KR20220083456A - Heteroaryl compound and use thereof - Google Patents

Abstract

The present invention relates to a heteroaryl compound or a pharmaceutically acceptable salt thereof, and a use thereof, wherein the compound of the present invention has high selectivity and low physiological activity against human immunodeficiency virus (HIV) and low toxicity, It is useful as a preventive or therapeutic agent for immunodeficiency virus (HIV) infection.

Description

Heteroaryl compounds and uses thereof

The present invention relates to heteroaryl compounds having antiviral activity, particularly compounds having high selectivity and physiological activity against human immunodeficiency virus (HIV), and uses thereof.

AIDS (Acquired Immuno Deficiency Syndrome; AIDS) is caused by infection with Human Immunodeficiency Virus (HIV). There are two forms of HIV, HIV-1 and HIV-2, and the most prevalent form worldwide is HIV-1. For the treatment of AIDS, enzyme inhibitors have been developed according to the mechanism of action of HIV, and these enzyme inhibitors are nucleic acid-based reverse transcriptase inhibitors (NRTI), protease inhibitors (PI), and fusion depending on the point of action. It is classified into an inhibitor (Fusion Inhibitor) and an integrase inhibitor (Integrase Inhibitor).

Integrase inhibitors are divided into catalytic site inhibitory action and non-catalytic site inhibitory action according to their mechanism of action. Studies on catalytic site integrase inhibitors have been actively conducted, and three drugs have been developed and sold on the market. Raltegravir, developed in 2008, is a representative drug. On the other hand, the non-catalytic site integrase inhibitory mechanism was introduced by Ziger Debyser et al. (Frauke Christ, Zeger Debyser at al., Nature Chemical Biology, 2010, Vol. 6, 442), and the development of inhibitors for this mechanism of action has been actively pursued.

In addition, various studies are being conducted to develop drugs to effectively treat viruses in which resistance is expressed. These chemotherapeutic agents are called Highly Active Anti-Retroviral Therapies (HAART), and 2-4 Concomitant administration of various drugs has shown a great effect of prolonging lifespan. However, despite these efforts, AIDS cannot be cured, and even the toxicity of drugs and the development of new therapeutic agents are continuously required due to the development of resistance to current therapeutic agents.

As an effort to solve these problems, as a result of repeated research for the development of a new AIDS therapeutic agent, it was discovered that a heteroaryl compound of a new skeleton has an effect of inhibiting the proliferation of HIV, and thus the present invention was completed.

WO 2009/062308 A1

Nature Chemical Biology, 2010, Vol. 6, 442

It is an object of the present invention to provide a heteroaryl compound or a pharmaceutically acceptable salt thereof that exhibits an effect of inhibiting proliferation of human immunodeficiency virus, particularly HIV-1.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating human immunodeficiency virus infection, comprising the heteroaryl compound.

As a result of research efforts by the present inventors to achieve the above object, the present invention was completed by confirming that the heteroaryl compound represented by the following Chemical Formula 1 exhibits an inhibitory effect on the proliferation of human immunodeficiency virus (HIV). Accordingly, technical means for solving the above-described problems in the present invention are as follows.

1. A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

Formula 1

In the formula,

X and Y each independently represent a carbon or nitrogen atom, at least one of which is a nitrogen atom, each of which may be substituted with C _1-6 alkyl, and when X is a carbon atom, it is bonded to an oxygen atom present outside the ring can form a carbonyl group,

는 X와 Y에 따라 단일 결합 또는 이중 결합으로 되고,

is a single bond or a double bond depending on X and Y,

R ₁ is substituted or unsubstituted C _1-6 alkyl, wherein when alkyl is substituted the substituent is selected from the group consisting of hydroxy, C _1-6 alkyloxy, aryl, heteroaryl and heterocyclyl, wherein aryl, hetero Aryl and heterocyclyl may each be further substituted with one or more substituents selected from the group consisting of halo, amino, hydroxy, cyano, C _1-6 alkyloxy and C _1-6 alkyl;

R ₂ is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and when they are substituted, the substituents are C _1-6 alkyl, halo, amino, cyano, hydroxy and one or more selected from the group consisting of aryl and wherein when two adjacent substituents are present on the aryl or heteroaryl, the two substituents may be joined together to form a cycloalkyl or heterocyclyl fused with an aryl or heteroaryl ring, wherein the cycloalkyl or heteroaryl formed therein Cyclyl may again be substituted with C _1-6 alkyl,

R ₃ may be a hydrogen atom, -(CH) _n R ₆ , -NR ₆ OR ₆ , -O(CH) _n OR ₆ or -OC(O)OR ₆ , where n is 0, or 1 to 3 of It is an integer, and R ₆ may be a hydrogen atom, C _1-6 alkyl, or heteroaryl or heterocyclyl substituted or unsubstituted with C _1-6 alkyl.

2. A pharmaceutical composition for preventing or treating viral infection, comprising the compound represented by Formula 1 of 1 above or a pharmaceutically acceptable salt thereof.

According to the present invention, there is provided a heteroaryl compound or a pharmaceutically acceptable salt thereof having high selectivity and physiological activity against viruses, particularly human immunodeficiency virus (HIV).

The compound of the present invention or a pharmaceutically acceptable salt thereof has high selectivity and physiological activity and low toxicity against viruses, particularly human immunodeficiency virus (HIV), and thus inhibits and prevents infection with viruses, particularly human immunodeficiency virus (HIV) Or it may be usefully used for treatment.

Definition of Terms

The terms used in this specification are briefly described.

The term “hydrate” means a compound of the invention or a salt thereof comprising a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

The term “solvate” means 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 administration to humans.

The term “prodrug” refers to a substance convertible into the compound of Formula 1 according to the present invention in vivo. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they may obtain physiological activity by oral administration whereas the parent drug may not. A prodrug may also have improved solubility in pharmaceutical formulations compared to the parent drug. For example, prodrugs are esters ("prodrugs") that facilitate passage through the cell membrane, where water solubility is detrimental to mobility, but once in cells where water solubility is beneficial, it is metabolized to the active carboxylic acid. drug") form. Another example of a prodrug may be a short peptide (polyamino acid) bound to an acid group where the peptide is metabolized to reveal the active site.

The term "stereoisomer" refers to isomers that have the same chemical formula or molecular formula but arise as a result of a different spatial arrangement of atoms in a molecule. , "diastereomer" means stereoisomers that are not in a mirror image relationship. All isomers and mixtures thereof, ie racemates, are also included within the scope of the present invention.

