Novel compounds as Endothelial to mesenchymal transition (EndMT) inhibitors and pharmaceutical compositions containing the same

Abstract

The present invention relates to a novel compound as an EndMT inhibitor and a pharmaceutical composition containing the same, and more particularly to a novel compound as an EndMT inhibitor and a pharmaceutical composition for the treatment of lung diseases containing the same as an active ingredient. The compound according to the present invention exhibits excellent EndMT inhibitory activity and has the advantage of being useful in the prevention and treatment of various lung diseases related to EndMT activity.

Description

[Technical Field]

[0001] The present invention relates to a novel compound as an EndMT inhibitor and a pharmaceutical composition containing the same, and more particularly to a novel compound as an EndMT inhibitor and a pharmaceutical composition for the treatment of lung diseases containing the same as an active ingredient. [Background technology]

[0002] Pulmonary fibrosis (PF) is a condition in which lung tissue thickens, hardens, and becomes scar tissue. The most common type of pulmonary fibrosis is idiopathic pulmonary fibrosis, in which the cause cannot be identified. It is also known to develop as a result of radiation therapy for lung cancer or breast cancer, along with pulmonary fibrosis caused by autoimmune diseases such as rheumatoid arthritis, viral infections, and gastroesophageal reflux disease, as well as pulmonary fibrosis caused by environmental factors or genetic predisposition.

[0003] Specifically, approximately 60% of non-small cell lung cancer patients receive radiation therapy, but unfortunately, traditional and extracorporeal radiation therapy are known to cause lung disease complications such as pneumonia and pulmonary fibrosis in cancer survivors. Radiation-induced pulmonary fibrosis (RIPF) causes abnormalities in the body's normal function, develops 6 to 12 months after radiation therapy, and is characterized by excessive extracellular matrix (ECM) deposition and fibroblast proliferation. Radiation-induced pulmonary fibrosis occurs within weeks after radiation exposure, with endothelial cell (EC) swelling leading to capillary narrowing and disappearance, the growth of new fibrin plugs, and endothelial cell proliferation, particularly in large blood vessels such as arteries and veins. The depletion of functional microvessels inevitably leads to tissue ischemia and hypoxia.

[0004] Furthermore, activated myofibroblasts play a central role in the production of collagen and ECM proteins in pulmonary fibrosis. Myofibroblasts originate from various cell types, including resident stromal fibroblasts, bone marrow-derived fibroblasts, and endothelial-to-mesenchymal transition (EMT) cells (Saito AJ Biochem. 2013;153:493-5). Various studies have shown that during the development of pulmonary fibrosis, including RIPF, alveolar type II endothelial cells undergo a transition from endothelial to mesenchymal cells (Balli D. et al. Foxm1 transcription factor is required for lung fibrosis and epithelial-to-mesenchymal transition. EMBO J. 2013;32:231-44.; Almeida C. et al. The role of alveolar epithelium in radiation-induced lung injury. PLoS ONE 2013;8:e53628). More recently, endothelial-to-mesenchymal transition (EndMT) has been reported to generate fibroblasts in cardiac and renal fibrosis and cancer (Saito AJ Biochem.2013;153:493-5;Potenta S et al.Br J Cancer.2008;99:1375-9;van Meeteren LA et al.Cell Tissue Res.2012;347:177-86). Furthermore, it has been demonstrated that EndMT can also play a role as a source of fibroblasts in bleomycin-induced pulmonary fibrosis (Hashimoto N. et al.Am J Respir Cell Mol Biol.2010;43:161-72).

[0005] EndMT is characterized by loss of intercellular junctions and the acquisition of invasive and migratory phenotypes. Mesenchymal cell markers such as α-smooth muscle actin (α-SMA), fibroblast-specific protein-1 (FSP-1), and vimentin are upregulated, while EC-specific markers, including CD31 and vascular endothelial (VE)-cadherin, are downregulated.

[0006] Treatment options for pulmonary fibrosis are very limited. Some types of pulmonary fibrosis may respond to corticosteroids or other immunosuppressants, but such treatments do not always yield positive results and are often ineffective in patients with idiopathic pulmonary fibrosis. Furthermore, pulmonary fibrosis often follows other lung diseases, and drug interactions with other medications used in the prior treatment can be problematic, sometimes leading to serious side effects.

[0007] In particular, there are currently no drugs that can improve radiation-induced pulmonary fibrosis. While nintedanib and pirfenidone, which are used as existing treatments for idiopathic pulmonary fibrosis, have been reported to be effective against radiation-induced pulmonary fibrosis, they do not improve pulmonary fibrosis and only slow the progression of the disease. Glucocorticosteroids such as prednisone to alleviate inflammation, colchicine to inhibit collagen synthesis, and antibiotics such as penicillamine are also used as treatments for radiation-induced pulmonary fibrosis, but these drugs are highly toxic and have significant side effects. Amifostine, a free radical scavenger developed for radiation damage to normal tissue, is also highly toxic and expensive, limiting its commercialization. Furthermore, steroid anti-inflammatory drugs, which are most commonly used to alleviate symptoms of radiation-induced pneumonia, cannot be considered a fundamental treatment for radiation-induced pulmonary fibrosis.

[0008] Based on the findings of a study (Choi S. et al., Clin Cancer Res. 2015;21(16):3716-3726) indicating that EndMT is a major pathogenesis mechanism in radiation-induced diseases, the present invention has made diligent efforts to develop a novel compound that can suppress EndMT and treat related diseases, such as radiation-induced pneumonia and pulmonary fibrosis. As a result, the present invention has been completed by synthesizing a new compound that can effectively suppress EndMT. [Overview of the project] [Problems that the invention aims to solve]

[0009] The present invention aims to provide novel compounds that can suppress EndMT and their pharmaceutical applications. [Means for solving the problem]

[0010] To achieve the above objective, the present invention provides a compound represented by the following chemical formula (1), its optical isomers, its racemic mixtures, its hydrates, its solvates, or pharmaceutically acceptable salts thereof: Chemical formula (1) [ka]

[0011] Here, R1 is a substituted or unsubstituted bicyclic fused ring formed by the fusion of an aryl ring and a non-aromatic cycloalkyl ring. R2 is hydrogen (H), halogen (X), or an alkynyl group.

[0012] In the present invention, the bicyclic fused ring is characterized by being a benzocycloalkyl group.

[0013] In the present invention, the substituted bicyclic fused ring has one or more hydrogens from the aryl ring and the non-aromatic cycloalkyl ring independently of C 1-6 Alkyl, halogen, C 1-6Characterized by being substituted with alkyl, CF3, CN, CO2Me, CONH2, or COOH.

[0014] In the present invention, the alkynyl group is characterized by being an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a 3-butynyl group, a 1-methyl-2-propynyl group, a 2-methyl-3-butynyl group, a 1-pentynyl group, a 2-pentynyl group, a 3-pentynyl group, a 4-pentynyl group, a 1-methyl-2-butynyl group, a 2-methyl-3-pentynyl group, a 1-hexynyl group, or a 1,1-dimethyl-2-butynyl group.

[0015] In the present invention, the compound is characterized by being selected from the following group: (1)(2R,3R,4S)-2-[6-[[(1R)-indan-1-yl]amino]-2-prop-1-inyl-purine-9-yl]tetrahydrothiophene-3,4-diol; (2)(2R,3R,4S)-2-[6-[[(1S)-indan-1-yl]amino]-2-prop-1-inyl-purine-9-yl]tetrahydrothiophene-3,4-diol; (3)(2R,3R,4S)-2-[2-buto-1-inyl-6-[[(1R)-indan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (4)(2R,3R,4S)-2-[2-buto-1-inyl-6-[[(1S)-indan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (5)(2R,3R,4S)-2-[6-[[(1R)-indan-1-yl]amino]-2-pento-1-inyl-purine-9-yl]tetrahydrothiophene-3,4-diol; (6)(2R,3R,4S)-2-[6-[[(1S)-indan-1-yl]amino]-2-pento-1-inyl-purine-9-yl]tetrahydrothiophene-3,4-diol; (7)(2R,3R,4S)-2-[2-chloro-6-(indan-2-ylamino)purine-9-yl]tetrahydrothiophene-3,4-diol; (8)(2R,3R,4S)-2-[2-chloro-6-(indan-1-ylamino)purine-9-yl]tetrahydrothiophene-3,4-diol; (9)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-indan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (10)(2R,3R,4S)-2-[2-chloro-6-[[(1S)-indan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (11)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-methoxyindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (12)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-methoxyindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (13)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-6-methoxyindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (14)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-7-methoxyindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (15)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-fluoroindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (16)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-fluoroindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (17)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-chloroindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (18)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-chloroindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (19)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-bromoindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (20)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-bromoindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (21)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-6-bromoindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (22)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-methylindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (23)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-(trifluoromethyl)indan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (24)(1R)-1-[[2-chloro-9-[(2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl]purine-6-yl]amino]indan-4-carbonitrile; (25)(R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purine-6-yl)amino)-2,3-dihydro-1H-indene-4-carboxamide; (26)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-7-bromoindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (27)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-methylindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (28)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-(trifluoromethyl)indan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (29)(1R)-1-[[2-chloro-9-[(2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl]purine-6-yl]amino]indan-5-carbonitrile; (30) Methyl(R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purine-6-yl)amino)-2,3-dihydro-1H-indene-4-carboxylate; (31) Methyl(R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purine-6-yl)amino)-2,3-dihydro-1H-indene-5-carboxylate; (32)(R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purine-6-yl)amino)-2,3-dihydro-1H-indene-4-carboxylic acid; (33)(R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purine-6-yl)amino)-2,3-dihydro-1H-indene-5-carboxylic acid; (34)(R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purine-6-yl)amino)-2,3-dihydro-1H-indene-5-carboxamide; (35)(2R,3R,4S)-2-(2-chloro-6-((1,2,3,4-tetrahydronaphthalene-2-yl);amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (36)(2R,3R,4S)-2-(2-chloro-6-(((S)-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (37)(2R,3R,4S)-2-(2-chloro-6-(((R)-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (38)(2R,3R,4S)-2-(2-chloro-6-((1,2,3,4-tetrahydronaphthalene-1-yl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (39)(2R,3R,4S)-2-(2-chloro-6-(((R)-1,2,3,4-tetrahydronaphthalene-1-yl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (40)(2R,3R,4S)-2-(2-chloro-6-(((S)-1,2,3,4-tetrahydronaphthalene-1-yl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (41)(2R,3R,4S)-2-(6-(((R)-Bicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)amino)-2-chloro-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (42)(2R,3R,4S)-2-(2-chloro-6-((6,7,8,9-tetrahydro-5H-benzo[7]anulen-5-yl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (43)(2R,3R,4S)-2-(2-chloro-6-((6,7,8,9-tetrahydro-5H-benzo[7]anulen-7-yl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (44)(2R,3R,4S)-2-(6-(((R)-2,3-dihydro-1H-inden-1-yl)amino)-2-iodo-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (45)(2R,3R,4S)-2-(6-(((R)-2,3-dihydro-1H-inden-1-yl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol.

[0016] In the present invention, the compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof is characterized by its ability to inhibit endothelial-to-mesenchymal transition (EndMT).

[0017] The present invention also aims to provide a pharmaceutical composition for the prevention or treatment of lung disease, comprising the aforementioned compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof, as an active ingredient.

[0018] In the present invention, the lung disease is characterized by being pneumonia, pulmonary fibrosis, or lung cancer.

[0019] In the present invention, the lung disease is characterized by being a radiation-induced lung disease.

[0020] In the present invention, the pharmaceutical composition is characterized by being used in conjunction with radiotherapy.

[0021] In the present invention, the pharmaceutical composition is characterized by being administered before and / or after radiation therapy.

[0022] The present invention also aims to provide an endothelial-to-mesenchymal transition (EndMT) inhibitor containing the aforementioned compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or a salt thereof as an active ingredient.

[0023] In the present invention, the compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or a salt thereof is characterized by its ability to suppress the formation of actin stress filaments in endothelial cells. [Effects of the Invention]

[0024] The compounds according to the present invention exhibit excellent EndMT inhibitory activity, and therefore have the advantage of being useful in the prevention and treatment of various lung diseases associated with EndMT activity. [Modes for carrying out the invention]

[0025] The descriptions disclosed herein or in the application are merely illustrative for the purpose of illustrating embodiments based on the technical concept of the present invention, and embodiments based on the technical concept of the present invention can be implemented in various forms other than those disclosed herein or in the application. The technical concept of the present invention should not be construed as being limited to the embodiments described herein or in the application.

[0026] The present invention will be described in detail below. In this invention, we have developed a novel compound that has EndMT inhibitory activity.

[0027] Therefore, in one aspect, the present invention relates to a compound represented by the following chemical formula (1), its optical isomers, its racemic mixtures, its hydrates, its solvates, or pharmaceutically acceptable salts thereof: Chemical formula (1) [ka]

[0028] In the above chemical formula (1), R1 is a substituted or unsubstituted bicyclic fused ring formed by the fusion of an aryl ring and a non-aromatic cycloalkyl ring. R2 is hydrogen (H), halogen (X), or an alkynyl group.

[0029] In the present invention, the bicyclic fused ring is characterized by being a benzocycloalkyl group, but is not limited thereto.

[0030] In the present invention, the bicyclic fused ring is a benzene ring (phenyl) with C 4-8It is characterized by being a bicyclic fused ring formed by the condensation of cycloalkyl rings, but is not limited to this.

[0031] In one embodiment, the bicyclic condensed ring may have one or more hydrogen atoms of the aryl ring and the non-aromatic cycloalkyl ring independently substituted with OCH3, F, Cl, Br, I, CH3, CF3, CN, CO2Me, CONH2, or COOH.

[0032] As one example, the two-ring fused ring is, [ka] As shown above, it may also be a bicyclic fused ring in which a benzene ring and a cyclobutyl ring are fused together.

[0033] In other forms, the aforementioned bicyclic fused ring is [ka] or [ka] As shown above, it may also be a bicyclic fused ring in which a benzene ring and a cyclopentyl ring are fused together.

[0034] Furthermore, in other forms, the bicyclic fused ring is, [ka] or [ka] As shown above, it may also be a bicyclic fused ring in which a benzene ring and a cyclohexyl ring are fused together.

