4'-substituted nucleosides and nucleotides as antiviral agents

Abstract

This application provides nucleoside analog compounds of formula IV for the treatment of dengue fever (DF). This application further provides compositions and combinations thereof, as well as methods for treating dengue fever using nucleoside compounds of formula IV and their compositions and combinations.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 498,910, filed on 28 April 2023, which is incorporated herein by reference in its entirety.

[0002] This application provides nucleoside analog compounds of formula IV for the treatment of dengue fever (DF). This application further provides compositions and combinations thereof, as well as methods for treating dengue fever using nucleoside compounds of formula IV and their compositions and combinations. [Background technology]

[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). Based on its clinical characteristics, dengue fever is classified into classic dengue fever, or, more severely, dengue hemorrhagic fever syndrome (DHF) and dengue shock syndrome (DSS). Recovery from infection with one serotype produces lifelong immunity to that particular serotype, but provides only short-lived and limited protection against any of the other serotypes. Dengue fever is a member of the Flaviviridae family, which are enveloped, positive sense RNA viruses, and their human pathogens also include, among others, West Nile virus (WNV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), and tick-borne encephalitis virus (TBEV). Transmission of dengue fever occurs primarily through the bite of infected Aedes aegypti mosquitoes, which are now found in tropical and subtropical regions worldwide.

[0004] Each year, regional dengue outbreaks cause significant morbidity and mortality, social disruption, and substantial economic burdens on affected societies in terms of both hospitalization and mosquito control. Dengue fever is considered by the World Health Organization (WHO) to be the most important arthropod-borne viral disease, with an estimated 50 million cases of dengue infection worldwide each year, including 500,000 DHF cases and 24,000 deaths. The WHO estimates that 40% of the world's population (2.5 billion people) are at risk of DF, DHF, and DSS. Dengue fever is also an NIAID Category A pathogen, representing a significant threat to U.S. soldiers abroad from a biological defense perspective. Dengue fever is a new threat to North America, with a dramatic increase in severity over the past 25 years, including major outbreaks in Cuba and Venezuela, as well as outbreaks in Texas and Hawaii.

[0005] The inability to control the mosquito vectors and increased long-distance travel are contributing to the rise and spread of dengue fever. The characteristics of dengue fever as a viral hemorrhagic fever virus (arthropod-borne, widely prevalent, inducing massive cell damage and potentially triggering an immune response leading to severe bleeding, shock, and death) make it a unique threat to deployed military personnel and travelers to tropical regions worldwide. Both biological defense and preparedness for the public health challenges posed by dengue fever necessitate the development of new vaccines and antiviral therapies.

[0006] Dengue fever causes several illnesses of increasing severity, partly determined by previous infections with different serotypes of the virus. Classical dengue fever (DF) develops 3 to 8 days after being bitten by an infected mosquito and is characterized by a sudden fever, headache, back pain, joint pain, a paralytic rash, as well as nausea and vomiting. DF is often called "fracture" fever because of these symptoms. The illness usually resolves after two weeks, but a prolonged recovery accompanied by weakness and depression is common.

[0007] DHF, a more severe form of the disease, has a similar onset and initial stage to illnesses like dengue fever. However, immediately after the onset, it is characterized by high fever, hepatomegaly, and hemorrhagic phenomena such as bleeding from the nose, mouth, and internal organs due to vascular permeability. DSS involves circulatory failure and hypovolemic shock due to plasma leakage, which can lead to death within 12 to 24 hours without plasma replacement. The case fatality rate for DHF / DSS can be as high as 20% if left untreated. DHF is a leading cause of hospitalization and death in children in many countries, with an estimated 500,000 cases requiring hospitalization each year and a case fatality rate of approximately 5%.

[0008] The etiology of DHF / DSS is still under investigation, but it is thought to be partly related to the enhancement of viral replication in macrophages by heterologous antibodies, known as antibody-dependent enhancement (ADE). Specifically, during secondary infection with different serotypes of dengue virus, non-neutralizing cross-reactive antibodies form viral-antibody complexes that promote Fc-mediated viral uptake into monocytes and Langerhans cells (dendritic cells), increasing the number of infected cells. This can lead to the activation of cytotoxic lymphocytes, resulting in plasma leakage and the hemorrhagic characteristics of DHF and DSS. This antibody-dependent spread of infection is one reason why the development of a successful vaccine has proven to be extremely difficult. Although infrequent, DHF / DSS can occur after primary infection, so viral pathogenicity and immune activation are also considered to be contributing factors to the disease's pathogenesis.

[0009] Dengue fever is endemic to more than 100 countries in Africa, the Americas, the eastern Mediterranean, Southeast Asia, and the Western Pacific. During outbreaks, the incidence rate can reach 80-90% of vulnerable populations. All four serotypes of the virus are newly emerging worldwide, and the number of cases and outbreaks of this disease is increasing. For example, in 2002, the United States alone reported 1,015,420 cases of dengue fever, including 14,374 cases of DHF, which is more than three times the number of dengue fever cases reported in the United States in 1995.

[0010] The dengue genome consists of a linear, single-stranded positive sense RNA approximately 11 kb long. This genome has a defined upper limit and lacks a poly(A) tail at its 3' end, but instead possesses 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-binding protein (M), and the envelope protein (E)—surround the viral RNA and constitute the virion.

[0011] During infection, the virus binds to cell receptors via the E protein, undergoes receptor-mediated endocytosis, and then undergoes low-pH fusion in lysosomes. Subsequently, the uncoated virion and viral RNA are released into the cytoplasm and translated into a single viral precursor polyprotein. The polyprotein consists of three structural proteins C, M, and E, as well as seven non-structural (NS) proteins. The precursor polyprotein is cleaved by cellular proteinases to separate the structural proteins, while the virus-encoded proteinase cleaves the non-structural regions of the polyprotein. Both in-translational and post-translational proteolytic processing separate the viral proteins. Specifically, structural proteins are primarily involved in viral particle formation, while non-structural proteins are involved in viral RNA replication and viral assembly, as well as contributing to immunomodulation and disease pathogenesis.

[0012] Nonstructural protein 5 (NS5) constitutes RNA-dependent RNA polymerase, which, along with cofactors, synthesizes minus-strand RNA that serves as a template for the synthesis of progeny positive-strand RNA. Viral replication is membrane-bound and occurs in specific endoplasmic reticulum (ER)-derived intracellular compartments. After replication, the genome forms a capsid, and the immature virus, surrounded by a lipid envelope, budding into the ER lumen, is transported through the transcellular network (TGN), where the envelope protein is glycosylated, and then the mature virus is finally released onto the cell surface.

[0013] Basic stages or processes in the life cycle of the virus may be potential targets for inhibition from antiviral drugs, including viral binding to cells via E protein, viral uptake into cells, capping mechanisms, viral proteinases, viral RNA-dependent RNA polymerases, and viral helicases.

[0014] Current management of dengue virus-related illnesses relies solely on vector control. There are no approved antiviral drugs or vaccines for the treatment or prevention of dengue fever.

[0015] Ribavirin, a guanosine analog, has been shown to be effective against various RNA virus infections, acting against dengue fever in tissue culture by inhibiting the dengue 2'-O-methyltransferase NS5 domain. However, ribavirin did not show protection against dengue fever in mouse or rhesus monkey models, instead inducing anemia and thrombocytosis. While several antiviral candidates targeting DENV NS4B are currently in clinical trials (i.e., JNJ-1802, NITD-688), no treatment has yet been approved, and the potential for drug resistance to direct-acting antivirals represents a serious and persistent threat to RNA viruses. This can only be overcome by developing antiviral molecules with alternative mechanisms of action, and therefore, the development of further antiviral candidates targeting this pathogen is urgently needed.

[0016] Currently, there are two available and approved vaccines (Dengubaxia and QDENGA). Denguebaxia is recommended only for people who have previously had dengue fever. QDENGA was recently approved in Indonesia and the European Union (EU). Overall, multivalent dengue vaccines have somewhat limited potential in humans due to the difficulties represented by the existence of four different serotypes of the virus, each of which causes the disease. Vaccine development also faces the challenge of ADE (Antimicrobial Deficiency), where the risk of more severe illness may actually increase if protection against the four serotypes of the virus is not equivalent.

[0017] Therefore, antiviral drugs targeting all serotypes of dengue fever are needed. Antiviral drugs administered early in dengue infection that inhibit viral replication would prevent the high viral load associated with DHF and would be an attractive strategy in the treatment and prevention of the disease. Antiviral drugs that inhibit viral replication could be administered prophylactically before travel to dengue-endemic areas to prevent disease acquisition, or, in individuals previously exposed to dengue fever, could prevent infection by other viral serotypes, reducing the likelihood of life-threatening DHF and DSS. Having antiviral drugs would also facilitate vaccine development by providing readily available tools to treat complications that may arise due to unequal immune protection against different serotypes. While successful vaccines can be a crucial component of effective defense, the typical delays to immunity onset, potential side effects, costs, and logistics associated with large-scale civilian vaccination against low-threat-risk agents suggest that comprehensive defense involves separate, fast-response elements.

[0018] Therefore, there is a clear and long-standing need to develop effective therapeutic drugs for the treatment of dengue fever virus. Specifically, there is a need to develop compounds that are useful in treating patients infected with dengue fever, and compounds that selectively inhibit the replication of the dengue fever virus. [Brief explanation of the drawing]

[0019] [Figure 1] Overview of the antiviral activities of Example 1 and other known Nucs. [Figure 2] Comparison of the selected antiviral activities of Compound 58 and AL611. SUMMARY OF THE INVENTION

[0020] The present disclosure provides a compound of formula (I),

Chemical formula

[0021] This disclosure further provides compounds having the formula (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol.

[0022] The disclosure further provides compounds having the formula isopropyl((R)-(((2S,3R,4S,5R)-5-(2-amino-6-(methylamino)-9H-purine-9-yl)-4-chloro-2,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate.

[0023] The disclosure further provides pharmaceutical compositions comprising a compound described in any one of Embodiments 1 to 38 (hereinafter) to be mixed with a pharmaceutically acceptable carrier, diluent, or excipient.

[0024] This disclosure further provides the above-mentioned pharmaceutical composition, further comprising one or more therapeutic compounds or compositions.

[0025] The disclosure further provides the above-mentioned pharmaceutical composition, wherein one or more therapeutic compounds or compositions are second antiviral compounds or compositions.

[0026] The disclosure further provides a method for inhibiting RNA-dependent RNA polymerase, comprising administering a therapeutically effective amount of a compound described in any one of Embodiments 1 to 38 (hereinafter) or a pharmaceutical composition described in Embodiments 39 to 43 (hereinafter) to a subject in need thereof.

[0027] The disclosure further provides a method for preventing, improving, or treating RNA virus infections, comprising administering a therapeutically effective amount of a compound described in any one of Embodiments 1 to 38 (hereinafter) or a pharmaceutical composition described in Embodiments 39 to 43 (hereinafter) to a subject in need thereof.

[0028] The disclosure further provides the above method, wherein the RNA virus infection is at least one virus selected from the group consisting of dengue virus, South Asian respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, Zika virus, yellow fever virus, Ebola (Makona) virus, Ebola (Kikwit) virus, Bundibugyo virus, Sudan virus, Marburg virus, respiratory fusion 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.

[0029] This disclosure further provides the above-mentioned methods, in which RNA virus infections are caused by dengue virus, SARS-CoV-2 virus, yellow fever virus, or Zika virus. [Modes for carrying out the invention]

[0030] RNA-dependent RNA polymerase (RdRp) is an enzyme essential for the replication of viral RNA genomes, and because the host lacks functional equivalents, RdRp is a critical therapeutic target for treating diseases caused by RNA viruses. Nucleosides and nucleotide analogues have been well-reported as successful antiviral strategies targeting RdRp (i.e., sofosbuvir and remdesivir). Nucleoside analogues are converted to active 5'-triphosphate metabolites, which then inhibit viral replication.

[0031] In this specification, the inventors disclose their findings regarding 4'-substituted nucleosides and nucleotides that exhibit good antiviral activity against dengue virus (DENV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Tubercidine (kCBN048) exhibits high antiviral efficacy against DENV and SARS-CoV-2, but screening identified it as having significant cytotoxicity. NITD-008 (kCMY389) is a reported tubercidine analog with a 2'-β-methyl substitution and showed improved selectivity compared to tubercidine (SI). kCMY389 =52 vs SI kCBN048 =2, DENV-2 HepG2 assay, Figure 1). NITD-008 showed good efficacy in a DENV-infected mouse model, but failed a 2-week toxicity test. 1 The inventors' strategy is to improve the selectivity and activity of tubercidine by utilizing 4'-substitution. Compound 1 having 4'-F showed improved activity and selectivity compared to tubercidine and NITD-008 (SI 化合物1 =73 vs SI kCBN048 =2,SI kCMY389 =52, HepG2 assay of DENV2 (Table 1). Compound 1 and its analogues may be used as therapeutic agents for DENV, COVID-19, and other RNA virus infections. SAR studies focusing on nucleobase, glycan, and prodrug strategies are underway to improve selectivity, activity, and physicochemical properties. For example, Compound 1 has been found to be more effective than RDV parent nucleosides and N-hydroxycytidine against flaviviruses (DENV-2, ZIKV, YFV), respiratory viruses (SARS-CoV-2, SARS-CoV-1, MERS-CoV, HCoV-OC43, HCoV-229E, HRV14, HRV16, MEV, RSV A2, Flu A H1N1, alphavirus CHIKV), and enteroviruses (polio PV-1, polio PV-3, COXV-B3) (Figure 1). Furthermore, compound 58 was found to be more effective than AL-611 in HRV-14, HRV-16, and DENV-2 (Figure 2).

[0032] There are no commercially available antiviral drugs for dengue fever. Remdesivir and mornupiravir were approved by the FDA as antiviral drugs for COVID-19 with the same mechanism of action (MOA), but remdesivir must be administered by intravenous (IV) infusion, and mornupiravir has been reported with potential mutagenic toxicity. There is a need for new antiviral drugs (oral) with higher safety and patient compliance. Lead compound 1 showed improved activity and selectivity against DENV and SARS-CoV-2 compared to known compounds with the same mechanism of action (MOA).

[0033] Embodiment Embodiment 1. A compound of formula (I), [ka] During the ceremony, R 1 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)heterocycloalkyl, -C(=O)(C1-C6)alkyl(C3-C7)heterocycloalkyl, -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)heterocycloalkyl, -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(=O)(NHR 1’ )NH(C1-C6)heteroalkyl, -P(=O)(NHR 1’ )NH(C1-C6)haloalkyl, -P(=O)(NHR 1’ )NH(C3-C7)cycloalkyl, -P(=O)(NHR 1’ )NH(C3-C7)heterocycloalkyl, -P(=O)(NHR 1’ )NH(C6-C 10 )Aryl, -P(=O)(NHR 1’ )NH(C1-C6)alkyl(C6-C 10 )Aryl, -P(=O)(NHR 1’ )NH(C5-C8)heteroaryl, -P(=O)(NHR 1’ )NH(C1-C6)alkyl(C5-C8)heteroaryl, -P(=O)(OR 1’)NH(C1-C6)alkyl-C(=O)O-(C1-C6)alkyl, -P(=O)(OR 1’ )NH(C1-C6)heteroalkyl-C(=O)O-(C1-C6)alkyl,-P(=O)(OR 1’ )NH(C1-C6)haloalkyl-C(=O)O-(C1-C6)alkyl,-P(=O)(OR 1’ )NH(C1-C6)alkyl-C(=O)O-(C1-C6)alkyl(C6-C 10 )aryl, -P(=O)(OR 1’ )NH(C1-C6)heteroalkyl-C(=O)O-(C1-C6)alkyl(C6-C 10 )aryl, -P(=O)(OR 1’ )NH(C1-C6)haloalkyl-C(=O)O-(C1-C6)alkyl(C6-C 10 )aryl, -P(=O)(OR 1’ )NH(C1-C6)alkyl-C(=O)O-(C6-C 10 )aryl, -P(=O)(OR 1’ )NH(C1-C6)heteroalkyl-C(=O)O-(C6-C 10 )aryl, and -P(=O)(OR 1’ )NH(C1-C6)haloalkyl-C(=O)O-(C6-C 10 ) Selected from the group consisting of aryls, Each R 1’ These are 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 -C≡CH, R 2b These are independently a halo or OH, R 3 These are independently H or OH, R 4 These are N3, halo, -C≡N, (C1-C3)haloalkyl, or -O(C1-C6)alkyl. R 5 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, (C1-C6) alkyl, (C2-C6) alkenyl, or (C2-C6) alkynyl, R 7 H, NH2, OH, halo, oxo, N(R) 1’ )2, or -O(C1-C6)alkyl, and R 8 H or halo, However, the compound of formula I is 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-A Mino-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]pyrimidine-7-yl)-4-ethynyl-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl) triphosphate, ((5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (-7-yl)-4-ethynyl-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl triphosphate, (5-(4-amino-5-carbamoyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-4-ethynyl-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate, (5-(4-amino-5-cyano-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-4-ethynyl-2-fluoro-3,4-dihydroxytetrahydro Not furan-2-yl)methyl tetrahydrogen triphosphate, 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]pyrimidine-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]pyrimidine-7-yl)-4-ethynyl-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol, The compound comprises an enantiomer, a racemic mixture, and a scaremic mixture, and further comprises a pharmaceutically acceptable salt thereof.

[0034] Embodiment 2. A compound of formula (II), [ka] During the ceremony, R 1 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)heterocycloalkyl, -C(=O)(C1-C6)alkyl(C3-C7)heterocycloalkyl, -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) heterocycloalkyl, -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(=O)(NHR 1’ )NH(C1-C6) heteroalkyl, -P(=O)(NHR 1’ )NH(C1-C6)haloalkyl, -P(=O)(NHR 1’ )NH(C3-C7)cycloalkyl, -P(=O)(NHR 1’ )NH(C3-C7) heterocycloalkyl, -P(=O)(NHR 1’ )NH(C6-C 10 )aryl, -P(=O)(NHR 1’ )NH(C1-C6)alkyl(C6-C 10 )aryl, -P(=O)(NHR 1’ )NH(C5-C8) heteroaryl, -P(=O)(NHR 1’ )NH(C1-C6)alkyl(C5-C8)heteroaryl, -P(=O)(OR 1’ )NH(C1-C6)alkyl-C(=O)O-(C1-C6)alkyl, -P(=O)(OR 1’ )NH(C1-C6)heteroalkyl-C(=O)O-(C1-C6)alkyl,-P(=O)(OR 1’ )NH(C1-C6)haloalkyl-C(=O)O-(C1-C6)alkyl,-P(=O)(OR 1’ )NH(C1-C6)alkyl-C(=O)O-(C1-C6)alkyl(C6-C 10)aryl, -P(=O)(OR 1’ )NH(C1-C6)heteroalkyl-C(=O)O-(C1-C6)alkyl(C6-C 10 )aryl, -P(=O)(OR 1’ )NH(C1-C6)haloalkyl-C(=O)O-(C1-C6)alkyl(C6-C 10 )aryl, -P(=O)(OR 1’ )NH(C1-C6)alkyl-C(=O)O-(C6-C 10 )aryl, -P(=O)(OR 1’ )NH(C1-C6)heteroalkyl-C(=O)O-(C6-C 10 )aryl, and -P(=O)(OR 1’ )NH(C1-C6)haloalkyl-C(=O)O-(C6-C 10 ) Selected from the group consisting of aryls, Each R 1’ These are 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 2 is H, (C1-C6) alkyl, or -C≡CH, R 4 is N3, halo, or -O(C1-C6) alkyl, R 5 H, halo, -C≡N, hetero(C1-C6)alkyl, hydroxy(C1-C6)alkyl, N(R 1’ )2, -C(=O)NH2, R 6is H, halo, NH2, (C1-C6) alkyl, (C2-C6) alkenyl, or (C2-C6) alkynyl, R 7 H, NH2, OH, halo, N(R) 1’ )2, or -O(C1-C6)alkyl, and R 8 H or halo, However, the compounds of formula II are (2S,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol, (2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-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]triazine-7-yl)-2-azido-2-(hydroxymethyl)tetrahydrofuran-3,4-diol, (2R,3S,4R,5S)-5 -(4-aminopyrrolo[2,1-f][1,2,4]triazine-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]triazine-7-yl)-2-azido-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate, or 2-ethylbutyl((((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-2-azido-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate, The compound comprises an enantiomer, a racemic mixture, and a scaremic mixture, and further comprises a pharmaceutically acceptable salt thereof.

[0035] Embodiment 3. A compound of formula (IIIa) or (IIIb), [ka] During the ceremony, R 1 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)heterocycloalkyl, -C(=O)(C1-C6)alkyl(C3-C7)heterocycloalkyl, -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) heterocycloalkyl, -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(=O)(NHR 1’ )NH(C1-C6) heteroalkyl, -P(=O)(NHR 1’ )NH(C1-C6)haloalkyl, -P(=O)(NHR 1’ )NH(C3-C7)cycloalkyl, -P(=O)(NHR 1’ )NH(C3-C7) heterocycloalkyl, -P(=O)(NHR 1’ )NH(C6-C 10 )aryl, -P(=O)(NHR 1’ )NH(C1-C6)alkyl(C6-C 10 )aryl, -P(=O)(NHR 1’ )NH(C5-C8) heteroaryl, -P(=O)(NHR 1’ )NH(C1-C6)alkyl(C5-C8)heteroaryl, -P(=O)(OR 1’ )NH(C1-C6)alkyl-C(=O)O-(C1-C6)alkyl, -P(=O)(OR 1’ )NH(C1-C6)heteroalkyl-C(=O)O-(C1-C6)alkyl,-P(=O)(OR 1’ )NH(C1-C6)haloalkyl-C(=O)O-(C1-C6)alkyl,-P(=O)(OR 1’ )NH(C1-C6)alkyl-C(=O)O-(C1-C6)alkyl(C6-C 10 )aryl, -P(=O)(OR 1’ )NH(C1-C6)heteroalkyl-C(=O)O-(C1-C6)alkyl(C6-C 10 )aryl, -P(=O)(OR 1’ )NH(C1-C6)haloalkyl-C(=O)O-(C1-C6)alkyl(C6-C 10 )aryl, -P(=O)(OR 1’ )NH(C1-C6)alkyl-C(=O)O-(C6-C10 )aryl, -P(=O)(OR 1’ )NH(C1-C6)heteroalkyl-C(=O)O-(C6-C 10 )aryl, and -P(=O)(OR 1’ )NH(C1-C6)haloalkyl-C(=O)O-(C6-C 10 ) Selected from the group consisting of aryls, Each R 1’ These are 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 These are H, OH, halo, (C1-C6) alkyl, or -C≡CH. R 2b is H, OH, halo, or (C1-C6) alkyl, R 3a is H, OH, halo, or (C1-C6) alkyl, R 3b is H, OH, halo, or (C1-C6) alkyl, R 4 These are N3, halo, -C≡N, (C1-C3)haloalkyl, or -O(C1-C6)alkyl. R 6 and R 6’ Each of these is independently halo, NH2, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, -OH, -O(C1-C6)alkyl, -oxo, or -C≡CH, and R 8 H or halo, However, the compounds of formula III are (((2R,3S,4R,5R)-5-(2,6-diamino-9H-purine-9-yl)-2-(difluoromethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl) triphosphate, (((2S,3S,4R,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-4-ethynyl-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl (Cyl) triphosphate, (2S,3S,4R,5R)-5-(2,6-diamino-9H-purine-9-yl)-2-fluoro-2-(hydroxymethyl)-4-methyltetrahydrofuran-3,4-diol, or (2S,3S,4R,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-4-ethynyl-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol, The compound comprises an enantiomer, a racemic mixture, and a scaremic mixture, and further comprises a pharmaceutically acceptable salt thereof.

[0036] Embodiment 4. A compound of formula (IV), [ka] During the ceremony, R 1 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)heterocycloalkyl, -C(=O)(C1-C6)alkyl(C3-C7)heterocycloalkyl, -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’ )NH(C1-C6)alkyl, -P(=O)(OR 1’ )NH(C1-C6) heteroalkyl, -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)haloalkyl, -P(=O)(OR 1’ )NH(C3-C7)cycloalkyl, -P(=O)(OR 1’ )NH(C3-C7) heterocycloalkyl, -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(=O)(NHR 1’ )NH(C1-C6) heteroalkyl, -P(=O)(NHR 1’ )NH(C1-C6)haloalkyl, -P(=O)(NHR1’ )NH(C3-C7)cycloalkyl, -P(=O)(NHR 1’ )NH(C3-C7) heterocycloalkyl, -P(=O)(NHR 1’ )NH(C6-C 10 )aryl, -P(=O)(NHR 1’ )NH(C1-C6)alkyl(C6-C 10 )aryl, -P(=O)(NHR 1’ )NH(C5-C8) heteroaryl, -P(=O)(NHR 1’ )NH(C1-C6)alkyl(C5-C8)heteroaryl, -P(=O)(OR 1’ )NH(C1-C6)alkyl-C(=O)O-(C1-C6)alkyl, -P(=O)(OR 1’ )NH(C1-C6)heteroalkyl-C(=O)O-(C1-C6)alkyl,-P(=O)(OR 1’ )NH(C1-C6)haloalkyl-C(=O)O-(C1-C6)alkyl,-P(=O)(OR 1’ )NH(C1-C6)alkyl-C(=O)O-(C1-C6)alkyl(C6-C 10 )aryl, -P(=O)(OR 1’ )NH(C1-C6)heteroalkyl-C(=O)O-(C1-C6)alkyl(C6-C 10 )aryl, -P(=O)(OR 1’ )NH(C1-C6)haloalkyl-C(=O)O-(C1-C6)alkyl(C6-C 10 )aryl, -P(=O)(OR 1’ )NH(C1-C6)alkyl-C(=O)O-(C6-C 10 )aryl, -P(=O)(OR 1’ )NH(C1-C6)heteroalkyl-C(=O)O-(C6-C 10 )aryl, and -P(=O)(OR 1’ )NH(C1-C6)haloalkyl-C(=O)O-(C6-C 10 ) Selected from the group consisting of aryls, Each R 1’These are 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 4 is N3, halo, or -O(C1-C6)alkyl, and R 6 is H, halo, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl, The compound comprises an enantiomer, a racemic mixture, and a scaremic mixture, and further comprises a pharmaceutically acceptable salt thereof.

[0037] Embodiment 5. A compound of formula (V), [ka] During the ceremony, R 1 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)heterocycloalkyl, -C(=O)(C1-C6)alkyl(C3-C7)heterocycloalkyl, -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) heterocycloalkyl, -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(=O)(NHR 1’ )NH(C1-C6) heteroalkyl, -P(=O)(NHR 1’ )NH(C1-C6)haloalkyl, -P(=O)(NHR1’ )NH(C3-C7)cycloalkyl, -P(=O)(NHR 1’ )NH(C3-C7) heterocycloalkyl, -P(=O)(NHR 1’ )NH(C6-C 10 )aryl, -P(=O)(NHR 1’ )NH(C1-C6)alkyl(C6-C 10 )aryl, -P(=O)(NHR 1’ )NH(C5-C8) heteroaryl, -P(=O)(NHR 1’ )NH(C1-C6)alkyl(C5-C8)heteroaryl, -P(=O)(OR 1’ )NH(C1-C6)alkyl-C(=O)O-(C1-C6)alkyl, -P(=O)(OR 1’ )NH(C1-C6)heteroalkyl-C(=O)O-(C1-C6)alkyl,-P(=O)(OR 1’ )NH(C1-C6)haloalkyl-C(=O)O-(C1-C6)alkyl,-P(=O)(OR 1’ )NH(C1-C6)alkyl-C(=O)O-(C1-C6)alkyl(C6-C 10 )aryl, -P(=O)(OR 1’ )NH(C1-C6)heteroalkyl-C(=O)O-(C1-C6)alkyl(C6-C 10 )aryl, -P(=O)(OR 1’ )NH(C1-C6)haloalkyl-C(=O)O-(C1-C6)alkyl(C6-C 10 )aryl, -P(=O)(OR 1’ )NH(C1-C6)alkyl-C(=O)O-(C6-C 10 )aryl, -P(=O)(OR 1’ )NH(C1-C6)heteroalkyl-C(=O)O-(C6-C 10 )aryl, and -P(=O)(OR 1’ )NH(C1-C6)haloalkyl-C(=O)O-(C6-C 10 ) Selected from the group consisting of aryls, 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, and R 2 is H, halo, (C1-C6)alkyl, or -C≡CH, and R 4 is N3, halo, -C≡N, (C1-C3)haloalkyl, or -O(C1-C6)alkyl, and 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, and R 6 is H, halo, NH2, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl, and R 7 is H, NH2, OH, halo, N(R 1’ )2, or -O(C1-C6)alkyl, and R 8 is H or halo, and the compound, including enantiomers, racemic mixtures and scalemic mixtures, and further including its pharmaceutically acceptable salts.

[0038] Embodiment 6. R 2b is OH or halo, the compound according to Embodiment 1.

[0039] Embodiment 7. R 2bThe compound described in Embodiment 3 is a halo.

[0040] Embodiment 8. R 2a The compound according to Embodiment 7, wherein is Me or a halo.

[0041] Embodiment 9. R 2a The compound according to any one of embodiments 6 to 8, wherein H is present.

[0042] Embodiment 10. R 2a The compound is a (C1-C6) alkyl compound as described in any one of embodiments 6 to 8.

[0043] Embodiment 11. R 2a The compound according to Embodiment 10, wherein the compound is Me.

[0044] Embodiment 12. R 2a The compound is a halo, as described in any one of embodiments 6 to 8.

[0045] Embodiment 13. R 2a The compound according to Embodiment 12, wherein the compound is Cl.

[0046] Embodiment 14. R 2 The compound according to either embodiment 2 or 5, wherein H is present.

[0047] Embodiment 15. R 2 The compound is a halo, as described in any one of Embodiments 2 or 5.

[0048] Embodiment 16. R 2 The compound described in Embodiment 15 is F.

[0049] Embodiment 17. R 2The compound according to any one of Embodiment 2 or 5, wherein R is (C1-C6) alkyl.

[0050] Embodiment 18. R 2 The compound according to Embodiment 17, wherein R is Me.

[0051] Embodiment 19. R 5 The compound according to any one of Embodiments 1 to 2 or 5, wherein R is H.

[0052] Embodiment 20. R 5 The compound according to any one of Embodiments 1 to 2 or 5, wherein R is -CH2OH.

[0053] Embodiment 21. R 5 The compound according to any one of Embodiments 1 to 2 or 5, wherein R is -C(=O)NH2.

[0054] Embodiment 22. R 3 The compound according to any one of Embodiments 1, 6 to 13, or 19 to 21, wherein R is OH.

[0055] Embodiment 23. R 3 The compound according to any one of Embodiments 1, 6 to 13, or 19 to 21, wherein R is H.

[0056] Embodiment 24. R 4 The compound according to any one of Embodiments 1 to 23, wherein R is halo.

[0057] Embodiment 25. R 4 The compound according to Embodiment 24, wherein R is F.

[0058] Embodiment 26. R 4 The compound according to Embodiment 24, wherein R is Cl.

[0059] Embodiment 27. R 4 The compound is N3, as described in any one of Embodiments 1 to 23.

[0060] Embodiment 28. R 4 The compound is a -O(C1-C6) alkyl compound as described in any one of Embodiments 1 to 23.

[0061] Embodiment 29. R 4 The compound according to Embodiment 28, wherein the compound is -OMe.

[0062] Embodiment 30. R 6 is H or NH2, and R 6’ The compound according to any one of Embodiments 1 to 29, wherein is an -NH(C1-C6) alkyl or an -O(C1-C6) alkyl.

[0063] Embodiment 31. R 6 The compound is a halo, as described in any one of Embodiments 1 to 29.

[0064] Embodiment 32. R 6 The compound described in Embodiment 31 is F.

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

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

[0067] Embodiment 35. R 1 is -P(=O)(OR 1’ )2, -P(=O)(OR 1’)-P(=O)(OR 1’ )2, or -P(=O)(OR 1’ )-P(=O)(OR 1’ )-P(=O)(OR 1’ The compound according to any one of Embodiments 1 to 33, which is )2.

[0068] Embodiment 36. R 1 is -P(=O)(OR 1’ A compound according to any one of Embodiments 1 to 33, which is NH(C1-C6)alkyl-C(=O)O-(C1-C6)alkyl.

[0069] Embodiment 37. Compounds having one of the following formulas selected from the group below: (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-azido-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-2-(hydroxymethyl)-2-methoxy-4-methyltetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3S,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3R,4S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-4-chloro-2,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol; (2R,3R,4S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-azido-4-chloro-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol; (2R,3R,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-5-azido-5-(hydroxymethyl)tetrahydrofuran-3-ol; (2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-2-azido-2-(hydroxymethyl)-4-methyltetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)-4-methyltetrahydrofuran-3,4-diol; (2R,3R,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-5-fluoro-5-(hydroxymethyl)tetrahydrofuran-3-ol; (2R,3R,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-5-fluoro-5-(hydroxymethyl)tetrahydrofuran-3-ol; (2S,3S,4R,5R)-2-fluoro-5-(4-fluoro-7H-pyrrolo[2,3-d]pyrimidine-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]pyrimidine-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]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(6-amino-2-ethynyl-9H-purine-9-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5S)-5-(4-aminoimidazo[2,1-f][1,2,4]triazine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-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]pyrimidine-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-2-fluoro-2-(hydroxymethyl)-5-(7H-pyrrolo[2,3-d]pyrimidine-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]pyrimidine-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-carbonitriel; (2S,3S,4R,5R)-5-(2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-2-fluoro-2-(hydroxymethyl)-5-(6-(methylthio)-9H-purine-9-yl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(4-chloro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (1S,2S,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3-fluoro-3-(hydroxymethyl)cyclopentan-1,2-diol; (2S,3S,4R,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydrofuran-2-carbonitrile; (2S,3S,4R,5R)-5-(4-amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; ((2S,3S,4R,5S)-5-(4-amino-5-carbamoylpyrrolo[2,1-f][1,2,4]triazine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl benzoate; (2S,3S,4R,5R)-2-fluoro-5-(5-fluoro-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(5-chloro-7H-pyrrolo[2,3-d]pyrimidine-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]pyrimidine-7-yl)tetrahydrofuran-3-ol; (2S,3S,4R,5R)-2-fluoro-2-(hydroxymethyl)-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidine-7-yl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(4-amino-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(6-amino-2-chloro-9H-purine-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)pyrimidine-2(1H)-one; (2S,3S,4R,5R)-2-((benzoyloxy)methyl)-5-(3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)-2-fluorotetrahydrofuran-3,4-diyldiacetate; ((2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate; (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-((isobutyryloxy)methyl)tetrahydrofuran-3,4-diylbis(methyl 2-propionate); Isopropyl((S)-(((2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; Isopropyl((R)-(((2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; ((2S,3S,4R,5R)-4-(benzoyloxy)-5-(4-cyano-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3-hydroxytetrahydrofuran-2-yl)methyl benzoate; (2R,3R,4S,5S)-2-(4-aminoimidazo[2,1-f][1,2,4]triazine-7-yl)-5-fluoro-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile; (2S,3S,4R,5R)-5-(4-amino-1H-pyrazolo[3,4-d]pyrimidine-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]pyrimidine-7-yl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3R,5R)-5-(4-amino-5-(benzo[d]thiazole-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2,4,4-trifluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol; ((2S,3S,4R,5R)-5-(2-amino-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl benzoate; (2S,3R,4S,5R)-5-(2-amino-6-(methylamino)-9H-purine-9-yl)-4-chloro-2,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol; Isopropyl((R)-(((2S,3R,4S,5R)-5-(2-amino-6-(methylamino)-9H-purine-9-yl)-4-chloro-2,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; Isopropyl((S)-(((2S,3R,4S,5R)-5-(2-amino-6-(methylamino)-9H-purine-9-yl)-4-chloro-2,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; (2S,3R,5R)-5-(2-amino-6-ethoxy-9H-purine-9-yl)-2,4,4-trifluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol; Isopropyl((((2S,3R,5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purine-9-yl)-2,4,4-trifluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; 2-amino-9-((2R,3R,4R,5S)-3-chloro-5-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)-1,9-dihydro-6H-purine-6-one; (2S,3R,4R,5R)-5-(2-amino-6-ethoxy-9H-purine-9-yl)-4-chloro-2-fluoro-2-(hydroxymethyl)-4-methyltetrahydrofuran-3-ol; Isopropyl((((2S,3R,4R,5R)-5-(2-amino-6-ethoxy-9H-purine-9-yl)-4-chloro-2-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; Neopentyl((((2S,3S,4R,5R)-5-(4-aminoimidazo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(naphthalene-1-yloxy)phosphoryl)-L-alaninate; (2S,3R,4S,5R)-5-(2-amino-6-ethoxy-9H-purine-9-yl)-4-chloro-2,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol; Isopropyl((((2S,3R,4S,5R)-5-(2-amino-6-ethoxy-9H-purine-9-yl)-4-chloro-2,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; (2S,3R,4S,5R)-5-(2-amino-6-ethoxy-9H-purine-9-yl)-4-bromo-2,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol; Isopropyl((((2S,3R,5R)-5-(2-amino-6-ethoxy-9H-purine-9-yl)-2,4,4-trifluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; (2S,3S,4R,5R)-4-ethynyl-2-fluoro-2-(hydroxymethyl)-5-(4-(propylamino)-7H-pyrrolo[2,3-d]pyrimidine-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-purine-6-one; (2S,3S,4R,5R)-2-fluoro-2-(hydroxymethyl)-5-(4-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)tetrahydrofuran-3,4-diol; ((2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl L-valinate; Neopentyl((((2S,3S,4R,5R)-5-(4-amino-1H-pyrazolo[3,4-d]pyrimidine-1-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(naphthalene-1-yloxy)phosphoryl)-L-alaninate; ((2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyltetrahydrogen triphosphate; ((2S,3S,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyltetrahydrogen triphosphate; ((2S,3S,4R,5R)-2-fluoro-3,4-dihydroxy-5-(4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)tetrahydrofuran-2-yl)methyltetrahydrogen triphosphate; ((2S,3S,4R,5R)-5-(5-carbamoyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyltetrahydrogen triphosphate; ((2S,3S,4R,5R)-5-(5-bromo-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyltetrahydrogen triphosphate; ((2S,3S,4R,5R)-2-fluoro-5-(5-fluoro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyltetrahydrogen triphosphate; ((2S,3S,4R,5R)-5-(4-aminoimidazo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyltetrahydrogen triphosphate; ((2S,3S,4R,5R)-5-(4-amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyltetrahydrogen triphosphate; ((2S,3S,4R,5R)-5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyltetrahydrogen triphosphate; ((2S,3R,4R,5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purine-9-yl)-4-chloro-2-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyltetrahydrogen triphosphate; and ((2S,3S,4S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate.

[0070] Embodiment 38. The compound according to Embodiment 37, having the formula (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol or isopropyl((R)-(((2S,3R,4S,5R)-5-(2-amino-6-(methylamino)-9H-purine-9-yl)-4-chloro-2,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate.

[0071] Embodiment 39. A pharmaceutical composition comprising a compound according to any one of Embodiments 1 to 38, which is mixed with a pharmaceutically acceptable carrier, diluent, or excipient.

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

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

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

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

[0076] Embodiment 44. A method for inhibiting RNA-dependent RNA polymerase, comprising administering a therapeutically effective amount of a compound described in any one of Embodiments 1 to 38 or a pharmaceutical composition described in Embodiments 39 to 43 to a subject requiring such inhibition.

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

[0078] Embodiment 46. The method according to Embodiment 45, wherein the RNA virus infection is at least one virus selected from the group consisting of dengue virus, South Asian respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, Zika virus, yellow fever virus, Ebola (Makona) virus, Ebola (Kikwit) virus, Bundibugyo virus, Sudan virus, Marburg virus, respiratory fusion 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 according to embodiment 46, wherein the RNA virus infection is caused by the dengue virus.

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

[0081] Embodiment 49. The method according to embodiment 46, wherein the RNA virus infection is caused by yellow fever virus.

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

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

[0084] Embodiment 52. The method according to Embodiment 51, wherein at least one of the one or more therapeutic compounds or compositions is a drug effective in treating or improving RNA virus infections.

[0085] Embodiment 53. The method according to Embodiment 52, wherein the drug for treating the RNA virus infection is selected from the group consisting of remdesivir, mornupiravir, or pachyrovid.

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

[0087] definition Where used herein, whether in a transitional clause or in the body of the claims, the terms “comprise(s)” and “comprising” should be interpreted as having an unrestricted meaning. That is, these terms should be interpreted as synonymous with the phrases “at least have” or “at least include.” Where used in the context of a process, “comprising” means that the process includes at least the steps described, but may include additional steps. Where used in the context of a compound or composition, “comprising” means that the compound or composition includes at least the enumerated features or components, but may also include additional features or components.

[0088] As used herein, unless otherwise specifically indicated, the word “or” is used in the “inclusive” sense of “and / or” and not in the “exclusive” sense of “either / or.”

[0089] The term “independently” is used herein to indicate that a variable applies to any one instance, regardless of whether the variable has the same or different definitions within the same compound. Thus, in a compound where “R” appears twice and is defined as “selected independently from,” it means that each instance of the R group is identified separately as one member of a set according to the definition of that R group. For example, “each R 1 and R 2 " is independently selected from carbon and nitrogen" is R 1 and R 2 Both can be carbon, R 1 and R 2 Both can be nitrogen, or R 1 Or R 2 This means that one could be carbon and the other could be nitrogen, and vice versa.

[0090] In any part or formula illustrating and describing a compound used or claimed in this invention, if any variable appears multiple times, its definition in each appearance is independent of its definition in any other appearance. Furthermore, any combination of substituents and / or variables is acceptable only if such a compound results in a stable compound.

[0091] The asterisk (*) at the end of a bond, the line drawn by the bond, or the symbol "~~~~" drawn by the bond each indicates a bonding point of a functional group or other chemical part to the remainder of a molecule.

[0092] Bonds drawn into a ring system (in contrast to those connected at separate vertices) indicate that the bond may be attached to any of the suitable ring atoms.

[0093] Where used herein, the terms “optional” or “occasionally” mean that the event or situation described below may or may not occur, and that the description includes both the event or situation that occurs and the situation that does not occur. For example, “occasionally substituted” means that the “occasionally substituted” portion may incorporate hydrogen or substituents.

[0094] The phrase "any bond" means that a bond may or may not exist, and that its description may include single, double, or triple bonds. If a substituent is specified as "bonded" or "absent," the atom bonded to the substituent is then directly linked.

[0095] The term “approximately” is used herein to mean about, within a range, roughly, or approximately. When the term “approximately” is used in conjunction with a numerical range, it modifies the range by extending the boundaries above and below the numerical value described. Generally, the term “approximately” is used herein to modify numerical values ​​above and below a given value with a 20% variation.

[0096] Certain compounds disclosed herein may exhibit tautomerism. Tautomer compounds may exist as two or more interconvertible species. Prototropic tautomers arise from the rearrangement of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate individual tautomers usually produce a mixture of compounds with matching chemical and physical properties. The position of the equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form is dominant, while in phenols, the enol form is dominant. Common prototropic tautomers include keto / enol (-C(=O)-CH-←→-C(-OH)=CH-), amide / imido 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 heterocyclic rings, and the present invention encompasses all tautomerization types of compounds.

[0097] Unless otherwise defined, the technical and scientific terms used herein have meanings that are generally understood by those skilled in the art to the extent of this invention. This specification refers to various methods and materials known to those skilled in the art. For a standard reference explaining the general principles of pharmacology, see Goodman and Gilman's *The Pharmacological Basis of Therapeutics*, 10 th Ed., McGraw Hill Company Inc., New York (2001) is cited as an example. Any suitable materials and / or methods known to those skilled in the art can be used to carry out the present invention. However, preferred materials and methods are described. The materials and reagents, etc., referenced in the following description and examples are available from commercial sources unless otherwise noted.

[0098] The definitions provided herein may be suffixed to form chemically related combinations such as “heteroalkylaryl,” “haloalkylheteroaryl,” “arylalkylheterocyclyl,” “alkylcarbonyl,” and “alkoxyalkyl.” When the term “alkyl” is used as a suffix following another term, as in “phenylalkyl” or “hydroxyalkyl,” it is intended to refer to an alkyl group substituted with one or two substituents selected from other specifically named groups, as defined above. For example, “phenylalkyl” refers to an alkyl group having one or two phenyl substituents, and thus includes benzyl, phenylethyl, and biphenyl. “Alkylaminoalkyl” is an alkyl group having one or 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. Therefore, as used herein, the term “hydroxyalkyl” is used to define a subset of heteroalkyl groups as defined below. The term –(ar)alkyl refers to either an unsubstituted alkyl or aralkyl group. The terms (hetero)aryl or (hetero)aryl refer to either an aryl group or a heteroaryl group.

[0099] As used herein, the term "acyl" refers to a group of the formula -C(=O)R, where R is hydrogen or a lower alkyl as defined herein. As used herein, the term "alkylcarbonyl" refers to a group of the formula C(=O)R, where R is an alkyl as defined herein. Term C 1-6 Acyl refers to a group containing six carbon atoms -C(=O)R. As used herein, the term “arylcarbonyl” means a group of formula C(=O)R, where R is an aryl group, and as used herein, the term “benzoyl” contains an “arylcarbonyl” group, where R is phenyl.

[0100] As used herein, the term “alkyl” refers to an unbranched or branched saturated monovalent hydrocarbon residue containing 1 to 12 carbon atoms. As used herein, the terms “lower alkyl” or “C1-C6 alkyl” refer to a linear or branched hydrocarbon residue containing 1 to 6 carbon atoms. As used herein, “C 1-12 "Alkyl" refers to alkyl groups composed of 1 to 12 carbon atoms. Examples of alkyl groups include, but are not limited to, lower alkyl groups including methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, 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,” it is intended to refer to an alkyl group substituted with one or two substituents selected from other specifically named groups, as defined above. Thus, for example, “phenylalkyl” represents the radical R'R''-, where R' is a phenyl radical and R'' is an alkylene radical as defined herein, understanding that the bonding site of the phenylalkyl moiety is on an alkylene radical. Examples of arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, and 3-phenylpropyl. The terms “arylalkyl” or “aralkyl” are similarly interpreted, except that R' is an aryl radical. The terms “(het)arylalkyl” or “(het)aralkyl” are similarly interpreted, except that R' is optionally an aryl or heteroaryl radical.

[0102] When a range of values ​​is enumerated, it is intended to include each value and subrange within that range. For example, "C1-C6 alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C2-6 , 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 It is intended to include alkyl groups.

[0103] "Alkyl" refers to a radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 ("alkyl"). In some embodiments, the alkyl group has 1 to 15 carbon atoms ("C"). 1-15 ("alkyl"). In some embodiments, the alkyl group has 1 to 14 carbon atoms ("C"). 1-14 (alkyl). In some embodiments, the alkyl group has 1 to 13 carbon atoms ("C"). 1-13 (alkyl). In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C"). 1-12 ("alkyl"). In some embodiments, the alkyl group has 1 to 11 carbon atoms ("C"). 1-11 ("alkyl"). In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C"). 1-10 (alkyl). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C"). 1-9 (alkyl). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C"). 1-8 (alkyl). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C"). 1-7 ("alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C"). 1-6 (alkyl). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C"). 1-5 (alkyl). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C"). 1-4 (alkyl). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C"). 1-3Alkyl). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C"). 1-2 In some embodiments, the alkyl group has one carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has two to six carbon atoms ("C1 alkyl"). 2-6 Alkyl). 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), iso-butyl (C4), n-pentyl (C5), 3-pentyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7) and n-octyl (C8).

[0104] "Alkenyl" or "olefin" refers to a radical of a linear or branched hydrocarbon group having 2 to 10 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds ("C 2-10 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C"). 2-9 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C"). 2-8 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C"). 2-7 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C"). 2-6 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C"). 2-5 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C"). 2-4 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C"). 2-3"Alkenyl"). In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds may be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), and butadienyl (C4). 2-6 An example of an alkenyl group is the aforementioned C 2-4 Examples of alkenyl groups include pentenyl (C5), pentadienyl (C5), and hexenyl (C6). Further examples of alkenyls include heptenyl (C7), octenyl (C8), and octatrienyl (C8).

[0105] "Alkynyl" refers to a radical of a linear or branched hydrocarbon group having 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C 2-10 In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C"). 2-9 In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C"). 2-8 In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C"). 2-7 In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C"). 2-6 In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C"). 2-5 In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C"). 2-4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C"). 2-3 "Alkynyl"). In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds may be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). C2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 2-6 An example of an alkynyl group is the aforementioned C 2-4 Examples include alkynyl groups, as well as pentynyl (C5) and hexynyl (C6). Further examples of alkynyls include heptynyl (C7) and octinyl (C8).

[0106] The terms "haloalkyl," "halo-lower alkyl," or "lower haloalkyl" refer to linear or branched hydrocarbon residues containing 1 to 6 carbon atoms, in which one or more carbon atoms are substituted with one or more halogen atoms.

[0107] Unless otherwise indicated, the terms “alkylene” or “alkylenyl” as used herein refer to a divalent saturated linear hydrocarbon radical (e.g., (CH2)) of 1 to 10 carbon atoms. n ), or a branched saturated divalent hydrocarbon radical of 2 to 10 carbon atoms (e.g., -CHMe- or -CH2CH(i-Pr)CH2-). Except for methylene, the open valence of the alkylene group is not bonded to the same atom. Examples of alkylene radicals include, but are not limited to, methylene, ethylene, propylene, 2-methylpropylene, 1,1-dimethylethylene, butylene, and 2-ethylbutylene.

[0108] As used herein, the term "alkoxy" means an -O-alkyl group, where alkyl is, as defined above, for example, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, pentyloxy, hexyloxy (including their isomers). As used herein, "lower alkoxy" refers to an alkoxy group having a "lower alkyl" group, as defined above. 1-10"Alkoxy" refers to -O-alkyl, where alkyl is C 1-10 That is the case.

[0109] As used herein, the term "hydroxyalkyl" refers to an alkyl radical as defined herein, in which one to three hydrogen atoms on different carbon atoms are replaced by a hydroxyl group.

[0110] As used herein, the terms “alkylsulfonyl” and “arylsulfonyl” refer to a group of the formula -S(=O)2R, where R is either alkyl or aryl, as defined herein. As used herein, the term “heteroalkylsulfonyl” refers to a group of the formula -S(=O)2R, where R is “heteroalkyl” as defined herein.

[0111] As used herein, the terms “alkylsulfonylamino” and “arylsulfonylamino” refer to a group of the formula -NR'S(=O)2R, where R is alkyl or aryl, respectively, and R' is hydrogen or C 1-3 It is alkyl, and alkyl and aryl are as defined herein.

[0112] As used herein, the term "cycloalkyl" refers to a saturated carbocyclic ring containing 3 to 8 carbon atoms, i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. 3-7 "Cycloalkyl" refers to a cycloalkyl group composed of 3 to 7 carbon atoms in a carbocyclic ring.

[0113] As used herein, the term carboxyalkyl refers to the alkyl moiety in which one hydrogen atom is replaced by a carboxyl atom, with the understanding that the bonding site of the heteroalkyl radical is via a carbon atom. The terms "carboxy" or "carboxyl" refer to the -CO2H moiety.

[0114] As used herein, the terms “heteroaryl” or “heterocyclic aromatic compound” mean a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing 4 to 8 atoms per ring, incorporating one or more N, O, or S heteroatoms, with the bond site of the heteroaryl radical located on an aromatic ring, and the remaining ring atoms being carbon. As is well known to those skilled in the art, heteroaryl rings are less aromatic than their all-carbon counter portion. Therefore, for the purposes of the present invention, the heteroaryl group only needs to have some degree of aromaticity. Examples of heteroaryl moieties include monocyclic aromatic heterocycles having 5-6 ring atoms and 1-3 heteroatoms, and which can be optionally substituted with one or more substituents, preferably one or two, selected from hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio, halo, lower haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino, and arylcarbonylamino, such as pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazole, isoxazole, thiazole, isothiazole, triazoline, thiadiazole, and oxadiaxolin. Examples of bicyclic moieties include, but are not limited to, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzoxazole, bendisoxazole, benzothiazole, and benzisothiazole. The bicyclic moiety may be substituted on any of the rings, but the bond site is located on a ring containing a heteroatom.

[0115] Unless otherwise indicated, the terms “heterocyclyl,” “heterocycloalkyl,” or “heterocyclic” as used herein mean one or more rings, preferably one to two rings (including spirocyclic ring systems), and three to eight atoms per ring, with one or more ring heteroatoms (N,O or S(O) 0-2 It represents a monovalent saturated cyclic radical (selected from) which can optionally be independently substituted with one or more substituents, preferably one or two, selected from hydroxy, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, lower haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, and arylcarbonylamino. Examples of heterocyclic radicals include, but are not limited to, azetidinyl, pyrrolidinyl, hexahydroazepinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, thiomorpholinyl, quinuclidinyl, and imidazolinyl.

[0116] A "heterocyclyl" or "heterocyclic" refers to a 3- to 14-membered non-aromatic cyclic group or radical having a ring carbon atom and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3- to 14-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the bond site may be either a carbon atom or a nitrogen atom, as long as the valence allows. Heterocyclyl groups may be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., condensed, bridging, or spirocyclic systems, e.g., bicyclic systems ("bicyclic heterocyclyl") or tricyclic systems ("tricyclic heterocyclyl")), and may be saturated or contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system in which a heterocyclyl ring is fused with one or more carbocyclyl groups, as defined above, where the bond site is either on the carbocyclyl ring or the heterocyclyl ring, or a ring system in which a heterocyclyl ring is fused with one or more aryl or heteroaryl groups, as defined above, where the bond site is on the heterocyclyl ring, in which case the number of ring members still refers to the number of ring members in the heterocyclyl ring system.

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

[0118] Examples of three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azilidinyl, oxyranil, and thiranil. Examples of four-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanil, and thietanil. Examples of five-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranil, dihydrofuranil, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of five-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanil, oxathiolanil, and dithiolanil. Examples of five-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, thiazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranil, dihydropyridinyl, and thianyl. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinil, dithianyl, and dioxanil. Examples of six-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinyl. Examples of seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Examples of eight-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azokanyl, oxecanyl, and thiokanyl.Examples of bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydroclomenyl, octahydroisoclomenyl, decahydronaphthilidinyl, decahydro-1,8-naphthilidinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthaliumidyl, naphthaliumidyl, chromanyl, clomenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7- Examples include, but are not limited to, tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-floo[3,2-b]pyrrolyl, 6,7-dihydro-5H-floo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofloo[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofloo[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, and 1,2,3,4-tetrahydro-1,6-naphthilidinyl.

[0119] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and zero heteroatoms provided to the aromatic ring system ("C"). 6-14 In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl" (e.g., naphthyl such as 1-naphthyl (α-naphthyl) and 2-naphthyl (β-naphthyl)). In some embodiments, the aryl group has 14 ring carbon atoms ("C"). 14"Aryl" (e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring is fused with one or more carbocykyl or heterocyclyl groups, as defined above, where the radical or bond site is on the aryl ring, and in such examples, the number of carbon atoms still indicates the number of carbon atoms in the aryl ring system.

[0120] "Heteroaryl" refers to a 5- to 14-membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) radical having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the bond site may be on either a carbon or nitrogen atom, as long as the valence allows. Heteroaryl polycyclic ring systems may contain one or more heteroatoms on one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring is fused with one or more carbocyryl or heterocyclyl groups, as defined above, where the bond site is on the heteroaryl ring, and in such examples, the number of ring members still indicates the number of ring members in the heteroaryl ring system. "Hyperaryl" also includes ring systems in which a heteroaryl ring is fused with one or more aryl groups, as defined above, where the bond site is either on the aryl ring or the heteroaryl ring, and in such examples, the number of ring members indicates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. The bond site of a polycyclic heteroaryl group in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, and carbazolyl) may be on either ring, i.e., the ring containing a heteroatom (e.g., 2-indolyl) or the ring not containing a heteroatom (e.g., 5-indolyl).

[0121] In some embodiments, the heteroaryl group is a 5-10 member aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 member heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 member aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 member heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 member aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 member heteroaryl"). In some embodiments, the 5-6 member heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 member heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0122] Examples of five-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Examples of five-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of five-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Examples of five-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of six-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Examples of six-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of six-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetradinyl, respectively. Examples of seven-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranil, benzoisofuranil, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolidinyl, and purinyl. Examples of 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthylidinyl, pteridinyl, quinolinyl, isoquinolinyl, sinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Examples of tricyclic heteroaryl groups include, but are not limited to, phenanthridine, dibenzofuranil, carbazolyl, acridinil, phenothiazinil, phenoxadinil, and phenazinil.

[0123] "Saturated" refers to a ring portion that does not contain double or triple bonds; that is, the ring contains all single bonds.

[0124] Alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may be optionally substituted. Optionally substituted means that the group may be substituted or unsubstituted. Generally, the term “substituted” means that at least one hydrogen atom present on the group is replaced by a non-hydrogen substituent, thereby resulting in a stable compound that does not spontaneously undergo transformations such as 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 valence of the heteroatom, resulting in the formation of a stable compound.

[0125] As used herein, an exemplary nonhydrogen substituent in which a portion is "optionally substituted" is defined as a 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(Rbb )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 -S(=O)R aa -OS(=O)R aa , -B(OR cc )2, C 1-10 Alkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 3-14 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 The group consists of aryls and 5- to 14-membered heteroaryls, but is not limited to these and may be substituted with any additional parts, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd Substituted by a group, or two geminal hydrogens on a carbon atom are substituted by an =O group; R aa Each example is independent of C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 3-14 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Selected from the group consisting of aryls and 5- to 14-membered heteroaryls, or two R aa The groups bond to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base; R bb Each example is independently hydrogen, -OH, -OR aa , -N(R cc)2, -CN, -C(=O)R aa -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -SO2N(R cc )2, -SOR aa , C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 3-14 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Selected from the group consisting of aryls and 5- to 14-membered heteroaryls, or two R bb The groups bond to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base; R cc Each example is independent of hydrogen, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 3-14 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Selected from the group consisting of aryls and 5- to 14-membered heteroaryls, or two R cc The groups bond to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base; R dd Each of these examples is independent: halogen, -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 1-6Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -C(=O)(C 1-6 Alkyl), -CO2H, -CO2(C 1-6 Alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl), -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), -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC(=NH)(C 1-6 Alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2,-C(=NH)NH(C 1-6 Alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2,-OC(NH)NH(C 1-6 Alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 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 Alkenil, C 2-6 Alkinyl, C 3-10 Carbocyclyl, C 6-10 Selected from the group consisting of aryls, 3-10 membered heterocyclines, and 5-10 membered heteroaryls; or two geminal Rs on a carbon atomdd Substituents may bond to form an =O group.

[0126] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iod, -I).

[0127] As used herein, the term “composition” is intended to encompass products containing specific components, as well as any products obtained directly or indirectly from combinations of specific components.

[0128] The term "salt" includes all types of salts. A "pharmaceutically acceptable salt" is a salt that is suitable for use in contact with human and lower animal tissues without causing excessive toxicity, irritation, or allergic reactions, within the normal range of reasonable medical judgment, and that balances with a reasonable benefit / risk ratio. Pharmacochemically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts include those derived from inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethanesulfonate. Examples include lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. Pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N + (C 1-4This includes alkyl)4 salts. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations (halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons, etc.) which are formed using counterions where appropriate.

[0129] Unless otherwise specified, the compounds described herein may contain one or more chiral centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of a mixture of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. Isomers may be isolated from the mixture by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC). The compounds described herein may be in the form of individual isomers substantially free of other isomers, or they may instead be in the form of a mixture of various isomers.

[0130] Unless otherwise specified, the structures shown herein also mean that the compounds differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the present invention, excluding the substitution of hydrogen with deuterium or tritium, the substitution of 19F with 18F, the substitution of carbon with 13C or 14C enriched carbon, and / or the substitution of oxygen atoms with 18O, are within the scope of this disclosure. Other examples of isotopes include 15N, 18O, 17O, 31P, 32P, 35S, 18F, 36Cl, and 123I. Compounds having such isotopically enriched atoms are useful, for example, as analytical tools or probes in biological assays.

[0131] Certain isotope-labeled compounds (e.g., compounds labeled with 3H and 14C) are useful in tissue distribution assays of compounds and / or substrates. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred due to their ease of preparation and detection capabilities.

[0132] Certain isotope-labeled compounds of formula (I) may be useful for medical imaging purposes. For example, those labeled with positron-emitting isotopes such as 11C or 18F may be useful for positron emission tomography (PET), and compounds labeled with gamma rays emitting isotopes such as 123I may be useful for single-photon emission tomography (SPECT). Furthermore, substitution with heavier isotopes such as deuterium (i.e., 2H) may result in specific therapeutic benefits derived from higher metabolic stability (e.g., extended in vivo half-life or reduced required dose), and may therefore be preferred in some environments. Furthermore, isotope substitution at epimerization sites may delay or reduce the epimerization process, thereby allowing for longer retention of a more active or effective form of the compound. Isotope-labeled compounds of formula (I), particularly those containing isotopes with longer half-lives (t1 / 2 > 1 day), can generally be prepared by using a suitable isotope-labeling reagent instead of a non-isotope-labeling reagent, following the procedure similar to that disclosed in the following scheme and / or examples herein.

[0133] In the event of any discrepancy between the shown structure and the name given to it, the shown structure shall prevail. Furthermore, if the stereochemistry of a structure or part of a structure is not indicated, for example, in bold or dashed, that structure or part of a structure shall be interpreted as encompassing all its stereoisomers. However, in some cases, where multiple chiral centers are present, the structure and name may be represented as a single enantiomer to facilitate the description of the relative stereochemistry. Those skilled in the art of organic synthesis will know whether a compound is prepared as a single enantiomer from the method used to prepare them.

[0134] Examples Table 1. In the various embodiments described herein, any one of the dengue fever inhibitors of formula IV, or a pharmaceutically acceptable salt and / or stereoisomer thereof, is selected from the compounds in Table 1 shown below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16]

[0135] Examples Common abbreviations Commonly used abbreviations include: acetyl (Ac), azo-bis-isobutyrylnitrile (AIBN), air (Atm), 9-borabicyclo[3.3.1]nonane (9-BBN or BBN), tert-butoxycarbonyl (Boc), di-tert-butyl pyrocarbonate or boc anhydride (BOC2O), benzyl (Bn), butyl (Bu), chemical abstract registry number (CASRN), benzyloxycarbonyl (CBZ) (Tah Z), carbonyl diimidazole (CDI), 1,4-diazabicyclo[2.2.2]octane (DABCO), diethylaminosulfur trifluoride (DAST), dibenzylideneacetone (dba), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), N,N'-dicyclohexylcarbodiimide (DCC), 1,2-dichloroethane (DCE), dichloromethane (DCM) Diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (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 (SiO), ethanol (EtOH), 2-ethoxy-2H-quinoline-1-carboxylate ethyl ester (EEDQ), diethyl ether (Et2O), O-(7-azabenzotriazol-1-yl)-N,N,N'N'-tetramethyluronium hexafluorophosphate acetate (HATU), acetic acid (HOAc), 1-N-hydroxybenzotriazole (HOBt), high-pressure liquid chromatography (HPLC), isopropanol (IPA), lithium hexamethyldisilazane (LiHMDS), methanol (MeOH), melting point (mp), MeSO2-(mesyl or Ms), methyl (Me), acetonitrile (MeCN), m-chloroperbenzoic acid (MCPBA), mass spectrum (ms), methyl t-butyl ether (MTBE), N-bromosuccinimide (NBS), N-carboxyhydride (NCA), N-chlorosuccinimide (NCS), N-methylmorpholine (NMM), N-methylpyrrolidone (NMP), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), phenyl (Ph), propyl (Pr), isopropyl (i-Pr), phenyl d per square inch (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-tetramethylheptan-2,6-dione (T MHD), 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 normal (n), iso (i-), secondary (sec-), tertiary (tert-), and neo, retains their usual meanings when used with alkyl moieties (J. Rigaudy and DPKlesney, Nomenclature in Organic Chemistry, IUPAC 1979 Pergamon Press, Oxford).

[0136] Example 1 Synthesis of Compound 1 Synthesis scheme: [ka]

[0137] Step 1: Synthesis of N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)benzamide: To a stirred solution of anhydrous pyridine (10 mL) containing (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (1.2 g, 4.51 mmol), TMSCl (2.57 mL, 20.3 mmol) was added dropwise at 0°C, and the resulting reaction mixture was stirred at the same temperature for 30 minutes. Then, benzoyl chloride (848 μL, 6.76 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was quenched with water (0.7 mL), followed by 25% NH4OH aqueous solution (1.8 mL), and the resulting mixture was stirred for a further 10 minutes. The solvent was removed under vacuum, the residue was diluted with water (20 mL), and extracted with HCl (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the filtrate was concentrated under vacuum to obtain the crude product (1.7 g). To a solution of the crude product in anhydrous THF (15 mL), TBAF (2.5 mL, 9.12 mmol) was added at 0°C. The resulting reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solvent was removed under vacuum. The residue was purified by silica gel column chromatography using 5-8% MeOH in DCM as the eluent to obtain N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-7H-pyrrolo[2,3d]pyrimidine-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]pyrimidine-4-yl)benzamide: To a stirred solution of anhydrous THF (8 mL) containing N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)benzamide (0.6 g, 1.62 mmol), PPh3 (1.19 g, 4.54 mmol), and 1H-imidazole (309 mg, 4.54 mmol), a solution of I2 (905 mg, 3.56 mmol) in THF (2 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was quenched with saturated sodium thiosulfate aqueous solution (10 mL) and extracted with siRNA (3 × 20 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as the eluent to obtain N-(7-((2R,3R,4S,5S)-3,4-dihydroxy-5-(iodomethyl)tetrahydrofuran-2-yl)-7H-pyrrolo[2,3d]pyrimidine-4-yl)benzamide (0.6 g, 77%) as an 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-methylenetetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)benzamide: 1,8-diazabicyclo[5.4.0]undeca-7-ene (275 μL, 1.84 mmol) was added to a stirred solution of anhydrous THF (8 mL) containing N-(7-((2R,3R,4S,5S)-3,4-dihydroxy-5-(iodomethyl)tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)benzamide (590 mg, 1.23 mmol) at room temperature. The reaction mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was removed under vacuum, and the residue was purified by silica gel column chromatography using 3-5% MeOH in DCM as the eluent to obtain N-(7-((2R,3R,4S)-3,4-dihydroxy-5-methylenetetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)benzamide (250 mg, 58%) as an 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]pyrimidine-4-yl)benzamide: TEA·3HF (139 μL, 0.851 mmol) was added at 0°C to a stirred solution of anhydrous ACN (12 mL) containing (7-((2R,3R,4S)-3,4-dihydroxy-5-methylenetetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)benzamide (250 mg, 0.710 mmol). Next, a solution of ACN (3 mL) containing NIS (192 mg, 0.851 mmol) was added, and the resulting reaction mixture was stirred at 0°C for 40 minutes. The reaction mixture was heated to room temperature and stirred for a further 40 minutes to form a solid precipitate. After the reaction was complete, the precipitate was filtered and washed with ACN to obtain N-(7-((2R,3R,4S,5R)-5-fluoro-3,4-dihydroxy-5-(iodomethyl)tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-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-benzamide-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(iodomethyl)tetrahydrofuran-3,4-diyldibenzoate: To a stirred solution of anhydrous ACN (5 mL) containing N-(7-((2R,3R,4S,5R)-5-fluoro-3,4-dihydroxy-5-(iodomethyl)tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)benzamide (190 mg, 0.381 mmol), benzoic anhydride (216 mg, 0.953 mmol) and DMAP (9.39 mg, 0.076 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 6 hours. After the reaction was complete, the mixture was diluted with 15 mL of toluene and washed with 15 mL of water. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using 10-40% toluene in heptane as the eluent to obtain (2R,3S,4R,5R)-5-(4-benzamide-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(iodomethyl)tetrahydrofuran-3,4-diyldibenzoate (180 mg, 67%) as an off-white solid. LCMS(ESI): m / z 706.80[M+H] + .

[0142] Step 6: Synthesis of (2S,3S,4R,5R)-5-(4-benzamide-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-((benzoyloxy)methyl)-2-fluorotetrahydrofuran-3,4-diyldibenzoate: Sodium benzoate (277 mg, 1.93 mmol) was added to a stirred solution of (2R,3S,4R,5R)-5-(4-benzamide-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(iodomethyl)tetrahydrofuran-3,4-diyldibenzoate (170 mg, 0.241 mmol) in DMF (17 mL) at room temperature. The reaction mixture was stirred at 120 °C for 16 hours. After the reaction was complete, the mixture was diluted with ELISA (20 mL) and washed with ice-cold water (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using 20-50% ethyl acetate in heptane as the eluent to obtain (2S,3S,4R,5R)-5-(4-benzamide-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-((benzoyloxy)methyl)-2-fluorotetrahydrofuran-3,4-diyldibenzoate (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]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol (1): A solution of methylamine (33% in ethanol, 2 mL) containing (2S,3S,4R,5R)-5-(4-benzamide-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-((benzoyloxy)methyl)-2-fluorotetrahydrofuran-3,4-diyldibenzoate (40 mg, 0.057 mmol) was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum at low temperature. The residue was purified using grinding with 5% MeOH in DCM to obtain (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol (4.5 mg, 28%) as an off-white solid. 1 H-NMR(400 MHz,DMSO-d6):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=3.2Hz,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] A procedure similar to that used for the synthesis of compound 1 was used for the synthesis of compounds 6, 10, 11, 12, 14-18, 21-26, 28, 31, 33, 35-45, 50, 52-55, and 72, among others.

[0145] Example 2 Synthesis of Compound 2 [ka] Step 1: Synthesis of (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-azido-2-(iodomethyl)tetrahydrofuran-3,4-diol: Sodium azide (576 mg, 8.86 mmol) was added at 0°C to a stirred solution of anhydrous DMF (4 mL) containing iodine monochloride (654 mg, 4.03 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled again to 0°C, and a solution of anhydrous DMF (2 mL) containing (2R,3R,4S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-5-methylenetetrahydrofuran-3,4-diol (0.4 g, 1.61 mmol) was added dropwise. The reaction mixture was stirred further at room temperature for 2 hours. After the reaction was complete, the reaction product was quenched with saturated sodium thiosulfate aqueous solution (10 mL) and extracted with toluene (3 × 15 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using 0-10% MeOH in DCM as the eluent to obtain (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-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-benzamide-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-(iodomethyl)tetrahydrofuran-3,4-diyldibenzoate: Benzoyl chloride (163 μL, 1.4 mmol) was added at 0°C to a stirred solution of anhydrous pyridine (2.6 mL) containing (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-azido-2-(iodomethyl)tetrahydrofuran-3,4-diol (130 mg, 0.312 mmol) and DMAP (11.4 mg, 0.093 mmol). The resulting mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction product was diluted with 10 mL of 10% sodium bicarbonate aqueous solution and extracted with siRNA (3 × 20 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using 30-50% siRNA in heptane as the eluent to obtain (2S,3S,4R,5R)-2-azido-5-(4-benzamide-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-(iodomethyl)tetrahydrofuran-3,4-diyldibenzoate (110 mg, 48%) as a white solid. LCMS (ESI): m / z 728.09 [MH] - .

[0147] Step 3: Synthesis of (2R,3S,4R,5R)-2-azido-5-(4-benzamide-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3,4-diyldibenzoate: 6 mL of Bu4NOH (55%) was adjusted to pH=4 by adding TFA (approximately 1.2 mL). The resulting buffer (2 mL) was added at 0°C to a stirred solution of anhydrous DCM (2 mL) containing (2S,3S,4R,5R)-2-azido-5-(4-benzamide-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-(iodomethyl)tetrahydrofuran-3,4-diyldibenzoate (105 mg, 0.144 mmol). mCPBA (149 mg, 0.864 mmol) was added in small amounts while vigorously stirring. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was diluted with DCM (10 mL) and washed with saturated sodium bicarbonate aqueous 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% ethyl acetate in heptane as the eluent to obtain (2R,3S,4R,5R)-2-azido-5-(4-benzamide-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3,4-diyldibenzoate (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]pyrimidine-7-yl)-2-azido-2-(hydroxymethyl)tetrahydrofuran-3,4-diol (2): A solution of (2R,3R,4S,5R)-5-azido-2-{4-benzamide-7H-pyrrolo[2,3-d]pyrimidine-7-yl}-4-(benzoyloxy)-5-(hydroxymethyl)oxolan-3-ylbenzoate (50 mg, 0.080 mmol) in NH3 (7 M in MeOH, 1 mL) was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated under vacuum. The residue was purified by reverse-phase preparative HPLC to obtain the desired (2R,3S,4R,5R)-5-{4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl}-2-azido-2-(hydroxymethyl)oxolane-3,4-diol (4.5 mg, 18%) as a white solid. 1 H-NMR(400 MHz,DMSO-d6with D2O@HT):δ8.06(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] A procedure similar to that used for the synthesis of compound 2 was used for the synthesis of compounds 7, 8, and 9, among others.

[0150] Example 3 Synthesis of Compound 3 [ka]

[0151] Step 1: Synthesis of (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-3-methyltetrahydrofuran-2-ol: To a stirred solution of 7-bromopyrrolo[2,1-f][1,2,4]triazine-4-amine (16.25 g, 76.298 mmol) in THF (380 mL), chloro[2-(chlorodimethylsilyl)ethyl]dimethylsilane (16.42 g, 76.298 mmol) was added. The resulting reaction mixture was stirred at 0°C for 10 minutes under a nitrogen atmosphere, and then 2,2,6,6-tetramethylpiperidine (10.78 g, 76.298 mmol) was added dropwise at the same temperature. The reaction mixture was stirred at 0°C for 30 minutes, and then cooled to -78°C. A solution of n-BuLi (240 mL, 1.6 M in hexane) was added dropwise over 30 minutes. The reaction mixture was stirred at -78°C for 1 hour under a nitrogen atmosphere. To the above mixture, 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) was added dropwise over 5 minutes at -78°C. The resulting reaction mixture was stirred for a further 2 hours at -78°C. The reaction mixture was quenched at -78°C with saturated NH4Cl aqueous solution. The resulting mixture was extracted with ELISA (3 × 500 mL). The combined organic layers were washed with brine (1 × 30 mL) and dried on anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with PE / THF (2:1) to obtain (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-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] + .

[0152] 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]triazine-4-amine: (3R,4R,5R)-2-{4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl}-3,4-bis(benzyl To a stirred solution of DCM (200 mL) containing oxy)-5-[(benzyloxy)methyl]-3-methyloxolan-2-ol (22 g, 38.824 mmol), Et3SiH (18.06 g, 155.296 mmol) was added. The resulting mixture was stirred at 0°C for 5 minutes under a nitrogen atmosphere, followed by the dropwise addition of BF3·Et2O (5.27 g, 77.648 mmol) at 0°C. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was complete, the reaction mixture was quenched at 0°C with saturated NH4Cl aqueous solution. The resulting mixture was extracted with RINKAN (3 × 500 mL). The combined organic layers were washed with brine (1 × 30 mL) and dried on anhydrous sodium sulfate. The residue was purified by silica gel column chromatography and eluted with PE / THF (2:1) to obtain 7-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-3-methyltetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazine-4-amine as a yellow oil (21.0 g, 98%). LCMS(ESI): m / z 551.3[M+H] + .

[0153] Step 3: Synthesis of (2S,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-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]triazine-4-amine (8 g, 14.528 mmol) in DCM (100 mL), boron trichloride (17.02 g, 145.3 mmol) was added, and the resulting reaction mixture was stirred at 0°C for 3 minutes under a nitrogen atmosphere. The reaction mixture was then stirred at room temperature under a nitrogen atmosphere for 30 minutes. After the reaction was complete, the reactants were quenched with saturated sodium bicarbonate aqueous solution (50 mL) at 0°C. The resulting mixture was separated using a separatory funnel. The aqueous phase was purified by reverse-phase flash chromatography. The fraction was freeze-dried and then further purified by preparative chiral SFC to obtain (2S,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol (1.56 g, 38%) (major peak on SFC). 1 H NMR(400 MHz,DMSO-d6)δ7.82(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] + .

[0154] Step 4: Synthesis of (2S,3R,4R,5S)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-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]triazine-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, a solution of THF (5 mL) containing iodine (2.73 g, 10.774 mmol) was added dropwise over 15 minutes at 0°C, and the resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (10:1) to obtain (2S,3R,4R,5S)-2-{4-aminopyrrolo[2,1-f][1,2,4]triazine-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] + .

[0155] Step 5: Synthesis of (2S,3R,4S)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3-methyl-5-methylenetetrahydrofuran-3,4-diol: To a stirred solution of THF (20 mL) containing (2S,3R,4R,5S)-2-{4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl}-5-(iodomethyl)-3-methyloxolane-3,4-diol (1.77 g, 4.537 mmol), sodium methoxide (1.77 mL, 9.558 mmol) was added dropwise at 0°C, and the resulting reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was concentrated under reduced pressure and extracted with ELISA (3 × 50 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried on anhydrous sodium sulfate. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography. Elution with DCM / MeOH (10:1) yielded (2S,3R,4S)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3-methyl-5-methylenetetrahydrofuran-3,4-diol (480.0 mg, 40%) as a yellow oily substance. LCMS(ESI): m / z 263.3[M+H] + .

[0156] Step 6: Synthesis of (2S,3S,4R)-2-(4-acetamidopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3-methyl-5-methylenetetrahydrofuran-3,4-diyldiacetate: Ac2O (934.21 mg, 9.150 mmol) was added at 0°C to a stirred solution of anhydrous pyridine (5 mL) containing (2S,3R,4S)-2-{4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl}-3-methyl-5-methylideneoxolane-3,4-diol (400 mg, 1.525 mmol). The reaction mixture was stirred at room temperature for 6 hours. After the reaction was complete, the reaction mixture was diluted with ELISA (15 mL) and washed with water (15 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica column chromatography using 10-40% ethyl acetate in heptane as the eluent to obtain (3R,4S,5S)-4-(acetyloxy)-5-{4-acetamidepyrrolo[2,1-f][1,2,4]triazine-7-yl}-4-methyl-2-methylideneoxolane-3-yl acetate (270 mg, 46%) as an off-white solid. LCMS(ESI): m / z 389.2[M+H] + .

[0157] Step 7: Synthesis of (2R,3S,4S,5S)-5-(4-acetamidopyrrolo[2,1-f][1,2,4]triazine-7-yl)-2-fluoro-2-(iodomethyl)-4-methyltetrahydrofuran-3,4-diyldiacetate: To a stirred solution of anhydrous DCM (3 mL, 47.192 mmol) containing (3R,4S,5S)-4-(acetyloxy)-5-{4-acetamidopyrrolo[2,1-f][1,2,4]triazine-7-yl}-4-methyl-2-methylideneoxolane-3-yl acetate (270 mg, 0.695 mmol), AgF (440.99 mg, 3.475 mmol) was added at 0°C, followed by the addition of a solution of I2 (352.89 mg, 1.390 mmol) in DCM. The reaction mixture was stirred at 0°C for 10 minutes, then warmed to room temperature and stirred for a further 2 hours to form a solid precipitate. After the reaction was complete, the precipitated solid was filtered and washed with ACN to obtain (2R,3S,4S,5S)-4-(acetyloxy)-5-{4-acetamidepyrrolo[2,1-f][1,24]triazine-7-yl}-2-fluoro-2-(iodomethyl)-4-methyloxolan-3-yl acetate (245 mg, 66%) as a white solid. LCMS(ESI): m / z 535.1[M+H] + .

[0158] Step 8: Synthesis of (2S,3S,4S,5S)-5-(4-acetamidopyrrolo[2,1-f][1,2,4]triazine-7-yl)-2-((benzoyloxy)methyl)-2-fluoro-4-methyltetrahydrofuran-3,4-diyldiacetate: Sodium benzoate (539.43 mg, 3.740 mmol) and 15-crown-5 ether (1.65 g, 7.480 mmol) were added at room temperature to a stirred solution of DMSO (5 mL) containing (2R,3S,4S,5S)-4-(acetyloxy)-5-{4-acetamidopyrrolo[2,1-f][1,2,4]triazine-7-yl}-2-fluoro-2-(iodomethyl)-4-methyloxolan-3-yl acetate (200 mg, 0.374 mmol). The resulting reaction mixture was stirred at 80°C for 48 hours. After the reaction was complete, the mixture was diluted with toluene (20 mL) and washed with ice-cold water (3 × 10 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica column chromatography using 20-50% toluene in heptane as the eluent to obtain [(2S,3S,4S,5S)-3,4-bis(acetyloxy)-5-{4-acetamidopyrrolo[2,1-f][1,2,4]triazine-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] + .

[0159] Step 9: Synthesis of (2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-2-(hydroxymethyl)-2-methoxy-4-methyltetrahydrofuran-3,4-diol (3): A solution of NH3 (7M in MeOH, 5mL) containing [(2S,3S,4S,5S)-3,4-bis(acetyloxy)-5-{4-acetamidopyrrolo[2,1-f][1,2,4]triazine-7-yl}-2-fluoro-4-methyloxolan-2-yl]methyl benzoate (40 mg, 0.076 mmol) was stirred at room temperature for 6 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC to obtain (2R,3S,4R,5S)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl}2-(hydroxymethyl)-2-methoxy-4-methyloxolane-3,4-diol (1.4 mg, 6%) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ7.82(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] + .

[0160] A procedure similar to that used for the synthesis of compound 3 was used for the synthesis of compounds 19, 34, and 51, among others.

[0161] Example 4 Synthesis of compounds 4 and 5 [ka]

[0162] Step 1: Synthesis of (2R,3R,4S,5S)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-5-(iodomethyl)tetrahydrofuran-3,4-diol: To a solution of (2R,3R,4S,5R)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (1.06 g, 3.7 mmol) in anhydrous THF (12 mL), PPh3 (1.2 g, 4.5 mmol) and imidazole (503 mg, 7.4 mmol) were added, and the resulting reaction mixture was stirred at room temperature for 30 minutes. Iodine (1.15 g, 4.5 mmol) was added to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reactants were quenched with a saturated aqueous solution of NaHCO3. The resulting mixture was concentrated under vacuum. 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 under vacuum to obtain the crude product (2R,3R,4S,5S)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-5-(iodomethyl)tetrahydrofuran-3,4-diol. LCMS(ESI): m / z 396.1[M+H] + .

[0163] Step 2: Synthesis of (2R,3R,4S)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-5-methylenetetrahydrofuran-3,4-diol: To a solution of (2R,3R,4S,5S)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-5-(iodomethyl)tetrahydrofuran-3,4-diol (crude product from Step 1) in anhydrous THF (15 mL), DBU (8.6 mL, 55.6 mmol) was added at 0°C. The resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, AcOH was added to adjust the pH to 7, followed by water. The resulting mixture was extracted with ELISA. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude product (2R,3R,4S)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-5-methylenetetrahydrofuran-3,4-diol. The crude product was used in the next step without further purification. LCMS(ESI): m / z 268.0[M+H] + .

[0164] Step 3: (2S,3S,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol(4) and (2R,3S,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol( Synthesis of 5): To a stirred solution of anhydrous DCM (6 mL) containing (2R,3R,4S)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-5-methylenetetrahydrofuran-3,4-diol (crude product from step 2, 230 mg, 0.86 mmol), mCPBA (297 mg, 1.7 mmol) was added at 0°C, followed by TEA.3HF (0.71 ml, 4.3 mmol). The reaction mixture was stirred at 0°C for 40 minutes. After the reaction was complete, the reaction mixture was concentrated under vacuum. The residue was purified by reverse-phase preparative HPLC to obtain the desired compounds 4 and 5 (3 mg, 6%; 3 mg, 6%). Compound 4: 1H NMR(400 MHz,DMSO-d6)δ8.69(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-d6)δ8.64(s,1H),7.84-7.71(d,1H),6.80(d,J=3.8 Hz,1H),6.44(t,J=7.1 Hz,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] + .

[0165] A procedure similar to that used for the synthesis of compound 4 was used for the synthesis of compounds 13, 27, and 29, among others.

[0166] Example 5 Synthesis of compound 20 [ka]

[0167] Step 1: Synthesis of ((5R,6S,6aR)-6-(benzyloxy)-5-((benzyloxy)methyl)-2,2-dimethyltetrahydrofluor[2,3-d][1,3]dioxol-5-yl)methanol: Benzyl bromide (3.62 g, 21.3 mmol) was added under N2 at 0°C to a stirred solution of ((3aR,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofluor[2,3-d][1,3]dioxol-5,5-diyl)dimethanol (6 g, 19.35 mmol) and anhydrous N,N-dimethylformamide (60 mL) containing 60% NaH (1.08 g, 27.09 mmol). The resulting mixture was stirred at room temperature for 1 hour, then quenched with water and extracted with ELISA. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain ((5R,6S,6aR)-6-(benzyloxy)-5-((benzyloxy)methyl)-2,2-dimethyltetrahydrofluor[2,3-d][1,3]dioxol-5-yl)methanol (5.2 g, 67%) as a yellow solid. LCMS(ESI): m / z 423.0[M+Na] + .

[0168] Step 2: Synthesis of (5R,6S,6aR)-6-(benzyloxy)-5-((benzyloxy)methyl)-5-(fluoromethyl)-2,2-dimethyltetrahydrofuran-2-ol [2,3-d][1,3]dioxole: DAST (6.28 g, 39 mmol) was added to a stirred solution of toluene (52 mL) containing (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol (5.2 g, 13 mmol) under N2 at 0°C. The resulting mixture was stirred at 60°C for 5 hours, then quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain (5R,6S,6aR)-6-(benzyloxy)-5-((benzyloxy)methyl)-5-(fluoromethyl)-2,2-dimethyltetrahydrofl[2,3-d][1,3]dioxol (2.7g, 52%) as a yellow oil. LCMS(ESI): m / z 425.1[M+Na] + .

[0169] Step 3: Synthesis of (3R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-5-(fluoromethyl)tetrahydrofuran-2,3-diyldiacetate: To a solution of acetic acid (36 mL) containing (5R,6S,6aR)-6-(benzyloxy)-5-((benzyloxy)methyl)-5-(fluoromethyl)-2,2-dimethyltetrahydrofuran[2,3-d][1,3]dioxol (2.7 g, 6.7 mmol), acetic anhydride (0.68 g, 6.7 mmol) and H2SO4 (65.7 mg, 0.67 mmol) were added at 10°C. The resulting mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, the reactants were quenched with H2O and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel column chromatography to obtain (3R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-5-(fluoromethyl)tetrahydrofuran-2,3-diyldiacetate (2.3 g, 77%) as a yellow solid. LCMS(ESI): m / z 469.0[M+Na] + .

[0170] Step 4: Synthesis of (2R,3R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-5-(fluoromethyl)tetrahydrofuran-3-yl acetate: (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) were added to a mixture of ACN (32 mL) containing 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (577.42 mg, 3.76 mmol) and BSA (764.9 mg, 3.76 mmol). The reaction mixture was stirred at 80°C for 3 hours. After the reaction was complete, the reaction mixture was quenched with an aqueous solution of NaHCO3 and extracted with ethyl acetate. The combined organic layer was dried, concentrated, and purified by silica gel column chromatography to obtain (2R,3R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-5-(fluoromethyl)tetrahydrofuran-3-yl acetate (215 mg, 11%) as a yellow solid. LCMS(ESI): m / z 540.0[M+H] + .

[0171] Step 5: Synthesis of (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-4-(benzyloxy)-5-((benzyloxy)methyl)-5-(fluoromethyl)tetrahydrofuran-3-ol: To a solution of 1,4-dioxane (4 mL) containing (215 mg, 0.4 mmol) of (2R,3R,4S,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-5-(fluoromethyl)tetrahydrofuran-3-yl acetate (215 mg, 0.4 mmol), NH3H2O ​​(4 mL) was added, and the resulting mixture was stirred at 100°C for 25 hours. The mixture was concentrated and purified by silica gel column to obtain (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-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] + .

[0172] Step 6: Synthesis of (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-(fluoromethyl)-2-(hydroxymethyl)tetrahydrofuran-3,4-diol (20): To a stirred solution of DCM (3 mL) containing (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-4-(benzyloxy)-5-((benzyloxy)methyl)-5-(fluoromethyl)tetrahydrofuran-3-ol (180 mg, 0.376 mmol), BCl3 (3.8 mL, 3.76 mmol, 1 M) was added under N2 at -78°C. The resulting mixture was stirred at -78°C for 2 hours and then quenched with MeOH (10 mL). Excess solvent was removed under reduced pressure. The residue was purified by preparative HPLC to obtain (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-(fluoromethyl)-2-(hydroxymethyl)tetrahydrofuran-3,4-diol as a solid (20, 35 mg of compound, 31% yield). 1 H NMR(400 MHz,MeOD-d4)δ8.06(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). 19 F NMR(377 MHz,MeOD-d4)δ-236.74.LCMS(ESI):m / z 299.0[M+H] + .

[0173] Example 6 Synthesis of compound 30 [ka]

[0174] Step 1: Synthesis of (1R,2S,3R,5R)-3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-5-(hydroxymethyl)cyclopentan-1,2-diol: To a solution of EtOH (50 mL) containing 2-(4,6-dichloropyrimidine-5-yl)acetaldehyde (1.91 g, 10.0 mmol) and (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentan-1,2-diol hydrochloride (1.84 g, 10.0 mmol), TEA (3.03 mg, 30.0 mmol) was added, 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 saturated NaHCO3 solution and then extracted with ELISA. The combined organic layers were washed with brine, dried over Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure to obtain crude (1R,2S,3R,5R)-3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-5-(hydroxymethyl)cyclopentan-1,2-diol (2.83 g) as a yellow, rubbery substance. This was used in the next step without further purification. LCMS(ESI): m / z = 284.1[M+H]+ .

[0175] Step 2: Synthesis of [(3aS,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidine-7-yl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]methanol: 4-methylbenzenesulfonic acid hydrate (194 mg, 1 mmol) was added to a solution of (1R,2S,3R,5R)-3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-5-(hydroxymethyl)cyclopentan-1,2-diol (2.83 g, 10.0 mmol) and 2,2-dimethoxypropane (2.08 g, 20 mmol) in acetone (60 mL). The mixture was stirred at room temperature for 2 hours, then refluxed for 24 hours. After the reaction was complete, the reactants were quenched with Et3N and then concentrated under reduced pressure. The residue was treated with saturated NaHCO3 solution and brine. The resulting mixture was extracted with RINKAN. The combined organic layers were washed with brine, dried over Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain [(3aS,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidine-7-yl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][l,3]dioxol-6-yl]methanol (3.0 g, 93% yield) as a yellow solid. LCMS(ESI): m / z=324.1[M+H] + .

[0176] Step 3: Synthesis of 7-[(3aS,4R,6S,6aR)-6-(iodomethyl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-4-chloropyrrolo[2,3-d]pyrimidine: I2 (4.72 g, 18.57 mmol) was added to a solution of THF (30 mL) containing PPh3 (4.86 g, 9.29 mmol) and imidazole (1.94 g, 19.51 mmol). The mixture was stirred under N2 at room temperature for 15 minutes, then a solution of THF (20 mL) containing [(3aS,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidine-7-yl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]methanol (3000 mg, 9.29 mmol) was added. The mixture was stirred under N2 at room temperature for 1.5 hours. After the reaction was complete, the reactants were quenched with a 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 obtain 7-[(3aS,4R,6S,6aR)-6-(iodomethyl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-4-chloropyrrolo[2,3-d]pyrimidine (3.0 g, 69% yield) as a yellow solid. LCMS(ESI): m / z=434.1[M+H] + .

[0177] Step 4: Synthesis of 4-chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-methylenetetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine: 1M t-BuOK (6.93 mL) in THF was added at 0°C to a solution of 7-[(3aS,4R,6S,6aR)-6-(iodomethyl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-4-chloropyrrolo[2,3-d]pyrimidine (3000 mg, 6.93 mmol) in THF (20 mL). The reaction mixture was stirred at 0°C for 30 minutes. After the reaction was complete, the reaction product was quenched with saturated NH4Cl aqueous solution. The mixture was extracted with ELISA. 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 obtain 4-chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-methylenetetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (2.12 g, 94% yield) as a colorless foam. LCMS(ESI): m / z = 306.1[M+H] + .

[0178] Step 5: Synthesis of (3aS,4R,6R,6aS)-6-(4-chloropyrrolo[2,3-d]pyrimidine-7-yl)-4-(hydroxymethyl)-2,2-dimethyl-3a,5,6,6atetrahydrocyclopenta[d][1,3]dioxol-4-ol: K2OsO4·2H2O (30.3 mg, 0.098 mmol) was added to a mixture of acetone (26 mL) and H2O (5.2 mL) containing 4-chloro-7-((3aS,4R,6aR)-2,2-dimethyl-6-methylenetetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (1300 mg, 4.024 mmol) and NMO (943 mg, 8.06 mmol). The mixture was stirred at room temperature for 20 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain (3aS,4R,6R,6aS)-6-(4-chloropyrrolo[2,3-d]pyrimidine-7-yl)-4-(hydroxymethyl)-2,2-dimethyl-3a,5,6,6atetrahydrocyclopenta[d][1,3]dioxol-4-ol (1300 mg, 95% yield) as a pale yellow foam. LCMS(ESI): m / z = 340.0[M+H] + .

[0179] Step 6: Synthesis of [(3aS,4R,6R,6aS)-6-(4-chloropyrrolo[2,3-d]pyrimidine-7-yl)-4-hydroxy-2,2-dimethyl-3a,5,6,6atetrahydrocyclopenta[d][1,3]dioxol-4-yl]methyl benzoate: (3aS,4R,6R,6aS)-6-(4-chloropyrrolo[2,3-d]pyrimidine-7-yl)-4-( To a solution of DCM (35 mL) containing hydroxymethyl)-2,2-dimethyl-3a,5,6,6a-tetrahydrocyclopenta[d][1,3]dioxol-4-ol (1300 mg, 3.83 mmol), DMAP (46.7 mg, 0.383 mmol), and Et3N (581 mg, 5.75 mmol), benzoyl chloride (1079 mg, 7.67 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain [(3aS,4R,6R,6aS)-6-(4-chloropyrrolo[2,3-d]pyrimidine-7-yl)-4-hydroxy-2,2-dimethyl-3a,5,6,6atetrahydrocyclopenta[d][1,3]dioxol-4-yl]methyl benzoate (1.3 g, 94% yield) as a white foam. LCMS(ESI): m / z = 444.1[M+H] + .

[0180] Step 7: Synthesis of ((3aS,4S,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-4-fluoro-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methyl benzoate: DAST (436.5 mg, 2.71 mmol) was added at 0°C to a solution of anhydrous DCM (30 mL) containing ((3aS,4R,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-4-hydroxy-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methyl benzoate (600 mg, 1.355 mmol) The mixture was quenched with saturated NaHCO3 aqueous solution 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 obtain ((3aS,4S,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-4-fluoro-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methyl benzoate (62 mg, 10%) as a white foam. LCMS(ESI): m / z = 446.2[M+H] + .

[0181] Step 8: Synthesis of ((3aS,4S,6R,6aS)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-4-fluoro-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methanol: Concentrated ammonia (2 mL) was added to a solution of dioxane (2 mL) containing ((3aS,4S,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-4-fluoro-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methyl benzoate (39 mg, 0.0876 mmol). The reaction mixture was then stirred at 100°C for 16 hours. The solvent was removed under vacuum to obtain ((3aS,4S,6R,6aS)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-4-fluoro-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methanol (20 mg, 71%) as a pale yellow foam. LCMS: m / z = 323.2 [M + H] + .

[0182] Step 9: Synthesis of (1S,2S,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3-fluoro-3-(hydroxymethyl)cyclopentan-1,2-diol (9): To a solution of THF (1 mL) containing ((3aS,4S,6R,6aS)-6-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-4-fluoro-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methanol (2 mg, 0.0062 mmol), 4 M HCl (0.5 mL) was added. The reaction mixture was then stirred at 0°C for 1 hour. After the reaction was complete, the solvent was removed under vacuum, and the compound was purified by reverse-phase preparative HPLC to obtain (1S,2S,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3-fluoro-3-(hydroxymethyl)cyclopentan-1,2-diol (compound 9, 1.5 mg, 83%) as a white foam. 1H NMR (400 MHz, methanol-d4) δ8.21(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] + .

[0183] Example 7 Synthesis of compound 47 [ka] Synthesis of (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-((isobutyryloxy)methyl)tetrahydrofuran-3,4-diyrbis(2-methylpropanoate)(47): To a solution of dichloromethane (10 mL) containing (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound 1, 500 mg, 1.76 mmol), isobutyric acid (511 mg, 5.81 mmol), 4-dimethylaminopyridine (65 mg, 0.53 mmol), and dicyclohexylcarbodiimide (1.2 g, 5.81 mmol) was added at room temperature. The mixture was stirred for 2 hours. After the reaction was complete, the insoluble solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2((isobutyryloxy)methyl)tetrahydrofuran-3,4-diyrbis(2-methylpropanoate) (compound 47, 450 mg, 52% yield) as a white solid. 1H NMR(300 MHz,DMSO-d6)δ8.09(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=6.9 Hz,6H),1.13-1.02(m,9H),0.97(d,J=7.0 Hz,3H).LCMS(ESI):m / z 495.3[M+H] + .

[0184] A procedure similar to that used for the synthesis of compound 47 was used for the synthesis of compounds 46 and 73.

[0185] Example 8 Synthesis of compounds 48 and 49 [ka]

[0186] Step 1: Synthesis of isopropyl(2S)-2-{[chloro(phenoxy)phosphoryl]amino}propanoate: A solution of isopropyl(2S)-2-aminopropanoate hydrochloride (3 g, 17.8 mmol) in DCM (60 mL) was treated with phenoxyphosphonoyl dichloride (4.15 g, 19.6 mmol) under a nitrogen atmosphere at -78°C for 30 minutes, followed by the dropwise addition of TEA (3.62 g, 35.7 mmol) at -78°C. The resulting mixture was stirred at room temperature for a further 1 hour. 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 × 10 mL). The filtrate was concentrated under reduced pressure. The crude product - isopropyl(chloro(phenoxy)phosphoryl)-L-alaninate (4.2 g) was used directly in the next step without further purification. LCMS(ESI)m / z 306.1[M+H] + .

[0187] Step 2: Synthesis of isopropyl(2S)-2-({[(2S,3S,4R,5R)-5-{4-aminopyrrolo[2,3-d]pyrimidine-7-yl}-2-fluoro-3,4-dihydroxyoxolan-2-yl]methoxy(phenoxy)phosphoryl}amino)propanoate (48 and 49): (2S,3S,4R,5R)-5-{4-aminopyrrolo[2,3-d]pyrimidine-7-yl}-2-fluoro-2-(hydroxymethyl To a stirred solution of THF (10 mL) containing 1-methyl-1H-imidazole (1.27 g, 15.4 mmol) and isopropyl(2S)-2-{[chloro(phenoxy)phosphoryl]amino}propanoate (2.15 g, 7.03 mmol) in THF (4 mL), a solution was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for a further 1 hour. The reaction was quenched with H2O at 0°C. The resulting mixture was extracted with SiO2. The combined organic layers were washed with brine (1 × 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 isopropyl(2S)-2-({[(2S,3S,4R,5R)-5-{4-aminopyrrolo[2,3-d]pyrimidine-7-yl}-2-fluoro-3,4-dihydroxyoxolan-2-yl]methoxy(phenoxy)phosphoryl}amino)propanoate (compound 48, 2.4 mg, second peak in preparative SFC) and isopropyl(2S)-2-({[(2S,3S,4R,5R)-5-{4-aminopyrrolo[2,3-d]pyrimidine-7-yl}-2-fluoro-3,4-dihydroxyoxolan-2-yl]methoxy(phenoxy)phosphoryl}amino)propanoate (compound 49, 5.3 mg, first peak in preparative SFC) as white solids. LCMS m / z[M+H] + 554.1. Compound 48: 1H NMR(300 MHz,DMSO-d6)δ8.08(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=5.6 Hz,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. Compound 49: 1 H NMR(300 MHz,DMSO-d6)δ8.08(s,1H),7.34(t,J=7.8 Hz,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=5.8Hz,9H). 19 F NMR(282 MHz,DMSO-d6)δ-120.27. A procedure similar to that used for the synthesis of compounds 48 and 49 was used for the synthesis of compound 74.

[0188] Example 9 Synthesis of compounds 57, 58, and 59 [ka]

[0189] Step 1: Synthesis of (4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}oxolan-2-one: Imidazole (64.41 g, 946.1 mmol), DMAP (2.31 g, 18.92 mmol), and TBSCl (119.8 g, 794.8 mmol) were added at 0°C to a solution of deoxyribonolactone (50 g, 378.458 mmol) in DMF (500 mL). The mixture was stirred at 20°C for 12 hours. The mixture was quenched with NaHCO3 (500 mL), extracted with SiO2 (3 × 500 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain (4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}oxolan-2-one (110 g, 81%) as a white solid. 1 ¹H 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 (3S,4R,5R)-4-[(Tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-fluorooxolan-2-one: LiHMDS (232.9 mL, 233.0 mmol) was added at -78°C to a solution of (4S,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}oxolan-2-one (60 g, 166.4 mmol) and NFSI (65.58 g, 208.0 mmol) in THF (1200 mL). The mixture was stirred at -78°C for 2 hours. The reaction was quenched with NH4Cl at -78°C. The resulting mixture was extracted with RINKAN. The combined organic layer was 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 (3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-fluorooxolan-2-one (30 g, 48%) as a colorless oil.

[0191] Step 3: Synthesis of (3S,4R,5R)-4-[(Tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-chloro-3-fluorooxolan-2-one: LiHMDS (184.9 mL, 174.9 mmol) was added at -78°C to a solution of THF (110 mL) containing (3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-fluorooxolan-2-one (28 g, 7.98 mmol) and NCS (23.52 g, 147.90 mmol). The mixture was stirred at -78°C for 2 hours. The reaction was quenched with saturated NH4Cl aqueous solution at -78°C. The resulting mixture was extracted with ELISA. The combined organic layers were washed with brine and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain (3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-chloro-3-fluorooxolan-2-one (12 g, 39%) as a yellow oil. 1 ¹H NMR (300 MHz, chloroform-d): δ 4.60 (dd, J=12.0, 5.7 Hz, 1H), 4.40-4.33 (m, 1H), 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: Synthesis of (3S,4R,5R)-4-[(Tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-chloro-3-fluorooxolan-2-ol: Li(t-BuO)3AlH (92.63 mL, 82.63 mmol) was added at 0°C to a solution of THF (120 mL) containing (3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-chloro-3-fluorooxolan-2-one (12 g, 29.05 mmol). The mixture was stirred at 20°C for 2 hours, then quenched at 0°C with saturated NH4Cl aqueous solution. 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 (3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-chloro-3-fluorooxolan-2-ol (12.2 g, 100%) as a yellow oily substance.

[0193] Step 5: Synthesis of tert-butyl N-(tert-butoxycarbonyl)-N-{9-[(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-chloro-3-fluorooxolan-2-yl]-6-chloropurin-2-yl}carbamate: (3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy To a solution of THF (320 mL) containing [(tert-butyldimethylsilyl)oxy]methyl 3-chloro-3-fluorooxolan-2-ol (11.25 g, 27.1 mmol) and tert-butyl N-(tert-butoxycarbonyl)-N-(6-chloro-9H-purine-2-yl)carbamate (12 g, 32.53 mmol), PPh3 (10.68 g, 40.65 mmol) was added. The mixture was cooled to 0°C, DIAD (6.6 g, 37.95 mmol) was added, and the mixture was stirred at 70°C for 1 hour. The resulting mixture was extracted with ELISA. 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 tert-butyl N-(tert-butoxycarbonyl)-N-{9-[(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-chloro-3-fluorooxolan-2-yl]-6-chloropurin-2-yl}carbamate (4.6 g, 22%) as a white solid. LCMS(ESI): m / z 766.7[M+H] + .

[0194] Step 6: Synthesis of tert-butyl N-(tert-butoxycarbonyl)-N-{9-[(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-chloro-3-fluorooxolan-2-yl]-6-(methylamino)purin-2-yl}carbamate: tert-butyl N-(tert-butoxycarbonyl A solution of 45 mL of EtOH containing 4.6 g, 6.01 mmol, 1 equivalent of vonyl)-N-{9-[(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-chloro-3-fluorooxolan-2-yl]-6-chloropurin-2-yl}carbamate was added. The mixture was stirred at 60°C for 2 hours, and the resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain tert-butyl N-(tert-butoxycarbonyl)-N-{9-[(2R,3S,4R,5R)-4-[(tert-butyldimethylsilyl)oxy]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-chloro-3-fluorooxolan-2-yl]-6-(methylamino)purine-2-yl}carbamate (4g, 98%) as an off-white solid. LCMS(ESI): m / z 661.5[M+H] + .

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

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

[0197] Step 9: Synthesis of tert-butyl N-{9-[(2R,3S,4R)-3-chloro-3-fluoro-4-hydroxy-5-methylideneoxolan-2-yl]-6-(methylamino)purin-2-yl}carbamate: DBU (3.37 g, 22.11 mmol) was added to a solution of tert-butyl N-{9-[(2R,3S,4R,5S)-3-chloro-3-fluoro-4-hydroxy-5-(iodomethyl)oxolan-2-yl]-6-(methylamino)purin-2-yl}carbamate (3 g, 5.528 mmol) in THF (50 mL). The mixture was stirred at 20°C for 7 hours, and the resulting mixture was extracted with ELISA. 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 tert-butyl N-{9-[(2R,3S,4R)-3-chloro-3-fluoro-4-hydroxy-5-methylideneoxolan-2-yl]-6-(methylamino)purine-2-yl}carbamate (830 mg, 36%) as a white solid. LCMS(ESI): m / z 415.2[M+H] + .

[0198] Step 10: Synthesis of tert-butyl N-{9-[(2R,3S,4R,5R)-3-chloro-3,5-difluoro-4-hydroxy-5-(iodomethyl)oxolan-2-yl]-6-(methylamino)purin-2-yl}carbamate: To a solution of tert-butyl N-{9-[(2R,3S,4R)-3-chloro-3-fluoro-4-hydroxy-5-methylideneoxolan-2-yl]-6-(methylamino)purin-2-yl}carbamate (600 mg, 1.446 mmol) in MeCN (6 mL), TEA·3HF (349.8 mg, 2.169 mmol) was added at 0°C. The mixture was stirred for 10 minutes. NIS (488.1 mg, 2.169 mmol) was added at 0°C, and the mixture was warmed to room temperature and stirred for 1 hour. After the reaction was complete, the reactants were slowly quenched with well-chilled water and extracted with ethyl acetate. The resulting mixture was concentrated under reduced pressure, and the crude product tert-butyl N-{9-[(2R,3S,4R,5R)-3-chloro-3,5-difluoro-4-hydroxy-5-(iodomethyl)oxolan-2-yl]-6-(methylamino)purine-2-yl}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 (2R,3R,4S,5R)-5-{2-[(tert-butoxycarbonyl)amino]-6-(methylamino)purin-9-yl}-4-chloro-2,4-difluoro-2-(iodomethyl)purin-2-yl benzoate: Benzoyl chloride (1378.8 mg, 9.80 mmol) was added at 0°C to a solution of pyridine (8 mL) containing tert-butyl N-{9-[(2R,3S,4R,5R)-3-chloro-3,5-difluoro-4-hydroxy-5-(iodomethyl)oxolan-2-yl]-6-(methylamino)purin-2-yl}carbamate (1.1 g, 1.96 mmol). The mixture was stirred for 45 minutes. After the reaction was complete, 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 product was purified by column chromatography to obtain (2R,3R,4S,5R)-5-{2-[(tert-butoxycarbonyl)amino]-6-(methylamino)purin-9-yl}-4-chloro-2,4-difluoro-2-(iodomethyl)oxolan-3-ylbenzoate (600 mg, 46%). LCMS(ESI): m / z 665.1[M+H] + .

[0200] Step 12: Synthesis of [(2S,3R,4S,5R)-3-(benzoyloxy)-5-{2-[(tert-butoxycarbonyl)amino]-6-(methylamino)purin-9-yl}-4-chloro-2,4-difluorooxolan-2-yl]methyl benzoate: Sodium benzoate (1.040 g, 7.224 mmol) was added to a solution of DMSO (10 mL) containing (2R,3R,4S,5R)-5-{2-[(tert-butoxycarbonyl)amino]-6-(methylamino)purin-9-yl}-4-chloro-2,4-difluoro-2-(iodomethyl)oxolan-3-yl benzoate (600 mg, 0.903 mmol). The mixture was stirred at 100°C for 12 hours, and the resulting mixture was extracted with ELISA. The combined organic layers were washed with brine and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain [(2S,3R,4S,5R)-3-(benzoyloxy)-5-{2-[(tert-butoxycarbonyl)amino]-6-(methylamino)purin-9-yl}-4-chloro-2,4-difluorooxolan-2-yl]methyl benzoate (400 mg, 67%) as a yellow oil. LCMS(ESI): m / z 659.2[M+H] + .

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

[0202] Step 14: Synthesis of (2S,3R,4S,5R)-5-[2-amino-6-(methylamino)purin-9-yl]-4-chloro-2,4-difluoro-2-(hydroxymethyl)oxolan-3-ol (57): A solution of methylamine (33% in ethanol) (4 mL) containing tert-butyl N-{9-[(2R,3S,4R,5S)-3-chloro-3,5-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(methylamino)purin-2-yl}carbamate (280 mg, 0.621 mmol) was stirred at 20°C for 2 hours. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC to obtain (2S,3R,4S,5R)-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] A procedure similar to that used for the synthesis of compound 57 was used for the synthesis of compounds 56, 60, 62, 63, 66, 68, 70, and 71, among others. [ka]

[0204] Step 15: Synthesis of isopropyl(2S)-2-({[(2S,3R,4S,5R)-5-[2-amino-6-(methylamino)purin-9-yl]-4-chloro-2,4-difluoro-3-hydroxyoxolan-2-yl]methoxy(phenoxy)phosphoryl}amino)propanoate (58 and 59): (2S,3R,4S,5R)-5-[2-amino-6-(methylamino)purin-9-yl]-4-chloro-2,4-difluoro-2-(hydroxyoxolan-2-yl) To a stirred mixture of THF (2 mL) and acetonitrile (0.2 mL) containing roxymethyl)oxolan-3-ol (compound 57, 50 mg, 0.143 mmol) and isopropyl(2S)-2-{[2,3,4,5,6-pentafluorophenoxy(phenoxy)phosphoryl]amino}propanoate (162 mg, 0.357 mmol), 1-methyl-1H-imidazole (29 mg, 0.357 mmol) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for a further 2 hours. MgCl2 (14 mg, 0.143 mmol) and DIEA (37 mg, 0.286 mmol) were added to the above mixture at room temperature. The resulting mixture was stirred at room temperature for a further 1 hour. After the completion of the reaction, the reactants were quenched with water. The crude product was purified by preparative HPLC and SFC, and each isomer (compound 58, 8.4 mg, second peak in preparative SFC and compound 59, 7.0 mg, first peak in preparative SFC) was obtained as a white solid. LCMS (ESI): m / z 619.2 [M+H] + . Compound 62: 1H NMR(400 MHz,DMSO-d6)δ7.86(s,1H),7.37(t,J=7.9 Hz,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. Compound 63: 1 H NMR(400 MHz,DMSO-d6)δ7.85(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 F NMR(376 MHz,DMSO-d6)δ-116.28.

[0205] A procedure similar to that used for the synthesis of compounds 58 and 59 was used for the synthesis of compounds 61, 64, 65, 67, and 69, among others.

[0206] Example 10 Synthesis of Compound 75 [ka]

[0207] To a solution of PO(OMe)3 (1.30 mL) containing 1 (130 mg, 457 μmol) and proton sponge (97.8 mg, 457 μmol), POCl3 (104 mg, 685 μmol, 63.5 μL) was added at -10°C. The mixture was stirred under N2 at 25°C for 1 hour. After the reaction was complete, the crude product (182 mg, crude) was used in the next step without further purification.

[0208] To a solution of the crude product (182 mg, 347 μmol) in PO(OMe)3 (1.30 mL), (Bu3N)2H4P2O7 (0.6 M, 2.30 mL) and Bu3N (257 mg, 1388 μmol, 4.00 equivalents) were added at -10°C. The mixture was stirred at 25°C for 40 minutes. 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 obtain ((2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyltetrahydrogen triphosphate (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] - .

[0209] A procedure similar to that used for the synthesis of compound 75 was used for the synthesis of compounds 76-85. [Table 2-1] [Table 2-2] Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 [Table 2-20] [Table 2-21] [Table 2-22]

[0210] Bioassay Generation of DENV-2 virus stock 5E6 Vero cells (ATCC CCL-81) were plated overnight in a T150 flask at 37°C with complete DMEM (Gibco, 11965-092) containing 10% FBS, 1×NEAA (Thermofisher, 11140-050), and 1×PenStrep (Thermofisher, 15140-122) in 5% CO2. The medium was removed from the flask, and 10 mL of DENV-2 16681 (GenBank NC_001474.2) diluted in DMEM containing 2% FBS was added to the flask at a MOI of 0.01. The flask was incubated at 37°C for 1 hour in 5% CO2. After incubation, 15 mL of complete DMEM was added, and the flask was incubated in a 33°C incubator with 5% CO2 for 15 days. The supernatant was collected every 2 / 3 days, and 25 mL of fresh medium was added to the flask. Specifically, the supernatant was collected, centrifuged at 2,000 × g at 4°C for 5 minutes, then divided into equal portions and stored at -80°C.

[0211] Preparation of Zika virus stock 5E6 Vero cells (ATCC CCL-81) were plated overnight in a T150 flask at 37°C with complete DMEM (Gibco, 11965-092) containing 10% FBS, 1×NEAA (Thermofisher, 11140-050), and 1×PenStrep (Thermofisher, 15140-122) in 5% CO2. The medium was removed from the flask, and 10 mL of ZIKV MR766 (BEI Resources NR-50065) diluted in DMEM containing 2% FBS was added to the flask at a MOI of 0.01. The flask was incubated at 37°C for 1 hour in 5% CO2. After incubation, 15 mL of complete DMEM was added, and the flask was incubated for 3 days in a 37°C incubator containing 5% CO2. Next, the supernatant was collected, centrifuged at 2,000 × g at 4°C for 5 minutes, then divided into equal portions and stored at -80°C.

[0212] Preparation of yellow fever virus stock 5E6 Vero cells (ATCC CCL-81) were plated overnight in a T150 flask at 37°C with complete DMEM (Gibco, 11965-092) containing 10% FBS, 1×NEAA (Thermofisher, 11140-050), and 1×PenStrep (Thermofisher, 15140-122) in 5% CO2. The medium was removed from the flask, and 10 mL of YFV strain 17D (BEI Resources NR-116), diluted in DMEM containing 2% FBS, was added to the flask at a MOI of 0.01. The flask was incubated at 37°C for 1 hour in 5% CO2. After incubation, 15 mL of complete DMEM was added, and the flask was incubated for 3 days in a 37°C incubator containing 5% CO2. Next, the supernatant was collected, centrifuged at 2,000 × g at 4°C for 5 minutes, then divided into equal portions and stored at -80°C.

[0213] Preparation of Chikungunya virus stock 5E6 Vero cells (ATCC CCL-81) were plated overnight in a T150 flask at 37°C with complete DMEM (Gibco, 11965-092) containing 10% FBS, 1×NEAA (Thermofisher, 11140-050), and 1×PenStrep (Thermofisher, 15140-122) in 5% CO2. The medium was removed from the flask, and 10 mL of CHIKV strain 181 / 25 (BEI Resources NR-56523), diluted in DMEM containing 2% FBS, was added to the flask at a MOI of 0.005. The flask was incubated at 37°C for 1 hour in 5% CO2. After incubation, 20 mL of complete DMEM was added to the flask, and the flask was incubated for 3 days in an incubator at 37°C with 5% CO2. Next, the supernatant was collected, centrifuged at 2,000 × g at 4°C for 5 minutes, then divided into equal portions and stored at -80°C.

[0214] Generation of SARS-CoV-2 virus stocks VeroE6 cells (ATCC CRL-1586) were plated overnight in a T150 flask at 37°C with complete DMEM (Corning 15-013-CV) containing 10% FBS, 1× PenStrep (Corning 20-002-CL), and 2 mM L-glutamine (Corning 25-005-CL) at 5% CO2. The medium was removed from the flask, and 10 mL of SARS-CoV-2 strain USA-WA1 / 2020 (BEI Resources NR-52281) in complete DMEM was added to the flask at a MOI of 0.05. The flask was incubated at 34°C for 30 minutes at 5% CO2. After incubation, 20 mL of complete DMEM was added to the flask. The flask was then placed in an incubator at 34°C with 5% CO2. Three days after infection, the cells were scraped off with the supernatant, the mixture was collected, and centrifuged at 2,000 × g for 5 minutes. The cell pellet was frozen and thawed three times, then resuspended in the collected supernatant, centrifuged again at 2,000 × g at 4°C for 5 minutes, divided into equal portions, and stored at -80°C.

[0215] HeLa-ACE2 stable cell line HeLa-ACE2 cells were generated by transduction of human ACE2 lentivirus. The lentivirus was created by simultaneously transducing the pBOB-hACE2 construct and the lentiviral packaging plasmids pMDL, pREV, and pVSV-G (Addgene) into HEK293T cells using Lipofectamine 2000 (Thermo Fisher Scientific, 11668019). The supernatant was collected 48 hours after transduction and then used to transduce pre-seeded HeLa cells. Stable cell lines were collected 12 hours after transduction, scaled up, and stored. The cells were maintained in DMEM (Gibco, 11965-092) at 37°C in 5% CO2 using 10% FBS (Gibco, 10438026) and 1× sodium pyruvate (Gibco, 11360070).

[0216] Preparation of RSV virus To propagate RSVA2 (ATCC VR-1540), Hep-2 cells were infected at 37°C in a humidified 5% CO2 atmosphere at a density of 80–90% in a MOI of approximately 0.01 for 1–2 hours, shaking every 20–30 minutes, and the inoculum was redistributed. The inoculum was then removed and replaced with assay medium (DMEM containing 2% HI FBS and 1× Pen / Strep). The flask was then incubated until significant CPE was observed, typically 2–3 days post-infection. The supernatant was collected and purified, and cell debris was removed by centrifugation. The virus was then stabilized by adding 25% sucrose and rapidly freezing aliquots, and stored at -80°C.

[0217] Preparation of seasonal coronavirus HCoV-OC43 and HCoV-229E viruses HCoV-OC43 was obtained from BEI Resources, NIAID, NIH: Human Coronavirus, OC43, NR-52725. To propagate the virus, HCT-8 cells were infected in 5% CO2 at 33°C for 2 hours at an approximate MOI of 0.01 in RPMI. After incubation, the inoculum was removed and replaced with assay medium (RPMI containing 2% HI FBS, 1× Pen / Strep, and 2 mM L-glutamine). The flask was incubated in 5% CO2 at 33°C until significant CPE was observed 3-4 days post-infection. Cells were scraped off and collected with the supernatant and centrifuged at 1,000×g for 5 minutes. The supernatant was collected, the cell pellet was subjected to one freeze-thaw cycle, resuspended in 5 mL of supernatant, and re-purified by centrifugation at 1,000×g for 5 minutes. The total supernatant was then pooled, divided equally, and stored at -80°C. HCoV-229E was obtained from BEI resource, NR52726. To propagate the virus, HCoV-229E was infected with MRC-5 pd25 in MEM at an approximate MOI of 0.01 and incubated at 37°C for 2 hours in 5% CO2. After incubation, the inoculum was removed and replaced with assay medium (MEM supplemented with 10% HI FBS, 2 mM L-glutamine, 1% NEAA, and 1×Pen / Strep). The flask was then placed in an incubator at 37°C in 5% CO2 until significant CPE was observed 3-4 days post-infection, and recovered as described for OC43 above.

[0218] Preparation of human rhinovirus stock Human rhinovirus strains 11757 (ATCC VR-283), 14 (ATCC VR-284), and 1B (ATCC VR-1645) were grown in H1 HeLa cells (ATCC CRL-1958). The cells were infected in 5% CO2 at 33°C for 2 hours at an approximate MOI of 0.01 in MEM. The inoculum was removed and replaced with assay medium (MEM + 2% FBS + 1XPS), and the flasks were incubated for 2-3 days until significant CPE was observed. The cells were then scraped off and collected with the supernatant, and centrifuged at 1,000 × g for 5 minutes. After subjecting the cell pellet to three freeze-thaw cycles, it was resuspended in 5 mL of supernatant and re-purified by centrifugation. The total supernatant was then pooled, divided equally, and stored at -80°C.

[0219] Preparation of poliovirus stock 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 the same protocol as for HRV.

[0220] DENV-2 / HepG2 High-Content Screening Antiviral Assay The antiviral activity of compounds against DENV-2 was evaluated in HepG2 (ATCC HB-8065) ​​cells using an image-based approach. Compounds were acoustically transferred to a 384-well μ-transparent bottom plate (Greiner, Part. No. 781090-2B) using an Echo 555 liquid handler (LabCyte Inc). Cells were then transferred to 20 μL of DMEM containing 2% FBS, with 2.0 × 10⁶ cells per well (HepG2). 3Cells were seeded at a specified cell density. After 4 hours, the plated cells were infected, and 10 μL of inoculum and DENV-2 diluted in assay medium (MOI=0.5) were added to achieve approximately 50% infection. The plates were incubated in 5% CO2 at 37°C for 24 hours, and then fixed with the final concentration of 4% formaldehyde at room temperature for 30 minutes. Between fixation and subsequent primary and secondary antibody staining, the plates were washed twice with 1×PBS 0.05% Tween20. Antiflavivirus 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. Each well was inoculated with 1 μg / mL of Alexa Fluor488 goat anti-mouse IgG H+L (Thermo Fisher Scientific A-11001) along with 8 μM anti-fade-46-diamidino-2-phenylindole (DAPI, Thermo Fisher Scientific D1306) diluted with PBST-0.3% BSA-0.2% saponin, and incubated in the dark at room temperature for 1 hour. The plates were imaged using an ImageXpress Micro Confocal high-content imaging system (Molecular Devices) with a 10x objective lens and four fields of view per well. Images were analyzed using the Multiwavelength Cell Scoring Application Module (MetaXpress), with host cell nuclei (total number of cells in the image) identified by DAPI staining and DENV immunofluorescence signals used to identify infected cells.

[0221] Zika virus / HepG2 high-content screening antiviral assay The antiviral activity of the compounds against ZIKV was evaluated using an image-based approach in HepG2 cells 24 hours post-infection, following essentially the same protocol as described above for DENV-2, but using a diluted ZIKV solution optimized to achieve approximately 50% infection within 24 hours as the inoculant.

[0222] Yellow fever virus / HepG2 high-content screening antiviral assay The antiviral activity of the compounds against YFV was evaluated using an image-based approach in HepG2 cells 24 hours post-infection, following essentially the same protocol as described above for DENV-2, but using a dilution of yellow fever virus as the inoculum.

[0223] Chikungunya / HepG2 High-Content Screening Antiviral Assay The antiviral activity of compounds against chikungunya was evaluated in HepG2 24 hours post-infection using an image-based approach, following a protocol very similar to that of DENV-2 described above, with the following substitutions: a dilution of chikungunya virus was used as the inoculum, and an anti-chikungunya virus antibody was used as the primary antibody (CHIKV antibody 11E7, monoclonal mouse IgG2b, Kerafast).

[0224] SARS-CoV-2 / HeLa-ACE2 High-Content Screening Assay The compounds were acoustically transferred to a 384-well μ-transparent bottom plate (Greiner, Part. No. 781090-2B) using an Echo 555 liquid handler (LabCyte Inc). HeLa-ACE2 cells were transferred to 13 μL of DMEM containing 2% FBS, at a rate of 1.0 × 10⁶ cells per well. 3Cells were seeded at a specified cell density. The plated cells were transferred to a BSL3 facility, where 13 μL of SARS-CoV-2 diluted in assay medium was added to achieve approximately 30-50% infected cells. The plates were incubated in 5% CO2 at 34°C for 24 hours, and then fixed with the final concentration of 4% formaldehyde in 5% CO2 at 34°C for 1 hour. Between fixation and subsequent primary and secondary antibody staining, the plates were washed with 1×PBS 0.05% Tween20. Human polyclonal plasma diluted 1:500 in Perm / wash buffer (BD Biosciences 554723) was added to the plates and incubated at room temperature for 2 hours. Plates were inoculated with 6 μg / mL of goat anti-human H+L complex Alexa 488 (Thermo Fisher Scientific A11013) along with 8 μM anti-fade-46-diamidino-2-phenylindole (DAPI, Thermo Fisher Scientific D1306) in SuperBlock T20 (PBS) buffer (Thermo Fisher Scientific 37515), and incubated in the dark at room temperature for 1.5–2 hours. Plates were imaged using an ImageXpress Micro Confocal high-content imaging system (Molecular Devices) with a 10x objective lens and four fields of view per well. Images were analyzed using the Multiwavelength Cell Scoring Application Module (MetaXpress) to identify host cell nuclei (total number of cells in the image) with DAPI staining, and SARS-CoV-2 immunofluorescence signals were used to identify infected cells.

[0225] OC-43 / HCT-8 High-Content Screening Assay The compound was acoustically transferred to a 384-well μ-transparent bottom plate (Greiner, Part. No. 781090-2B) using an Echo liquid handler in a dose-response manner. HCT-8 cells were seeded at 4000 cells per plate in assay medium (RPMI-1640 + L-glutamine + 2% FBS + 1X penicillin / streptomycin solution). After allowing the plated cells to settle at 37°C for 1 hour, they were infected with HCoV-OC43 diluted in assay medium to achieve approximately 30-60% infected cells. The plates were incubated in 5% CO2 at 33°C for 48 hours and then fixed with the final concentration of 4% formaldehyde. The fixed cells were blocked with Superblock and 0.2% Triton, permeabilized, and then stained overnight with mouse monoclonal antibody OC-43 strain clone 541-8F (Sigma Millipore MAB9012). Next, the goat anti-mouse H+L complex Alexa 488 (Thermo Fisher Scientific A11001) and anti-fade-46-diamidino-2-phenylindole (DAPI, Thermo Fisher Scientific D1306) were administered, and the plates were washed with PBS 0.05% Tween 20 between fixation and subsequent primary and secondary antibody staining. The plates were then imaged and analyzed in the same manner as the SARS-CoV-2 / HeLa-ACE2 assay.

[0226] 229E / MRC5 CPE-based screening assay The compound was acoustically transferred to a 384-well μ-transparent bottom plate (Greiner, Part. No. 781090-2B) using an Echo liquid handler in a dose-response manner (1:3 serial dilutions starting at a final peak assay concentration of 10 μM). MRC-5 PD25 cells were seeded into the assay-ready plate at a density of 500 cells per well. After allowing the plated cells to settle at 37°C for 1 hour, they were infected with hCoV-229E diluted in assay medium. The plate was incubated in 5% CO2 at 33°C for 120 hours. To assess the virus-induced cytopathic effect (CPE) through cell viability measurement, 20 μL of 50% Cell-Titer Glo (Promega No. G7573) diluted in water was added to the cells, and luminescence was measured.

[0227] HRV / H1 HeLa CPE-based screening assay The compounds were acoustically transferred in a dose-response manner to 384-well or 1536-well μ-transparent bottom plates (Greiner, Part. No. 781090-2B) using an Echo liquid handler. H1 HeLa cells were seeded into assay-ready plates at a density of 2000 cells per well for 384-well plates or 600 cells per well for 1536-well plates. After allowing the plated cells to settle at 33°C for 4 hours, they were infected with HRV16, 14, or 1B diluted in assay medium. The plates were incubated in 5% CO2 at 33°C for 48 hours. To assess the virus-induced cytopathic effect (CPE) through cell viability measurement, 50% Cell-Titer Glo (Promega No. G7573) diluted in water was added to the cells and luminescence was measured.

[0228] PV / HeLa S3 CPE-based screening assay The compound was acoustically transferred to a 384-well μ-transparent bottom plate (Greiner, Part. No. 781090-2B) using an Echo liquid handler in a dose-response manner. HeLa S3 cells were seeded into the assay-ready plate at a density of 4000 cells per well. After allowing the plated cells to settle at 37°C for 4 hours, they were infected with PV-1 CHAT or PV-3 WM-3 diluted in assay medium. The plates were incubated in 5% CO2 at 37°C for 48 hours. To assess the virus-induced cytopathic effect (CPE) through cell viability measurement, 50% Cell-Titer Glo (Promega No. G7573) diluted in water was added to the cells, and luminescence was measured.

[0229] RSV / Hep2 CPE-based screening assay The compound was acoustically transferred to a 1536-well μ-transparent bottom plate (Greiner, Part. No. 781090-2B) using an Echo liquid handler in a dose-response manner. Hep2 was seeded into the assay-ready plate at a density of 300 cells per well. After allowing the plated cells to settle at 37°C for 1-2 hours, they were infected with RSV A2 diluted in assay medium. The plates were incubated for 72 hours. To assess the virus-induced cytopathic effect (CPE) through cell viability measurement, 50% Cell-Titer Glo (Promega No. G7573) diluted in water was added to the cells, and luminescence was measured.

[0230] Cytotoxicity counterscreen for uninfected host cells The ability of compounds to induce cytotoxicity in uninfected cells was quantified by an ATP-based cell viability assay. Briefly, compounds were acoustically transferred to both HepG2 and HeLa-ACE2 cells using an Echo 555 liquid handler (LabCyte Inc.) into 1,536-well black-bottom plates (Greiner, Part. No. 789176-F). Cells were seeded into assay-ready plates at 450 cells / well (HepG2) or 400 cells / well (Hela-ACE2) in 5 μL of DMEM containing 2% FBS, and the plates were incubated at 37°C in 5% CO2 for 72 hours (HepG2) or 24 hours (Hela-ACE2). To assess cell viability, 2 μL of 50% Cell-Titer Glo (Promega No. G7573), diluted with water, was added to cells, and luminescence was measured using a PheraStar or ClarioStar plate reader (BMG LabTech).

[0231] Data analysis and statistical methods Results from DENV, ZIKV, YFV, CHIKV, SARS-CoV-2, HCoV-OC43, HCoV-229E, RSV, HRV, and PV infection assays, as well as uninfected host cell cytotoxicity counterscreen data, were uploaded to the Geneda screener, version 16.0. For high-content imaging assays, two outputs from image analysis were analyzed: W2 or virus-positive % and total cells as antiviral readouts. Data were normalized against neutral (DMSO)-negative inhibitor controls (either 10 μM or 2.5 μM remdesivir for antiviral efficacy against DENV, SARS-CoV-2, HCoV-OC43, and RSV, and 10 μM puromycin dihydrochloride for cytotoxicity of infected host cells). For uninfected host cell cytotoxicity counterscreens, 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 the neutral control (DMSO) minus the stimulation control (2.5 μM remdesivir for RSV and HCoV-229E, and 1 μM AG-7404 for HRV). In dose-response studies, compounds were tested in technical triples, and a four-parameter Hill equation was fitted to the dose curves. EC 90 The values ​​were calculated in Excel using the formula "POWER(9,1 / nHill)*EC50" from the EC50 and nHill values ​​exported from the GeneData screener.

[0232] Antiviral profiling via NIAID / Utah All other antiviral assays were performed by the NIAID Preclinical Services at Justin Julander, Utah. The following virus and cell lines were used: [Table 3] Before adding the virus, the compounds were added to cells at an appropriate MOI to induce a visible CPE. If a maximum CPE was observed in the viral control, the cells were stained with a neutral red dye for the dye uptake assay. Using these data, EC50, CC50, and the selection index (SI = CC50 / EC50) were calculated for each compound. For compounds with an SI of 5, a viral yield reduction assay was performed, and the supernatant collected from the CPE assay was used for viral titer determination. EC90 was calculated as the amount of compound required to reduce the viral titer by 1 log 10. The following data table displays the biological assay data using the range codes shown below. EC 50 :<0.1μM:**** 0.1~<1μM:*** 1 to <10 μM** >10μM* CC 50 :>99:#### 10~<99:### 1~<10:## <1:# [Table 4-1] [Table 4-2] [Table 4-3] [Table 5-1] [Table 5-2] [Table 6] [Table 7]

[0233] The foregoing disclosure has been described in some detail with figures and examples for the purposes of clarity and understanding. It will be apparent to those skilled in the art that changes and modifications can be made within the scope of the attached claims. Therefore, it should be understood that the above description is intended to be illustrative, not restrictive. Accordingly, the scope of this disclosure should not be determined by reference to the above description, but rather by reference to the attached claims below, together with the entire scope of equivalents covered by such claims.

[0234] This application references various issued patents, published patent applications, academic articles, and other publications, each of which is incorporated herein by reference.

Claims

1. A compound of formula (I), 【Chemistry 1】 During the ceremony, R １ is H, -C(=O)(C １ -C ６ ), alkyl, -C(=O)(C １ -C ６ ), heteroalkyl, -C(=O)(C ３ -C ７ ), cycloalkyl, -C(=O)(C １ -C ６ )(alkyl)(C ３ -C ７ )(cycloalkyl), -C(=O)(C ３ -C ７ )(heterocycloalkyl), -C(=O)(C １ -C ６ )(alkyl)(C ３ -C ７ )(heterocycloalkyl), -C(=O)(C ６ -C １０ )(aryl), -C(=O)(C １ -C ６ )(alkyl)(C ６ -C １０ )(aryl), -C(=O)(C ５ -C ８ )(heteroaryl), -C(=O)(C １ -C ６ )(alkyl)(C ５ -C ８ )(heteroaryl), -C(=O)CH(NH ２ )(C １ -C ６ )(alkyl), -C(=O)CH(NH(C １ -C ６ )(alkyl))(C １ -C ６ )(alkyl), -C(=O)CH(N((C １ -C ６ )(alkyl)) ２ )(C １ -C ６ )(alkyl), -C(=O)CH(NH ２ )(C １ -C ６ )(alkyl)(C ６ -C １０ )(aryl), -C(=O)CH(NH(C １ -C ６ )(alkyl))(C １ -C ６ )(C ６ -C １０ )(C １ -C ６ )(C ２ )(C １ -C ６ )(C ６ -C １０ )(C １’ ), -P(=O)(OR ２ ), -P(=O)(OR １’ )-P(=O)(OR １’ ), -P(=O)(OR ２ )-P(=O)(OR １’ )-P(=O)(OR １’ )-P(=O)(OR １’ ), -P(=O)(OR ２ )-P(=O)(OR １’ )-NH(C １ -C ６ ), -P(=O)(OR １’ )-NH(C １ -C ６ ), -P(=O)(OR １’ )-NH(C １ -C ６ ), -P(=O)(OR １’ )-NH(C ３ -C ７ ), -P(=O)(OR １’ )-NH(C ３ -C ７ ), -P(=O)(OR １’ )-NH(C ６ -C １０ ), -P(=O)(OR １’ )-NH(C １ -C ６ ), -P(=O)(OR ６ -C １０ ), -P(=O)(OR １’ )-NH(C ５ -C ８ ), -P(=O)(OR １’ )-NH(C １ -C ６ ), -P(=O)(OR ５ -C ８ ) Heteroaryl, -P(=O)(NHR １’ )NH(C １ -C ６ ) alkyl, -P (=O) (NHR １’ )NH(C １ -C ６ ) Heteroalkyl, -P(=O)(NHR １’ )NH(C １ -C ６ ) Haloalkyl, -P(=O)(NHR １’ )NH(C ３ -C ７ ) Cycloalkyl, -P(=O)(NHR １’ )NH(C ３ -C ７ ) Heterocycloalkyl, -P(=O)(NHR １’ )NH(C ６ -C １０ )aryl, -P (=O) (NHR １’ )NH(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -P (=O) (NHR １’ )NH(C ５ -C ８ ) Heteroaryl, -P(=O)(NHR １’ )NH(C １ -C ６ ) Alkyl (C ５ -C ８ ) Heteroaryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Alkyl-C(=O)O-(C １ -C ６ ) alkyl, -P (=O) (OR １’ )NH(C １ -C ６ ) Heteroalkyl-C(=O)O-(C １ -C ６ ) alkyl, -P (=O) (OR １’ )NH(C １ -C ６ ) Haloalkyl-C(=O)O-(C １ -C ６ ) alkyl, -P (=O) (OR １’ )NH(C １ -C ６ ) Alkyl-C(=O)O-(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Heteroalkyl-C(=O)O-(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Haloalkyl-C(=O)O-(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Alkyl-C(=O)O-(C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Heteroalkyl-C(=O)O-(C ６ -C １０ )aryl, and -P(=O)(OR １’ )NH(C １ -C ６ ) Haloalkyl-C(=O)O-(C ６ -C １０ ) Selected from a group consisting of aryls, Each R １’ H, -(C) １ -C ６ ) alkyl, -(C １ -C ６ ) Heteroalkyl, -(C １ -C ６ ) Haloalkyl, -(C ２ -C ６ ) Alkenil, - (C ２ -C ６ ) Heteroalkenyl, -(C ２ -C ６ ) Haloalkenyl, -(C ２ -C ６ ) Alkinyl, -(C ２ -C ６ ) Heteroalkynyl, -(C ２ -C ６ ) Haloalkynyl, -(C ３ -C ７ ) Cycloalkyl, -(C ３ -C ７ ) Heterocycloalkyl, -(C ６ -C １０ ) Aryl, - (C １ -C ６ ) Alkyl (C ６ -C １０ ) Aryl, - (C ５ -C ８ ) heteroaryl, or -(C １ -C ６ ) Alkyl (C ５ -C ８ ) is a heteroaryl, R ２ａ H, Halo, (C １ -C ６ ) Alkyl, or -C≡CH, R ２ｂ These are independently a halo or OH, R ３ These are independently H or OH, R ４ is, N ３ , Halo, -C≡N, (C １ -C ３ ) Haloalkyl, or -O(C １ -C ６ ) is alkyl, R ５ H, halo, -C≡N, (C １ -C ６ ) alkyl, hetero(C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkyl, N(R １’ ) ２ , -C(=O)NH ２ And, R ６ H, Halo, NH ２ , (C １ -C ６ ) alkyl, (C ２ -C ６ ) Alkenil, or (C ２ -C ６ ) is alkinyl, R ７ H, NH ２ OH, oxo, halo, N(R) １’ ) ２ , or -O(C １ -C ６ ) is alkyl, and R ８ is H or halo, However, the compound of formula I is 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-carbonitride, ((5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-4-ethynyl-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl)triphosphate, ((5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-4-ethynyl-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl)triphosphate (5-(4-amino-5-carbamoyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-4-ethynyl-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate, (5-(4-amino-5-cyano-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-4-ethynyl-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate, 4-amino-7-((2R,3R,4S,5S)-3-ethynyl-5-fluoro-3,4-dihydroxy-5-(hydroxymethyl (Tyl)tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide, (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-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]pyrimidine-7-yl)-4-ethynyl-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol, The compound comprises an enantiomer, a racemic mixture, and a scaremic mixture, and further comprises a pharmaceutically acceptable salt thereof.

2. A compound of formula (II), 【Chemistry 2】 During the ceremony, R １ is H, -C (=O) (C １ -C ６ ) alkyl, -C (=O) (C １ -C ６ ) Heteroalkyl, -C(=O)(C ３ -C ７ ) Cycloalkyl, -C(=O)(C １ -C ６ ) