KR101273763B1 - A2A adenosine derivatives, method for the synthesis thereof, and the pharmaceutical compositions for the prevention or treatment of the inflammatory diseases containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to A _2A adenosine receptor, a method for preparing the same, and a pharmaceutical composition for preventing or treating an inflammatory disease comprising the same as an active ingredient. The present invention relates to a pharmaceutical composition for preventing or treating an inflammatory disease comprising a compound represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt thereof. Since the compound of Formula 1 shows high binding affinity and selectivity for the A _2A adenosine receptor, it may be usefully used for the prevention or treatment of inflammatory diseases.
[Formula 1]

Description

A2A adenosine receptor, method for preparing the same, and pharmaceutical composition for preventing or treating inflammatory disease comprising the same as an active ingredient for the prevention or treatment of the inflammatory diseases containing the same as an active ingredient}

The present invention relates to an A _2A adenosine receptor, and more particularly to a pharmaceutical composition for preventing or treating an inflammatory disease comprising the A _2A adenosine receptor, a preparation method thereof, and an active ingredient thereof.

Adenosine is a substance that performs many physiological functions through receptors on specific cell membranes and has a wide range of physiological reactions, including immune and inflammatory responses that are mediated by receptors and interact with four or more types of plasma membrane receptors. Have activity.

Adenosine receptors have, to date, been classified as P1 and P2 receptors through pharmacological studies and molecular cloning. The P1 receptor acts as a substrate for adenosine, and the P2 receptor acts as a substrate for ATP, ADP, UTP and UDP to express physiological activity. Among them, P1 receptors have been identified, four different subtypes of the adenosine receptors, are classified according to affinity, the body distribution of the ligand (ligand), or the like acting path by A _1, A ₂ or A _3, A ₂ is again A _2A and A _2B .

Adenosine action is also regulated by interacting with specific receptors of other cell membranes belonging to the receptor family associated with the G protein. In addition to the molecular biology supposedly biological and pharmacological studies as four kinds of subtypes, for at least the adenosine receptor, A ₁ and A _2A receptors with a high affinity A _2B and A ₃ receptors, the adenosine A ₁ that has a lower affinity Identity of the A, A _2A , A _2B and A ₃ receptors has been allowed. Analogs of adenosine can interact with A ₁ , A _2A , A _2B as antagonists and A ₃ receptors have been identified.

A ₁ and A ₂ agonists of adenosine receptors are mainly derivatives of adenosine, and have been studied as antihypertensive agents, antipsychotics, arrhythmia agents, anti-lipabolic agents (diabetic agents), and brain protectants, and their antagonists are large. It is a xanthine derivative or a combination of several bicyclic rings, and is being developed as an asthma medicine, antidepressant medicine, arrhythmia medicine, kidney protector, Parkinson's disease medicine, and intelligence development agent.

A _2A adenosine receptors are also known to be present in lymphocytes, neutrophils, eosinophils, basophils, monocytes / macrophages, epithelial cells, and vascular endothelial tissues that interact with them. Adenosine that binds to the A _2A receptor can affect many of these types of cellular activities and reduce inflammation. For example, A _2A receptor agonists are known to significantly inhibit oxidative species induced by physiological stimulators such as neutrophil chemotactic, cytokine and lipid products.

A ₃ adenosine agonists inhibit the release of the tumor necrosis factor TNF-a (tumor necrosis factor), which is an inflammatory mediator, and the production of inflammatory mediators MIP-1a, interleukin-12 and interferon- It is known to have a protective effect against the heart and brain diseases such as epilepsy.

Among the previously developed materials, representative human adenosine A ₃ agonists are N6- (3-iodobenzyl) -2-chloro-5 '-(N-methylcarbamoyl) -adenosine (CI-IB-MECA), Compared to adenosine A ₁ and A ₂ receptors, it shows high affinity and selectivity for A ₃ receptor.

In addition, 4'-thioadenosine derivatives similar to CI-IB-MECA have a binding affinity (Ki) of 1.66 nM and act as an A ₃ antagonist, indicating high affinity and selectivity. Therefore, nucleoside A ₃ antagonists are applicable to new therapeutic drugs for various diseases such as asthma, inflammation, cerebral ischemia, heart disease, and cancer.

Thus, the present inventors studied a method for preparing A _2A adenosine receptors similar to CI-IB-MECA and 4'-thioadenosine derivatives, and showed that the A _2A adenosine receptor exhibits high affinity and selectivity, A _2A agonists and A ₃ The present invention was completed by confirming that it can effectively prevent and treat inflammatory diseases by acting as an antagonist.

The present invention provides a pharmaceutical composition for the prevention or treatment of A _2A adenosine receptor, a method for preparing the same and an inflammatory disease comprising the same as an active ingredient.

The present invention also provides a method for preparing a compound represented by the following formula (1) having high binding affinity and selectivity as an A _2A adenosine agonist, or a pharmaceutically acceptable salt thereof.

In order to achieve the above object, the present invention provides, as one embodiment, a compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof.

[Formula 1]

Where

X is S or O and Y is CH ₂ ; Or X and Y together form a cyclopropyl;

R ₁ is hydrogen, C _4-8 alkyl, C _4-8 alkenyl, or C _4-8 alkynyl;

R ₂ is hydrogen, C _4-8 alkyl, C _4-8 alkenyl, C _4-8 alkynyl, or furanyl; And

R ₃ is amine or C _4-8 alkynyl.

Preferably, R ₁ is hydrogen and R ₂ is C _4-8 alkyl, C _4-8 alkenyl, or C _4-8 alkynyl.

Also preferably, R ₁ is C _4-8 alkyl, C _4-8 alkenyl, or C _4-8 alkynyl, and R ₂ is hydrogen.

Also preferably, R ₁ is hydrogen, hexyl, (E) -1-hex-1-enyl, or 1-hex-1-ynyl.

Also preferably, R ₂ is hydrogen, hexyl, (E) -1-hex-1-enyl, 1-hex-1-ynyl, or furan-3-yl.

Also preferably, R ₃ is amine or 1-hex-1-ynyl.

Examples of the compound represented by Formula 1 according to the present invention are as follows.

1) (2R, 3S, 4R) -2- (6-amino-2- (hex-1-ynyl) -9H-purin-9-yl) -tetrahydrothiophene-3,4-diol,

2) (2R, 3S, 4R, E) -2- (6-amino-2- (hex-1-enyl) -9H-purin-9-yl) -tetrahydrothiophene-3,4-diol,

3) (2R, 3S, 4R) -2- (6-amino-8- (hex-1-ynyl) -9H-purin-9-yl) -tetrahydrothiophene-3,4-diol,

4) (2R, 3S, 4R, E) -2- (6-amino-8- (hex-1-enyl) -9H-purin-9-yl) -tetrahydrothiophene-3,4-diol,

5) (2R, 3S, 4S) -2- (6-amino-2- (hex-1-ynyl) -9H-purin-9-yl) -tetrahydrofuran-3,4-diol,

6) (2R, 3S, 4S) -2- (6-amino-2-hexyl-9H-purin-9-yl) -tetrahydrofuran-3,4-diol,

7) (2R, 3S, 4S, E) -2- (6-amino-2- (hex-1-enyl) -9H-purin-9-yl) -tetrahydrofuran-3,4-diol,

8) (2R, 3S, 4S) -2- (6-amino-8- (hex-1-ynyl) -9H-purin-9-yl) -tetrahydrofuran-3,4-diol,

9) (2R, 3S, 4S) -2- (6-amino-8-hexyl-9H-purin-9-yl) -tetrahydrofuran-3,4-diol,

10) (2R, 3S, 4S, E) -2- (6-amino-8- (hex-1-enyl) -9H-purin-9-yl) -tetrahydrofuran-3,4-diol,

11) (2R, 3S, 4S) -2- (6-Amino-8- (furan-3-yl) -2- (hex-1-ynyl) -9H-purin-9-yl) -tetrahydrofuran- 3,4-diol,

12) (1R, 2R, 3S, 4R, 5S) -4- (6-amino-2- (hex-1-ynyl) -9H-purin-9-yl) bicyclo [3.1.0] hexane-2, 3-diol,

13) (1R, 2R, 3S, 4R, 5S, E) -4- (6-amino-2- (hex-1-enyl) -9H-purin-9-yl) bicyclo [3.1.0] hexane- 2,3-diol,

14) (1R, 2R, 3S, 4R, 5S, E) -4- (2- (hex-1-enyl) -6- (hex-1-ynyl) -9H-purin-9-yl) bicyclo [ 3.1.0] hexane-2,3-diol, and

15) (1R, 2R, 3S, 4R, 5S) -4- (6-amino-8- (furan-3-yl) -2- (hex-1-ynyl) -9H-purin-9-yl) bi Cyclo [3.1.0] hexane-2,3-diol.

In another embodiment, the present invention provides a method for preparing a compound represented by Chemical Formula 1, for example, as in Scheme 1. In the following Scheme 1, the compound of Formula 2 is prepared from J. Med. It manufactures by the well-known method described in Chem (2006) 49, 273-281.

As shown in Scheme 1, 1) the compound of formula 2 is reacted with 2-amino-6-chloropurine silylated in the presence of Lewis acid catalyst Obtaining a compound; 2) obtaining a compound of formula 4 by reacting the halogenated compound with isoamyl nitrite to the compound of formula 3; 3) adding ammonia to the compound of Formula 4 to obtain a compound of Formula 5; 4) reacting the compound of Formula 5 with an iodine compound and 1-hexyne (1-Hexyne) in the presence of a palladium catalyst to obtain a compound of Formula 6; 5) adding hydrochloric acid to the compound of Formula 6 to obtain a compound of Formula 1a; 6) reacting the compound of Formula 5 with an inorganic base in the presence of a palladium catalyst (E) -1-catecholboranylhexene ((E) -1-catecholboranylhexene) to obtain a compound of Formula 7; 7) adding hydrochloric acid to the compound of Formula 7 to obtain a compound of Formula 1b.

[Reaction Scheme 1]

The step 1) is preferably reacted in a dichloroethane (DCE) solvent, and the steps 2) and 5) are preferably reacted in a tetrahydrofuran (THF) solvent. In addition, the step 4) is preferably reacted in a dimethylformamide (DMF), triethylamine (TEA) solvent.

Step 1) in the present invention is a step of obtaining a compound of formula 3 by reacting a compound of formula 2 with 2-amino-6-chloropurine silylated in the presence of a Lewis acid catalyst Means.

As the Lewis acid, trimethylsilyl trifluoromethanesulfonate (TMSOTf) is preferably used.

Specifically, step 1) is a compound of formula 2 is added to the reaction mixture of 2-amino-6-chloropurine, hexamethyldisilazane (HMDS) and ammonium sulfate reflux overnight in the presence of TMSOTf 0 ℃ 30 minutes at room temperature, 1 hour at room temperature, 2 hours at 90 ℃ to obtain a compound of formula (3).

In the present invention, step 2) is a step of reacting a compound of formula 3 with a halogenated compound and isoamyl nitrite to obtain a compound of formula 4, wherein the halogenated compound is CuI, I ₂ , CH ₂ I ₂ Preference is given to using.

Specifically, in step 2), CuI, I ₂ , CH ₂ I ₂ and isoamyl nitrite are added to the compound of Formula 3, stirred at room temperature, refluxed for 45 minutes, and then cooled to room temperature to obtain a compound of Formula 4 To obtain.

Step 3) is a step of obtaining a compound of formula 5 by adding an amine compound or alkene to the compound of formula 4, the amine compound is preferably using ammonia (NH ₃ ), methanol as the reaction solvent Can be.

Step 4) means a step of reacting the compound of Formula 5 with the iodine compound and the alkyne or alkene in the presence of a palladium catalyst to obtain a compound of Formula 6.

The palladium catalyst is bis (triphenylphosphine) palladium dichloride (bis (triphenylphosphine) palladium dichloride, (PPh ₃ ) ₂ PdCl ₂ ) or tetrakistriphenylphosphinepalladium (0) (tetrakis (triphenyl phosphine) palladium ( 0) is preferably used, and the iodine compound is preferably CuI.

