Heteroaryl compound and use thereof

Abstract

The present invention relates to: a heteroaryl compound having antiviral activity, in particular, a compound of chemical formula 1, having high selectivity and physiological activity against human immunodeficiency virus (HIV), or a pharmaceutically acceptable salt, a stereoisomer, a hydrate, a solvate, a tautomer, or a prodrug thereof; and a use thereof. [Chemical formula 1]

Description

Heteroaryl compounds and uses thereof

[0001] The present invention relates to heteroaryl compounds having antiviral activity, particularly compounds having high selectivity and physiological activity against human immunodeficiency virus (HIV), or pharmaceutically acceptable salts, stereoisomers, hydrates, solvates, tautomers or prodrugs thereof, and uses thereof.

[0002] Acquired Immunodeficiency Syndrome (AIDS) is caused by infection with the human immunodeficiency virus (HIV). There are two types of HIV, HIV-1 and HIV-2, and HIV-1 is the most prevalent type worldwide. Enzyme inhibitors have been developed to treat AIDS based on the mechanism of action of HIV. These enzyme inhibitors are classified into nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), fusion inhibitors, and integrase inhibitors based on their site of action.

[0003] Integrase inhibitors are classified into catalytic site inhibition and non-catalytic site inhibition depending on their mechanism of action. Research on catalytic site integrase inhibitors has been actively conducted, and three types of drugs have been developed and are commercially available, with raltegravir, developed in 2008, being a representative drug. On the other hand, the non-catalytic site integrase inhibition mechanism was introduced by Ziger Debyser et al. (Frauke Christ, Zeger Debyser et al., Nature Chemical Biology, 2010, Vol. 6, 442), and the development of inhibitors for this mechanism of action has been actively progressing.

[0004] In addition, various studies are underway to develop drugs that can effectively treat resistant viruses. These chemotherapeutic agents, known as Highly Active Anti-Retroviral Therapies (HAART), combine two to four drugs that inhibit different mechanisms of action, demonstrating significant life-extension benefits. However, despite these efforts, AIDS remains incurable, and drug toxicity and the emergence of resistance to existing treatments continue to necessitate the development of new treatments.

[0005] The object of the present invention is to provide a heteroaryl compound exhibiting an inhibitory effect on the proliferation of human immunodeficiency virus, particularly HIV-1, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer or prodrug thereof.

[0006] Another object of the present invention is to provide a pharmaceutical composition for inhibiting, preventing or treating a virus, particularly a human immunodeficiency virus infection, comprising the heteroaryl compound or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer or prodrug thereof.

[0007] Another object of the present invention is to provide a method for inhibiting, preventing or treating a virus, particularly a human immunodeficiency virus infection, comprising administering the heteroaryl compound, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer or prodrug thereof, to a subject in need thereof.

[0008] Another object of the present invention is to provide a use of the heteroaryl compound, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer or prodrug thereof, for inhibiting, preventing or treating virus infection, particularly human immunodeficiency virus infection.

[0009] As part of efforts to address the aforementioned technical challenges, the inventors of the present invention conducted extensive research to develop a novel AIDS treatment. As a result, they discovered that a heteroaryl compound with a novel skeleton exhibited an inhibitory effect on HIV proliferation, leading to the completion of the present invention. The method for solving the technical challenges of the present invention is as follows:

[0010] 1. A compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer, or prodrug thereof:

[0011] Chemical Formula 1

[0012]

[0013] Among the foods,

[0014] R1 is hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6Selected from the group consisting of alkyloxy, halo and cyano;

[0015] R2 is hydrogen, C 1-20 Alkyl, C 1-6 Alkyl-O-(CH2) n -O-(CH2) n -, C 1-6 Alkyl-OC(O)O-(CH2) n -, substituted or unsubstituted C 3-7 Cycloalkyl-OC(O)O-(CH3)CH-, substituted or unsubstituted heterocyclyl-(CH2) n -, substituted or unsubstituted heteroaryl-(CH2) n -, and unsubstituted or C 1-6 Alkyl-substituted oxo-dioxolyl-(CH2) n - is selected from the group consisting of, wherein when the cycloalkyl, heterocyclyl and heteroaryl are substituted, they are each unsubstituted C 1-6 C substituted with alkyl, halo, amino or hydroxy 1-6 Alkyl, C 1-6 which may be substituted with one or more substituents selected from the group consisting of alkyloxy, cyano, carboxy, amino, nitro, azido, hydroxy, carbamoyl, thio and halo;

[0016] R3 is C 1-6 Alkyl, C 1-6 Alkyloxy, and unsubstituted or substituted C 3-7 Selected from the group consisting of cycloalkyloxy, wherein said C 3-7 When cycloalkyloxy is substituted, the substituent is unsubstituted C 1-6 C substituted with alkyl, halo, amino or hydroxy 1-6 Alkyl, C 1-6 At least one selected from the group consisting of alkyloxy, cyano, carboxy, amino, nitro, azido, hydroxy, carbamoyl, thio and halo;

