Pyrrolopyridine derivative and uses thereof

Abstract

To provide an HIV-1 integrase inhibitor.SOLUTION: The present invention provides the compound of the formula where A is -COR1, or -tetrazolyl; R1 is -OR5; R5 is -(CH2)n-OCOO-CH3, -(CH)CH3-OCOO-C3-6 cycloalkyl, or 5-methyl-2-oxo-1,3-dioxole-4-yl-CH2.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an antiviral compound, in particular, a compound having high selectivity and biological activity against human immunodeficiency virus (HIV), and uses thereof. [Background technology]

[0002] AIDS (Acquired Immuno Deficiency Syndrome; AIDS) is induced by infection with the Human Immunodeficiency Virus (HIV). There are two forms of HIV, HIV-1 and HIV-2, but the form that is widespread throughout the world is HIV-1. To treat AIDS, enzyme inhibitors have been developed according to the mechanism of action of HIV, and are classified according to their point of action into nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), fusion inhibitors, and integrase inhibitors.

[0003] Integrase inhibitors are classified into catalytic site inhibitory action and non-catalytic site inhibitory action according to their mechanism. Research on catalytic site integrase inhibitors has been actively conducted so far, and three drugs have been developed and sold on the market, with Raltegravir, developed in 2008, being the representative drug. Meanwhile, the mechanism of action of non-catalytic site integrase inhibitory action was introduced by Zeger Debyser et al. (Frauke Christ, Zeger Debyser at al., Nature Chemical Biology, 2010, Vol. 6, 442-448), and the development of inhibitors against this mechanism of action has been actively conducted.

[0004] In addition, various researches are being conducted to develop drugs to effectively treat viruses that have developed resistance, and these chemotherapeutic drugs, called Highly Active Anti Retroviral Therapies (HAART), are administered in combination with 2 to 4 drugs that inhibit each other's mechanisms, and have a significant effect on extending lifespan. However, despite these efforts, AIDS cannot be cured completely, and the development of new therapeutic drugs is continuously required due to the problem of drug toxicity and the development of resistance to current therapeutic drugs.

[0005] As part of our efforts to solve these problems, we have conducted extensive research to develop new AIDS treatments, and as a result, we have discovered that a pyrrolopyridine derivative compound with a new skeleton has the effect of inhibiting the proliferation of HIV, which has led to the completion of the present invention. Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention provides a pyrrolopyridine derivative, a racemate thereof, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, which has the effect of suppressing the proliferation of HIV-1 by inhibiting the activity of HIV-1 integrase enzyme.

[0007] Another object of the present invention is to provide a process for preparing a novel pyrrolopyridine derivative, its racemate, its stereoisomer or a pharma- ceutically acceptable salt thereof.

[0008] It is yet another object of the present invention to provide a pharmaceutical use of said compound. [Means for solving the problem]

[0009] In order to achieve the above object, the present inventors have conducted extensive research and have found that a pyrrolopyridine derivative compound represented by Chemical Formula I below inhibits HIV proliferation, thereby completing the present invention.

[0010] Pyrrolopyridine derivative compounds The present invention provides a compound represented by Formula I below, a racemate thereof, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: [ka] In the above formula, A is -hydroxy, -amino, -azido, -cyano, -trifluoromethyl, -COR1, -C=NOHR2, -B(OH)2, -SO3H, -P=O(OH)2, or -heteroaryl; R1 and R2 are each independently -NR3R4, -NR3OR4, or -OR5; R3 and R4 are each independently -hydrogen, -C 1-6 -alkyl, or -heteroaryl; R5 is -C 5-20 Alkyl, -(CH2)nO-(CH2)-O-CH3, -(CH2)n-OCOO-CH3, -(CH)CH3-OCOO-C 3-6 cycloalkyl, or -(CH2)n-heteroaryl; B is -(CH2)n-R6; R6 is -hydroxy, -amino, -azido, -cyano, -trifluoromethyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkoxy, -CONH(C 1-3 alkyl), -CON(C 1-3 Alkyl)2, -COOH, -S-(C 1-6 Alkyl), -SO2-(C 1-6 Alkyl), -carbamoyl, -C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, -aryl, or -heteroaryl {wherein the -C 3-6 One or more H in cycloalkyl, 4-6 membered heterocycloalkyl, -aryl, or -heteroaryl is -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Aminoalkyl, -C1-6 Hydroxyalkyl, -C 1-6 substituted with alkoxy, -cyano, -carboxy, -amino, -nitro, -azido, -hydroxy, -carbamoyl, -thiol, or -halogen}; n is 1, 2, 3 or 4.

[0011] According to one embodiment of the present invention, the compound represented by Formula I above, its racemate, its stereoisomer or a pharma- ceutically acceptable salt thereof may be as follows:

[0012] A is -cyano, -COR1, -C=NOHR2, -B(OH)2, -SO3H, -P=O(OH)2, or -heteroaryl; R1 and R2 are each independently -NR3R4, -NR3OR4, or -OR5; R3 and R4 are each independently -hydrogen, -C 1-6 -alkyl, or -heteroaryl; R5 is -C 5-20 Alkyl, -(CH2)nO-(CH2)-O-CH3, -(CH2)n-OCOO-CH3, -(CH)CH3-OCOO-C 3-6 cycloalkyl, or -(CH2)n-heteroaryl; B is -(CH2)n-R6; R6 is -C 1-6 Alkoxy, 4-6 membered heterocycloalkyl, -C 3-6 -cycloalkyl, -aryl, or -heteroaryl {wherein the -C 3-6 One or more H in cycloalkyl, 4-6 membered heterocycloalkyl, -aryl, or -heteroaryl is -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 substituted with alkoxy, -cyano, -carboxy, -amino, -nitro, -azido, -hydroxy, -carbamoyl, -thiol, or -halogen}; n is 1, 2 or 3.

[0013] According to one embodiment of the present invention, the compound represented by the above formula I, its racemate, its stereoisomer or its pharma- ceutically acceptable salt may be as follows:

[0014] A is -cyano, -COR1, -C=NOHR2, or -heteroaryl; R1 and R2 are each independently -NR3R4, -NR3OR4, or -OR5; R3 and R4 are each independently -hydrogen, -C 1-6 -alkyl, or -heteroaryl; R5 is -C 5-20 Alkyl, -(CH2)nO-(CH2)-O-CH3, -(CH2)n-OCOO-CH3, -(CH)CH3-OCOO-C 3-6 cycloalkyl, or -(CH2)n-heteroaryl; B is -(CH2)n-R6; R6 is -C 1-6 alkoxy, 4-6 membered heterocycloalkyl, -aryl, or -heteroaryl, wherein one or more H of the 4-6 membered heterocycloalkyl, -aryl, or -heteroaryl is -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 substituted with alkoxy, -cyano, -carboxy, -amino, -nitro, -azido, -hydroxy, -carbamoyl, -thiol, or -halogen}; n is 1, 2 or 3.

[0015] According to one embodiment of the present invention, the compound represented by the above formula I, its racemate, its stereoisomer or its pharma- ceutically acceptable salt may be as follows:

[0016] A is -cyano, -COR1, -C=NOHR2, or -heteroaryl; R1 is -NR3R4, -NR3OR4, or -OR5; R2 is -NR3R4; R3 and R4 are each independently -hydrogen, -C 1-6 -alkyl, or -heteroaryl; R5 is -C 5-20 Alkyl, -(CH2)nO-(CH2)-O-CH3, -(CH2)n-OCOO-CH3, -(CH)CH3-OCOO-C 3-6 cycloalkyl, or -(CH2)n-heteroaryl; B is -(CH2)n-R6; R6 is -C 1-6 alkoxy, 4-6 membered heterocycloalkyl, -aryl, or -heteroaryl, wherein one or more H of the 4-6 membered heterocycloalkyl, -aryl, or -heteroaryl is -C 1-6 may be substituted with alkyl or -halogen}; n is 1 or 2.

