) 7-((4-bromophenyl)amino)-1-(4-(tert-butyl)benzyl)-5-fluoroindolein-2,3-dione,

17) 1-(4-(tert-butyl)benzyl)-5-fluoro-7-((5-fluoropyridin-2-yl)amino)indolein-2,3-dione,

18) 1-(4-(tert-butyl)benzyl)-5-fluoro-7-((5-(trifluoromethyl)pyridin-2-yl)amino)indolein-2,3-dione,

19) 1-(4-(tert-butyl)benzyl)-7-((5-chloropyridin-2-yl)amino)-5-fluoroindolein-2,3-dione,

20) 1-(4-(tert-butyl)benzyl)-5-fluoro-7-((6-morpholinopyridin-3-yl)amino)indolein-2,3-dione,

21) 7-(4-(tert-butyl)phenyl)-1-(4-morpholinobenzyl)indolein-2,3-dione,

22) 7-(4-(tert-butyl)phenyl)-1-(4-((4-fluorophenyl)amino)benzyl)indolein-2,3-dione,

23) 7-(4-(tert-butyl)phenyl)-1-(4-((4-fluorophenyl)(methyl)amino)benzyl)indolein-2,3-dione,

24) 7-(4-(tert-butyl)phenyl)-1-(4-((4-chlorophenyl)amino)benzyl)indolein-2,3-dione,

25) 7-(4-(tert-butyl)phenyl)-1-(4-((2,4-difluorophenyl)amino)benzyl)indolein-2,3-dione,

26) 7-(4-(tert-butyl)phenyl)-1-(4-((4-chlorobenzyl)amino)benzyl)indolein-2,3-dione,

27) 7-(4-(tert-butyl)phenyl)-1-(4-((pyridin-3-ylmethyl)amino)benzyl)indolein-2,3-dione,

28) 1-(4-(diisopropylamino)benzyl)-7-(4-fluorophenyl)indolein-2,3-dione,

29) 1-(4-((4-(tert-butyl)phenyl)amino)benzyl)-7-(4-fluorophenyl)indolein-2,3-dione,

30) 7-(4-fluorophenyl)-1-(4-((4-(trifluoromethyl)phenyl)amino)benzyl)indolein-2,3-dione,

31) 1-(4-((2,4-difluorophenyl)amino)benzyl)-7-(4-fluorophenyl)indolein-2,3-dione,

32) 1-(4-((4-fluorophenyl)amino)benzyl)-7-(6-fluoropyridin-3-yl)indolein-2,3-dione and

33) 1-(4-((2,4-difluorophenyl)amino)benzyl)-5-fluoro-7-(6-fluoropyridin-3-yl)indolein-2,3-dione.

The compound represented by Formula 1 according to the present invention can form a salt, particularly a pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts, such as acid addition salts, are not particularly limited to those commonly used in the art (see J. Pharm. Sci., 66, 1 (1977)). Examples of acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, orthophosphoric acid or sulfuric acid; or, for example, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, acetic acid, propionic acid, lactic acid, citric acid, Organic acids such as fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid, glycerophosphoric acid or acetylsalicylic acid.

In addition, a pharmaceutically acceptable metal salt can be obtained by a conventional method using a base. For example, the compound represented by Formula 1 may be dissolved in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, and the non-dissolved compound salt is filtered, and the filtrate is evaporated and dried to obtain a pharmaceutically acceptable metal salt. At this time, it is preferable to prepare a sodium salt, a potassium salt, or a calcium salt as the metal salt, and these metal salts can be reacted with a suitable salt (eg, nitrate).

In addition, the compound represented by Formula 1 according to the present invention includes not only a pharmaceutically acceptable salt thereof, but also all possible solvates and hydrates that can be prepared therefrom, and includes all possible stereoisomers. Solvates, hydrates, and stereoisomers of the compound represented by Formula 1 can be prepared from the compound represented by Formula 1 using conventional methods.

In addition, the compound represented by Formula 1 according to the present invention may be prepared in a crystalline form or an amorphous form, and if prepared in a crystalline form, it may be optionally hydrated or solvated. In the present invention, a compound containing various amounts of water as well as a stoichiometric hydrate of the compound represented by Formula 1 may be included. The solvate of the compound represented by Formula 1 according to the present invention includes both a stoichiometric solvate and a non-stoichiometric solvate.

In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of peptic ulcer, gastritis, or reflux esophagitis, including the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof.

The term "prevention" as used in the present invention is any action of inhibiting or delaying peptic ulcer, gastritis or reflux esophagitis by administration of a pharmaceutical composition containing a compound represented by Formula 1, or a pharmaceutically acceptable salt thereof Means. In addition, the term "treatment" used in the present invention is to improve symptoms of peptic ulcer, gastritis or reflux esophagitis by administration of a pharmaceutical composition containing a compound represented by Formula 1, or a pharmaceutically acceptable salt thereof It means all actions that are cured.

The compound represented by Formula 1 according to the present invention, or a pharmaceutically acceptable salt thereof, has an inhibitory effect on proton pump (H ⁺ /K ⁺ -ATPase) activity, and secretion of basal gastric acid in pyloric-ligated rats It has an effect of inhibiting, and thus can be usefully used in the prevention or treatment of peptic ulcer, gastritis or reflux esophagitis.

The pharmaceutical composition of the present invention can be formulated in an oral or parenteral dosage form according to standard pharmaceutical practice. These formulations may contain additives such as a pharmaceutically acceptable carrier, adjuvant, or diluent in addition to the active ingredient. Suitable carriers include, for example, physiological saline, polyethylene glycol, ethanol, vegetable oil and isopropyl myristate, and diluents include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/ Or glycine and the like, but are not limited thereto. In addition, the compound according to the present invention, or a pharmaceutically acceptable salt thereof, can be dissolved in oil, propylene glycol or other solvents commonly used in the preparation of injection solutions. In addition, the compound according to the present invention, or a pharmaceutically acceptable salt thereof, may be formulated as an ointment or cream for topical action.

A preferred dosage of the compound according to the present invention, or a pharmaceutically acceptable salt thereof, depends on the condition and weight of the patient, the degree of disease, the form of the drug, the route and duration of administration, but may be appropriately selected by those skilled in the art. However, for a desirable effect, it is good to administer the compound according to the present invention at 0.0001 to 100 mg/kg (body weight), preferably 0.001 to 100 mg/kg (body weight) per day. Administration may be administered once a day or in divided doses via an oral or parenteral route. Depending on the method of administration, the pharmaceutical composition may contain 0.001 to 99% by weight, preferably 0.01 to 60% by weight of the compound according to the present invention.

The pharmaceutical composition according to the present invention can be administered to mammals, including mice, mice, livestock, and humans by various routes. All modes of administration can be expected and can be administered by, for example, oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dura mater or intracerbroventricular injection.

In addition, the present invention provides a method for preparing the compound represented by Chemical Formula 1.

For example, in Formula 1, when R ₂ is hydrogen, R ₃ is XR ₆ , and where X is NH, it can be prepared as shown in Scheme 1 below.