[0017] R4 is substituted or unsubstituted heteroaryl, C 1-10A substituted or unsubstituted heteroaryl fused with a cycloalkyl, or a substituted or unsubstituted heteroaryl fused with a heterocyclyl containing one or more heteroatoms in the ring, wherein when the heteroaryl is substituted, the substituent is a substituted or unsubstituted C 1-6 Alkyl, C 1-6 At least one selected from the group consisting of alkyloxy, cyano, carboxy, amino, nitro, azido, hydroxy, carbamoyl, thio and halo, and when said alkyl is substituted, the substituent is halo, amino, hydroxy and C 1-6 At least one selected from the group consisting of alkyloxy;

[0018] R5 is hydrogen, C 3-7 Cycloalkyl or C 1-6 Alkyl, R6 is hydrogen, C 3-7 Cycloalkyl, C 1-6 Alkyl, (C 1-6 alkyl)-OC(O)-, (C 1-6 Alkyl)-C(O)- or R8-(CH2) n - or R5 and R6 are combined with each other to form C 3-7 It can be a cycloalkyl or a 4-7 membered heterocyclyl containing one or more heteroatoms in the ring;

[0019] R7 is hydrogen, C 3-7 Cycloalkyl, (C 1-6 alkyl)-OC(O)-, (C 1-6 Alkyl)-C(O)- and R8-(CH2) n - is selected from the group consisting of;

[0020] R8 is hydrogen, halo, hydroxy, amino, azido, cyano, C substituted with 1 to 3 halo 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 1-6 Alkyloxy, (C 1-3 alkyl)NHC(O)-, (C 1-3 alkyl)2NC(O)-, HOOC-, (C 1-6 alkyl)-S-, (C1-6 alkyl)-S(O)2-, carbamoyl, substituted or unsubstituted C 3-7 Selected from the group consisting of cycloalkyl, substituted or unsubstituted 4-7 membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein when the cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted, they are each unsubstituted C 1-6 C substituted with alkyl, halo, amino or hydroxy 1-6 Alkyl, C 1-6 which may be substituted with one or more substituents selected from the group consisting of alkyloxy, cyano, carboxy, amino, nitro, azido, hydroxy, carbamoyl, thio and halo;

[0021] n is an integer from 0 to 5.

[0022] 2. A pharmaceutical composition for inhibiting, preventing or treating viral infection, comprising the compound of the above 1, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer or prodrug thereof.

[0023] 3. A pharmaceutical composition for inhibiting, preventing or treating the above-mentioned virus infection, wherein the virus is human immunodeficiency virus (HIV).

[0024] 4. A method for inhibiting, preventing or treating a viral infection, comprising administering the compound of the above 1, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer or prodrug thereof, to a subject in need thereof.

[0025] 5. A method for suppressing, preventing, or treating a viral infection according to the above 4, wherein the virus is human immunodeficiency virus (HIV).

[0026] 6. A use for inhibiting, preventing or treating viral infection, comprising the compound of the above 1, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer or prodrug thereof.

[0027] 7. Use for inhibiting, preventing or treating the above 6 virus infection, wherein the virus is human immunodeficiency virus (HIV).

[0028] According to the present invention, there are provided heteroaryl compounds having high selectivity and physiological activity against viruses, particularly human immunodeficiency virus (HIV), or pharmaceutically acceptable salts, stereoisomers, hydrates, solvates, tautomers or prodrugs thereof, and uses thereof for inhibiting or treating viral infections.

[0029] The heteroaryl compound according to the present invention, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer or prodrug thereof, has high selectivity and physiological activity against viruses, particularly human immunodeficiency virus (HIV), and low toxicity, and thus can be usefully used for the inhibition, prevention or treatment of virus infection, particularly human immunodeficiency virus (HIV).

[0030] Definition of terms

[0031] Briefly explain the terms used in this specification.

[0032] The term "hydrate" means a compound of the present invention or a salt thereof comprising a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0033] The term "solvate" refers to a compound of the present invention or a salt thereof comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. The solvent for the solvate may be any solvent that is volatile, non-toxic, and / or suitable for human administration.

[0034] The term "prodrug" refers to a substance that can be converted in vivo into the compound of formula 1 according to the present invention. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they may achieve physiological activity upon oral administration, whereas the parent drug may not. Prodrugs may also have improved solubility in pharmaceutical formulations compared to the parent drug. For example, a prodrug may be in the form of an ester ("prodrug") that facilitates passage through cell membranes, where aqueous solubility would be detrimental to mobility, but once in cells where aqueous solubility is beneficial, it is metabolically hydrolyzed to the active carboxylic acid. Another example of a prodrug is a short peptide (polyamino acid) linked to an acid group that is metabolically converted to reveal the active site.

