4apos as an antiviral agent; -substituted nucleosides and nucleotides

Abstract

The present application provides nucleoside analog compounds of Formula I-V for use in the treatment of dengue (DF). The present application further provides compositions and combinations thereof and methods of treating dengue fever using the nucleoside compounds of Formula I-V and compositions and combinations thereof.

Description

Cross Reference to Related Applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 498,910, filed April 28, 2023, which is hereby incorporated by reference in its entirety. TECHNICAL FIELD

[0002] The present application provides nucleoside analog compounds of Formulae I-V for the treatment of dengue fever (DF). The present application further provides compositions and combinations thereof and methods of using the nucleoside compounds of Formulae I-V and compositions and combinations thereof for the treatment of dengue fever. BACKGROUND

[0003] Dengue fever is an acute febrile illness caused by one of four closely related viral serotypes (DENV-1, DENV-2, DENV-3, and DENV-4). Dengue fever is classified according to its clinical features into classic dengue fever or more severe forms, i.e., dengue hemorrhagic fever syndrome (DHF) and dengue shock syndrome (DSS). Recovery from infection with one serotype confers lifelong immunity to that particular serotype, but provides only transient and limited protection against any of the other serotypes. Dengue fever is a member of the Flaviviridae family of enveloped, positive-sense RNA viruses, whose human pathogens also include the West Nile virus (WNV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), and tick-borne encephalitis virus (TBEV), among others. Dengue fever transmission occurs primarily via the bite of infected Aedes aegypti mosquitoes, which are now found throughout the tropics and subtropics of the world.

[0004] Annual regional dengue epidemics cause significant morbidity and mortality, social disruption, and heavy economic burden in terms of hospitalization and mosquito control in affected societies. Dengue fever is considered by the World Health Organization (WHO) to be the most important arthropod-borne viral disease, with an estimated 50 million dengue fever infections, including 500,000 cases of DHF and 24,000 deaths, worldwide each year. The WHO estimates that 40 percent of the world’s population (2.5 billion people) are at risk for DF, DHF, and DSS. Dengue virus is also an NIAID Category A pathogen and poses a significant threat to U.S. military personnel stationed overseas from a biodefense perspective. Dengue fever is an emerging threat in North America, with a dramatic increase in severe disease over the past 25 years, including large-scale epidemics in Cuba and Venezuela and outbreaks in Texas and Hawaii.

[0005] Failure to control mosquito vectors and increased long-distance travel have contributed to the increase and spread of dengue disease. As a viral hemorrhagic fever virus (arthropod-borne, widely spread, and capable of inducing massive cell damage and triggering an immune response that can lead to severe hemorrhage, shock, and death), dengue poses a unique threat to deployed military personnel and travelers to tropical regions worldwide. To address the bio-defense and public health challenges posed by dengue, new vaccines and antiviral therapies will need to be developed.

[0006] Dengue causes several diseases, the severity of which depends in part on prior infection with different serotypes of the virus. Classic dengue fever (DF) begins 3-8 days after the bite of an infected mosquito and is characterized by sudden onset of fever, headache, backache, joint pains, a measles-like rash, and nausea and vomiting. DF is often referred to as "break-bone" fever because of these symptoms. The disease usually resolves after two weeks, but recovery is prolonged and often accompanied by weakness and depression.

[0007] DHF is a more severe form of the disease that is similar to dengue in its onset and early stages. However, soon after onset, the disease exhibits high fever, liver enlargement, and signs of hemorrhage due to vascular permeability (such as nosebleeds, bleeding in the mouth, and internal organ bleeding). In DSS, circulatory collapse and hypovolemic shock due to plasma leakage occur, and can lead to death within 12-24 hours without plasma replacement. The fatality rate of DHF / DSS can be as high as 20% if left untreated. DHF has become a leading cause of childhood hospitalization and death in many countries, with an estimated 500,000 hospitalizations per year and a mortality rate of about 5%.

[0008] The pathogenesis of DHF / DSS is still under investigation, but is thought to be related in part to heterotypic antibody-enhanced viral replication in macrophages, a phenomenon known as antibody-dependent enhancement (ADE). Specifically, during secondary infection with a different serotype of dengue virus, non-neutralizing, cross-reactive antibodies form virus-antibody complexes that facilitate Fc-mediated uptake of the virus into monocytes and Langerhans cells (dendritic cells), increasing the number of infected cells. This leads to the activation of cytotoxic lymphocytes, which can cause plasma leakage and the hemorrhagic features characteristic of DHF and DSS. This antibody-dependent enhancement of infection is one reason it has been so difficult to develop a successful vaccine. Although less common, DHF / DSS can occur after primary infection, so viral virulence and immune activation are also thought to contribute to the pathogenesis of the disease.

[0009] Dengue fever is endemic in over 100 countries in Africa, the Americas, the Eastern Mediterranean, South-East Asia and the Western Pacific. During epidemics, attack rates can be as high as 80-90% of the susceptible population. All four serotypes of the virus are present worldwide, increasing the number of cases of the disease and the number of outbreaks. For example, in 2002, 1,015,420 cases of dengue fever were reported in the Americas, of which 14,374 were DHF, more than three times the number of dengue cases reported in the Americas in 1995.

[0010] The dengue virus genome consists of a linear single-stranded positive sense RNA of approximately 11 kb in length. This genome is capped and does not have a poly(A) tail at the 3' end, but rather a stable stem loop structure necessary for the stability and replication of the viral genomic RNA. Three structural proteins, the nucleocapsid protein (C), the membrane associated protein (M) and the envelope protein (E), surround the viral RNA and constitute the virion.

[0011] During infection, the virus binds to a cellular receptor via the E protein and undergoes receptor-mediated endocytosis, followed by low pH fusion in the lysosome. The virion then uncoats, releasing the viral RNA in the cytoplasm and translating into a single viral precursor polyprotein. The polyprotein consists of the three structural proteins C, M and E and seven non-structural (NS) proteins. The precursor polyprotein is cleaved by cellular proteases to separate the structural proteins, while a viral-encoded protease cleaves the non-structural region of the polyprotein. Both co- and post-translational proteolytic processing separate the viral proteins. Specifically, the structural proteins are primarily involved in virion formation, while the non-structural proteins are involved in viral RNA replication and viral assembly as well as immune modulation and contribute to the pathogenesis of the disease.

[0012] The non-structural protein 5 (NS5) constitutes an RNA-dependent RNA polymerase that, together with a cofactor, synthesizes a negative strand RNA that serves as a template for the synthesis of a positive strand progeny RNA. Viral replication is membrane-associated and occurs in a specific ER-derived subcellular compartment. After replication, the genome is encapsidated and the immature virus, surrounded by a lipid envelope, buds into the ER lumen, traffics through the TGN where the envelope proteins are glycosylated, and finally is released as a mature virus at the cell surface.

[0013] Essential stages or processes during the viral life cycle can be possible targets for inhibition by antiviral drugs and include the binding of the virus to the cell via the E protein, the uptake of the virus into the cell, the capping mechanism, the viral proteases, the viral RNA-dependent RNA polymerase and the viral helicase.

[0014] Current management of dengue virus-related diseases relies solely on vector control. No antiviral drugs or vaccines have been approved for the treatment or prevention of dengue fever.

[0015] Ribavirin is a guanosine analog that has shown to be effective against a range of RNA viral infections and exerts anti-dengue effect in tissue culture by inhibiting dengue 2'-0-methyltransferase NS5 domain. However, ribavirin has not shown protection against dengue in mouse models or rhesus monkey models, instead it induced anemia and thrombocytosis. While some antiviral drug candidates targeting DENV NS4B are currently in clinical trials (i.e. JNJ-1802, NITD-688), none have been approved for treatment and the possibility of emergence of resistance to directly acting antivirals is a serious and persistent threat for RNA viruses. This can only be overcome by developing antiviral molecules with alternative mechanisms of action, thus there is an urgent need for further development of antiviral drug candidates targeting this pathogen.

[0016] While there are currently two approved vaccines available (Dengvaxia and QDENGA). Dengvaxia is only recommended for people who have had dengue before. QDENGA was recently approved in Indonesia and the European Union. Overall, multivalent dengue vaccines have shown some limited potential in humans, due to the presence of four different viral serotypes, each of which causes disease, which presents a challenge. Vaccine development also faces the challenge of ADE, where unequal protection against the four viral serotypes can actually increase the risk of more severe disease.

[0017] Therefore, there is a need to develop antiviral drugs that target all dengue virus serotypes. Antiviral drugs that inhibit viral replication early during dengue infection will prevent high viral loads associated with DHF and are a strategy worth considering for the treatment and prevention of the disease. Antiviral drugs that inhibit viral replication can be administered as a prophylactic measure before traveling to dengue-endemic areas to prevent infection with the disease, or for people who have been previously exposed to dengue virus, to prevent infection with another viral serotype and reduce the chances of developing life-threatening DHF and DSS. Having an antiviral drug will also aid vaccine development as a ready tool to treat complications that can arise due to unequal immunoprotection against different serotypes. While a successful vaccine can be a key component of effective biological defense, the typical delay in the onset of immunity associated with mass civilian vaccination against low-threat risk factors, potential side effects, cost, and logistics suggest that a comprehensive biological defense includes a separate rapid response element.

[0018] Therefore, it is apparent and has long been a need to develop effective therapies for treating dengue virus. In particular, there is a need to develop compounds that can be used to treat patients infected with dengue and compounds that selectively inhibit dengue virus replication. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 Summary of antiviral activity of Example 1 and other known nucleoside compounds (Nucs).

[0020] Figure 2 Comparison of selective antiviral activity of compound 58 and AL-611. SUMMARY

[0021] The present disclosure provides a compound of Formula (I) wherein: R 1 is selected from H, -C(=0)(Ci-C6)alkyl, -C(=0)(Ci-C6)heteroalkyl, -C(=0)(C3-C7)cycloalkyl, -C(=0)(Ci-C6)alkyl(C3-C7)cycloalkyl, -C(=0)(C3-C7)heterocycloalkyl, -C(=0)(Ci-C6)alkyl(C3-C7)heterocycloalkyl, -C(=0)(C6-Cio)aryl, -C(=0)(Ci-C6)alkyl(C6-Cio)aryl, -C(=0)(C5-C8)heteroaryl, -C(=0)(Ci-C6)alkyl(C5-C8)heteroaryl, -C(=0)CH(NH2)(Ci-C6)alkyl, -C(=0)CH(NH(Ci-C6)alkyl)(Ci-C6)alkyl, -C(=0)CH(N((Ci-C6)alkyl)2)(Ci-C6)alkyl, -C(=0)CH(NH2)(Ci-C6)alkyl(C6-Cio)aryl, -C(=0)CH(NH(Ci-C6)alkyl)(Ci-C6)alkyl(C6-Cio)aryl, -C(=0)CH(N((Ci-C6)alkyl)2)(Ci-C6)alkyl(C6-Cio)aryl, -P(=0)(OR 10 )2, -P(=0)(OR 10 )-P(=0)(OR 10 )2, -P(=0)(OR 10 )-P(=0)(OR 10 )2, -P(=0)(OR 1’ )NH(Ci-C6)alkyl, -P(=0)(OR 1’ )NH(Ci-C6)heteroalkyl, -P(=0)(OR 1’ )NH(Ci-C6)haloalkyl, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’)NH(C3-C7)heterocycloalkyl, -P(=0)(OR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 10 )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 10 )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 10 )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 10 )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 10 )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 10 )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 10 )NH(C3-C7)heterocycloalkyl, -P(=0)(OR1’ )NH(C1-C6)alkyl-C(=0)0-(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl-C(=0)0-(C6-C 10 )aryl and -P(=0)(OR 1’ )NH(C1-C6)haloalkyl-C(=0)0-(C6-C 10 )aryl; each R 1’ is independently H, -(C1-C6)alkyl, -(C1-C6)heteroalkyl, -(C1-C6)haloalkyl, -(C2-C6)alkenyl, -(C2-C6)heteroalkenyl, -(C2-C6)haloalkenyl, -(C2-C6)alkynyl, -(C2-C6)heteroalkynyl, -(C2-C6)haloalkynyl, -(C3-C7)cycloalkyl, -(C3-C7)heterocycloalkyl, -(C6-C 10 )aryl, -(C1-C6)alkyl(C6-C 10 )aryl, -(C5-C8)heteroaryl, or -(C1-C6)alkyl(C5-C8)heteroaryl; R 2a is H, halo, (C1-C6)alkyl, or -CºCH; R 2b is independently halo or OH; R 3 is independently H or OH; R 4 is N3, halo, -CºN, (C1-C3)haloalkyl, or -0(C1-C6)alkyl; R 5 is H, halo, -CºN, (C1-C6)alkyl, hetero(C1-C6)alkyl, hydroxy(C1-C6)alkyl, N(R 1’ )2, -C(=0)NH2; R 6 is H, halo, NH2, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; R 7 is H, NH2, OH, halo, oxo, N(R 1’ )2, or -0(C1-C6)alkyl; and R 8 is H or halo; provided that the compound of Formula I is not 4-amino-7-((2R,3R,4S,5S)-5-fluoro-3,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5- carboxamide; 4-amino-7-((2R,3R,4S,5R)-5-azido-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; 4-amino-7-((2R,3R,4S,5S)-3-ethynyl-5-fluoro-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile; ((5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-ethynyl-2-fluoro-3,4-dihydroxytetrahydrofuran-2- yl)methyl)triphosphonic acid; ((5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-ethynyl-2-fluoro-3,4- dihydroxytetrahydrofuran-2-yl)methyl)triphosphonic acid; (5-(4-amino-5-carbamoyl-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-4-ethynyl-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrotriphosphonate; (5-(4-amino-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-ethynyl-2- fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrotriphosphonate; 4-amino-7-((2R,3R,4S,5S)-3-ethynyl-5-fluoro-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-ethynyl-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; or (2S,3S,4R,5R)-5-(4-amino-5-fluoro-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-4-ethynyl-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; including enantiomers, racemic and non-racemic mixtures, and further including pharmaceutically acceptable salts thereof.

[0022] The present disclosure further provides compounds having the formula (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol.

[0023] The disclosure further provides a compound having the formula ((R)-(((2S,3R,4S,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-chloro-2,4-difluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester.

[0024] The disclosure further provides a pharmaceutical composition comprising a compound as described in any one of embodiments 1-38 (below) in admixture with a pharmaceutically acceptable carrier, diluent, or excipient.

[0025] The disclosure further provides the above pharmaceutical composition further comprising one or more therapeutic compounds or compositions.

[0026] The disclosure further provides the above pharmaceutical composition wherein the one or more therapeutic compounds or compositions is a second antiviral compound or composition.

[0027] The disclosure further provides a method of inhibiting an RNA-dependent RNA polymerase comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described in any one of embodiments 1-38 (below) or a pharmaceutical composition as described in embodiments 39-43 (below).

[0028] The disclosure further provides a method of preventing, ameliorating, or treating an RNA viral infection comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described in any one of embodiments 1-38 (below) or a pharmaceutical composition as described in embodiments 39-43 (below).

[0029] The disclosure further provides the above method wherein the RNA viral infection is at least one virus selected from the group consisting of dengue virus, severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, Zika virus, yellow fever virus, Ebola (Makona) virus, Ebola (Kikwit) virus, O'nyong'nyong virus, Sudan virus, Marburg virus, respiratory syncytial virus (RSV), Nipah virus, measles virus, parainfluenza virus, Middle East respiratory syndrome (MERS) virus, hepatitis C virus (HCV), West Nile virus, Lassa virus, influenza, HRV, MEV, LCMV, polio, CHIKV, COXV, and Junin virus.

[0030] The disclosure further provides the above method wherein the RNA viral infection is caused by dengue virus, SARS-CoV-2 virus, yellow fever virus, or Zika virus. DETAILED DESCRIPTION

[0031] RNA-dependent RNA polymerases (RdRp) are important therapeutic targets for treating diseases caused by RNA viruses because RdRp is an enzyme essential for replication of the viral RNA genome and the host lacks a functional equivalent. Nucleoside and nucleotide analogs are well reported as successful antiviral strategies targeting RdRp (i.e. sofosbuvir and remdesivir). Nucleoside analogs are converted to active 5'-triphosphate metabolites that in turn inhibit viral replication.

[0032] We disclose herein that we discovered 4'-substituted nucleosides and nucleotides with good antiviral activity against dengue virus (DENV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). From the screen, kCBN048 was identified with high antiviral potency against DENV and SARS-CoV-2, but was significantly cytotoxic. NITD-008 (kCMY389) is a reported kCBN analog with a 2'-beta-methyl substitution and showed a selectivity improvement (SI kCMY389 = 52 vs SI kCBN048 = 2, DENV-2 HepG2 assay, Figure 1 ). NITD-008 showed good efficacy in a mouse model of DENV infection, but failed in a two-week toxicity study. 1 Our strategy was to utilize a 4'-substitution to improve the selectivity and activity of kCBN. Compound 1 with a 4'-F showed an activity and selectivity improvement (SI 化合物1 = 73 vs SI kCBN048 = 2, SI kCMY389 = 52; DENV2 HepG2 assay, Table 1). Compound 1 and its analogs are useful for treating DENV, COVID-19, and other RNA viral infections. SAR studies are ongoing around the nucleobase, sugar ring, and prodrug strategies to improve selectivity, activity, and physicochemical properties. For example, compound 1 was found to be more effective than RDV parent nucleoside and N-hydroxycytidine in flaviviruses (DENV-2, ZIKV, YFV), respiratory viruses (SARS-CoV-2, SARS-CoV-1, MERS-CoV, HCoV-OC43, HCoV-229E, HRV14, HRV16, MEV, RSV A2, influenza A H1N1, alphavirus CHIKV), and enteroviruses (polio PV-1, polio PV-3, COXV-B3) Figure 1 ). Additionally, compound 58 was found to be more effective than AL-611 in HRV-14, HRV-16, and DENV-2 Figure 2 ).

[0033] There are no antiviral therapeutics for dengue fever in the market today. While remdesivir and molnupiravir are FDA approved for antiviral therapy for COVID-19 with the same MOA, remdesivir has to be administered by intravenous (IV) infusion and molnupiravir is reported to have potential mutagenic toxicity. There is a need to develop new antiviral drugs (oral drugs) with better safety and patient compliance. Lead compound 1 shows improved activity and selectivity compared to known compounds with the same mechanism of action (MOA) for DENV and SARS-CoV-2.

[0034] Embodiments Embodiment 1. A compound of formula (I) wherein: R 1 is selected from H, -C(=0)(Ci-C6)alkyl, -C(=0)(Ci-C6)heteroalkyl, -C(=0)(C3-C7)cycloalkyl, -C(=0)(Ci-C6)alkyl(C3-C7)cycloalkyl, -C(=0)(C3-C7)heterocycloalkyl, -C(=0)(Ci-C6)alkyl(C3-C7)heterocycloalkyl, -C(=0)(C6-Cio)aryl, -C(=0)(Ci-C6)alkyl(C6-Cio)aryl, -C(=0)(C5-C8)heteroaryl, -C(=0)(Ci-C6)alkyl(C5-C8)heteroaryl, -C(=0)CH(NH2)(Ci-C6)alkyl, -C(=0)CH(NH(Ci-C6)alkyl)(Ci-C6)alkyl, -C(=0)CH(N((Ci-C6)alkyl)2)(Ci-C6)alkyl, -C(=0)CH(NH2)(Ci-C6)alkyl(C6-Cio)aryl, -C(=0)CH(NH(Ci-C6)alkyl)(Ci-C6)alkyl(C6-Cio)aryl, -C(=0)CH(N((Ci-C6)alkyl)2)(Ci-C6)alkyl(C6-Cio)aryl, -P(=0)(OR 10 )2, -P(=0)(OR 10 )-P(=0)(OR 10 )2, -P(=0)(OR 10 )-P(=0)(OR 10 )2, -P(=0)(OR 1’ )-P(=0)(OR 1’ )2, -P(=0)(OR 1’ )-P(=0)(OR 1’ )2, -P(=0)(OR 1’ )-P(=0)(OR 1’ )2, -P(=0)(OR 1’)NH(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl, -P(=0)(OR 1’ )NH(C1-C6)haloalkyl, -P(=0)(OR 1’ )NH(C3-C7)cycloalkyl, -P(=0)(OR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 1’ )NH(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C5-C8)heteroaryl, -P(=0)(OR 1’ )NH(C1-C6)alkyl(C5-C8)heteroaryl, -P(=0)(OR 1’ )NH(C1-C6)alkyl, -P(=0)(NHR 1’ )NH(C1-C6)heteroalkyl, -P(=0)(NHR 1’ )NH(C1-C6)haloalkyl, -P(=0)(NHR 1’ )NH(C3-C7)cycloalkyl, -P(=0)(NHR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(NHR 1’ )NH(C6-C 10 )aryl, -P(=0)(NHR 1’ )NH(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(NHR 1’ )NH(C5-C8)heteroaryl, -P(=0)(NHR 1’ )NH(C1-C6)alkyl(C5-C8)heteroaryl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)haloalkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’)NH(Ci-C6)heteroalkyl-C(=0)0-(Ci-C6)alkyl(C6-Ci0)aryl; 10 )aryl, -P(=0)(OR 1’ )NH(Ci-C6)heteroalkyl-C(=0)0-(Ci-C6)alkyl(C6-Ci0)aryl; 10 )aryl, -P(=0)(OR 1’ )NH(Ci-C6)heteroalkyl-C(=0)0-(Ci-C6)alkyl(C6-Ci0)aryl; 10 )aryl, -P(=0)(OR 1’ )NH(Ci-C6)heteroalkyl-C(=0)0-(Ci-C6)alkyl(C6-Ci0)aryl; 10 )aryl, -P(=0)(OR 1’ )NH(Ci-C6)heteroalkyl-C(=0)0-(Ci-C6)alkyl(C6-Ci0)aryl; 10 )aryl; each R 1’ is independently H, -(Ci-C6)alkyl, -(Ci-C6)heteroalkyl, -(Ci-C6)haloalkyl, -(C2-C6)alkenyl, -(C2-C6)heteroalkenyl, -(C2-C6)haloalkenyl, -(C2-C6)alkynyl, -(C2-C6)heteroalkynyl, -(C2-C6)haloalkynyl, -(C3-C7)cycloalkyl, -(C3-C7)heterocycloalkyl, -(C6-Ci0)aryl, or -(Cs-C8)heteroaryl; 10 )aryl, -(Ci-C6)alkyl(C6-Ci0)aryl, -(C5-C8)heteroaryl, or -(Ci-C6)alkyl(C5-C8)heteroaryl; 10 )aryl, -(Ci-C6)alkyl(C6-Ci0)aryl, -(C5-C8)heteroaryl, or -(Ci-C6)alkyl(C5-C8)heteroaryl; R 2a is H, halo, (Ci-C6)alkyl, or -C≡CH; R 2b is independently halo or OH; R 3 is independently H or OH; R 4 is N3, halo, -C≡N, (Ci-C3)haloalkyl, or -0(Ci-C6)alkyl; R 5 is H, halo, -C≡N, (Ci-C6)alkyl, hetero(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, N(R 1’ )2, -C(=0)NH2; R 6 is H, halo, NH2, (Ci-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; R 7 is H, NH2, OH, halo, oxo, N(R 1’)2 or -0(C1-C6)alkyl; and R 8 is H or halo; provided that the compound of Formula I is not 4-amino-7-((2R,3R,4S,5S)-5-fluoro-3,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5- carboxamide; 4-amino-7-((2R,3R,4S,5R)-5-azido-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; 4-amino-7-((2R,3R,4S,5S)-3-ethynyl-5-fluoro-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile; ((5-(4- amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-ethynyl-2-fluoro-3,4-dihydroxytetrahydrofuran-2- yl)methyl)triphosphonic acid; ((5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4- ethynyl-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl)triphosphonic acid; (5-(4-amino-5- carbamoyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-ethynyl-2-fluoro-3,4-dihydroxytetrahydrofuran- 2-yl)methyl tetrahydrotriphosphonate; (5-(4-amino-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-4-ethynyl-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrotriphosphonate; 4-amino-7-((2R,3R,4S,5S)-3-ethynyl-5-fluoro-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-ethynyl-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; or (2S,3S,4R,5R)-5-(4-amino-5-fluoro-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-4-ethynyl-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; including enantiomeric, racemic and non-racemic mixtures, and further including pharmaceutically acceptable salts thereof.

[0035] Embodiment 2. A compound of Formula (II) wherein: R 1Selected from H, -C(=O)(C1-C6)alkyl, -C(=O)(C1-C6)heteroalkyl, -C(=O)(C3-C7)cycloalkyl, -C(=O)(C1-C6)alkyl(C3-C7)cycloalkyl, -C(=O)(C3-C7)heteroalkyl, -C(=O)(C1-C6)alkyl(C3-C7)heteroalkyl, -C(=O)(C6-C 10 )aryl, -C(=O)(C1-C6)alkyl(C6-C 10 aryl, -C(=O)(C5-C8)heteroaryl, -C(=O)(C1-C6)alkyl(C5-C8)heteroaryl, -C(=O)CH(NH2)(C1-C6)alkyl, -C(=O)CH(NH(C1-C6)alkyl)(C1-C6)alkyl, -C(=O)CH(N((C1-C6)alkyl)2)(C1-C6)alkyl, -C(=O)CH(NH2)(C1-C6)alkyl(C6-C 10 )aryl, -C(=O)CH(NH(C1-C6)alkyl)(C1-C6)alkyl(C6-C 10 )aryl, -C(=O)CH(N((C1-C6)alkyl)2)(C1-C6)alkyl(C6-C 10 )Aryl, -P(=O)(OR 1’ )2、-P(=O)(OR 1’ )-P(=O)(OR 1’ )2、-P(=O)(OR 1’ )-P(=O)(OR 1’ )-P(=O)(OR 1’ )2、-P(=O)(OR 1’ )NH(C1-C6)alkyl, -P(=O)(OR 1’ )NH(C1-C6) heteroalkyl, -P(=O)(OR 1’ )NH(C1-C6) haloalkyl, -P(=O)(OR 1’ )NH(C3-C7)cycloalkyl, -P(=O)(OR 1’ )NH(C3-C7) heterocyclic alkyl, -P(=O)(OR 1’ )NH(C6-C 10 )Aryl, -P(=O)(OR 1’ )NH(C1-C6)alkyl(C6-C 10 )Aryl, -P(=O)(OR 1’ )NH(C5-C8) heteroaryl, -P(=O)(OR 1’ )NH(C1-C6)alkyl(C5-C8)heteroaryl, -P(=O)(NHR 1’)NH(C1-C6)alkyl, -P(=0)(NHR 1’ )NH(C1-C6)heteroalkyl, -P(=0)(NHR 1’ )NH(C1-C6)haloalkyl, -P(=0)(NHR 1’ )NH(C3-C7)cycloalkyl, -P(=0)(NHR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(NHR 1’ )NH(C6-C 10 )aryl, -P(=0)(NHR 1’ )NH(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(NHR 1’ )NH(C5-C8)heteroaryl, -P(=0)(NHR 1’ )NH(C1-C6)alkyl(C5-C8)heteroaryl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)haloalkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl-C(=0)0-(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)haloalkyl-C(=0)0-(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl-C(=0)0-(C6-C 10 )aryl, and -P(=0)(OR 1’ )NH(C1-C6)haloalkyl-C(=0)0-(C6-C 10 )aryl; each R 1’independently H, -(C1-C6)alkyl, -(C1-C6)heteroalkyl, -(C1-C6)haloalkyl, -(C2-C6)alkenyl, -(C2-C6)heteroalkenyl, -(C2-C6)haloalkenyl, -(C2-C6)alkynyl, -(C2-C6)heteroalkynyl, -(C2-C6)haloalkynyl, -(C3-C7)cycloalkyl, -(C3-C7)heterocycloalkyl, -(C6-C10)aryl, -(C1-C6)alkyl(C6-C10)aryl, -(C5-C8)heteroaryl, or -(C1-C6)alkyl(C5-C8)heteroaryl; 10 )aryl, -(C1-C6)alkyl(C6-C 10 )aryl, -(C5-C8)heteroaryl, or -(C1-C6)alkyl(C5-C8)heteroaryl; R 2 is H, (C1-C6)alkyl, or -C≡CH; R 4 is N3, halo, or -O(C1-C6)alkyl; R 5 is H, halo, -C≡N, hetero(C1-C6)alkyl, hydroxy(C1-C6)alkyl, N(R 1’ )2, -C(=O)NH2; R 6 is H, halo, NH2, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; R 7 is H, NH2, OH, halo, N(R 1’ )2, or -O(C1-C6)alkyl; and R 8 is H or halo; with the proviso that the compound of Formula II is not (2S,3S,4R,5S)-5-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol, (2R,3S,4R,5S)-5-(4-amino-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-azido-2- (hydroxymethyl)tetrahydrofuran-3,4-diol, (2R,3S,4R,5S)-5-(4-amino-5-fluoro- pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-azido-2-(hydroxymethyl)tetrahydrofuran-3,4- diol; (2R,3S,4R,5S)-5-(4-amino-pyrrolo[2,1-f][1,2,4]triazin-7-yl-5- d)-2-azido-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-azido-3,4- dihydroxytetrahydrofuran-2-yl)methyl tetrahydrotriphosphate or (((2R,3S,4R,5S)-5-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-azido-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alanine 2-ethylbutyl ester; including enantiomeric, racemic and non-racemic mixtures, and further including pharmaceutically acceptable salts thereof.

