Pyrimidine-Annulated Triazole Derivatives and Their Use in Inhibiting Platelet Aggregation

Abstract

The present disclosure relates to novel pyrimidine cyclized derivatives of formula (I) and methods for preparing these compounds, as well as the use of P2Y 12 and their use as receptor antagonists. [Case 1] TIFF2024545365000028.tif48170

Description

[Technical Field]

[0001] The present invention relates to novel pyrimidine-annulated triazole derivatives of formula (I) and methods for preparing these compounds, as well as to the use of P2Y agonists in the treatment and / or prevention of thrombosis or related disorders. 12 and their use as receptor antagonists. [Background technology]

[0002] Cardiovascular and cerebrovascular diseases are among the most common causes of mortality and morbidity worldwide. Atherothrombosis, an acute complication resulting from ruptured atherosclerotic plaques or endothelial erosion, can lead to myocardial infarction or ischemic stroke (Davi, G et al., New Engl. J. Med., 2007, 357, 2482; Michelson, A. et al., Nat. Rev. Drug Discovery 2010, 9, 154). Platelets are essential cellular components in the blood that prevent excessive blood loss after vascular injury by rapidly forming solid clots. Platelet activation and aggregation are essential for normal hemostasis but, under pathological conditions, are also a key mechanism for triggering potentially life-threatening acute arterial thrombotic events.

[0003] Several converging pathways lead to platelet aggregation. The final step in aggregation is cross-linking of platelets by binding of fibrinogen to membrane glycoprotein receptors (GP IIb / IIIa). Thrombin can induce platelet aggregation largely independently of other pathways, but significant amounts of thrombin are unlikely to be present without prior platelet activation by other mechanisms. Most currently available antiplatelet therapeutics function by inhibiting the production of platelet agonists or by blocking specific platelet receptors (Thijs, T, Clin. Chem. Lab. Med., 2010, 48 Suppl. 1, S3; Sakhuja, R. et al. Curr. Probl. Cardiol. 2010, 35, 123). For example, aspirin reduces the production of thromboxane A2 (Tohgi, H et al, Stroke, 1992, 23, 1400), abciximab, epitifibatide, and tirofiban inhibit GP IIb / IIIa receptors (Epic Investigators, New Engl. J. Med, 1994, 330, 956; Gibson, C. Am Heart J., 2006, 152, 668; Hartman, G. et al, J Med. Chem. 1992, 35, 4640), and clopidogrel, prasugrel, ticlopidine, cangrelor, and ticagrelor antagonize the inductive effects of adenosine-5'-diphosphate (ADP) on purinergic receptors (Horiuchi, H, Ann. Med. 2066, 38, 162).

[0004] ADP is a key signaling molecule that induces platelet activation and aggregation, and therefore plays a key role in the initiation and progression of arterial thrombus formation (Gachet, C, Thromb. Haemostasis 2001, 86, 222). ADP-induced platelet aggregation is mediated by two specific P2Y receptors, P2Y1 and P2Y2. 12The binding of ADP to these P2Y receptors on the plasma membrane induces the inhibition of adenylyl cyclase, modulating intracellular signaling pathways such as the influx and mobilization of intracellular calcium ions, activation of phosphoinositide-3 kinase (PI3K), platelet aggregation, and secretion of other mediators, thus amplifying the initial preaggregation signal (Cateneo, M, Dru News Persp. 2006, 19, 253; Dangelmaier, C. et al., Thromb. Haemost., 2001, 85, 341; Bourdon, D. et al., J. Thromb. Haemost., 2006, 4, 861; Pfefferkom, A. et al., Bioog. Med. Chem. Lett. 2008, 18, 3338). However, while P2Y1 is ubiquitously expressed, P2Y 12 The receptor is expressed primarily on platelets (Boeynaems, J., et al., Semin. Thromb. Haemast., 2005, 31, 139; Jacobson, K. et al., Drug Disc. Today, 2010, 15, 570). Furthermore, experimental studies have shown that P2Y receptors are involved in the inhibition and prevention of platelet aggregation. 12 (Andre, P. et al, J. Cnin. Invest., 2003, 112, 398; Judge, H. et al, Thromb. Haemost., 2010, 103, 1210; Power, R. et al, Expert Rev. Cardiovasc. Ther. 2012, 10, 1261; Ji, X. et al, J. Hematol. Oncol. 2012, 4, 4).

[0005] For many years, P2Y 12Significant efforts have been made to investigate the possibility of P2Y as a molecular target for treating and preventing pathological atherothrombosis, and substantial progress has been achieved (Dorsam, R. et al, J Clin. Invest., 2004, 113, 340; Norgard, N. et al, Recent Patents Cardiovasc. Drug Disc. 2008, 3, 194; Patel, P. et al, J. Cardiothor. Vascul. Anesth. 2013, 27, 620), and several P2Y 12 P2Y inhibitor therapeutics have been successfully developed for clinical use (Angiolillo, D., Am. Heart. J., 2008, 156, 510; Michelson, A., Curr. Opin. Hematol. 2009, 16, 371). These P2Y inhibitors, such as clopidogrel, prasugrel, ticlopidine, cangrelor, and ticagrelor, 12 Inhibitors have proven highly effective in the treatment and prevention of cardiovascular disorders. They are suggested for use in treating, ameliorating, and / or preventing acute myocardial infarction, arterial and venous thrombosis (primary arterial thrombotic complications of atherosclerosis (such as thrombotic or embolic stroke, transient ischemic attack, or peripheral vascular disease), arterial complications due to interventions in atherosclerosis (such as angioplasty and reocclusion after angioplasty), thrombotic complications due to surgical or mechanical injury (such as reocclusion after thrombotic therapy), arterial thrombosis, venous thrombosis, conditions in which platelets may contribute to an underlying inflammatory disease process in the vessel wall (such as atherosclerotic plaque formation / progression, stenosis / restenosis), and angina or unstable angina.

[0006] However, these clinically available P2Y 12All therapeutic drugs have been observed and documented to have certain undesirable properties or side effects associated with their clinical use. For example, clopidogrel and ticlopidine require activation by metabolic enzymes to form active metabolites that irreversibly inhibit platelet aggregation. They have been found to be associated with high patient variability and significant drug-drug interactions (Collect, J., et al., Lancet, 2009, 373, 309; Simon, T., et al., New Engl. J. Med., 2009, 360, 363; Bhatt, D., N Engl. J Med., 2010, 363, 1909). Resistance to clopidogrel has also been reported (Barragan, P., et al., Catheter Cardiovasc. Interv., 2003, 59, 295; Matetzky, S., Circulation, 2004, 109, 3171). As irreversible inhibitors, prasugrel and clopidogrel have been observed to be associated with an increased risk of bleeding during treatment (Koski, RP&T, 2018, 42, 352; Wiviott, S., N Engl. J Med., 2007, 357, 2001). Cangrelor is only administered parenterally, limiting its potential for long-term therapeutic and prophylactic use. Ticagrelor is a potent and reversible platelet aggregation inhibitor. It is a potential P2Y inhibitor for reducing thrombotic cardiovascular events in patients with acute coronary syndromes (unstable angina, non-ST-segment elevation myocardial infarction, or ST-segment elevation myocardial infarction). 12 It is widely used as a platelet inhibitor (Husted, S., Cardiovasc. Therap. 2009, 27, 259). Despite its success in clinical use, ticagrelor has been associated with serious side effects, including dyspnea and bradycardia. Furthermore, ticagrelor is not recommended for patients with impaired liver function (Prescribing Information, Brilinta, 2011).

[0007] Given the fact that cardiovascular and cerebrovascular diseases remain among the most serious human diseases, affecting millions of patients, and the currently available P2Y 12Considering the fact that antiplatelet drugs are associated with various undesirable properties, the clinical use of these P2Y 12 There remains a great need to overcome or at least mitigate some of the drawbacks of inhibitors and to provide new, effective and safe drugs for treating and preventing arterial thrombotic events.

[0008] It is therefore an object of the present invention to provide novel compounds, methods and compositions for the treatment and / or prevention of human cardiovascular disorders. Summary of the Invention

[0009] The present invention comprises novel pyrimidine-annulated triazole derivatives, methods for preparing these compounds, and pharmaceutical compositions containing such compounds, as well as methods for treating or preventing arterial thrombosis.

[0010] Accordingly, the present invention provides a compound of general formula (I) or a pharmaceutically acceptable salt or prodrug thereof: [ka] During the ceremony, X represents O, S, -S(O)- or -S(O)-; Z is S, O, NH, NR 10、 or a single bond, R 10 is C 1-6 represents alkyl, R9 is hydrogen, halogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkyl-carbonyl, C 3-8 cycloalkyl, aryl, aralkyl, 4- to 6-membered heterocyclyl, or 4- to 6-membered heterocyclylalkyl, provided that each of the above groups is not substituted with halogen, hydroxyl, C 1-3 Alkoxy, C 1-3optionally substituted by one or more substituents independently selected from alkylthio, amino, N-monoalkylamino, N,N-di-alkylamino, cyano, and nitro; R8 is hydrogen, C 1-6 Alkyl, C 1-6 Alkyloxycarbonyl, NC 1-3 Alkylcarbamoyl or N,N-diC 1-3 alkylcarbamoyl, provided that the C 1-6 Alkyl groups and NC 1-3 Alkylcarbamoyl group and N,N-diC 1-3 Alkylcarbamoyl is hydroxyl, halogen, C 1-3 optionally substituted by one or more substituents selected from alkoxy; Y is H, C 1-8 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkyl-thio-C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl-C 1-3 Alkyl, Phenyl-C 1-3 Alkyl, Phenyl-C 3-8 Cycloalkyl, 4- to 10-membered heterocyclyl, 4- to 10-membered heterocyclyl-C 1-3 Alkyl or 4-10 membered heterocyclyl-C 3-8 cycloalkyl, provided that each of the above groups is selected from halogen, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, C 1-3 Alkoxy-C 1-3 Alkyl, Halo-C 1-3 optionally substituted with one or more substituents independently selected from alkyl, amino, N-alkylamino, and N,N-dialkylamino; R1 is H, cyano, C 1-3 Alkyl, Halo-C1-3 Alkyl, hydroxymethyl, 2-hydroxyethyl, C 1-8 alkylcarboxymethyl, or benzoylmethyl, provided that the above C 1-8 The alkylcarboxylmethyl group and the benzoylmethyl group are free from halogen, carboxyl, and C 1-6 optionally substituted by one or more substituents selected from alkoxycarbonyl; R2 and R3 are independently hydrogen, C 1-3 Alkyl, Halo-C 1-3 Alkyl, C 1-3 Alkoxy, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, -C(O)OH, -CHC(O)OH, C 1-6 Alkoxycarbonyl, C 1-6 represents alkoxycarbonylmethyl or cyano; Or, R2 and R3 together with the carbon to which they are attached form a C 3-5 Forms a carbocyclyl, provided that the carbocyclyl is not substituted with halogen, OH, C 1-3 Alkyl or C 1-3 optionally substituted by one or more substituents selected from alkoxy; R4 and R5 are independently hydrogen, halogen, hydroxyl, C 1-3 Alkyl, Halo-C 1-3 Alkyl, C 1-3 Alkoxy, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, -C(O)OH, C 1-6 Alkoxycarbonyl, C 1-6 represents alkoxycarbonylmethyl, cyano, amino, N-alkylamino or N,N-dialkylamino; Or, R4 and R5 together with the carbon to which they are attached form a C 3-5 forming a carbocyclyl, wherein the carbocyclyl is selected from the group consisting of halogen, OH, C 1-3 Alkyl or C 1-3 optionally substituted by one or more substituents selected from alkoxy; R6 is hydrogen, cyano, C 1-3alkyl, hydroxymethyl or 2-hydroxyethyl; R7 is hydrogen, F, C 1-3 alkyl, hydroxymethyl, 2-hydroxyethyl, or carboxymethyl, or R and R 12 together represent one oxo, A represents a single bond, hydrogen, O, S, —CH—, —CHCH—, CHF, CF, or —C(O)—; E is hydrogen, F, OH, R 11 O-, R 11 OC(O)-, R 11 C(O)-, R 11 C(O)O- or a partial structure represented by G1, G2 or G3, [ka] R 11 is hydrogen, C 1-8 Alkyl, C 3-8 Alkenyl, C 3-8 Alkynyl, C 3-8 represents cycloalkyl, benzyl, aryl or heterocyclyl, provided that the above groups are not substituted with halogen, OH, nitro, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, carboxyl, C 1-6 Alkoxycarbonyl and C 1-6 optionally substituted by one or more substituents selected from alkoxycarbonyloxy; R 12 represents hydrogen, or R 12 and R7 together represent an oxo; However, if R8 is H, then Y is not H, However, when Y is H, R8 is not H, However, when Z is a single bond, R9 is not H.

[0011] In one embodiment of the present invention, there is provided a compound of general formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein X is O and R6 is H; However, if R8 is H, then Y is not H, However, when Y is H, R8 is not H, However, when Z is a single bond, R9 is not H.

[0012] In another embodiment of the present invention, there is provided a compound of general formula (I), wherein X is O, R is H, R is H, and R 12 is H, R8 is H, and Z is S.

[0013] In yet another embodiment of the present invention, there is provided a compound of general formula (I), wherein X is O, R is H, R is H, and R 12 is H, R8 is H, Z is S, R7 is H, and R9 is C 1-5 Alkyl, C 3-8 is a cycloalkyl or phenyl group, and Y is phenyl or hetero Cyclyl cyclopropyl substituted with phenyl or hetero Cyclyl are halogens, CN, nitro, OH, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 It may be optionally substituted with one or more substituents independently selected from cycloalkyl, amino, N-alkylamino and N,N-dialkylamino.

[0014] In yet another embodiment of the present invention, there is provided a compound of general formula (I), wherein A is a single bond, hydrogen, or O, X is O, R is H, R is H, and R 12 is H, R8 is H, Z is S, R7 is H, and R9 is C 1-5 Alkyl, C 3-8 is a cycloalkyl or phenyl group, and Y is phenyl or hetero Cyclyl cyclopropyl substituted with phenyl or hetero Cyclyl are halogens, CN, nitro, OH, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6It may be optionally substituted with one or more substituents independently selected from cycloalkyl, amino, N-alkylamino and N,N-dialkylamino.

[0015] In yet another embodiment of the present invention, there is provided a compound of general formula (I), wherein R1 is H, R6 is H, and R 12 is H, R8 is H, Z is S, and R4 and R5 are independently selected from H, OH, fluorine and hydroxymethyl.