Step 5) is a step of obtaining a compound of Formula 1 by adding hydrochloric acid to the compound of Formula 6, dissolving the compound of Formula 6 in THF and then the reaction of the compound of Formula 1 by adding 1N hydrochloric acid for 1 day at room temperature To obtain.

As another aspect, the present invention provides a method for preparing a compound represented by the formula (1) as shown in Scheme 2.

[Reaction Scheme 2]

As shown in Scheme 2, the present invention comprises the steps of: 1) reacting a compound of formula 2 with silylated 8-bromoadenine in the presence of a Lewis acid catalyst to obtain a compound of formula 7; 2) reacting the compound of Formula 7 with an iodine compound and an alkene, alkyne or furan in the presence of a palladium catalyst to obtain a compound of Formula 8; 3) adding hydrochloric acid to the compound of Formula 8 to obtain a compound of Formula 1.

The step 1) is preferably reacted in a dichloroethane solvent, and the step 2) is preferably reacted in a dimethylformamide and triethylamine solvent. In addition, the step 3) is preferably reacted in a tetrahydrofuran solvent.

Step 1) in the present invention refers to a step of obtaining a compound of formula 8 by reacting the compound of formula 2 with silylated 8-bromoadenine in the presence of a Lewis acid catalyst.

Specifically, step 1) is added to the reaction mixture of the compound of formula 2 refluxed 8-bromoadenine, hexamethyldisilazane and ammonium sulfate overnight in the presence of TMSOTf for 30 minutes at 0 ℃, 1 hour at room temperature , And reacted at 90 ° C. for 2 hours to obtain a compound of Formula 8.

Step 2) is a step of obtaining a compound of formula 8 by reacting the compound of formula 8 with an iodine compound and an alkene, alkyne or furan in the presence of a palladium catalyst.

Step 3) is a step of obtaining a compound of Formula 1 by adding hydrochloric acid to the compound of Formula 8, dissolving the compound of Formula 8 in THF and then reacting for 1 day at room temperature by adding 1N hydrochloric acid to the compound of Formula 1 To obtain.

In another embodiment, the present invention provides a method for preparing a compound represented by Chemical Formula 1, for example, as in Scheme 3.

Scheme 3

As shown in Scheme 3, 1) the compound of formula 2 is reacted with silylated 2-amino-6-chloropurine in the presence of Lewis acid catalyst Obtaining a compound; 2) obtaining a compound of formula 4 by reacting the halogenated compound with isoamyl nitrite to the compound of formula 3; 3) adding ammonia to the compound of Formula 4 to obtain a compound of Formula 5; 4) reacting the compound of Formula 5 with an iodine compound and 1-hexyne (1-Hexyne) in the presence of a palladium catalyst, and then adding hydrochloric acid to obtain a compound of Formula 2a; 5) obtaining the compound of Formula 2a in the presence of a Pd / C catalyst; 6) reacting the compound of Formula 5 with an inorganic base in the presence of a palladium catalyst (E) -1-catecholboranylhexene ((E) -1-catecholboranylhexene), and then adding hydrochloric acid to obtain a compound of Formula 2c. It includes a step.

As another aspect, the present invention provides a method for preparing a compound represented by the formula (1) as shown in Scheme 4.

[Reaction Scheme 4]

As shown in Scheme 4, 1) reacting a compound of Formula 2 with 6-chloropurine in the presence of a Lewis acid catalyst to obtain a compound of Formula 6; 2) adding ammonia to the compound of Formula 6 to obtain a compound of Chemical Time 7; 3) reacting the compound of Formula 7 with bromine (Br ₂ ) to obtain a compound of Chemical Time 8; 4) reacting the compound of Formula 8 with the iodine compound and 1-hexyne (1-Hexyne) in the presence of a palladium catalyst, and then adding hydrochloric acid to obtain a compound of Formula 2d; 5) obtaining the compound of Formula 2d in the presence of a Pd / C catalyst; 6) reacting the compound of Formula 2e with an inorganic base in the presence of a palladium catalyst (E) -1-catecholboranylhexene ((E) -1-catecholboranylhexene) to obtain a compound of Formula 2f.

As a result of evaluating the binding affinity and selectivity of the compound represented by Formula 1 according to the present invention, it was confirmed that high binding affinity and selectivity in the human A _2A and A ₃ adenosine receptor.

In addition, as a result of analyzing the antagonistic effect and cAMP inhibitory effect on the A ₃ adenosine receptor of the compound according to the present invention, it acts as a selective agonist as a human A _2A adenosine receptor, a competitive antagonist to the human A ₃ adenosine receptor I could confirm it.

Therefore, the compound represented by Formula 1 of the present invention shows high affinity and selectivity for A _2A and A ₃ adenosine receptors, and thus can be used for the prevention or treatment of A _2A adenosine receptor related diseases.

The present invention provides a pharmaceutical composition for preventing or treating a disease related to A _2A adenosine receptor, comprising the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, in the present invention, the A _2A adenosine receptor-related disease may be an inflammatory disease, and specifically, the inflammatory disease may be any one selected from the group consisting of degenerative inflammation, exudative inflammation, purulent inflammation, hemorrhagic inflammation, and proliferative inflammation. It may include one disease, but is not limited thereto.

As used herein, the term "prophylaxis or treatment of a disease" refers to the prevention, complete or partial treatment of the disease. It also includes reducing symptoms, improving symptoms, alleviating symptoms of pain, and reducing the incidence of disease.

The composition of the present invention may further comprise a pharmaceutically acceptable carrier. The composition comprising a pharmaceutically acceptable carrier can be in various oral or parenteral formulations. When formulated, it may be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. which are commonly used.

Solid preparations for oral administration include tablets, troches, lozenges, aqueous or oily suspensions, prepared powders or granules, emulsions, hard or soft capsules, syrups or elixirs, and the like. Binders such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin for preparation in formulations such as tablets and capsules; Excipients such as dicalcium phosphate; Disintegrants such as corn starch or sweet potato starch; Lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate or polyethylene glycol wax. In the case of capsule formulations, liquid carriers such as fatty oils may be used in addition to the substances mentioned above.

In order to formulate the formulation for parenteral administration, the compound of Formula 1 is mixed with a stabilizer, a buffer, a sterile aqueous solution, a non-aqueous solvent, a suspension, an emulsion, a lyophilized agent and a suppository, and prepared as a solution or suspension, which is ampoule. Formulated in unit dosage form as a vial. As the non-aqueous solvent and suspending agent, vegetable oils such as propylene glycol, polyethylene glycol and olive oil, injectable esters such as ethyl oleate and the like can be used. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.

The composition of the present invention may be administered via any general route as long as it can reach the desired tissue. The composition of the present invention may be administered conventionally or locally, and may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, intradermally, orally, intranasally, intrapulmonally, or rectally. It is not limited.

In addition, the dosage of the active ingredient, such as a compound of the invention or a pharmaceutically acceptable salt thereof, depends on the subject being treated, the severity of the disease or condition, the rate of administration and the judgment of the prescribing physician. The compound of formula 1, which is an active ingredient, may be administered once or in divided doses in an amount of 0.001 to 100 mg / kg (body weight) per day, and the route of administration may vary depending on the condition of the patient and its severity. Thus, the dosage amounts are not intended to limit the scope of the invention in any manner.

The A _2A adenosine receptor of the present invention exhibits high affinity and selectivity for A _2A and A ₃ receptors, and acts as an A _2A agonist and A ₃ antagonist, thus exhibiting anti-inflammatory activity, and thus, a pharmaceutical composition containing the same as an active ingredient. May be usefully used as an agent for preventing and treating inflammatory diseases.

Figure 1 (a) shows the antagonistic effect and cAMP inhibition experiments on the CHO cells of the compound 1a prepared in Example 1 of the present invention, 1 (b) 1a ~ prepared in Examples 1 to 4 of the present invention It shows the dissociation constant k _b value according to the Schild analysis of the 1d compound, 1 (c) shows the activity of the 1a compound as an agonist of the human A _2A adenosine receptor expressed in CHO compared to CGS21680.
2 (a), (b) show the predicted binding modes of 1a, 1b compounds in the human A _2A adenosine receptor crystal structure.

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.

Example 1 Preparation of (2R, 3S, 4R) -2- (6-amino-2- (hex-1-ynyl) -9H-purin-9-yl) -tetrahydrothiophene-3,4-diol

Step 1) 6-Chloro-9-((3a S , 4 R , 6a R ) -tetrahydro-2,2-dimethylthieno [3,4-d] [1,3] dioxol-4-yl) Preparation of -9H-purin-2-amine

Inert by dissolving 0.91 g (5.35 mmol) of 2-amino-6-chloropurine and 106 mg (0.80 mmol) of ammonium sulfate in 10 mL of hexamethyldisilazane (HMDS). At reflux overnight under dry conditions. The reaction mixture was concentrated under reduced pressure, and then the obtained solid mixture was dissolved in 5 mL of 1,2-dichloroethane and cooled at 0 ° C. 0.58 g (2.68 mmol) of (3aR, 4R, 6aS) -2,2-dimethyltetrahydrothieno [3,4-d] [1,3] dioxol-4-yl acetate was added to 1,2-dichloroethane 5 It was dissolved in mL and added dropwise to the reaction mixture. 0.97 mL (5.35 mmol) of trimethylsilyl trifluoromethanesulfonate (TMSOTf) was added dropwise to the reaction mixture, stirred at 0 ° C. for 30 minutes, stirred at room temperature for 1 hour, and then heated to 90 ° C. and stirred for 2 hours. After cooling the reaction mixture, it was diluted with dichloromethane (CH ₂ Cl ₂ ) and washed with saturated aqueous sodium bicarbonate (NaHCO ₃ ). The organic layer was dried over anhydrous magnesium sulfate (MgSO ₄ ), filtered, and concentrated under reduced pressure, followed by silica gel column chromatography using a mixed solvent of hexane (Hexane): ethyl acetate (EtOAc) (1: 1, v / v) as a developing solvent. The title compound (0.27 g, 30%) was obtained by flash silica gel column chromatography.

Solid. mp 199.1-199.2; UV (CH ₂ Cl ₂ ) _max 305.0 nm; ¹ H NMR (CDCl ₃ ) d 7.87 (s, 1H), 5.73 (s, 1H), 5.29 (brs, 2H, NH ₂ ), 5.16-5.21 (m, 2H), 3.64 (dd, 1H, J = 4.4, 13.2 Hz), 3.20 (d, 1H, J = 13.2 Hz), 1.58 (s, 3H), 1.35 (s, 3H); ¹³ C NMR (CDCl ₃ ) d 159.14, 153.21, 151.91, 141.14, 126.24, 111.96, 89.50, 84.23, 69.48, 40.78, 26.54, 24.83; [a] ²⁵ _D -42.23 (c 0.16, CH ₂ Cl ₂ ); (ESI ⁺ ) (M + Na ⁺ ) m / z 350.04.

Step 2) 6-Chloro-9- (3aS, 4R, 6aR) -tetrahydro-2,2-dimethylthier [3,4-d] [1,3] dioxol-4-yl) -2-iodo Preparation of -9H-Purine

A compound 248 mg (0.76 mmol) and _{I 2 192 mg (0.76 mmol)} , CH 2 I 2 0.95 mL (7.60 mmol) and CuI 159 mg (0.83 mmol) prepared in Step 1), isoamyl nitrite (Isoamylnitrite) 0.55 mL (4.06 mmol) was added, dissolved in 10 mL of tetrahydrofuran (THF), and stirred at room temperature. The reaction mixture was refluxed for 45 minutes and then cooled at room temperature. The undissolved material was removed by a filter, and the obtained filtrate was dried and concentrated and washed with hexane until the color of iodine disappeared. The residue was purified by silica gel column chromatography using hexane: ethyl acetate mixed solvent (7: 1, v / v) as a developing solvent to obtain the title compound (233 mg, 72%).

syrup. UV (CH ₂ Cl ₂ ) _max 282.0 nm; ¹ H NMR (CDCl ₃ ) d 8.06 (s, 1H), 5.84 (s, 1H), 5.33 (pseudo t, 1H, J = 5.2 Hz), 5.21 (d, 1H, J = 5.6 Hz), 3.80 (dd , 1H, J = 4.4, 12.8 Hz), 3.26 (d, 1H, J = 12.8 Hz), 1.59 (s, 3H), 1.37 (s, 3H); ¹³ C NMR (CDCl ₃ ) d 151.91, 151.21, 144.39, 132.65, 116.74, 112.13, 89.97, 84.85, 70.73, 41.48, 26.60, 24.78; [a] ²⁵ _D -66.33 (c 0.10, CH ₂ Cl ₂ ); (ESI ⁺ ) (M + Na ⁺ ) m / z 438.94.