[0017] Furthermore, the compound represented by Chemical Formula I of the present invention may be selected from the group consisting of the following compounds:

[0018] 1) Tridecyl (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate; 2) (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (2S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-(oxetan-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate; 3) (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-1-(2-methoxyethyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate; 4) (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate; 5) (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetamide; 6) (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetonitrile; 7) (S)-5-(tert-butoxy(1H-tetrazol-5-yl)methyl)-4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridine; 8) (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylacetamide; 9) (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methoxyacetamide; 10) (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methoxy-N-methylacetamide; 11) (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-hydroxyacetamide; 12) (S,Z)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N'-hydroxyacetimidamide; 13) (S)-3-(tert-butoxy(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-5-methyl-1,2,4-oxadiazole; 14) (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(2H-tetrazol-5-yl)acetamide; 15) ((Methoxycarbonyl)oxy)methyl (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate; 16) 2-(2-methoxyethoxy)ethyl (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate; 17) 1-(((cyclohexyloxy)carbonyl)oxy)ethyl (2S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-parazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate; and 18) (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-1-(3,4-difluorobenzyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate.

[0019] The compound of the present invention prepared in this manner can form a salt, particularly a pharma- ceutically acceptable salt. The pharma-ceutically acceptable salt is, for example, an acid addition salt, and is not particularly limited to those commonly used in the art.

[0020] Preferred pharma- ceutically acceptable acid addition salts include those with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, orthophosphoric acid, or sulfuric acid; or those with organic acids such as, for example, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid, glycerophosphoric acid, or acetylsalicylic acid.

[0021] Also, pharmaceutically acceptable metal salts can be obtained by using bases in the usual way. For example, the compound of formula I can be dissolved in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, the undissolved compound salts can be filtered, and the filtrate can be evaporated to dryness to obtain pharmaceutically acceptable metal salts. The pharmaceutically unacceptable salts or solvates of the compound of formula I can be used as intermediates in the preparation of the compound of formula I, its pharmaceutically acceptable salts or solvates.

[0022] The compounds of formula I of the present invention include not only their pharma- ceutically acceptable salts, but also all possible solvates and hydrates that can be prepared from them. Stereoisomers of the compounds of formula I and intermediates can be prepared using conventional methods.

[0023] Additionally, the compounds of formula I according to the present invention may be prepared in crystalline or non-crystalline form, and if the compounds of formula I are prepared in crystalline form, they may optionally be hydrated or solvated.

[0024] Uses of pyrrolopyridine derivative compounds The present invention provides a pharmaceutical use of the compound of formula I above, its racemate, its stereoisomer or a pharma- ceutically acceptable salt thereof.

[0025] According to a specific embodiment of the present invention, there is provided an antiviral pharmaceutical composition comprising the compound of formula I, its racemate, its stereoisomer or a pharma- ceutically acceptable salt thereof as an active ingredient. Specifically, the antiviral composition may be an anti-human immunodeficiency virus (HIV) composition.

[0026] In the experimental examples of the present invention, the compound of formula I has excellent HIV inhibitory effect while having low cytotoxicity, and has various advantages in drug development such as improved physicochemical properties, improved drug absorption, and adjustment of safety and toxicity as a bioisostere and prodrug.

[0027] The composition of the present invention can be formulated for oral or injectable administration. Oral dosage forms include, for example, tablets and capsules, which contain diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine) and lubricants (e.g., silica, talc, stearic acid and its magnesium calcium salt, or polyethylene glycol) in addition to the active ingredient. Tablets can further contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidine, and can optionally contain disintegrants such as starch, agar, alginic acid, or its sodium salt, or boiling mixtures and / or absorbents, colorants, flavorings, and sweeteners. As an injectable dosage form, an isotonic aqueous solution or suspension is preferred.

[0028] The compositions may be / are sterilized and may contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, salts for regulating the osmotic pressure and / or buffers, and other therapeutically valuable substances.

[0029] The dosage form can be prepared by a conventional mixing, granulating, or coating method and can contain the active ingredient in the range of about 0.1 to 75% by weight, preferably about 1 to 50% by weight. A unit dosage form for a mammal weighing about 50 to 70 kg contains about 10 to 200 mg of the active ingredient.

[0030] The desired dose of the compound of the present invention varies depending on the condition and weight of the patient, the severity of the disease, the drug form, the administration route and period, but can be appropriately selected by those skilled in the art. The dose can be administered once a day or in divided doses via oral or parenteral routes.

