Carbobicyclic nucleosides for the treatment of viral infections

Abstract

Carbobicyclic nucleoside compounds useful for treating coronavirus disease 2019 (COVID-19), RSV, and other viral infections are provided. The carbobicyclic nucleoside compounds can be compounds described herein. Pharmaceutical formulations useful for treating COVID-19 and RSV are also described.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

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

[0003] SARS-CoV-2, a novel pneumonia-causing virus, has been declared a global emergency by the World Health Organization (WHO) and is expected to continue to spread. As of 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. It has been reported that existing nucleoside analogues, such as remdesivir, are effective against SARS-CoV-2. Remdesivir, a ribose-based nucleoside, is sensitive to host metabolic pathways, but renders it susceptible to degradation in vivo. Also, the target enzyme of remdesivir, RNA-dependent RNA polymerase (RdRp), may develop resistance to ribose-based nucleoside analogues. This is known, for example, in the case of ribavirin-resistant severe acute respiratory syndrome coronavirus (SARS-CoV).

[0004] Summary of the Invention [Means for solving the problem]

[0005] In certain aspects, the disclosure provides a compound of the following formula: [ka] During the ceremony: R1 is a nitrogen-containing monocyclic or bicyclic heterocyclyl; R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each independently H, deuterium, hydroxyl, amino, halo, 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 are each independently H, deuterium, hydroxyl, amino, halo, 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, or OP x or not present;P x is a monophosphate, diphosphate, triphosphate, C2-6 acyl, or phosphate prodrug moiety; each dashed line represents a single or double bond, with the proviso that only one double bond is present.

[0006] In some embodiments, the compound, or a pharma- ceutically acceptable salt thereof, comprises a structure of the following formula: [ka]

[0007] In certain embodiments, the compound, or a pharma- ceutically acceptable salt thereof, comprises a structure of the following formula: [ka] In some embodiments, the compound, or a pharma- ceutically acceptable salt thereof, comprises a structure of the following formula: [ka] Specifically, the compound or a pharma- ceutically acceptable salt thereof comprises a structure of the formula: [ka] More specifically, the compound or a pharma- ceutically acceptable salt thereof comprises a structure of the formula: [ka] In some embodiments, the compound, or a pharma- ceutically acceptable salt thereof, comprises a structure of the following formula: [ka] In some embodiments, the compound, or a pharma- ceutically acceptable salt thereof, comprises a structure of the following formula: [ka]

[0008] In some embodiments, the compound, or a pharma- ceutically acceptable salt thereof, comprises a structure of the following formula: [ka] In certain embodiments, the compound, or a pharma- ceutically acceptable salt thereof, comprises a structure of the following formula: [ka] In some embodiments, the compound, or a pharma- ceutically acceptable salt thereof, comprises a structure of the following formula: [ka]

[0009] In some embodiments of the above formula, R 2 , R 3 , R 4 , and R 5 are each 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 are each 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 , an optionally substituted carboxylate, or OP x ;P x are monophosphate, diphosphate, triphosphate, C 2~6 acyl, or phosphate prodrug moiety; R xare each independently H, hydroxyl, amino, halo, 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.

[0010] In some embodiments of the disclosure, the compound, or a pharma- ceutically acceptable salt thereof, comprises a structure of the following formula: [ka] During the ceremony: R 1 is an optionally substituted nitrogen-containing monocyclic or bicyclic heterocyclyl; 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 are each independently H, deuterium, hydroxyl, amino, halo, 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 Wherein, P xis a monophosphate, diphosphate, triphosphate, C2-6 acyl, or phosphate prodrug moiety. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof comprises a structure of the formula: [ka] During the ceremony: R 1 is an optionally substituted nitrogen-containing monocyclic or bicyclic heterocyclyl; R 10 , R 11 , R 12 , and R 13 are each 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 are each 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 and P x is a monophosphate, diphosphate, triphosphate, C2-6 acyl, or phosphate prodrug moiety; R xare each independently H, hydroxyl, amino, halo, 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 pharma- ceutically acceptable salt thereof comprises a structure of the formula: [ka]

[0011] In any of the above formulas, in some embodiments, R 1 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. 1 Adenine, cytosine, and N 4 -hydroxycytosine.

[0012] In some embodiments of the formulae described herein, R 1 is as follows: [ka] In the formula, X and R a are each 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 and R x are each independently H, hydroxyl, amino, halo, 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; Y is N or C. In some embodiments, X and R a are each independently H, deuterium, hydroxyl, Cl, F, N(R x ) 2 , or R x and R x are each independently H, hydroxyl, amino, halo, 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; Y is N or C. In certain embodiments, R 1 is as follows: [ka]

[0013] In some embodiments of the formulae described herein, R 1 is as follows. [ka] In the formula, R aare each 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 and R x are each independently H, hydroxyl, amino, halo, 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. 1 is as follows. [ka]

[0014] In some embodiments of the formulae described herein, R 1 is as follows. [ka] In the formula, 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 , or NOR xand R x are each independently H, hydroxyl, amino, halo, 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. 1 is as follows. [ka]

[0015] In some embodiments of the formulas described herein, P x is a phosphate prodrug moiety, for example, the phosphate prodrug moiety is selected from the group consisting of phosphonic acid, carbonyloxymethyl phosphate ester, S-acyl-2-thioethyl phosphate ester, S-[(2-hydroxyethyl)]sulfidyl]-thioethyl phosphate ester, cyclosaligenyl phosphate diester, cyclic 1-aryl-1,3-propanyl phosphate diester, alkoxyalkyl phosphate ester, aryloxy phosphoramidate, aryloxy phosphonamidate, amino acid phosphoramidate, amino acid phosphonamidate, and methylaryl haloalkyl phosphoramidate.

[0016] In other aspects, the disclosure also provides compounds comprising one of the following formulas, or a pharma- ceutically acceptable salt thereof: [ka]

[0017] In other aspects, the disclosure also provides compounds comprising one of the following formulas, or a pharma- ceutically acceptable salt thereof: [ka]

[0018] In some embodiments, the compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, comprises the formula: [ka]

[0019] In some embodiments, the compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, comprises the formula: [ka]

[0020] In some embodiments, the compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, comprises the formula: [ka]

[0021] In another aspect, the disclosure provides a pharmaceutical composition comprising any of the compounds described herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0022] In another aspect, the disclosure provides a method of treating a viral infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein or a pharma- ceutical acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition described herein.

[0023] In some embodiments, the viral infection is a respiratory viral infection.

[0024] 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.

[0025] In some embodiments of the method, the compound is administered to the subject orally or via injection. In some embodiments, the method further comprises administering one or more agents selected from the group consisting of anti-inflammatory agents, analgesics, and antiviral agents. The antiviral agent may be selected from the group consisting of RNA-dependent RNA polymerase inhibitors, 3C-like protease inhibitors, and cytochrome P450 3A4 inhibitors. [Brief description of the drawings]

[0026] [Figure 1A] Shows the effect of molnupiravir and carbobicyclic nucleoside 48 according to the present disclosure on infectivity (of SARS-CoV-2 S-pseudotyped lentivirus) in the A549-ACE2 cell model. Experiments were performed in triplicate. [Figure 1B] 1 shows the effect of molnupiravir and carbobicyclic nucleoside 48 according to the present disclosure on cell viability (for A549-ACE2) in an A549-ACE2 cell model. Experiments were performed in triplicate.

[0027] [Diagram 2] Compound 48 inhibits the replication of different SARS-CoV-2 virus strains (including the original strain and the delta and omicron mutants) in the A549-ACE2 cell model. Results for molnupiravir are also shown. Experiments were performed in triplicate.

[0028] [Figure 3A] 1 shows the antiviral activity of compounds disclosed herein at different concentrations. [Figure 3B] 1 shows the antiviral activity of compounds disclosed herein at different concentrations. [Figure 3C] 1 shows the antiviral activity of compounds disclosed herein at different concentrations. [Figure 3D] 1 shows the antiviral activity of compounds disclosed herein at different concentrations.

[0029] [Figure 4A] 1 shows a cytotoxicity assay at different concentrations of compounds disclosed herein. [Figure 4B] 1 shows a cytotoxicity assay at different concentrations of compounds disclosed herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] Provided herein are compounds useful for the treatment of viral infections (e.g., respiratory viral infections), including, but not limited to, the treatment of COVID-19 caused by SARS-CoV-2, as well as infections caused by influenza viruses (e.g., influenza A virus (IAV)) and respiratory syncytial virus (RSV). To access several nucleoside analogs for the inhibition of viral replication, an efficient and structurally distinct route has been developed, featuring an intermolecular Diels-Alder reaction as a key step. Advantageously, several compounds have now been discovered that exhibit higher binding affinity than the currently known inhibitor molnupiravir. Compounds according to the present disclosure contain a carba sugar instead of ribose as the parent nucleus, making them more metabolically stable than molnupiravir and other existing ribose-based inhibitors, such as anti-SARS-CoV-2 inhibitors.

[0031] I. Definition

[0032] As used herein, the term “alkyl,” by itself or as part of another substituent, refers to a straight- or branched-chain saturated aliphatic radical having the designated number of carbon atoms. 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 , C 2~4 , 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, pentyl, isopentyl, hexyl, and the like. Alkyl can also refer to alkyl groups having up to 20 carbon atoms, such as, for example, heptyl, octyl, nonyl, decyl, and the like. Alkyl groups can be substituted or unsubstituted. A "substituted alkyl" group can be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy.

[0033] As used herein, the term "aryl" by itself or as part of another substituent refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. Aryl groups can contain any suitable number of ring atoms, such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms, and 6-10, 6-12, or 6-14 ring members. Aryl groups can be monocyclic or fused to form bicyclic (e.g., benzocyclohexyl) or tricyclic groups, or linked by bonds to form biaryl groups. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl with a methylene linking group. Some aryl groups have 6-12 ring members, such as phenyl, naphthyl, or biphenyl. Other aryl groups have 6-10 ring members, such as phenyl or naphthyl. Some other aryl groups have six ring members, such as phenyl. Aryl groups can be substituted or unsubstituted. "Substituted aryl" groups can be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy.

[0034] As used herein, the term "arylalkyl" refers to an aryl group attached to a compound via an alkylene group, as described herein. Examples of arylalkyl groups include, but are not limited to, benzyl and phenethyl.

[0035] 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, where 1 to 5 ring atoms are heteroatoms such as N, O, or S. Additional heteroatoms may also be useful, including, but not limited to, B, Al, Si, and P. The heteroatoms may be oxidized to include, but are not limited to, -S(O)- and -S(O) 2-, etc. Heteroaryl groups can contain any number of ring atoms, such as, for example, 3-6, 4-6, 5-6, 3-8, 4-8, 5-8, 6-8, 3-9, 3-10, 3-11, or 3-12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl group, such as 1, 2, 3, 4, or 5, or 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, or 3-5. Heteroaryl groups can have 5-8 ring members and 1-4 heteroatoms, 5-8 ring members and 1-3 heteroatoms, 5-6 ring members and 1-4 heteroatoms, or 5-6 ring members and 1-3 heteroatoms. Heteroaryl groups may include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-isomer, 1,2,4-isomer, and 1,3,5-isomer), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Heteroaryl groups may also be fused with aromatic ring systems such as phenyl rings to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by bonds, such as bipyridine. Heteroaryl groups may be substituted or unsubstituted. A "substituted heteroaryl" group can be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy.