Step 3) 9-((3aS, 4R, 6aR) -tetrahydro-2,2-dimethylthieno [3,4-d] [1,3] dioxol-4-yl) -2-iodo-9H Preparation of Purine-6-amine

535 mg (1.22 mmol) of the compound prepared in step 2) was dissolved in 5 mL of NH ₃ / MeOH, and stirred at 80 ° C. for 2 hours. The reaction mixture was dried and concentrated, and the residue was subjected to silica gel column chromatography using a hexane: ethyl acetate mixed solvent (1: 1, v / v) as a developing solvent to give the following compound (439 mg, 85%). Got it.

syrup: UV (CH ₂ Cl ₂ ) _max 267.0 nm; ¹ H NMR (CD ₃ OD) d 8.20 (s, 1H), 5.97 (s, 1H), 5.30 (pseudo t, 1H, J = 5.2 Hz), 5.23 (d, 1H, J = 5.6 Hz), 3.80 ( dd, 1H, J = 4.4, 12.8 Hz), 3.14 (d, 1H, J = 12.8 Hz), 1.54 (s, 3H), 1.35 (s, 3H); ¹³ C NMR (CD ₃ OD) d 156.11, 150.37, 141.97, 119.96, 117.99, 112.68, 91.19, 86.37, 71.30, 41.58, 26.84, 24.86; [a] ²⁵ _D -61.90, (c 0.08, CH ₂ Cl ₂ ); (ESI ⁺ ) (M + Na ⁺ ) m / z 419.99.

Step 4) Preparation of (2R, 3S, 4R) -2- (6-amino-2- (hex-1-ynyl) -9H-purin-9-yl) -tetrahydrothiophene-3,4-diol

96 mg (0.23 mmol) of the compound prepared in step 3) was dissolved in 1.5 mL of triethylamine (TEA) and 1.5 mL of DMF and purged with nitrogen, followed by bis (triphenylphosphine) palladium dichloride (bis ( 16 mg (0.023 mmol) of triphenylphosphine) palladium dichloride, (PPh ₃ ) ₂ PdCl ₂ ) and 4.3 mg (0.023 mmol) of CuI were added. 0.065 mL (0.57 mmol) of 1-hexyne (1-Hexyne) was added dropwise to the reaction mixture, followed by stirring at room temperature for 3 hours. The solution was removed under reduced pressure to give a crude compound, which was dissolved in 5 mL of THF, and then 5 mL of 1 N HCl was added and stirred for 1 day at room temperature. The reaction mixture was neutralized with 1 N NaOH solution, and then concentrated under reduced pressure, followed by silica gel column chromatography using dichloromethane (CH ₂ Cl ₂ ): methanol (MeOH) mixed solvent (20: 1, v / v) as a developing solvent. The chromatography gave the title compound (50 mg, 65%).

white solid. mp 234.2-234.8; UV (MeOH) _max 289.5 nm; ¹ H NMR (CD ₃ OD) d 8.45 (s, 1H), 5.98 (d, 1H, J = 6.4 Hz), 4.56-4.59 (m, 1H), 4.44 (dd, 1H, J = 4.4, 8.0 Hz) , 3.51 (dd, 1H, J = 4.8, 10.8 Hz), 2.96 (dd, 1H, J = 4.0, 10.8 Hz), 2.46 (t, 2H, J = 6.8 Hz), 1.60-1.67 (m, 2H), 1.48-1.57 (m, 2H), 0.98 (t, 3H, J = 7.2 Hz); ¹³ C NMR (CD ₃ OD) d 157.08, 151.32, 147.94, 142.27, 119.80, 88.50, 81.20, 80.90, 74.37, 63.94, 35.11, 31.55, 23.11, 19.46, 13.97; [a] ²⁵ _D -28.36 (c 0.20, MeOH); (ESI ⁺ ) (M + Na ⁺ ) m / z 334.1335.

Example 2: (2R, 3S, 4R, E) -2- (6-amino-2- (hex-1-enyl) -9H-purin-9-yl) -tetrahydrothiophene-3,4-diol Manufacture

46 mg (0.11 mmmol) of the compound prepared in step 3) of Example 1 and 13 mg (0.011 mmol) of tetrakistriphenylphosphine palladium (0) and sodium carbonate (Na) ₂ CO ₃ ) 35 mg (0.33 mmol) and (E) -1-catecholboranylhexene ((E) -1-catecholboranylhexane) 67 mg (0.33 mmol) in 5 mL of DMF: H ₂ O (8: 1) It was dissolved in and stirred overnight at 90 ℃. The reaction mixture was filtered and concentrated through a celite bed to obtain a crude compound, which was dissolved in 5 mL of THF, and then 5 mL of 1 N HCl was added and stirred at room temperature for 1 day. The reaction mixture was neutralized with 1 N NaOH solution, concentrated under reduced pressure, and subjected to silica gel column chromatography using a dichloromethane: methanol mixed solvent (20: 1, v / v) as a developing solvent (23 mg). , 63%).

white solid. mp 209.1-209.6; UV (MeOH) _max 274.5 nm; ¹ H NMR (DMSO-d ₆ ) d 8.37 (s, 1H), 7.11 (brs, 2H, NH 2), 6.87-6.94 (m, 1H), 6.29 (d, 1H, J = 15.2 Hz), 5.89 (d , 1H, J = 7.2 Hz), 5.52 (d, 1H, OH, J = 6.0 Hz), 5.36 (d, 1H, OH, J = 4.0 Hz), 4.63-4.67 (m, 1H), 4.37 (pseudo t , 1H, J = 3.2 Hz), 3.42 (dd, 1H, J = 4.4, 10.8 Hz), 2.80 (dd, 1H, J = 2.8, 10.8 Hz); 2.20-2.26 (m, 2H), 1.41-1.48 (m, 2H), 1.29-1.38 (m, 2H), 0.90 (t, 3H, J = 7.2 Hz); ¹³ C NMR (DMSO-d ₆ ) d 158.20, 155.49, 150.61, 139.60, 138.18, 130.44, 117.70, 78.51, 72.28, 61.02, 34.39, 31.40, 30.54, 21.73, 13.75. [a] ²⁵ _D -28.36 (c 0.20, MeOH); (ESI ⁺ ) (M + Na ⁺ ) m / z 336.1494; [a] ²⁵ _D -44.80 (c 0.12, MeOH).

Example 3: Preparation of (2R, 3S, 4R) -2- (6-amino-8- (hex-1-ynyl) -9H-purin-9-yl) -tetrahydrothiophene-3,4-diol

Step 1) 8-Bromo-9-((3aR, 6R, 6aS) -tetrahydro-2,2-dimethylthieno [3,4-d] [1,3] dioxol-6-yl) -9H Purin-2-amine

0.40 g (1.84 mmol) of 8-Bromoadenine and 37 mg (0.27 mmol) of ammonium sulfate were dissolved in 10 mL of hexamethyldisilazane (HMDS) and refluxed under inert, dried conditions overnight. The reaction mixture was concentrated under reduced pressure, and then the obtained solid mixture was dissolved in 5 mL of 1,2-dichloroethane and cooled at 0 ° C. 0.20 g (0.92 mmol) of (3aR, 4R, 6aS) -2,2-dimethyltetrahydrothieno [3,4-d] [1,3] dioxol-4-yl acetate, 1,2-dichloroethane 5 It was dissolved in mL and added dropwise to the reaction mixture. 0.33 mL (1.84 mmol) of TMSOTf was added dropwise to the reaction mixture, which was stirred for 30 minutes at 0 ° C. The mixture was stirred at room temperature for 1 hour, and then heated to 90 ° C and stirred for 2 hours. After cooling the reaction mixture was diluted with CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ solution. The organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The title compound (69 mg, 20%) was purified by silica gel column chromatography using a hexane: ethyl acetate mixed solvent (1: 1, v / v) as a developing solvent. )

syrup. UV (MeOH) _max 263.5 nm; ¹ H NMR (CDCl ₃ ) d 8.25 (s, 1H), 5.91 (s, 1H), 5.81 (brs, 2H, NH ₂ ), 5.54 (d, 1H, J = 5.2 Hz), 5.50 (pseudo t, 1H , J = 5.2 Hz), 3.87 (dd, 1H, J = 4.0, 12.4 Hz), 3.14 (d, 1H, J = 12.4 Hz), 1.60 (s, 3H), 1.38 (s, 3H); ¹³ C NMR (CDCl ₃ ) d 154.29, 153.03, 150.70, 127.76, 120.42, 111.41, 88.98, 85.99, 71.91, 41.35, 26.59, 24.65. [a] ²⁵ _D -77.07 (c 0.16, CH ₂ Cl ₂ ); (ESI ⁺ ) (M + Na ⁺ ) m / z 373.01.

Step 2) Preparation of (2R, 3S, 4R) -2- (6-amino-8- (hex-1-ynyl) -9H-purin-9-yl) -tetrahydrothiophene-3,4-diol

69 mg (0.19 mmol) of the compound prepared in step 1) was dissolved in 1.5 mL of TEA and 1 mL of DMF and purged with nitrogen, followed by (PPh ₃ ) ₂ PdCl ₂ 14 mg (0.019 mmol) and CuI 3.7 mg (0.019 mmol). ) Was added. 0.056 mL (0.48 mmol) of 1-hexyne was added dropwise to the reaction mixture, followed by stirring at room temperature for 3 hours. The solution was removed under reduced pressure to give a crude compound, which was dissolved in 3 mL of THF, and then 3 mL of 1 N HCl was added and stirred for 1 day at room temperature. The reaction mixture was neutralized with 1 N NaOH solution, concentrated under reduced pressure, and the title compound (36 mg) was purified by silica gel column chromatography using a dichloromethane: methanol mixed solvent (20: 1, v / v) as a developing solvent. , 58%).

white solid. mp 233.8-234.9; UV (MeOH) _max 294.0 nm; ¹ H NMR (DMSO-d ₆ ) d 8.16 (s, 1H), 7.40 (brs, 2H, NH ₂ ), 6.03 (d, 1H, J = 7.6 Hz), 5.44 (d, 1H, -OH, J = 6.4 Hz), 5.33 (d, 1H, OH, J = 4.0 Hz), 5.24-5.29 (m, 1H), 4.40 (dd, 1H, J = 1.6, 3.2 Hz), 3.42 (dd, 1H, J = 3.6 , 11.2 Hz), 2.80 (dd, 1H, J = 2.0, 11.2 Hz), 2.59 (t, 2H, J = 6.8 Hz), 1.55-1.62 (m, 2H), 1.44-1.51 (m, 2H), 0.93 (t, 3H, J = 7.2 Hz); ¹³ C NMR (DMSO-d ₆ ) d 55.71, 153.11, 149.10, 133.74, 118.91, 97.97, 76.51, 72.33, 70.72, 63.18, 35.52, 29.59, 21.38, 18.31, 13.41. [a] ²⁵ _D -112.2 (c 0.14, MeOH); (ESI ⁺ ) (M + Na ⁺ ) m / z 334.1339.