[0036] Embodiment 3. A compound of Formula (IIIa) or (IIIb) wherein: R 1 selected from H, -C(=0)(Ci-C6)alkyl, -C(=0)(Ci-C6)heteroalkyl, -C(=0)(C3-C7)cycloalkyl, -C(=0)(Ci-C6)alkyl(C3-C7)cycloalkyl, -C(=0)(C3-C7)heterocycloalkyl, -C(=0)(Ci-C6)alkyl(C3-C7)heterocycloalkyl, -C(=0)(C6-C 10 )aryl, -C(=0)(Ci-C6)alkyl(C6-C 10 )aryl, -C(=0)(C5-C8)heteroaryl, -C(=0)(Ci-C6)alkyl(C5-C8)heteroaryl, -C(=0)CH(NH2)(Ci-C6)alkyl, -C(=0)CH(NH(Ci-C6)alkyl)(Ci-C6)alkyl, -C(=0)CH(N((Ci-C6)alkyl)2)(Ci-C6)alkyl, -C(=0)CH(NH2)(Ci-C6)alkyl(C6-C 10 )aryl, -C(=0)CH(NH(Ci-C6)alkyl)(Ci-C6)alkyl(C6-C 10 )aryl, -C(=0)CH(N((Ci-C6)alkyl)2)(Ci-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )-P(=0)(OR 1’ )2, -P(=0)(OR 1’ )-P(=0)(OR 1’ )-P(=0)(OR 1’ )2, -P(=0)(OR1’ )NH(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl, -P(=0)(OR 1’ )NH(C1-C6)haloalkyl, -P(=0)(OR 1’ )NH(C3-C7)cycloalkyl, -P(=0)(OR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 1’ )NH(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C5-C8)heteroaryl, -P(=0)(OR 1’ )NH(C1-C6)alkyl(C5-C8)heteroaryl, -P(=0)(NHR 1’ )NH(C1-C6)alkyl, -P(=0)(NHR 1’ )NH(C1-C6)heteroalkyl, -P(=0)(NHR 1’ )NH(C1-C6)haloalkyl, -P(=0)(NHR 1’ )NH(C3-C7)cycloalkyl, -P(=0)(NHR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(NHR 1’ )NH(C6-C 10 )aryl, -P(=0)(NHR 1’ )NH(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(NHR 1’ )NH(C5-C8)heteroaryl, -P(=0)(NHR 1’ )NH(C1-C6)alkyl(C5-C8)heteroaryl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)haloalkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’)NH(Ci-C6)heteroalkyl-C(=0)0-(Ci-C6)alkyl(C6-Ci0)aryl; 10 )aryl, -P(=0)(OR 1’ )NH(Ci-C6)heteroalkyl-C(=0)0-(Ci-C6)alkyl(C6-Ci0)aryl; 10 )aryl, -P(=0)(OR 1’ )NH(Ci-C6)heteroalkyl-C(=0)0-(Ci-C6)alkyl(C6-Ci0)aryl; 10 )aryl, -P(=0)(OR 1’ )NH(Ci-C6)heteroalkyl-C(=0)0-(Ci-C6)alkyl(C6-Ci0)aryl; 10 )aryl, -P(=0)(OR 1’ )NH(Ci-C6)heteroalkyl-C(=0)0-(Ci-C6)alkyl(C6-Ci0)aryl; 10 )aryl; each R 1’ is independently H, -(Ci-C6)alkyl, -(Ci-C6)heteroalkyl, -(Ci-C6)haloalkyl, -(C2-C6)alkenyl, -(C2-C6)heteroalkenyl, -(C2-C6)haloalkenyl, -(C2-C6)alkynyl, -(C2-C6)heteroalkynyl, -(C2-C6)haloalkynyl, -(C3-C7)cycloalkyl, -(C3-C7)heterocycloalkyl, -(C6-Ci0)aryl, -(C5-C8)heteroaryl, or -(Ci-C6)alkyl(C6-Ci0)aryl; 10 )aryl, -(Ci-C6)alkyl(C6-Ci0)aryl, -(C5-C8)heteroaryl, or -(Ci-C6)alkyl(C5-C8)heteroaryl; 10 )aryl, -(Ci-C6)alkyl(C6-Ci0)aryl, -(C5-C8)heteroaryl, or -(Ci-C6)alkyl(C5-C8)heteroaryl; R 2a is H, OH, halo, (Ci-C6)alkyl, or -C≡CH; R 2b is H, OH, halo, or (Ci-C6)alkyl; R 3a is H, OH, halo, or (Ci-C6)alkyl; R 3b is H, OH, halo, or (Ci-C6)alkyl; R 4 is N3, halo, -C≡N, (Ci-C3)haloalkyl, or -0(Ci-C6)alkyl; R 6 and R 6’ are each independently halo, NH2, NH(Ci-C6)alkyl, N((Ci-C6)alkyl)2, -OH, -0(Ci-C6)alkyl, -oxo, or -C≡CH; and R 8 is H or halo; provided that the compound of Formula III is not (((2R,3S,4R,5R)-5-(2,6-diamino-9H-purin-9-yl)-2-(difluoromethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl) triphosphate; (((2S,3S,4R,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-4-ethynyl-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl) triphosphate; (2S,3S,4R,5R)-5-(2,6-diamino-9H-purin-9-yl)-2-fluoro-2-(hydroxymethyl)-4-methyltetrahydrofuran-3,4-diol; or (2S,3S,4R,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-4-ethynyl-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; including enantiomeric, racemic and non-racemic mixtures, and further including pharmaceutically acceptable salts thereof.

[0037] Embodiment 4. A compound of Formula (IV) wherein: R 1 selected from H, -C(=0)(Ci-C6)alkyl, -C(=0)(Ci-C6)heteroalkyl, -C(=0)(C3-C7)cycloalkyl, -C(=0)(Ci-C6)alkyl(C3-C7)cycloalkyl, -C(=0)(C3-C7)heterocycloalkyl, -C(=0)(Ci-C6)alkyl(C3-C7)heterocycloalkyl, -C(=0)(C6-C 10 )aryl, -C(=0)(Ci-C6)alkyl(C6-C 10 )aryl, -C(=0)(C5-C8)heteroaryl, -C(=0)(Ci-C6)alkyl(C5-C8)heteroaryl, -C(=0)CH(NH2)(Ci-C6)alkyl, -C(=0)CH(NH(Ci-C6)alkyl)(Ci-C6)alkyl, -C(=0)CH(N((Ci-C6)alkyl)2)(Ci-C6)alkyl, -C(=0)CH(NH2)(Ci-C6)alkyl(C6-C 10 )aryl, -C(=0)CH(NH(Ci-C6)alkyl)(Ci-C6)alkyl(C6-C 10 )aryl, -C(=0)CH(N((Ci-C6)alkyl)2)(Ci-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(Ci-C6)alkyl, -P(=0)(OR 1’ )NH(Ci-C6)heteroalkyl, -P(=0)(OR1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 10 )2, -P(=0)(OR 1’ )2, -P(=0)(OR 10 )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 10 )2, -P(=0)(OR 1’ )2, -P(=0)(OR 10 )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR)NH(Ci-C6)alkyl-C(=0)0-(Ci-C6)alkyl(C6-Ci0)aryl; 10 )NH(Ci-C6)alkyl-C(=0)0-(Ci-C6)alkyl(C6-Ci0)aryl; 1’ )NH(Ci-C6)alkyl-C(=0)0-(Ci-C6)alkyl(C6-Ci0)aryl; 10 )NH(Ci-C6)alkyl-C(=0)0-(Ci-C6)alkyl(C6-Ci0)aryl; 1’ )NH(Ci-C6)alkyl-C(=0)0-(Ci-C6)alkyl(C6-Ci0)aryl; 10 )NH(Ci-C6)alkyl-C(=0)0-(Ci-C6)alkyl(C6-Ci0)aryl; 1’ )NH(Ci-C6)alkyl-C(=0)0-(Ci-C6)alkyl(C6-Ci0)aryl; 10 )NH(Ci-C6)alkyl-C(=0)0-(Ci-C6)alkyl(C6-Ci0)aryl; 1’ )NH(Ci-C6)alkyl-C(=0)0-(Ci-C6)alkyl(C6-Ci0)aryl; 10 )NH(Ci-C6)alkyl-C(=0)0-(Ci-C6)alkyl(C6-Ci0)aryl; 1’ )NH(Ci-C6)alkyl-C(=0)0-(Ci-C6)alkyl(C6-Ci0)aryl; 10 )NH(Ci-C6)alkyl-C(=0)0-(Ci-C6)alkyl(C6-Ci0)aryl; each R 1’ is independently H, -(Ci-C6)alkyl, -(Ci-C6)heteroalkyl, -(Ci-C6)haloalkyl, -(C2-C6)alkenyl, -(C2-C6)heteroalkenyl, -(C2-C6)haloalkenyl, -(C2-C6)alkynyl, -(C2-C6)heteroalkynyl, -(C2-C6)haloalkynyl, -(C3-C7)cycloalkyl, -(C3-C7)heterocycloalkyl, -(C6-Ci0)aryl, -(C5-C8)heteroaryl, or -(Ci-C6)alkyl(C6-Ci0)aryl; 10 is independently H, -(Ci-C6)alkyl, -(Ci-C6)heteroalkyl, -(Ci-C6)haloalkyl, -(C2-C6)alkenyl, -(C2-C6)heteroalkenyl, -(C2-C6)haloalkenyl, -(C2-C6)alkynyl, -(C2-C6)heteroalkynyl, -(C2-C6)haloalkynyl, -(C3-C7)cycloalkyl, -(C3-C7)heterocycloalkyl, -(C6-Ci0)aryl, -(C5-C8)heteroaryl, or -(Ci-C6)alkyl(C6-Ci0)aryl; 10 is independently H, -(Ci-C6)alkyl, -(Ci-C6)heteroalkyl, -(Ci-C6)haloalkyl, -(C2-C6)alkenyl, -(C2-C6)heteroalkenyl, -(C2-C6)haloalkenyl, -(C2-C6)alkynyl, -(C2-C6)heteroalkynyl, -(C2-C6)haloalkynyl, -(C3-C7)cycloalkyl, -(C3-C7)heterocycloalkyl, -(C6-Ci0)aryl, -(C5-C8)heteroaryl, or -(Ci-C6)alkyl(C6-Ci0)aryl; R 4 is N3, halo, or -0(Ci-C6)alkyl; and R 6 is H, halo, (Ci-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; including enantiomers, racemic and non-racemic mixtures, and further including pharmaceutically acceptable salts thereof.

[0038] Embodiment 5. A compound of Formula (V) wherein: R 1Selected from H, -C(=O)(C1-C6)alkyl, -C(=O)(C1-C6)heteroalkyl, -C(=O)(C3-C7)cycloalkyl, -C(=O)(C1-C6)alkyl(C3-C7)cycloalkyl, -C(=O)(C3-C7)heteroalkyl, -C(=O)(C1-C6)alkyl(C3-C7)heteroalkyl, -C(=O)(C6-C 10 )aryl, -C(=O)(C1-C6)alkyl(C6-C 10 aryl, -C(=O)(C5-C8)heteroaryl, -C(=O)(C1-C6)alkyl(C5-C8)heteroaryl, -C(=O)CH(NH2)(C1-C6)alkyl, -C(=O)CH(NH(C1-C6)alkyl)(C1-C6)alkyl, -C(=O)CH(N((C1-C6)alkyl)2)(C1-C6)alkyl, -C(=O)CH(NH2)(C1-C6)alkyl(C6-C 10 )aryl, -C(=O)CH(NH(C1-C6)alkyl)(C1-C6)alkyl(C6-C 10 )aryl, -C(=O)CH(N((C1-C6)alkyl)2)(C1-C6)alkyl(C6-C 10 )Aryl, -P(=O)(OR 1’ )2、-P(=O)(OR 1’ )-P(=O)(OR 1’ )2、-P(=O)(OR 1’ )-P(=O)(OR 1’ )-P(=O)(OR 1’ )2、-P(=O)(OR 1’ )NH(C1-C6)alkyl, -P(=O)(OR 1’ )NH(C1-C6) heteroalkyl, -P(=O)(OR 1’ )NH(C1-C6) haloalkyl, -P(=O)(OR 1’ )NH(C3-C7)cycloalkyl, -P(=O)(OR 1’ )NH(C3-C7) heterocyclic alkyl, -P(=O)(OR 1’ )NH(C6-C 10 )Aryl, -P(=O)(OR 1’ )NH(C1-C6)alkyl(C6-C 10 )Aryl, -P(=O)(OR 1’ )NH(C5-C8) heteroaryl, -P(=O)(OR 1’ )NH(C1-C6)alkyl(C5-C8)heteroaryl, -P(=O)(NHR 1’)NH(C1-C6)alkyl, -P(=0)(NHR 1’ )NH(C1-C6)heteroalkyl, -P(=0)(NHR 1’ )NH(C1-C6)haloalkyl, -P(=0)(NHR 1’ )NH(C3-C7)cycloalkyl, -P(=0)(NHR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(NHR 1’ )NH(C6-C 10 )aryl, -P(=0)(NHR 1’ )NH(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(NHR 1’ )NH(C5-C8)heteroaryl, -P(=0)(NHR 1’ )NH(C1-C6)alkyl(C5-C8)heteroaryl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)haloalkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl-C(=0)0-(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)haloalkyl-C(=0)0-(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl-C(=0)0-(C6-C 10 )aryl, and -P(=0)(OR 1’ )NH(C1-C6)haloalkyl-C(=0)0-(C6-C 10 )aryl; each R 1’independently H, -(C1-C6)alkyl, -(C1-C6)heteroalkyl, -(C1-C6)haloalkyl, -(C2-C6)alkenyl, -(C2-C6)heteroalkenyl, -(C2-C6)haloalkenyl, -(C2-C6)alkynyl, -(C2-C6)heteroalkynyl, -(C2-C6)haloalkynyl, -(C3-C7)cycloalkyl, -(C3-C7)heterocycloalkyl, -(C6-C10)aryl, -(C1-C6)alkyl(C6-C10)aryl, -(C5-C8)heteroaryl, or -(C1-C6)alkyl(C5-C8)heteroaryl; 10 )aryl, -(C1-C6)alkyl(C6-C 10 )aryl, -(C5-C8)heteroaryl, or -(C1-C6)alkyl(C5-C8)heteroaryl; R 2 is H, halo, (C1-C6)alkyl, or -C≡CH; R 4 is N3, halo, -C≡N, (C1-C3)haloalkyl, or -O(C1-C6)alkyl; R 5 is H, halo, -C≡N, hetero(C1-C6)alkyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, N(R 1’ )2, -(C(=O)NH2; R 6 is H, halo, NH2, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; R 7 is H, NH2, OH, halo, N(R 1’ )2, or -O(C1-C6)alkyl; and R 8 is H or halo; including enantiomeric, racemic and non-racemic mixtures, and further including pharmaceutically acceptable salts thereof.

[0039] Embodiment 6. The compound of Embodiment 1, wherein R 2b is OH or halo.

[0040] Embodiment 7. The compound of Embodiment 3, wherein R 2b is halo.

[0041] Embodiment 8. The compound of Embodiment 7, wherein R 2a is Me or halo.

[0042] Embodiment 9. The compound of any one of Embodiments 6-8, wherein R 2a is H.

[0043] Embodiment 10. The compound of any one of Embodiments 6-8, wherein R2a It is a (C1-C6) alkyl group.

[0044] Implementation Scheme 11. The compound as described in Implementation Scheme 10, wherein R 2a It's me.

[0045] Implementation Scheme 12. The compound as described in any one of Implementation Schemes 6-8, wherein R 2a It is halogenated.

[0046] Implementation Scheme 13. The compound as described in Implementation Scheme 12, wherein R 2a It is Cl.

[0047] Implementation Scheme 14. The compound as described in any one of Implementation Schemes 2 or 5, wherein R 2 It's H.

[0048] Implementation Scheme 15. The compound as described in any one of Implementation Schemes 2 or 5, wherein R 2 It is halogenated.

[0049] Implementation Scheme 16. The compound as described in Implementation Scheme 15, wherein R 2 It is F.

[0050] Implementation Scheme 17. The compound as described in any one of Implementation Schemes 2 or 5, wherein R 2 It is a (C1-C6) alkyl group.

[0051] Implementation Scheme 18. The compound as described in Implementation Scheme 17, wherein R 2 It's me.

[0052] Implementation Scheme 19. The compound as described in any one of Implementation Schemes 1-2 or 5, wherein R 5 It's H.

[0053] Implementation Scheme 20. The compound as described in any one of Implementation Schemes 1-2 or 5, wherein R 5 It is -CH2OH.

[0054] Implementation Scheme 21. The compound as described in any one of Implementation Schemes 1-2 or 5, wherein R 5 It is -C(=O)NH2.

[0055] Implementation Scheme 22. The compound as described in any one of Implementation Schemes 1, 6-13 or 19-21, wherein R 3 It is OH.

[0056] Implementation Scheme 23. The compound as described in any one of Implementation Schemes 1, 6-13 or 19-21, wherein R 3 It is H.

[0057] Embodiment 24. The compound of any one of embodiments 1-23, wherein R 4 is halo.

[0058] Embodiment 25. The compound of embodiment 24, wherein R 4 is F.

[0059] Embodiment 26. The compound of embodiment 24, wherein R 4 is Cl.

[0060] Embodiment 27. The compound of any one of embodiments 1-23, wherein R 4 is N3.

[0061] Embodiment 28. The compound of any one of embodiments 1-23, wherein R 4 is -O(C1-C6)alkyl.

[0062] Embodiment 29. The compound of embodiment 28, wherein R 4 is -OMe.

[0063] Embodiment 30. The compound of any one of embodiments 1-29, wherein R 6 is H or NH2, and R 6’ is -NH(C1-C6)alkyl or -O(C1-C6)alkyl Embodiment 31. The compound of any one of embodiments 1-29, wherein R 6 is halo.

[0064] Embodiment 32. The compound of embodiment 31, wherein R 6 is F.

[0065] Embodiment 33. The compound of any one of embodiments 1-29, wherein R 6 is -C≡CH.

[0066] Embodiment 34. The compound of any one of embodiments 1-33, wherein R 1 is H.

[0067] Embodiment 35. The compound of any one of embodiments 1-33, wherein R 1 is -P(=O)(OR 1’ )2, -P(=O)(OR 1’ )-P(=O)(OR 1’ )2, or -P(=O)(OR 1’ )-P(=O)(OR1’ )-P(=0)(OR 1’ )2.

[0068] Embodiment 36. The compound of any one of embodiments 1-33, wherein R 1 is -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C1-C6)alkyl.

[0069] Embodiment 37. A compound having a formula selected from any one of: (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-azido-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3S,4R,5S)-5-(4-amino-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-azido-2- (hydroxymethyl)-4-methyltetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3S,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3R,4S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-chloro-2,4- difluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol; (2R,3R,4S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-azido-4-chloro- 4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol; (2R,3R,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-azido-5- (hydroxymethyl)tetrahydrofuran-3-ol; (2R,3S,4R,5S)-5-(4-amino-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-azido-2- (hydroxymethyl)-4-methyltetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3R,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-fluoro-5- (hydroxymethyl)tetrahydrofuran-3-ol; (2R,3R,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-fluoro-5- (hydroxymethyl)tetrahydrofuran-3-ol; (2S,3S,4R,5R)-2-fluoro-5-(4-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; 4-amino-7-((2R,3R,4S,5S)-5-fluoro-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (2S,3S,4R,5R)-5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; 7-((2R,3R,4S,5S)-5-fluoro-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidine-4- one; (2S,3S,4R,5R)-5-(4-amino-5-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(6-amino-2-ethynyl-9H-purin-9-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5S)-5-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (fluoromethyl)-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; 5-fluoro-7-((2R,3R,4S,5S)-5-fluoro-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidine-4- one; (2S,3S,4R,5R)-2-fluoro-5-(5-fluoro-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-2-fluoro-2-(hydroxymethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol; 7-((2R,3R,4S,5S)-5-fluoro-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-7H- pyrrolo[2,3-d]pyrimidine-5-carboxamide; (2S,3S,4R,5R)-5-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; 4-amino-7-((2R,3R,4S,5S)-5-fluoro-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2- yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile; (2S,3S,4R,5R)-5-(2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-2-fluoro-2-(hydroxymethyl)-5-(6-(methylthio)-9H-purin-9-yl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(4-chloro-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; (1S,2S,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-3- (hydroxymethyl)cyclopentane-1,2-diol; (2S,3S,4R,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxy-2- (hydroxymethyl)tetrahydrofuran-2-carbonitrile; (2S,3S,4R,5R)-5-(4-amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; Benzoic acid ((2S,3S,4R,5S)-5-(4-amino-5-aminocarbonylpyrrolo[2,1- f][1,2,4]triazin-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl ester; (2S,3S,4R,5R)-2-fluoro-5-(5-fluoro-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(5-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; 7-((2R,3R,4S,5S)-5-fluoro-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4- oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile; 7-((2R,3R,4S,5S)-5-fluoro-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4- methoxy-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (2R,3R,5R)-5-fluoro-5-(hydroxymethyl)-2-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrofuran-3-ol; (2S,3S,4R,5R)-2-fluoro-2-(hydroxymethyl)-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(4-amino-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; 4-amino-1-((2R,3R,4S,5S)-3-ethynyl-5-fluoro-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one; (2S,3S,4R,5R)-2-((benzoyloxy)methyl)-5-(3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)- yl)-2-fluorotetrahydrofuran-3,4-diyl diacetate; Isobutyric acid ((2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl ester; (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2- ((isobutyryloxy)methyl)tetrahydrofuran-3,4-diyl bis(2-methylpropanoate); ((S)-(((2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester; ((R)-(((2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester; Benzoic acid ((2S,3S,4R,5R)-4-(benzoyloxy)-5-(4-cyano-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-2-fluoro-3-hydroxytetrahydrofuran-2-yl)methyl ester; (2R,3R,4S,5S)-2-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-5-fluoro-3,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile; (2S,3S,4R,5R)-5-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-2-fluoro-2-(hydroxymethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3R,5R)-5-(4-amino-5-(benzo[d]thiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 2,4,4-trifluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol; Benzoic acid ((2S,3S,4R,5R)-5-(2-amino-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl ester; (2S,3R,4S,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-chloro-2,4-difluoro-2- (hydroxymethyl)tetrahydrofuran-3-ol; ((R)-(((2S,3R,4S,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-chloro-2,4-difluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester; ((S)-(((2S,3R,4S,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-chloro-2,4-difluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester; (2S,3R,5R)-5-(2-amino-6-ethoxy-9H-purin-9-yl)-2,4,4-trifluoro-2- (hydroxymethyl)tetrahydrofuran-3-ol; ((((2S,3R,5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-2,4,4-trifluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester; 2-amino-9-((2R,3R,4R,5S)-3-chloro-5-fluoro-4-hydroxy-5-(hydroxymethyl)-3- methyltetrahydrofuran-2-yl)-1,9-dihydro-6H-purin-6-one; (2S,3R,4R,5R)-5-(2-amino-6-ethoxy-9H-purin-9-yl)-4-chloro-2-fluoro-2- (hydroxymethyl)-4-methyltetrahydrofuran-3-ol; ((((2S,3R,4R,5R)-5-(2-amino-6-ethoxy-9H-purin-9-yl)-4-chloro-2-fluoro-3- hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester; ((((2S,3S,4R,5R)-5-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-2-fluoro-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)-L-alanine neopentyl ester; (2S,3R,4S,5R)-5-(2-amino-6-ethoxy-9H-purin-9-yl)-4-chloro-2,4-difluoro-2- (hydroxymethyl)tetrahydrofuran-3-ol; ((((2S,3R,4S,5R)-5-(2-amino-6-ethoxy-9H-purin-9-yl)-4-chloro-2,4-difluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester; 2S,3R,4S,5R)-5-(2-amino-6-ethoxy-9H-purin-9-yl)-4-bromo-2,4-difluoro-2- (hydroxymethyl)tetrahydrofuran-3-ol; ((((2S,3R,5R)-5-(2-amino-6-ethoxy-9H-purin-9-yl)-2,4,4-trifluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)(phenyloxy)phosphoryl)-L-alanine isopropyl ester; (2S,3S,4R,5R)-4-ethynyl-2-fluoro-2-(hydroxymethyl)-5-(4-(propylamino)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol; 2-amino-9-((2R,4R,5S)-3,3,5-trifluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran- 2-yl)-1,9-dihydro-6H-purin-6-one; (2S,3S,4R,5R)-2-fluoro-2-(hydroxymethyl)-5-(4-(methylthio)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol; L-valine ((2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-3,4- dihydroxytetrahydrofuran-2-yl)methyl ester; ((((2S,3S,4R,5R)-5-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluoro-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)-L- alanine neopentyl ester; ((2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-3,4- dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate; ((2S,3S,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-3,4- dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate; ((2S,3S,4R,5R)-2-fluoro-3,4-dihydroxy-5-(4-oxo-3,4-dihydro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate; ((2S,3S,4R,5R)-5-(5-carbamoyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-3,4- dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate; ((2S,3S,4R,5R)-5-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-3,4- dihydroxytetrahydrofuran-2-yl)methyl tetrahydro pyrophosphonate; ((2S,3S,4R,5R)-2-fluoro-5-(5-fluoro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydro pyrophosphonate; ((2S,3S,4R,5R)-5-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-2-fluoro-3,4- dihydroxytetrahydrofuran-2-yl)methyl tetrahydro pyrophosphonate; ((2S,3S,4R,5R)-5-(4-amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-3,4- dihydroxytetrahydrofuran-2-yl)methyl tetrahydro pyrophosphonate; ((2S,3S,4R,5R)-5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-3,4- dihydroxytetrahydrofuran-2-yl)methyl tetrahydro pyrophosphonate; ((2S,3R,4R,5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-4-chloro-2-fluoro-3- hydroxy-4-methyltetrahydrofuran-2-yl)methyl tetrahydro pyrophosphonate; and ((2S,3S,4S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-3,4- dihydroxy-4-methyltetrahydrofuran-2-yl)methyl tetrahydro pyrophosphonate.