[0036] The heteroaryl group can be linked through 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, and triazole includes 1-triazole, 4-triazole, and 5-triazole. Examples of the azoles include tetrazoles such as 1-tetrazole and 5-tetrazole, examples of the pyrimidines include 2-pyrimidine, 4-pyrimidine, 5-pyrimidine, and 6-pyrimidine, examples of the pyridazines include 3-pyridazine and 4-pyridazine, examples of the 1,2,3-triazines include 4-triazine and 5-triazine, examples of the 1,2,4-triazines include 3-triazine, 5-triazine, and 6-triazine, examples of the 1,3,5-triazines include 2-triazines, thiophenes include 2-thiophene and 3-thiophene, furans include 2-furan and 3-furan, thiazoles include 2-thiazole, 4-thiazole, and 5-thiazole, isothiazoles include 3-isothiazole, 4-isothiazole, and 5-isothiazole, oxazoles include 2-oxazole, 4-oxazole, and 5-oxazole, isoxazoles include 3-isoxazole, 4-isoxazole, and 5-isoxazole, and indoles include 1-indole. , 2-indoles, and 3-indoles; isoindoles include 1-isoindole and 2-isoindole; quinolines include 2-quinoline, 3-quinoline, and 4-quinoline; isoquinolines include 1-isoquinoline, 3-isoquinoline, and 4-isoquinoline; quinazolines include 2-quinazoline and 4-quinazoline; cinnolines include 3-cinnoline and 4-cinnoline; benzothiophenes include 2-benzothiophene and 3-benzothiophene; and benzofurans include 2-benzofuran and 3-benzofuran.

[0037] The terms "halo" and "halogen," as used herein, by themselves or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom.

[0038] 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, a -C≡N moiety).

[0039] As used herein, the term “carbonyl,” by itself or as part of another substituent, refers to —C(O)—, i.e., a carbon atom double-bonded to an oxygen and bonded to two other groups in a carbonyl-containing moiety.

[0040] As used herein, the term “amino” by itself or as part of another substituent means —NR 3 refers to the moiety, where each R group is H or alkyl. The amino moiety can be ionized to form the corresponding ammonium cation.

[0041] As used herein, the term "hydroxy" by itself or as part of another substituent refers to an --OH moiety.

[0042] As used herein, the term “amide” by itself or as part of another substituent refers to a —NRC(O)R moiety or a —C(O)NR 2 refers to the moiety where each R group is H or alkyl.

[0043] As used herein, the term “acyl,” by itself or as part of another substituent, refers to a —C(O)R moiety, where R is alkyl.

[0044] As used herein, the term “nitro” by itself or as part of another substituent means —NO 2 Refers to a part.

[0045] As used herein, the term "salt" refers to a compound that includes at least one cation (e.g., organic or inorganic cation) and at least one anion (e.g., organic or inorganic anion). The salt may be an acid or base salt of a carbobicyclic nucleoside compound or other active agent. Acid salts of basic compounds include, but are not limited to, mineral acid salts (e.g., salts formed with hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), organic acid salts (e.g., salts formed with acetic acid, propionic acid, glutamic acid, citric acid, etc.), and quaternary ammonium salts (e.g., salts formed with methyl iodide, ethyl iodide, etc.). Acidic compounds may be contacted with bases to obtain basic salts, such as alkali metal and alkaline earth metal salts (e.g., sodium, lithium, potassium, calcium, and magnesium salts), and ammonium salts (e.g., ammonium, trimethylammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts).

[0046] In some embodiments, the neutral form of the active agent may be regenerated by contacting the salt with a base or acid, and, if necessary, isolating the parent compound in the conventional manner. In some embodiments, the parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but the salt forms may otherwise be identical to the parent form of the compound.

[0047] As used herein, the term "formulation excipient" refers to a substance that aids in the administration of an active agent to a subject. Pharmaceutical formulation excipients useful in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, glidants, coating agents, sweeteners, flavoring agents, and coloring agents.

[0048] "Pharmaceutically acceptable" means that the substance so designated (e.g., a salt or formulation additive) is not deleterious to the recipient thereof and is compatible with other substances with which it is formulated.

[0049] As used herein, the terms "treat", "treatment" and "treating" refer to any indication of success in treating or ameliorating a viral infection or a symptom thereof (e.g., shortness of breath). Treatment may be evaluated by objective or subjective parameters, such as relief; remission; reducing symptoms or making a symptom, injury, pathology, or condition more tolerable to the patient; slowing the rate of progression of a symptom; reducing the frequency or duration of a symptom or condition. Treatment or amelioration of a symptom may be based on any objective or subjective parameter, including, for example, the results of a physical examination.

[0050] 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, into a subject.

[0051] As used herein, the term "subject" refers to a person or other animal to which a compound or composition described herein is administered. In some embodiments, the subject is a human.

[0052] As used herein, the terms "effective amount" and "therapeutically effective amount" refer to a dose of a compound, such as a carbobicyclic nucleoside, that produces a therapeutic effect on the subject to which it is administered. The exact dose will depend on the purpose of the treatment and can be determined by known techniques (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 thEdition, 2006, Brunton, Ed., McGraw-Hill; and Remington: The Science and Practice of Pharmacy, 21 st The present invention may be ascertained by one of ordinary skill in the art using the methods described herein (see, for example, Hendrickson, Ed., Lippincott, Williams & Wilkins, 2005 Edition).

[0053] The terms "about" and "approximately" as used herein to modify a numerical value (e.g., degree of polymerization) refer to a close range surrounding the explicit value. When "X" is a value, "about X" or "approximately X" refers to a value between 0.9X and 1.1X. Thus, "about X" includes, for example, values ​​between 0.95X and 1.05X, between 0.98X and 1.02X, or between 0.99X and 1.01X. Any reference to "about X" or "approximately X" specifically refers to at least the values ​​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 a statement supporting the claim limitation, for example, "0.98X."

[0054] II. Carbobicyclic Nucleoside Analogues

[0055] "Carbocyclic nucleoside" refers to a synthetic compound that has a substituted cyclopentane ring where naturally occurring nucleosides have a furanose ring. "Carbobicyclic nucleoside" refers to a compound in which the cyclopentane ring is fused to a second ring carbon, such as a cyclohexane ring in the case of octahydroindene-type carbobicyclic nucleosides. As described in more detail below, carbobicyclic nucleoside compounds have been developed and studied for their potency and specificity against SARS-CoV-2 and RSV. Carbobicyclic nucleoside analogs can be prepared via a synthetic route using an intermolecular Diels-Alder reaction.

[0056] The disclosure provides a compound of the following formula, a pharma- ceutically acceptable salt thereof, or an enantiomer thereof:

[0057] [ka] In this formula, R 1 is a nitrogen-containing monocyclic or bicyclic heterocyclyl; R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each independently H, deuterium, hydroxyl, amino, halo, 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 are each independently H, deuterium, hydroxyl, amino, halo, 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, or OP x or not present;Px is a monophosphate, diphosphate, triphosphate, C2-6 acyl, or phosphate prodrug moiety; each dashed line represents a single or double bond, with the proviso that only one double bond is present.

[0058] Specifically, the dashed line in the above formula represents an optional double bond, such that compounds of the disclosure may have any one of the following formulae: [ka]

[0059] In some embodiments, the compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, comprises the formula: [ka] Specifically, the compound may have the formula: [ka] Additionally, the compound may have the formula: [ka] More specifically, the compound may have the formula: [ka]

[0060] In some embodiments, the compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, comprises the formula: [ka] Specifically, the compound may have the formula: [ka] Additionally, the compound may have the formula: [ka]

[0061] In some embodiments, in any of the above formulas, R 2 , R 3 , R 4 , and R 5 are each 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 are each 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 , an optionally substituted carboxylate, or OP x ;P x are monophosphate, diphosphate, triphosphate, C 2~6 acyl, or phosphate prodrug moiety; R xare each independently H, hydroxyl, amino, halo, 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.

[0062] In some embodiments, the compounds of the present disclosure, or pharma- ceutically acceptable salts thereof, may also have the formula: [ka] In the formula, R 1 is an optionally substituted nitrogen-containing monocyclic or bicyclic heterocyclyl; 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 are each independently H, deuterium, hydroxyl, amino, halo, 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 Wherein, P xis a monophosphate, diphosphate, triphosphate, C2-6 acyl, or phosphate prodrug moiety.

[0063] In particular, in some embodiments, the compound may have the formula: [ka] In the formula, R 1 is an optionally substituted nitrogen-containing monocyclic or bicyclic heterocyclyl; R 10 , R 11 , R 12 , and R 13 are each 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 are each 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 and P x is a monophosphate, diphosphate, triphosphate, C2-6 acyl, or phosphate prodrug moiety; R xare each independently H, hydroxyl, amino, halo, 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.

[0064] In certain embodiments, the compound may have the formula: [ka]

[0065] In any of the above formulas, R 1 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. 1 Adenine, cytosine, and N 4 -hydroxycytosine.

[0066] In certain embodiments, in any of the formulas described herein, R 1 is as follows. [ka] In the formula, X and R a are each 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(Rx ) 2 , or R x and R x are each independently H, hydroxyl, amino, halo, 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; Y is N or C. In some embodiments, X and R a are each independently H, deuterium, hydroxyl, Cl, F, N(R x ) 2 , or R x and R x are each independently H, hydroxyl, amino, halo, 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; Y is N or C. In some embodiments, R 1 is as follows. [ka]

[0067] In certain embodiments, in any of the formulas described herein, R 1 is as follows. [ka] In the formula, R aare each 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 and R x are each independently H, hydroxyl, amino, halo, 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. 1 is as follows. [ka]

[0068] In certain embodiments, in any of the formulas described herein, R 1 is as follows. [ka] In the formula, 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 xand X is O, NR x , or NOR x and R x are each independently H, hydroxyl, amino, halo, 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 is as follows. [ka]

[0069] In any of the above formulas, in some embodiments, P x is a phosphate prodrug moiety. For example, the phosphate prodrug moiety can be selected from the group consisting of phosphonic acid, carbonyloxymethyl phosphate ester, S-acyl-2-thioethyl phosphate ester, S-[(2-hydroxyethyl)]sulfidyl]-thioethyl phosphate ester, cyclosaligenyl phosphate diester, cyclic 1-aryl-1,3-propanyl phosphate diester, alkoxyalkyl phosphate ester, aryloxyphosphoramidate, aryloxyphosphonamidate, amino acid phosphoramidate, amino acid phosphonamidate, and methylarylhaloalkylphosphoramidate.

[0070] The disclosure provides compounds having any one of the following formulas, or a pharma- ceutically acceptable salt thereof:

[0071] [ka] In some embodiments, the compounds described herein can exist as prodrug molecules, i.e., one or more hydroxyl groups in the compound can be reacted with [ka] and the like.

[0072] The disclosure provides compounds having any one of the following formulas, or a pharma- ceutically acceptable salt thereof:

[0073] [ka] In some embodiments, the compounds described herein can exist as prodrug molecules, i.e., one or more hydroxyl groups in the compound can be reacted with [ka] and the like.

[0074] The disclosure provides compounds having any one of the following formulas, or a pharma- ceutically acceptable salt thereof:

[0075] [ka] In some embodiments, the compounds described herein can exist as prodrug molecules, i.e., one or more hydroxyl groups in the compound can be reacted with [ka] and the like.

[0076] The disclosure provides compounds having any one of the following formulas, or a pharma- ceutically acceptable salt thereof:

[0077] [ka] In some embodiments, the compounds described herein can exist as prodrug molecules, i.e., one or more hydroxyl groups in the compound can be reacted with [ka] and the like.

[0078] The disclosure provides compounds having any one of the following formulas, or a pharma- ceutically acceptable salt thereof:

[0079] [ka] In some embodiments, the compounds described herein can exist as prodrug molecules, i.e., one or more hydroxyl groups in the compound can be reacted with [ka] and the like.

[0080] The disclosure provides compounds having any one of the following formulas, or a pharma- ceutically acceptable salt thereof:

[0081] [ka] In some embodiments, the compounds described herein can exist as prodrug molecules, i.e., one or more hydroxyl groups in the compound can be reacted with [ka] and the like.

[0082] Provided herein are carbobicyclic nucleoside compounds according to the following formula: [ka]

[0083] or a pharma- ceutically acceptable salt thereof.

[0084] In the formula, R 1 is a nitrogen-containing monocyclic or bicyclic heterocyclyl;

[0085] R 2 -OH and -OR 2a wherein R 2a is C 2~6 is acyl;

[0086] R 3 -OH, -OR 3a and halogen, where R 3a is C 2~6 is acyl;

[0087] R 2 and R 3 may together form a cyclic phosphate ester;

[0088] R 4 is selected from the group consisting of hydrogen and halogen;

[0089] (i)R 5 -OH, -OR 5a , -CH 2 OH and -CH 2 OR 5a and

[0090] R 5a are monophosphate, diphosphate, triphosphate, C 2~6 acyl, and phosphate prodrug moieties;

[0091] Or,

[0092] (ii)R 5 is hydrogen,

[0093] In the formula, each dashed line represents a single or double bond, provided that only one double bond is present.