[0031] The compositions of the present invention can be administered to mammals, including rats, mice, livestock, and humans, by a variety of routes, for example, orally, rectally, or by intravenous, intramuscular, subcutaneous, intrauterine, intradural, or intracerebral vascular (intracerebroventricular) injection, although any mode of administration is contemplated.

[0032] According to an embodiment of the present invention, the present invention also provides a method for preventing or treating a viral infection, particularly an HIV infection, comprising administering a therapeutically effective amount of a compound represented by formula I above, a racemate thereof, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

[0033] Further, according to an embodiment of the present invention, the present invention also provides the use of the compound represented by formula I above, its racemate, its stereoisomer, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of viral infections, particularly HIV infections.

[0034] All references to uses, compositions, and methods of treatment of the present invention apply equally unless they contradict each other. Effect of the Invention

[0035] The compound of the present invention, its racemate, its stereoisomer or a pharma- ceutically acceptable salt thereof has high selectivity and physiological activity against viruses, particularly human immunodeficiency virus (HIV), and low toxicity, and therefore can be usefully used in the treatment of virus, particularly human immunodeficiency virus (HIV) infection. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] The present invention will be described in more detail with reference to the following examples and experimental examples. However, the following examples and experimental examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

[0037] Example 1: Tridecyl (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid (200 mg, 0.40 mmol) was added with cesium carbonate (112 mg, 0.81 mmol), 1-bromotridecane (128 mg, 0.49 mmol), and dimethylacetamide (1.3 mL), and the mixture was stirred at 55-60 ° C for 12 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with purified water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography to obtain the title compound (255 mg) as a yellow oil. LC-MS (ESI, m / z) = 677.2 (M+H + ).

[0038] Example 2: (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (2S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-(oxetan-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (2S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-(oxetan-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid (47 mg, 0.10 mmol) and 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (22 mg, 0.15 mmol) were reacted in a manner similar to that of Example 1 to obtain the title compound (20 mg) as a pale white solid. LC-MS (ESI, m / z) = 583.2 (M+H + ).

[0039] Example 3: (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-1-(2-methoxyethyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-1-(2-methoxyethyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid (342 mg, 0.75 mmol) and 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (184 mg, 1.12 mmol) were reacted in a manner similar to that of Example 1 to obtain the title compound (272 mg) as a pale white solid. LC-MS (ESI, m / z) = 571.1 (M+H + ).

[0040] Example 4: (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid (70 mg, 0.14 mmol) and 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (34 mg, 0.21 mmol) were reacted in a manner similar to that of Example 1 to obtain the title compound (55 mg) as a pale white solid. LC-MS (ESI, m / z) = 607.2 (M+H + ).

[0041] Example 5: (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetamide (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid (200 mg, 0.40 mmol) was added with ammonium chloride (32 mg, 0.61 mmol), diisopropylethylamine (157 mg, 1.21 mmol), PyBOP (315 mg, 0.61 mmol), and dimethylformamide (1.3 mL) and stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with purified water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography to obtain the title compound (100 mg) as a pale white solid. LC-MS (ESI, m / z) = 494.2 (M+H + ).

[0042] Example 6: (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetonitrile The compound (100 mg, 0.20 mmol) obtained in Example 5 was dissolved in DCM (0.7 mL), cooled to 0-5°C, triethylamine (31 μL, 0.61 mmol) and TFAA (31 μL, 0.22 mmol) were added, and the mixture was stirred at 0-5°C for 2 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate and aqueous sodium bicarbonate solution, and the organic layer was extracted and washed with purified water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography to obtain the title compound (53 mg) as a pale white solid. LC-MS (ESI, m / z) = 476.2 (M+H + ).

[0043] Example 7: (S)-5-(tert-butoxy(1H-tetrazol-5-yl)methyl)-4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridine Sodium azide (10 mg, 0.16 mmol), ammonium hydrochloride (8 mg, 0.16 mmol), and dimethylformamide (0.4 mL) were added to the compound obtained in Example 6 (50 mg, 0.11 mmol), and the mixture was stirred at 95 to 100 ° C for 20 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with purified water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography to obtain the title compound (21 mg) as a pale white solid. LC-MS (ESI, m / z) = 519.2 (M+H + ).

[0044] Example 8: (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylacetamide (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid (200 mg, 0.404 mmol) and methylamine hydrochloride (40.9 mg, 0.606 mmol) were reacted in a similar manner to Example 5 to obtain 158 mg of the title compound as a pale white solid. LC-MS (ESI, m / z) = 508.1 (M+H + ).

[0045] Example 9: (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methoxyacetamide (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid (200 mg, 0.404 mmol) and O-methylhydroxylamine hydrochloride (50.6 mg, 0.606 mmol) were reacted in a manner similar to that of Example 5 to obtain the title compound (141.6 mg) as a pale white solid. LC-MS (ESI, m / z) = 524.2 (M+H + ).

[0046] Example 10: (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methoxy-N-methylacetamide (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid (200 mg, 0.404 mmol) and N,O-dimethylhydroxyamine hydrochloride (59.1 mg, 0.606 mmol) were reacted in a similar manner to Example 5 to obtain the title compound (71.2 mg) as a pale white solid. LC-MS (ESI, m / z) = 538.2 (M+H + ).

[0047] Example 11: (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-hydroxyacetamide (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid (300 mg, 0.606 mmol) and hydroxylamine hydrochloride (473 mg, 0.909 mmol) were reacted in the same manner as in Example 5 to obtain the title compound (100 mg) as a pale white solid. LC-MS (ESI, m / z) = 510.1 (M+H + ).

[0048] Example 12: (S,Z)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N'-hydroxyacetimidamide Hydroxylamine hydrochloride (121 mg, 1.74 mmol), sodium bicarbonate (146 mg, 1.74 mmol), and ethanol (4.3 mL) were added to the compound obtained in Example 6 (413 mg, 0.87 mmol), and the mixture was stirred at 80° C. for 4 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with purified water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography to obtain the title compound (390 mg) as a pale white solid. LC-MS (ESI, m / z) = 509.3 (M+H + ).

[0049] Example 13: (S)-3-(tert-butoxy(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-5-methyl-1,2,4-oxadiazole To the compound obtained in Example 12 (325 mg, 0.64 mmol), p-toluenesulfonic acid hydrate (36 mg, 0.19 mmol), zinc chloride (26 mg, 0.19 mmol), and acetonitrile (2.1 mL) were added and stirred at 80°C for 3 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with purified water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography to obtain the title compound (9 mg) as a pale white solid. LC-MS (ESI, m / z) = 533.3 (M+H + ).

[0050] Example 14: (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(2H-tetrazol-5-yl)acetamide (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid (200 mg, 0.404 mmol) and 5-amino-1H-tetrazole (51.6 mg, 0.606 mmol) were reacted in the same manner as in Example 5 to obtain the title compound (83.5 mg) as a pale white solid. LC-MS (ESI, m / z) = 562.1 (M+H + ).

[0051] Example 15: ((Methoxycarbonyl)oxy)methyl (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid (300 mg, 0.606 mmol) was diluted in DMF (1.21 mL), and then chloromethyl methyl carbonate (113 mg, 0.909 mmol) and cesium carbonate (592 mg, 1.818 mmol) were added and stirred at room temperature for 22 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with purified water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography to obtain the title compound (316 mg) as a pale white solid. LC-MS (ESI, m / z) = 583.1 (M+H + ).

[0052] Example 16: 2-(2-Methoxyethoxy)ethyl (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid (200 mg, 0.404 mmol) and 1-bromo-2-(2-methoxyethoxy)ethane (123 mg, 0.606 mmol) were reacted in the same manner as in Example 15 to obtain the title compound (118.6 mg) as a pale white solid. LC-MS (ESI, m / z) = 597.2 (M+H + ).

[0053] Example 17: 1-(((cyclohexyloxy)carbonyl)oxy)ethyl (2S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-parazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid (700 mg, 2.121 mmol) and 1-chloroethylcyclohexyl carbonate (438 mg, 2.121 mmol) were reacted in the same manner as in Example 15 to obtain the title compound (912 mg) as a pale yellow solid. LC-MS (ESI, m / z) = 665.2 (M+H + ).

