Carbonicyclic nucleosides for treatment of viral infections

Abstract

Provided are carbobicyclic nucleoside compounds for use in the treatment of coronavirus disease 2019 (COVID-19), RSV, and other viral infections. The carbobicyclic nucleoside compounds may be compounds as set forth herein. Pharmaceutical formulations for the treatment of COVID-19 and RSV are also described.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 331,670, filed on April 15, 2022, the disclosure of which is incorporated herein by reference in its entirety for all purposes. Background Art

[0003] The novel pneumonia virus SARS-CoV-2 has been declared a global emergency by the World Health Organization (WHO) and continued spread is expected. By early February 2022, there have been more than 380,000,000 confirmed cases of COVID-19, including more than 5,600,000 deaths reported to the WHO. The search for effective antiviral agents to mitigate the epidemic is ongoing. Existing nucleoside analogs such as remdesivir have been reported to be effective against SARS-CoV-2. Remdesivir (a ribose-based nucleoside) is susceptible to the host's metabolic pathways, however, making it susceptible to degradation in the body. In addition, remdesivir's target enzyme (RNA-dependent RNA polymerase (RdRp)) has the potential to develop resistance to ribose-based nucleoside analogs. This is known, for example, in the case of ribavirin-resistant severe acute respiratory syndrome coronavirus (SARS-CoV). Summary of the invention

[0004] In one aspect, the present disclosure provides compounds according to the formula: A pharmaceutically acceptable salt thereof or an enantiomer thereof, wherein: R 1 is a nitrogen-containing monocyclic or bicyclic heterocyclic group; R 2 , R 3 , R 4 , R 5 , R 6 and R 7 wherein each of the above is independently H, deuterium, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, optionally substituted heteroaryloxy, optionally substituted carboxylate, or OP x ; R 8 , R 9 , R 10 , R 11 , R 12 and R 13wherein each of the above is independently H, deuterium, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, optionally substituted heteroaryloxy, OP x , or does not exist; P x is a monophosphate, diphosphate, triphosphate, C2-6 acyl, or phosphate prodrug moiety; and each dashed line represents a single bond or a double bond, provided that more than one double bond is not present.

[0005] In some embodiments, the compound or a pharmaceutically acceptable salt thereof includes a structure according to the following formula:

[0006]

[0007] In certain embodiments, the compound or a pharmaceutically acceptable salt thereof comprises a structure according to the following formula: In some embodiments, the compound or a pharmaceutically acceptable salt thereof includes a structure according to the following formula: Specifically, the compound or a pharmaceutically acceptable salt thereof includes a structure according to the following formula: More specifically, the compound or a pharmaceutically acceptable salt thereof includes a structure according to the following formula: In some embodiments, the compound or a pharmaceutically acceptable salt thereof includes a structure according to the following formula: In some embodiments, the compound or a pharmaceutically acceptable salt thereof includes a structure according to the following formula:

[0008]

[0009] In some embodiments, the compound or a pharmaceutically acceptable salt thereof includes a structure according to the following formula: In certain embodiments, the compound or a pharmaceutically acceptable salt thereof comprises a structure according to the following formula: In some embodiments, the compound or a pharmaceutically acceptable salt thereof includes a structure according to the following formula:

[0010] In some embodiments of the above formula, R 2 , R 3 , R 4 and R 5Each of which is independently H, deuterium, hydroxyl, Cl, F, CN, Me, Et, (C 1-6 )OH、OR x , (C 1-6 )COOR x or (C 1-6 )CON(R x )2; R 6 and R 7 Each of which is independently H, deuterium, hydroxyl, Cl, F, CN, Me, Et, (C 1-6 )OH、OR x , (C 1-6 )COOR x , (C 1-6 )CON(R x )2, optionally substituted carboxylic acid ester or OP x ;P x It is monophosphate, diphosphate, triphosphate, C 2-6 an acyl or phosphate prodrug moiety; and each R x and R is independently H, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy.

[0011] In some embodiments of the present disclosure, the compound, or a pharmaceutically acceptable salt thereof, comprises a structure according to the following formula: Where: R 1 is an optionally substituted nitrogen-containing monocyclic or bicyclic heterocyclic group; R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 wherein each of the above is independently H, deuterium, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy, optionally substituted carboxylate, or OP x , where P xis a monophosphate, a diphosphate, a triphosphate, a C2-6 acyl, or a phosphate prodrug moiety. In some embodiments, the compound or a pharmaceutically acceptable salt thereof comprises a structure according to the following formula: Where: R 1 is an optionally substituted nitrogen-containing monocyclic or bicyclic heterocyclic group; R 10 , R 11 , R 12 and R 13 Each of which is independently H, deuterium, hydroxyl, Cl, F, CN, Me, Et, (C 1-6 )OH、OR x , (C 1-6 )COOR x , (C 1-6 )CON(R x )2, epoxide or cyclopropane; R 8 , R 9 Each of which is independently H, deuterium, hydroxyl, Cl, F, CN, Me, Et, (C 1-6 )OH、OR x , (C 1-6 )COOR x , (C 1-6 )CON(R x )2. Epoxide, cyclopropane or OP x , P x is a monophosphate, diphosphate, triphosphate, C2-6 acyl or phosphate prodrug moiety; each R x and R is independently H, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy. In certain embodiments, the compound or a pharmaceutically acceptable salt thereof includes a structure according to the formula:

[0012] In any of the above formulae, in some embodiments, R 1 Selected from adenine, guanine, cytosine, N 4 -hydroxycytosine, thymine, uracil, pyrrolo[2,1-f][1,2,4]triazine-4-amine and 1,2,4-triazole-3-carboxamide. In some embodiments, R 1 Selected from adenine, cytosine and N 4 -Hydroxycytosine.

[0013] In some embodiments of the formulae described herein, R 1 yes Where X and R a Each of which is independently H, deuterium, hydroxyl, Cl, F, CN, Me, Et, (C 1-6 )OH、OR x , (C 1-6 )COOR x , (C 1-6 )CON(R x )2、N(R x )2 or R x , where each R x X and R are independently H, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy; and Y is N or C. In some embodiments, X and R a Each of which is independently H, deuterium, hydroxyl, Cl, F, N(R x )2 or R x , where each R x R is independently H, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy; and Y is N or C. In certain embodiments, R 1 yes:

[0014] In some embodiments of the formulae described herein, R 1 yes Each of the R a are independently H, deuterium, hydroxyl, Cl, F, CN, Me, Et, (C 1-6 )OH、OR x , (C 1-6 )COOR x , (C 1-6 )CON(R x )2、N(R x )2 or R x , where each R xR is independently H, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy. In some embodiments, R 1 yes

[0015] In some embodiments of the formulae described herein, R 1 yes Where R a H, deuterium, hydroxyl, Cl, F, CN, Me, Et, (C 1-6 )OH、OR x , (C 1-6 )COOR x , (C 1-6 )CON(R x )2、N(R x )2 or R x ; and X is O, NR x NOR x , where each R x R is independently H, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy. In some embodiments, R 1 yes

[0016] In some embodiments of the formulae described herein, P x is a phosphate prodrug moiety, for example, the phosphate prodrug moiety is selected from phosphonate, carbonyloxymethyl phosphate, S-acyl-2-thioethyl phosphate, S-[(2-hydroxyethyl)]thioether]-thioethyl phosphate, cyclosaligenyl phosphodiester, cyclo-1-aryl-1,3-propyl phosphodiester, alkoxyalkyl phosphate, aryloxyphosphoramidate, aryloxyphosphoramidate, amino acid phosphoramidate, amino acid phosphoramidate and methylarylhaloalkylphosphoramidate.

[0017] In another aspect, the present disclosure also provides a compound comprising one of the following formulae or a pharmaceutically acceptable salt thereof:

[0018]

[0019] In another aspect, the present disclosure also provides a compound comprising one of the following formulae or a pharmaceutically acceptable salt thereof:

[0020]

[0021] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, include the formula:

[0022]

[0023] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, include the formula:

[0024]

[0025] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, include the formula:

[0026]

[0027] In another aspect, the present disclosure provides a pharmaceutical composition comprising any compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0028] In another aspect, the present disclosure provides a method for treating a viral infection, comprising administering to an individual in need thereof a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition described herein.

[0029] In some embodiments, the viral infection is a respiratory viral infection.

[0030] In some embodiments, the viral infection is a coronavirus infection, an adenovirus infection, an influenza virus infection, a parainfluenza virus infection, a rhinovirus infection, or a respiratory syncytial virus (RSV) infection. In certain embodiments, the coronavirus infection is a SARS-CoV-2 infection. In certain embodiments, the influenza virus infection is an influenza A virus (IAV) infection.

[0031] In some embodiments of the method, the compound is administered to the individual orally or via injection. In some embodiments, the method further comprises administering one or more agents selected from anti-inflammatory agents, analgesics, and antiviral agents. The antiviral agent may be selected from RNA-dependent RNA polymerase inhibitors, 3C-like protease inhibitors, and cytochrome P450 3A4 inhibitors. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1A and Figure 1BIt is shown that in the A549-ACE2 cell model, the infection rate of monolavin and the carbon bicyclic nucleoside 48 according to the present disclosure (SARS-CoV-2S-pseudotyped lentivirus) ( Figure 1A ) and (A549-ACE2) cell activity ( Figure 1B The experiment was performed in triplicate.

[0033] Figure 2 Compound 48 was shown to inhibit the replication of different SARS-CoV-2 strains (including the original strain as well as the Deta variant and the Omiclon variant) in the A549-ACE2 cell model. The results for Monolavir are also described. The experiment was performed in triplicate.

[0034] FIG. 3A to FIG. 3D The antiviral activity of the compounds disclosed herein at various concentrations is shown.

[0035] Figure 4A and Figure 4B Shown are cytotoxicity assays of various concentrations of compounds disclosed herein. DETAILED DESCRIPTION

[0036] Provided herein are compounds for treating viral infections (e.g., respiratory viral infections), including but not limited to treating COVID-19 caused by SARS-CoV-2 and infections caused by influenza viruses (e.g., influenza A virus (IAV) and respiratory syncytial virus (RSV)). An effective and structured divergent approach has been developed, characterized in that the intermolecular Diels-Alder reaction as a key step is used to obtain several nucleoside analogs for inhibiting viral replication. Advantageously, several compounds showing higher binding affinity than currently known inhibitors (monolavir) have now been found. Compounds according to the present disclosure contain carbocyclic sugars rather than ribose as the core, making them more metabolically stable than monolavir and other existing ribose-based inhibitors (e.g., anti-SARS-CoV-2E inhibitors).

[0037] I. Definitions

[0038] As used herein, the term "alkyl" by itself or as part of another substituent refers to a straight or branched chain saturated aliphatic group having the indicated number of carbon atoms. Alkyl groups may include any number of carbon atoms, such as C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 For example, C 1-6 Alkyl includes but is not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isopentyl, hexyl etc.Alkyl can also refer to alkyl with up to 20 carbon atoms, such as but not limited to heptyl, octyl, nonyl, decyl etc.Alkyl can be substituted or unsubstituted. "Substituted alkyl" can be substituted by one or more groups selected from halogen, hydroxyl, amino, alkylamino, acylamino, acyl, nitro, cyano and alkoxy.

[0039] As used herein, the term "aryl" itself or as part of other substituents refers to an aromatic ring system with any suitable number of ring atoms and any suitable number of rings. Aryl can include any suitable number of ring atoms, such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, and 6 to 10, 6 to 12 or 6 to 14 ring members. Aryl can be monocyclic, fused to form a dicyclic (e.g., benzocyclohexyl) or tricyclic group, or connected by a bond to form a biaryl. Representative aryl includes phenyl, naphthyl and biphenyl. Other aryl includes benzyl with a methylene linking group. Some aryl has 6 to 12 ring members, such as phenyl, naphthyl or biphenyl. Other aryl has 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl has 6 ring members, such as phenyl. Heteroaryl can be substituted or unsubstituted. The "substituted aryl" may be substituted with one or more groups selected from halogen, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano and alkoxy.

[0040] As used herein, the term "arylalkyl" refers to an aryl group bonded to a compound via an alkylene group as described herein. Examples of arylalkyl groups include, but are not limited to, benzyl and phenethyl.

[0041] As used herein, the term "heteroaryl" by itself or as part of another substituent refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, wherein 1 to 5 of the ring atoms are heteroatoms, such as N, O or S. Additional heteroatoms may also be available, including but not limited to B, Al, Si and P. Heteroatoms may be oxidized to form moieties such as, but not limited to, -S(O)- and -S(O)2-. Heteroaryl may contain any number of ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11 or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl group, for example 1, 2, 3, 4 or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4 or 3 to 5. The heteroaryl group can have 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. The heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-isomers, 1,2,4-isomers and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole and isoxazole. Heteroaryl can also be fused to an aromatic ring system (e.g., a phenyl ring) to form members including, but not limited to, benzopyrroles (e.g., indole and isoindole), benzopyridines (e.g., quinoline and isoquinoline), benzopyrazines (quinoxalines), benzopyrimidines (quinazolines), benzopyridazines (e.g., phthalazine and cinnoline), benzothiophenes, and benzofurans. Other heteroaryl groups include heteroaryl rings connected by bonds, such as bipyridine. Heteroaryl can be substituted or unsubstituted. "Substituted heteroaryl" can be substituted by one or more groups selected from halogen, hydroxy, amino, alkylamino, acylamino, acyl, nitro, cyano, and alkoxy.

[0042] The heteroaryl group may be attached via any position on the ring. For example, pyrrole includes 1-pyrrole, 2-pyrrole and 3-pyrrole, pyridine includes 2-pyridine, 3-pyridine and 4-pyridine, imidazole includes 1-imidazole, 2-imidazole, 4-imidazole and 5-imidazole, pyrazole includes 1-pyrazole, 3-pyrazole, 4-pyrazole and 5-pyrazole, triazole includes 1-triazole, 4-triazole and 5-triazole, tetrazole includes 1-tetrazole and 5-tetrazole, pyrimidine includes 2-pyrimidine, 4-pyrimidine, 5-pyrimidine and 6-pyrimidine, pyridazine includes 3-pyridazine and 4-pyridazine, 1,2,3-triazine includes 4-triazine and 5-triazine, 1,2,4-triazine includes 3-triazine, 5-triazine and 6-triazine, 1,3,5-triazine includes 2-triazine, thiophene includes 2-thiophene and 3-thiophene, furan includes 2- The invention also includes furan and 3-furan, thiazole includes 2-thiazole, 4-thiazole and 5-thiazole, isothiazole includes 3-isothiazole, 4-isothiazole and 5-isothiazole, oxazole includes 2-oxazole, 4-oxazole and 5-oxazole, isoxazole includes 3-isoxazole, 4-isoxazole and 5-isoxazole, indole includes 1-indole, 2-indole and 3-indole, isoindole includes 1-isoindole and 2-isoindole, quinoline includes 2-quinoline, 3-quinoline and 4-quinoline, isoquinoline includes 1-isoquinoline, 3-isoquinoline and 4-isoquinoline, quinazoline includes 2-quinazoline and 4-quinazoline, cinnoline includes 3-cinnoline and 4-cinnoline, benzothiophene includes 2-benzothiophene and 3-benzothiophene, and benzofuran includes 2-benzofuran and 3-benzofuran.

[0043]

[0046] As used herein, the terms "halo" and "halogen," by themselves or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom.

[0044] As used herein, the term "cyano," by itself or as part of another substituent, refers to a carbon atom triple-bonded to a nitrogen atom (ie, the moiety -C≡N).

[0045] As used herein, the term "carbonyl" by itself or as part of another substituent refers to -C(O)-, ie, a carbon atom that is double-bonded to the oxygen and to two other groups in the carbonyl-bearing moiety.

[0046] As used herein, the term "amino" by itself or as part of another substituent refers to the moiety -NR3, wherein each R group is H or alkyl. The amino moiety can be ionized to form the corresponding ammonium cation.

[0047] As used herein, the term "hydroxy," by itself or as part of another substituent, refers to the moiety -OH.

[0048] As used herein, the term "amido" by itself or as part of another substituent refers to the moiety -NRC(O)R or -C(O)NR2, wherein each R group is H or alkyl.

[0049] As used herein, the term "acyl," by itself or as part of another substituent, refers to the moiety -C(O)R, where R is alkyl.

[0050] As used herein, the term "nitro," by itself or as part of another substituent, refers to the moiety -NO2.

[0051] As used herein, the term "salt" refers to a compound comprising at least one cation (e.g., an organic cation or an inorganic cation) and at least one anion (e.g., an organic anion or an inorganic anion). Salt can be an acid salt or an alkali salt or another activating agent of a carbon bicyclic nucleoside compound. The acid salt of an alkaline compound includes but is not limited to an inorganic acid salt (e.g., a salt formed using hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), an organic acid salt (e.g., a salt formed using acetic acid, propionic acid, glutamic acid, citric acid, etc.) and a quaternary ammonium salt (e.g., a salt formed using methyl iodide, ethyl iodide, etc.). Acidic compounds can be contacted with a base to provide an alkali salt, such as an alkali metal salt and an alkaline earth metal salt (e.g., a sodium salt, a lithium salt, a potassium salt, a calcium salt and a magnesium salt), and an ammonium salt (e.g., ammonium, trimethyl-ammonium, diethylammonium and tri-(hydroxymethyl)-methyl-ammonium salt).

[0052] In some embodiments, the neutral form of the active agent can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner if necessary. In some embodiments, the parent form of the compound may differ from the various salt forms in certain physical properties (e.g., solubility in polar solvents), but otherwise, the salt form may be equivalent to the parent form of the compound.

[0053] As used herein, the term "excipient" refers to a substance that facilitates administration of an active agent to an individual. Pharmaceutical excipients that can be used in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, glidants, coating agents, sweeteners, flavoring agents, and coloring agents.

[0054] "Pharmaceutically acceptable" means that the material so specified (eg, a salt or excipient) is not deleterious to the recipient thereof and is compatible with the other materials with which it is formulated.

[0055] "Treat," "treatment," and "treating" refer to any marker of success in treating or ameliorating a viral infection or a symptom thereof (e.g., shortness of breath). Treatment can be assessed by objective or subjective parameters, such as ablation; remission; alleviation of symptoms or making symptoms, damage, pathology, or condition more tolerable to the patient; reduction in the rate of progression of symptoms; reduction in the frequency or duration of symptoms or condition. Treatment or amelioration of symptoms can be based on any objective or subjective parameter; including, for example, the results of a physical examination.

[0056] As used herein, the term "administering" refers to oral, topical, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal, subcutaneous, or intrathecal administration to a subject, as well as administration as a suppository or implantation of a sustained release device, such as a mini-osmotic pump, in a subject.