[0035] Furthermore, in other forms, the bicyclic fused ring is, [ka] , [ka] or [ka] As shown above, it may also be a bicyclic fused ring in which a benzene ring and a cycloheptyl ring are fused together.

[0036] In the present invention, the substituted bicyclic fused ring has one or more hydrogens from the aryl ring and the non-aromatic cycloalkyl ring independently of C 1-6 Alkyl, halogen, C 1-6 Characterized by substitution with alkyl, CF3, CN, CO2Me, CONH2, or COOH, but not limited to these.

[0037] As one example, the substituted bicyclic condensed ring is characterized in that, in any bicyclic condensed ring selected from the group consisting of the following structural formulas, one or more hydrogens are independently substituted with OCH3, F, Cl, Br, I, CH3, CF3, CN, CO2Me, CONH2, or COOH, but is not limited to these: [ka]

[0038] Specifically, in the substituted bicyclic fused ring, R1 may be any one selected from the group consisting of the following structural formulas: [ka] [ka]

[0039] As one example, the alkynyl group may be, but is not limited to, an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a 3-butynyl group, a 1-methyl-2-propynyl group, a 2-methyl-3-butynyl group, a 1-pentynyl group, a 2-pentynyl group, a 3-pentynyl group, a 4-pentynyl group, a 1-methyl-2-butynyl group, a 2-methyl-3-pentynyl group, a 1-hexynyl group, or a 1,1-dimethyl-2-butynyl group.

[0040] As one example, R2 may be H, F, Cl, Br, I, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, or 2-pentynyl.

[0041] As one example, R2 is [ka] or [ka] That's fine.

[0042] In the present invention, the compound may be any one of the following Examples 1 to 45, which may be selected from the following group. (1)(2R,3R,4S)-2-[6-[[(1R)-indan-1-yl]amino]-2-prop-1-inyl-purine-9-yl]tetrahydrothiophene-3,4-diol; (2)(2R,3R,4S)-2-[6-[[(1S)-indan-1-yl]amino]-2-prop-1-inyl-purine-9-yl]tetrahydrothiophene-3,4-diol; (3)(2R,3R,4S)-2-[2-buto-1-inyl-6-[[(1R)-indan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (4)(2R,3R,4S)-2-[2-buto-1-inyl-6-[[(1S)-indan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (5)(2R,3R,4S)-2-[6-[[(1R)-indan-1-yl]amino]-2-pento-1-inyl-purine-9-yl]tetrahydrothiophene-3,4-diol; (6)(2R,3R,4S)-2-[6-[[(1S)-indan-1-yl]amino]-2-pento-1-inyl-purine-9-yl]tetrahydrothiophene-3,4-diol; (7)(2R,3R,4S)-2-[2-chloro-6-(indan-2-ylamino)purine-9-yl]tetrahydrothiophene-3,4-diol; (8)(2R,3R,4S)-2-[2-chloro-6-(indan-1-ylamino)purine-9-yl]tetrahydrothiophene-3,4-diol; (9)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-indan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (10)(2R,3R,4S)-2-[2-chloro-6-[[(1S)-indan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (11)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-methoxyindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (12)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-methoxyindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (13)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-6-methoxyindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (14)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-7-methoxyindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (15)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-fluoroindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (16)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-fluoroindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (17)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-chloroindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (18)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-chloroindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (19)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-bromoindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (20)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-bromoindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (21)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-6-bromoindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (22)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-methylindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (23)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-(trifluoromethyl)indan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (24)(1R)-1-[[2-chloro-9-[(2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl]purine-6-yl]amino]indan-4-carbonitrile; (25)(R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purine-6-yl)amino)-2,3-dihydro-1H-indene-4-carboxamide; (26)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-7-bromoindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (27)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-methylindan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (28)(2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-(trifluoromethyl)indan-1-yl]amino]purine-9-yl]tetrahydrothiophene-3,4-diol; (29)(1R)-1-[[2-chloro-9-[(2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl]purine-6-yl]amino]indan-5-carbonitrile; (30) Methyl(R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purine-6-yl)amino)-2,3-dihydro-1H-indene-4-carboxylate; (31) Methyl(R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purine-6-yl)amino)-2,3-dihydro-1H-indene-5-carboxylate; (32)(R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purine-6-yl)amino)-2,3-dihydro-1H-indene-4-carboxylic acid; (33)(R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purine-6-yl)amino)-2,3-dihydro-1H-indene-5-carboxylic acid; (34)(R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purine-6-yl)amino)-2,3-dihydro-1H-indene-5-carboxamide; (35)(2R,3R,4S)-2-(2-chloro-6-((1,2,3,4-tetrahydronaphthalene-2-yl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (36)(2R,3R,4S)-2-(2-chloro-6-(((S)-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (37)(2R,3R,4S)-2-(2-chloro-6-(((R)-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (38)(2R,3R,4S)-2-(2-chloro-6-((1,2,3,4-tetrahydronaphthalene-1-yl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (39)(2R,3R,4S)-2-(2-chloro-6-(((R)-1,2,3,4-tetrahydronaphthalene-1-yl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (40)(2R,3R,4S)-2-(2-chloro-6-(((S)-1,2,3,4-tetrahydronaphthalene-1-yl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (41)(2R,3R,4S)-2-(6-(((R)-Bicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)amino)-2-chloro-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (42)(2R,3R,4S)-2-(2-chloro-6-((6,7,8,9-tetrahydro-5H-benzo[7]anulen-5-yl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (43)(2R,3R,4S)-2-(2-chloro-6-((6,7,8,9-tetrahydro-5H-benzo[7]anulen-7-yl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (44)(2R,3R,4S)-2-(6-(((R)-2,3-dihydro-1H-inden-1-yl)amino)-2-iodo-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; (45)(2R,3R,4S)-2-(6-(((R)-2,3-dihydro-1H-inden-1-yl)amino)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol.

[0043] In the present invention, the compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof is characterized by its ability to inhibit endothelial-to-mesenchymal transition (EndMT).

[0044] In the present invention, the following definitions apply when defining the compound of chemical formula (1), unless otherwise specified.

[0045] The term "alkyl" refers to a linear or branched saturated hydrocarbon, C 1-10 Alkyl is preferred. For example, the alkyl includes, but is not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0046] In this specification, the term "aryl" means aromatic hydrocarbon and includes polycyclic aromatic ring systems in which a carbocyclic aromatic ring or a heteroaryl ring is fused with one or more other rings. Preferably, C 5-12 Aryl, more preferably C 5-10It is aryl. For example, the aryl includes, but is not limited to, phenyl, naphthyl, tetrahydronaphthyl, etc.

[0047] The term "cycloalkyl" is a partially or fully saturated monocyclic or fused cyclic hydrocarbon, C 3-10 Cycloalkyl is preferred. For example, it includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexynyl, etc.

[0048] The term "halogen" or "halo" means fluorine / fluoro (F), chlorine (Cl), bromine (Br) or iodine (I).

[0049] The term "alkynyl group" refers to an unsaturated branched or straight-chain hydrocarbon group having two or more carbon atoms and at least one triple bond. In the present invention, the alkynyl group includes, but is not limited to, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 2-methyl-3-butynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-methyl-2-butynyl group, 2-methyl-3-pentynyl group, 1-hexynyl group, 1,1-dimethyl-2-butynyl group, etc.

[0050] Phalloidin is a highly selective bicyclic peptide used for staining actin filaments (also known as F-actin). The EndMT process is characterized by the formation of actin stress fibers by the filaments (Maddaluno L. et al., EndMT contributes to the onset and progression of cerebral cavernous malformations. Nature 2013;498:492-6.; Wojciech Micha=Ciszewski et al., Cytoskeleton Reorganization in EndMT-The Role in Cancer and Fibrotic Diseases. Int J Mol Sci. 2021 Nov;22(21):11607). In this invention, we confirmed the effect of a novel compound on inhibiting phalloidin, thereby confirming its effect on inhibiting actin stress fiber formation, i.e., its effect on inhibiting EndMT.

[0051] The Endothelial-to-Mesenchymal Transition (ENDMT) mechanism is one of the mechanisms that induce fibrosis. Radiation induces EndMT in pulmonary vascular endothelial cells, leading to the conversion of mesenchymal stem cells. This is known to cause various factors (e.g., the secretion of TGF-β, which induces the proliferation of surrounding cells (smooth muscle cells, epithelial cells) and mutation into myofibroblasts, thereby causing pulmonary fibrosis. It has been reported that a decrease in such EndMT in radiation-induced pulmonary fibrosis models leads to a decrease in pulmonary fibrosis (Seo-Hyun Choi et al., A Hypoxia-Induced Vascular Endothelial-to-Mesenchymal Transition in Development of Radiation-Induced Pulmonary Fibrosis. Clin Cancer Res. 2015). (Aug;21(16):3716). Furthermore, Endothelial mesenchymal transition in bleomycin-induced pulmonary fibrosis has been reported to play a role in the development of idiopathic pulmonary fibrosis by inducing vascular remodeling, and that suppression of Endothelial mesenchymal transition in bleomycin-induced pulmonary fibrosis is reduced in pulmonary fibrosis models (Hashimoto N et al., 2010. Endothelial mesenchymal transition in bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol. 43(2):161-172., Eunsik Yun et al., 2023. Ginsenoside Rg3 attenuates pulmonary fibrosis by inhibiting endothelial to mesenchymal transition, Animal Cells and Systems, 27:1, 159-170).Furthermore, Endothelial-to-mesenchymal transition in anticancer therapy and normal tissue damage has been reported to promote cancer development through the accumulation of cancer-associated fibroblasts (CAFs), and suppression of such Endothelial-to-mesenchymal transition in cancer can increase the effectiveness of lung cancer treatment (Choi, K.Jet al. Endothelial-to-mesenchymal transition in anticancer therapy and normal tissue damage. Exp Mol Med 52, 781-792 (2020), Clere N, Renault S and Corre I (2020) Endothelial-to-mesenchymal Transition in Cancer. Front. Cell Dev. Biol. 8: 747). From this perspective, the present inventors have confirmed using animal models that the compound according to the present invention can actually exert a therapeutic effect on the aforementioned disease.

[0052] Accordingly, the present invention relates in other aspects to pharmaceutical compositions for the EndMT inhibitory use of the compound of chemical formula (1), its optical isomers, its racemic mixtures, its hydrates, its solvates, or pharmaceutically acceptable salts thereof, and for the prevention or treatment of diseases associated with EndMT activity.

[0053] Specifically, the EndMT inhibitory applications and diseases associated with EndMT activity may include lung diseases.

[0054] In one aspect, the present invention relates to a pharmaceutical composition for the prevention or treatment of lung disease, comprising the compound, its optical isomers, its racemic mixtures, its hydrates, its solvates, or pharmaceutically acceptable salts thereof as an active ingredient.

[0055] In the present invention, the lung disease is characterized by being pneumonia, pulmonary fibrosis, or lung cancer, but is not limited to these.

[0056] In the present invention, the lung disease is characterized by being a radiation-induced lung disease, but is not limited thereto.

[0057] As one manifestation, the pulmonary fibrosis may be radiation-induced pulmonary fibrosis or idiopathic pulmonary fibrosis.

[0058] Furthermore, in other forms, the lung cancer may be small cell lung cancer or non-small cell lung cancer.

[0059] When the compounds according to the present invention, their optical isomers, their racemic mixtures, their hydrates, their solvates, or their pharmaceutically acceptable salts are used for the prevention or treatment of lung diseases, this is characterized by, but is not limited to, use in conjunction with radiotherapy.

[0060] When the compounds according to the present invention, their optical isomers, their racemic mixtures, their hydrates, their solvates, or their pharmaceutically acceptable salts are used in conjunction with radiotherapy, the compounds according to the present invention, their optical isomers, their racemic mixtures, their hydrates, their solvates, or their pharmaceutically acceptable salts can suppress the side effects of radiotherapy while simultaneously enhancing the therapeutic effect of radiotherapy.

[0061] When the compounds according to the present invention, their optical isomers, their racemic mixtures, their hydrates, their solvates, or pharmaceutically acceptable salts thereof are used as active ingredients for the prophylactic or therapeutic use of lung diseases, such as pneumonia, fibrosis, or lung cancer, the compounds according to the present invention, their optical isomers, their racemic mixtures, their hydrates, their solvates, or pharmaceutically acceptable salts thereof may be administered before and / or after radiotherapy.

[0062] As one example, when a compound according to the present invention, its optical isomer, its racemic mixture, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof is used as an active ingredient for the prevention or treatment of lung diseases, such as pneumonia, fibrosis, or lung cancer, it is characterized by being administered approximately 48 hours to 10 minutes before radiation therapy, for example, approximately 36 hours to 6 hours or approximately 24 hours to 12 hours before radiation therapy, but is not limited to these examples.

[0063] In other ways, when the compounds according to the present invention, their optical isomers, their racemic mixtures, their hydrates, their solvates, or pharmaceutically acceptable salts thereof are used for the prophylactic or therapeutic purposes of pulmonary fibrosis, this applies from immediately after radiotherapy to days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 It is characterized by being administered up to day 100, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100.

[0064] The compound represented by chemical formula (1) according to the present invention can be prepared and used in the form of a prodrug, hydrate, solvate, and pharmaceutically acceptable salt to enhance bioavailability or increase solubility; therefore, the prodrug, hydrate, solvate, and pharmaceutically acceptable salt also fall within the scope of the present invention. Furthermore, the compound represented by chemical formula (1) has a chiral carbon and stereoisomers exist, and such stereoisomers are also included within the scope of the present invention.

[0065] The term "prodrug" refers to a substance that is converted into a parent drug in vivo. Prodrugs are often used because, in some cases, they are easier to administer than parent drugs. For example, they may be viable when administered orally, whereas the parent drug may not. Prodrugs may also have improved solubility in pharmaceutical compositions compared to parent drugs. For example, a prodrug may be a biohydrolyzable ester of a compound according to the present invention and a pharmaceutically acceptable salt thereof. Yet another example of a prodrug may be a short peptide (polyamino acid) to which a peptide is bound to an acid group that is converted by metabolism so that the peptide represents an active site.

[0066] The term "hydrate" refers to the compound or salt of the present invention that contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0067] The term "solvate" refers to a compound or salt thereof of the present invention that contains a stoichiometric or non-stoichiometric amount of solvent bonded by non-covalent intermolecular forces. Preferred solvents relating thereto are volatile, non-toxic, and / or solvents suitable for administration to humans.

[0068] The term "isomer" refers to a compound or salt of the present invention that has the same chemical or molecular formula but is structurally or sterically different. Such isomers include structural isomers such as tautomers, and stereoisomers such as R or S isomers with asymmetric carbon centers, and geometric isomers (trans, cis). All of these isomers and mixtures thereof are also included in the scope of the present invention.

[0069] The term "pharmaceutically acceptable salt" refers to a salt form of a compound that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity or physical properties of the compound. Such pharmaceutically acceptable salts include acid addition salts formed by acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids like hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and hydroiodic acid; organic carbon acids like tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, and salicylic acid; and sulfonic acids like methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. For example, pharmaceutically acceptable carboxylate salts include metal salts or alkaline earth metal salts formed from lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, and guanidine, and organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine. The compound of chemical formula (1) according to the present invention can be converted to its salt by conventional methods.

[0070] Furthermore, the present invention provides a method for producing the compound of chemical formula (1). While the synthesis methods of Examples 1 to 45 are exemplified as methods for producing the compound of chemical formula (1) according to the present invention, the synthesis methods of Examples 1 to 45 are not limited to the method for producing the compound of chemical formula (1) according to the present invention. The synthesis methods of Examples 1 to 45 are illustrative and it is obvious that they can be easily modified by an ordinary person using specific substituted compounds.

[0071] The present invention also provides a pharmaceutical composition for the prevention or treatment of diseases related to EndMT activity, comprising as an active ingredient a compound of chemical formula (1), its optical isomer, its racemic mixture, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof.

[0072] The present invention also provides a method for preventing or treating diseases associated with EndMT inhibition and / or EndMT activity (e.g., lung disease), comprising the step of administering a compound of chemical formula (1), its optical isomers, its racemic mixtures, its hydrates, its solvates, or pharmaceutically acceptable salts thereof to a patient in need.

[0073] The present invention also provides applications for the prevention or treatment of diseases (e.g., lung diseases) associated with EndMT inhibition and / or EndMT activity of the compound of chemical formula (1), its optical isomers, its racemic mixtures, its hydrates, its solvates, or pharmaceutically acceptable salts thereof.

[0074] The present invention also provides uses of the compound of chemical formula (1), its optical isomers, its racemic mixtures, its hydrates, its solvates, or pharmaceutically acceptable salts thereof in the manufacture of drugs for the prevention or treatment of diseases associated with EndMT inhibition and / or EndMT activity (e.g., lung diseases).

[0075] The present invention also provides compositions or dosage forms comprising the compound of chemical formula (1), its optical isomers, its racemic mixtures, its hydrates, its solvates, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable additives.

[0076] The composition may also be a pharmaceutical composition for treating diseases associated with EndMT suppression and / or EndMT activity (e.g., lung diseases).

[0077] The additive may include pharmaceutically acceptable carriers such as commonly used excipients, disintegrants, sweeteners, lubricants, or flavoring agents, and can be formulated by conventional methods into oral formulations such as tablets, capsules, powders, granules, and suspensions, emulsions, or syrups; or into parenteral formulations such as topical solutions, topical suspensions, topical emulsions, gels (such as ointments), inhalants, sprays, and injections. The formulation can be formulated in various forms, for example, single-dose or multi-dose dosage forms.

[0078] The pharmaceutical composition of the present invention may contain excipients such as lactose and corn starch, lubricants such as magnesium stearate, emulsifiers, suspending agents, stabilizers, and isotonic agents. Sweeteners and / or flavoring agents may be added as needed.

[0079] The pharmaceutical compositions of the present invention can be administered to mammals such as livestock and humans via various routes, for example, by oral, cutaneous, subcutaneous, intramuscular, intravenous, intraperitoneal, intrarectal, intrauterine dura mater, or intracerebral injection, or by topical administration. Accordingly, the compositions of the present invention can be formulated in various forms such as tablets, capsules, aqueous solutions, or suspensions. For oral tablets, carriers such as lactose and corn starch and lubricants such as magnesium stearate can usually be added. For oral capsules, lactose and / or dried corn starch can be used as diluents. If an aqueous suspension for oral administration is required, the active ingredient can be combined with an emulsifier and / or suspending agent. Specific sweeteners and / or flavorings can be added as needed. For intramuscular, intraperitoneal, subcutaneous, and intravenous administration, a sterile solution of the active ingredient is usually prepared, and the pH of the solution must be appropriately adjusted and buffered. For intravenous administration, the total concentration of the solute must be adjusted so that the formulation isotonic. The composition according to the present invention may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier, such as saline solution with a pH of 7.4. The solution can be introduced into the patient's intramuscular blood flow by local injection.

[0080] The dosage of the active ingredient contained in the pharmaceutical composition of the present invention varies depending on the patient's condition and weight, the severity of the disease, the form of the active ingredient, the route of administration, and the duration of administration, and can be adjusted as appropriate for each patient. For example, the active ingredient can be administered at a dose of 0.0001 to 1000 mg / kg per day, preferably 0.01 to 100 mg / kg, and this administration can be done once a day or divided into several doses. Furthermore, the pharmaceutical composition of the present invention may contain the active ingredient at a weight percentage of 0.001 to 90% of the total weight of the composition.

[0081] The pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, and humans via various routes, for example, by oral, cutaneous, peritoneal, rectal, or intravenous, intramuscular, subcutaneous, intrauterine dura mater, or intracerebral (intracerebroventricular) injection.

[0082] The effective amount of the pharmaceutical composition according to the present invention varies depending on the patient's condition and weight, the severity of the disease, the form of the active ingredient, the route of administration, and the duration, and can be adjusted as appropriate for each patient. The pharmaceutical composition of the present invention may contain the compound, its optical isomers, its racemic mixtures, its hydrates, its solvates, or pharmaceutically acceptable salts thereof as active ingredients in a weight percentage of 0.001 to 90% of the total weight of the composition.

[0083] As used in this application, “to treat” means, in whole or in part, the relief of one or more symptoms of a disorder, disease or condition, or a disorder, disease or condition associated with it, or the slowing or interruption of further progression or worsening of such symptoms, or the relief or eradication of the cause of the disorder, disease or condition.

[0084] As used in this application, “prevent” means a method of delaying, delaying, or preventing the onset, recurrence, or spread of a disability, disease, or condition, in whole or in part; excluding an object from acquiring a disability, disease, or condition; or reducing the risk of an object acquiring a disability, disease, or condition.

[0085] The term "effective dose" means an amount that can treat or prevent the disorder, disease, condition, or symptoms thereof disclosed herein.

[0086] The term "subject" includes animals, but is not limited to, cattle, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs, and in one mode of implementation, mammals, and in other modes of implementation, humans.

[0087] In yet another aspect, the present invention can be provided as an endothelial-to-mesenchymal transition (EndMT) inhibitor containing the compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or a salt thereof as an active ingredient.

[0088] In the present invention, the compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or a salt thereof is characterized by its ability to suppress the formation of actin stress filaments in endothelial cells.

[0089] The EndMT inhibitor may be an experimental reagent used to inhibit the conversion of endothelial cells to mesenchymal cells in a test tube. [Examples]

[0090] The present invention will be described in more detail below based on manufacturing examples, embodiments, and test examples. However, the following manufacturing examples, embodiments, and test examples are illustrative of the present invention, and the scope of the present invention is not limited thereto.

[0091] <Production example 1> Production of 6-chloro-9-((3aR,4R,6aS)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-2-iodo-9H-purine [ka]

[0092] 6-chloro-2-iodopurine (5.01 g, 17.87 mmol) and ACN (89 mL) were added to 250 mL Rbf, and N,O-Bis(trimethylsilyl)acetamide (BSA) (6.72 mL, 27.5 mmol) was added under a nitrogen stream, followed by stirring at 40°C for 1 hour. A solution of (3aR,4R,6aS)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl acetate (3.0 g, 13.74 mmol) in ACN (15 mL) was slowly added to the reaction mixture at room temperature, followed by the addition of TMSOTf (2.75 mL). After stirring at 80°C for 3 hours, saturated NaHCO3 aqueous solution was added to the reaction mixture to adjust the pH to 8, and the mixture was extracted with ELISA. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The concentrated residue was purified by column chromatography (0-1% MeOH / DCM) to obtain the title compound as a pale yellow solid (2.88 g, 46%).

[0093] 1 H NMR (400MHz, CDCl3) δ8.06(s, 1H), 5.85(s, 1H), 5.33(t, J=4.7Hz, 1H), 5.22(d, J=5.4Hz, LCMS m / z 439[M+H] +

[0094] <Production Example 2> Production of 2,6-dichloro-9-((3aR,4R,6aS)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-9H-purine [ka]

[0095] The title compound was obtained as a white solid (1.1 g, 73%) using the same method as in Preparation Example 1, with 2,6-dichloropurine (1.07 g, 5.66 mmol), BSA (2.13 mL, 8.70 mmol), (3aR,4R,6aS)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl acetate (950 mg, 4.35 mmol), ACN (33.2 mL), and TMSOTf (0.87 mL).

[0096] 1 H NMR (400MHz, CDCl3) δ8.17(s, 1H), 5.86(s, 1H), 5.33(t, J=4.7Hz, 1H), 5.21(d, J=5.3Hz, LCMS m / z 347[M+H] +

[0097] <Production Example 3> Production of (2R,3R,4S)-2-(6-chloro-2-(prop-1-yn-1-yl)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol Step 1: Production of 6-chloro-9-((3aR,4R,6aS)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-2-(prop-1-yn-1-yl)-9H-purine [ka]

[0098] To a solution of 6-chloro-9-((3aR,4R,6aS)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-2-iodo-9H-purine (700 mg, 1.6 mmol) in DMF (16 mL), Pd(PPh3)4 (203 mg, 0.176 mmol), CuI (37 mg, 0.192 mmol), and CS2CO3 (521 mg, 1.6 mmol) were added, and the mixture was degassed. Propyne (1 M in DMF, 4.8 mL) was added, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated and used in the next reaction without further purification. LCMS m / z 351[M+H] +

[0099] Step 2: Production of (2R,3R,4S)-2-(6-chloro-2-(prop-1-yn-1-yl)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol [ka]

[0100] 6-chloro-9-((3aR,4R,6aS)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-2-(prop-1-yn-1-yl)-9H-purine (1.6 mmol) was dissolved in 80% HCOOH (40 mL) and stirred at room temperature for 4 hours. ELISA was added to the reaction mixture, followed by saturated NaHCO3. 3 Washed with an aqueous solution. The organic layer was then converted to MgSO4. 4 The mixture was dried, filtered, and concentrated. The concentrated residue was purified by column chromatography (0-3% MeOH / DCM) to obtain the title compound as a white solid (279 mg, 2 steps 56%).

[0101] 1H NMR (400MHz, CD3OD) δ8.88(s, 1H), 6.10(d, J=6.6Hz, 1H), 4.72(dd, J=6.6, 3.4Hz, 1H), 4.49(dd, LCMS m / z 311[M+H] +

[0102] <Production Example 4> Production of (2R,3R,4S)-2-(2-(but-1-yn-1-yl)-6-chloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol Step 1: Preparation of 2-(but-1-yn-1-yl)-6-chloro-9-((3aR,4R,6aS)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-9H-purine [ka]

[0103] 6-chloro-9-((3aR,4R,6aS)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-2-iodo-9H-purine (500 mg, 1.14 mmol) was dissolved in DMF (7.7 mL), then Pd(PPh3)4 (133 mg, 0.114 mmol), CuI (26 mg, 0.137 mmol), and CS2CO3 (372 mg, 1.14 mmol) were added, and the mixture was degassed. The reaction mixture was stirred for 3 hours while bubbling with 1-Butyne(gas). The reaction mixture was diluted with ethyl alcohol, washed with DW and brine, dried over MgSO4, filtered, and concentrated. The concentrated residue was purified by column chromatography (0-25% ethyl alcohol / HX) to obtain the title compound as a yellow solid (295 mg, 71%).

[0104] 1H NMR (400MHz, CDCl3) δ8.16(s, 1H), 5.91(s, 1H), 5.33(t, J=4.8Hz, 1H), 5.22(d, J=5.3Hz, 1H), 3.79(dd, J=12.9, LCMS m / z 365[M+H] +

[0105] Step 2: Production of (2R,3R,4S)-2-(2-(but-1-yn-1-yl)-6-chloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol [ka]

[0106] The title compound was obtained as a white solid (25 mg, 76%) using 2-(but-1-yn-1-yl)-6-chloro-9-((3aR,4R,6aS)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-9H-purine (37 mg, 0.101 mmol) and 80% HCOOH (2 mL) in the same manner as in step 2 of preparation example 3.

[0107] 1 H NMR (400MHz, DMSO-d6) δ9.06(s, 1H), 5.96(d, J=7.2Hz, 1H), 4.62(dd, J=7.2, 3.1Hz, 1H), 4.35(d, J=2.9Hz, 1H) ), 3.45 (dd, J=10.7, 4.0Hz, 1H), 2.83 (dd, J=10.8, 2.7Hz, 1H), 2.55-2.51 (m, 2H), 1.21 (t, J=7.5Hz, 3H); LCMS m / z 325[M+H] +

[0108] <Production Example 5> Production of (2R,3R,4S)-2-(6-chloro-2-(pent-1-yn-1-yl)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol Step 1: Preparation of 6-chloro-9-((3aR,4R,6aS)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-2-(pent-1-yn-1-yl)-9H-purine [ka]

[0109] The title compound was obtained as a yellow solid (265 mg, 61%) using the same method as in Step 1 of Preparation Example 3, with 1-pentyne (0.17 mL, 1.71 mmol), DMF (7.7 mL), Pd(PPh3)4 (328 mg, 0.284 mmol), CuI (26 mg, 0.137 mmol), and CS2CO3 (372 mg, 1.14 mmol).

