KR20150097208A - Isatin derivatives and method for preparation thereof - Google Patents

Abstract

Provided are a compound represented by chemical formula 1, which can be used effectively for preventing or treating acid reflux, gastritis, or peptic ulcer, pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition comprising the same. In the chemical formula 1, R1 to R4 are defined in the specification of the present invention.

Description

[0001] The present invention relates to isatin derivatives and methods for preparing the same,

The present invention relates to a isatin derivative, a process for producing the same, and a pharmaceutical composition containing the same, which can be usefully used for the prevention or treatment of peptic ulcer, gastritis or reflux esophagitis.

The development of a therapeutic agent for peptic ulcer has been developed in two major ways (control of the attack factor and strengthening of the defense factor), and a typical treatment method is controlling the attack factor. 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 It is leading the market.

Since 1880, Prout has been found to secrete high levels of hydrochloric acid from the gastric mucosa, studies on acid secretion have been actively conducted for almost 100 years. Since the use of Belladonna as the first anti-ulcer drug, anticholinergic drugs have been used predominantly, and in 1920 it was found that gastric acid secretion was stimulated by histamine. In 1977, 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 drug is developed Ranitidine (Zantac®), developed in 1985 Famotidine histamine represented by (Gaster® / Pepcid®) such as H ₂ receptor antagonists of the drug system developed in 1981, are done in the mainstream of the world market antiulcer come. In 1983, Helicobacter pylori was first isolated as a causative organism of gastritis and ulcer. It has been developed as a combination therapy consisting of proton pump inhibitor or H ₂ antagonist and chemotherapeutic agent to eradicate it.

Recently, the need for drugs for reversible inhibition of proton pump inhibitors has been increasing, and research is being actively conducted by global pharmaceutical companies. The reversible proton pump inhibitor is called the potassium competitive acid blocker (P-CAB) or the acid pump antagonist (APA) to distinguish it from the existing PPI drugs represented by omeprazole. Accordingly, the present invention relates to a reversible proton pump inhibitor (P-CAB).

On the other hand, the process of H ⁺ secretion in stomach wall cells but not unknown for a long time, in recent years, within the gastrointestinal H ⁺ secretion by the H ⁺ / K ⁺ -ATPase enzymes in the microsomal fraction of the gastric wall cells act to perform the H ⁺ and K ⁺ exchange And this H ⁺ / K ⁺ -ATPAse was named "proton pump". In vivo, H ⁺ / K ⁺ -ATPAse secretes H ⁺ in the stomach by decomposing the 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 1: 1, and the presence of H ⁺ / K ⁺ -ATPase has been confirmed in many animals that secrete H ⁺ , including humans.

In other words, the receptors present on the cell membranes of the gastric wall cells produce a series of gastric acid secretion by binding to various acid stimulating substances (histamine, acetylcholine, gastrin). In the final step of this reaction, H ⁺ It is called as ⁺ proton pump which absorbs the H ⁺ / K ⁺ -ATPAse acts. Compounds that inhibit gastric acid secretion by inhibiting the proton pump, which is the final step of gastric acid secretion, do not have anticholinergic action or antagonistic action of H ₂ receptor and are absorbed into the inactive form of prodrugs when they are absorbed into the body It is a unique acid compartment in the human body. It is concentrated and distributed in the secretory tubules of the gastric mucosa. It blocks the proton pump, which is the final stage of gastric acid production.

Omeprazole, lansoprazole, pantoprazole, and Esomepraole have been developed to control these proton pumps. These drugs have been shown to be more potent and persistent in inhibiting gastric acid secretion than conventional drugs, and they are now widely used as therapeutic agents for peptic ulcers. In addition, omeprazole compounds strongly inhibit gastric acid secretion and have cytoprotective activity (gastrointestinal mucosal protection). These compounds are characterized by both aggressive and protective actions, and are more potent against H ₂ receptor antagonists than during nighttime It inhibits the secretion of acid and is known to have a low recurrence rate.

However, proton pump inhibitors with irreversible mechanism of action cause long-term inhibition of gastric acid secretion in the stomach, resulting in the possibility of tumor cell formation due to gastric bacterial proliferation, promotion of proton pump expression, and increase in gastrin concentration. The development of a substance that inhibits gastric acid secretion for a certain period only when the drug is administered through the development of an inhibitor of proton pump, Yuhan's revaprazan (Revanex®), which was launched in January 2007, is the only drug related to this, and research and development of anti-ulcer drugs by major pharmaceutical companies in the world is focused on reversible proton pump inhibitors. Is expected.