[0094] In some embodiments of the above formula, R 5 and R 3 is -OH. In some embodiments, R 5 is a phosphate prodrug moiety, R 3 is -OH.

[0095] 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.

[0096] Examples of phosphate prodrug moieties include, but are not limited to, phosphonic acids, carbonyloxymethyl phosphates, S-acyl-2-thioethyl phosphates, S-[(2-hydroxyethyl)]sulfidyl]-thioethyl phosphates, cyclosaligenyl phosphate diesters, cyclic 1-aryl-1,3-propanyl phosphate diesters, alkoxyalkyl phosphates, aryloxy phosphoramidates, aryloxy phosphonamidates, amino acid phosphoramidates, amino acid phosphonamidates, and methylaryl haloalkyl phosphoramidates.

[0097] In some embodiments, the phosphate prodrug moiety is a carbonyloxymethyl phosphate or phosphonate as shown below. [ka]

[0098] In the formula, each R is independently 1~6 Alkyl or C 1~6 alkoxy; -Z- is -O- or -CH 2 -; the wavy line is R 2 and the carbobicyclic nucleoside.

[0099] In some embodiments, the phosphate prodrug moiety is an S-acyl-2-thioethyl phosphate or phosphonate as shown below. [ka]

[0100] In the formula, R is C 1~6 Alkyl or C 1~6 (hydroxy)alkyl; R' is RC(O)SCH 2 CH 2 O-, C 1~6 Alkoxy, C 1~6 Aryloxy, or (C 7~20 arylalkyl)amino; -Z- is -O- or -CH 2 -; the wavy line is R 2 and the carbobicyclic nucleoside.

[0101] In some embodiments, the phosphate prodrug moiety is S-[(2-hydroxyethyl)]sulfidyl]-thioethyl phosphate or phosphonate as shown below: [ka]

[0102] In the formula, R is C 1~6 alkyl; R' is RSSCH 2 CH 2 O-, C 1~6 Alkoxy, C 1~6 Aryloxy, or (C 7~20 arylalkyl)amino; -Z- is -O- or -CH 2 - and the wavy line is R 2 and the carbobicyclic nucleoside.

[0103] In some embodiments, the phosphate prodrug moiety is a cyclosaligenyl phosphate or phosphonate as shown below. [ka]

[0104] where the subscript n is an integer ranging from 0 to 4; each R is independently hydrogen, halogen, or C. 1~6 alkyl; -Z- is -O- or -CH 2 -; the wavy line is R 2 and the carbobicyclic nucleoside.

[0105] In some embodiments, the phosphate prodrug moiety is a cyclic 1-aryl-1,3-propanyl phosphate or phosphonate as shown below. [ka]

[0106] In the formula, Ar is C 6~14 aryl or 5-12 membered heteroaryl, each of which is selected from one or more independently selected halogen or C 1~6 -Z- may be substituted with -O- or -CH 2 - and the wavy line is R 2and the carbobicyclic nucleoside.

[0107] In some embodiments, the phosphate prodrug moiety is an alkoxyalkyl phosphate or phosphonate as shown below. [ka]

[0108] In the formula, m and n are independently an integer ranging from 1 to 16; -Z- is -O- or -CH 2 -; the wavy line is R 2 and the carbobicyclic nucleoside.

[0109] In some embodiments, the phosphate prodrug moiety is an alkoxyamino acid phosphoramidate or phosphonamidate as shown below. [ka]

[0110] In the formula, R is C 1~6 R is an alkyl group; R' is an amino acid side chain; R" is C 6~14 aryl; -Z- is -O- or -CH 2 -; the wavy line is R 2 and the carbobicyclic nucleoside. R' can represent, for example, a side chain of a naturally occurring amino acid (e.g., an alanine side chain, an arginine side chain, an asparagine side chain, an aspartic acid side chain, a cysteine ​​side chain, a glutamine side chain, a glutamic acid side chain, a glycine side chain, a histidine side chain, an isoleucine side chain, a leucine side chain, a lysine side chain, a methionine side chain, a phenylalanine side chain, a proline side chain, a selenocysteine ​​side chain, a serine side chain, a threonine side chain, a tryptophan side chain, a tyrosine side chain, or a valine side chain) or a side chain of a non-naturally occurring amino acid (e.g., an azidohomoalanine side chain, a propargylglycine side chain, or a p-acetylphenylalanine side chain, etc.).

[0111] In some embodiments, the phosphate prodrug moiety is a methylaryl haloalkyl phosphoramidate or phosphonamidate as shown below. [ka]

[0112] In the formula, R is hydrogen, C 1~6 Alkyl or C 1~6 (hydroxy)alkyl; X is halogen; n is an integer ranging from 1 to 16; Ar is C 6~14 aryl or 5-12 membered heteroaryl, each of which is selected from halogen, hydroxy, nitro, and C 1~6 alkyl; -Z- is -O- or -CH 2 - and the wavy line is R 2 and the carbobicyclic nucleoside.

[0113] In some embodiments, the carbobicyclic nucleoside has a structure selected from the group consisting of: and pharma- ceutically acceptable salts thereof.

[0114] [ka]

[0115] In some embodiments of the above formula, R 2 -OR 2a and R 3 and R 5 is -OH. In some embodiments, R 3 -OR 3a and R 2 and R 5 is -OH. In some embodiments, R 5 -OR 5a and R 2 and R 3 is -OH. R 2a, R 3a , and R 5a may be, for example, acetyl, propionyl, n-butyryl, or iso-butyryl. In some such embodiments, R 4 is H.

[0116] In some embodiments, R 3 is hydrogen, and R 4 is halogen (e.g., fluorine, chlorine, or bromine). In some embodiments, R 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, R 4 is hydrogen. In some embodiments, R 3 is hydrogen, and R 4 is fluorine.

[0117] Carbobicyclic nucleosides according to the present disclosure may include a variety of naturally occurring and synthetic nucleobases. 1 may be, for example, a purine, a pyrimidine, or a benzimidazole. 1 is adenine, guanine, 7-methylguanine, xanthine, or hypoxanthine. 1 is cytosine, 5-methylcytosine, 5-hydroxymethylcytosine, thymine, uracil, or 5,6-dihydrouracil. 1 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. 1 Adenine, cytosine, and N 4 -hydroxycytosine.

[0118] Also provided herein are processes for preparing the compounds and salts described herein. By way of example, the compounds may be synthesized using the methods described below, along with synthetic methods known in the art of synthetic organic chemistry or variations thereof. Preferred methods include, but are not limited to, those described in the Examples and Schemes 1-6 below. Starting materials and reagents used in the preparation of the compounds of the present disclosure are available from commercial suppliers or may be prepared as described in Fieser and Fieser's Reagents for Organic Synthesis, Vol. 1-28 (Wiley, 2016); March's Advanced Organic Chemistry, 7 th Ed. (Wiley, 2013); and Larock's Comprehensive Organic Transformations, 2 nd Ed. (Wiley, 1999) or by methods known to those skilled in the art. The starting materials and intermediates of the reactions may be isolated and purified, if necessary, using conventional techniques, including but not limited to filtration, distillation, crystallization, and chromatography. Such materials may be characterized using conventional techniques, including measurement of physical constants and acquisition of spectral data.

[0119] Those skilled in the art will recognize whether a stereocenter exists in the compounds disclosed herein. Thus, the present disclosure includes both possible stereoisomers (unless specified in the synthesis), including racemates as well as individual enantiomers and / or diastereomers. If a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, intermediate, or starting material may be affected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by EL Eliel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[0120] As shown in Scheme 1, cyclopentenone (i) can be prepared by reacting a heterocyclic ring R 1 The cyclopentene moiety can be reduced to an enol substituted with a cyclopentene group (e.g., under Mitsunobu-type conditions) to form a cyclopentene acetal (ii). The acetal moiety can be removed and the resulting diol can be oxidized to form a ketol moiety in intermediate (iii). The cyclopentene moiety can then be used as a dienophile for reaction with a protected diene (iv) to give the Diels-Alder product (v). The ketol can be reduced to form the diol (vi), followed by deprotection to give the desired triol product.

[0121] Scheme 1 [ka]

[0122] Alternatively, as shown in Scheme 2, cyclopentenones (i) can be converted to dienes (xiv) which are used in Diels-Alder reactions with suitable dienophiles. The cyclopentenones can be converted to halides (xi) to afford heterocyclic rings R. 1to form intermediate (xii). Reaction with stannane (xiii) in a Stille-type coupling gives diene (xiv) for reaction with boronic acid dienophile (xv) and formation of Diels-Alder product (xvi). Hydrolysis of the boronic ester gives alcohol R, respectively. 4 Get R 5 can be converted to various phosphate prodrug moieties, for example, as described by Prader et al. (Chemical Reviews, 2014, 114, 9154-9218), which is incorporated herein by reference. Deprotection of intermediate (xvii) gives the desired product (vii).

[0123] Scheme 2 [ka]

[0124] 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 to xxii and Stille coupling to a diene (xxiii). Diels-Alder reaction with xv then leads to the adduct xxiv, which can be oxidized to xxv. Deprotection of intermediate (xxv) gives the desired product (xviii).

[0125] Scheme 3 [ka]

[0126] The unsaturated Diels-Alder products shown in Scheme 1, Scheme 2, and Scheme 3 can be hydrogenated to give compounds with a saturated carbobicyclic core.

[0127] Alternatively, as shown in Scheme 4, nucleoside analogs of structure (vii) or structure (xviii) can be protected to produce two regioisomers (xxxi) and (xxxii) (e.g., PG=tert-butyldimethylsilyl). Here, the free alcohol can be converted to thioester (xxxiv) and thioester (xxxv) using xxxiii. Deoxygenation under radical conditions then gives intermediates (xxxvi) and (xxxvii). Deprotection then gives the desired products (xxxviii) and (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).

[0128] Scheme 4 [ka]

[0129] Halogenated compounds can be prepared as shown in Scheme 5. The intermediates (xxxi) and (xxxii) described can be directly treated with diethylaminosulfur trifluoride (DAST) to give the monofluorides (xli) and (xlii). Deprotection then gives the desired products (xliii) and (xliv). Further difluorinated species can be achieved by oxidation to ketones (xlv) and (xlvi), followed by reaction with DAST to difluorides (xlvii) and (xlviii). Deprotection then gives the desired products (xlix) and (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).

[0130] Scheme 5 [ka]

[0131] Alkylated compounds can be prepared as shown in Scheme 6. In Scheme 4, (xxxi) and (xxxii) as described can be reacted with a base and an alkyl halide (e.g., MeI) to obtain (li) and (lii). Deprotection then gives the desired products (liii) and (liv). Also, in Scheme 5, (lv) and (lvi) as described can be reacted with a Grignard reagent RMgX (e.g., MeMgBr) to synthesize (lv) and (lvi). Deprotection then gives the desired products (lvii) and (lviii).

[0132] Scheme 6 [ka]

[0133] As used herein, the term "protecting group" refers to a chemical moiety that renders a functional group (e.g., a hydroxy group or an amino group) unreactive, but can 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); acetamide; phthalimide; silyl groups, such as trimethylsilyl, triethylsilyl, and (tert-butyl)dimethylsilyl. Other protecting groups are known to those skilled in the art and are described, for example, in Green and Wuts (Protective Groups in Organic Synthesis, 4 th Ed. 2007, Wiley-Interscience, New York.

[0134] III. Methods for Treating COVID-19 and Other Viral Infections

[0135] Also provided herein is a method of treating an infection caused by a virus, including coronavirus and other respiratory viruses. The infection may be, for example, a coronavirus infection, an adenovirus infection, an influenza virus infection (e.g., an influenza A virus (IAV) infection), a parainfluenza virus infection, a rhinovirus infection, or a respiratory syncytial virus (RSV) infection. The infection may be, but is not limited to, a SARS-CoV-2 infection, a SARS-CoV infection, a MERS-CoV infection, an HCoV-229E infection, an HCoV-OC43 infection, or an HCoV-NL63 infection. The method includes administering a therapeutically effective amount of a carbobicyclic nucleoside (e.g., a compound described herein) or a pharma- ceutically acceptable salt thereof to a subject in need thereof. In some embodiments, the subject has coronavirus disease 2019 (COVID-19).