[0035] The term "stereoisomer" refers to isomers that have the same chemical formula or molecular formula but are formed due to different spatial arrangements of atoms within the molecule. "Enantiomer" refers to an isomer that is not superimposable with its mirror image, like the relationship between right and left hands, and "diastereoisomer" refers to a stereoisomer that is not a mirror image relationship. All of these isomers and their mixtures, i.e., racemates, are also included in the scope of the present invention.

[0036] The term "alkyl" refers to straight, branched and cyclic aliphatic hydrocarbon groups, including both "saturated alkyl" and "unsaturated alkyl" having at least one double or triple bond moiety in the chain.

[0037] The term "aryl" refers to an aromatic ring group having 6 to 10 carbon atoms, "heterocyclyl" refers to a 3- to 7-membered ring group having at least one heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S) atoms within the ring, and "heteroaryl" refers to a 5- to 10-membered heteroaromatic ring group having at least one heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S) atoms within the ring, and a two- or three-ring group in which the 5- to 10-membered heteroaromatic ring group is fused with an aromatic ring group having 6 to 10 carbon atoms.

[0038] The contents of the present invention are described in detail below.

[0039] The first aspect of the present invention relates to a compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer or prodrug thereof:

[0040] Chemical Formula 1

[0041]

[0042] Among the foods,

[0043] R1 is hydrogen C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Selected from the group consisting of alkyloxy, halo and cyano;

[0044] R2 is hydrogen, C 1-20 Alkyl, C 1-6 Alkyl-O-(CH2) n -O-(CH2) n -, C 1-6 Alkyl-OC(O)O-(CH2) n -, substituted or unsubstituted C 3-7 Cycloalkyl-OC(O)O-(CH3)CH-, substituted or unsubstituted heterocyclyl-(CH2) n -, substituted or unsubstituted heteroaryl-(CH2) n -, and unsubstituted or C 1-6Alkyl-substituted oxo-dioxolyl-(CH2) n - is selected from the group consisting of, wherein when the cycloalkyl, heterocyclyl and heteroaryl are substituted, they are each unsubstituted C 1-6 C substituted with alkyl, halo, amino or hydroxy 1-6 Alkyl C 1-6 which may be substituted with one or more substituents selected from the group consisting of alkyloxy, cyano, carboxy, amino, nitro, azido, hydroxy, carbamoyl, thio and halo;

[0045] R3 is C 1-6 Alkyl, C 1-6 Alkyloxy, and unsubstituted or substituted C 3-7 Selected from the group consisting of cycloalkyloxy, wherein said C 3-7 When cycloalkyloxy is substituted, the substituent is unsubstituted C 1-6 C substituted with alkyl, halo, amino or hydroxy 1-6 Alkyl, C 1-6 At least one selected from the group consisting of alkyloxy, cyano, carboxy, amino, nitro, azido, hydroxy, carbamoyl, thio and halo;

[0046] R4 is substituted or unsubstituted heteroaryl, C 1-10 A substituted or unsubstituted heteroaryl fused with a cycloalkyl, or a substituted or unsubstituted heteroaryl fused with a heterocyclyl containing one or more heteroatoms in the ring, wherein when the heteroaryl is substituted, the substituent is a substituted or unsubstituted C 1-6 Alkyl, C 1-6 At least one selected from the group consisting of alkyloxy, cyano, carboxy, amino, nitro, azido, hydroxy, carbamoyl, thio and halo, and when said alkyl is substituted, the substituent is halo, amino, hydroxy and C 1-6 At least one selected from the group consisting of alkyloxy;

[0047] R5 is hydrogen, C 3-7Cycloalkyl or C 1-6 Alkyl, R6 is hydrogen, C 3-7 Cycloalkyl, C 1-6 Alkyl, (C 1-6 alkyl)-OC(O)-, (C 1-6 Alkyl)-C(O)- or R8-(CH2) n - or R5 and R6 are combined with each other to form C 3-7 It can be a cycloalkyl or a 4-7 membered heterocyclyl containing one or more heteroatoms in the ring;

[0048] R7 is hydrogen, C 3-7 Cycloalkyl, (C 1-6 alkyl)-OC(O)-, (C 1-6 Alkyl)-C(O)- and R8-(CH2) n - is selected from the group consisting of;

[0049] R8 is hydrogen, halo, hydroxy, amino, azido, cyano, C substituted with 1 to 3 halo 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 1-6 Alkyloxy, (C 1-3 alkyl)NHC(O)-, (C 1-3 alkyl)2NC(O)-, HOOC-, (C 1-6 alkyl)-S-, (C 1-6 alkyl)-S(O)2-, carbamoyl, C 3-7 Selected from the group consisting of substituted or unsubstituted cycloalkyl, 4-7 membered substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein when the cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted, they are each unsubstituted C 1-6 C substituted with alkyl, halo, amino or hydroxy 1-6 Alkyl, C 1-6 which may be substituted with one or more substituents selected from the group consisting of alkyloxy, cyano, carboxy, amino, nitro, azido, hydroxy, carbamoyl, thio and halo;

[0050] n is an integer from 0 to 5.

