KR20240018000A - Novel purine derivative compounds as A3 adenosine receptor agonists - Google Patents

Abstract

The present invention provides novel purine derivative compounds, hydrates thereof, solvates thereof, or pharmaceutically acceptable salts thereof as A ₃ adenosine receptor agonists. It was confirmed that the novel purine derivative compound of the present invention exhibits excellent activity as an A ₃ adenosine receptor agonist and at the same time exhibits an effect in treating pulmonary fibrosis. Accordingly, the A ₃ adenosine receptor agonist can be used for the prevention or treatment of pulmonary fibrosis. It turned out that it can be done.
Therefore, the novel purine derivative compounds of the present invention can be usefully used in the prevention or treatment of A ₃ adenosine receptor-related diseases, and the A ₃ adenosine receptor agonists, including the novel purine derivative compounds of the present invention, can be used to prevent or treat pulmonary fibrosis. It can be usefully used.

Description

Novel purine derivative compounds as A3 adenosine receptor agonists}

The present invention relates to novel purine derivatives, and more specifically, to purine derivative compounds as A ₃ adenosine receptor agonists and pharmaceutical compositions containing the same for preventing or treating pulmonary fibrosis.

Pulmonary Fibrosis (PF) is a condition in which lung tissue thickens, hardens, and becomes scar tissue. The cause of pulmonary fibrosis may be the result of other lung diseases, such as autoimmune diseases, viral and/or bacterial infections of the lung, or may be caused by radiation therapy for lung or breast cancer. Additionally, pulmonary fibrosis can be caused by cigarette smoking, environmental factors (eg, occupational exposure to gases, chemicals, asbestos fibers or dust), or genetic predisposition.

However, in many cases, the cause of pulmonary fibrosis cannot be clearly identified, and when the cause of pulmonary fibrosis is unknown (and meets the radiological and/or pathological criteria for pulmonary fibrosis), it is called idiopathic pulmonary fibrosis. It is referred to as Pulmonary Fibrosis (IPF). Pulmonary fibrosis can lead to pulmonary hypertension, right-sided heart failure, respiratory failure, hypoxia, cough, blood clot formation, pneumonia, and lung cancer.

In addition, since pulmonary fibrosis often follows other lung diseases, drug interactions with other drugs used in prior treatment may be problematic, causing serious side effects.

Treatment methods for such pulmonary fibrosis are known to be very limited. Some types of pulmonary fibrosis may respond to corticosteroids or other immunosuppressants, but these treatments do not always produce positive results and are often ineffective in people with idiopathic pulmonary fibrosis. There are treatment methods for idiopathic pulmonary fibrosis, such as lung transplantation, but the reality is that there is no effective treatment other than surgical treatment. Therefore, there is a need for drugs to prevent or treat pulmonary fibrosis and diseases related thereto.

Meanwhile, adenosine receptors are G-protein-coupled receptors, and there are four subtypes: A ₁ , A _2A , A _2B , and A _3. A _2A and A _2B are cyclic adenosine monophosphate (cAMP). On the other hand, A ₁ and A ₃ decrease cAMP, so intracellular signaling is known to be affected depending on which receptor is expressed (Fredholm BB et al. , Pharmacol Rev, 53, 527-552, 2001; Jacobson KA et al. , Trends pharmacol Sci, 19, 184-191, 1998). Adenosine receptors are known to be widely expressed in various cells, and activation of _A3AR is involved in inflammatory or immune responses, so agonists for _A3AR are effective in treating inflammation such as cardiovascular disease, immune disease, rheumatoid arthritis, and colitis. It is known to be effective in suppressing related diseases and cancer cells (Merighi S et al. , Pharmacol Ther. 100, 31-48, 2003).

WO 2019/053723 A1 (2019.03.21)

The problem to be solved by the present invention is to provide an A ₃ adenosine receptor agonist compound with a novel structure that exhibits excellent agonist activity toward the A ₃ adenosine receptor.

In addition, the problem of the present invention is to discover that A ₃ adenosine receptor agonist is associated with pulmonary fibrosis, and to provide a pharmaceutical composition for preventing or treating pulmonary fibrosis containing an A ₃ adenosine receptor agonist as an active ingredient, and an A ₃ adenosine receptor agonist. A method for preventing or treating pulmonary fibrosis using an _A3 adenosine receptor agonist is provided.

In addition, the problem of the present invention is to provide a pharmaceutical composition for preventing or treating A ₃ adenosine receptor-related diseases, including the A ₃ adenosine receptor agonist compound having the novel structure.

In addition, the problem of the present invention is to provide a method for preventing or treating A ₃ adenosine receptor-related diseases using the A ₃ adenosine receptor agonist compound having the novel structure.

In addition, the problem of the present invention is to provide a use of the A ₃ adenosine receptor agonist compound having the novel structure for the prevention or treatment of A ₃ adenosine receptor-related diseases.

In addition, the problem of the present invention is to provide a method for producing the A ₃ adenosine receptor agonist compound having the novel structure.

The problem to be solved by the present invention is not limited to the problems mentioned above, and other technical problems not mentioned can be clearly understood by those skilled in the art from the description below. There will be.

In order to solve the above problem, according to one aspect of the present invention, a purine derivative compound represented by the following formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof is provided.

<Formula Ⅰ>

In the above equation,

R is Q ₁ -Q ₂ -Q ₃ ,

Q ₁ is C _1-4 alkyl,

Q ₂ is heteroaryl of a 5- or 6-membered ring having 1 to 3 N, and the replaceable nitrogen in the heteroaryl is optionally substituted with =O,

Q ₃ is C _1-4 alkyl, C _1-4 alkoxy, halogen, or C _1-4 haloalkyl, and 1 to 3 independent Q ₃ are substituted on Q ₂ ,

X is C _2-10 alkynyl, or halogen,

Y is S or S=O.

According to another aspect of the present invention, a pharmaceutical composition for preventing or treating pulmonary fibrosis comprising an A ₃ adenosine receptor agonist as an active ingredient is provided.

According to another aspect of the present invention, a method for preventing or treating pulmonary fibrosis using an A ₃ adenosine receptor agonist is provided.

According to another aspect of the present invention, use of an A ₃ adenosine receptor agonist for preventing or treating pulmonary fibrosis is provided.

According to another aspect of the present invention, a purine derivative compound represented by Formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof is used for the prevention or treatment of A ₃ adenosine receptor-related diseases as an active ingredient. Pharmaceutical compositions are provided.

According to another aspect of the present invention, a method for preventing or treating diseases related to A ₃ adenosine receptor is provided using the purine derivative compound represented by Formula I, its hydrate, its solvate, or its pharmaceutically acceptable salt.

According to another aspect of the present invention, the use of the purine derivative compound represented by Formula I, its hydrate, its solvate, or its pharmaceutically acceptable salt for the prevention or treatment of A ₃ adenosine receptor-related diseases is provided.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a purine derivative compound represented by Formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. .

According to another aspect of the present invention, dissolving a compound of formula II below in an aqueous formic acid solution to prepare a compound of formula III below; and reacting the compound of Formula III below with RNH ₂ to prepare a compound of Formula Ia.

<Formula Ⅰa>

<Formula Ⅱ>

<Formula Ⅲ>

The definitions of X and R are the same as those of Chemical Formula I in Clause 1.

According to another aspect of the present invention, there is provided a method for preparing a compound of Formula Ib, comprising the step of reacting a compound of Formula Ia below with mCPBA in an organic solvent to prepare a compound of Formula Ib below.

<Formula Ⅰa>

<Formula Ⅰb>

The definitions of X and R are the same as those of Chemical Formula I in Clause 1.

It was confirmed that the novel purine derivative compound of the present invention exhibits excellent activity as an A ₃ adenosine receptor agonist and at the same time exhibits an effect in treating pulmonary fibrosis. Accordingly, the A ₃ adenosine receptor agonist can be used for the prevention or treatment of pulmonary fibrosis. It turned out that it can be done.

Therefore, the novel purine derivative compounds of the present invention can be usefully used in the prevention or treatment of A ₃ adenosine receptor-related diseases, and the A ₃ adenosine receptor agonists, including the novel purine derivative compounds of the present invention, can be used to prevent or treat pulmonary fibrosis. It can be usefully used.

The effects of the present invention are not limited to the effects described above, and should be understood to include all effects that can be inferred from the configuration of the invention described in the description or claims of the present invention.

Figure 1 shows the results of confirming collagen, a protein that appears during fibrosis of pulmonary vascular endothelial cells, in the aortic cross section of mouse lung tissue after irradiation of 17.5 Gy to the lung area of a C57BL/6 mouse (**: p<0.01). Each compound (Example compounds 3, 5, and 7) was orally administered in an amount of 30 mg/kg 1 hour before irradiation.

The present invention provides a purine derivative compound represented by the following formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

<Formula Ⅰ>

In the above equation,

R is Q ₁ -Q ₂ -Q ₃ ,

Q ₁ is C _1-4 alkyl,

Q ₂ is heteroaryl of a 5- or 6-membered ring having 1 to 3 N, and the replaceable nitrogen in the heteroaryl is optionally substituted with =O,

Q ₃ is C _1-4 alkyl, C _1-4 alkoxy, halogen, or C _1-4 haloalkyl, and 1 to 3 independent Q ₃ are substituted on Q ₂ ,

X is C _2-10 alkynyl, or halogen,

Y is S or S=O.

In one embodiment, Q ₁ may be an alkyl selected from the group consisting of methyl, ethyl, and propyl.

In one embodiment, Q ₂ is heteroaryl selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl and triazinyl, or oxopyrrolyl, oxo It may be an oxoheteroaryl selected from the group consisting of imidazolyl, oxopyrazolyl, oxotriazolyl, oxopyridyl, oxopyrazinyl, oxopyrimidyl, oxopyridazinyl and oxotriazinyl.

In one embodiment, Q ₃ may be a substituent selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, propoxy, F, Cl, Br, I, CH ₂ F, CHF ₂ and CF ₃ .

In one embodiment, .

