Novel A3 adenosine receptor antagonist and preparing method thereof

Abstract

The present invention relates to a novel A3 adenosine receptor antagonist, a method for manufacturing the same, and uses thereof, and more specifically, to a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; a method for manufacturing said compound; a pharmaceutical composition for preventing or treating inflammatory diseases, fibrotic diseases, obesity, ischemic diseases, stroke, glaucoma, or cancer, comprising said compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient; and a health functional food composition for preventing or improving inflammatory diseases, fibrotic diseases, obesity, ischemic diseases, stroke, glaucoma, or cancer, comprising said compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

Description

Technology Field

[0001] The present invention relates to a novel A3 adenosine receptor antagonist, a method for preparing the same, and uses thereof, and more specifically, to a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; a method for preparing said compound; a pharmaceutical composition for preventing or treating inflammatory diseases, fibrotic diseases, obesity, ischemic diseases, stroke, glaucoma, or cancer, comprising said compound, its stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient; and a health functional food composition for preventing or improving inflammatory diseases, fibrotic diseases, obesity, ischemic diseases, stroke, glaucoma, or cancer, comprising said compound, its stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient. Background Technology

[0002] Adenosine receptors (ARs) are a subgroup belonging to the G protein-coupled receptor (GPCR) superfamily that plays an important role in regulating various physiological functions of the human body. The AR family includes A1, A 2A , A 2B It consists of four subtypes, including A1 and A3, each possessing a unique distribution pattern and signaling pathway. A1 and A3 adenosine receptors primarily inhibit adenylate cyclase to reduce intracellular cAMP levels, thereby inducing potassium efflux, inhibition of neural activity, and relaxation of smooth muscle cells. On the other hand, A 2A and A 2B Adenosine receptors activate adenylate cyclase to increase cAMP levels, which plays an important role in vasodilation and the regulation of immune responses.

[0003] While adenosine receptors share a common adenosine binding site, the sequence of amino acid residues in the binding site varies slightly depending on the receptor. These differences allow for the selective inhibition or activation of specific adenosine receptors through minor structural changes.

[0004] In this regard, the A3 adenosine receptor (A3AR) performs various physiological functions such as immune response, inflammation, and neurotransmission regulation, plays an important role in various physiological systems including the central nervous system and peripheral immune cells, and exhibits a wide range of biological effects by regulating intracellular cAMP levels through various signaling pathways. In particular, it is attracting attention as an important therapeutic target in various diseases such as neurodegenerative diseases, cardiovascular diseases, and inflammatory diseases, and various compounds targeting the said receptor are currently being developed (Patent Document 1). Prior art literature

[0005] Republic of Korea Published Patent No. 10-2023-0125800 The problem to be solved

[0006] Against this background, the present invention aimed to develop a substance with excellent binding ability to A3 adenosine receptors and high selectivity and antagonistic ability by introducing an ethyl group at the 4' position of a truncated 4'-thioadenosine structure, and the present invention was completed by confirming that a compound represented by Chemical Formula 1 exhibits excellent selectivity and antagonistic ability to A3 adenosine receptors.

[0007] Accordingly, the object of the present invention is to provide a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0008] [Chemical Formula 1]

[0009]

[0010] In the above formula,

[0011] The above R is a benzyl substituted with H, a C1-C6 alkyl, or a halogen, and

[0012] The above X is H, a halogen, or a C3-C12 alkynyl.

[0013] Another objective of the present invention is, as shown in the following reaction scheme 1,

[0014] A step of preparing a compound represented by chemical formula 13a by reacting EtMgBr in a THF solvent with a compound represented by chemical formula 12 prepared from D-ribose (step a);

[0015] A step of preparing a compound represented by chemical formula 14a by protecting the primary alcohol group of the compound represented by chemical formula 13a prepared in step a above with trimethylacetyl chloride (step b);

[0016] A step of oxidizing the compound represented by chemical formula 14a prepared in step b above to prepare a compound represented by chemical formula 15a (step c);

[0017] A step of reducing the compound represented by Chemical Formula 15a prepared in step c above to prepare a compound represented by Chemical Formula 16a (step d);

[0018] A step of preparing a compound represented by chemical formula 17a by mesylating the compound represented by chemical formula 16a prepared in step d above (step e);

[0019] A step of reacting the compound represented by chemical formula 17a prepared in step e with Na2S·9H2O to prepare a compound represented by chemical formula 18a (step f);

[0020] A step of oxidizing the compound represented by chemical formula 18a prepared in step f above with m-CPBA to prepare a compound represented by chemical formula 19a (step g);

[0021] A step (step h) of reacting the compound represented by chemical formula 19a prepared in step g with acetic anhydride to prepare the compound represented by chemical formula 20a through a Pummerer reaction;

[0022] A step of preparing compounds represented by chemical formula 21a and 23a, respectively, by Vorbruggen reaction with 6-chloropurine or 2,6-dichloropurine, the compound represented by chemical formula 20a prepared in step h above (step i);

[0023] A step (step j) of acid hydrolyzing the compounds represented by chemical formulas 21a and 23a prepared in step i, respectively, to prepare compounds represented by chemical formulas 22a and 24a; and

[0024] The present invention provides a method for preparing a compound represented by Formula 1 of claim 1, comprising the step (step k) of reacting the compounds represented by Formulas 22a and 24a prepared in step j under NH3 / t-BuOH, RNH2, Et3N, or EtOH conditions to prepare a compound represented by Formula 1:

[0025] [Reaction Equation 1]

[0026]

[0027] (In the above reaction scheme 1,

[0028] The above R is H, methyl, 3-F-benzyl, 3-Cl-benzyl, 3-Br-benzyl, or 3-I-benzyl, and

[0029] The above X is H or Cl).

[0030] Another objective of the present invention is, as shown in the following reaction scheme 2,

[0031] A step of preparing a compound represented by chemical formula 13a by reacting EtMgBr in a THF solvent with a compound represented by chemical formula 12 prepared from D-ribose (step a);

[0032] A step of preparing a compound represented by chemical formula 14a by protecting the primary alcohol group of the compound represented by chemical formula 13a prepared in step a above with trimethylacetyl chloride (step b);

[0033] A step of oxidizing the compound represented by chemical formula 14a prepared in step b above to prepare a compound represented by chemical formula 15a (step c);

[0034] A step of reducing the compound represented by Chemical Formula 15a prepared in step c above to prepare a compound represented by Chemical Formula 16a (step d);

[0035] A step of preparing a compound represented by chemical formula 17a by mesylating the compound represented by chemical formula 16a prepared in step d above (step e);

[0036] A step of reacting the compound represented by chemical formula 17a prepared in step e with Na2S·9H2O to prepare a compound represented by chemical formula 18a (step f);

[0037] A step of oxidizing the compound represented by chemical formula 18a prepared in step f above with m-CPBA to prepare a compound represented by chemical formula 19a (step g);

[0038] Step (step h) of reacting the compound represented by chemical formula 19a prepared in step g with acetic anhydride to prepare the compound represented by chemical formula 20a through a Pummerer reaction.

[0039] A step of preparing a compound represented by chemical formula 31 by reacting the compound represented by chemical formula 20a prepared in step h with 6-chloro-2-iodopurine and Vorbruggen (step l);

[0040] A step of preparing a compound represented by Chemical Formula 32 by reacting the compound represented by Chemical Formula 31 prepared in step l with 1-hexine in a Sonogashira bonding reaction (step m);

[0041] A step of acid hydrolyzing the compound represented by Chemical Formula 32 prepared in step m above to prepare a compound represented by Chemical Formula 33 (step n); and

[0042] The compound represented by Chemical Formula 33 prepared in step n above is NH3 / t The present invention provides a method for preparing a compound represented by Formula 1 of claim 1, comprising the step (step o) of reacting under conditions of -BuOH, RNH2, Et3N, or EtOH to prepare a compound represented by Formula 1:

[0043] [Reaction Equation 2]

[0044]

[0045] (In the above reaction scheme 2,

[0046] The above R is H, methyl, 3-F-benzyl, 3-Cl-benzyl, 3-Br-benzyl, or 3-I-benzyl, and

[0047] The above X is 1-hexinyl).

[0048] In addition, another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of inflammatory diseases, fibrotic diseases, obesity, ischemic diseases, stroke, glaucoma, or cancer, comprising the compound, its stereoisomer, or its pharmaceutically acceptable salt as an active ingredient.

[0049] Another object of the present invention is to provide a health functional food composition for the prevention or improvement of inflammatory diseases, fibrotic diseases, obesity, ischemic diseases, stroke, glaucoma, or cancer, comprising the said compound, its stereoisomer, or a pharmaceutically acceptable salt thereof. means of solving the problem

[0050] To solve the above-mentioned problem, the present invention provides a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0051] [Chemical Formula 1]

[0052]

[0053] In the above formula,

[0054] The above R is a benzyl substituted with H, a C1-C6 alkyl, or a halogen, and

[0055] The above X is H, a halogen, or a C3-C12 alkynyl.

[0056] At this time, the above compound may be any one selected from the group of compounds below:

[0057] (1) (2R,3R,4S,5R)-2-(6-amino-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol;

[0058] (2) (2R,3S,4R,5R)-2-ethyl-5-(6-(methylamino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol;

[0059] (3) (2R,3S,4R,5R)-2-ethyl-5-(6-((3-fluorobenzyl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol;

[0060] (4) (2R,3R,4S,5R)-2-(6-((3-chlorobenzyl)amino)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol;

[0061] (5) (2R,3R,4S,5R)-2-(6-((3-bromobenzyl)amino)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol;

[0062] (6) (2R,3S,4R,5R)-2-ethyl-5-(6-((3-iodobenzyl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol;

[0063] (7) (2R,3R,4S,5R)-2-(6-amino-2-chloro-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol;

[0064] (8) (2R,3R,4S,5R)-2-(2-chloro-6-(methylamino)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol;

[0065] (9) (2R,3R,4S,5R)-2-(2-chloro-6-((3-fluorobenzyl)amino)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol;

[0066] (10) (2R,3R,4S,5R)-2-(2-chloro-6-((3-chlorobenzyl)amino)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol;

[0067] (11) (2R,3R,4S,5R)-2-(6-((3-bromobenzyl)amino)-2-chloro-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol;

[0068] (12) (2R,3R,4S,5R)-2-(2-chloro-6-((3-iodobenzyl)amino)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol;

[0069] (13) 2R,3R,4S,5R)-2-(6-amino-2-(hex-1-in-1-yl)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol;

[0070] (14) (2R,3S,4R,5R)-2-ethyl-5-(2-(hex-1-in-1-yl)-6-(methylamino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol;

[0071] (15) (2R,3S,4R,5R)-2-ethyl-5-(6-((3-fluorobenzyl)amino)-2-(hex-1-in-1-yl)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol;

[0072] (16) (2R,3R,4S,5R)-2-(6-((3-chlorobenzyl)amino)-2-(hex-1-in-1-yl)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol;

[0073] (17) (2R,3R,4S,5R)-2-(6-((3-bromobenzyl)amino)-2-(hex-1-in-1-yl)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol; and

[0074] (18) (2R,3S,4R,5R)-2-ethyl-5-(2-(hex-1-in-1-yl)-6-((3-iodobenzyl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol.

[0075] In this case, the above compound may bind to an adenosine receptor.

[0076] In this case, the above compound may be an A3 adenosine receptor antagonist.

[0077] At this time, the stereoisomer may include a racemic mixture, a mirror image isomer, a diastereomer, a mixture of mirror image isomers, or a mixture of diastereomers.

[0078] In addition, in the present invention, as shown in the following reaction scheme 1,

[0079] A step of preparing a compound represented by chemical formula 13a by reacting EtMgBr in a THF solvent with a compound represented by chemical formula 12 prepared from D-ribose (step a);

[0080] A step of preparing a compound represented by chemical formula 14a by protecting the primary alcohol group of the compound represented by chemical formula 13a prepared in step a above with trimethylacetyl chloride (step b);

[0081] A step of oxidizing the compound represented by chemical formula 14a prepared in step b above to prepare a compound represented by chemical formula 15a (step c);

[0082] A step of reducing the compound represented by Chemical Formula 15a prepared in step c above to prepare a compound represented by Chemical Formula 16a (step d);

[0083] A step of preparing a compound represented by chemical formula 17a by mesylating the compound represented by chemical formula 16a prepared in step d above (step e);

[0084] A step of reacting the compound represented by chemical formula 17a prepared in step e with Na2S·9H2O to prepare a compound represented by chemical formula 18a (step f);

[0085] A step of oxidizing the compound represented by chemical formula 18a prepared in step f above with m-CPBA to prepare a compound represented by chemical formula 19a (step g);

[0086] A step (step h) of reacting the compound represented by chemical formula 19a prepared in step g with acetic anhydride to prepare the compound represented by chemical formula 20a through a Pummerer reaction;

[0087] A step of preparing compounds represented by chemical formula 21a and 23a, respectively, by Vorbruggen reaction with 6-chloropurine or 2,6-dichloropurine, the compound represented by chemical formula 20a prepared in step h above (step i);

[0088] A step (step j) of acid hydrolyzing the compounds represented by chemical formulas 21a and 23a prepared in step i, respectively, to prepare compounds represented by chemical formulas 22a and 24a; and

[0089] A method for preparing a compound represented by Formula 1 of claim 1 is provided, comprising the step (step k) of reacting the compounds represented by Formulas 22a and 24a prepared in step j under NH3 / t-BuOH, RNH2, Et3N, or EtOH conditions to prepare a compound represented by Formula 1:

[0090] [Reaction Equation 1]

[0091]

[0092] (In the above reaction scheme 1,

[0093] The above R is H, methyl, 3-F-benzyl, 3-Cl-benzyl, 3-Br-benzyl, or 3-I-benzyl, and

[0094] The above X is H or Cl).