[0051] In one specific example of the present invention, the compound of formula 1 is wherein R1 is hydrogen or C 1-6 It may be an alkyl compound.

[0052] In another specific example of the present invention, the compound of formula 1 is wherein R2 is hydrogen, C 1-20 Alkyl, and unsubstituted or C 1-6 Alkyl-substituted oxo-dioxolyl-(CH2) n - may be a compound selected from the group consisting of.

[0053] In another specific example of the present invention, the compound of formula 1 is wherein R3 is C 1-6 Alkyl or C 1-6 It may be an alkyloxy compound.

[0054] In another specific example of the present invention, the compound of formula 1 is wherein R4 is unsubstituted, or C 1-6 It may be a heteroaryl compound substituted with one or more substituents selected from the group consisting of alkyl and halo.

[0055] In another specific example of the present invention, the compound of formula 1 is wherein R5 and R6 are each hydrogen or C 1-6 It may be an alkyl compound.

[0056] In another specific example of the present invention, the compound of formula 1 is wherein R7 is hydrogen or R8-(CH2) n - and R8 is hydrogen, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and when the aryl and heteroaryl are substituted, the substituents are each C 1-6 It may be a compound selected from the group consisting of alkyl and halo.

[0057] In the present invention, the C 6-10 Aryl can be phenyl or naphthyl.

[0058] In the present invention, the heterocyclyl may be selected from the group consisting of piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dioxanyl, tetrahydrofuranyl, and tetrahydropyranyl.

[0059] In the present invention, examples of the heteroaryl include quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolinyl, isoindolyl, indolizinyl, indazolinyl, azaindolyl, benzoimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzoxazinyl, benzothiazolyl, carbazolyl, pyrrolopyrrolyl, furopyrrolyl, thienopyrrolyl, azaindazolyl, pyrazolopyrimidinyl, purinyl, adeninyl, guaninyl, naphthapyridinyl, pyrrolopyrimidinyl, pyridopyrazinyl, pteridinyl, Examples include, but are not limited to, chromenyl, dioxoisoindolinyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, pyranyl, thiophenyl, 2-oxopyrrolidinyl, pyrazolyl, thiazolyl, isothiazolyl, etc., and C 6-10 Any fused bicyclic or tricyclic group of aryl and 5-6 membered heteroaryl or fused two or more 5-6 membered heteroaryl groups is possible.

[0060] In the present invention, examples of the heteroaryl fused with the heterocyclyl include, but are not limited to, tetrahydrocyclopyrrolyl, dihydrofuropyridinyl, dihydrothienopyridinyl, dihydropyrrolopyridinyl, dihydroimidazopyridinyl, dihydrooxazolopyridinyl, etc., and any two-ring or three-ring group in which the heterocyclyl and heteroaryl exemplified herein are fused may be used.

[0061] In the present invention, the halo may be selected from the group consisting of fluoro, chloro, bromo, and iodo.

[0062] The compound of the above chemical formula 1 according to the present invention may be selected from the group consisting of compounds having the following structure:

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071] The second aspect of the present invention relates to a pharmaceutical composition for inhibiting, preventing or treating viral infection, comprising a compound of the above chemical formula 1, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer or prodrug thereof.

[0072] A third aspect of the present invention relates to a method for inhibiting, preventing or treating a viral infection, comprising administering to a subject in need thereof a compound of the above-described chemical formula 1, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer or prodrug thereof.

[0073] The fourth aspect of the present invention relates to a use for inhibiting, preventing or treating viral infection, comprising the compound of the above 1, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer or prodrug thereof.

[0074] In the present invention, the virus may be human immunodeficiency virus (HIV).

[0075] Example

[0076] The present invention will be described in more detail below through examples. However, the following examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention solely to these examples.

[0077] Example 1: Preparation of ethyl (S)-2-(tert-butoxy)-2-(4-(5-chloropyridin-2-yl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (Compound 1)

[0078]

[0079] [Step 1] Preparation of (2-amino-4,5-dimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrol-3-yl)(5-chloropyridin-2-yl)methanone

[0080] (1-Methyl-1H-pyrazol-4-yl)methanamine hydrochloride (277 mg, 1.877 mmol) was dissolved in ethanol (3.74 mL, 13.5 vol), and diisopropylethylamine (820 μL, 4.69 mmol) and 3-(5-chloropyridin-2-yl)-3-oxapropanenitrile (373 mg, 2.065 mmol) were sequentially added dropwise. After the temperature of the reaction solution was raised to 35–40 °C, 3-chlorobutan-2-one (284 μL, 2.82 mmol) was slowly added dropwise over 30 minutes. After the addition, the reaction solution was stirred for 2 hours while maintaining the temperature at 35–40 °C. After the completion of the reaction, the temperature of the reaction solution was lowered to 10 °C, and distilled water was added dropwise over 10 minutes. The aqueous layer was extracted three times with ethyl acetate and washed with a saturated aqueous ammonium chloride solution. The washed organic layer was dried over sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography to obtain the title compound (Intermediate 1) (492.6 mg, 1.433 mmol, yield: 76%) as an orange oil.