Specific examples of purine derivative compounds according to the present invention are as follows:

[1] (2R)-2-[6-[(2-bromo-4-pyridyl)methylamino]-2-chloro-purin-9-yl]tetrahydrothiophene-3,4-diol,

[2] (2R)-2-[2-chloro-6-[(5-chloro-3-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol,

[3] (2R)-2-[2-chloro-6-[(2-chloro-4-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol,

[4] (2R)-2-[2-chloro-6-[[2-(trifluoromethyl)-4-pyridyl]methylamino]purin-9-yl]tetrahydrothiophene-3,4- dior,

[5] (2R)-2-[6-[(5-bromo-3-pyridyl)methylamino]-2-chloro-purin-9-yl]tetrahydrothiophene-3,4-diol,

[6] (2R)-2-[2-chloro-6-[[5-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl]tetrahydrothiophene-3,4- dior,

[7] (2R,3R,4S)-2-[2-chloro-6-[(2-methyl-4-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol ,

[8] (2R,3R,4S)-2-[2-chloro-6-[(6-methyl-3-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol ,

[9] (2R,3R,4S)-2-[2-chloro-6-[(6-methyl-2-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol ,

[10] (2R,3R,4S)-2-[2-chloro-6-[(6-methoxy-3-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4- dior,

[11] (2R,3R,4S)-2-[2-chloro-6-[(6-methoxy-2-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4- dior,

[12] (2R,3R,4S)-2-[2-chloro-6-[[6-(trifluoromethyl)-2-pyridyl]methylamino]purin-9-yl]tetrahydrothiophene- 3,4-diol,

[13] (2R,3R,4S)-2-[2-chloro-6-[[6-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl]tetrahydrothiophene- 3,4-diol,

[14] (2R,3R,4S)-2-[2-chloro-6-[(6-fluoro-3-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4- dior,

[15] (2R,3R,4S)-2-[2-chloro-6-[(2-methoxy-4-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4- dior,

[16] (2R,3R,4S)-2-[2-chloro-6-[(6-fluoro-2-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4- dior,

[17] (2R,3R,4S)-2-[2-chloro-6-[[6-chloro-5-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl]tetra Hydrothiophene-3,4-diol,

[18] (2R)-2-[6-[(5-chloro-3-pyridyl)methylamino]-2-prop-1-ynyl-purin-9-yl]tetrahydrothiophene-3,4 - Dior,

[19] (2R)-2-[6-[(2-bromo-4-pyridyl)methylamino]-2-prop-1-ynyl-purin-9-yl]tetrahydrothiophen-3, 4-dior,

[20] (2R)-2-[2-prop-1-ynyl-6-[[2-(trifluoromotel)-4-pyridyl]methylamino]purin-9-yl]tetrahydrothiophene -3,4-diol,

[21] (2R)-2-[6-[(2-chloro-4-pyridyl)methylamino]-2-prop-1-ynyl-purin-9-yl]tetrahydrothiophene-3,4 - Dior,

[22] (2R)-2-[2-prop-1-ynyl-6-[[5-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl]tetrahydrothiophene -3,4-diol,

[23] (2R,3R,4S)-2-[2-hex-1-ynyl-6-[[5-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl]tetra Hydrothiophene-3,4-diol,

[24] (2R,3R,4S)-2-[6-[(2-bromo-4-pyridyl)methylamino]-2-hex-1-ynyl-purin-9-yl]tetrahydrothiophene -3,4-diol

[25] (2R)-2-[2-chloro-6-[[5-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl]-1-oxo-thiorane-3 ,4-diol,

[26] (2R)-2-[2-chloro-6-[[1-oxo-5-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl]-1-oxo- thiorane-3,4-diol, and

[27] (2R,3R,4S)-2-[2-chloro-6-[[1-oxido-5-(trifluoromethyl)pyridin-1-ium-3-yl]methylamino]purine- 9-yl]tetrahydrothiophene-3,4-diol.

The compound represented by Formula I according to the present invention can be prepared and used in the form of a prodrug, hydrate, solvate, and pharmaceutically acceptable salt to enhance in vivo absorption or increase solubility, so the above prodrug, Hydrates, solvates and pharmaceutically acceptable salts are also within the scope of the present invention. In addition, the compound represented by Formula I has a chiral carbon, so stereoisomers thereof exist, and these stereoisomers are also included within the scope of the present invention.

The term “prodrug” refers to a substance that is transformed in vivo into the parent drug. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they may be bioactive by oral administration, whereas the parent drug may not be. A prodrug may also have improved solubility in a pharmaceutical composition than the parent drug. For example, prodrugs may be in vivo hydrolyzable esters of compounds according to the invention and pharmaceutically acceptable salts thereof. Another example of a prodrug may be a short peptide (polyamino acid) in which the peptide is linked to an acid group that is metabolically converted to reveal the active site.

The term “hydrate” refers to a compound of the present invention containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. or its salt.

The term “solvate” refers to a compound of the invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Preferred solvents therefor are solvents that are volatile, non-toxic, and/or suitable for administration to humans.

The term “isomer” refers to a compound of the present invention or a salt thereof that has the same chemical or molecular formula but is structurally or sterically different. These isomers include both structural isomers such as tautomers, and stereoisomers such as R or S isomers and geometric isomers (trans, cis) having an asymmetric carbon center. All these isomers and mixtures thereof are also included within the scope of the present invention.

The term “pharmaceutically acceptable salt” refers to a salt form of a compound that does not cause significant irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The pharmaceutical salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, and formic acid. , organic carbonic acids such as citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicic acid, etc., methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Acid addition salts formed with the same sulfonic acid, etc. are included. For example, pharmaceutically acceptable carboxylic acid salts include metal or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, guanidine, dicyclohexylamine, N- Organic salts such as methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine are included. The compound of formula I according to the present invention can also be converted into its salt by conventional methods.

Additionally, the present invention provides a method for preparing the compound of Formula I above. Hereinafter, compounds of Formula I will be described divided into compounds of Formula Ia and compounds of Formula Ib.

<Formula Ⅰa>

<Formula Ⅰb>

The present invention includes the steps of dissolving a compound of formula II below in an aqueous solution of formic acid to prepare a compound of formula III below; and reacting the compound of Formula III below with RNH ₂ to prepare a compound of Formula Ia.

<Formula Ⅱ>

<Formula Ⅲ>

The definitions of X and R are the same as those in Chemical Formula I.

In the step of preparing the compound of the formula III, the reaction can proceed by dissolving the compound of the formula II in an aqueous solution of formic acid and stirring at room temperature. If necessary, processes such as washing, extraction, drying, and filtration are performed to obtain the compound of the formula Ⅲ Compound can be obtained. The formic acid aqueous solution can be used without limitation as long as it has a concentration that can proceed the reaction, for example, it can be at a concentration of 50 to 90%.

Compounds of formula II can be synthesized by compound synthesis methods commonly used in the art, or commercially sold materials can also be used. The method for producing a compound of Formula II can be illustrated as shown in Scheme 1 below.

<Scheme 1>

In the step of preparing the compound of formula Ia, the compound of formula III can be reacted with RNH ₂ in the presence of triethylamine and stirred at room temperature to proceed with the reaction. If necessary, the compound of formula Ia can be obtained through concentration and purification processes. . The solvent that can be used is without limitation as long as it is an organic solvent that can proceed with the reaction. For example, it may be ethanol.

An example of a method for preparing a compound of Formula Ia is shown in Scheme 2 below.

<Scheme 2>

In Scheme 2, an example of a compound of Formula II is Compound 7b, an example of a compound of Formula III is Compound 8, and an example of a compound of Formula Ia are Compounds 9a-q.

If the compound of Formula Ⅱ in Scheme 1 corresponds to compound 7a, the desired substituent is substituted at the position of the Phosphorus compounds 11a-e and compounds 14a-b can be prepared.

<Scheme 3>

<Scheme 4>

The present invention also provides a method for preparing a compound of Formula Ib, comprising the step of reacting a compound of Formula Ia with mCPBA (meta-Chloroperoxybenzoic acid) in an organic solvent to prepare a compound of Formula Ib below.

<Formula Ⅰb>

The definitions of X and R are the same as those in Chemical Formula I.

The step of preparing the compound of Formula Ib involves reacting the compound of Formula Ia with mCPBA in an organic solvent to convert S of the thiophene ring structure to S=O. The organic solvent may be used without limitation as long as it is capable of promoting the reaction. For example, it may be a mixed solvent of dichloromethane and acetonitrile. An example of a method for preparing a compound of formula Ib is shown in Scheme 5 below.

<Scheme 5>

RNH ₂ used in the present invention can be synthesized by a commonly used compound synthesis method, or commercially sold materials can also be used. Scheme 6 below shows an embodiment of synthesizing an exemplary compound of RNH ₂ (Compound 20) and using it to synthesize an exemplary compound of Formula Ib (Compound 21).

<Scheme 6>

Reaction Schemes 1 to 6 are exemplified as above as a method for producing the compound of Formula I of the present invention, and the above production method does not limit the method of producing the compound of Formula I according to the present invention. It is obvious that the preparation methods of Schemes 1 to 6 are merely examples and can be easily modified by those skilled in the art depending on the specific substituent.

In the present specification, A ₃ adenosine receptor (A ₃ AR) is a type of subtype of adenosine receptor, a G-protein-coupled receptor, and the agonist for A ₃ adenosine receptor is cyclic adenosine monophosphate. : cAMP) is known to decrease.

In the present invention, in order to confirm the relationship between A ₃ adenosine receptor agonist activity and pulmonary fibrosis, the degree of effect of each compound was confirmed in each experimental model. As a result, the purine derivative compound of the present invention exhibited A ₃ adenosine receptor agonist activity by reducing cAMP release at the cellular level and showed the effect of reducing pulmonary fibrosis caused by radiation irradiation. That is, in the present invention, the effect expression mechanism in terms of intracellular cytokines was confirmed as described above, and the therapeutic effect on pulmonary fibrosis, the final disease, was confirmed, and the A ₃ adenosine receptor agonist showed a therapeutic effect for pulmonary fibrosis. revealed.

Accordingly, the present invention provides a pharmaceutical composition for preventing or treating pulmonary fibrosis comprising an A ₃ adenosine receptor agonist as an active ingredient, a method for preventing or treating pulmonary fibrosis using an A ₃ adenosine receptor agonist, and a method for preventing or treating pulmonary fibrosis using an A ₃ adenosine receptor agonist. Provides preventive or therapeutic use.

