Pyrrolopyridine derivatives and uses thereof

Abstract

The present invention relates to pyrrolopyridine derivatives, racemates, stereoisomers or pharmaceutically acceptable salts thereof, and uses thereof. The compounds of the present invention have high selectivity and biological activity against human immunodeficiency virus (HIV), as well as low toxicity, and can therefore be used as therapeutic agents for viral infection, particularly human immunodeficiency virus (HIV) infection.

Description

[Technical field]

[0001] The present disclosure relates to antiviral compounds, particularly compounds having high selectivity and biological activity against human immunodeficiency virus (HIV), and uses thereof. [Background technology]

[0002] Acquired immunodeficiency syndrome (AIDS) is caused by infection with human immunodeficiency virus (HIV). There are two forms of HIV, HIV-1 and HIV-2, of which HIV-1 is the most common worldwide. For the treatment of AIDS, enzyme inhibitors have been developed based on the mechanism of action of HIV. According to the site of action, enzyme inhibitors are classified into nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), fusion inhibitors and integrase inhibitors.

[0003] Integrase inhibitors are divided into catalytic site inhibition and non-catalytic site inhibition according to the mechanism. Research on catalytic site integrase inhibitors has been actively carried out so far, and three types of inhibitor drugs have been developed and sold on the market. Among them, Raltegravir, developed in 2008, is a representative drug. On the other hand, Zeger Debyser et al. (Frauke Christ, Zeger Debyser et al., Nature Chemical Biology, 2010, Vol. 6, 442-448) introduced the non-catalytic site integrase inhibition mechanism, and the development of inhibitors about this mechanism has been actively carried out.

[0004] In addition, various studies are being conducted to develop drugs that effectively treat viruses with drug resistance, wherein these therapeutic agents show a large life-extending effect by combining and administering 2 to 4 drugs that inhibit different mechanisms. However, despite these efforts, AIDS is still not cured, and even the toxicity problems of drugs and the research and development of drug resistance to current therapeutic agents continue to exist. Therefore, there is a constant need to develop novel therapeutic agents.

[0005] As part of efforts to solve these problems, the present inventors have repeatedly conducted studies to develop novel AIDS therapeutic drugs, and as a result found that pyrrolopyridine derivative compounds having a novel skeleton have an effect of inhibiting HIV proliferation, and completed the present invention. [Summary of the invention]

[0006]

Technical issues

[0007] An object of the present invention is to provide a pyrrolopyridine derivative, a racemate thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof which has the effect of inhibiting HIV-1 proliferation by inhibiting the activity of HIV-1 integrase.

[0008] Another object of the present invention is to provide a method for preparing novel pyrrolopyridine derivatives, their racemates, their stereoisomers or pharmaceutically acceptable salts thereof.

[0009] Another object of the present invention is to provide medical uses of the compounds.

[0010]

Technical solution

[0011] The present inventors have conducted studies and made efforts to achieve the object, and as a result, have confirmed that a pyrrolopyridine derivative compound represented by the following formula I inhibits HIV proliferation, and have completed the present invention.

[0012] Pyrrolopyridine derivatives

[0013] The present invention provides a compound represented by the following formula I, its racemate, its stereoisomer or a pharmaceutically acceptable salt thereof:

[0014] [Formula I]

[0015]

[0016] In the above formula,

[0017] A is -hydroxy, -amino, -azido, -cyano, -trifluoromethyl, -COR1, -C=NOHR2, -B(OH)2, -SO3H, -P=O(OH)2 or -heteroaryl;

[0018] R1 and R2 are each independently -NR3R4, -NR3OR4 or -OR5;

[0019] R3 and R4 are each independently -hydrogen, -C 1-6 alkyl or -heteroaryl;

[0020] 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;

[0021] B is -(CH2)n-R6;

[0022] R6 is -hydroxy, -amino, -azido, -cyano, -trifluoromethyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C1-6 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 At least one H in the cycloalkyl, 4-6 membered heterocycloalkyl, -aryl or -heteroaryl group may be replaced by -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 -alkoxy, -cyano, -carboxy, -amino, -nitro, -azido, -hydroxy, -carbamoyl, -thiol or -halogen substituted}; and

[0023] n is 1, 2, 3 or 4.