[0081] LCMS: m / z 344.0 [M+H + ].

[0082] [Step 2] Preparation of ethyl 2-(4-(5-chloropyridin-2-yl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-oxoacetate

[0083] Intermediate 1 (490.6 mg, 1.427 mmol) obtained in the above step 1 was dissolved in acetonitrile (1.903 mL) and dimethylformamide (951 μL) (2:1, 0.5 M), and ethyl acetopyruvate (301 μL, 2.14 mmol) and 4 M dioxane hydrochloride solution (1.07 mL, 4.28 mmol) were sequentially added dropwise. The temperature of the reaction solution was raised to 65°C and stirred for 14 hours. After completion of the reaction, the reaction solution was concentrated, the temperature was lowered to 0°C, and ethyl acetate and 7 wt% sodium bicarbonate aqueous solution were added. After stirring for 10 minutes, the mixture was extracted three times with ethyl acetate at room temperature, and then 5 wt% sodium bicarbonate aqueous solution was added. The residue was washed with an aqueous solution. The washed organic layer was dried over sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography to obtain the title compound (Intermediate 2) (177.6 mg, 0.381 mmol, yield: 26.7%) as a white solid.

[0084] LCMS: m / z 466.0 [M+H + ]

[0085] [Step 3] Preparation of ethyl (S)-2-(4-(5-chloropyridin-2-yl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-hydroxyacetate

[0086] Intermediate 2 (125.9 mg, 0.270 mmol) of Step 2 was dissolved in acetonitrile (901 μL), and triethylamine (75 μL, 0.540 mmol) was added dropwise. The reaction solution was cooled to -5°C, and formic acid (31.1 μL, 0.811 mmol) was slowly added dropwise. In another reactor, (pentamethylcyclopentadanyl)rhodium(III) dichloride dimer (33.4 mg, 0.056 mmol) and (1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (47.52 mg, 0.128 mmol) were dissolved in acetonitrile (1.244 mL), and the mixture was stirred for 10 minutes. While maintaining the internal temperature at 0 to 5°C, triethylamine (75.32 μL, 0.54 mmol) was added, stirred for 1 hour, and then added dropwise to the reaction solution. The reaction solution was reacted for 22 hours while maintaining the internal temperature at -5 to 5°C. The reaction solution was diluted with distilled water and extracted three times with ethyl acetate. The organic layer was dehydrated over sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography to obtain the title compound (Intermediate 3) (83.3 mg, 0.178 mmol, yield: 65.9%) as a white solid.

[0087] LCMS: m / z 468.1 [M+H + ].

[0088] [Step 4] Preparation of ethyl (S)-2-(tert-butoxy)-2-(4-(5-chloropyridin-2-yl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate

[0089] Intermediate 3 (81.4 mg, 0.174 mmol) obtained in step 3 was dissolved in dichloromethane (348 μL), and tert-butyl acetate (2.444 mL, 18.09 mmol) was added dropwise. The temperature of the reaction solution was lowered to 0°C, and 70% perchloric acid (59.8 μL, 0.696 mmol) was slowly added dropwise over 1 hour. The temperature of the reaction solution was increased to 20°C and reacted for 2 hours. After completion of the reaction, dichloromethane and a saturated aqueous sodium carbonate solution were added dropwise to the reaction solution, and the mixture was stirred for 20 minutes. The reaction solution was diluted with distilled water and extracted three times with dichloromethane. The extracted organic layer was dried over sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography to obtain compound 1 (19.2 mg, 0.037 mmol, yield: 21.06%) as a white solid.

[0090] LCMS: m / z 524.1 [M+H + ].

[0091] Example 2: Preparation of (S)-2-(tert-butoxy)-2-(4-(5-chloropyridin-2-yl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid (Compound 2)

[0092]

[0093] Compound 1 (19.2 mg, 0.037 mmol) was dissolved in tetrahydrofuran (147 μL) and methanol (36.6 μL) (2:1, 0.2 M), and sodium hydroxide (4.4 mg, 0.110 mmol) was added dropwise. The reaction solution was stirred at 40–45°C for 3 hours. The reaction solution was concentrated, diluted with distilled water, and adjusted to pH 6–7 with 0.5 N aqueous hydrochloric acid. The aqueous layer was extracted twice with dichloromethane. The extracted organic layer was dried over sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography to obtain compound 2 (15.6 mg, 0.031 mmol, yield: 86%) as a white solid.