Example 4: (2R, 3S, 4R, E) -2- (6-amino-8- (hex-1-enyl) -9H-purin-9-yl) -tetrahydrothiophene-3,4-diol Manufacture

42 mg (0.12 mmol) of the compound prepared in step 1) of Example 3 was added to 14 mg (0.012 mmol) of tetrakistriphenylphosphinepalladium (0), 37 mg (0.35 mmol) of sodium carbonate, and (E) -1. 72 mg (0.35 mmol) of catecholboranylhexene was dissolved in 5 mL of DMF: H ₂ O (8: 1) and stirred overnight at 90 ° C. The reaction mixture was filtered and concentrated to a celite bed to obtain a crude compound, which was dissolved in 3 mL of THF, and then added 3 mL of 1 N HCl, and stirred at room temperature for one day. The reaction mixture was neutralized with 1 N NaOH solution, concentrated under reduced pressure, and the title compound (25 mg) was purified by silica gel column chromatography using a dichloromethane: methanol mixed solvent (20: 1, v / v) as a developing solvent. , 65%).

white solid. mp 248.6-248.8; UV (MeOH) _max 297.5 nm; ¹ H NMR (CD ₃ OD) d 8.15 (s, 1H), 6.94-7.01 (m, 1H), 6.60 (d, 1H, J = 15.2 Hz), 6.15 (d, 1H, J = 8.0 Hz), 5.27 (dd, 1H, J = 3.6, 8.0 Hz), 4.48-4.50 (m, 1H), 3.65 (dd, 1H, J = 3.6, 11.6 Hz), 2.93 (dd, 1H, J = 1.6, 11.6 Hz), 2.36-2.42 (m, 2H), 1.53-1.58 (m, 2H), 1.42-1.50 (m, 2H), 0.98 (t, 3H, J = 7.2 Hz); ¹³ C NMR (CD ₃ OD) d 153.00, 144.03, 117.51, 78.91, 74.49, 64.05, 36.36, 34.04, 32.11, 23.47, 14.38; [a] ²⁵ _D -71.56 (c 0.10, MeOH); (ESI ⁺ ) (M + Na ⁺ ) m / z 336.14.

Example 5: Preparation of (2R, 3S, 4S) -2- (6-amino-2- (hex-1-ynyl) -9H-purin-9-yl) -tetrahydrofuran-3,4-diol

Step 1) 6-Chloro-9-((3aS, 4R, 6aS) -tetrahydro-2,2-dimethylfuro [3,4-d] [1,3] dioxol-4-yl) -9H- Preparation of Purin-2-amine

0.84 g (4.94 mmol) of 2-amino-6-chloropurine and 98 mg (0.74 mmol) of ammonium sulfate were dissolved in 10 mL of hexamethyldisilazane (HMDS). At reflux overnight under dried conditions. The reaction mixture was concentrated under reduced pressure, and then the obtained solid mixture was dissolved in 5 mL of 1,2-dichloroethane and cooled at 0 ° C. 0.50 g (2.47 mmol) of (3aR, 4R, 6aS) -2,2-dimethyltetrahydrothieno [3,4-d] [1,3] dioxol-4-yl acetate was added to 1,2-dichloroethane 10 It was dissolved in mL and added dropwise to the reaction mixture. To the reaction mixture, 0.89 mL (4.94 mmol) of trimethylsilyl trifluoromethanesulfonate (TMSOTf) was added dropwise and stirred at 0 ° C for 30 minutes, stirred at room temperature for 1 hour, and then heated to 75 ° C and stirred for 4 hours. After cooling the reaction mixture, it was diluted with dichloromethane (CH ₂ Cl ₂ ) and washed with saturated aqueous sodium bicarbonate (NaHCO ₃ ). The organic layer was dried over anhydrous magnesium sulfate (MgSO ₄ ), filtered, and concentrated under reduced pressure, followed by silica gel column chromatography using a hexane (Hexane): ethyl acetate (EtOAc) mixed solvent (2: 1, v / v) as a developing solvent. The title compound was used to give the title compound (0.20 g, 26%).

solid. UV (CH ₂ Cl ₂ ) _max 306.0 nm; 1 H NMR (CDCl ₃ ) d 7.80 (s, 1 H), 5.95 (s, 1 H), 5.41 (d, 1 H, J = 6.0 Hz), 5.22 (brs, 2 H, NH 2), 5.16-5.18 ( m, 1H), 4.23 (dd, 2H, J = 10.4, 13.2 Hz), 1.57 (s, 3H), 1.40 (s, 3H); 13 C NMR (CDCl ₃ ) d 159.11, 153.29, 152.05, 141.85, 126.04, 113.54, 91.50, 84.38, 81.47, 75.93, 26.62, 24.14; [a] ²⁵ _D -28.41 (c 0.09, CH ₂ Cl ₂ ); (ESI +) (M + Na +) m / z 340.690.

Step 2) 6-Chloro-9- (3aS, 4R, 6aS) -tetrahydro-2,2-dimethylfuro [3,4-d] [1,3] dioxol-4-yl) -2-io Figure 9H Preparation of Purine

Isoamylnitrite in 422 mg (1.35 mmol) of the compound prepared in step 1) and 3.43 mg (1.35 mmol) of I ₂ , 1.70 mL (13.5 mmol) of CH ₂ I ₂ , and 258 mg (1.35 mmol) of CuI. 0.55 mL (4.06 mmol) was added, dissolved in 10 mL of tetrahydrofuran (THF), and stirred at room temperature. The reaction mixture was refluxed for 45 minutes and then cooled at room temperature. The undissolved material was removed by a filter, and the obtained filtrate was dried and concentrated and washed with nucleic acid until the color of iodine disappeared. The residue was purified by silica gel column chromatography using hexane: ethyl acetate mixed solvent (3: 1, v / v) as a developing solvent to obtain the title compound (403 mg, 70%).

white solid. UV (CH ₂ Cl ₂ ) _max 282.5 nm; 1 H NMR (CDCl ₃ ) d 8.06 (s, 1 H), 6.05 (s, 1 H), 5.41 (d, 1 H, J = 5.6 Hz), 5.26-5.28 (m, 1H), 4.25-4.31 ( m, 2H), 1.58 (s, 3H), 1.42 (s, 3H); 13 C NMR (CDCl ₃ ) d 152.15, 151.32, 145.11, 132.48, 116.77, 113.81, 92.18, 84.75, 81.52, 76.80, 26.65, 25.11; [a] ²⁵ _D -3.05 (c 0.13, CH ₂ Cl ₂ ); (ESI +) (M + H +) m / z 422.97

Step 3) 9-((3aS, 4R, 6aS) -tetrahydro-2,2-dimethylpuro [3,4-d] [1,3] dioxol-4-yl) -2-iodo-9H Preparation of Purine-6-amine

303 mg (0.72 mmol) of the compound prepared in step 2) was dissolved in 5 mL of NH ₃ / MeOH and stirred at 100 ° C. for 1 hour. The reaction mixture was dried and concentrated, and the residue was subjected to silica gel column chromatography using a hexane: ethyl acetate mixed solvent (1: 1, v / v) as a developing solvent to obtain the title compound (205 mg, 71%). Got it.

white solid. UV (CH ₂ Cl ₂ ) _max 262.0 nm; 1 H NMR (DMSO-d 6) d 8.16 (s, 1 H), 7.74 (br s, 2 H, NH ₂ ), 6.11 (s, 1 H), 5.27 (d, 1 H, J = 5.6 Hz), 5.13 -5.15 (m, 1H), 4.06-4.12 (m, 2H), 1.47 (s, 3H), 1.33 (s, 3H); 13C NMR (DMSO-d6) d 155.93, 149.34, 139.76, 120.92, 118.85, 112.00, 89.18, 83.97, 80.66, 74.47, 26.22, 24.62; [a] ²⁵ _D -13.25 (c 0.08, CH ₂ Cl ₂ ); (ESI +) (M + H < + >) m / z 404.02.

Step 4) Preparation of (2R, 3S, 4S) -2- (6-amino-2- (hex-1-ynyl) -9H-purin-9-yl) -tetrahydrofuran-3,4-diol

96 mg (0.23 mmol) of the compound prepared in step 3) was dissolved in 1.5 mL of triethylamine (TEA) and 1.5 mL of DMF and purged with nitrogen, followed by bis (triphenylphosphine) palladium dichloride (bis ( 16 mg (0.023 mmol) of triphenylphosphine) palladium dichloride, (PPh ₃ ) ₂ PdCl ₂ ) and 4.3 mg (0.023 mmol) of CuI were added. 0.065 mL (0.57 mmol) of 1-hexyne (1-Hexyne) was added dropwise to the reaction mixture, followed by stirring at room temperature for 3 hours. The solution was removed under reduced pressure to give a crude compound, which was dissolved in 5 mL of THF, and then 5 mL of 1 N HCl was added and stirred for 1 day at room temperature. The reaction mixture was neutralized with 1 N NaOH solution, and then concentrated under reduced pressure, followed by silica gel column chromatography using dichloromethane (CH ₂ Cl ₂ ): methanol (MeOH) mixed solvent (20: 1, v / v) as a developing solvent. The chromatography gave the title compound (50 mg, 65%).

white solid. mp 234.2-234.8; UV (MeOH) _max 289.5 nm; 1 H NMR (CD ₃ OD) d 8.19 (s, 1 H), 6.14 (d, 1 H, J = 6.4 Hz), 5.33 (dd, 1 H, J = 4.8, 6.4 Hz), 4.57 (dd, 1 H , J = 3.2, 9.2 Hz), 4.43-4.45 (m, 1H), 3.99 (dd, 1H, J = 1.6, 10.0 Hz), 2.60 (t, 2H, J = 6.8 Hz), 1.64-1.72 (m, 2H), 1.50-1.59 (m, 2H), 1.00 (t, 3H, J = 7.2 Hz); 13 C NMR (CD ₃ OD) d 157.16, 151.08, 148.12, 142.29, 120.10, 99.38, 88.39, 81.39, 76.58, 75.40, 72.31, 31.65, 23.20, 19.55, 14.06; [a] ²⁵ _D -39.50 (c 0.16, MeOH); (ESI +) (M + H < + >) m / z 334.13.

Example 6: Preparation of (2R, 3S, 4S) -2- (6-amino-2-hexyl-9H-purin-9-yl) -tetrahydrofuran-3,4-diol

22 mg (0.069 mmol) of the compound prepared in Example 5, 5 mL of ethanol, and 5 mg of 10% palladium / carbon were hydrogenated overnight at 40 psi using a Parr apparatus. The mixture was filtered and concentrated to give the title compound (15 mg, 68%) by silica gel column chromatography using dichloromethane: methanol mixed solvent (20: 1, v / v) as the developing solvent.

white solid. 1 H NMR (CD ₃ OD) d 8.19 (s, 1 H), 5.95 (d, 1 H, J = 6.4 Hz), 4.94 (dd, 1 H, J = 4.8, 6.4 Hz), 4.52 (dd, 1 H , J = 4.0, 9.6 Hz), 4.42-4.44 (m, 1H), 3.99 (dd, 1H, J = 1.6, 9.6 Hz), 2.74 (t, 2H, J = 7.6 Hz), 1.74-1.80 (m, 2H), 1.30-1.39 (m, 6H), 0.88-0.92 (m, 3H); 13 C NMR (CD ₃ OD) d167.24, 157.14, 151.75, 141.47, 118.97, 90.48, 76.56, 75.51, 72.52, 39.95, 33.03, 30.28, 29.96, 23.80, 14.56; [a] ²⁵ _D -54.05 (c 0.11, MeOH); (ESI +) (M + H < + >) m / z 334.13.