[0016] In yet another embodiment of the present invention, there is provided a compound of general formula (I), wherein R1 is H, R6 is H, and R 12 is H, R8 is H, Z is S, R3 is H, A is O or a single bond, E is H, R 11 O- or R 11 C(O)- and R 11 is C 1-8 alkyl, benzyl, or phenyl, and the benzyl and phenyl groups are not halogen, OH, C 1-3 Alkyl, C 1-3 Alkoxy, carboxyl, C 1-6 Alkoxycarbonyl and C 1-6 It may be optionally substituted with one or more substituents selected from alkoxycarbonyloxy.

[0017] In yet another embodiment of the present invention, there is provided a compound of general formula (I), wherein R1 is H, R6 is H, and R 12 is H, R8 is H, Z is S, R3 is H and R2 is hydroxymethyl.

[0018] In yet another embodiment of the present invention, there is provided a compound of general formula (I), wherein Y is cyclopropyl substituted with phenyl, said phenyl being substituted with 1 to 4 fluorine atoms.

[0019] In yet another embodiment of the present invention, ((2R,3R,4R,5S)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-4-hydroxytetrahydrofuran-2,5-diyl)dimethanol [ka] , ((2R,3R,5R)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2,5-diyl)dimethanol [ka] , (2S,3R,4S)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol [ka] , ((2R,4R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl)methanol [ka] , ((2R,3S,4S,5S)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-4-fluorotetrahydrofuran-2,5-diyl)dimethanol [ka] , ((2R,3S,4R,5S)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-4-fluorotetrahydrofuran-2,5-diyl)dimethanol [ka] , (2R,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-carboxylic acid [ka] , (2R,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylsulfinyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-carboxylic acid [ka] , ((2R,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(methoxymethyl)tetrahydrofuran-2-yl)methanol [ka] , 2-((2R,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-yl)ethan-1-ol [ka] , 2-(((2R,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-yl)methoxy)ethan-1-ol [ka] , 3-((2S,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-yl)propanoic acid [ka] , 2-(((((2R,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-yl)methoxy)methyl)benzoic acid [ka] , and 2-(((2R,4R,5R)-4-(7-(((1S,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-yl)methoxy)acetic acid [ka] The present invention provides a compound of general formula (I) selected from:

[0020] In yet another embodiment of the present invention, there is provided a pharmaceutical composition for treating, ameliorating, or preventing platelet-mediated thrombotic diseases, disorders, or conditions in a host, including, but not limited to, myocardial infarction, thrombotic stroke, transient ischemic attack, peripheral vascular disease, angina pectoris, and unstable angina, comprising an effective amount of a compound of general formula (I).

[0021] In yet another embodiment of the present invention, there is provided a pharmaceutical composition as described above further comprising one or more additional antiplatelet agents, anticoagulants, antifibrinolytic agents, or other therapeutic agents having cardiovascular activity, including, but not limited to, aspirin, triflusal, heparin, cilostazol, vorapaxal, abciximab, epitifibatide, tirofiban, dipyridamole, thromboxane synthase inhibitors, terutroban, apixaban, rivaroxaban, and dabigatran. , Hi Ludzin, edoxaban, inogatran, ximelagatran, and vitamin K antagonists.

[0022] In yet another embodiment of the present invention there is provided a compound of general formula (I) for use in therapy.

[0023] In yet another embodiment of the present invention, there is provided a compound of general formula (I) for use in the treatment, amelioration or prevention of platelet-mediated thrombotic diseases, disorders or conditions including, but not limited to, myocardial infarction, thrombotic stroke, transient ischemic attack, peripheral vascular disease, angina pectoris and unstable angina pectoris.

[0024] In yet another embodiment of the present invention, there is provided a compound of general formula (I) for use in the treatment, amelioration or prevention as described above, further comprising one or more additional therapeutic agents selected from the group consisting of antiplatelet agents, anticoagulants and antifibrinolytic agents, or any combination thereof. Such additional agents may include, but are not limited to, aspirin, triflusal, heparin, cilostazol, vorapaxal, abciximab, epitifibatide, tirofiban, dipyridamole, thromboxane synthase inhibitors, terutroban, apixaban, rivaroxaban, and dabigatran. , Hi Ludzin, edoxaban, inogatran, ximelagatran and vitamin K antagonists.

[0025] In yet another embodiment of the present invention, there is provided the use of a compound of general formula (I) in the manufacture of a medicament for treating, ameliorating or preventing platelet-mediated thrombotic diseases, disorders or conditions, including but not limited to myocardial infarction, thrombotic stroke, transient ischemic attack, peripheral vascular disease, angina pectoris and unstable angina pectoris.

[0026] In yet another embodiment of the present invention, there is provided the use of a compound of general formula (I) in the manufacture of a medicament for the treatment or prevention of the above, further comprising one or more additional therapeutic agents selected from the group consisting of antiplatelet agents, anticoagulants and antifibrinolytic agents, or any combination thereof. Such additional agents may include, but are not limited to, aspirin, triflusal, heparin, cilostazol, vorapaxal, abciximab, epitifibatide, tirofiban, dipyridamole, thromboxane synthase inhibitors, terutroban, apixaban, rivaroxaban, and dabigatran. , Hi Ludzin, edoxaban, inogatran, and vitamin K antagonists.

[0027] In yet another embodiment of the present invention, there is provided a method for treating, ameliorating or preventing platelet-mediated thrombotic diseases, disorders or conditions, including but not limited to myocardial infarction, thrombotic stroke, transient ischemic attack, peripheral vascular disease, angina pectoris and unstable angina, in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of general formula (I).

[0028] In another aspect of the present invention, there is provided the above method, further comprising one or more additional therapeutic agents selected from the group consisting of antiplatelet agents, anticoagulants, and antifibrinolytic agents, or any combination thereof, including, but not limited to, aspirin, triflusal, heparin, cilostazol, vorapaxal, abciximab, epitifibatide, tirofiban, dipyridamole, thromboxane synthase inhibitors, terutroban, apixaban, rivaroxaban, and dabigatran. , Hi Ludzin, edoxaban, inogatran, ximelagatran and vitamin K antagonists.

[0029] The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. DETAILED DESCRIPTION OF THE INVENTION

[0030] definition Whenever the term "compounds of formula (I)" or "compounds of the invention" or similar terminology is used above and below, it is meant to include compounds of formula (I), their pharmaceutically acceptable prodrugs, salts, solvates, quaternary amines and metal complexes.

[0031] The term "prodrug" as used throughout this specification refers to a pharmacologically acceptable derivative such as an ester, carbamate, carbonate, ether, amide, phosphate ester, phosphonate ester, phosphoramidate, phosphonamidate, phosphodiamide, phosphonodiamide, etc. Such derivatives are prepared such that the in vivo biotransformation product of the resulting derivative is the active drug as defined in the compound of formula (I). References describing prodrugs are generally incorporated herein (Goodman and Gilman, The Pharmacological Basis of Therapeutics, 8 thed,McGraw-Hill,Int.Ed.1992,“Biotransformation of Drugs”,p 13-15;H.Bundgaard,Design of Prodrugs,H.Bundgaard ed.Elsevier Science Publisher,1985;M.Taylor,Adv.Drug Delivery 1996,19,131;H.Bundgaard,Drugs of the Future, 1991, 16, 443; A. Simplicio, Molecules, 2008, 13, 519; P. Ettmayer, J. Med. Chem. 2004, 47, 2393). Of particular relevance are prodrugs that have been described to produce nucleoside or nucleotide prodrugs (S. Hecker et al, J. Med. Chem., 2008, 51, 2328; P. Poijarvi-Virta et al, Current Med. Chem. 2006, 13, 3441; N. Gisch et al, J. Med. Chem. 2008, 51, 6752; L. Wiebe et al, Adv. Drug Delivery Rev. 1999, 39, 63; J. Cooperwood et al, Nucleoside and Nucleotide Prodrugs, in Recent Advances in Nucleosides: Chemistry and Chemotherapy, CK Chu ed. Elsevier, 2002, pp. 91-147), which prodrugs preferably have excellent aqueous solubility, increased bioavailability, and are readily metabolized in vivo to compounds of formula (I). Prodrugs that can increase the cell membrane penetration of the compounds of the present invention are particularly preferred and are part of the present invention. Prodrugs of the compounds of the present invention can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved by routine manipulation or in vivo to yield the parent compounds.

[0032] Preferred are pharmaceutically acceptable ester, ether, carbonate, phosphodiester, phosphomonoester, phosphotriester, phosphonodiester, phosphoramidate, phosphonamidate, phosphodiamide, phosphonodiamide, and carbamate prodrugs derived from these compounds of formula (I) that are hydrolyzable in vivo and contain hydroxy and / or amino and / or phosphate and / or phosphonate groups. The in vivo hydrolyzable esters, ethers, carbonates, phosphodiesters, phosphomonoesters, phosphotriesters, phosphonodiesters, phosphoramidates, phosphonamidates, phosphodiamides, phosphonodiamides, and carbamates are hydrolyzed in the human or animal body to produce the parent alcohol, amine, phosphate, or phosphonate present in the compounds of the present invention. Hydrolysis of the prodrugs can be chemical or enzymatic, with enzymatic hydrolysis being the preferred mechanism. Enzymes commonly involved in the hydrolysis of nucleoside / nucleotide prodrugs include, but are not limited to, carboxylesterases, cholinesterases, cathepsin A, lipases, valacyclovirase, and paraoxonase.

[0033] Pharmaceutically acceptable salts of the compounds of formula (I) of the present invention are also provided. The term "pharmaceutically acceptable salts" refers to salts derived from pharmaceutically acceptable inorganic and organic acids and bases. Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of the compounds of the present invention that are sufficiently basic, for example, acid addition salts with inorganic or organic acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, methanesulfonic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, para-toluenesulfonic acid, 2-mesitylenesulfonic acid, citric acid, acetic acid, tartaric acid, fumaric acid, lactic acid, succinic acid, malic acid, malonic acid, maleic acid, 1,2-ethanedisulfonic acid, adipic acid, aspartic acid, benzenesulfonic acid, benzoic acid, ethanesulfonic acid, or nicotinic acid). Further suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, base addition salts of compounds of the present invention that are sufficiently acidic, such as metal salts (e.g., sodium, potassium, calcium, magnesium, zinc, or aluminum), ammonium salts, salts with organic bases that provide physiologically acceptable cations, including quaternary ammonium ions (e.g., methylamine, ethylamine, diethylamine, trimethylamine, tert-butylamine, triethylamine, dibenzylamine, N,N-dibenzylethylamine, cyclohexylethylamine, tris-(2-hydroxyethyl)amine, hydroxyethyldiethylamine, (IR,2S)-2-hydroxyinden-1-amine, morpholine, N-methylpiperidine, N-ethylpiperidine, piperazine, methylpiperazine, adamantylamine, choline hydroxide, tetrabutylammonium hydroxide, tris-(hydroxymethyl)methylamine hydroxide, L-arginine, N-methyl-D-glucamine, lysine, arginine, etc.).

[0034] Certain compounds of the present invention may exist as solvates or hydrates, and it is to be understood that the present invention encompasses all such solvates and hydrates.

[0035] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain unnatural proportions of atomic isotopes, such as tritium ( 3 H), deuterium ( 2 H), iodine-125( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0036] Where tautomers exist in the compounds of the invention, all individual tautomeric forms and combinations thereof are disclosed as individual specific embodiments of the invention.

[0037] The compounds according to the present invention have a core structure of a five-membered tetrahydrofuran, tetrahydrothiophene, tetrahydrothiophene-1-oxide, or tetrahydrothiophene-1,1-dioxide ring with the defined stereochemistry at the 2-, 3-, 4-, and 5-positions of the five-membered ring. The compounds of formula (I) may contain one or more asymmetrically substituted carbon atoms, asymmetric centers, or chiral centers. The presence of one or more of these asymmetric centers in the compounds according to the present invention may give rise to stereochemically isomeric forms, stereoisomers (e.g., racemates, enantiomers, diastereomers, or E- or Z-isomers). It should be understood that unless the stereochemistry is explicitly defined by the chemical structure, in each case, the present invention may extend to all such stereoisomers, both in pure form and mixed with one another, including enantiomers and diastereomers, and mixtures thereof, including racemic mixtures.

[0038] It is understood that compounds of formula (I) may have metal binding, chelating or complexing properties and therefore may exist as metal complexes or metal chelates, and such metallated derivatives of compounds of formula (I) are intended to be included within the scope of the present invention.

[0039] The scientific and technical terms and nomenclature used above and below have the same meaning as commonly understood by one of ordinary skill in the art, and unless specifically stated otherwise, the following definitions shall apply throughout this specification and the appended claims.

[0040] The term "halogen" refers to fluoro, chloro, bromo and iodo groups.

[0041] In this specification, a "-" symbol may be added to clarify which bond is the point of attachment. For example, heterocyclyl-C 1-3 Alkyl is a C substituted with a heterocyclyl moiety. 1-3 represents an alkyl radical. Additionally, RO- represents a radical in which R is attached to an oxygen atom, which is the attachment point for the entire radical.

[0042] "C 1-n The term "alkyl" means a straight-chain or branched saturated alkyl group having 1 to n carbon atoms, where "n" is an integer from 1 to 18. Examples of "n" include 2, 3, 4, 5, 6, 7, 8, and 18. Examples of said alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, and hexyl.

[0043] "C 2-n The term "alkenyl" means a straight or branched alkenyl group having a saturated carbon-carbon bond and at least one carbon-carbon double bond, and having 2 to n carbon atoms, where "n" is an integer from 2 to 18. Examples of "n" include 2, 3, 4, 5, 6, 7, 8, and 18. Examples of said alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, isopropenyl, and butenyl.

[0044] "C 3-6The term "cycloalkyl" means a saturated monocyclic ring having 3 to 6 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0045] "C 1-n The term "alkoxy" refers to a C, as defined above, bonded to an oxygen atom. 1-n Alkyl, i.e. C 1-n It means alkyl-O-. Examples of said alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and butyloxy.

[0046] The term "aryl" means an aromatic ring or an aromatic ring fused with an aromatic or non-aromatic carbocyclic or heterocyclic ring or rings forming a monocyclic, bicyclic or tricyclic ring system composed of 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms. Examples of said aryl include, but are not limited to, phenyl, naphthyl, biphenyl, 2-naphthalenyl, tetrahydronaphthyl, 2-indenyl, 4-indenyl and indanyl.