[0057] As used herein, the term "subject" refers to a human or other animal to which a compound or composition as described herein is administered. In some embodiments, the subject is a human.

[0058] As used herein, the terms "effective amount" and "therapeutically effective amount" refer to the dosage of a compound (e.g., a carbobicyclic nucleoside) that produces the therapeutic effect for which it is administered. The exact dosage will depend on the purpose of the treatment and will be determined by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11 th Edition, 2006, Brunton, Ed., McGraw-Hill; and Remington: The Science and Practice of Pharmacy, 21 st Edition, 2005, Hendrickson, Ed., Lippincott, Williams & Wilkins).

[0059] As used herein, the terms "about" and "approximately" used to modify numerical values ​​(e.g., degree of polymerization) represent a close range around a clear value. If "X" is a described value, "about X" or "approximately X" will represent a value of 0.9X to 1.1X. Therefore, "about X" includes, for example, values ​​of 0.95X to 1.05X, or 0.98X to 1.02X, or 0.99X to 1.01X. Any reference to "about X" or "approximately X" specifically represents at least the described value X, 0.90X, 0.91X, 0.92X, 0.93X, 0.94X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, 1.05X, 1.07X, 1.08X, 1.09X, and 1.10X. Thus, "about X" and "approximately X" are intended to teach and provide written descriptive support for a claim limitation such as "0.98X."

[0060] II. Carbobicyclic nucleoside analogs

[0061] "Carbocyclic nucleoside" refers to a synthetic compound with a substituted cyclopentane ring, wherein a naturally occurring nucleoside will have a furanose ring. "Carbobicyclic nucleoside" refers to a compound in which a cyclopentane ring is fused to a second carbocyclic fused compound, such as a cyclohexane ring in the case of an octahydroindene-type carbobicyclic nucleoside. As described in more detail below, the effectiveness and specificity of carbobicyclic nucleoside compounds to SARS-CoV-2 and RSV have been developed and studied. Carbobicyclic nucleoside analogs can be prepared via a synthetic route using an intermolecular Diels-Alder reaction.

[0062] The present disclosure provides compounds of the formula:

[0063] Its pharmaceutically acceptable salt, or its enantiomer. In this formula, R 1 is a nitrogen-containing monocyclic or bicyclic heterocyclic group; R 2 , R 3 , R 4 , R 5 , R 6 and R 7 wherein each of the above is independently H, deuterium, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, optionally substituted heteroaryloxy, optionally substituted carboxylate, or OP x ; R 8 , R 9 , R 10 , R 11 , R12 and R 13 wherein each of the above is independently H, deuterium, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, optionally substituted heteroaryloxy, OP x , or does not exist; P x is a monophosphate, diphosphate, triphosphate, C2-6 acyl, or phosphate prodrug moiety; and each dashed line represents a single bond or a double bond, provided that more than one double bond is not present.

[0064] Specifically, since the dashed line in the above formula represents an optional double bond, the compounds of the present disclosure may have any of the following formulae:

[0065]

[0066] In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof include the following formula: Specifically, the compound may have the following formula: Further, the compound may have the formula: More specifically, the compound may have the formula:

[0067] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, include the formula: Specifically, the compound may have the formula: Further, the compound may have the formula:

[0068] In some embodiments, in any of the above formulae, R 2 , R 3 , R 4 and R 5 Each of which is independently H, deuterium, hydroxyl, Cl, F, CN, Me, Et, (C 1-6 )OH、OR x , (C 1-6 )COOR x or (C 1-6 )CON(R x )2; R 6 and R 7 Each of which is independently H, deuterium, hydroxyl, Cl, F, CN, Me, Et, (C 1-6 )OH、OR x , (C 1-6 )COOR x, (C 1-6 )CON(R x ) 2, optionally substituted carboxylic acid ester or OP x ;P x It is monophosphate, diphosphate, triphosphate, C 2-6 an acyl or phosphate prodrug moiety; and each R x and R is independently H, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy.

[0069] In some embodiments, the compounds or pharmaceutically acceptable salts of the present disclosure may also have the following formula: Where R 1 is an optionally substituted nitrogen-containing monocyclic or bicyclic heterocyclic group; R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 wherein each of the above is independently H, deuterium, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy, optionally substituted carboxylate, or OP x , where P x It is a monophosphate, diphosphate, triphosphate, C2-6 acyl, or phosphate prodrug moiety.

[0070] Specifically, in some embodiments, the compound may have the formula: Where R 1 is an optionally substituted nitrogen-containing monocyclic or bicyclic heterocyclic group; R 10 , R 11 , R 12 and R 13 Each of which is independently H, deuterium, hydroxyl, Cl, F, CN, Me, Et, (C 1-6 )OH、OR x , (C 1-6 )COORx , (C 1-6 )CON(R x )2, epoxide or cyclopropane; R 8 , R 9 Each of which is independently H, deuterium, hydroxyl, Cl, F, CN, Me, Et, (C 1-6 )OH、OR x , (C 1-6 )COOR x , (C 1-6 )CON(R x )2. Epoxide, cyclopropane or OP x , P x is a monophosphate, diphosphate, triphosphate, C2-6 acyl or phosphate prodrug moiety; each R x and R is independently H, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy.

[0071] In certain embodiments, the compound may have the formula:

[0072] In any of the above formulae, R 1 Can be selected from adenine, guanine, cytosine, N 4 -hydroxycytosine, thymine, uracil, pyrrolo[2,1-f][1,2,4]triazine-4-amine and 1,2,4-triazole-3-carboxamide. In some embodiments, R 1 Can be selected from adenine, cytosine and N 4 -Hydroxycytosine.

[0073] In any of the above formulas, in any of the formulas described herein, R 1 yes Where X and R a Each of which is independently H, deuterium, hydroxyl, Cl, F, CN, Me, Et, (C 1-6 )OH、OR x , (C 1-6 )COOR x , (C 1-6 )CON(R x )2、N(R x )2 or R x , where each R xX and R are independently H, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy; and Y is N or C. In some embodiments, X and R a Each of which is independently H, deuterium, hydroxyl, Cl, F, N(R x )2 or R x , where each R x R is independently H, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy; and Y is N or C. In some embodiments, R 1 yes:

[0074]

[0075] In certain embodiments, in any of the formulas described herein, R 1 yes Each of the R a are independently H, deuterium, hydroxyl, Cl, F, CN, Me, Et, (C 1-6 )OH、OR x , (C 1-6 )COOR x 、CON(R x 2. (C 1-6 )CON(R x )2、N(R x )2 or R x , where each R x R is independently H, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy. In some embodiments, R 1 yes

[0076] In certain embodiments, in any of the formulas described herein, R 1 yes Where R aH, deuterium, hydroxyl, Cl, F, CN, Me, Et, (C 1-6 )OH、OR x , (C 1-6 )COOR x , (C 1-6 )CON(R x )2、N(R x )2 or R x ; and X is O, NR x NOR x , where each R x R is independently H, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy. In certain embodiments, R 1 yes

[0077] In any of the above formulas, in some embodiments, P x It is a phosphate prodrug moiety. For example, the phosphate prodrug moiety can be selected from phosphonate, carbonyloxymethyl phosphate, S-acyl-2-thioethyl phosphate, S-[(2-hydroxyethyl)]thioether]-thioethyl phosphate, cyclosalicylic phosphodiester, cyclo-1-aryl-1,3-propyl phosphodiester, alkoxyalkyl phosphate, aryloxyphosphoramidate, aryloxyphosphoramidate, amino acid phosphoramidate, amino acid phosphoramidate and methylaryl haloalkylphosphoramidate.

[0078] The present disclosure provides a compound or a pharmaceutically acceptable salt thereof having any of the following formulae:

[0079]

[0080] In some embodiments, the compounds described herein may exist as prodrug molecules, that is, one or more hydroxyl groups in the compound may be protected as an optionally substituted carboxylate (e.g. ).

[0081] The present disclosure provides a compound or a pharmaceutically acceptable salt thereof having any of the following formulae:

[0082]

[0083] In some embodiments, the compounds described herein may exist as prodrug molecules, that is, one or more hydroxyl groups in the compound may be protected as an optionally substituted carboxylate (e.g. ).

[0084] The present disclosure provides a compound or a pharmaceutically acceptable salt thereof having any of the following formulae:

[0085]

[0086] In some embodiments, the compounds described herein may exist as prodrug molecules, that is, one or more hydroxyl groups in the compound may be protected as an optionally substituted carboxylate (e.g. ).

[0087] The present disclosure provides a compound or a pharmaceutically acceptable salt thereof having any of the following formulae:

[0088]

[0089] In some embodiments, the compounds described herein may exist as prodrug molecules, that is, one or more hydroxyl groups in the compound may be protected as an optionally substituted carboxylate (e.g. ).

[0090] The present disclosure provides a compound or a pharmaceutically acceptable salt thereof having any of the following formulae:

[0091]

[0092] In some embodiments, the compounds described herein may exist as prodrug molecules, that is, one or more hydroxyl groups in the compound may be protected as an optionally substituted carboxylate (e.g. ).

[0093] The present disclosure provides a compound or a pharmaceutically acceptable salt thereof having any of the following formulae:

[0094]

[0095] In some embodiments, the compounds described herein may exist as prodrug molecules, that is, one or more hydroxyl groups in the compound may be protected as an optionally substituted carboxylate (e.g. ).

[0096] Provided herein are carbobicyclic nucleoside compounds according to the formula:

[0097]

[0098] or a pharmaceutically acceptable salt thereof, wherein:

[0099] R 1 is a nitrogen-containing monocyclic or bicyclic heterocyclic group;

[0100] R 2 Selected from –OH and –OR 2a , where R 2a It is C 2-6 acyl group;

[0101] R 3 Selected from –OH, –OR 3a and halogen, where R 3a It is C 2-6 acyl group;

[0102] Optionally, R 2 and R 3 together to form a cyclic phosphate;

[0103] R 4 is selected from hydrogen and halogen; and

[0104] (i)R 5 Selected from –OH, –OR 5a , –CH2OH and -CH2OR 5a ,as well as

[0105] R 5a Selected from monophosphate, diphosphate, triphosphate, C 2-6 Acyl and phosphate prodrug moieties,

[0106] or

[0107] (ii) R 5 It is hydrogen,

[0108] Therein each dashed line represents a single bond or a double bond, provided that more than one double bond is not present.

[0109] In some embodiments of the above formula, R 5 and R 3 is -OH. In some embodiments, R 5 is the phosphate prodrug moiety and R 3 It is –OH.

[0110] The phosphate prodrug moieties according to the present disclosure can be converted to active nucleoside triphosphates by the action of intracellular kinases, often in concert with other enzymes such as esterases, cytochrome P450s, and phospholipases.

[0111] Examples of phosphate prodrug moieties include, but are not limited to, phosphonates, carbonyloxymethyl phosphates, S-acyl-2-thioethyl phosphates, S-[(2-hydroxyethyl)]thioether]-thioethyl phosphates, cyclosalicylic phosphodiesters, cyclo-1-aryl-1,3-propyl phosphodiesters, alkoxyalkyl phosphates, aryloxyphosphoramidates, aryloxyphosphoramidates, amino acid phosphoramidates, amino acid phosphoramidates, and methylarylhaloalkylphosphoramidates.

[0112] In some embodiments, the phosphate prodrug moiety is a carbonyloxymethyl phosphate or phosphonate as shown below:

[0113]

[0114] Where each R is independently C 1-6 Alkyl or C 1-6 Alkoxy; –Z– is -O- or -CH2-; and the wavy line represents R 2 The point of attachment between the carbon bicyclic nucleoside.

[0115] In some embodiments, the phosphate prodrug moiety is an S-acyl-2-thioethyl phosphate or phosphonate as shown below:

[0116]

[0117] Where R is C 1-6 Alkyl or C 1-6 (Hydroxy)alkyl; R' is RC(O)SCH2CH2O–, C 1-6 Alkoxy, C 1-6 Aryloxy or (C 7-20 Arylalkyl)amino; -Z- is -O- or -CH2-; and the wavy line indicates R 2 The point of attachment between the carbon bicyclic nucleoside.

[0118] In some embodiments, the phosphate prodrug moiety is S-[(2-hydroxyethyl)]thioetheryl]-thioethyl phosphate or phosphonate as shown below:

[0119]

[0120] Where R is C 1-6 Alkyl; R' is RSSCH2CH2O–, C 1-6 Alkoxy, C 1-6 Aryloxy or (C 7-20 Arylalkyl)amino; -Z- is -O- or -CH2-, and the wavy line represents R 2 The point of attachment between the carbon bicyclic nucleoside.

[0121] In some embodiments, the phosphate prodrug moiety is a cyclosalicylic phosphate or phosphonate as shown below:

[0122]

[0123] wherein the subscript n is an integer from 0 to 4; each R is independently hydrogen, halogen or C 1-6 Alkyl; –Z– is -O- or -CH2-, and the wavy line represents R 2 The point of attachment between the carbon bicyclic nucleoside.

[0124] In some embodiments, the phosphate prodrug moiety is a cyclo-1-aryl-1,3-propyl phosphate or phosphonate as shown below:

[0125]

[0126] Where Ar is C 6-14 aryl or 5- to 12-membered heteroaryl, each of which is substituted by one or more independently selected halogen or C 1-6 Alkyl is optionally substituted; -Z- is -O- or -CH2-; and the wavy line indicates R 2 The point of attachment between the carbon bicyclic nucleoside.

[0127] In some embodiments, the phosphate prodrug moiety is an alkoxyalkyl phosphate or phosphonate as shown below:

[0128]

[0129] wherein m and n are independently integers from 1 to 16; -Z- is -O- or -CH2-; and the wavy line represents R 2 The point of attachment between the carbon bicyclic nucleoside.

[0130] In some embodiments, the phosphate prodrug moiety is an aryloxyamino acid phosphoramidate or phosphoramidate as shown below:

[0131]

[0132] Where R is C 1-6 Alkyl; R' is an amino acid side chain; R" is C 6-14 Aryl; –Z– is -O- or -CH2-; and the wavy line represents R 2The point of connection between the amino acid and the carbon bicyclic nucleoside. R' can represent, for example, the side chain of a naturally occurring amino acid (e.g., alanine side chain, arginine side chain, asparagine side chain, aspartic acid side chain, cysteine ​​side chain, glutamine side chain, glutamic acid side chain, glycine side chain, histidine side chain, isoleucine side chain, leucine side chain, lysine side chain, methionine side chain, phenylalanine side chain, proline side chain, selenocysteine ​​side chain, serine side chain, threonine side chain, tryptophan side chain, tyrosine side chain or valine side chain) or the side chain of a non-naturally occurring amino acid (e.g., azidohomoalanine side chain, propargylglycine side chain, p-acetylphenylalanine side chain, etc.).

[0133] In some embodiments, the phosphate prodrug moiety is a methylarylhaloalkylphosphoramidate or phosphoramidate as shown below:

[0134]

[0135] Where R is hydrogen, C 1-6 Alkyl or C 1-6 (Hydroxy)alkyl; X is halogen; n is an integer from 1 to 16; Ar is C 6-14 aryl or 5- to 12-membered heteroaryl, each of which is independently selected from halogen, hydroxy, nitro and C 1-6 Alkyl is substituted with one or more groups; –Z– is -O- or -CH2-, and the wavy line indicates R 2 The point of attachment between the carbon bicyclic nucleoside.

[0136] In some embodiments, the carbobicyclic nucleoside has a structure selected from the group consisting of:

[0137]

[0138] and pharmaceutically acceptable salts thereof.

[0139] In some embodiments of the above formula, R 2 Yes – OR 2a , and R 3 and R 5 is -OH. In some embodiments, R 3 Yes – OR 3a , and R 2 and R 5 is -OH. In some embodiments, R 5 Yes – OR 5a , and R 2 and R 3 It is –OH. 2a , R 3a and R 5aCan be, for example, acetyl, propionyl, n-butyryl or isobutyryl. In some such embodiments, R 4 It's H.

[0140] In some embodiments, R 3 is hydrogen and R 4 is halogen (eg, fluorine, chlorine, or bromine). 3 is a halogen and R 4 is hydrogen. In some embodiments, R 3 and R 4 is halogen. In some embodiments, R 3 is fluorine and R 4 is hydrogen. In some embodiments, R 3 is hydrogen and R 4 It's fluorine.

[0141] The carbobicyclic nucleosides according to the present disclosure may contain a variety of naturally occurring nucleobases and synthetic nucleobases. 1 It can be, for example, purine, pyrimidine, benzimidazole, etc. In some embodiments, R 1 is adenine, guanine, 7-methylguanine, xanthine or hypoxanthine. In some embodiments, R 1 is cytosine, 5-methylcytosine, 5-hydroxymethylcytosine, thymine, uracil or 5,6-dihydrouracil. 1 Selected from adenine, guanine, cytosine, N 4 -hydroxycytosine, thymine, uracil, pyrrolo[2,1-f][1,2,4]triazine-4-amine and 1,2,4-triazole-3-carboxamide. In some embodiments, R 1 Selected from adenine, cytosine and N 4 -Hydroxycytosine.

[0142] Also provided herein are processes for preparing the compounds and salts described herein. For example, the compounds can be synthesized using the methods described below together with synthetic methods known in the field of synthetic organic chemistry or variants thereof. Preferred methods include, but are not limited to, the methods described in the working examples and the following schemes 1 to 6. The starting materials and reagents for preparing the compounds of the present disclosure can be obtained from commercial suppliers or prepared by methods known to those skilled in the art according to the procedures described in the references (e.g., Fieser and Fieser's Reagents for Organic Synthesis, Vol. 1-28 (Wiley, 2016); March's Advanced Organic Chemistry, 7 thEd. (Wiley, 2013); and Larock's Comprehensive Organic Transformations, 2 nd Ed. (Wiley, 1999). If necessary, the starting materials and intermediates of the reaction can be separated and purified using conventional techniques (including but not limited to filtration, distillation, crystallization, chromatography, etc.). These materials can be characterized using conventional means, including measuring physical constants and obtaining spectral data.

[0143] Those skilled in the art will recognize whether a stereocenter is present in a compound disclosed herein. Therefore, the present disclosure includes two possible stereoisomers (unless specified in the synthesis), and not only includes racemic compounds, but also includes individual enantiomers and / or diastereomers. When the desired compound is as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by the splitting of the final product or any convenient intermediate. The splitting of the final product, intermediate or starting material can be affected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by ELEiel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[0144] As shown in Scheme 1, cyclopentenone (i) can be reduced to a heterocyclic R 1 The cyclopentene acetal (ii) can be formed by substituted enols (e.g., under Mitsunobu-type conditions). The acetal portion can be removed and the resulting diol can be oxidized to form the ketoalcohol portion in the intermediate (iii). The cyclopentene portion can then be used as a dienophile for reaction with the protected diene (iv) to provide the Diels Alder product (v). Reduction of the ketoalcohol to form the diol (vi) followed by deprotection gives the desired triol product.