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

The term "aryl" is an aromatic ring group having 6 to 10 carbon atoms, and "heterocyclyl" is 3 having at least one hetero atom selected from nitrogen (N), oxygen (O) and sulfur (S) atoms in the ring. represents a 7-membered ring group, "heteroaryl" represents a 5-10 membered heteroaromatic ring group having at least one hetero atom selected from nitrogen (N), oxygen (O) and sulfur (S) atoms in the ring .

Hereinafter, the present invention will be described in detail.

A compound of Formula 1 or a pharmaceutically acceptable salt thereof

A first aspect of the present invention relates to a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

Formula 1

In the formula,

X and Y each independently represent a carbon or nitrogen atom, at least one of which is a nitrogen atom, each of which may be substituted with C _1-6 alkyl, and when X is a carbon atom, it is bonded to an oxygen atom present outside the ring can form a carbonyl group,

는 X와 Y에 따라 단일 결합 또는 이중 결합으로 되고,

is a single bond or a double bond depending on X and Y,

R ₁ is substituted or unsubstituted C _1-6 alkyl, wherein when alkyl is substituted the substituent is selected from the group consisting of hydroxy, C _1-6 alkyloxy, aryl, heteroaryl and heterocyclyl, wherein aryl, hetero Aryl and heterocyclyl may each be further substituted with one or more substituents selected from the group consisting of halo, amino, hydroxy, cyano, C _1-6 alkyloxy and C _1-6 alkyl;

R ₂ is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and when they are substituted, the substituents are C _1-6 alkyl, halo, amino, cyano, hydroxy and one or more selected from the group consisting of aryl and wherein when two adjacent substituents are present on the aryl or heteroaryl, the two substituents may be joined together to form a cycloalkyl or heterocyclyl fused with an aryl or heteroaryl ring, wherein the cycloalkyl or heteroaryl formed therein Cyclyl may again be substituted with C _1-6 alkyl,

R ₃ may be a hydrogen atom, -(CH) _n R ₆ , -NR ₆ OR ₆ , -O(CH) _n OR ₆ or -OC(O)OR ₆ , where n is 0, or 1 to 3 of It is an integer, and R ₆ may be a hydrogen atom, C _1-6 alkyl, or heteroaryl or heterocyclyl substituted or unsubstituted with C _1-6 alkyl.

In the present invention, the compound of Formula 1 may have a chemical structure represented by any one of Formulas 1-1 to 1-3:

Formula 1-1

Formula 1-2

Formula 1-3

는 R₄ 및 R₅에 따라 단일 결합 또는 이중 결합으로 된다.In Formulas 1-1 to 1-3, R ₁ , R ₂ and R ₃ are the same as defined for Formula 1, R ₄ is a hydrogen atom, C _1-6 alkyl, or an oxygen atom, R ₅ is a hydrogen atom or C _1-6 alkyl;

is a single bond or a double bond depending on R ₄ and R ₅ .

In one embodiment of the present invention, the aryl may be phenyl, biphenyl or naphthyl, wherein the heteroaryl is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, pyridinyl, pyrazinyl , pyrimidinyl and quinolinyl, wherein the heterocyclyl is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl and morphopoly. It may be selected from the group consisting of neil.

In one embodiment of the present invention, R ₁ is unsubstituted C _1-6 alkyl, or C _1-6 alkyl substituted with hydroxy, alkyloxy, oxetanyl, phenyl or pyrazolyl, and the oxeta Nyl, phenyl and pyrazolyl may each be further substituted with one or more substituents selected from the group consisting of halo and C _1-6 alkyl.

In one embodiment of the present invention, the substituent R ₁ in Formulas 1 and 1-1 to 1-3 may preferably be any one selected from those having the following structures:

In one embodiment of the present invention, R ₂ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo and C _1-6 alkyl, biphenyl, chromanyl, tetrahydronaphthylyl, dihydrobenzooxazinyl or dihydropyranoquinolinyl.

In one embodiment of the present invention, R ₂ may preferably be any one selected from those having the following structure:

In one embodiment of the present invention, R ₃ is a conventional protecting group for a carboxyl group well known in the art, or a group that can be hydrolyzed in vivo. Accordingly, compounds in which R ₃ is not a hydrogen atom in Formulas 1 and 1-1 to 1-3 may be prodrugs of compounds represented by Formulas 1 and 1-1 to 1-3.

In one embodiment of the present invention, when R ₃ is not hydrogen, that is, in the prodrugs of Formula 1 and Formulas 1-1 to 1-3, R ₃ may have the following structure:

In the present invention, specific examples of the compound represented by Formula 1 may be any one of compounds having the following chemical structure:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

및

.

and

.

The compound of Formula 1 of the present invention may be provided in the form of a salt, particularly a pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts are not particularly limited to those commonly used in the art, such as acid addition salts.

Preferred pharmaceutically acceptable acid addition salts include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, orthophosphoric acid or sulfuric acid; or 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.

In addition, a pharmaceutically acceptable metal salt can be obtained by a conventional method using a base. For example, a pharmaceutically acceptable metal salt can be obtained by dissolving the compound of Formula 1 in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. A salt or solvate of the compound of Formula 1 that is not pharmaceutically acceptable may be used as an intermediate in the preparation of the compound of Formula 1, a pharmaceutically acceptable salt or solvate thereof.

The compound of Formula 1 of the present invention includes all possible solvates and hydrates prepared therefrom as well as pharmaceutically acceptable salts thereof. Stereoisomers of the compound of Formula 1 and intermediates may be prepared using conventional methods.

In addition, the compound of Formula 1 according to the present invention may be prepared in a crystalline form or an amorphous form, and when the compound of Formula 1 is prepared in a crystalline form, it may optionally be hydrated or solvated.

Use of the compound of formula 1 or a pharmaceutically acceptable salt thereof

A second aspect of the present invention relates to a pharmaceutical composition for preventing or treating viral infection, comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof. Preferably, the virus is a retrovirus, more preferably a human immunodeficiency virus (HIV).

The compound of Formula 1 according to the present invention has low cytotoxicity, excellent antiviral effect, especially HIV suppression effect, high physiological activity, shows safe results in basic toxicity test, and excellent substance having solubility suitable for drug properties it has been confirmed that

The pharmaceutical composition of the present invention may be formulated in oral or injection dosage form. Formulations for oral administration include, for example, tablets and capsules, and these formulations include, in addition to the active ingredient, diluents (eg, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants ( Examples: silica, talc, stearic acid and its magnesium calcium salt or polyethylene glycol). Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose or polyvinylpicolidine, optionally starch, agar, alginic acid or its sodium salt It may contain disintegrants or effervescent mixtures and/or absorbents, colorants, flavoring agents and sweetening agents such as As an injectable formulation, an isotonic aqueous solution or suspension is preferred.