[0047] "Aryl-C 1-n The term "alkyl" refers to a C as defined above substituted with an aryl as defined above. 1-n It means alkyl.

[0048] "Aryl-C 2-n The term "alkyl" refers to a C as defined above substituted with an aryl as defined above. 2-n It means alkenyl.

[0049] The term "heterocyclyl" means a saturated, partially unsaturated, or aromatic monocyclic, bicyclic, or tricyclic ring system composed of 4 to 18 atoms, in which 1, 2, 3, or 4 atoms in the ring are elements other than carbon independently selected from one or more of nitrogen, oxygen, or sulfur. Examples of heterocyclyl include, but are not limited to, pyrrolidino, piperidino, oxetanyl, pyridinyl, piperazino, morpholino, dioxanyl, thiomorpholino, furanyl, tetrahydrofuranyl, pyranyl, tetrahydropyranyl, thiazolyl, oxazolyl, thiazinolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, indolinyl, isoindolinyl, isoquinolinyl, quinazolinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, indolyl, and isoindolinyl.

[0050] "C 3-p Cycloalkyl-C 1-n The term "alkyl" refers to a C alkyl group as defined above. 3-p C as defined above substituted with cycloalkyl 1-n It means alkyl.

[0051] Unless otherwise indicated, alkyl, alkenyl, alkoxy, and cycloalkyl (e.g., C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, etc.) may be optionally substituted with one or more substituents independently selected from halogen, hydroxyl, amino, oxo, mercapto, amido, cyano, azido, nitro, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, and C1-C4 alkoxy. It should be noted that the radical positions on any molecular moiety used in the definitions may be anywhere on such moiety as long as it is chemically permissible and stable.

[0052] As used herein, the term "optionally substituted" means that substitution is optional, i.e., substitution may or may not occur. For example, the phrase "an alkyl group optionally substituted with one or more substituents" means that the alkyl group is substituted with zero, one, or more substituents.

[0053] The term "substituted" refers to a molecule in which at least one hydrogen atom has been replaced with a substituent.

[0054] Radicals used in the definitions of the variables include all possible isomers unless otherwise specified. For example, pyridyl includes 2-pyridyl, 3-pyridyl, and 4-pyridyl, pentyl includes 1-pentyl, 2-pentyl, 3-pentyl, etc. When any variable occurs more than once in any constituent, each definition is independent.

[0055] The term "subject" refers to any mammal, including a human. In one embodiment of the invention, the subject is a human.

[0056] The term "independently" is used herein to indicate that independently applied variables vary independently from application to application.

[0057] It is understood that some compounds of formula (I) can be further modified to obtain desired compounds that can also be represented by formula (I). The method of such modification depends on the structure of the desired product and the structure of the compound of formula (I) as the starting material. Such modification reactions can include deprotection, substitution, addition, oxidation, reduction, and other chemical transformations common in organic synthesis.

[0058] Pharmaceutical preparations It will be understood that the amount of the compound of formula (I) of the present invention required for therapeutic use will vary not only with the particular compound selected, but also with the route of administration, the nature of the condition requiring treatment, and the age, weight, and condition of the patient, and will ultimately be left to the discretion of the attending physician. However, in general, a suitable dose may be in the range of about 0.005 to about 30 mg / kg body weight per day, preferably 0.05 to 20 mg / kg / day.

[0059] The desired dose will usually be given in a single dose or as divided doses administered at appropriate intervals, for example, two, three, four or more doses per day. Depending on the therapeutic and / or prophylactic needs, the desired dose may also be, for example, once every two days, once every three days, or even once a week.

[0060] The compound is conveniently administered in unit dosage form, for example containing 0.5 to 1500 mg, conveniently 1 to 1000 mg, most conveniently 5 to 700 mg of active ingredient per unit dosage form.

[0061] The compounds of the present invention are usually administered orally, parenterally, intravenously, intramuscularly, subcutaneously or other injectable methods, via the buccal, rectal, vaginal, transdermal and / or nasal routes and / or by inhalation in the form of a pharmaceutical formulation containing the active ingredient or a pharmaceutically acceptable salt or prodrug or solvate thereof, or a solvate of such a salt, in a pharmaceutically acceptable dosage form. Depending on the disorder and patient to be treated and the route of administration, the composition may be administered in various doses.

[0062] Although it is possible for the compounds of formula (I) of the present invention to be administered as raw chemicals for use in therapy, it is preferred, according to one embodiment of the present invention, to provide the active ingredient as a pharmaceutical composition. Accordingly, the present invention further provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof, together with one or more pharmaceutically acceptable carriers. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. According to one embodiment of the present invention, pharmaceutical formulations include, but are not limited to, those suitable for oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, or parenteral (including intramuscular, subcutaneous, and intravenous) administration, or those in a form suitable for administration by inhalation or insufflation. The formulations may conveniently be presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods according to this embodiment include the step of bringing the active compound into association with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired composition.

[0063] Pharmaceutical compositions suitable for oral administration are usually presented as powders or granules, as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient. In another embodiment, the formulation is presented as a solution, suspension, or emulsion. Alternatively, the active ingredient is presented as a bolus, electuary, or paste.

[0064] Tablets and capsules for oral administration may contain conventional excipients such as binders, fillers, lubricants, disintegrants, or wetting agents. Tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be provided as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives.

[0065] The compound of formula (I) can be formulated for parenteral administration (e.g., injection, e.g., bolus injection or continuous infusion), and can be provided in unit dosage form in ampoules, pre-filled syringes, small injections, or multi-dose containers with added preservatives. The composition can take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and can also contain formulating agents such as suspending agents, stabilizers, and / or dispersing agents. Alternatively, the active ingredient can be in the form of a powder obtained by aseptic isolation of a sterile solid or lyophilization from a solution, which can be mixed with a suitable vehicle (e.g., sterilized pyrogen-free water) before use.

[0066] The above-described formulations are adapted to give sustained release of the active ingredient.

[0067] General synthesis method The present invention also relates to methods for preparing the compounds of the present invention. The compounds can be prepared by any of the applicable methods and techniques of organic synthesis. Many such methods and techniques are well known in the art, and some of the known methods and techniques are detailed in *Compendium of Organic Synthetic Methods*, in 12 volumes (John Wiley & Sons, New York); *Advanced Organic Chemistry*, 5th ed. M. Smith & J. March (John Wiley & Sons, New York, 2001); *Comprehensive Organic Synthesis. Selectivity. Strategy & Efficiency in Modern Organic Chemistry*, in 9 volumes. Barry M. Trost, Editor-in-Chief (Pergamon Press, New York, 1993); and *Chemistry of Nucleosides and Nucleotides*, Townsend, L.B., Ed. (Plenum Press; New York, 1988).

[0068] A number of exemplary methods for preparing the compounds of the present invention are provided below. These methods are intended to illustrate the nature of such preparations and are not intended to limit the scope of applicable methods. As shown in the following general schemes and preparative examples, alternative routes readily apparent to those skilled in the art of organic chemistry can alternatively be used to synthesize the compounds of the present invention or their intermediates. The preparation of the various starting materials used in the schemes is well within the skill of one of ordinary skill in the art.

[0069] During the process described below for preparing compounds of formula (I), functional groups in the starting materials prone to undesired side reactions, particularly amino, amido, carboxy, hydroxy, phosphate, phosphonate, and mercapto groups, can be protected by suitable conventional protecting groups commonly used in organic synthesis. These protecting groups may already be present in the precursors and are intended to protect the functional groups from undesired secondary reactions, such as acylation, etherification, esterification, alkylation, oxidation, reduction, and solvolysis. In certain cases, the protecting groups can also allow reactions to proceed selectively, e.g., regioselectively or stereoselectively. A characteristic of protecting groups is that they can be easily removed without undesired secondary reactions, for example, by acid treatment, fluoride treatment, solvolysis, reduction, or by photolysis. The protection of functional groups by such protecting groups, the protecting groups themselves, and reactions for their removal are described in standard works such as, for example, M. Schelhaas et al., Angew. Chem. International. Ed. (1996), 35(18), 2056 and GDT. W. Greene and PGM Wuts "Protective Groups in Organic Synthesis" John Wiley & Sons, Inc., New York 1999.

[0070] Schemes 1-6 show different processes for synthesizing compounds of formula (I) or compounds that can be converted to compounds of formula (I).

[0071] [ka]

[0072] Scheme 1 illustrates a general method for preparing compounds according to formula (I). A suitable starting material, a compound of formula (II) (wherein R1, R2, R3, R4, R5, R6, R7, R 12, X, A and E are as defined for formula (I)) can be prepared using applicable methods and techniques in organic synthesis well known in the literature and to organic chemists skilled in the art (Smith M., et al., Compendium of Organic Synthetic Methods, in 12 volumes (John Wiley & Sons, New York); Comprehensive Organic Synthesis. Selectivity. Strategy & Efficiency in Modern Organic Chemistry, in 9 Volumes. Barry M. Trost, Editor-in-Chief (Pergamon Press, New York)). New York, 1993). Compounds of formula (II), optionally suitably protected as necessary, are reacted with an appropriately substituted 4,6-dichloro-pyrimidin-5-amine in the presence of a base in a polar solvent to give compounds of formula (III). Suitable bases for the reaction include triethylamine, DIPEA, DMAP, potassium carbonate, sodium carbonate, cesium carbonate, DBU, pyridine, or other organic or inorganic bases common in such reactions. Solvents for the reaction include DMF, THF, 1,4-dioxane, acetonitrile, ethanol, and other common solvents suitable for substitution reactions (Springthorpe, B. et al, Bioorg. Med. Chem. Lett., 2007, 17, 6013; Zhang, H., et al. al, Bioorg. Med. Chem. Lett., 2012, 22, 3598). Alternatively, compound (II) can be reacted with an appropriately substituted 4,6-dichloro-5-nitro-pyrimidine using a similar method, followed by converting the resulting intermediate to compound (III) by reducing the nitro group to an amino group (Tu, W. et al, Bioorg. Med. Chem. Lett., 2014, 24, 141). Reduction conditions include Fe in AcOH, Fe / FeSO4 in aqueous solvents, Zn in aprotic solvents, catalytic hydrogenation, and metal hydrides.The compound of formula (III) is converted to a triazolopyrimidine of formula (IV) under diazotization conditions such as isoamylnitrile in acetonitrile or NaNO in AcOH / HO. The compound of formula (IV) is reacted on its pyrimidine ring by displacement with an appropriate amine in an organic solvent such as MeCN, DMF, THF, dichloromethane, dichloroethane, dioxane, or a mixture of solvents. An additional base such as triethylamine, dipropylethylamine, 2,6-lutidine, pyridine, DMAP, or DBU is preferred in the reaction. The resulting intermediate can be optionally further modified to obtain the desired compound of formula (I) after deprotection.

[0073] [ka]

[0074] Scheme 2 illustrates another method for preparing compounds according to formula (I). A suitable five-membered heterocyclic epoxide, formula (V) (wherein R, R, R, R, R, R) is 12(wherein X, A, and E are as defined for formula (I) and are optionally suitably protected as necessary) is reacted with an azide, such as potassium azide, sodium azide, or tetrabutylammonium azide, in a suitable solvent or mixture of solvents. The azide group of the resulting compound of formula (VI) can be reduced to an amine using suitable reaction conditions, such as metal hydrides, palladium-catalyzed hydrogenation, or triphenylphosphine, and methods well known in the literature (Scriven E et al., Chem Rev. 1988, 88, 297; Rolla, FJ Org. Che. 198, 47, 4327; Kim, B, et al., Tetrahedron Lett. 1998, 39, 6921; Staudinger, H.; Helv. Chim. Acta, 1919, 2, 635). After the amino group is appropriately protected, the compound of formula (VI) can be converted to a compound of formula (VII) having the desired R4 and R5 in a multi-step process using commonly known approaches in the literature (Smith M., et al., Compendium of Organic Synthetic Methods, Smith M., et al. ed. in 12 volumes, John Wiley & Sons, New York; Advanced Organic Chemistry, 5 ed. M. Smith & J. March, John Wiley & Sons, New York, 2001). Subsequently, the amino group of the compound of formula (VII) is converted to the appropriate pyrimidine-annulated triazole of formula (I) in a multi-step process using the method described in Scheme 1.

[0075] [ka]

[0076] Scheme 3 illustrates yet another synthetic strategy for preparing compounds according to formula (I). A suitable 5-membered heterocycle having a hydroxyl group at the 3-position, formula (IX) (wherein R1, R2, R3, R4, R5, R6, R7, R 12, X, A and E are as defined for formula (I) and optionally suitably protected as necessary) is converted to a sulfonylate such as mesylate, tosylate or triflate, and the resulting compound of formula (X) is subjected to nucleophilic substitution with azide to give a compound of formula (XI) (Kenneth A. et al, J. Med. Chem. (1995), 38, 1720; Taichi K. eatl., Chemical Communications, 2012, 48(56), 7038; B. Lv et al., Tetrahedron Letters, 2018 59, 1473, Chen YDet al, CN111333598). Alternatively, the compound of formula (IX) can be subjected to Mitsunobu reaction conditions in the presence of azide to directly obtain the compound of formula (XI) (Mitsunobu, O., Synthesis, 1981, 1; Green, J. et al., Org. Lett. 2009, 11, 807; G. Gosselin et al., Nucleosides and Nucleotides, 1998, 17, 1731). The azide group of the resulting compound of formula (XI) can be reduced to an amine, which can then be further converted to the appropriate pyrimidine-annulated triazole of formula (I) as described in Scheme 1.

[0077] [ka]

[0078] Scheme 4 illustrates the synthesis of compounds of general formula (I) where R6 is hydrogen and R 12Another general method for preparing compounds of formula (XIII) (where R, R, R, R, X, A, and E are as defined for formula (I) and are optionally suitably protected as necessary) has been described. An appropriate five-membered heterocyclic epoxide, formula (XIII), is reacted with an azide, such as potassium azide, sodium azide, or tetrabutylammonium azide. After protecting the hydroxyl with a suitable protecting group, the azide group of the resulting compound of formula (XV) can be reduced to an amine, which can then be converted to the appropriate pyrimidine-annulated triazole of formula (XVIII) in several steps as described in the previous scheme. Finally, the desired R4 and R5 were introduced in a multi-step process using commonly known approaches (Smith M., et al., Compendium of Organic Synthetic Methods, Smith M., et al. ed. in 12 volumes, John Wiley & Sons, New York; Advanced Organic Chemistry, 5 ed. M. Smith & J. March, John Wiley & Sons, New York, 2001; Koushi H. et al., J. Med. Chem. 2018, 61, 5140; B. Lv et al., Tetrahedron Letters 2018, 59, 1473).

[0079] [ka]

[0080] Scheme 5 illustrates a compound of formula (I) where R6 is hydrogen and R 12Another general method for preparing compounds of formula (XVI) (where R, R, R, R, R, X, A, and E are as defined for formula (I) and optionally suitably protected as necessary) is described below by reacting an appropriate 5-membered heterocyclic epoxide of formula (XVI) with an azide, such as potassium azide, sodium azide, tetrabutylammonium azide, or the like, in a suitable solvent or mixture of solvents. The resulting heterocyclic azide can be converted to a compound of formula (XVIII) having the desired R4 and R5 in a multi-step process using commonly known approaches in the literature (Smith M., et al., Compendium of Organic Synthetic Methods, Smith M., et al., ed., in 12 volumes, John Wiley & Sons, New York; Advanced Organic Chemistry, 5 ed. M. Smith & J. March, John Wiley & Sons, New York, 2001; Koushi H. et al., J. Med. Chem. 2018, 61, 5140). The amino group of the compound of formula (XVIII) is then converted to the appropriate pyrimidine-annulated triazole of formula (I) in a multi-step process using methods well known to organic chemists skilled in the art.

[0081] [ka]

[0082] Scheme 6 illustrates a compound of formula (I) where R6 is hydrogen and R 12 Another method for preparing compounds according to formula (XIX) (where R6 is hydrogen and R 12is hydrogen, and R, R, R, R, R, R, X, A, and E are as defined for formula (I), optionally suitably protected as necessary) was subjected to reductive amination (B. Unterhait et al., Seientia Pharmaeeutiea, 2000, 68, 102; Michael Aaron B. et al., US2018 / 208608; Michael J. et al., US6355660; Dong Bo Li et al., Org. Lett., 2013, 15(18), 4767) or transaminase-catalyzed reaction (Matteo P. et al., Chem. Sci., 2019, 10, 5955) to give amine compound (XX), which was then further converted to the appropriate pyrimidine-annulated triazole of formula (I) as described in the above scheme.

[0083] [ka]

[0084] Scheme 7 illustrates yet another alternative approach to preparing compounds of formula (I). Compounds of formula (XXI) (wherein R1, R2, R3, R4, R5, R6, R 12, R7, and X are as defined for Formula (I), and A is as defined for Formula (I), or A is a functional group that can be converted to A as defined for Formula (I). As described in the scheme above, the compound of formula (XXI) is optionally suitably protected, if necessary. The compound of formula (XXI) is converted to a compound of formula (XXII) in a multi-step reaction using the methods described in the scheme above. The compound of formula (XXIII) is then converted to a compound of formula (XXIII) having the desired E and A as defined according to Formula (I) using known methods for functional group transformations and derivatizations in the organic synthetic chemistry literature (Smith M., et al., Compendium of Organic Synthetic Methods, Smith M., et al., ed. in 12 volumes, John Wiley & Sons, New York). The compound of formula (XXIII) is then further modified using the methods described in the scheme above to obtain a compound of formula (I). [Example]

[0085] The examples and preparations provided below further describe and illustrate the compounds of the present invention and methods for preparing such compounds. It should be understood that the scope of the present invention is not limited by the scope of the following examples and preparations.

[0086] The naming of compounds herein was performed using the program "ChemDraw 19.0" provided by Cambridge Scientific Computing Inc. In the event of a discrepancy between the chemical name of an exemplified compound and the corresponding structure of the Example, the chemical structure should be used to determine the compound of the Example.

[0087] Abbreviation DIPEA N,N-Diisopropylethylamine DMAP 4-dimethylaminopyridine DBU 2,3,4,6,7,8,9,10-octahydropyrimidol[1,2-a]azepine EtOAc ethyl acetate Et3N Triethylamine THF tetrahydrofuran DMF N,N-dimethylformamide DCM dichloromethane MS(ESI) Mass spectrometry (electrospray ionization) MeCN acetonitrile RT room temperature TBDPS t-butyldiphenylsilyl TBDPSCl t-butyldiphenylsilyl chloride TBAF Tetrabutylammonium fluoride TFA trifluoroacetic acid DAST (Diethylamino) Sulfur Trifluoride Ms methanesulfonyl Ts p-Toluenesulfonyl Tf Trifluoromethanesulfonyl MeOH Methanol EtOH ethanol AcOH acetic acid Me methyl Ac2O acetic anhydride Tf2O Trifluoromethanesulfonic anhydride AIBN Azobisisobutyronitrile aq water-based Sat saturation FBS fetal bovine serum PBS Phosphate Buffered Saline

[0088] Example 1 Preparation of ((2R,3R,4R,5S)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-4-hydroxytetrahydrofuran-2,5-diyl)dimethanol (Compound 8)

[0089] [ka]

[0090] tert-Butyl(((1R,2S,4R,5R)-4-(dimethoxymethyl)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)methoxy)diphenylsilane (Compound 1): A mixture of compound SM1 (910.00 mg, 4.79 mmol), DMAP (1.17 g, 9.58 mmol), and TBDPSCl (1.97 g, 7.20 mmol) in dichloromethane (30 ml) was stirred at room temperature for 23 hours. It was then washed with saturated aqueous NaHCO (50 ml) and brine (50 ml), dried over anhydrous NaSO, and evaporated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate, 8:1) to give compound 1 (2.00 g). MS (ESI) m / z: 446 [M+NH] + .

[0091] (2R,3R,4R,5R)-4-azido-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(dimethoxymethyl)tetrahydrofuran-3-ol (compound 2): A mixture of compound 1 (2.00 g, 4.67 mmol), sodium azide (2.72 g, 41.84 mmol), and ammonium chloride (2.75 g, 51.41 mmol) in water (12 ml) and ethanol (60 ml) was heated under reflux for 2 days. The mixture was concentrated to one-third volume, diluted with water (50 ml), and extracted with dichloromethane (100 ml × 2). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum, 1:12) to give compound 2 (1.50 g) as an oil. MS (ESI) m / z: 489 [M+NH4] + .

[0092] (2R,3R,4R,5R)-4-amino-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(dimethoxymethyl)tetrahydrofuran-3-ol (compound 3): To a solution of compound 2 (50 mg, 0.11 mmol) in ethyl acetate (5 ml), Pd / C (20 mg) was added, and the mixture was hydrogenated under hydrogen overnight. The mixture was filtered, and the filtrate was concentrated to give compound 3 (46.00 mg). MS (ESI) m / z: 446 [M+H] +

[0093] (2R,3R,4R,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-((6-chloro-5-nitro-2-(propylthio)pyrimidin-4-yl)amino)-2-(dimethoxymethyl)tetrahydrofuran-3-ol (compound 4): A solution of compound 3 (370.00 mg, 0.83 mmol), 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine (245.00 mg, 0.92 mmol), and triethylamine (251 mg, 0.92 mmol) in tetrahydrofuran (10 ml) was stirred for 23 hours. The mixture was diluted with ethyl acetate (50 ml) and washed with brine (50 ml). The organic layer was dried over anhydrous Na2SO4 and evaporated, and the residue was purified by column chromatography (hexane / ethyl acetate, 5:1) to give compound 4 (440.00 mg). MS (ESI) m / z: 677 [M+H] + .

[0094] (2R,3R,4R,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-(dimethoxymethyl)tetrahydrofuran-3-ol (compound 6): To a solution of compound 4 (440.00 mg, 0.65 mmol) in acetic acid (9 ml) and water (2 ml), Fe powder (182.00 mg, 3.26 mmol) was added, and the mixture was stirred at room temperature for 16 hours (compound 5 was prepared and used without purification). Sodium nitrite (90.00 mg, 1.30 mmol) was then added, and the mixture was stirred at room temperature for 2 hours. The mixture was then partitioned between ethyl acetate (200 ml) and saturated aqueous NaHCO (200 ml). The organic layer was washed with brine (200 ml), dried over anhydrous NaSO, filtered, and evaporated. The residue was purified by column chromatography (hexane / ethyl acetate, 4:1) to give compound 6 (300.00 mg). MS (ESI) m / z: 658 [M+H] + .

[0095] (2R,3R,4R,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-(dimethoxymethyl)tetrahydrofuran-3-ol (compound 7): A solution of (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (147 mg, 0.87 mmol), compound 6 (300 mg, 0.46 mmol), and DIPEA (119.00 mg, 0.92 mmol) in ethyl acetate (20 ml) was stirred at room temperature for 20 minutes. The solution was washed with 1N aqueous HCl (20 ml), saturated aqueous NaHCO (20 ml), and brine (20 ml), dried over NaSO, and evaporated. The residue was purified by column chromatography (hexane-ethyl acetate, 3:1) to give compound 7 (302.00 mg). ES-API m / z: 791 [M+H] + .

[0096] ((2R,3R,4R,5S)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-4-hydroxytetrahydrofuran-2,5-diyl)dimethanol (compound 8). Compound 7 (150.00 mg, 0.19 mmol) was dissolved in 1,4-dioxane (5 ml) and 2% aqueous HCl (5 ml) was added. The reaction solution was heated at 90 °C for 3 hours. After cooling to room temperature, the mixture was neutralized with saturated aqueous NaHCO (pH 8) and extracted with ethyl acetate (50 ml). The combined organic phase was washed with saturated brine (50 ml), dried over anhydrous NaSO, and evaporated under reduced pressure. The residue (150 mg) was dissolved in methanol (10 ml), sodium borohydride (100 mg, 2.64 mmol) was added, and the solution was stirred at room temperature for 2 hours. The solution was partitioned between ethyl acetate (50 ml) and water (50 ml). The organic layer was dried over anhydrous NaSO, filtered, and evaporated. The residue was purified by column chromatography (dichloromethane / methanol, 15:1) to give compound 8 (58.00 mg). MS(ESI) m / z:509[M+H] + . 1 H-NMR(400MHz,DMSO-d6):9.137(1H,d),7.228-7.450(3H,m),5.132-5.620(1H,m),4.624-5.110(3H,m),3.746-4.17 5(3H,m,),3.386-3.584(4H,m),2.801-3.144(3H,m),2.050-2.119(1H,m),1.377-1.821(4H,m),0.815-0.996(3H,m).

[0097] Example 2 Preparation of ((2R,3R,5R)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2,5-diyl)dimethanol (Compound 19)

[0098] [ka]

[0099] (2R,3R,4S,5R)-4-azido-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(dimethoxymethyl)tetrahydrofuran-3-yl acetate (compound 9): A solution of compound 2 (600.00 mg, 1.27 mmol), DMAP (728.00 mg, 5.96 mmol), and AcO (510.00 mg, 5.00 mmol) in dichloromethane (15 ml) was stirred at room temperature for 2 hours. The solution was partitioned between dichloromethane and water. The organic layer was washed with brine (20 ml), dried over NaSO, and evaporated. The residue was purified by column chromatography (hexane / ethyl acetate, 8:1) to give compound 9 (650.00 mg). MS (ESI) m / z: 531 [M+NH] + .

[0100] (2R,3R,4S,5R)-4-amino-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(dimethoxymethyl)tetrahydrofuran-3-yl acetate (compound 10): A solution of compound 9 (650.00 mg, 1.27 mmol) in ethyl acetate (10 ml) was stirred with Pd / C (20%, 130 mg) under hydrogen overnight. The mixture was then filtered through Celite and evaporated to give compound 10 (610.00 mg). MS (ESI) m / z: 488 [M+H] + .

[0101] (2R,3R,4S,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-((6-chloro-5-nitro-2-(propylthio)pyrimidin-4-yl)amino)-2-(dimethoxymethyl)tetrahydrofuran-3-yl acetate (compound 11): A solution of compound 10 (610.00 mg, 1.25 mmol), NEt (190 mg, 0.10 mmol), and 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine (403.00 mg, 1.51 mmol) in THF (10 ml) was stirred at room temperature for 3 hours. The mixture was partitioned between dichloromethane (50 ml) and saturated aqueous NaHCO (50 ml). The organic layer was washed with brine (50 ml), dried over NaSO, and evaporated. The residue was purified by column chromatography (hexane / ethyl acetate, 10:1) to give compound 11 (750.00 mg). MS (ESI) m / z: 719 [M+H] + .

[0102] (2R,3R,4S,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-(dimethoxymethyl)tetrahydrofuran-3-yl acetate (compound 13): A solution of compound 11 (750.00 mg, 0.10 mmol) in acetic acid (10 ml) and water (2.5 ml) was stirred with Fe powder (292.00 mg, 5.23 mmol) at room temperature overnight. Compound 12 was produced and used directly. Sodium nitrite (144.00 mg, 2.09 mmol) was added, and the mixture was stirred at room temperature for 3 hours. It was then neutralized with saturated aqueous NaHCO3 (pH > 7), and ethyl acetate (50 ml) was added. After filtration through Celite, the filtrate was partitioned between ethyl acetate and water, and the aqueous phase was extracted with ethyl acetate (50 ml). The combined organic phase was washed with brine (100 ml), dried over anhydrous Na2SO4, filtered, and evaporated to give compound 12 (610.00 mg). ES-API m / z: 700 [M+H] + .

[0103] (2R,3R,4S,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-(dimethoxymethyl)tetrahydrofuran-3-yl acetate (compound 14): A solution of (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (198 mg, 1.17 mmol), compound 13 (610.00 mg, 0.87 mmol), and DIPEA (376.00 mg, 2.91 mmol) in ethyl acetate (20 ml) was stirred at room temperature for 16 hours. The solution was washed with saturated aqueous NaHCO (20 ml) and brine (20 ml), dried over NaSO, filtered, and evaporated. The residue was purified by column chromatography (hexane / ethyl acetate, 4:1) to give compound 14 (660.00 mg). MS (ESI) m / z: 833 [M+H] + .

[0104] (2R,3R,4S,5R)-4-(7-((tert-butoxycarbonyl)((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(dimethoxymethyl)tetrahydrofuran-3-yl acetate (compound 15): To a solution of compound 14 (660.00 mg, 0.79 mmol) and DMAP (116.00 mg, 0.95 mmol) in dichloromethane (10 ml), (Boc)2O (208.00 mg, 0.95 mmol) was added, and the reaction solution was stirred at room temperature for 24 hours. It was then washed with water (50 ml) and brine (50 ml), dried over Na2SO4, and evaporated. The residue was purified by column chromatography (hexane / ethyl acetate, 8:1) to give compound 15 (630.00 mg). MS (ESI) m / z: 933 [M+H] + .