[0145] Solution 1

[0146]

[0147] Alternatively, as shown in Scheme 2, the cyclopentenone (i) can be converted to the diene (xiv) used in the DielsAlder reaction with a suitable dienophile. The cyclopentenone can be converted to the halide (xi) and reacted with the heterocyclic R 1Condensation to form intermediate (xii). Reaction with stannane (xiii) in a Stille-type coupling provides diene (xiv) for reaction with boronate dienophile (xv) and formation of Diels Alder product (xvi). Hydrolysis of the boronate ester provides alcohol R 4 or R 5 , which can be converted to various phosphate prodrug moieties as described, for example, by Pradere et al. (Chemical Reviews, 2014, 114, 9154-9218), which is incorporated herein by reference. Deprotection of intermediate (xvii) provides the desired product (vii).

[0148] Solution 2

[0149]

[0150] Alternatively, as shown in Scheme 3, enone (xxi) (Org. Synth. 1996, 73, 44) can be converted to xxv using the same conditions as described in Scheme 2. Halogenation to xxii is followed by coupling with xxii and Stille coupling with diene (xxiii). Diels Alder reaction with xv then provides adduct xxiv which can be oxidized to xxv. Deprotection of intermediate (xxv) provides the desired product (xviii).

[0151] Solution 3

[0152]

[0153] The unsaturated Diels Alder products shown in Schemes 1, 2 and 3 can be hydrogenated to provide compounds with a saturated carbobicyclic core.

[0154] Alternatively, as shown in Scheme 4, the nucleoside analogs of structure (vii) or structure (xviii) can be protected to produce two regioisomers (xxxi) and (xxxii) (e.g., PG = tert-butyldimethylsilyl). Free alcohol can now be converted into thioester (xxxiv) and thioester (xxxv) using xxxiii. Deoxygenation is then carried out under free radical conditions to obtain intermediate (xxxvi) and intermediate (xxxvii). Deprotection then provides the desired product (xxxviii) and the desired product (xxxiv). See, for example, Nandanan et al. (J. Med. Chem. 2000, 43, 5, 829–842) and Meier et al. (Synlett 1991, 1991, 4, 227-228).

[0155] Solution 4

[0156]

[0157] Halogenated compounds can be prepared as shown in scheme 5. The intermediate (xxxi) and the intermediate (xxxii) can be directly treated with diethylamino sulfur trifluoride (DAST) to produce monofluoride (xli) and monofluoride (xlii). Deprotection then provides desired product (xliii) and desired product (xliv). In addition, difluorinated substances can be oxidized to ketone (xlv) and ketone (xlvi), and then reacted with DAST to form difluoride (xlvii) and difluoride (xlviii) to achieve. Deprotection then provides desired product (xlix) and desired product (l). See, for example, Roy et al. (Bioorganic & Medicinal Chemistry, 2006, 14, 4980-4986) and Shi et al. (Bioorganic & Medicinal Chemistry 2005, 13, 1641-1652).

[0158] Solution 5

[0159]

[0160] Alkylated compounds can be prepared as shown in Scheme 6. In Scheme 4, (xxxi) and (xxxii) can be reacted with a base and an alkyl halide (e.g., MeI) to provide (li) and (lii). Deprotection then provides the desired product (xliii) and the desired product (liv). In addition, in Scheme 5, (lv) and (lvi) can be reacted with a Grignard reagent RMgX (e.g., MeMgBr) to synthesize (lv) and (lvi). Deprotection then provides the desired product (lvii) and the desired product (lviii).

[0161] Solution 6

[0162]

[0163] As used herein, the term "protecting group" refers to a chemical moiety that renders a functional group (e.g., hydroxyl or amino) unreactive but can also be removed to restore the amino group. Examples of protecting groups include, but are not limited to, benzyloxy-carbonyl (Z or Cbz); 9-fluorenylmethyloxycarbonyl (Fmoc); tert-butyloxycarbonyl (Boc); allyloxycarbonyl (Alloc); p-toluenesulfonyl (Tos); 2,2,5,7,8-pentamethylchroman-6-sulfonyl (Pmc); 2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonyl (Pbf); mesityl-2-sulfonyl (Mts); 4-methoxy-2,3,6-trimethylphenylsulfonyl (Mtr); acetamido; phthalimido; silyl, such as trimethylsilyl, triethylsilyl, and (tert-butyl)dimethylsilyl; and the like. Other protecting groups are known to those skilled in the art and include, for example, those described by Green and Wuts (Protective Groups in Organic Synthesis, 4 th Ed. 2007, Wiley-Interscience, New York).

[0164] III. Methods for treating COVID-19 and other viral infections

[0165] Also provided herein is a method for treating an infection caused by a virus including coronavirus and other respiratory viruses. Infection can be, for example, coronavirus infection, adenovirus infection, influenza virus infection (e.g., influenza A virus (IAV) infection), parainfluenza virus infection, rhinovirus infection, or respiratory syncytial virus (RSV) infection. Infection can be, but is not limited to, SARS-CoV-2 infection, SARS-CoV infection, MERs-CoV infection, HCoV-229E infection, HCoV-OC43 infection, or HCoV-NL63 infection. The method includes administering a therapeutically effective amount of a carbon bicyclic nucleoside (e.g., a compound described herein) or a pharmaceutically acceptable salt thereof to an individual in need. In some embodiments, the individual suffers from coronavirus disease 2019 (COVID-19).

[0166] In some embodiments, the subject is a human, an agricultural animal (e.g., livestock such as cattle, sheep, pigs, etc.), or a companion animal (e.g., a pet such as a cat or dog). In some embodiments, the subject is a human over the age of 50.

[0167] According to the carbon bicyclic nucleoside compounds disclosed herein and other activating agents used in the combination therapy as described herein, it can be applied to an individual orally, intravenously, intramuscularly, intraperitoneally, subcutaneously, intrathecally, intraarterially, nasally, rectally or via other routes (if necessary). In some embodiments, the carbon bicyclic nucleoside compounds are applied orally or via injection. In the methods provided herein, the activating agent can be applied in any suitable dosage. Typically, the carbon bicyclic nucleoside compounds or other activating agents are applied in a dosage of about 0.1 mg / kg individual body weight to about 1000 mg / kg individual body weight (that is, about 0.1-1000mg / kg). The dosage of the carbon bicyclic nucleoside compounds can be, for example, about 0.1-1000mg / kg, or about 1-500mg / kg, or about 25-250mg / kg, or about 50-100mg / kg. The dosage of the carbobicyclic nucleoside compound can be about 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg. In some embodiments, the carbon bicyclic nucleoside compound is used with the amount of about 0.1mg / kg / day to about 100mg / kg / day. In some embodiments, the carbon bicyclic nucleoside compound is used with the amount of about 0.1mg / kg / day to about 1.0mg / kg / day. Dosage can be changed according to the needs of the patient, the severity of infection, the route of application and the specific preparation of application. The dosage applied to the patient should be enough to produce a beneficial therapeutic response in the patient. The size of the dose will also be determined by the presence, nature, and extent of any adverse side effects that accompany the administration of the drug in a particular patient. Determining the appropriate dose for a particular situation is within the skill of a typical practitioner. The total dose may be divided and administered in batches over a period of time suitable for treating COVID-19.

[0168] The carbon bicyclic nucleoside compound or other active agent can be administered for a period of time, which will also vary according to the severity of COVID-19 and the overall condition of the individual to whom the active agent is administered. Administration can be performed, for example, every hour, every 2 hours, every 3 hours, every 4 hours, every 6 hours, every 8 hours, or twice a day (including every 12 hours), or any interval thereof. Administration can be performed once a day, or once every 36 hours or 48 hours, once a week, twice a week, or three times a week. After treatment, the changes in his or her illness of the individual and the alleviation of the symptoms of COVID-19 can be monitored. The dose of the active agent can be increased when the individual has no significant response to a particular dose level, or if symptoms are observed to be alleviated, or if COVID-19 has been cured, or if unacceptable side effects are observed at a particular dose, the dose can be reduced. Treatment of COVID-19 according to the method disclosed herein may include alleviating one or more symptoms including but not limited to fever, cough, and shortness of breath. In some embodiments, treatment of COVID-19 can prevent serious life-threatening diseases, such as pneumonia.

[0169] The methods and compositions described herein can also be administered prophylactically to individuals at risk for infection with SARS-CoV-2 to reduce the risk of infection with COVID-19.

[0170] The application of carbon bicyclic nucleoside compounds according to the methods provided herein can result in a reduction in the level of SARS-CoV-2 RdRp activity in an individual. For example, the level of RdRp activity can be reduced by about 25% to about 95%, or about 35% to about 95%, or about 40% to about 85%, or about 40% to about 80%, compared to the corresponding level of RdRp activity before the first administration of the active agent (e.g., 24 hours before the first administration of the active agent). In some embodiments, the carbon bicyclic nucleoside binds to the SARS-CoV-2 nonstructural protein 12 (nsp12) in the RdRp complex, thereby reducing RdRp activity.

[0171] In some embodiments, the method also includes applying analgesics (including anti-inflammatory analgesics), antivirals and antitussives to individuals, or a combination thereof. Examples of nonsteroidal anti-inflammatory agents (NSAIDs) include but are not limited to aceclofenac, 5-aminosalicylic acid, aspirin, celecoxib, dexibuprofen, diclofenac, diflunisal, etodolac, fenoprofen, flufenamic acid, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, loxoprofen, mefenamic acid, nabumetone, naproxen, nimesulide, sulindac, and pharmaceutically acceptable salts thereof. NSAID can effectively alleviate symptoms such as fever and pain. Other analgesics such as, for example, paracetamol (acetaminophen) can also be co-administered with carbon bicyclic nucleoside compounds. Examples of other antiviral agents include, but are not limited to, protease inhibitors (e.g., nematevir, ritonavir, lopinavir, saquinavir, indinavir, etc.), nucleic acid polymerase inhibitors (e.g., acyclovir, foscarnet, ganciclovir, ribavirin, etc.), neuraminidase inhibitors (e.g., zanamivir, oseltamivir, etc.), interferons, and ion channel blockers (e.g., amantadine, rimantadine, etc.). Examples of antitussives include, but are not limited to, codeine, hydrocodone, benzonatate, dextromethorphan, and chlorpheniramine. In some embodiments, the method comprises administering a CYP3A4 inhibitor to an individual. Administration of a CYP3A4 inhibitor can prevent premature metabolism of carbon bicyclic nucleosides and increase plasma concentration levels after oral or another route of administration. Examples of CYP3A4 inhibitors include, but are not limited to, aprepitant, azamorelin, boceprevir, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cobicistat, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, fosaprepitant, grapefruit juice, imatinib, istradefylline, itraconazole, ivacaftor, ketoconazole, lomitapide, posaconazole, ranitidine, ranolazine, ritonavir, telaprevir, telithromycin, ticagrelor, tofisopam, troleandomycin, verapamil, and voriconazole. It should be understood that active agents can be classified into more than one class; for example, ritonavir can be classified as a protease inhibitor and a CYP3A4 inhibitor.

[0172] In some embodiments, the carbon bicyclic nucleoside is administered as a pharmaceutical composition containing at least one pharmaceutically acceptable excipient and a carbon bicyclic nucleoside or a pharmaceutically acceptable salt thereof. The carbon bicyclic nucleoside compound can be administered to an individual before administering one or more additional active substances, after administering one or more additional active substances, or while administering one or more additional active substances. The carbon bicyclic nucleoside compound can be administered with a composition separated from one or more additional active substances, or with a composition containing one or more additional active substances. Compositions are also provided herein, comprising: (i) one or more carbon bicyclic nucleoside compounds; (ii) one or more pharmaceutically acceptable excipients; and optionally (iii) optionally one or more additional active agents, each of which is independently an anti-inflammatory agent, analgesic, antiviral agent or antitussive. The composition can be formulated, for example, for oral administration, intravenous administration, intramuscular administration, intraperitoneal administration, subcutaneous administration, intrathecal administration, intraarterial administration, nasal administration or rectal administration.

[0173] Pharmaceutical compositions can be prepared by any method known in the field of pharmacy and drug delivery. Generally, the preparation of the composition includes the step of combining the active ingredient with a carrier containing one or more auxiliary ingredients. The pharmaceutical composition is usually prepared by uniformly and closely combining the active ingredient with a liquid carrier or a finely dispersed solid carrier or both, and then, if necessary, the product is molded into a desired formulation. The composition can be easily prepared and / or packaged into a unit dosage form.

[0174] The pharmaceutical composition can be in a form suitable for oral use. Suitable compositions for oral administration include, but are not limited to, tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, elixirs, solutions, oral patches, oral gels, chewing gums, chewable tablets, effervescent powders, and effervescent tablets. Such compositions can contain one or more agents selected from sweeteners, flavoring agents, coloring agents, antioxidants, and preservatives to provide pharmaceutically high quality and palatable preparations.

[0175] Tablets usually contain active ingredients mixed with non-toxic pharmaceutically acceptable excipients, including: inert diluents, such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate and sodium phosphate; granulating agents and disintegrants, such as corn starch and alginic acid; binders, such as polyvinyl pyrrolidone (PVP), cellulose, polyethylene glycol (PEG), starch, gelatin and gum arabic; and lubricants, such as magnesium stearate, stearic acid and talc. Tablets can be uncoated or coated, enteric or other types, using known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over a longer period of time. For example, time delay materials, such as monostearate glyceryl or distearate glyceryl, can be used. Tablets can also be coated with a semipermeable membrane and optional polymer osmotic agent according to known techniques to form an osmotic pump composition for controlled release. Compositions for oral administration can be prepared as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g. calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (e.g. peanut oil, liquid paraffin or olive oil).

[0176] Pharmaceutical compositions can also be in the form of injectable aqueous or oily solutions or suspensions. Aseptic injection preparations can be prepared using nontoxic vehicles suitable for parenteral administration, including water, Ringer's solution and isotonic sodium chloride solution, and acceptable solvents such as 1,3-butylene glycol. In addition, sterile fixed oils are generally used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can be used for the preparation of injections.

[0177] Aqueous suspensions contain active agents mixed with excipients suitable for preparing aqueous suspensions. Such excipients include, but are not limited to, suspending agents such as sodium carboxymethylcellulose, methylcellulose, oleyl-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum arabic; dispersants or wetting agents such as lecithin, polyoxyethylene stearate and polyethylene sorbitan monooleate; and preservatives such as ethyl paraben, n-propyl paraben and parabens. Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil (e.g., peanut oil, olive oil, sesame oil or coconut oil) or a mineral oil (e.g., liquid paraffin). Oily suspensions can contain thickeners such as beeswax, hard paraffin or cetyl alcohol. These compositions can be preserved by adding antioxidants such as ascorbic acid. Dispersible powders and granules (suitable for preparing aqueous suspensions by adding water) can contain active ingredients mixed with dispersants, wetting agents, suspending agents or combinations thereof. Additional excipients may also be present.

[0178] The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil (e.g., olive oil or peanut oil) or a mineral oil (e.g., liquid paraffin) or a mixture of these. Suitable emulsifiers can be naturally occurring gums, such as gum arabic or tragacanth; naturally occurring phospholipids, such as soybean lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate; and condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0179] Transdermal delivery can be achieved by iontophoresis patches and the like. The active ingredient can also be administered in the form of a suppository for rectal administration of the drug. These compositions can be prepared by mixing the active agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol.

[0180] IV. Examples

[0181] Example 1. Preparation of (1R,2S,3R,3aR,7R,7aR)-3-(6-amino-9H-purin-9-yl)-2,3,3a,4,7,7a-hexahydro-1H-indene-1,2,7-triol (7)

[0182]

[0183] To enone 1 (50 mg, 0.32 mmol) and CeCl3 at 0 °C . 7H2O (179mg, 0.48mmol) in methanol (8mL) stirring solution was added NaBH4 (15mg, 0.39mmol) in batches, and the resulting solution was kept at the same temperature for 30min. Then the reaction was quenched with saturated NH4Cl aqueous solution (30mL) and extracted with DCM (15mL x 2). The organic phase merged was dried and concentrated through Na2SO4 to obtain a crude allyl alcohol intermediate, which was directly used in the next step.

[0184] To a stirred solution of the above allyl alcohol (crude, 50 mg), 6-chloropurine (56 mg, 0.36 mmol) and PPh3 (168 mg, 0.64 mmol) in anhydrous THF (8 mL) was added DEAD (0.1 mL, 0.64 mmol) at 0°C, and the resulting mixture was stirred at room temperature overnight. After TLC showed that the reaction was complete, the solvent was removed to give a crude material, which was purified by column chromatography (hexane / ethyl acetate 3:1) to give compound 2 (70 mg, 75%, 2 steps). 1H NMR(400M Hz, CDCl3)ppm8.78(s,1H),7.99(s,1H),6.40(dt,J=5.6,1.6Hz,1H),5.98-5.96(m,1H),5.70( d, J=1.6Hz, 1H), 5.31 (dd, J=5.6, 1.2Hz, 1H), 4.71 (d, J=5.6Hz, 1H), 1.50 (s, 3H), 1.36 (s, 3H).

[0185]

[0186] To a stirred solution of compound 2 (430 mg, 1.47 mmol) in H2O (10 mL) and THF (4 mL) was added TFA (0.09 mL) and the reaction was stirred at room temperature overnight. The solvent was then removed to give the crude product, which was purified by silica gel column chromatography (DCM / MeOH 20:1) to give diol 3 (330 mg, 90%) as a white solid. 1 H NMR (400M Hz, CDCl3) ppm 8.74(s,1H),8.12(s,1H),6.35(dt,J=6.0,2.0Hz,1H),6.13(dd,J=6.0,1.6Hz ,1H),5.56(d,J=4.4,1.6Hz,1H),4.79(d,J=6.0Hz,1H),4.30(t,J=5.2Hz,1H).

[0187]

[0188] To a stirred solution of compound 3 (30 mg, 0.12 mmol) in DCM (5 mL) and THF (1 mL) was added PDC (43 mg, 0.12 mmol) at 0°C, and the reaction was stirred at room temperature for 1.5 hours. The mixture was then filtered, and the resulting crude material was purified by silica gel column chromatography (DCM / MeOH 30:1) to give enone 4 (9 mg, 30%, 36% BRSM), and 4 (4 mg) was recovered. 1 H NMR (400M Hz, CDCl3) ppm 8.72 (s, 1H), 8.24 (s, 1H), 7.67 (d, J = 4.8Hz, 1H), 6.60 (dd, J = 4.8Hz, 1H), 5.58 (s, 1H), 4.68 (s, 1H).