[0024] According to one embodiment of the present invention, the compound represented by Formula I, its racemate, its stereoisomer or a pharmaceutically acceptable salt thereof may be the same as the following.

[0025] A is -cyano, -COR1, -C=NOHR2, -B(OH)2, -SO3H, -P=O(OH)2 or -heteroaryl;

[0026] R1 and R2 are each independently -NR3R4, -NR3OR4 or -OR5;

[0027] R3 and R4 are each independently -hydrogen, -C 1-6 alkyl or -heteroaryl;

[0028] 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;

[0029] B is -(CH2)n-R6;

[0030] R6 is -C 1-6 Alkoxy, 4-6 membered heterocycloalkyl, -C 3-6 Cycloalkyl, -aryl or -heteroaryl {wherein the -C 3-6 At least one H in the cycloalkyl, 4-6 membered heterocycloalkyl, -aryl or -heteroaryl group may be replaced by -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 -alkoxy, -cyano, -carboxy, -amino, -nitro, -azido, -hydroxy, -carbamoyl, -thiol or -halogen substituted}; and

[0031] n is 1, 2 or 3.

[0032] In addition, according to one embodiment of the present invention, the compound represented by Formula I, its racemate, its stereoisomer, or a pharmaceutically acceptable salt thereof may be the same as the following.

[0033] A is -cyano, -COR1, -C=NOHR2 or -heteroaryl;

[0034] R1 and R2 are each independently -NR3R4, -NR3OR4 or -OR5;

[0035] R3 and R4 are each independently -hydrogen, -C 1-6 alkyl or -heteroaryl;

[0036] 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;

[0037] B is -(CH2)n-R6;

[0038] R6 is -C 1-6 Alkoxy, 4-6 membered heterocycloalkyl, -aryl or -heteroaryl {wherein at least one H in the 4-6 membered heterocycloalkyl, -aryl or -heteroaryl may be -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 -alkoxy, -cyano, -carboxy, -amino, -nitro, -azido, -hydroxy, -carbamoyl, -thiol or -halogen substituted}; and

[0039] n is 1, 2 or 3.

[0040] In addition, according to one embodiment of the present invention, the compound represented by Formula I, its racemate, its stereoisomer, or a pharmaceutically acceptable salt thereof may be the same as the following.

[0041] A is -cyano, -COR1, -C=NOHR2 or -heteroaryl;

[0042] R1 is -NR3R4, -NR3OR4 or -OR5;

[0043] R2 is -NR3R4;

[0044] R3 and R4 are each independently -hydrogen, -C 1-6 alkyl or -heteroaryl;

[0045] 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;

[0046] B is -(CH2)n-R6;

[0047] R6 is -C 1-6 Alkoxy, 4-6 membered heterocycloalkyl, -aryl or -heteroaryl {wherein at least one H in the 4-6 membered heterocycloalkyl, -aryl or -heteroaryl may be -C 1-6 alkyl or -halogen substituted}; and

[0048] n is 1 or 2.

[0049] In addition, the compound represented by Formula I of the present invention may be selected from the group consisting of the following compounds:

[0050] 1)(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 tridecyl ester;

[0051] 2)(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 (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester;

[0052] 3) (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-1-(2-methoxyethyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester;

[0053] 4)(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-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester;

[0054] 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;

[0055] 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;

[0056] 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;

[0057] 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;

[0058] 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;

[0059] 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;

[0060] 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;

[0061] 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'-hydroxyacetamidine;

[0062] 13)(S)-3-(tert-butoxy(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-5-methyl-1,2,4-oxadiazole;

[0063] 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-tetrazolyl-5-yl)acetamide;

[0064] 15) (S)-((methoxycarbonyl)oxy)methyl 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;

[0065] 16)(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 2-(2-methoxyethoxy)ethyl ester;

[0066] 17) (2S)-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, 1-((cyclohexyloxy)carbonyl)oxy)ethyl ester; and

[0067] 18)(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 (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester.