The compositions may be sterilized and/or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, salts and/or buffers for regulating osmotic pressure, and other therapeutically useful substances.

The formulation may be prepared by a conventional mixing, granulating or coating method, and may 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 may contain from about 10 to 200 mg of active ingredient.

The preferred dosage of the compound of the present invention varies depending on the condition and weight of the patient, the severity of the disease, the form of the drug, the route and duration of administration, but may be appropriately selected by those skilled in the art. Administration may be administered once a day or in divided doses via oral or parenteral routes.

The pharmaceutical composition of the present invention may be administered to mammals, including rats, mice, livestock, and humans, by various routes. Any mode of administration can be envisaged, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerbroventricular injection.

In addition, the present invention provides a method for preventing or treating a virus, particularly HIV, comprising administration of a therapeutically effective amount of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

The present invention also provides the use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of viruses, particularly HIV.

Matters mentioned in the uses, compositions, and treatment methods of the present invention are equally applicable as long as they do not contradict each other.

Example

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

Example 1: Methyl (S)-2-(t-butoxy)-2-(7-(4-chlorophenyl)-5-methyl-3-((1-methyl-1H-pyrazol-4-yl) )methyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)acetate

Step 1: Ethyl 4,6-dihydroxy-2-methyl-5-nitronicotinate (3 g, 12.39 mmol) was dissolved in POCl ₃ (11.55 mL, 124 mmol) and stirred at 105° C. for 20 hours. . After the reaction was completed, the reaction solution was slowly added dropwise to ice water and extracted with ethyl acetate. The organic layer was dehydrated over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 2.1 g of ethyl 4,6-dichloro-2-methyl-5-nitronicotinate as an off-white oil.

LC-MS (ESI, m/z) = 279.0 (M+H ⁺ )

Step 2: The compound obtained in step 1 (1.58 g, 5.66 mmol) and potassium carbonate (1.174 g, 8.49 mmol) were diluted in dimethylformamide (9.44 mL) (1-methyl-1H-pyrazole-4- Day) Methanamine hydrochloride (0.418 g, 2.83 mmol) was slowly added in portions, followed by stirring at room temperature 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 over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to give 799 mg of ethyl 4-chloro-2-methyl-6-(((1-methyl-1H-pyrazol-4-yl) as a pale yellow solid. methyl)amino)-5-nitronicotinate is obtained.

LC-MS (ESI, m/z) = 354.0 (M+H ⁺ )

Step 3: After dissolving the compound (2 g, 5.65 mmol) obtained in step 2 in tetrahydrofuran (18.85 mL), 1 M LAH in THF (16.96 mmol) was slowly added at -78°C and stirred for 30 minutes at room temperature. Stir for an additional 30 minutes. After the reaction was completed, the reaction solution was lowered to -78°C, distilled water was slowly added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dehydrated over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to give 1.53 g of (4-chloro-2-methyl-6-(((1-methyl-1H-pyrazol-4-yl) as a pale yellow solid) methyl)amino)-5-nitropyridin-3-yl)methanol was obtained.

LC-MS (ESI, m/z) = 312.0 (M+H ⁺ )

Step 4: After diluting the compound (1.53 g, 4.91 mmol) obtained in step 3 in methanol (16.36 mL), Platinum, 5% on activated carbon powder, sulfied, 0.5% S(as sulfide) (612 mg, 40 wt) %) and stirred at room temperature under hydrogen gas for 1 hour. After completion of the reaction, the reaction solution was filtered with celite, concentrated under reduced pressure, and separated by column chromatography to obtain 1.145 g of (5-amino-4-chloro-2-methyl-6-(((1-methyl-1H-pyra) as an off-white solid. Zol-4-yl)methyl)amino)pyridin-3-yl)methanol was obtained.

LC-MS (ESI, m/z) = 282.0 (M+H ⁺ )

Step 5: The compound (1.145 g, 4.06 mmol) obtained in step 4 was dissolved in 1 M aqueous hydrochloric acid solution (20.32 mL), and then sodium nitrite (0.477 g, 6.91 mmol) dissolved in distilled water (5.7 mL) was added at 0 °C. It was added slowly and stirred at room temperature for 1 hour. After the reaction was completed, the precipitated solid was filtered, washed with distilled water, and dried to obtain 1.085 g of (7-chloro-5-methyl-3-((1-methyl-1H-pyrazol-4-yl)methyl -3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)methanol was obtained.

LC-MS (ESI, m/z) = 293.0 (M+H ⁺ )

Step 6: The compound obtained in step 5 (1.045 g, 3.57 mmol) was dissolved in dichloromethane (16.3 mL), and then Dess-Martin periodinane (2.27 mg, 5.35 mmol) was added at 0° C. and stirred at room temperature for 1 hour. . After the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with distilled water and a saturated aqueous sodium hydrogen carbonate solution. The organic layer was dehydrated over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 751 mg of 7-chloro-5-methyl-3-((1-methyl-1H-pyrazol-4-yl)methyl)- as an off-white solid. 3H-[1,2,3]triazolo[4,5-b]pyridine-6-carbaldehyde was obtained.

LC-MS (ESI, m/z) = 291.0 (M+H ⁺ )

Step 7: The compound obtained in step 6 (751 mg, 2.58 mmol) and 2-(4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (678) mg, 2.84 mmol), tetrakis (triphenylphosphine) palladium (0) (149 mg, 0.129 mmol), potassium carbonate (892 mg, 6.45 mmol) in 1,4-dioxane: distilled water mixture (3:1, 8.61 mL) and stirred at 100° C. for 19 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with distilled water. The organic layer was dehydrated over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to give 192 mg of 7-(4-chlorophenyl)-5-methyl-3-((1-methyl-1H-pyrazole-4) as a pale yellow solid. -yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6-carbaldehyde and 200 mg of 7-(4'-chloro-[1,1'-biphenyl) ]-4-yl)-5-methyl-3-((1-methyl-1H-pyrazol-4-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridine -6-carbaldehyde was obtained.