In one embodiment, the pulmonary fibrosis may be selected from the group consisting of idiopathic pulmonary fibrosis (IPF), interstitial lung disease, radiation-induced fibrosis, and asbestos-induced pulmonary fibrosis.

The present invention also provides a pharmaceutical composition for the prevention or treatment of A ₃ adenosine receptor-related diseases, comprising a purine derivative compound represented by the above formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. do.

The present invention also provides treatment of A ₃ adenosine receptor-related diseases by administering a purine derivative compound represented by Formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof to a patient in need thereof. Or provide a preventive method.

The present invention also provides the use of the purine derivative compound represented by Formula I, its hydrate, its solvate, or its pharmaceutically acceptable salt for the prevention or treatment of A ₃ adenosine receptor-related diseases.

As a result of measuring the A ₃ adenosine receptor agonistic activity of the purine derivative compound of the present invention, it showed excellent A ₃ adenosine receptor agonist activity by reducing the cAMP level at a compound concentration of about μM, preventing and preventing diseases related to the A ₃ adenosine receptor. It has been confirmed that it can be used for therapeutic purposes.

In one embodiment, the A ₃ adenosine receptor-related disease may be pulmonary fibrosis, and in particular, may be idiopathic pulmonary fibrosis (IPF), interstitial lung disease, radiation-induced fibrosis, asbestos-induced pulmonary fibrosis, etc.

The present invention also provides a pharmaceutical composition comprising a purine derivative compound represented by the above formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

The additive may include a pharmaceutically acceptable carrier or diluent, and can be used in oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, topical preparations, suppositories, and sterilization products according to conventional methods. It can be formulated in the form of an injectable solution.

The pharmaceutically acceptable carriers include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, and microcrystalline. Contains cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It also includes diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Oral solid preparations include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient, such as starch, calcium carbonate, sucrose, or lactose. ), gelatin, etc., and may include lubricants such as magnesium stearate and talc. Oral liquid preparations include suspensions, oral solutions, emulsions, syrups, etc., and may include diluents such as water and liquid paraffin, humectants, sweeteners, fragrances, and preservatives. Parenteral preparations include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, creams, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, and vegetable oils such as olive oil. Includes injectable esters such as oil and ethyl oleate. As a base for suppositories, witepsol, macrogol, tween 61, cacao, laurel, glycerogelatin, etc. can be used.

The dosage of the active ingredient contained in the pharmaceutical composition of the present invention varies depending on the patient's condition and weight, degree of disease, form of the active ingredient, route and period of administration, and can be appropriately adjusted depending on the patient. For example, the active ingredient can be administered at a dose of 0.0001 to 1000 mg/kg per day, preferably 0.01 to 100 mg/kg, and the administration may be administered once a day or in divided doses. Additionally, the pharmaceutical composition of the present invention may contain the active ingredient at a weight percentage of 0.001 to 90% based on the total weight of the composition.

The pharmaceutical composition of the present invention is administered to mammals such as rats, mice, livestock, and humans by various routes, for example, orally, through the skin, abdominal cavity, rectum, or intravenously, into muscle, subcutaneously, intrauterine dura, or intracerebroventricularly. It can be administered by injection.

Hereinafter, the present invention will be described in more detail through synthesis examples, examples, and experimental examples. However, the following synthesis examples, examples, and experimental examples are for illustrating the present invention, and the scope of the present invention is not limited thereto.

Synthesis Example 1. Preparation of intermediates 7a-7b

Intermediates 7a-7b were synthesized as shown in Scheme 1 below.

<Scheme 1>

(1) Step 1: Preparation of Compound 1

D-mannose (45.0 g, 250 mmol) and 2,2-dimethoxypropane (92.2 ml, 750 mmol) were added to acetone (1.14 L), stirred and mixed, and cooled to 0°C. Camphorsulfonic acid (10-CSA, 17.4 g, 75.0 mmol) was added thereto and stirred at room temperature for 5.5 hours. The reaction mixture was neutralized by adding triethylamine and concentrated under reduced pressure. The residue was extracted using ethyl acetate and water, and the organic layer was dried over anhydrous magnesium sulfate (MgSO ₄ ), filtered, and concentrated under reduced pressure. The residue was stirred under hexane and filtered to obtain the target compound (59.5 g, 92%) as a white solid.

1H NMR (400 MHz, DMSO) δ 5.39 (d, J = 2.4 Hz, 1H), 4.82 (dd, J = 5.9, 3.7 Hz, 1H), 4.63 (d, J = 5.9 Hz, 1H), 4.41 (dd , J = 11.9, 6.3 Hz, 1H), 4.19 (dd, J = 7.3, 3.6 Hz, 1H), 4.12 - 4.02 (m, 2H), 2.43 (d, J = 2.4 Hz, 1H), 1.47 (s, 3H), 1.46 (s, 3H), 1.38 (s, 3H), 1.33 (s, 3H)

(2) Step 2: Preparation of Compound 2

Compound 1 (59.5 g, 229 mmol) prepared in the above step was added to ethanol (500 ml) and cooled to 0°C. Sodium borohydride (NaBH ₄ , 4.30 g, 114 mmol) was added here, and after 30 minutes, the same amount was added once more. After stirring at room temperature for 1 hour, it was neutralized with acetic acid and concentrated under reduced pressure. The mixture was extracted using ethyl acetate and water, dried over anhydrous magnesium sulfate (MgSO ₄ ), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain the target compound in syrup form (58.6 g, 98%).

1H NMR (400 MHz, DMSO) δ 4.40 (dd, J = 7.3, 1.4 Hz, 1H), 4.34 - 4.29 (m, 1H), 4.15 - 4.06 (m, 2H), 4.06 - 4.00 (m, 1H), 3.94 - 3.80 (m, 2H), 3.59 (t, J = 6.4 Hz, 1H), 3.11 (d, J = 6.3 Hz, 1H), 2.62 (t, J = 6.1 Hz, 1H), 1.53 (s, 3H) ), 1.42 (s, 3H), 1.41 (s, 3H), 1.36 (s, 3H)

(3) Step 3: Preparation of Compound 3

Compound 2 (58.5 g, 223 mmol) and 4-dimethylaminopyridine (4-DMAP, 8.18 g, 66.9 mmol) prepared in the above step were added to dichloromethane (456 ml) and cooled to 0°C. Dimethanesulfonyl chloride (65.4 ml, 669 mmol) and triethylamine (218 ml, 1.56 mol) were carefully added dropwise here. After stirring at room temperature for 2.5 hours, the reaction mixture was washed with saturated NH ₄ Cl aqueous solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate (MgSO ₄ ), filtered, and concentrated under reduced pressure. The brown syrup-like residue obtained after concentration was used without purification.

(4) Step 4: Preparation of Compound 4

After dissolving Compound 3 prepared in the above step in DMF (2 L), sodium sulfide (12.8 g, 164 mmol) was added, and the mixture was refluxed and stirred at 80°C overnight. The solvent was removed by concentration under reduced pressure, and the reaction residue was extracted using ethyl acetate and water. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate (MgSO ₄ ), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain the target compound (22.2 g, 78% from Compound 2) as a yellow-brown solid.

1H NMR (400 MHz, DMSO) δ 4.93 (td, J = 5.5, 1.6 Hz, 1H), 4.73 (dd, J = 5.7, 1.8 Hz, 1H), 4.32 - 4.25 (m, 1H), 4.05 (dd, J = 8.1, 6.2 Hz, 1H), 3.80 (t, J = 7.8 Hz, 1H), 3.32 (dd, J = 4.0, 1.8 Hz, 1H), 3.21 (dd, J = 12.3, 5.2 Hz, 1H), 2.85 (dd, J = 12.3, 1.5 Hz, 1H), 1.52 (s, 3H), 1.44 (s, 3H), 1.34 (s, 3H), 1.33 (s, 3H)

(5) Step 5: Preparation of Compound 5

Compound 4 (22.1 g, 84.9 mmol) prepared in the above step was dissolved in 60% acetic acid aqueous solution (243 ml) and stirred at room temperature for 4 hours. The reaction mixture was cooled to 0°C, washed with saturated aqueous NaHCO ₃ solution, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate (MgSO ₄ ), filtered, and concentrated under reduced pressure. The residue was stirred in a mixture of hexane (less than 5% dichloromethane) and filtered to obtain the target compound (9.30 g, 50%) as a white solid.

1H NMR (400 MHz, DMSO) δ 4.93 (td, J = 5.4, 1.7 Hz, 1H), 4.76 (dd, J = 5.7, 1.9 Hz, 1H), 3.82 - 3.61 (m, 3H), 3.40 (dd, J = 5.2, 1.8 Hz, 1H), 3.16 (dd, J = 12.6, 5.1 Hz, 1H), 2.90 (dd, J = 12.6, 1.7 Hz, 1H), 2.56 (d, J = 5.2 Hz, 1H), 2.09 (dd, J = 6.7, 5.2 Hz, 1H), 1.52 (s, 3H), 1.33 (s, 3H)

(6) Step 6: Preparation of Compound 6

Compound 5 (5.70 g, 25.9 mmol) prepared in the above step was dissolved in ethyl acetate (116 ml) and cooled to 0°C. Red tetraacetate (Pb(OAc) ₄ , 57.4 g, 130 mmol) was added thereto, and then stirred at room temperature for 17 hours. The reaction mixture was filtered through Celite, and the filtrate was diluted with ethyl acetate and washed with saturated aqueous NaHCO ₃ solution. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate (MgSO ₄ ), filtered, and concentrated under reduced pressure. The residue was purified by MPLC (ethyl acetate:hexane=1:9) on silica gel to obtain the target compound (4.26 g, 75%) as a white solid.