[0054] Example 18: (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-1-(3,4-difluorobenzyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate [Step 1] Preparation of methyl (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-1-(3,4-difluorobenzyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate Methyl (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (150 mg, 0.362 mmol), 4-(bromomethyl)-1,2-difluorobenzene (374 mg, 1.808 mmol), potassium hydroxide (50.7 mg, 0.904 mmol), TBAB (11.65 mg, 0.036 mmol) were diluted in DCM (3.23 mL) and stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with purified water. The organic layer was dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and then separated by column chromatography to obtain the title compound (122 mg) as a light yellow solid. LC-MS (ESI, m / z) = 541.1 (M+H + ). [Step 2] Preparation of (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-1-(3,4-difluorobenzyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid The compound obtained in step 1 above (122 mg, 0.225 mmol) was dissolved in a mixture of THF:MeOH (1:1), and then NaOH (27.1 mg, 0.676 mmol) was added and stirred at 40°C for 13 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with purified water. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography to obtain the title compound (89.5 mg) as a pale white solid. LC-MS (ESI, m / z) = 527.2 (M+H + ). [Step 3] Preparation of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-1-(3,4-difluorobenzyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate The compound obtained in step 2 above (20 mg, 0.038 mmol) and 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (9 mg, 0.057 mmol) were reacted in a manner similar to that in Example 15 to obtain the title compound (3.1 mg) as a pale yellow solid. LC-MS (ESI, m / z) = 639.1 (M+H + ).

[0055] Experimental Example 1: Investigation of the HIV-1 (Wild type) inhibitory effect of the compound of the present invention and cytotoxicity test In order to examine the inhibitory effect of the compound of the present invention on HIV-1 (wild type), the following test was carried out. MT-4 cells were used as the host cells, and the NL4-3 strain of HIV-1 was used as the viral strain. The virus and cells were mixed in the presence of the compound of the present invention and incubated for 6 days. The antiviral effect was measured as the percentage reduction in viral cytopathic effect (CPE), and the cytotoxicity of the compound was evaluated by MTS (CellTiter (registered trademark) 96 Reagent, Promega, Madison WI) dye reduction. The results are shown in Table 1 below. [Table 1] Although certain parts of the present invention have been described in detail above, it will be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments and are not intended to limit the scope of the present invention. Therefore, the true scope of the present invention is to be defined by the appended claims and their equivalents.

Claims

1. A compound represented by the following formula I, a racemate thereof, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: [Formula 1] In the above formula, A is -COR １ or -tetrazolyl; R １ is -OR ５ and R ５ is -(CH ２ ) ｎ -OCOO-CH ３ , -(CH)CH ３ -OCOO-C ３－６ Cycloalkyl or 5-methyl-2-oxo-1,3-dioxol-4-yl-CH ２ and B is -(CH ２ ) ｎ -R ６ and R ６ is -methoxy, -oxetanyl, or -pyrazolyl {wherein one or more H of said -oxetanyl or said -pyrazolyl can be replaced by methyl}; n is 1 or 2.

2. A compound represented by formula I of claim 1, its racemate, its stereoisomer or a pharma- ceutically acceptable salt thereof, The compound has the following chemical formula: 1) (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (2S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-(oxetan-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate; 2) (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-1-(2-methoxyethyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate; 3) (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate; 4) (S)-5-(tert-butoxy(1H-tetrazol-5-yl)methyl)-4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridine; 5) ((Methoxycarbonyl)oxy)methyl (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate; and 6) 1-(((cyclohexyloxy)carbonyl)oxy)ethyl (2S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-parazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate; The compound represented by formula I according to claim 1, characterized in that it is selected from the group consisting of:

3. 10. An antiviral pharmaceutical composition comprising the compound represented by formula I according to claim 1 or 2, its racemate, its stereoisomer or a pharma- ceutically acceptable salt thereof as an active ingredient.

4. An anti-human immunodeficiency virus (HIV) pharmaceutical composition contained in the anti-viral pharmaceutical composition according to claim 3.

5. Use of a compound represented by formula I according to claim 1 or claim 2, its racemate, its stereoisomer or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of viral infections.

Images