Exemplary reversible proton pump inhibitors include pyrrole derivatives described in International Patent Publication No. WO 2007/026916 (Takeda Pharmaceutical Co. Ltd.), pyrrolo [2,3-c] pyridine derivatives disclosed in International Patent Publication No. WO 2006/025716 (Yuhan Corp.), and benzimidazole derivatives are described in International Patent Publication No. WO 2007/072146 (Pfizer Inc., Japan; Raqualia Pharma Inc.).

Accordingly, the inventors of the present invention have been studying a novel compound having a proton pump inhibiting effect, and it has been confirmed that the isatin derivative has an effect of inhibiting the proton pump and can be effectively used for the prevention or treatment of peptic ulcer, gastritis or reflux esophagitis Thus completing the present invention.

The present invention is to provide a isatin derivative, a method for producing the same, and a pharmaceutical composition containing the same, which can be usefully used for the prevention or treatment of peptic ulcer, gastritis or reflux esophagitis.

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

[Chemical Formula 1]

In this 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 ,

Wherein 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 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,

Provided that 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 optionally substituted with one or more substituents selected from methyl, tert-butyl, And is substituted with one or two substituents each independently selected from the group consisting of. More preferably, said 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; Or 2 methyl.

Preferably, R ₄ is tert-butyl, morpholino, and no or YR _7, wherein, Y is _{NH, NH (CH 2),} N (CH 3) or N (isopropyl), R ₇ is isopropyl, Phenyl or pyridinyl, wherein said 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, said phenyl or pyridinyl is substituted with a substituent selected from the group consisting of tert-butyl, trifluoromethyl, fluoro and chloro; Or two fluoro.

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 the above formula (1) are as follows:

One) (4- (tert-butyl) benzyl) -7 - ((2-chlorophenyl) amino) indole-

2) (4- (tert-butyl) benzyl) -7 - ((3-chlorophenyl) amino) indole-

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

4) Benzyl) -7 - ((4-fluorophenyl) amino) indole-2,3-dione,

5) (4- (tert-butyl) benzyl) -7 - ((4-chlorophenyl) amino) indole-

6) (4-tert-butyl) benzyl) indole-2, 3-dione,

7) (4- (tert-butyl) phenyl) amino) indole-2, 3-dione,

8) (4- (tert-butyl) benzyl) -7 - ((4- (trifluoromethyl) phenyl) amino) indole-

9) (4- (tert-butyl) benzyl) -7 - ((4-methoxyphenyl) amino) indole-

10) (4- (tert-butyl) benzyl) -7 - ((4- (trifluoromethoxy) phenyl) amino) indole-

11) Benzyl) -7 - ((2,4-dimethylphenyl) amino) indole-2,3-dione,

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

13) Benzyl) -6 - ((4-fluorophenyl) amino) indole-2,3-dione,

14) (4- (tert-butyl) benzyl) -6 - ((4-chlorophenyl) amino) indole-

15) 6 - ((4-bromophenyl) amino) -1- (4- (tert- butyl) benzyl) indole-

16) 7- ((4-bromophenyl) amino) -1- (4- (tert -butyl) benzyl) -5- fluoroindole-

17) 7- ((5-fluoropyridin-2-yl) amino) indole-2, 3-dione,

18) 2-yl) amino) indole-2, 3-dione, 2-fluoro-4- (4- (tert-

19) Amino-5-fluoroindole-2, 3-dione, 2-amino-3- (4- (tert-

20) 7- ((6-morpholinopyridin-3-yl) amino) indole-2,3-dione,

21) 7- (4- (tert-butyl) phenyl) -1- (4-morpholinobenzyl) indole-

22) 7- (4- (tert-butyl) phenyl) -1- (4- (4-fluorophenyl) amino) benzyl) indole-

23) Amino) benzyl) indole-2, 3-dione, < RTI ID = 0.0 &

24) 7- (4- (tert-butyl) phenyl) -1- (4- (4-chlorophenyl) amino) benzyl) indole-

25) (4 - ((2,4-difluorophenyl) amino) benzyl) indole-2,3-dione,

26) 7- (4- (tert-butyl) phenyl) -1- (4- (4-chlorobenzyl) amino) benzyl) indole-

27) 7- (4- (tert-butyl) phenyl) -1- (4- (pyridin-3- ylmethyl) amino) benzyl) indole-

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

29) Benzyl) -7- (4-fluorophenyl) indole-2, 3-dione,

30) 7- (4-fluorophenyl) -1- (4 - ((4- (trifluoromethyl) phenyl) amino) benzyl) indole-

31) Benzyl) -7- (4-fluorophenyl) indole-2, 3-dione,

32) Benzyl) -7- (6-fluoropyridin-3-yl) indole-2, 3-dione and

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

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

In addition, a pharmaceutically acceptable metal salt can be obtained by a conventional method using a base. For example, a compound represented by the formula (1) is dissolved in an excess of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, the non-soluble 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 metal salts, in particular, sodium salts, potassium salts or calcium salts, and these metal salts can be reacted with a suitable salt (for example, nitrate).