(7) Step 7

1) Preparation of compound 7a (CAS No. 1246033-85-1)

2-Iodo-6-chloropurine (11.5 g, 10.6 mmol) and N,O-bis(trimethylsilyl)-acetamide (13.4 ml, 54.7 mmol) were added to acetonitrile (179 ml) and incubated at 40°C for 20 minutes. It was stirred for a minute. After cooling to room temperature, Compound 6 (27.4 mmol) prepared in the above step was dissolved in acetonitrile (35 ml) and carefully added dropwise to the stirring reaction solution. Trifluoromethanesulfonate (TMSOTf, 5.44 ml, 30.1 mmol) was added thereto and stirred at 80°C for 6 hours, then washed with saturated NaHCO ₃ solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate (MgSO ₄ ), filtered, and concentrated under reduced pressure. The residue was purified by MPLC (ethyl acetate:hexane=1:4) on silica gel to obtain the target compound (3.6 g, 30% from Compound 5 ) as a white solid in the form of foam.

1H NMR (400 MHz, DMSO) δ 8.06 (s, 1H), 5.84 (s, 1H), 5.33 (t, J = 4.6 Hz, 1H), 5.22 (d, J = 5.4 Hz, 1H), 3.81 (dd , J = 12.9, 4.2 Hz, 1H), 3.26 (d, J = 13.0 Hz, 1H), 1.60 (s, 3H), 1.37 (s, 3H)

MS (ESI) m/z 439 [M+H]+

2) Preparation of compound 7b (CAS No. 945457-81-8)

2,6-dichloropurine (2.00 g, 10.6 mmol) and N,O-bis(trimethylsilyl)acetamide (3.46 ml, 14.2 mmol) were added to acetonitrile (46 ml) and stirred at 40°C for 1.5 hours. . After cooling to room temperature, Compound 6 (1.55 g, 7.08 mmol) prepared in the above step was dissolved in acetonitrile (7.70 ml) and carefully added dropwise to the stirring reaction solution. Trifluoromethanesulfonate (TMSOTf, 1.42 ml, 5.00 M) was added thereto and stirred at 80°C for 2.5 hours, then washed with saturated NaHCO ₃ solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate (MgSO ₄ ), filtered, and concentrated under reduced pressure. The residue was purified by MPLC (ethyl acetate:hexane=1:4) on silica gel to obtain the target compound (1.13 g, 46%) as a white solid in the form of foam.

1H NMR (400 MHz, DMSO) δ 8.17 (s, 1H), 5.87 (s, 1H), 5.33 (t, J = 4.8 Hz, 1H), 5.22 (d, J = 5.3 Hz, 1H), 3.80 (dd , J = 12.9, 4.3 Hz, 1H), 3.27 (d, J = 12.9 Hz, 1H), 1.60 (s, 3H), 1.37 (s, 3H)

MS (ESI) m/z 347 [M+H]+

Synthesis Example 2. Preparation of Compound 9a-9q

Compounds 9a-9q were synthesized as shown in Scheme 2 below.

<Scheme 2>

Example 1. (2R)-2-[6-[(2-bromo-4-pyridyl)methylamino]-2-chloro-purin-9-yl]tetrahydrothiophene-3,4-diol ( 9a) Preparation of [(2R)-2-[6-[(2-bromo-4-pyridyl)methylamino]-2-chloro-purin-9-yl]tetrahydrothiophene-3,4-diol]

(1) Step 1: Preparation of Compound 8

Compound 7b (1.13 g, 3.25 mmol) prepared in the above step was dissolved in 80% formic acid aqueous solution (65.0 ml, 0.05M) and stirred at room temperature for 2.5 hours. It was washed with saturated NaHCO ₃ solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate (MgSO ₄ ), filtered, and concentrated under reduced pressure. The residue was purified by MPLC (dichloromethane:methanol=1:19) on silica gel to obtain the target compound (758 mg, 76%) as a white solid.

1H NMR (400 MHz, DMSO) δ 8.88 (s, 1H), 6.07 (d, J = 6.7 Hz, 1H), 4.68 (dd, J = 6.7, 3.4 Hz, 1H), 4.47 (q, J = 3.7 Hz) , 1H), 3.56 (dd, J = 11.1, 4.3 Hz, 1H), 3.34 (s, 2H), 2.97 (dd, J = 11.1, 3.3 Hz, 1H)

MS (ESI) m/z 307 [M+H]+

(2) Step 2: (2R)-2-[6-[(2-bromo-4-pyridyl)methylamino]-2-chloro-purin-9-yl]tetrahydrothiophene-3,4- Preparation of diol (9a)

Compound 8 (260 mg, 0.85 mmol) and (2-bromopyridin-4-yl)methanamine (396 mg, 2.12 mmol) prepared in the above step were dissolved in ethanol (25ml), and triethylamine ( 0.49 ml) was added and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was adsorbed on silica gel and purified by MPLC (dichloromethane:methanol=1:19) on silica gel to obtain the target compound (247 mg, 64%) as a white solid.

1H NMR (400 MHz, DMSO) δ 9.02 - 8.90 (m, 1H), 8.55 (s, 1H), 8.33 - 8.30 (m, 1H), 7.61 - 7.56 (m, 1H), 7.37 (d, J = 4.8 Hz, 1H), 5.82 (d, J = 7.2 Hz, 1H), 5.57 (d, J = 6.1 Hz, 1H), 5.38 (d, J = 4.1 Hz, 1H), 4.67 (d, J = 5.1 Hz, 2H), 4.61 (s, 1H), 4.34 (s, 1H), 3.41 (dd, J = 10.0, 3.0 Hz, 1H), 2.80 (dd, J = 10.9, 1.8 Hz, 1H)

MS (ESI) m/z 457 [M+H]+

Example 2. (2R)-2-[2-chloro-6-[(5-chloro-3-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol (9b) Preparation of [(2R)-2-[2-chloro-6-[(5-chloro-3-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol]

The target compound (94%) was obtained by the same method as compound 9a .

1H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.57 - 8.50 (m, 3H), 7.89 (s, 1H), 5.81 (d, J = 7.3 Hz, 1H), 5.59 (d, J = 4.7 Hz, 1H), 5.40 (d, J = 3.0 Hz, 1H), 4.67 (d, J = 4.3 Hz, 2H), 4.59 (s, 1H), 4.33 (s, 1H), 3.41 (dd, J = 10.9, 4.1 Hz, 1H), 2.79 (dd, J = 10.9, 2.8 Hz, 1H)

MS (ESI) m/z 413 [M+H]+

Example 3. (2R)-2-[2-chloro-6-[(2-chloro-4-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol (9c) Preparation of [(2R)-2-[2-chloro-6-[(2-chloro-4-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol]

The target compound (70%) was obtained by the same method as compound 9a .

1H NMR (400 MHz, DMSO) δ 8.96 (s, 1H), 8.55 (s, 1H), 8.34 (d, J = 5.1 Hz, 1H), 7.44 (s, 1H), 7.34 (d, J = 4.2 Hz) , 1H), 5.82 (d, J = 7.3 Hz, 1H), 5.57 (d, J = 6.0 Hz, 1H), 5.39 (d, J = 3.8 Hz, 1H), 4.68 (d, J = 4.8 Hz, 2H) ), 4.61 (s, 1H), 4.34 (s, 1H), 3.41 (dd, J = 10.6, 3.0 Hz, 1H), 2.80 (dd, J = 10.5, 1.6 Hz, 1H)

MS (ESI) m/z 413 [M+H]+

Example 4. (2R)-2-[2-chloro-6-[[2-(trifluoromethyl)-4-pyridyl]methylamino]purin-9-yl]tetrahydrothiophene-3,4 -Preparation of diol (9d) [(2R)-2-[2-chloro-6-[[2-(trifluoromethyl)-4-pyridyl]methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol]

The target compound (91%) was obtained by the same method as compound 9a .

1H NMR (400 MHz, DMSO) δ 9.01 (s, 1H), 8.70 (d, J = 4.9 Hz, 1H), 8.56 (s, 1H), 7.89 (s, 1H), 7.64 (s, 1H), 5.83 (d, J = 7.3 Hz, 1H), 5.56 (d, J = 6.2 Hz, 1H), 5.38 (d, J = 4.0 Hz, 1H), 4.78 (d, J = 4.6 Hz, 2H), 4.61 (s) , 1H), 4.34 (s, 1H), 3.42 (dd, J = 10.5, 3.2 Hz, 1H), 2.80 (d, J = 10.7 Hz, 1H)

MS (ESI) m/z 447 [M+H]+

Example 5. (2R)-2-[6-[(5-bromo-3-pyridyl)methylamino]-2-chloro-purin-9-yl]tetrahydrothiophene-3,4-diol ( 9e) Preparation of [(2R)-2-[6-[(5-bromo-3-pyridyl)methylamino]-2-chloro-purin-9-yl]tetrahydrothiophene-3,4-diol]

The target compound (46%) was obtained by the same method as compound 9a .

1H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.59 (d, J = 2.1 Hz, 1H), 8.57 (s, 1H), 8.52 (s, 1H), 8.02 (s, 1H), 5.81 (d, J = 7.3 Hz, 1H), 5.59 (s, 1H), 5.40 (s, 1H), 4.66 (d, J = 3.6 Hz, 2H), 4.60 (s, 1H), 4.34 (s, 1H) , 3.41 (dd, J = 10.8, 4.2 Hz, 1H), 2.79 (dd, J = 10.9, 2.8 Hz, 1H)

MS (ESI) m/z 457 [M+H]+

Example 6. (2R)-2-[2-chloro-6-[[5-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl]tetrahydrothiophene-3,4 -Preparation of diol (9f) [(2R)-2-[2-chloro-6-[[5-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol]

The target compound (56%) was obtained by the same method as compound 9a .

1H NMR (400 MHz, DMSO) δ 8.98 (s, 1H), 8.87 (s, 2H), 8.53 (s, 1H), 8.20 (s, 1H), 5.81 (d, J = 7.2 Hz, 1H), 5.56 (d, J = 6.2 Hz, 1H), 5.38 (d, J = 3.9 Hz, 1H), 4.75 (d, J = 4.9 Hz, 2H), 4.60 (s, 1H), 4.33 (s, 1H), 3.41 (dd, J = 10.8, 3.6 Hz, 1H), 2.79 (dd, J = 11.0, 2.6 Hz, 1H)

MS (ESI) m/z 447 [M+H]+

Example 7. (2R,3R,4S)-2-[2-chloro-6-[(2-methyl-4-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4- Preparation of diol (9 g) [(2R,3R,4S)-2-[2-chloro-6-[(2-methyl-4-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol]

The target compound (61%) was obtained by the same method as compound 9a .