[0094] LCMS: m / z 496.1 [M+H + ].

[0095] Example 3: Preparation of ethyl (2S)-2-(tert-butoxy)-2-(4-(5-chloro-3-fluoropyridin-2-yl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (Compound 3)

[0096] Using (1-methyl-1H-pyrazol-4-yl)methanamine hydrochloride and 3-(5-chloro-3-fluoropyridin-2-yl)-3-oxapropanenitrile as starting materials, a reaction was performed in a similar manner to steps 1 to 4 of Example 1 to prepare compound 3 (10.8 mg, 0.020 mmol, yield: 16.72%) as a white solid.

[0097] LCMS: m / z 542.2 [M+H + ].

[0098] Example 4: Preparation of (2S)-2-(tert-butoxy)-2-(4-(5-chloro-3-fluoropyridin-2-yl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid (Compound 4)

[0099] Compound 4 (8.3 mg, 0.016 mmol, yield: 33.4%) as a white solid was prepared from compound 3 (26.2 mg, 0.048 mmol) by a similar method to Example 2.

[0100] LCMS: m / z 514.2 [M+H + ].

[0101] Example 5: Preparation of ethyl (S)-2-(4-(benzofuran-2-yl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(tert-butoxy)acetate (Compound 5)

[0102] Using (1-methyl-1H-pyrazol-4-yl)methanamine hydrochloride and 3-(benzofuran-2-yl)-3-oxopropanenitrile as starting materials, a reaction was performed in a similar manner to steps 1 to 4 of Example 1 to prepare compound 5 (69.6 mg, 0.132 mmol, yield: 48.1%) as a white solid.

[0103] LCMS: m / z 529.6 [M+H + ].

[0104] Example 6: Preparation of (S)-2-(4-(benzofuran-2-yl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(tert-butoxy)acetic acid (Compound 6)

[0105] Compound 6 (41.4 mg, 0.083 mmol, yield: 83%) as a white solid was prepared from compound 5 (52.7 mg, 0.10 mmol) by a similar method to Example 2.

[0106] LCMS: m / z 501.0 [M+H + ].

[0107] Example 7: Preparation of ethyl (S)-2-(tert-butoxy)-2-(2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (Compound 7)

[0108] Using (1-methyl-1H-pyrazol-4-yl)methanamine hydrochloride and 3-oxo-3-(thiophen-2-yl)propanenitrile as starting materials, a reaction was performed in a similar manner to steps 1 to 4 of Example 1 to prepare compound 7 (14.6 mg, 0.030 mmol, yield: 47.8%) as a white solid.

[0109] LCMS: m / z 495.2 [M+H + ].

[0110] Example 8: Preparation of (S)-2-(tert-butoxy)-2-(2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-4-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid (Compound 8)

[0111] Compound 8 (13.3 mg, 0.029 mmol, yield: 35.4%) as a white solid was prepared from compound 7 (39.8 mg, 0.08 mmol) by a similar method to Example 2.

[0112] LCMS: m / z 467.1 [M+H + ].

[0113] Example 9: Preparation of ethyl (S)-2-(tert-butoxy)-2-(4-(furan-2-yl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (Compound 9)

[0114] Using (1-methyl-1H-pyrazol-4-yl)methanamine hydrochloride and 3-(furan-2-yl)-3-oxopropanenitrile as starting materials, a reaction was performed in a similar manner to steps 1 to 4 of Example 1 to prepare compound 9 (9 mg, 0.019 mmol, yield: 27.4%) as a white solid.

[0115] LCMS: m / z 479.4 [M+H + ].

[0116] Example 10: Preparation of (S)-2-(tert-butoxy)-2-(4-(furan-2-yl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid (Compound 10)

[0117] Compound 10 (4.4 mg, 9.77 μmol, yield: 33.9%) as a white solid was prepared from compound 9 (13.8 mg, 0.029 mmol) by a reaction similar to Example 2.

[0118] LCMS: m / z 451.4 [M+H + ].

[0119] Example 11: Preparation of ethyl (2S)-2-(tert-butoxy)-2-(4-(5-chloro-3-methylpyridin-2-yl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (Compound 11)

[0120] Using (1-methyl-1H-pyrazol-4-yl)methanamine hydrochloride and 3-(5-chloro-3-methylpyridin-2-yl)-3-oxopropanenitrile as starting materials, a reaction was performed in a similar manner to steps 1 to 4 of Example 1 to prepare compound 11 (11.1 mg, 0.099 mmol, yield: 20.89%) as a white solid.

[0121] LCMS: m / z 538.1 [M+H + ].

[0122] Example 12: Preparation of (2S)-2-(tert-butoxy)-2-(4-(5-chloro-3-methylpyridin-2-yl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid (Compound 12)

[0123] Compound 12 (10.1 mg, 0.020 mmol, yield: 55.5%) as a white solid was prepared from compound 11 (19.2 mg, 0.036 mmol) by a similar method to Example 2.