Example 7: of (2R, 3S, 4S, E) -2- (6-amino-2- (hex-1-enyl) -9H-purin-9-yl) -tetrahydrofuran-3,4-diol Produce

96 mg (0.24 mmmol) of the compound prepared in step 3) of Example 5 and 28 mg (0.024 mmol) of tetrakistriphenylphosphine palladium (0) and sodium carbonate (Na) ₂ CO ₃ ) 76 mg (0.72 mmol) and (E) -1-catecholboranylhexene ((E) -1-catecholboranylhexene) 67 mg (0.33 mmol) in 5 mL of DMF: H ₂ O (8: 1) It was dissolved in and stirred overnight at 90 ℃. The reaction mixture was filtered and concentrated through a celite bed to obtain a crude compound, which was dissolved in 5 mL of THF, and then 5 mL of 1 N HCl was added and stirred at room temperature for 1 day. The reaction mixture was neutralized with 1 N NaOH solution, concentrated under reduced pressure, and the title compound (48 mg) was purified by silica gel column chromatography using a dichloromethane: methanol mixed solvent (20: 1, v / v) as a developing solvent. , 63%).

white solid. mp 209.1-209.6; UV (MeOH) _max 293.0 nm; 1 H NMR (CD ₃ OD) d 8.20 (s, 1 H), 6.99-7.06 (m, 1 H), 6.36 (d, 1 H, J = 15.6 Hz), 5.97 (d, 1 H, J = 6.4 Hz ), 4.94 (dd, 1H, J = 4.8, 6 Hz), 4.53 (dd, 1H, J = 4.0, 9.6 Hz); 4.43-4.46 (m, 1H), 3.99 (dd, 1H, J = 2.0, 9.6 Hz), 2.25-2.31 (m, 2H), 1.47-1.54 (m, 2H), 1.36-1.45 (m , 2H), 0.95 (t, 3H, J = 7.2 Hz); 13 C NMR (CD ₃ OD) d 160.87, 156.94, 151.70, 141.55, 141.31, 130.66, 90.33, 76.42, 75.36, 72.40, 57.90, 33.31, 32.27, 23.39; 14.29; [a] ²⁵ _D -47.05 (c 0.12, MeOH); (ESI +) (M + H < + >) m / z 330.1717; [a] ²⁵ _D -44.80 (c 0.12, MeOH).

Example 8: Preparation of (2R, 3S, 4S) -2- (6-amino-8- (hex-1-ynyl) -9H-purin-9-yl) -tetrahydrofuran-3,4-diol

Step 1) 6-Chloro-9-((3aS, 6R, 6aS) -tetrahydro-2,2-dimethylpuro [3,4-d] [1,3] dioxol-6-yl) -9H- Preparation of Purine

618 mg (4.00 mmol) of 6-Chloropurine and 79 mg (0.60 mmol) of ammonium sulfate were dissolved in 15 mL of hexamethyldisilazane (HMDS) and refluxed under inert, dry conditions overnight. The reaction mixture was concentrated under reduced pressure, and then the obtained solid mixture was dissolved in 10 mL of 1,2-dichloroethane and cooled at 0 ° C. 404 g (2.00 mmol) of (3aR, 4R, 6aS) -2,2-dimethyltetrahydrothieno [3,4-d] [1,3] dioxol-4-yl acetate were mixed with 1,2-dichloroethane 10 It was dissolved in mL and added dropwise to the reaction mixture. 0.72 mL (4.00 mmol) of TMSOTf was added to the reaction mixture by a dropwise method, stirred at 0 ° C. for 30 minutes, stirred at room temperature for 1 hour, and then heated to 75 ° C. for 5 hours. After cooling the reaction mixture was diluted with CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ solution. The organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure to obtain the title compound (420 mg, 71%) by silica gel column chromatography using a hexane: ethyl acetate mixed solvent (2: 1, v / v) as a developing solvent. )

white solid. UV (CH ₂ CL ₂ ) _max 264 nm; 1 H NMR (CDCl ₃ ) d 8.74 (s, 1 H), 8.18 (s, 1 H), 6.11 (s, 1 H), 5.50 (d, 1 H, J = 6.0 Hz), 5.28-5.30 (m, 1 H), 4.25-4.32 (m, 2H), 1.59 (s, 3H), 1.42 (s, 3H); 13 C NMR (CDCl ₃ ) d 152.35, 151.83, 151.34, 145.08, 132.47, 113.71, 92.26, 84.69, 81.50, 76.32, 26.62, 25.04; [a] ²⁵ _D -37.03 (c 0.17, CH ₂ Cl ₂ ); (ESI +) (M + H < + >) m / z 297.07.

Step 2) 9-((3aS, 6R, 6aS) -tetrahydro-2,2-dimethylpuro [3,4-d] [1,3] dioxol-6-yl) -9H-purin-6- Preparation of Amine

370 mg (1.25 mmol) of the compound prepared in step 1) was dissolved in 5 mL of NH ₃ / MeOH and stirred at 80 ° C. for 2 hours. The reaction mixture was dried and concentrated, and the residue was subjected to silica gel column chromatography using a hexane: ethyl acetate mixed solvent (1: 1, v / v) as a developing solvent to obtain the title compound (270 mg, 78%). Got it.

white solid. UV (CH ₂ Cl ₂ ) _max 255 nm; 1 H NMR (CDCl ₃ ) d 8.32 (s, 1 H), 7.89 (s, 1 H), 6.19 (brs, 2 H), 6.03 (s, 1 H), 5.48 (d, 1 H, J = 6.0 Hz ), 5.26-5.28 (m, 1H), 4.24-4.31 (m, 2H), 1.58 (s, 3H), 1.41 (s, 3H); 13 C NMR (CDCl ₃ ) d 154.74, 151.30, 149.47, 141.18, 120.29, 113.47, 91.91, 84.76, 81.68, 76.07, 26.64, 25.06; [a] ²⁵ _D -35.48 (c 0.09, CH ₂ Cl ₂ ); (ESI +) (M + H < + >) m / z 278.12.

Step 3) 8-Bromo-9-((3aS, 6R, 6aS) -tetrahydro-2,2-dimethylpuro [3,4-d] [1,3] dioxol-6-yl) -9H Preparation of Purine-6-amine

89 g (0.32 mmol) of the compound prepared in step 2) was dissolved in MeOH (10 mL) / 1M sodium acetate (1.7 mL), and then 0.033 mL (0.64 mmol) of bromine was added thereto. Stir at room temperature for 40 minutes. The reaction mixture was diluted with sodium metabisulfite and stirred until the red color disappeared. The volatiles were depressurized and the resulting solution layer was extracted with EtOAc. The organic layer was washed with distilled water, dried over MgSO ₄ , concentrated under reduced pressure until it became pale yellow, and was subjected to silica gel column chromatography using a hexane: ethyl acetate mixed solvent (1: 1, v / v) as a developing solvent. To give the title compound (63 mg, 55%).

solid. (63 mg, 55%). UV (CH ₂ Cl ₂ ) _max 262 nm; 1 H NMR (CDCl ₃ ) d 8.26 (s, 1 H), 6.20 (brs, 2 H), 6.16 (s, 1 H), 5.61 (d, 1 H, J = 5.6 Hz), 5.36-5.38 (m, 1 H), 4.20-4.21 (m, 2H), 1.59 (s, 3H), 1.42 (s, 3H); 13 C NMR (CDCl ₃ ) d 153.81, 151.93, 150.91, 128.80, 120.02, 113.24, 92.35, 84.25, 82.18, 76.51, 26.60, 24.96; [a] ²⁵ _D -28.08 (c 0.26, CH ₂ Cl ₂ ); (ESI +) (M + H < + >) m / z 356.03.

Step 4) Preparation of (2R, 3S, 4S) -2- (6-amino-8- (hex-1-ynyl) -9H-purin-9-yl) -tetrahydrofuran-3,4-diol

605 mg (0.19 mmol) of the compound prepared in step 3) was dissolved in 10 mL of triethylamine (TEA) and 10 mL of DMF and purged with nitrogen, followed by bis (triphenylphosphine) palladium dichloride (bis ( 238 mg (0.34 mmol) of triphenylphosphine) palladium dichloride, (PPh ₃ ) ₂ PdCl ₂ ) and 65 mg (0.34 mmol) of CuI were added. 0.49 mL (4.25 mmol) of 1-hexyne (1-Hexyne) was added dropwise to the reaction mixture, followed by stirring at room temperature for 3 hours. The solution was removed under reduced pressure to give a crude compound, which was dissolved in 10 mL of THF, and then 10 mL of 1 N HCl was added and stirred for 1 day at room temperature. The reaction mixture was neutralized with 1 N NaOH solution, and then concentrated under reduced pressure, followed by silica gel column chromatography using dichloromethane (CH ₂ Cl ₂ ): methanol (MeOH) mixed solvent (10: 1, v / v) as a developing solvent. The chromatography gave the title compound (334 mg, 62%).

white solid: UV (MeOH) _max 291.5 nm; 1 H NMR (CD ₃ OD) d 8.19 (s, 1 H), 6.14 (d, 1 H, J = 7.2 Hz), 5.32 (dd, 1 H, J = 4.8 Hz, 6.8 Hz), 4.57 (dd, 1 H, J = 3.2 Hz, 9.6 Hz), 4.27-4.45 (m, 1 H), 3.99 (dd, 1 H, J = 1.2 Hz, 9.6 Hz), 2.59 (t, 2 H, J = 6.8 Hz), 1.64-1.70 (m, 2H), 1.52-1.58 (m, 2H), 1.00 (t, 3H, J = 7.2 Hz); 13C NMR (CD ₃ OD) d 156.90, 154.44, 150.57, 136.73, 120.25, 99.98, 91.14, 76.05, 75.11, 72.86, 70.79, 31.21, 23.11, 19.74, 13.91; [a] ²⁵ _D -42.75 (c 0.14, MeOH).

Example 9: Preparation of (2R, 3S, 4S) -2- (6-amino-8-hexyl-9H-purin-9-yl) -tetrahydrofuran-3,4-diol

116 mg (0.36 mmol) of the compound prepared in Example 8, 20 mL of ethanol, and 20 mg of 10% palladium / carbon were hydrogenated overnight at 40 psi using a Parr apparatus. The mixture was filtered and concentrated to give the title compound (81 mg, 69%) using silica gel column chromatography using a dichloromethane: methanol mixed solvent (20: 1, v / v) as the developing solvent.

white solid. UV (MeOH) _max 259.5 nm; 1 H NMR (DMSO-d 6) d 8.14 (s, 1 H), 7.41 (brs, 2 H, NH ₂ ), 5.76 (d, 1 H, J = 6.8 Hz), 5.37 (brs, 1 H, OH), 5.25 (brs, 1H, OH), 5.13-5.15 (m, 1H), 4.40 (dd, 1H, J = 3.2, 9.2 Hz), 4.28 (pseudo t, 1H, J = 3.2 Hz), 3.83 (d, 1H, J = 9.2 Hz), 2.82-2.87 (m, 2H), 1.69-1.77 (m, 2H), 1.32-1.39 (m, 2H), 1.26-1.31 (m, 4H ), 0.86 (t, 3H, J = 6.8 Hz); 13C NMR (DMSO-d6) d 154.27, 152.94, 150.45, 150.05, 118.11, 88.30, 74.25, 73.20, 70.67, 30.92, 28.35, 27.57, 27.36, 22.00, 13.92; [a] ²⁵ _D -36.50 (c 0.13, MeOH).

Example 10: of (2R, 3S, 4S, E) -2- (6-amino-8- (hex-1-enyl) -9H-purin-9-yl) -tetrahydrofuran-3,4-diol Produce

78.8 mg (0.22 mmmol) of the compound prepared in step 3) of Example 8 and tetrakis (triphenylphosphine) palladium (0)) 26 mg (0.022 mmol), sodium carbonate (Na ₂ CO ₃ ) 70 mg (0.66 mmol) and (E) -1-catecholboranylhexene ((E) -1-catecholboranylhexene) 134 mg (0.66 mmol) in 5 mL of DMF: H ₂ O (8: 1) It was dissolved in and stirred overnight at 90 ℃. The reaction mixture was filtered and concentrated through a celite bed to obtain a crude compound, which was dissolved in 3 mL of THF, and then 3 mL of 1 N HCl was added and stirred at room temperature for one day. The reaction mixture was neutralized with 1 N NaOH solution, concentrated under reduced pressure, and purified by silica gel column chromatography using dichloromethane: methanol mixed solvent (20: 1, v / v) as a developing solvent (41 mg). , 58%).

white solid. UV (MeOH) _max 296.5 nm; 1 H NMR (DMSO-d 6) d 8.08 (s, 1 H), 7.18 (brs, 2 H, NH ₂ ), 6.84-6.92 (m, 1 H), 6.58 (d, 1 H, J = 15.6 Hz), 5.91 (d, 1 H, J = 6.8 Hz), 5.36 (d, 1 H, OH, J = 6.8 Hz), 5.21 (d, 1 H, OH, J = 4.0 Hz), 5.05-5.06 (m, 1 H), 4.37 (dd, 1H, J = 3.6, 9.6 Hz), 4.28 (d, 1H, J = 3.6 Hz), 3.82 (dd, 1H, J = 1.2, 9.6 Hz); 2.28-2.34 (m, 2H), 1.43-1.50 (m, 2H), 1.31-1.40 (m, 2H), 0.91 (t, 3H, J = 7.6 Hz); 13C NMR (DMSO-d6) d 155.39, 151.92, 150.21, 147.97, 140.77, 118.82, 116.59, 87.60, 74.05, 73.28, 70.51,31.97, 30.33, 21.71, 13.73; [a] ²⁵ _D -24.76 (c 0.11, MeOH).