1H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.54 (s, 1H), 8.34 (d, J = 5.0 Hz, 1H), 7.16 (s, 1H), 7.09 (d, J = 4.3 Hz) , 1H), 5.82 (d, J = 7.5 Hz, 1H), 5.58 (s, 1H), 5.41 (s, 1H), 4.65 - 4.57 (m, 3H), 4.33 (s, 1H), 3.41 (d, J = 10.4 Hz, 1H), 2.79 (d, J = 10.9 Hz, 1H), 2.42 (s, 3H)

MS (ESI) m/z 393 [M+H]+

Example 8. (2R,3R,4S)-2-[2-chloro-6-[(6-methyl-3-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4- Preparation of diol (9h) [(2R,3R,4S)-2-[2-chloro-6-[(6-methyl-3-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol]

The target compound (56%) was obtained by the same method as compound 9a .

1H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.51 (s, 1H), 8.44 (s, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.19 (d, J = 7.9 Hz) , 1H), 5.81 (d, J = 7.2 Hz, 1H), 5.59 (d, J = 6.0 Hz, 1H), 5.41 (d, J = 4.0 Hz, 1H), 4.59 (d, J = 4.2 Hz, 3H) ), 4.33 (s, 1H), 3.40 (dd, J = 11.2, 4.1 Hz, 1H), 2.79 (dd, J = 10.9, 2.3 Hz, 1H), 2.41 (s, 3H)

MS (ESI) m/z 393 [M+H]+

Example 9. (2R,3R,4S)-2-[2-chloro-6-[(6-methyl-2-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4- Preparation of diol (9i) [(2R,3R,4S)-2-[2-chloro-6-[(6-methyl-2-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol]

The target compound (63%) was obtained by the same method as compound 9a .

1H NMR (400 MHz, DMSO) δ 8.83 (s, 1H), 8.54 (s, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 7.06 (d) , J = 7.4 Hz, 1H), 5.82 (d, J = 7.1 Hz, 1H), 5.60 (d, J = 7.5 Hz, 1H), 5.41 (s, 1H), 4.68 (s, 2H), 4.62 (s , 1H), 4.34 (s, 1H), 3.41 (d, J = 9.9 Hz, 1H), 2.79 (d, J = 9.0 Hz, 1H), 2.46 (s, 3H)

MS (ESI) m/z 393 [M+H]+

Example 10. (2R,3R,4S)-2-[2-chloro-6-[(6-methoxy-3-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4 -Preparation of diol (9j) [(2R,3R,4S)-2-[2-chloro-6-[(6-methoxy-3-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol ]

The target compound (79%) was obtained by the same method as compound 9a .

1H NMR (400 MHz, DMSO) δ 8.89 (s, 1H), 8.50 (s, 1H), 8.16 (s, 1H), 7.69 (dd, J = 8.4, 1.9 Hz, 1H), 6.78 (d, J = 8.5 Hz, 1H), 5.80 (d, J = 6.9 Hz, 1H), 5.58 (d, J = 6.0 Hz, 1H), 5.41 (s, 1H), 4.59 (s, 1H), 4.55 (d, J = 5.7 Hz, 2H), 4.33 (s, 1H), 3.81 (s, 3H), 3.40 (dd, J = 10.8, 4.1 Hz, 1H), 2.79 (dd, J = 10.7, 2.4 Hz, 1H)

MS (ESI) m/z 409 [M+H]+

Example 11. (2R,3R,4S)-2-[2-chloro-6-[(6-methoxy-2-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4 -Preparation of diol (9k) [(2R,3R,4S)-2-[2-chloro-6-[(6-methoxy-2-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol ]

The target compound (79%) was obtained by the same method as compound 9a .

1H NMR (400 MHz, DMSO) δ 8.85 (s, 1H), 8.55 (s, 1H), 7.62 (t, J = 7.7 Hz, 1H), 6.82 (d, J = 7.2 Hz, 1H), 6.68 (d) , J = 8.1 Hz, 1H), 5.83 (d, J = 7.5 Hz, 1H), 5.60 (d, J = 6.0 Hz, 1H), 5.42 (d, J = 3.5 Hz, 1H), 4.69 - 4.59 (m , 3H), 4.34 (s, 1H), 3.82 (s, 3H), 3.42 (dd, J = 9.7, 3.7 Hz, 1H), 2.80 (dd, J = 10.6, 2.0 Hz, 1H)

MS (ESI) m/z 409 [M+H]+

Example 12. (2R,3R,4S)-2-[2-chloro-6-[[6-(trifluoromethyl)-2-pyridyl]methylamino]purin-9-yl]tetrahydrothiophene Preparation of -3,4-diol (9l) [(2R,3R,4S)-2-[2-chloro-6-[[6-(trifluoromethyl)-2-pyridyl]methylamino]purin-9-yl]tetrahydrothiophene -3,4-diol]

The target compound (72%) was obtained by the same method as compound 9a .

1H NMR (400 MHz, DMSO) δ 8.99 (s, 1H), 8.57 (s, 1H), 7.64 (d, J = 9.1 Hz, 1H), 7.51 (d, J = 2.5 Hz, 1H), 7.49 (d) , J = 2.5 Hz, 1H), 5.83 (d, J = 7.4 Hz, 1H), 5.59 (s, 1H), 5.41 (s, 1H), 4.80 (s, 2H), 4.62 (s, 1H), 4.34 (s, 1H), 3.42 (dd, J = 11.0, 4.0 Hz, 1H), 2.79 (d, J = 10.8 Hz, 1H)

MS (ESI) m/z 447 [M+H]+

Example 13. (2R,3R,4S)-2-[2-chloro-6-[[6-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl]tetrahydrothiophene Preparation of -3,4-diol (9m) [(2R,3R,4S)-2-[2-chloro-6-[[6-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl]tetrahydrothiophene -3,4-diol]

The target compound (87%) was obtained by the same method as compound 9a .

1H NMR (400 MHz, DMSO) δ 9.02 (s, 1H), 8.77 (s, 1H), 8.54 (s, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.87 (d, J = 8.1 Hz) , 1H), 5.81 (d, J = 7.4 Hz, 1H), 5.57 (d, J = 5.9 Hz, 1H), 5.40 (s, 1H), 4.76 (d, J = 5.1 Hz, 2H), 4.60 (s) , 1H), 4.33 (s, 1H), 3.41 (dd, J = 10.9, 4.1 Hz, 1H), 2.79 (dd, J = 10.8, 2.6 Hz, 1H)

MS (ESI) m/z 447 [M+H]+

Example 14. (2R,3R,4S)-2-[2-chloro-6-[(6-fluoro-3-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4 -Preparation of diol (9n) [(2R,3R,4S)-2-[2-chloro-6-[(6-fluoro-3-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol ]

The target compound (76%) was obtained by the same method as compound 9a .

1H NMR (400 MHz, DMSO) δ 8.88 (s, 1H), 8.50 (s, 1H), 8.23 (s, 1H), 7.96 (td, J = 8.2, 2.3 Hz, 1H), 7.13 (d, J = 8.7 Hz, 1H), 5.81 (d, J = 7.3 Hz, 1H), 5.52 (s, 1H), 5.34 (s, 1H), 4.64 (s, 2H), 4.59 (td, J = 6.9, 3.3 Hz, 1H), 4.34 (s, 1H), 3.41 (dd, J = 10.8, 4.2 Hz, 1H), 2.80 (dd, J = 10.8, 2.0 Hz, 1H)

MS (ESI) m/z 397 [M+H]+

Example 15. (2R,3R,4S)-2-[2-chloro-6-[(2-methoxy-4-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4 -Preparation of diol (9o) [(2R,3R,4S)-2-[2-chloro-6-[(2-methoxy-4-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol ]

The target compound (13%) was obtained by the same method as compound 9a .

1H NMR (400 MHz, DMSO) δ 8.96 (s, 1H), 8.54 (s, 1H), 8.08 (d, J = 5.2 Hz, 1H), 6.92 (d, J = 4.8 Hz, 1H), 6.68 (s) , 1H), 5.81 (d, J = 7.6 Hz, 1H), 5.60 (d, J = 6.2 Hz, 1H), 5.41 (d, J = 4.1 Hz, 1H), 4.61 (d, J = 5.1 Hz, 3H) ), 4.33 (s, 1H), 3.81 (s, 3H), 3.42 (d, J = 4.7 Hz, 1H), 2.79 (dd, J = 10.8, 2.6 Hz, 1H)

MS (ESI) m/z 409 [M+H]+

Example 16. (2R,3R,4S)-2-[2-chloro-6-[(6-fluoro-2-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4 -Preparation of diol (9p) [(2R,3R,4S)-2-[2-chloro-6-[(6-fluoro-2-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol ]

The target compound (78%) was obtained by the same method as compound 9a .

1H NMR (400 MHz, DMSO) δ 8.94 (t, J = 6.1 Hz, 1H), 8.56 (s, 1H), 7.93 (dd, J = 15.9, 8.1 Hz, 1H), 7.25 (dd, J = 7.3, 2.0 Hz, 1H), 7.05 (dd, J = 8.0, 2.2 Hz, 1H), 5.83 (d, J = 7.3 Hz, 1H), 5.61 (d, J = 6.3 Hz, 1H), 5.43 (d, J = 4.0 Hz, 1H), 4.68 (d, J = 6.1 Hz, 2H), 4.65 - 4.59 (m, 1H), 4.34 (s, 1H), 3.42 (dd, J = 11.4, 3.1 Hz, 1H), 2.80 ( dd, J = 10.7, 2.4 Hz, 1H)

MS (ESI) m/z 397 [M+H]+

Example 17. (2R,3R,4S)-2-[2-chloro-6-[[6-chloro-5-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl] Preparation of tetrahydrothiophene-3,4-diol (9q) [(2R,3R,4S)-2-[2-chloro-6-[[6-chloro-5-(trifluoromethyl)-3-pyridinyl]methylamino ]purin-9-yl]tetrahydrothiophene-3,4-diol]

The target compound (38%) was obtained by the same method as compound 9a .