[0095] In addition, in the present invention, as shown in the following reaction scheme 2,

[0096] A step of preparing a compound represented by chemical formula 13a by reacting EtMgBr in a THF solvent with a compound represented by chemical formula 12 prepared from D-ribose (step a);

[0097] A step of preparing a compound represented by chemical formula 14a by protecting the primary alcohol group of the compound represented by chemical formula 13a prepared in step a above with trimethylacetyl chloride (step b);

[0098] A step of oxidizing the compound represented by chemical formula 14a prepared in step b above to prepare a compound represented by chemical formula 15a (step c);

[0099] A step of reducing the compound represented by Chemical Formula 15a prepared in step c above to prepare a compound represented by Chemical Formula 16a (step d);

[0100] A step of preparing a compound represented by chemical formula 17a by mesylating the compound represented by chemical formula 16a prepared in step d above (step e);

[0101] A step of reacting the compound represented by chemical formula 17a prepared in step e with Na2S·9H2O to prepare a compound represented by chemical formula 18a (step f);

[0102] A step of oxidizing the compound represented by chemical formula 18a prepared in step f above with m-CPBA to prepare a compound represented by chemical formula 19a (step g);

[0103] Step (step h) of reacting the compound represented by chemical formula 19a prepared in step g with acetic anhydride to prepare the compound represented by chemical formula 20a through a Pummerer reaction.

[0104] A step of preparing a compound represented by chemical formula 31 by reacting the compound represented by chemical formula 20a prepared in step h with 6-chloro-2-iodopurine and Vorbruggen (step l);

[0105] A step of preparing a compound represented by Chemical Formula 32 by reacting the compound represented by Chemical Formula 31 prepared in step l with 1-hexine in a Sonogashira bonding reaction (step m);

[0106] A step of acid hydrolyzing the compound represented by Chemical Formula 32 prepared in step m above to prepare a compound represented by Chemical Formula 33 (step n); and

[0107] The compound represented by Chemical Formula 33 prepared in step n above is NH3 / t - A method for preparing a compound represented by Formula 1 of claim 1 is provided, comprising the step (step o) of reacting under conditions of -BuOH, RNH2, Et3N, or EtOH to prepare a compound represented by Formula 1:

[0108] [Reaction Equation 2]

[0109]

[0110] (In the above reaction scheme 2,

[0111] The above R is H, methyl, 3-F-benzyl, 3-Cl-benzyl, 3-Br-benzyl, or 3-I-benzyl, and

[0112] The above X is 1-hexinyl).

[0113] In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of inflammatory diseases, fibrotic diseases, obesity, ischemic diseases, stroke, glaucoma, or cancer, comprising the above compound, its stereoisomer, or its pharmaceutically acceptable salt as an active ingredient.

[0114] At this time, the cancer may be any one selected from the group consisting of breast cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, liver cancer, colorectal cancer, skin cancer, head or neck cancer, brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, kidney cancer, rectal cancer, leukemia, and blood cancer.

[0115] At this time, the above-mentioned ischemic disease may be ischemic myocardial infarction, ischemic heart disease, ischemic vascular disease, ischemic enteritis, ischemic eye disease, ischemic glaucoma, ischemic renal failure, ischemic retinopathy, ischemic stroke, ischemic muscle disease, or ischemic limb disease.

[0116] At this time, the above inflammatory disease may be acne, seborrheic dermatitis, contact dermatitis, atopic dermatitis, allergic dermatitis, lupus erythematosus, papular urticaria, psoriasis, asthma, gastritis, edema, conjunctivitis, periodontitis, rhinitis, otitis media, pharyngitis, tonsillitis, pneumonia, hepatitis, esophagitis, gastric ulcer, enteritis, pancreatitis, duodenal ulcer, colitis, cholangitis, nephritis, hemorrhoids, gout, ankylosing spondylitis, lupus, osteoarthritis, rheumatoid arthritis, periarthritis of the shoulder, tendinitis, tenosynovitis, tenosynovitis, myositis, cystitis, nephritis, multiple sclerosis, non-alcoholic fatty liver disease, or sepsis.

[0117] At this time, the above fibrotic disease may be pulmonary fibrosis, liver fibrosis, cutaneous fibrosis, renal fibrosis, pancreatic fibrosis, systemic sclerosis, or cardiac fibrosis.

[0118] Furthermore, the present invention provides a health functional food composition for the prevention or improvement of inflammatory diseases, fibrotic diseases, obesity, ischemic diseases, stroke, glaucoma, or cancer, comprising the above compound, its stereoisomer, or a pharmaceutically acceptable salt thereof. Effects of the invention

[0119] Currently, there are no approved drugs for A3AR, necessitating the development of materials with novel structures. Accordingly, the inventors introduced an ethyl group at the 4' position and evaluated the effects of structural changes resulting from this introduction on binding affinity and antagonistic activity. The results confirmed that binding affinity was maintained or increased, while selectivity and antagonistic activity against A3AR were significantly enhanced. Furthermore, nucleoside-based drugs offer high patient convenience due to their oral administration capabilities; their structural characteristics make it relatively easy to identify the causes of side effects; the absence of approved drugs based on this mechanism creates significant potential for new drug development; and combination therapy offers the potential to enhance efficacy and mitigate side effects. As such, the compound of the present invention, based on a modified nucleic acid backbone, provides advantages distinct from existing materials; its high hydrophilicity results in excellent pharmacological properties; and it is capable of targeting various diseases. This is expected to secure a technological advantage in the development of selective or multi-targeted new drugs and enable competitiveness in the global market; thus, the compound of the present invention, as well as pharmaceutical compositions and health functional food compositions containing it, possess high utility value. Specific details for implementing the invention

[0120] The present invention will be described in more detail below.

[0121] Meanwhile, each description and embodiment disclosed herein may be applied to each other description and embodiment. That is, all combinations of the various elements disclosed herein fall within the scope of the present invention. Furthermore, the scope of the present invention is not to be limited by the specific descriptions provided below.

[0122] In addition, a person skilled in the art can recognize or identify a number of equivalents to the specific embodiments of the invention described in this application using only ordinary experiments. In addition, such equivalents are intended to be included in the invention.

[0123] As described above, the inventors confirmed that a compound represented by Chemical Formula 1 exhibits excellent binding affinity and antagonistic ability to the A3 adenosine receptor and completed the present invention.

[0124] In a specific embodiment of the present invention, an adenosine derivative with an ethyl group introduced at the 4' position was synthesized.

[0125] Accordingly, the first aspect of the present invention relates to a compound represented by the following formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0126] [Chemical Formula 1]

[0127]

[0128] In the above formula,

[0129] The above R is a benzyl substituted with H, a C1-C6 alkyl, or a halogen, and

[0130] The above X may be H, a halogen, or a C3-C12 alkynyl.

[0131] As used herein, the term "C1-6 alkyl" refers to a monovalent alkyl group having 1 to 6 carbon atoms, and said alkyl may be optionally substituted with one or more substituents. Examples of functional groups for this term include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, etc. Substituents comprising the alkyl and other alkyl portions described in the present invention include both straight-chain and branched forms.

[0132] As used herein, the term “halogen” means an atom of fluorine (F), chlorine (Cl), bromine (Br), or iodine (I), either independently or as part of another substituent, unless otherwise noted. The term “halide” means an atom of fluoride, chloride, bromide, or iodide, either in itself or as part of another substituent.

[0133] As used herein, the term "C3-12 alkynyl" refers to a monovalent unsaturated hydrocarbon group having 3 to 12 carbon atoms and comprising at least one carbon-carbon triple bond, wherein the alkynyl may be optionally substituted with one or more substituents. This term includes, but is not limited to, functional groups such as, for example, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexinyl, 1-octinyl, 1-decinyl, etc. Substituents comprising the alkynyl and other alkynyl portions described in the present invention include both straight-chain and branched (branched) forms.

[0134] In the present invention, R may be H, methyl, 3-F-benzyl, 3-Cl-benzyl, 3-Br-benzyl, or 3-I-benzyl, and

[0135] The above X may be H, a halogen, or 1-hexinyl.

[0136] In the present invention, the compound may be any one selected from the group of compounds below:

[0137] (1) (2R,3R,4S,5R)-2-(6-amino-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol;

[0138] (2) (2R,3S,4R,5R)-2-ethyl-5-(6-(methylamino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol;

[0139] (3) (2R,3S,4R,5R)-2-ethyl-5-(6-((3-fluorobenzyl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol;

[0140] (4) (2R,3R,4S,5R)-2-(6-((3-chlorobenzyl)amino)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol;

[0141] (5) (2R,3R,4S,5R)-2-(6-((3-bromobenzyl)amino)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol;

[0142] (6) (2R,3S,4R,5R)-2-ethyl-5-(6-((3-iodobenzyl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol;

[0143] (7) (2R,3R,4S,5R)-2-(6-amino-2-chloro-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol;

[0144] (8) (2R,3R,4S,5R)-2-(2-chloro-6-(methylamino)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol;

[0145] (9) (2R,3R,4S,5R)-2-(2-chloro-6-((3-fluorobenzyl)amino)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol;

[0146] (10) (2R,3R,4S,5R)-2-(2-chloro-6-((3-chlorobenzyl)amino)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol;

[0147] (11) (2R,3R,4S,5R)-2-(6-((3-bromobenzyl)amino)-2-chloro-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol;

[0148] (12) (2R,3R,4S,5R)-2-(2-chloro-6-((3-iodobenzyl)amino)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol;

[0149] (13) 2R,3R,4S,5R)-2-(6-amino-2-(hex-1-in-1-yl)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol;

[0150] (14) (2R,3S,4R,5R)-2-ethyl-5-(2-(hex-1-in-1-yl)-6-(methylamino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol;

[0151] (15) (2R,3S,4R,5R)-2-ethyl-5-(6-((3-fluorobenzyl)amino)-2-(hex-1-in-1-yl)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol;

[0152] (16) (2R,3R,4S,5R)-2-(6-((3-chlorobenzyl)amino)-2-(hex-1-in-1-yl)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol;

[0153] (17) (2R,3R,4S,5R)-2-(6-((3-bromobenzyl)amino)-2-(hex-1-in-1-yl)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol; and

[0154] (18) (2R,3S,4R,5R)-2-ethyl-5-(2-(hex-1-in-1-yl)-6-((3-iodobenzyl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol.

[0155] In one specific embodiment of the present invention, it was confirmed that a compound represented by Formula 1 exhibits excellent binding affinity to an A3 adenosine receptor (Tables 2 and 4), and in another specific embodiment, it was confirmed that it exhibits excellent antagonistic ability to the receptor (Table 6).

[0156] Accordingly, in the present invention, the compound may bind to an adenosine receptor.

[0157] In the present invention, the compound may be an A3 adenosine receptor antagonist.

[0158] In the present invention, the stereoisomer may include a racemic mixture, a mirror image isomer, a diastereomer, a mixture of mirror image isomers, or a mixture of diastereomers.

[0159] In addition, a second aspect of the present invention is, as shown in the following reaction scheme 1,

[0160] A step of preparing a compound represented by chemical formula 13a by reacting EtMgBr in a THF solvent with a compound represented by chemical formula 12 prepared from D-ribose (step a);

[0161] A step of preparing a compound represented by chemical formula 14a by protecting the primary alcohol group of the compound represented by chemical formula 13a prepared in step a above with trimethylacetyl chloride (step b);

[0162] A step of oxidizing the compound represented by chemical formula 14a prepared in step b above to prepare a compound represented by chemical formula 15a (step c);

[0163] A step of reducing the compound represented by Chemical Formula 15a prepared in step c above to prepare a compound represented by Chemical Formula 16a (step d);

[0164] A step of preparing a compound represented by chemical formula 17a by mesylating the compound represented by chemical formula 16a prepared in step d above (step e);

[0165] A step of reacting the compound represented by chemical formula 17a prepared in step e with Na2S·9H2O to prepare a compound represented by chemical formula 18a (step f);

[0166] A step of oxidizing the compound represented by chemical formula 18a prepared in step f above with m-CPBA to prepare a compound represented by chemical formula 19a (step g);

[0167] A step (step h) of reacting the compound represented by chemical formula 19a prepared in step g with acetic anhydride to prepare the compound represented by chemical formula 20a through a Pummerer reaction;

[0168] A step of preparing compounds represented by chemical formula 21a and 23a, respectively, by Vorbruggen reaction with 6-chloropurine or 2,6-dichloropurine, the compound represented by chemical formula 20a prepared in step h above (step i);

[0169] A step (step j) of acid hydrolyzing the compounds represented by chemical formulas 21a and 23a prepared in step i, respectively, to prepare compounds represented by chemical formulas 22a and 24a; and

[0170] The present invention relates to a method for preparing a compound represented by Formula 1 of claim 1, comprising the step (step k) of reacting the compounds represented by Formulas 22a and 24a prepared in step j under NH3 / t-BuOH, RNH2, Et3N, or EtOH conditions to prepare a compound represented by Formula 1:

[0171] [Reaction Equation 1]

[0172]

[0173] (In the above reaction scheme 1,

[0174] The above R is H, methyl, 3-F-benzyl, 3-Cl-benzyl, 3-Br-benzyl, or 3-I-benzyl, and

[0175] The above X is H or Cl).

[0176] In addition, a third aspect of the present invention is, as shown in the following reaction scheme 2,

[0177] A step of preparing a compound represented by chemical formula 13a by reacting EtMgBr in a THF solvent with a compound represented by chemical formula 12 prepared from D-ribose (step a);

[0178] A step of preparing a compound represented by chemical formula 14a by protecting the primary alcohol group of the compound represented by chemical formula 13a prepared in step a above with trimethylacetyl chloride (step b);

[0179] A step of oxidizing the compound represented by chemical formula 14a prepared in step b above to prepare a compound represented by chemical formula 15a (step c);

[0180] A step of reducing the compound represented by Chemical Formula 15a prepared in step c above to prepare a compound represented by Chemical Formula 16a (step d);

[0181] A step of preparing a compound represented by chemical formula 17a by mesylating the compound represented by chemical formula 16a prepared in step d above (step e);

[0182] A step of reacting the compound represented by chemical formula 17a prepared in step e with Na2S·9H2O to prepare a compound represented by chemical formula 18a (step f);

[0183] A step of oxidizing the compound represented by chemical formula 18a prepared in step f above with m-CPBA to prepare a compound represented by chemical formula 19a (step g);

[0184] Step (step h) of reacting the compound represented by chemical formula 19a prepared in step g with acetic anhydride to prepare the compound represented by chemical formula 20a through a Pummerer reaction.