[0105] tert-Butyl (3-((2R,3R,4R,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(dimethoxymethyl)-4-hydroxytetrahydrofuran-3-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate (compound 16). Compound 15 (630.00 mg, 0.68 mmol) was dissolved in THF (5 ml) and methanol (5 ml), ammonium chloride (1 ml) was added, and the solution was stirred at 50° C. for 8.5 hours. After cooling to room temperature, water (20 ml) was added, and the mixture was extracted with ethyl acetate (40 ml × 2). The organic layer was washed with brine (40 ml), dried over NaSO, filtered, and evaporated. The residue was purified by column chromatography (hexane / ethyl acetate, 6:1) to give compound 16 (530.00 mg). MS (ESI) m / z: 933 [M+H] + .

[0106] tert-Butyl (1-((2R,3S,4R,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(dimethoxymethyl)-4-((phenoxycarbonothioyl)oxy)tetrahydrofuran-3-yl)-6-(propylthio)-1H-[1,2,3]triazolo[4,5-c]pyridin-4-yl)((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate (compound 17): A mixture of compound 16 (530.00 mg, 0.60 mmol), DMAP (727.00 mg, 5.95 mmol), and phenyl thiochloroformate (513.00 mg, 2.97 mmol) in MeCN (20 mL) was heated at 70 °C for 5 h. After cooling to room temperature and evaporation, the residue was partitioned between water (50 mL) and dichloromethane (100 mL), and the aqueous phase was extracted with dichloromethane (100 mL). The combined organic phases were washed with brine (100 mL), dried over NaSO, and evaporated. The residue was purified by column chromatography (hexane / ethyl acetate, 8:1) to give compound 17 (360.00 mg). ES-API m / z: 1027 [M+H] + .

[0107] tert-Butyl (3-((2R,3R,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(dimethoxymethyl)tetrahydrofuran-3-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate (compound 18). Compound 17 (360.00 mg, 0.35 mmol) was dissolved in toluene (5 ml), AIBN (73.00 mg, 0.44 mmol) and Bu3SnH (306.00 mg, 1.05 mmol) were added, and the mixture was heated at 90 °C for 4 h. After cooling to room temperature and evaporation, the residue was partitioned between saturated aqueous NaHCO3 (50 ml) and dichloromethane (100 ml). The organic phase was washed with brine (50 ml), dried over Na2SO4, filtered, and evaporated. The residue was purified by column chromatography (hexane-ethyl acetate, 10:1) to give compound 18 (230.00 mg). MS (ESI) m / z: 875 [M+H] + .

[0108] ((2R,3R,5R)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2,5-diyl)dimethanol (compound 19): A solution of compound 18 (220.00 mg, 0.25 mmol) in 1,4-dioxane (10 ml) and 2% HCl (10 ml) was heated at 90 °C for 3 h. After cooling to room temperature, the mixture was neutralized with saturated aqueous NaHCO (50 ml) and extracted with ethyl acetate (50 ml × 2). The organic layer was washed with brine (100 ml), dried, and evaporated under reduced pressure. The residue (195.00 mg) was dissolved in methanol (10 ml), sodium borohydride (26.00 mg, 0.69 mmol) was added, and the solution was stirred at room temperature for 25 min. Water (50 ml) was added, and the mixture was extracted with ethyl acetate (50 ml × 2). The organic phase was washed with brine (50 ml), dried over NaSO, filtered, and evaporated. The residue was purified by column chromatography (dichloromethane / methanol, 20:1) to give compound 19 (23.00 mg). MS(ESI) m / z:493[M+H] + . 1 H-NMR(400MHz,MeOH-d4):7.21-7.07(3H,m),5.38-5.35(1H,q),4.56-4.52(1 H,m),4.40-4.36(1H,m),3.70-3.80(3H,m),3.62-3.56(1H,dd),3.13-3.09(1H ,m),3.06-3.03(1H,m),2.96-2.94(1H,m),2.68-2.64(2H,m),2.13-2.12(1H,m ),1.65-1.60(2H,m),1.48-1.46(1H,m),1.40-1.36(1H,m),0.94-0.91(3H,t).

[0109] Example 3 Preparation of (2S,3R,4S)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol (Compound 27)

[0110] [ka]

[0111] (2R,3R,4S)-4-Azido-2-(dimethoxymethyl)tetrahydrofuran-3-ol (compound 20): A mixture of compound SM2 (7.32 g, 45.56 mmol), sodium azide (11.89 g, 0.18 mol), and ammonium chloride (12.22 g, 0.23 mol) in water (73.2 ml) and ethanol (293 ml) was refluxed for 22 hours. After cooling and evaporation, water (200 ml) was added, and the mixture was extracted with dichloromethane (200 ml x 2). The organic layer was washed with brine (200 ml), dried overnight, and evaporated to give compound 20 (7.77 g). MS (ESI) m / z: 221 [M+NH4] + .

[0112] (2R,3R,4S)-4-Azido-2-(dimethoxymethyl)tetrahydrofuran-3-yl acetate (compound 21): A solution of compound 20 (7.77 g, 38.26 mmol), AcO (15.60 g, 0.15 mol), and DMAP (23.40 g, 0.19 mol) in 1,2-dichloroethane (200 mL) was heated at 55 °C for 3.5 h. After cooling, it was partitioned between dichloroethane and 1 N aqueous HCl (200 mL). The organic phase was further washed with saturated aqueous NaHCO (200 mL) and brine (200 mL), dried over anhydrous NaSO, filtered, and evaporated. The residue was purified by column chromatography (hexane / ethyl acetate = 10:1) to give compound 21 (8.83 g). MS (ESI) m / z: 263 [M+NH] + .

[0113] (2R,3R,4S)-4-amino-2-(dimethoxymethyl)tetrahydrofuran-3-yl acetate (compound 22): A solution of compound 21 (8.83 g, 36.03 mmol) in methanol (100 ml) was stirred with Pd / C (10%, 883.00 mg) under hydrogen overnight. The mixture was then filtered through Celite and concentrated to give compound 22 (7.04 g). MS (ESI) m / z: 220 [M+H] + .

[0114] (2R,3R,4S)-4-((6-chloro-5-nitro-2-(propylthio)pyrimidin-4-yl)amino)-2-(dimethoxymethyl)tetrahydrofuran-3-yl acetate (compound 23): 4,6-Dichloro-5-nitro-2-(propylthio)pyrimidine (6.75 g, 25.28 mmol) was dissolved in THF (135 mL), and a solution of compound 22 (5.50 g, 25.10 mmol) in THF (110 mL) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 17 h. The mixture was then evaporated, and the residue was purified by column chromatography (hexane / ethyl acetate, 6:1) to give compound 23 (3.45 g). MS (ESI) m / z: 451 [M+H] + .

[0115] (2R,3R,4S)-4-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-(dimethoxymethyl)tetrahydrofuran-3-yl acetate (compound 25): A solution of compound 23 (688.00 mg, 1.53 mmol) in acetic acid (5 ml) and water (1 ml) was stirred with Fe powder (427.00 mg, 7.65 mmol) at room temperature overnight (compound 24 was monitored by LC-MS). Sodium nitrite (212.00 mg, 3.07 mmol) was added, and the mixture was stirred for an additional hour. Ethyl acetate (50 ml) and water (50 ml) were added. The mixture was partitioned between ethyl acetate and water, and the aqueous phase was extracted with ethyl acetate (50 ml). The combined organic layers were washed with saturated aqueous NaHCO3 (50 ml x 2) and brine (50 ml), dried over Na2SO4, filtered, and evaporated to give crude compound 25 (680.00 mg). MS (ESI) m / z: 432 [M+H] + .

[0116] (2R,3R,4S)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-(dimethoxymethyl)tetrahydrofuran-3-yl acetate (compound 26): (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (264 mg, 1.56 mmol), compound 25 (56 0m g, 1.30 mmol) and DIPEA (50 4m A solution of 26 (26.2 g, 3.90 mmol) in ethyl acetate (20 ml) was stirred overnight at room temperature. It was washed with saturated aqueous NaHCO (50 ml) and brine (50 ml), dried over anhydrous NaSO, filtered, and evaporated. The residue was purified by column chromatography (hexane / ethyl acetate, 3:1) to give compound 26 (570.00 mg). MS (ESI) m / z: 565 [M+H] + .

[0117] (2S,3R,4S)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol (compound 27): A solution of compound 28 (100.00 mg, 0.18 mmol) in 1,4-dioxane (2 ml) and 2% aqueous HCl (2 ml) was heated at 85 °C for 2 h. After cooling, saturated aqueous NaHCO (20 ml) was added, and the mixture was extracted with ethyl acetate (40 ml × 2). The organic phase was washed with brine (40 ml), dried over anhydrous NaSO, filtered, and evaporated under reduced pressure. The residue (108.00 mg, 0.23 mmol) was dissolved in methanol (5 ml), sodium borohydride (15 mg) was added, and the solution was stirred at room temperature for 20 min. Water (70 ml) was added, and the mixture was extracted with ethyl acetate (50 ml × 2). The organic layer was washed with brine (50 ml), dried over anhydrous NaSO, filtered, and evaporated. The residue was purified by column chromatography (DCM / isopropanol, 10:1) to give compound 27 (40.00 mg). MS(ESI) m / z:479[M+H] + . 1 H-NMR(400MHz,MeOH-d4):7.09-7.26(3H,m),4.90-5.36(1H,m),4.81-4.84(1H,t),4.31-4.42(2H ,m),374-3.96(3H,m),2.91-3.17(3H,m),2.13-2.21(1H,m),1.32-1.54(4H,m),0.91-1.07(3H,m).

[0118] Example 4 Preparation of ((2R,4R)-4-(7-(((1S,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl)methanol (Compound 32)

[0119] [ka]

[0120] (2R,3R,4S)-4-(7-((tert-butoxycarbonyl)((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-(dimethoxymethyl)tetrahydrofuran-3-yl acetate (compound 28): To a solution of compound 26 (1.3 g, 2.5 mmol) and DMAP (843 mg, 6.9 mmol) in dichloromethane (20 ml) was added (Boc)2O (754.00 mg, 3.46 mmol). The resulting solution was stirred at room temperature for 24 hours. The solution was partitioned between dichloromethane and water (30 ml). The organic layer was washed with 1N aqueous HCl (10 ml), saturated aqueous NaHCO3 (10 ml), and brine (30 ml), dried over anhydrous Na2SO4, and evaporated. The residue was purified by column chromatography (dichloromethane-ethyl acetate, 10:1) to give compound 28 (1.317 g). MS (ESI) m / z: 665 [M+H] + .

[0121] tert-Butyl ((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)(3-((3S,4R,5R)-5-(dimethoxymethyl)-4-hydroxytetrahydrofuran-3-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)carbamate (compound 29): Compound 28 (1.317 g, 1.98 mmol) was dissolved in THF (15 mL) and methanol (15 mL) and NH . H2O (41 ml) was added. The reaction solution was stirred at 50 °C for 8 hours. After cooling and evaporation, water (20 ml) was added and the mixture was extracted with ethyl acetate (20 ml x 2). The organic layer was washed with brine (25 ml), dried over Na2SO4 and evaporated under reduced pressure. The residue was chromatographed on silica (dichloromethane-ethyl acetate, 6:1) to give compound 29 (945 mg). MS (ESI) m / z: 623 [M+H]+ .

[0122] tert-Butyl ((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)(1-((3S,4R,5R)-5-(dimethoxymethyl)-4-((phenoxycarbonothioyl)oxy)tetrahydrofuran-3-yl)-6-(propylthio)-1H-[1,2,3]triazolo[4,5-c]pyridin-4-yl)carbamate (compound 30). To a solution of compound 29 (945.00 mg, 1.52 mmol) in MeCN (10 ml) were added DMAP (1.86 g, 15.19 mmol) and phenyl thiochloroformate (1.31 g, 7.59 mmol), and the mixture was heated at 70 °C for 5 h. After cooling and evaporation, water (30 ml) was added, and the mixture was extracted with DCM (25 ml × 2). The organic layer was washed with brine (15 ml), dried over Na2SO4, and evaporated. The residue was chromatographed on silica using n-hexane-ethyl acetate (5:1) as the eluent to give compound 30 (865 mg). MS (ESI) m / z: 758 [M+H] + .

[0123] tert-Butyl ((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)(3-((3R,5R)-5-(dimethoxymethyl)tetrahydrofuran-3-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)carbamate (compound 31). To a solution of compound 30 (865 mg, 1.14 mmol) in toluene (20 ml) were added AIBN (187 mg, 1.14 mmol) and Bu3SnH (830 mg, 2.85 mmol), and the mixture was stirred at 90 °C for 4 h. After cooling and evaporation, saturated aqueous NaHCO3 (50 ml) was added, and the mixture was extracted with DCM (30 ml × 2). The organic layer was washed with saturated aqueous NaHCO3 (50 ml), dried over Na2SO4, and evaporated. The residue was chromatographed on silica (dichloromethane-ethyl acetate, 20:1) to give compound 31 (646 mg). MS (ESI) m / z: 607 [M+H] + .

[0124] ((2R,4R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl)methanol (compound 32). To a solution of compound 31 (370 mg, 0.61 mmol) in 1,4-dioxane (5 ml) was added 2% aqueous HCl (5 ml), and the mixture was heated at 90 °C for 2 h. After cooling, saturated aqueous NaHCO (30 ml) was added, and the mixture was extracted with ethyl acetate (30 ml × 2). The combined organic layers were washed with brine (30 ml), dried over NaSO, and evaporated under reduced pressure. The residue (280 mg) was dissolved in methanol (10 ml), sodium borohydride (16.00 mg, 0.69 mmol) was added, and the resulting mixture was stirred at room temperature for 30 min. The solution was partitioned between ethyl acetate (100 ml) and water (50 ml). The organic layer was washed with brine (50 ml), dried over NaSO, and evaporated. The residue was chromatographed on silica (DCM / methanol, 40:1) to give compound 32 (18.7 mg). MS(ESI) m / z:463[M+H] + . 1 H-NMR(400MHz,CDCl3):7.12-7.00(3H,m),6.77(1H,s),5.52-5.48(1H,m),4.38- 4.36(1H,dd),4.35-4.27(1H,m),4.20-4.17(1H,m),3.98-3.96(1H,dd),3.79-3.7 6(1H,dd),3.12-3.06(2H,m),2.99-2.95(1H,m),2.68-2.62(2H,m),2.27-2.16(1 H,m),1.68-1.64(2H,m),1.44-1.41(1H,m),1.38-1.35(1H,m),0.96-0.93(3H,t).