1H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.69 (s, 1H), 8.53 (s, 1H), 8.38 (s, 1H), 5.81 (d, J = 7.2 Hz, 1H), 5.56 (s, 1H), 5.40 (s, 1H), 4.72 (s, 2H), 4.59 (s, 1H), 4.33 (s, 1H), 2.79 (dd, J = 10.7, 2.4 Hz, 1H)

*1H around 3.38 ppm overlapped with the water peak.

MS (ESI) m/z 481 [M+H]+

Synthesis Example 3. Preparation of compounds 11a-11e

Compounds 11a-11e were synthesized as shown in Scheme 3 below.

<Scheme 3>

Example 18. (2R)-2-[6-[(5-chloro-3-pyridyl)methylamino]-2-prop-1-ynyl-purin-9-yl]tetrahydrothiophen-3, Preparation of 4-diol (11a) [(2R)-2-[6-[(5-chloro-3-pyridyl)methylamino]-2-prop-1-ynyl-purin-9-yl]tetrahydrothiophene-3,4 -diol]

(1) Step 1: Preparation of compound 10

Compound 7a (700 mg, 1.60 mmol), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh ₃ ) ₄ , 203 mg, 0.18 mmol), cuprous iodide (CuI, 37 mmol) in DMF (16 ml) mg, 0.19 mmol), cesium carbonate (Cs ₂ CO ₃ , 521 mg, 1.60 mmol), and propine (4.80 ml, 1M in DMF) were added and stirred at room temperature for 2 hours. 2 equivalents of propine were added, stirred for an additional 1.5 hours, and concentrated under reduced pressure. 80% formic acid aqueous solution (0.04M) was added to the concentrated mixture and stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO ₃ solution. The organic layer was dried over anhydrous magnesium sulfate (MgSO ₄ ), filtered, and concentrated under reduced pressure. The residue was purified by MPLC (dichloromethane:methanol=97:3) on silica gel to obtain the target compound (279 mg, 56%) as a white solid.

MS (ESI) m/z 311 [M+H]+

(2) Step 2: (2R)-2-[6-[(5-chloro-3-pyridyl)methylamino]-2-prop-1-ynyl-purin-9-yl]tetrahydrothiophene- Preparation of 3,4-diol (11a)

Compound 10 (130 mg, 0.42 mmol), (5-chloropyridin-3-yl)methanamine (165 mg, 1.16 mmol) and triethylamine (0.3 ml, 2.09 mmol) prepared in the above step were added to ethanol (12.5 ml). ) was added and stirred at room temperature for 1.5 days. After concentrating the reaction mixture, the residue was adsorbed on silica gel and purified by MPLC (dichloromethane:methanol=97:3) on silica gel to obtain the target compound (110 mg, 63%) as a solid.

1H NMR (400 MHz, DMSO) δ 8.61 - 8.41 (m, 4H), 7.86 (s, 1H), 5.86 (d, J = 7.2 Hz, 1H), 5.56 (d, J = 5.9 Hz, 1H), 5.37 (d, J = 3.3 Hz, 1H), 4.70 (s, 2H), 4.61 (s, 1H), 4.34 (s, 1H), 3.40 (dd, J = 10.8, 3.9 Hz, 1H), 2.80 (dd, J = 10.8, 2.8 Hz, 1H), 2.03 (s, 3H)

MS (ESI) m/z 417 [M+H]+

Example 19. (2R)-2-[6-[(2-bromo-4-pyridyl)methylamino]-2-prop-1-ynyl-purin-9-yl]tetrahydrothiophene-3 , Preparation of 4-diol (11b) [(2R)-2-[6-[(2-bromo-4-pyridyl)methylamino]-2-prop-1-ynyl-purin-9-yl]tetrahydrothiophene-3, 4-diol]

The target compound (36%) was obtained by the same method as compound 11a .

1H NMR (400 MHz, DMSO): δ 8.54 (s, 2H), 8.30 (d, J = 5.1 Hz, 1H), 7.56 (s, 1H), 7.35 (d, J = 4.8 Hz, 1H), 5.87 ( d, J = 7.1 Hz, 1H), 5.54 (d, J = 6.3 Hz, 1H), 5.35 (d, J = 4.1 Hz, 1H), 4.69 (s, 2H), 4.62 (s, 1H), 4.34 ( s, 1H), 3.41 (dd, J = 10.8, 4.1 Hz, 1H), 2.80 (dd, J = 10.7, 2.4 Hz, 1H), 2.01 (s, 3H)

MS (ESI) m/z 461 [M+H]+

Example 20. (2R)-2-[2-prop-1-ynyl-6-[[2-(trifluoromotel)-4-pyridyl]methylamino]purin-9-yl]tetrahydroti Preparation of ophene-3,4-diol (11c) [(2R)-2-[2-prop-1-ynyl-6-[[2-(trifluoromethyl)-4-pyridyl]methylamino]purin-9-yl] tetrahydrothiophene-3,4-diol]

The target compound (43%) was obtained by the same method as compound 11a .

1H NMR (400 MHz, DMSO) δ 8.68 (d, J = 4.9 Hz, 1H), 8.61 (br s, 1H), 8.55 (s, 1H), 7.87 (s, 1H), 7.60 (d, J = 4.4 Hz, 1H), 5.87 (d, J = 7.3 Hz, 1H), 5.56 (d, J = 6.1 Hz, 1H), 5.38 (d, J = 4.1 Hz, 1H), 4.80 (s, 2H), 4.62 ( s, 1H), 4.34 (s, 1H), 3.40 (dd, J = 11.3, 3.7 Hz, 1H), 2.80 (dd, J = 10.5, 2.3 Hz, 1H), 2.00 (s, 3H)

MS (ESI) m/z 451 [M+H]+

Example 21. (2R)-2-[6-[(2-chloro-4-pyridyl)methylamino]-2-prop-1-ynyl-purin-9-yl]tetrahydrothiophen-3, Preparation of 4-diol (11d) [(2R)-2-[6-[(2-chloro-4-pyridyl)methylamino]-2-prop-1-ynyl-purin-9-yl]tetrahydrothiophene-3,4 -diol]

The target compound (29%) was obtained by the same method as compound 11a .

1H NMR (400 MHz, DMSO) δ 8.54 (s, 2H), 8.32 (d, J = 5.1 Hz, 1H), 7.41 (s, 1H), 7.32 (d, J = 4.8 Hz, 1H), 5.87 (d) , J = 7.1 Hz, 1H), 5.56 (d, J = 4.2 Hz, 1H), 5.38 (s, 1H), 4.71 (s, 2H), 4.62 (s, 1H), 4.34 (s, 1H), 3.40 (dd, J = 11.4, 3.6 Hz, 1H), 2.80 (dd, J = 10.7, 2.5 Hz, 1H), 2.01 (s, 3H)

MS (ESI) m/z 417 [M+H]+

Example 22. (2R)-2-[2-prop-1-ynyl-6-[[5-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl]tetrahydrothiophen-3, Preparation of 4-diol (11e) [(2R)-2-[2-prop-1-ynyl-6-[[5-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl]tetrahydrothiophene-3, 4-diol]

The target compound (55%) was obtained by the same method as compound 11a .

1H NMR (400 MHz, DMSO) δ 8.86 (s, 2H), 8.55 (br s, 1H), 8.53 (s, 1H), 8.19 (s, 1H), 5.85 (d, J = 3.5 Hz, 1H), 5.54 (s, 1H), 5.35 (s, 1H), 4.77 (s, 2H), 4.61 (s, 1H), 4.34 (s, 1H), 3.39 (d, J = 12.1 Hz, 1H), 2.79 (d , J = 10.8 Hz, 1H), 2.03 (s, 3H)

MS (ESI) m/z 451 [M+H]+

Synthesis Example 4. Preparation of compounds 14a-14b

Compounds 14a-14b were synthesized as shown in Scheme 4 below.

<Scheme 4>

Example 23. (2R,3R,4S)-2-[2-hex-1-ynyl-6-[[5-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl] Preparation of tetrahydrothiophene-3,4-diol (14a) [(2R,3R,4S)-2-[2-hex-1-ynyl-6-[[5-(trifluoromethyl)-3-pyridyl]methyl ]amino]purin-9-yl]tetrahydrothiophene-3,4-diol]

(1) Step 1: Preparation of compound 12

Compound 7a (300 mg, 0.68 mmol), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh ₃ ) ₄ , 200 mg, 0.17 mmol), cuprous iodide (CuI, 15.6 mg) in DMF (6ml) , 0.08 mmol) and cesium carbonate (Cs ₂ CO ₃ , 223 mg, 0.68 mmol) were added and dissolved, and then nitrogen was blown into the solution for 15 minutes. 1-hexyne (102 uL, 0.89 mmol) was added thereto and stirred at room temperature for 3 hours. The reaction mixture was washed with water and extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous NaCl solution. The organic layer was dried over anhydrous magnesium sulfate (MgSO ₄ ), filtered, and concentrated under reduced pressure. The residue was purified by MPLC (ethyl acetate:hexane=1:3) on silica gel to obtain the target compound (216 mg, 80%) as a yellow solid in the form of foam.

MS (ESI) m/z 393 [M+H]+

(2) Step 2: Preparation of compound 13

Compound 12 (210 mg, 0.53 mmol) prepared in the above step was dissolved in 80% formic acid aqueous solution (10 ml) and stirred at room temperature for 3 hours. The reaction mixture was cooled to 0°C, washed with saturated aqueous NaHCO3 solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate (MgSO ₄ ), filtered, and concentrated under reduced pressure. The residue was purified by MPLC (dichloromethane:methanol=97:3) on silica gel to obtain the target compound (90.5 mg, 48%) as a yellow solid.

MS (ESI) m/z 353 [M+H]+

(3) Step 3: (2R,3R,4S)-2-[2-hex-1-ynyl-6-[[5-(trifluoromethyl)-3-pyridyl]methylamino]purine-9- Production of [1] tetrahydrothiophene-3,4-diol (14a)

Compound 13 (45.9 mg, 0.13 mmol), (5-(trifluoromethyl)pyridin-3-yl)methanamine (57 mg, 0.33 mmol) prepared in the above step and TEA (76 ul) in EtOH (3.9 ml) , 0.55 mmol) was dissolved and stirred for 2.5 days. The reaction mixture was concentrated, the residue was adsorbed on silica gel, and purified by MPLC (dichloromethane:methanol=95:5) on silica gel to obtain the target compound (51 mg, 51%) as a solid.