[0110] 1 H NMR (400MHz, CDCl3) δ8.16(s, 1H), 5.90(s, 1H), 5.33(t, J=4.7Hz, 1H), 5.23(d, J=5.4Hz, 1H), 3.81(dd, J=12.9, 4.4Hz, 1H ), 3.25(d, J=12.8Hz, 1H), 2.47(t, J=7.1Hz, 2H), 1.79-1.64(m, 2H), 1.59(s, 3H), 1.37(s, 3H), 1.08(t, J=7.4Hz, 3H);LCMS m / z 379[M+H] +

[0111] Step 2: Production of (2R,3R,4S)-2-(6-chloro-2-(pent-1-yn-1-yl)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol [ka]

[0112] The title compound was obtained as a white solid (167 mg, 70%) using 6-chloro-9-((3aR,4R,6aS)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-2-(pent-1-yn-1-yl)-9H-purine (265 mg, 0.7 mmol) and 80% HCOOH (14 mL) in the same manner as in step 2 of preparation example 3.

[0113] 1 H NMR (400MHz, DMSO-d6) δ9.06(s, 1H), 5.96(d, J=7.2Hz, 1H), 5.63(d, J=5.9Hz, 1H), 5.44(d, J=4.1Hz, 1H), 4.62(td, J=7.2, 3.4Hz, 1H), 4.39 LCMS m / z 339[M+H] +

[0114] <Manufacturing Example 6> Manufacturing of (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol [ka]

[0115] 2,6-dichloro-9-((3aR,4R,6aS)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-9H-purine (5.00 g, 14.4 mmol) was dissolved in 80% HCOOH (100 mL) and stirred at room temperature for 4 hours. The mixture was adjusted to pH 8 with saturated NaHCO3 aqueous solution and extracted with ELISA. The organic layer was dried over MgSO4, filtered, and concentrated. DCM was added to the concentrated residue, filtered, and dried to obtain the title compound as a white solid without further purification (3.23 g, 73%).

[0116] 1 H NMR (400MHz, CD3OD) δ8.88(s, 1H), 6.08(d, J=6.6Hz, 1H), 4.69(dd, J=6.4, 2.9Hz, 1H), 4.48(d, J=3.3Hz, 1H), 3.56(dd, J=10.9, 4.2Hz, 1H), 2.97(dd, J=11.1, 2.8Hz, 1H); LCMS m / z 307[M+H] +

[0117] [Example 1] (2R,3R,4S)-2-[6-[[(1R)-indan-1-yl]amino]-2-prop-1-ynyl-purin-9-yl]tetrahydrothiophene-3,4-diol [ka]

[0118] (2R,3R,4S)-2-(6-chloro-2-(prop-1-yn-1-yl)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (20 mg, 0.064 mmol) and (R)-(-)-1-Indanamine (9.4 mg, 0.071 mmol) were dissolved in DMF (0.6 mL), and then DIPEA (13 μL, 0.071 mmol) was added. After stirring at room temperature for 4.5 days, DW was added to the reaction mixture and stirred for 30 minutes. The resulting solid was filtered and dried to obtain the title compound as a brown solid (12.3 mg, 47%).

[0119] 1H NMR (400MHz, DMSO-d6) δ8.49(s, 1H), 8.26-8.09(m, 1H), 7.32-7.05(m, 4H), 5.8 8(d, J=6.6Hz, 2H), 5.56(d, J=6.3Hz, 1H), 5.37(d, J=3.9Hz, 1H), 4.63(dd, J=9. 8, 6.8Hz, 1H), 4.39-4.30(m, 1H), 3.41(dd, J=10.8, 4.1Hz, 1H), 3.05-2.95(m, 1 LCMS m / z 408[M+H] +

[0120] [Example 2] (2R,3R,4S)-2-[6-[[(1S)-indan-1-yl]amino]-2-prop-1-ynyl-purin-9-yl]tetrahydrothiophene-3,4-diol [ka]

[0121] The title compound was obtained as a pale yellow solid (12.4 mg, 48%) using the same method as in Example 1, with (2R,3R,4S)-2-(6-chloro-2-(prop-1-yn-1-yl)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (20 mg, 0.064 mmol), (S)-(+)-1-Indanamine (9.4 mg, 0.071 mmol), DMF (0.6 mL), and DIPEA (13 μL, 0.071 mmol).

[0122] 1H NMR (400MHz, DMSO-d6) δ8.49(s, 1H), 8.27-8.08(m, 1H), 7.31-7.06(m, 4H), 5.88(d, J=6.7Hz, 2H), 5.56(d, J=6.3Hz, 1H), 5.37(d, J=4.2Hz, 1H), 4.62(br s, 1H), 4.35(s, 1H), 3.41(dd, J=10.8, 4.0Hz, 1H), 3.04-2.95(m, 1H), 2.90-2.77(m, 2H), 2.45-2.38(m, 1H), 2.20-2.07(m, 1H), 2.03(s, 3H);LCMS m / z 408[M+H] +

[0123] [Example 3] (2R,3R,4S)-2-[2-but-1-ynyl-6-[[(1R)-indan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol [ka]

[0124] (2R,3R,4S)-2-(2-(but-1-yn-1-yl)-6-chloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (30 mg, 0.092 mmol) and (R)-(-)-1-Indanamine (13.5 mg, 0.102 mmol) were dissolved in DMF (0.77 mL), and then DIPEA (18.1 μL, 0.102 mmol) was added. The mixture was stirred at room temperature for 18 hours and at 50°C for 32 hours. After adding DW to the reaction mixture, the mixture was stirred for 30 minutes. The resulting solid was filtered and dried to obtain the title compound as a pale yellow solid (15 mg, 38%).

[0125] 1H NMR (400MHz, DMSO-d6) δ8.51(s, 1H), 8.25-8.10(m, 1H), 7.30-7.07(m, 4H), 5.89(d, J=7.3Hz, 2H), 5.58(br s, 1H), 5.40(br s, 1H), 4.61(br s, 1H), 4.35(br s, 1H), 3.41(dd, J=10.9, 4.2Hz, 1H), 3.05-2.94(m, 1H), 2.91-2.77(m, 2H), 2.46-2.38(m, 3H), 2.22-1.93(m, 1H), 1.17(t, J=7.5Hz, 3H);LCMS m / z 422[M+H] +

[0126] [Example 4] (2R,3R,4S)-2-[2-but-1-ynyl-6-[[(1S)-indan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol [ka]

[0127] The title compound was obtained as a white solid (15 mg, 38%) using the same method as in Example 3, with (2R,3R,4S)-2-(2-(but-1-yn-1-yl)-6-chloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (30 mg, 0.092 mmol), (S)-(+)-1-Indanamine (13.5 mg, 0.102 mmol), DMF (0.77 mL), and DIPEA (18.1 uL, 0.102 mmol).

[0128] 1H NMR (400MHz, DMSO-d6) δ8.52(s, 1H), 8.21(br s, 1H), 7.35-7.03(m, 4H), 5.98-5.83(m, 2H), 5.65-5.51(m, 1H), 5.47-5.31(m, 1H), 4.61(br s, 1H), 4.35(s, 1H), 3.46-3.39(m, 1H), 3.07-2.93(m, 1H), 2.93-2.74(m, 2H), 2.46-2.35(m, 3H), 2.21-2.01(m, 1H), 1.25-1.07(m, 3H);LCMS m / z 422[M+H] +

[0129] [Example 5] (2R,3R,4S)-2-[6-[[(1R)-indan-1-yl]amino]-2-pent-1-ynyl-purin-9-yl]tetrahydrothiophene-3,4-diol [ka]

[0130] (2R,3R,4S)-2-(6-chloro-2-(pent-1-yn-1-yl)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (23 mg, 0.068 mmol) and (R)-(-)-1-Indanamine (10 mg, 0.075 mmol) were dissolved in DMF (0.68 mL), and then DIPEA (14 μL, 0.075 mmol) was added and the mixture was stirred at room temperature for 60 hours. DW was added to the reaction mixture and stirred for 30 minutes, after which the resulting solid was filtered and dried. MeOH was added to the obtained solid, and then filtered and dried to obtain the title compound as a white solid (1.4 mg, 4.7%).

[0131] 1H NMR (400MHz, DMSO-d6) δ8.51(s, 1H), 8.25-8.13(m, 1H), 7.30-7.08(m, 4H), 5.89(d, J=7.0Hz) , 2H), 5.57(d, J=5.8Hz, 1H), 5.38(d, J=4.0Hz, 1H), 4.65-4.57(m, 1H), 4.38-4.32(m, 1H), 3. 41(dd, J=10.9, 4.2Hz, 1H), 3.05-2.96(m, 1H), 2.91-2.77(m, 2H), 2.46-2.42(m, 1H), 2.40(t , J=7.0Hz, 2H), 2.18-2.06(m, 1H), 1.57(dd, J=14.4, 7.4Hz, 2H), 0.99(t, J=7.4Hz, 3H);LCMS m / z 436[M+H] +

[0132] [Example 6] (2R,3R,4S)-2-[6-[[(1S)-indan-1-yl]amino]-2-pent-1-ynyl-purin-9-yl]tetrahydrothiophene-3,4-diol [ka]

[0133] (2R,3R,4S)-2-(6-chloro-2-(pent-1-yn-1-yl)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (40 mg, 0.118 mmol) and (S)-(+)-1-Indanamine (17.3 mg, 0.13 mmol) were dissolved in DMF (0.98 mL), and then DIPEA (23.2 μL, 0.13 mmol) was added. After stirring at 50°C for 64 hours, DW was added to the reaction mixture and stirred for 30 minutes. The resulting solid was filtered and finally washed with DCM. The obtained solid was dried, the filtrate was extracted with DCM, dried with MgSO4, filtered, and concentrated. The concentrated residue was purified by column chromatography (0-2% MeOH / DCM) and combined with the dried solid above to obtain the title compound as a pale yellow solid (26 mg, 51%).

[0134] 1 H NMR (400MHz, DMSO-d6) δ8.51(s, 1H), 8.25-8.09(m, 1H), 7.33-7.00(m, 4H), 5.90(d, J=7.1Hz, 2 H), 5.56(d, J=6.3Hz, 1H), 5.37(d, J=4.1Hz, 1H), 4.60(dd, J=9.6, 7.2Hz, 1H), 4.39-4.29(m, 1H) ), 3.42(dd, J=10.8, 4.0Hz, 1H), 3.06-2.95(m, 1H), 2.92-2.76(m, 2H), 2.48-2.43(m, 1H), 2.40 (t, J=7.1Hz, 2H), 2.21-2.06(m, 1H), 1.57(dd, J=14.5, 7.2Hz, 2H), 0.99(t, J=7.4Hz, 3H);LCMS m / z 436[M+H] +

[0135] [Example 7] (2R,3R,4S)-2-[2-chloro-6-(indan-2-ylamino)purin-9-yl]tetrahydrothiophene-3,4-diol [ka]

[0136] (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (50 mg, 0.163 mmol) and 2-Aminoindan (24 mg, 0.179 mmol) were dissolved in DMF (1.4 mL), and then DIPEA (31 μL, 0.179 mmol) was added. After stirring at 50°C for 24 hours, DW was added to the reaction mixture and stirred for 30 minutes. The resulting solid was filtered and dried to obtain the title compound as a pale yellow solid (17 mg, 26%).

[0137] 1H NMR (400MHz, DMSO-d6) δ8.69-8.58(m, 1H), 8.50(s, 1H), 7.30-7.06(m, 4H), 5.82(d, J=6.5Hz, 1H), 5.58(d, J=6.1Hz, 1H), 5.39(d, J=3.8Hz, 1H), 4.88(dd, J=14.2, 6.9Hz , 1H), 4.60(td, J=7.3, 3.3Hz, 1H), 4.37-4.29(m, 1H), 3.41(dd, J=10.8, 4.0Hz, 1H), 3.26(dd, J=16.3, 8.1Hz, 2H), 3.08-2.92(m, 2H), 2.80(dd, J=10.8, 2.5Hz, 1H);LCMS m / z 404[M+H] +

[0138] [Example 8] (2R,3R,4S)-2-[2-chloro-6-(indan-1-ylamino)purin-9-yl]tetrahydrothiophene-3,4-diol [ka]

[0139] (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (307 mg, 1.00 mmol) and 1-Aminoindan (147 mg, 1.10 mmol) were dissolved in DMF (10 mL), and then DIPEA (197 μL, 1.10 mmol) was added. After stirring at room temperature for 22 hours, DW was added to the reaction mixture and stirred for 30 minutes. The resulting solid was filtered and dried to obtain the title compound as a gray solid (250 mg, 62%).

[0140] 1H NMR (400MHz, DMSO-d6) δ8.71(d, J=8.0Hz, 1H), 8.50(s, 1H), 7.34-7.01(m, 4H), 5.90-5.77(m, 2H), 5.59(d, J=6.1Hz, 1H), 5.40(d, J=3.4Hz, 1H), 4. 67-4.52(m, 1H), 4.40-4.28(m, 1H), 3.42(dd, J=11.0, 3.8Hz, 1H), 3.07-2 .95(m, 1H), 2.91-2.76(m, 2H), 2.47-2.38(m, 1H), 2.22-2.07(m, 1H);LCMS m / z 404[M+H] +

[0141] [Example 9] (2R,3R,4S)-2-[2-chloro-6-[[(1R)-indan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol [ka]

[0142] The title compound was obtained as a pale yellow solid (300 mg, 74%) using the same method as in Example 8, with (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (307 mg, 1.00 mmol), (R)-(-)-1-Indanamine (147 mg, 1.10 mmol), DMF (10 mL), and DIPEA (197 μL, 1.10 mmol).

[0143] 1H NMR (400MHz, DMSO-d6) δ8.71(d, J=8.4Hz, 1H), 8.50(d, J=5.9Hz, 1H), 7.34-7.03(m, 4H), 5.91- 5.72(m, 2H), 5.59(d, J=6.2Hz, 1H), 5.39(d, J=4.0Hz, 1H), 4.62(dd, J=9.6, 7.1Hz, 1H), 4.35(br s, 1H), 3.42(dd, J=10.8, 3.6Hz, 1H), 3.07-2.96(m, 1H), 2.91-2.76(m, 2H), 2.48-2.39(m, 1H), 2.21-2.06(m, 1H);LCMS m / z 404[M+H] +

[0144] [Example 10] (2R,3R,4S)-2-[2-chloro-6-[[(1S)-indan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol [ka]

[0145] The title compound was obtained as a pale yellow solid (41 mg, 62%) using the same method as in Example 7, with (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (50 mg, 0.163 mmol), (S)-(+)-1-Indanamine (24 mg, 0.179 mmol), DMF (1.4 mL), and DIPEA (31 μL, 0.179 mmol).