LC-MS (ESI, m/z) = 367.0 (M+H ⁺ )

LC-MS (ESI, m/z) = 443.0 (M+H ⁺ )

Step 8: 7-(4-chlorophenyl)-5-methyl-3-((1-methyl-1H-pyrazol-4-yl)methyl)-3H-[1,2,3] obtained in step 7 Triazolo[4,5-b]pyridine-6-carbaldehyde (192 mg, 0.523 mmol) was dissolved in dichloromethane (3.27 mL) at 0 ° C. ZnI ₂ (251 mg, 0.785 mmol) and TMS-CN ( 281 μL, 2.09 mmol) was added and stirred at room temperature for 3 hours. After the reaction was completed, ice water was added dropwise to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow oil of 220 mg of 2-(7-(4-chlorophenyl)-5-methyl-3-((1-methyl-1H-pyrazol-4-yl)methyl )-3H-[1,2,3]triazolo[4,5-b]pyridin-6yl)-2-((trimethylsilyl)oxy)acetonitrile was obtained.

LC-MS (ESI, m/z) = 466.1 (M+H ⁺ )

Step 9: After dissolving the compound (220 mg, 0.472 mmol) obtained in step 8 in methanol (3.93 mL), sulfuric acid (956 μL, 17.94 mmol) was slowly added at 0° C., the temperature was rapidly raised, and the mixture was stirred at 85° C. for 8 hours. did After completion of the reaction, the reaction was concentrated under reduced pressure, the solvent was removed, diluted in distilled water, and the pH was adjusted to 6 using a 2N aqueous NaOH solution at 0° C., followed by extraction with ethyl acetate. The organic layer was dehydrated over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 150 mg of methyl 2-(7-(4-chlorophenyl)-5-methyl-3-((1-methyl-1H-pyra) as an off-white solid. Zol-4-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)2-hydroxyacetate was obtained.

LC-MS (ESI, m/z) = 427.0 (M+H ⁺ )

Step 10: The compound obtained in step 9 (150 mg, 0.351 mmol) was reacted in a similar manner to step 6 to give 125 mg of methyl 2-(7-(4-chlorophenyl)-5-methyl-3 as a pale yellow solid -((1-methyl-1H-pyrazol-4-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)2-oxoacetate was obtained .

LC-MS (ESI, m/z) = 425.0 (M+H ⁺ )

Step 11: The compound obtained in step 10 (125 mg, 0.294 mmol) and triethylamine (82 μL, 0.59 mmol) were dissolved in acetonitrile (0.8 mL), and then formic acid (33.9 μL, 0.88 mmol) was added at 0° C. and stirred at the same temperature for 10 minutes (Mixture A). Pentamethylcyclopentadienyrhodium (III) chloride dimer (8.73 mg, 0.014 mmol) and (S,S)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide (12.83 mg, 0.035 mmol) and triethylamine (20.5 μL, 0.15 mmol) were dissolved in acetonitrile (0.4 mL) and stirred at 0° C. for 30 minutes (Mixture B). The mixed solution B is slowly added dropwise to the mixed solution A at 0°C, maintained at 5°C or lower, and stirred for 3 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with distilled water. The organic layer was dehydrated over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 121.5 mg of methyl (S)-2-(7-(4-chlorophenyl)-5-methyl-3-((1-) as a pale yellow solid. Methyl-1H-pyrazol-4-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-2-hydroxyacetate was obtained.

LC-MS (ESI, m/z) = 427.0 (M+H ⁺ )

Step 12: The compound obtained in step 11 (121 mg, 0.283 mmol) and tert-butyl acetate (4.02 mL, 29.8 mmol) were dissolved in a dichloromethane:tetrahydrofuran mixture (1:1, 566 μL), and then 0° C. After slowly dropwise addition of perchloric acid (97 μL, 1.134 mmol), the temperature was raised, and the mixture was stirred at room temperature for 1 hour and at 45° C. for 3 hours. After the reaction was completed, saturated aqueous sodium sulfite solution was added to the reaction solution to adjust the pH to 6, followed by extraction with ethyl acetate. The organic layer was dehydrated over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 39.5 mg of methyl (S)-2-(t-butoxy)-2-(7-(4-chlorophenyl)-5 as a pale yellow solid. -Methyl-3-((1-methyl-1H-pyrazol-4-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)acetate was obtained. did

LC-MS (ESI, m/z) = 483.0 (M+H ⁺ )

Example 2: (S)-2-(t-butoxy)-2-(7-(4-chlorophenyl)-5-methyl-3-((1-methyl-1H-pyrazol-4-yl) methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)acetic acid

The compound of Example 1 (39.5 mg, 0.082 mmol) was dissolved in a tetrohydrofuran:methanol mixture (2:1, 273 μL), sodium hydroxide (9.81 mg, 0.245 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. . After completion of the reaction, the mixture was concentrated under reduced pressure, the solvent was removed, diluted in distilled water, and the pH was adjusted to 6 using a 1 M aqueous hydrochloric acid solution at 0°C. The precipitated solid was filtered, washed with water and hexane, and dried to obtain 24.6 mg of the title compound as a pale yellow solid.

LC-MS (ESI, m/z) = 469.1 (M+H ⁺ )

Example 3: (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (S)-2-(t-butoxy)-2-(7-(4-chlorophenyl)- 5-methyl-3-((1-methyl-1H-pyrazol-4-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)acetate

The compound of Example 2 (7.6 mg, 0.016 mmol) with cesium carbonate (15.84 mg, 0.049 mmol), 4-(chloromethyl)-3-methyl-1,3-dioxol-2-one (3.84 mg, 0.024 mmol) ) was diluted in dimethylformamide (54 μL) and stirred at room temperature for 20 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with distilled water. The organic layer was dehydrated over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 3.7 mg of the title compound as a pale yellow solid.

LC-MS (ESI, m/z) = 581.0 (M+H ⁺ )

Example 4: (S)-2-(t-butoxy)-2-(7-(4'-chloro-[1,1'-biphenyl]-4-yl)-5-methyl-3-( (1-methyl-1H-pyrazol-4-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)acetate

Step 1: 7-(4'-chloro-[1,1'-biphenyl]-4-yl)-5-methyl-3-((1-methyl-1H-pyra) obtained in step 7 of Example 1 Zol-4-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6-carbaldehyde (423 mg, 0.955 mmol) was prepared in a similar manner to step 8 of Example 1 502 mg of 2-(7-(4'-chloro-[1,1'-biphenyl]-4-yl)-5-methyl-3-((1-methyl-1H- Pyrazol-4-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-2-((trimethylsilyl)oxy)acetonitrile was obtained.