1H NMR (400 MHz, DMSO) δ 8.86 (d, J = 7.4 Hz, 2H), 8.54 (s, 2H), 8.20 (s, 1H), 5.86 (d, J = 7.3 Hz, 1H), 5.54 (d) , J = 6.2 Hz, 1H), 5.36 (d, J = 4.1 Hz, 1H), 4.76 (s, 2H), 4.59 (s, 1H), 4.34 (s, 1H), 3.40 (dd, J = 10.3, 4.5 Hz, 1H), 2.80 (dd, J = 10.9, 2.6 Hz, 1H), 2.42 (t, J = 6.9 Hz, 2H), 1.58 - 1.49 (m, 2H), 1.48 - 1.38 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H)

MS (ESI) m/z 493 [M+H]+

Example 24. (2R,3R,4S)-2-[6-[(2-bromo-4-pyridyl)methylamino]-2-hex-1-ynyl-purin-9-yl]tetrahydroti Preparation of ophene-3,4-diol (14b) [(2R,3R,4S)-2-[6-[(2-bromo-4-pyridyl)methylamino]-2-hex-1-ynyl-purin-9 -yl]tetrahydrothiophene-3,4-diol]

The target compound (51%) was obtained by the same method as compound 14a .

1H NMR (400 MHz, DMSO) δ 8.55 (s, 2H), 8.30 (d, J = 4.8 Hz, 1H), 7.57 (s, 1H), 7.36 (d, J = 5.6 Hz, 1H), 5.87 (d) , J = 7.2 Hz, 1H), 5.55 (d, J = 6.2 Hz, 1H), 5.37 (d, J = 4.1 Hz, 1H), 4.69 (s, 2H), 4.60 (s, 1H), 4.34 (s , 1H), 3.41 (dd, J = 11.0, 3.7 Hz, 1H), 2.80 (dd, J = 10.3, 2.5 Hz, 1H), 2.41 (t, J = 6.8 Hz, 2H), 1.57 - 1.48 (m, 2H), 1.46 - 1.37 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H)

MS (ESI) m/z 503 [M+H]+

Examples 25-26. (2R)-2-[2-chloro-6-[[5-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl]-1-oxo-thiorane-3,4- Diol (15) [(2R)-2-[2-chloro-6-[[5-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl]-1-oxo-thiolane-3,4-diol ] and (2R)-2-[2-chloro-6-[[1-oxo-5-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl]-1-oxo-thio Lan-3,4-diol (16) [(2R)-2-[2-chloro-6-[[1-oxo-5-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl]-1 Preparation of -oxo-thiolane-3,4-diol]

Compounds 15 and 16 were synthesized as shown in Scheme 5 below.

<Scheme 5>

Compound 9f (10 mg, 0.02 mmol) and mCPBA (6.6 mg, 0.03 mmol) were added to a mixed solvent of dichloromethane/acetonitrile (0.32 ml, 1:1, v/v) and stirred at room temperature for 2 hours. The reaction mixture was washed with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. The residue was purified by MPLC (dichloromethane:methanol=95:5) on silica gel to obtain the target compounds 15 (2.9 mg, 28%) and 16 (3 mg, 28%) as white solids.

1H NMR of 15 (400 MHz, DMSO) δ 9.11 (s, 1H), 8.88 (s, 2H), 8.41 (s, 1H), 8.22 (s, 1H), 5.89 (d, J = 6.6 Hz, 1H) , 5.80 (d, J = 3.6 Hz, 1H), 5.61 (d, J = 10.2 Hz, 1H), 5.03 (s, 1H), 4.77 (d, J = 5.7 Hz, 2H), 4.42 (d, J = 3.2 Hz, 1H), 3.86 (d, J = 13.9 Hz, 1H), 2.91 (dd, J = 13.8, 3.5 Hz, 1H)

MS (ESI) m/z 463 [M+H]+

1H NMR of 16 (400 MHz, DMSO) δ 9.14 (s, 1H), 8.89 (d, J = 4.5 Hz, 2H), 8.49 (s, 1H), 8.22 (s, 1H), 6.22 (d, J = 6.7 Hz, 1H), 6.16 (d, J = 1.8 Hz, 1H), 5.71 (d, J = 10.3 Hz, 1H), 4.95 (s, 1H), 4.77 (d, J = 5.5 Hz, 2H), 4.49 (s, 1H), 3.61 - 3.57 (m, 2H)

MS (ESI) m/z 479[M+H]+

Example 27. (2R,3R,4S)-2-[2-chloro-6-[[1-oxido-5-(trifluoromethyl)pyridin-1-ium-3-yl]methylamino]purine Preparation of -9-yl]tetrahydrothiophene-3,4-diol (21) [(2R,3R,4S)-2-[2-chloro-6-[[1-oxido-5-(trifluoromethyl)pyridin -1-ium-3-yl]methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol]

Compound 21 was synthesized as shown in Scheme 6 below.

<Scheme 6>

(1) Step 1: Preparation of compound 18

Dissolve (5-(trifluoromethyl)pyridin-3-yl)methanamine (250 mg, 1.42 mmol) and 4-dimethylaminopyridine (DMAP, 69 mg, 0.006 mmol) in acetonitrile (5.3 ml). Di-tert-butyl dicarbonate (Boc ₂ O, 1.24 g, 5.68 mmol) was added thereto and stirred at 45°C overnight. The reaction mixture was washed with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate (MgSO ₄ ), filtered, and concentrated under reduced pressure. The residue was purified by MPLC (ethyl acetate:hexane=1:3) on silica gel to obtain the target compound (484 mg, 91%).

MS (ESI) m/z 377 [M+H]+

(2) Step 2: Preparation of compound 19

Compound 18 (484 mg, 1.29 mmol) and m-chloroperoxybenzoic acid (mCPBA, 490 mg, 2.19 mmol) prepared in the above step were dissolved in acetone (52 ml) and stirred at room temperature for 3.5 days. After concentrating the reaction mixture under reduced pressure, the residue was adsorbed on silica gel and purified by MPLC (dichloromethane:methanol=97:3) on silica gel to obtain the target compound (330 mg, 65%).

MS (ESI) m/z 393[M+H]+

(3) Step 3: Preparation of compound 20

Compound 19 (330 mg, 0.84 mmol) and trifluoroacetic acid (1.15 ml) prepared in the above step were dissolved in dichloromethane (4.2 ml) and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and used in the next reaction without further purification.

MS (ESI) m/z 193 [M+H]+

(4) Step 4: Compound (2R,3R,4S)-2-[2-chloro-6-[[1-oxido-5-(trifluoromethyl)pyridin-1-ium-3-yl]methyl Preparation of amino] purin-9-yl] tetrahydrothiophene-3,4-diol (21)

Compound 20 (162 mg, 0.84 mmol) prepared in the above step was dissolved in ethanol (11.2 ml), cooled to 0°C, and triethylamine (0.56 ml, 4.04 mmol) was added. Compound 8 (104 mg, 0.34 mmol) was added thereto and stirred at room temperature overnight. The residue obtained by concentrating the reaction mixture under reduced pressure was adsorbed on silica gel and purified by MPLC (dichloromethane:methanol=95:5) on silica gel to obtain the target compound (73 mg, 47%) as a white solid.

1H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.66 (s, 1H), 8.55 (s, 1H), 8.44 (s, 1H), 7.72 (s, 1H), 5.82 (d, J = 7.4 Hz, 1H), 5.57 (d, J = 6.1 Hz, 1H), 5.39 (d, J = 3.9 Hz, 1H), 4.67 (s, 2H), 4.60 (s, 1H), 4.33 (s, 1H) , 3.41 (dd, J = 11.1, 3.8 Hz, 1H), 2.79 (dd, J = 11.1, 2.4 Hz, 1H)

MS (ESI) m/z 463 [M+H]+

Experimental Example 1. Evaluation of cyclic AMP (cAMP) agonism activity

(1) Experimental method

The experimental cell line [CHO-K1/ADORA3/Ga15 Stable cell line (Chinese Hamster Ovary Cell)] was purchased from Genscript, and culture medium (Ham's F12K, Fetal bovine serum, 100 μg/ml Hygromycin B, 8 μg/ml Puromycin) was used. The cells were dispensed into a 96-well White/ClearFlat Bottom plate and cultured in a 37°C, 5% CO ₂ incubator for 24 hours. The cAMP assay was performed according to the analysis method of Promega's cAMP-Glo assay kit (V1502).

To evaluate the degree of agonism, the activity percentage value (Agonism %) was obtained according to the following calculation formula 1. EC ₅₀ results were calculated using the SoftMax Pro program.

<Calculation 1>

Action activity (%) = (RLU _{test group} - RLU _{forskolin control} / RLU _{Induction control} - RLU _{forskolin control} )

Take the assay plate out of the 37℃, 5% CO ₂ incubator, discard the culture medium, and add induction buffer (500 μM IBMX, 100 μM Ro 20-1724, PBS), 5 μM Forskolin in induction buffer, 5 μM 20 μL of each compound diluted with forskolin-containing buffer was treated at each concentration. After 15 minutes, 20 μL of Lysis buffer was added and reacted on a stirrer for 20 minutes.

After adding 40 μL of cAMP detection solution (PKA in reaction buffer), the mixture was reacted on a stirrer for 1 minute and then reacted at room temperature for 20 minutes. After adding 80 μL of Kinase Glo Reagent, luminescence values were measured using SpectraMax iD3 Multi mode plate readers (MOLECULAR DEVICES).

(2) Results

The cAMP agonism activity (%) measured as above by treating each compound at 1 μM and 10 μM is shown in Table 1 below.