[0146] 1H NMR (400MHz, DMSO-d6) δ8.71(d, J=8.2Hz, 1H), 8.50(s, 1H), 7.31-7.08(m, 4H), 5.89-5.75(m, 2H), 5.59(d, J=6.0Hz, 1H), 5.40(d, J=4.0Hz, 1H), 4.61(br s, 1H), 4.34(s, 1H), 3.42(dd, J=10.8, 3.9Hz, 1H), 3.07-2.96(m, 1H), 2.90-2.77(m, 2H), 2.47-2.39(m, 1H), 2.21-2.06(m, 1H);LCMS m / z 404[M+H] +

[0147] [Example 11] (2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-methoxyindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol [ka]

[0148] (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (30 mg, 0.098 mmol) and (1R)-4-Methoxy-2,3-dihydro-1H-inden-1-amine hydrochloride (21.5 mg, 0.107 mmol) were dissolved in DMF (0.98 mL), and then DIPEA (37 μL, 0.215 mmol) was added. After stirring at 50°C for 24 hours, DW was added to the reaction mixture and stirred for 30 minutes. The resulting solid was filtered and dried. The obtained solid was dissolved in 0.5 mL of DCM, and then 3 mL of hexane was added and stirred at room temperature for 30 minutes. The resulting solid was filtered and dried to obtain the title compound as a brown solid (18 mg, 42%).

[0149] 1H NMR (400MHz, DMSO-d6) δ8.69(d, J=8.5Hz, 1H), 8.50(d, J=9.0Hz, 1H), 7.13(t, J=7.7Hz, 1H), 6 .81(dd, J=14.8, 7.9Hz, 2H), 5.89-5.74(m, 2H), 5.59(d, J=6.5Hz, 1H), 5.40(d, J=3.7Hz, 1H), 4.67-4.54(m, 1H), 4.34(s, 1H), 3.79(s, 3H), 3.41(dd, J=10.7, 3.3Hz, 1H), 3.02-2.88(m, 1H) , 2.80(dd, J=10.9, 2.5Hz, 1H), 2.76-2.62(m, 1H), 2.47-2.37(m, 1H), 2.18-2.02(m, 1H); LCMS m / z 434[M+H] +

[0150] [Example 12] (2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-methoxyindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol [ka]

[0151] The title compound was obtained as a pale yellow solid (19 mg, 45%) using the same method as in Example 11, with (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (30 mg, 0.098 mmol), (1R)-5-Methoxy-2,3-dihydro-1H-inden-1-amine hydrochloride (21.5 mg, 0.107 mmol), DMF (0.98 mL), and DIPEA (37 μL, 0.215 mmol).

[0152] 1H NMR (400MHz, DMSO-d6) δ8.63(d, J=7.7Hz, 1H), 8.50(d, J=11.0Hz, 1H), 7.07(dd, J=32.9, 8.0Hz, 1 H), 6.83(s, 1H), 6.70(d, J=7.8Hz, 1H), 5.83(d, J=7.5Hz, 1H), 5.72(dd, J=15.3, 7.1Hz, 1H), 5.59( d, J=6.0Hz, 1H), 5.40(d, J=3.9Hz, 1H), 4.65-4.55(m, 1H), 4.34(s, 1H), 3.72(s, 3H), 3.41(dd, J=1 LCMS m / z 434[M+H] +

[0153] [Example 13] (2R,3R,4S)-2-[2-chloro-6-[[(1R)-6-methoxyindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol [ka]

[0154] The title compound was obtained as a pale yellow solid (45 mg, 53%) using the same method as in Example 11, with (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (60 mg, 0.195 mmol), (1R)-6-Methoxy-2,3-dihydro-1H-inden-1-amine hydrochloride (43 mg, 0.215 mmol), DMF (1.95 mL), and DIPEA (74 μL, 0.43 mmol).

[0155] 11H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 8.3 Hz, 1H), 8.51 (d, J = 8.1 Hz, 1H), 7.16 (d, J = 9.0 Hz, 1H), 6.84 - 6.67 (m, 2H), 5.83 (d, J = 7.0 Hz, 1H), 5.74 (dd, J = 15.2, 8.3 Hz, 1H), 5.59 (d, J = 6.2 Hz, 1H), 5.41 (s, 1H), 4.61 (dd, J = 9.4, 7.3 Hz, 1H), 4.34 (s, 1H), 3.66 (s, 3H), 3.42 (dd, J = 10.9, 4.4 Hz, 1H), 3.00 - 2.88 (m, 1H), 2.85 - 2.70 (m, 2H), 2.47 - 2.38 (m, 1H), 2.20 - 2.05 (m, 1H); LCMS m / z 434 [M+H] +

[0156] [Example 14] (2R,3R,4S)-2-[2-chloro-6-[[(1R)-7-methoxyindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol

Chem.

[0157] The title compound was obtained as a pale yellow solid (80 mg, 94%) using (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (60 mg, 0.195 mmol), (1R)-7-Methoxy-2,3-dihydro-1H-inden-1-amine hydrochloride (43 mg, 0.215 mmol), DMF (1.95 mL), and DIPEA (74 μL, 0.43 mmol) in the same manner as in Example 11.

[0158] 1H NMR (400MHz, DMSO-d6) δ8.55-8.29(m, 2H), 7.23(t, J=7.8Hz, 1H), 6.86(d, J=7.5Hz, 1H), 6.77(d, J=8.1Hz, 1H), 5.82(d, J=7.1Hz, 2H), 5.58(d, J=5.5Hz, 1H), 5.40(s, 1H) , 4.67-4.53(m, 1H), 4.34(s, 1H), 3.59(d, J=23.9Hz, 3H), 3.41(dd, J=10.6, 3.3Hz, 1 LCMS m / z 434[M+H] +

[0159] [Example 15] (2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-fluoroindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol [ka]

[0160] The title compound was obtained as a pale yellow solid (44 mg, 54%) using the same method as in Example 11, with (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (60 mg, 0.195 mmol), (R)-4-Fluoroindan-1-amine hydrochloride (40.3 mg, 0.215 mmol), DMF (1.95 mL), and DIPEA (74 μL, 0.43 mmol).

[0161] 1H NMR (400MHz, DMSO-d6) δ8.78(d, J=7.8Hz, 1H), 8.52(d, J=8.4Hz, 1H), 7.20(dd, J=13.2 , 7.6Hz, 1H), 7.11-6.95(m, 2H), 5.83(d, J=6.4Hz, 2H), 5.59(d, J=6.2Hz, 1H), 5.40(d, J=4.0Hz, 1H), 4.61(dd, J=9.9,7.4Hz, 1H), 4.39-4.30(m, 1H), 3.42(dd, J=11.1, 4.0Hz , 1H), 3.13-3.01(m, 1H), 2.92-2.76(m, 2H), 2.47-2.41(m, 1H), 2.25-2.10(m, 1H);LCMS m / z 422[M+H] +

[0162] [Example 16] (2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-fluoroindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol [ka]

[0163] The title compound was obtained as a pale yellow solid (33 mg, 40%) using the same method as in Example 11, with (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (60 mg, 0.195 mmol), (R)-5-Fluoroindan-1-amine hydrochloride (40.3 mg, 0.215 mmol), DMF (1.95 mL), and DIPEA (74 μL, 0.43 mmol).

[0164] 1H NMR (400MHz, DMSO-d6) δ8.73 (d, J=8.4Hz, 1H), 8.51 (d, J=8.8Hz, 1H), 7.21 (dd, J=7.2, 5.7Hz, 1H), 7.10(d, J=8.7Hz, 1H), 6.95(t, J=8.8Hz, 1H), 5.83(d, J=7.3Hz, 1H), 5.75(dd, J=16.5, 8.0Hz, 1H), 5 .59(d, J=5.8Hz, 1H), 5.40(d, J=3.0Hz, 1H), 4.61(td, J=6.9, 3.2Hz, 1H), 4.34(s, 1H), 3.41(dd, J= LCMS m / z 422[M+H] +

[0165] [Example 17] (2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-chloroindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol [ka]

[0166] The title compound was obtained as a gray solid (18.5 mg, 43%) using the same method as in Example 11, with (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (30 mg, 0.098 mmol), (1R)-4-Chloro-2,3-dihydro-1H-inden-1-amine hydrochloride (21.5 mg, 0.107 mmol), DMF (0.98 mL), and DIPEA (37 μL, 0.215 mmol).

[0167] 1H NMR (400MHz, DMSO-d6) δ8.82(d, J=8.9Hz, 1H), 8.52(d, J=8.6Hz, 1H), 7.30(d, J=6 .1Hz, 1H), 7.25-7.06(m, 2H), 5.94-5.79(m, 2H), 5.60(d, J=6.4Hz, 1H), 5.41(d, J= 3.7Hz, 1H), 4.61(dd, J=9.3, 7.4Hz, 1H), 4.34(s, 1H), 3.42(dd, J=11.0, 3.7Hz, 1H) , 3.12-2.99(m, 1H), 2.94-2.76(m, 2H), 2.49-2.44(m, 1H), 2.23-2.09(m, 1H);LCMS m / z 438[M+H] +

[0168] [Example 18] (2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-chloroindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol [ka]

[0169] The title compound was obtained as a pale yellow solid (19.8 mg, 21%) using the same method as in Example 11, with (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (60 mg, 0.195 mmol), (R)-5-Chloro-2,3-dihydro-1H-inden-1-amine (36 mg, 0.215 mmol), DMF (1.95 mL), and DIPEA (37 μL, 0.215 mmol).

[0170] 11H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J = 7.9 Hz, 1H), 8.51 (s, 1H), 7.34 (s, 1H), 7.26 - 7.09 (m, 2H), 5.83 (d, J = 7.0 Hz, 1H), 5.76 (dd, J = 16.4, 7.9 Hz, 1H), 5.58 (d, J = 6.2 Hz, 1H), 5.39 (d, J = 3.6 Hz, 1H), 4.61 (td, J = 7.0, 3.3 Hz, 1H), 4.39 - 4.30 (m, 1H), 3.42 (dd, J = 11.0, 4.0 Hz, 1H), 3.07 - 2.96 (m, 1H), 2.92 - 2.76 (m, 2H), 2.47 - 2.40 (m, 1H), 2.23 - 2.08 (m, 1H); LCMS m / z 438 [M+H] +

[0171] [Example 19] (2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-bromoindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol [Chemical formula]

[0172] The title compound was obtained as a brown solid (54 mg, 45%) using (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (76.2 mg, 0.248 mmol), (R)-4-Bromo-2,3-dihydro-1H-inden-1-amine (58 mg, 0.271 mmol), DMF (2.5 mL), and DIPEA (47 μL, 0.271 mmol) in the same manner as in Example 11.

[0173] 1H NMR (400MHz, DMSO-d6) δ8.82(d, J=8.2Hz, 1H), 8.52(d, J=7.8Hz, 1H), 7.45(d, J=7.6Hz, 1H ), 7.21(d, J=7.4Hz, 1H), 7.11(t, J=7.7Hz, 1H), 5.95-5.80(m, 2H), 5.59(d, J=6.3Hz, 1H), 5 .40(d, J=3.8Hz, 1H), 4.61(td, J=7.2, 3.3Hz, 1H), 4.40-4.29(m, 1H), 3.42(dd, J=10.9, 4. LCMS m / z 482[M+H] +

[0174] [Example 20] (2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-bromoindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol [ka]

[0175] The title compound was obtained as a white solid (28 mg, 59%) using the same method as in Example 11, with (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (30 mg, 0.098 mmol), (R)-5-Bromo-2,3-dihydro-1H-inden-1-amine (22.7 mg, 0.107 mmol), DMF (0.98 mL), and DIPEA (18.3 μL, 0.107 mmol).

[0176] 1H NMR (400MHz, DMSO-d6) δ8.76(d, J=7.7Hz, 1H), 8.51(br s, 1H), 7.48(s, 1H), 7.32(d, J=8.3Hz, 1H), 7.11(dd, J=23.4, 8.5Hz, 1H), 5.83 (d, J=7.0Hz, 1H), 5.75(dd, J=16.2, 7.8Hz, 1H), 5.59(d, J=6.3Hz, 1H), 5.40(d, J=3.6Hz, 1H), 4.67-4.55(m, 1H), 4.34(s, 1H), 3.42(dd, J=10.7, 3.7Hz, 1H), 3. 08-2.96(m, 1H), 2.92-2.75(m, 2H), 2.47-2.38(m, 1H), 2.21-2.09(m, 1H);LCMS m / z 482[M+H] +

[0177] [Example 21] (2R,3R,4S)-2-[2-chloro-6-[[(1R)-6-bromoindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol [ka]

[0178] The title compound was obtained as a white solid (33 mg, 70%) using the same method as in Example 11, with (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (30 mg, 0.098 mmol), (R)-6-Bromo-2,3-dihydro-1H-inden-1-amine (22.7 mg, 0.107 mmol), DMF (0.98 mL), and DIPEA (18.3 μL, 0.107 mmol).

[0179] 1H NMR (400MHz, DMSO-d6) δ8.80(d, J=8.8Hz, 1H), 8.52(d, J=7.6Hz, 1H), 7.40(d, J=7.3Hz, 1H ), 7.34(s, 1H), 7.24(d, J=7.7Hz, 1H), 5.81(dd, J=20.2, 7.9Hz, 2H), 5.59(d, J=6.5Hz, 1H), 5.40(d, J=3.7Hz, 1H), 4.62(td, J=7.0, 3.3Hz, 1H), 4.39-4.30(m, 1H), 3.42(dd, J=11.0, 4. LCMS m / z 482[M+H] +

[0180] [Example 22] (2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-methylindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol [ka]

[0181] The title compound was obtained as a brown solid (22 mg, 54%) using the same method as in Example 11, with (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (30 mg, 0.098 mmol), (R)-4-Methyl-indan-1-ylamine hydrochloride (21.5 mg, 0.107 mmol), DMF (0.98 mL), and DIPEA (37 μL, 0.215 mmol).