[0185] A step of preparing a compound represented by chemical formula 31 by reacting the compound represented by chemical formula 20a prepared in step h with 6-chloro-2-iodopurine and Vorbruggen (step l);

[0186] A step of preparing a compound represented by Chemical Formula 32 by reacting the compound represented by Chemical Formula 31 prepared in step l with 1-hexine in a Sonogashira bonding reaction (step m);

[0187] A step of acid hydrolyzing the compound represented by Chemical Formula 32 prepared in step m above to prepare a compound represented by Chemical Formula 33 (step n); and

[0188] The compound represented by Chemical Formula 33 prepared in step n above is NH3 / t The present invention relates to a method for preparing a compound represented by Formula 1 of claim 1, comprising the step (step o) of reacting under conditions of -BuOH, RNH2, Et3N, or EtOH to prepare a compound represented by Formula 1:

[0189] [Reaction Equation 2]

[0190]

[0191] (In the above reaction scheme 2,

[0192] The above R is H, methyl, 3-F-benzyl, 3-Cl-benzyl, 3-Br-benzyl, or 3-I-benzyl, and

[0193] The above X is 1-hexinyl).

[0194] Additionally, a fourth aspect of the present invention relates to a pharmaceutical composition for the prevention or treatment of inflammatory diseases, fibrotic diseases, obesity, ischemic diseases, stroke, glaucoma, or cancer, comprising the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0195] The composition and effect of the compound included in the pharmaceutical composition of the present invention are identical to the composition and effect of the first aspect compound, so the description thereof is omitted.

[0196] As used in the present invention, the term "prevention" refers to any act that causes inflammatory diseases, fibrotic diseases, obesity, ischemic diseases, stroke, glaucoma, or cancer or related diseases to be suppressed or their onset delayed by the compound of the present invention.

[0197] The term "treatment" as used in this invention refers to any act that causes parameters, such as the degree of symptoms, related to inflammatory diseases, fibrotic diseases, obesity, ischemic diseases, stroke, glaucoma, or cancer or related diseases to improve or benefit from the compound of this invention.

[0198] The pharmaceutical composition of the present invention may be in various oral or parenteral formulations.

[0199] When formulating the above composition, it may be prepared using one or more buffers (e.g., saline solution or PBS), antioxidants, bacteriostatic agents, chelating agents (e.g., EDTA or glutathione), fillers, extenders, binders, adjuvants (e.g., aluminum hydroxide), suspending agents, thickeners, wetting agents, disintegrants or surfactants, diluents or excipients.

[0200] Solid dosage forms for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid dosage forms are prepared by mixing at least one excipient with one or more compounds, for example, starch (including corn starch, wheat starch, rice starch, potato starch, etc.), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol, maltitol, cellulose, methyl cellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose, or gelatin, etc. For example, tablets or sugar-coated tablets can be obtained by combining an active ingredient with a solid excipient, grinding the mixture, adding a suitable auxiliary agent, and processing it into a granular mixture.

[0201] In addition, lubricants such as magnesium stearate and talc are also used in addition to simple excipients. Liquid formulations for oral administration include suspensions, liquid formulations, emulsions, or syrups, and may contain various excipients, such as humectants, sweeteners, flavorings, or preservatives, in addition to commonly used simple diluents like water and liquid paraffin. Additionally, cross-linked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may be added as disintegrants, and may additionally include anticoagulants, flavorings, emulsifiers, solubilizers, dispersants, flavorings, antioxidants, packaging agents, pigments, and preservatives.

[0202] Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, or suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspensions. Witepsol, macrogol, Tween 61, cocoa paste, laurin paste, glycerol, gelatin, etc. may be used as bases for suppositories.

[0203] The composition of the present invention may be administered orally or parenterally, and when administered parenterally, may be formulated in the form of an injectable administered intraperitoneally, rectum, vein, muscle, or subcutaneously; or a nasal inhalant according to methods known in the art.

[0204] The above-mentioned injectable must be sterilized and protected from contamination by microorganisms such as bacteria and fungi. Suitable carriers for the injectable may include, but are not limited to, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), mixtures thereof, and / or vegetable oils, as solvents or dispersion media. More preferably, suitable carriers may include Hanks' solution, Ringer's solution, PBS (phosphate buffered saline) containing triethanolamine, sterile water for injection, isotonic solutions such as 10% ethanol, 40% propylene glycol, and 5% dextrose. To protect the injectable from microbial contamination, various antimicrobial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal may be additionally included. Additionally, the injectable may, in most cases, further include isotonic agents such as sugars or sodium chloride.

[0205] In the case of an inhalation dose, the compound used according to the present invention can be conveniently delivered in the form of an aerosol spray from a pressurized pack or atomizer using a suitable propellant, for example, dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosing unit can be determined by providing a valve that delivers a metered amount. For example, gelatin capsules and cartridges used in an inhaler or blower can be formulated to contain the compound and a powder mixture of a suitable powder base, such as lactose or starch.

[0206] The pharmaceutical composition of the present invention may be a pharmaceutical composition or a quasi-pharmaceutical composition.

[0207] The term "quasi-drug" as used in the present invention refers to articles used for the purpose of diagnosing, treating, improving, alleviating, managing, or preventing diseases of humans or animals, which have a milder effect than pharmaceuticals. For example, according to the Pharmaceutical Affairs Act, quasi-drugs are defined as articles excluding those used for pharmaceutical purposes, and include products used for the treatment or prevention of diseases of humans or animals, and products that have a mild effect on the human body or do not act directly on it.

[0208] The above-mentioned quasi-drug composition of the present invention may be manufactured in a formulation selected from the group consisting of body cleansers, disinfectants, detergents, kitchen detergents, cleaning detergents, toothpaste, mouthwash, wet wipes, detergents, soaps, hand washes, hair cleansers, hair softeners, humidifier fillers, masks, ointments, and filter fillers, but is not limited thereto.

[0209] The composition of the present invention is administered in a pharmaceutically effective amount. A pharmaceutically effective amount refers to an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level may be determined based on factors including the type and severity of the patient's disease, drug activity, sensitivity to the drug, time of administration, route of administration and elimination rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered as a single or multiple doses. That is, the total effective amount of the composition of the present invention may be administered to the patient as a single dose, or administered via a fractionated treatment protocol involving long-term administration of multiple doses. It is important to administer an amount that obtains maximum effect with a minimum amount without side effects by considering all the aforementioned factors, and this can be easily determined by a person skilled in the art.

[0210] The dosage of the pharmaceutical composition of the present invention may vary depending on the patient's weight, age, gender, health condition, diet, time of administration, method of administration, excretion rate, and severity of the disease.

[0211] In the present invention, the cancer may be any one selected from the group consisting of breast cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, liver cancer, colorectal cancer, skin cancer, head or neck cancer, brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, kidney cancer, rectal cancer, leukemia, and blood cancer, and the ischemic disease may be ischemic myocardial infarction, ischemic heart disease, ischemic vascular disease, ischemic enteritis, ischemic eye disease, ischemic glaucoma, ischemic renal failure, ischemic retinopathy, ischemic stroke, ischemic muscle disease, or ischemic limb disease.

[0212] In the present invention, the inflammatory disease may be acne, seborrheic dermatitis, contact dermatitis, atopic dermatitis, allergic dermatitis, lupus erythematosus, papular urticaria, psoriasis, asthma, gastritis, edema, conjunctivitis, periodontitis, rhinitis, otitis media, pharyngitis, tonsillitis, pneumonia, hepatitis, esophagitis, gastric ulcer, enteritis, pancreatitis, duodenal ulcer, colitis, cholangitis, nephritis, hemorrhoids, gout, ankylosing spondylitis, lupus, osteoarthritis, rheumatoid arthritis, periarthritis of the shoulder, tendinitis, tenosynovitis, tenosynovitis, myositis, cystitis, nephritis, multiple sclerosis, non-alcoholic fatty liver disease, or sepsis.

[0213] In the present invention, the fibrotic disease may be pulmonary fibrosis, liver fibrosis, cutaneous fibrosis, renal fibrosis, pancreatic fibrosis, systemic sclerosis, or cardiac fibrosis.

[0214] The composition of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.

[0215] Furthermore, a fifth aspect of the present invention relates to a food or health functional food composition for the prevention or improvement of inflammatory diseases, fibrotic diseases, obesity, ischemic diseases, stroke, glaucoma, or cancer, comprising a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0216] The composition and effect of the compound included in the food or health functional food composition of the present invention are identical to the composition and effect of the compound of the first aspect above, so the description thereof is omitted.

[0217] The food composition according to the present invention can be prepared in various forms according to conventional methods known in the art. General foods may be prepared by adding the compound of the present invention to beverages (including alcoholic beverages), fruits and their processed foods (e.g., canned fruit, bottled fruit, jam, marmalade, etc.), fish, meat and its processed foods (e.g., ham, sausage, corned beef, etc.), breads and noodles (e.g., udon, buckwheat noodles, ramen, spaghetti, macaroni, etc.), fruit juices, various drinks, cookies, malt syrup, dairy products (e.g., butter, cheese, etc.), edible vegetable oils, margarine, vegetable proteins, retort foods, frozen foods, and various seasonings (e.g., soybean paste, soy sauce, sauces, etc.), although not limited thereto. Additionally, nutritional supplements may be prepared by adding the compound of the present invention to capsules, tablets, pills, etc. In addition, health functional foods are not limited thereto, but for example, the compound of the present invention itself can be consumed by liquefying, granulating, encapsulating, and powdering it so that it can be prepared in the form of tea, juice, and drink (health beverage). In addition, to use the compound of the present invention as a food additive, it can be prepared and used in the form of a powder or a concentrate.

[0218] When the compound of the present invention is used as a health drink, the health drink composition may contain various flavoring agents or natural carbohydrates as additional ingredients, as in conventional beverages. The aforementioned natural carbohydrates may be monosaccharides such as glucose and fructose; disaccharides such as maltose and sucrose; polysaccharides such as dextrin and cyclodextrin; or sugar alcohols such as xylitol, sorbitol, and erythritol. Sweeteners may include natural sweeteners such as thaumatin and stevia extract; or synthetic sweeteners such as saccharin and aspartame. The proportion of the natural carbohydrates is generally about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 mL of the composition of the present invention.

[0219] In addition, the compound of the present invention may be contained as an active ingredient in a health functional food composition for the prevention or improvement of inflammatory diseases, fibrotic diseases, obesity, ischemic diseases, stroke, glaucoma, or cancer. The amount is not specifically limited to an amount effective for achieving the prevention or improvement of the said diseases, but it is preferably 0.01 to 100 weight% with respect to the total weight of the composition. The health functional food composition of the present invention may be prepared by mixing the compound with other active ingredients known to be effective against ischemic diseases, stroke, or cancer-related diseases.

[0220] In addition to the above, the health functional food of the present invention may contain various nutritional supplements, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid, salts of pectic acid, alginic acid, salts of alginic acid, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, or carbonating agents. Furthermore, the health functional food of the present invention may contain fruit pulp for the production of natural fruit juice, fruit juice beverages, or vegetable beverages. These ingredients may be used independently or in combination.

[0221] The present invention will be explained in more detail below through the following examples. However, the following examples are merely illustrative of the present invention and do not limit the scope of the present invention.

[0222] 1. Synthesis of intermediate 18a

[0223]

[0224] Reaction reagents and conditions: 1.0 M EtMgBr in THF for 13a, 2.0 M in THF for 13b iso-(b) PrMgCl, THF, from -78 ℃ to room temperature, 12 hours; (b) trimethylacetyl chloride, DMAP, DIPEA, CH2Cl2, 0 ℃, 30 minutes; (c) i. (COCl)2, DMSO, CH2Cl2, -78 ℃, 1 hour; ii. Et3N, room temperature, 1 hour; (d) i. NaBH4, MeOH, 0 ℃, 30 minutes; ii. NaOMe, MeOH, 50 ℃, 15 hours; (e) MsCl, Et3N, DMAP, CH2Cl2, 0 ℃, 3 hours; (f) Na2S·9H2O, DMF, 100 ℃, 12 hours.

[0225] 2,3-O-isopropylidene-L-erythrofuranose (Compound 12) was synthesized using D-ribose as the starting material and as the major intermediate. When Compound 12 (Lactol 12) was reacted with the corresponding Grignard reagent at -78 °C, mainly diol 13a-b was produced, along with a small amount of diol 16a-b in a 9:1 ratio. The resulting compounds were effectively separated using silica gel column chromatography. To selectively obtain intermediate 16a-b, a stereochemical inversion process was performed on diol 13a-b. During this process, the primary hydroxyl group of 13a-b was protected by a pivaloyl group to obtain intermediate 14a-b, which was then oxidized to synthesize ketone 15a-b. Subsequently, 16a-b with the desired stereoselectivity was synthesized in high yield through a reduction reaction using NaBH4, and a small amount of diol was produced as a byproduct. The generated diol intermediates were converted into thio-sugar intermediates 18a-b through a reduction cyclization reaction using Na2S·9H2O following mesylation.

[0226] 1-1. Synthesis of (R)-1-((4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)propan-1-ol ((R)-1-((4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)propan-1-ol) (13a).

[0227] Ethyl magnesium bromide (1.0 M solution in THF, 37.5 mL, 37.5 mmol) was dropwise added to a solution of Compound 12 (2.01 g, 12.5 mmol) dissolved in anhydrous THF (104 mL) while stirring at -78 °C. The reaction mixture was maintained at -78 °C for 20 minutes, then slowly heated to room temperature and stirred for an additional 15 hours. The reaction was terminated by adding a saturated aqueous ammonium chloride solution, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with anhydrous MgSO4, filtered, and the solvent removed under reduced pressure. The resulting crude product was purified by silica gel column chromatography using hexane / ethyl acetate (95:5) as the developing solvent to obtain Compound 13a (1.81 g, yield 76%), a colorless syrup.

[0228] 1 ¹H NMR (400 MHz, CDCl3): δ 4.28-4.23 (m, 1H), 3.97 (dd, J = 8.9, 5.7 Hz, 1H), 3.82-3.65 (m, 3H), 3.48 (s, 2H), 1.80 (tdd, J = 14.6, 7.2, 3.0 Hz, 1H), 1.51-1.40 (m, 1H), 1.37 (s, 3H), 1.32 (s, 3H), 1.00 (t, J = 7.5 Hz, 3H); 13 1C NMR (100 MHz, CD3OD): δ 109.5, 80.8, 79.3, 71.5, 61.9, 28.3, 28.3, 25.7, 9.6.