Example 1 uM (%) 10 uM (%) One +++ ++ 2 +++ +++ 3 +++ ++ 4 ++ ++ 5 +++ +++ 6 ++ ++ 7 ++ ++ 8 + ++ 9 + ++ 10 ++ +++ 11 ++ ++ 12 + + 13 + + 14 + + 15 +++ +++ 16 + ++ 17 +++ +++ 18 +++ +++ 19 +++ +++ 20 ++ ++ 21 +++ +++ 22 ++ ++ 23 + ++ 24 +++ +++ 25 + + 26 + + 27 + +

[* Below 30% (+), Above 30% ~70% (++), Above 70% (+++)]

As shown in Table 1, treatment of 27 example compounds at concentrations of 1 μM and 10 μM reduced cAMP levels, confirming that the example compounds exhibit A ₃ adenosine receptor agonist activity.

Experimental Example 2. Evaluation of CYP enzyme metabolism

After the example compound (10 μM) was treated with five types of CYP enzymes, the degree of inhibition on enzyme metabolism was measured, and the results are shown in Table 2 below.

Example 1A2 2C9 2C19 2D6 3A4 One 3.1 21.9 12.6 9.8 9.7 2 11.7 2.3 0 0 62.0 3 0 16.6 11.6 3.2 0.8 4 0 15.8 11.7 8.7 0 5 10.2 6.5 9.5 6.4 48.0 6 0 15.6 19.8 0.2 57.5 13 4.9 17.3 4.7 5 0 15 10.4 15.7 24.8 3.2 0 17 0 33.6 27.1 0.1 0 18 13.7 6.3 13.4 1.1 48.1 24 14.9 52.2 46.9 40.3 0 25 2.5 5.6 5.3 0.2 21.7 26 10.5 33.4 6.6 8.1 29.8 27 4.7 4.2 2.6 0.9 0

As shown in Table 2, the test example compounds showed a low degree of inhibition against five representative CYP enzymes, confirming that there is a low risk of drug interaction when administered in combination with other drugs in the future.

Experimental Example 3. Pulmonary fibrosis inhibition test in experimental animal model

To observe whether pulmonary fibrosis of vascular endothelial cells occurs in pulmonary fibrosis symptoms that occur after radiation therapy, 17.5 Gy of radiation was irradiated to the lungs of C57BL/6 mice. Afterwards, the lungs were removed from the mouse, and collagen, a protein that appears during fibrosis of pulmonary vascular endothelial cells, was confirmed using trichrome staining on the aortic cross section of the lung tissue, and the results are shown in Figure 1.

In order to evaluate the degree of inhibition of radiation-induced pulmonary fibrosis by the example compounds, each compound (Example compounds 3, 5, and 7) was orally administered in an amount of 30 mg/kg 1 hour before radiation irradiation. As shown in Figure 1, the example compounds of the present invention were confirmed to significantly reduce pulmonary fibrosis caused by radiation irradiation.

The description of the present invention described above is for illustrative purposes, and those skilled in the art will understand that the present invention can be easily modified into other specific forms without changing the technical idea or essential features of the present invention. will be. Therefore, the embodiments described above should be understood in all respects as illustrative and not restrictive. For example, each component described as unitary may be implemented in a distributed manner, and similarly, components described as distributed may also be implemented in a combined form.

The scope of the present invention is indicated by the claims described below, and all changes or modified forms derived from the meaning and scope of the claims and their equivalent concepts should be construed as being included in the scope of the present invention.

Claims (14)

A purine derivative compound represented by the following formula (Ⅰ), its hydrate, its solvate, or its pharmaceutically acceptable salt:
<Formula Ⅰ>

In the above equation,
R is Q ₁ -Q ₂ -Q ₃ ,
Q ₁ is C _1-4 alkyl,
Q ₂ is heteroaryl of a 5- or 6-membered ring having 1 to 3 N, and the replaceable nitrogen in the heteroaryl is optionally substituted with =O,
Q ₃ is C _1-4 alkyl, C _1-4 alkoxy, halogen, or C _1-4 haloalkyl, and 1 to 3 independent Q ₃ are substituted on Q ₂ ,
X is C _2-10 alkynyl, or halogen,
Y is S or S=O. The purine derivative compound of claim 1, wherein Q ₁ is selected from the group consisting of methyl, ethyl, and propyl, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein Q ₂ is heteroaryl selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl and triazinyl; or oxoheteroaryl selected from the group consisting of oxopyrrolyl, oxoimidazolyl, oxopyrazolyl, oxotriazolyl, oxopyridyl, oxopyrazinyl, oxopyrimidyl, oxopyridazinyl and oxotriazinyl. A purine derivative compound, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein Q ₃ is selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, propoxy, F, Cl, Br, I, CH ₂ F, CHF ₂ and CF ₃ A purine derivative compound, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. The purine derivative compound according to claim 1, wherein Salts that are generally acceptable. The purine derivative compound according to claim 1, wherein the purine derivative compound represented by Formula I is any one selected from the group consisting of the following compounds, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. :
[1] (2R)-2-[6-[(2-bromo-4-pyridyl)methylamino]-2-chloro-purin-9-yl]tetrahydrothiophene-3,4-diol,
[2] (2R)-2-[2-chloro-6-[(5-chloro-3-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol,
[3] (2R)-2-[2-chloro-6-[(2-chloro-4-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol,
[4] (2R)-2-[2-chloro-6-[[2-(trifluoromethyl)-4-pyridyl]methylamino]purin-9-yl]tetrahydrothiophene-3,4- dior,
[5] (2R)-2-[6-[(5-bromo-3-pyridyl)methylamino]-2-chloro-purin-9-yl]tetrahydrothiophene-3,4-diol,
[6] (2R)-2-[2-chloro-6-[[5-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl]tetrahydrothiophene-3,4- dior,
[7] (2R,3R,4S)-2-[2-chloro-6-[(2-methyl-4-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol ,
[8] (2R,3R,4S)-2-[2-chloro-6-[(6-methyl-3-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol ,
[9] (2R,3R,4S)-2-[2-chloro-6-[(6-methyl-2-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4-diol ,
[10] (2R,3R,4S)-2-[2-chloro-6-[(6-methoxy-3-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4- dior,
[11] (2R,3R,4S)-2-[2-chloro-6-[(6-methoxy-2-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4- dior,
[12] (2R,3R,4S)-2-[2-chloro-6-[[6-(trifluoromethyl)-2-pyridyl]methylamino]purin-9-yl]tetrahydrothiophene- 3,4-diol,
[13] (2R,3R,4S)-2-[2-chloro-6-[[6-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl]tetrahydrothiophene- 3,4-diol,
[14] (2R,3R,4S)-2-[2-chloro-6-[(6-fluoro-3-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4- dior,
[15] (2R,3R,4S)-2-[2-chloro-6-[(2-methoxy-4-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4- dior,
[16] (2R,3R,4S)-2-[2-chloro-6-[(6-fluoro-2-pyridyl)methylamino]purin-9-yl]tetrahydrothiophene-3,4- dior,
[17] (2R,3R,4S)-2-[2-chloro-6-[[6-chloro-5-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl]tetra Hydrothiophene-3,4-diol,
[18] (2R)-2-[6-[(5-chloro-3-pyridyl)methylamino]-2-prop-1-ynyl-purin-9-yl]tetrahydrothiophene-3,4 -Dior,
[19] (2R)-2-[6-[(2-bromo-4-pyridyl)methylamino]-2-prop-1-ynyl-purin-9-yl]tetrahydrothiophen-3, 4-dior,
[20] (2R)-2-[2-prop-1-ynyl-6-[[2-(trifluoromotel)-4-pyridyl]methylamino]purin-9-yl]tetrahydrothiophene -3,4-diol,
[21] (2R)-2-[6-[(2-chloro-4-pyridyl)methylamino]-2-prop-1-ynyl-purin-9-yl]tetrahydrothiophene-3,4 -Dior,
[22] (2R)-2-[2-prop-1-ynyl-6-[[5-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl]tetrahydrothiophene -3,4-diol,
[23] (2R,3R,4S)-2-[2-hex-1-ynyl-6-[[5-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl]tetra Hydrothiophene-3,4-diol,
[24] (2R,3R,4S)-2-[6-[(2-bromo-4-pyridyl)methylamino]-2-hex-1-ynyl-purin-9-yl]tetrahydrothiophene -3,4-diol
[25] (2R)-2-[2-chloro-6-[[5-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl]-1-oxo-thiorane-3 ,4-diol,
[26] (2R)-2-[2-chloro-6-[[1-oxo-5-(trifluoromethyl)-3-pyridyl]methylamino]purin-9-yl]-1-oxo- thiorane-3,4-diol, and
[27] (2R,3R,4S)-2-[2-chloro-6-[[1-oxido-5-(trifluoromethyl)pyridin-1-ium-3-yl]methylamino]purine- 9-yl]tetrahydrothiophene-3,4-diol. A pharmaceutical composition for preventing or treating pulmonary fibrosis comprising an _adenosine receptor agonist as an active ingredient. The pharmaceutical composition according to claim 7, wherein the pulmonary fibrosis is one or more types selected from the group consisting of idiopathic pulmonary fibrosis (IPF), interstitial lung disease, radiation-induced fibrosis, and asbestos-induced pulmonary fibrosis. A pharmaceutical composition for the prevention or treatment of A ₃ adenosine receptor-related diseases, comprising the derivative compound of any one of claims 1 to 6, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition according to claim 9, wherein the A ₃ adenosine receptor-related disease is pulmonary fibrosis. The pharmaceutical composition according to claim 10, wherein the pulmonary fibrosis is one or more types selected from the group consisting of idiopathic pulmonary fibrosis (IPF), interstitial lung disease, radiation-induced fibrosis, and asbestos-induced pulmonary fibrosis. A pharmaceutical composition comprising the purine derivative compound of any one of claims 1 to 6, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. Preparing a compound of formula III below by dissolving a compound of formula II below in an aqueous solution of formic acid; and
Preparing a compound of Formula Ia by reacting a compound of Formula III below with RNH ₂
Method for preparing a compound of formula Ia comprising:
<Formula Ⅰa>

<Formula Ⅱ>

<Formula Ⅲ>

The definitions of X and R are the same as those of Chemical Formula I in Clause 1. A method for producing a compound of Formula Ib, comprising the step of reacting a compound of Formula Ia below with mCPBA in an organic solvent to prepare a compound of Formula Ib below:
<Formula Ⅰa>

<Formula Ⅰb>

The definitions of X and R are the same as those of Chemical Formula I in Clause 1.