[0182] 1H NMR (400MHz, DMSO-d6) δ8.68(d, J=8.1Hz, 1H), 8.50(d, J=6.8Hz, 1H), 7.13-6 .89(m, 3H), 5.89-5.75(m, 2H), 5.65-5.55(m, 1H), 5.40(d, J=4.0Hz, 1H), 4.61 (t, J=8.4Hz, 1H), 4.34(s, 1H), 3.42(dd, J=10.8, 3.8Hz, 1H), 3.03-2.91(m, 1H) ), 2.85-2.69(m, 2H), 2.47-2.39(m, 1H), 2.24(s, 3H), 2.17-2.03(m, 1H);LCMS m / z 418[M+H] +

[0183] [Example 23] (2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-(trifluoromethyl)indan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol [ka]

[0184] The title compound was obtained as a pale yellow solid (18 mg, 39%) using the same method as in Example 11, with (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (30 mg, 0.098 mmol), (1R)-4-(trifluoromethyl)-2,3-Dihydro-1H-inden-1-amine (22 mg, 0.107 mmol), DMF (0.98 mL), and DIPEA (18.3 μL, 0.107 mmol).

[0185] 1H NMR (400MHz, DMSO-d6) δ8.82(d, J=8.1Hz, 1H), 8.52(br s, 1H), 7.58(d, J=7.8Hz, 1H), 7.50(d, J=7.3Hz, 1H), 7.38(t, J=7.4Hz, 1H), 5.85(t, J=7.7Hz, 2H), 5.60(d, J=5.0Hz, 1H), 5.42(d, J=3.5Hz, 1H), 4.61(br s, 1H), 4.34(s, 1H), 3.42(dd, J=10.5, 3.8Hz, 1H), 3.25-3.13(m, 1H), 3.06-2.94 (m, 1H), 2.86-2.75(m, J=10.5Hz, 1H), 2.58-2.52(m, 1H), 2.27-2.13(m, 1H);LCMS m / z 472[M+H] +

[0186] [Example 24] (1R)-1-[[2-chloro-9-[(2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl]purin-6-yl]amino]indane-4-carbonitrile [ka]

[0187] The title compound was obtained as a white solid (22 mg, 52%) using the same method as in Example 11, with (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (30 mg, 0.098 mmol), (R)-1-Amino-2,3-dihydro-1H-indene-4-carbonitrile hydrochloride (21 mg, 0.107 mmol), DMF (0.98 mL), and DIPEA (37 μL, 0.215 mmol).

[0188] 1H NMR (400MHz, DMSO-d6) δ8.85(d, J=8.1Hz, 1H), 8.52(br s, 1H), 7.70(d, J=7.7Hz, 1H), 7.51(dd, J=23.4, 8.0Hz, 1H), 7.36(t, J=7.6Hz, 1H), 5.93-5.79(m, 2H), 5.60(d, J=5.6Hz, 1H), 5.42(s, 1H), 4.61(br s, 1H), 4.34(s, 1H), 3.42(dd, J=10.5, 3.9Hz, 1H), 3.22-3.11(m, 1H), 3.10-2. 97(m, 1H), 2.80(d, J=10.3Hz, 1H), 2.59-2.52(m, 1H), 2.27-2.13(m, 1H);LCMS m / z 429[M+H] +

[0189] [Example 25] (R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purin-6-yl)amino)-2,3-dihydro-1H-indene-4-carboxamide [ka]

[0190] (1R)-1-[[2-chloro-9-[(2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl]purin-6-yl]amino]indane-4-carbonitrile (10 mg, 0.023 mmol) was dissolved in DMSO (0.1 mL), and then K2CO3 (5.7 mg, 0.042 mmol) and H2O2 (35% in H2O, 33 μL) were added. After stirring at room temperature for 2 hours, the mixture was diluted with ethyl acetate and washed with dark water. The organic layer was dried over MgSO4, filtered, and concentrated. The resulting residue was purified by prep TLC (5% MeOH / DCM) to obtain the title compound as a white solid (3.2 mg, 32%).

[0191] 1H NMR (400MHz, DMSO-d6) δ8.75(d, J=8.5Hz, 1H), 8.50(s, 1H), 7.72(s, 1H), 7.52(d, J=7.4Hz, 1H) ), 7.30(d, J=8.2Hz, 2H), 7.24-7.17(m, 1H), 5.90-5.74(m, 2H), 5.59(d, J=5.7Hz, 1H), 5.40(d, J=3.6Hz, 1H), 4.67-4.56(m, 1H), 4.34(s, 1H), 3.42(dd, J=10.6, 4.0Hz, 1H), 3.29-3.22(m, 1H) ), 3.09-2.95(m, 1H), 2.80(dd, J=11.1, 2.2Hz, 1H), 2.47-2.37(m, 1H), 2.18-2.02(m, 1H);LCMS m / z 447[M+H] +

[0192] [Example 26] (2R,3R,4S)-2-[2-chloro-6-[[(1R)-7-bromoindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol [ka]

[0193] (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (60 mg, 0.195 mmol) and (1R)-7-Bromoindanylamine (45.6 mg, 0.215 mmol) were dissolved in 1,4-dioxane (2 mL), and then DIPEA (37 μL, 0.215 mmol) was added. After stirring at 50°C for 42.5 hours, the reaction mixture was concentrated under reduced pressure. DCM was added to the resulting solid, and then the mixture was filtered and dried to obtain the title compound as a white solid (54 mg, 57%).

[0194] 1H NMR (400MHz, DMSO-d6) δ8.75(d, J=8.9Hz, 1H), 8.45(s, 1H), 7.39(d, J=7.3Hz, 1H), 7.30 (d, J=7.1Hz, 1H), 7.21(t, J=7.6Hz, 1H), 5.82(d, J=7.0Hz, 2H), 5.64-5.53(m, 1H), 5.45 -5.34(m, 1H), 4.61(s, 1H), 4.34(s, 1H), 3.41(dd, J=10.4, 3.8Hz, 1H), 3.29-3.14(m, 1H) ), 2.95-2.84(m, 1H), 2.80(d, J=10.8Hz, 1H), 2.48-2.41(m, 1H), 2.10-1.93(m, 1H);LCMS m / z 482[M+H] +

[0195] [Example 27] (2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-methylindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol [ka]

[0196] The title compound was obtained as a white solid (63 mg, 77%) using the same method as in Example 26, with (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (60 mg, 0.195 mmol), (1R)-5-methyl-2,3-dihydro-1H-indan-1-amine (32 mg, 0.215 mmol), DMF (1.95 mL), and DIPEA (37 μL, 0.215 mmol).

[0197] 1H NMR (400MHz, DMSO-d6) δ8.66(d, J=8.4Hz, 1H), 8.49(s, 1H), 7.07(s, 2H), 6.94(d, J=7.5Hz, 1H), 5.89-5.80(m, 1H), 5.75(dd, J=16.0, 7.6Hz, 1H), 5.66-5.54(m, 1H), 5.41(s, 1H), 4.62(s, 1H), 4.34(s, 1H), 3.41(dd, J=10.9, 4.0Hz, 1H), 3.03-2.91( LCMS m / z 418[M+H] +

[0198] [Example 28] (2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-(trifluoromethyl)indan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol [ka]

[0199] (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (60 mg, 0.195 mmol) and (R)-5-(Trifluoromethyl)-2,3-Dihydro-1H-inden-1-Amine Hydrochloride (43.3 mg, 0.215 mmol) were dissolved in 1,4-dioxane (2 mL), and then DIPEA (74 μL, 0.43 mmol) was added and the mixture was stirred at 50°C for 42.5 hours. After concentrating the reaction mixture under reduced pressure, the resulting residue was purified by column chromatography (0-1% MeOH in DCM), and recrystallized in DCM to obtain the title compound as a white solid (21 mg, 23%).

[0200] 1H NMR (400MHz, DMSO-d6) δ8.82(d, J=8.2Hz, 1H), 8.52(s, 1H), 7.63(s, 1H), 7.50(d, J=8.0 Hz, 1H), 7.39(d, J=7.6Hz, 1H), 5.85(t, J=7.3Hz, 2H), 5.59(d, J=5.7Hz, 1H), 5.40(s, 1H) ), 4.66-4.58(m, 1H), 4.35(s, 1H), 3.42(dd, J=10.5, 4.0Hz, 1H), 3.15-3.03(m, 1H), 3.0 1-2.88(m, 1H), 2.81(dd, J=11.0, 2.5Hz, 1H), 2.62-2.54(m, 1H), 2.28-2.02(m, 1H);LCMS m / z 472[M+H] +

[0201] [Example 29] (1R)-1-[[2-chloro-9-[(2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl]purin-6-yl]amino]indane-5-carbonitrile [ka]

[0202] The title compound was obtained as a pale yellow solid (54 mg, 64%) using the same method as in Example 28, with (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (60 mg, 0.195 mmol), (1R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile (34 mg, 0.215 mmol), DIPEA (37 μL, 0.215 mmol), and 1,4-dioxane (2 mL).

[0203] 1H NMR (400MHz, DMSO-d6) δ8.84(d, J=8.4Hz, 1H), 8.52(s, 1H), 7.75(s, 1H), 7.60(d, J=7. 9Hz, 1H), 7.37(d, J=7.8Hz, 1H), 5.84(d, J=6.7Hz, 2H), 5.59(d, J=6.2Hz, 1H), 5.41(s, 1H), 4.61(s, 1H), 4.35(s, 1H), 3.42(dd, J=10.9, 3.9Hz, 1H), 3.10-3.01(m, 1H), 2.98- 2.86(m, 1H), 2.80(dd, J=10.9, 2.5Hz, 1H), 2.49-2.40(m, 1H), 2.25-2.01(m, 1H);LCMS m / z 429[M+H] +

[0204] [Example 30] Methyl(R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purin-6-yl)amino)-2,3-dihydro-1H-indene-4-carboxylate [ka]

[0205] The title compound was obtained as a pale yellow solid (50 mg, 56%) using the same method as in Example 11, with (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (60 mg, 0.195 mmol), methyl(1R)-1-amino-2,3-dihydro-1H-indene-4-carboxylate hydrochloride (49 mg, 0.215 mmol), DMF (1.95 mL), and DIPEA (74 μL, 0.43 mmol).

[0206] 1H NMR (400MHz, DMSO-d6) δ8.79(d, J=8.3Hz, 1H), 8.51(s, 1H), 7.82(d, J=7.1Hz, 1H), 7.4 6(d, J=7.7Hz, 1H), 7.31(t, J=7.7Hz, 1H), 5.83(d, J=7.8Hz, 2H), 5.59(d, J=7.0Hz, 1H), 5.40(d, J=3.6Hz, 1H), 4.66-4.57(m, 1H), 4.35(s, 1H), 3.85(s, 3H), 3.49-3.36(m, 2H) , 3.15-3.02(m, 1H), 2.81(d, J=10.9Hz, 1H), 2.47-2.43(m, 1H), 2.23-1.96(m, 1H); LCMS m / z 462[M+H] +

[0207] [Example 31] Methyl(R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purin-6-yl)amino)-2,3-dihydro-1H-indene-5-carboxylate [ka]

[0208] The title compound was obtained as a brown solid (72 mg, 80%) using the same method as in Example 11, with (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (60 mg, 0.195 mmol), methyl(1R)-1-amino-2,3-dihydro-1H-indene-5-carboxylate hydrochloride (49 mg, 0.215 mmol), DMF (1.95 mL), and DIPEA (74 μL, 0.43 mmol).

[0209] 11H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 8.6 Hz, 1H), 8.51 (s, 1H), 7.86 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 5.85 (t, J = 6.9 Hz, 2H), 5.59 (d, J = 5.8 Hz, 1H), 5.40 (d, J = 4.1 Hz, 1H), 4.62 (s, 1H), 4.35 (s, 1H), 3.84 (s, 3H), 3.42 (dd, J = 11.0, 3.9 Hz, 1H), 3.12 - 3.00 (m, 1H), 2.99 - 2.85 (m, 1H), 2.81 (dd, J = 11.0, 2.3 Hz, 1H), 2.47 - 2.44 (m, 1H), 2.27 - 2.00 (m, 1H); LCMS m / z 462 [M + H] +

[0210] [Example 32] (R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purin-6-yl)amino)-2,3-dihydro-1H-indene-4-carboxylic acid [Chemical formula]

[0211] To Methyl (R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purin-6-yl)amino)-2,3-dihydro-1H-indene-4-carboxylate (30 mg, 0.065 mmol), MeOH (0.65 mL) and 2M NaOH (0.163 mL) were added. After stirring at room temperature for 2 hours, THF (0.5 mL) and 2M NaOH (33 μL) were added and stirring was continued for an additional 7 hours. After adding IM HCl to the reaction mixture, the resulting solid was filtered and dried to obtain the title compound as an orange solid (22 mg, 76%).

[0212] 1H NMR (400MHz, DMSO-d6) δ12.83(s, 1H), 8.80(d, J=8.1Hz, 1H), 8.51(s, 1H), 7.83(s, 1H) ), 7.75(d, J=8.1Hz, 1H), 7.28(d, J=7.8Hz, 1H), 5.84(d, J=7.0Hz, 2H), 5.60(s, 1H), 5 .41(s, 1H), 4.62(s, 1H), 4.35(s, 1H), 3.42(dd, J=10.9, 3.9Hz, 1H), 3.06(dd, J=14.8 , 8.3Hz, 1H), 2.97-2.85(m, 1H), 2.81(dd, J=10.9, 2.5Hz, 1H), 2.26-1.98(m, 1H); LCMS m / z 448[M+H] +

[0213] [Example 33] (R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purin-6-yl)amino)-2,3-dihydro-1H-indene-5-carboxylic acid [ka]

[0214] The title compound was obtained as a brown solid (21 mg, 72%) using Methyl(R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purin-6-yl)amino)-2,3-dihydro-1H-indene-5-carboxylate (30 mg, 0.065 mmol), MeOH (0.65 mL), THF (0.5 mL), and 2M NaOH (0.163 mL) in the same manner as in Example 32.