[0229] 1-2. Synthesis of ((4R,5S)-5-((R)-1-hydroxypropyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl pivalate (((4R,5S)-5-((R)-1-hydroxypropyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl pivalate) (14a).

[0230] 4-dimethylaminopyridine (DMAP, 50 mg, 0.42 mmol), N,N-diisopropylethylamine (DIPEA, 2.90 mL, 16.7 mmol), and pivaloyl chloride (1.12 mL, 9.20 mmol) were sequentially added to a solution of compound 13a (1.59 g, 8.36 mmol) dissolved in stirring dichloromethane (CH2Cl2, 41 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 30 minutes. The reaction was terminated by adding a saturated aqueous ammonium chloride solution, and the aqueous layer was extracted with CH2Cl2. The combined organic layer was washed with brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography using hexane / ethyl acetate (5:1) as the developing solvent to obtain compound 14a (2.25 g, yield 98%) in the form of a colorless syrup.

[0231] 1 ¹H NMR (400 MHz, CDCl3): δ 4.38-4.30 (m, 2H), 4.24-4.18 (m, 1H), 3.98 (dd, J = 8.7, 5.5 Hz, 1H), 3.67 (td, J = 8.6, 3.0 Hz, 1H), 1.90-1.85 (m, 1H), 1.84-1.76 (m, 1H), 1.53-1.44 (m, 1H), 1.43 (s, 3H), 1.36 (d, J = 11.0 Hz, 3H), 1.25-1.18 (m, 9H), 1.00 (t, J = 7.5 Hz, 3H); 13 13C NMR (100 MHz, CDCl3) δ 178.4, 108.8, 79.5, 75.6, 71.0, 63.5, 38.9, 28.1, 27.4, 27.3, 25.7, 9.4.

[0232] 1-3. Synthesis of ((4R,5R)-2,2-dimethyl-5-propionyl-1,3-dioxolan-4-yl)methyl pivalate (((4R,5R)-2,2-dimethyl-5-propionyl-1,3-dioxolan-4-yl)methyl pivalate) (15a).

[0233] Dimethyl sulfoxide (DMSO, 0.69 mL, 9.75 mmol) was dropwise added to a solution of 2.0 M oxalyl chloride (2.92 mL, 5.85 mmol) dissolved in dichloromethane (CH2Cl2, 20 mL) at -78 °C. The reaction mixture was stirred at the same temperature for 30 minutes. Subsequently, a solution of compound 14a (1.07 g, 3.90 mmol) dissolved in CH2Cl2 (20 mL) was added, and the mixture was stirred for an additional 1 hour at -78 °C. Afterward, triethylamine (Et3N, 4.89 mL, 35.0 mmol) was added at -78 °C, and the reaction mixture was slowly heated to room temperature. The reaction was stirred for 3 hours until completion. The reaction was terminated by carefully adding an aqueous solution of saturated ammonium chloride at 0 °C. The aqueous layer was extracted with CH2Cl2, and the combined organic layer was washed with brine, dried with anhydrous MgSO4, and filtered. It was then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography using hexane / ethyl acetate (97:3) as the developing solvent to obtain compound 15a (977 mg, yield 92%) in the form of a colorless oil.

[0234] 1 ¹H NMR (400 MHz, CDCl3): δ 4.55 (s, 2H), 4.24-4.20 (m, 1H), 4.00-3.96 (m, 1H), 2.76-2.58 (m, 2H), 1.56 (s, 3H), 1.37 (s, 3H), 1.18 (s, 9H), 1.04 (t, J = 7.3 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 210.1, 178.1, 110.2, 80.9, 75.7, 62.2, 38.9, 33.6, 27.3, 27.0, 24.8, 6.9.

[0235] 1-4. Synthesis of (S)-1-((4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)propan-1-ol ((S)-1-((4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)propan-1-ol) (16a).

[0236] Sodium borohydride (NaBH4, 887 mg, 23.46 mmol) was slowly added to a stirred solution of compound 15a (2.13 g, 7.82 mmol) dissolved in methanol (MeOH, 78.2 mL) at 0 °C. After stirring the reaction mixture at room temperature for 30 minutes, a 25 wt% sodium methoxide (NaOMe) solution in methanol (5.36 mL, 23.46 mmol) was added. The reaction mixture was then stirred at room temperature for 2 hours, followed by heating at 50 °C for 15 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The organic layer was separated, dried with anhydrous MgSO4, filtered, and concentrated. The obtained crude product was purified by silica gel column chromatography using hexane / ethyl acetate (20:1) as the developing solvent to obtain compound 16a (997 mg, yield 67%) in the form of a colorless oil. The NMR data of compound 16a was consistent with the data of the isomer obtained from lactol 12.

[0237] 1 ¹H NMR (400 MHz, CD3OD): δ 4.17 (q, J = 5.6 Hz, 1H), 4.06 (dd, J = 6.4, 4.1 Hz, 1H), 3.74-3.66 (m, 2H), 3.60-3.55 (m, 1H), 1.62-1.50 (m, 2H), 1.47 (s, 3H), 1.35 (s, 3H), 1.00 (t, J = 7.3 Hz, 3H); 13 1C NMR (100 MHz, CD3OD): δ 109.2, 80.8, 79.2, 71.7, 62.0, 28.5, 27.6, 25.4, 10.7.

[0238] 1-5. Synthesis of (3aS,4R,6aR)-4-ethyl-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxole ((3aS,4R,6aR)-4-ethyl-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxole) (18a).

[0239] Triethylamine (Et3N, 6.19 mL, 44.6 mmol) and methanesulfonyl chloride (1.72 mL, 22.3 mmol) were dropwise added to a stirred solution of diol 16a (1.06 g, 5.57 mmol) and DMAP (20 mg, 0.17 mmol) dissolved in dichloromethane (CH2Cl2, 24 mL) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 3 hours, after which the reaction was terminated by adding an aqueous solution of saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with an aqueous solution of saturated sodium bicarbonate (NaHCO3), dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain crude dimesylate 17a. This crude product was used in the next step without further purification. Sodium sulfide nonahydrate (Na2S·9H2O, 3.74 g, 15.6 mmol) was added to a stirred solution in which crude dimesylate 17a was dissolved in dimethylformamide (DMF, 100 mL). The reaction mixture was heated to 100 °C under a nitrogen atmosphere and stirred for 3 hours. After cooling to room temperature, water was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography using hexane / ethyl acetate (20:1) as the developing solvent to obtain compound 18a (788 mg, yield 76% relative to 16a), which is a colorless oil.

[0240] 1 ¹H NMR (400 MHz, CDCl3): δ 4.86 (td, J = 5.6, 2.5 Hz, 1H), 4.47 (q, J = 2.8 Hz, 1H), 3.15-3.10 (m, 1H), 3.00 (dd, J = 12.9, 5.1 Hz, 1H), 2.85 (dd, J= 12.8, 2.2 Hz, 1H), 1.71-1.60 (m, 1H), 1.50 (s, 3H), 1.46-1.34 (m, 1H), 1.30 (s, 3H), 1.00 (t, J = 7.5 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 111.6, 88.4, 83.2, 56.2, 36.4, 26.9, 26.5, 25.0, 12.9.

[0241] 2. Synthesis of Glycosyl Donor 20a

[0242]

[0243] In the next step, sulfoxide 19a-b was synthesized by oxidizing thiosugar intermediate 18a-b with m-CPBA at -78 °C. The synthesized sulfoxide 19a-b was heated with acetic anhydride to carry out a Pummerer reaction, thereby obtaining glycosyl donor acetate 20a-b with high efficiency.

[0244] 2-1. Synthesis of (3aR,6R,6aS)-6-ethyl-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl acetate (20a).

[0245] A solution of m-chloroperbenzoic acid (m-CPBA, 77 wt%, 672 mg, 3.0 mmol) dissolved in CH2Cl2 (12 mL) was dropwise added to a stirred solution of compound 18a (470 mg, 2.50 mmol) dissolved in dichloromethane (CH2Cl2, 13 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 45 minutes, after which the reaction was terminated by adding an aqueous solution of saturated sodium bicarbonate (NaHCO3). The resulting mixture was extracted with CH2Cl2, the organic layer was dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain crude sulfoxide 19a, which was used in the next step without further purification. Acetic anhydride (12.5 mL) was added to a stirred solution of crude sulfoxide 19a, and the mixture was heated to 100 °C under a nitrogen atmosphere and stirred for 6 hours. After the reaction was complete, the solvent was removed from the mixture under reduced pressure, and the residue was dissolved in ethyl acetate. Subsequently, the mixture was stirred with sodium bicarbonate (NaHCO3) for 5 minutes. The organic layer was separated, dried with MgSO4, and filtered. It was then purified by silica gel column chromatography using hexane / ethyl acetate (20:1) as the developing solvent to obtain compound 20a (437 mg, yield 78% relative to 18a), which is a colorless oil.

[0246] 1 ¹H NMR (400 MHz, CDCl3): δ 6.01 (s, 1H), 4.87 (d, J = 5.5 Hz, 1H), 4.75 (d, J = 5.5 Hz, 1H), 3.27 (dd, J = 9.4, 6.6 Hz, 1H), 2.05 (s, 3H), 1.83-1.72 (m, 1H), 1.60-1.53 ​​(m, 1H), 1.50 (s, 3H), 1.31 (s, 3H), 1.03 (t, J = 7.3 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 169.5, 111.2, 88.9, 88.1, 87.8, 58.5, 29.9, 26.7, 24.9, 21.4, 12.9.

[0247] 3. Synthesis of 4'-ethyl nucleoside 1a-l and C2-hexinyl-4'-ethyl nucleoside 6a-6f

[0248]

[0249] Reaction reagents and conditions: (a) 6-Chloropurine or 2,6-dichloropurine, BSA, MeCN, from room temperature to 50 °C for 45 min, followed by TMSOTf at 90 °C for 1.5 hours; (b) 60% TFA / THF (1:1), room temperature for 2 hours; (c) NH3 / t -BuOH, 100 ℃, 12 hours or RNH2, Et3N, EtOH, 50 ℃, 12 hours.

[0250] Glycosyl donor acetate 20a was subjected to a Vorbruggen condensation reaction with silylated 6-chloropurine or 2,6-dichloropurine in the presence of TMSOTf to selectively synthesize β-anomers 21a and 23a. Subsequently, the acetonide protecting group of the intermediate was removed by acid hydrolysis using a 60% TFA / THF (1:1) solution, thereby obtaining the protected-group-removed 6-chloro and 2,6-dichloro nucleoside derivatives 22a and 24a. These intermediates were further functionalized at the N6 position by reaction with ammonia, methylamine, and 3-halobenzylamine to synthesize the final nucleoside compounds 1a-l.

[0251]

[0252] Reaction reagents and conditions: (a) 6-Chloro-2-iodopurine, BSA, MeCN, from room temperature to 50 °C, 45 min, then TMSOTf, 90 °C, 1.5 h; (b) 1-Hexyne, CuI, Pd(PPh3)4, DMF, room temperature, 12 h; (c) 60% TFA / THF (1:1), room temperature, 2 h; (d) NH3 / t -BuOH, 100 ℃, 12 hours or RNH2, Et3N, EtOH, 50 ℃, 12 hours.

[0253] To synthesize C2-hexine derivatives, glycosyl donor 20a was selectively synthesized into compound 31, a β-anomer, by undergoing a Vorbruggen condensation reaction with silylated 6-chloro-2-iodopurine in the presence of TMSOTf. Subsequently, using 31, a 4'-ethyl nucleoside intermediate, as a starting material, the final nucleoside C2-hexinyl 4'-ethyl series compounds 6a-f were synthesized by reacting them with ammonia, methylamine, hydroxylamine, and 3-halobenzylamine for N6-position functionalization.

[0254] 3-1. General procedure for the synthesis of 21a, 23a, and 31

[0255] Under a nitrogen atmosphere, the corresponding nucleobase (1.1 equivalents) was suspended in acetonitrile (0.1 M), and then bis(trimethylsilyl)acetamide [bis(trimethylsilyl)acetamide, 1.5 equivalents] was added at room temperature. The reaction mixture was heated to 50 °C and stirred for 45 minutes, then cooled to room temperature. Subsequently, the corresponding acetate (1 equivalent) dissolved in acetonitrile (0.1 M) was dropwise added to the silylated nucleobase solution at room temperature, followed by the addition of trimethylsilyl trifluoromethanesulfonate (0.7 equivalents). The reaction mixture was stirred at 90 °C for 1.5 hours. After the reaction was complete, the mixture was cooled to room temperature, and an aqueous solution of saturated sodium bicarbonate (NaHCO3) was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and the combined organic extract was washed with brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain condensation products, compounds 21a, 23a, and 31.

[0256] 3-2. General procedure for the synthesis of 22a, 24a, and 33

[0257] After adding 60% trifluoroacetic acid / tetrahydrofuran (TFA / THF = 1:1, 3 mL) to compounds 21a, 23a, or 32, the reaction mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography using methylene chloride / methanol (97:3) as the developing solvent to obtain compounds 22a, 24a, 30, and 33 in the form of white solids.

[0258] 3-3. 6-chloro-9-((3aR,4R,6R,6aS)-6-ethyl-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-9H-purine(6-chloro-9-((3aR,4R,6R,6aS)-6-ethyl-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-9H-purine) (21a).

[0259] Yield: 57%; Liquid; 1 ¹H NMR (400 MHz, CDCl3): δ8.80 (s, 1H), 8.44 (s, 1H), 6.04 (d, J = 2.3 Hz, 1H), 5.25 (q, J = 6.0, 2.8 Hz, 1H), 4.77 (dd, J = 5.6, 2.8 Hz, 1H), 3.57-3.52 (m, 1H), 1.93-1.83 (m, 1H), 1.69-1.63 (m, 1H), 1.61 (s, 3H), 1.34 (s, 3H), 1.09 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 152.4, 151.6, 151.5, 144.2, 132.6, 113.2, 89.0, 87.6, 67.3, 57.5, 28.4, 27.3, 25.3, 13.0; HRMS (FAB): found 341.0846 [calcd for C 14 H 18 ClN4O2S + (M + H) + 341.0839].

[0260] 3-4. (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol((2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol) (22a).

[0261] 수율: 79%; mp 95-97 ℃; 1 H NMR (400 MHz, CD3OD): δ 8.81 (s, 1H), 8.75 (s, 1H), 6.11 (d, J = 5.5 Hz, 1H), 4.76 (dd, J = 5.5, 3.7 Hz, 1H), 4.16 (t, J = 4.1 Hz, 1H), 3.38-3.33 (m, 1H), 2.14-2.04 (m, 1H), 1.90-1.78 (m, 1H), 1.08 (t, J = 7.3 Hz, 3H); 13 C NMR (100 MHz, CD3OD): δ153.2, 153.0, 151.4, 147.4, 133.0, 79.2, 78.4, 64.3, 54.9, 29.5, 13.3; HRMS (FAB): found 301.0520 [calcd for C 11 H 14 ClN4O2S + (M + H) + 301.0526].

[0262] 3-5. 2,6-dichloro-9-((3aR,4R,6R,6aS)-6-ethyl-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-9H-purine(2,6-dichloro-9-((3aR,4R,6R,6aS)-6-ethyl-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-9H-purine)(23a).

[0263] 수율: 74%; mp 60-62 ℃; 1 H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 6.04 (d, J = 3.2 Hz, 1H), 5.18 (q, J = 3.1 Hz, 1H), 4.80 (q, J = 3.2 Hz, 1H), 3.58-3.53 (m, 1H), 1.99-1.89 (m, 1H), 1.76-1.65 (m, 1H), 1.60 (s, 3H), 1.33 (s, 3H), 1.07 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 153.3, 152.7, 152.2, 144.7, 131.6, 113.5, 88.7, 87.5, 66.3, 57.0, 28.2, 27.5, 25.4, 12.9; HRMS (FAB): found 375.0461 [calcd for C 14 H 17 Cl2N4O2S + (M + H) + 375.0449].

[0264] 3-6. (2R,3R,4S,5R)-2-(2,6-dichloro-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol((2R,3R,4S,5R)-2-(2,6-dichloro-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol) (24a).

[0265] 수율: 86%; mp 160-162 ℃; 1 H NMR (400 MHz, CD3OD): δ 8.79 (s, 1H), 6.02 (d, J= 5.5 Hz, 1H), 4.71 (dd, J = 5.4, 3.8 Hz, 1H), 4.15 (dd, J = 4.6, 3.7 Hz, 1H), 3.38-3.33 (m, 1H), 2.14-2.04 (m, 1H), 1.92-1.81 (m, 1H), 1.08 (t, J = 7.3 Hz, 3H); 13 C NMR (100 MHz, CD3OD): δ 154.6, 153.7, 152.1, 148.1, 132.5, 79.2, 78.4, 64.6, 55.1, 29.4, 13.3; HRMS (FAB): found 335.0129 [calcd for C 11 H 13 Cl2N4O2S + (M + H) + 335.0136].

[0266] 3-7. 6-chloro-9-((3aR,4R,6R,6aS)-6-ethyl-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-2-iodo-9H-purine (6-chloro-9-((3aR,4R,6R,6aS)-6-ethyl-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-2-iodo-9H-purine) (31).

[0267] 수율: 44%; 액체, 1 H NMR (400 MHz, CDCl3): δ 8.23 (s, 1H), 6.04 (d, J = 3.2 Hz, 1H), 5.17 (q, J = 2.9 Hz, 1H), 4.82 (q, J = 3.0 Hz, 1H), 3.58-3.53 (m, 1H), 2.00-1.93 (m, 1H), 1.77-1.70 (m, 1H), 1.61 (s, 3H), 1.34 (s, 3H), 1.07 (t, J = 7.3 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 152.0, 150.9, 144.1, 132.5, 116.8, 113.4, 88.7, 87.6, 66.3, 57.2, 28.2, 27.6, 25.5, 13.0; HRMS (FAB): found 466.9797 [calcd for C 14 H 17 ClIN4O2S+ (M + H) + 466.9805].

[0268] 3-8. Synthesis of 6-chloro-9-((3aR,4R,6R,6aS)-6-ethyl-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-2-(hex-1-yn-1-yl)-9H-purine (6-chloro-9-((3aR,4R,6R,6aS)-6-ethyl-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-2-(hex-1-yn-1-yl)-9H-purine) (32).

[0269] Pd(PPh3)4 (33.6 mg, 0.029 mmol), CuI (11.1 mg, 0.0583 mmol), and Cs2CO3 (142 mg, 0.436 mmol) were added sequentially to a stirred solution of compound 31 (136 mg, 0.291 mmol) dissolved in anhydrous DMF (5 mL), followed by the addition of 1-hexane (0.0351 mL, 0.306 mmol). The reaction mixture was stirred at room temperature (rt) for 12 hours. After the reaction, water (H2O) was added to terminate the reaction, diluted with diethyl ether, and the aqueous layer was extracted with diethyl ether. The combined organic layer was washed with saturated brine, dried with anhydrous MgSO4, and filtered. The solvent was then removed to obtain the crude product of combined product 32, which was used in the next reaction step without further purification.

[0270] HRMS (FAB): found 421.1477 [calcd for C20H26ClN4O2S+ (M + H)+ 421.1465].

[0271] 3-9. (2R,3R,4S,5R)-2-(6-chloro-2-(hex-1-yn-1-yl)-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol((2R,3R,4S,5R)-2-(6-chloro-2-(hex-1-yn-1-yl)-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol) (33).

[0272] Yield: 68% from 31; mp 107-109 ℃; 1 ¹H NMR (400 MHz, CD3OD): δ 8.79 (s, 1H), 6.04 (d, J = 5.5 Hz, 1H), 4.71 (dd, J = 5.3, 3.4 Hz, 1H), 4.14 (dd, J = 5.0, 3.7 Hz, 1H), 3.39-3.34 (m, 1H), 2.51 (t, J= 6.9 Hz, 2H), 2.13-2.05 (m, 1H), 1.91-1.83 (m, 1H), 1.69-1.61 (m, 2H), 1.58-1.51 (m, 2H), 1.09 (t, J = 7.3 Hz, 3H), 0.99 (t, J = 7.1 Hz, 3H); 13 1C NMR (100 MHz, CD3OD): δ 153.2, 151.0, 147.9, 147.0, 132.0, 91.4, 80.4, 79.3, 78.4, 64.4, 54.9, 31.3, 29.3, 23.0, 19.4, 13.9, 13.3; HRMS (FAB): found 381.1138 [calcd for C 17 H 22 ClN4O2S + (M + H) + 381.1152].

[0273] 3-10. General procedure for the synthesis of 1a and 6a

[0274] The corresponding diol (1 equivalent) was dissolved in a mixed solvent of NH3 / t-BuOH (0.05 M), and then stirred for 12 hours at 100 °C in a closed steel bomb reactor. After the reaction was complete, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography using methylene chloride / methanol (9:1) as the developing solvent to obtain compounds 1a and 6a in the form of white solids.

[0275] 3-11. General procedure for the synthesis of 1b-l and 6b-f

[0276] The corresponding amine (3 equivalents) and triethylamine (Et3N, 6 equivalents) were added at room temperature to a solution of compounds 22a, 24a, or 33 (1 equivalent) dissolved in ethanol (EtOH, 0.05 M). The reaction mixture was stirred at room temperature for 15 hours, after which the solvent was removed under reduced pressure. The resulting residue was purified by silica gel flash column chromatography using methylene chloride / methanol (20:1) as the developing solvent to obtain compounds 1b-l and 6b-f.

[0277] 3-12. (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol((2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol) (1a).

[0278] Yield: 80%; white solid; mp 123-126 ℃; 1 ¹H NMR (400 MHz, DMSO- d 6 ): δ 8.39 (s, 1H), 8.14 (s, 1H), 7.28 (s, 2H), 5.86 (d, J = 6.4 Hz, 1H), 5.57 (d, J = 6.0 Hz, 1H), 5.31 (d, J = 5.1 Hz, 1H), 4.64 (td, J = 6.0, 3.7 Hz, 1H), 4.05 (q, J = 4.3 Hz, 1H), 3.20-3.15 (m, 1H), 2.00-1.94 (m, 1H), 1.76-1.69 (m, 1H), 0.95 (t, J = 7.4 Hz, 3H); 13 13C NMR (100 MHz, DMSO- d 6 ): δ 156.1, 152.8, 149.8, 139.9, 119.1, 77.1, 76.7, 61.3, 53.5, 28.3, 13.1; HRMS (EI): found 281.0940 [calcd for C 11 H 16 N5O2S + (M + H) + 281.0946].

[0279] 3-13. (2R,3S,4R,5R)-2-ethyl-5-(6-(methylamino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol((2R,3S,4R,5R)-2-ethyl-5-(6-(methylamino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol) (1b).

[0280] Yield: 75%; white solid; mp 164-167 ℃; 1 ¹H NMR (400 MHz, DMSO- d 6 ): δ 8.38 (s, 1H), 8.24 (s, 1H), 7.77 (s, 1H), 5.87 (d, J = 6.1 Hz, 1H), 5.57 (d, J = 6.1 Hz, 1H), 5.32 (d, J = 4.9 Hz, 1H), 4.64 (dd, J = 9.5, 5.8 Hz, 1H), 4.05 (q, J = 4.1 Hz, 1H), 3.20-3.15 (m, 1H), 2.94 (s, 3H), 2.02-1.94 (m, 1H), 1.78-1.67 (m, 1H), 0.95 (t, J = 7.3 Hz, 3H); 13 13C NMR (100 MHz, DMSO- d 6 ): δ 155.1, 152.7, 148.8, 139.5, 119.7, 77.1, 76.6, 61.3, 53.5, 28.2, 27.1, 13.0; HRMS (EI): found 295.1106 [calcd for C 12 H 18 N5O2S + (M + H) + 295.1022]; HPLC purity: > 95%.

[0281] 3-14. (2R,3S,4R,5R)-2-ethyl-5-(6-((3-fluorobenzyl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol((2R,3S,4R,5R)-2-ethyl-5-(6-((3-fluorobenzyl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol) (1c).

[0282] Yield: 73%; white solid; mp 141-143 ℃; 1 ¹H NMR (400 MHz, DMSO- d 6 ): δ 8.47 (s, 1H), 8.44 (s, 1H), 8.22 (s, 1H), 7.33 (q, J= 7.3 Hz, 1H), 7.18-7.12 (m, 2H), 7.04 (t, J = 8.6 Hz, 1H), 5.88 (d, J = 6.1 Hz, 1H), 5.58 (d, J = 5.5 Hz, 1H), 5.33 (d, J = 4.9 Hz, 1H), 4.70 (s, 3H), 4.06 (d, J = 4.3 Hz, 1H), 3.20-3.15 (m, 1H), 2.000-1.91 (m, 1H), 1.77-1.69 (m, 1H), 0.95 (t, J = 7.3 Hz, 3H); 13 C NMR (100 MHz, DMSO- d 6 ): δ 163.5, 161.1, 159.5, 152.6, 140.0, 130.4, 130.3, 123.2, 123.2, 113.9, 113.7, 113.6, 113.4, 77.0, 76.6, 61.3, 53.5, 42.6, 28.2, 13.0; HRMS (EI): found 389.1315 [calcd for C 18 H 21 FN5O2S + (M + H) + 389.1322].

[0283] 3-15. (2R,3R,4S,5R)-2-(6-((3-chlorobenzyl)amino)-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol((2R,3R,4S,5R)-2-(6-((3-chlorobenzyl)amino)-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol) (1d).

[0284] 수율: 81%; 백색 고체; mp 136-139 ℃; 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.47 (brs, 1H), 8.44 (s, 1H), 8.22 (s, 1H), 7.38-7.26 (m, 4H), 5.88 (d, J = 6.1 Hz, 1H), 5.57 (d, J = 5.5 Hz, 1H), 5.32 (d, J = 4.3 Hz, 1H), 4.68 (d, J= 5.5 Hz, 3H), 4.06 (t, J = 4.0 Hz, 1H), 3.20-3.15 (m, 1H), 2.00-1.91 (m, 1H), 1.77-1.69 (m, 1H), 0.95 (t, J = 7.3 Hz, 3H); 13 C NMR (100 MHz, DMSO- d 6 ): δ 154.3, 152.5, 149.2, 142.8, 140.0, 132.9, 130.2, 126.9, 126.6, 125.9, 119.5, 77.0, 76.5, 61.3, 53.4, 42.5, 28.1, 12.9; HRMS (EI): found 405.1021 [calcd for C 18 H 21 ClN5O2S + (M + H) + 405.1026].

[0285] 3-16. (2R,3R,4S,5R)-2-(6-((3-bromobenzyl)amino)-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol((2R,3R,4S,5R)-2-(6-((3-bromobenzyl)amino)-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol) (1e).

[0286] 수율: 77%; 백색 고체; mp 153-155 ℃; 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.48 (brs, 1H), 8.44 (s, 1H), 8.22 (s, 1H), 7.53 (s, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H), 5.88 (d, J = 6.1 Hz, 1H), 5.58 (d, J = 6.1 Hz, 1H), 5.33 (d, J = 4.9 Hz, 1H), 4.67 (brs, 3H), 4.06 (q, J= 4.1 Hz, 1H), 3.20-3.15 (m, 1H), 2.00-1.91 (m, 1H), 1.77-1.69 (m, 1H), 0.95 (t, J = 7.3 Hz, 3H); 13 C NMR (100 MHz, DMSO- d 6 ): δ 154.5, 152.8, 149.4, 143.2, 143.2, 140.2, 130.8, 130.0, 129.9, 126.5, 121.9, 119.7, 77.2, 76.7, 61.5, 53.7, 42.7, 28.4, 13.2; HRMS (EI): found 449.0528 [calcd for C 18 H 21 BrN5O2S + (M + H) + 449.0521].

[0287] 3-17. (2R,3S,4R,5R)-2-ethyl-5-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol((2R,3S,4R,5R)-2-ethyl-5-(6-((3-iodobenzyl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol) (1f).

[0288] 수율: 72%; 백색 고체; mp 160-162 ℃; 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.46 (brs, 1H), 8.44 (s, 1H), 8.22 (s, 1H), 7.72 (s, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 7.3 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 5.88 (d, J = 6.1 Hz, 1H), 5.58 (d, J = 6.1 Hz, 1H), 5.32 (d, J = 4.9 Hz, 1H), 4.66 (s, 3H), 4.06 (q, J = 3.9 Hz, 1H), 3.20-3.15 (m, 1H), 2.00-1.94 (m, 1H), 1.75-1.71 (m, 1H), 0.95 (t, J = 7.0 Hz, 3H);13 C NMR (100 MHz, DMSO- d 6 ): δ 154.4, 152.7, 149.3, 143.0, 140.1, 135.9, 135.6, 130.7, 126.8, 119.6, 94.9, 77.1, 76.7, 61.4, 53.6, 42.4, 28.3, 13.1;HRMS (EI): found 497.0384 [calcd for C 18 H 21 IN5O2S + (M + H) + 497.0382].

[0289] 3-18. (2R,3R,4S,5R)-2-(6-amino-2-chloro-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol((2R,3R,4S,5R)-2-(6-amino-2-chloro-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol) (1g).

[0290] 수율: 78%; 백색 고체; mp 156-158 ℃; 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.43 (s, 1H), 7.83 (s, 2H), 5.78 (d, J = 6.4 Hz, 1H), 5.59 (d, J = 6.0 Hz, 1H), 5.35 (d, J = 4.6 Hz, 1H), 4.61 (td, J = 6.2, 3.4 Hz, 1H), 4.04 (q, J = 4.0 Hz, 1H), 3.19-3.14 (m, 1H), 1.99-1.91 (m, 1H), 1.79-1.71 (m, 1H), 0.95 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, DMSO- d 6 ): δ 157.0, 153.3, 150.9, 140.7, 118.3, 77.2, 76.6, 61.6, 53.9, 28.3, 13.1; HRMS (EI): found 315.0549 [calcd for C 11 H 15 ClN5O2S +(M + H) + 315.0557].

[0291] 3-19. (2R,3R,4S,5R)-2-(2-chloro-6-(methylamino)-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol((2R,3R,4S,5R)-2-(2-chloro-6-(methylamino)-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol) (1h).

[0292] Yield: 80%; white solid; mp 235-236 ℃; 1 ¹H NMR (400 MHz, DMSO- d 6): δ 8.42 (s, 1H), 8.30 (d, J = 4.3 Hz, 1H), 5.78 (d, J = 6.1 Hz, 1H), 5.60 (d, J = 6.4 Hz, 1H), 5.35 (d, J = 4.9 Hz, 1H), 4.63-4.58 (m, 1H), 4.04 (q, J = 4.1 Hz, 1H), 3.19-3.14 (m, 1H), 2.91 (d, J = 4.9 Hz, 3H), 1.99-1.93 (m, 1H), 1.80-1.69 (m, 1H), 0.95 (t, J = 7.3 Hz, 3H); 13 13C NMR (100 MHz, DMSO- d 6): δ 155.7, 153.4, 149.7, 140.2, 118.7, 77.1, 76.5, 61.4, 53.8, 28.2, 27.4, 13.0; HRMS (EI): found 329.0710 [calcd for C 12 H 17 ClN5O2S + (M + H) + 329.0713].

[0293] 3-20. (2R,3R,4S,5R)-2-(2-chloro-6-((3-fluorobenzyl)amino)-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol((2R,3R,4S,5R)-2-(2-chloro-6-((3-fluorobenzyl)amino)-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol) (1i).

[0294] Yield: 72%; white solid; mp 120-122 ℃; 1 ¹H NMR (400 MHz, DMSO- d 6): δ 8.95 (t, J = 6.1 Hz, 1H), 8.47 (s, 1H), 7.36 (q,J = 7.3 Hz, 1H), 7.18-7.13 (m, 2H), 7.09-7.04 (m, 1H), 5.79 (d, J = 6.7 Hz, 1H), 5.60 (d, J = 6.1 Hz, 1H), 5.36 (d, J = 4.9 Hz, 1H), 4.66-4.60 (m, 3H), 4.04 (d, J = 3.7 Hz, 1H), 3.19-3.14 (m, 1H), 1.95 (td, J = 13.0, 6.9 Hz, 1H), 1.79-1.72 (m, 1H), 0.95 (t, J = 7.3 Hz, 3H); 13 C NMR (100 MHz, DMSO- d 6): δ 163.6, 161.2, 155.1, 153.3, 150.3, 142.4, 142.4, 140.8, 130.6, 130.5, 123.5, 118.7, 114.3, 114.0, 113.8, 77.2, 76.6, 61.6, 53.9, 42.9, 28.2, 13.0; HRMS (EI): found 423.0926 [calcd for C 18 H 20 ClFN5O2S + (M + H) + 423.0932].

[0295] 3-21. (2R,3R,4S,5R)-2-(2-chloro-6-((3-chlorobenzyl)amino)-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol((2R,3R,4S,5R)-2-(2-chloro-6-((3-chlorobenzyl)amino)-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol) (1j).

[0296] 수율: 77%; 백색 고체; mp 160-162 ℃; 1 H NMR (400 MHz, DMSO- d 6): δ 8.96 (t, J = 6.1 Hz, 1H), 8.48 (s, 1H), 7.40-7.29 (m, 4H), 5.79 (d, J = 6.1 Hz, 1H), 5.60 (d, J = 5.5 Hz, 1H), 5.36 (d, J= 4.9 Hz, 1H), 4.64-4.61 (m, 3H), 4.04 (d, J = 4.3 Hz, 1H), 3.19-3.14 (m, 1H), 1.95 (q, J = 6.3 Hz, 1H), 1.79-1.72 (m, 1H), 0.95 (t, J = 7.3 Hz, 3H); 13 C NMR (100 MHz, DMSO- d 6): δ 155.1, 153.3, 150.3, 142.0, 140.8, 133.2, 130.6, 127.4, 127.2, 126.3, 118.8, 77.3, 76.6, 61.7, 53.9, 43.0, 28.3, 13.1; HRMS (EI): found 439.0641 [calcd for C 18 H 20 Cl2N5O2S + (M + H) + 439.0637].

[0297] 3-22. (2R,3R,4S,5R)-2-(6-((3-bromobenzyl)amino)-2-chloro-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol((2R,3R,4S,5R)-2-(6-((3-bromobenzyl)amino)-2-chloro-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol) (1k).

[0298] 수율: 80%; 백색 고체; mp 162-164 ℃; 1 H NMR (400 MHz, DMSO- d 6): δ 8.94 (t, J = 6.2 Hz, 1H), 8.47 (s, 1H), 7.54 (s, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.29 (q, J = 7.5 Hz, 1H), 5.80-5.75 (m, 1H), 5.61 (d, J = 5.9 Hz, 1H), 5.37 (d, J = 4.6 Hz, 1H), 4.63 (d, J = 5.9 Hz, 3H), 4.04 (d, J= 3.7 Hz, 1H), 3.19-3.14 (m, 1H), 1.98-1.92 (m, 1H), 1.79-1.71 (m, 1H), 0.95 (t, J = 7.3 Hz, 3H); 13 C NMR (100 MHz, DMSO- d 6): δ 155.1, 153.4, 150.4, 142.3, 140.9, 130.9, 130.3, 130.1, 126.7, 121.9, 118.8, 77.3, 76.7, 61.7, 54.0, 42.9, 28.4, 13.1; HRMS (EI): found 483.0125 [calcd for C 18 H 20 BrClN5O2S + (M + H) + 483.0131].

[0299] 3-23. (2R,3R,4S,5R)-2-(2-chloro-6-((3-iodobenzyl)amino)-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol ((2R,3R,4S,5R)-2-(2-chloro-6-((3-iodobenzyl)amino)-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol) (1l).

[0300] 수율: 78%; 백색 고체; mp 167-170 ℃; 1 H NMR (400 MHz, DMSO- d 6): δ 8.94 (t, J = 5.8 Hz, 1H), 8.47 (s, 1H), 7.74 (s, 1H), 7.60 (d, J = 7.3 Hz, 1H), 7.35 (d, J = 7.3 Hz, 1H), 7.13 (t, J = 8.1 Hz, 1H), 5.79 (d, J = 6.1 Hz, 1H), 5.60 (d, J = 5.5 Hz, 1H), 5.35 (d, J = 4.9 Hz, 1H), 4.59 (d, J = 6.1 Hz, 3H), 4.04 (s, 1H), 3.16 (t, J = 4.6 Hz, 1H), 1.99-1.92 (m, 1H), 1.79-1.72 (m, 1H), 0.95 (t, J= 7.0 Hz, 3H); 13 C NMR (100 MHz, DMSO- d 6): δ 154.8, 153.0, 150.1, 141.9, 140.7, 136.1, 135.6, 130.6, 126.9, 118.6, 94.8, 77.0, 76.4, 61.4, 53.7, 42.6, 28.1, 12.9; HRMS (EI): found 530.9986 [calcd for C 18 H 20 ClIN5O2S + (M + H) + 530.9993].

[0301] 3-24. (2R,3R,4S,5R)-2-(6-amino-2-(hex-1-yn-1-yl)-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol((2R,3R,4S,5R)-2-(6-amino-2-(hex-1-yn-1-yl)-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol) (6a).

[0302] 수율: 72%; mp 89-90 ℃; 1 H NMR (400 MHz, DMSO- d 6): δ 8.44 (s, 1H), 7.38 (s, 2H), 5.82 (d, J = 6.4 Hz, 1H), 5.57 (d, J = 6.0 Hz, 1H), 5.32 (d, J = 4.6 Hz, 1H), 4.59 (td, J = 6.1, 3.5 Hz, 1H), 4.03 (q, J = 4.1 Hz, 1H), 3.20-3.15 (m, 1H), 2.41 (t, J = 6.9 Hz, 2H), 2.00-1.93 (m, 1H), 1.79-1.71 (m, 1H), 1.56-1.49 (m, 2H), 1.47-1.38 (m, 2H), 0.89-0.98 (m, 6H); 13 C NMR (100 MHz, DMSO- d 6): δ155.8, 149.9, 145.9, 140.5, 118.4, 85.6, 81.4, 77.2, 76.6, 61.1, 53.6, 30.0, 28.1, 21.5, 17.9, 13.6, 13.0; HRMS (FAB): found 362.1639 [calcd for C 17 H 24 N5O2S + (M + H) + 362.1650].

[0303] 3-25. (2R,3S,4R,5R)-2-ethyl-5-(2-(hex-1-yn-1-yl)-6-(methylamino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol((2R,3S,4R,5R)-2-ethyl-5-(2-(hex-1-yn-1-yl)-6-(methylamino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol) (6b).

[0304] 수율: 78%; 백색 고체; mp 226-228 ℃; 1 H NMR (400 MHz, DMSO- d 6): δ 8.42 (s, 1H), 7.83 (s, 1H), 5.83 (d, J = 6.4 Hz, 1H), 5.58 (d, J = 5.9 Hz, 1H), 5.34 (d, J = 5.0 Hz, 1H), 4.59 (dd, J = 9.6, 5.9 Hz, 1H), 4.03 (q, J = 4.1 Hz, 1H), 3.19-3.15 (m, 1H), 2.91 (s, 3H), 2.42 (t, J = 7.1 Hz, 2H), 1.99-1.93 (m, 1H), 1.79-1.71 (m, 1H), 1.57-1.50 (m, 2H), 1.47-1.40 (m, 2H), 0.97-0.90 (m, 6H); 13 C NMR (100 MHz, DMSO- d 6): δ 154.7, 148.8, 145.8, 140.1, 118.9, 85.5, 81.7, 77.1, 76.5, 61.0, 53.5, 29.9, 28.0, 27.1, 21.5, 18.0, 13.5, 12.9; HRMS (FAB): found 376.1795 [calcd for C 18 H 26N5O2S + (M + H) + 376.1807]; HPLC 순도: 99.5372%.

[0305] 3-26. (2R,3S,4R,5R)-2-ethyl-5-(6-((3-fluorobenzyl)amino)-2-(hex-1-yn-1-yl)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol((2R,3S,4R,5R)-2-ethyl-5-(6-((3-fluorobenzyl)amino)-2-(hex-1-yn-1-yl)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol) (6c).

[0306] 수율: 71%; 백색 고체; mp 146-148 ℃; 1 H NMR (400 MHz, DMSO- d 6): δ 8.47 (s, 2H), 7.37-7.31 (m, 1H), 7.16-7.11 (m, 2H), 7.07-7.01 (m, 1H), 5.84 (d, J = 6.4 Hz, 1H), 5.59 (d, J = 5.9 Hz, 1H), 5.36 (d, J = 4.6 Hz, 1H), 4.67 (s, 2H), 4.62 (s, 1H), 4.04 (d, J = 3.2 Hz, 1H), 3.19 (td, J = 9.7, 4.4 Hz, 1H), 2.40 (t, J = 6.9 Hz, 2H), 1.99-1.93 (m, 1H), 1.79-1.72 (m, 1H), 1.55-1.48 (m, 2H), 1.42 (td, J = 14.6, 7.2 Hz, 2H), 0.97-0.88 (m, 6H); 13 C NMR (100 MHz, DMSO- d 6): δ 163.7, 161.3, 154.3, 149.4, 146.0, 143.1, 140.8, 130.6, 130.5, 123.4, 119.0, 114.2, 114.0, 113.9, 113.7, 86.3, 81.8, 77.3, 76.7, 61.4, 53.9, 42.7, 30.1, 28.3, 21.7, 18.2, 13.7, 13.1; HRMS (FAB): found 470.203 [calcd for C 24 H 29 FN5O2S + (M + H) +470.2025].

[0307] 3-27. (2R,3R,4S,5R)-2-(6-((3-chlorobenzyl)amino)-2-(hex-1-yn-1-yl)-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol((2R,3R,4S,5R)-2-(6-((3-chlorobenzyl)amino)-2-(hex-1-yn-1-yl)-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol) (6d).

[0308] Yield: 77%; white solid; mp 163-165 ℃; 1 ¹H NMR (400 MHz, DMSO- d 6): δ 8.51 (brs, 1H), 8.48 (s, 1H), 7.38-7.27 (m, 4H), 5.84 (d, J = 5.9 Hz, 1H), 5.59 (d, J = 5.9 Hz, 1H), 5.34 (d, J = 5.0 Hz, 1H), 4.66 (s, 2H), 4.62 (s, 1H), 4.04 (d, J = 3.7 Hz, 1H), 3.20-3.15 (m, 1H), 2.41 (t, J = 7.1 Hz, 2H), 2.00-1.93 (m, 1H), 1.80-1.72 (m, 1H), 1.56-1.49 (m, 2H), 1.47-1.38 (m, 2H), 0.97-0.88 (m, 6H); 13 13C NMR (100 MHz, DMSO- d 6): δ 154.2, 149.4, 145.9, 142.6, 140.7, 133.1, 130.4, 127.2, 126.9, 126.1, 119.0, 86.2, 81.7, 77.3, 76.7, 61.3, 53.8, 42.6, 30.0, 28.2, 21.6, 18.1, 13.6, 13.0; HRMS (FAB): found 486.1734 [calcd for C 24 H 29 ClN5O2S + (M + H) + 486.1730].

[0309] 3-28. (2R,3R,4S,5R)-2-(6-((3-bromobenzyl)amino)-2-(hex-1-yn-1-yl)-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol((2R,3R,4S,5R)-2-(6-((3-bromobenzyl)amino)-2-(hex-1-yn-1-yl)-9H-purin-9-yl)-5-ethyltetrahydrothiophene-3,4-diol) (6e).

[0310] Yield: 80%; white solid; mp 178-180 ℃; 1 ¹H NMR (400 MHz, DMSO-d 6): δ 8.51 (brs, 1H), 8.48 (s, 1H), 7.53 (s, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H), 5.84 (d, J = 6.4 Hz, 1H), 5.59 (d, J = 5.9 Hz, 1H), 5.34 (d, J = 5.0 Hz, 1H), 4.65 (s, 2H), 4.62 (s, 1H), 4.04 (d, J = 3.7 Hz, 1H), 3.19-3.15 (m, 1H), 2.41 (t, J = 7.1 Hz, 2H), 2.00-1.93 (m, 1H), 1.80-1.72 (m, 1H), 1.56-1.49 (m, 2H), 1.43 (td, J = 14.5, 7.5 Hz, 2H), 0.97-0.89 (m, 6H); 13 C NMR (100 MHz, DMSO- d 6): δ 154.0, 149.3, 145.7, 142.8, 140.6, 130.6, 130.0, 129.7, 126.3, 121.6, 118.8, 85.9, 81.6, 77.2, 76.5, 61.1, 53.6, 42.4, 29.9, 28.1, 21.5, 18.0, 13.6, 12.9; HRMS (FAB): found 530.1227 [calcd for C 24 H 29 BrN5O2S + (M + H) + 530.122].

[0311] 3-29. (2R,3S,4R,5R)-2-ethyl-5-(2-(hex-1-yn-1-yl)-6-((3-iodobenzyl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol((2R,3S,4R,5R)-2-ethyl-5-(2-(hex-1-yn-1-yl)-6-((3-iodobenzyl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol) (6f).

[0312] 수율: 78%; 백색 고체; mp 197-199 ℃; 1 H NMR (400 MHz, DMSO- d 6): δ 8.48 (s, 2H), 7.72 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 5.84 (d, J = 6.4 Hz, 1H), 5.58 (d, J = 6.4 Hz, 1H), 5.33 (d, J = 4.6 Hz, 1H), 4.62 (s, 3H), 4.04 (d, J = 3.7 Hz, 1H), 3.19-3.15 (m, 1H), 2.41 (t, J = 6.9 Hz, 2H), 2.00-1.93 (m, 1H), 1.80-1.72 (m, 1H), 1.56-1.49 (m, 2H), 1.46-1.38 (m, 2H), 0.97-0.89 (m, 6H); 13 C NMR (100 MHz, DMSO- d 6): δ 154.0, 149.3, 145.7, 142.7, 140.7, 136.0, 135.5, 130.6, 126.7, 118.8, 94.8, 85.9, 81.6, 77.1, 76.5, 61.1, 53.6, 42.3, 29.9, 28.1, 21.6, 18.0, 13.6, 13.0; HRMS (FAB): found 578.1093 [calcd for C 24 H 29 IN5O2S + (M + H) + 578.1086].

[0313] 4. Evaluation of binding affinity to adenosine receptors

[0314] 4-1. hA 1 AR Combined analysis

[0315] Competitive binding experiments for adenosine A1 receptors were performed using membrane fractions obtained from CHO-A1 cells (Euroscreen, Gosselies, Belgium). On the day of the experiment, the membrane samples were thawed and resuspended in incubation buffer (pH = 7.4) containing 20 mM Hepes, 100 mM NaCl, 10 mM MgCl2, and 2 IU / mL adenosine deaminase. In each reaction well of a GF / C Multiscreen plate (Millipore, Madrid, Spain), 15 μg of protein and 2 nM [ 3 [H]DPCPX and the test compound were included, and all experiments were performed in duplicate. Non-specific binding was measured in the presence of 10 μM (R)-PIA. The reaction mixture was incubated at 25 °C for 60 minutes, filtered, and radioactivity was measured using a microplate beta scintillation counter (Microbeta Trilux, Perkin Elmer, Madrid, Spain).

[0316] 4-2. h A2 AAR Combined analysis

[0317] Adenosine A 2A Receptor competitive binding experiments are HeLa-A 2A The experiment was performed using membrane fractions obtained from cells. On the day of the experiment, the membrane samples were thawed and resuspended in incubation buffer (pH = 7.4) containing 50 mM Tris-HCl, 1 mM EDTA, 10 mM MgCl2, and 2 IU / mL adenosine deaminase. In each reaction well of a GF / C multiscreen plate (Millipore, Madrid, Spain), 10 μg of protein, 3 nM [ 3[H]ZM241385 and the test compound were included, and all experiments were performed in duplicate. Non-specific binding was measured in the presence of 50 μM NECA. The reaction mixture was incubated at 25 °C for 30 minutes, filtered, and radioactivity was measured using a microplate beta scintillation counter (Microbeta Trilux, Perkin Elmer, Madrid, Spain).

[0318] 4-3. h A2 BAR Combined analysis

[0319] Adenosine A 2B Receptor competitive binding experiments were performed on the HEK-293-A prepared according to the supplier's protocol. 2B The experiment was performed using membrane fractions derived from cells (Euroscreen, Gosselies, Belgium). On the day of the experiment, the membrane samples were thawed and resuspended in incubation buffer (pH = 6.5) containing 50 mM Tris-HCl, 1 mM EDTA, 10 mM MgCl2, 0.1 mM benzamidine, 10 μg / mL bacitracine, and 2 IU / mL adenosine deaminase. In each duplicate reaction well, 18 μg of protein, 35 nM [ 3 [H]DPCPX and the test compound were included. Non-specific binding was measured in the presence of 400 μM NECA. The reaction mixture was incubated at 25 °C for 30 minutes, filtered through a multiscreen GF / C microplate, and radioactivity was measured using a microplate beta scintillation counter (Microbeta Trilux, Perkin Elmer, Madrid, Spain).

[0320] 4-4. h A3 AR Combined analysis

[0321] Adenosine A3 receptor competitive binding experiments were performed in multiscreen GF / B 96-well plates (Millipore, Madrid, Spain) pretreated with binding buffer (Tris-HCl 50 mM, EDTA 1 mM, MgCl 25 mM, adenosine deaminase 2 U / mL, pH = 7.4). In each well, 30 μg of laboratory-prepared membrane fraction derived from Hela-A3 cell line (Lot: A005 / 05-07-2019, protein concentration = 3925 μg / mL), 10 nM [ 3 [H]-NECA (26.3 Ci / mmol, 1 mCi / mL, Perkin Elmer NET811250UC) and the test compound were added according to standard methods. Non-specific binding was measured in the presence of 100 μM R-PIA (Sigma P4532). The total reaction volume (Vt) was 200 μL per well, and the reaction mixture was incubated at 25 °C for 180 minutes. Subsequently, the sample was filtered and washed six times with 250 μL of wash buffer (Tris-HCl 50 mM, pH = 7.4), after which radioactivity was measured using a microplate beta scintillation counter (Microbeta Trilux, PerkinElmer, Madrid, Spain).

[0322] The structures of 1a-1l and 2a-2l subject to evaluation are as shown in Chemical Formula 2 and Table 1 below.

[0323] [Chemical Formula 2]

[0324]

[0325] compound R 1 R 2 R 3 1a Ethyl H H 1b Me 1c 3-F-Bn 1d 3-Cl-Bn 1e 3-Br-Bn 1f 3-I-Bn 1g Ethyl Cl H 1h Me 1i 3-F-Bn 1j 3-Cl-Bn 1k 3-Br-Bn 1l 3-I-Bn 2a iso -propyl H H 2b Me 2c 3-F-Bn 2d 3-Cl-Bn 2e 3-Br-Bn 2f 3-I-Bn 2g iso -propyl Cl H 2h Me 2i 3-F-Bn 2j 3-Cl-Bn 2k 3-Br-Bn 2l 3-I-Bn

[0326] The results of the binding affinity evaluation of 1a-1l and 2a-2l to adenosine receptors are shown in Table 2.

[0327] compound K i (nM ± SEM a or % displacement at 10 μM b ) hA 1 AR h A2 AAR hA 2B AR hA 3 AR 1a 9±3% 51±2% 41±1% 278.3±29.1 nM 1b 21±2% 7±1% 18±3% 58.7±5.2 nM 1c 39±3% 13±4% 32±2% 173.1±30.2 nM 1d 78±1% 39±4% 37±1% 113.4±13.4 nM 1e 70±3% 48±1% 42±2% 59.5±2.6 nM 1f 65±1% 34±1% 25±3% 49.9±4.2 nM 1g 72±2% 39±5% 26±1% 158.1±13.9 nM 1h 46±2% 2±2% 11±1% 13.1±1.8 nM 1i 63±1% 15±2% 27±3% 151.6±11.5 nM 1j 696.1±88.6 nM 35±5% 28±1% 117.1±10.6 nM 1k 55±4% 11±3% 27±4% 77.4±5.9 nM 1l 86±2% 41±1% 23±3% 102.9±11.0 nM 2a 23±4% 4±2% 39±1% 17±1% 2b 9±2% 5±1% 13±1% 49±1% 2c 5±3% 7±2% 20±4% 34±4% 2d 8±2% 5±1% 20±1% 54±4% 2e 15±1% 5±3% 27±3% 54±5% 2f 20±3% 1±2% 12±2% 39±3% 2g 20±4% 2±2% 11±1% 26±1% 2h 9±3% 1±1% 7±2% 59±1% 2i 10±3% 6±3% 19±3% 27±1% 2j 14±4% 6±2% 11±3% 20±2% 2k 14±3% 3±2% 13±1% 29±1% 2l 11±1% 6±2% 11±1% 14±3%

[0328] aAll binding experiments were performed using adherent CHO, HEK293, and HeLa cells stably transduced with cDNA encoding the appropriate human adenosine receptor (hAR). Binding experiments were performed on A1, A 2A , A 2B The study was performed on the A3 adenosine receptor (AR) using tritium-labeled radioligands DPCPX 1 nM, ZM241385 1 nM, DPCPX 25 nM, and NECA 10 nM, respectively. Results were expressed as mean ± standard error (SEM) (n = 3-4, outliers removed) and normalized based on the non-specific binding agent R-PIA or NECA.

[0329] b Where a percentage value is presented, it represents the inhibition rate (%) of a specific radioactive ligand binding at a concentration of 10 μM, and non-specific binding was defined using R-PIA or NECA.

[0330] The structure of 3a-3f, which is the subject of evaluation, is as shown in Chemical Formula 3 and Table 3 below, and the structures of 4a-4f, 5a-5g and 6a-6f are as shown in Chemical Formula 2 and Table 3 below.

[0331] [Chemical Formula 3]

[0332]

[0333] [Chemical Formula 2]

[0334]

[0335] compound R 1 R 2 R 3 3a Methyl 1-propynyl H 3b Me 3c 3-F-Bn 3d 3-Cl-Bn 3e 3-Br-Bn 3f 3-I-Bn 4a Methyl 1-propynyl H 4b Me 4c 3-F-Bn 4d 3-Cl-Bn 4e 3-Br-Bn 4f 3-I-Bn 5a Methyl 1-hexynyl H 5b Me 5c 3-F-Bn 5d 3-Cl-Bn 5e 3-Br-Bn 5f 3-I-Bn 5g OH 6a Ethyl 1-hexynyl H 6b Me 6c 3-F-Bn 6d 3-Cl-Bn 6e 3-Br-Bn 6f 3-I-Bn

[0336] The results of the binding affinity evaluation of 3a-3f, 4a-4f, 5a-5g and 6a-6f to adenosine receptors are shown in Table 4.

[0337] compound K i (nM ± SEM a or % displacement at 10 μM b ) hA 1 AR h A2 AAR hA 2B AR hA 3 AR 3a 1 ± 3% 2 ± 2% 1 ± 3% 33 ± 1% 3b 1 ± 4% 3 ± 2% 1 ± 4% 64 ± 5% 3c 22 ± 4% 5 ± 4% 2 ± 4% 35 ± 2% 3d 41 ± 3% 4 ± 4% 8 ± 3% 41 ± 2% 3e 37 ± 6% 6 ± 3% 15 ± 6% 52 ± 5% 3f 33 ± 1% 1 ± 4% 15 ± 2% 56 ± 4% 4a 16 ± 4% 2 ± 3% 3 ± 3% 54 ± 3% 4b 9 ± 2% 4 ± 3% 1 ± 2% 9.5 ± 0.9 nM 4c 51 ± 1% 27 ± 2% 7 ± 4% 57.7 ± 7.3 nM 4d 73 ± 1% 20 ± 4% 10 ± 4% 27.6 ± 1.7 nM 4e 67 ± 2% 16 ± 1% 8 ± 3% 44.9 ± 3.0 nM 4f 48 ± 2% 1 ± 3% 18 ± 5% 81 ± 6% 5a 43±1% 92.8±18.8 nM 12±5% 4.2±0.64 nM 5b 30±5% 22±1% 7±1% 1.1±0.1 nM 5c 34±4% 25±1% 4±2% 25.7±2.5 nM 5d 46±5% 15±3% 2±1% 51.6±3.6 nM 5e 26±5% 30±1% 6±3% 50.5±7.8 nM 5f 30±4% 15±4% 3±1% 84±1% 5g 34±2% 23±3% 10±3% 69.5±14.4 nM 6a 60±2% 215.2±15.8 nM 25±1% 58.7±6.6 nM 6b 4±3% 6±3% 9±4% 6.4±0.6 nM 6c 38±1% 19±4% 1±2% 255.4±35.3 nM 6d 28±1% 2±2% 3±2% 68±5% 6e 27±1% 21±4% 2±1% 68±1% 6f 11±2% 7±2% 1±2% 57±5%

[0338] 5. Evaluation of agonist / antagonist function for adenosine receptors

[0339] 5-1. Antagonist Mode

[0340] Human adenosine A3 receptor function experiments were performed on the CHO-A3#18 cell line. One day prior to the experiment, cells were seeded into 96-well culture plates (Falcon 353072). On the day of the experiment, cells were washed with wash buffer (Dulbecco's modified Eagle's medium nutrient mixture F-12 Ham [Sigma D8062], 25 mM HEPES, pH 7.4). Subsequently, the wash buffer was replaced with incubation buffer (Dulbecco's modified Eagle's medium nutrient mixture F-12 Ham [Sigma D8062], 25 mM HEPES, 30 μM Rolipram [Sigma R6520], pH 7.4). After adding the test compound and MRS1220 (Sigma M228) as the reference compound, the cells were incubated at 37°C for 15 minutes. Next, 0.1 μM of 5'-(N-Ethylcarboxamido) adenosine (NECA, Sigma E2387) was added and incubated at 37°C for 10 minutes. Subsequently, FSK (Sigma F3917) was added and incubated at 37°C for 5 minutes. After all reactions were completed, the amount of cAMP was measured using the cAMP Biotrak Enzyme Immunoassay (EIA) System Kit (GE Healthcare RPN225).

[0341] 5-2. Agonist Mode

[0342] Human adenosine A3 receptor function experiments were performed on the CHO-A3#18 cell line. One day before the experiment, cells were seeded into a 96-well culture plate (Falcon 353072). On the day of the experiment, the cells were washed with wash buffer (Dulbecco's modified Eagle's medium nutrient mixture F-12 Ham [Sigma D8062], 25 mM HEPES, pH 7.4). Subsequently, the wash buffer was replaced with incubation buffer (Dulbecco's modified Eagle's medium nutrient mixture F-12 Ham [Sigma D8062], 25 mM HEPES, 30 μM Rolipram [Sigma R6520], pH 7.4). After preincubating the cells at 37°C for 15 minutes, 5'-(N-Ethylcarboxamido) adenosine (NECA, Sigma E2387) was added as the test compound and reference compound, and the cells were incubated at 37°C for 10 minutes. Subsequently, FSK (Sigma F3917) was added, and the cells were incubated for an additional 5 minutes at 37°C. After the incubation was completed, the amount of cAMP was measured using the cAMP Biotrak Enzyme Immunoassay (EIA) System Kit (GE Healthcare RPN225).

[0343] The structures of 1f, 1h, 4b, 5a, 5b, 6a, 6b, 9a and 10a, which are the subjects of evaluation, are as shown in Chemical Formula 4 and Table 5 below.

[0344] [Chemical Formula 4]

[0345]

[0346] compound R 1 X R 2 1f Et H 3-I-Bn 1h Et Cl Me 4b Me Propynyl Me 5a Me 1-hexynyl H 5b Me 1-hexynyl Me 6a Et 1-hexynyl H 6b Et 1-hexynyl Me 9a Me Cl Me 10a H Cl 3-Cl-Bn

[0347] The results of the functional evaluation of adenosine receptors for 1f, 1h, 4b, 5a, 5b, 6a, 6b, 9a and 10a are shown in Table 6.

[0348] compound hA 2A AR b hA 3 AR c % stimulation % Inhib. NECA % stimulation % Inhib. NECA 1f - - 10±4% 65±4% 1h - - 30±4% 84±5% 4b - - 53±3% 42±5% 5a 67±4% 48±4% 24±2% 82±2% 5b - - 39±1% 68±1% 6a 99±1% 18±3% 11±2% 86±3% 6b - - 5±1% 93±1% 9a - - 63±2% 38±3% 10a - - 55±3% 34±1%

[0349] b cAMP production mediated by the hA2A adenosine receptor (hA2AAR) was measured using CHO-A2A cells in antagonist and agonist modes. After treating cells with the test compound and reference compound (CGS-15493 in antagonist mode and NECA in agonist mode), cAMP was quantified using the cAMP Biotrak EIA System Kit.

[0350] c Functional experiments on the human adenosine A3 receptor were performed in CHO-A3#18 cells in antagonist and agonist modes. In both modes, cells were seeded into 96-well plates, washed, and treated with the test compound or reference compound (MRS1220 or NECA) under specified conditions. After treatment, intracellular cAMP levels were measured using the cAMP Biotrak Enzyme Immunoassay (EIA) System Kit (GE Healthcare, RPN225).

Claims

Claim 1 A compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] A compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, wherein R is a benzyl substituted with H, a C1-C6 alkyl or a halogen, and X is H, a halogen, or a C3-C12 alkynyl in the above formula. Claim 2 In claim 1, the compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof is characterized in that the compound is selected from any one of the following groups of compounds: (1) (2R,3R,4S,5R)-2-(6-amino-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol; (2) (2R,3S,4R,5R)-2-ethyl-5-(6-(methylamino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (3) (2R,3S,4R,5R)-2-ethyl-5-(6-((3-fluorobenzyl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (4) (2R,3R,4S,5R)-2-(6-((3-chlorobenzyl)amino)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol; (5) (2R,3R,4S,5R)-2-(6-((3-bromobenzyl)amino)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol; (6) (2R,3S,4R,5R)-2-ethyl-5-(6-((3-iodobenzyl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (7) (2R,3R,4S,5R)-2-(6-amino-2-chloro-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol; (8) (2R,3R,4S,5R)-2-(2-chloro-6-(methylamino)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol; (9) (2R,3R,4S,5R)-2-(2-chloro-6-((3-fluorobenzyl)amino)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol; (10) (2R,3R,4S,5R)-2-(2-chloro-6-((3-chlorobenzyl)amino)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol; (11) (2R,3R,4S,5R)-2-(6-((3-bromobenzyl)amino)-2-chloro-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol; (12) (2R,3R,4S,5R)-2-(2-chloro-6-((3-iodobenzyl)amino)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol;(13) 2R,3R,4S,5R)-2-(6-amino-2-(hex-1-phosph-1-yl)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol; (14) (2R,3S,4R,5R)-2-ethyl-5-(2-(hex-1-phosph-1-yl)-6-(methylamino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (15) (2R,3S,4R,5R)-2-ethyl-5-(6-((3-fluorobenzyl)amino)-2-(hex-1-phosph-1-yl)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (16) (2R,3R,4S,5R)-2-(6-((3-chlorobenzyl)amino)-2-(hex-1-in-1-yl)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol; (17) (2R,3R,4S,5R)-2-(6-((3-bromobenzyl)amino)-2-(hex-1-in-1-yl)-9H-purine-9-yl)-5-ethyltetrahydrothiophene-3,4-diol; and (18) (2R,3S,4R,5R)-2-ethyl-5-(2-(hex-1-in-1-yl)-6-((3-iodobenzyl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol.; Claim 3 In claim 1, the compound is a compound characterized by binding to an adenosine receptor, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Claim 4 In claim 1, the compound is characterized as being an A3 adenosine receptor antagonist, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Claim 5 A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that the stereoisomer comprises a racemic mixture, a mirror image isomer, a diastereomer, a mixture of mirror image isomers, or a mixture of diastereomers. Claim 6 As shown in Reaction Scheme 1 below, a step of preparing a compound represented by Formula 13a by reacting EtMgBr with a compound represented by Formula 12 prepared from D-ribose in a THF solvent (Step a); a step of preparing a compound represented by Formula 14a by protecting the primary alcohol group of the compound represented by Formula 13a prepared in Step a with trimethylacetyl chloride (Step b); a step of preparing a compound represented by Formula 15a by oxidizing the compound represented by Formula 14a prepared in Step b (Step c); a step of preparing a compound represented by Formula 16a by reducing the compound represented by Formula 15a prepared in Step c (Step d); a step of preparing a compound represented by Formula 17a by methylating the compound represented by Formula 16a prepared in Step d (Step e); a step of preparing a compound represented by Formula 18a by reacting the compound represented by Formula 17a prepared in Step e with Na2S·9H2O (Step f); the above step A step of oxidizing the compound represented by Formula 18a prepared in f with m-CPBA to prepare the compound represented by Formula 19a (step g); a step of reacting the compound represented by Formula 19a prepared in step g with acetic anhydride to prepare the compound represented by Formula 20a through a Pummerer reaction (step h); a step of Vorbruggen reacting the compound represented by Formula 20a prepared in step h with 6-chloropurine or 2,6-dichloropurine to prepare compounds represented by Formulas 21a and 23a, respectively (step i); a step of acid hydrolyzing the compounds represented by Formulas 21a and 23a prepared in step i, respectively to prepare compounds represented by Formulas 22a and 24a (step j);A method for preparing a compound represented by Formula 1 of claim 1, comprising the step (step k) of reacting the compounds represented by Formulas 22a and 24a prepared in step j under NH3 / t-BuOH, RNH2, Et3N, or EtOH conditions to prepare a compound represented by Formula 1: [Reaction Formula 1]; (In the above reaction scheme 1, R is H, methyl, 3-F-benzyl, 3-Cl-benzyl, 3-Br-benzyl, or 3-I-benzyl, and X is H or Cl). Claim 7 As shown in Reaction Scheme 2 below, a step of preparing a compound represented by Formula 13a by reacting EtMgBr with a compound represented by Formula 12 prepared from D-ribose in a THF solvent (Step a); a step of preparing a compound represented by Formula 14a by protecting the primary alcohol group of the compound represented by Formula 13a prepared in Step a with trimethylacetyl chloride (Step b); a step of preparing a compound represented by Formula 15a by oxidizing the compound represented by Formula 14a prepared in Step b (Step c); a step of preparing a compound represented by Formula 16a by reducing the compound represented by Formula 15a prepared in Step c (Step d); a step of preparing a compound represented by Formula 17a by methylating the compound represented by Formula 16a prepared in Step d (Step e); a step of preparing a compound represented by Formula 18a by reacting the compound represented by Formula 17a prepared in Step e with Na2S·9H2O (Step f); the above step A step of oxidizing the compound represented by Formula 18a prepared in f with m-CPBA to prepare the compound represented by Formula 19a (step g); a step of reacting the compound represented by Formula 19a prepared in step g with acetic anhydride to prepare the compound represented by Formula 20a through a Pummerer reaction (step h); a step of Vorbruggen reacting the compound represented by Formula 20a prepared in step h with 6-chloro-2-iodopurine to prepare the compound represented by Formula 31 (step l); a step of Sonogashira reaction of the compound represented by Formula 31 prepared in step l with 1-hexine to prepare the compound represented by Formula 32 (step m); a step of acid hydrolyzing the compound represented by Formula 32 prepared in step m to prepare the compound represented by Formula 33 (step n); and the compound represented by Formula 33 prepared in step n is NH3 / t - A method for preparing a compound represented by Formula 1 of Claim 1, comprising the step of reacting under conditions of -BuOH, RNH2, Et3N, or EtOH to prepare a compound represented by Formula 1 (step o): [Reaction Formula 2] (In the above reaction scheme 2, R is H, methyl, 3-F-benzyl, 3-Cl-benzyl, 3-Br-benzyl, or 3-I-benzyl, and X is 1-hexinyl). Claim 8 A pharmaceutical composition for the prevention or treatment of inflammatory diseases, fibrotic diseases, obesity, ischemic diseases, stroke, glaucoma, or cancer, comprising as an active ingredient a compound of any one of claims 1 to 5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Claim 9 A pharmaceutical composition according to claim 8, characterized in that the cancer is any one selected from the group consisting of breast cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, liver cancer, colorectal cancer, skin cancer, head or neck cancer, brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, kidney cancer, rectal cancer, leukemia, and blood cancer. Claim 10 A pharmaceutical composition according to claim 8, characterized in that the ischemic disease is ischemic myocardial infarction, ischemic heart disease, ischemic vascular disease, ischemic enteritis, ischemic eye disease, ischemic glaucoma, ischemic renal failure, ischemic retinopathy, ischemic stroke, ischemic muscle disease, or ischemic limb disease. Claim 11 A pharmaceutical composition according to claim 8, wherein the inflammatory disease is acne, seborrheic dermatitis, contact dermatitis, atopic dermatitis, allergic dermatitis, lupus erythematosus, papular urticaria, psoriasis, asthma, gastritis, edema, conjunctivitis, periodontitis, rhinitis, otitis media, pharyngitis, tonsillitis, pneumonia, hepatitis, esophagitis, gastric ulcer, enteritis, pancreatitis, duodenal ulcer, colitis, cholangitis, nephritis, hemorrhoids, gout, ankylosing spondylitis, lupus, osteoarthritis, rheumatoid arthritis, periarthritis of the shoulder, tendinitis, tenosynovitis, tenosynovitis, myositis, cystitis, nephritis, multiple sclerosis, non-alcoholic fatty liver disease, or sepsis. Claim 12 A pharmaceutical composition according to claim 8, characterized in that the fibrotic disease is pulmonary fibrosis, hepatic fibrosis, cutaneous fibrosis, renal fibrosis, pancreatic fibrosis, systemic sclerosis, or cardiac fibrosis. Claim 13 A health functional food composition for the prevention or improvement of inflammatory diseases, fibrotic diseases, obesity, ischemic diseases, stroke, glaucoma, or cancer, comprising a compound of any one of claims 1 to 5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

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