[0070] Embodiment 38. The compound of Embodiment 37, which is (2S,3S,4R,5R)-5-(4- amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4- diol or ((R)-(((2S,3R,4S,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-chloro-2,4- difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester.

[0071] Embodiment 39. A pharmaceutical composition comprising a compound of any one of Embodiments 1-38 in admixture with a pharmaceutically acceptable carrier, diluent, or excipient.

[0072] Embodiment 40. The pharmaceutical composition of Embodiment 39, further comprising one or more therapeutic compounds or compositions.

[0073] Embodiment 41. The pharmaceutical composition of embodiment 40, wherein the one or more therapeutic compounds or compositions is a second antiviral compound or composition.

[0074] Embodiment 42. The pharmaceutical composition of embodiment 41, wherein the second antiviral compound or composition is an RdRp inhibitor.

[0075] Embodiment 43. The pharmaceutical composition of embodiment 41, wherein the second antiviral compound or composition is an RNA polymerase inhibitor.

[0076] Embodiment 44. A method of inhibiting an RNA-dependent RNA polymerase comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 1-38 or a pharmaceutical composition of embodiments 39-43.

[0077] Embodiment 45. A method of preventing, ameliorating, or treating an RNA viral infection comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 1-38 or a pharmaceutical composition of embodiments 39-43.

[0078] Embodiment 46. The method of embodiment 45, wherein the RNA viral infection is at least one virus selected from the group consisting of: Dengue virus, Severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, Zika virus, Yellow fever virus, Ebola (Makona) virus, Ebola (Kikwit) virus, O'nyong'nyong virus, Sudan virus, Marburg virus, Respiratory syncytial virus (RSV), Nipah virus, Measles virus, Parainfluenza virus, Middle East respiratory syndrome (MERS) virus, Hepatitis C virus (HCV), West Nile virus, Lassa virus, Influenza, HRV, MEV, LCMV, Polio, CHIKV, COXV, and Junin virus.

[0079] Embodiment 47. The method of embodiment 46, wherein the RNA viral infection is caused by a Dengue virus.

[0080] Embodiment 48. The method of embodiment 46, wherein the RNA viral infection is caused by a SARS-CoV-2 virus.

[0081] Embodiment 49. The method of embodiment 46, wherein the RNA viral infection is caused by a Yellow fever virus.

[0082] Embodiment 50. The method of embodiment 46, wherein the RNA viral infection is caused by a Zika virus.

[0083] Embodiment 51. The method of any one of embodiments 44-50, further comprising treatment with one or more additional therapeutic compounds or compositions.

[0084] Embodiment 52. The method of embodiment 51, wherein at least one of the one or more therapeutic compounds or compositions is a drug effective to treat or ameliorate an RNA virus infection.

[0085] Embodiment 53. The method of embodiment 52, wherein the drug to treat an RNA virus infection is selected from remdesivir, monolupiravir, or paroquetide.

[0086] Embodiment 54. Any compound, composition, or method described herein.

[0087] Definitions As used in this specification, the terms “comprises,” “comprising,” “consisting of’ and “consisting essentially of’ have the open-ended meaning synonymous with the phrases “has at least” or “including at least” and are used in their normal sense, unless specifically stated otherwise. The term “comprise,” when used in a contextual sense of a method, means the method comprises at least the recited steps, but can include additional steps. The term “comprise,” when used in a contextual sense of a compound or composition, means the compound or composition comprises at least the recited features or components, but can also include additional features or components.

[0088] As used herein, the word “or” is used in the “inclusive” sense, unless otherwise stated, rather than the “exclusive” sense. In other words, the phrase “A or B” means “A, B, or

[0089] The term “independently” is used herein to indicate that the variable is applied in any one instance without regard to the presence or absence of a variable having the same or different definition within the same compound. Thus, in a compound in which “R” appears twice and is defined as “independently selected from,” it is intended that each occurrence of the R group is individually identified as a member of the set following the definition of the R group. For example, “each R is independently selected from carbon and nitrogen” means that R 1 and R 2 may both be carbon, R 1 and R 2 may both be nitrogen, or R 1 or R 2 may be carbon and the other nitrogen, or vice versa. 1 2

[0090] ​​When any variable appears more than once in any part or chemical formula of a compound used in or claimed in the description and illustration of this invention, its definition for each occurrence is independent of its definition for each subsequent occurrence. Furthermore, combinations of substituents and / or variables are permitted only if the resulting compound is a stable compound.

[0091] The symbol “*” at the end of a bond, or the line or “~~~~” that passes through a bond, respectively indicates the connection point between a functional group or other chemical part and the rest of the molecule to which it belongs.

[0092] A bond drawn into a ring system (as opposed to a bond attached to a specific vertex) indicates that the bond can be attached to any suitable ring atom.

[0093] As used herein, the terms “optional” or “optionally” mean that an event or situation described below may occur but does not have to occur, and the description includes instances where the event or situation occurs and instances where it does not occur. For example, “optionally substituted” means that the “optionally substituted” portion may contain hydrogen or substituents.

[0094] The phrase "optional bond" means that the bond may or may not be present, and the description includes single, double, or triple bonds. If a substituent is specified as "bonded" or "not present," the atom attached to the substituent is directly connected.

[0095] The term “about” as used herein means approximately, roughly, roughly, or about. When the term “about” is used in conjunction with a numerical range, it modifies the range by extending the upper and lower boundaries of the listed numerical value. Generally, the term “about” is used herein to modify a numerical value that fluctuates by 20%.

[0096] Some of the compounds disclosed herein exhibit tautomerism. Tautomers can exist in the form of two or more interconvertible substances. Proton transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers typically exist in equilibrium, and attempts to separate individual tautomers usually yield mixtures with chemical and physical properties consistent with those of the mixture of compounds. The position of equilibrium depends on the intramolecular chemical signature. For example, in many aliphatic aldehydes and ketones (such as acetaldehyde), the ketone form is dominant; while in phenols, the enol form is dominant. Common proton transfer tautomers include ketone / enol (-C(=O)-CH- -C(-OH)=CH-), amide / imino acid (-C(=O)-NH-) -C(-OH)=N-) and amidine (-C(=NR)-NH-) - C(=NHR)=N-) tautomers. The latter two are particularly common in heteroaryl and heterocyclo groups, and all tautomeric forms of the compounds are encompassed by the present application.

[0097] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Various methods and materials described herein are those commonly used by those skilled in the art. Standard reference works setting forth the general principles of pharmacology include Goodman and Gilman's The Pharmacological Basis of Therapeutics The practice of the present application will employ, unless otherwise indicated, conventional methods of chemistry, biochemistry, molecular biology, microbiology, immunology and pharmacology, within the skill of the art. Such methods are explained fully in the literature. See, e.g., Gennaro, ed., Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995); and

[0098] Definitions set forth herein can be appended to additional chemically relevant combinations, such as "heteroalkylaryl", "haloalkylheteroaryl", "arylalkylheterocyclyl", "alkylcarbonyl", "alkoxyalkyl", and the like. When the term "alkyl" is used as a suffix following another term, as in "phenylalkyl" or "hydroxyalkyl", this is intended to refer to an alkyl radical as defined above substituted with one to two substituents selected from the additional term explicitly named. Thus, for example, "phenylalkyl" refers to an alkyl radical having one to two phenyl substituents, and thus includes benzyl, phenylethyl, and biphenyl. "Alkylaminoalkyl" is an alkyl radical having one to two alkylamino substituents. "Hydroxyalkyl" includes 2-hydroxyethyl, 2-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 2,3-dihydroxybutyl, 2-(hydroxymethyl), 3-hydroxypropyl, and the like. Thus, as used herein, the term "hydroxyalkyl" is used to define a subset of heteroalkyl as defined below. The term -(ar)alkyl refers to unsubstituted alkyl or aralkyl groups. The term "(hetero)aryl" refers to aryl or heteroaryl groups.

[0099] The term "acyl" as used herein denotes a group of the formula -C(=O)R, wherein R is hydrogen or lower alkyl as defined herein. The term "alkylcarbonyl" as used herein denotes a group of the formula C(=O)R, wherein R is alkyl as defined herein. The term C 1-6 Acyi refers to a group -C(=O)R containing 6 carbon atoms. The term "arylcarbonyl" as used herein means a group of the formula C(=O)R, wherein R is aryl; the term "benzoyl" as used herein means "arylcarbonyl" wherein R is phenyl.

[0100] The term "alkyl" as used herein denotes unbranched or branched saturated monovalent hydrocarbon radicals containing 1 to 12 carbon atoms. The term "lower alkyl" or "Ci-C6alkyl" as used herein denotes straight chain or branched chain hydrocarbon radicals containing 1 to 6 carbon atoms. "Ci-C6alkyl" as used herein means an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, lower alkyl groups including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. 12 "alkyl" refers to an alkyl group consisting of 1 to 12 carbons. Examples of alkyl groups include, but are not limited to, lower alkyl groups including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.

[0101] When the term "alkyl" is used as a suffix following another term, as in "phenylalkyl" or "hydroxyalkyl", this is intended to refer to an alkyl radical as defined above which is substituted with one to two substituents selected from the additional named moieties. Thus, for example, "phenylalkyl" represents a radical R'R"- where R' is phenyl, and R" is an alkylene radical as defined herein, it being understood that the point of attachment of the phenylalkyl moiety will be on the alkylene group. Examples of arylalkyl groups include, but are not limited to, benzyl, phenethyl, 3-phenylpropyl. The interpretation of the terms "arylalkyl" or "aralkyl" is analogous, except that R' is aryl. The interpretation of the terms "(hetero)arylalkyl" or "(hetero)aralkyl" is analogous, except that R' is optionally aryl or heteroaryl.

[0102] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, "C 1-6 "alkyl" is intended to encompass Ci, C2, C3, C4, C5, C6, C 1–6 , C 1–5 , C 1–4 , C 1–3 , C 1–2 , C 2–6 , C 2–5 , C 2–4 , C 2–3 , C 3–6 , C 3–5 , C 3–4 , C 4–6 , C 4–5 , and C 5–6 alkyl.

[0103] "alkyl" refers to a straight chain or branched chain saturated hydrocarbon group having from 1 to 20 carbon atoms ("C 1-20 alkyl"). In some embodiments, the alkyl group has from 1 to 15 carbon atoms ("C 1-15 alkyl"). In some embodiments, the alkyl group has from 1 to 14 carbon atoms ("C 1-14 alkyl"). In some embodiments, the alkyl group has from 1 to 13 carbon atoms ("C 1-13 alkyl"). In some embodiments, the alkyl group has from 1 to 12 carbon atoms ("C1-12 Alkyl group). In some embodiments, the alkyl group has 1 to 11 carbon atoms (“C1”). 1-11 Alkyl group). In some embodiments, the alkyl group has 1 to 10 carbon atoms (“C10”). 1-10 Alkyl group). In some embodiments, the alkyl group has 1 to 9 carbon atoms (“C1”). 1-9 Alkyl group). In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C1”). 1-8 Alkyl group). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C1”). 1-7 Alkyl group (“C”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C”). 1-6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1-5 Alkyl group). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1”). 1-4 Alkyl group). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2 Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C1 alkyl”). 2-6 Alkyl group). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Other examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc.

[0104] "Alkenyl" or "olefin" refers to a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds ("C"). 2-10 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 9 carbon atoms (“C”). 2-9 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 8 carbon atoms (“C”). 2-8 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 7 carbon atoms (“C”). 2-7 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C”). 2-6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C”). 2-5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C”). 2-4("C2alkenyl"). The one or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 1-butenyl).C 2-3 ("C2alkenyl"). The one or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 1-butenyl).C 2-4 Examples of alkenyl groups include ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like.C 2-6 Examples of alkenyl groups include the foregoing C 2-4 Examples of alkenyl groups include the foregoing C

[0105] "Alkynyl" refers to a straight or branched hydrocarbon group ("C2-C10alkynyl") having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds). In some embodiments, alkynyl groups have 2 to 9 carbon atoms ("C2-C9alkynyl"). In some embodiments, alkynyl groups have 2 to 8 carbon atoms ("C2-C8alkynyl"). In some embodiments, alkynyl groups have 2 to 7 carbon atoms ("C2-C7alkynyl"). In some embodiments, alkynyl groups have 2 to 6 carbon atoms ("C2-C6alkynyl"). In some embodiments, alkynyl groups have 2 to 5 carbon atoms ("C2-C5alkynyl"). In some embodiments, alkynyl groups have 2 to 4 carbon atoms ("C2-C4alkynyl"). In some embodiments, alkynyl groups have 2 to 3 carbon atoms ("C2-C3alkynyl"). In some embodiments, alkynyl groups have 2 carbon atoms ("C2alkynyl"). The one or more carbon-carbon triple bonds can be internal (as in 2-butynyl) or terminal (as in 1-butynyl). 2-10 ("C2alkenyl"). The one or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 1-butenyl).C 2-9 ("C2alkenyl"). The one or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 1-butenyl).C 2-8 ("C2alkenyl"). The one or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 1-butenyl).C 2-7 ("C2alkenyl"). The one or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 1-butenyl).C 2-6 ("C2alkenyl"). The one or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 1-butenyl).C 2-5 ("C2alkenyl"). The one or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 1-butenyl).C C2-4 ("C2alkenyl"). The one or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 1-butenyl).C C2-3 ("C2alkenyl"). The one or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 1-butenyl).C 2-4 Examples of alkenyl groups include the foregoing C 2-6 Examples of alkenyl groups include the foregoing C 2-4 Examples of alkenyl groups include the foregoing C

[0105] "Alkynyl" refers to a straight or branched hydrocarbon group ("C2-C10alkynyl") having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds). In some embodiments, alkynyl groups have 2 to 9 carbon atoms ("C2-C9alkynyl"). In some embodiments, alkynyl groups have 2 to 8 carbon atoms ("C2-C8alkynyl"). In some embodiments, alkynyl groups have 2 to 7 carbon atoms ("C2-C7alkynyl"). In some embodiments, alkynyl groups have 2 to 6 carbon atoms ("C2-C6alkynyl"). In some embodiments, alkynyl groups have 2 to 5 carbon atoms ("C2-C5alkynyl"). In some embodiments, alkynyl groups have 2 to 4 carbon atoms ("C2-C4alkynyl"). In some embodiments, alkynyl groups have 2 to 3 carbon atoms ("C2-C3alkynyl"). In some embodiments, alkynyl groups have 2 carbon atoms ("C2alkynyl"). The one or more carbon-carbon triple bonds can be internal (as in 2-butynyl) or terminal (as in 1-butynyl). n Examples of alkenyl groups include the foregoing C 10 Examples of alkenyl groups include the foregoing CThe term "haloalkyl" or "halo lower alkyl" or "lower haloalkyl" means a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms wherein one or more of the carbon atoms are substituted with one or more halogen atoms.

[0107] The term "alkylene" or "alkylidene", as used herein, denotes a bivalent saturated straight chain hydrocarbon group of 1 to 10 carbon atoms (e.g., (CH2) n ) or a branched saturated bivalent hydrocarbon group of 2 to 10 carbon atoms (e.g., -CHMe- or -CH2CH( i -Pr)CH2-). Except in the case of methylene, the free valences of the alkylene group are not attached to the same atom. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, 2-methyl-propylene, 1,1 -dimethyl-ethylene, butylene, 2-ethylbutylene.

[0108] The term "alkoxy", as used herein, means -O-alkyl, wherein alkyl is as defined above, such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, pentoxy, hexyloxy, including their isomers. "Lower alkoxy", as used herein, denotes an alkoxy group having "lower alkyl" as previously defined. "C1- 10 alkoxy", as used herein, means -O-alkyl, wherein alkyl is C 1-10 .

[0109] The term "hydroxyalkyl", as used herein, denotes an alkyl group, as defined herein, wherein one to three of the hydrogen atoms on a different carbon atom are replaced by a hydroxyl group.

[0110] The terms "alkylsulfonyl" and "arylsulfonyl", as used herein, mean a group of the formula -S(=O)2R, wherein R is alkyl or aryl, respectively, and alkyl and aryl are as defined herein. The term "heteroalkylsulfonyl", as used herein, denotes a group of the formula -S(=O)2R, wherein R is "heteroalkyl" as defined herein.

[0111] The terms "alkylsulfonylamino" and "arylsulfonylamino", as used herein, mean a group of the formula -NR'S(=O)2R, wherein R is alkyl or aryl, respectively, R' is hydrogen or C 1-3 alkyl, and alkyl and aryl are as defined herein.

[0112] The term "cycloalkyl", as used herein, means a saturated carbocyclic ring containing 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. "C 3-7 cycloalkyl", as used herein, means a cycloalkyl group consisting of 3 to 7 carbons in the carbocyclic ring.

[0113] The term carboxy-alkyl as used herein refers to an alkyl moiety in which one hydrogen atom has been replaced with a carboxy group, it being understood that the point of attachment of the heteroalkyl group is through a carbon atom. The term "carboxy" or "carboxyl" refers to the -CO2H moiety.

[0114] The term "heteroaryl" or "heteroaromatic" as used herein means a monocyclic or bicyclic radical of 5 to 12 ring atoms per ring, each ring containing four to eight atoms, incorporating one or more N, O, or S heteroatoms, the remainder of the ring atoms being carbon, it being understood that the point of attachment of the heteroaryl group will be on the aromatic ring. As is well known to those skilled in the art, the aromatic character of heteroaryl rings is weaker than that of their all-carbon counterparts. Thus, for the purposes of the present invention, a heteroaryl need only possess some degree of aromatic character. Examples of heteroaryl moieties include monocyclic aromatic heterocycles having 5 to 6 ring atoms and 1 to 3 heteroatoms, including but not limited to pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoles, isoxazoles, thiazoles, isothiazoles, triazolines, thiadiazoles, and oxadiazolines, which can be optionally substituted with one or more, preferably one or two, substituents selected from the group consisting of hydroxy, cyano, alkyl, alkoxy, thio, lower halogenated alkoxy, alkylthio, halo, lower halogenated alkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl, nitro, alkoxycarbonyl, and carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino, and arylcarbonylamino. Examples of bicyclic moieties include, but are not limited to, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, benzoxazole, benzisoxazole, benzothiazole, and benzisothiazole. The bicyclic moiety can be optionally substituted on either ring; however, the point of attachment is on the ring containing the heteroatom.

[0115] The term "heterocyclyl," "heterocycloalkyl," or "heterocycle" as used herein, means a monovalent saturated cyclic radical consisting of one or more rings, preferably one to two rings, including spiro systems having three to eight atoms per ring, incorporating one or more ring heteroatoms (selected from N, O, or S(O) 0-2), and can be optionally independently substituted with one or more, preferably one or two, substituents selected from hydroxy, oxo, cyano, lower alkyl, lower alkoxy, lower halogenoalkoxy, alkylthio, halo, lower halogenoalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino. Examples of heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, hexahydroazepinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, thiomorpholinyl, quinuclidinyl, and imidazolinyl.

[0116] "Heterocyclyl" or "heterocyclic" refers to a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-14 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. Heterocyclyl groups can be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., a fused ring, bridged ring, or spiro ring system, such as a bicyclic ring system ("bicyclic heterocyclyl") or a tricyclic ring system ("tricyclic heterocyclyl")), and can be saturated, or can contain one or more carbon-carbon double bonds, or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more carbocyclyl rings, wherein the point of attachment is on the carbocyclyl or heterocyclyl ring, or a ring system in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl rings, wherein the point of attachment is on the heterocyclyl ring, and in such cases the number of ring members also refers to the number of ring members in the heterocyclyl ring system.

[0117] In some embodiments, the heterocyclyl is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl"). In some embodiments, the heterocyclyl is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, the heterocyclyl is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0118] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridinyl, oxetane, and thiopyrane. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridanebutane, oxetanebutane, and thiopyranebutane. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-diketone. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxopentyl, oxothiopentanyl, and dithiopentanyl. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiadialkyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiaalkyl, and dioxane. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazinealkyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary bicyclic heterocyclic groups include, but are not limited to, indololinyl, isoindololinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, tetrahydrobenzothiophenyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphridyl, decahydro-1,8-naphridyl, octahydropyrrolo[3,2-b]pyrrole, indololinyl, phthalimide, naphthalimide, chromenyl, 1H-benzo[e][1,4]diazazolyl, 1,4,5,7-tetrahydropyranolo[3,4-b]pyrrole, 5, 6-Dihydro-4H-furano[3,2-b]pyrrolithyl, 6,7-Dihydro-5H-furano[3,2-b]pyrrolithyl, 5,7-Dihydro-4H-thieno[2,3-c]pyrrolithyl, 2,3-Dihydro-1H-pyrroli[2,3-b]pyridyl, 2,3-Dihydrofurano[2,3-b]pyridyl, 4,5,6,7-Tetrahydro-1H-pyrroli[2,3-b]pyridyl, 4,5,6,7-Tetrahydrofurano[3,2-c]pyridyl, 4,5,6,7-Tetrahydrothieno[3,2-b]pyridyl, 1,2,3,4-Tetrahydro-1,6-naphthidyl, etc.

[0119] "Aryl" refers to a monocyclic or polycyclic aromatic ring (e.g., bicyclic or tricyclic) group having 6-14 ring carbon atoms and no heteroatoms in the aromatic ring system (e.g., a 4n+2 aromatic ring system in which 6, 10, or 14 π electrons are enjoyed in a ring array). 6-14“aryl” refers to a 6-14 membered (e.g., C6-C10) aromatic ring system (e.g., a cyclic array sharing 6, 10, or 14 p-electrons) having the number of ring carbon atoms specified (e.g., “C6-C10 aryl”; for example, phenyl). In some embodiments, aryl has 6 ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, aryl has 10 ring carbon atoms (“C10 aryl”; for example, naphthyl, such as 1-naphthyl (a-naphthyl) and 2-naphthyl (b-naphthyl)). In some embodiments, aryl has 14 ring carbon atoms (“C14 aryl”; for example, anthryl). “Aryl” also includes ring systems in which an aryl ring as defined above is fused with one or more carbocyclyl or heterocyclyl groups, where the point of attachment is on the aryl ring, and in such cases the number of carbon atoms also refers to the number of carbon atoms in the aryl ring system. 10 “aryl” refers to a 6-14 membered (e.g., C6-C10) aromatic ring system (e.g., a cyclic array sharing 6, 10, or 14 p-electrons) having the number of ring carbon atoms specified (e.g., “C6-C10 aryl”; for example, phenyl). In some embodiments, aryl has 6 ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, aryl has 10 ring carbon atoms (“C10 aryl”; for example, naphthyl, such as 1-naphthyl (a-naphthyl) and 2-naphthyl (b-naphthyl)). In some embodiments, aryl has 14 ring carbon atoms (“C14 aryl”; for example, anthryl). “Aryl” also includes ring systems in which an aryl ring as defined above is fused with one or more carbocyclyl or heterocyclyl groups, where the point of attachment is on the aryl ring, and in such cases the number of carbon atoms also refers to the number of carbon atoms in the aryl ring system. 14 “aryl” refers to a 6-14 membered (e.g., C6-C10) aromatic ring system (e.g., a cyclic array sharing 6, 10, or 14 p-electrons) having the number of ring carbon atoms specified (e.g., “C6-C10 aryl”; for example, phenyl). In some embodiments, aryl has 6 ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, aryl has 10 ring carbon atoms (“C10 aryl”; for example, naphthyl, such as 1-naphthyl (a-naphthyl) and 2-naphthyl (b-naphthyl)). In some embodiments, aryl has 14 ring carbon atoms (“C14 aryl”; for example, anthryl). “Aryl” also includes ring systems in which an aryl ring as defined above is fused with one or more carbocyclyl or heterocyclyl groups, where the point of attachment is on the aryl ring, and in such cases the number of carbon atoms also refers to the number of carbon atoms in the aryl ring system.

[0120] “heteroaryl” refers to a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., a cyclic array sharing 6, 10, or 14 p-electrons) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems in which a heteroaryl ring as defined above is fused with one or more carbocyclyl or heterocyclyl groups, where the point of attachment is on the heteroaryl ring, and in such cases the number of ring members also refers to the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, where the point of attachment is on the aryl or heteroaryl ring, and in such cases the number of ring members also refers to the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. In polycyclic heteroaryl groups in which one ring contains no heteroatoms (e.g., indolyl, quinolyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring bearing a heteroatom (e.g., 2-indolyl) or the ring containing no heteroatoms (e.g., 5-indolyl).

[0121] In some embodiments, heteroaryl is a 5-10 membered aromatic ring system having ring carbon atoms and providing 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, heteroaryl is a 5-8 membered aromatic ring system having ring carbon atoms and providing 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, heteroaryl is a 5-6 membered aromatic ring system having ring carbon atoms and providing 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0122] Exemplary 5-membered heteroaryls containing 1 heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryls containing 2 heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryls containing 3 heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryls containing 4 heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryls containing 1 heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryls containing 2 heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryls containing 3 or 4 heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryls containing 1 heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryls include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryls include, but are not limited to, phenanthridinyl, phenoxathiinyl, carbazolyl, acridinyl, phenazinyl, phenoxazinyl, and phenothiazinyl.

[0123] “Saturated” refers to a ring moiety that contains no double or triple bonds, i.e., all of the bonds between the ring members are single bonds.

[0124] Alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be substituted. Optional substitution refers to groups that can be substituted or are not substituted. Generally, the term "substituted" means that at least one hydrogen atom present on the group is replaced by a non-hydrogen substituent, and the substitution results in a stable compound, such as a compound that does not spontaneously undergo transformations such as through rearrangement, cyclization, elimination, or other reactions. Heteroatoms such as nitrogen, oxygen, and sulfur may have hydrogen substituents and / or non-hydrogen substituents that satisfy the heteroatom's valence state and lead to the formation of a stable compound.