[0124] LCMS: m / z 510.1 [M+H + ].

[0125] Example 13: Preparation of ethyl (S)-2-(tert-butoxy)-2-(4-(5-chloropyridin-2-yl)-1-(3,4-difluorobenzyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (Compound 13)

[0126] Using (3,4-difluorophenyl)methanamine and 3-(5-chloropyridin-2-yl)-3-oxopropanenitrile as starting materials, a reaction was performed in a similar manner to steps 1 to 4 of Example 1 to prepare compound 13 (131 mg, 0.236 mmol, yield: 62.7%) as a white solid.

[0127] LCMS: m / z 556.1 [M+H + ].

[0128] Example 14: Preparation of (S)-2-(tert-butoxy)-2-(4-(5-chloropyridin-2-yl)-1-(3,4-difluorobenzyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid (Compound 14)

[0129] Compound 14 (20.5 mg, 0.039 mmol, yield: 43.2%) as a white solid was prepared from compound 13 (50 mg, 0.09 mmol) by a similar method to Example 2.

[0130] LCMS: m / z 528.2 [M+H + ].

[0131] Example 15: Preparation of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (S)-2-(tert-butoxy)-2-(4-(5-chloropyridin-2-yl)-2,3,6-trimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (Compound 15)

[0132]

[0133] Compound 2 (7.6 mg, 0.015 mmol) was dissolved in N,N-dimethylformamide (51.1 μL), and 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (2.50 μL, 0.023 mmol) and cesium carbonate (14.98 mg, 0.046 mmol) were sequentially added dropwise. The reaction solution was reacted at room temperature overnight. After completion of the reaction, the reaction solution was diluted with water, and the aqueous layer was extracted three times with ethyl acetate and washed with a saturated aqueous ammonium chloride solution. The washed organic layer was dried over sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography to obtain compound 15 (2.7 mg, 4.44 μmol, yield: 29.0%) as a colorless oil.

[0134] LCMS: m / z 608.2 [M+H + ].

[0135] Experimental example

[0136] Experimental Example 1: HIV-1 (Wild Type) Inhibitory Effect and Cytotoxicity Test of the Compound of the Present Invention

[0137] To determine the inhibitory effect of the compound of the present invention on HIV-1 (Wild Type), the following experiment was conducted. MT-4 cells were used as host cells, and the NL4-3 strain of HIV-1 was used as the virus 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 compound cytotoxicity was assessed by XTT dye reduction. The results are shown in Table 1 below.

[0138]

[0139] While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the art that these specific descriptions are merely preferred embodiments and that the scope of the present invention is not limited by these embodiments. Therefore, the actual scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer, or prodrug thereof: Chemical Formula 1 Among the foods, R1 is hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Selected from the group consisting of alkyloxy, halo and cyano; R2 is hydrogen, C 1-20 Alkyl, C 1-6 Alkyl-O-(CH2) n -O-(CH2) n -, C 1-6 Alkyl-OC(O)O-(CH2) n -, substituted or unsubstituted C 3-7 Cycloalkyl-OC(O)O-(CH3)CH-, substituted or unsubstituted heterocyclyl-(CH2) n -, substituted or unsubstituted heteroaryl-(CH2) n -, and unsubstituted or C 1-6 Alkyl-substituted oxo-dioxolyl-(CH2) n - is selected from the group consisting of, wherein when the cycloalkyl, heterocyclyl and heteroaryl are substituted, they are each unsubstituted C 1-6 C substituted with alkyl, halo, amino or hydroxy 1-6 Alkyl, C 1-6 which may be substituted with one or more substituents selected from the group consisting of alkyloxy, cyano, carboxy, amino, nitro, azido, hydroxy, carbamoyl, thio and halo; R3 is C 1-6 Alkyl, C 1-6 Alkyloxy, and unsubstituted or substituted C 3-7 Selected from the group consisting of cycloalkyloxy, wherein said C 3-7 When cycloalkyloxy is substituted, the substituent is unsubstituted C 1-6 C substituted with alkyl, halo, amino or hydroxy 1-6 Alkyl, C 1-6 At least one selected from the group consisting of alkyloxy, cyano, carboxy, amino, nitro, azido, hydroxy, carbamoyl, thio and halo; R4 is substituted or unsubstituted heteroaryl, C 1-10 A substituted or unsubstituted heteroaryl fused with a cycloalkyl, or a substituted or unsubstituted heteroaryl fused with a heterocyclyl containing one or more heteroatoms in the ring, wherein when the heteroaryl is substituted, the substituent is a substituted or unsubstituted C 1-6 Alkyl, C 1-6 At least one selected from the group consisting of alkyloxy, cyano, carboxy, amino, nitro, azido, hydroxy, carbamoyl, thio and halo, and when said alkyl is substituted, the substituent is halo, amino, hydroxy and C 1-6 At least one selected from the group consisting of alkyloxy; R5 is hydrogen, C 3-7 Cycloalkyl or C 1-6 Alkyl, R6 is hydrogen, C 3-7 Cycloalkyl, C 1-6 Alkyl, (C 1-6 alkyl)-OC(O)-, (C 1-6 Alkyl)-C(O)- or R8-(CH2) n - or R5 and R6 are combined with each other to form C 3-7 It can be a cycloalkyl or a 4-7 membered heterocyclyl containing one or more heteroatoms in the ring; R7 is hydrogen, C 3-7 Cycloalkyl, (C 1-6 alkyl)-OC(O)-, (C 1-6 Alkyl)-C(O)- and R8-(CH2) n - is selected from the group consisting of; R8 is hydrogen, halo, hydroxy, amino, azido, cyano, C substituted with 1 to 3 halo 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 1-6 Alkyloxy, (C 1-3 alkyl)NHC(O)-, (C 1-3 alkyl)2NC(O)-, HOOC-, (C 1-6 alkyl)-S-, (C 1-6 alkyl)-S(O)2-, carbamoyl, substituted or unsubstituted C 3-7 Selected from the group consisting of cycloalkyl, substituted or unsubstituted 4-7 membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein when the cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted, they are each unsubstituted C 1-6 C substituted with alkyl, halo, amino or hydroxy 1-6 Alkyl, C 1-6 which may be substituted with one or more substituents selected from the group consisting of alkyloxy, cyano, carboxy, amino, nitro, azido, hydroxy, carbamoyl, thio and halo; n is an integer from 0 to 5.

2. In the first paragraph, R1 is hydrogen or C 1-6 An alkyl compound, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer or prodrug thereof.

3. In the first paragraph, R2 is hydrogen, C 1-20 Alkyl, and unsubstituted or C 1-6 Alkyl-substituted oxo-dioxolyl-(CH2) n A compound selected from the group consisting of -, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer or prodrug thereof.

4. In the first paragraph, R3 is C 1-6 Alkyl or C 1-6 An alkyloxy compound, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer or prodrug thereof.

5. In the first paragraph, R4 is unsubstituted or C 1-6 A compound which is a heteroaryl substituted with one or more substituents selected from the group consisting of alkyl and halo, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer or prodrug thereof.

6. In paragraph 1, R5 and R6 are each hydrogen or C 1-6 An alkyl compound, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer or prodrug thereof.

7. In the first paragraph, R7 is hydrogen or R8-(CH2) n - and R8 is hydrogen, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and when the aryl and heteroaryl are substituted, the substituents are each C 1-6 A compound comprising at least one selected from the group consisting of alkyl and halo, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer or prodrug thereof.

8. In the first paragraph, the C 6-10 Aryl is phenyl or naphthyl; and said heterocyclyl is selected from the group consisting of piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dioxanyl, tetrahydrofuranyl, and tetrahydropyranyl; The above heteroaryl is selected from the group consisting of quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolinyl, isoindolyl, indolizinyl, indazolinyl, azaindolyl, benzoimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzoxazinyl, benzothiazolyl, carbazolyl, pyrrolopyrrolyl, furopyrrolyl, thienopyrrolyl, azaindazolyl, pyrazolopyrimidinyl, purinyl, adeninyl, guaninyl, naphthapyridinyl, pyrrolopyrimidinyl, pyridopyrazinyl, pteridinyl, chromenyl, A compound, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer or prodrug thereof, wherein the heteroaryl fused with the heterocyclyl is selected from the group consisting of tetrahydrocyclopyrrolyl, dihydrofuropyridinyl, dihydrothienopyridinyl, dihydropyrrolopyridinyl, dihydroimidazopyridinyl and dihydrooxazolopyridinyl.

9. In paragraph 1, the compound of formula 1 is a compound selected from the group consisting of compounds having the following structure, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer or prodrug thereof:

10. A pharmaceutical composition for inhibiting, preventing or treating viral infection, comprising a compound of formula 1 according to paragraph 1, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer or prodrug thereof.

11. A pharmaceutical composition for inhibiting, preventing or treating a viral infection, wherein the virus in paragraph 10 is human immunodeficiency virus (HIV).

12. A method for inhibiting, preventing or treating a viral infection, comprising administering to a subject in need thereof a compound of formula 1 according to paragraph 1, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer or prodrug thereof.

13. A method for inhibiting, preventing or treating a viral infection in claim 12, wherein the virus is human immunodeficiency virus (HIV).

14. Use of a compound according to the chemical formula 1 in Article 1, or a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate, tautomer or prodrug thereof for inhibiting, preventing or treating viral infection.

15. In the 14th paragraph, the use for suppressing, preventing or treating viral infection, wherein the virus is human immunodeficiency virus (HIV).

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