Example 11) (2R, 3S, 4S) -2- (6-Amino-8- (furan-3-yl) -2- (hex-1-ynyl) -9H-purin-9-yl) -tetrahydro Preparation of furan-3,4-diol

Step 1) 8-Bromo-6-chloro-9-((3aS, 4R, 6aS) -tetrahydro-2,2-dimethylfuro [3,4-d] [1,3] dioxol-4- I) -9H-purin-2-amine preparation

6-chloro-9-((3aS, 4R, 6aS) -2,2-dimethyl-tetrahydropuro [3,4-d] [1,3] dioxol-4-yl) -9H-purin-2 To a methanol (6 mL) / 1 M sodium acetate solution (50 g, 0.16 mmol) of amine was added bromine (0.016 mL, 0.32 mmol) at room temperature and stirred for 2 hours. The mixture was diluted with saturated sodium metabisulphate solution and stirred until the red color disappeared. The volatiles were evaporated and the aqueous layer obtained was extracted with EtOAc. The organic layers extracted together were washed with water, dried over MgSO ₄ and evaporated to a cloudy yellow form. It was purified by column chromatography (hexane: EtOAc = 3: 1) to give the title compound as a solid (34 mg, 54%).

¹ H NMR (CDCl ₃ ) d6.10 (s, 1H), 5.54 (d, 1H, J = 5.6 Hz), 5.27-5.29 (m, 1H), 5.10 (br s, 2H, NH ₂ ) , 4.20 (d, 2H, J = 2.0 Hz), 1.58 (s, 3H), 1.41 (s, 3H);

Step 2) 6-Chloro-8- (furan-2-yl) -9-((3aS, 4R, 6aS) -tetrahydro-2,2-dimethylpuro [3,4-d] [1,3] Preparation of Dioxol-4-yl) -9H-purin-2-amine

The compound prepared in step 1 (27 mg, 0.069 mmol) was dissolved in THF (3.0 mL), (PPh ₃ ) ₂ PdCl ₂ (9.7 mg, 0.014 mmol) and 2- (tributylstannyl) furan (0.024 mL) , 0.076 mmol) was added. The mixture was stirred at 110 ° C. for 2 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane: EtOAc = 2: 1) to afford the title compound as a solid.

¹ H NMR (CDCl ₃ ) d 7.69 (dd, 1 H, J = 0.8, 1.6 Hz), 7.25 (d, 1 H, J = 0.8 Hz), 6.61 (dd, 1 H, J = 2.0, 3.6 Hz) , 6.39 (s, 1H), 5.63 (d, 1H, J = 5.6 Hz), 5.32 (dd, 1H, J = 3.2, 6.0 Hz), 5.09 (br s, 2H, NH ₂ ), 4.20- 4.28 (m, 2H), 1.58 (s, 3H), 1.41 (s, 3H);

Step 3) 6-Chloro-8- (furan-2-yl) -9-((3aS, 4R, 6aS) -tetrahydro-2,2-dimethylpuro [3,4-d] [1,3] Preparation of Dioxol-4-yl) -2-iodo-9H-purine

5 mL THF mixture of compound (13.3 mg, 0.035 mmol), I ₂ (8.9 mg, 0.035 mmol), CH ₂ I ₂ (0.044 mL, 0.35 mmol) and CuI (7.3 mg, 0.035 mmol) prepared in step 2 above To the solution isoamylnitrite (0.014 mL, 0.105 mmol) was added at room temperature. The mixture was refluxed for 45 minutes and finally cooled to room temperature. Insoluble materials were removed by filter, dried and concentrated. The mixture was washed with hexane until the color of iodine disappeared and then purified by silica gel column chromatography by separation of Hexane: EtOAc = 3: 1 to obtain the title compound as a white solid (12 mg 71%).

¹ H NMR (CDCl ₃ ) d 7.77 (dd, 1 H, J = 0.8, 2.0 Hz), 7.45 (dd, 1 H, J = 0.8, 4.0 Hz), 6.68 (dd, 1 H, J = 2.0, 3.6 Hz), 6.56 (s, 1H), 5.60 (d, 1H, J = 6.0 Hz), 5.39 (dd, 1H, J = 3.2, 6.0 Hz), 4.24-4.28 (m, 2H), 1.60 ( s, 3H), 1.44 (s, 3H);

Step 4) 8- (Furan-2-yl) -9-((3aS, 4R, 6aS) -tetrahydro-2,2-dimethylpuro [3,4-d] [1,3] dioxol-4 Preparation of -yl) -2-iodo-9H-purin-6-amine

Methanolic ammonia (5 mL) of the compound (74 mg, 0.15 mmol) prepared in step 3 was stirred at 100 ° C. for 1 hour. The reaction mixture was dried to concentrate and silica gel column chromatography (hexane: EtOAc = 1: 1) to give the title compound (43 mg, 61%).

¹ H NMR (CDCl ₃ ) d 7.69 (dd, 1 H, J = 0.8, 2.0 Hz), 7.15 (dd, 1 H, J = 0.4, 3.6 Hz), 6.61 (dd, 1 H, J = 1.6, 3.6 Hz), 6.32 (s, 1H), 6.23 (br s, 2H, NH ₂ ), 5.60 (d, 1H, J = 6.0 Hz), 5.36 (dd, 1H, J = 2.0, 5.6 Hz), 4.21-4.27 (m, 2H), 1.57 (s, 3H), 1.42 (s, 3H);

Step 5) Preparation of 2- (6-amino-8-furan-2-yl-2-hex-1-ynyl-purin-9-yl) -tetrahydro-furan-3,4-diol

The compound prepared in step 4 (43 mg, 0.092 mmol) was dissolved in Et ₃ N (1.5 mL) and DMF (1.5 mL). After purging the solution with nitrogen, (PPh ₃ ) ₂ PdCl ₂ (6.4 mg, 0.0092 mmol) and CuI (1.8 mg, 0.0092 mmol) were added. 1-hexine (0.026 mL, 0.23 mmol) was added dropwise, followed by stirring at room temperature for 3 hours. The reaction solution was filtered through celite and the residue was concentrated. 1N hydrochloric acid (3 mL) was added to the THF (3 mL) solution of the concentrate and stirred at room temperature for one day. Neutralized with 1N NaOH and then removed under reduced pressure. Silica gel column chromatography (CH ₂ Cl ₂ : MeOH = 20: 1) was carried out with the mixture to give the title compound as a white solid (64%).

¹ H NMR (CDCl ₃ ) d7.69 (dd, 1 H, J = 0.8, 2.0 Hz), 7.16 (dd, 1 H, J = 0.8, 3.6 Hz), 6.62 (dd, 1 H, J = 2.0, 3.6 Hz), 6.35 (s, 1 H), 5.69 (d, 1 H, J = 6.0 Hz), 5.57 (br s, 2 H, NH ₂ ), 5.46 (dd, 1H, J = 3.6, 6.0 Hz) , 4.48 (m, 2H), 4.29 (dd, 1H, J = 3.6, 10.4 Hz) 4.22 (d, 1H, J = 10.4 Hz), 2.46 (t, 2H, J = 7.2 Hz), 1.62- 1.69 (m, 2H), 1.49-1.54 (m, 2H), 0.97 (t, 3H, J = 7.6 Hz);

Example 12) (1R, 2R, 3S, 4R, 5S) -4- (6-amino-2- (hex-1-ynyl) -9H-purin-9-yl) bicyclo [3.1.0] hexane- Preparation of 2,3-diol

Step 1) Preparation of 3,3-Dimethyl-hexahydro-2,4-dioxa-cyclopropa [a] pentalen-5-ol

Methylene chloride solution of (3aS, 4S, 6aR) -2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta [d] [1,3] dioxol-4-ol (2.07 g, 13.26 mmol) To (28 mL), diethyl zinc (26.52 mL, 26.52 mmol, 1.0 M solution of hexane) was added at 0 ° C., stirred for 30 minutes, and diiodomethane (4.28 mL, 53.05 mmol) was added at 0 ° C. After stirring for 1.5 hours. The ice bath was removed and the mixture was stirred at room temperature overnight. After quenching with cold ammonia chloride solution, it was extracted with methylene chloride. The organic layer was dried (MgSO ₄ ), filtered and depressurized, and then purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give the title compound as a colorless syrup (1.94 g 92.4%).

¹ H NMR (CDCl ₃ ) d0.59 (m, 1H), 0.94 (m, 1H), 1.25 (s, 3H), 1.51 (s, 3H), 1.60 (m, 1H), 1.81 (m, 1H) , 2.43 (d, 1 H), 4.43 (t, 1 H), 4.48 (m, 1 H), 4.84 (t, 1 H); FAB-MS m / z 190.08 [M + Na] ⁺ .

Step 2) Preparation of 6-Chloro-9- (3,3-dimethyl-hexahydro-2,4-dioxa-cyclopropa [a] pentalen-5-yl) -9H-purin-2-ylamine

To anhydrous THF solution (14 mL) of compound (301 mg, 1.9 mmol), PPh ₃ (1.5 g, 5.7 mmol), and 2-amino-6-chloropurine (1 g, 5.7 mmol) prepared in step 1 Ethyl azodicarboxylate (1 mL, 5.7 mmol) was added dropwise at 0 ° C. The reaction solution was stirred at room temperature for 3 hours, concentrated in vacuo and purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to afford the title compound (343 mg, 56%).

¹ H NMR (CDCl ₃ ) d 0.96 (m, 2H), 1.24 (s, 3H), 1.54 (s, 3H), 1.69 (m, 1H), 2.08 (m, 1H), 4.59 (d, 1H) , 4.90 (s, 1 H), 5.27 (t, 1 H), 5.33 (s, 2 H), 7.82 (s, 1 H); FAB-MS m / z 322.11 [M + H] ⁺ .

Step 3) Preparation of 6-Chloro-9- (3,3-dimethyl-hexahydro-2,4-dioxa-cyclopropa [a] pentalen-5-yl) -2-iodo-9H-purine Way

THF solution of compound (155 mg, 0.48 mmol), I ₂ (124 mg, 0.48 mmol), diiodomethane (6.2 mL, 48 mmol) and CuI (93 mg, 0.48 mmol) prepared in step 2 (15 mL) To isoamylnitrite (0.2 mL, 1.5 mmol) was added. The mixture was refluxed for 40 minutes and then cooled to room temperature. Insoluble materials were removed by filter, dried and concentrated. The mixture was washed with hexane until the color of iodine disappeared and then purified by silica gel column chromatography by separation of hexane / ethyl acetate = 5/1 to obtain the title compound in a yield of 80%.

¹ H NMR (CDCl ₃ ) d 0.92 (m, 2H), 1.20 (s, 3H), 1.49 (s, 3H), 1.63 (m, 1H), 2.11 (m, 1H), 4.63 (d, 1H), 5.00 (s, 1 H), 5.32 (t, 1 H), 8.06 (s, 1 H); FAB-MS m / z 432.99 [ M + H] +.

Step 4) of 9- (3,3-Dimethyl-hexahydro-2,4-dioxa-cyclopropa [a] pentalen-5-yl) -2-iodo-9H-purin-6-ylamine Produce

The compound prepared in step 3 (291.5 mg, 0.67 mmol) and saturated methanolic ammonia mixture were stirred at 80 ° C. for 2 hours and then evaporated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) and then purified by methylene chloride / methanol = 20/1 to give the title compound (yield 48%).

¹ H NMR (CDCl ₃ ) d 0.91 (m, 2H), 1.22 (s, 3H), 1.51 (s, 3H), 1.62 (m, 1H), 2.06 (m, 1H), 4.63 (d, 1H), 4.92 (s, 1 H), 5.31 (t, 1 H), 6.80 (s, 2 H), 7.72 (s, 1 H); FAB-MS m / z 414.04 [M + H] ⁺ .