[0125] Example 5 Preparation of ((2R,3S,4S,5S)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-4-fluorotetrahydrofuran-2,5-diyl)dimethanol (compound 39a)

[0126] [ka]

[0127] (((2R,3S,4R,5S)-3-azido-5-(dimethoxymethyl)-4-fluorotetrahydrofuran-2-yl)methoxy)(tert-butyl)diphenylsilane (Compound 33a) and (((2R,3S,4S,5S)-3-azido-5-(dimethoxymethyl)-4-fluorotetrahydrofuran-2-yl)methoxy)(tert-butyl)diphenylsilane (Compound 33b) To a solution of compound 2 (4.50 g, 9.55 mmol) in 50 ml of THF was added DAST (3.08 g, 19.1 mmol), and the reaction mixture was stirred under N for 3 h. After cooling to 0 °C, it was neutralized with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (100 ml × 2), the organic layer was washed with brine (100 ml), dried over anhydrous NaSO, evaporated, and the residue was purified by column chromatography on silica (n-hexane-ethyl acetate, 10:1) to give compounds 33a and 33b (approximately 2:1, 2.38 g, 59.5%). MS (ESI) m / z: 491 [M+18] + .

[0128] (2R,3S,4S,5S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(dimethoxymethyl)-4-fluorotetrahydrofuran-3-amine (Compound 34a) and (2R,3S,4R,5S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(dimethoxymethyl)-4-fluorotetrahydrofuran-3-amine (Compound 34b) A solution of compounds 33a and 33b (2.38 g, 5.03 mmol) in ethyl acetate (25 ml) was stirred with Pd / C (238 mg) under hydrogen overnight. Filtration through Celite and evaporation gave compounds 34a and 34b (2.00 g). MS (ESI) m / z: 448 [M+H] + .

[0129] N-((2R,3S,4S,5S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(dimethoxymethyl)-4-fluorotetrahydrofuran-3-yl)-6-chloro-5-nitro-2-(propylthio)pyrimidin-4-amine (Compound 35a) and N-((2R,3S,4R,5S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(dimethoxymethyl)-4-fluorotetrahydrofuran-3-yl)-6-chloro-5-nitro-2-(propylthio)pyrimidin-4-amine (Compound 35b) A solution of compounds 34a and 34b (2.00 g, 4.47 mmol) and 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine (1.19 g, 4.47 mmol) in tetrahydrofuran (45 ml) was stirred for 20 hours. The solution was partitioned between ethyl acetate (50 ml) and water (40 ml). The organic layer was dried over anhydrous Na2SO4, evaporated, and the residue was chromatographed on silica (n-hexane-ethyl acetate, 25:1) to give compound 35a (1.24 g) and compound 35b (690 mg). MS (ESI) m / z: 679 [M+H] + .

[0130] 3-((2R,3S,4S,5S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(dimethoxymethyl)-4-fluorotetrahydrofuran-3-yl)-7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (compound 36a) A solution of compound 35a (1.24 g, 1.83 mmol) in acetic acid (24 ml) and water (6 ml) was stirred with iron powder (511.00 mg, 9.15 mmol) at room temperature. After 16 h, sodium nitrite (253.00 mg, 2.04 mmol) was added. After stirring at room temperature for 2 h, the mixture was partitioned between ethyl acetate (200 ml) and saturated aqueous NaHCO3 (200 ml). The organic layer was washed with brine (200 ml), dried over anhydrous Na2SO4, evaporated in vacuo, and the residue was chromatographed on silica (n-hexane-ethyl acetate, 10:1) to give compound 36a (540.00 mg). MS (ESI) m / z: 660 [M+H] + .

[0131] 3-((2R,3S,4S,5S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(dimethoxymethyl)-4-fluorotetrahydrofuran-3-yl)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-amine (Compound 37a) A solution of (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (78 mg, 0.455 mmol), compound 36a (250 mg, 0.379 mmol), and DIPEA (150.00 mg, 1.14 mmol) in ethyl acetate (20 mL) was stirred at room temperature for 1 h. It was partitioned between ethyl acetate (50 mL) and saturated aqueous NaHCO3 (20 mL). The organic layer was washed with saturated aqueous NaHCO3 (20 mL), dried over anhydrous Na2SO4, evaporated, and the residue was chromatographed on silica (eluting with n-hexane-ethyl acetate, 5:1) to give compound 37a (220.00 mg). ES (ESI) m / z: 793 [M+H] + .

[0132] ((2S,3S,4S,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3-fluorotetrahydrofuran-2-yl)methanol (Compound 38a) To a solution of compound 37a (220.00 mg, 0.278 mmol) in 23 ml of dichloromethane, trifluoroacetic acid (10 ml) was added, and the reaction mixture was stirred at room temperature for 4 hours. It was then poured into 300 ml of saturated aqueous NaHCO3. After stirring for 10 minutes, the mixture was extracted with dichloromethane (100 ml × 2). The organic phase was washed with brine (100 ml), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue (207 mg) was dissolved in methanol (5 ml), and sodium borohydride (23 mg, 0.55 mmol) was added. The solution was stirred at room temperature for 0.5 hours. The solution was partitioned between ethyl acetate (50 ml) and water (50 ml). The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The residue was chromatographed on silica gel (n-hexane-ethyl acetate, 3:1) to give compound 38a (178.00 mg). MS(ESI) m / z:749[M+H] + .

[0133] ((2R,3S,4S,5S)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-4-fluorotetrahydrofuran-2,5-diyl)dimethanol (compound 39a) Under an inert atmosphere (N), TBAF (1M in THF, 1 ml) was added to a solution of compound 43 (178 mg) in THF (5 ml), and the mixture was stirred at room temperature for 4 hours. It was then diluted with ethyl acetate (20 ml) and washed with water (10 ml × 2) and brine (10 ml). The organic phase was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography (dichloromethane / methanol, 40:11) to give compound 39a (36 mg). MS (ESI) m / z: 511 [M+H] + . 1 H-NMR(400MHz,CDCl3):7.14-6.98(3H,m),5.65(0.5H,m),5.55(0.5H,m),5.48-5.45(0 .5H,m),5.39-5.37(1.5H,m),4.60-4.57(0.5H,m),4.52-4.50(0.5H,m),4.11-4.08(1H ,m),4.01-3.92(2H,m),3.80-3.77(1H,m),3.15-3.13(1H,m),3.08-3.01(2H,m),2.96- 2.91(1H,m),2.15-2.13(1H,t),1.66-1.61(2H,m),1.43-1.25(2H,m),0.94-0.90(3H,t)

[0134] Example 6 Preparation of ((2R,3S,4R,5S)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-4-fluorotetrahydrofuran-2,5-diyl)dimethanol (compound 39b)

[0135] [ka]

[0136] 3-((2R,3S,4R,5S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(dimethoxymethyl)-4-fluorotetrahydrofuran-3-yl)-7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (compound 36b) A solution of compound 35b (690.00 mg, 1.02 mmol) in acetic acid (12 mL) and water (3 mL) was stirred with iron powder (285.00 mg, 5.09 mmol) at room temperature. After 16 h, sodium nitrite (141.00 mg, 2.04 mmol) was added. The mixture was stirred at room temperature for an additional 2 h. The mixture was partitioned between ethyl acetate (200 mL) and saturated aqueous NaHCO3 (200 mL). The organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was subjected to silica gel chromatography (hexane-ethyl acetate, 10:1) to give compound 36b (280.00 mg, 41.72%). MS (ESI) m / z: 660 [M+H] + .

[0137] 3-((2R,3S,4R,5S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(dimethoxymethyl)-4-fluorotetrahydrofuran-3-yl)-N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-amine (Compound 37b) A solution of (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (62 mg, 0.364 mmol), compound 37b (200 mg, 0.303 mmol), and DIPEA (120.00 mg, 0.91 mmol) in ethyl acetate (10 mL) was stirred at room temperature for 1 hour. The solution was partitioned between ethyl acetate (50 mL) and saturated aqueous NaHCO3 (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified on a silica gel column (n-hexane-ethyl acetate, 5:1) to give compound 37b (224.00 mg). MS (ESI) m / z: 793 [M+H] +.

[0138] ((2S,3R,4S,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3-fluorotetrahydrofuran-2-yl)methanol (Compound 38b) To a solution of 38b (200.00 mg, 0.278 mmol) in 23 ml of dichloromethane was added 10 ml of trifluoroacetic acid. The reaction was stirred at room temperature for 4 hours. The mixture was then added dropwise to saturated aqueous NaHCO3 (300 ml), stirred for an additional 10 minutes, and extracted with dichloromethane (2 × 100 ml). The organic phase was washed with brine (100 ml), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The residue (205 mg) was dissolved in methanol (5 ml), sodium borohydride (22 mg, 0.55 mmol) was added, and the solution was stirred at room temperature for 0.5 hours. The solution was partitioned between ethyl acetate (50 ml) and water (50 ml). The organic layer was dried and evaporated in vacuo. The residue was purified on a silica gel column (n-hexane-ethyl acetate, 3:1) to give compound 38b (135.00 mg). MS(ESI) m / z:749[M+H] + .

[0139] ((2R,3S,4R,5S)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-4-fluorotetrahydrofuran-2,5-diyl)dimethanol (compound 39b) To a solution of compound 38b (135 mg, 0.18 mmol) in 5 ml of THF was added TBAF (1 M in THF, 1 ml), and the mixture was stirred at room temperature for 4 hours. It was then partitioned between ethyl acetate (20 ml) and water (10 ml). The organic phase was washed with water (10 ml) and brine (10 ml), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol, 40:1) to give compound 39b (26 mg). MS (ESI) m / z: 511 [M+H] + . 1 H-NMR(400MHz,CDCl3):7.63-6.98(4H,m),6.08-6.07(0.5H,t),5.95-5.9 3(0.5H,t),5.64-5.58(1H,m),4.59-4.50(1H,m),4.49-4.44(1H,m),3.99 -3.93(3H,m),3.73-3.69(1H,m),3.16-3.05(2H,m),2.96-2.91(1H,m),2. 17-2.15(1H,m),1.66-1.61(2H,m),1.44-1.39(2H,m),1.05-1.01(3H,t).

[0140] Example 7 Preparation of (2R,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-carboxylic acid (compound 42)

[0141] [ka]

[0142] (2R,4R,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-carbaldehyde (Compound 40) To a solution of compound 18 (960 mg, 1.10 mmol) in dichloromethane (15 ml) was added TFA (5 ml), and the reaction solution was stirred at room temperature for 3 hours. The mixture was then added dropwise to saturated aqueous NaHCO3 (100 ml) and extracted with dichloromethane (2 x 30 ml). The organic phase was washed with brine (100 ml), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give compound 40 (760 mg) as a pale yellow foamy solid. MS (ESI) m / z: 747 [M + HO + H] +

[0143] (2R,4R,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-carboxylic acid (Compound 41) To a solution of compound 40 (400 mg, 0.56 mmol) in a mixture of THF (3 mL), DMSO (3 mL), and HO (3 mL), 0.2 M aqueous NaHPO (2 mL) and NaClO (75 mg, 1.00 mmol) were added, and the resulting mixture was stirred at room temperature for 1.5 h. The reaction was quenched with saturated aqueous NaSO (10 mL), adjusted to pH 4-5 with 1 N aqueous HCl, and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and evaporated under reduced pressure to give compound 41 (400 mg) as a white foamy solid. MS (ESI) m / z: 745 [M+H] + .

[0144] (2R,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-carboxylic acid (Compound 42) To a solution of compound 41 (400 mg, 0.54 mmol) in dry THF (10 ml) was added TBAF (1 ml, 1 M in THF), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then diluted with ethyl acetate (50 ml) and washed with 1 M aqueous HCl (20 ml) and brine (20 ml). The organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by C 18 Purification by column chromatography (acetonitrile / HO, 6:4 to 5:5) gave compound 42 (110 mg) as a white foamy solid. MS (ESI) m / z: 507 [M+H] + . 1 H-NMR(400MHz,DMSO):9.0(1H,s),7.38-7.29(2H,m),7.09-7.07(1H,m),5. 30-5.24(4H,q),4.70-4.67(1H,t),4.55-4.46(1H,m),3.61-3.57(1H,dd),3 .50-3.46(1H,dd),3.18-3.07(2H,m),2.97-2.78(3H,m),2.15-2.10(1H,m), 1.57-1.47(2H,m),1.41-1.36(1H,q),1.01-0.97(1H,q),0.85-0.81(3H,t).

[0145] Example 8 Preparation of (2R,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylsulfinyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-carboxylic acid (compound 43)

[0146] [ka]

[0147] To a solution of compound 42 (80 mg, 0.16 mmol) in DCM (20 ml) was added m-CPBA (27.3 mg, 0.16 mmol), and the resulting mixture was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure, and the residue was purified by C 18 Purification by column chromatography (acetonitrile / HO, 1:5 to 1:4) gave compound 43 (28 mg) as a white solid. MS (ESI) m / z: 523 [M+H] + . 1 H-NMR(400MHz,CDCl3):7.11-6.94(3H,m),5.62-5.58(1H,m),4.90-4.88(1H,m),4.65-4.50(1H,m),3.97-3.93(1H,dd),3.77-3 .74(1H,dd),3.30-3.26(2H,m),3.17-3.01(3H,m),2.20-2.13(1H,m),1.72-1.67(2H,m),1.45-1.35(2H,m),,1.05-0.98(3H,t).

[0148] Example 9 Preparation of ((2R,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(methoxymethyl)tetrahydrofuran-2-yl)methanol (Compound 49)

[0149] [ka]

[0150] tert-Butyl (3-((2R,3R,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-formyltetrahydrofuran-3-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate (Compound 44) To a solution of compound 40 (850 mg, 1.14 mmol) in dichloromethane (50 mL) was added DMAP (310 mg, 2.54 mmol) and BocO (300 mg, 1.37 mmol), and the resulting solution was stirred overnight. The solution was then washed with 1 N aqueous HCl (10 mL), and the organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and evaporated under reduced pressure to give compound 44 (960 mg). MS (ESI) m / z: 847 [M + HO + H] + .