[0125] As used herein, an exemplary non-hydrogen substituent where a portion is "optionally substituted" means that the portion may be substituted by any other portion selected from, but not limited to, the following: halogen, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –OR aa –N(R) bb 2. –N(OR) cc )R bb –SH, –SR aa –C(=O)R aa –CO2H, –CHO, –CO2R aa –OC(=O)R aa –OCO2R aa –C(=O)N(R) bb )2、–OC(=O)N(R bb )2、–NR bb C(=O)R aa –NR bb CO2R aa –NR bb C(=O)N(R bb )2、–C(=NR bb )R aa –C(=NR) bb OR aa –OC(=NR) bb )R aa –OC(=NR) bb OR aa –C(=NR) bb )N(R bb )2、–OC(=NR bb )N(R bb )2、–NR bb C(=NR bb )N(R bb )2、–C(=O)NR bb SO2R aa –NR bb SO2R aa –SO2N(R) bb)2, -SO2R aa )2, -SO2R aa )2, -SO2R aa )2, -SO2R cc )2, -SO2R 1–10 )2, -SO2R 2–10 )2, -SO2R 2–10 )2, -SO2R 3–14 )2, -SO2R 6–14 )2, -SO2R dd )2, -SO2R aa )2, -SO2R 1–10 )2, -SO2R 1–10 )2, -SO2R 2–10 )2, -SO2R 2–10 )2, -SO2R 3–14 )2, -SO2R 6–14 )2, -SO2R aa )2, -SO2R dd )2, -SO2R bb )2, -SO2R aa )2, -SO2R cc )2, -SO2R aa )2, -SO2R cc )2, -SO2R aa )2, -SO2R aa )2, -SO2R cc )2, -SO2R aa )2, -SO2R 1–10 )2, -SO2R 1–10 )2, -SO2R 2–10 )2, -SO2R 2–10 )2, -SO2R 3–14 )2, -SO2R 6–14 )2, -SO2R bb )2, -SO2R dd )2, -SO2R cc )2, -SO2R 1–10 )2, -SO2R1–10 All-halogenated alkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 3–14 Carbocyclic groups, 3 to 14-membered heterocyclic groups, C 6–14 aryl and 5 to 14 heteroaryl, or two R cc The groups are linked to form a 3- to 14-membered heterocyclic group or a 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; and each R that appears dd Independently selected from halogens, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –OC 1–6 Alkyl, –ON(C 1–6 Alkyl)2、–N(C 1–6 Alkyl)2、–N(OC) 1–6 Alkyl)(C 1–6 Alkyl), –N(OH)(C 1–6 Alkyl groups, –NH(OH), –SH, –SC 1–6 Alkyl group, –C(=O)(C 1–6 Alkyl group), –CO2H, –CO2(C 1–6 Alkyl), –OC (=O)(C 1–6 Alkyl), –OCO2(C 1–6 Alkyl groups, –C(=O)NH2, –C(=O)N(C 1–6 Alkyl)2、–OC(=O)NH(C 1–6 Alkyl), –NHC(=O)(C 1–6 Alkyl), –N(C) 1–6 Alkyl)C(=O)( C 1–6 Alkyl), –NHCO2(C 1–6 Alkyl), –NHC(=O)N(C 1–6 Alkyl)2、–NHC(=O)NH(C 1–6 Alkyl groups), –NHC(=O)NH2, –C(=NH)O(C 1–6 Alkyl), –OC(=NH)(C 1–6 Alkyl group), –OC (=NH)OC 1–6 Alkyl group, –C(=NH)N(C 1–6 Alkyl)2、–C(=NH)NH(C 1–6 Alkyl groups, –C(=NH)NH2, –OC(=NH)N(C 1–6 Alkyl)2、–OC(NH)NH(C 1–6 Alkyl groups), –OC(NH)NH2, –NHC(NH)N(C 1–6haloalkyl, -B(OH)2, -B(OC 1–6 alkyl), -SO2N(C 1–6 alkyl)2, -SO2NH(C 1–6 alkyl), -SO2NH2, -SO2C 1–6 alkyl, -B(OH)2, -B(OC 1–6 alkyl)2, C 1–6 alkyl, C 1–6 perhaloalkyl, C 2–6 alkenyl, C 2–6 alkynyl, C 3–10 carbocyclyl, C 6–10 aryl, 3- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl; or two geminal R dd substituents can be joined to form =0.

[0126] “halo” or “halogen” means fluoro (fluorinated, -F), chloro (chlorinated, -Cl), bromo (brominated, -Br), or iodo (iodinated, -I).

[0127] The term “composition” as used herein is intended to encompass a product comprising the specified ingredients as well as any product which results, directly or indirectly, from combinations of the specified ingredients.

[0128] “salt” includes any and all salts. “Pharmaceutically acceptable salt” means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharm. Sci. 66: 1-19 (1977). Pharmaceutically acceptable salts of the compounds of this application include those derived from pharmaceutically acceptable inorganic and organic acids and bases. See, e.g., S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci. 66: 1-19 (1977). J. Pharmaceutical SciencesPharmaceutically acceptable salts are described in detail in Berge et al. (1977) 66:1-19. Pharmaceutically acceptable salts include salts of inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts include salts of an amino group with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acid, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acid, or by using other methods such as ion exchange resins as used in the art. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1–4 Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0129] Unless otherwise stated, the compounds described herein can comprise one or more asymmetric centers and thus can exist in various stereoisomeric forms, e.g., enantiomeric and / or diastereomeric forms. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and one or more stereoisomer-enriched mixtures. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC). The forms of the compounds described herein can be individual isomers substantially free of other isomers, or mixtures of various isomers.

[0130] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present application but for the replacement of a hydrogen by a deuterium or tritium, 19F by 18F, a carbon by 13C- or 14C-enriched carbon, and / or an oxygen atom by 18O are within the scope of the present disclosure. Other examples of isotopes include 15N, 18O, 17O, 31P, 32P, 35S, 18F, 36CI, and 123I. Compounds with such isotopically enriched atoms can be used, for example, as analytical tools or probes in assay or in vivo.

[0131] Certain isotopically labeled compounds (e.g., those labeled with 3H and 14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (i.e., 3H), and carbon-14 (i.e., 14C), isotopes are particularly preferred for their ease of preparation and detectability. 14C isotopes are particularly useful in drug and / or substrate tissue distribution assays.

[0132] Certain isotopically labeled compounds of Formula (I) can be used in medical imaging purposes, for example, compounds labeled with a positron emitting isotope such as 11C or 18F can be used in positron emission tomography (PET) applications, and compounds labeled with a gamma ray emitting isotope such as 123I can be used in single photon emission computed tomography (SPECT) applications. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) can afford certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence can be preferred in some circumstances. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) can afford certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence can be preferred in some circumstances. Additionally, isotopic substitution at sites where epimerization occurs can slow or attenuate the epimerization process, thereby maintaining the more active or potent form of the compound for a longer period of time. Isotopically labeled compounds of Formula (I), particularly those containing heavier isotopes such as deuterium (i.e., 2H) can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0133] If there is a discrepancy between an depicted structure and a name given to that structure, the depicted structure controls. Additionally, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers. In some cases, however, where there is more than one chiral center, the structure and name can be represented as a single enantiomer to aid in the description of the relative stereochemistry. One skilled in the art of organic synthesis will know from the methods used to prepare the compounds whether the compounds are prepared as single enantiomers.

[0134] Table 1. In various embodiments described herein, the Dengue inhibitor of any of Formulae I-V or a pharmaceutically acceptable salt and / or stereoisomer thereof is selected from one of the compounds shown in Table 1 below.

[0135] Examples General Abbreviations Commonly used abbreviations include: Acetyl (Ac), Azobisisobutyronitrile (AIBN), Atmospheric pressure (Atm), 9-boronbicyclo[3.3.1]nonane (9-BBN or BBN), tert-butyloxycarbonyl (Boc), di-tert-butyl pyrocarbonate or boc anhydride (BOC2O), benzyl (Bn), butyl (Bu), Chemical Abstracts Service Registry Number (CASRN), benzyloxycarbonyl (CBZ or Z), carbonyl diimidazole (CDI), 1,4-diazabicyclo[2.2.2]octane (DABCO), diethylaminosulfur trifluoride (DAST), dibenzylacetone (dba), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N'-dicyclohexylcarbodiimide (DCC), 1,2-dichloro Ethane (DCE), dichloromethane (DCM), diethyl azodicarbonate (DEAD), diisopropyl azodicarbonate (DIAD), diisobutylaluminum hydride (DIBAL or DIBAL-H), 1,3-diisopropylcarbodiimide (DIC), diisopropylethylamine (DIPEA), N,N-dimethylacetamide (DMA), 4-N,N-dimethylaminopyridine (DMAP), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,1'-bis-(diphenylphosphino)ethane (dppe), 1,1'-bis-(diphenylphosphino)ferrocene (dppf), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), ethyl (Et), ethyl acetate (EtOAc), ethanol (EtOH), 2-ethoxy-2 H 1-Quinoline-1-carboxylic acid ethyl ester (EEDQ), diethyl ether (Et2O), O-(7-azabenzotriazol-1-yl)-N,N,N'N'-tetramethylureonium hexafluorophosphate acetic acid (HATU), acetic acid (HOAc), 1-N-hydroxybenzotriazole (HOBt), high-performance liquid chromatography (HPLC), isopropanol (IPA), lithium hexamethyldisilazane (LiHMDS), methanol (MeOH), melting point (mp), MeSO2- (Methanesulfonyl or Ms), Methyl (Me), Acetonitrile (MeCN), m-chloroperoxybenzoic acid (MCPBA), Mass spectrometry (ms), Methyl tert-butyl ether (MTBE), N-bromosuccinimide (NBS), N-carboxylic anhydride (NCA), N-chlorosuccinimide (NCS), N-methylmorpholine (NMM), N-methylpyrrolidone (NMP), Pyridinium chlorochromate (PCC), Pyridinium dichromate (PDC), Phenyl (Ph), Propyl (Pr), Isopropyl ( i -Pr), psi, pyridine (pyr), room temperature (rt or RT), tert-butyldimethylsilyl or t-BuMe2Si (TBDMS), triethylamine (TEA or Et3N), 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), triflate or CF3SO2- (Tf), trifluoroacetic acid (TFA), 1,1'-bis-2,2,6,6-tetramethylheptane-2,6-dione (TMHD), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), thin layer chromatography (TLC), tetrahydrofuran (THF), trimethylsilyl or Me3Si (TMS), p-toluenesulfonic acid monohydrate (TsOH or pTsOH), 4-Me-C6H4SO2- or tosyl (Ts), N-urethane-N-carboxyanhydride (UNCA). Conventional nomenclature including the prefixes n- n ), iso- i- ), sec- sec- ), tert- tert- ), and neo- neo ) have their usual meanings when used in connection with alkyl moieties. (J. Rigaudy and D. P. Klesney, Nomenclature in Organic Chemistry, IUPAC 1979 Pergamon Press, Oxford).

[0136] Example 1 Synthesis of Compound 1 Synthetic Scheme: Step 1: Synthesis of N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzamide: To a stirred solution of (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol (1.2 g, 4.51 mmol) in anhydrous pyridine (10 mL) was added dropwise TMSCl (2.57 mL, 20.3 mmol) at 0 °C and the resulting reaction mixture was stirred at the same temperature for 30 min. Then benzoyl chloride (848 µL, 6.76 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, it was quenched with water (0.7 mL) followed by 25% aqueous NH4OH (1.8 ml) and the resulting mixture was further stirred for 10 min. The solvent was removed under vacuum, the residue was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and the filtrate was concentrated under vacuum to get the crude product (1.7 g).

[0137] To a solution of crude product in anhydrous THF (15 mL) was added TBAF (2.5 mL, 9.12 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the solvent was removed in vacuum. The residue was purified by silica gel column chromatography using 5-8% MeOH in DCM as eluent to afford N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)benzamide (700 mg, 50%) as a white solid. LCMS (ESI): m / z 371.05 [M+H] + .

[0138] Step 2: Synthesis of N-(7-((2R,3R,4S,5S)-3,4-dihydroxy-5-(iodomethyl)tetrahydrofuran-2- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzamide: To a stirred solution of N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)benzamide (0.6 g, 1.62 mmol), PPh3 (1.19 g, 4.54 mmol) and 1H-imidazole (309 mg, 4.54 mmol) in anhydrous THF (8 mL) was added a solution of I2 (905 mg, 3.56 mmol) in THF (2 ml) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the mixture was quenched with saturated aqueous sodium thiosulfate solution (10 mL) and extracted with EtOAc (3 X 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to afford N-(7-((2R,3R,4S,5S)-3,4-dihydroxy-5-(iodomethyl)tetrahydrofuran-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)benzamide (0.6 g, 77%) as off-white solid. LCMS (ESI): m / z 481.00 [M+H] + .

[0139] Step 3: Synthesis of N-(7-((2R,3R,4S)-3,4-dihydroxy-5-methylidenetetrahydrofuran-2- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzamide: To a stirred solution of N-(7-((2R,3R,4S,5S)-3,4-dihydroxy-5-(iodomethyl)tetrahydrofuran-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)benzamide (590 mg, 1.23 mmol) in dry THF (8 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (275 µL, 1.84 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 2 h. After completion of the reaction, the solvent was removed in vacuo and the residue was purified by silica gel column chromatography using 3-5% MeOH in DCM as eluent to afford N-(7-((2R,3R,4S)-3,4-dihydroxy-5-methylidenetetrahydrofuran-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)benzamide (250 mg, 58%) as off-white solid. LCMS (ESI): m / z 353.00 [M+H] + .

[0140] Step 4: Synthesis of N-(7-((2R,3R,4S,5R)-5-fluoro-3,4-dihydroxy-5- (iodomethyl)tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzamide: To a stirred solution of (7-((2R,3R,4S)-3,4-dihydroxy-5-methylidenetetrahydrofuran-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)benzamide (250 mg, 0.710 mmol) in dry ACN (12 mL) was added TEA·3HF (139 µL, 0.851 mmol) at 0 °C. Then, a solution of NIS (192 mg, 0.851 mmol) in ACN (3 mL) was added and the resulting reaction mixture was stirred at 0 °C for 40 min. The reaction was warmed to room temperature and stirred for another 40 min, forming a solid precipitate. After completion of the reaction, the precipitate was filtered and washed with ACN to afford N-(7-((2R,3R,4S,5R)-5-fluoro-3,4-dihydroxy-5- (iodomethyl)tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzamide (200 mg, 57%) as a white solid. LCMS (ESI): m / z 498.75 [M+H] + .

[0141] Step 5: Synthesis of (2R,3S,4R,5R)-5-(4-benzamido-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2-fluoro-2-(iodomethyl)tetrahydrofuran-3,4-diyl dibenzoate: To a stirred solution of N-(7-((2R,3R,4S,5R)-5-fluoro-3,4-dihydroxy-5- (iodomethyl)tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzamide (190 mg, 0.381 mmol) in anhydrous ACN (5 mL) was added benzoic anhydride (216 mg, 0.953 mmol) and DMAP (9.39 mg, 0.076 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 6 h. After completion of the reaction, the mixture was diluted with EtOAc (15 mL) and washed with water (15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography using 10-40% EtOAc in heptane as eluent to afford (2R,3S,4R,5R)-5-(4-benzamido-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2- (iodomethyl)tetrahydrofuran-3,4-diyl dibenzoate (180 mg, 67%) as off-white solid. LCMS (ESI): m / z 706.80 [M+H] + .

[0142] Step 6: Synthesis of (2S,3S,4R,5R)-5-(4-benzamido-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2-((benzoyloxy)methyl)-2-fluorotetrahydrofuran-3,4-diyl dibenzoate: To a stirred solution of (2R,3S,4R,5R)-5-(4-benzamido-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2-fluoro-2-(iodomethyl)tetrahydrofuran-3,4-diyl dibenzoate (170 mg, 0.241 mmol) in DMF (17 mL) was added sodium benzoate (277 mg, 1.93 mmol) at room temperature. The reaction was stirred at 120 °C for 16 h. After completion of the reaction, the mixture was diluted with EtOAc (20 mL) and washed with ice cold water (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography using 20-50% EtOAc in heptane as eluent to afford (2S,3S,4R,5R)-5-(4-benzamido-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (benzoyloxy)methyl)-2-fluorotetrahydrofuran-3,4-diyl dibenzoate (130 mg, 77%) as a white solid. LCMS (ESI): m / z 700.95 [M+H] + .

[0143] Step 7: Synthesis of (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol (1): A solution of (2S,3S,4R,5R)-5-(4-benzamido-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((benzoyloxy)methyl)-2- fluorotetrahydrofuran-3,4-diyl dibenzoate (40 mg, 0.057 mmol) in methylamine (33% in ethanol, 2 mL) was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was concentrated in vacuo at low temperature. The residue was purified by trituration in 5% MeOH in DCM to afford (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol (4.5 mg, 28%) as off-white solid. 1 H-NMR (400 MHz, DMSO- d 6) : δ 8.07 (s, 1H), 7.26 (d, J = 3.6, 1H), 7.08 (s, 2H), 6.61 (d, J= 3.6 Hz, 1H), 6.33 (d, J = 3.2 Hz, 1H), 5.66(d, J = 5.6 Hz, 1H), 5.38 (t, J = 6.4 Hz, 1H), 5.16 (d, J = 8.8 Hz, 1H),4.52-4.44 (m, 1H), 4.38-4.34 (m, 1H), 3.54 (t, J = 6.4 Hz, 2H)。LCMS(ESI):m / z 285.15 [M+H] + .

[0144] Compounds 6, 10, 11, 12, 14-18, 21-26, 28, 31, 33, 35-45, 50, 52-55, and 72, etc. were synthesized using a procedure similar to that of compound 1.

[0145] Example 2 Synthesis of compound 2 Step 1: Synthesis of (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-azido-2- (iodomethyl)tetrahydrofuran-3,4-diol: To a stirred solution of iodine monochloride (654 mg, 4.03 mmol) in dry DMF (4 mL) was added sodium azide (576 mg, 8.86 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was again cooled to 0 °C and a solution of (2R,3R,4S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-methylene tetrahydrofuran-3,4-diol (0.4 g, 1.61 mmol) in dry DMF (2 mL) was added dropwise. The reaction mixture was further stirred at room temperature for 2 h. After completion of the reaction, the reaction was quenched with saturated aqueous sodium thiosulfate solution (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography using 0-10% MeOH in DCM as eluent to afford (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-azido-2-(iodomethyl)tetrahydrofuran-3,4-diol (105 mg, 16%) as a yellow sticky gum. LCMS (ESI): m / z 417.85 [M+H] + .

[0146] Step 2: Synthesis of (2S,3S,4R,5R)-2-azido-5-(4-benzamido-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2-(iodomethyl)tetrahydrofuran-3,4-diyl dibenzoate: To a stirred solution of (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-azido-2- (iodomethyl)tetrahydrofuran-3,4-diol (130 mg, 0.312 mmol) and DMAP (11.4 mg, 0.093 mmol) in dry pyridine (2.6 mL) was added benzoyl chloride (163 µL, 1.4 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was diluted with 10% aqueous sodium bicarbonate solution (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography using 30-50% EtOAc in heptane as eluent to afford (2S,3S,4R,5R)-2-azido-5-(4-benzamido-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (iodomethyl)tetrahydrofuran-3,4-diyl dibenzoate (110 mg, 48%) as a white solid. LCMS (ESI): m / z 728.09 [M-H] - .

[0147] Step 3: Synthesis of (2R,3S,4R,5R)-2-azido-5-(4-benzoylamino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3,4-dimethyldibenzoate: The pH of Bu4NOH (55%) (6 mL) was adjusted to 4 by adding TFA (approximately 1.2 mL). The resulting buffer solution (2 mL) was added to a stirred solution of (2S,3S,4R,5R)-2-azido-5-(4-benzoylamino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(iodomethyl)tetrahydrofuran-3,4-dimethyldibenzoate (105 mg, 0.144 mmol) in anhydrous DCM (2 mL) at 0 °C. mCPBA (149 mg, 0.864 mmol) was added in portions under vigorous stirring. The reaction mixture was stirred at room temperature for 16 h. After the reaction was complete, the mixture was diluted with DCM (10 mL) and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using 10–60% EtOAc in heptane as the eluent to give (2R,3S,4R,5R)-2-azido-5-(4-benzoylamino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3,4-dimethylbenzoate (50 mg, 56%) as a white solid. LCMS (ESI): m / z 620.1 [M+H] + .

[0148] Step 4: Synthesis of (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-azido-2-(hydroxymethyl)tetrahydrofuran-3,4-diol (2): A solution of (2R,3R,4S,5R)-5-azido-2-{4-benzoylamino-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-4-(benzoyloxy)-5-(hydroxymethyl)oxacyclopentane-3-ylbenzoate (50 mg, 0.080 mmol) in NH3 (7M in MeOH, 1 mL) was stirred at room temperature for 16 h. After the reaction was complete, the mixture was concentrated under vacuum. The residue was purified by reversed-phase preparative HPLC to obtain the desired (2R,3S,4R,5R)-5-{4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-azido-2-(hydroxymethyl)oxacyclopentane-3,4-diol (4.5 mg, 18%), as a white solid. 1 H-NMR (400 MHz, DMSO- d 6. (using D2O under HT): δ 8.06 (s, 1H), 7.29 (d,J = 3.6, 1H), 6.62 (d, J = 3.2 Hz, 1H), 6.25 (d, J = 6 Hz, 1H), 4.61 (t, J =6.4 Hz, 1H), 4.33 (d, J = 5.6 Hz, 1H), 3.56 (d, J = 12 Hz, 1H), 3.46 (d, J =11.6 Hz, 1H)。LCMS (ESI): m / z 308.2 [M+H] + .

[0149] Compounds 7, 8 and 9 etc. were synthesized using a procedure similar to that of compound 2.

[0150] Example 3 Synthesis of compound 3 Step 1: Synthesis of (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4- bis(benzyloxy)-5-((benzyloxy)methyl)-3-methyltetrahydrofuran-2-ol: To a stirred solution of 7-bromo-pyrrolo[2,1-f][1,2,4]triazin-4-amine (16.25 g, 76.298 mmol) in THF (380 mL) was added chloro[2-(chlorodimethylsilyl)ethyl]dimethylsilane (16.42 g, 76.298 mmol) and the resulting reaction mixture was stirred for 10 min at 0 °C under nitrogen atmosphere followed by dropwise addition of 2,2,6,6-tetramethylpiperidine (10.78 g, 76.298 mmol) at same temperature. The reaction was stirred for 30 min at 0 °C and then cooled to -78 °C. To this was added dropwise a solution of (3R,4R,5R)-3,4,5-trihydroxy-3-methyltetrahydrofuran-2- one (10.00 g, 76.298 mmol) in THF (380 mL) over a period of 30 min. The reaction was stirred for 16 h at -78 °C. The reaction mixture was allowed to warm to 0 °C and stirred for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were washed with water (2 x 100 mL), brine (1 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 100-200 mesh; 330 g, 60-80% EtOAc in hexane) to afford the title compound (20.00 g, 63.5% yield). nA solution of BuLi (240 mL, 1.6 M in hexane). The reaction mixture was stirred at -78 °C under nitrogen atmosphere for 1 h. To the above mixture was added dropwise a solution of (3R,4R,5R)-3,4-bis(benzyloxy)-5-[(benzyloxy)methyl]-3-methyloxolan-2-one (30 g, 69.362 mmol) in THF (100 mL) at -78 °C over 5 min. The resulting reaction mixture was stirred at -78 °C for another 2 h. The reaction was quenched with saturated aqueous NH4Cl solution at -78 °C. The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (1 x 30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / THF (2:1) to give (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-3-methyltetrahydrofuran-2-ol as a yellow oil (24.0 g, 61%). LCMS (ESI): m / z 589.3 [M+H] + .

[0151] Step 2: Synthesis of 7-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)- 3-methyltetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine: To a stirred solution of (3R,4R,5R)-2-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-3,4-bis(benzyloxy)-5- [(benzyloxy)methyl]-3-methyloxolane-2-ol (22 g, 38.824 mmol) in DCM (200 mL) was added Et3SiH (18.06 g, 155.296 mmol) and the resulting mixture was stirred for 5 min at 0 °C under nitrogen atmosphere followed by dropwise addition of BF3.Et20 (5.27 g, 77.648 mmol) at 0 °C. The reaction mixture was stirred for 1 h at room temperature under nitrogen atmosphere. After completion of the reaction, the reaction was quenched with saturated aqueous NH4C1 solution at 0 °C. The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (1x30 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography eluting with PE / THF (2:1) to afford 7-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-3- methyltetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine as a yellow oil (21.0 g, 98%). LCMS (ESI): m / z 551.3 [M+H] + .

[0152] Step 3: Synthesis of (2S,3R,4R,5R)-2-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol: To a stirred solution of 7-[(2S,3S,4R,5R)-3,4-bis(benzyloxy)-5- [(benzyloxy)methyl]-3-methyloxolan-2-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (8 g, 14.528 mmol) in DCM (100 mL) was added boron trichloride (17.02 g, 145.3 mmol) and the resulting reaction mixture was stirred at 0 °C under nitrogen atmosphere for 3 min. The reaction was stirred at room temperature under nitrogen atmosphere for 30 min. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate solution (50 mL) at 0 °C. The resulting mixture was separated with a separatory funnel. The aqueous phase was purified by reverse phase flash chromatography. The fractions were lyophilized and further purified by preparative chiral SFC to afford (2S,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- (hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol (1.56 g, 38%) (major peak in SFC). 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.82 (s, 1H), 7.64 (s,2H), 6.84 (d, J = 4.4 Hz, 1H), 6.70 (d, J = 4.4 Hz, 1H), 5.39 (s, 1H), 3.78-3.73 (m, 2H), 3.69 (d, J = 8.0 Hz, 1H), 3.61-3.57 (m, 1H), 0.79 (s, 3H). LCMS (ESI): m / z 281.2 [M+H] + .

[0153] Step 4: Synthesis of (2S,3R,4R,5S)-2-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-(iodomethyl)-3-methyltetrahydrofuran-3,4-diol: A solution of (2S,3R,4R,5R)-2-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5- (hydroxymethyl)-3-methyloxolane-3,4-diol (1.51 g, 5.387 mmol) in THF (80 mL) was treated with triphenylphosphine (3.53 g, 13.458 mmol), imidazole (526 mg, 7.726 mmol) and pyridine (3.0 mL, 37.28 mmol) at room temperature. To the above mixture was added dropwise iodine (2.73 g, 10.774 mmol) in THF (5 mL) at 0 °C over 15 min and the resulting mixture was stirred at room temperature for 4 h. The resulting mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with DCM / MeOH (10:1) to give (2S,3R,4R,5S)-2-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5- (iodomethyl)-3-methyloxolane-3,4-diol (1.77 g, 84%) as a brown solid. LCMS (ESI): m / z 391.0 [M+H] + .

[0154] Step 5: Synthesis of (2S,3R,4S)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3- methyl-5-methylene tetrahydrofuran-3,4-diol: To a stirred solution of (2S,3R,4R,5S)-2-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5-(iodomethyl)-3- methyloxolane-3,4-diol (1.77 g, 4.537 mmol) in THF (20 mL) was added sodium methoxide (1.77 mL, 9.558 mmol) dropwise at 0 °C and the resulting reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 10 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel eluting with DCM / MeOH (10:1) to give (2S,3R,4S)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3- methyl-5-methylene tetrahydrofuran-3,4-diol (480.0 mg, 40%) as a yellow oil. LCMS (ESI): m / z 263.3 [M+H] + .