LC-MS (ESI, m/z) = 542.2 (M+H ⁺ )

Step 2: The compound obtained in Step 1 (521 mg, 0.961 mmol) was reacted in a similar manner to Step 9 of Example 1 to give 40 mg of methyl 2-(7-(4'-chloro-[1, 1'-biphenyl]-4-yl)-5-methyl-3-((1-methyl-1H-pyrazol-4-yl)methyl)-3H-[1,2,3]triazolo[4, 5-b]pyridin-6-yl)-2-hydroxyacetate was obtained.

LC-MS (ESI, m/z) = 503.0 (M+H ⁺ )

Step 3: The compound obtained in step 2 (200 mg, 0.398 mmol) was reacted in a similar manner to step 10 of Example 1 to give 183 mg of methyl 2-(7-(4'-chloro-[1) ,1'-biphenyl]-4-yl)-5-methyl-3-((1-methyl-1H-pyrazol-4-yl)methyl)-3H-[1,2,3]triazolo[4 ,5-b]pyridin-6-yl)-2-oxoacetate was obtained.

LC-MS (ESI, m/z) = 501.1 (M+H ⁺ )

Step 4: The compound obtained in step 3 (180 mg, 0.359 mmol) was reacted in a similar manner to step 11 of Example 1 to give 145 mg of methyl (S)-2-(7-(4'-) as a pale yellow solid. Chloro-[1,1'-biphenyl]-4-yl)-5-methyl-3-((1-methyl-1H-pyrazol-4-yl)methyl)-3H-[1,2,3] Triazolo[4,5-b]pyridin-6-yl)-2-hydroxyacetate was obtained.

LC-MS (ESI, m/z) = 503.1 (M+H ⁺ )

Step 5: The compound obtained in step 4 (145 mg, 0.288 mmol) was reacted in a similar manner to step 12 of Example 1 to give 161 mg of methyl (S)-2-(t-butoxy)- 2-(7-(4'-Chloro-[1,1'-biphenyl]-4-yl)-5-methyl-3-((1-methyl-1H-pyrazol-4-yl)methyl)- 3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)acetate was obtained.

LC-MS (ESI, m/z) = 559.1 (M+H ⁺ )

Example 5: (S)-2-(t-butoxy)-2-(7-(4'-chloro-[1,1'-biphenyl]-4-yl)-5-methyl-3-( (1-methyl-1H-pyrazol-4-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)acetic acid

The compound of Example 4 (40 mg, 0.072 mmol) was reacted in a similar manner to Example 2 to give 39 mg of the title compound as a pale yellow solid.

LC-MS (ESI, m/z) = 545.2 (M+H ⁺ )

Example 6: Methyl (S)-2-(t-butoxy)-2-(7-(4-chlorophenyl)-2,5-dimethyl-3-((1-methyl-1H-pyrazole-4) -yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)acetate

Step 1: The compound (357 mg, 1.01 mmol) obtained in Step 2 of Example 1 was reacted in a similar manner to Step 4 of Example 1 to give 318 mg of ethyl 5-amino-4-chloro-2 as a pale yellow oil -Methyl-6-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)nicotinate was obtained.

LC-MS (ESI, m/z) = 324.0 (M+H ⁺ )

Step 2: Triethyl orthoacetate (839 μl, 4.60 mmol) and acetic acid (3.1 mL) were added to the compound (298 mg, 0.92 mmol) obtained in step 1, followed by stirring at 120° C. for 30 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure and diluted with ethyl acetate and an aqueous sodium hydrogen carbonate solution. The organic layer was dehydrated over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to give 231 mg of ethyl 7-chloro-2,5-dimethyl-3-((1-methyl-1H-pyrazol-4-yl)methyl)- 3H-imidazo[4,5-b]pyridine-6-carboxylate was obtained.

LC-MS (ESI, m/z) = 348.0 (M+H ⁺ )

Step 3: The compound obtained in step 2 (211 mg, 0.607 mmol) was reacted in a similar manner to step 3 of Example 1 to give 137 mg of (7-chloro-2,5-dimethyl-3-(( 1-methyl-1H-pyrazol-4-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)methanol was obtained.

LC-MS (ESI, m/z) = 306.0 (M+H ⁺ )

Step 4: The compound obtained in step 3 (137 mg, 0.448 mmol) was reacted in a similar manner to step 6 of Example 1 to give 126 mg of 7-chloro-2,5-dimethyl-3-((1) -Methyl-1H-pyrazol-4-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carbaldehyde was obtained.

LC-MS (ESI, m/z) = 304.0 (M+H ⁺ )

Step 5: The compound obtained in step 4 (104 mg, 0.342 mmol) was reacted in a similar manner to step 7 of Example 1 to form a yellow solid 110 mg of 7-(4-chlorophenyl)-2,5-dimethyl- Obtained 3-((1-methyl-1H-pyrazol-4-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carbaldehyde.

LC-MS (ESI, m/z) = 380.1 (M+H ⁺ )

Step 6: The compound obtained in step 5 (101 mg, 0.266 mmol) was reacted in a similar manner to step 8 of Example 1 to give 170 mg of 2-(7-(4-chlorophenyl)-2,5 as a yellow oil -dimethyl-3-((1-methyl-1H-pyrazol-4-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2-((trimethylsilyl)oxy) Acetonitrile was obtained.

LC-MS (ESI, m/z) = 479.1 (M+H ⁺ )

Step 7: The compound obtained in step 6 (127 mg, 0.0.265 mmol) was reacted in a similar manner to step 9 of Example 1 to give 42 mg of methyl 2-(7-(4-chlorophenyl) as a pale yellow oil -2,5-dimethyl-3-((1-methyl-1H-pyrazol-4-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2-hydroxyacetate was obtained.

LC-MS (ESI, m/z) = 440.1 (M+H ⁺ )

Step 8: The compound obtained in step 7 (50 mg, 0.114 mmol) was reacted in a similar manner to step 10 of Example 1 to give 42 mg of methyl 2-(7-(4-chlorophenyl)-2 as a pale yellow solid Obtained ,5-dimethyl-3-((1-methyl-1H-pyrazol-4-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2-oxoacetate .

LC-MS (ESI, m/z) = 438.0 (M+H ⁺ )

Step 9: The compound obtained in step 8 (42 mg, 0.096 mmol) was reacted in a similar manner to step 11 of Example 1 to give 35 mg of methyl (S)-2-(7-(4-chloro) as a pale yellow solid. Phenyl)-2,5-dimethyl-3-((1-methyl-1H-pyrazol-4-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2-hydro Roxy acetate was obtained.

LC-MS (ESI, m/z) = 440.0 (M+H ⁺ )

Step 10: The compound (35 mg, 0.08 mmol) obtained in step 9 was reacted in a similar manner to step 12 of Example 1 to give a pale yellow oil in 10 mg of methyl (S)-2-(t-butoxy)- 2-(7-(4-chlorophenyl)-2,5-dimethyl-3-((1-methyl-1H-pyrazol-4-yl)methyl)-3H-imidazo[4,5-b]pyridine -6-yl) acetate was obtained.

LC-MS (ESI, m/z) = 496.1 (M+H ⁺ )

Example 7: (S)-2-(t-butoxy)-2-(7-(4-chlorophenyl)-2,5-dimethyl-3-((1-methyl-1H-pyrazole-4- yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)acetic acid

The compound of Example 6 (10 mg, 0.02 mmol) was reacted in a similar manner to Example 2 to obtain 3.1 mg of the title compound as an off-white solid.

LC-MS (ESI, m/z) = 482.1 (M+H ⁺ )

Example 8: (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (S)-2-(t-butoxy)-2-(-(4-chlorophenyl)-2 ,5-Dimethyl-3-((1-methyl-1H-pyrazol-4-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)acetate

The compound of Example 7 (10 mg, 0.02 mmol) was reacted in a similar manner to Example 3 to obtain 2.2 mg of the title compound as an off-white solid.

LC-MS (ESI, m/z) = 594.0 (M+H ⁺ )

Example 9: Methyl (S)-2-(t-butoxy)-2-(7-(4-chlorophenyl)-1,5-dimethyl-3-((1-methyl-1H-pyrazole-4) -yl)methyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)acetate

Step 1: The compound obtained in step 1 of Example 6 (1.73 g, 5.33 mmol) and triethylamine (2.23 mL, 15.99 mmol) were dissolved in dichloromethane (29.6 mL), and then triphosgene (1.04) was dissolved at 0° C. g, 3.52 mmol) was slowly added in portions, stirred at the same temperature for 30 minutes, then heated to room temperature and further stirred for 30 minutes. After the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with a concentrated aqueous sodium hydrogen carbonate solution. The organic layer was dehydrated over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 1.8 g of ethyl 7-chloro-5-methyl-3-((1-methyl-1H-pyrazol-4-yl)methyl) as an off-white solid. Obtained -2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carboxylate.

LC-MS (ESI, m/z) = 350.0 (M+H ⁺ )

Step 2: The compound obtained in Step 1 (1.80 g, 5.14 mmol) was reacted in a similar manner to Step 3 of Example 1 to give 1.37 g of 7-chloro-6-(hydroxymethyl)-5-methyl as an off-white solid. Obtained -3-((1-methyl-1H-pyrazol-4-yl)methyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one.

LC-MS (ESI, m/z) = 308.0 (M+H ⁺ )

Step 3: The compound obtained in step 2 (1.37 g, 4.45 mmol) and imidazole (0.91 g, 13.36 mmol) were dissolved in dimethylformamide (14.84 mL) at 0 ° C. TBDMS-Cl (1.01 g, 6.68 mmol) ) was slowly added in portions and stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with distilled water. The organic layer was dehydrated over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 1.67 g of 6-(((tert-butyldimethylsilyl)oxy)methyl)-7-chloro-5-methyl-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-chloro-5-methyl-3-(( Obtained 1-methyl-1H-pyrazol-4-yl)methyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one.

LC-MS (ESI, m/z) = 422.1 (M+H ⁺ )

Step 4: After dissolving 60% sodium hydride (317 mg, 13.22 mmol) washed with tetrahydrofuran in dimethylformamide (5 mL), the compound obtained in step 3 (1.67 g, 4.41 mmol) at 0° C. It was diluted in dimethylformamide (10 mL) and slowly added dropwise, followed by stirring at the same temperature for 30 minutes. To the stirred reaction solution, iodomethane (0.413 mL, 6.61 mmol) was slowly added in portions at 0° C., followed by stirring at room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched with water and extracted with ethyl acetate. The organic layer was dehydrated over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to give 1.67 g of 6-(((tert-butyldimethylsilyl)oxy)methyl)-7-chloro-1,5-dimethyl-3- ((1-methyl-1H-pyrazol-4-yl)methyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one is obtained.

LC-MS (ESI, m/z) = 436.1 (M+H ⁺ )

Step 5: After dissolving the compound obtained in step 4 (1.63 g, 4.14 mmol) in tetrahydrofuran (20.72 mL), 1 M TBAF in THF (4.97 mL, 4.97 mmol) was slowly divided at -5°C under nitrogen. did After the reaction was completed, the reaction solution was quenched with water and extracted with ethyl acetate. The organic layer was dehydrated over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 1.03 g of 7-chloro-6-(hydroxymethyl)-1,5-dimethyl-3-((1-methyl-1H-) as an off-white solid. Pyrazol-4-yl)methyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one was obtained.

LC-MS (ESI, m/z) = 322.0 (M+H ⁺ )

Step 6: The compound obtained in step 5 (1.03 g, 3.20 mmol) was reacted in a similar manner to step 6 of Example 1 to give 979.6 mg of 7-chloro-1,5-dimethyl-3-((1) -Methyl-1H-pyrazol-4-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbaldehyde was obtained.

LC-MS (ESI, m/z) = 320.0 (M+H ⁺ )

Step 7: The compound obtained in step 6 (966 mg, 3.02 mmol) was reacted in a similar manner to step 7 of Example 1 to form a pale yellow solid in 753 mg of 7-(4-chlorophenyl)-1,5-dimethyl -3-((1-methyl-1H-pyrazol-4-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbaldehyde is obtained did

LC-MS (ESI, m/z) = 396.0 (M+H ⁺ )

Step 8: The compound (753 mg, 1.90 mmol) obtained in step 7 was always reacted in a similar manner to step 8 of Example 1 to give 942 mg of 2-(7-(4-chlorophenyl)-1 as a pale yellow oil ,5-Dimethyl-3-((1-methyl-1H-pyrazol-4-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6 -yl)2-((trimethylsilyl)oxy)acetonitrile was obtained.

LC-MS (ESI, m/z) = 495.1 (M+H ⁺ )

Step 9: The compound (942 mg, 1.90 mmol) obtained in step 8 was reacted in a similar manner to step 9 of Example 1 to give 613 mg of methyl 2-(7-(4-chlorophenyl)-1, 5-Dimethyl-3-((1-methyl-1H-pyrazol-4-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6- yl)-2-hydroxyacetate was obtained.

LC-MS (ESI, m/z) = 456.0 (M+H ⁺ )

Step 10: The compound obtained in step 9 (613 mg, 1.35 mmol) was reacted in a similar manner to step 10 of Example 1 to form a pale yellow solid, 564.3 mg of methyl 2-(7-(4-chlorophenyl)-1 ,5-Dimethyl-3-((1-methyl-1H-pyrazol-4-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6 -yl)-2-oxoacetate was obtained.

LC-MS (ESI, m/z) = 454.0 (M+H ⁺ )

Step 11: The compound obtained in step 10 (564 mg, 1.24 mmol) was reacted in a similar manner to step 11 of Example 1 to give 551 mg of methyl (S)-2-(7-(4-chloro) as a pale yellow solid. Phenyl)-1,5-dimethyl-3-((1-methyl-1H-pyrazol-4-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b ]Pyridin-6-yl)-2-hydroxyacetate was obtained.

LC-MS (ESI, m/z) = 456.0 (M+H ⁺ )

Step 12: The compound (551 mg, 4.23 mmol) obtained in Step 11 was reacted in a similar manner to Step 12 of Example 1 to give 124 mg of methyl (S)-2-(t-butoxy)- 2-(7-(4-chlorophenyl)-1,5-dimethyl-3-((1-methyl-1H-pyrazol-4-yl)methyl)-2-oxo-2,3-dihydro-1H -imidazo [4,5-b] pyridin-6-yl) acetate was obtained.

LC-MS (ESI, m/z) = 512.2 (M+H ⁺ )

Example 10: (S)-2-(t-butoxy)-2-(7-(4-chlorophenyl)-1,5-dimethyl-3-((1-methyl-1H-pyrazole-4- yl)methyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)acetic acid

The compound of Example 9 (70 mg, 0.14 mmol) was reacted in a similar manner to Example 2 to obtain 44.4 mg of the title compound as an off-white solid.

LC-MS (ESI, m/z) = 498.0 (M+H ⁺ )

Example 11: (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (S)-2-(t-butoxy)-2-(7-(4-chlorophenyl)- 1,5-Dimethyl-3-((1-methyl-1H-pyrazol-4-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine- 6-day) acetate

The compound of Example 10 (25 mg, 0.05 mmol) was reacted in a similar manner to Example 3 to obtain 23.6 mg of the title compound as an off-white solid.

LC-MS (ESI, m/z) = 610.0 (M+H ⁺ )

Example 12: Methyl (S)-2-(t-butoxy)-2-(4-(4-chlorophenyl)-3,6-dimethyl-1-((1-methyl-1H-pyrazole-4) -yl)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)acetate

Step 1: Perform 4-iodo-1-(4-methoxybenzyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (2 g, 4.75 mmol) 1.38 g of 4-(4-chlorophenyl)-1-(4-methoxybenzyl)-3,6-dimethyl-1H-pyrazolo[3, 4-b]pyridine-5-carbaldehyde was obtained.

LC-MS (ESI, m/z) = 406.1 (M+H ⁺ )

Step 2: The compound obtained in step 1 (1.22 g. 3.00 mmol) was reacted in a similar manner to step 8 of Example 1 to give 1.52 g of 2-(4-(4-chlorophenyl)-1 as a pale yellow oil. -(4-methoxybenzyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-2-((trimethylsilyl)oxo)acetonitrile was obtained.

LC-MS (ESI, m/z) = 505.1 (M+H ⁺ )

Step 3: The compound obtained in step 2 (1.52 g, 3.00 mmol) was dissolved in 35% hydrochloric acid and stirred at 100° C. for 18 hours. After the reaction was completed, the reaction solution was concentrated to form a light brown solid in 955 mg of 2-(4-(4-chlorophenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-5- yl)-2-hydroxyacetic acid was obtained.

LC-MS (ESI, m/z) = 332.0 (M+H ⁺ )

Step 4: After dissolving the compound (955 mg, 3.00 mmol) obtained in step 3 in methanol (7.9 mL), sulfuric acid (2.08 mL, 39.00 mmol) was slowly added at 0°C, the temperature was rapidly raised, and the mixture was stirred at 65°C for 3 hours. did After completion of the reaction, the mixture was concentrated under reduced pressure, the solvent was removed, and the mixture was diluted with distilled water, adjusted to pH 6 at 0° C. using 2N NaOH aqueous solution, and extracted with ethyl acetate. The organic layer was dehydrated over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 713.1 mg of methyl 2-(4-(4-chlorophenyl)-3,6-dimethyl-1H-pyrazolo[3,4] as a light brown solid. -b]pyridin-5-yl)-2-hydroxyacetate was obtained.

LC-MS (ESI, m/z) = 346.0 (M+H ⁺ )

Step 5: The compound (713 mg, 2.06 mmol) obtained in step 4 was reacted in a similar manner to step 10 of Example 1 to give 564 mg of methyl 2-(4-(4-chlorophenyl)-3 as a pale yellow solid ,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-2-oxoacetate was obtained.

LC-MS (ESI, m/z) = 344.0 (M+H ⁺ )

Step 6: The compound obtained in step 5 (529 mg, 1.54 mmol) and cesium carbonate (1.50 g, 4.62 mmol) were dissolved in dimethylformamide (3.08 mL) and then 4-(chloromethyl)-1- Methyl-1H-pyrazole hydrochloride (386 mg, 2.31 mmol) was slowly added in portions and stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with distilled water. The organic layer was dehydrated over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 296 mg of methyl 2-(4-(4-chlorophenyl)-3,6-dimethyl-1-((1-methyl-) as a pale yellow oil. 1H-pyrazol-4-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-2-oxoacetate was obtained.

LC-MS (ESI, m/z) = 438.0 (M+H ⁺ )

Step 7: The compound (291 mg, 0.67 mmol) obtained in step 6 was reacted in a similar manner to step 11 of Example 1 to give 292 mg of methyl (S)-2-(4-(4-chloro) as a pale yellow solid. Phenyl)-3,6-dimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-2-hydro Roxy acetate was obtained.

LC-MS (ESI, m/z) = 440.0 (M+H ⁺ )

Step 8: The compound (292 mg, 0.67 mmol) obtained in step 7 was reacted in a similar manner to step 12 of Example 1 to give 143 mg of methyl (S)-2-(t-butoxy)- 2-(4-(4-chlorophenyl)-3,6-dimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[3,4-b]pyridine -5-yl) acetate was obtained.