[0068] The compound represented by Formula I of the present invention prepared as above can form a salt, particularly a pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts are those commonly used in the art, such as acid addition salts, and are not particularly limited.

[0069] Examples of preferred pharmaceutically acceptable acid addition salts may include: 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, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid, glycerophosphoric acid or acetylsalicylic acid.

[0070] In addition, pharmaceutical metal salts can be obtained by conventional methods using alkali. For example, pharmaceutical metal salts can be obtained by dissolving the compound represented by Formula I in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. Non-pharmaceutical salts or solvates of the compound represented by Formula I can be used as intermediates for preparing the compound represented by Formula I or its pharmaceutical salt or solvate.

[0071] The compounds represented by Formula I of the present invention include not only pharmaceutically acceptable salts thereof but also all possible solvates and hydrates that can be prepared from pharmaceutically acceptable salts thereof. Stereoisomers and intermediates of the compounds represented by Formula I can be prepared using conventional methods.

[0072] In addition, the compound represented by Formula I according to the present invention may be prepared in a crystalline or amorphous form, and when the compound represented by Formula I is prepared in a crystalline form, the compound may be optionally made into a hydrate or a solvate.

[0073] Uses of pyrrolopyridine derivative compounds

[0074] The present invention provides the medical use of the compound represented by formula I, its racemate, its stereoisomer or its pharmaceutically acceptable salt.

[0075] According to an embodiment of the present invention, the present invention provides an antiviral pharmaceutical composition, which comprises a compound represented by Formula I, a racemate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Specifically, the antiviral composition can be an anti-human immunodeficiency virus (HIV) composition.

[0076] In the experimental examples of the present invention, the compounds represented by Formula I have excellent HIV inhibitory effects and low cytotoxicity, and have various advantages in drug development, such as improved physicochemical properties as bioisosteres and prodrugs, improved drug absorption, and regulation of stability and toxicity.

[0077] Compositions of the present invention can be formulated as oral or injectable dosage forms.Preparations for oral administration can include, for example, tablets and capsules, and in addition to active ingredients, these preparations also contain diluents (for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine) or lubricants (for example, silicon dioxide, talcum, stearic acid and magnesium calcium salts thereof, or polyethylene glycol).Tablets can also contain binding agents, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose or polyvinylpyrrolidine, and optionally can contain disintegrants, such as starch, agar, alginic acid or its sodium salt or similar mixtures, and / or absorbents, coloring agents, flavoring agents and sweeteners.As preparations for injection, isotonic aqueous solutions or suspensoids are preferred.

[0078] The composition may be sterile, and / or contain adjuvants, such as preservatives, stabilizers, hydrating or emulsifying agents, salts for osmotic pressure control and / or buffers, and other therapeutically useful substances.

[0079] The preparation can be prepared by conventional mixing, granulation or coating methods, and can contain an active ingredient in an amount of about 0.1% to 75% by weight, preferably about 1% to 50% by weight. A unit dosage form for a mammal of about 50 to 70 kg contains an active ingredient of about 10 to 200 mg.

[0080] The preferred dosage of the compound of the present invention varies according to the patient's state and body weight, disease severity, drug type, route and time of administration, but can be appropriately selected by those skilled in the art. The compound of the present invention can be administered once or in divided doses via oral or parenteral routes.

[0081] The compositions of the present invention can be administered to mammals, including rats, mice, livestock and humans, by various routes. All modes of administration are contemplated, for example, the compositions of the present invention can be administered by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine epidural or intracerebroventricular injection.

[0082] In addition, according to an embodiment of the present invention, the present invention provides a method for preventing or treating viral infection, particularly HIV infection, comprising administering a therapeutically effective amount of a compound represented by formula I as described above, its racemate, its stereoisomer or a pharmaceutically acceptable salt thereof.

[0083] In addition, according to an embodiment of the present invention, the present invention provides the use of the compound represented by formula I as described above, its racemate, its stereoisomer or its pharmaceutically acceptable salt for preparing a drug for treating viral infection, especially HIV infection.

[0084] Matters described in the uses, compositions and methods of treatment of the present invention apply equally unless they contradict each other.

[0085]

Beneficial Effects

[0086] The compounds of the present invention, their racemates, stereoisomers or pharmaceutically acceptable salts thereof can have high selectivity and biological activity against viruses, especially human immunodeficiency virus (HIV), and low toxicity, and are therefore particularly useful for treating human immunodeficiency virus (HIV) infection. [Specific implementation method]

[0087] Hereinafter, the present invention will be described in more detail by the following examples and experimental examples. However, the following examples and experimental examples are only intended to illustrate the present invention, and the scope of the present invention is not limited only to these examples.

[0088] Example 1: (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 tridecyl ester

[0089] Cesium carbonate (112 mg, 0.81 mmol), 1-bromotridecane (128 mg, 0.49 mmol) and dimethylacetamide (1.3 mL) were added to (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) and stirred at 55 to 60 ° C for 12 hours. After the reaction was complete, the reaction solution was diluted with ethyl acetate and washed with purified water. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the desired product (255 mg) as a yellow oil.

[0090] LC-MS (ESI, m / z) = 677.2 (M+H + ).

[0091] Example 2: (2S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-(oxetane- 2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) Methyl ester

[0092] In a manner similar to Example 1, (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-dioxocyclopentene-2-one (22 mg, 0.15 mmol) were reacted to give the desired product (20 mg) as an off-white solid.

[0093] LC-MS (ESI, m / z) = 583.2 (M+H + ).

[0094] Example 3: (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-1-(2-methoxyethyl)-2,3,6-trimethylol 5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 1H-pyrrolo[2,3-b]pyridin-5-yl)acetate

[0095] In a manner similar to Example 1, (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 to give the desired product (272 mg) as an off-white solid.

[0096] LC-MS (ESI, m / z) = 571.1 (M+H + ).

[0097] Example 4: (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 (5-methyl-2-oxo-1,3-dioxolane 4-O-Fluoro-1-yl)methyl ester

[0098] In a manner similar to Example 1, (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 to give the desired product (55 mg) as an off-white solid.

[0099] LC-MS (ESI, m / z) = 607.2 (M+H + ).

[0100] 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

[0101] Ammonium chloride (32 mg, 0.61 mmol), diisopropylethylamine (157 mg, 1.21 mmol), PyBOP (315 mg, 0.61 mmol) and dimethylformamide (1.3 mL) were added to (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) and stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with ethyl acetate and washed with purified water. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the desired product (100 mg) as an off-white solid.

[0102] LC-MS (ESI, m / z) = 494.2 (M+H + ).

[0103] 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

[0104] The compound (100mg, 0.20mmol) obtained in Example 5 was dissolved in DCM (0.7mL), cooled to 0 to 5°C, and triethylamine (31μL, 0.61mmol) and TFAA (31μL, 0.22mmol) were added, followed by stirring at 0 to 5°C for 2 hours. After the reaction was complete, the reaction solution was diluted with ethyl acetate and sodium bicarbonate aqueous solution, and the organic layer was extracted and washed with pure water. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the desired product (53mg) as a pale white solid.

[0105] LC-MS (ESI, m / z) = 476.2 (M+H + ).

[0106] 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

[0107] Sodium azide (10 mg, 0.16 mmol), ammonium hydrochloride (8 mg, 0.16 mmol) and dimethylformamide (0.4 mL) were added to the compound (50 mg, 0.11 mmol) obtained in Example 6, and 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 pure water. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the desired product (21 mg), which was a pale solid.

[0108] LC-MS (ESI, m / z) = 519.2 (M+H +).