[0136] In some embodiments, the subject is a human, an agricultural animal (e.g., a livestock animal such as a cow, sheep, or pig), 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.

[0137] The carbobicyclic nucleoside compounds according to the present disclosure, as well as other active agents used in the combination therapy described herein, may be administered to a subject orally, intravenously, intramuscularly, intraperitoneally, subcutaneously, intrathecally, intraarterially, intranasally, rectally, or via other routes as indicated. In some embodiments, the carbobicyclic nucleoside compounds are administered orally or via injection. The active agents may be administered in any suitable dose in the methods provided herein. Generally, the carbobicyclic nucleoside compounds or other active agents are administered in a dose ranging from about 0.1 milligrams to about 1000 milligrams per kilogram of the subject's body weight (i.e., about 0.1-1000 mg / kg). The dose of the carbobicyclic nucleoside compound may be, for example, about 0.1-1000 mg / kg, or about 1-500 mg / kg, or about 25-250 mg / kg, or about 50-100 mg / kg. Doses of the carbobicyclic nucleoside compounds are about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 100 mg / kg, about 150 mg / kg, about 160 mg / kg, about 170 mg / kg, about 180 mg / kg, about 190 mg / kg, about 210 mg / kg, about 220 mg / kg, about 230 mg / kg, about 240 mg / kg, about 250 mg / kg, about 260 mg / kg, about 270 mg / kg, about 280 mg / kg, about 290 mg / kg, about 300 mg / kg, about 310 mg / kg, about 320 mg / kg, about 330 mg / kg, about 340 mg / kg, about 350 mg / kg, about 360 mg / kg, about 370 mg / kg, about 380 mg / kg, about 390 mg / kg, about 400 mg / kg, about 400 mg / kg, about 450 mg / kg, about 500 mg / kg, about 550 mg / kg, about 600 mg / kg, about 650 mg / kg, about 700 mg / kg, about 750 mg / kg, about 800 mg / kg, about 850 mg / kg, about The dose may be about 95 mg / kg, about 100 mg / kg, about 150 mg / kg, about 200 mg / kg, about 250 mg / kg, about 300 mg / kg, about 350 mg / kg, about 400 mg / kg, about 450 mg / kg, about 500 mg / kg, about 550 mg / kg, about 600 mg / kg, about 650 mg / kg, about 700 mg / kg, about 750 mg / kg, about 800 mg / kg, about 850 mg / kg, about 900 mg / kg, about 950 mg / kg, or about 1000 mg / kg. In some embodiments, the carbobicyclic nucleoside compound is administered in an amount ranging from about 0.1 mg / kg to about 100 mg / kg per day. In some embodiments, the carbobicyclic nucleoside compound is administered in an amount ranging from about 0.1 mg / kg to about 1.0 mg / kg per day. Dosages may vary depending on the requirements of the patient, the severity of the infection, the route of administration, and the particular formulation administered.The dose administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects that accompany the administration of the drug in a particular patient. Determination of the appropriate dosage for a particular situation is within the skill of the ordinary practitioner. The total dose may be divided and administered in portions over a period suitable for the treatment of COVID-19.

[0138] The carbobicyclic nucleoside compound or other active agent may be administered for a period of time that may also vary depending on the severity of COVID-19 and the overall condition of the subject to whom the active agent is administered. Administration may be performed twice a day, including, for example, every hour, every 2 hours, every 3 hours, every 4 hours, every 6 hours, every 8 hours, or every 12 hours, or any intervening interval therebetween. Administration may be performed once a day, or once every 36 or 48 hours, once a week, twice a week, or three times a week. After treatment, the subject may be monitored for changes in the subject's condition and relief of COVID-19 symptoms. The dosage of the active agent may be increased if the subject does not respond significantly to a particular dosage level, or the dosage may be decreased if relief of symptoms is observed, or if COVID-19 improves, or if unacceptable side effects are seen at a particular dosage. Treating COVID-19 according to the methods of the present disclosure may include alleviating one or more symptoms, including, but not limited to, fever, cough, and shortness of breath. In some embodiments, treating COVID-19 may prevent severe, life-threatening illness, such as pneumonia.

[0139] The methods and compositions described herein may also be administered prophylactically to subjects at risk of infection with SARS-CoV-2 to reduce the risk of developing COVID-19.

[0140] Administration of a carbobicyclic nucleoside compound according to the methods provided herein can result in a reduction in the level of SARS-CoV-2 RdRp activity in a subject. For example, the level of RdRp activity can be reduced by about 25% to about 95%, about 35% to about 95%, about 40% to about 85%, or about 40% to about 80% compared to the level of corresponding RdRp activity prior to the first administration of an active agent (e.g., 24 hours prior to the first administration of an active agent). In some embodiments, the carbobicyclic nucleoside binds to SARS-CoV-2 nonstructural protein 12 (nsp12) in the RdRp complex in a manner that reduces RdRp activity.

[0141] In some embodiments, the method further comprises administering to the subject an analgesic (including anti-inflammatory analgesic), an antiviral agent, and an antitussive, or a combination thereof. Examples of nonsteroidal anti-inflammatory drugs (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 pharma- ceutically acceptable salts thereof. NSAIDs may be effective in reducing symptoms such as fever and pain. Additional analgesics, such as paracetamol (acetaminophen), may also be administered in conjunction with the carbobicyclic nucleoside compound. Examples of other antiviral agents include, but are not limited to, protease inhibitors (e.g., nirmatrevir, ritonavir, lopinavir, saquinavir, or indinavir), nucleic acid polymerase inhibitors (e.g., acyclovir, foscarnet, ganciclovir, or ribavirin), neuraminidase inhibitors (e.g., zanamivir or oseltamivir), interferons, and ion channel blockers (e.g., amantadine or rimantadine). Examples of antitussives include, but are not limited to, codeine, hydrocodone, benzonatate, dextromethorphan, and chlophedianol. In some embodiments, the method includes administering a CYP3A4 inhibitor to the subject. Administration of a CYP3A4 inhibitor can prevent premature metabolism of carbobicyclic nucleosides and increase plasma concentration levels after oral or other route of administration.Examples of CYP3A4 inhibitors include, but are not limited to, aprepitant, azamulin, 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 will be understood that an active agent may be classified into more than one category. For example, ritonavir can be classified as a protease inhibitor and a CYP3A4 inhibitor.

[0142] In some embodiments, the carbobicyclic nucleoside is administered as a pharmaceutical composition comprising at least one pharma- ceutically acceptable formulation excipient and the carbobicyclic nucleoside or a pharma- ceutically acceptable salt thereof. The carbobicyclic nucleoside compound may be administered to the subject before, after, or simultaneously with the administration of one or more additional active agents. The carbobicyclic nucleoside compound may be administered in a composition separate from the one or more additional active agents or in a composition comprising the one or more additional active agents. Also provided herein are compositions that contain (i) one or more carbobicyclic nucleoside compounds; (ii) one or more pharma-ceutically acceptable formulation excipients; and, optionally, (iii) one or more additional active agents, each of which is independently an anti-inflammatory agent, an analgesic agent, an antiviral agent, or an antitussive agent. The compositions may be formulated, for example, for oral, intravenous, intramuscular, intraperitoneal, subcutaneous, intrathecal, intraarterial, intranasal, or rectal administration.

[0143] Pharmaceutical composition can be prepared by any method well known in the field of medicine and drug delivery.Generally, the preparation of composition comprises the step of associating active ingredient with carrier containing one or more auxiliary ingredients.Pharmaceutical composition is usually prepared by uniformly and intimately associating active ingredient with liquid carrier or finely divided solid carrier or both, and then, if necessary, shaping the product into desired formulation.Composition can be conveniently prepared and / or packaged in unit dosage form.

[0144] Pharmaceutical compositions may be in a form suitable for oral use.Compositions suitable for oral administration include, but are not limited to, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, elixirs, solutions, buccal patches, oral gels, chewing gums, chewable tablets, effervescent powders, and effervescent tablets.Such compositions may contain one or more agents selected from sweeteners, flavorings, colorings, antioxidants, and preservatives to obtain medicament-elegant and palatable preparations.

[0145] Tablets usually contain the active ingredient mixed with non-toxic pharma- ceutically acceptable formulation additives, including inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents such as corn starch and alginic acid; binders such as polyvinylpyrrolidone (PVP), cellulose, polyethylene glycol (PEG), starch, gelatin, and acacia; and lubricants such as magnesium stearate, stearic acid, and talc. Tablets may be uncoated or enteric or otherwise coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. Tablets may also be coated with a semipermeable membrane and an optional polymeric osmotic agent according to known techniques to form an osmotic pump composition for controlled release. Compositions for oral administration may be formulated as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (such as, for example, calcium carbonate, calcium phosphate, or kaolin) or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (such as peanut oil, liquid paraffin, or olive oil).

[0146] The pharmaceutical composition may also be in the form of an injectable aqueous or oily solution or suspension. Sterile injectable preparations may be formulated using non-toxic parenterally acceptable vehicles, including water, Ringer's solution, and isotonic sodium chloride solution, as well as acceptable solvents, such as 1,3-butanediol. Sterile fixed oils are also conventionally used as solvents or suspending media. For this purpose, any bland fixed oil may be used, including synthetic monoglycerides or diglycerides. Fatty acids, such as oleic acid, are also used in the preparation of injectables.

[0147] Aqueous suspensions contain the active agent mixed with formulation additives suitable for the manufacture of aqueous suspensions. Such formulation additives include, but are not limited to, suspending agents such as sodium carboxymethylcellulose, methylcellulose, oleaginopropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic; dispersing or wetting agents such as lecithin, polyoxyethylene stearate, polyethylene sorbitan monooleate; and preservatives such as ethyl, n-propyl, and p-hydroxybenzoate. Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or in a mineral oil (e.g., liquid paraffin). Oily suspensions can contain a thickening agent, for example, beeswax, hard paraffin, or cetyl alcohol. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules, suitable for preparation of an aqueous suspension by the addition of water, may contain the active ingredient in admixture with a dispersing agent, wetting agent, suspending agent, or combinations thereof. Additional formulation additives may also be present.

[0148] The pharmaceutical composition of the present invention can also be in the form of oil-in-water emulsion.The oily phase can be vegetable oil (e.g. olive oil or peanut oil), mineral oil (e.g. liquid paraffin) or mixtures thereof.Suitable emulsifiers can be natural gums such as gum acacia or gum 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 above partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.

[0149] Transdermal delivery can be achieved by iontophoretic patches and the like. The active ingredient can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the active agent with suitable non-irritating formulation additives that are solid at ordinary temperatures but liquid at rectal temperature, and therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol. EXAMPLES

[0150] IV. Working Examples

[0151] 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) [ka]

[0152] Enone 1 (50 mg, 0.32 mmol) and CeCl 3 7H 2 To a stirred solution of 2,4-dimethylformamide (179 mg, 0.48 mmol) in methanol (8 mL) at 0 °C, NaBH 4 (15 mg, 0.39 mmol) was added in small portions and the resulting solution was kept at the same temperature for 30 min. The reaction was then diluted with saturated NH 4 The mixture was quenched with aqueous Cl (30 mL) and extracted with DCM (15 mL x 2). The combined organic phase was washed with Na 2 SO 4 Drying at 40° C. and concentration gave the crude allylic alcohol intermediate which was used directly in the next step.