In addition, the compounds represented by Formula 1 according to the present invention include all possible stereoisomers, including pharmaceutically acceptable salts thereof, as well as possible solvates and hydrates thereof, which can be prepared therefrom. The solvates, hydrates and stereoisomers of the compound represented by the formula (1) can be prepared from the compound represented by the formula (1) using conventional methods.

The compound represented by the formula (1) according to the present invention may be prepared in a crystalline form or in an amorphous form, and may be optionally hydrated or solvated when prepared in crystalline form. In the present invention, compounds containing various amounts of water as well as stoichiometric hydrates of the compound represented by the formula (1) may be included. Solvates of the compounds of formula (I) according to the present invention include both stoichiometric solvates and non-stoichiometric solvates.

The present invention also provides a pharmaceutical composition for preventing or treating peptic ulcer, gastritis or reflux esophagitis, which comprises a compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof.

The term "prophylactic" as used herein refers to any action that inhibits or delays peptic ulcer, gastritis, or reflux esophagitis by administration of a pharmaceutical composition comprising a compound of Formula 1, or a pharmaceutically acceptable salt thereof, . The term "treatment ", as used herein, refers to the treatment of a symptom of peptic ulcer, gastritis, or reflux esophagitis by the administration of a pharmaceutical composition comprising the compound of formula 1, or a pharmaceutically acceptable salt thereof, It means all actions that are cured.

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

The pharmaceutical compositions of the present invention may be formulated into oral or parenteral administration forms according to standard pharmaceutical practice. These formulations may contain, in addition to the active ingredient, an additive such as a pharmaceutically acceptable carrier, adjuvant or diluent. Suitable diluents include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or lactose such as physiological saline, polyethylene glycol, ethanol, vegetable oil and isopropyl myristate. Or glycine, but are not limited thereto. In addition, the compounds according to the invention, or pharmaceutically acceptable salts thereof, may be dissolved in oils, 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, for topical administration can be formulated into ointments or creams.

The preferred dosage of a compound according to the present invention, or a pharmaceutically acceptable salt thereof, will vary depending on the condition and the weight of the patient, the degree of disease, the type of the drug, the route of administration and the period of time, but can be appropriately selected by those skilled in the art. However, for the desired effect, it is preferable to administer the compound according to the present invention at a daily dose of 0.0001 to 100 mg / kg (body weight), preferably 0.001 to 100 mg / kg (body weight). Administration may be by oral or parenteral route, once or divided once a day. Depending on the administration method, 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 rats, mice, livestock and humans in various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerbroventricular injections.

The present invention also provides a process for producing the compound represented by the above formula (1).

For example, in the above formula (1), when R ₂ is hydrogen and R ₃ is XR ₆ , where X is NH, the following scheme 1 can be prepared.

[Reaction Scheme 1]

Step 1-1 is a reaction for introducing benzyl substituted by R ₄ into 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 Formula 1-4. The reaction is preferably carried out in the presence of benzyltriethylammonium chloride and potassium carbonate. As the solvent, acetonitrile is preferably used.

Step 1-2 is a step of introducing NH-R ₆ into the compound represented by Formula 1-4, and reacting the compound represented by Formula 1-4 with R ₆ -NH ₂ , Is a step of preparing a compound represented by the formula The reaction is preferably carried out in the presence of palladium acetate, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl and cesium carbonate. As the solvent, 1,4-dioxane is preferably used.

In the above formula (1), when R ₂ is NHR ₅ and R ₃ is hydrogen, it can be prepared according to the following reaction formula (2).

[Reaction Scheme 2]

In step 2-1, the compound represented by formula 2-2 is reacted with the compound represented by formula 2-3 by the same reaction as in step 1-1 and the starting material, Is a step of preparing a compound represented by the formula

Step 2-2 is a step for reacting the compound represented by Formula 2-4 with R ₅ -NH ₂ in the same reaction as in Step 1-2 and the starting material to obtain the compound represented by Formula 2-1 .

In the above formula (1), when R ₂ is hydrogen and R ₃ is XR ₆ , where X is a bond,

[Reaction Scheme 3]

Step 3-1 is a step of introducing R ₆ into 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, -4. ≪ / RTI > The reaction is preferably carried out in the presence of tetrakis (triphenylphosphine) palladium (0) and sodium carbonate. As the solvent, it is preferable to use benzene, ethanol, water, toluene, N, N-dimethylformamide or a mixture thereof.

Step 3-2 is a step of reacting the compound represented by Formula 3-4 with the compound represented by Formula 3-5 by the same reaction as in Steps 1-1 and 2-1 and the starting material, Is a step for preparing a compound represented by the formula (3-1).