[0189]

[0190] A mixture of enone 4 (5 mg, 0.02 mmol), diene and BHT (trace) in toluene in a sealed tube was heated to 140 °C for 40 h under N2, then the solvent was removed to give a residue, which was purified by silica gel column chromatography (DCM / MeOH 40:1) to give enone 5 (3 mg, 30%) as a mixture of inseparable regioisomers and diastereomers. 1 HNMR(400M Hz, CDCl3)ppm8.83(s,0.5H),8.75(s,1H),8.62(s,0.6H),8.32(s,1H),6. 15-6.11(m,1H),6.08-6.04(m,1H),5.14(d,J=9.6Hz,1H),4.82(dd,J=8.8, 6.8Hz,1H),4.66(t,J=4.4Hz,1H),3.30-3.25(m,2H),2.98-2.94(m,1H),2 .76-2.74(m,1H),2.00-1.94(m,3H),0.91-0.86(s,9H),0.07-0.03(m,6H). HRMS: Theoretical mass: [M+H]+435.1614, found: 435.1615.

[0191]

[0192] To a stirred solution of ketone 5 (8 mg, 0.018 mmol) and Yb(OTf)3 (12.4 mg, 0.02 mmol) in methanol was added NaBH4 (~1 mg, 0.025 mmol) and the resulting solution was kept at room temperature for 30 min. The reaction was then quenched with saturated aqueous NH4Cl (30 mL) and extracted with DCM (15 mL x 2), the combined organic phases were dried over Na2SO4 and concentrated to give the crude material, which was purified by silica gel column chromatography (DCM / MeOH 40:1) to give diol 6 (7 mg, 87%). 1 H NMR(400MHz,CDCl3)ppm 8.77(s,1H),8.74(s,1H),5.71-5.70(m,1H),5.09(dd,J=8.4,2.4Hz,1H),4.84-4.80(m,2H),4.33-4.30(m,1H),3 .02-2.96(m,1H),2.81-2.76(m,1H),2.11-2.03(m,2H),1.55-1.48(m,1H),0.98(s,9H),0.19(s,3H),0.18(s,3H).

[0193]

[0194] To a sealed tube was added 6 (7 mg) and aqueous ammonia solution (0.5 mL) in THF (1 mL).The tube was heated to 105 °C for 6 h and then the solvent was removed under vacuum to give a residue which was used directly in the next step.

[0195] To a stirred solution of the above crude product (5 mg) in THF (2 mL) was added HF at 0 °C. . Pyridine (70% in pyridine, 2 drops) and the reaction was then allowed to warm to room temperature and stirred overnight. Removal of the solvent gave a residue which was purified by silica gel column chromatography (DCM / MeOH 40:1) to give triol 7 (1 mg). 1 H NMR(400M Hz, CDCl3)ppm8.36(s,1H),8.23(s,1H),5.86-5.83(m,1H),5.75-5.72(m,1H),4.74-4. 70(m,2H),4.37-4.35(m,1H),2.95-2.91(m,1H),1.91-1.86(m,1H),1.59-1.53(m,1H). MS:304.1(M+H),326.1(M+Na)

[0196] Example 2. Preparation of (1R,2S,3R,7R,7aR)-3-(6-amino-9H-purin-9-yl)-2,3,5,6,7,7a-hexahydro-1H-indene-1,2,7-triol (13)

[0197]

[0198] To a stirred solution of unsaturated ketone 1 (0.77 g, 5.00 mmol, 1.00 equiv) in anhydrous DMF (25 mL) was added iodine (3.17 g, 12.5 mmol, 2.50 equiv). Pyridine (0.50 mL, 6.25 mmol, 1.25 equiv) and DMAP (30.5 mg, 0.25 mmol, 5 mol%) were then added at 0 °C. The reaction was then stirred at room temperature. After 1.5 h, the reaction was quenched by aqueous Na2S2O3 solution (15 g / 50 mL H2O) and extracted with DCM (20 mL x 2). The combined organic phases were washed with brine (30 mL), dried over MgSO4 and concentrated to give a crude product, which was purified by silica gel column chromatography (Hex / EA4:1). Iodide 8 was isolated as a white crystalline solid (1.27 g, 0.45 mmol, 90%).

[0199] R f =0.38(Hex / EA4:1); 1H-NMR (400MHz, CDCl3) δ [ppm] = 7.96

[0200] (d,J=2.6Hz,1H),5.21(dd,J=5.6,2.6Hz,1H),4.51(d,J=5.6Hz,1H),1.40(s,3H),1.36(s,3H); 13 C{ 1 H}-NMR (101MHz, CDCl3) δ [ppm] = 197.7, 165.0, 115.9, 105.8, 79.8, 73.8, 27.4, 26.5.

[0201]

[0202] The unsaturated ketone 8 (1.28 g, 4.53 mmol, 1.00 equiv) was dissolved in MeOH (40 mL) and CeCl3*7H2O (1.94 g, 5.22 mmol, 1.15 equiv) was added. Then, at 0°C, NaBH4 (197 mg, 5.22 mmol, 1.15 equiv) was added. The reaction was stirred for 1 h and then quenched with saturated NH4Cl solution (3 mL). The mixture was concentrated in vacuo and the crude product was redissolved in EtOAc / H2O mixture (1:1, 40 mL). After separation of the organic phase, the aqueous phase was extracted with EtOAc (3 x 15 mL). The combined organic phases were washed with brine (25 mL), dried over MgSO4 and concentrated in vacuo. Alcohol 9 (1.18 g, 4.18 mmol, 92%) was isolated as a white solid of sufficient purity.

[0203] R f =0.32 (Hex:EtOAc 4:1); 1 H-NMR (400MHz, CDCl3) δ [ppm] =

[0204] 6.31(t,J=1.5Hz,1H),4.92(dd,J=1.8,5.6Hz,1H),4.69(t,J=4.7Hz,1H),4.42( ddd,J=1.3,5.6,10.4Hz,1H),2.81(d,J=10.5Hz,1H),1.43(s,3H),1.40(s,3H).

[0205]

[0206] Intermediate 9 was converted to compound 10 using the procedure described for the preparation of compound 2 in Example 1. 1HNMR (400M Hz, CDCl3) ppm δ 8.71 (s, 1H), 8.08 (s, 1H), 6.66 (s, 1H), 5.50 (d, J = 1.6Hz, 2H), 4.92 (d, J = 6.1Hz, 1H), 1.50 (s, 3H), 1.35 (s, 3H).

[0207]

[0208] To a stirred solution of compound 10 (530 mg, 1.27 mmol), Pd(PhCN)2Cl2 (24 mg, 0.063 mmol, 0.05 eq.), Ph3As (39 mg, 0.127 mmol, 0.1 eq.) and CuI (24 mg, 0.127 mmol, 0.1 eq.) in N2 (10 mL) was added vinyltributyltin (0.45 mL, 1.52 mmol, 1.2 eq.) dropwise at room temperature under N2. After stirring at room temperature for 2 hours, the reaction was quenched with water (80 mL) and extracted with ethyl acetate (15 mL×3). The combined organic phases were dried over Na2SO4 and concentrated to give a residue, which was purified by silica gel column chromatography (hexane / ethyl acetate 3:1) to give diene 11 (383 mg, 95%). 1 H NMR(400MHz, CDCl3)ppmδ8.79(s,1H),7.88(s,1H),6.48(dd,J=17.8,11.0Hz,1H),6.27(s,1H),5.89(s,1H),5.49 (d,J=5.6Hz,1H),5.18(d,J=11.0Hz,1H),4.98(d,J=17.8Hz,1H),4.65(d,J=5.6Hz,1H),1.46(s,3H),1.33(s,4H).

[0209]

[0210] To a stirred solution of 11 (0.69 g, 2.17 mmol, 1.00 equiv) was added BHT (47.8 mg, 0.22 mmol, 0.10 equiv). Toluene (15 mL) and pinacol ester (1.10 mL, 6.50 mmol, 3.00 equiv) were then added. The reaction was heated in an oil bath (145 °C) for 3 days. The volatiles were then removed in vacuo. The crude product was dissolved in pH 7 buffer (10 mL), THF (10 mL) and NaBO3·4H2O (1.33 g, 8.67 mmol, 4.00 equiv) were added. The reaction was stirred at room temperature for 2 hours, then quenched with saturated sodium thiosulfate solution (10 mL) and stirred for 10 minutes. After phase separation, the aqueous layer was extracted with ethyl acetate (3×15 mL), and the combined organic phases were dried over MgSO4 and filtered. The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (hexane / ethyl acetate 1:1, DCM / ethyl acetate 1:2) to yield 12a and 12b (175 mg and 355 mg, 1.46 mmol, 67% overall yield, respectively). f 0.31,0.21(DCM / ethyl acetate 1:2); 1 H-NMR (600MHz, CDCl3) δ [ppm] = 8.74 (s, 1H), 8.16 (s, 1H), 5.50 (s, 1H), 5.04 (t, J = 5.86Hz, 1H), 4.92 (s, 1H), 4.80 (t, J = 6 .17Hz,1H),3.69(t,J=10.23Hz,1H),2.72(s,1H),2.00-2.29(m,4H),1.82(s,1H),1.49-1.70(m,4H),1.24-1.40(m,3H); 13 C{ 1 H}-NMR (150MHz, CDCl3) δ [ppm] = 152.2, 151.7, 151.5, 144.7, 136.6, 132.0, 122.0, 114.5, 83.7, 82.7, 71.7, 63.6, 52.7, 31.2, 27.5, 25.2, 25.0

[0211]

[0212] To a stirred solution of 12a (18 mg) in THF (2 mL) and H2O (2 mL) was added TFA (0.02 mL), and the resulting mixture was stirred at room temperature overnight. The solvent was then removed to give a crude residue which was used without further purification. THF (1 mL) and aqueous ammonia (0.8 mL) were added to the crude residue in a sealed tube, and the tube was heated to 120° C. overnight under N2. The solvent was then removed to give a residue which was purified by silica gel column chromatography (DCM / MeOH 7:1) to give compound 13 (14 mg, 94%). 15: 1 H NMR(400M Hz,MeOD)ppm 8.17(s,1H),8.15(s,1H),5.36(m,1H),4.94(m,1H),4.38(t,J=6.8Hz,1H),4.24(t,J=4.9H z,1H),3.66(m,1H),2.55(m,1H),2.18-2.15(m,2H),1.96-1.95(m,1H),1.64-1.59(m,1H); 13 C{ 1 H}-NMR (150MHz, MeOD) δ [ppm] = 155.9, 152.2, 152.0, 149.8, 140.4, 134.7, 120. 0, 118.7, 74.7, 71.0, 70.3, 62.3, 52.5, 31.0, 24.5; MS (ESI+): m / z=303.2 (M+H).

[0213] Example 3. Preparation of (1R,2S,3R,7R,7aR)-3-(6-amino-9H-purin-9-yl)octahydro-1H-indene-1,2,7-triol (14)

[0214]

[0215] Pd / C (wet, 15 mg) was added to a solution of compound 13 (16 mg) in methanol (2 mL), and the resulting solution was stirred for 3 days under a balloon filled with H2 (1 atm). The mixture was filtered and the filtrate was concentrated to give a residue, which was purified by silica gel column chromatography (DCM / MeOH 7:1) to give product 14 (1 mg, 6%). Unreacted compound 13 (11 mg, 69%) was recovered. 14: 1H NMR (400M Hz, CDCl3) ppm 8.30(s,1H),8.19(s,1H),4.77(t,J=7.2Hz,1H),4.35-4.32(m,1H),4.14-4.10(m,2H),2.69-2.64( m,1H),2.23-2.16(m,1H),1.99-1,92(m,2H),1.67-1.60(m,2H),0.89-0.87(m,2H).MS:306.2(M+H).

[0216] Example 4. Preparation of (1R,2S,3R,6S,7aS)-3-(6-amino-9H-purin-9-yl)-2,3,5,6,7,7a-hexahydro-1H-indene-1,2,6-triol (16) and (1R,2S,3R,6S,7aS)-3-(6-methoxy-9H-purin-9-yl)-2,3,5,6,7,7a-hexahydro-1H-indene-1,2,6-triol (17)

[0217]

[0218] To a stirred solution of 12b (195 mg, 0.54 mmol, 1.00 equiv) in acetonitrile (6 mL) was added triethylamine (118 μL, 0.85 mmol, 1.50 equiv), isobutyric anhydride (141 μL, 0.85 mmol, 1.50 equiv) and DMAP (6.92 mg, 0.06 mmol, 0.10 equiv) at room temperature and stirred overnight. The reaction was quenched with NaHCO3 (10 mL) and stirred for 10 minutes. After phase separation, the aqueous layer was extracted with ethyl acetate (4×5 mL), and the combined organic phases were dried over MgSO4 and filtered. The solvent was removed in vacuo, and the crude product was purified by silica gel column chromatography (hexane / ethyl acetate). Elution ratios of 2:1 and 1:2 were used to produce 15a and 15b (132 mg and 36.8 mg, 0.39 mmol, 72%, respectively). 15a:R f 0.44 (hexane / ethyl acetate 2:1); 1 H-NMR (400MHz, CDCl3) δ [ppm] = 8.74 (s, 1H), 8.14 (s, 1H), 5.47 (s, 1H), 4.87-5.12 (m, 3H), 4.57 (t, J = 6.12Hz, 1H), 2.88 (brs, 1H), 2.32-2.60(m,3H),1.85-2.03(m,1H),1.53-1.63(m,6H),1.17-1.30(m,1H),1.16(d,J=1.75Hz,3H),1.14(d,J=1.84Hz,3H).15b:Rf 0.24 (hexane / ethyl acetate 2:1); 1 H-NMR (600MHz, CDCl3) δ [ppm] = 8.73 (s, 1H), 8.16 (s, 1H), 5.53 (s, 1H), 5.25 (s, 1H), 5.06 (t, J = 5.78Hz, 1H), 4.89 (s, 1H), 4.58 (t, J = 6.23Hz, 1H), 2 .83(s,1H),2.48-2.60(m,2H),2.24-2.31(m,1H),2.03-2.12(m,1H),1.6 0(s,3H),1.55(t,J=12.61Hz,1H),1.33(s,3H),1.15(dd,J=11.19Hz,6H); 13 C{ 1 H}-NMR (150MHz, CDCl3) δ [ppm] = 178.0, 156.0, 151.2, 150.6, 142.7, 137.9, 120.4, 119.8, 76.8, 76.5, 68.7, 64.3, 35.3, 31.2, 31.2, 19.2, 19.2

[0219]

[0220] To a stirred solution of 15a (50.0 mg, 0.12 mmol, 1.00 equiv) in a glass vial was added acetonitrile (1 mL) and aqueous NH3 (25% in water, 1 mL) and stirred at 80 °C for 1 day. The remaining water was removed in vacuo using acetonitrile (3×2 mL). Methanol (3 mL) and K2CO3 (24.2 mg, 0.18 mmol, 1.50 equiv) were added at room temperature and stirred for 1 day. The reaction was quenched with brine (3 mL) and water (3 mL). After phase separation, the aqueous layer was extracted with ethyl acetate (3×5 mL), and the combined organic phases were dried over MgSO4 and filtered. Methanol (0.5 mL), TFA (20% in water, 0.5 mL) and water (0.5 mL) were added and stirred at room temperature for 1 day. The solvent was removed in vacuo using acetonitrile (3×2 mL), and the crude product was purified by silica gel column chromatography (methanol / ethyl acetate, 10%) to yield adenosine analog 16 (22.0 mg, 0.07 mmol, 63%), with 17 (8.50 mg, 0.03 mmol) as a side product. f 0.07 (methanol / ethyl acetate, 5%); 1H-NHR (600MHz, MeOD-d4) δ [ppm] = 8.19 (s, 1H), 8.14 (s, 1H), 5.31 (s, 1H), 5.07 (s, 1H), 4.31 (t, J = 5.2Hz, 1H) ,4.06(dd,J=5.9,7.9Hz,1H),3.95(m,1H),2.75(brs,1H),2.39(m,2H),1.92(m,1H),1.44(q,J=11.9Hz,1H); 13 C{ 1 H}-NMR (150MHz, MeOD-d4) δ [ppm] = 155.9, 152.2, 149.5, 140.5, 137.1, 120.0, 118.7, 75.9, 74.9, 66.8, 62.4, 44.0, 35.8, 33.917: R f 0.13 (methanol / ethyl acetate, 5%); 1 H-NHR(600MHz,MeOD-d4)δ[ppm]=8.52(s,1H),8.33(s,1H),5.39(s,1H),5.03(m,1H),4.35(m,1H),4.20(s,3H),4 .11-4.15(m,1H),3.91-3.98(m,1H),2.77(brs,1H),2.34-2.42(m,2H),1.84-1.93(m,1H),1.44(q,J=17.4Hz,1H)

[0221] Example 5. Preparation of (1R,2S,3R,6R,7aS)-3-(6-amino-9H-purin-9-yl)-2,3,5,6,7,7a-hexahydro-1H-indene-1,2,6-triol (18)

[0222]

[0223] To a stirred solution of 15b (31.5 mg, 0.07 mmol, 1.00 equiv) in a glass vial was added acetonitrile (1 mL) and aqueous NH3 (25% in water, 1 mL) and stirred at 85 °C for 1 day. The remaining water was removed in vacuo using acetonitrile (3×2 mL). Methanol (1 mL) and K2CO3 (15.8 mg, 0.11 mmol, 1.50 equiv) were added at room temperature and stirred for 1 day. The reaction was quenched and diluted with brine (3 mL) and water (3 mL). After phase separation, the aqueous layer was extracted with ethyl acetate (3×5 mL), and the combined organic phases were dried over MgSO4 and filtered. Methanol (0.5 mL), TFA (20% in water, 0.5 mL) and water (0.5 mL) were added and stirred at room temperature for 1 day. The solvent was removed in vacuo using acetonitrile (3 x 2 mL), and the crude product was purified by silica gel column chromatography (methanol / ethyl acetate, 10%) to yield adenosine analog 18 (7.90 mg, 0.03 mmol, 36%). f 0.05 (methanol / ethyl acetate, 10%); 1 H-NMR (600MHz, MeOD-d4) δ [ppm] = 8.19 (s, 1H), 8.14 (s, 1H), 5.36 (s, 1H), 5.04 (t, J = 2.87Hz, 1H), 4.32 (t, J = 5.27Hz, 1H), 4.21 (brs, 1H), 4.07 (m, 1H), 2.86 (brs, 1H), 2.27-2.34 (m, 2H), 2.08 (d, J = 19.4Hz, 1H), 1.50 (t, J = 12.3Hz, 1H).