[0155] Step 6: Synthesis of (2S,3S,4R)-2-(4-acetylamino pyrrolo[2,1-f][1,2,4]triazin-7-yl)-3- methyl-5-methylene tetrahydrofuran-3,4-diyl diacetate: To a stirred solution of (2S,3R,4S)-2-{4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl}-3-methyl-5-methylene oxolane-3,4-diol (400 mg, 1.525 mmol) in anhydrous pyridine (5 mL) was added Ac2O (934.21 mg, 9.150 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 6 h. After completion of the reaction, the reaction mixture was diluted with EtOAc (15 mL) and washed with water (15 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography using 10-40% EtOAc in heptane as eluent to afford (3R,4S,5S)-4-(acetyloxy)-5-{4-acetylamino pyrrolo[2,1-f][1,2,4]triazin-7-yl}-4-methyl-2-methylene oxolane-3-yl acetate (270 mg, 46%) as off-white solid. LCMS (ESI): m / z 389.2 [M+H] + .

[0156] Step 7: Synthesis of (2R,3S,4S,5S)-5-(4-acetylamino pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2- fluoro-2-(iodomethyl)-4-methyl tetrahydrofuran-3,4-diyl diacetate: To a stirred solution of (3R,4S,5S)-4-(acetyloxy)-5-{4-acetylamino pyrrolo[2,1-f][1,2,4]triazin-7-yl}-4-methyl-2-methylene oxolane-3-yl acetate (270 mg, 0.695 mmol) in anhydrous DCM (3 mL, 47.192 mmol) was added AgF (440.99 mg, 3.475 mmol) followed by a solution of I2 (352.89 mg, 1.390 mmol) in DCM at 0 °C. The reaction mixture was stirred at 0 °C for 10 min, then warmed to room temperature and stirred for another 2 h, forming a solid precipitate. After completion of the reaction, the precipitated solid was filtered and washed with ACN to afford (2R,3S,4S,5S)-4-(acetyloxy)-5-{4-acetylamino pyrrolo[2,1-f][1,2,4]triazin-7-yl}-2-fluoro-2-(iodomethyl)-4-methyl oxolane-3-yl acetate (245 mg, 66%) as a white solid. LCMS (ESI): m / z 535.1 [M+H]+ .

[0157] Step 8: Synthesis of (2S,3S,4S,5S)-5-(4-acetylamino pyrrolo[2,1- f][1,2,4]triazin-7-yl)-2-((benzoyloxy)methyl)-2-fluoro-4-methyltetrahydrofuran- 3,4-diyl diacetate: To a stirred solution of (2R,3S,4S,5S)-4-(acetyloxy)-5-{4- acetylamino pyrrolo[2,1-f][1,2,4]triazin-7-yl}-2-fluoro-2-(iodomethyl)-4- methyl oxolan-3-yl acetate (200 mg, 0.374 mmol) in DMSO (5 mL) was added sodium benzoate (539.43 mg, 3.740 mmol) and 15-crown-5 ether (1.65 g, 7.480 mmol) at room temperature. The resulting reaction mixture was stirred at 80 °C for 48 h. After completion of the reaction, the mixture was diluted with EtOAc (20 mL) and washed with ice cold water (3 x 10 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography using 20-50% EtOAc in heptane as eluent to afford [(2S,3S,4S,5S)-3,4-bis(acetyloxy)-5-{4-acetylamino pyrrolo[2,1- f][1,2,4]triazin-7-yl}-2-fluoro-4-methyloxolan-2-yl]methyl benzoate (50 mg, 25%) as a white solid. LCMS (ESI): m / z 529.1 [M+H] + .

[0158] Step 9: Synthesis of (2R,3S,4R,5S)-5-(4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 2-(hydroxymethyl)-2-methoxy-4-methyltetrahydrofuran-3,4-diol (3): A solution of [(2S,3S,4S,5S)-3,4-bis(acetyloxy)-5-{4-acetylamino pyrrolo[2,1-f][1,2,4]triazin-7- yl}-2-fluoro-4-methyloxolan-2-yl]methyl benzoate (40 mg, 0.076 mmol) in NH3 (7M in MeOH, 5 mL) was stirred at room temperature for 6 h. After completion of the reaction, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford (2R,3S,4R,5S)-5-{4-amino pyrrolo[2,1-f][1,2,4]triazin-7-yl}-2- (hydroxymethyl)-2-methoxy-4-methyloxolan-3,4-diol (1.4 mg, 6%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.82 (s, 1H), 7.64 (s, 2H), 6.84 (d, J = 4.4 Hz, 1H), 6.72 (d, J = 4.4 Hz, 1H), 5.55 (s, 1H),4.95 (d, J = 6.0 Hz, 1H), 4.49 (d, J = 9.2 Hz, 1H), 4.32 (s, 1H), 3.93 (d, J = 9.2 Hz, 1H), 3.69 (d, J = 5.6 Hz, 1H), 3.48 (d, J = 11.2 Hz, 1H), 3.27 (s,3H), 0.75 (s, 3H). LCMS (ESI): m / z 311.1 [M+H] + .

[0159] Compounds 19, 34 and 51 were synthesized using a procedure similar to that used for the synthesis of compound 3.

[0160] Example 4 Synthesis of compounds 4 and 5 Step 1: Synthesis of (2R,3R,4S,5S)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (iodomethyl)tetrahydrofuran-3,4-diol: To a solution of (2R,3R,4S,5R)-2-(4-chloro-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (1.06 g, 3.7 mmol) in anhydrous THF (12 mL) was added PPh3(1.2 g, 4.5 mmol) and imidazole (503 mg, 7.4 mmol) and the resulting reaction mixture was stirred at room temperature for 30 min. Iodine (1.15 g, 4.5 mmol) was added to the above reaction mixture at 0 °C. The reaction was stirred at room temperature for 12 h. After completion of the reaction, the reaction was quenched with saturated aqueous NaHCO3solution. The resulting mixture was concentrated in vacuo. The residue was diluted with DCM and extracted three times. The combined organic layers were dried over anhydrous sodium sulfate and the filtrate was concentrated in vacuo to give the crude product (2R,3R,4S,5S)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (iodomethyl)tetrahydrofuran-3,4-diol. LCMS (ESI): m / z 396.1 [M+H] + .

[0161] Step 2: Synthesis of (2R,3R,4S)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- methylenetetrahydrofuran-3,4-diol: To a solution of (2R,3R,4S,5S)-2-(4-chloro-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-5-(iodomethyl)tetrahydrofuran-3,4-diol (crude from step 1) in anhydrous THF (15 mL) was added DBU (8.6 mL, 55.6 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 12 h. After completion of the reaction, the pH was adjusted to 7 by the addition of AcOH followed by water. The resulting mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product (2R,3R,4S)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- methylenetetrahydrofuran-3,4-diol. The crude product was used for the next step without further purification. LCMS (ESI): m / z 268.0 [M+H] + .

[0162] Step 3: Synthesis of (2S,3S,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol (4) and (2R,3S,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol (5): To a stirred solution of (2R,3R,4S)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-methylene tetrahydrofuran-3,4-diol (crude from step 2, 230 mg, 0.86 mmol) in dry DCM (6 mL) was added mCPBA (297 mg, 1.7 mmol) followed by TEA.3HF (0.71 ml, 4.3 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 40 min. After completion of the reaction, the reaction mixture was concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to afford the desired compounds 4 and 5 (3 mg, 6%; 3 mg, 6%). Compound 4: 1 H NMR (400 MHz, DMSO -d 6 ) δ 8.69 (d, J = 1.4 Hz, 1H), 7.87 (d, J =3.7 Hz, 1H), 6.79 (d, J = 3.7 Hz, 1H), 6.47 (d, J = 3.0 Hz, 1H), 4.54 (dd, J= 16.4, 6.4 Hz, 1H), 4.44 (t, J = 4.8 Hz, 1H), 3.60 – 3.53 (m, 2H). LCMS (ESI): m / z 304.2 [M+H] + Compound 5:1H NMR (400 MHz, DMSO) 1 H NMR (400 MHz, DMSO- d 6 ) δ8.64 (s, 1H), 7.84 – 7.71 (d, 1H), 6.80 (d, J = 3.8 Hz, 1H), 6.44 (t, J = 7.1Hz, 1H), 4.84 (dt, J= 7.3, 3.5 Hz, 1H), 4.16 – 4.05 (m, 1H), 3.73 (s, 1H),3.52 – 3.40 (m, 1H). LCMS (ESI): m / z 304.2 [M+H] + .

[0163] Compounds 13, 27 and 29 were synthesized using a procedure similar to that of compound 4, and the like.

[0164] Example 5 Synthesis of compound 20 Step 1: Synthesis of ((5R,6S,6aR)-6-(benzyloxy)-5-((benzyloxy)methyl)-2,2- dimethyltetrahydrofuro[2,3-d][l,3]dioxol-5-yl)methanol: To a stirred solution of ((3aR,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][l,3]dioxol-5,5- diyl)dimethanol (6 g, 19.35 mmol) and 60% NaH (1.08 g, 27.09 mmol) in anhydrous N,N-dimethylformamide (60 mL) was added benzyl bromide (3.62 g, 21.3 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 1 h, then quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column to afford ((5R,6S,6aR)-6-(benzyloxy)-5-((benzyloxy)methyl)-2,2-dimethyltetrahydrofuro[2,3-d][l,3]dioxol-5-yl)methanol (5.2 g, 67%) as a yellow solid. LCMS (ESI): m / z 423.0 [M+Na] + .

[0165] Step 2: Synthesis of (5R,6S,6aR)-6-(benzyloxy)-5-((benzyloxy)methyl)-5- (fluoromethyl)-2,2-dimethyltetrahydrofuro[2,3-d][l,3]dioxole: To a stirred solution of (3R,4R,5R)-2-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5- ((benzyloxy)methyl)tetrahydrofuran-2-ol (5.2 g, 13 mmol) in toluene (52 mL) was added DAST (6.28 g, 39 mmol) at 0 °C under N2. The resulting mixture was stirred at 60 °C for 5 h, then quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column to afford (5R,6S,6aR)-6-(benzyloxy)-5-((benzyloxy)methyl)-5-(fluoromethyl)-2,2- dimethyltetrahydrofuro[2,3-d][l,3]dioxole (2.7 g, 52%) as yellow oil. LCMS (ESI): m / z 425.1 [M+Na] + .

[0166] Step 3: Synthesis of (3R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-5- (fluoromethyl)tetrahydrofuran-2,3-diyl diacetate: To (5R,6S,6aR)-6-(benzyloxy)-5- ((benzyloxy)methyl)-5-(fluoromethyl)-2,2-dimethyltetrahydrofuro[2,3-d][l,3]dioxole (2.7 g, 6.7 mmol) in acetic acid (36 mL) was added acetic anhydride (0.68 g, 6.7 mmol) and H2SO4(65.7 mg, 0.67 mmol) at 10 °C. The resulting mixture was stirred at room temperature for 1.5 h. After completion of the reaction, the reaction was quenched with H2O and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product. The residue was purified by silica gel column to afford (3R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-5- (fluoromethyl)tetrahydrofuran-2,3-diyl diacetate (2.3 g, 77%) as yellow solid. LCMS (ESI): m / z 469.0 [M+Na] + .

[0167] Step 4: Synthesis of (2R,3R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-2-(4- chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(fluoromethyl)tetrahydrofuran-3-yl acetate: To a mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (577.42 mg, 3.76 mmol) and BSA (764.9 mg, 3.76 mmol) in ACN (32 mL) was added (3R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-5- (fluoromethyl)tetrahydrofuran-2,3-diyl diacetate (1.6 g, 3.76 mmol) and TMSOTf (834.72 mg, 3.76 mmol). The reaction was stirred at 80 °C for 3 h. After the reaction was completed, the reaction was quenched with NaHC03(aq) and extracted with EtOAc. The combined organic layers were dried, concentrated, and purified by silica gel column to give (2R,3R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-2-(4-chloro-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-5-(fluoromethyl)tetrahydrofuran-3-yl acetate (215 mg, 11%) as a yellow solid. LCMS (ESI): m / z 540.0 [M+H] + .

[0168] Step 5: Synthesis of (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4- (benzyloxy)-5-((benzyloxy)methyl)-5-(fluoromethyl)tetrahydrofuran-3-ol: To a solution of (2R,3R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-2-(4-chloro-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-5-(fluoromethyl)tetrahydrofuran-3-yl acetate (215 mg, 0.4 mmol) in 1,4-dioxane (4 mL) was added NH3H2O (4 mL) and the resulting mixture was stirred at 100 °C for 25 h. The mixture was concentrated and purified by silica gel column to give (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-(benzyloxy)-5- ((benzyloxy)methyl)-5-(fluoromethyl)tetrahydrofuran-3-ol (180 mg, 94% yield) as a yellow solid. LCMS (ESI): m / z 479.2 [M+H] + .

[0169] Step 6: Synthesis of (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (fluoromethyl)-2-(hydroxymethyl)tetrahydrofuran-3,4-diol (20): To a stirred solution of (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-(benzyloxy)-5- ((benzyloxy)methyl)-5-(fluoromethyl)tetrahydrofuran-3-ol (180 mg, 0.376 mmol) in DCM (3 mL) was added BC13(3.8 mL, 3.76 mmol, 1M) at -78 °C under N2. The resulting mixture was stirred at -78 °C for 2 h, then quenched with MeOH (10 mL). The excess solvent was removed under reduced pressure. The residue was purified by preparative HPLC to give (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(fluoromethyl)-2- (hydroxymethyl)tetrahydrofuran-3,4-diol as a solid (Compound 20, 35 mg, 31% yield).

[0170] 1 H NMR (400 MHz, MeOD- d4 ) δ 8.06 (s, 1H), 7.32 (d, J = 3.1 Hz, 1H),6.61 (d, J = 2.7 Hz, 1H), 5.98 (d, J = 7.7 Hz, 1H), 4.84 – 4.83 (m, 1H), 4.74(d, J = 9.8 Hz, 1H), 4.60 (dd, J = 20.2, 9.8 Hz, 1H), 4.45 (d, J = 9.8 Hz,1H), 4.32 (d, J = 5.1 Hz, 1H), 3.76 (s, 2H)。

[0171] 19 F NMR (377 MHz, MeOD -d4 ) δ -236.74.

[0172] LCMS (ESI): m / z 299.0 [M+H] + .

[0173] Example 6 Synthesis of Compound 30 Step 1: (1 R ,2 S ,3 R 5 R )-3-(4-chloro-7 H -pyrrolo[2,3- d Synthesis of pyrimidin-7-yl)-5-(hydroxymethyl)cyclopentane-1,2-diol: TEA (3.03 mg, 30.0 mmol) was added to a solution of 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (1.91 g, 10.0 mmol) and (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol hydrochloride (1.84 g, 10.0 mmol) in EtOH (50 mL), and the reaction mixture was stirred at 80 °C for 24 hours. After the reaction was complete, the mixture was concentrated under vacuum. The residue was dissolved in a saturated NaHCO3 solution and then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure to give crude (1 R ,2 S ,3 R 5 R )-3-(4-chloro-7 H -pyrrolo[2,3- d Pyrimidin-7-yl)-5-(hydroxymethyl)cyclopentane-1,2-diol (2.83 g), a yellow gelatinous substance, was used in the next step without further purification. LCMS (ESI): m / z =284.1 [M+H] + .

[0174] Step 2: [(3a S 4 R 6 R ,6a R )-4-(4-chloropyrrolo[2,3- d ]pyrimidin-7-yl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -Cyclopenta[ d Synthesis of [l,3]dioxacyclopenten-6-yl]methanol: towards (1 R ,2 S ,3 R 5 R )-3-(4-chloro-7 H -pyrrolo[2,3- dTo a solution of (3aR,4S,6R,6aS)-4-(4-chloropyrrolo[2,3- b]pyrimidin-7-yl)-5-(hydroxymethyl)cyclopentane-1,2-diol (2.83 g, 10.0 mmol) and 2,2-dimethoxypropane (2.08 g, 20 mmol) in acetone (60 mL) was added 4-methylbenzenesulfonic acid hydrate (194 mg, 1 mmol). The mixture was stirred at room temperature for 2 h, then refluxed for 24 h. After the reaction was completed, the reaction was quenched by Et3N, then concentrated under reduced pressure. The residue was treated with saturated NaHCO3 solution and brine. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give [(3a S ,4 R ,6 R ,6a R )-4-(4-chloropyrrolo[2,3- d ]pyrimidin-7-yl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -cyclopenta[ d ][1,3]dioxol-6-yl]methanol (3.0 g, 93% yield) as a yellow solid. LCMS (ESI): m / z = 324.1 [M+H] m / z . + .

[0175] Step 3: Synthesis of 7-[(3aR,4S,6R,6aS)-6-(iodomethyl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[ S ,4 R ,6 S ,6a R ]-cyclopenta[ H ][1,3]dioxol-4-yl]-4-chloropyrrolo[2,3- d ]pyrimidine: To a solution of PPh3 (4.86 g, 9.29 mmol) and imidazole (1.94 g, 19.51 mmol) in THF (30 mL) was added I2 (4.72 g, 18.57 mmol). The mixture was stirred at room temperature under N2for 15 min, then [(3aR,4S,6R,6aS)-4-(4-chloropyrrolo[2,3- d ]pyrimidin-7-yl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[ S ,4 R ,6 R ,6a R ]-cyclopenta[ d ][1,3]dioxol-6-yl]methanol (3.0 g, 93% yield) as a yellow solid. LCMS (ESI): m / z = 324.1 [M+H] H . dA solution of [l,3]dioxacyclopenten-6-yl]methanol (3000 mg, 9.29 mmol) in THF (20 mL). The mixture was stirred at room temperature and under N2 for 1.5 h. After the reaction was complete, the reaction was quenched with saturated Na2S2O3 solution and then extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and then filtered. The filtrate was concentrated under vacuum. The residue was purified by column chromatography to give 7-[(3a S 4 R 6 S ,6a R )-6-(iodomethyl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -Cyclopenta[ d [l,3]dioxacyclopenten-4-yl]-4-chloropyrrolo[2,3-] d Pyrimidine (3.0 g, 69% yield) is a yellow solid. LCMS (ESI): m / z = 434.1 [M+H] + .

[0176] Step 4: 4-Chloro-7-((3a) S 4 R ,6a R )-2,2-Dimethyl-6-methylenetetrahydro-4H-cyclopenta[ d [1,3]dioxacyclopenten-4-yl)-7 H -pyrrolo[2,3- d Synthesis of pyrimidines: At 0°C, 7-[(3a]pyrimidines were synthesized... S 4 R 6 S ,6a R )-6-(iodomethyl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H -Cyclopenta[ d [l,3]dioxacyclopenten-4-yl]-4-chloropyrrolo[2,3-] d A solution of pyrimidine (3000 mg, 6.93 mmol) in THF (20 mL) was added to 1 M of THF (6.93 mL). t -BuOK. Stir the reaction mixture at 0°C for 30 minutes. After the reaction is complete, quench the reaction with a saturated aqueous solution of NH4Cl. Extract the mixture with EtOAc. Combine the separated organic layers, wash with brine, dry over anhydrous Na2SO4, and concentrate under reduced pressure. Purify the residue by silica gel chromatography to give 4-chloro-7-((3a S 4 R ,6a R)-2,2-dimethyl-6-methylenetetrahydro-4H-cyclopenta[ d ][1,3]dioxol-4-yl)-7 H -pyrrolo[2,3- d ]pyrimidine (2.12 g, 94% yield) as a colorless foam. LCMS (ESI): m / z = 306.1 [M+H] + .

[0177] Step 5: Synthesis of (3a S ,4 R ,6 R ,6a S )-6-(4-chloropyrrolo[2,3- d ]pyrimidin-7-yl)-4-(hydroxymethyl)-2,2-dimethyl-3a,5,6,6a tetrahydrocyclopenta[ d ][1,3]dioxol-4-ol: To a mixture of 4-chloro-7-((3a S ,4 R ,6a R )-2,2-dimethyl-6-methylenetetrahydro-4H-cyclopenta[ d ][1,3]dioxol-4-yl)-7 H -pyrrolo[2,3- d ]pyrimidine (1300 mg, 4.024 mmol) and NMO (943 mg, 8.06 mmol) in a mixed solvent of acetone (26 mL) and H2O (5.2 mL) was added K2OsO4.2H2O (30.3 mg, 0.098 mmol). The mixture was stirred at room temperature for 20 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give (3a S ,4 R ,6 R ,6a S )-6-(4-chloropyrrolo[2,3- d ]pyrimidin-7-yl)-4-(hydroxymethyl)-2,2-dimethyl-3a,5,6,6a tetrahydrocyclopenta[ d ][1,3]dioxol-4-ol (1300 mg, 95% yield) as a light yellow foam. LCMS (ESI): m / z = 340.0 [M+H] + .

[0178] Step 6: Benzoic acid [(3a S ,4 R ,6 R ,6a S)-6-(4-chloropyrrolo[2,3- d]pyrimidin-7-yl)-4-hydroxy-2,2-dimethyl- 3a,5,6,6a tetrahydrocyclopenta[ d ]pyrrolo[2,3- d]pyrimidin-7-yl)-4-(hydroxymethyl)-2,2-dimethyl- 3a,5,6,6a tetrahydrocyclopenta[ d ]pyrrolo[2,3- d]pyrimidin-7-yl)-4-(hydroxymethyl)-2,2-dimethyl- 3a,5,6,6a tetrahydrocyclopenta[ S ,4 R ,6 R ,6a S )-6-(4-chloropyrrolo[2,3- d]pyrimidin-7-yl)-4-(hydroxymethyl)-2,2-dimethyl- 3a,5,6,6a tetrahydrocyclopenta[ d ]pyrrolo[2,3- d]pyrimidin-7-yl)-4-(hydroxymethyl)-2,2-dimethyl- 3a,5,6,6a tetrahydrocyclopenta[ d ]pyrrolo[2,3- d]pyrimidin-7-yl)-4-(hydroxymethyl)-2,2-dimethyl- 3a,5,6,6a tetrahydrocyclopenta[ S ,4 R ,6 R ,6a S )-6-(4-chloropyrrolo[2,3- d]pyrimidin-7-yl)-4-(hydroxymethyl)-2,2-dimethyl- 3a,5,6,6a tetrahydrocyclopenta[ d ]pyrrolo[2,3- d]pyrimidin-7-yl)-4-(hydroxymethyl)-2,2-dimethyl- 3a,5,6,6a tetrahydrocyclopenta[ d ]pyrrolo[2,3- d]pyrimidin-7-yl)-4-(hydroxymethyl)-2,2-dimethyl- 3a,5,6,6a tetrahydrocyclopenta[ m / z = 444.1 [M+H] + .

[0179] Step 7: Synthesis of benzoic acid ((3a S ,4 S ,6 R ,6a S )-6-(4-chloro-7 H -pyrrolo[2,3- d]pyrimidin-7-yl)-4-fluoro-2,2-dimethyltetrahydro-4 H -cyclopenta[ d ] [1,3]dioxol-4-yl)methyl ester: To a solution of benzoic acid ((3a S ,4 R ,6 R ,6a S )-6-(4-chloro-7 H -pyrrolo[2,3- d]pyrimidin-7-yl)-4-fluoro-2,2-dimethyltetrahydro-4 d]pyrimidin-7-yl)-4-hydroxy-2,2-dimethyltetrahydro-4 H -Cyclopenta[ d [1,3]dioxane-4-yl)methyl ester (600 mg, 1.355 mmol) was added to a solution of DAST (436.5 mg, 2.71 mmol) in anhydrous DCM (30 mL). The reaction mixture was stirred at 0 °C for 1 hour. The mixture was quenched with a saturated aqueous solution of NaHCO3 and extracted with DCM. The separated organic layers were combined, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give benzoic acid ((3a) S 4 S 6 R ,6a S )-6-(4-chloro-7 H -pyrrolo[2,3-d]pyrimidin-7-yl)-4-fluoro-2,2-dimethyltetrahydro-4 H -Cyclopenta[ d [1,3]dioxacyclopenten-4-yl)methyl ester (62 mg, 10%), is a white foamy substance. LCMS (ESI): m / z =446.2 [M+H] + .

[0180] Step 8: ((3a) S 4 S 6 R ,6a S )-6-(4-amino-7 H -pyrrolo[2,3-d]pyrimidin-7-yl)-4-fluoro-2,2-dimethyltetrahydro-4 H -Cyclopenta[ d Synthesis of [1,3]dioxacyclopenten-4-yl)methanol: [The text abruptly ends here, so the translation stops as well.] S 4 S 6 R ,6a S )-6-(4-chloro-7 H -pyrrolo[2,3-d]pyrimidin-7-yl)-4-fluoro-2,2-dimethyltetrahydro-4 H -Cyclopenta[ d [1,3]dioxane-4-yl)methyl ester (39 mg, 0.0876 mmol) was reacted with concentrated ammonia (2 mL) in a solution of dioxane (2 mL). The reaction mixture was then stirred at 100 °C for 16 hours. The solvent was removed under vacuum to obtain ((3a)methyl ester. S 4 S 6 R ,6a S)-6-(4-amino-7 H -pyrrolo[2,3-d]pyrimidin-7-yl)-4-fluoro-2,2-dimethyltetrahydro-4 H -Cyclopenta[ d [1,3]dioxacyclopenten-4-yl)methanol (20 mg, 71%), a pale yellow foamy substance. LCMS: m / z =323.2 [M+H] + .

[0181] Step 9: (1) S ,2 S ,3 S 5 R )-5-(4-amino-7 H -pyrrolo[2,3- d Synthesis of pyrimidin-7-yl)-3-fluoro-3-(hydroxymethyl)cyclopentane-1,2-diol (9): To ((3a S 4 S 6 R ,6a S )-6-(4-amino-7 H -pyrrolo[2,3-d]pyrimidin-7-yl)-4-fluoro-2,2-dimethyltetrahydro-4 H -Cyclopenta[ d [1,3]dioxacyclopenten-4-yl)methanol (2 mg, 0.0062 mmol) was dissolved in THF (1 mL) with 4 M HCl (0.5 mL). The reaction mixture was then stirred at 0 °C for 1 hour. After the reaction was complete, the solvent was removed under vacuum and purified by reversed-phase preparative HPLC to obtain (1 S ,2 S ,3 S 5 R )-5-(4-amino-7 H -pyrrolo[2,3- d Pyrimidin-7-yl)-3-fluoro-3-(hydroxymethyl)cyclopentane-1,2-diol (compound 9, 1.5 mg, 83%) is a white foamy substance. 1 H NMR (400 MHz, methanol-) d 4) δ 8.21 (s, 1H), 7.49 (d, J =3.7 Hz, 1H), 6.85 (d, J = 3.6 Hz, 1H), 5.22 (dd, J = 17.0, 9.7 Hz, 1H), 4.47(t, J= 6.7 Hz, 1H), 4.21 (dd, J = 13.0, 6.2 Hz, 1H), 3.88 – 3.69 (m, 2H), 2.52 (ddd, J = 20.0, 14.8, 9.5 Hz, 1H), 2.42 – 2.25 (m, 1H). LCMS(ESI): m / z =283.0 [M+H] + .