LC-MS (ESI, m/z) = 496.1 (M+H ⁺ )

Example 13: (S)-2-(t-butoxy)-2-(4-(4-chlorophenyl)-3,6-dimethyl-1-((1-methyl-1H-pyrazole-4- yl)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)acetic acid

The compound of Example 12 (143 mg, 0.29 mmol) was reacted in a similar manner to Example 2 to obtain 92.5 mg of the title compound as an off-white solid.

LC-MS (ESI, m/z) = 482.1 (M+H ⁺ )

Example 14: (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (S)-2-(t-butoxy)-2-(4-(4-chlorophenyl)- 3,6-dimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)acetate

The compound of Example 13 (25 mg, 0.05 mmol) was reacted in a similar manner to Example 3 to obtain 12.6 mg of the title compound as an off-white solid.

LC-MS (ESI, m/z) = 594.0 (M+H ⁺ )

Experimental example

Experimental Example 1: HIV-1 (Wild type) inhibitory effect investigation and cytotoxicity test

In order to examine the HIV-1 (Wild type) inhibitory effect of the Example compound, the test was carried out as follows.

MT-4 cells were used as host cells, and NL4-3 strain of HIV-1 was used as the virus strain. Viruses and cells were mixed in the presence of a compound of the present invention and cultured for 6 days. Antiviral effect was measured as a percentage reduction in viral cytopathic effect (CPE), and compound cytotoxicity was assessed by MTS (CellTiter® 96 Reagent, Promega, Madison WI) dye reduction.

As the specific part of the present invention has been described in detail above, for those of ordinary skill in the art, it is clear that this specific description is only a preferred embodiment, and the scope of the present invention is not limited thereby. something to do. Accordingly, it is intended that the substantial scope of the present invention be defined by the appended claims and their equivalents.

Claims (8)

A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
Formula 1

In the formula,
X and Y each independently represent a carbon or nitrogen atom, at least one of which is a nitrogen atom, each of which may be substituted with C _1-6 alkyl, and when X is a carbon atom, it is bonded to an oxygen atom present outside the ring can form a carbonyl group,

is a single bond or a double bond depending on X and Y,
R ₁ is substituted or unsubstituted C _1-6 alkyl, wherein when alkyl is substituted the substituent is selected from the group consisting of hydroxy, C _1-6 alkyloxy, aryl, heteroaryl and heterocyclyl, wherein aryl, hetero Aryl and heterocyclyl may each be further substituted with one or more substituents selected from the group consisting of halo, amino, hydroxy, cyano, C _1-6 alkyloxy and C _1-6 alkyl;
R ₂ is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and when they are substituted, the substituents are C _1-6 alkyl, halo, amino, cyano, hydroxy and one or more selected from the group consisting of aryl and wherein when two adjacent substituents are present on the aryl or heteroaryl, the two substituents may be joined together to form a cycloalkyl or heterocyclyl fused with an aryl or heteroaryl ring, wherein the cycloalkyl or heteroaryl formed therein Cyclyl may again be substituted with C _1-6 alkyl,
R ₃ may be a hydrogen atom, -(CH) _n R ₆ , -NR ₆ OR ₆ , -O(CH) _n OR ₆ or -OC(O)OR ₆ , where n is 0, or 1 to 3 of It is an integer, and R ₆ may be a hydrogen atom, C _1-6 alkyl, or heteroaryl or heterocyclyl substituted or unsubstituted with C _1-6 alkyl. According to claim 1, wherein the compound represented by any one of Formulas 1-1 to 1-3, or a pharmaceutically acceptable salt thereof:
Formula 1-1

Formula 1-2

Formula 1-3

In the formula,
R ₁ is substituted or unsubstituted C _1-6 alkyl, wherein when alkyl is substituted the substituent is selected from the group consisting of hydroxy, C _1-6 alkyloxy, aryl, heteroaryl and heterocyclyl, wherein aryl, hetero Aryl and heterocyclyl may each be further substituted with one or more substituents selected from the group consisting of halo, amino, hydroxy, cyano, C _1-6 alkyloxy and C _1-6 alkyl;
R ₂ is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and when they are substituted, the substituents are C _1-6 alkyl, halo, amino, cyano, hydroxy and one or more selected from the group consisting of aryl and wherein when two adjacent substituents are present on the aryl or heteroaryl, the two substituents may be joined together to form a cycloalkyl or heterocyclyl fused with an aryl or heteroaryl ring, wherein the cycloalkyl or heteroaryl formed therein Cyclyl may again be substituted with C _1-6 alkyl,
R ₃ may be a hydrogen atom, -(CH) _n R ₆ , -NR ₆ OR ₆ , -O(CH) _n OR ₆ or -OC(O)OR ₆ , where n is 0, or 1 to 3 of is an integer, and R ₆ may be a hydrogen atom, C _1-6 alkyl, or heteroaryl or heterocyclyl substituted or unsubstituted with C _1-6 alkyl,
R ₄ is a hydrogen atom, C _1-6 alkyl or an oxygen atom,
R ₅ is a hydrogen atom or C _1-6 alkyl,

is a single bond or a double bond depending on R ₄ and R ₅ . According to claim 1, wherein the aryl can be phenyl, biphenyl or naphthyl, the heteroaryl is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, pyridinyl, pyrazinyl, pyrimidi is selected from the group consisting of nyl and quinolinyl, wherein said heterocyclyl is selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl A compound selected from or a pharmaceutically acceptable salt thereof. According to claim 1, wherein R ₁ is unsubstituted C _1-6 alkyl, or C _1-6 alkyl substituted with hydroxy, alkyloxy, oxetanyl, phenyl or pyrazolyl, the oxetanyl, phenyl and Pyrazolyl is a compound or a pharmaceutically acceptable salt thereof, each of which may be further substituted with one or more substituents selected from the group consisting of halo and C _1-6 alkyl. The method of claim 1, wherein R ₂ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo and C _1-6 alkyl, phenyl, biphenyl, chromanyl, tetrahydronaphthylyl, dihydrobenzo A compound which is oxazinyl or dihydropyranoquinolinyl, or a pharmaceutically acceptable salt thereof. According to claim 1, wherein the compound having the following chemical structure, or a pharmaceutically acceptable salt thereof:

,

,

,

,

,

,

,

,

,

,

,

,

and

. A pharmaceutical composition for preventing or treating viral infection, comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof. The pharmaceutical composition for preventing or treating viral infection according to claim 7, wherein the virus is human immunodeficiency virus.