[0224] Example 6. Preparation of 1-((1R,2S,3R,3aR,4R)-2,3,4-trihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-1-yl)-1H-1,2,4-triazole-3-carboxamide (23)

[0225]

[0226] Alcohol 9 (1.00 g, 3.55 mmol, 1.00 equiv) was dissolved in DCM (50 mL). Triazole 19 (0.52 g, 4.08 mmol, 1.15 equiv) and After MS, the mixture was stirred for 2 h. Then, at 0 °C, PPh3 (1.12 g, 4.25 mmol, 1.20 equiv) and DIAD (0.84 mL, 4.25 mmol, 1.20 equiv) were first added. The reaction was stirred for 18 h. The reaction was then filtered and the solvent removed in vacuo. Purification by column chromatography (SiO2, Hex:EtOAc 3:1 to 1:1) first gave 20b as a yellow oil (0.59 g, 1.51 mmol, 42%) and then 20a as a white foam (0.49 g, 1.25 mmol, 36%). 20a:R f =0.13 (Hex:EtOAc 3:1); 1 H-NMR (400MHz, CDCl3) δ [ppm] = 8.26 (s, 1H), 6.60 (s, 1H), 5.36 (m, 2H), 4.89 (d, J = 6.8Hz, 1H), 3.99 (s, 3H), 1.47 (s, 3H), 1.34 (s, 3H); 13 C{ 1 H}-NMR (101MHz, CDCl3) δ [ppm] = 160.0, 156.1, 146.3, 145.3, 113.1, 96.1, 85.0, 82.5, 77.7, 53.0, 27.2, 25.9; [M+Na] + C 12 H 14 IN3O4Na + HRMS (ESI, 3.5 kV) calculated value: 413.99212, found value: 413.99171. 20b: R f =0.24 (Hex:EtOAc 3:1); 1 H-NMR (400MHz, CDCl3) δ [ppm] = 8.03 (s, 1H), 6.58 (s, 1H), 6.54 (s, 1H), 5.35 (dt, J=1.8,5.7Hz,1H),4.84(d,J=5.8Hz,1H),4.06(s,3H),1.50(s,3H),1.37(s,3H); 13 C{ 1 H}-NMR (101MHz, CDCl3) δ [ppm] = 158.3, 151.9, 145.4, 145.2, 112.9, 96.9, 85.3, 83.0, 76.8, 53.5, 27.4, 26.1; HRMS (ESI, 3.5kV) [M+Na] + C 12 H 14 IN3O4Na +Calculated value: 413.99212, measured value: 413.99183.

[0227]

[0228] Iodide 20a (478 mg, 1.22 mmol, 1.00 equiv) was dissolved in NMP (4 mL, freshly distilled) and [Pd(PhCN)2Cl2] (14.1 mg, 36.7 μmol, 3 mol%), CuI (14.0 mg, 73.3 μmol, 6 mol%) and Ph3As (22.5 mg, 73.3 μmol, 6 mol%) were added. Vinyl tributyltin (430 μL, 1.47 mmol, 1.20 equiv) was then added dropwise at 0 °C. The reaction was stirred for 3 hours at this temperature. The reaction was quenched with saturated NaHCO3 solution (10 mL) and EtOAc (10 mL). After separation of the organic phase, the aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic phase was washed with brine (15 mL), dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (SiO2, Hex:EtOAc 2:1 to 1:1) gave 21 as a white solid (349 mg, 1.20 mmol, 98%). f =0.29 (Hex:EtOAc 1:1); 1 H-NMR (400MHz, CDCl3) δ [ppm] = 8.07 (s, 1H), 6.47 (dd, J = 11.2, 17.6Hz, 1H), 6.21 (s, 1H), 5.68 (s, 1H), 5.4 2(d,J=5.4Hz,1H),5.23(d,J=17.7Hz,1H),4.70(d,J=5.6Hz,1H),3.99(s,3H),1.42(s,3H),1.33(s,3H); 13 C{ 1 H}-NMR (101MHz, CDCl3) δ [ppm] = 160.1, 155.6, 143.9, 138.8, 136.5, 130.0, 119.7, 112.4, 84.4, 83.4, 69.4, 53.0, 27.5, 26.0; HRMS (ESI, 3.5kV) [M+Na] + C 14 H 17 N3O4Na + Calculated value: 314.11113, measured value: 314.11088.

[0229]

[0230] Diene 21 (320 mg, 1.10 mmol, 1.00 equiv) was dissolved in toluene (freshly distilled over CaH2, 15 mL) and BHT (29.0 mg, 0.11 mmol, 10 mol%) and vinylboronic acid pinacol ester (477 mL, 2.82 mmol, 2.50 equiv) were added. The reaction was heated to 135 °C (oil bath temperature) for 96 h in a sealed tube. The volatiles were then removed and the crude mixture was dissolved in THF / H2O (20 mL, 1:1). NaBO3 x 4H2O (866 mg, 3.56 mmol, 3.00 equiv) was then added. After 90 min, the reaction was complete and diluted with EtOAc / brine (1:1, 20 mL). After separation of the organic phase, the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (SiO2, DCM:EtOAc 1:1 to EtOAc / DCM 1:3 to pure EtOAc) afforded 2a (114 mg, 0.34 mmol, 31%) as a white solid and 22b (179 mg, 0.53 mmol, 49%) as a mixture of isomers. f =0.30 (EtOAc:DCM 1:1); 1 H-NMR (400MHz, CDCl3) δ [ppm] = 8.25 (s, 1H), 5.20 (brs, 1H), 5.06 (dd, J = 5.6, 7.7Hz, 1H), 4.92 (m, 1H), 4.64 (dd, J = 5.0, 7.7Hz, 1 H),4.00(s,3H),3.69(m,1H),2.63(m,1H),2.11-2.20(m,2H),1.95-2.05(m,2H),1.52-1.65(m,1H),1.56(s,3H),1.33(s,3H); 13 C{ 1 H}-NMR (101MHz, CDCl3) δ [ppm] = 160.2, 155.6, 145.7, 136.4, 122.5, 114.5, 83.3, 82.3,71.5,68.6,53.0,52.5,31.3,27.3,25.04,24.97; [M+Na] of HRMS (ESI, 3.5kV) + C 16 H 21 N3O5Na + Calculated value: 358.13734, measured value: 358.13714.22b:R f =0.16 (EtOAc:DCM 1:1).

[0231]

[0232] A solution of 22a (26.0 mg, 77.5 mmol) in MeOH (0.5 mL) was prepared and NH3 (7 M in MeOH, 0.5 mL) was added. The solution was stirred for 16 h and the volatiles were removed. The crude product was then dissolved in MeOH (0.5 mL), TFA (10% in H2O, 0.5 mL) was added, and the reaction was stirred for another 23 h. Removal of volatiles followed by purification by column chromatography (SiO2, EtOAc 5% to 10% MeOH) gave the nucleoside analog 23 (17.8 mg, 63.5 mmol, 82% yield over 2 steps) as a white solid. f =0.08 (EtOAc, 5% MeOH); 1 H-NMR (400MHz, MeOD-d4) δ [ppm] = 8.60 (s, 1H), 5.25 (brs, 1H), 5.03 (m, 1H), 4.25 (dd, J = 6.2, 6.8Hz, 1H), 4.16 (dd, J = 5.0, 5.6Hz, 1H),3.57(ddd,J=3.8,9.7,11.3Hz,1H),2.48(m,1H),2.08-2.28(m,2H),1.91-2.00(m,1H),1.57(ddt,J=7.3,11.3,11.8Hz,1H); 13 C{ 1 H}-NMR (101MHz, CDCl3) δ [ppm] = 163.5, 158.1, 147.1, 135.9, 122.7, 76.6, 73.8, 71.8, 68.6, 53.7, 32.3, 26.1; HRMS (ESI, 3.5kV) [M+Na] + C 12 H 16 N4O4Na + Calculated value: 303.10638, measured value: 303.10631.

[0233]

[0234] Example 7. Preparation of (1R,2S,3R,3aS,4R)-1-(3-carbamoyl-1H-1,2,4-triazol-1-yl)-2,3-dihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-4-yl isobutyrate (24)

[0235]

[0236] Alcohol 22a (32 mg, 95.5 μmol, 1.00 equiv) was dissolved in MeOH (0.35 mL) and NH3 (7M in MeOH, 0.35 mL) was added. After 16 h, the solvent was removed in vacuo. The residue was dissolved in anhydrous ACN (1.5 mL) and DMAP (14.6 mg, 0.12 mmol, 1.25 equiv) and isobutyric anhydride (22.7 mg, 24 μL, 1.50 equiv) were added at 0 °C. After 20 min, the reaction was quenched with saturated NaHCO3 (5 mL) and ethyl acetate (5 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (4 x 5 mL). The combined organic phase was dried over MgSO4 and the solvent was removed in vacuo. Purification by column chromatography (SiO2, DCM:EtOAc 3:1) gave the butyrate, which was directly deprotected by redissolving in MeOH (0.5 mL) and adding TFA (10% in H2O, 0.5 mL). After 24 h, the solvent was removed in vacuo. Purification by column chromatography (SiO2, EtOAc 5% MeOH) gave nucleoside analog 24 (18.6 mg, 53.1 μmol, 5% yield in 3 steps) as a white solid. f = 0.33 (EtOAc 5% MeOH); 1 H-NMR (400MHz, CDCl3) δ [ppm] = 8.63 (s, 1H), 5.25 (s, 1H), 5.17 (m, 1H), 4.91 (m, 1H), 4.22 (dd, J = 5.6, 5.8Hz, 1H), 4.08 (dd, J = 5.9, 6.0Hz, 1H), 2.74 (m, 1 H),2.61(sept,J=6.9Hz,1H),2.14-2.33(m,2H),1.93-2.03(m,1H),1.68(d dt,J=7.3,11.4,11.4Hz,1H),1.21(d,J=7.2Hz,3H),1.91(d,J=7.1Hz,3H); 13 C{ 1 H}-NMR (101MHz, CDCl3) δ [ppm] = 178.7, 157.6, # 146.9*,135.6,123.8,76.7,74.4,74.3,68.5,50.5,35.4,28.9,25.8,19.3(2x); HRMS (ESI, 3.5kV) [M+Na] + C 15 H 22 N4O5Na +Calculated: 373.14824, Found: 373.14822. # Obtained by HMBC, * Obtained by HSQC, Note: No carbamoyl carbon was observed.

[0237] Example 8. Preparation of 1-((1R,2S,3R,3aS,5R)-2,3,5-trihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-1-yl)-1H-1,2,4-triazole-3-carboxamide (26)

[0238]

[0239] The diastereomeric mixture 22b (175.5 mg, 0.52 mmol, 1.00 equiv) was dissolved in MeCN (6 mL) and isobutyric anhydride (173 μL, 1.04 mmol, 2.00 equiv). Et3N (145 μL, 1.04 mmol, 2.00 equiv) and DMAP (6.4 mg, 52.2 μmol, 10 mol%) were added sequentially. After 18 h, the reaction was quenched by adding saturated NaHCO3 solution and diluted with EtOAc. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3x10 mL). The combined organic phase was washed with brine (15 mL), dried over MgSO4, and the solvent was removed in vacuo. Purification by column chromatography (SiO2, Hex:EtOAc 1:1) gave 25a (48.1 mg, 11.8 μmol, 23%) and 25b (108.8 mg, 26.8 μmol, 52%) as white solids. f =0.49 (Hex:EtOAc 1:2); 1 H-NMR (600MHz, CDCl3) δ [ppm] = 8.26 (s, 1H), 5.25 (brs, 1H), 5.21 (brs, 1H), 5.08 (dd, J = 5.4, 7.3H z,1H),4.88(m,1H),4.43(dd,J=7.4,9.3Hz,1H),3.99(s,3H),2.27(brs,1H),2.50(hep,J=7.0Hz ,1H),2.44(ddd,J=4.0,5.3,13.6Hz,1H),2.32-2.35(m,1H),2.09(d,J=19.1Hz,1H),1.55(s,3H) ,1.46(ddd,J=2.2,11.9,13.6Hz,1H),1.31(s,3H),1.14(d,J=7.0Hz,3H),1.12(d,J=7.0Hz,3H); 13 C{ 1H}-NMR (151MHz, CDCl3) δ [ppm] = 176.6, 160.2, 155.7, 145.7, 138.4, 119.1, 114.2, 83.5, 83.3, 68.5,66.7,53.0,39.3,34.2,30.5,29.8,27.4,25.1,19.12,19.05; [M+Na] of HRMS (ESI, 3.5kV) + C 20 H 27 N3O6Na + Calculated value: 428.17921, measured value: 428.17857.25b:R f =0.56 (Hex:EtOAc 1:2); 1 H-NMR (600MHz, CDCl3) δ [ppm] = 8.25 (s, 1H), 5.19 (brs, 1H), 5.05 (ddd, J = 1.0, 5.1,7.2Hz,1H),4.95(m,1H),4.91(m,1H),4.41(ddd,J=0.9,5.6,7.1Hz,1H), 3.99(s,3H),2.80(brs,1H),2.50(hep,J=7.0Hz,1H),2.35-2.43(m,2H),1.94 -2.03(m,1H),1.51(m,3H),1.47(q,J=12.0Hz,1H),1.29(s,3H),1.13(m,6H); 13 C{ 1 H}-NMR (151MHz, CDCl3) δ [ppm] = 176.7, 160.2, 155.7, 145.7, 138.5, 120.5, 114.1, 83.5, 82.8, 68.9,67.9,53.0,44.2,34.1,32.4,30.2,27.4,25.1,19.04,19.02; [M+Na] of HRMS (ESI, 3.5kV) + C 20 H 27 N3O6Na + Calculated value: 428.17921, measured value: 428.17857.

[0240]

[0241] Ester 25a (24.8 mg, 61.2 μmol, 1.00 equiv) was dissolved in MeOH (0.5 mL) and NH3 (7M in MeOH, 0.5 mL) was added. The reaction was stirred for 16 h, then K2CO3 (16.9 mg, 0.12 mmol, 2.00 equiv) was added. After stirring for an additional 16 h, a mixture of brine / EtOAc (10 mL, 1:1) was added. The organic phase was separated, and the aqueous phase was extracted with EtOAc (4 x 4 mL). The combined organic phases were dried over MgSO4, and the solvent was removed in vacuo. The crude product was redissolved in MeOH (0.5 mL) and TFA (10% in H2O, 0.5 mL) was added. The reaction was stirred for 24 h, then the solvent was removed in vacuo. Purification by column chromatography (SiO2, EtOAc 7% MeOH) gave nucleoside analog 26 (16.0 mg, 57.1 μmol, 93% yield in 3 steps) as a white solid. f =0.21 (EtOAc, 5% MeOH); 1 H-NMR (400MHz, MeOD-d4) δ [ppm] = 8.60 (s, 1H), 5.24 (brs, 1H), 5.11 (m, 1H), 4.25 (dd, J = 4.1, 5.7Hz, 1H), 4.18 (m, 1H), 3.9 6(dd,J=5.7,8.0Hz,1H),2.80(brs,1H),2.23-2.34(m,1H),2.09(d,J=19.1Hz,1H),1.40(ddd,J=1.8,11.8,13.3Hz,1H); 13 C{ 1 H}-NMR (101MHz, MeOD-d4) δ [ppm] = 163.5, 158.2, 148.9, 138.1, 121.2, 77.1, 76.9, 69.1, 65.0, 39.3, 34.2, 34.0; HRMS (ESI, 3.5kV) [M+H] + C 12 H 16 N4O4H + Calculated value: 281.12443, measured value: 281.12393.

[0242]

[0243] Example 9. Preparation of (1R,2S,3R,3aS,5R)-1-(3-carbamoyl-1H-1,2,4-triazol-1-yl)-2,3-dihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-5-yl isobutyrate (27)

[0244]

[0245] Ester 25a (20.1 mg, 49.6 μmol) was dissolved in MeOH (0.5 mL) and NH3 (7M in MeOH, 0.5 mL) was added. The reaction was stirred for 16 h and then the volatiles were removed in vacuo. The crude product was redissolved in MeOH (0.75 mL) and TFA (10% in H2O, 0.75 mL) was added. After 24 h, the solvent was removed in vacuo. Purification by column chromatography (SiO2, EtOAc 5% MeOH) gave nucleoside analog 27c (16.2 mg, 46.2 μmol, 93% over 2 steps) as a white solid. f =0.17 (EtOAc, 5% MeOH); 1 H-NMR (400MHz, CDCl3) δ [ppm] = 8.70 (s, 1H), 5.28 (brs, 1H), 5.23 (brs, 1H), 5.17 (brs, 1H), 4.26 (dd, J = 4.3, 5.1Hz, 1H), 3.99 (dd, J = 5.8, 8.0Hz, 1H), 2. 77(brs,1H),2.52(sept,J=7.0Hz,1H),2.31-2.45(m,2H),2.16(d,J=19.3H z,1H),1.48(t,J=12.5Hz,1H),1.16(d,J=7.0Hz,3H,1.13(d,J=7.0Hz,3H); 13 C{ 1 H}-NMR (101 MHz, CDCl3) δ [ppm] = #178.3, 138.3, 121.1, 77.1, 77.0, 69.0, 68.8, 39.7, 35.4, 31.4, 19.34, 19.26; HRMS (ESI, 3.5 kV) C 16 H 22 N4O5Na + [M+Na] + Calculated value: 373.14824, Found: 373.14763. #Due to the broad signal, not all carbon signals can be found.

[0246] Example 10. Preparation of 1-((1R,2S,3R,3aS,5S)-2,3,5-trihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-1-yl)-1H-1,2,4-triazole-3-carboxamide (28)

[0247]

[0248] Ester 25b (21.6 mg, 53.3 μmol, 1.00 equiv) was dissolved in MeOH (0.5 mL) and NH3 (7M in MeOH, 0.5 mL) was added. The reaction was stirred for 17.5 h, then K2CO3 (14.7 mg, 0.11 mmol, 2.00 equiv) was added. After another 24 h, H2O / EtOAc (10 mL, 1:1) was added. The organic phase was separated and the aqueous phase was extracted with EtOAc (4 x 4 mL). The combined organic phases were dried over MgSO4 and the solvent was removed in vacuo. The crude product was redissolved in MeOH (0.5 mL) and TFA (10% in H2O, 0.5 mL) was added. The reaction was stirred for 27 h, then the solvent was removed in vacuo. Purification by column chromatography (SiO2, EtOAc 7.5% MeOH) gave nucleoside analog 28 (10.8 mg, 38.5 μmol, 72% over 3 steps) as a white solid. f =0.08 (EtOAc, 7.5% MeOH); 1 H-NMR (400MHz, MeOD-d4) δ [ppm] = 8.59 (s, 1H), 5.19 (s, 1H), 5.16 (m, 1H), 4.24 (dd, J = 3.8, 5.5Hz, 1H), 3.95 (dd, J = 5.9, 8.3Hz, 1 H),3.90(m,1H),2.70(m,1H),2.37-2.46(m,1H),2.34(ddd,J=3.6,5.2,11.6Hz,1H),1.83-1.94(m,1H),1.34(q,J=11.6Hz,1H); 13 C{ 1 H}-NMR (101MHz, CDCl3) δ [ppm] = 163.5, 158.3, 146.9, 138.3, 122.6, 77.5, 76.6, 68.6, 68.2, 45.3, 37.2, 35.4; HRMS (ESI, 3.5kV) [M+H] + C 12 H 16 N4O4H + Calculated value: 281.12375, measured value: 281.12443.

[0249]

[0250] Example 11. Preparation of (1R,2S,3R,3aS,5S)-1-(3-carbamoyl-1H-1,2,4-triazol-1-yl)-2,3-dihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-5-yl isobutyrate (29)

[0251]

[0252] Ester 25b (20.8 mg, 51.3 μmol) was dissolved in MeOH (0.5 mL) and NH3 (7 M in MeOH, 0.5 mL) was added. The reaction was stirred for 17.5 h and then the volatiles were removed in vacuo. The crude product was redissolved in MeOH (0.5 mL) and TFA (10% in H2O, 0.5 mL) was added. After 24 h, the solvent was removed in vacuo. Purification by column chromatography (SiO2, EtOAc 3% MeOH) gave nucleoside analog 29 (15.7 mg, 44.8 μmol, 87% yield in 2 steps) as a white solid. f =0.37 (EtOAc, 5% MeOH); 1 H-NMR (600MHz, CDCl3) δ [ppm] = 8.61 (s, 1H), 5.22 (brs, 1H), 5.19 (m, 1H), 5.00 (dddd, J = 3 .8,6.4,9.7,12.3,1H),4.24(dd,J=3.5,5.6Hz,1H),3.97(dd,J=5.7,8.4Hz,1H),2.77(b rs,1H),2.54(hep,J=7.0Hz,1H),2.46-2.51(m,1H),2.37(ddd,J=3.5,5.4,11.4Hz,1H), 1.99-2.06(m,1H),1.47(q,J=11.5Hz,1H),1.15(d,J=7.0Hz,3H),1.14(d,J=7.0Hz,3H); 13 C{ 1 H}-NMR (151 MHz, CDCl3) δ [ppm] = 178.4, 163.4, 158.3, 147.0, 138.5, 122.1, 77.5, 76.6, 71.1, 68.9, 44.6, 35.3, 33.4, 31.9, 19.3 (2x); HRMS (ESI, 3.5 kV) [M+Na] + Calculated value: C 16 H 22 N4O5Na + 373.14824, measured value: 373.14768.

[0253]

[0254] Example 12. Preparation of 1-((1R,2S,3R,3aR,4R)-2,3,4-trihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-1-yl)-1H-1,2,4-triazole-5-carboxamide (30)

[0255]

[0256] Intermediate 20b was used to synthesize nucleoside analog 30 using the method described in Example 6. f =0.23 (EtOAc / MeOH 3%); 1 H-NMR (400MHz, CDCl3) δ [ppm] = 7.98 (s, 1H), 6.28 (s, 1H), 4.91 (m, 1H), 4.33 (dd, J = 5.7, 5.7Hz, 1H), 4.19 (dd, J = 5.9, 6.0Hz, 1H), 3.56 (d dd,J=3.7,9.2,11.4Hz,1H),2.51(brs,1H),2.14-2.24(m,1H),2.00-2.13(m,1H),1.89-1.97(m,1H),1.57(ddt,J=6.9,11.4,11.5,1H); 13 C{ 1 H}-NMR (101MHz, CDCl3) δ [ppm] = 161.0, 151.2, 148.8, 136.6, 122.3, 76.8, 75.2, 72.6, 68.1, 53.1, 32.3, 26.1; HRMS (ESI, 3.5kV) [M+Na] + C 12 H 16 N4O4Na + Calculated value: 303.10638, measured value: 303.10612.

[0257] Example 13. Preparation of (1R,2S,3R,3aS,4R)-1-(5-carbamoyl-1H-1,2,4-triazol-1-yl)-2,3-dihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-4-yl isobutyrate (31)

[0258]

[0259] Intermediate 20b was used to synthesize nucleoside analog 31 using the methods described in Examples 6 and 7. f =0.54 (EtOAc, 5% MeOH); 1 H-NMR (400MHz, CDCl3) δ [ppm] = 7.98 (s, 1H), 6.29 (s, 1H), 5.04 (m, 1H), 4.87 (m, 1 H),4.27(dd,J=4.4,5.5Hz,1H),4.14(dd,J=5.9,7.4Hz,1H),2.75(m,1H),2.60( sept,J=7.0Hz,1H),2.19-2.29(m,1H),2.07-2.19(m,1H),1.89-1.98(m,1H),1. 67(ddt,J=6.8,11.6,11.9Hz,1H),1.20(d,J=7.0Hz,3H),1.18(d,J=7.0Hz,3H); 13 C{ 1 H}-NMR (101MHz, CDCl3) δ [ppm] = 178.7, 161.0, 151.3, 148.5, 136.5, 123.2, 77.0 ,75.7,74.8,67.9,50.0,35.4,28.9,25.8,19.4,19.3; [M+Na] of HRMS (ESI, 3.5kV) + C 16 H 22 N4O5Na + Calculated value: 373.14824, measured value: 373.14786.

[0260] Example 14. Preparation of 1-((1R,2S,3R,3aS,5R)-2,3,5-trihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-1-yl)-1H-1,2,4-triazole-5-carboxamide (32)

[0261]

[0262] Intermediate 20b was used to synthesize nucleoside analog 32 using the methods described in Example 6 and Example 8. f =0.21 (EtOAc, 5% MeOH); 1H-NMR (600MHz, CDCl3) δ [ppm] = 7.95 (s, 1H), 6.29 (s, 1H), 4.97 (s, 1H), 4.32 (dd, J = 3.3, 5.6Hz, 1H), 4.15 (brs, 1H), 4.02 (dd, J = 5.5 ,8.9Hz,1H),2.81(brs,1H),2.28(ddd,J=3.7,5.3,12.9Hz,1H),2.17-2.24(m,1H),2.07(d,J=19.2Hz,1H),1.34(t,J=11.9Hz,1H); 13 C{ 1 H}-NMR (151MHz, CDCl3) δ [ppm] = 161.1, 151.3, 148.5, 138.8, 120.3, 77.8, 77.3, 68.5, 65.1, 39.1, 34.4, 30.0; HRMS (ESI, 3.5kV) [M+Na] + C 12 H 16 N4O4Na + Calculated value: 303.10638, measured value: 303.10603.

[0263] Example 15. Preparation of (1R,2S,3R,3aS,5R)-1-(5-carbamoyl-1H-1,2,4-triazol-1-yl)-2,3-dihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-5-yl isobutyrate (33)

[0264]

[0265] Intermediate 20b was used to synthesize nucleoside analog 33 using the methods described in Example 6 and Example 9. f =0.53 (EtOAc, 7.5% MeOH); 1H-NMR (400MHz, MeOD-d4) δ [ppm] = 7.96 (s, 1H), 6.31 (brs, 1H), 5.21 (brs, 1H), 5.03 (brs, 1H),4.30(dd,J=2.8,5.5Hz,1H),4.04(dd,J=5.6,9.2Hz,1H),2.77(brs,1H),2.54(sept ,J=7.0Hz,1H),2.40(ddd,J=4.5,4.6,13.3Hz,1H),2.23-2.34(m,1H),2.13(d,J=19.7Hz ,1H),1.40(ddd,J=1.5,11.6,13.2Hz,1H),1.16(d,J=7.2Hz,3H),1.14(d,J=7.2Hz,3H); 13 C{ 1 H}-NMR(101MHz,MeOD-d4)δ[ppm]=177.1,159.8,150.1,147.1,137.9,119.0,76. 6,76.1,67.6,67.1,38.1,34.1,30.3,30.2,18.1,18.0; [M+Na] of HRMS (ESI, 3.5kV) + C 16 H 22 N4O5Na + Calculated value: 373.14824, measured value: 373.14778.

[0266] Example 16. Preparation of 1-((1R,2S,3R,3aS,5S)-2,3,5-trihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-1-yl)-1H-1,2,4-triazole-5-carboxamide (34)

[0267]

[0268] Intermediate 20b was used to synthesize nucleoside analog 34 using the methods described in Example 6 and Example 10. f =0.35 (EtOAc, 5% MeOH); 1H-NMR (400MHz, CDCl3) δ [ppm] = 7.96 (s, 1H), 6.23 (brs, 1H), 4.99 (m, 1H), 4.30 (dd, J = 2.6, 5.6Hz, 1H), 3.99 ( dd,J=5.5,9.2Hz,1H),3.90(m,1H),2.71(brs,1H),2.28-2.44(m,2H),1.81(m,1H),1.27(q,J=11.5Hz,1H); 13 C{ 1 H}-NMR (101MHz, CDCl3) δ [ppm] = 161.1, 151.3, 148.3, 139.1, 121.7, 77.8, 77.5, 68.2, 68.0, 45.1, 37.4, 35.5; HRMS (ESI, 3.5kV) [M+Na] + C 12 H 16 N4O4Na + Calculated value: 303.10638, measured value: 303.10603.

[0269] Example 17. Preparation of 1-((1R,2S,3R,3aS,5S)-2,3,5-trihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-1-yl)-1H-1,2,4-triazole-5-carboxamide (35)

[0270]

[0271] Intermediate 20b was used to synthesize nucleoside analog 35 using the methods described in Example 6 and Example 11. f =0.56 (EtOAc, 7.5% MeOH); 1 H-NMR (400MHz, CDCl3) δ [ppm] = 7.97 (s, 1H), 6.27 (s, 1H), 5.04 (m, 1H), 4.94-5.02 ( m,1H),4.33(dd,J=2.4,5.5Hz,1H),4.03(dd,J=5.4,9.2Hz,1H),2.78(brs,1H),2.5 3(sept,J=7.0Hz,1H),2.41-2.50(m,1H),2.37(ddd,J=4.5,5.0,11.5Hz,1H),1.89 -2.00(m,1H),1.40(q,J=11.5Hz,1H),1.14(d,J=7.0Hz,3H),1.13(d,J=7.0Hz,3H); 13 C{1 H}-NMR (101MHz, CDCl3) δ [ppm] = 178.4, 161.0, 151.4, 148.4, 139.3, 121.2, 77 .8,77.4,71.2,68.0,44.5,35.3,33.6,31.9,19.3; [M+Na] of HRMS (ESI, 3.5kV) + C 16 H 22 N4O5Na + Calculated value: 373.14824, measured value: 373.14765.

[0272] Example 18. Preparation of 1-((1R,2S,3R,3aS)-2,3-dihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-1-yl)-1H-1,2,4-triazole-5-carboxamide (36)

[0273]

[0274] Ester 22a (1.00 eq., 0.10 mmol, 35 mg) was dissolved in MeOH (1 mL) and NH (7 M in MeOH, 1 mL) was added. After 19 h, the solvent was removed in vacuo and ACN (2 mL) was added. PhOCSCl (4.00 eq., 0.40 mmol, 72 mg, 58 μL) and DMAP (4.00 eq., 0.40 mmol, 51 mg) were then added and the reaction was stirred for 1 d. Saturated NaHCO sol was then added and the aqueous phase was extracted with EtOAc (4x10 mL). The combined organic layers were dried over MgSO and the solvent was removed in vacuo. The crude product was purified using column chromatography (SiO , EA / DCM 1:2) to yield thiocarbonate (28.3 mg, 62 μmol, 62%).

[0275] The product was dissolved in toluene (3 mL) and Bu3SnH (4.00 eq, 0.24 mmol, 72.2 mg, 67 μL) and AIBN (0.25 eq, 15.5 μmol, 2.5 mg) were added. The reaction was stirred at reflux for 5 h. The mixture was directly separated by column chromatography (SiO2, EA / DCM 1:2) and the resulting product was redissolved in MeOH (0.5 mL) and TFA (10% in H2O, 0.5 mL) was added. After 22 h, the solvent was removed and the crude product was subjected to column chromatography (SiO2, EA 5% MeOH) to yield deoxygenated 36 (18.4 mg). f =0.48 (EtOAc, 5% MeOH); 1H-NMR (600MHz, MeOD-d4) δ [ppm] = 7.94 (s, 1H), 6.24 (s, 1H), 5.03 (s, 1H), 4.28 (dd, J = 2.9, 5.5Hz, 1H), 3.93 (dd, J = 5.6, 8. 8Hz,1H),2.52(brs,1H),2.17-2.23(m,1H),2.00-2.08(m,1H),1.81-1.95(m,2H),1.47-1.56(m,1H),1.12-1.21(m,1H); 13 C{ 1 H}-NMR (150MHz, MeOD-d4) δ [ppm] = 161.1, 151.2, 148.4, 139.2, 123.4, 78.2, 77.3, 68.6, 44.7, 28.1, 25.8, 22.8.

[0276] Example 19. Preparation of 1-((1R,2S,3R,3aR,4R)-2,3,4-trihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-1-yl)pyrimidine-2,4(1H,3H)-dione (42)

[0277]

[0278] A solution of alcohol 9 (705 mg, 2.50 mmol, 1.00 eq) and protected uracil 37 (649 mg, 3.00 mmol, 1.2 eq) in THF (50 mL) was prepared and activated MS MS, and the mixture was stirred for 2 h. Then at 0 ° C, PPh3 (0.98 g, 3.75 mmol, 1.50 equiv) was added first, followed by DIAD (0.74 mL, 3.75 mmol, 1.50 equiv). The reaction was stirred for 16 h. The reaction was then filtered and the solvent was removed in vacuo. Purification by column chromatography (SiO2, Hex:EtOAc 4:1 to 1:1) gave 38 (0.96 g, 2.00 mmol, 80%) as a white foam. R f =0.45(Hex / EA 1:1); 1H-NMR (400MHz, CDCl3) δ [ppm] = 7.93 (d, J = 7.5Hz, 2H), 7.66 (tt, J = 1.2, 7.5Hz, 1H), 7.50 (t, J = 7.9Hz, 2H), 7.20 (brs, 1H) ,6.53(brs,1H),5.87(d,J=8.0Hz,1H),5.22(d,J=5.7Hz,1H),4.97(brs,1H),4.55(brs,1H),1.45(s,3H),1.33(s,3H); 13 C{ 1 H}-NMR(101MHz, CDCl3)δ[ppm]=168.3,162.0,149.1,145.8,135.5,131.1,1 30.7,129.4,112.7,103.1,85.6,80.6,27.1,25.7; [M+Na] of HRMS (ESI, 3.5kV) + C 19 H 17 IN2O5Na + Calculated: 503.00743, Found: 503.00744. Note: Broad signals were observed in the proton spectrum as well as in the carbon spectrum. Therefore, despite the intensive 2D NMR experiments, not all carbon signals could be detected.

[0279]

[0280] Vinyl iodide 38 (1.70 g, 3.54 mmol, 1.00 equiv), [Pd(PhCN)2Cl2] (67.9 mg, 0.18 mmol, 5 mol%), CuI (67.4 mg, 0.35 mmol, 10 mol%) and Ph3As (108.4 mg, 0.35 mmol, 10 mol%) were dissolved in freshly distilled NMP (over CaH2, 11 mL). Tributyl(vinyl)stannane (1.35 g, 1.24 mL, 4.25 mmol, 1.20 equiv) was then added at 0°C and the reaction was stirred for 4 hours at this temperature. The reaction was then quenched with half-saturated NaHCO3 solution (20 mL) and the aqueous phase was extracted with EtOAc (3 x 30 mL). The combined organic phase was washed with brine (30 mL) and the brine was re-extracted with EtOAc (1 x 15 mL). The combined organic phases were dried over MgSO4 and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (first column: Hex / EA 2:1 to 1:2, second column for removal of residual NMP and impurities: DCM / EA 3:1). Diolefin 39 was isolated as a white crystalline solid (1.28 g, 3.36 mmol, 95%).f =0.53 (Hex / EA 1:2); 1 H-NMR (400MHz, CDCl3) δ [ppm] = 7.91 (d, J = 7.3Hz, 2H), 7.66 (tt, J = 1.2, 7.5Hz, 1 H),7.50(t,J=8.0Hz,2H),6.96(brs,1H),6.47(dd,J=11.0,17.8Hz,1H),6.19(b rs,1H),5.79(d,J=8.1Hz,1H),5.69(brs,1H),5.39(d,J=11.0Hz,1H),5.34(d, J=4.6Hz,1H),5.25(d,J=18.0Hz,1H),4.63(brs,1H),1.41(s,3H),1.34(s,3H); 13 C{ 1 H}-NMR (101MHz, CDCl3) δ [ppm] = 168.5, 162.0, 149.8, 139.8, 136.7, 135.3, 131.5, 130.6, 1 30.0,129.3,120.3,112.4,102.8,84.4,83.3,65.8,27.4,25.8; [M+Na] of HRMS (ESI, 3.5kV) + C 21 H 20 N2O5Na + Calculated: 403.12644, Found: 403.12626. Note: Broad signals were observed in the proton spectrum as well as the carbon spectrum. Therefore, despite the long measurement time, not all carbon signals could be detected.

[0281]

[0282] To a solution of ester 39 (1.23 g, 3.24 mmol, 1.00 equiv) in anhydrous MeOH (32 mL) was added NaOMe (0.52 g, 9.71 mmol, 3.00 equiv) at 0°C. The reaction was stirred at room temperature for 21 h, then saturated NH4Cl solution (50 mL) was added. The mixture was extracted with EtOAc (4 x 50 mL), and the combined organic phases were dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (SiO2, 2:1 to 1:2 DCM / EtOAc) gave deprotected 40 as a white solid (0.88 g, 3.18 mmol, 98%). f =0.19(DCM / EA3:1); 1H-NMR (400MHz, CDCl3) δ [ppm] = 9.17 (s, 1H), 6.84 (brs, 1H), 6.43 (dd, J = 11.0, 17.6Hz, 1H), 6.17 (s, 1H), 5.74 (brs, 1H) ),5.68(dd,J=2.1,8.0Hz,1H),5.31(m,2H),5.20(d,J=17.8Hz,1H),4.56(d,J=3.9Hz,1H),1.43(s,3H),1.34(s,3H); 13 C{ 1 H}-NMR (101MHz, CDCl3) δ [ppm] = 163.3, 150.8, 139.9 (2x), 136.4, 129.8, 120.6, 112.3, 102.8, 84.5, 83.2, 65.1, 27.4, 25.8; HRMS (ESI, 3.5kV) [M+Na] + C 14 H 16 N2O4Na + Calculated value: 299.10023, measured value: 299.09993.

[0283]

[0284] To a solution of 40 (227 mg, 0.82 mmol, 1.00 equiv) in toluene (8 mL) was added BHT and vinyl pinacol borate (0.70 mL, 4.11 mmol, 5.00 equiv). The reaction was stirred for 4 d in a sealed tube at 140 ° C (oil bath temperature). The volatiles were then removed and the crude product was dissolved in THF / ph 7 buffer (16 mL, 1: 1). NaBO3 4H2O (505 mg, 3.29 mmol, 4.00 equiv) was then added and the mixture was stirred for 1.5 h. The reaction was then quenched by saturated Na2S2O3 solution (10 mL). After phase separation, the aqueous phase was extracted with EtOAc (3x15 mL). The combined organic phases were dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (SiO2, DCM:EtOAc 1:1 to DCM:acetone 4:1 to 1:1) gave 41a (64.3 mg, 0.20 mmol, 24%), 41b (21.0 mg, 65.6 μmol, 8%) and 41c (79.0 mg, 0.25 mmol, 30%) as white powders. f =0.23 (DCM / acetone 3:1); 1H-NMR (600MHz, 315K, CDCl3) δ [ppm] = 8.59 (s, 1H), 7.08 (brs, 1H), 5.73 (d, J = 6.0Hz, 1H), 5.58 (brs, 0.3H), 5.27 (s, 1H), 4.21-5.1 0(brs,2.7H),3.66(brs,1H),2.55(brs,1H),2.13-2.31(m,2H),1.91-2.03(m,2H),1.57(s,3H),1.34(s,3H),1.25-1.29(m,1H); 13 C{ 1 H}-NMR (150MHz, 315K, CDCl3) δ [ppm] = 121.2, 114.8, 102.7, 83.1, 71.8, 53.5, 31.1, 27.4, 25.2, 24.8; HRMS (ESI, 3.5kV) [M+Na] + C 16 H 20 N2O5Na + Calculated value: 343.12644, measured value: 343.12623.41b:R f =0.19 (DCM / acetone 3:1); 1 H-NMR (600MHz, 315K, CDCl3) δ [ppm] = 8.97 (s, 1H), 7.10 (brs, 1H), 5.72 (d, J = 7.0Hz, 1H), 5.23 (s, 1H), 4.30-5.10 (b rs,3H),4.25(s,1H),2.78(brs,1H),2.29-2.38(m,2H),2.09-2.19(m,1H),1.55(s,3H),1.43(m,1H),1.33(s,3H); 13 C{ 1 H}-NMR (150 MHz, 315 K, CDCl3) δ [ppm] = 140.6, 139.0, 117.9, 113.4, 102.3, 83.8 (2x), 64.4, 39.7, 33.5, 33.0, 27.8, 25.6; HRMS (ESI, 3.5 kV) [M+Na] + C 16 H 20 N2O5Na + Calculated value: 343.12644, measured value: 343.12638.41c:R f =0.16 (DCM / acetone 3:1); 1H-NMR (600MHz, 315K, CDCl3) δ [ppm] = 9.18 (brs, 1H), 7.08 (brs, 1H), 5.74 (d, J = 7.4Hz, 1H), 5.25 (s, 1H), 4.21-5.11 (brs ,3H),3.97(brs,1H),2.67(brs,1H),2.35-2.50(m,2H),1.93-2.01(m,2H),1.54(s,3H),1.40-1.47(m,1H),1.31(s,3H); 13 C{ 1 H}-NMR (150 MHz, 315 K, CDCl3) δ [ppm] = 163.2, 150.7, 142.8, 139.2, 119.6, 113.8, 102.2, 83.3 (2x), 67.1, 64.5, 45.1, 36.5, 33.9, 27.5, 25.5; HRMS (ESI, 3.5 kV) [M+Na] + C 16 H 20 N2O5Na + Calculated value: 343.12644, measured value: 343.12604.

[0285]

[0286] Alcohol 41a (20.0 mg, 62.4 μmol, 1.00 equiv) was dissolved in THF (0.5 ml) and TFA (1.0 mL, 10% in H2O) was added. After 21 h, the solvent was removed in vacuo. Purification by column chromatography (SiO2, EtOAc 5% MeOH) gave nucleoside analog 42 (17.0 mg, 60.7 μmol, 97%) as a white solid. f = 0.23 (EtOAc 5% MeOH); 1 H-NMR (400MHz, MeOD) δ [ppm] = 7.47 (d, J = 8.1Hz, 1H), 5.70 (d, J = 8.0Hz, 1H), 5.30 (brs, 1H), 5.22 (m, 1H), 4.07 (b rs,1H),3.97(brs,1H),3.56(ddd,J=3.8,9.5,11.3Hz,1H),2.41(m,1H),2.23(m,2H),1.96(m,1H),1.58(m,1H); 13 C{ 1H}-NMR (100MHz, MeOD) δ [ppm] = 166.2, 153.4, 135.4, 121.2, 102.6, 75.5, 73.8, 71.9, 53.5, 32.4, 26.0; HRMS (ESI, 3.5kV) [M+Na] + C 13 H 16 N2O5Na + Calculated value: 303.09514, measured value: 303.09520.

[0287] Example 20. Preparation of (1R,2S,3R,3aS,4R)-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,3-dihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-4-yl isobutyrate (43)

[0288]

[0289] Alcohol 41a (50 mg, 0.16 mmol, 1.00 equiv) was dissolved in acetonitrile (3 mL) and isobutyric anhydride (52 μL, 0.31 mmol, 2.00 equiv) and Et3N (44 μL, 0.31 mmol, 2.00 equiv) and DMAP (1.9 mg, 15.6 μmol, 10 mol%) were added. The reaction was stirred for 4 h, then saturated NaHCO3 (10 mL) and EtOAc (10 mL) were added. After phase separation, the aqueous phase was extracted with EtOAc (3 x 15 mL). The combined organic phases were dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (SiO2, DCM: EtOAc 1: 1) gave the ester (58.0 mg, 0.15 mmol, 97%) as a white solid. For deprotection, a portion of the sample (15.2 mg, 38.9 μmol) was dissolved in THF (0.5 ml) and TFA (1.0 mL, 10% in H2O) was added. After 16 h, the solvent was removed in vacuo. Purification by column chromatography (SiO2, EtOAc 5% MeOH) gave nucleoside analog 43 (12.6 mg, 35.9 μmol, 92%, 90% yield in two steps) as a white solid. f =0.53 (EtOAc 5% MeOH); 1H-NMR (400MHz, MeOD) δ [ppm] = 7.50 (d, J = 8.1Hz, 1H), 5.71 (d, J = 8.0Hz, 1H), 5.32 (m, 1H), 5.27 (brs, 1H), 4.86 (m, 1H), 3.99 (brs, 2H), 2 .66(m,1H),2.59(sep,J=7.0Hz,1H),2.28(m,2H),1.94-2.02(m,1H),1.61-1.73(m,1H),1.20(d,J=6.9Hz,3H),1.18(d,J=7.0Hz,3H); 13 C{ 1 H}-NMR (100 MHz, MeOD) δ [ppm] = 178.8, 165.0, 151.8, 144.9, 135.2, 121.5, 102.4, 75.7, 74.0, 73.8, 50.1, 35.4, 29.0, 25.6, 19.4 (2x); HRMS (ESI, 3.5 kV) [M+Na] + C 17 H 22 N2O6Na + Calculated value: 373.13701, measured value: 373.13701.

[0290] Example 21. Preparation of 1-((1R,2S,3R,3aS,5R)-2,3,5-trihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-1-yl)pyrimidine-2,4(1H,3H)-dione (44)

[0291]

[0292] Alcohol 41b (20.0 mg, 62.4 μmol, 1.00 equiv) was dissolved in MeOH (0.5 ml) and TFA (0.5 mL, 10% in H2O) was added. After 16 h, the solvent was removed in vacuo. Purification by column chromatography (SiO2, EtOAc 5% MeOH) gave nucleoside analog 44 (16.0 mg, 60.7 μmol, 91%) as a white solid. f =0.15 (EtOAc 5% MeOH); 1H-NMR (600MHz, MeOD, 315K) δ [ppm] = 7.43 (d, J = 7.9Hz, 1H), 5.69 (d, J = 7.9Hz, 1H), 5.25 (m, 1H), 5.19 (brs, 1H), 4.17 (s, 1H), 4.05 (s, 1H), 3.84(s,1H),2.71(s,1H),2.30-2.37(m,1H),2.25(dt,J=4.8,12.9Hz,1H),2.12(d,J=18.8Hz,1H),1.40(ddd,J=2.0,11.2,15.1Hz,1H); 13 C{ 1 H}-NMR (150MHz, MeOD, 315K) δ [ppm] = 166.3, 152.9, 145.3, 137.6, 119.4, 102.6, 76.9, 76.4, 65.1, 59.3, 39.4, 34.2, 34.0; HRMS (ESI, 3.5kV) [M+Na] + C 13 H 16 N2O5Na + Calculated value: 303.09514, measured value: 303.09498.

[0293]

[0294]

[0295] Example 22. Preparation of (1R,2S,3R,3aS,5R)-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,3-dihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-5-yl isobutyrate (45)

[0296]

[0297] Alcohol 41b (40.0 mg, 0.13 mmol, 1.00 equiv) was dissolved in acetonitrile (2 mL) and isobutyric anhydride (41 μL, 0.25 mmol, 2.00 equiv) and Et3N (35 μL, 0.25 mmol, 2.00 equiv) and DMAP (1.5 mg, 12.5 μmol, 10 mol%) were added. The reaction was stirred for 22 h, then saturated NaHCO3 (10 mL) and EtOAc (10 mL) were added. After phase separation, the aqueous phase was extracted with EtOAc (3x15 mL). The combined organic phases were dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (SiO2, DCM:EtOAc 1:1) gave the ester (27.9 mg, 71.5 μmol, 57%) as a white solid. For deprotection, a portion of the sample (20.0 mg, 51.2 μmol) was dissolved in MeOH (0.75 ml) and TFA (0.25 mL, 10% in H2O) was added. After 44 h, the solvent was removed in vacuo. Purification by column chromatography (SiO2, EtOAc 3% MeOH) gave nucleoside analog 45 (17.1 mg, 48.8 μmol, 96%, 55% yield in two steps) as a white solid. nR f = 0.23 (EtOAc 3% MeOH); 1 H-NMR (400MHz, MeOD, 295K) δ [ppm] = 7.45 (d, J = 7.9Hz, 1H), 5.69 (d, J = 7.9Hz, 1H) ,5.29(m,1H),5.22(s,1H),5.18(brs,1H),4.08(brs,1H),3.86(brs,1H),2.66( brs,1H),2.52(sep,J=7.0Hz,1H),2.35-2.45(m,2H),2.18(d,J=19.7Hz,1H),1. 47(ddd,J=2.0,11.5,15.2Hz,1H),1.15(d,J=7.0Hz,3H),1.14(d,J=7.0Hz,3H); 13 C{ 1 H}-NMR (150MHz, CDCl 3, 315K)δ[ppm]=178.3,166.5,153.1,146.0,137.9,118.7,102.7,76.9,76.4,68.9,62.9,39.8,35.4,31.4(2x),19.3,19.2;HRMS(ESI,3.5kV)[M+Na] + C 17 H 22 N2O6Na +Calculated value: 373.13701, measured value: 373.13674.

[0298] Example 23. Preparation of 1-((1R,2S,3R,3aS,5S)-2,3,5-trihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-1-yl)pyrimidine-2,4(1H,3H)-dione (46)

[0299]

[0300] Alcohol 41c (24.2 mg, 75.5 μmol, 1.00 equiv) was dissolved in THF (0.5 ml) and TFA (1 mL, 10% in H2O) was added. After 44 h, the solvent was removed in vacuo. Purification by column chromatography (SiO2, EtOAc 7.5% MeOH) gave nucleoside analog 46 (19.9 mg, 71.0 μmol, 94%) as a white solid. f =0.15 (EtOAc 5% MeOH); 1 H-NMR (600MHz, MeOD, 315K) δ [ppm] = 7.43 (d, J = 7.4Hz, 1H), 5.69 (d, J = 7.8Hz, 1H), 5.28 (s, 1H), 5.15 (brs, 1H), 4.05 (brs, 1H) ,3.90(m,1H),3.82(brs,1H),2.61(brs,1H),2.42(d,J=17.4Hz,1H),2.32(m,1H),1.93-1.97(m,1H),1.32(q,J=11.6Hz,1H); 13 C{ 1 H}-NMR (150MHz, MeOD, 315K) δ [ppm] = 166.4, 153.0, 145.5, 137.8, 120.6, 102.6, 76.8, 76.6, 68.2, 62.4, 45.3, 37.2, 35.4; HRMS (ESI, 3.5kV) [M+Na] + C 13 H 16 N2O5Na + Calculated value: 303.09514, measured value: 303.09489.

[0301]

[0302]

[0303] Example 24. Preparation of (1R,2S,3R,3aS,5S)-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,3-dihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-5-yl isobutyrate (47)

[0304]

[0305] Alcohol 17 (40.0 mg, 0.13 mmol, 1.00 equiv) was dissolved in acetonitrile (2 mL) and isobutyric anhydride (41 mL, 0.25 mmol, 2.00 equiv) and Et3N (35 mL, 0.25 mmol, 2.00 equiv) and DMAP (1.5 mg, 12.5 μmol, 10 mol%) were added. The reaction was stirred for 24 h, then saturated NaHCO3 (10 mL) and EtOAc (10 mL) were added. After phase separation, the aqueous phase was extracted with EtOAc (3x15 mL). The combined organic phases were dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (SiO2, DCM:EtOAc 1:1) gave the ester (45.0 mg, 0.12 mmol, 92%) as a white solid. For deprotection, a portion of the sample (20.5 mg, 52.5 μmol) was dissolved in MeOH (0.75 ml) and TFA (0.25 mL, 10% in H2O) was added. After 40 h, the solvent was removed in vacuo. Purification by column chromatography (SiO2, EtOAc 2% MeOH) gave nucleoside analog 21b (18.4 mg, 52.5 μmol, quantitative two-step yield 92%) as a white solid. f = 0.33 (EtOAc 5% MeOH); 1 H-NMR (600MHz, MeOD, 315K) δ [ppm] = 7.43 (d, J = 7.40Hz, 1H), 5.70 (d, J = 7.7Hz, 1 H),5.31(s,1H),5.12(brs,1H),4.99(m,1H),4.08(brs,1H),3.87(brs,1H),2. 68(brs,1H),2.54(sep,J=6.9Hz,1H),2.50(m,1H),2.33-2.38(m,1H),2.05-2. 12(m,1H),1.46(q,J=11.6Hz,1H),1.15(d,J=6.9Hz,3H),1.14(d,J=6.9Hz,3H); 13 C{ 1H}-NMR (100 MHz, CDCl3) δ [ppm] = 178.4, 166.3, 152.7, 145.3, 138.0, 119.8, 102.7, 76.8, 76.6, 71.2, 44.7, 35.3, 33.5, 31.8, 19.2 (2x); HRMS (ESI, 3.5 kV) [M+Na] + C 17 H 22 N2O6Na + Calculated value: 373.13701, measured value: 373.13688.

[0306] Example 25. Preparation of 4-(hydroxyimino)-1-((1R,2S,3R,3aR,4R)-2,3,4-trihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-1-yl)-3,4-dihydropyrimidin-2(1H)-one (48)

[0307]

[0308] Uracil analog 42 (1.00 eq., 0.13 mmol, 35 mg) was dissolved in HMDS (1.5 mL) and NH4HSO4 (4.00 eq., 0.50 mmol, 57 mg), (NH2OH)xH2SO4 (2.00 eq., 0.25 mmol, 41 mg) and imidazole (0.50 eq., 62.4 μmol, 4.3 mg) were added. The solution was stirred at 85 °C for 24 h. The reaction was then quenched with water (3 mL) and the slurry was extracted with hexane (2 x 5 mL). The combined organic phases were dried over MgSO4. The solvent was removed in vacuo, the residue was dissolved in MeOH (1 mL) and TFA (50 μL) was added. After 15 min, the volatiles were removed in vacuo. Purification by column chromatography (SiO2, EtOAc 5% MeOH) gave nucleoside analog 48 (25.7 mg, 87.0 μmol, 69%) as a white solid. f = 0.25 (EtOAc 5% MeOH); 1 H-NMR (400MHz, MeOD) δ [ppm] = 6.88 (d, J = 8.20Hz, 1H), 5.66 (d, J = 8.0Hz, 1H), 5.28 (s, 1H), 4.03 (brs, 1H), 3. 92(brs,1H),3.55(m,1H),2.39(brs,1H),2.23(m,2H),1.96(m,1H),1.58(m,1H).HRMS(ESI,3.5kV)[M+Na] + C 13 H17 N3O5Na + Calculated value: 318.10604, measured value: 318.10579.

[0309] Example 26. Preparation of (1R,2S,3R,3aS,4R)-2,3-dihydroxy-1-(4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin-1(2H)-yl)-2,3,3a,4,5,6-hexahydro-1H-inden-4-yl isobutyrate (49)

[0310]

[0311] Intermediate 41a was used to synthesize analog 49 using the methods outlined in Example 20 and Example 25. f =0.34 (EtOAc 5% MeOH); 1 H-NMR (400MHz, MeOD) δ [ppm] = 7.10 (d, J = 7.6Hz, 1H), 5.74 (d, J = 8.0Hz, 1H), 5.36 (s, 1H), 4.89 (m, 1H), 3.94 (m, 2H), 2.64(brs,1H),2.58(m,1H),2.26(brs,2H),1.95(m,1H),1.66(m,1H),1.18(d,J=6.7Hz,3H),1.16(d,J=6.7Hz,3H). [M+Na] + C 17 H 23 N3O6Na + 388.14791, measured value: 388.14748.

[0312] Example 27. Preparation of 4-(hydroxyimino)-1-((1R,2S,3R,3aS,5R)-2,3,5-trihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-1-yl)-3,4-dihydropyrimidin-2(1H)-one (50)

[0313]

[0314] Intermediate 41b was used to synthesize analog 50 using the methods outlined in Example 21 and Example 25. f = 0.22 (EtOAc 5% MeOH); 1H-NMR (400MHz, MeOD) δ [ppm] = 6.79 (brs, 1H), 5.62 (d, J = 8.2Hz, 1H), 5.29 (brs, 1H), 4.17 (brs, 1H), 4.00 (brs, 1 H),3.78(m,1H),2.67(brs,1H),2.19-2.40(m,2H),2.11(d,J=18.8Hz,1H),1.38(ddd,J=1.9,11.2,12.7Hz,1H). [M+Na] + C 13 H 17 N3O5Na + 318.10604, measured value: 318.10593.

[0315] Example 28. Preparation of (1R,2S,3R,3aS,5R)-2,3-dihydroxy-1-(4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin-1(2H)-yl)-2,3,3a,4,5,6-hexahydro-1H-inden-5-yl isobutyrate (51)

[0316]

[0317] Intermediate 41b was used to synthesize analog 51 using the methods outlined in Example 22 and Example 25. f = 0.30 (EtOAc 5% MeOH); 1 H-NMR (400MHz, MeOD) δ [ppm] = 6.72 (brs, 1H), 5.59 (d, J = 7.9Hz, 1H), 5.32 (brs, 1H), 5.21 (brs, 1H), 4.01 (brs, 1H), 3.79 (brs, 1H), 2.62 (brs, 1H), 2. 53(hep,J=7.1Hz,1H),2.32-2.47(m,2H),2.17(d,J=19.9Hz,1H),1.44(dd d,J=1.9,11.8,13.3Hz,1H), 1.15(d,J=7.0Hz,3H), 1.13(d,J=7.0Hz,3H). [M+Na] + C 17 H 23 N3O6Na + 388.14791, measured value: 388.14730.

[0318] Example 29. Preparation of 4-(hydroxyimino)-1-((1R,2S,3R,3aS,5S)-2,3,5-trihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-1-yl)-3,4-dihydropyrimidin-2(1H)-one (52)

[0319]

[0320] Intermediate 41c was used to synthesize analog 52 using the methods outlined in Example 23 and Example 25. f = 0.25 (EtOAc 5% MeOH); 1 H-NMR (400MHz, MeOD) δ [ppm] = 6.86 (brs, 1H), 5.68 (d, J = 8.1Hz, 1H), 5.32 (brs, 1H), 4.01 (brs, 1H), 3.9 0(brs,1H),3.78(m,1H),2.59(brs,1H),2.42(m,1H),2.31(m,1H),1.95(m,1H),1.30(q,J=11.3Hz,1H). [M+Na] + C 13 H 17 N3O5Na + 318.10604, measured value: 318.10587.

[0321] Example 30. Preparation of (1R,2S,3R,3aS,5S)-2,3-dihydroxy-1-(4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin-1(2H)-yl)-2,3,3a,4,5,6-hexahydro-1H-inden-5-yl isobutyrate (53)

[0322]

[0323] Intermediate 41c was used to synthesize analog 53 using the methods outlined in Example 24 and Example 25. f =0.27 (EtOAc 5% MeOH).

[0324] Example 31. Preparation of 4-amino-1-((1R,2S,3R,3aR,4R)-2,3,4-trihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-1-yl)pyrimidin-2(1H)-one (55)

[0325]

[0326] Intermediate 41a (1.00 eq., 1.00 mmol) was dissolved in ACN (10 mL) and Et3N (2.50 eq.), isobutyric anhydride (2.50 eq.) and DMAP (0.10 eq.) were added. The reaction was stirred until completion. Workup and purification yielded the isobutyrate. Intermediate (1.00 eq., 1.00 mmol) was dissolved in ACN (10 mL) and 2,4,6-triisopropylbenzenesulfonyl chloride (2.00 eq.), Et3N (2.00 eq.) and DMAP (0.1 eq.) were added. After completion of the reaction, NH4OH (25% in water) was added. After 2 h, workup and purification afforded the protected cytidine analog 54. For deprotection, 54 (1.00 eq., 1.00 mmol) was dissolved in MeOH (5 mL) and K2CO3 (1.50 eq.) was added. After complete saponification, TFA (20% in H2O, 5 mL) was added and the reaction was stirred until completion. Workup and purification afforded the final cytidine analog 55.

[0327] Example 32. Preparation of 4-amino-1-((1R,2S,3R,3aS,5R)-2,3,5-trihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-1-yl)pyrimidin-2(1H)-one (56)

[0328]

[0329] Analog 56 was synthesized using the method outlined in Example 31 using intermediate 41b.

[0330] Example 33. Preparation of 4-amino-1-((1R,2S,3R,3aS,5S)-2,3,5-trihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-1-yl)pyrimidin-2(1H)-one (57)

[0331]

[0332] Analog 57 was synthesized using the method outlined in Example 31 using intermediate 41c.

[0333] Example 34. Preparation of 5-fluoro-1-((1R,2S,3R,3aR,4R)-2,3,4-trihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-1-yl)pyrimidine-2,4(1H,3H)-dione (59)

[0334]

[0335] Analog 59 was synthesized using the method outlined in Example 19 using Intermediate 9 and Intermediate 58.

[0336] Example 35. Preparation of 5-fluoro-1-((1R,2S,3R,3aS,5R)-2,3,5-trihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-1-yl)pyrimidine-2,4(1H,3H)-dione (60)

[0337]

[0338] Analog 60 was synthesized using Intermediate 9 and Intermediate 58 using the methods outlined in Example 19 and Example 21.

[0339] Example 36. Preparation of 5-fluoro-1-((1R,2S,3R,3aS,5S)-2,3,5-trihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-1-yl)pyrimidine-2,4(1H,3H)-dione (61)

[0340]

[0341] Analog 61 was synthesized using the methods outlined in Example 19 and Example 23 using Intermediate 9 and Intermediate 58.

[0342] Example 37. Preparation of (1R,2S,3R,7R,7aR)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3,5,6,7,7a-hexahydro-1H-indene-1,2,7-triol (63)

[0343]

[0344] Analog 63 was synthesized using the method outlined in Example 2 using intermediate 9 and intermediate 62. 1 H-NMR (600MHz, MeOD) δ [ppm] = 8.07 (s, 1H), 7.09 (d, J = 3.8Hz, 1H), 6.64 (d, J = 3.9Hz, 1H), 5.48 (brs, 1H),4.90(m,1H),4.15(m,2H),3.61(m,1H),2.52(brs,1H),2.15(m,2H),1.96(m,1H),1.59(m,1H).

[0345] Example 38. Preparation of (1R,2S,3R,6S,7aS)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3,5,6,7,7a-hexahydro-1H-indene-1,2,6-triol (64)

[0346]

[0347] Analog 64 was synthesized using the methods outlined in Examples 2 and 4 using Intermediate 9 and Intermediate 62. 1 H-NMR (400MHz, MeOD) δ [ppm] = 8.07 (s, 1H), 7.02 (d, J = 3.9Hz, 1H), 6.62 (d, J = 3.9Hz, 1H), 5.43 (brs, 1H), 5.01(m,1H),4.10(m,1H),3.91(m,2H),2.72(brs,1H),2.36(m,2H),1.88(m,1H),1.36(q,J=12.0Hz,1H).

[0348] Example 39. Preparation of (1S,3S,7R,7aR)-3-(6-amino-9H-purin-9-yl)-2,3,5,6,7,7a-hexahydro-1H-indene-1,7-diol (67)

[0349]

[0350] The protected diol 12a (1.00 mmol) was dissolved in MeOH (5 mL) and TFA (20% in H2O, 5 mL) was added. After 1 d, the volatiles were removed in vacuo. The crude was then dissolved in DMF (5 mL) and imidazole (2.50 eq) and TBSCl (2.50 eq) was subsequently added.

[0351] The reaction was stirred for 5 h before workup and purification to yield 65a and 65b.

[0352]

[0353] Alcohol 65a (1.00 eq., 1.00 mmol) was dissolved in DCM (10 mL) and PhOCSCl (3.00 eq., 3.00 mmol), DMAP (0.10 eq., 0.10 mmol) and Et3N (3.00 eq., 3.00 mmol) were added. The reaction was stirred until completion, then post-processed and purified to produce the thiocarbonate intermediate. The thiocarbonate intermediate was dissolved in toluene (10 mL) and Bu3SNH (4.00 eq.) and AIBN (0.10 eq.) were added. The reaction was stirred at reflux until completion, then post-processed and purified to produce 66. Finally, 66 was dissolved in THF (10 mL) and TBAF (1 M in THF, 1.00 eq.) was added. After complete deprotection post-processing, the crude product was produced, which was dissolved in ACN (5 mL) and NH4OH solution (25% in H2O, 3 mL) was added. The reaction was stirred at 85°C until completion. Work-up and purification gave the desired analog 67.

[0354] Example 40. Preparation of (1R,2S,3R,3aR,4R)-1-(6-amino-9H-purin-9-yl)-3-methoxy-2,3,3a,4,5,6-hexahydro-1H-indene-2,4-diol (69)

[0355]

[0356] Alcohol 65b (1.00 eq., 1.00 mmol) was dissolved in THF (10 mL) and NaH (1.20 eq., 60%) and MeI (5.00 eq.) were added at 0° C. The reaction was stirred until completion, worked up and purified to give 68. The protected 68 was converted to 69 using the method described in Example 39.

[0357] Example 41. Preparation of 1-((1S,3S,3aS,5S)-3,5-dihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-1-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (71)

[0358]

[0359] Analog 71 was synthesized using the methods outlined in Example 19 and Example 39 using Intermediate 9 and Intermediate 70.

[0360] Example 42. Preparation of 2-amino-9-((1R,2S,3R,3aR,4R)-2,3,4-trihydroxy-2,3,3a,4,5,6-hexahydro-1H-inden-1-yl)-1,9-dihydro-6H-purin-6-one

[0361]

[0362] Analog 73 was synthesized using intermediate 9 and intermediate 72 using the method outlined in Example 2. Protected 73 (1.00 equiv., 1.00 mmol) was then dissolved in MeOH (10 mL) and HCl (2M in H2O, 10 mL) was added. Upon completion of the reaction, workup and purification gave 74.

[0363] Example 43. Antiviral and cellular activity

[0364] Antiviral data were obtained using HEp-2 cells and RSV-A long strain (HRSVA / Maryland USA / Long / 1956, sequence ID: OK649668.1], 99% identity at positions 1716-2119 and 100% identity at positions 5186-5590).

[0365] For antiviral evaluation, HEp-2 cells were plated at 5 × 10 cells per well one day before infection. 4 Cells were seeded in 96-well plates. All compounds were dissolved in dimethyl sulfoxide at 8 mM and further serially diluted to final concentrations in DMEM containing 0.5% DMSO. 48 hours after infection, culture supernatants were collected and stored frozen at -80°C for cell viability analysis and virus titration.

[0366] Hep-2 cells were seeded on 96-well tissue culture plates one day before the virus titration assay. Virus samples or culture supernatants were titrated with the corresponding culture medium in serial half-log10 dilutions, and the diluted viruses were then added to the cell plates in quadruplicate. The highest virus dilution that resulted in CPE was recorded, and the 50% tissue culture infectious dose (TCID50) was calculated using the Spearman-Karber method. FIG. 3A to FIG. 3D The results are displayed in .

[0367] In addition, cytotoxicity assays were performed using Thiazolyl Blue Tetrazolium Bromide (MTT, Thermo Fisher, Carlsbad, CA, M6494) cell viability assays after 48 h of incubation with compounds. Figure 4A and Figure 4B The results are displayed in .

[0368] exist FIG. 3A to FIG. 3D , Figure 4A and Figure 4B The compounds used in are as follows:

[0369]

[0370] Although the above content has been described in detail by way of illustration and example for the purpose of clarity and understanding, it will be appreciated by those skilled in the art that certain changes and modifications may be implemented within the scope of the appended claims. In addition, each reference provided herein is incorporated herein by reference in its entirety to the same extent as if each reference was independently incorporated herein by reference.

Claims

1. A compound according to the formula: A pharmaceutically acceptable salt thereof or an enantiomer thereof, wherein: R 1 is a nitrogen-containing monocyclic or bicyclic heterocyclic group; R 2 , R 3 , R 4 , R 5 , R 6 and R 7 wherein each of the above is independently H, deuterium, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, optionally substituted heteroaryloxy, optionally substituted carboxylate, or OP x ; R 8 , R 9 , R 10 , R 11 , R 12 and R 13 wherein each of the above is independently H, deuterium, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, optionally substituted heteroaryloxy, optionally substituted carboxylate, OP x or does not exist; P x is a monophosphate, diphosphate, triphosphate, C2-6 acyl or phosphate prodrug moiety; and Each dashed line represents a single bond or a double bond, provided that more than one double bond is not present.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, comprising a structure according to the following formula:

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, comprising a structure according to the following formula:

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, comprising a structure according to the following formula:

5. The compound of claim 3 or 4, or a pharmaceutically acceptable salt thereof, comprising a structure according to the following formula:

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, comprising a structure according to the following formula:

7. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, comprising a structure according to the following formula:

8. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, comprising a structure according to the following formula:

9. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, comprising a structure according to the following formula:

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, comprising a structure according to the following formula:

11. The compound of claim 9 or 10, or a pharmaceutically acceptable salt thereof, comprising a structure according to the following formula:

12. A compound as claimed in any one of claims 1 to 11, wherein R 2 , R 3 , R 4 and R 5 Each of which is independently H, deuterium, hydroxyl, Cl, F, CN, Me, Et, (C 1-6 )OH、OR x , (C 1-6 )COOR x or (C 1-6 )CON(R x )2; R 6 and R 7 Each of which is independently H, deuterium, hydroxyl, Cl, F, CN, Me, Et, (C 1-6 )OH、OR x , (C 1-6 )COOR x , (C 1-6 )CON(R x )2, optionally substituted carboxylic acid ester or OP x ; P x It is monophosphate, diphosphate, triphosphate, C 2-6 an acyl or phosphate prodrug moiety; and Every R x and R is independently H, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, optionally substituted carboxylate, or optionally substituted heteroaryloxy.

13. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, comprising a structure according to the following formula: in: R 1 is an optionally substituted nitrogen-containing monocyclic or bicyclic heterocyclic group; R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 wherein each of the above is independently H, deuterium, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy, optionally substituted carboxylate, or OP x , Where P x It is a monophosphate, diphosphate, triphosphate, C2-6 acyl or phosphate prodrug moiety.

14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, comprising a structure according to the following formula: in: R 1 is an optionally substituted nitrogen-containing monocyclic or bicyclic heterocyclic group; R 10 , R 11 , R 12 and R 13 Each of which is independently H, deuterium, hydroxyl, Cl, F, CN, Me, Et, (C 1-6 )OH、OR x , (C 1-6 )COOR x , (C 1-6 )CON(R x )2, epoxide or cyclopropane, R 8 and R 9 Each of which is independently H, deuterium, hydroxyl, Cl, F, CN, Me, Et, (C 1-6 )OH、OR x , (C 1-6 )COOR x , (C 1-6 )CON(R x )2. Epoxide, cyclopropane or OP x , P x is a monophosphate, diphosphate, triphosphate, C2-6 acyl or phosphate prodrug moiety, Every R x and R is independently H, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, optionally substituted carboxylate, or optionally substituted heteroaryloxy.

15. The compound of claim 13 or 14, or a pharmaceutically acceptable salt thereof, comprising a structure according to the following formula:

16. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein R 1 Selected from adenine, guanine, cytosine, N 4 -hydroxycytosine, thymine, uracil, pyrrolo[2,1-f][1,2,4]triazine-4-amine and 1,2,4-triazole-3-carboxamide.

17. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from adenine, cytosine and N 4 -Hydroxycytosine.

18. A compound as described in any one of claims 1 to 15, wherein R 1 yes Where X and R a Each of which is independently H, deuterium, hydroxyl, Cl, F, CN, Me, Et, (C 1-6 )OH、OR x , (C 1-6 )COOR x , (C 1-6 )CON(R x )2、N(R x )2 or R x , Each of the R x is independently H, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy; and Y is N or C.

19. The compound of claim 18, wherein X and R a Each of which is independently H, deuterium, hydroxyl, Cl, F, N(R x )2 or R x , Each of the R x is independently H, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy; and Y is N or C.

20. The compound of claim 18 or 19, wherein R 1 yes:

21. A compound as described in any one of claims 1 to 14, wherein R 1 yes Each of the R a are independently H, deuterium, hydroxyl, Cl, F, CN, Me, Et, (C 1-6 )OH、OR x , (C 1-6 )COOR x 、CON(R x 2. (C 1-6 )CON(R x )2、N(R x )2 or R x , Each of the R x and R is independently H, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, optionally substituted carboxy, or optionally substituted heteroaryloxy.

22. The compound of claim 21, wherein R 1 yes 23. A compound as described in any one of claims 1 to 14, wherein R 1 yes Where R a H, deuterium, hydroxyl, Cl, F, CN, Me, Et, (C 1-6 )OH、OR x , (C 1-6 )COOR x , (C 1-6 )CON(R x )2、N(R x )2 or R x ;as well as X is O, NR x NOR x , Each of the R x and R is independently H, hydroxy, amino, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy.

24. The compound of claim 23, wherein R 1 yes 25. A compound as described in any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein P x It is the phosphate prodrug moiety.

26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein the phosphate prodrug moiety is selected from phosphonates, carbonyloxymethyl phosphates, S-acyl-2-thioethyl phosphates, S-[(2-hydroxyethyl)]thioether]-thioethyl phosphates, cyclosalicylic phosphodiester, cyclo-1-aryl-1,3-propyl phosphodiester, alkoxyalkyl phosphates, aryloxyphosphoramidates, aryloxyphosphoramidates, amino acid phosphoramidates, amino acid phosphoramidates, and methylarylhaloalkylphosphoramidates.

27. A compound comprising one of the following formulae or a pharmaceutically acceptable salt thereof:

28. A compound comprising one of the following formulae or a pharmaceutically acceptable salt thereof:

29. The compound of claim 28 or a pharmaceutically acceptable salt thereof, comprising the formula:

30. The compound of claim 28 or a pharmaceutically acceptable salt thereof, comprising the formula:

31. The compound of claim 28 or a pharmaceutically acceptable salt thereof, comprising the formula:

32. A pharmaceutical composition comprising a compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

33. A method for treating a viral infection, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition according to claim 32.

34. The method of claim 33, wherein the viral infection is a respiratory viral infection.

35. The method of claim 33 or 34, wherein the viral infection is a coronavirus infection, an adenovirus infection, an influenza virus infection, a parainfluenza virus infection, a rhinovirus infection, or a respiratory syncytial virus (RSV) infection.

36. The method of claim 35, wherein the coronavirus infection is a SARS-CoV-2 infection.

37. The method of claim 35, wherein the influenza virus infection is an influenza A virus (IAV) infection.

38. The method of any one of claims 33 to 37, wherein the compound is administered to the subject orally or via injection.

39. The method of any one of claims 33 to 38, further comprising administering one or more agents selected from anti-inflammatory agents, analgesics, and antiviral agents.

40. The method of claim 39, wherein the antiviral agent is selected from the group consisting of RNA-dependent RNA polymerase inhibitors, 3C-like protease inhibitors, and cytochrome P450 3A4 inhibitors.

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