[0153] The above allyl alcohol (crude product, 50 mg), 6-chloropurine (56 mg, 0.36 mmol), and PPh 3To a stirred solution of (168 mg, 0.64 mmol) in anhydrous THF (8 mL) at 0° C., DEAD (0.1 mL, 0.64 mmol) was added, and the resulting mixture was stirred at room temperature overnight. After TLC showed the reaction was complete, the solvent was removed to give the crude material, which was purified by column chromatography (hexane / ethyl acetate 3:1) to give compound 2 (70 mg, 75%, 2 steps). 1 H NMR (400 MHz, CDCl 3 )ppm 8.78(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). [ka]

[0154] Compound 2 (430 mg, 1.47 mmol) 2 To a stirred solution in 2H (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 column chromatography on silica gel (DCM / MeOH 20:1) to give diol 3 (330 mg, 90%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )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). [ka]

[0155] To a stirred solution of compound 3 (30 mg, 0.12 mmol) in DCM (5 mL) and THF (1 mL) at 0° C. was added PDC (43 mg, 0.12 mmol), and the reaction was then stirred at room temperature for 1.5 h. The mixture was then filtered and the resulting crude material was purified by column chromatography on silica gel (DCM / MeOH 30:1) to give enone 4 (9 mg, 30%, 36% BRSM) and 4 (4 mg) was recovered. 1 H NMR (400 MHz, CDCl 3 )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). [ka]

[0156] A mixture of enone 4 (5 mg, 0.02 mmol), diene, and BHT (trace amount) in toluene in a sealed tube was heated under N 2 The mixture was heated to 140° C. under reduced pressure, and then the solvent was removed to give a residue which was purified by column chromatography on silica gel (DCM / MeOH 40:1) to give enone 5 (3 mg, 30%) as an inseparable mixture of regioisomers and diastereomers. 1 H NMR (400 MHz, CDCl 3 )ppm 8.83(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, actual value: 435.1615. [ka]

[0157] Ketone 5 (8 mg, 0.018 mmol) and Yb(OTf) 3 (12.4 mg, 0.02 mmol) in methanol was stirred with NaBH 4 (ca. 1 mg, 0.025 mmol) was added and the resulting solution was kept at room temperature for 30 min. The reaction was then diluted with saturated NH 4 The mixture was quenched with aqueous Cl (30 mL), extracted with DCM (15 mL x 2), and the combined organic phase was washed with Na 2 SO 4 Drying at rt and concentration gave the crude material which was purified by column chromatography on silica gel (DCM / MeOH 40:1) to give the diol 6 (7 mg, 87%). 1 H NMR (400 MHz, CDCl 3 )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). [ka]

[0158] To a sealed tube was added 6 (7 mg) in THF (1 mL) and ammonia solution (0.5 mL). The tube was heated to 105° C. for 6 h, then the solvent was removed under vacuum to give a residue which was used directly in the next step.

[0159] To a stirred solution of the above crude product (5 mg) in THF (2 mL) was added HF·pyridine (70% in pyridine, 2 drops) at 0° C., then the reaction was allowed to warm to room temperature and stirred overnight. The solvent was removed to give a residue which was purified by column chromatography on silica gel (DCM / MeOH 40:1) to give triol 7 (1 mg). 1 H NMR (400 MHz, CDCl 3 )ppm 8.36(s,1H),8.23(s,1H),5.86-5.83(m,1H),5.75-5.72(m,1H),4.74-4.70(m,2 H),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).

[0160] 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) [ka]

[0161] To a stirred solution of unsaturated ketone 1 (0.77 g, 5.00 mmol, 1.00 equiv) in dry DCM (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 successively at 0° C. The reaction was then stirred at room temperature. After 1.5 h, the reaction was cooled to room temperature and cooled to room temperature with Na 2 S 2 O 3 Aqueous solution (15g / 50mL H 2 The mixture was quenched with 20 mL of DCM (20 mL x 2) and extracted with DCM (20 mL x 2). The combined organic phase was washed with brine (30 mL) and MgSO 4Drying at 40° C. and concentration gave the crude product which was purified by column chromatography on silica gel (hexane / EA 4:1). Iodide 8 was isolated as a white crystalline solid (1.27 g, 0.45 mmol, 90%).

[0162] R f =0.38(Hexane / EA 4:1); 1 H-NMR (400MHz, CDCl 3 )δ[ppm]=7.96(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 (101 MHz, CDCl 3 )δ[ppm]=197.7,165.0,115.9,105.8,79.8,73.8,27.4,26.5. [ka]

[0163] The unsaturated ketone 8 (1.28 g, 4.53 mmol, 1.00 equiv.) was dissolved in MeOH (40 mL) and treated with CeCl 3 *7H 2 2H2O (1.94 g, 5.22 mmol, 1.15 equiv.) was added. Then, NaBH 4 (197 mg, 5.22 mmol, 1.15 equiv.) was added. The reaction was stirred for 1 h and then saturated NH 4 The mixture was concentrated in vacuo and the crude product was extracted with EtOAc / H 2 The mixture was redissolved in 1:1 2H2O (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) and MgSO 4 After elution with 50 ml of ethyl acetate and drying at 40° C., the mixture was concentrated in vacuo to give the alcohol 9 (1.18 g, 4.18 mmol, 92%), which was isolated in sufficient purity as a white solid.

[0164] R f= 0.32 (Hexane: EtOAc 4:1); 1 H-NMR (400MHz, CDCl 3 )δ[ppm]=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). [ka]

[0165] Intermediate 9 was converted to compound 10 using the procedure described for the preparation of compound 2 in Example 1. 1 H NMR (400 MHz, CDCl 3 )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). [ka]

[0166] Compound 10 (530mg, 1.27mmol), Pd(PhCN) 2 Cl 2 (24mg, 0.063mmol, 0.05eq), Ph 3 To a stirred solution of As (39 mg, 0.127 mmol, 0.1 equiv) and CuI (24 mg, 0.127 mmol, 0.1 equiv) in NMP (10 mL) was added vinyltributyltin (0.45 mL, 1.52 mmol, 1.2 equiv) in N 2 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 phase was diluted with Na 2 SO 4Drying at rt and concentration gave a residue which was purified by column chromatography on silica gel (hexane / ethyl acetate 3:1) to give diene 11 (383 mg, 95%). 1 H NMR (400 MHz, CDCl 3 )ppm δ 8.79(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). [ka]

[0167] 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) and washed with THF (10 mL) and NaBO. 3 4H 2 O (1.33 g, 8.67 mmol, 4.00 equiv.) was added. The reaction was stirred at room temperature for 2 h, then quenched with saturated sodium thiosulfate solution (10 mL) and stirred for 10 min. After phase separation, the aqueous layer was extracted with ethyl acetate (3×15 mL) and the combined organic phases were washed with MgSO 4 The mixture was dried at 40° C. 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 give 12a and 12b (175 mg and 355 mg, respectively, 1.46 mmol, 67% overall yield). f 0.31, 0.21 (DCM / ethyl acetate 1:2); 1 H-NMR (600MHz, CDCl 3)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 (150 MHz, CDCl 3 )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 [ka]

[0168] 12a (18 mg) in THF (2 mL) and H 2 To a stirred solution in 2 mL of O 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. To the crude residue in a sealed tube was added THF (1 mL) and aqueous ammonia (0.8 mL) and the tube was covered with N 2 The mixture was heated to 120° C. under reduced pressure overnight. The solvent was then removed to give a residue which was purified by column chromatography on silica gel (DCM / MeOH 7:1) to give compound 13 (14 mg, 94%). 1 H NMR(400MHz,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{ 1H}-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).

[0169] Example 3: Preparation of (1R,2S,3R,7R,7aR)-3-(6-amino-9H-purin-9-yl)octahydro-1H-indene-1,2,7-triol (14) [ka]

[0170] To a solution of compound 13 (16 mg) in methanol (2 mL) was added Pd / C (wet, 15 mg) and the resulting solution was subjected to H 2 The mixture was stirred under a packed balloon (1 atm) for 3 days. The mixture was filtered and the filtrate was concentrated to give a residue, which was purified by column chromatography on silica gel (DCM / MeOH 7:1) to give product 14 (1 mg, 6%). Unreacted compound 13 (11 mg, 69%) was recovered. 14: 1 H NMR (400 MHz, CDCl 3 )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),2.6 9-2.64(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).

[0171] 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) [ka]

[0172] 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 diluted with NaHCO 3 (10 mL) and stirred for 10 min. After phase separation, the aqueous layer was extracted with ethyl acetate (4 x 5 mL) and the combined organic phases were washed with MgSO 4 The mixture was dried at 40° C. and filtered. The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (hexane / ethyl acetate). Using 2:1 and 1:2 eluent ratios, 15a and 15b were obtained (132 mg and 36.8 mg, respectively, 0.39 mmol, 72%). 15a:R f 0.44 (hexane / ethyl acetate 2:1); 1 H-NMR (400MHz, CDCl 3 )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:R f 0.24 (hexane / ethyl acetate 2:1); 1 H-NMR (600MHz, CDCl 3)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),1.60(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 (150 MHz, CDCl 3 )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 [ka]

[0173] 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 NH 3 Aqueous solution (25% aqueous solution, 1 mL) was added and stirred at 80° C. for 1 day. Residual water was removed in vacuum with acetonitrile (3×2 mL). Methanol (3 mL) and K 2 CO 3 (24.2 mg, 0.18 mmol, 1.50 equiv) was 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 washed with MgSO 4The mixture was dried at 40° C. 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 with acetonitrile (3×2 mL) and the crude product was purified by silica gel column chromatography (methanol / ethyl acetate, 10%) to give adenosine analog 16 (22.0 mg, 0.07 mmol, 63%) along with 17 as a by-product (8.50 mg, 0.03 mmol). 16:R f 0.07 (methanol / ethyl acetate, 5%); 1 H-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]=155.9,152.2,149.5,140.5,137.1,120.0,118.7,75.9,74.9,66.8,62.4,44.0,35.8,33.9 17: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).

[0174] 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) [ka]

[0175] 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 NH 3 Aqueous solution (25% aqueous solution, 1 mL) was added and stirred at 85° C. for 1 day. Residual water was removed in vacuum with acetonitrile (3×2 mL). Methanol (1 mL) and K 2 CO 3 (15.8 mg, 0.11 mmol, 1.50 equiv) was 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 washed with MgSO 4 The mixture was dried over 1000 ml and filtered. Methanol (0.5 mL), TFA (20% aqueous solution, 0.5 mL), and water (0.5 mL) were added and stirred at room temperature for 1 day. The solvent was removed in vacuo with acetonitrile (3×2 mL) and the crude product was purified by silica gel column chromatography (methanol / ethyl acetate, 10%) to give 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).

[0176] 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) [ka]

[0177] 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 4 Å MS were added, and the mixture was stirred for 2 h. Then, at 0 °C, PPh 3 - (1.12 g, 4.25 mmol, 1.20 equiv.) and DIAD (0.84 mL, 4.25 mmol, 1.20 equiv.) were added. The reaction was stirred for 18 h. The reaction was then filtered and the solvent removed in vacuo. Column chromatography (SiO 2 Purification with hexanes:EtOAc 3:1 to 1:1 gave first 20b as a yellow oil (0.59 g, 1.51 mmol, 42%) and later 20a as a white foam (0.49 g, 1.25 mmol, 36%). f = 0.13 (Hexane: EtOAc 3:1); 1 H-NMR (400MHz, CDCl 3 )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 (101 MHz, CDCl 3 )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;HRMS(ESI,3.5kV)[M+Na] + C 12 H 14 IN 3 O 4 Na + Calculated value 413.99212, measured value 413.99171. 20b:R f = 0.24 (Hexane: EtOAc 3:1); 1 H-NMR (400MHz, CDCl 3)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 (101 MHz, CDCl 3 )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 IN 3 O 4 Na + The calculated value was 413.99212, and the actual value was 413.99183. [ka]

[0178] Iodide 20a (478 mg, 1.22 mmol, 1.00 equiv.) was dissolved in NMP (4 mL, freshly distilled) and [Pd(PhCN) 2 Cl- 2 ] (14.1 mg, 36.7 μmol, 3 mol%), and dissolved in CuI (14.0 mg, 73.3 μmol, 6 mol%) and Ph 3 As (22.5 mg, 73.3 μmol, 6 mol%) was added. Vinyltributyltin (430 μL, 1.47 mmol, 1.20 equiv) was then added dropwise at 0° C. The reaction was stirred at this temperature for 3 h. The reaction was diluted with saturated NaHCO 3 The reaction mixture was quenched with EtOAc (10 mL) and EtOAc (10 mL). After separation of the organic phase, the aqueous phase was extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (15 mL) and MgSO 4 The mixture was dried over 1000 ml of ethyl acetate and concentrated in vacuo. 2 Purification with hexanes (Hex:EtOAc 2:1 to 1:1) afforded 21 as a white solid (349 mg, 1.20 mmol, 98%). f= 0.29 (Hexane: EtOAc 1:1); 1 H-NMR (400MHz, CDCl 3 )δ[ppm]=8.07(s,1H),6.47(dd,J=11.2,17.6Hz,1H),6.21(s,1H),5.68(s,1H),5.42(d,J=5.4 Hz,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 (101 MHz, CDCl 3 )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 N 3 O 4 Na + The calculated value was 314.11113, and the measured value was 314.11088. [ka]