[0109] 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

[0110] (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 manner similar to Example 5 to give the desired product (158 mg) as an off-white solid.

[0111] LC-MS (ESI, m / z) = 508.1 (M+H + ).

[0112] 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 Example 5 to give the desired product (141.6 mg) as an off-white solid.

[0113] LC-MS (ESI, m / z) = 524.2 (M+H + ).

[0114] Example 10: (S)-2-(tert-Butyloxy)-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

[0115] (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-dimethylhydroxylamine hydrochloride (59.1 mg, 0.606 mmol) were reacted in a manner similar to Example 5 to give the desired product (71.2 mg) as an off-white solid.

[0116] LC-MS (ESI, m / z) = 538.2 (M+H + ).

[0117] 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

[0118] (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 a manner similar to Example 5 to give the desired product (100 mg) as an off-white solid.

[0119] LC-MS (ESI, m / z) = 510.1 (M+H + ).

[0120] 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'-hydroxyacetamidine

[0121] In the compound (413mg, 0.87mmol) obtained in Example 6, hydroxylamine hydrochloride (121mg, 1.74mmol), sodium bicarbonate (146mg, 1.74mmol) and ethanol (4.3mL) were added, and stirred for 4 hours at 80°C. After the reaction was completed, the reaction solution was diluted with ethyl acetate, and washed with pure water. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the required product (390mg), which was a pale solid.

[0122] LC-MS (ESI, m / z) = 509.3 (M+H + ).

[0123] Example 13: (S)-3-(tert-butoxy(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrrolidone) oxadiazole-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-5-methyl-1,2,4-oxadiazole

[0124] In the compound (325mg, 0.64mmol) obtained in Example 12, p-toluenesulfonic acid hydrate (36mg, 0.19mmol), zinc chloride (26mg, 0.19mmol) and acetonitrile (2.1mL) were added, and stirred for 3 hours at 80°C. After the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with pure water. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the desired product (9mg), which was a pale solid.

[0125] LC-MS (ESI, m / z) = 533.3 (M+H + ).

[0126] 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-tetrazolyl-5-yl)acetamide

[0127] (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 a manner similar to Example 5 to give the desired product (83.5 mg) as an off-white solid.

[0128] LC-MS (ESI, m / z) = 562.1 (M+H + ).

[0129] Example 15: (S)-2-(tert-Butyloxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H- ((Methoxycarbonyl)oxy)methyl pyrazol-4-yl)methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate

[0130] By (S) -2- (tert-butoxy) -2- (4- (4- chlorophenyl) -2,3,6- trimethyl -1- ( (1- methyl -1H- pyrazol -4- base) methyl) -1H- pyrrolo [2,3-b] pyridin -5- base) acetic acid (300mg, 0.606mmol) in DMF (1.21mL) dilution, then add chloromethyl methyl carbonate (113mg, 0.909mmol) and cesium carbonate (592mg, 1.818mmol), and the mixture is stirred at room temperature for 22 hours. After the reaction is complete, the reaction solution is diluted with ethyl acetate, and washed with pure water. The organic layer is passed through anhydrous sodium sulfate drying, concentrated under reduced pressure, and purified by column chromatography to obtain the desired product (316mg), which is a pale solid.

[0131] LC-MS (ESI, m / z) = 583.1 (M+H + ).

[0132] Example 16: (S)-2-(tert-Butyloxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl-1H- 2-(2-methoxyethoxy)ethyl pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate

[0133] (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 a manner similar to Example 15 to give the desired product (118.6 mg) as an off-white solid.

[0134] LC-MS (ESI, m / z) = 597.2 (M+H + ).

[0135] Example 17: (2S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-((1-methyl- 1-(((cyclohexyloxy)carbonyl)oxy)ethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid ester

[0136] (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-chloroethyl cyclohexyl carbonate (438 mg, 2.121 mmol) were reacted in a manner similar to Example 15 to give the desired product (912 mg) as a light yellow solid.

[0137] LC-MS (ESI, m / z) = 665.2 (M+H + ).