[0151] tert-Butyl (3-((2R,3R,5R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(hydroxymethyl)tetrahydrofuran-3-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate (Compound 45) To a solution of compound 44 (960 mg, 1.13 mmol) in methanol (20 ml) was added NaBH4 (55 mg, 1.44 mmol), and the resulting mixture was stirred at 0 °C for 1 h. The mixture was then partitioned between dichloromethane (60 ml) and water (60 ml). The organic phase was washed with brine (20 ml), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give compound 45 (831 mg). MS (ESI) m / z: 831 [M+H] + .

[0152] tert-Butyl (3-((2R,3R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-2-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-3-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate (Compound 46) To a solution of compound 45 (831 mg, 1.00 mmol) in dry pyridine (20 ml) was added DMTrCl (507 mg, 1.50 mmol), and the resulting mixture was stirred overnight at room temperature. The mixture was then diluted with dichloromethane (50 ml) and washed with brine (30 ml × 3). The organic phase was dried over anhydrous NaSO, filtered, and evaporated under reduced pressure. The residue was further purified by column chromatography (n-hexane / ethyl acetate, 15:1 to 5:1) to give compound 46 (660 mg). MS (ESI) m / z: 1133 [M+H] + .

[0153] tert-Butyl (3-((2R,3R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-2-(hydroxymethyl)tetrahydrofuran-3-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate (Compound 47) To a solution of compound 46 (660 mg, 0.58 mmol) in THF (10 mL), TBAF (2.5 mL, 1 M in THF) was added, and the reaction solution was stirred at room temperature for 3 hours. After evaporation, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate, 3:1) to give compound 47 (190 mg). MS (ESI) m / z: 895 [M+H] + .

[0154] tert-Butyl (3-((2R,3R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-2-(methoxymethyl)tetrahydrofuran-3-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate (Compound 48) A mixture of compound 47 (145 mg, 0.16 mmol), MeI (350 mg, 2.46 mmol), and AgO (600 mg, 4.84 mmol) in acetonitrile (6 mL) was stirred overnight. After filtration, the filter cake was washed with ethyl acetate (30 mL), and the filtrate was evaporated under reduced pressure to give compound 48 (100 mg). MS (ESI) m / z: 909 [M+H] + .

[0155] ((2R,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(methoxymethyl)tetrahydrofuran-2-yl)methanol (Compound 49) To a solution of compound 48 (100 mg, 0.11 mmol) in dichloromethane (10 ml), TFA (2 ml) was added, and the reaction solution was stirred for 1 hour. The reaction was then quenched with saturated aqueous NaHCO3 (30 ml) and extracted with DCM (30 ml). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate, 1:2) to give compound 49 (50 mg). MS (ESI) m / z: 507 [M+H] + . 1 H-NMR(400MHz,CDCl3):7.20-6.95(3H,m),6.68(1H,s),5.46-5.40(1H,q),4.67-4 .64(1H,m),4.50-4.47(1H,m),3.90-3.86(1H,dd),3.81-3.72(2H,m),3.63-3.60(1 H,dd),3.52-3.48(1H,m),3.39(3H,s),3.07(3H,m),2.81-2.75(1H,m),2.67-2.60( 1H,m),2.16-2.14(1H,m),1.68-1.66(2H,m),1.42-1.38(2H,m),0.99-0.96(3H,t).

[0156] Example 10 Preparation of 2-((2R,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-yl)ethan-1-ol (compound 54)

[0157] [ka]

[0158] ((2R,4R,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl)methanol (Compound 50) To a stirred solution of compound 40 (1.50 g, 2.06 mmol) in methanol (30 mL) was added NaBH4 (273 mg, 7.21 mmol) at 0 °C, and the reaction mixture was stirred for 4 h. The reaction was then quenched with 2% aqueous HCl to pH = 7, concentrated, and extracted with dichloromethane (100 mL x 3). The organic layer was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate, 5:1 to 3:1) to give compound 50 (900 mg). MS (ESI) m / z: 731 [M+H] + .

[0159] tert-Butyl (3-((2R,3R,5R)-5-(bromomethyl)-2-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-3-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate (Compound 51) A solution of PPh3 (197 mg, 0.75 mmol) and CBr4 (259 mg, 0.75 mmol) in toluene (20 ml) was stirred at 0 °C for 15 min. Compound 50 (500 mg, 0.68 mmol) was added, and the resulting solution was stirred at room temperature for an additional 2 h. After evaporation, the residue was purified by gel column chromatography (n-hexane / ethyl acetate, 5:1 to 3:1) to give compound 51 (300 mg). MS (ESI) m / z: 793 [M+H] + .

[0160] 2-((2R,4R,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl)acetaldehyde (Compound 52) To a solution of compound 51 (200 mg, 0.25 mmol) in THF (20 ml) was added n-BuLi (0.9 ml, 1.6 M in THF) under a N2 atmosphere at -78 °C, and the mixture was stirred at this temperature for 15 minutes. DMF (4.5 ml) was added, and the resulting mixture was then stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous NH4Cl (10 ml) and extracted with ethyl acetate (50 ml). The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (20 ml). The combined organic phase was washed with brine (10 ml × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was further washed with n-hexane (5 ml × 2), and the solid was collected to give compound 52 (180 mg). MS (ESI) m / z: 743 [M+H] + .

[0161] 2-((2R,4R,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl)ethan-1-ol (Compound 53) To a stirred solution of compound 52 (180 mg, 0.24 mmol) in methanol (10 ml) was added NaBH (90 mg, 2.37 mmol) at 0 °C, and the reaction mixture was stirred overnight. The mixture was then partitioned between ethyl acetate (40 ml) and brine (40 ml). The aqueous layer was extracted with ethyl acetate (20 ml). The combined organic layers were washed with brine (10 ml × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate, 2:1) to give compound 53 (80 mg). MS (ESI) m / z: 745 [M+H] + .

[0162] 2-((2R,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-yl)ethan-1-ol (Compound 54) To a solution of compound 53 (80 mg, 0.11 mmol) in THF (10 ml), TBAF (1 ml, 1 M in THF) was added, and the reaction solution was stirred overnight at room temperature. It was then concentrated, and the residue was partitioned between dichloromethane (30 ml) and water (10 ml). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by gel column chromatography (dichloromethane / methanol, 20:1) to give compound 54 (50 mg). MS (ESI) m / z: 507 [M+H] + . 1 H-NMR(400MHz,CDCl3):7.33(1H,m),7.20(1H,d),7.10-7.00(1H,m),5.55-5.65(1H,m),4.99-4.80(3H,m),4.18-4.17(1H,m),3.68-3.61(1 H,m),3.50-3.48(1H,m),3.10-3.01(4H,m),2.93-2.85(1H,m),2.19- 2.17(1H,t),1.73-1.68(2H,m),1.51-1.29(4H,m),1.01-0.97(1H,t).

[0163] Example 11 Preparation of 2-(((2R,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-yl)methoxy)ethan-1-ol (Compound 56)

[0164] [ka]

[0165] 2-(((2R,4R,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl)methoxy)ethan-1-ol (Compound 55) To a solution of compound 50 (200 mg, 0.27 mmol) in THF (3 ml) was added n-BuLi (1 ml, 1.6 M in THF) under a N2 atmosphere at -78 °C, and the mixture was stirred at this temperature for 15 minutes. Ethylene oxide (2.7 ml, 1 M in THF) was added, and the mixture was then stirred at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl (10 ml) and partitioned between ethyl acetate (50 ml) and water (20 ml). The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (30 ml). The combined organic phase was washed with brine (10 ml × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give compound 55 (207 mg). MS (ESI) m / z: 775 [M+H] + .

[0166] 2-(((2R,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-yl)methoxy)ethan-1-ol (Compound 56) To a solution of compound 55 (207 mg, 0.27 mmol) in THF (6 ml) was added TBAF (2 ml, 1 M in THF), and the reaction solution was stirred at room temperature overnight. It was then concentrated, and the residue was partitioned between dichloromethane (50 ml) and water (10 ml). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by C 18 Purification by column chromatography (acetonitrile / water, 20:1) gave compound 56 (50 mg). MS (ESI) m / z: 537 [M+H] + . 1 H-NMR(400MHz,CDCl3):7.10-6.99(2H,m),6.82-6.73(1H,m),4.48-4,37(1H, m),4.33-4.22(1H,m),4.09-4.06(1H,m),4.00-3.86(2H,m),3.82-3.73(2H,m ),3.56-3.53(2H,m),3.53-3.40(2H,m),3.30-2.89(4H,m),2.80-2.60(1H,m) ,2.28-2.18(1H,m),1.70-1.60(2H,m),1.59-1.43(2H,m),0.92-0.89(3H,t).

[0167] Example 12 Preparation of 3-((2S,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-yl)propanoic acid (compound 60)

[0168] [ka]

[0169] Ethyl (E)-3-((2R,4R,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl)acrylate (Compound 57) To a solution of (carbethoxymethyl)triphenylphosphonium bromide (1.71 g, 4 mmol) in THF (5 mL) was added dropwise n-BuLi (1 mL, 4 M in THF) under a N2 atmosphere at -78 °C, and the resulting mixture was stirred at this temperature for 15 min. A solution of compound 40 (200 mg, 0.27 mmol) in THF (1.5 mL) was added, and the reaction mixture was further stirred at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl (5 mL) and partitioned between ethyl acetate (30 mL) and water (30 mL). The organic phase was washed with brine (10 mL × 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate, 15:1 to 5:1) to give compound 57 (100 mg). MS (ESI) m / z: 799 [M+H].

[0170] Ethyl 3-((2S,4R,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl)propanoate (Compound 58) A mixture of compound 57 (95 mg, 0.12 mmol) and Pd / C (20 mg) in methanol (10 mL) and ethyl acetate (10 mL) was stirred overnight under an H atmosphere. The mixture was then filtered and concentrated under reduced pressure to give compound 58 (90 mg). MS (ESI) m / z: 801 [M+H] + .

[0171] Ethyl 3-((2S,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-yl)propanoate (Compound 59) To a solution of compound 58 (90 mg, 0.11 mmol) in THF (3 mL) was added TBAF (0.5 mL, 1 M in THF), and the reaction mixture was stirred overnight at room temperature. The solution was then concentrated and partitioned between ethyl acetate (20 mL) and water (20 mL). The organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate, 5:1 to 1:1) to give compound 59 (53 mg). MS (ESI) m / z: 563 [M+H] + .

[0172] 3-((2S,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-yl)propanoic acid (Compound 60) To a solution of compound 59 (50 mg, 0.09 mmol) in THF (3 ml) and water (3 ml) was added LiOH (10 mg, 0.42 mmol), and the resulting reaction mixture was stirred overnight at room temperature. The pH was then adjusted to 4 and partitioned between ethyl acetate (20 ml) and water (20 ml). The aqueous phase was further extracted with ethyl acetate (10 ml × 2). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by C 18 Purification by column chromatography (methanol / water, 1:5) gave compound 60 (30 mg). MS (ESI) m / z: 535 [M+H] + . 1H-NMR(400MHz,CDCl3):7.17-7.00(3H,m),6.49(1H,s),5.36-5.34(1H,q),4.45-4.43(1H,q),4.40-4.34(1H,m),3.85-3.81(1H,dd),3.66-3.63 ((1H,dd),3.10-3.07(3H,m),2.77-2.71(1H,m),2.52-2.48(1H,m),2.15 -2.05((3H,m),1.73-1.68(2H,m),1.40-1.37(2H,m),1.00-0.97(3H,t).

[0173] Example 13 Preparation of 2-(((((2R,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-yl)methoxy)methyl)benzoic acid (Compound 63)

[0174] [ka]

[0175] tert-Butyl 2-(((((2R,4R,5R)-4-(7-((tert-butoxycarbonyl)((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-((((tert-butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-2-yl)methoxy)methyl)benzoate (Compound 61) To a solution of compound 45 (125 mg, 0.15 mmol) in dry THF (15 ml) was added 60% NaH in mineral oil (60 mg, 1.5 mmol) under a N2 atmosphere at 0 °C, and the resulting mixture was stirred for 30 min. tert-Butyl 2-(bromomethyl)benzoate (200 mg, 0.74 mmol) was then added, and the mixture was allowed to warm to room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl (20 ml) and extracted with ethyl acetate (30 ml × 3). The organic phase was washed with brine (30 ml), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was further purified using a silica gel column (n-hexane / ethyl acetate, 10:1) to give compound 61 (110 mg). MS (ESI) m / z: 1021 [M+H] + .

[0176] 2-(((((2R,4R,5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl)methoxy)methyl)benzoic acid (Compound 62) Compound 61 (110 mg, 0.11 mmol) was dissolved in dichloromethane (6 ml) and TFA (2 ml) was added. The resulting solution was stirred for 3 hours. Then, saturated aqueous NaHCO3 was added to adjust the pH to 7, and the mixture was extracted with dichloromethane (30 ml x 2). The organic phase was washed with brine (30 ml), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate, 6:1) to give compound 62 (60 mg). MS (ESI) m / z: 865 [M+H] + .

[0177] 2-(((((2R,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-yl)methoxy)methyl)benzoic acid (Compound 63) To a solution of compound 62 (60 mg, 0.07 mmol) in dry THF (6 ml) was added TBAF (1 M in THF, 0.5 ml), and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was then partitioned between ethyl acetate (60 ml) and water (30 ml). The organic phase was washed with brine (30 ml), dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by C 18 Purification by column chromatography (acetonitrile / HO, 9:1 to 1:1) gave compound 63 (25 mg). MS (ESI) m / z: 627 [M+H] + . 1 H-NMR(400MHz,MeOD)8.03-8.01(1H,dd),7.44-7.40(1H,t),7.35-7.31(1H,t),7.23-7.18(1H,d),7 .15-6.78(3H,m),6.22-6.10(0.5H,m),5.83-5.59(1H,m),5.50-5.44(0.5H,m),5.41-5.35(1H,q),4 .53(1H,s),4.41-4.32(1H,s),3.81-3.78(3H.m),3.65-3.59(1H,m),3.18-3.11(1H,m),2.98-2.79( 2H,m),2.66-2.62(2H,t),2.46-2.25(1H,m),1.72-1.63(2H,m),1.43-1.26(2H,m),1.03-0.89(3H,t)

[0178] Example 14 Preparation of 2-(((2R,4R,5R)-4-(7-(((1S,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-yl)methoxy)acetic acid (Compound 65)

[0179] [ka]

[0180] tert-Butyl 2-(((2R,4R,5R)-4-(7-((tert-butoxycarbonyl)((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-2-yl)methoxy)acetate (Compound 64) To a solution of compound 45 (200 mg, 0.24 mmol) in acetonitrile (10 mL), ethyl 2-iodoacetate (513 mg, 2.4 mmol) and AgO (557 mg, 2.4 mmol) were added, and the resulting mixture was stirred at 60 °C for 3 days. The mixture was then filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate, 10:1) to give compound 64 (120 mg). MS (ESI) m / z: 945 [M+H] + .

[0181] 2-(((2R,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-yl)methoxy)acetic acid (Compound 65) To a solution of compound 64 (120 mg, 0.13 mmol) in dichloromethane (10 ml) was added TFA (3 ml), and the resulting solution was stirred at room temperature overnight. It was then partitioned between dichloromethane (50 ml) and saturated aqueous NaHCO3 (30 ml). The organic phase was washed with brine (20 ml), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in THF (5 ml), followed by the addition of TBAF (1 ml, 1 M in THF). The mixture was stirred overnight at room temperature and partitioned between ethyl acetate (50 ml) and saturated aqueous NH4Cl (30 ml). The organic phase was washed with brine (10 ml), dried over anhydrous Na2SO4, filtered, and evaporated. The residue was C 18 Purification by column chromatography (acetonitrile / water, 1:10) gave compound 64 (50 mg). MS (ESI) m / z: 551 [M+H] + . 1 H-NMR(400MHz,DMSO):,7.36-7.31(2H,m),7.10-7.03(1H,m),5.34-5.28(1H,q ),4.44-4.35(2H,m),3.78-3.72(1.5H,m),3.61-3.53(2.5H,m),3.48-3.43(2H, m),3.12-3.07(2H,m),2.97-2.85(2H,m),2.64-2.58(1H,m),2.15-2.11(1H,m), 1.57-1.48(3H,m),1.41-1.34(1H,m),1.01-0.98(0.4m,t),0.85-0.81(2.6H,t)

[0182] Biological assays Human P2Y 12 Inhibition studies in receptor-transfected CHO cells: Human P2Y 12A CHO cell line stably expressing the receptor was used to study the inhibitory effects of the compounds of the present invention (the cell line was constructed by Beijing Ion Channel Explorer Co.). hP2Y12-CHO cells were cultured in Ham's F-12 medium (Ham's F-12 medium: +10% FBS + 200 μg / ml hygromycin B) and incubated at 37°C and 5% CO2. The poor medium was removed, and the cells were washed with PBS. Next, 1 mL of trypsin solution was added to digest / detach the cells. The culture dish was incubated at 37°C for 2 minutes. As soon as the cells detached, 5 mL of complete medium preheated to 37°C was added. The cell suspension was transferred to a sterile pipette, and cell aggregates were dissociated by gentle homogenization. The cell suspension was transferred to a sterile tube and centrifuged at 1000 rpm for 5 minutes. To maintain the physiological activity of the cells, the degree of cell confluence was controlled at approximately 80%.

[0183] After cell counting, cells were cultured in 384-well plates. Test compounds were serially diluted 5-fold at 10 concentrations starting from 10,000 nM, with triplicates. Ticagrelor was used as the reference compound, and 2-MeSADP was used as the inducer. After 15 minutes of incubation at 37°C, forskolin buffer was added to all wells to induce cAMP production. The plates were centrifuged at 1000 pm for 1 minute, followed by incubation at 37°C for 30 minutes. After lysis, cAMP expression was quantified using PerkinElmer's LANCE® Ultra cAMP Kit method. The inhibitory effect of the test compound was calculated as the percent response to 2-MeSADP in the absence of antagonist, and the IC was calculated by fitting the % inhibition value and the logarithm of the compound concentration to a nonlinear regression using GraphPad 7.0. 50 was calculated.

[0184] Representative results from the assay for several exemplary compounds of the present invention are shown in Table 1.

[0185] Human P2Y 12 P2Y in receptor-transfected CHO cells 12 Inhibitory effect on Category A: <0.05 μM, Category B: 0.05–0.25 μM, Category C: 0.25–1.25 μM, Category D: >1.25 μM.

[0186] [Table 1]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: 【Chemical 1】 (In the formula, X is O, S, -S(O)- or -S(O) ２ represents -, Z is S, O, NR １０、 represents NH or a single bond, R １０ is C １－６ represents alkyl, R ９ is H, halogen, C １－８ Alkyl, C ２－８ Alkenyl, C ２－８ Alkynyl, C １－８ Alkyl-carbonyl, C ３－８ cycloalkyl, aryl, aralkyl, 4- to 6-membered heterocyclyl, or 4- to 6-membered heterocyclylalkyl, provided that each of the above groups is selected from halogen, hydroxyl, C １－３ Alkoxy, C １－３ optionally substituted with one or more substituents independently selected from alkylthio, amino, N-monoalkylamino, N,N-di-alkylamino, cyano, and nitro; R ８ is hydrogen, C １－６ Alkyl, C １－６ Alkyloxycarbonyl, N—C １－３ Alkylcarbamoyl or N,N-diC １－３ alkylcarbamoyl, provided that the C １－６ Alkyl group, N-C １－３ Alkylcarbamoyl group and N,N-diC １－３ The alkylcarbamoyl group is hydroxyl, halogen, C １－３ optionally substituted by one or more substituents selected from alkoxy; Y is H, C １－８ Alkyl, C １－６ Alkoxy-C １－６ Alkyl, C １－６ Alkyl-thio-C １－６ Alkyl, C ３－８ Cycloalkyl, C ３－８ Cycloalkyl-C １－３ Alkyl, phenyl-C １－３ Alkyl, phenyl-C ３－８ Cycloalkyl, 4- to 10-membered heterocyclyl, 4- to 10-membered heterocyclyl-C １－３ Alkyl or 4- to 10-membered heterocyclyl-C ３－８ cycloalkyl, wherein each of the above groups is selected from halogen, hydroxyl, cyano, nitro, C １－３ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－３ Alkoxy, C ３－６ Cycloalkyl, C １－３ Alkoxy-C １－３ Alkyl, halo-C １－３ optionally substituted with one or more substituents independently selected from alkyl, amino, N-alkylamino, and N,N-dialkylamino; R １ is H, cyano, C １－３ Alkyl, halo-C １－３ Alkyl, hydroxymethyl, 2-hydroxyethyl, C １－８ alkylcarboxymethyl, or benzoylmethyl, provided that the C １－８ The alkylcarboxylmethyl group and the benzoylmethyl group are free from halogen, carboxyl and C １－６ optionally substituted by one or more substituents selected from alkoxy-carbonyl; R ２ and R ３ are independently hydrogen, C １－３ Alkyl, halo-C １－３ Alkyl, C １－３ Alkoxy, hydroxylmethyl, 2-hydroxyethyl, 3-hydroxypropyl, —C(O)OH, —CH ２ C(O)OH, C １－６ Alkoxycarbonyl, C １－６ alkoxycarbonylmethyl or cyano, or R ２ and R ３ C together with the carbon to which they are attached ３－５ forming a carbocyclyl, wherein the carbocyclyl is selected from halogen, OH, C １－３ Alkyl or C １－３ optionally substituted by one or more substituents selected from alkoxy; R ４ and R ５ are independently hydrogen, halogen, hydroxyl, C １－３ Alkyl, halo-C １－３ Alkyl, C １－３ Alkoxy, hydroxylmethyl, 2-hydroxyethyl, 3-hydroxypropyl, —C(O)OH, C １－６ Alkoxycarbonyl, C １－６ alkoxycarbonylmethyl, cyano, amino, N-alkylamino or N,N-dialkylamino, or R ４ and R ５ are C together with the carbon to which they are attached. ３－５ forming a carbocyclyl, wherein the carbocyclyl is selected from halogen, OH, C １－３ Alkyl or C １－３ optionally substituted by one or more substituents selected from alkoxy; R ６ is hydrogen, cyano, C １－３ alkyl, hydroxymethyl or 2-hydroxyethyl; R ７ is H, F, C １－３ Alkyl, hydroxymethyl, 2-hydroxyethyl or HOC(O)CH ２ -, or R ７ and R １２ together represent one oxo, A is a single bond, H, O, S, or CH ２ , C.H. ２ CH ２ , CHF, CF ２ or C(O), E is hydrogen, F, —OH, R １１ O-, R １１ OC(O)-, R １１ C(O)-, R １１ C(O)O— or a partial structure selected from G1, G2 and G3; 【Chemistry 2】 R １１ is hydrogen, C １－８ Alkyl, C ３－８ Alkenyl, C ３－８ Alkynyl, C ３－８ represents cycloalkyl, benzyl, aryl or heterocyclyl, provided that the groups are not halogen, OH, nitro, cyano, C １－３ Alkyl, C １－３ Alkoxy, —C(O)OH, C １－６ Alkoxycarbonyl and C １－６ optionally substituted by one or more substituents selected from alkoxycarbonyloxy; R １２ represents hydrogen, or R １２ and R ７ together represent one oxo, However, R ８ is H, then Y is not H, However, when Y is H, R ８ is not H, However, when Z is a single bond, R ９ is not H.)

2. During the ceremony, X is O and R ６ is H, However, R ８ is H, then Y is not H, However, when Y is H, R ８ is not H, However, when Z is a single bond, R ９ is not H, 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

3. where X is O and R １ is H and R ６ is H and R １２ is H and R ８ 3. The compound of claim 1 or claim 2, wherein: is H and Z is S.

4. where X is O and R ６ is H and R １ is H and R １２ is H and R ８ is H, Z is S, and R ７ is H and R ９ is C １－５ Alkyl, C ３－８ Y is a cycloalkyl or phenyl group, and Y is a cyclopropyl substituted with phenyl or heterocyclyl, provided that said phenyl or heterocyclyl is not substituted with halogen, CN, nitro, OH, C １－３ Alkyl, C １－３ Alkoxy, C ３－６ 3. The compound of claim 1 or claim 2, optionally substituted with one or more substituents independently selected from cycloalkyl, amino, N-alkylamino, and N,N-dialkylamino.

5. In the formula, A is a single bond, H, or O, X is O, and R ６ is H and R １ is H and R １２ is H and R ８ is H, Z is S, and R ７ is H and R ９ is C １－５ Alkyl, C ３－８ Y is a cycloalkyl or phenyl group, and Y is a cyclopropyl substituted with phenyl or heterocyclyl, provided that said phenyl or heterocyclyl is not substituted with halogen, CN, nitro, OH, C １－３ Alkyl, C １－３ Alkoxy, C ３－６ 3. The compound of claim 1 or claim 2, optionally substituted with one or more substituents independently selected from cycloalkyl, amino, N-alkylamino, and N,N-dialkylamino.

6. In the formula, R １２ is H and R ４ and R ５ is independently selected from H, fluorine and hydroxyl.

7. In the formula, R １ is H and R ６ is H and R １２ is H and R ８ is H, Z is S, and R ３ is H, A is O or a single bond, E is H, R １１ O- or R １１ C(O)—, and R １１ is C １－８ alkyl, benzyl, heterocyclyl or phenyl, １－８ The alkyl, benzyl, phenyl or heterocyclyl group may be substituted with halogen, OH, C １－３ Alkyl, C １－３ Alkoxy, carboxyl, C １－６ Alkoxycarbonyl and C １－６ 3. The compound of claim 1 or claim 2, optionally substituted with one or more substituents selected from alkoxycarbonyloxy.

8. In the formula, R １２ is H and R ３ is H and R ２ The compound of claim 1 or claim 2, wherein is hydroxymethyl.

9. 3. The compound according to claim 1 or claim 2, wherein Y is cyclopropyl substituted with phenyl, said phenyl being substituted with 1 to 4 fluorine atoms.

10. ((2R,3R,4R,5S)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-4-hydroxytetrahydrofuran-2,5-diyl)dimethanol, ((2R,3R,5R)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2,5-diyl)dimethanol, ((2R,4R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl)methanol, (2S,3R,4S)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol, ((2R,3S,4S,5S)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-4-fluorotetrahydrofuran-2,5-diyl)dimethanol, ((2R,3S,4R,5S)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-4-fluorotetrahydrofuran-2,5-diyl)dimethanol, (2R,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-carboxylic acid, (2R,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylsulfinyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-carboxylic acid, ((2R,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(methoxymethyl)tetrahydrofuran-2-yl)methanol, 2-((2R,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-yl)ethan-1-ol, 2-(((2R,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-yl)methoxy)ethan-1-ol, 3-((2S,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-yl)propanoic acid, 2-(((((2R,4R,5R)-4-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-yl)methoxy)methyl)benzoic acid, and 2-(((2R,4R,5R)-4-(7-(((1S,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-2-yl)methoxy)acetic acid; 3. A compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition for treating, ameliorating, or preventing a platelet-mediated thrombotic disease, disorder, or condition in a host, including myocardial infarction, thrombotic stroke, transient ischemic attack, peripheral vascular disease, angina pectoris, and unstable angina, comprising an effective amount of a compound of claim 1 or claim 2.

12. 12. The pharmaceutical composition of claim 11, further comprising one or more additional antiplatelet agents, anticoagulants, antifibrinolytic agents, or other therapeutic agents with cardiovascular activity.

13. 10. A compound according to claim 1 or claim 2 for use in therapy.

14. 3. A compound according to claim 1 or claim 2 for use in the treatment, amelioration or prevention of platelet-mediated thrombotic diseases, disorders or conditions including myocardial infarction, thrombotic stroke, transient ischemic attack, peripheral vascular disease, angina pectoris and unstable angina pectoris.

15. 15. The compound of claim 14, wherein the use further comprises one or more additional antiplatelet agents, anticoagulants, antifibrinolytic agents, or other therapeutic agents with cardiovascular activity.

16. Use of a compound according to claim 1 or claim 2 in the manufacture of a medicament for treating, ameliorating or preventing platelet-mediated thrombotic diseases, disorders or conditions, including myocardial infarction, thrombotic stroke, transient ischemic attack, peripheral vascular disease, angina and unstable angina.

17. Use of a compound according to claim 16 in the manufacture of a medicament for the above treatment or prevention, further comprising one or more additional antiplatelet agents, anticoagulants, antifibrinolytic agents, or other therapeutic agents having cardiovascular effects.

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