[0179] Diene 21 (320 mg, 1.10 mmol, 1.00 equiv.) was dissolved in toluene (CaH 2 The reaction was dissolved in 100 mL of freshly distilled ethyl acetate (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) in a sealed tube for 96 h. The volatiles were then removed and the crude mixture was diluted with THF / H 2 The mixture was then dissolved in NaBO (20 mL, 1:1). 3 ×4H 2 0 (866 mg, 3.56 mmol, 3.00 equiv.) was 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 (3×20 mL). The combined organic phase was washed with MgSO 4The mixture was dried over 1000 ml of ethyl acetate and concentrated in vacuo. 2 Purification with DCM:EtOAc 1:1 to EtOAc / DCM 1:3 to pure EtOAc) gave 2a as a white solid (114 mg, 0.34 mmol, 31%) and 22b (179 mg, 0.53 mmol, 49%) as a mixture of isomers. f = 0.30 (EtOAc:DCM 1:1); 1 H-NMR (400MHz, CDCl 3 )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,1H),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 (101 MHz, CDCl 3 )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;HRMS(ESI,3.5kV)[M+Na] + C 16 H 21 N 3 O 5 Na + Calculated value 358.13734, measured value 358.13714.22b:R f = 0.16 (EtOAc:DCM 1:1). [ka]

[0180] Prepare a solution of 22a (26.0 mg, 77.5 mmol) in MeOH (0.5 mL) and dilute it with NH 3(7M 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) followed by TFA (H 2 10% in O, 0.5 mL) was added and the reaction was stirred for an additional 23 h. After removal of volatiles, column chromatography (SiO 2 Purification with 5% EtOAc to 10% MeOH) afforded nucleoside analog 23 (17.8 mg, 63.5 mmol, 82% over two steps) as a white solid. f = 0.08 (EtOAc, 5% MeOH);

number

[0181] 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) [ka]

[0182] Alcohol 22a (32 mg, 95.5 μmol, 1.00 equiv) was dissolved in MeOH (0.35 mL) and reacted with NH 3 (7M in MeOH, 0.35 mL) was added. After 16 h, the solvent was removed in vacuo. The residue was dissolved in dry 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 washed with saturated NaHCO 3 (5 mL) and quenched with 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 washed with MgSO 4 The mixture was dried over 1000 ml of ethyl acetate and the solvent was removed in vacuo. 2 Purification with DCM:EtOAc 3:1) gave the butyrate ester, which was redissolved in MeOH (0.5 mL) and diluted with TFA (H 2 The product was directly deprotected by addition of 10% HCl in O (0.5 mL). After 24 h, the solvent was removed in vacuo. 2 Purification with 5% MeOH (EtOAc 5% MeOH) afforded nucleoside analog 24 (18.6 mg, 53.1 μmol, 55% over three steps) as a white solid. f =0.33(EtOAc 5% MeOH);

number

[0183] 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) [ka]

[0184] 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). 3 N (145 μL, 1.04 mmol, 2.00 equiv.) and DMAP (6.4 mg, 52.2 μmol, 10 mol%) were added. After 18 h, the reaction was diluted with saturated NaHCO3 The mixture was quenched by the addition of aqueous solution and diluted with EtOAc. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3×10 mL). The combined organic phase was washed with brine (15 mL) and MgSO 4 The mixture was dried over 1000 ml of ethyl acetate and the solvent was removed in vacuo. 2 Purification with hexane:EtOAc 1:1) afforded both 25a (48.1 mg, 11.8 μmol, 23%) and 25b (108.8 mg, 26.8 μmol, 52%) as white solids. f = 0.49 (Hexane: EtOAc 1:2); 1 H-NMR (600MHz, CDCl 3 )δ[ppm]=8.26(s,1H),5.25(brs,1H),5.21(brs,1H),5.08(dd,J=5.4,7.3Hz,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),1.4 6(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{ 1 H}-NMR (151 MHz, CDCl 3 )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;HRMS(ESI,3.5kV)[M+Na] + C 20 H 27 N 3 O 6 Na + Calculated value 428.17921, measured value 428.17857. 25b:R f =0.56(Hex:EtOAc 1:2); 1H-NMR (600MHz, CDCl 3 )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),1.94-2.0 3(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 (151 MHz, CDCl 3 )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;HRMS(ESI,3.5kV)[M+Na] + C 20 H 27 N 3 O 6 Na + The calculated value was 428.17921, and the measured value was 428.17857. [ka]

[0185] Ester 25a (24.8 mg, 61.2 μmol, 1.00 equiv) was dissolved in MeOH (0.5 mL) and reacted with NH 3 (7M in MeOH, 0.5 mL) was added. The reaction was stirred for 16 h and then K 2 CO 3 (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 (4×4 mL). The combined organic phase was washed with MgSO 4 The crude product was redissolved in MeOH (0.5 mL) and TFA ( 210% in O, 0.5 mL) was added. The reaction was stirred for 24 h and then the solvent was removed in vacuo. Column chromatography (SiO 2 Purification with 5% MeOH (EtOAc 7% MeOH) afforded nucleoside analog 26 (16.0 mg, 57.1 μmol, 93% over three steps) as a white solid. f = 0.21 (EtOAc, 5% MeOH);

number

[0186] 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) [ka]

[0187] Ester 25a (20.1 mg, 49.6 μmol) was dissolved in MeOH (0.5 mL) and reacted with NH 3 (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 ( 2 10% in O, 0.75 mL) was added. After 24 h, the solvent was removed in vacuo. Column chromatography (SiO 2 Purification with 5% MeOH (EtOAc 5% MeOH) afforded nucleoside analog 27c (16.2 mg, 46.2 μmol, 93% over two steps) as a white solid. f = 0.17 (EtOAc, 5% MeOH);

number

[0188] 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) [ka]

[0189] Ester 25b (21.6 mg, 53.3 μmol, 1.00 equiv) was dissolved in MeOH (0.5 mL) and reacted with NH 3 (7M in MeOH, 0.5 mL) was added. The reaction was stirred for 17.5 h and then K 2 CO 3 (14.7 mg, 0.11 mmol, 2.00 equiv.) was added. After an additional 24 h, H 2 O / EtOAc (10 mL, 1:1) was added. The organic phase was separated and the aqueous phase was extracted with EtOAc (4×4 mL). The combined organic phase was washed with MgSO 4 The crude product was redissolved in MeOH (0.5 mL) and TFA ( 2 10% in O, 0.5 mL) was added. The reaction was stirred for 27 h and then the solvent was removed in vacuo. Column chromatography (SiO 2 Purification with 50% MeOH (EtOAc 7.5% MeOH) afforded nucleoside analog 28 (10.8 mg, 38.5 μmol, 72% over three steps) as a white solid. f = 0.08 (EtOAc, 7.5% MeOH);

number

[0190] 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) [ka]

[0191] Ester 25b (20.8 mg, 51.3 μmol) was dissolved in MeOH (0.5 mL) and reacted with NH 3 (7M 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 ( 210% in O, 0.5 mL) was added. After 24 h, the solvent was removed in vacuo. Column chromatography (SiO 2 Purification with 3% MeOH (EtOAc 3% MeOH) afforded nucleoside analog 29 (15.7 mg, 44.8 μmol, 87% over two steps) as a white solid. f = 0.37 (EtOAc, 5% MeOH);

number

[0192] 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) [ka]

[0193] Nucleoside analog 30 was synthesized using intermediate 20b using the method described in Example 6. f = 0.23 (EtOAc / MeOH 3%);

number

[0194] 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) [ka]

[0195] Nucleoside analog 31 was synthesized using intermediate 20b using the methods described in Examples 6 and 7. f = 0.54 (EtOAc, 5% MeOH);

number

[0196] 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) [ka]

[0197] Nucleoside analog 32 was synthesized using intermediate 20b using the methods described in Examples 6 and 8. f = 0.21 (EtOAc, 5% MeOH);

number

[0198] 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) [ka]

[0199] Nucleoside analog 33 was synthesized using intermediate 20b using the methods described in Examples 6 and 9. f = 0.53 (EtOAc, 7.5% MeOH);

number

[0200] 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) [ka]

[0201] Nucleoside analog 34 was synthesized using intermediate 20b using the methods described in Examples 6 and 10. f = 0.35 (EtOAc, 5% MeOH);

number

[0202] 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) [ka]

[0203] Nucleoside analog 35 was synthesized using intermediate 20b using the methods described in Examples 6 and 11. f = 0.56 (EtOAc, 7.5% MeOH);

number

[0204] 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) [ka]

[0205] Ester 22a (1.00 equiv, 0.10 mmol, 35 mg) was dissolved in MeOH (1 mL) and reacted with NH 3 (7M in MeOH, 1 mL) was added. After 19 h, the solvent was removed in vacuo and ACN (2 mL) was added. PhOCSCl (4.00 equiv, 0.40 mmol, 72 mg, 58 μL) and DMAP (4.00 equiv, 0.40 mmol, 51 mg) were then added and the reaction was stirred for 1 day. Then saturated NaHCO 3 Aqueous solution (5 mL) was added and the aqueous phase was extracted with EtOAc (4×10 mL). The combined organic layers were washed with MgSO 4 The mixture was dried over 1000 ml of ethyl acetate and the solvent was removed in vacuo. The crude product was purified by column chromatography (SiO 2 , EA / DCM 1:2) to give the thionocarbonate (28.3 mg, 62 μmol, 62%).

[0206] The product was dissolved in toluene (3 mL) and added with Bu 3 SnH (4.00 equiv., 0.24 mmol, 72.2 mg, 67 μL) and AIBN (0.25 equiv., 15.5 μmol, 2.5 mg) were added and the reaction was stirred at reflux for 5 h. The mixture was purified by column chromatography (SiO 2 The product was directly separated by ethyl acetate / DCM 1:2) and the resulting product was redissolved in MeOH (0.5 mL) and TFA ( 2 After 22 h, the solvent was removed and the crude product was subjected to column chromatography (SiO, EA 5% MeOH) to give the deoxygenated product 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.