[0215] 1H NMR (400MHz, DMSO-d6) δ12.87(s, 1H), 8.77(d, J=8.3Hz, 1H), 8.50(s, 1H), 7. 81(d, J=7.7Hz, 1H), 7.42(d, J=7.2Hz, 1H), 7.27(t, J=7.7Hz, 1H), 5.91-5.76 (m, 1H), 5.60(s, 1H), 5.40(s, 1H), 4.62(s, 1H), 4.35(s, 1H), 3.51-3.39(m, 2 LCMS m / z 448[M+H] +

[0216] [Example 34] (R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purin-6-yl)amino)-2,3-dihydro-1H-indene-5-carboxamide [ka]

[0217] (1R)-1-[[2-chloro-9-[(2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl]purin-6-yl]amino]indane-5-carbonitrile (25 mg, 0.058 mmol) was dissolved in DMSO (0.3 mL), and then K2CO3 (14.3 mg, 0.105 mmol) and H2O2 (35% in H2O, 82.5 μL) were added. After stirring at room temperature for 2 hours, the mixture was diluted with ethyl acetate and washed with dark water. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The resulting residue was purified by column chromatography (0-3% MeOH / DCM) to obtain the title compound as a white solid (10 mg, 38%).

[0218] 11H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J = 7.8 Hz, 1H), 8.51 (s, 1H), 7.90 (s, 1H), 7.76 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.34 - 7.15 (m, 2H), 5.91 - 5.76 (m, 2H), 5.58 (d, J = 6.4 Hz, 1H), 5.39 (d, J = 4.0 Hz, 1H), 4.61 (s, 1H), 4.35 (s, 1H), 3.42 (dd, J = 10.7, 4.0 Hz, 1H), 3.17 (d, J = 5.2 Hz, 1H), 3.09 - 2.97 (m, 1H), 2.95 - 2.84 (m, 1H), 2.81 (dd, J = 11.0, 2.1 Hz, 1H), 2.26 - 1.98 (m, 1H); LCMS m / z 447 [M+H] +

[0219] [Example 35] (2R,3R,4S)-2-(2-chloro-6-((1,2,3,4-tetrahydronaphthalen-2-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol [Chemical formula]

[0220] (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (60 mg, 0.195 mmol) and 1,2,3,4-Tetrahydronaphthalen-2-amine hydrochloride (39.5 mg, 0.215 mmol) were dissolved in DMF (1.95 mL), and then DIPEA (74 μL, 0.43 mmol) was added. After stirring at 50 °C for 20 hours, DW was added, and after stirring for 30 minutes, it was filtered and dried. The obtained solid was dissolved in DCM, washed with DW, dried over MgSO4, filtered, and concentrated to obtain the title compound as a pale yellow solid (26 mg, 32%).

[0221] 1H NMR (400MHz, DMSO-d6) δ8.50 (s, 1H), 8.40 (d, J=7.9Hz, 1H), 7.16-7.02 (m, 4H), 5. 82(d, J=7.2Hz, 1H), 5.58(d, J=6.2Hz, 1H), 5.39(d, J=3.8Hz, 1H), 4.61(s, 1H), 4.4 0(s, 1H), 4.34(s, 1H), 3.41(dd, J=10.8, 3.3Hz, 1H), 3.17-2.98(m, 1H), 2.98-2.8 3(m, 3H), 2.80(dd, J=10.9, 2.3Hz, 1H), 2.18-1.98(m, 1H), 1.96-1.70(m, 1H);LCMS m / z 418[M+H] +

[0222] [Example 36] (2R,3R,4S)-2-(2-chloro-6-(((S)-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol [ka]

[0223] (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (60 mg, 0.195 mmol) and (S)-1,2,3,4-Tetrahydronaphthalen-2-amine (31.7 mg, 0.215 mmol) were dissolved in DCM (2 mL), and then DIPEA (37 μL, 0.215 mmol) was added. After stirring at room temperature for 41.5 hours and at 45°C for 4 hours, the reaction mixture was diluted with DCM and washed with DW. The organic layer was dried over MgSO4, filtered, and concentrated. The resulting residue was purified by column chromatography (0-1% MeOH / DCM) to obtain the title compound as an orange solid (46 mg, 56%).

[0224] 1H NMR (400MHz, DMSO-d6) δ8.50(s, 1H), 8.41(d, J=7.9Hz, 1H), 7.10(dd, J=6.6, 3.4Hz, 4H), 5.82(d, J=7.4Hz, 1H), 5.58(d, J=6.2Hz, 1H), 5.39(d, J=4.0Hz, 1H), 4.60(s, 1H) , 4.41(s, 1H), 4.34(s, 1H), 3.41(dd, J=10.6, 3.7Hz, 1H), 3.19-2.98(m, 1H), 2.97-2 .83(m, 3H), 2.80(dd, J=11.0, 1.7Hz, 1H), 2.18-2.00(m, 1H), 1.94-1.70(m, 1H);LCMS m / z 418[M+H] +

[0225] [Example 37] (2R,3R,4S)-2-(2-chloro-6-(((R)-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol [ka]

[0226] The title compound was obtained as a brown solid (56 mg, 69%) using the same method as in Example 35, with (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (60 mg, 0.195 mmol), (R)-1,2,3,4-Tetrahydronaphthalen-2-amine (31.7 mg, 0.215 mmol), DMF (1.95 mL), and DIPEA (37 μL, 0.215 mmol).

[0227] 1H NMR (400MHz, DMSO-d6) δ8.50(s, 1H), 8.40(d, J=7.8Hz, 1H), 7.18-6.99(m, 4H ), 5.82(d, J=7.2Hz, 1H), 5.58(d, J=6.3Hz, 1H), 5.39(d, J=4.0Hz, 1H), 4.60( s, 1H), 4.48-4.26(m, 2H), 3.41(d, J=9.8Hz, 1H), 3.18-2.99(m, 1H), 2.99-2. 83(m, 3H), 2.80(d, J=9.2Hz, 1H), 2.19-1.96(m, 1H), 1.94-1.71(m, 1H);LCMS m / z 418[M+H] +

[0228] [Example 38] (2R,3R,4S)-2-(2-chloro-6-((1,2,3,4-tetrahydronaphthalen-1-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol [ka]

[0229] The title compound was obtained as a yellow solid (30 mg, 37%) using the same method as in Example 35, with (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (60 mg, 0.195 mmol), 1,2,3,4-Tetrahydro-1-naphthylamine (31.7 mg, 0.215 mmol), DMF (1.95 mL), and DIPEA (37 μL, 0.215 mmol).

[0230] 1H NMR (400MHz, DMSO-d6) δ8.64(d, J=8.6Hz, 1H), 8.49(s, 1H), 7.22-7.03(m, 4H), 5.83(d, J=7.0Hz, 1H), 5.59(d, J=6.2Hz, 1H), LCMS m / z 418[M+H] +

[0231] [Example 39] (2R,3R,4S)-2-(2-chloro-6-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol [ka]

[0232] The title compound was obtained as a yellow solid (44 mg, 54%) using the same method as in Example 35, with (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (60 mg, 0.195 mmol), (R)-1,2,3,4-Tetrahydronaphthalen-1-amine (31.7 mg, 0.215 mmol), DMF (1.95 mL), and DIPEA (37 μL, 0.215 mmol).

[0233] 1H NMR (400MHz, DMSO-d6) δ8.64(d, J=8.8Hz, 1H), 8.57-8.42(m, 1H), 7.23-7.01(m, 4H), 5.83(d, J=7.2Hz, 1H), 5.59(d, J=6.0Hz, 1H), 5. LCMS m / z 418[M+H] +

[0234] [Example 40] (2R,3R,4S)-2-(2-chloro-6-(((S)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol [ka]

[0235] The reaction was carried out in the same manner as in Example 35, using (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (60 mg, 0.195 mmol), (S)-1,2,3,4-Tetrahydronaphthalen-1-amine (31.7 mg, 0.215 mmol), DMF (1.95 mL), and DIPEA (37 μL, 0.215 mmol). The resulting residue was purified by column chromatography (0-1% MeOH / DCM) to obtain the title compound as a pale yellow solid (45 mg, 55%).

[0236] 1H NMR (400MHz, DMSO-d6) δ8.65(d, J=8.9Hz, 1H), 8.49(s, 1H), 7.23-7.02(m, 4H), 5.83(d, J=7.3Hz, 1H), 5.59(d, J=6.3Hz, 1H), 5.51 LCMS m / z 418[M+H] +

[0237] [Example 41] (2R,3R,4S)-2-(6-(((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)amino)-2-chloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol [ka]

[0238] (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (100 mg, 0.326 mmol) and Bicyclo[4.2.0]octa-1(6), 2,4-trien-7-amine hydrochloride (58.4 mg, 0.375 mmol) were dissolved in DCM (3 mL), and then DIPEA (128 μL, 0.75 mmol) was added. After stirring at room temperature for 24 hours, the reaction mixture was diluted with DCM and washed with DW. The organic layer was dried over MgSO4, filtered, and concentrated. The resulting residue was purified by column chromatography (0-1% MeOH / DCM) to obtain the title compound as a white solid (90 mg, 71%).

[0239] 1H NMR (400MHz, DMSO-d6) δ9.09(d, J=6.0Hz, 1H), 8.51(s, 1H), 7.38-7.04(m, 4H), 5.84(d, J=7.2Hz, 1H), 5.59(d, J=5.2Hz, 2H), 5 .40(d, J=3.9Hz, 1H), 4.61(s, 1H), 4.34(s, 1H), 3.63(dd, J=14.8, 4.5Hz, 1H), 3.48-3.35(m, 2H), 2.81(d, J=11.5Hz, 1H);LCMS m / z 390[M+H] +

[0240] [Example 42] (2R,3R,4S)-2-(2-chloro-6-((6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol [ka]

[0241] The title compound was obtained as a white solid (42 mg, 50%) using the same method as in Example 41, with (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (60 mg, 0.195 mmol), 6,7,8,9-Tetrahydro-5H-benzo[7]annulen-5-amine (34.6 mg, 0.215 mmol), DCM (2 mL), and DIPEA (37 μL, 0.215 mmol).

[0242] 1H NMR (400MHz, DMSO-d6) δ8.93(d, J=8.4Hz, 1H), 8.55(d, J=3.9Hz, 1H), 7.35-6.98(m, 4H), 5.88-5.76(m, 1H), 5.58(d, J=5.9Hz, 1H) ), 5.49-5.30(m, 2H), 4.62(s, 1H), 4.35(s, 1H), 3.42(d, J=11.0Hz, 1H), 3.03-2.69(m, 3H), 2.15-1.55(m, 5H), 1.27(s, 1H);LCMS m / z 432[M+H] +

[0243] [Example 43] (2R,3R,4S)-2-(2-chloro-6-((6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol [ka]

[0244] The title compound was obtained as a white solid (38 mg, 45%) using the same method as in Example 41, with (2R,3R,4S)-2-(2,6-dichloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (60 mg, 0.195 mmol), 6,7,8,9-Tetrahydro-5H-benzocyclohepten-7-ylamine Hydrochloride (42.5 mg, 0.215 mmol), DCM (2 mL), and DIPEA (74 μL, 0.43 mmol).

[0245] 1H NMR (400MHz, DMSO-d6) δ8.46(s, 1H), 8.29(d, J=8.8Hz, 1H), 7.24-7.00(m, 4H), 5.81(d, J=7.2Hz, 1H), 5.57(d, J=6.1Hz, 1H), 5.38 LCMS m / z 432[M+H] +

[0246] [Example 44] (2R,3R,4S)-2-(6-(((R)-2,3-dihydro-1H-inden-1-yl)amino)-2-iodo-9H-purin-9-yl)tetrahydrothiophene-3,4-diol Step 1: (2R,3R,4S)-2-(6-chloro-2-iodo-9H-purin-9-yl)tetrahydrothiophene-3,4-diol [ka]

[0247] The title compound was obtained as a white solid (57 mg, 42%) using 6-chloro-9-((3aR,4R,6aS)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-2-iodo-9H-purine (150 mg, 0.342 mmol) and 80% HCOOH (6.8 mL) in the same manner as in Preparation Example 6.

[0248] 1H NMR (400MHz, DMSO-d6) δ8.99(s, 1H), 5.91(d, J=7.3Hz, 1H), 5.64(d, J=5.8Hz, 1H), 5.45(d, J=4.0Hz, 1H), 4.6 1(td, J=6.7, 3.2Hz, 1H), 4.39-4.31(m, 1H), 3.45(dd, J=10.8, 3.9Hz, 1H), 2.82(dd, J=10.8, 2.4Hz, 1H);LCMS m / z 399[M+H] +

[0249] Step 2: (2R,3R,4S)-2-(6-(((R)-2,3-dihydro-1H-inden-1-yl)amino)-2-iodo-9H-purin-9-yl)tetrahydrothiophene-3,4-diol [ka]

[0250] (2R,3R,4S)-2-(6-chloro-2-iodo-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (55 mg, 0.138 mmol) and (R)-(-)-1-Aminoindane (20.2 mg, 0.152 mmol) were dissolved in DMF (1.38 mL), and then DIPEA (26 μL, 0.152 mmol) was added. After stirring at room temperature for 63.5 hours, DW was added and the mixture was stirred for 30 minutes. The resulting solid was filtered, dissolved in 0.5 mL of DCM, and 3 mL of hexane was added, and the mixture was stirred at room temperature for 30 minutes. The resulting solid was filtered and dried to obtain the title compound as a yellow solid (42.6 mg, 62%).

[0251] 1H NMR (400MHz, DMSO-d6) δ8.54(d, J=7.8Hz, 1H), 8.42(s, 1H), 7.33-7.07(m, 4 H), 5.82(d, J=7.3Hz, 1H), 5.76(d, J=7.2Hz, 1H), 5.58(d, J=5.9Hz, 1H), 5.40 (s, 1H), 4.65-4.54(m, 1H), 4.34(s, 1H), 3.41(dd, J=10.9, 3.4Hz, 1H), 3.06 -2.96(m, 1H), 2.90-2.78(m, 2H), 2.47-2.37(m, 1H), 2.21-1.95(m, 1H); LCMS m / z 496[M+H] +

[0252] [Example 45] (2R,3R,4S)-2-(6-(((R)-2,3-dihydro-1H-inden-1-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol Step 1: (2R,3R,4S)-2-(6-chloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol [ka]

[0253] The title compound was obtained as a white solid (180 mg, 40%) using 6-chloro-9-((3aR,4R,6aS)-2,2-dimethyltetrahydrothieno[3,4-d][1,3]dioxol-4-yl)-9H-purine (510 mg, 1.63 mmol) and 80% HCOOH (32 mL) in the same manner as in Preparation Example 6. LCMS m / z 273[M+H] +

[0254] Step 2: (2R,3R,4S)-2-(6-(((R)-2,3-dihydro-1H-inden-1-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol [ka]

[0255] (2R,3R,4S)-2-(6-chloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol (25 mg, 0.092 mmol) and (R)-(-)-1-Aminoindane (13.4 mg, 0.101 mmol) were dissolved in DMF (1 mL), and then DIPEA (17.1 μL, 0.101 mmol) was added. After stirring at room temperature for 61.5 hours, DW was added to the reaction mixture and extracted with EA. The organic layer was dried over MgSO4, filtered, and concentrated. The resulting residue was purified by column chromatography (0-1% MeOH / DCM) to obtain the title compound as a pale yellow solid (6 mg, 18%).