[0138] Example 18: (S)-2-(tert-Butyloxy)-2-(4-(4-chlorophenyl)-1-(3,4-difluorobenzyl)-2,3,6-trimethylol 5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 1H-pyrrolo[2,3-b]pyridin-5-yl)acetate

[0139] [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

[0140] (S) -2- (tert-butoxy) -2- (4- (4- chlorophenyl) -2,3,6- trimethyl -1H- pyrrolo [2,3-b] pyridin-5-yl) methyl acetate (150mg, 0.362mmol), 4- (bromomethyl) -1,2- difluorobenzene (374mg, 1.808mmol), potassium hydroxide (50.7mg, 0.904mmol) and TBAB (11.65mg, 0.036mmol) were diluted in DCM (3.23mL) 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 dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the desired product (122mg) as a light yellow solid.

[0141] LC-MS (ESI, m / z) = 541.1 (M+H + ).

[0142] [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

[0143] The compound (122mg, 0.225mmol) obtained in step 1 is dissolved in a mixture of THF:MeOH (1:1), then NaOH (27.1mg, 0.676mmol) is added, and the mixture is stirred at 40°C for 13 hours. After the reaction is complete, the reaction solution is diluted with ethyl acetate and washed with pure water. The organic layer is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the desired product (89.5mg), which is a pale solid.

[0144] LC-MS (ESI, m / z) = 527.2 (M+H + ).

[0145] [Step 3] 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 (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester

[0146] The compound obtained in step 2 (20 mg, 0.038 mmol) and 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (9 mg, 0.057 mmol) were prepared in a similar manner to Example 15 to give the desired product (3.1 mg) as a light yellow solid.

[0147] LC-MS (ESI, m / z) = 639.1 (M+H + ).

[0148] Experimental Example 1: HIV-1 (wild type) inhibitory effect study and cytotoxicity test of the compounds of the present invention

[0149] In order to determine the HIV-1 (wild type) inhibitory effect of the compounds of the present invention, the test was performed as follows. The host cells were MT-4 cells, and the virus strain was the NL4-3 strain of HIV-1. The virus and cells were mixed in the presence of the compounds of the present invention and then incubated for 6 days. The antiviral effect was measured as a percentage reduction in the viral cytopathic effect (CPE), and the cytotoxicity of the compounds was measured by MTS ( The results are shown in Table 1.

[0150]

[0151] The specific parts of the present invention have been described in detail. It is obvious to those skilled in the art that these specific descriptions are only preferred embodiments, and the scope of the present invention is not limited thereto. Therefore, the actual scope of the present invention will be limited by the appended claims and their equivalents.

Claims

1. A compound represented by the following formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof: [Formula I] In the above formula, A is -COR1; R1 is -OR5; R5 is -(CH2)n-OCOO-CH3 or -(CH)CH3-OCOO-C 3-6 Cycloalkyl; B is -(CH2)n-R6; R6 is -C 1-6 Alkoxy, 4-6 membered heterocycloalkyl, -phenyl or -pyrazolyl, wherein at least one H in the -phenyl or -pyrazolyl is optionally replaced by -C 1-6 Alkyl or -halogen substituted; and n is 1 or 2.

2. A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of the following formulae: 2) (2S)-2-(tert-Butoxy)-2-(4-(4-chlorophenyl)-2,3,6-trimethyl-1-(oxetan-2-yl-methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-acetic acid-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester; 3) (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-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester; 4) (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-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester; 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; 15) (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-((methoxycarbonyl)oxy)methyl ester; 17) (2S)-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-1-(((cyclohexyloxy)carbonyl)oxy)ethyl ester; and 18) (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-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester.

3. An antiviral pharmaceutical composition comprising the compound according to any one of claims 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof as an active ingredient.

4. Use of the compound according to any one of claims 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof for preparing a medicament for treating viral infection.

5. The use according to claim 4, wherein the drug is used to fight human immunodeficiency virus.

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