[0182] Example 7 Synthesis of Compound 47 Synthesis of (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2-((isobutyryloxy)methyl)tetrahydrofuran-3,4-diylbis(2-methylpropionate) (47): Isobutyric acid (511 mg, 5.81 mmol), 4-dimethylaminopyridine (65 mg, 0.53 mmol), and dicyclohexylcarbodiimide (1.2 g, 5.81 mmol) were added to a solution of (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound 1, 500 mg, 1.76 mmol) in dichloromethane (10 mL) at room temperature. The mixture was stirred for 2 hours. After the reaction was complete, insoluble solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain (2 S ,3 S 4 R 5 R )-5-(4-amino-7 H -pyrrolo[2,3- d Pyrimidin-7-yl)-2-fluoro-2-((isobutyryloxy)methyl)tetrahydrofuran-3,4-diylbis(2-methylpropionate) (compound 47,450 mg, 52% yield) is a white solid. 1 H NMR (300 MHz, DMSO- d 6) δ 8.09 (s, 1H), 7.37 (d, J = 3.6 Hz,1H), 7.17 (s, 2H), 6.64 (d, J = 3.6 Hz, 1H), 6.50 (d, J= 1.8 Hz, 1H), 6.25 (dd, J = 19.1, 7.0 Hz, 1H), 5.93 (dd, J = 7.0, 2.1 Hz, 1H), 4.42 – 4.23 (m,2H), 2.63 (dt, J = 13.9, 6.9 Hz, 2H), 2.48 – 2.40 (m, 1H), 1.15 (d, J = 6.9Hz, 6H), 1.13 – 1.02 (m, 9H), 0.97 (d, J = 7.0 Hz, 3H). LCMS(ESI): m / z 495.3 [M+H] + .

[0183] Compounds 46 and 73 were synthesized using a procedure similar to that used for synthesizing compound 47.

[0184] Example 8 Synthesis of compounds 48 and 49 Step 1: (2) S Synthesis of isopropyl 2-{[chloro(phenoxy)phosphoryl]amino}propionate: (2 S A solution of 2-aminopropionic acid isopropyl hydrochloride (3 g, 17.8 mmol) in DCM (60 mL) was treated with phenoxyphosphonyl dichlorochloride (4.15 g, 19.6 mmol) at -78 °C under a nitrogen atmosphere for 30 min, followed by dropwise addition of TEA (3.62 g, 35.7 mmol) at -78 °C. The resulting mixture was stirred at room temperature for another 1 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with MTBE (30 mL). The resulting mixture was filtered, and the filter cake was washed with MTBE (2 x 10 mL). The filtrate was concentrated under reduced pressure. The crude product (chloro(phenoxy)phosphonyl)-L-alanine isopropyl ester (4.2 g) was used directly in the next step without further purification. LCMS (ESI) m / z 306.1 [M+H] + .

[0185] Step 2: (2) S )-2-({[(2 S ,3 S 4 R 5 R )-5-{4-aminopyrrolo[2,3- dSynthesis of isopropyl pyrimidin-7-yl}-2-fluoro-3,4-dihydroxyoxacyclopentan-2-yl]methoxy(phenoxy)phosphoryl}amino)propionate (48 and 49): synthesized by synthesis of (2...) under 0°C and nitrogen atmosphere. S ,3 S 4 R 5 R )-5-{4-aminopyrrolo[2,3- d A solution of 1-methyl-1H-imidazol (1.27 g, 15.4 mmol) and (2S)-2-{[chloro(phenoxy)phosphoryl]amino}propionate isopropyl ester (2.15 g, 7.03 mmol) in THF (4 mL) was added dropwise to a stirred solution of pyrimidin-7-yl}-2-fluoro-2-(hydroxymethyl)oxacyclopentane-3,4-diol (compound 1, 800 mg, 2.81 mmol) in THF (10 mL) and trimethyl phosphate (1 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with H2O at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine (1 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC and preparative SFC to obtain (2 S )-2-({[(2 S ,3 S 4 R 5 R )-5-{4-aminopyrrolo[2,3- d [Pyrimidin-7-yl]-2-fluoro-3,4-dihydroxyoxacyclopentan-2-yl]methoxy(phenoxy)phosphoryl]amino)isopropyl propionate (compound 48, 2.4 mg, second peak in preparative SFC) and (2 S )-2-({[(2 S ,3 S 4 R 5 R )-5-{4-aminopyrrolo[2,3- d Isopropyl pyrimidin-7-yl}-2-fluoro-3,4-dihydroxyoxacyclopentan-2-yl]methoxy(phenoxy)phosphoryl}amino)propionate (compound 49, 5.3 mg, first peak in preparative SFC), is a white solid. LCMS m / z [M+H] + 554.1.

[0186] Compound 48: 1 H NMR (300 MHz, DMSO- d6 ) δ 8.08 (s, 1H), 7.32 (t,J = 7.7 Hz, 2H), 7.24 (d, J = 3.6 Hz, 1H), 7.15 (m, 5H), 6.62 (d, J = 3.7 Hz, 1H),6.35 (d, J = 3.2 Hz, 1H), 6.06 (dd, J = 13.1, 10.1 Hz, 1H), 5.81 (d, J = 5.6Hz, 1H), 5.40 (d, J = 8.5 Hz, 1H), 4.82 (m, 1H), 4.58 (m, 1H), 4.46 (m, 1H),4.14 (m, 2H), 3.83 – 3.65 (m, 1H), 1.22 – 0.98 (m, 9H). 19 F NMR (282 MHz, DMSO- d6 ) δ -120.63.

[0187] Compound 49: 1 H NMR (300 MHz, DMSO- d6 ) δ 8.08 (s, 1H), 7.34 (t, J = 7.8Hz, 2H), 7.24 – 7.08 (m, 6H), 6.63 (d, J = 3.7 Hz, 1H), 6.36 (d, J = 3.0 Hz,1H), 6.03 (dd, J = 13.4, 9.9 Hz, 1H), 5.82 (d, J = 5.4 Hz, 1H), 5.43 (d, J =8.7 Hz, 1H), 4.83 (m, 1H), 4.58 (m, 1H), 4.46 (s, 1H), 4.17 (m, 2H), 3.69 (m,1H), 1.13 (d, J = 5.8 Hz, 9H). 19 F NMR (282 MHz, DMSO- d6 ) δ -120.27.

[0188] Compound 74 was synthesized using a procedure similar to that for synthesizing compounds 48 and 49.

[0189] Example 9 Synthesis of compounds 57, 58 and 59 Step 1: Synthesis of (4 S ,5 R )-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}oxolan-2-one: To a solution of deoxyribofuranose lactone (50 g, 378.458 mmol) in DMF (500 mL) was added imidazole (64.41 g, 946.1 mmol) and DMAP (2.31 g, 18.92 mmol) and TBSCl (119.8 g, 794.8 mmol) at 0 °C. The mixture was stirred at 20 °C for 12 h. The mixture was quenched with NaHCO3 (500 mL) and extracted with EtOAc (3 x 500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography to give (4 S ,5 R )-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}oxolan-2-one (110 g, 81%) as a white solid. 1 H NMR (300 MHz, Chloroform- d ) δ 4.52 (m, 1H), 4.35 (m, 1H), 3.87 – 3.74 (m, 2H), 2.84 (dd, J = 17.6,6.7 Hz, 1H), 2.40 (dd, J = 17.6, 2.6 Hz, 1H), 0.91 (s, 18H), 0.14 – 0.06 (m,12H).

[0190] Step 2: Synthesis of (3 S ,4 R ,5 R )-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3- fluorooxolan-2-one: To a solution of (4 S ,5 RA solution of 4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}oxacyclopentan-2-one (60 g, 166.4 mmol) and NFSI (65.58 g, 208.0 mmol) in THF (1200 mL) was mixed with LiHMDS (232.9 mL, 233.0 mmol). The mixture was stirred at -78 °C for 2 h. The reaction was quenched with NH4Cl at -78 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine (300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain (3 S 4 R 5 R )-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-fluorooxocyclopentan-2-one (30 g, 48%) is a colorless oil.

[0191] Step 3: (3) S 4 R 5 R Synthesis of 3-chloro-3-fluorooxocyclopentan-2-one: The methyl group was synthesized at -78°C to (3-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-chloro-3-fluorooxocyclopentan-2-one. S 4 R 5 R A solution of 28 g (7.98 mmol) of 4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-fluorooxocyclopentan-2-one and NCS (23.52 g, 147.90 mmol) in THF (110 mL) was mixed with LiHMDS (184.9 mL, 174.9 mmol). The mixture was stirred at -78 °C for 2 h. The reaction was quenched with saturated NH4Cl (aqueous solution) at -78 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain (3 S 4 R 5 R )-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-chloro-3-fluorooxetane-2-one (12 g, 39%) is a yellow oil. 1 H NMR (300 MHz, chloroform-) d ) δ4.60(dd, J = 12.0, 5.7 Hz, 1H), 4.40 – 4.33 (m, 1 H), 4.00 (dd, J = 12.1, 3.9 Hz,1H), 3.90 – 3.83 (m, 1H), 0.95 (s, 9H), 0.91 (s, 9H), 0.23 (s, 3H), 0.19 (s,3H), 0.11 (d, J = 2.7 Hz, 6H).

[0192] Step 4: (3) S 4 R 5 R Synthesis of 3-(3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-chloro-3-fluorooxetane-2-ol: Li(t-BuO)3AlH (92.63 mL, 82.63 mmol) was added to a solution of (3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-chloro-3-fluorooxetane-2-one (12 g, 29.05 mmol) in THF (120 mL) at 0 °C. The mixture was stirred at 20 °C for 2 h, and then quenched with saturated NH4Cl (aqueous solution) at 0 °C. The resulting mixture was extracted with EA. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain (3) S 4 R 5 R )-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-chloro-3-fluorooxocyclopentan-2-ol (12.2 g, 100%) is a yellow oil.

[0193] Step 5: N -(tert-Butoxycarbonyl)-N-{9-[(2 R ,3 S 4 R 5 R Synthesis of tert-butyl carbamate: (3)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-chloro-3-fluorooxocyclopentan-2-yl]-6-chloropurine-2-yl}carbamate S 4 R 5 R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3- chloro-3-fluorooxolan-2-ol (11.25 g, 27.1 mmol) and N -(tert-butoxycarbonyl)- N -(tert-butoxycarbonyl)- N -(tert-butoxycarbonyl)-N-{9-[(2 R ,3 S ,4 R ,5 R )-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3- chloro-3-fluorooxolan-2-yl]-6-(methylamino)purin-2-yl}carbamic acid tert-butyl ester (4.6 g, 22%) as a white solid. LCMS (ESI): m / z 766.7 [M+H] + .

[0194] Step 6: Synthesis of N-(tert-butoxycarbonyl)-N-{9-[(2 R ,3 S ,4 R ,5 R )-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3- chloro-3-fluorooxolan-2-yl]-6-(methylamino)purin-2-yl}carbamic acid tert-butyl ester: To N -(tert-butoxycarbonyl)- N -{9-[(2 R ,3 S ,4 R ,5 RTo a solution of tert-butyl {9-[(2,3-dichloro-4-oxo-3-(2,2,2-trifluoroethoxy)- 5-(2,2,2-trifluoroethyl)oxolan-2-yl]-6-oxo-1,6-dihydropyrimidin-5-yl}aminoformate (4.6 g, 6.01 mmol, 1 equiv) in EtOH (45 mL) was added methylamine (33% in ethanol). The mixture was stirred at 60 °C for 2 h, and the resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to give tert-butyl {9-[(2,3-dichloro-4-oxo-3-(2,2,2-trifluoroethoxy)-5-(2,2,2- trifluoroethyl)oxolan-2-yl]-6-oxo-1,6-dihydropyrimidin-5-yl}aminoformate (4.6 g, 6.01 mmol, 1 equiv) as a white solid. LCMS (ESI): m / z 661.5 [M+H] N -(tert-butoxycarbonyl)- N -{9-[(2 R ,3 S ,4 R ,5 R )-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3- chloro-3-fluorooxolan-2-yl]-6-(methylamino)purin-2-yl}aminoformate (4 g, 98%) as an off-white solid. LCMS (ESI): m / z 661.5 [M+H] + .

[0195] Step 7: N -{9-[(2 R ,3 S ,4 R ,5 R )-3-chloro-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(methylamino)purin- 2-yl}aminoformate: To a solution of tert-butyl {9-[(2,3-dichloro-4-oxo-3-(2,2,2- trifluoroethoxy)-5-(2,2,2-trifluoroethyl)oxolan-2-yl]-6-oxo-1,6-dihydropyrimidin-5-yl} aminoformate (4 g, 6.048 mmol) in MeOH (80 mL) was added KF (3.51 g, 60.48 mmol). The mixture was stirred at 60 °C for 6 h, and the resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to give tert-butyl {9-[(2,3-dichloro-4-oxo-3-(2,2,2-trifluoroethoxy)-5-(2,2,2- trifluoroethyl)oxolan-2-yl]-6-oxo-1,6-dihydropyrimidin-5-yl}aminoformate (4 g, 6.048 mmol) as a white solid. LCMS (ESI): m / z 661.5 [M+H] N -{9-[(2 R ,3 S ,4 R ,5 R )-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3- chloro-3-fluorooxolan-2-yl]-6-(methylamino)purin-2-yl}aminoformate (4 g, 98%) as an off-white solid. LCMS (ESI): m / z 661.5 [M+H] N -{9-[(2 R ,3 S ,4 R ,5 R3-Chloro-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxacyclopentan-2-yl]-6-(methylamino)purine-2-yl} tert-butyl carbamate (2.5 g, 96%) is a white solid. LCMS (ESI): m / z 433.0 [M+H] + .

[0196] Step 8: N -{9-[(2 R ,3 S 4 R 5 S Synthesis of tert-butyl carbamate: [3-chloro-3-fluoro-4-hydroxy-5-(iodomethyl)oxepane-2-yl]-6-(methylamino)purine-2-yl]carbamate N -{9-[(2 R ,3 S 4 R 5 R 3-Chloro-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxacyclopentan-2-yl]-6-(methylamino)purine-2-yl} tert-butyl carbamate (2.5 g, 5.776 mmol) was added to a solution of 3-chloro-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxacyclopentan-2-yl]-6-(methylamino)purine-2-yl}carbamate (4.5 g, 5.776 mmol) in THF (40 mL) with PPh3 (4.545 g, 17.33 mmol), pyridine (4.569 g, 57.76 mmol), and I2 (2.932 g, 11.55 mmol). The mixture was stirred at 20 °C for 12 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography after elution with PE / THF (2 / 1) to obtain N -{9-[(2 R ,3 S 4 R 5 S 3-Chloro-3-fluoro-4-hydroxy-5-(iodomethyl)oxetane-2-yl]-6-(methylamino)purine-2-yl} tert-butyl carbamate (3 g, 96%) is a yellow oil. LCMS (ESI): m / z 543.0 [M+H] + .

[0197] Step 9: N-{9-[(2 R ,3 S 4 R Synthesis of tert-butyl carbamate: [3-chloro-3-fluoro-4-hydroxy-5-methyleneoxepane-2-yl]-6-(methylamino)purine-2-yl]carbamate N -{9-[(2 R ,3 S 4 R 5 S3-chloro-3-fluoro-4-hydroxy-5-(iodomethyl)oxacyclopentan-2-yl]-6-(methylamino)purine-2-yl} tert-butyl carbamate (3 g, 5.528 mmol) was added to a solution of DBU (3.37 g, 22.11 mmol) in THF (50 mL). The mixture was stirred at 20 °C for 7 h, and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain... N 9-[(2R,3S,4R)-3-chloro-3-fluoro-4-hydroxy-5-methyleneoxetane-2-yl]-6-(methylamino)purine-2-yl} tert-butyl carbamate (830 mg, 36%) is a white solid. LCMS (ESI): m / z 415.2 [M+H] + .

[0198] Step 10: N -{9-[(2 R ,3 S 4 R 5 R Synthesis of tert-butyl carbamate: [3-chloro-3,5-difluoro-4-hydroxy-5-(iodomethyl)oxepane-2-yl]-6-(methylamino)purine-2-yl]carbamate: [The following text appears to be a separate, unrelated section:] ...at 0℃... N -{9-[(2 R ,3 S 4 R 3-Chloro-3-fluoro-4-hydroxy-5-methyleneoxepane-2-yl]-6-(methylamino)purine-2-yl} tert-butyl carbamate (600 mg, 1.446 mmol) was added to a solution in MeCN (6 mL) with TEA·3HF (349.8 mg, 2.169 mmol). The mixture was stirred for 10 minutes. NIS (488.1 mg, 2.169 mmol) was added at 0 °C, and the mixture was heated to room temperature and stirred for 1 hour. After the reaction was complete, the reaction was slowly quenched with ice-cold water and extracted with EtOAc. The resulting mixture was concentrated under reduced pressure, and the crude product was obtained. N -{9-[(2 R ,3 S 4 R 5 R 3-Chloro-3,5-difluoro-4-hydroxy-5-(iodomethyl)oxetane-2-yl]-6-(methylamino)purine-2-yl} tert-butyl carbamate (1.1 g, crude) was used directly in the next step without further purification. LCMS (ESI): m / z 561.0 [M+H] + .

[0199] Step 11 : Synthesis of (2 R ,3 R ,4 S ,5 R )-5-{2-[(tert-butoxycarbonyl)amino]-6-(methylamino)purin-9-yl}-4-chloro-2,4-difluoro-2- (iodomethyl)oxolan-3-yl benzoate: To a solution of tert-butyl {9-[(2 R ,3 S ,4 R ,5 R )-3-chloro-3,5-difluoro-4-hydroxy-5-(iodomethyl)oxolan-2-yl]-6-(methylamino)purin-2-yl} carbamate (1.1 g, 1.96 mmol) in pyridine (8 mL) was added benzoyl chloride (1378.8 mg, 9.80 mmol) at 0 °C. The mixture was stirred for 45 min. After completion of the reaction, the mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to afford (2 R ,3 R ,4 S ,5 R )-5-{2-[(tert-butoxycarbonyl)amino]-6-(methylamino)purin-9-yl}-4-chloro-2,4-difluoro-2- (iodomethyl)oxolan-3-yl benzoate (600 mg, 46%). LCMS (ESI): m / z 665.1 [M+H] + .

[0200] Step 12: Synthesis of benzoic acid [(2 S ,3 R ,4 S ,5 R )-3-(benzoyloxy)-5-{2-[(tert-butoxycarbonyl)amino]-6-(methylamino)purin-9-yl}-4-chloro-2,4- difluorooxolan-2-yl]methyl ester: To (2 R ,3R,4 S ,5 R)-5-{2-[(tert-butyloxycarbonyl)amino]-6-(methylamino)purine-9-yl}-4-chloro-2,4-difluoro-2-(iodomethyl)oxacyclopentane-3-ylbenzoate (600 mg, 0.903 mmol) was added to a solution of sodium benzoate (1.040 g, 7.224 mmol) in DMSO (10 mL). The mixture was stirred at 100 °C for 12 h, and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain benzoic acid [(2 S ,3 R 4 S 5 R 3-(benzoyloxy)-5-{2-[(tert-butoxycarbonyl)amino]-6-(methylamino)purin-9-yl}-4-chloro-2,4-difluorooxetane-2-yl]methyl ester (400 mg, 67%) is a yellow oil. LCMS (ESI): m / z 659.2 [M+H] + .

[0201] Step 13: Benzoic acid [(2 S ,3 R 4 S 5 R Synthesis of methyl benzoic acid [(2-[2-amino-6-(methylamino)purine-9-yl]-3-(benzoyloxy)-4-chloro-2,4-difluorooxetane-2-yl] ester: S ,3 R 4 S 5 R A solution of methyl benzoic acid [(2-(benzoyloxy)-5-{2-[(tert-butyloxycarbonyl)amino]-6-(methylamino)purine-9-yl}-4-chloro-2,4-difluorooxetane-2-yl]methyl ester (400 mg, 0.304 mmol) and HCl (1 mL, 4.0 mmol) in DCM (3 mL) was stirred at 20 °C for 4 h. The mixture was alkalized to pH = 7 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give benzoic acid [(2-(benzoyloxy)-5-{2-[(tert-butyloxycarbonyl)amino]-6-(methylamino)purine-9-yl}-4-chloro-2,4-difluorooxetane-2-yl]methyl ester (400 mg, 0.304 mmol) and HCl (1 mL, 4.0 mmol) in DCM (3 mL) was stirred at 20 °C for 4 h. S ,3 R 4 S 5 R)-5-[2-amino-6-(methylamino)purin-9-yl]-3-(benzoyloxy)-4-chloro-2,4- difluoro oxolan-2-yl]methyl ester (300 mg, 89%) as yellow oil. LCMS (ESI): m / z 559.2 [M+H] + .

[0202] Step 14: Synthesis of (2 S ,3 R ,4 S ,5 R )-5-[2-amino-6-(methylamino)purin-9-yl]-4-chloro-2,4-difluoro-2- (hydroxymethyl)oxolan-3-ol (57): A solution of tert-butyl {9-[(2 N -{9-[(2 R ,3 S ,4 R ,5 S )-3-chloro-3,5-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-6- (methylamino)purin-2-yl}carbamate (280 mg, 0.621 mmol) in methylamine (33% in ethanol) was stirred at 20 °C for 2 h. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC to give (2 S ,3 R ,4 S ,5 R )-5-[2-amino-6-(methylamino)purin-9-yl]-4-chloro-2,4-difluoro-2- (hydroxymethyl)oxolan-3-ol (Compound 57, 95 mg, 51%) as a white solid. LCMS (ESI): m / z 351.0 [M+H] + .

[0203] Compounds 56, 60, 62, 63, 66, 68, 70 and 71 were synthesized using a procedure similar to that of Compound 57.

[0204] Step 15: Synthesis of isopropyl (2S)-2-({[(2 S ,3 R ,4 S ,5 R )-5-[2-amino-6-(methylamino)purin-9-yl]-4-chloro-2,4-difluoro-3- hydroxyoxolan-2-yl]methoxy(phenyloxy)phosphoryl}amino)propanoate (58 and 59): To (2 S ,3 R ,4 S ,5R )-5-[2-amino-6-(methylamino)purine-9-yl]-4-chloro-2,4-difluoro-2-(hydroxymethyl)oxacyclopentan-3-ol (compound 57, 50 mg, 0.143 mmol) and (2 S Isopropyl propionate (162 mg, 0.357 mmol) was added dropwise to a stirred mixture of THF (2 mL) and acetonitrile (0.2 mL) with 1-methyl-1H-imidazolium (29 mg, 0.357 mmol). The resulting mixture was stirred at room temperature for 2 h. MgCl2 (14 mg, 0.143 mmol) and DIEA (37 mg, 0.286 mmol) were added to the mixture at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction was quenched with water. The crude product was purified by preparative HPLC and SFC to give each isomer (compound 58, 8.4 mg, second peak in preparative SFC, and compound 59, 7.0 mg, first peak in preparative SFC) as a white solid. LCMS (ESI): m / z 619.2 [M+H] + .

[0205] Compound 62: 1 H NMR (400 MHz, DMSO- d6 ) δ 7.86 (s, 1H), 7.37 (t, J = 7.9Hz, 3H), 7.29 – 7.21 (m, 2H), 7.19 (t, J = 7.3 Hz, 1H), 6.72 (d, J = 15.0 Hz,2H), 6.21 – 6.13 (m, 2H), 6.07 (dd, J = 13.1, 10.0 Hz, 1H), 4.82 (m, 1H), 4.70 (brs, 1H), 4.33 (m, 1H), 3.85 – 3.73 (m, 1H), 2.88 (s, 3H), 1.19 (d, J =7.1 Hz, 3H), 1.12 (dd, J = 6.3, 4.0 Hz, 6H). 19 F NMR (376 MHz, DMSO- d6 ) δ -116.58.

[0206] Compound 63: 1 H NMR (400 MHz, DMSO- d6 ) δ 7.85 (s, 1H), 7.41 – 7.29 (m,3H), 7.17 (d, J = 7.6 Hz, 3H), 6.79 (s, 1H), 6.72 (d, J = 14.9 Hz, 1H), 6.15(s, 2H), 6.10 – 6.02 (m, 1H), 4.84 (m, 1H), 4.63 (s, 1H), 4.43 (m, 1H), 3.81(m, 1H), 2.88 (s, 3H), 1.23 (d, J = 7.1 Hz, 3H), 1.14 (d, J = 6.2 Hz, 6H)。 19 FNMR (376 MHz, DMSO- d6 ) δ -116.28.

[0207] Compounds 61, 64, 65, 67, and 69, etc. were synthesized using a procedure similar to that of synthesizing compounds 58 and 59.

[0208] Example 10 Synthesis of compound 75 To a solution of 1 (130 mg, 457 μmol), proton sponge (97.8 mg, 457 μmol) in PO(OMe)3(1.30 mL) was added POCl3(104 mg, 685 μmol, 63.5 μL) at -10 °C. The mixture was stirred at 25 °C under N2for 1 hour. After the reaction was completed, the crude product s (182 mg, crude) was carried to the next step without further purification.

[0209] (Bu3N)2H4P2O7 (0.6 M, 2.30 mL) and Bu3N (257 mg, 1388 μmol, 4.00 equivalent) were added to a solution of crude product (182 mg, 347 μmol) in PO(OMe)3 (1.30 mL) at -10 °C. The mixture was stirred at 25 °C for 40 min. After the reaction was complete, 1.00 M TEAB was added to adjust the pH to 7. The solution was diluted with H2O and extracted with MTBE. The aqueous phase was concentrated under reduced pressure. The residue was purified by preparative HPLC to give ((2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyltetrahydrotriphosphate (compound 75, 13.0 mg, 24.0 μmol, 10% yield) as a brown solid. 1 H NMR (400 MHz, D2O) δ ppm 8.15 (s,1H), 7.32 (d, J = 3.60 Hz, 1H), 6.67 (d, J = 4.0 Hz, 1H), 6.44 (d, J = 2.0Hz,1H), 4.80-4.78 (m, 1H), 4.39-4.29 (m, 3H). 31 P NMR (162 MHz, D2O) δ ppm -10.4--10.1 (1P), -11.9--11.8 (1P), -22.9--22.7 (1P) LCMS(ESI): 522.9 [MH] - .

[0210] Compounds 76-85 were synthesized using a procedure similar to that used for synthesizing compound 75.

[0211] Bioassay DENV-2 virus stock generation Five million Vero cells (ATCC CCL-81) were plated in T150 flasks with complete DMEM (Gibco, 11965-092) containing 10% FBS, 1x NEAA (Thermofisher, 11140-050) 1x PenStrep (Thermofisher, 15140-122) overnight at 37°C 5% CO2. The media was removed from the flasks and 10 mL DENV-2 16681 (GenBank NC_001474.2) diluted in DMEM containing 2% FBS was added to the flasks at a MOI of 0.01 and allowed to incubate for one hour at 37°C 5% CO2. Following incubation, 15 mL complete DMEM was added and the flasks were incubated in a 33°C incubator with 5% CO2 for 15 days. The supernatant was harvested every two / three days and 25 mL of fresh media was added to the flasks. Specifically, the supernatant was harvested and centrifuged at 2,000 x g for 5 minutes at 4°C, then aliquoted and stored at -80°C.

[0212] Zika virus stock preparation Five million Vero cells (ATCC CCL-81) were plated in T150 flasks with complete DMEM (Gibco, 11965-092) containing 10% FBS, 1x NEAA (Thermofisher, 11140-050) 1x PenStrep (Thermofisher, 15140-122) overnight at 37°C 5% CO2. The media was removed from the flasks and 10 mL ZIKV MR766 (BEI Resources NR-50065) diluted in DMEM containing 2% FBS was added to the flasks at a MOI of 0.01 and allowed to incubate for one hour at 37°C 5% CO2. Following incubation, 15 mL complete DMEM was added and the flasks were incubated in a 37°C incubator with 5% CO2 for 3 days. The supernatant was then harvested and centrifuged at 2,000 x g for 5 minutes at 4°C, then aliquoted and stored at -80°C.

[0213] Yellow fever virus stock preparation Vero cells (ATCC CCL-81) were plated in T150 flasks with complete DMEM (Gibco, 11965-092) containing 10% FBS, 1x NEAA (Thermofisher, 11140-050) 1x PenStrep (Thermofisher, 15140-122) overnight at 37°C 5% CO2. The media was removed from the flasks and 10 mL of YFV strain 17D (BEI Resources NR-116) diluted in DMEM containing 2% FBS was added to the flasks at a MOI of 0.01 and allowed to incubate for one hour at 37°C 5% CO2. After incubation, 15 mL of complete DMEM was added and the flasks were incubated in a 37°C incubator with 5% CO2 for 3 days. The supernatant was then harvested and centrifuged at 2,000 x g for 5 minutes at 4°C, then aliquoted and stored at -80°C.

[0214] Chikungunya virus stock preparation Vero cells (ATCC CCL-81) were plated in T150 flasks with complete DMEM (Gibco, 11965-092) containing 10% FBS, 1x NEAA (Thermofisher, 11140-050) 1x PenStrep (Thermofisher, 15140-122) overnight at 37°C 5% CO2. The media was removed from the flasks and 10 mL of CHIKV strain 181 / 25 (BEI Resources NR-56523) diluted in DMEM containing 2% FBS was added to the flasks at a MOI of 0.005 and allowed to incubate for one hour at 37°C 5% CO2. After incubation, 20 mL of complete DMEM was added to the flasks and the flasks were incubated in a 37°C incubator with 5% CO2 for 3 days. The supernatant was then harvested and centrifuged at 2,000 x g for 5 minutes at 4°C, then aliquoted and stored at -80°C.

[0215] SARS-CoV-2 virus stock generation Vero E6 cells (ATCC CRL-1586) were plated in T150 flasks containing complete DMEM (Corning 15-013-CV) with 10% FBS, 1x PenStrep (Corning 20-002-CL), 2 mM L-glutamine (Corning 25-005-CL) overnight at 37°C 5% CO2. The media was removed from the flasks and 10 mL of SARS-CoV-2 strain USA-WA1 / 2020 (BEI Resources NR-52281) in complete DMEM was added to the flasks at a MOI of 0.05 and allowed to incubate for 30 minutes at 34°C 5% CO2. After incubation, 20 mL of complete DMEM was added to the flasks. The flasks were then placed in a 34°C incubator at 5% CO2. On day 3 post-infection, cells were scraped in the supernatant, the harvest was centrifuged at 2,000 x g for 5 minutes. The cell pellet was freeze-thawed three times, then resuspended in the collected supernatant and centrifuged again at 2,000 x g for 5 minutes at 4°C, then aliquoted and stored at -80°C.

[0216] HeLa-ACE2 stable cell line HeLa-ACE2 cells were generated by transduction of human ACE2 lentivirus. Lentivirus was generated by co-transfecting HEK293T cells with pBOB-hACE2 construct and lentivirus packaging plasmids pMDL, pREV, and pVSV-G (Addgene) using Lipofectamine 2000 (Thermo Fisher Scientific, 11668019). Supernatant was collected 48 h post-transfection and then used to transduce pre-seeded HeLa cells. Stable cell lines were collected 12 h post-transduction, expanded in culture and stored. Cells were maintained in DMEM (Gibco, 11965-092) with 10% FBS (Gibco, 10438026) and 1x sodium pyruvate (Gibco, 11360070) at 37°C 5% CO2.

[0217] RSV virus preparation.

[0218] To propagate RSV A2 (ATCC VR-1540), Hep-2 cells at 80-90% confluency were infected at an MOI of approximately 0.01 for 1-2 hours at 37°C in a humidified 5% CO2 atmosphere, shaking every 20-30 minutes to redistribute the inoculum. After this time, the inoculum was removed and replaced with assay medium (DMEM containing 2% HI FBS, 1x Pen / Strep). The flasks were then incubated until significant CPE was observed, typically 2-3 days post-infection. Supernatant was collected and clarified by centrifugation to remove cellular debris. Virus was then stabilized by the addition of 25% sucrose and aliquots were snap-frozen, after which they were stored at -80°C.

[0219] Seasonal coronaviruses HCoV-OC43 and HCoV-229E virus preparation 。

[0220] HCoV-OC43 was obtained from BEI Resources, NIAID, NIH: Human Coronavirus, OC43, NR-52725. To propagate the virus, HCT-8 cells were infected with HCoV-OC43 at an MOI of approximately 0.01 for two hours at 33°C in 5% CO2. After incubation, the inoculum was removed and replaced with assay medium (RPMI containing 2% HI FBS, 1x Pen / Strep, and 2 mM L-glutamine). The flasks were incubated at 33°C in 5% CO2 until significant CPE was observed 3-4 days post-infection. Cells were scraped off and harvested with the supernatant and centrifuged at 1,000 x g for 5 minutes. The supernatant was collected and the cell pellet was subjected to one freeze-thaw cycle, after which it was resuspended in 5 mL of supernatant and re-clarified by centrifugation at 1,000 x g for 5 minutes. The total supernatant was then pooled, aliquoted, and stored at -80°C. HCoV-229E was obtained from BEI Resources, NR52726. To propagate the virus, MRC-5 pd25 were infected with HCoV-229E at an MOI of approximately 0.01 and allowed to incubate at 37°C in 5% CO2 for two hours. After incubation, the inoculum was removed and replaced with assay medium (MEM supplemented with 10% HI FBS, 2 mM L-glutamine, 1% NEAA, and 1x Pen / Strep). The flasks were then placed in a 37°C incubator in 5% CO2 until significant CPE was observed 3-4 days post-infection and harvested as described above for OC43.

[0221] Human rhinovirus stock preparation 。

[0222] Human rhinovirus 16 strain 11757 (ATCC VR-283), 14 strain 1059 (ATCC VR-284), and 1B strain B632 (ATCC VR-1645) were propagated in H1 HeLa cells (ATCC CRL-1958). Cells were infected at an MOI of approximately 0.01 in MEM for 2 hours at 33°C, 5% C02. The inoculum was removed and replaced with assay medium (MEM + 2% FBS + IX PS), and flasks were incubated for 2-3 days until significant CPE was observed. Cells were then scraped, harvested with supernatant, and centrifuged at 1,000 x g for 5 minutes. The cell pellet was subjected to three freeze-thaw cycles, after which it was resuspended in 5 mL of supernatant and reclarified by centrifugation. The total supernatant was then pooled, aliquoted, and stored at -80°C.

[0223] Poliovirus stock preparation 。

[0224] Attenuated poliovirus strains PV-1 CHAT (VR-1562) and PV-3 WM-3 (ATCC VR-300) were propagated in HeLa S3 cells (ATCC CCL-2.2) following a similar protocol to that for HRV.

[0225] DENV-2 / HepG2 high content screening antiviral assay Compounds were evaluated for antiviral activity against DENV-2 in HepG2 (ATCC HB-8065) cells using an image-based method. An Echo 555 liquid handler (LabCyte Inc) was used to acoustically transfer compounds into 384-well µ-clear bottom plates (Greiner, part number 781090-2B). Cells were plated at 2.0 x 10 3Cells were seeded at a density of one cell per well in 20 pL DMEM containing 2% FBS (HepG2). Four hours later, plated cells were infected with 10 pL inoculum (DENV-2 diluted in assay medium, MOI = 0.5) to obtain ~50% of infected cells. Plates were incubated at 37°C 5% C02for 24 h, then fixed with formaldehyde at a final concentration of 4% for 30 min at room temperature. Plates were washed twice with lx PBS 0.05% Tween 20 between fixation and subsequent primary and secondary antibody staining. Anti-Flavivirus envelope (E) protein [D1-4G2-4-15] antibody (Millipore) diluted 1 :2000 in PBST-0.3% BSA-0.2% saponin was added to the plates and incubated overnight at 4°C. Alexa Fluor 488 goat anti-mouse IgG H+L: (Thermo Fisher Scientific A-11001) at 1 pg / mL was added to each well along with 8 pM of anti-fluorescence quencher-46-diamidino-2-phenylindole (DAPI; Thermo Fisher Scientific D1306) diluted in PBST-0.3% BSA-0.2% saponin and incubated for 1 h at room temperature protected from light. Plates were imaged using an ImageXpress Micro Confocal High Content Imaging System (Molecular Devices) with a 10x objective, 4 fields of view per well. Images were analyzed using the Multi-Wavelength Cell Scoring Application Module (MetaXpress), DAPI staining confirmed host cell nuclei (total number of cells in the image) and DENV immunofluorescence signal confirmed infected cells.

[0226] Zika virus / HepG2 high content screening antiviral assay The anti-viral activity of compounds against ZIKV was evaluated in HepG2 cells at 24 hours post-infection using an image-based method following essentially the same protocol as described above for DENV-2, but using a dilution of ZIKV optimized to achieve ~50% infection at 24 hours as inoculum.

[0227] Yellow fever virus / HepG2 high content screening antiviral assay The anti-viral activity of compounds against YFV was evaluated in HepG2 cells at 24 hours post-infection using an image-based method following essentially the same protocol as described above for DENV-2 and ZIKV, but using a dilution of Yellow Fever Virus as inoculum.

[0228] Chikungunya / HepG2 high content screening antiviral assay The anti-viral activity of compounds against Chikungunya was assessed in HepG2 at 24 hours post-infection using an image-based method and following a very similar protocol as described above for DENV-2, but with the following substitutions: a dilution of Chikungunya virus was used as inoculum and an anti-Chikungunya virus antibody was used as primary antibody (CHIKV antibody 11E7, monoclonal mouse IgG2b, Kerafast).

[0229] SARS-CoV-2 / HeLa-ACE2 high content screening assay Compounds were acoustically transferred into 384-well µ-clear bottom plates (Greiner, part number 781090-2B) using an Echo 555 liquid handler (LabCyte Inc). HeLa-ACE2 cells were seeded at a density of 1.0 x 10 3 cells per well in 13 µL DMEM containing 2% FBS. The plated cells were transported to a BSL3 facility where 13 µL of SARS-CoV-2 diluted in assay medium was added to obtain ~30-50% of infected cells. The plates were incubated at 34°C 5% CO2for 24 h and then fixed with formaldehyde at a final concentration of 4% for 1 h at 34°C 5% CO2. The plates were washed with 1xPBS 0.05% Tween 20 between fixation and subsequent primary and secondary antibody staining. Human polyclonal plasma diluted 1:500 in Perm / Wash Buffer (BD Biosciences 554723) was added to the plates and incubated for 2 h at room temperature. Goat anti-human H+L conjugated Alexa 488 (Thermo Fisher Scientific A11013) at 6 µg / mL was added to the plates along with 8 µM of anti-fluorescence quencher-46-diamidino-2-phenylindole (DAPI; Thermo Fisher Scientific D1306) in SuperBlock T20 (PBS) buffer (Thermo Fisher Scientific 37515) and incubated for 1.5-2 hours at room temperature protected from light. The plates were imaged using an ImageXpress Micro Confocal High Content Imaging System (Molecular Devices) with a 10x objective, 4 fields of view per well. Images were analyzed using the Multi-Wavelength Cell Scoring Application Module (MetaXpress), DAPI staining confirmed host cell nuclei (total number of cells in the image) and infected cells by means of SARS-CoV-2 immunofluorescence signal.

[0230] OC-43 / HCT-8 high content screening assay 。

[0231] An Echo 555 liquid handler (LabCyte Inc) was used to acoustically transfer compounds into 384-well µ-clear bottom plates (Greiner, part number 781090-2B). HCT-8 cells were seeded into assay preparation plates to have 4000 cells in assay medium (RPMI-1640 + L-glutamine + 2% FBS + 1X penicillin / streptomycin solution). The plated cells were allowed to settle for 1 hour at 37°C before infection with HCoV-OC43 diluted in assay medium to obtain ~30-60% of infected cells. The plates were incubated for 48 h at 33°C 5% CO2 before fixation with formaldehyde at a final concentration of 4%. The fixed cells were blocked and permeabilized with Superblock and 0.2% Triton before staining overnight with mouse monoclonal antibody OC-43 strain clone 541-8F (Sigma Millipore MAB9012). This was followed by goat anti-mouse H+L conjugated Alexa 488 (Thermo Fisher Scientific A11001) and anti-fluorescence quencher-46-diamidino-2-phenylindole (DAPI; Thermo Fisher Scientific D1306) with PBS 0.05% Tween 20 washes between fixation and subsequent primary and secondary antibody staining. The plates were then imaged and analyzed as for the SARS-CoV-2 / HeLa-ACE2 assay.

[0232] 229E / MRC5 CPE-based screening assay 。

[0233] An Echo liquid handler was used to acoustically transfer compounds in a dose response fashion (1:3 serial dilution starting at a final top assay concentration of 10 µM) into 384-well µ-clear bottom plates (Greiner, part number 781090-2B). MRC-5 PD25 cells were seeded into assay preparation plates at a density of 500 cells per well. The plated cells were allowed to settle for 1 hour at 37°C before infection with hCoV-229E diluted in assay medium. The plates were incubated for 120 h at 33°C 5% CO2. To assess the virus-induced cytopathic effect (CPE) by measuring cell viability, 20 μL of 50% Cell-Titer Glo (Promega number G7573) diluted in water was added to the cells and luminescence was measured.

[0234] HRV / H1 HeLa CPE-based screening assay.

[0235] Compounds were acoustically transferred into 384-well or 1536-well µ clear bottom plates (Greiner, part number 781090-2B) using an Echo liquid handler in a dose response fashion. H1 HeLa cells were seeded into assay preparation plates at a density of 2000 cells per well in 384-well plates or 600 cells per well in 1536-well plates. The plated cells were allowed to settle for 4 hours at 33°C before infection with HRV 16, 14 or IB diluted in assay medium. The plates were incubated for 48h at 33°C 5% CO2. To assess the virus-induced cytopathic effect (CPE) by measuring cell viability, 50% Cell-Titer Glo (Promega, number G7573) diluted in water was added to the cells and luminescence was measured.

[0236] PV / HeLa S3 CPE-based screening assay 。

[0237] Compounds were acoustically transferred into 384-well µ clear bottom plates (Greiner, part number 781090-2B) using an Echo liquid handler in a dose response fashion. HeLa S3 were seeded into assay preparation plates at a density of 4000 cells per well. The plated cells were allowed to settle for 4 hours at 37°C before infection with PV-1 CHAT or PV-3 WM-3 diluted in assay medium. The plates were incubated for 48h at 37°C 5% CO2. To assess the virus-induced cytopathic effect (CPE) by measuring cell viability, 50% Cell-Titer Glo (Promega number G7573) diluted in water was added to the cells and luminescence was measured.

[0238] RSV / Hep2 CPE-based screening assay 。

[0239] Compounds were acoustically transferred into 1536-well µ clear bottom plates (Greiner, part number 781090-2B) using an Echo liquid handler in a dose response fashion. Hep2 were seeded into assay preparation plates at a density of 300 cells per well. The plated cells were allowed to settle for 1-2 hours at 37°C before infection with RSV A2 diluted in assay medium. The plates were incubated for 72h. To assess the virus-induced cytopathic effect (CPE) by measuring cell viability, 50% Cell-Titer Glo (Promega number G7573) diluted in water was added to the cells and luminescence was measured.

[0240] Uninfected host cell cytotoxicity counter screen The ability of compounds to cause cytotoxicity in uninfected cells was quantified by ATP-based cell viability assay. Briefly, for both HepG2 and HeLa-ACE2 cells, compounds were acoustically transferred into 1,536-well black-bottom plates (Greiner, part number 789176-F) using an Echo 555 liquid handler (LabCyte Inc). Cells were seeded in assay preparation plates at a density of 450 cells / well (HepG2) or 400 cells / well (Hela-ACE2) in 5 µL DMEM containing 2% FBS and the plates were incubated at 37°C 5% CO2 for 72 h (HepG2) or 24 h (Hela-ACE2). To assess cell viability, 2 µL of 50% Cell-Titer Glo (Promega number G7573) diluted in water was added to the cells and luminescence was measured using a PheraStar or ClarioStar plate reader (BMG LabTech).

[0241] Data analysis and statistical methods Results of DENV, ZIKV, YFV, CHIKV, SARS-CoV-2, HCoV-OC43, HCoV-229E, RSV, HRV and PV infection assays and uninfected cell cytotoxicity counter screen data were uploaded into Genedata Screener version 16.0. For high content imaging assays, two outputs from image analysis were analyzed: % W2 or virus positivity rate as an antiviral readout and total cell number. Data were normalized to neutral (DMSO) minus inhibitor controls (10 µM or 2.5 µM remdesivir for DENV, SARS-CoV2, HCoV-OC43 and RSV antiviral effect and 10 µM puromycin dihydrochloride for infected host cytotoxicity). For cytotoxicity counter screen of uninfected host cells, 30 µM puromycin dihydrochloride (Sigma) was used as a positive control. For HCoV-229E, RSV, HRV and PV cell viability / CPE readouts, data were normalized to neutral control (DMSO) minus stimulant control (2.5 µM remdesivir for RSV and HCoV-229E, 1 µM AG-7404 for HRV). For dose response experiments, compounds were tested in triplicate technical replicates and dose curves were fitted with a four-parameter Hill equation. EC50 and nHill values exported from GeneData Screener in Excel were used to calculate EC 90 values according to the formula “POWER(9,1 / nHill)*EC50” in Excel.

[0242] Antiviral profiling analysis by NIAID / University of Utah All other antiviral assays were performed at Utah State University / Justin Julander through the NIAID Preclinical Services. The following viral strains and cell lines were used:

[0243] Compounds were added to cells prior to the addition of virus at an appropriate MOI to cause visible CPE. When maximum CPE was observed in the virus control, cells were stained with neutral red dye for a dye uptake assay. These data were used to calculate the EC50, CC50, and selectivity index (SI = CC50 / EC50) for each compound. For compounds with an SI > 5, a viral reduction assay was performed in which supernatant collected from the CPE assay was titrated for virus. The EC90 was calculated as the amount of compound required to reduce the viral titer by 1 logio.

[0244] The following data table shows the biological assay data using the range codes shown below:

[0245] For the purposes of clarity and understanding, the foregoing disclosure has been set forth in terms of a certain degree of particularity. It will be apparent to one of ordinary skill in the art that variations and modifications of the foregoing disclosure can be made without departing from the scope of the claims. It is to be understood that the foregoing description is intended to be illustrative only and not limiting of the scope of the disclosure. Thus, the scope of the disclosure should be determined by reference to the claims and the full scope of equivalents to which such claims are entitled.

[0246] The present application makes reference to various granted patents, published patent applications, journal articles, and other publications, each of which is incorporated herein by reference.

Claims

1. A compound of Formula (I) wherein: R 1 selected from H, -C(=0)(Ci-C6)alkyl, -C(=0)(Ci-C6)heteroalkyl, -C(=0)(C3-C7)cycloalkyl, -C(=0)(Ci-C6)alkyl(C3-C7)cycloalkyl, -C(=0)(C3-C7)heterocycloalkyl, -C(=0)(Ci-C6)alkyl(C3-C7)heterocycloalkyl, -C(=0)(C6-Cio)aryl, -C(=0)(Ci-C6)alkyl(C6-Cio)aryl, -C(=0)(C5-C8)heteroaryl, -C(=0)(Ci-C6)alkyl(C5-C8)heteroaryl, -C(=0)CH(NH2)(Ci-C6)alkyl, -C(=0)CH(NH(Ci-C6)alkyl)(Ci-C6)alkyl, -C(=0)CH(N((Ci-C6)alkyl)2)(Ci-C6)alkyl, -C(=0)CH(NH2)(Ci-C6)alkyl(C6-Cio)aryl, -C(=0)CH(NH(Ci-C6)alkyl)(Ci-C6)alkyl(C6-Cio)aryl, -C(=0)CH(N((Ci-C6)alkyl)2)(Ci-C6)alkyl(C6-Cio)aryl, -P(=0)(OR 10 )2, -P(=0)(OR 10 )-P(=0)(OR 10 )2, -P(=0)(OR 10 )-P(=0)(OR 10 )2, -P(=0)(OR 1’ )NH(Ci-C6)alkyl, -P(=0)(OR 1’ )NH(Ci-C6)heteroalkyl, -P(=0)(OR 1’ )NH(Ci-C6)haloalkyl, -P(=0)(OR 1’ )NH(C3-C7)cycloalkyl, -P(=0)(OR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 1’ )NH(C6-Cio)aryl, -P(=0)(OR 1’ )NH(Ci-C6)alkyl(C6-Cio)aryl, -P(=0)(OR 1’ )NH(C5-C8)heteroaryl, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 10 )2, -P(=0)(OR 1’ )2, -P(=0)(OR 10 )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )NH(C1-C6)alkyl(C5-C8)heteroaryl, -P(=0)(NHR 1’ )NH(C1-C6)alkyl, -P(=0)(NHR 1’ )NH(C1-C6)heteroalkyl, -P(=0)(NHR 1’ )NH(C1-C6)haloalkyl, -P(=0)(NHR 1’ )NH(C3-C7)cycloalkyl, -P(=0)(NHR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(NHR 1’ )NH(C6-C 10 )aryl, -P(=0)(NHR 1’ )NH(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(NHR 1’ )NH(C5-C8)heteroaryl, -P(=0)(NHR 1’ )NH(C1-C6)alkyl(C5-C8)heteroaryl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)haloalkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl-C(=0)0-(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)haloalkyl-C(=0)0-(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl-C(=0)0-(C6-C 10 )aryl, and -P(=0)(OR 1’ )NH(C1-C6)haloalkyl-C(=0)0-(C6-C 10 )aryl; Each R 1’ Independently, it is H, -(C1-C6)alkyl, -(C1-C6)heteroalkyl, -(C1-C6)haloalkyl, -(C2-C6)alkenyl, -(C2-C6)heteroalkenyl, -(C2-C6)haloalkenyl, -(C2-C6)ynyl, -(C2-C6)heteroynyl, -(C2-C6)haloynyl, -(C3-C7)cycloalkyl, -(C3-C7)heterocycloalkyl, -(C6-C 10 aryl, -(C1-C6)alkyl (C6-C 10 aryl, -(C5-C8)heteroaryl or -(C1-C6)alkyl(C5-C8)heteroaryl; R 2a is H, halo, (Ci-C6)alkyl, or -CºCH; R 2b independently halo or OH; R 3 independently H or OH; R 4 is N3, halo, -CºN, (C1-C3)haloalkyl, or -O(C1-C6)alkyl; R 5 is H, halo, -C≡N, (C1-C6)alkyl, hetero(C1-C6)alkyl, hydroxy(C1-C6)alkyl, N(R 1’ )2, -C(=O)NH2; R 6 is H, halo, NH2, (Ci-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; R 7 is H, NH2, OH, oxo, halo, N(R 1’ )2, or -O(C1-C6)alkyl; and R 8 is H or halo; with the proviso that the compound of Formula I is not 4-amino-7-((2R,3R,4S,5S)-5- fluoro-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3- d]pyrimidine-5-carboxamide; 4-amino-7-((2R,3R,4S,5R)-5-azido-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5- carboxamide; 4-amino-7-((2R,3R,4S,5S)-3-ethynyl-5-fluoro-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile; ((5-(4- amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-ethynyl-2-fluoro-3,4-dihydroxytetrahydrofuran- 2-yl)methyl)triphosphonic acid; ((5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4- ethynyl-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl)triphosphonic acid; (5-(4-amino- 5-carbamoyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-ethynyl-2-fluoro-3,4-dihydroxytetrahydro- furan-2-yl)methyl tetrahydrotriphosphonate; (5-(4-amino-5-cyano-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-4-ethynyl-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrotriphosphonate; 4-amino-7-((2R,3R,4S,5S)-3-ethynyl-5-fluoro-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-ethynyl-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; or (2S,3S,4R,5R)-5-(4-amino-5-fluoro-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-4-ethynyl-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4- diol; including enantiomeric, racemic and non-racemic mixtures, and further including pharmaceutically acceptable salts thereof.

2. A compound of Formula (II) wherein: R 1 Selected from H, -C(=O)(C1-C6)alkyl, -C(=O)(C1-C6)heteroalkyl, -C(=O)(C3-C7)cycloalkyl, -C(=O)(C1-C6)alkyl(C3-C7)cycloalkyl, -C(=O)(C3-C7)heteroalkyl, -C(=O)(C1-C6)alkyl(C3-C7)heteroalkyl, -C(=O)(C6-C 10 )aryl, -C(=O)(C1-C6)alkyl(C6-C 10 aryl, -C(=O)(C5-C8)heteroaryl, -C(=O)(C1-C6)alkyl(C5-C8)heteroaryl, -C(=O)CH(NH2)(C1-C6)alkyl, -C(=O)CH(NH(C1-C6)alkyl)(C1-C6)alkyl, -C(=O)CH(N((C1-C6)alkyl)2)(C1-C6)alkyl, -C(=O)CH(NH2)(C1-C6)alkyl(C6-C 10 )aryl, -C(=O)CH(NH(C1-C6)alkyl)(C1-C6)alkyl(C6-C 10 )aryl, -C(=O)CH(N((C1-C6)alkyl)2)(C1-C6)alkyl(C6-C 10 )Aryl, -P(=O)(OR 1’ )2、-P(=O)(OR 1’ )-P(=O)(OR 1’ )2、-P(=O)(OR 1’ )-P(=O)(OR 1’ )-P(=O)(OR 1’ )2、-P(=O)(OR 1’ )NH(C1-C6)alkyl, -P(=O)(OR 1’ )NH(C1-C6) heteroalkyl, -P(=O)(OR 1’ )NH(C1-C6) haloalkyl, -P(=O)(OR 1’ )NH(C3-C7)cycloalkyl, -P(=O)(OR 1’ )NH(C3-C7) heterocyclic alkyl, -P(=O)(OR 1’ )NH(C6-C 10 )Aryl, -P(=O)(OR 1’ )NH(C1-C6)alkyl(C6-C 10 )Aryl, -P(=O)(OR 1’ )NH(C5-C8) heteroaryl, -P(=O)(OR 1’ )NH(C1-C6)alkyl(C5-C8)heteroaryl, -P(=0)(NHR 1’ )NH(C1-C6)alkyl, -P(=0)(NHR 1’ )NH(C1-C6)heteroalkyl, -P(=0)(NHR 1’ )NH(C1-C6)haloalkyl, -P(=0)(NHR 1’ )NH(C3-C7)cycloalkyl, -P(=0)(NHR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(NHR 1’ )NH(C6-C 10 )aryl, -P(=0)(NHR 1’ )NH(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(NHR 1’ )NH(C5-C8)heteroaryl, -P(=0)(NHR 1’ )NH(C1-C6)alkyl(C5-C8)heteroaryl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)haloalkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl-C(=0)0-(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)haloalkyl-C(=0)0-(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl-C(=0)0-(C6-C 10 )aryl, and -P(=0)(OR 1’ )NH(C1-C6)haloalkyl-C(=0)0-(C6-C 10 )aryl; Each R 1’ Independently, it is H, -(C1-C6)alkyl, -(C1-C6)heteroalkyl, -(C1-C6)haloalkyl, -(C2-C6)alkenyl, -(C2-C6)heteroalkenyl, -(C2-C6)haloalkenyl, -(C2-C6)ynyl, -(C2-C6)heteroynyl, -(C2-C6)haloynyl, -(C3-C7)cycloalkyl, -(C3-C7)heterocycloalkyl, -(C6-C 10 aryl, -(C1-C6)alkyl (C6-C 10 aryl, -(C5-C8)heteroaryl or -(C1-C6)alkyl(C5-C8)heteroaryl; R 2 is H, (Ci-C6)alkyl or -CºCH; R 4 is N3, halo, or -O(Ci-C6)alkyl; R 5 is H, halo, -C≡N, hetero(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, N(R 1’ )2, -C(=O)NH2; R 6 is H, halo, NH2, (Ci-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; R 7 is H, NH2, OH, halo, N(R 1’ )2, or -O(C1-C6)alkyl; and R 8 is H or halo; provided that the compound of Formula II is not (2S,3S,4R,5S)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol, (2R,3S,4R,5S)-5- (4-amino-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-azido-2-(hydroxymethyl)tetrahydrofuran-3,4- diol, (2R,3S,4R,5S)-5-(4-amino-5-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-azido-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3S,4R,5S)-5-(4-amino-pyrrolo[2,1-f][1,2,4]triazin-7- yl-5-fluoro-2-azido-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; ((2R,3S,4R,5S)-5-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-azido-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrotriphosphate or ((((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-azido-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alanine 2-ethylbutyl ester. d ) including enantiomeric, racemic and non-racemic mixtures, and further including pharmaceutically acceptable salts thereof.

3. A compound of Formula (Ilia) or (Illb) wherein: R 1 H, -C(=0)(Ci-C6)alkyl, -C(=0)(Ci-C6)heteroalkyl, -C(=0)(C3-C7)cycloalkyl, -C(=0)(Ci-C6)alkyl(C3-C7)cycloalkyl, -C(=0)(C3-C7)heterocycloalkyl, -C(=0)(Ci-C6)alkyl(C3-C7)heterocycloalkyl, -C(=0)(C6-Cio)aryl, -C(=0)(Ci-C6)alkyl(C6-Cio)aryl, -C(=0)(C5-C8)heteroaryl, -C(=0)(Ci-C6)alkyl(C5-C8)heteroaryl, -C(=0)CH(NH2)(Ci-C6)alkyl, -C(=0)CH(NH(Ci-C6)alkyl)(Ci-C6)alkyl, -C(=0)CH(N((Ci-C6)alkyl)2)(Ci-C6)alkyl, -C(=0)CH(NH2)(Ci-C6)alkyl(C6-Cio)aryl, -C(=0)CH(NH(Ci-C6)alkyl)(Ci-C6)alkyl(C6-Cio)aryl, -C(=0)CH(N((Ci-C6)alkyl)2)(Ci-C6)alkyl(C6-Cio)aryl, -P(=0)(OR 10 )2, -P(=0)(OR 10 )2, -P(=0)(OR 10 )2, -P(=0)(OR 10 )2, -P(=0)(OR 10 )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 10 )2, -P(=0)(OR 1’ )2, -P(=0)(OR 10 )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )NH(C1-C6)alkyl(C5-C8)heteroaryl, -P(=0)(NHR 1’ )NH(C1-C6)alkyl, -P(=0)(NHR 1’ )NH(C1-C6)heteroalkyl, -P(=0)(NHR 1’ )NH(C1-C6)haloalkyl, -P(=0)(NHR 1’ )NH(C3-C7)cycloalkyl, -P(=0)(NHR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(NHR 1’ )NH(C6-C 10 )aryl, -P(=0)(NHR 1’ )NH(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(NHR 1’ )NH(C5-C8)heteroaryl, -P(=0)(NHR 1’ )NH(C1-C6)alkyl(C5-C8)heteroaryl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)haloalkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl-C(=0)0-(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)haloalkyl-C(=0)0-(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl-C(=0)0-(C6-C 10 )aryl, and -P(=0)(OR 1’ )NH(C1-C6)haloalkyl-C(=0)0-(C6-C 10 )aryl; Each R 1’ Independently, it is H, -(C1-C6)alkyl, -(C1-C6)heteroalkyl, -(C1-C6)haloalkyl, -(C2-C6)alkenyl, -(C2-C6)heteroalkenyl, -(C2-C6)haloalkenyl, -(C2-C6)ynyl, -(C2-C6)heteroynyl, -(C2-C6)haloynyl, -(C3-C7)cycloalkyl, -(C3-C7)heterocycloalkyl, -(C6-C 10 aryl, -(C1-C6)alkyl (C6-C 10 aryl, -(C5-C8)heteroaryl or -(C1-C6)alkyl(C5-C8)heteroaryl; R 2a is H, OH, halo, (Ci-C6)alkyl, or -CºCH; R 2b is H, OH, halo, or (Ci-C6)alkyl; R 3a is H, OH, halo, or (Ci-C6)alkyl; R 3b is H, OH, halo, or (Ci-C6)alkyl; R 4 is N3, halo, -CºN, (C1-C3)haloalkyl, or -O(C1-C6)alkyl; R 6 and R 6’ each independently halo, NH2, NH(Ci-C6)alkyl, N((Ci-C6)alkyl)2, -OH, -0(Ci-C6)alkyl, -oxo, or -CºCH; and R 8 is H or halo; provided that the compound of Formula III is not (((2R,3S,4R,5R)-5-(2,6-diamino-9H-purin-9-yl)-2- (difluoromethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl) triphosphate; (((2S,3S,4R,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-4-ethynyl-2-fluoro-3,4- dihydroxytetrahydrofuran-2-yl)methyl) triphosphate; (2S,3S,4R,5R)-5-(2,6-diamino-9H-purin-9-yl)-2-fluoro-2- (hydroxymethyl)-4-methyltetrahydrofuran-3,4-diol; or (2S,3S,4R,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-4-ethynyl-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; including enantiomeric, racemic and non-racemic mixtures, and further including pharmaceutically acceptable salts thereof.

4. A compound of Formula (IV) wherein: R 1 H, -C(=0)(Ci-C6)alkyl, -C(=0)(Ci-C6)heteroalkyl, -C(=0)(C3-C7)cycloalkyl, -C(=0)(Ci-C6)alkyl(C3-C7)cycloalkyl, -C(=0)(C3-C7)heterocycloalkyl, -C(=0)(Ci-C6)alkyl(C3-C7)heterocycloalkyl, -C(=0)(C6-Cio)aryl, -C(=0)(Ci-C6)alkyl(C6-Cio)aryl, -C(=0)(C5-C8)heteroaryl, -C(=0)(Ci-C6)alkyl(C5-C8)heteroaryl, -C(=0)CH(NH2)(Ci-C6)alkyl, -C(=0)CH(NH(Ci-C6)alkyl)(Ci-C6)alkyl, -C(=0)CH(N((Ci-C6)alkyl)2)(Ci-C6)alkyl, -C(=0)CH(NH2)(Ci-C6)alkyl(C6-Cio)aryl, -C(=0)CH(NH(Ci-C6)alkyl)(Ci-C6)alkyl(C6-Cio)aryl, -C(=0)CH(N((Ci-C6)alkyl)2)(Ci-C6)alkyl(C6-Cio)aryl, -P(=0)(OR 10 )2, -P(=0)(OR 10 )2, -P(=0)(OR 10 )2, -P(=0)(OR 10 )2, -P(=0)(OR 10 )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )2, -P(=0)(OR 10 )2, -P(=0)(OR 1’ )2, -P(=0)(OR 10 )2, -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )NH(C1-C6)alkyl(C5-C8)heteroaryl, -P(=0)(NHR 1’ )NH(C1-C6)alkyl, -P(=0)(NHR 1’ )NH(C1-C6)heteroalkyl, -P(=0)(NHR 1’ )NH(C1-C6)haloalkyl, -P(=0)(NHR 1’ )NH(C3-C7)cycloalkyl, -P(=0)(NHR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(NHR 1’ )NH(C6-C 10 )aryl, -P(=0)(NHR 1’ )NH(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(NHR 1’ )NH(C5-C8)heteroaryl, -P(=0)(NHR 1’ )NH(C1-C6)alkyl(C5-C8)heteroaryl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)haloalkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl-C(=0)0-(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)haloalkyl-C(=0)0-(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl-C(=0)0-(C6-C 10 )aryl, and -P(=0)(OR 1’ )NH(C1-C6)haloalkyl-C(=0)0-(C6-C 10 )aryl; Each R 1’ Independently, it is H, -(C1-C6)alkyl, -(C1-C6)heteroalkyl, -(C1-C6)haloalkyl, -(C2-C6)alkenyl, -(C2-C6)heteroalkenyl, -(C2-C6)haloalkenyl, -(C2-C6)ynyl, -(C2-C6)heteroynyl, -(C2-C6)haloynyl, -(C3-C7)cycloalkyl, -(C3-C7)heterocycloalkyl, -(C6-C 10 aryl, -(C1-C6)alkyl (C6-C 10 aryl, -(C5-C8)heteroaryl or -(C1-C6)alkyl(C5-C8)heteroaryl; R 4 is N3, halo, or -0(Ci-C6)alkyl; and R 6 is H, halo, (Ci-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; including enantiomeric, racemic and non-racemic mixtures, and further including pharmaceutically acceptable salts thereof.

5. A compound of Formula (V) wherein: R 1 H, -C(=0)(Ci-C6)alkyl, -C(=0)(Ci-C6)heteroalkyl, -C(=0)(C3-C7)cycloalkyl, -C(=0)(Ci-C6)alkyl(C3-C7)cycloalkyl, -C(=0)(C3-C7)heterocycloalkyl, -C(=0)(Ci-C6)alkyl(C3-C7)heterocycloalkyl, -C(=0)(C6-Cio)aryl, -C(=0)(Ci-C6)alkyl(C6-Cio)aryl, -C(=0)(C5-C8)heteroaryl, -C(=0)(Ci-C6)alkyl(C5-C8)heteroaryl, -C(=0)CH(NH2)(Ci-C6)alkyl, -C(=0)CH(NH(Ci-C6)alkyl)(Ci-C6)alkyl, -C(=0)CH(N((Ci-C6)alkyl)2)(Ci-C6)alkyl, -C(=0)CH(NH2)(Ci-C6)alkyl(C6-Cio)aryl, -C(=0)CH(NH(Ci-C6)alkyl)(Ci-C6)alkyl(C6-Cio)aryl, -C(=0)CH(N((Ci-C6)alkyl)2)(Ci-C6)alkyl(C6-Cio)aryl, -P(=0)(OR 10 )2, -P(=0)(OR 10 )-P(=0)(OR 10 )2, -P(=0)(OR 10 )-P(=0)(OR 10 )2, -P(=0)(OR 1’ )NH(Ci-C6)alkyl, -P(=0)(OR 1’ )NH(Ci-C6)heteroalkyl, -P(=0)(OR 1’ )NH(Ci-C6)haloalkyl, -P(=0)(OR 1’ )NH(C3-C7)cycloalkyl, -P(=0)(OR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(OR 1’ )NH(C6-Cio)aryl, -P(=0)(OR 1’ )NH(Ci-C6)alkyl(C6-Cio)aryl, -P(=0)(OR 1’ )NH(C5-C8)heteroaryl, -S(=0)(NR 1’ )2, -S(=0)(NR 1’ )2, -S(=0)(NR 1’ )2, -S(=0)(NR 1’ )2, -S(=0)(NR 10 )2, -S(=0)(NR 1’ )2, -S(=0)(NR 10 )2, -S(=0)(NR 1’ )2, -S(=0)(NR 1’ )NH(C1-C6)alkyl(C5-C8)heteroaryl, -P(=0)(NHR 1’ )NH(C1-C6)alkyl, -P(=0)(NHR 1’ )NH(C1-C6)heteroalkyl, -P(=0)(NHR 1’ )NH(C1-C6)haloalkyl, -P(=0)(NHR 1’ )NH(C3-C7)cycloalkyl, -P(=0)(NHR 1’ )NH(C3-C7)heterocycloalkyl, -P(=0)(NHR 1’ )NH(C6-C 10 )aryl, -P(=0)(NHR 1’ )NH(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(NHR 1’ )NH(C5-C8)heteroaryl, -P(=0)(NHR 1’ )NH(C1-C6)alkyl(C5-C8)heteroaryl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)haloalkyl-C(=0)0-(C1-C6)alkyl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl-C(=0)0-(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)haloalkyl-C(=0)0-(C1-C6)alkyl(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)alkyl-C(=0)0-(C6-C 10 )aryl, -P(=0)(OR 1’ )NH(C1-C6)heteroalkyl-C(=0)0-(C6-C 10 )aryl, and -P(=0)(OR 1’ )NH(C1-C6)haloalkyl-C(=0)0-(C6-C 10 )aryl; Each R 1’ Independently, it is H, -(C1-C6)alkyl, -(C1-C6)heteroalkyl, -(C1-C6)haloalkyl, -(C2-C6)alkenyl, -(C2-C6)heteroalkenyl, -(C2-C6)haloalkenyl, -(C2-C6)ynyl, -(C2-C6)heteroynyl, -(C2-C6)haloynyl, -(C3-C7)cycloalkyl, -(C3-C7)heterocycloalkyl, -(C6-C 10 aryl, -(C1-C6)alkyl (C6-C 10 aryl, -(C5-C8)heteroaryl or -(C1-C6)alkyl(C5-C8)heteroaryl; R 2 is H, halo, (Ci-C6)alkyl, or -CºCH; R 4 is N3, halo, -CºN, (C1-C3)haloalkyl, or -O(C1-C6)alkyl; R 5 is H, halo, -C≡N, hetero(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, halo(Ci-C6)alkyl, N(R 1’ )2, -(C(=O)NH2; R 6 is H, halo, NH2, (Ci-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; R 7 is H, NH2, OH, halo, N(R 1’ )2, or -O(C1-C6)alkyl; and R 8 is H or halo; including enantiomeric, racemic and non-racemic mixtures, and further including pharmaceutically acceptable salts thereof.

6. The compound of claim 1, wherein R 2b is OH or halo.

7. The compound of claim 3, wherein R 2b is halo.

8. The compound of claim 7, wherein R 2a is Me or halo.

9. The compound of any one of claims 6-8, wherein R 2a is H.

10. The compound of any one of claims 6-8, wherein R 2a is (Ci-C6)alkyl.

11. The compound of claim 10, wherein R 2a is Me.​ 12. The compound of any one of claims 6-8, wherein R 2a is halo.

13. The compound of claim 12, wherein R 2a is Cl.​ 14. The compound of any one of claims 2 or 5, wherein R 2 is H.

15. The compound of any one of claims 2 or 5, wherein R 2 is halo.

16. The compound of claim 15, wherein R 2 is F.​ 17. The compound of any one of claims 2 or 5, wherein R 2 is (Ci-C6)alkyl.

18. The compound of claim 17, wherein R 2 is Me.​ 19. The compound of any one of claims 1-2 or 5, wherein R 5 is H.

20. The compound of any one of claims 1-2 or 5, wherein R 5 is -CH2OH.

21. The compound of any one of claims 1-2 or 5, wherein R 5 is -C(=0)NH2.

22. The compound of any one of claims 1, 6-13, or 19-21, wherein R 3 is OH.

23. The compound of any one of claims 1, 6-13, or 19-21, wherein R 3 is H.

24. The compound of any one of claims 1-23, wherein R 4 is halo.

25. The compound of claim 24, wherein R 4 is F.

26. The compound of claim 24, wherein R 4 is Cl.​ 27. The compound of any one of claims 1-23, wherein R 4 is N3.

28. The compound of any one of claims 1-23, wherein R 4 is -0(Ci-C6)alkyl.

29. The compound of claim 28, wherein R 4 is -OMe.​ 30. The compound of any one of claims 1-29, wherein R 6 is H or NH2, and R 6’ is -NH(Ci-C6)alkyl or -0(Ci-C6)alkyl.

31. The compound of any one of claims 1-29, wherein R 6 is halo.

32. The compound of claim 31, wherein R 6 is F.

33. The compound of any one of claims 1-29, wherein R 6 is -CºCH.

34. The compound of any one of claims 1-33, wherein R 1 is H.

35. The compound of any one of claims 1-33, wherein R 1 is -P(=0)(OR 1’ )2, -P(=0)(OR 1’ )-P(=0)(OR 1’ )2, or -P(=0)(OR 1’ )-P(=0)(OR 1’ )-P(=0)(OR 1’ )2.

36. The compound of any one of claims 1-33, wherein R 1 is -P(=0)(OR 1’ )NH(Ci-C6)alkyl-C(=0)0-(Ci-C6)alkyl.

37. A compound having a formula selected from any one of: (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-azido-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2- (hydroxymethyl)-2-methoxy-4-methyltetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3S,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3R,4S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-chloro-2,4- difluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol; (2R,3R,4S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-azido-4-chloro- 4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol; (2R,3R,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-azido-5- (hydroxymethyl)tetrahydrofuran-3-ol; (2R,3S,4R,5S)-5-(4-amino-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-azido-2- (hydroxymethyl)-4-methyltetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3R,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-fluoro-5- (hydroxymethyl)tetrahydrofuran-3-ol; (2R,3R,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-fluoro-5- (hydroxymethyl)tetrahydrofuran-3-ol; (2S,3S,4R,5R)-2-fluoro-5-(4-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; 4-amino-7-((2R,3R,4S,5S)-5-fluoro-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (2S,3S,4R,5R)-5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro- 2-(hydroxymethyl)tetrahydrofuran-3,4-diol; 7-((2R,3R,4S,5S)-5-fluoro-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2- yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one; (2S,3S,4R,5R)-5-(4-amino-5-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(6-amino-2-ethynyl-9H-purin-9-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5S)-5-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(fluoromethyl)- 2-(hydroxymethyl)tetrahydrofuran-3,4-diol; 5-fluoro-7-((2R,3R,4S,5S)-5-fluoro-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4- one; (2S,3S,4R,5R)-2-fluoro-5-(5-fluoro-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-2-Fluoro-2-(hydroxymethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol; 7-((2R,3R,4S,5S)-5-Fluoro-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (2S,3S,4R,5R)-5-(5-Bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; 4-Amino-7-((2R,3R,4S,5S)-5-fluoro-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile; (2S,3S,4R,5R)-5-(2-Amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-2-Fluoro-2-(hydroxymethyl)-5-(6-(methylthio)-9H-purin-9-yl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(4-Chloro-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (1S,2S,3S,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-3-(hydroxymethyl)cyclopentane-1,2-diol; (2S,3S,4R,5R)-5-(6-Amino-2-fluoro-9H-purin-9-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (3S,4R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydrofuran-2-carbonitrile; (2S,3S,4R,5R)-5-(4-Amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; Benzoic acid ((2S,3S,4R,5S)-5-(4-amino-5-carbamoylpyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl ester; (2S,3S,4R,5R)-2-Fluoro-5-(5-fluoro-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(5-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; 7-((2R,3R,4S,5S)-5-Fluoro-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile; 7-((2R,3R,4S,5S)-5-Fluoro-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile; (2R,3R,5R)-5-Fluoro-5-(hydroxymethyl)-2-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3-ol; (2S,3S,4R,5R)-2-Fluoro-2-(hydroxymethyl)-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(4-Amino-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(6-Amino-2-chloro-9H-purin-9-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; 4-Amino-1-((2R,3R,4S,5S)-3-ethynyl-5-fluoro-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one; (2S,3S,4R,5R)-2-((Benzoyloxy)methyl)-5-(3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorotetrahydrofuran-3,4-diyl diacetate; Isobutyric acid ((2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl) methyl ester; (2S,3S,4R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2-((isobutyryloxy)methyl)tetrahydrofuran-3,4-diyl bis(2-methylpropanoate); ((S)-(((2S,3S,4R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester; ((R)-(((2S,3S,4R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester; Benzoic acid ((2S,3S,4R,5R)-4-(benzoyloxy)-5-(4-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-3-hydroxytetrahydrofuran-2-yl) methyl ester; (2R,3R,4S,5S)-2-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-5-fluoro-3,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile; (2S,3S,4R,5R)-5-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-2-fluoro-2-(hydroxymethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2- (hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3R,5R)-5-(4-amino-5-(benzo[d]thiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)- 2,4,4-trifluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol; Benzoic acid ((2S,3S,4R,5R)-5-(2-amino-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl ester; (2S,3R,4S,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-chloro-2,4-difluoro-2- (hydroxymethyl)tetrahydrofuran-3-ol; ((R)-(((2S,3R,4S,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-chloro-2,4- difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester; ((S)-(((2S,3R,4S,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-chloro-2,4- difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester; (2S,3R,5R)-5-(2-amino-6-ethoxy-9H-purin-9-yl)-2,4,4-trifluoro-2- (hydroxymethyl)tetrahydrofuran-3-ol; ((((2S,3R,5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-2,4,4-trifluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester; 2-amino-9-((2R,3R,4R,5S)-3-chloro-5-fluoro-4-hydroxy-5-(hydroxymethyl)-3- methyltetrahydrofuran-2-yl)-1,9-dihydro-6H-purin-6-one; (2S,3R,4R,5R)-5-(2-amino-6-ethoxy-9H-purin-9-yl)-4-chloro-2-fluoro-2- (hydroxymethyl)-4-methyltetrahydrofuran-3-ol; ((((2S,3R,4R,5R)-5-(2-amino-6-ethoxy-9H-purin-9-yl)-4-chloro-2-fluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester; ((((2S,3S,4R,5R)-5-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-2-fluoro-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)-L-alanine neopentyl ester; (2S,3R,4S,5R)-5-(2-amino-6-ethoxy-9H-purin-9-yl)-4-chloro-2,4-difluoro-2- (hydroxymethyl)tetrahydrofuran-3-ol; ((((2S,3R,4S,5R)-5-(2-amino-6-ethoxy-9H-purin-9-yl)-4-chloro-2,4-difluoro-3- hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester; (2S,3R,4S,5R)-5-(2-amino-6-ethoxy-9H-purin-9-yl)-4-bromo-2,4-difluoro-2- (hydroxymethyl)tetrahydrofuran-3-ol; ((((2S,3R,5R)-5-(2-amino-6-ethoxy-9H-purin-9-yl)-2,4,4-trifluoro-3-hydroxytetrahydrofuran- 2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester; (2S,3S,4R,5R)-4-ethynyl-2-fluoro-2-(hydroxymethyl)-5-(4-(propylamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol; 2-amino-9-((2R,4R,5S)-3,3,5-trifluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)- 1,9-dihydro-6H-purin-6-one; (2S,3S,4R,5R)-2-fluoro-2-(hydroxymethyl)-5-(4-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrofuran-3,4-diol; L-valine ((2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-3,4- dihydroxytetrahydrofuran-2-yl)methyl ester; ((((2S,3S,4R,5R)-5-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-fluoro-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)-L-alanine neopentyl ester; ((2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-3,4- dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate; ((2S,3S,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-3,4- dihydroxytetrahydrofuran-2-yl)methyl tetrahydro pyrophosphoric acid ester; ((2S,3S,4R,5R)-2-fluoro-3,4-dihydroxy-5-(4-oxo-3,4-dihydro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl)methyl tetrahydro pyrophosphoric acid ester; ((2S,3S,4R,5R)-5-(5-carbamoyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-3,4- dihydroxytetrahydrofuran-2-yl)methyl tetrahydro pyrophosphoric acid ester; ((2S,3S,4R,5R)-5-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-3,4- dihydroxytetrahydrofuran-2-yl)methyl tetrahydro pyrophosphoric acid ester; ((2S,3S,4R,5R)-2-fluoro-5-(5-fluoro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydro pyrophosphoric acid ester; ((2S,3S,4R,5R)-5-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-2-fluoro-3,4- dihydroxytetrahydrofuran-2-yl)methyl tetrahydro pyrophosphoric acid ester; ((2S,3S,4R,5R)-5-(4-amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-3,4- dihydroxytetrahydrofuran-2-yl)methyl tetrahydro pyrophosphoric acid ester; ((2S,3S,4R,5R)-5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-3,4- dihydroxytetrahydrofuran-2-yl)methyl tetrahydro pyrophosphoric acid ester; ((2S,3R,4R,5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-4-chloro-2-fluoro-3- hydroxy-4-methyltetrahydrofuran-2-yl)methyl tetrahydro pyrophosphoric acid ester; and ((2S,3S,4S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-3,4- dihydroxy-4-methyltetrahydrofuran-2-yl)methyl tetrahydro pyrophosphoric acid ester.

38. The compound of claim 37 having the chemical formula (2S,3S,4R,5R)-5-(4- amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran- 3,4-diol or ((R)-(((2S,3R,4S,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4- chloro-2,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)- L-alanine isopropyl ester.

39. A pharmaceutical composition comprising a compound of any one of claims 1-38 in admixture with a pharmaceutically acceptable carrier, diluent, or excipient.

40. The pharmaceutical composition of claim 39, further comprising one or more therapeutic compounds or compositions.

41. The pharmaceutical composition of claim 40, wherein the one or more therapeutic compounds or compositions is a second antiviral compound or composition.

42. The pharmaceutical composition of claim 41, wherein the second antiviral compound or composition is an RdRp inhibitor.

43. The pharmaceutical composition of claim 41, wherein the second antiviral compound or composition is an RNA polymerase inhibitor.

44. A method of inhibiting an RNA-dependent RNA polymerase comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-38 or a pharmaceutical composition of claims 39-43.

45. A method of preventing, ameliorating, or treating an RNA viral infection comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-38 or a pharmaceutical composition of claims 39-43.

46. The method of claim 45, wherein the RNA viral infection is at least one virus selected from the group consisting of dengue virus, severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-COV-2, Zika virus, yellow fever virus, Ebola (Makona) virus, Ebola (Kikwit) virus, O'nyong'nyong virus, Sudan virus, Marburg virus, respiratory syncytial virus (RSV), Nipah virus, measles virus, parainfluenza virus, Middle East respiratory syndrome (MERS) virus, hepatitis C virus (HCV), West Nile virus, Lassa virus, influenza, HRV, MEV, LCMV, polio, CHIKV, COXV, and Junin virus.

47. The method of claim 46, wherein the RNA viral infection is caused by dengue virus.

48. The method of claim 46, wherein the RNA viral infection is caused by SARS-COV-2 virus.

49. The method of claim 46, wherein the RNA viral infection is caused by yellow fever virus.

50. The method of claim 46, wherein the RNA viral infection is caused by Zika virus.

51. The method of any one of claims 44-50, further comprising treatment with one or more additional therapeutic compounds or compositions.

52. The method of claim 51, wherein at least one of the one or more therapeutic compounds or compositions is a drug effective to treat or ameliorate an RNA viral infection.

53. The method of claim 52, wherein the drug to treat an RNA viral infection is selected from remdesivir, monolupiravir, or paroquatreve.

54. Any compound, composition, or method described herein.

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