[0256] 1 H NMR (400MHz, DMSO-d6) δ8.44(s, 1H), 8.28(s, 1H), 8.08(s, 1H), 7.26(d, J=7.5Hz, 1H) , 7.23-7.08(m, 3H), 5.93(d, J=7.1Hz, 2H), 5.55(d, J=6.2Hz, 1H), 5.36(d, J=3.9Hz, 1H ), 4.70(dd, J=9.1, 6.9Hz, 1H), 4.43-4.30(m, 1H), 3.42(dd, J=10.8, 4.0Hz, 1H), 3.01( dd, J=15.5, 8.9Hz, 1H), 2.90-2.76(m, 2H), 2.47-2.40(m, 1H), 2.20-2.04(m, 1H);LCMS m / z 370[M+H] +

[0257] Test Example 1. Suppression of Endothelial Cell Transition Phenomenon by Radiation Using Immunofluorescence Staining The test substances (Examples 1 to 45) were prepared by treating a 10 mM DMSO solution at a ratio of 1 μL per 1 mL of cell culture medium to a final concentration of 10 μM. The test substances were pre-treated with human vascular endothelial cell lines (Promocell, Germany) for 1 hour before irradiation, and then irradiated at an intensity of 10 Gy. 72 hours after irradiation, the human vascular endothelial cell lines were fixed with 10% formalin, and experiments were performed using palloidin (Invitrogen, USA) according to the manufacturer's method to confirm the increase in cytoskeleton filaments during fibrosis. Palloidin is a protein that binds to actin in cytoskeletal filaments, and palloidin bound to FITC fluorescent agent was used to make the cytoskeletal filaments appear green during microscopic observation.

[0258] After processing the test material, the area, length, and density of phalloidin were measured using a confocal microscope, and the relative percentages were shown with the group irradiated with 10 Gy alone (IR group) set to 100% (Tables 1-3).

[0259] [Table 1]

[0260] [Table 2]

[0261] [Table 3]

[0262] ++++:<20% +++: 20%~50% ++: 50%~80% +:>80%

[0263] As can be seen from Tables 1-3, phalloidin was hardly observed in the group that was not irradiated (No IR group), but phalloidin increased significantly in the irradiated group (IR group). When treated with the compound according to the present invention, although there were differences in degree, it was shown that the increase in phalloidin caused by radiation was suppressed in all cases, confirming that the compound according to the present invention can reduce the conversion of endothelial cells to mesenchymal cells (EndMT) caused by radiation.

[0264] Through the results described above, it was found that the compound according to the present invention can exert an EndMT inhibitory effect and a preventive or therapeutic effect against diseases related to EndMT activity (e.g., lung diseases) when treated with the compound.

[0265] National research and development project that supported this invention [Project-Specific Number] 1711187521 [Issue Number] NRF-2020M2D9A2093963 [Department Name] Department of Science, Technology and ICT [Project Management (Specialized) Institution Name] Korea Research Foundation [Research Project Name] Nuclear Research and Development Project - Advanced Radiation Fusion Therapy Technology Development Project [Research Project Title] Development of Leading Technology Platform for Targeted Therapies for Radiation-Induced Pulmonary Fibrosis [Contribution Rate] 1 / 1 [Project Implementation Organizations] Korea Institute of Nuclear Medicine, NextGen Bioscience Co., Ltd., Yonsei University [Research Period] 2020.07.31~2023.12.31

Claims

1. Compounds represented by the following chemical formula (1), their optical isomers, their racemic mixtures, their hydrates, their solvates, or their pharmaceutically acceptable salts: Chemical formula (1) 【Chemistry 1】 R １ This is a substituted or unsubstituted bicyclic fused ring formed by the fusion of an aryl ring and a non-aromatic cycloalkyl ring. R ２ These are hydrogen (H), halogen (X), or an alkynyl group.

2. The compound according to claim 1, wherein the bicyclic fused ring is benzocycloalkyl, an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

3. The aforementioned substituted bicyclic fused ring has one or more hydrogens from the aryl ring and the non-aromatic cycloalkyl ring independently of C １－６ Alkoxy, halogen, C １－６ Alkyl, CF ３ , CN, CO ２ Me, CONH ２ The compound according to claim 1, or substituted with COOH, its optical isomer, its racemic mixture, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the alkynyl group is an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a 3-butynyl group, a 1-methyl-2-butynyl group, a 2-methyl-3-pentynyl group, a 1-hexynyl group, or a 1,1-dimethyl-2-butynyl group.

5. The compound is selected from the following group: the compound described in claim 1, its optical isomer, its racemic mixture, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof: (1) (2R,3R,4S)-2-[6-[[(1R)-indan-1-yl]amino]-2-prop-1-inyl-purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[6-[[(1R)-indan-1-yl]amino]-2-prop-1-ynyl-purin-9-yl]tetrahydrothiophene-3,4-diol); (2) (2R,3R,4S)-2-[6-[[(1S)-indan-1-yl]amino]-2-prop-1-inyl-purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[6-[[(1S)-indan-1-yl]amino]-2-prop-1-ynyl-purin-9-yl]tetrahydrothiophene-3,4-diol); (3) (2R,3R,4S)-2-[2-but-1-ynyl-6-[[(1R)-indan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[2-but-1-ynyl-6-[[(1R)-indan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol); (4) (2R,3R,4S)-2-[2-but-1-ynyl-6-[[(1S)-indan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[2-but-1-ynyl-6-[[(1S)-indan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol); (5) (2R,3R,4S)-2-[6-[[(1R)-indan-1-yl]amino]-2-pent-1-inyl-purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[6-[[(1R)-indan-1-yl]amino]-2-pent-1-ynyl-purin-9-yl]tetrahydrothiophene-3,4-diol); (6) (2R,3R,4S)-2-[6-[[(1S)-indan-1-yl]amino]-2-pent-1-inyl-purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[6-[[(1S)-indan-1-yl]amino]-2-pent-1-ynyl-purin-9-yl]tetrahydrothiophene-3,4-diol); (7) (2R,3R,4S)-2-[2-chloro-6-(indan-2-ylamino)purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[2-chloro-6-(indan-2-ylamino)purin-9-yl]tetrahydrothiophene-3,4-diol); (8) (2R,3R,4S)-2-[2-chloro-6-(indan-1-ylamino)purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[2-chloro-6-(indan-1-ylamino)purin-9-yl]tetrahydrothiophene-3,4-diol); (9) (2R,3R,4S)-2-[2-chloro-6-[[(1R)-indan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[2-chloro-6-[[(1R)-indan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol); (10) (2R,3R,4S)-2-[2-chloro-6-[[(1S)-indan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[2-chloro-6-[[(1S)-indan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol); (11) (2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-methoxyindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-methoxyindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol); (12) (2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-methoxyindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-methoxyindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol); (13) (2R,3R,4S)-2-[2-chloro-6-[[(1R)-6-methoxyindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[2-chloro-6-[[(1R)-6-methoxyindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol); (14) (2R,3R,4S)-2-[2-chloro-6-[[(1R)-7-methoxyindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[2-chloro-6-[[(1R)-7-methoxyindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol); (15) (2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-fluoroindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-fluoroindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol); (16) (2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-fluoroindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-fluoroindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol); (17) (2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-chloroindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-chloroindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol); (18) (2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-chloroindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-chloroindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol); (19) (2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-bromoindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-bromoindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol); (20) (2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-bromoindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-bromoindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol); (21) (2R,3R,4S)-2-[2-chloro-6-[[(1R)-6-bromoindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[2-chloro-6-[[(1R)-6-bromoindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol); (22) (2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-methylindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-methylindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol); (23) (2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-(trifluoromethyl)indan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[2-chloro-6-[[(1R)-4-(trifluoromethyl)indan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol); (24) (1R)-1-[[2-chloro-9-[(2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl]purin-6-yl]amino]indan-4-carbonitrile((1R)-1-[[2-chloro-9-[(2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl]purin-6-yl]amino]indan-4-carbonitrile); (25)(R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purin-6-yl)amino)-2,3-dihydro-1H-inden-4-carboxamide((R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purin-6-yl)amino)-2,3-dihydro-1H-indene-4-carboxamide); (26) (2R,3R,4S)-2-[2-chloro-6-[[(1R)-7-bromoindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[2-chloro-6-[[(1R)-7-bromoindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol); (27) (2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-methylindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-methylindan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol); (28) (2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-(trifluoromethyl)indan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-[2-chloro-6-[[(1R)-5-(trifluoromethyl)indan-1-yl]amino]purin-9-yl]tetrahydrothiophene-3,4-diol); (29) (1R)-1-[[2-chloro-9-[(2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl]purin-6-yl]amino]indan-5-carbonitrile((1R)-1-[[2-chloro-9-[(2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl]purin-6-yl]amino]indan-5-carbonitrile); (30) Methyl(R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purin-6-yl)amino)-2,3-dihydro-1H-indene-4-carboxylate; (31) Methyl(R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purin-6-yl)amino)-2,3-dihydro-1H-indene-5-carboxylate; (32)(R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purin-6-yl)amino)-2,3-dihydro-1H-inden-4-carboxylic acid((R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purin-6-yl)amino)-2,3-dihydro-1H-indene-4-carboxylic acid); (33)(R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purin-6-yl)amino)-2,3-dihydro-1H-inden-5-carboxylic acid((R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purin-6-yl)amino)-2,3-dihydro-1H-indene-5-carboxylic acid); (34)(R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purin-6-yl)amino)-2,3-dihydro-1H-indene-5-carboxamide((R)-1-((2-chloro-9-((2R,3R,4S)-3,4-dihydroxytetrahydrothiophen-2-yl)-9H-purin-6-yl)amino)-2,3-dihydro-1H-indene-5-carboxamide); (35) (2R,3R,4S)-2-(2-chloro-6-((1,2,3,4-tetrahydronaphthalene-2-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol((2R,3R,4S)-2-(2-chloro-6-((1,2,3,4-tetrahydronaphthalene-2-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol); (36) (2R,3R,4S)-2-(2-chloro-6-(((S)-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol((2R,3R,4S)-2-(2-chloro-6-(((S)-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol); (37) (2R,3R,4S)-2-(2-chloro-6-(((R)-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol((2R,3R,4S)-2-(2-chloro-6-(((R)-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol); (38) (2R,3R,4S)-2-(2-chloro-6-((1,2,3,4-tetrahydronaphthalene-1-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol((2R,3R,4S)-2-(2-chloro-6-((1,2,3,4-tetrahydronaphthalene-1-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol); (39) (2R,3R,4S)-2-(2-chloro-6-(((R)-1,2,3,4-tetrahydronaphthalene-1-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol((2R,3R,4S)-2-(2-chloro-6-(((R)-1,2,3,4-tetrahydronaphthalene-1-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol); (40) (2R,3R,4S)-2-(2-chloro-6-(((S)-1,2,3,4-tetrahydronaphthalene-1-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol((2R,3R,4S)-2-(2-chloro-6-(((S)-1,2,3,4-tetrahydronaphthalene-1-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol); (41) (2R,3R,4S)-2-(6-(((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)amino)-2-chloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol((2R,3R,4S)-2-(6-(((R)-bicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)amino)-2-chloro-9H-purin-9-yl)tetrahydrothiophene-3,4-diol); (42) (2R,3R,4S)-2-(2-chloro-6-((6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol((2R,3R,4S)-2-(2-chloro-6-((6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol); (43) (2R,3R,4S)-2-(2-chloro-6-((6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol((2R,3R,4S)-2-(2-chloro-6-((6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol); (44) (2R,3R,4S)-2-(6-(((R)-2,3-dihydro-1H-inden-1-yl)amino)-2-iodo-9H-purin-9-yl)tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-(6-(((R)-2,3-dihydro-1H-inden-1-yl)amino)-2-iodo-9H-purin-9-yl)tetrahydrothiophene-3,4-diol); and (45) (2R,3R,4S)-2-(6-(((R)-2,3-dihydro-1H-inden-1-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol ((2R,3R,4S)-2-(6-(((R)-2,3-dihydro-1H-inden-1-yl)amino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol).

6. The compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof, as described in claim 1, is characterized by inhibiting endothelial-to-mesenchymal transition (EndMT).

7. A pharmaceutical composition for the prevention or treatment of lung disease, comprising as an active ingredient a compound according to any one of claims 1 to 6, an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition for the prevention or treatment of a lung disease according to claim 7, characterized in that the lung disease is pneumonia, pulmonary fibrosis, or lung cancer.

9. The pharmaceutical composition for the prevention or treatment of lung disease according to claim 7, characterized in that the lung disease is a radiation-induced lung disease.

10. The pharmaceutical composition for the prevention or treatment of lung disease according to claim 7, characterized in that it is used in combination with radiotherapy.

11. The pharmaceutical composition for the prevention or treatment of lung disease according to claim 10, characterized in that it is administered before and / or after radiation therapy.

12. An endothelial-to-mesenchymal transition (EndMT) inhibitor comprising, as an active ingredient, a compound according to any one of claims 1 to 6, an optical isomer thereof, a racemic mixture thereof, a hydrate thereof, a solvate thereof, or a salt thereof.

13. The endothelial cell to mesenchymal cell conversion inhibitor according to claim 12, characterized in that the compound, its optical isomer, its racemic mixture, its hydrate, its solvate, or a salt thereof suppresses the formation of actin stress filaments in endothelial cells.

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