[Scheme 1]

The step 1-1 is a reaction of introducing benzyl substituted with R ₄ to the compound represented by Formula 1-2, wherein the compound represented by Formula 1-2 is reacted with the compound represented by Formula 1-3. To prepare a compound represented by Chemical Formula 1-4. The reaction is preferably carried out in the presence of benzyltriethylammonium chloride and potassium carbonate. In addition, it is preferable to use acetonitrile as a solvent.

Step 1-2 is a reaction of introducing NH-R ₆ to the compound represented by Formula 1-4, wherein the compound represented by Formula 1-4 is reacted with R ₆ -NH ₂ to react the compound represented by Formula 1-1. This is a step of preparing a compound represented by. The reaction is preferably carried out in the presence of palladium acetate, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and cesium carbonate. Moreover, it is preferable to use 1,4-dioxane as a solvent.

In addition, in Formula 1, when R ₂ is NHR ₅ and R ₃ is hydrogen, it can be prepared as shown in Scheme 2 below.

[Scheme 2]

The step 2-1 is the same reaction except for the step 1-1 and the starting material, by reacting the compound represented by the formula 2-2 with the compound represented by the formula 2-3, and the formula 2-4 This is a step of preparing a compound represented by.

The step 2-2 is the same reaction except for the step 1-2 and the starting material, and the compound represented by Formula 2-1 by reacting the compound represented by Formula 2-4 with R ₅ -NH ₂ It is a step of manufacturing.

In addition, in Formula 1, when R ₂ is hydrogen, R ₃ is XR ₆ , where X is a bond, it can be prepared as shown in Scheme 3 below.

[Scheme 3]

Step 3-1 is a reaction of introducing R ₆ to the compound represented by Formula 3-2, wherein the compound represented by Formula 3-2 is reacted with the compound represented by Formula 3-3 to This is a step of preparing a compound represented by -4. The reaction is preferably carried out in the presence of tetrakis(triphenylphosphine)palladium(0) and sodium carbonate. In addition, it is preferable to use benzene, ethanol, water, toluene, N,N-dimethylformamide, or a mixture thereof as the solvent.

The step 3-2 is the same reaction except for the starting material and the steps 1-1 and 2-1, by reacting the compound represented by Formula 3-4 with the compound represented by Formula 3-5 This is a step of preparing a compound represented by Chemical Formula 3-1.

In addition, in Formula 1, when R ₂ is hydrogen, R ₃ is XR ₆ , where X is a bond, and R ₄ is morpholino or YR ₇ , it can be prepared as shown in Scheme 4 below.

[Scheme 4]

Step 4-1 is the same reaction as Step 3-1, wherein the compound represented by Formula 4-2 is reacted with the compound represented by Formula 4-3 to prepare a compound represented by Formula 4-4. This is the step.

The step 4-2 is a reaction of introducing phenyl substituted with bromo to the compound represented by Formula 4-4, by reacting the compound represented by Formula 4-4 with the compound represented by Formula 4-5. This is a step of preparing a compound represented by Formula 4-6. The reaction is preferably carried out in the presence of benzyltriethylammonium chloride and potassium carbonate. In addition, it is preferable to use acetonitrile as a solvent.

The step 4-3 is a reaction of introducing morpholino or YR ₇ to the compound represented by Formula 4-6, wherein the compound represented by Formula 4-6 is reacted with HR ₄ to obtain Formula 4-1. This is the step of preparing the displayed compound. The reaction is preferably carried out in the presence of palladium acetate, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and cesium carbonate. Moreover, it is preferable to use 1,4-dioxane as a solvent.

The compound represented by Formula 1 according to the present invention can be usefully used in the prevention or treatment of peptic ulcer, gastritis or reflux esophagitis by effectively inhibiting the proton pump.

Hereinafter, the present invention will be described in more detail by the following Preparation Examples and Examples. However, the following Preparation Examples and Examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Manufacturing example 1: 7- Bromo -1-(4-( Turt -Butyl)benzyl) Indole -2,3- Dion's Produce

7-bromoindolein-2,3-dione (500.0 mg, 2.2 mmol), benzyltriethylammonium chloride (251.9 mg, 1.1 mmol) and potassium carbonate (764.3 mg, 5.5 mmol) in acetonitrile solution (15.0 mL) After dissolving in, the mixture was stirred at room temperature for 30 minutes. 4-(tertbutyl)benzyl bromide (813.1 µl, 4.4 mmol) was added to the mixture, followed by stirring at 60°C for 5 hours. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The separated organic layer was washed with 0.1N hydrochloric acid solution, saturated sodium hydrogen carbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:10→1:4 (v/v)) to give 84.8 mg of the title compound (yield 10.3%).

¹ H NMR (500 MHz, CDCl ₃ ): 7.67 (d, 1H), 7.65 (d, 1H), 7.33 (d, 2H), 7.21 (d, 2H), 6.99 (t, 1H), 5.40 (s, 2H), 1.28 (s, 9H)

Example 1: 1-(4-( Turt -Butyl)benzyl)-7-((2- Chlorophenyl )Amino) Indole -2,3- Dion's Produce

After dissolving the compound (20 mg, 0.05 mmol) prepared in Preparation Example 1 in 1,4-dioxane (1 mL), 2-chloroaniline (8.2 mg, 0.06 mmol), palladium acetate (1.2 mg, 0.005 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (3.3 mg, 0.005 mmol) and cesium carbonate (35 mg, 0.1 mmol) were added, and the mixture was added at 110° C. for 12 hours. Stirred. The reaction mixture was cooled to room temperature, saturated ammonium chloride solution was added and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:4 (v/v)) to prepare 1.2 mg of the title compound (yield 5.3%).

¹ H NMR (500 MHz, CDCl ₃ ): 7.93 (dd, 1H), 7.77 (d, 1H), 7.43 (dd, 1H), 7.35-7.39 (m, 1H), 7.27-7.29 (m, 4H), 7.02-7.15 (m, 3H), 5.06 (s, 2H), 1.37 (s, 9H)

In Examples 2 to 11 below, it was prepared in the same manner as in Example 1, but was prepared by appropriately changing the reaction material in consideration of the structure of the compound to be prepared.