[0207] 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) [ka]

[0208] A solution of alcohol 9 (705 mg, 2.50 mmol, 1.00 equiv) and protected uracil 37 (649 mg, 3.00 mmol, 1.2 equiv) in THF (50 mL) was prepared and activated with 4 Å MS. MS was added and the mixture was stirred for 2 h. Then, PPh was first added at 0 °C. 3 - (0.98 g, 3.75 mmol, 1.50 equiv.) followed by DIAD (0.74 mL, 3.75 mmol, 1.50 equiv.) was added. The reaction was stirred for 16 h. The reaction was then filtered and the solvent removed in vacuo. Column chromatography (SiO 2 Purification with hexanes (Hex:EtOAc 4:1 to 1:1) afforded 38 (0.96 g, 2.00 mmol, 80%) as a white foam. f =0.45(Hexane / EA 1:1); 1 H-NMR (400MHz, CDCl 3)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 (101 MHz, CDCl 3 )δ[ppm]=168.3,162.0,149.1,145.8,135.5,131.1,130.7,129.4,112.7,103.1,85.6,80.6,27.1,25.7;HRMS(ESI,3.5kV)[M+Na] + C 19 H 17 IN 2 O 5 Na + Calculated value of 503.00743, found value of 503.00744. Note: Broad signals were observed in the proton and carbon spectra. Therefore, despite extensive 2D NMR experiments, not all carbon signals could be found. [ka]

[0209] Vinyl iodide 38 (1.70 g, 3.54 mmol, 1.00 equiv.), [Pd(PhCN) 2 Cl 2 ] (67.9 mg, 0.18 mmol, 5 mol%), CuI (67.4 mg, 0.35 mmol, 10 mol%), and Ph 3 As (108.4 mg, 0.35 mmol, 10 mol%) was dissolved in freshly distilled NMP (CaH 2 The reaction was then dissolved in half-saturated NaHCO (11 mL) at 0° C. 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 at this temperature for 4 h. The reaction was then dissolved in half-saturated NaHCO 3The mixture was quenched with ethyl acetate (20 mL) and the aqueous phase was extracted with EtOAc (3×30 mL). The combined organic phase was washed with brine (30 mL) and the brine was re-extracted with EtOAc (1×15 mL). The combined organic phase was washed with MgSO 4 The mixture was dried at 40° C. and concentrated to give the crude product, which was purified by column chromatography on silica gel (first column: hexane / EA 2:1 to 1:2, second column: DCM / EA 3:1 to remove residual NMP and impurities). Diene 39 was isolated as a white crystalline solid (1.28 g, 3.36 mmol, 95%). f = 0.53 (Hexane / EA 1:2); 1 H-NMR (400MHz, CDCl 3 )δ[ppm]=7.91(d,J=7.3Hz,2H),7.66(tt,J=1.2,7.5Hz,1H),7.50(t,J=8.0Hz,2H),6.96(brs,1H),6.47(dd,J=11.0,17.8Hz,1H),6.19(brs,1H),5. 79(d,J=8.1Hz,1H),5.69(brs,1H),5.39(d,J=11.0Hz,1H),5.34(d,J=4.6 Hz,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 (101 MHz, CDCl 3 )δ[ppm]=168.5,162.0,149.8,139.8,136.7,135.3,131.5,130.6,130.0,129. 3,120.3,112.4,102.8,84.4,83.3,65.8,27.4,25.8;HRMS(ESI,3.5kV)[M+Na] + C 21 H 20 N 2 O 5 Na + Calculated value of 403.12644, measured value of 403.12626. Note: Broad signals were observed in the proton and carbon spectra. Therefore, despite the long measurement time, not all carbon signals could be found. [ka]

[0210] To a solution of ester 39 (1.23 g, 3.24 mmol, 1.00 equiv) in dry 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 and then washed with saturated NH 4 Aqueous Cl was added (50 mL). The mixture was extracted with EtOAc (4×50 mL) and the combined organic phases were washed with MgSO 4 The mixture was dried over 1000 ml of ethyl acetate and concentrated in vacuo. 2 Purification with 2:1 to 1:2 DCM / EtOAc) afforded the deprotected 40 as a white solid (0.88 g, 3.18 mmol, 98%). f =0.19(DCM / EA3:1); 1 H-NMR (400MHz, CDCl 3 )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 (101 MHz, CDCl 3 )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 N 2 O 4 Na + The calculated value was 299.10023, and the actual value was 299.09993. [ka]

[0211] To a solution of diene 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 in a sealed tube at 140 °C (oil bath temperature) for 4 days. The volatiles were then removed and the crude product was dissolved in THF / ph7 buffer (16 mL, 1:1). NaBO 3 4H 2 O (505 mg, 3.29 mmol, 4.00 equiv) was added and the mixture was stirred for 1.5 h. The reaction was then washed with saturated Na 2 S 2 O 3 The mixture was quenched with 10 mL of ethyl acetate. After phase separation, the aqueous phase was extracted with EtOAc (3×15 mL). The combined organic phase was washed with MgSO 4 The mixture was dried over 1000 ml of ethyl acetate and concentrated in vacuo. 2 Purification with 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); 1 H-NMR (600MHz, 315K, CDCl 3 )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),4.21-5.10(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 (150 MHz, 315 K, CDCl 3 )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] + C16 H 20 N 2 O 5 Na + Calculated value: 343.12644, measured value: 343.12623. 41b: R f = 0.19 (DCM / acetone 3:1); 1 H-NMR (600 MHz, 315 K, CDCl 3 ) δ [ppm] = 8.97 (s, 1H), 7.10 (brs, 1H), 5.72 (d, J = 7.0 Hz, 1H), 5.23 (s, 1H), 4.30 - 5.10 (brs, 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, CDCl 3 ) 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 N 2 O 5 Na + Calculated value: 343.12644, measured value: 343.12638. 41c: R f = 0.16 (DCM / acetone 3:1); 1 H-NMR (600 MHz, 315 K, CDCl 3 ) δ [ppm] = 9.18 (brs, 1H), 7.08 (brs, 1H), 5.74 (d, J = 7.4 Hz, 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, CDCl 3)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,3.5kV)[M+Na] + C 16 H 20 N 2 O 5 Na + The calculated value was 343.12644, and the measured value was 343.12604. [ka]

[0212] Alcohol 41a (20.0 mg, 62.4 μmol, 1.00 equiv.) was dissolved in THF (0.5 mL) and TFA (1.0 mL, H 2 After 21 h, the solvent was removed in vacuo. Column chromatography (SiO 2 Purification with 5% MeOH (EtOAc 5% MeOH) afforded nucleoside analog 42 (17.0 mg, 60.7 μmol, 97%) as a white solid. f =0.23 (EtOAc 5% MeOH);

number

[0213] 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) [ka]

[0214] Alcohol 41a (50 mg, 0.16 mmol, 1.00 equiv) was dissolved in acetonitrile (3 mL) and treated with isobutyric anhydride (52 μL, 0.31 mmol, 2.00 equiv), Et 3 N (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 and then saturated NaHCO 3 (10 mL) and EtOAc (10 mL) were added. After phase separation, the aqueous phase was extracted with EtOAc (3×15 mL). The combined organic phase was washed with MgSO 4 The mixture was dried over 1000 ml of ethyl acetate and concentrated in vacuo. 2 Purification with 1:1 DCM:EtOAc gave the ester (58.0 mg, 0.15 mmol, 97%) as a white solid. For deprotection, an aliquot (15.2 mg, 38.9 μmol) was dissolved in THF (0.5 mL) and TFA (1.0 mL, H 2 After 16 h, the solvent was removed in vacuo. Column chromatography (SiO 2 Purification with 5% MeOH (EtOAc 5% MeOH) afforded nucleoside analog 43 (12.6 mg, 35.9 μmol, 92%, 90% for two steps) as a white solid. f =0.53(EtOAc 5% MeOH);

number

[0215] 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) [ka]

[0216] Alcohol 41b (20.0 mg, 62.4 μmol, 1.00 equiv.) was dissolved in MeOH (0.5 mL) and TFA (0.5 mL, H 2 After 16 h, the solvent was removed in vacuo. Column chromatography (SiO 2Purification with 5% MeOH (EtOAc 5% MeOH) afforded nucleoside analog 44 (16.0 mg, 60.7 μmol, 91%) as a white solid. f =0.15(EtOAc 5% MeOH);

number

[0217] 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) [ka]

[0218] Alcohol 41b (40.0 mg, 0.13 mmol, 1.00 equiv) was dissolved in acetonitrile (2 mL) and treated with isobutyric anhydride (41 μL, 0.25 mmol, 2.00 equiv), Et 3 N (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 and then saturated NaHCO 3 (10 mL) and EtOAc (10 mL) were added. After phase separation, the aqueous phase was extracted with EtOAc (3×15 mL). The combined organic phase was washed with MgSO 4 The mixture was dried over 1000 ml of ethyl acetate and concentrated in vacuo. 2 Purification with 1:1 DCM:EtOAc gave the ester (27.9 mg, 71.5 μmol, 57%) as a white solid. For deprotection, an aliquot (20.0 mg, 51.2 μmol) was dissolved in MeOH (0.75 mL) and TFA (0.25 mL, H 2 After 44 h, the solvent was removed in vacuo. Column chromatography (SiO 2 Purification with 3% MeOH (EtOAc 3% MeOH) afforded nucleoside analog 45 (17.1 mg, 48.8 μmol, 96%, 55% for two steps) as a white solid. f =0.23 (EtOAc 3% MeOH);

number

[0219] 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) [ka]

[0220] Alcohol 41c (24.2 mg, 75.5 μmol, 1.00 equiv.) was dissolved in THF (0.5 mL) and TFA (1 mL, H 2 After 44 h, the solvent was removed in vacuo. Column chromatography (SiO 2Purification with 50% EtOAc (7.5% MeOH) afforded nucleoside analog 46 (19.9 mg, 71.0 μmol, 94%) as a white solid. f =0.15(EtOAc 5% MeOH);

number

[0221] 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) [ka]

[0222] Alcohol 17 (40.0 mg, 0.13 mmol, 1.00 equiv) was dissolved in acetonitrile (2 mL) and treated with isobutyric anhydride (41 μL, 0.25 mmol, 2.00 equiv), Et 3 N (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 24 h and then saturated NaHCO 3 (10 mL) and EtOAc (10 mL) were added. After phase separation, the aqueous phase was extracted with EtOAc (3×15 mL). The combined organic phase was washed with MgSO 4 The mixture was dried over 1000 ml of ethyl acetate and concentrated in vacuo. 2 Purification with 1:1 DCM:EtOAc gave the ester (45.0 mg, 0.12 mmol, 92%) as a white solid. For deprotection, an aliquot (20.5 mg, 52.5 μmol) was dissolved in MeOH (0.75 mL) and TFA (0.25 mL, H 2 After 40 h, the solvent was removed in vacuo. Column chromatography (SiO 2 Purification with 2% MeOH (EtOAc 2% MeOH) afforded nucleoside analog 21b (18.4 mg, 52.5 μmol, quantitative, 92% over two steps) as a white solid. f =0.33(EtOAc 5% MeOH);

number

[0223] 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) [ka]

[0224] Uracil analog 42 (1.00 equiv., 0.13 mmol, 35 mg) was dissolved in HMDS (1.5 mL) and NH 4 HSO 4 (4.00 eq., 0.50 mmol, 57 mg), (NH 2 OH)xH 2 SO 4 (2.00 equiv, 0.25 mmol, 41 mg), and imidazole (0.50 equiv, 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 hexanes (2×5 mL). The combined organic phases were dried over MgSO4. The solvent was removed in vacuo and the residue was dissolved in MeOH (1 mL) and TFA (50 μL) was added. After 15 min, the volatiles were removed in vacuo. Column chromatography (SiO 2 Purification with 5% MeOH (EtOAc 5% MeOH) afforded 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 H 17 N 3 O 5 Na + The calculated value was 318.10604, and the measured value was 318.10579.

[0225] 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) [ka]

[0226] Analog 49 was synthesized using intermediate 41a using the methods outlined in Examples 20 and 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 N 3 O 6 Na + 388.14791, actual value 388.14748.

[0227] 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) [ka]

[0228] Analog 50 was synthesized using intermediate 41b using the methods outlined in Examples 21 and 25. f = 0.22 (EtOAc 5% MeOH); 1 H-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 N 3 O 5 Na + 318.10604, actual value 318.10593.

[0229] 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) [ka]

[0230] Analog 51 was synthesized using intermediate 41b using the methods outlined in Examples 22 and 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 N 3 O 6 Na + 388.14791, actual value 388.14730.

[0231] 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) [ka]

[0232] Analog 52 was synthesized using intermediate 41c using the methods outlined in Examples 23 and 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 N 3 O 5 Na+ 318.10604, actual value 318.10587.

[0233] 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) [ka]

[0234] Analog 53 was synthesized using intermediate 41c using the methods outlined in Examples 24 and 25. f =0.27 (EtOAc 5% MeOH).

[0235] 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) [ka]

[0236] Intermediate 41a (1.00 equiv, 1.00 mmol) was dissolved in ACN (10 mL) and Et 3 N (2.50 equiv.) and add isobutyric anhydride (2.50 equiv.) and DMAP (0.10 equiv.). The reaction is stirred until complete. Workup and purification gives the isobutyric ester. The intermediate (1.00 equiv., 1.00 mmol) is dissolved in ACN (10 mL) and tripsyl chloride (2.00 equiv.) and added with Et 3 N (2.00 equiv.) and DMAP (0.1 equiv.) are added. After completion of the reaction, NH 4 OH (25% in water) is added. After 2 h of workup and purification, the protected cytidine-type analog 54 was obtained. For deprotection, 54 (1.00 equiv., 1.00 mmol) was dissolved in MeOH (5 mL) and K2 CO 3 (1.50 equiv.) is added. After complete saponification, TFA (H 2 Add 20% HO (5 mL). Stir the reaction until completion. Workup and purification gives the final cytidine analog 55.