Step 5) 9- (3,3-Dimethyl-hexahydro-2,4-dioxa-cyclopropa [a] pentalen-5-yl) -2-hex-1-ynyl-9H-purin-6 Preparation of Ilamine

Et ₃ N (2 mL) / DMF of compound (69 mg, 0.17 mmol), bis (triphenylphosphine) palladium dichloride (12 mg, 0.017 mmol) and CuI (3.2 mg, 0.017 mmol) prepared in step 4 1-hexine (48 μL, 0.42 mmol) was added to (1.5 mL) mixed solvent. The mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was purified by silica gel column chromatography (methylene chloride / methanol = 40/1) to afford the title compound (55 mg, 88%).

¹ H NMR (CDCl ₃ ) d0.94 (m, 5H), 1.24 (s, 3H), 1.48 (m, 2H), 1.53 (s, 3H), 1.65 (m, 3H), 2.08 (m, 1H) , 2.45 (t, 2H), 4.61 (d, 1H), 5.09 (s, 1H), 5.33 (t, 1H), 5.84 (s, 2H), 7.89 (s, 1H); FAB-MS m / z 368.21 [M + H] ⁺ .

Step 6) Preparation of 4- (6-amino-2-hex-1-ynyl-purin-9-yl) -bicyclo [3.1.0] hexane-2,3-diol

To a THF solution (2.5 mL) of the compound (56 mg, 0.15 mmol) prepared in step 5 was added 1N HCl (2.5 mL). The mixture was stirred at room temperature for 3 hours, then neutralized with NaOH and concentrated in vacuo. The residue was purified by silica gel column chromatography (methylene chloride / methanol = 40/1) to afford the title compound (83%).

¹ H NMR (CD ₃ OD) d 0.76 (m, 1H), 0.97 (t, 3H), 1.35 (q, 1H), 1.52 (m, 2H), 1.62 (m, 2H), 1.68 (m, 1H) , 1.99 (m, 1H), 2.45 (t, 2H), 3.87 (d, 1H), 4.68 (t, 1H), 4.83 (s, 1H), 8.24 (s, 1H); FAB-MS m / z 328.12 [M + H] ⁺ .

Example 13) (1R, 2R, 3S, 4R, 5S, E) -4- (6-amino-2- (hex-1-enyl) -9H-purin-9-yl) bicyclo [3.1.0] Preparation of Hexane-2,3-diol

Step 1) 9- (3,3-Dimethyl-hexahydro-2,4-dioxa-cyclopropa [a] pentalen-5-yl) -2-hex-1-enyl-9H-purin-6- Preparation of Ilamine

DMF (111 mg, 0.27 mmol), tetrakis (triphenylphosphine) palladium (31 mg, 0.027 mmol) and Na ₂ CO ₃ (86 mg, 0.81 mmol) prepared in step 4) of Example 12 ( 20 mL) / H ₂ O (2.5 mL) solution was added (E) -1-catecholboranylhexene (164 mg, 0.81 mmol). The mixture was stirred at 90 ° C. overnight. The undissolved material was removed by filter, dried to concentrate, and then purified by silica gel column chromatography (methylene chloride / methanol = 40/1) to give the title compound (72 mg, 72%).

¹ H NMR (CDCl ₃ ) d 0.93 (m, 5H), 1.25 (s, 3H), 1.39 (m, 2H), 1.51 (m, 2H), 1.55 (s, 3H), 1.68 (m, 1H), 2.10 (m, 1H), 2.29 (q, 2H), 4.70 (d, 1H), 4.97 (s, 1H), 5.41 (t, 1H), 5.53 (s, 2H), 6.44 (d, 1H), 7.07 (m, 1 H), 7.76 (s, 1 H); FAB-MS m / z 370.22 [M + H] ⁺ .

Step 2) Preparation of 4- (6-amino-2-hex-1-enyl-purin-9-yl) -bicyclo [3.1.0] hexane-2,3-diol

To a THF solution (5 mL) of the compound (177 mg, 0.48 mmol) prepared in step 1 was added 1N HCl (5 mL). The mixture was stirred at room temperature for 3 hours, then neutralized with NaOH and concentrated in vacuo. The remaining mule was purified by silica gel column chromatography (methylene chloride / methanol = 40/1) to afford the title compound (yield 79%).

¹ H NMR (CD ₃ OD) d 0.76 (m, 1H), 0.95 (t, 3H), 1.31 (q, 1H), 1.41 (m, 2H), 1.50 (m, 2H), 1.65 (m, 1H) , 1.98 (m, 1H), 2.28 (q, 2H), 3.91 (d, 1H), 4.77 (t, 1H), 4.88 (s, 1H), 6.38 (d, 1H), 7.05 (m, 1), 8.14 (s, 1 H); FAB-MS m / z 330.19 [M + H] ⁺ .

Example 14) (1R, 2R, 3S, 4R, 5S, E) -4- (2- (hex-1-enyl) -6- (hex-1-ynyl) -9H-purin-9-yl) bi Preparation of cyclo [3.1.0] hexane-2,3-diol

Step 1) 8-Bromo-6-chloro-9- (3,3-dimethyl-hexahydro-2,4-dioxacyclopropa [a] pentalen-5-yl) -9H-purin-2- Preparation of Ilamine

6-chloro-9- (3,3-dimethyl-hexahydro-2,4-dioxacyclopropa [a] pentalen-5-yl) -9H-purin-2-ylamine (200 mg, 0.62 mmol N-bromosuccinimide was added to a solution of CH ₃ CN) at 0 ° C. The mixture was stirred at room temperature overnight. The reaction was quenched with NaHCO ₃ and extracted with ethyl acetate and evaporated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 8/1) to give the title compound (129 mg, 50%).

¹ H NMR (CDCl ₃ ) d0.91 (m, 2H), 1.27 (s, 3H), 1.55 (m, 4H), 2.06 (m, 1H), 4.90 (d, 1H), 4.96 (s, 1H) , 5.10 (s, 2 H), 5.46 (t, 1 H); FAB-MS m / z 400.02 [M + H] ⁺ .

Step 2) 6-Chloro-9- (3,3-dimethyl-hexahydro-2,4-dioxa-cyclopropa [a] pentalen-5-yl) -8-furan-2-yl-9H Preparation of Purin-2-yl Amine

To anhydrous tetrahydrofuran solution (6 mL) of compound (68 mg, 0.17 mmol) and dichlorobis (triphenylphosphine) -Pd (II) (24 mg, 0.034 mmol) prepared in step 1 2- (tributyl) Stannyl) furan (107 μL, 0.34 mmol) was added to a pressure tube and heated to 60 ° C. overnight. The mixture was evaporated and purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to afford the title compound (56 mg, 85%).

¹ H NMR (CDCl ₃ ) d 0.92 (m, 2H), 1.27 (s, 3H), 1.55 (s, 3H), 1.63 (m, 1H), 2.05 (m, 1H), 5.02 (d, 1H), 5.08 (s, 2H), 5.32 (s, 1H), 5.51 (t, 1H), 6.62 (m, 1H), 7.21 (d, 1H), 7.68 (s, 1H); FAB-MS m / z 388.12 [M + H] ⁺ .

Step 3) 6-Chloro-9- (3,3-dimethyl-hexahydro-2,4-dioxa-cyclopropa [a] pentalen-5-yl) -8-furan-2-yl-2- Preparation of Iodo-9H-Purine

THF solution of compound of step 2) (50 mg, 0.13 mmol), I ₂ (33 mg, 0.13 mmol), iodomethane (163 μL, 1.3 mmol) and CuI (25 mg, 0.13 mmol) (6 mL) To isoamylnitrite (52 μL, 0.39 mmol) was added. The mixture was refluxed for 2 hours and then cooled to room temperature. Insoluble materials were removed by filter, dried and concentrated. The mixture was washed with hexane until the color of iodine disappeared and then purified by silica gel column chromatography by separation of hexane / ethyl acetate = 6/1 to give the title compound in a yield of 70%.

¹ H NMR (CDCl ₃ ) d 0.95 (m, 2H), 1.29 (s, 3H), 1.56 (s, 3H), 1.62 (m, 1H), 2.15 (m, 1H), 5.00 (d, 1H) , 5.52 (s, 1 H), 5.56 (t, 1 H), 6.68 (m, 1 H), 7.42 (d, 1 H), 7.77 (s, 1 H); FAB-MS m / z 499.00 [M + H] ⁺ .

Step 4) 9- (3,3-Dimethyl-hexahydro-2,4-dioxa-cyclopropa [a] pentalen-5-yl) -8-furan-2-yl-2,6-di- Preparation of hex-1-ynyl-9H-purine

Et ₃ N (2 mL) / of compound (66 mg, 0.13 mmol), bis (triphenylphosphine) palladium dichloride (9 mg, 0.013 mmol) and CuI (2.5 mg, 0.013 mmol) prepared in step ₃ ) To DMF (1.5 mL) mixed solvent, 1-hexyne (37 μL, 0.33 mmol) was added. The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was purified by silica gel column chromatography (methylene chloride / methanol = 50/1) to give the title compound (74%).

¹ H NMR (CDCl ₃ ) d 0.94 (m, 7H), 1.27 (s, 3H), 1.50 (m, 4H), 1.55 (s, 3H), 1.62 (m, 6H), 2.13 (m, 1H), 2.47 (t, 2H), 2.56 (t, 2H), 5.04 (d, 1H), 5.47 (s, 1H), 5.65 (t, 1H), 6.64 (m, 1H), 7.34 (d, 1H), 7.72 (s, 1 H); FAB-MS m / z 499.27 [M + H] ⁺ .

Step 5) Preparation of 4- (8-purin-2-yl-2,6-di-hex-1-ynyl-purin-9-yl) -bicyclo [3.1.0] hexane-2,3-diol

To a THF solution (2.5 mL) of compound (28 mg, 0.056 mmol) prepared in step 4) was added 1N HCl (2.5 mL). The reaction was neutralized with 1N NaOH and then concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to afford the title compound (80%).

¹ H NMR (CDCl ₃ ) d0.81 (m, 1H), 0.97 (m, 6H), 1.03 (m, 1H), 1.43 (m, 2H), 1.55 (m, 4H), 1.66 (m, 2H) , 1.73 (m, 1H), 2.14 (m, 1H), 2.48 (t, 2H), 3.11 (s, 1H), 3.32 (t, 2H), 4.58 (d, 1H), 5.25 (s, 1H), 5.46 (s, 1 H), 6.65 (m, 1 H), 7.30 (d, 1 H), 7.72 (s, 1 H); FAB-MS m / z 459.24 [M + H] ⁺ .

Example 15) (1R, 2R, 3S, 4R, 5S) -4- (6-amino-8- (furan-3-yl) -2- (hex-1-ynyl) -9H-purin-9-yl Preparation of Bicyclo [3.1.0] hexane-2,3-diol

Step 1) 9- (3,3-Dimethyl-hexahydro-2,4-dioxa-cyclopropa [a] pentalen-5-yl) -8-furan-2-yl-2-iodo-9H Preparation of Purine-6-ylamine

A mixture of compound (45 mg, 0.09 mmol) and saturated methanolic ammonia prepared in step 3) of Example 14 was stirred at 100 ° C. for 1 hour and evaporated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to afford the title compound (40%).

¹ H NMR (CDCl ₃ ) d0.90 (m, 2H), 1.29 (s, 3H), 1. (s, 3H), 1.60 (m, 1H), (m, 1H), 5.01 (d, 1H) , 5.27 (s, 1 H), 5.56 (t, 1 H), 5.65 (s, 2 H), 6.63 (m, 1 H), 7.10 (d, 1 H), 7.69 (s, 1 H); FAB-MS m / z 480.05 [M + H] ⁺ .

Step 2) 9- (3,3-Dimethyl-hexahydro-2,4-dioxa-cyclopropa [a] pentalen-5-yl) -8-furan-2-yl-2-hex-1- Preparation of Inyl-9H-purin-6-ylamine

Et ₃ N (1 mL) / DMF (0.5) of compound of step 1 (17 mg, 0.035 mmol), bis (triphenylphosphine) palladium dichloride (2.5 mg, 0.035 mmol) and CuI (0.67 mg, 0.0035 mmol) 1-hexine (10 μL, 0.0035 mmol) was added to the mixed solvent. The mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to afford the title compound (20%).

¹ H NMR (CDCl ₃ ) d0.90 (m, 2H), 0.97 (t, 3H), 1.28 (s, 3H), 1.51 (m, 2H), 1.57 (s, 3H), 1.65 (m, 3H) , 2.13 (m, 1H), 2.47 (t, 2H), 5.05 (d, 1H), 5.30 (s, 1H), 5.57 (s, 2H), 5.65 (t, 1H), 6.63 (m, 1H), 7.09 (d, 1 H), 7.69 (s, 1 H); FAB-MS m / z 434.22 [M + H] ⁺ .

Step 3) Preparation of 4- (6-amino-8-furan-2-yl-2-hex-1-ynyl-purin-9-yl) -bicyclo [3.1.0] hexane-2,3-diol

To a THF solution (2.5 mL) of compound (25 mg, 0.059 mmol) prepared in step 2 was added 1N HCl (2.5 mL). The mixture was stirred at room temperature for 3 hours. The reaction was neutralized with 1N NaOH and then concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to afford the title compound (70%).

¹ H NMR (CDCl ₃ ) d 0.80 (m, 1H), 0.94 (m, 3H), 1.00 (m, 1H), 1.48 (m, 2H), 1.54 (m, 1H), 1.63 (m, 2H), 2.09 (m, 1H), 2.42 (t, 2H), 2.85 (s, 1H), 4.66 (d, 1H), 5.04 (s, 1H), 5.33 (s, 1H), 5.93 (s, 2H), 6.57 (s, 1 H), 7.07 (s, 1 H), 7.62 (s, 1 H); FAB-MS m / z 396.19 [M + H] ⁺ .

Experimental Example 1 Evaluation of Binding Affinity

Human A ₁ and A to assess binding affinity and selectivity of A ₁ , A _2A and A ₃ adenosine receptors in human adenosine receptors (hAR) of the compounds prepared in Examples 1 to 10 above Chinese hamster ovary (CHO) cells showing stable expression of ₃ adenosine receptors, HEK-293 cells showing stable expression of human A _2A adenosine receptors were performed.

1 nM [ ³ H] CCPA, 10 nM [ ³ H] CGS21680 or 0.5 nM [ ¹²⁵ I] IAB-MECA, which is a labeling ligand that selectively binds to the A ₁ , A _2A and A ₃ adenosine receptors, was used. Mean ± SEMs (n = 3, 4) are shown, and the percentage (%) of the data values shows% inhibition of specific labeled ligand binding at 10 μM. In addition, nonspecific binding was analyzed using a non-labeled ligand, 10 μM 5'-N-ethylcarboxamidomadein (5'-N-ehylcarboxamidoadenosine; NECA), where specific binding was subtracted from non-specific binding by total binding. It was calculated and the results obtained are shown in Table 1.

Example rescue affinity A ₁ A _2A A ₃ (ki, nM)
% Inhibitoin or Ki % Inhibitoin or Ki % Inhibitoin or Ki One

38.9 ± 9.9% 97.2 ± 4.1% 11.8 ± 1.3 2

16.2 ± 8.4% 95.9 ± 8.7% 13.2 ± 0.8 3

49.3 ± 4.9% 46.5 ± 4.3% 20.0 ± 4.0 4

3.7 ± 2.9% 22.8 ± 6.4% 259 ± 10 5

63.5 ± 6.9% 63.2 ± 15 138 ± 44 6

10.2 ± 5.4% 2160 ± 270 39.1 ± 5.2% 7

31.9 ± 1.2% 178 ± 26 218 ± 79 8

84.9 ± 4.0% 27.2 ± 2.9% 31.7 ± 7.4 9

18.1 ± 5.0% 5.8 ± 4.6% 24.7 ± 2.1% 10

76.5 ± 4.2% 27.3 ± 6.3% 94.2 ± 30.0 11

2.5 ± 1.3% 96.3 ± 6.4% 11.3 ± 0.5 12

28.8% 97.8% 16.2 ± 6.7 13

33.8% 98.4% 31 ± 11 14

14.5% 65.4% 35.3 ± 1.2 15

11.4% 95.7% 15.4 ± 2.8

Experimental Example 2: Adenosine A ₃  Antagonist effect on receptor and cAMP inhibition experiment

Cl-IB- as a compound and an agonist as a compound and an agonist in Chinese hamster ovary (CHO) cells in order to examine the antagonistic effect and cAMP inhibition experiment on human adenosine receptors of the compounds prepared in Examples 1 to 4 above MECA was treated together and performed, and the obtained results are shown in FIGS. 1 (a) to (c).

Figure 1 (a) shows the antagonistic effect and cAMP inhibition experiments on CHO cells of Example 1 of the present invention, 1 (b) is the dissociation constant k _b value according to Schild analysis of Examples 1 to 4 of the present invention 1 (c) shows the activity of Example 1 as an agonist of human A _2A adenosine receptor expressed in CHO compared to CGS21680.

As shown in Figure 1 (a), by treating the concentration of the compound of Example 1 differently to measure the effect of the effect of Cl-IB-MECA 100% pure agonist in CHO cells, concentration-dependent on Example 1 It was confirmed to be inhibited. This confirmed that Example 1 and Cl-IB-MECA competitively act on the same binding site of the receptor.

In addition, as a result of cAMP inhibition mediated by human A ₃ adenosine receptor in CHO cells, it was confirmed that Example 1 is a 100% pure A ₃ adenosine antagonist.

As shown in Figure 1 (b), the results of measuring the Examples 1 to 4 according to the Schild analysis, the dissociation constant K _B value was 1.69 nM, through which the compound of the present invention has a human A ₃ adenosine antagonistic effect I could confirm that.

As shown in FIG. 1 (c), as a result of cAMP inhibition of human A _2A adenosine receptor expressed in CHO cells, Example 1 shows 2- [p- (2-carboxyethyl) which is a selective agonist of A _2A receptor. It was confirmed to act as an agonist compared to) phenyl-ethylamino] -5'-N-ethylcarboxamidoadenosine (CGS21680). In addition, the EC ₅₀ value of the human A _2A adenosine receptor expressed in CHO cells was 12 nM, it was confirmed that the EC ₅₀ value acts as a weak partial agonist at 10 nM or less.

Through this, Example 1 was confirmed to be a selective agonist as a human A _2A adenosine receptor, it was confirmed that it acts as a competitive antagonist for the human A ₃ adenosine receptor.

Example 3 X-ray Crystallography Structure

In order to determine the binding mode for the human A _2A adenosine receptors of Examples 1 to 4, the X-ray crystallographic structure (PDB code: 3EML) was analyzed for the usefulness of the residues of the binding structure using GOLD software. Are shown in Fig. 2 (a), (b).

2 (a) and 2 (b) show the predicted binding modes of Examples 1 and 2 in the human A _2A adenosine receptor crystal structure, wherein the interaction moiety is a white carbon atom and a ball-and-stick Phe168. Except for the capped-stick. In addition, the ligands of Examples 1 and 2 are represented by a carbon atom and a ball-and-stick in magenta 1a and purple 1b, hydrogen bonds are represented by yellow dotted lines, and van der Waals ( The surface of the vander Waals was analyzed by MOLCAD and the red color by hydrogen bonding showed the donating position and the blue color was the hydrogen accepting position.

As shown in Figure 2 (a), (b), it was confirmed that the binding affinity of Examples 1 and 2 is well bound to the binding site in the nanomolar range, bulky and immobilized C2-substituted The residue was directed out of the cell by hydrophobic interaction, and part of the adenine had three hydrogen bonds (H-bond) with Glu169 and Asn253. In addition, the ring has a P-Py stacking interaction with Phe168, the thio-sugar ring is located deep inside the bond structure, and the 3'-OH group is hydrogen-bonded to Ser277. .

Claims (10)

A compound represented by Formula 1, or a pharmaceutically acceptable salt thereof:
[Formula 1]

In this formula,
X is S or O and Y is CH ₂ ; Or X and Y together form a cyclopropyl;
1) R ₁ is hydrogen; R ₂ is C _4-8 alkyl, C _4-8 alkenyl, or C _4-8 alkynyl; or
2) R ₁ is C _4-8 alkyl, C _4-8 alkenyl, or C _4-8 alkynyl; R ₂ is hydrogen; And
R ₃ is amine or C _4-8 alkynyl.
delete delete The method of claim 1,
R ₁ is hexyl, (E) -1-hex-1-enyl, or 1-hex-1-ynyl; R ₂ is hydrogen, or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ₁ is hydrogen; R ₂ is hexyl, (E) -1-hex-1-enyl or 1-hex-1-ynyl, or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ₃ is an amine or 1-hex-1-ynyl, or a pharmaceutically acceptable salt thereof.
1) (2R, 3S, 4R) -2- (6-amino-2- (hex-1-ynyl) -9H-purin-9-yl) -tetrahydrothiophene-3,4-diol,
2) (2R, 3S, 4R, E) -2- (6-amino-2- (hex-1-enyl) -9H-purin-9-yl) -tetrahydrothiophene-3,4-diol,
3) (2R, 3S, 4R) -2- (6-amino-8- (hex-1-ynyl) -9H-purin-9-yl) -tetrahydrothiophene-3,4-diol,
4) (2R, 3S, 4R, E) -2- (6-amino-8- (hex-1-enyl) -9H-purin-9-yl) -tetrahydrothiophene-3,4-diol,
5) (2R, 3S, 4S) -2- (6-amino-2- (hex-1-ynyl) -9H-purin-9-yl) -tetrahydrofuran-3,4-diol,
6) (2R, 3S, 4S) -2- (6-amino-2-hexyl-9H-purin-9-yl) -tetrahydrofuran-3,4-diol,
7) (2R, 3S, 4S, E) -2- (6-amino-2- (hex-1-enyl) -9H-purin-9-yl) -tetrahydrofuran-3,4-diol,
8) (2R, 3S, 4S) -2- (6-amino-8- (hex-1-ynyl) -9H-purin-9-yl) -tetrahydrofuran-3,4-diol,
9) (2R, 3S, 4S) -2- (6-amino-8-hexyl-9H-purin-9-yl) -tetrahydrofuran-3,4-diol,
10) (2R, 3S, 4S, E) -2- (6-amino-8- (hex-1-enyl) -9H-purin-9-yl) -tetrahydrofuran-3,4-diol,
11) (2R, 3S, 4S) -2- (6-Amino-8- (furan-3-yl) -2- (hex-1-ynyl) -9H-purin-9-yl) -tetrahydrofuran- 3,4-diol,
12) (1R, 2R, 3S, 4R, 5S) -4- (6-amino-2- (hex-1-ynyl) -9H-purin-9-yl) bicyclo [3.1.0] hexane-2, 3-diol,
13) (1R, 2R, 3S, 4R, 5S, E) -4- (6-amino-2- (hex-1-enyl) -9H-purin-9-yl) bicyclo [3.1.0] hexane- 2,3-diol,
14) (1R, 2R, 3S, 4R, 5S, E) -4- (2- (hex-1-enyl) -6- (hex-1-ynyl) -9H-purin-9-yl) bicyclo [ 3.1.0] hexane-2,3-diol, and
15) (1R, 2R, 3S, 4R, 5S) -4- (6-amino-8- (furan-3-yl) -2- (hex-1-ynyl) -9H-purin-9-yl) bi Cyclo [3.1.0] hexane-2,3-diol
Any one compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition for the prophylaxis or treatment of an A2A adenosine receptor-related inflammatory disease comprising the compound of any one of claims 1, 4 to 7, or a pharmaceutically acceptable salt thereof as an active ingredient.
delete The pharmaceutical composition of claim 8, wherein the inflammatory disease is any one selected from the group consisting of degenerative inflammation, exudative inflammation, purulent inflammation, hemorrhagic inflammation and proliferative inflammation.

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