Example 2: 1-(4-( Turt -Butyl)benzyl)-7-((3- Chlorophenyl )Amino) Indole -2,3- Dion Manufacture of

¹ H NMR (500 MHz, CDCl ₃ ): 7.53 (dd, 1H), 7.40 (d, 1H), 7.03-7.17 (m, 3H), 6.82 (dd, 1H), 6.72 (d, 1H), 6.66 ( t, 1H), 6.54 (dd, 1H), 6.45 (t, 1H), 6.37 (dd, 1H), 5.02 (s, 2H), 1.32 (s, 9H)

Example 3: 1-(4-( Turt -Butyl)benzyl)-7-(p- Tolylamino ) Indole -2,3- Dion's Produce

¹ H NMR (500 MHz, CDCl ₃ ): 7.37-7.44 (m, 4H), 7.18 (d, 2H), 7.01-7.04 (m, 3H), 6.44 (d, 2H), 5.06 (s, 2H), 2.27 (s, 3H), 1.32 (s, 9H)

Example 4: 1-(4-( Turt -Butyl)benzyl)-7-((4- Fluorophenyl )Amino) Indole -2,3- Dion's Produce

¹ H NMR (500 MHz, CD ₃ OD): 7.49 (dd, 1H), 7.36 (dd, 1H), 7.24 (d, 1H), 7.14 (t, 1H), 7.09 (t, 1H), 7.08 (s , 1H), 7.00 (d, 1H), 6.86 (t, 2H), 6.46-6.49 (m, 2H), 5.05 (s, 2H), 1.27 (s, 9H)

Example 5: 1-(4-( Turt -Butyl)benzyl)-7-((4- Chlorophenyl )Amino) Indole -2,3- Dion's Produce

¹ H NMR (500 MHz, CD ₃ OD): 7.49 (dd, 1H), 7.31-7.38 (m, 2H), 7.16 (d, 1H), 7.12 (d, 1H), 7.01 (d, 2H), 6.95 (d, 1H), 6.91 (d, 1H), 6.39 (d, 1H), 6.30 (d, 1H), 5.00 (s, 2H), 1.27 (s, 9H)

Example 6: 7-((4- Bromophenyl )Amino)-1-(4-( Turt -Butyl)benzyl) Indole -2,3- Dion's Produce

¹ H NMR (500 MHz, CDCl ₃ ): 7.51 (d, 1H), 7.37-7.39 (m, 3H), 7.29 (d, 2H), 7.13 (d, 2H), 7.08 (t, 1H), 6.37 ( d, 2H), 5.02 (s, 2H), 1.32 (s, 9H)

Example 7: 1-(4-( Turt -Butyl)benzyl)-7-((4-( Turt -Butyl) Phenyl )Amino) Indole Preparation of -2,3-dione

¹ H NMR (500 MHz, CDCl ₃ ): 7.41-7.43 (m, 4H), 7.19-7.24 (m, 4H), 7.03 (t, 1H), 6.49 (d, 2H), 5.07 (s, 2H), 1.33 (s, 9H), 1.29 (s, 9H)

Example 8: 1-(4-( Turt -Butyl)benzyl)-7-((4-( Trifluoromethyl ) Phenyl )Amino) Indole -2,3- Dion's Produce

¹ H NMR (500 MHz, CD ₃ OD): 7.54 (dd, 1H), 7.35-7.38 (m, 1H), 7.28 (d, 1H), 7.24 (d, 1H), 7.12 (d, 1H), 7.09 -7.10 (m, 2H), 6.97 (d, 1H), 6.88 (d, 1H), 6.49 (d, 1H), 6.40 (d, 1H), 5.01 (s, 2H), 1.17 (s, 9H)

Example 9: 1-(4-( Turt -Butyl)benzyl)-7-((4- Methoxyphenyl )Amino) Indole -2,3- Dion's Produce

¹ H NMR (500 MHz, CDCl ₃ ): 7.27-7.41 (m, 4H), 7.20 (d, 2H), 7.00 (t, 1H), 6.79 (d, 2H), 6.50 (d, 2H), 5.10 ( s, 2H), 3.77 (s, 3H), 1.32 (s, 9H)

Example 10: 1-(4-( Turt -Butyl)benzyl)-7-((4-( Trifluoromethoxy ) Phenyl )Amino)indolein-2,3- Dion's Produce

¹ H NMR (500 MHz, CDCl ₃ ): 7.51 (dd, 1H), 7.40 (d, 3H), 7.15 (d, 2H), 7.09 (d, 1H), 7.06 (d, 2H), 6.48 (d, 2H), 5.05 (s, 2H), 1.32 (s, 9H)

Example 11: 1-(4-( Turt -Butyl)benzyl)-7-((2,4- Dimethylphenyl )Amino) Indole Preparation of -2,3-dione

¹ H NMR (500 MHz, CDCl ₃ ): 7.39 (d, 2H), 7.36 (dd, 1H), 7.19 (d, 2H), 7.11 (d, 1H), 6.97 (t, 1H), 6.91 (s, 1H), 6.88 (d, 1H), 6.55 (d, 1H), 5.16 (s, 2H), 2.25 (s, 3H), 1.63 (s, 3H), 1.30 (s, 9H)

In Examples 12 to 15 below, prepared in the same manner as in Example 1, but using 6-bromoindolein-2,3-dione instead of the compound prepared in Preparation Example 1, and the structure of the compound to be prepared was It was prepared by appropriately changing the reaction material in consideration.

Example 12: 1-(4-( Turt -Butyl)benzyl)-6-(p- Tolylamino ) Indole -2,3- Dion's Produce

¹ H NMR (500 MHz, CD ₃ OD): 7.40 (d, 3H), 7.19 (d, 2H), 7.15 (d, 2H), 6.91 (d, 2H), 6.46 (d, 1H), 6.30 (s , 1H), 4.81 (s, 2H), 2.40 (s, 3H), 1.19 (s, 9H)

Example 13: 1-(4-( Turt -Butyl)benzyl)-6-((4- Fluorophenyl )Amino) Indole Preparation of -2,3-dione

¹ H NMR (500 MHz, CD ₃ OD): 7.41 (t, 3H), 7.20 (d, 2H), 7.10-7.03 (m, 4H), 6.45 (d, 1H), 6.26 (s, 1H), 4.73 (s, 2H), 1.28 (s, 9H)

Example 14: 1-(4-( Turt -Butyl)benzyl)-6-((4- Chlorophenyl )Amino) Indole -2,3- Dion's Produce

¹ H NMR (500 MHz, CD ₃ OD): 7.45-7.40 (m, 3H), 7.30 (d, 2H), 7.22 (d, 2H), 7.00 (d, 2H), 6.53-6.51 (m, 1H) , 6.33 (s, 1H), 4.80 (s, 2H), 2.30 (s, 9H)

Example 15: 6-((4- Bromophenyl )Amino)-1-(4-( Turt -Butyl)benzyl) Indole -2,3- Dion's Produce

¹ H NMR (500 MHz, CDCl ₃ ): 7.48 (d, 1H), 7.44 (d, 2H), 7.36 (d, 2H), 7.18 (d, 2H), 6.90 (d, 2H), 6.40 (dd, 1H), 6.34 (s, 1H), 6.22 (d, 1H), 4.80 (s, 2H), 1.29 (s, 9H)

Manufacturing example 2: 7- Bromo -1-(4-( Turt -Butyl)benzyl)-5- Fluoroindole -2,3- Dion's Produce

7-bromo-5-fluoroindolein-2,3-dione (1.0 g, 4.1 mmol), benzyltriethylammonium chloride (466.7 mg, 2.0 mmol) and potassium carbonate (1.4 g, 10.3 mmol) in acetonitrile After dissolving in a solution (30.0 mL), it was stirred at room temperature for 30 minutes. 4-(tertbutyl)benzyl bromide (1.9 mL, 8.2 mmol) was added to the mixture, followed by stirring at 60° C. for 5 hours. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The separated organic layer was washed with 0.1N hydrochloric acid solution, saturated sodium hydrogen carbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under conjugation. The obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:10→1:2 (v/v)) to give 1.3 g of the title compound (yield 81.2%).

¹ H NMR (500 MHz, CDCl ₃ ): 7.42-7.46 (m, 1H), 7.32-7.36 (m, 3H), 7.17-7.21 (m, 2H), 5.38 (s, 2H), 1.29 (s, 9H) )

Example 16: 7-((4- Bromophenyl )Amino)-1-(4-( Turt -Butyl)benzyl)-5- Fluoroin Stone Inn-2,3- Dion's Produce

After dissolving the compound (20 mg, 0.05 mmol) prepared in Preparation Example 2 in 1,4-dioxane (1 mL), 4-bromoaniline (7.8 mg, 0.06 mmol), palladium acetate (1.1 mg, 0.005 mmol) , 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (3.2 mg, 0.005 mmol), cesium carbonate (33 mg, 0.1 mmol) were added, and the mixture was 120 using a microwave reactor. It was stirred at °C for 90 minutes. The reaction mixture was cooled to room temperature, saturated ammonium chloride solution was added and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3 (v/v)) to prepare 1.3 mg of the title compound (yield 5.4%).

¹ H NMR (500 MHz, CDCl ₃ ): 7.42 (d, 2H), 7.33 (d, 2H), 7.16 (d, 2H), 7.14-7.08 (m, 2H), 6.40 (d, 2H), 5.07 ( s, 2H), 1.31 (s, 9H)

In Examples 17 to 20 below, it was prepared in the same manner as in Example 16, but was prepared by appropriately changing the reaction material in consideration of the structure of the compound to be prepared.

Example 17: 1-(4-( Turt -Butyl)benzyl)-5- Fluoro -7-((5- Fluoropyridine -2-yl)amino) Indole -2,3- Dion's Produce

¹ H NMR (500 MHz, CDCl ₃ ): 8.02 (d, 1H), 7.45 (dd, 1H), 7.38 (d, 2H), 7.22 (m, 1H), 7.17 (d, 2H), 6.05 (dd, 1H), 5.81 (s, 1H), 5.06 (s, 2H), 1.27 (s, 9H)

Example 18: 1-(4-( Turt -Butyl)benzyl)-5- Fluoro -7-((5-( Trifluoromethyl )Pyridin-2-yl)amino) Indole -2,3- Dion's Produce

¹ H NMR (500 MHz, CDCl ₃ ): 8.42 (s, 1H), 7.62 (dd, 1H), 7.37 (d, 2H), 7.30 (m, 1H), 7.13 (d, 2H), 6.16 (d, 1H), 6.08 (s, 1H), 5.04 (s, 2H), 1.31 (s, 9H)

Example 19: 1-(4-( Turt -Butyl)benzyl)-7-((5- Chloropyridine -2-yl)amino)-5- Fluoroindole -2,3- Dion's Produce

¹ H NMR (500 MHz, CDCl ₃ ): 8.10 (d, 1H), 7.42-7.36 (m, 4H), 7.14 (d, 2H), 6.02 (d, 1H), 5.86 (s, 1H), 5.05 ( s, 2H), 1.30 (s, 9H)

Example 20: 1-(4-( Turt -Butyl)benzyl)-5- Fluoro -7-((6- Morpholinopyridine -3-yl)amino) Indole -2,3- Dion's Produce

¹ H NMR (500 MHz, CDCl ₃ ): 7.54 (d, 1H), 7.45 (d, 2H), 7.22 (d, 2H), 7.07 (s, 1H), 6.95 (dd, 1H), 6.87 (dd, 1H), 6.79 (dd, 1H), 6.58 (d, 1H), 5.18 (s, 2H), 3.82 (m, 4H), 3.43 (m, 4H), 2.32 (s, 9H)

Manufacturing example 3: 7-(4-( Turt -Butyl) Phenyl ) Indole -2,3- Dion's Produce

7-bromoindolein-2,3-dione (50 mg, 0.02 mmol), 4-tert-butylboronic acid (79 mg, 0.5 mmol), tetrakis (triphenylphosphine) palladium (0) (51 mg , 0.04 mmol) and sodium carbonate (233 mg, 2.2 mmol) were dissolved in a benzene/ethanol/water solution (2.0 mL), followed by stirring at 100° C. for 24 hours. The reaction mixture was cooled to room temperature and then extracted with water and ethyl acetate. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1 (v/v)) to prepare 10.0 mg of the title compound (yield 16.3%).

¹ H NMR (500 MHz, CDCl ₃ ): 7.98 (d, 1H), 7.46 (d, 2H), 7.35 (d, 2H), 7.25 (d, 1H), 6.68 (t, 1H), 5.99 (s, 1H), 1.36 (s, 9H)

Manufacturing example 4: 1-(4- Bromobenzyl )-7-(4-( Turt -Butyl) Phenyl ) Indole -2,3- Dion's Produce

After dissolving the compound (200 mg, 0.7 mmol), benzyltriethylammonium chloride (82 mg, 0.4 mmol) and potassium carbonate (248 mg, 1.8 mmol) prepared in Preparation Example 3 in acetonitrile solution (5 mL), at room temperature Stir for 30 minutes. 4-bromobenzyl bromide (450 mg, 1.8 mmol) was added to the mixture, followed by stirring at 60°C for 4 hours. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The separated organic layer was washed with 0.1N hydrochloric acid solution, saturated sodium hydrogen carbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2 (v/v)) to prepare 89.9 mg of the title compound (yield 27.9%).

¹ H NMR (500 MHz, CDCl ₃ ): 7.67 (d, 1H), 7.50 (t, 1H), 7.31 (d, 2H), 7.19 (d, 2H), 7.12 (t, 1H), 6.94 (d, 2H), 6.35 (d, 2H), 4.67 (s, 2H), 1.39 (s, 9H)

Example 21: 7-(4-( Turt -Butyl) Phenyl )-1-(4- Morpholinobenzyl ) Indole -2,3- Dion's Produce

After dissolving the compound (20 mg, 0.05 mmol) prepared in Preparation Example 4 in 1,4-dioxane (1 mL), morpholine (5.4 mg, 0.06 mmol), palladium acetate (1.0 mg, 0.004 mmol), 2, 2'-bis(diphenylphosphino)-1,1'-binaphthyl (2.8 mg, 0.004 mmol) and cesium carbonate (29 mg, 0.09 mmol) were added, and the mixture was added at 120°C using a microwave reactor. Stir for 90 minutes. The reaction mixture was cooled to room temperature, saturated ammonium chloride solution was added and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:2 (v/v)) to prepare 1.2 mg of the title compound (yield 3.2%).

¹ H NMR (500 MHz, CDCl ₃ ): 7.64 (d, 1H), 7.32-7.27 (m, 3H), 7.09 (t, 1H), 6.99 (d, 2H), 6.60-6.68 (m, 2H), 6.41 (d, 2H), 4.64 (s, 2H), 3.87-3.85 (m, 4H), 3.07 (t, 4H), 1.38 (s, 9H)

In Examples 22 to 27 below, it was prepared in the same manner as in Example 21, but was prepared by appropriately changing the reaction material in consideration of the structure of the compound to be prepared.

Example 22: 7-(4-( Turt -Butyl) Phenyl )-1-(4-((4- Fluorophenyl )Amino)benzyl) Indole -2,3- Dion's Produce

¹ H NMR (500 MHz, CDCl ₃ ): 7.66 (d, 2H), 7.33-7.30 (m, 3H), 7.10 (t, 1H), 7.03-6.93 (m, 6H), 6.69 (d, 2H), 6.37 (d, 2H), 4.64 (s, 2H), 1.37 (s, 9H)

Example 23: 7-(4-( Turt -Butyl) Phenyl )-1-(4-((4- Fluorophenyl )( methyl )Amino)benzyl) Indole -2,3- Dion's Produce

¹ H NMR (500 MHz, CDCl ₃ ): 7.64 (t, 1H), 7.33-7.26 (m, 3H), 7.10 (t, 1H), 7.02-6.92 (m, 4H), 6.81-6.83 (m, 2H) ), 6.57 (d, 2H), 6.35 (d, 2H), 4.64 (s, 2H), 2.86 (s, 3H), 1.35 (s, 9H)

Example 24: 7-(4-( Turt -Butyl) Phenyl )-1-(4-((4- Chlorophenyl )Amino)benzyl) Indole Preparation of -2,3-dione

¹ H NMR (500 MHz, CDCl ₃ ): 7.67 (d, 1H), 7.43-7.41 (m, 3H), 7.31 (d, 1H), 7.27 (d, 1H), 7.18 (d, 2H), 7.13 ( d, 1H), 7.10 (d, 2H), 6.94 (d, 2H), 6.36 (d, 2H), 4.67 (s, 1H), 1.37 (s, 9H)

Example 25: 7-(4-( Turt -Butyl) Phenyl )-1-(4-((2,4- Difluorophenyl )Amino)benzyl)indolein-2,3- Dion's Produce

¹ H NMR (500 MHz, CDCl ₃ ): 7.65 (d, 1H), 7.32 (m, 3H), 7.19-7.08 (m, 2H), 7.01 (d, 2H), 6.86 (t, 1H), 6.7 ( t, 1H), 6.68 (d, 2H), 6.39 (d, 2H), 4.66 (s, 2H), 1.37 (s, 9H)

Example 26: 7-(4-( Turt -Butyl) Phenyl )-1-(4-((4- Chlorobenzyl )Amino)benzyl) Indole Preparation of -2,3-dione

¹ H NMR (500 MHz, CDCl ₃ ): 7.75 (d, 1H), 7.63-7.75 (m, 5H), 7.49-7.47 (m, 3H), 7.42-7.38 (m, 5H), 7.10 (d, 1H) ), 4.72 (s, 2H), 4.25 (s, 2H), 1.37 (s, 9H)

Example 27: 7-(4-( Turt -Butyl) Phenyl )-1-(4-((pyridin-3- Monomethyl )Amino)benzyl) Indole -2,3- Dion's Produce

¹ H NMR (500 MHz, CDCl ₃ ): 7.74 (d, 2H), 7.63-7.56 (m, 6H), 7.49-7.37 (m, 5H), 7.09 (d, 2H), 4.71 (s, 2H), 4.25 (s, 2H), 1.35 (s, 9H)

Manufacturing example 5: 7-(4- Fluorophenyl ) Indole -2,3- Dion's Produce

7-bromoindolein-2,3-dione (500 mg, 2.2 mmol), 4-fluorophenylboronic acid (773.8 mg, 3.3 mmol), tetrakis (triphenylphosphine) palladium (0) (128.1 mg , 0.1 mmol) and sodium carbonate (611.5 mg, 4.4 mmol) were dissolved in toluene/N,N-dimethylformamide solution (10 mL), and the mixture was stirred at 170° C. for 30 minutes using a microreactor. The reaction mixture was cooled to room temperature and then extracted with water and ethyl acetate. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:2 (v/v)) to give 485.0 mg of the title compound (yield 91.0%).

¹ H NMR (300 MHz, CDCl ₃ ): 7.76 (s, 1H), 7.62-7.53 (m, 4H), 7.36-7.32 (m, 2H), 7.25-7.17 (m, 1H)

Manufacturing example 6: 1-(4- Bromobenzyl )-7-(4- Fluorophenyl ) Indole -2,3- Dion's Produce

After dissolving the compound (500 mg, 2.0 mmol), benzyltriethylammonium chloride (228 mg, 1.0 mmol) and potassium carbonate (691 mg, 5.0 mmol) prepared in Preparation Example 5 in acetonitrile solution (10 mL), at room temperature Stir for 30 minutes. 4-bromobenzyl bromide (2.2 g, 5.0 mmol) was added to the mixture, followed by stirring at 60°C for 4 hours. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The separated organic layer was washed with 0.1N hydrochloric acid solution, saturated sodium hydrogen carbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:4 (v/v)) to prepare 0.481 g of the title compound (yield 58.6%).

¹ H NMR (500 MHz, CDCl ₃ ): 7.69 (d, 1H), 7.28-7.24 (m, 2H), 7.16-7.13 (m, 2H), 7.04-6.93 (m, 4H), 6.47 (d, 2H) ), 4.65 (s, 2H)

Example 28: 1-(4-( Diisopropylamino )Benzyl)-7-(4- Fluorophenyl ) Indole Preparation of -2,3-dione

After dissolving the compound (15 mg, 0.04 mmol) prepared in Preparation Example 6 in 1,4-dioxane (1 mL), diisopropylamine (7.3 mg, 0.07 mmol), palladium acetate (0.08 mg, 0.004 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (2.3 mg, 0.004 mmol) and cesium carbonate (24 mg, 0.07 mmol) were added, and the mixture was 120 using a microwave reactor. It was stirred at °C for 90 minutes. The reaction mixture was cooled to room temperature, saturated ammonium chloride solution was added and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:4 (v/v)) to prepare 10.4 mg of the title compound (yield 6.5%).

¹ H NMR (500 MHz, CDCl ₃ ): 7.69 (d, 1H), 7.29-7.23 (m, 3H), 7.14 (t, 1H), 6.98-6.94 (m, 4H), 6.46 (d, 2H), 4.64 (s, 2H), 2.90 (m, 2H), 1.01 (d, 12H)

In Examples 29 to 31 below, it was prepared in the same manner as in Example 28, but was prepared by appropriately changing the reaction material in consideration of the structure of the compound to be prepared.

Example 29: 1-(4-((4-( Turt -Butyl) Phenyl )Amino)benzyl)-7-(4- Fluorophenyl ) Indole -2,3- Dion's Produce

¹ H NMR (500 MHz, CDCl ₃ ): 7.68 (d, 1H), 7.34-7.27 (m, 2H), 7.15-7.10 (m, 2H), 7.07-6.85 (m, 8H), 6.57-6.45 (m) , 2H), 4.65 (s, 2H), 1.28 (s, 9H)

Example 30: 7-(4- Fluorophenyl )-1-(4-((4-( Trifluoromethyl ) Phenyl )Amino)benzyl) Indole -2,3- Dion's Produce

¹ H NMR (500 MHz, CDCl ₃ ): 7.69 (d, 1H), 7.58 (t, 1H), 7.47 (d, 2H), 7.14 (m, 2H), 7.07-6.97 (m, 5H), 6.88 ( d, 2H), 6.56 (d, 2H), 4.67 (s, 2H)

Example 31: 1-(4-((2,4- Difluorophenyl )Amino)benzyl)-7-(4- Fluorophenyl ) Indole -2,3- Dion's Produce

¹ H NMR (500 MHz, CDCl ₃ ): 7.68 (d, 1H), 7.28 (d, 1H), 7.20-7.10 (m, 2H), 7.06-6.94 (m, 4H), 6.87 (t, 1H), 6.78 (m, 1H), 6.75 (d, 2H), 6.49 (d, 2H), 4.64 (s, 2H)

Manufacturing example 7: 7-(6- Fluoropyridine -3 days) Indole -2,3- Dion's Produce

7-bromoindolein-2,3-dione (500 mg, 2.2 mmol), 2-fluoro-5-pyridine boronic acid (465 mg, 3.3 mmol), tetrakis (triphenylphosphine) palladium (0) (255 mg, 0.22 mmol) and sodium carbonate (608 mg, 4.4 mmol) were dissolved in toluene/N,N-dimethylformamide solution (10 mL), and the mixture was stirred at 170° C. for 30 minutes using a microreactor. I did. The reaction mixture was cooled to room temperature and then extracted with water and ethyl acetate. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3 (v/v)) to prepare 0.3 g of the title compound (yield 56.0%).

¹ H NMR (500 MHz, CDCl ₃ ): 8.45 (s, 1H), 8.32 (d, 1H), 7.88 (t, 1H), 7.68 (d, 1H), 7.53 (d, 1H), 7.22 (d, 1H), 7.11 (d, 1H)

Manufacturing example 8: 1-(4- Bromobenzyl )-7-(6- Fluoropyridine -3 days) Indole -2,3- Dion's Produce

After dissolving the compound (300 mg, 1.2 mmol), benzyltriethylammonium chloride (140 mg, 0.6 mmol) and potassium carbonate (430 mg, 3.1 mmol) prepared in Preparation Example 7 in acetonitrile solution (10 mL), at room temperature Stir for 30 minutes. 4-bromobenzyl bromide (770 mg, 3.1 mmol) was added to the mixture, and the mixture was stirred at 60° C. for 4 hours. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The separated organic layer was washed with 0.1N hydrochloric acid solution, saturated sodium hydrogen carbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3 (v/v)) to prepare 0.27 g of the title compound (yield 54.0%).

¹ H NMR (500 MHz, CDCl ₃ ): 7.94 (d, 1H), 7.78 (d, 1H), 7.32-7.26 (m, 3H), 7.25-7.22 (m, 2H), 6.75 (d, 1H), 6.46 (d, 2H), 4.82 (d, 1H), 4.57 (d, 1H)

Example 32: 1-(4-((4- Fluorophenyl )Amino)benzyl)-7-(6- Fluoropyridine -3-yl)indolein-2,3- Dion's Produce

After dissolving the compound (20 mg, 0.05 mmol) prepared in Preparation Example 8 in 1,4-dioxane (1 mL), 4-fluoroaniline (7 µl, 0.07 mmol), palladium acetate (1.1 mg, 0.005 mmol) , 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (3 mg, 0.005 mmol), cesium carbonate (32 mg, 0.1 mmol) were added, and the mixture was 120 using a microwave reactor. It was stirred at °C for 90 minutes. The reaction mixture was cooled to room temperature, saturated ammonium chloride solution was added and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2 (v/v)) to prepare 1.03 mg of the title compound (yield 4.8%).

¹ H NMR (500 MHz, CDCl ₃ ): 7.88 (s, 1H), 7.74 (d, 1H), 7.44-7.40 (m, 1H), 7.24 (d, 1H), 7.18 (t, 1H), 7.02- 6.95 (m, 4H), 6.83 (dd, 1H), 6.73 (d, 2H), 6.41 (d, 2H), 4.70-4.58 (m, 2H)

Manufacturing example 9: 5- Fluoro -7-(6- Fluoropyridine -3 days) Indole -2,3- Dion's Produce

7-bromo-5-fluoroindolein-2,3-dione (1 g, 4.1 mmol), 2-fluoro-5-pyridine boronic acid (1.44 g, 10 mmol), tetrakis (triphenylphosphine ) Palladium (0) (410 mg, 0.5 mmol) and sodium carbonate (1.4 g, 10 mmol) were dissolved in toluene/N,N-dimethylformamide solution (10 mL), and the mixture was dissolved at 170°C at 30°C using a microreactor. Stir for a minute. The reaction mixture was cooled to room temperature and then extracted with water and ethyl acetate. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:4 (v/v)) to prepare 0.25 g of the title compound (yield 24%).

¹ H NMR (500 MHz, CDCl ₃ ): 8.31 (s, 1H), 7.89-7.80 (m, 1H), 7.79 (s, 1H), 7.42 (d, 1H), 7.30 (d, 1H), 7.14 ( d, 1H)

Manufacturing example 10: 1-(4- Bromobenzyl )-5- Fluoro -7-(6- Fluoropyridine -3 days) Indole Preparation of -2,3-dione

After dissolving the compound (250 mg, 0.9 mmol), benzyltriethylammonium chloride (109 mg, 0.5 mmol) and potassium carbonate (332 mg, 2.4 mmol) prepared in Preparation Example 9 in acetonitrile solution (5 mL), at room temperature Stir for 30 minutes. 4-bromobenzyl bromide (600 mg, 2.4 mmol) was added to the mixture, followed by stirring at 60°C for 4 hours. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The separated organic layer was washed with 0.1N hydrochloric acid solution, saturated sodium hydrogen carbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2 (v/v)) to prepare 0.24 g of the title compound (yield 58%).

¹ H NMR (500 MHz, CDCl ₃ ): 7.95 (d, 1H), 7.48 (dd, 1H), 7.29 (dd, 3H), 7.01 (dd, 1H), 6.77 (dd, 1H), 6.44 (d, 2H), 4.82 (d, 1H), 4.52 (d, 1H)

Example 33: 1-(4-((2,4- Difluorophenyl )Amino)benzyl)-5- Fluoro -7-(6- Fluoropyridine -3 days) Indole -2,3- Dion's Produce

After dissolving the compound (20 mg, 0.05 mmol) prepared in Preparation Example 10 in 1,4-dioxane (1 mL), 2,4-difluoroaniline (8 µl, 0.07 mmol), palladium acetate (1 mg, 0.005 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (2.9 mg, 0.005 mmol) and cesium carbonate (30 mg, 0.09 mmol) were added, and the mixture was added to a Microwave reactor. It was stirred for 90 minutes at 120 ℃ using. The reaction mixture was cooled to room temperature, saturated ammonium chloride solution was added and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2 (v/v)) to prepare 1.2 mg of the title compound (yield 5.4%).

¹ H NMR (500 MHz, CDCl ₃ ): 7.90 (d, 1H), 7.45 (q, 1H), 7.39 (td, 1H), 7.19-7.23 (m, 1H), 7.00 (dd, 1H), 6.86- 6.90 (m, 1H), 6.81-6.84 (m, 2H), 6.75 (d, 2H), 6.41 (d, 2H), 5.52 (s, 1H), 4.65 (s, 2H)

Experimental example

1) gastrointestinal vesicles ( gastric vesicles ) Of manufacture

Gastric vesicles were centrifuged from the hog stomach (Edd C. Rabon et al., Preparation of Gastric H ⁺ ,K ⁺ -ATPase., Methods in enzymology, vol. 157 Academic Press Inc. , (1988), pp.649-654). The protein contents of the prepared gastrointestinal vesicles were quantified with the Bicinchoninic Acid (BCA) kit.

2) Proton pump (H ⁺ /K ⁺ - ATPase ) Measurement of inhibitory effect on activity

The inhibitory effect of the compounds of the present invention on proton pump activity was measured in 96-well plates. K ⁺ specific H ⁺ / K ⁺ -ATPase activity in the present experimental example is based on the difference between the time of K ⁺ ions H ⁺ / K ⁺ -ATPase activity with K ⁺ ion ratio H ⁺ / K ⁺ -ATPase activity in the presence Was calculated as. In a 96-well plate, 0.5% dimethyl sulfoxide (DMSO) in buffer was added to the negative and positive controls, and the compound according to the present invention was diluted and added to the test group. All analyzes were performed at room temperature with a reaction volume of 100 μl. After adding DMSO and compounds of each concentration to the reaction buffer solution (60 mmol/L Tris-HCl buffer, pH 7.4) containing hog gastric vesicle, 10 μl of 10 mmol/L adenosine triphosphate Tris buffer (60 mmol/L Tris-HCl buffer, pH 7.4) was added to start the enzyme reaction. The enzymatic reaction was carried out at 37° C. for 40 minutes, and 50 μl of malachite green solution (0.12% malachite green solution in 6.2N sulfuric acid, 5.8% ammonium molybdate, and 11% Tween 20 were mixed in a ratio of 100:67:2. ) Was added to stop the reaction, and 50 μl of 15.1% sodium citrate was added. The amount of monophosphate (Pi) during the reaction was measured at 570 nm using a micro plate reader (FLUOstar Omega, BMG). The percent inhibition (%) was determined from the activity values of the control group and the activity values of various concentrations of the test compound, and the IC ₅₀ of the test compound was calculated from each% inhibition value of the compound using the Logistic 4-parameter function of the Sigmaplot 8.0 program. The results are shown in Table 1 below.

Example number IC ₅₀ (μM) Example number IC ₅₀ (μM) Example number IC ₅₀ (μM) One 0.68 12 0.66 23 0.1 2 0.2 13 0.48 24 0.33 3 0.23 14 0.47 25 0.09 4 0.8 15 0.6 26 0.07 5 1.5 16 0.24 27 0.15 6 0.56 17 2 28 0.39 7 0.09 18 0.68 29 0.66 8 0.57 19 0.1 30 0.13 9 0.87 20 0.2 31 0.63 10 0.95 21 0.26 32 0.98 11 0.23 22 0.08 33 0.59

3) Pylori- Ligated ( pylorus - ligated ) In the rat Basal gastric acid secretion ( basal gastric acid secretion ) On inhibitory effect

The inhibitory effect of the compounds according to the present invention on basal gastric acid secretion was performed according to the Shay's rat model (Shay, H., et al., 1945, gastroenterology, 5, p43-61). Male Sprague Dawley (SD) rats (weight 180-220 g) were divided into group X (n=5) and fasted while supplying only water for 18 hours. Under isoflurane anesthesia, the rat's abdominal cavity was incised and the pylorus was ligated. Immediately after ligation, the control group was administered only 10% ethanol, 20% polyethylene glycol (PEG) 400, and 10% cremophor aqueous solution into the duodenum. The test compound suspended in ethanol, 20% polyethylene glycol 400, and 10% cremophor aqueous solution was administered intraduodenum at a dose of 10 mg/kg/2 mL. Five hours after ligation, the test animals were killed and the contents of the stomach were removed. The obtained contents were centrifuged at 4,000×g for 10 minutes to separate only the supernatant to obtain gastric juice. The amount and pH of the obtained gastric juice were measured, and the acidity of the gastric juice was measured as the volume of 0.1 N-NaOH (ueq/mL) required for automatic titration of gastric acid up to pH 7.0. output) was obtained. The% inhibitory activity of the representative substance is shown in Table 2 below.

% Inhibitory activity of test compound = (total acid secretion of control group-total acid secretion of group treated with test compound) / total acid secretion of control group × 100

Example number % Inhibitory activity 3 38% 6 35% 13 35% 22 34% 29 30% 31 40%

Claims (13)

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

In the above formula,
R ₁ is hydrogen or halogen,
R ₂ is hydrogen or NHR ₅ ,
Wherein, R ₅ is phenyl substituted by any of the substituents selected from the group consisting of a C _{1 -4} alkyl and halogen,
R ₃ is hydrogen or XR ₆ ,
Where X is a bond or NH,
R ₆ is phenyl or pyridinyl,
Here, one in which the phenyl or pyridinyl is C _{1 -4} alkyl, C _{1 -4} alkoxy, C _{1 -4} haloalkyl, C _{1 -4} haloalkoxy, each independently selected from halogen, and morpholino group consisting of furnace Or substituted with two substituents,
R ₄ is a C _{1 -4} alkyl, morpholinophenyl or YR _7,
Here, Y is NH, NH (CH ₂₎ or N (C _{1 -4} alkyl),
R ₇ is C _{1 -4} alkyl, phenyl or pyridinyl,
Wherein said phenyl or pyridinyl is substituted with one or two substituents each independently selected from the group consisting of unsubstituted or substituted C _{1 -4} alkyl, C _{1 -4} haloalkyl, and halogen,
However, one of R ₂ and R ₃ is hydrogen, and the other is not hydrogen.
The method of claim 1,
R ₁ is hydrogen or fluoro,
A compound or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ₅ is characterized in that phenyl substituted with any one substituent selected from the group consisting of methyl, fluoro, chloro and bromo,
A compound or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ₆ is phenyl or pyridinyl,
Here, the phenyl or pyridinyl is one independently selected from the group consisting of methyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, fluoro, chloro, bromo, and morpholino, or Characterized in that substituted with two substituents,
A compound or a pharmaceutically acceptable salt thereof.
The method of claim 4,
The phenyl or pyridinyl is substituted with a substituent selected from the group consisting of methyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, fluoro, chloro, bromo, and morpholino; Or characterized in that substituted with two methyl,
A compound or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ₄ is tert-butyl, morpholino or YR ₇ ,
Here, Y is NH, NH (CH ₂ ), N (CH ₃ ) or N (isopropyl),
R ₇ is isopropyl, phenyl or pyridinyl,
Here, the phenyl or pyridinyl is unsubstituted or substituted with one or two substituents each independently selected from the group consisting of tert-butyl, trifluoromethyl, fluoro and chloro,
A compound or a pharmaceutically acceptable salt thereof.
The method of claim 6,
The phenyl or pyridinyl is substituted with a substituent selected from the group consisting of tert-butyl, trifluoromethyl, fluoro and chloro; Or characterized by being substituted with two fluoro,
A compound or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ₁ is hydrogen,
R ₂ is NHR ₅ ,
Wherein, R ₅ is phenyl substituted by any of the substituents selected from the group consisting of a C _{1 -4} alkyl and halogen,
R ₃ is hydrogen,
R ₄ is characterized in that the C _{1 -4} alkyl,
A compound or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ₁ is hydrogen or halogen,
R ₂ is hydrogen,
R ₃ is characterized in that XR ₆ ,
A compound or a pharmaceutically acceptable salt thereof.
The method of claim 9,
X is a bond,
R ₆ is phenyl or pyridinyl,
Wherein said phenyl or pyridinyl is optionally substituted by C _{1 -4} alkyl or halogen,
R ₄ is morpholino or YR ₇ ,
Here, Y is NH, NH (CH ₂₎ or N (C _{1 -4} alkyl),
R ₇ is C _{1 -4} alkyl, phenyl or pyridinyl,
Wherein said phenyl or pyridinyl is characterized in that the optionally substituted with one or two substituents each independently selected from the group consisting of unsubstituted or substituted C _{1 -4} alkyl, C _{1 -4} haloalkyl, and halogen,
A compound or a pharmaceutically acceptable salt thereof.
The method of claim 9,
X is NH,
R ₆ is phenyl or pyridinyl,
Here, one in which the phenyl or pyridinyl is C _{1 -4} alkyl, C _{1 -4} alkoxy, C _{1 -4} haloalkyl, C _{1 -4} haloalkoxy, each independently selected from halogen, and morpholino group consisting of furnace Or substituted with two substituents,
R ₄ is characterized in that the C _{1 -4} alkyl,
A compound or a pharmaceutically acceptable salt thereof.
The method of claim 1, wherein the compound is
1) 1-(4-(tert-butyl)benzyl)-7-((2-chlorophenyl)amino)indolein-2,3-dione,
2) 1-(4-(tert-butyl)benzyl)-7-((3-chlorophenyl)amino)indolein-2,3-dione,
3) 1-(4-(tert-butyl)benzyl)-7-(p-tolylamino)indolein-2,3-dione,
4) 1-(4-(tert-butyl)benzyl)-7-((4-fluorophenyl)amino)indolein-2,3-dione,
5) 1-(4-(tert-butyl)benzyl)-7-((4-chlorophenyl)amino)indolein-2,3-dione,
6) 7-((4-bromophenyl)amino)-1-(4-(tert-butyl)benzyl)indolein-2,3-dione,
7) 1-(4-(tert-butyl)benzyl)-7-((4-(tert-butyl)phenyl)amino)indolein-2,3-dione,
8) 1-(4-(tert-butyl)benzyl)-7-((4-(trifluoromethyl)phenyl)amino)indolein-2,3-dione,
9) 1-(4-(tert-butyl)benzyl)-7-((4-methoxyphenyl)amino)indolein-2,3-dione,
10) 1-(4-(tert-butyl)benzyl)-7-((4-(trifluoromethoxy)phenyl)amino)indolein-2,3-dione,
11) 1-(4-(tert-butyl)benzyl)-7-((2,4-dimethylphenyl)amino)indolein-2,3-dione,
12) 1-(4-(tert-butyl)benzyl)-6-(p-tolylamino)indolein-2,3-dione,
13) 1-(4-(tert-butyl)benzyl)-6-((4-fluorophenyl)amino)indolein-2,3-dione,
14) 1-(4-(tert-butyl)benzyl)-6-((4-chlorophenyl)amino)indolein-2,3-dione,
15) 6-((4-bromophenyl)amino)-1-(4-(tert-butyl)benzyl)indolein-2,3-dione,
16) 7-((4-bromophenyl)amino)-1-(4-(tert-butyl)benzyl)-5-fluoroindolein-2,3-dione,
17) 1-(4-(tert-butyl)benzyl)-5-fluoro-7-((5-fluoropyridin-2-yl)amino)indolein-2,3-dione,
18) 1-(4-(tert-butyl)benzyl)-5-fluoro-7-((5-(trifluoromethyl)pyridin-2-yl)amino)indolein-2,3-dione,
19) 1-(4-(tert-butyl)benzyl)-7-((5-chloropyridin-2-yl)amino)-5-fluoroindolein-2,3-dione,
20) 1-(4-(tert-butyl)benzyl)-5-fluoro-7-((6-morpholinopyridin-3-yl)amino)indolein-2,3-dione,
21) 7-(4-(tert-butyl)phenyl)-1-(4-morpholinobenzyl)indolein-2,3-dione,
22) 7-(4-(tert-butyl)phenyl)-1-(4-((4-fluorophenyl)amino)benzyl)indolein-2,3-dione,
23) 7-(4-(tert-butyl)phenyl)-1-(4-((4-fluorophenyl)(methyl)amino)benzyl)indolein-2,3-dione,
24) 7-(4-(tert-butyl)phenyl)-1-(4-((4-chlorophenyl)amino)benzyl)indolein-2,3-dione,
25) 7-(4-(tert-butyl)phenyl)-1-(4-((2,4-difluorophenyl)amino)benzyl)indolein-2,3-dione,
26) 7-(4-(tert-butyl)phenyl)-1-(4-((4-chlorobenzyl)amino)benzyl)indolein-2,3-dione,
27) 7-(4-(tert-butyl)phenyl)-1-(4-((pyridin-3-ylmethyl)amino)benzyl)indolein-2,3-dione,
28) 1-(4-(diisopropylamino)benzyl)-7-(4-fluorophenyl)indolein-2,3-dione,
29) 1-(4-((4-(tert-butyl)phenyl)amino)benzyl)-7-(4-fluorophenyl)indolein-2,3-dione,
30) 7-(4-fluorophenyl)-1-(4-((4-(trifluoromethyl)phenyl)amino)benzyl)indolein-2,3-dione,
31) 1-(4-((2,4-difluorophenyl)amino)benzyl)-7-(4-fluorophenyl)indolein-2,3-dione,
32) 1-(4-((4-fluorophenyl)amino)benzyl)-7-(6-fluoropyridin-3-yl)indolein-2,3-dione, and
33) 1-(4-((2,4-difluorophenyl)amino)benzyl)-5-fluoro-7-(6-fluoropyridin-3-yl)indolein-2,3-dione Characterized in that selected from the group consisting of,
A compound or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition for the prevention or treatment of peptic ulcer, gastritis, or reflux esophagitis, comprising the compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.