In the above formula (1), when R ₂ is hydrogen and R ₃ is XR ₆ , where X is a bond and R ₄ is a molypolino or YR ₇ , the following reaction scheme 4 can be prepared.

[Reaction Scheme 4]

Step 4-1 is the same reaction as in Step 3-1, except that the compound represented by Formula 4-2 is reacted with the compound represented by Formula 4-3 to prepare the compound represented by Formula 4-4 .

Step 4-2 is a step of introducing bromo-substituted phenyl into the compound represented by Formula 4-4, wherein the compound represented by Formula 4-4 is reacted with the compound represented by Formula 4-5 To prepare the compound represented by Formula 4-6. The reaction is preferably carried out in the presence of benzyltriethylammonium chloride and potassium carbonate. As the solvent, acetonitrile is preferably used.

Step 4-3 is a step of introducing molpolino or YR ₇ into the compound represented by Formula 4-6, and reacting the compound represented by Formula 4-6 with HR ₄ to obtain the compound represented by Formula 4-1 Is a step for preparing a compound to be displayed. The reaction is preferably carried out in the presence of palladium acetate, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl and cesium carbonate. As the solvent, 1,4-dioxane is preferably used.

The compound represented by the formula (1) according to the present invention can be effectively used for 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 with reference to the following Production Examples and Examples. However, the following Preparation Examples and Examples are for illustrating the present invention, but the scope of the present invention is not limited thereto.

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

(500.0 mg, 2.2 mmol), benzyltriethylammonium chloride (251.9 mg, 1.1 mmol) and potassium carbonate (764.3 mg, 5.5 mmol) were dissolved in acetonitrile solution (15.0 mL) And the mixture was stirred at room temperature for 30 minutes. To this mixture was added 4- (tertbutyl) benzyl bromide (813.1 [mu] L, 4.4 mmol) and the mixture was stirred at 60 [deg.] 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 bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 10 → 1: 4 (v / v)) to give the title compound (84.8 mg, 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- ( Rat -Butyl) benzyl) -7 - ((2- Chlorophenyl ) Amino) Indole phosphorus -2,3- Dion's  Produce

2-Chloroaniline (8.2 mg, 0.06 mmol), palladium acetate (1.2 mg, 0.005 mmol) was dissolved in 1,4-dioxane (1 mL) (3.3 mg, 0.005 mmol) and cesium carbonate (35 mg, 0.1 mmol) were added to the mixture, and the mixture was stirred at 110 ° C for 12 hours Lt; / RTI > 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 concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4 (v / v)) to give 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)

Examples 2 to 11 were prepared in the same manner as in Example 1, except that the reactants were appropriately prepared in consideration of the structure of the compound to be produced.

Example  2: 1- (4- ( Rat -Butyl) benzyl) -7 - ((3- Chlorophenyl ) Amino) Indole phosphorus -2,3- Dion Manufacturing

^{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 ( 2H), 1.32 (s, 9H), 6.54 (d, 1H)

Example  3: 1- (4- ( Rat -Butyl) benzyl) -7- (p- Tolylamino ) Indole phosphorus -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, 3 H), 1.32 (s, 9 H)

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

¹ H NMR (500 MHz, CD ₃ OD): 7.49 (dd, 1 H), 7.36 (dd, 1 H), 7.24 2H), 5.07 (s, 3H), 2.45 (s, 3H)

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

¹ H NMR (500 MHz, CD ₃ OD): 7.49 (dd, 1 H), 7.31-7.38 (m, 2H), 7.16 (d, IH), 6.91 (d, IH), 6.39 (d, IH), 6.30

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

¹ H NMR (500 MHz, CD ₃ OD): 7.54 (dd, 1 H), 7.35-7.38 (m, 1 H), 7.28 2H), 1.17 (s, 9H), 6.99 (d, 1H), 6.99 (d,

Example  9: 1- (4- ( Rat -Butyl) benzyl) -7 - ((4- Methoxyphenyl ) Amino) Indole phosphorus -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- ( Rat -Butyl) benzyl) -7 - ((4- ( Trifluoromethoxy ) Phenyl ) Amino) indole-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- ( Rat -Butyl) benzyl) -7 - ((2,4- Dimethylphenyl ) Amino) Indole phosphorus -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, (S, 3H), 1.30 (s, 3H), 1.30 (s, 3H)

Examples 12 to 15 were prepared in the same manner as in Example 1, except that 6-bromoindoline-2,3-dione was used in place of the compound prepared in Preparation Example 1, And the reaction material was appropriately changed.

Example  12: 1- (4- ( Rat -Butyl) benzyl) -6- (p- Tolylamino ) Indole phosphorus -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 (S, 3H), 1.19 (s, 9H), < RTI ID =

Example  13: 1- (4- ( Rat -Butyl) benzyl) -6 - ((4- Fluorophenyl ) Amino) Indole phosphorus -2,3-dione

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

Example  14: 1- (4- ( Rat -Butyl) benzyl) -6 - ((4- Chlorophenyl ) Amino) Indole phosphorus -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, 1 H), 4.80 (s, 2 H), 2.30 (s, 9 H)

Example  15: 6 - ((4- Bromophenyl ) Amino) -1- (4- ( Rat -Butyl) benzyl) Indole phosphorus -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, IH), 6.22 (d, IH), 4.80 (s, 2H), 1.29

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

(1.0 g, 4.1 mmol), benzyltriethylammonium chloride (466.7 mg, 2.0 mmol) and potassium carbonate (1.4 g, 10.3 mmol) were added to a solution of acetonitrile Solution (30.0 mL), followed by stirring at room temperature for 30 minutes. 4- (Tertbutyl) benzyl bromide (1.9 mL, 8.2 mmol) was added to the mixture, and the mixture was stirred 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 a 0.1N hydrochloric acid solution and a saturated sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under a combined atmosphere. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 10 → 1: 2 (v / v)) to obtain 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- ( Rat -Butyl) benzyl) -5- Fluorine 2,3- Dion's  Produce

4-bromoaniline (7.8 mg, 0.06 mmol) and palladium acetate (1.1 mg, 0.005 mmol) were dissolved in 1,4-dioxane (1 mL) (3.2 mg, 0.005 mmol) and cesium carbonate (33 mg, 0.1 mmol) were added to the mixture, and the mixture was stirred at 120 [deg.] C using a Microwave reactor. Lt; 0 > 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 concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 3 (v / v)) to give the title compound (1.3 mg, 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)

Examples 17 to 20 were prepared in the same manner as in Example 16, except that the reactants were appropriately prepared in consideration of the structure of the compound to be produced.

Example  17: 1- (4- ( Rat -Butyl) benzyl) -5- Fluoro -7 - ((5- Fluoropyridine Yl) amino) Indole phosphorus -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, IH), 5.06 (s, 2H), 1.27 (s, 9H)

Example  18: 1- (4- ( Rat -Butyl) benzyl) -5- Fluoro -7 - ((5- ( Trifluoromethyl ) Pyridin-2-yl) amino) Indole phosphorus -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, IH), 5.04 (s, 2H), 1.31 (s, 9H)

Example  19: 1- (4- ( Rat -Butyl) benzyl) -7 - ((5- Chloropyridine 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- ( Rat -Butyl) benzyl) -5- Fluoro -7 - ((6- Morpholino pyridine Yl) amino) Indole phosphorus -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, 2H), 3.82 (m, 4H), 3.43 (m, 4H), 2.32 (s, 9H)

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

(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 benzene / ethanol / water solution (2.0 mL) and stirred at 100 ° C for 24 hours. The reaction mixture was cooled to room temperature and extracted with water and ethyl acetate. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1 (v / v)) to give the title compound (10.0 mg, 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- ( Rat -Butyl) Phenyl ) Indole phosphorus -2,3- Dion's  Produce

(200 mg, 0.7 mmol), benzyltriethylammonium chloride (82 mg, 0.4 mmol) and potassium carbonate (248 mg, 1.8 mmol) were dissolved in acetonitrile solution (5 mL) And stirred for 30 minutes. 4-Bromobenzyl bromide (450 mg, 1.8 mmol) was added to the mixture, and the mixture was stirred at 60 占 폚 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 bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2 (v / v)) to give the title compound (89.9 mg, 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- ( Rat -Butyl) Phenyl ) -1- (4- Morpholinobenzyl ) Indole phosphorus -2,3- Dion's  Produce

The compound (20 mg, 0.05 mmol) prepared in Preparation Example 4 was dissolved in 1,4-dioxane (1 mL), and morpholine (5.4 mg, 0.06 mmol), palladium acetate (1.0 mg, (2.8 mg, 0.004 mmol) and cesium carbonate (29 mg, 0.09 mmol) were added to the mixture, and the mixture was stirred 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 concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2 (v / v)) to give 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), 4H), 1.38 (s, 9H), 3.48 (s, 2H)

Examples 22 to 27 were prepared in the same manner as in Example 21, except that the reactants were appropriately prepared in consideration of the structure of the compound to be produced.

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

¹ H NMR (500 MHz, CDCl ₃ ): 7.64 (t, 1 H), 7.33-7.26 (m, 3H), 7.10 ), 6.57 (d, 2H), 6.35 (s, 2H), 4.64 (s, 2H), 2.86

Example  24: 7- (4- ( Rat -Butyl) Phenyl ) -1- (4 - ((4- Chlorophenyl ) Amino) benzyl) Indole phosphorus -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, 2H), 4.67 (s, 1H), 1.37 (s, 9H)

Example  25: 7- (4- ( Rat -Butyl) Phenyl ) -1- (4 - ((2,4- Difluorophenyl ) Amino) benzyl) indole-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 ( 2H), 1.37 (s, 9H), < RTI ID = 0.0 &

Example  26: 7- (4- ( Rat -Butyl) Phenyl ) -1- (4 - ((4- Chlorobenzyl ) Amino) benzyl) Indole phosphorus -2,3-dione

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

Example  27: 7- (4- ( Rat -Butyl) Phenyl ) -1- (4 - ((Pyridin-3- Yl methyl ) Amino) benzyl) Indole phosphorus -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, 2 H), 1.35 (s, 9 H)

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

(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 extracted with water and ethyl acetate. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and 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 phosphorus -2,3- Dion's  Produce

The compound (500 mg, 2.0 mmol), benzyltriethylammonium chloride (228 mg, 1.0 mmol) and potassium carbonate (691 mg, 5.0 mmol) were dissolved in acetonitrile solution (10 mL) at room temperature And stirred for 30 minutes. 4-Bromobenzyl bromide (2.2 g, 5.0 mmol) was added to the mixture, and the mixture was stirred at 60 占 폚 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 bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4 (v / v)) to give 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, 2 H)

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

The compound (15 mg, 0.04 mmol) prepared in Preparation Example 6 was dissolved in 1,4-dioxane (1 mL), diisopropylamine (7.3 mg, 0.07 mmol), palladium acetate (0.08 mg, (2.3 mg, 0.004 mmol) and cesium carbonate (24 mg, 0.07 mmol) were added to the mixture, and the mixture was stirred at 120 [deg.] C using a Microwave reactor Lt; 0 > 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 concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4 (v / v)) to give the title compound (10.4 mg, 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)

Examples 29 to 31 were prepared in the same manner as in Example 28, except that the reactants were appropriately prepared in consideration of the structure of the compound to be prepared.

Example  29: 1- (4 - ((4- ( Rat -Butyl) Phenyl ) Amino) benzyl) -7- (4- Fluorophenyl ) Indole phosphorus -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 phosphorus -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 phosphorus -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), 2H), 4.64 (s, 2H), 6.78 (d, 2H)

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

(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 캜 for 30 minutes using a microreactor Respectively. The reaction mixture was cooled to room temperature and extracted with water and ethyl acetate. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 3 (v / v)) to obtain 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, 1 H)

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

The compound (300 mg, 1.2 mmol), benzyltriethylammonium chloride (140 mg, 0.6 mmol) and potassium carbonate (430 mg, 3.1 mmol) were dissolved in acetonitrile solution (10 mL) And stirred for 30 minutes. 4-Bromobenzyl bromide (770 mg, 3.1 mmol) was added to the mixture, and the mixture was stirred at 60 占 폚 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 bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 3 (v / v)) to give 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, IH), 4.57 (d, IH)

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

(20 mg, 0.05 mmol) was dissolved in 1,4-dioxane (1 mL), and then 4-fluoroaniline (7 μL, 0.07 mmol) and palladium acetate (1.1 mg, 0.005 mmol) (3 mg, 0.005 mmol) and cesium carbonate (32 mg, 0.1 mmol) were added to the mixture, and the mixture was stirred at 120 [deg.] C using a Microwave reactor. Lt; 0 > 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 concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2 (v / v)) to give 1.03 mg (yield: 4.8%) of the title compound.

^{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- 2H), 6.41 (d, 2H), 4.70-4.58 (m, 2H), 6.95

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

Fluoroindole-2,3-dione (1 g, 4.1 mmol), 2-fluoro-5-pyridine boronic acid (1.44 g, 10 mmol), tetrakis ) Palladium (0) (410 mg, 0.5 mmol) and sodium carbonate (1.4 g, 10 mmol) were dissolved in a toluene / N, N-dimethylformamide solution (10 mL) Lt; / RTI > The reaction mixture was cooled to room temperature and extracted with water and ethyl acetate. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4 (v / v)) to obtain 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, 1 H)

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

The compound (250 mg, 0.9 mmol), benzyltriethylammonium chloride (109 mg, 0.5 mmol) and potassium carbonate (332 mg, 2.4 mmol) were dissolved in acetonitrile solution (5 mL) at room temperature And stirred for 30 minutes. 4-Bromobenzyl bromide (600 mg, 2.4 mmol) was added to the mixture, and the mixture was stirred at 60 占 폚 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 bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2 (v / v)) to give the title compound (0.24 g, 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, 1 H), 4.52 (d, 1 H)

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

(20 mg, 0.05 mmol) was dissolved in 1,4-dioxane (1 mL), and 2,4-difluoroaniline (8 L, 0.07 mmol) and palladium acetate (1 mg, (2.9 mg, 0.005 mmol) and cesium carbonate (30 mg, 0.09 mmol) were added to the mixture, and the mixture was added to a Microwave reactor Lt; RTI ID = 0.0 > 120 C < / RTI > 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 concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2 (v / v)) to give 1.2 mg of the title compound (yield: 5.4%).

¹ H NMR (500 MHz, CDCl ₃ ): 7.90 (d, IH), 7.45 (q, IH), 7.39 (td, IH), 7.19-7.23 2H), 6.65 (s, 2H), 6.90 (d, 2H), 6.90 (m,

Experimental Example

1) Gastrointestinal vesicles ( gastric vesicles )

Gastric vesicles are prepared from the hog stomach by centrifugation (Edd C. Rabon et al., Preparation of Gastric H ⁺ , K ⁺ -ATPase., Methods in Enzymology, vol. , (1988), pp.649-654). The protein content of gastrointestinal vesicles was quantitated by Bicinchoninic Acid (BCA) kit.

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

The inhibitory effect of the compounds of the 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 Respectively. In the 96-well plate, 0.5% dimethylsulfoxide (DMSO) in buffer was added to the negative and positive control, and the test compound was diluted with the compound according to the present invention. All analyzes were carried out at room temperature with a reaction volume of 100 [mu] l. After addition of DMSO and each concentration of compound to the reaction buffer solution (60 mmol / L Tris-HCl buffer, pH 7.4) containing the 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 initiate the enzyme reaction. The enzyme reaction was carried out at 37 캜 for 40 minutes and 50 의 of malachite green solution (0.12% malachite green solution in 6.2 N sulfuric acid, 5.8% ammonium molybdate and 11% tween 20 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) in the reaction was measured at 570 nm using a microplate reader (FLUOstar Omega, BMG). The% inhibition was determined from the activity values of the control and the activity values of the 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 No. IC ₅₀ ([mu] M) Example No. IC ₅₀ ([mu] M) Example No. IC ₅₀ ([mu] M) 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) Pylon - Ligature ( pylorus - ligated ) In rats  Basal gastric acid secretion basal gastric  acid secretion )

The inhibitory effect of compounds according to the 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 (body weight 180-220 g) were divided into group X (n = 5) and fasted for 18 hours with only water. Immediately after ligation, 10% ethanol, 20% polyethylene glycol (PEG) 400 and 10% cremophor water alone were administered into the duodenum, while the other groups received 10% Test compounds suspended in ethanol, 20% polyethylene glycol 400, 10% cremophor aqueous solution were administered into the duodenum at a dose of 10 mg / kg / 2 mL. Five hours after the ligation, the test animals were sacrificed and stomach contents were extracted. The obtained contents were centrifuged at 4,000 x g for 10 minutes, and only the supernatant was separated to obtain a gastric juice. The amount and pH of gastric juice were measured, and the pH of the gastric juice was measured by the volume of 0.1 N NaOH (ueq / mL) required for automatic titration of gastric acid to pH 7.0. The acidity of the gastric juice was multiplied by the gastric juice volume, output. The% inhibitory activity of representative substances is shown in Table 2 below.

% Inhibition activity of the test compound = (total acid ratio of the control - total acid ratio of the group treated with the test compound) / total acid ratio of the control x 100

Example No. % Inhibitory activity 3 38% 6 35% 13 35% 22 34% 29 30% 31 40%

Claims (13)

1. A compound represented by the following formula (1): < EMI ID =
[Chemical Formula 1]

In this 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 ,
Wherein 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 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,
Provided that one of R ₂ and R ₃ is hydrogen and the other is not hydrogen.
The method according to claim 1,
R < ₁ > is hydrogen or fluoro.
Or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
And R < ₅ > is phenyl substituted by any one substituent selected from the group consisting of methyl, fluoro, chloro and bromo.
Or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
R < ₆ > is phenyl or pyridinyl,
Wherein said phenyl or pyridinyl is optionally substituted with one or more groups independently selected from the group consisting of methyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, fluoro, chloro, ≪ / RTI > is substituted with two substituents.
Or a pharmaceutically acceptable salt thereof.
5. The method of claim 4,
Wherein said 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 two methyl. ≪ RTI ID = 0.0 >
Or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
R ₄ is tert-butyl, morpholino or YR ₇ ,
Wherein Y is NH, NH (CH ₂ ), N (CH ₃ ), or N (isopropyl)
R < ₇ > is isopropyl, phenyl or pyridinyl,
Wherein said 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.
Or a pharmaceutically acceptable salt thereof.
The method according to claim 6,
Wherein said phenyl or pyridinyl is substituted with a substituent selected from the group consisting of tert-butyl, trifluoromethyl, fluoro and chloro; ≪ / RTI > or 2 fluoro.
Or a pharmaceutically acceptable salt thereof.
The method according to 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,
Or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
R < ₁ > is hydrogen or halogen,
R < ₂ > is hydrogen,
And R < ₃ > is XR < _{6 &} gt ;.
Or a pharmaceutically acceptable salt thereof.
10. 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 a molpolino 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,
Or a pharmaceutically acceptable salt thereof.
10. 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 two substituents,
R ₄ is characterized in that the C _{1 -4} alkyl,
Or a pharmaceutically acceptable salt thereof.
The compound according to claim 1, wherein the compound is
1) 1- (4- (tert-Butyl) benzyl) -7 - ((2- chlorophenyl) amino) indole-
2) 1- (4- (tert-Butyl) benzyl) -7 - ((3-chlorophenyl) amino) indole-
3) Preparation of 1- (4- (tert-butyl) benzyl) -7- (p-tolylamino) indole-
4) Synthesis of 1- (4- (tert-butyl) benzyl) -7 - ((4-fluorophenyl) amino) indole-
5) 1- (4- (tert-Butyl) benzyl) -7 - ((4-chlorophenyl) amino) indole-
6) Preparation of 7 - ((4-bromophenyl) amino) -1- (4- (tert- butyl) benzyl) indole-
7) 1- (4- (tert-Butyl) phenyl) amino) indole-2,3-dione,
8) 1- (4- (tert-Butyl) benzyl) -7 - ((4- (trifluoromethyl) phenyl) amino) indole-
9) 1- (4- (tert-Butyl) benzyl) -7 - ((4-methoxyphenyl) amino) indole-
10) 1- (4- (tert-Butyl) benzyl) -7 - ((4- (trifluoromethoxy) phenyl) amino) indole-
11) 1- (4- (tert-Butyl) benzyl) -7 - ((2,4-dimethylphenyl) amino) indole-
12) 1- (4- (tert-Butyl) benzyl) -6- (p-tolylamino) indole-
13) 1- (4- (tert-Butyl) benzyl) -6 - ((4-fluorophenyl) amino) indole-
14) 1- (4- (tert-Butyl) benzyl) -6 - ((4-chlorophenyl) amino) indole-
15) 6- ((4-bromophenyl) amino) -1- (4- (tert- butyl) benzyl) indole-
16) 7- ((4-bromophenyl) amino) -1- (4- (tert- butyl) benzyl) -5- fluoroindole-
17) 1- (4- (tert-Butyl) benzyl) -5-fluoro-7 - ((5-fluoropyridin-
18) 1- (4- (tert-Butyl) benzyl) -5-fluoro-7 - ((5- (trifluoromethyl) pyridin-
19) 1- (4- (tert-Butyl) benzyl) -7- (5-chloropyridin- 2- yl) amino) -5- fluoroindole-
20) 1- (4- (tert-Butyl) benzyl) -5-fluoro-7 - ((6-morpholinopyridin- 3- yl) amino) indole-
21) 7- (4- (tert-butyl) phenyl) -1- (4-morpholinobenzyl) indole-
22) 7- (4- (tert-Butyl) phenyl) -1- (4- (4-fluorophenyl) amino) benzyl) indole-
23) 7- (4- (tert-butyl) phenyl) -1- (4- (4-fluorophenyl) (methyl) amino) benzyl) indole-
24) 7- (4- (tert-butyl) phenyl) -1- (4- (4-chlorophenyl) amino) benzyl) indole-
25) 7- (4- (tert-butyl) phenyl) -1- (4 - ((2,4- difluorophenyl) amino) benzyl) indole-
26) 7- (4- (tert-butyl) phenyl) -1- (4- (4-chlorobenzyl) amino) benzyl) indole-
27) 7- (4- (tert-butyl) phenyl) -1- (4- (pyridin- 3- ylmethyl) amino) benzyl) indole-
28) 1- (4- (Diisopropylamino) benzyl) -7- (4-fluorophenyl) indole-
29) 1- (4 - ((4- (tert-butyl) phenyl) amino) benzyl) -7- (4- fluorophenyl) indole-
30) 7- (4-Fluorophenyl) -1- (4 - ((4- (trifluoromethyl) phenyl) amino) benzyl) indole-
31) 1- (4 - ((2,4-difluorophenyl) amino) benzyl) -7- (4- fluorophenyl) indole-
32) 1- (4 - ((4-fluorophenyl) amino) benzyl) -7- (6-fluoropyridin-3-yl) indole-
33) To a solution of 1- (4 - ((2,4-difluorophenyl) amino) benzyl) -5-fluoro-7- (6-fluoropyridin- ≪ RTI ID = 0.0 > and / or < / RTI >
Or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition for preventing or treating peptic ulcer, gastritis or reflux esophagitis, comprising a compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.