[0237] 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) [ka]

[0238] Analog 56 is synthesized using the method outlined in Example 31 using intermediate 41b.

[0239] 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) [ka]

[0240] Analog 57 is synthesized using the method outlined in Example 31 using intermediate 41c.

[0241] 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) [ka]

[0242] Analog 59 is synthesized using intermediates 9 and 58 using the methods outlined in Example 19.

[0243] 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) [ka]

[0244] Analog 60 is synthesized using intermediates 9 and 58 using the methods outlined in Examples 19 and 21.

[0245] 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) [ka]

[0246] Analog 61 is synthesized using intermediates 9 and 58 using the methods outlined in Examples 19 and 23.

[0247] 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) [ka]

[0248] Analog 63 was synthesized using intermediate 9 and intermediate 62 using the method outlined in Example 2. 1H-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).

[0249] 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) [ka]

[0250] Analog 64 was synthesized using intermediate 9 and intermediate 62 using the methods outlined in Examples 2 and 4. 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).

[0251] 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) [ka]

[0252] The protected diol 12a (1.00 mmol) was dissolved in MeOH (5 mL) and TFA ( 220% in 0, 5 mL) is added. After 1 day, the volatiles are removed in vacuo. The crude product is then dissolved in DMF (5 mL) and imidazole (2.50 equiv.) followed by the addition of TBSCl (2.50 equiv.). The reaction is stirred for 5 h and then worked up and purified to give 65a and 65b. [ka]

[0253] Alcohol 65a (1.00 equiv, 1.00 mmol) was dissolved in DCM (10 mL) and PhOCSCl (3.00 equiv, 3.00 mmol) and treated with DMAP (0.10 equiv, 0.10 mmol) and Et 3 N (3.00 equiv, 3.00 mmol) is added. The reaction is stirred until completion, followed by work-up and purification to give the thionocarbonate intermediate, which is dissolved in toluene (10 mL) and added Bu 3 SNH (4.00 equiv.) and AIBN (0.10 equiv.) are added. The reaction is stirred under reflux until completion, followed by workup and purification yield 66. Finally, 66 is dissolved in THF (10 mL) and TBAF (1 M in THF, 1.00 equiv.) is added. After complete deprotection workup, the crude product is obtained, which is dissolved in ACN (5 mL) and NH 4 OH solution (25% in H2O, 3 mL) is added. The reaction is stirred at 85° C. until completion. Workup and purification gives the desired analog 67.

[0254] 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) [ka]

[0255] Alcohol 65b (1.00 equiv, 1.00 mmol) is dissolved in THF (10 mL) and NaH (1.20 equiv 60%) and MeI (5.00 equiv) are added at 0° C. The reaction is stirred until completion and is worked up and purified to give 68. The protected 68 is converted to 69 as described in Example 39.

[0256] 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) [ka]

[0257] Analog 71 is synthesized using intermediates 9 and 70 using the methods outlined in Examples 19 and 39.

[0258] 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 [ka]

[0259] Analog 73 is synthesized using the method outlined in Example 2 using intermediate 9 and intermediate 72. Protected 73 (1.00 equiv., 1.00 mmol) is then dissolved in MeOH (10 mL) and HCl (H 2 2M in 0, 10 mL) is added. After completion of the reaction, work-up and purification gives 74.

[0260] Example 43: Antiviral activity and cell viability

[0261] Antiviral data were obtained using HEp-2 cells and the 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).

[0262] For antiviral evaluation, HEp-2 cells were plated in 96-well plates at 5 × 10 4 Cells were seeded at 1000 x g / well. All compounds were dissolved in dimethyl sulfoxide at 8 mM and further serially diluted to final concentrations in DMEM containing 0.5% DMSO. Culture supernatants were collected and frozen at -80°C 48 hours post-infection for cell viability analysis and virus titration.

[0263] One day before the virus titration assay, HEp-2 cells were seeded in 96-well tissue culture plates. Virus samples or culture supernatants were titrated in serial half-log 10 dilutions in the corresponding culture medium, and then the diluted viruses were added to the cell plates in quadruplicate. The maximum virus dilution resulting in CPE was recorded, and the 50% tissue culture infectious dose (TCID50) was calculated using the Spearman-Karber method. The results are shown in Figure 3A-D.

[0264] Cytotoxicity assays were also performed using a thiazolyl blue tetrazolium bromide (MTT, Thermo Fisher, Carlsbad, Calif., M6494) cell viability assay after 48 hours of incubation with the compounds, and the results are shown in Figures 4A and 4B.

[0265] The compounds used in Figures 3A-3D, 4A, and 4B are as follows: [ka]

[0266] Although the foregoing has been described in some detail by way of illustration and example for purposes of clarity and understanding, those skilled in the art will understand that certain changes and modifications can be practiced within the scope of the appended claims. Additionally, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference.

Claims

1. A compound of the formula: a pharma- ceutically acceptable salt thereof, or an enantiomer thereof. 【Chemistry 1】 During the ceremony: R １ is a nitrogen-containing monocyclic or bicyclic heterocyclyl; R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ are each independently H, deuterium, hydroxyl, amino, halo, 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 and R ８ , R ９ , R １０ , R １１ , R １２ , and R １３ are each independently H, deuterium, hydroxyl, amino, halo, 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 absent; P ｘ is a monophosphate, diphosphate, triphosphate, C2-6 acyl, or phosphate prodrug moiety; Each dashed line represents a single or double bond, provided that only one double bond is present.

2. 2. The compound of claim 1 comprising the structure of the following formula: or a pharma- ceutically acceptable salt thereof. 【Chemistry 2】

3. 3. The compound of claim 1 or claim 2, comprising the structure of the following formula: or a pharma- ceutically acceptable salt thereof. 【Chemistry 3】

4. 4. The compound of claim 3, comprising the structure of the following formula: or a pharma- ceutically acceptable salt thereof. 【Chemistry 4】

5. 5. The compound of claim 3 or claim 4, comprising the structure of the following formula: or a pharma- ceutically acceptable salt thereof. 【Chemistry 5】

6. 6. The compound of claim 5, comprising the structure of the following formula: or a pharma- ceutically acceptable salt thereof. 【Chemistry 6】

7. 3. The compound of claim 1 or claim 2, comprising the structure of the following formula: or a pharma- ceutically acceptable salt thereof. 【Chemistry 7】

8. 3. The compound of claim 1 or claim 2, comprising the structure of the following formula: or a pharma- ceutically acceptable salt thereof. 【Chemistry 8】

9. 3. The compound of claim 1 or claim 2, comprising the structure of the following formula: or a pharma- ceutically acceptable salt thereof. 【Chemistry 9】

10. 10. The compound of claim 9, comprising the structure of the following formula: or a pharma- ceutically acceptable salt thereof. 【Chemistry 10】

11. 11. The compound of claim 9 or claim 10, comprising the structure of the following formula: or a pharma- ceutically acceptable salt thereof. 【Chemistry 11】

12. R ２ , R ３ , R ４ , and R ５ are each 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 and R ６ and R ７ are each 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 , an optionally substituted carboxylate, or OP ｘ and P ｘ are monophosphate, diphosphate, triphosphate, C ２～６ an acyl, or phosphate prodrug moiety; R ｘ are each independently H, hydroxyl, amino, halo, 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; The compound according to any one of claims 1 to 11.

13. 3. The compound of claim 1 or claim 2, comprising the structure of the following formula: or a pharma- ceutically acceptable salt thereof. 【Chemistry 12】 During the ceremony: R １ is an optionally substituted nitrogen-containing monocyclic or bicyclic heterocyclyl; 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 are each independently H, deuterium, hydroxyl, amino, halo, 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 and In the formula, P ｘ is a monophosphate, diphosphate, triphosphate, C2-6 acyl, or phosphate prodrug moiety.

14. 14. The compound of claim 13, comprising the structure of the following formula: or a pharma- ceutically acceptable salt thereof. 【Chemistry 13】 During the ceremony: R １ is an optionally substituted nitrogen-containing monocyclic or bicyclic heterocyclyl; R １０ , R １１ , R １２ , and R １３ are each 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 are each 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 and P ｘ is a monophosphate, diphosphate, triphosphate, C2-6 acyl, or phosphate prodrug moiety; R ｘ are each independently H, hydroxyl, amino, halo, 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. 15. The compound of claim 13 or claim 14, comprising the structure of the following formula: or a pharma- ceutically acceptable salt thereof. 【Chemistry 14】

16. R １ Adenine, guanine, cytosine, N ４ 16. The compound according to any one of claims 1 to 15, wherein the compound is selected from the group consisting of -hydroxycytosine, thymine, uracil, pyrrolo[2,1-f][1,2,4]triazine-4-amine, and 1,2,4-triazole-3-carboxamide, or a pharma- ceutically acceptable salt thereof.

17. R １ is adenine, cytosine, and N ４ -hydroxycytosine or a pharma- ceutically acceptable salt thereof.

18. R １ The compound according to any one of claims 1 to 15, wherein: 【Chemistry 15】 During the ceremony, X and R ａ are each 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 and R ｘ are each independently H, hydroxyl, amino, halo, 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; Y is N or C.

19. X and R ａ are each independently H, deuterium, hydroxyl, Cl, F, N(R ｘ ) ２ , or R ｘ and R ｘ are each independently H, hydroxyl, amino, halo, 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; Y is N or C; 19. The compound of claim 18.

20. R １ 20. The compound of claim 18 or claim 19, wherein: 【Chemistry 16】

21. R １ The compound according to any one of claims 1 to 14, wherein: 【Chemistry 17】 During the ceremony: R ａ are each 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 and R ｘ are each independently H, hydroxyl, amino, halo, 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 carboxyl, or optionally substituted heteroaryloxy.

22. R １ 22. The compound of claim 21 , wherein: 【Chemistry 18】

23. R １ The compound according to any one of claims 1 to 14, wherein: 【Chemistry 19】 During the ceremony: R ａ is 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 , or NOR ｘ and R ｘ are each independently H, hydroxyl, amino, halo, 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. R １ 24. The compound of claim 23, wherein: 【Chemistry 20】

25. P ｘ 25. The compound of any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof, wherein: is a phosphate prodrug moiety.

26. 26. The compound of claim 25, or a pharma- ceutically acceptable salt thereof, wherein the phosphate prodrug moiety is selected from the group consisting of phosphonic acids, carbonyloxymethyl phosphates, S-acyl-2-thioethyl phosphates, S-[(2-hydroxyethyl)]sulfidyl]-thioethyl phosphates, cyclosaligenyl phosphate diesters, cyclic 1-aryl-1,3-propanyl phosphate diesters, alkoxyalkyl phosphates, aryloxy phosphoramidates, aryloxy phosphonamidates, amino acid phosphoramidates, amino acid phosphonamidates, and methylaryl haloalkyl phosphoramidates.

27. A compound comprising one of the following formulas or a pharma- ceutically acceptable salt thereof: 【Chemistry 21】

28. A compound comprising one of the following formulas or a pharma- ceutically acceptable salt thereof: 【Chemical 22】

29. 30. The compound of claim 28 comprising the formula: or a pharma- ceutically acceptable salt thereof. 【Chemistry 23】

30. 30. The compound of claim 28 comprising the formula: or a pharma- ceutically acceptable salt thereof. 【Chemistry 24】

31. 30. The compound of claim 28 comprising the formula: or a pharma- ceutically acceptable salt thereof. 【Chemistry 25】

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

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

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

35. 35. The method of claim 33 or claim 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. 36. The method of claim 35, wherein the coronavirus infection is a SARS-CoV-2 infection.

37. 36. 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. 39. The method of any one of claims 33 to 38, further comprising administering one or more agents selected from the group consisting of anti-inflammatory agents, analgesics, and antiviral agents.

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

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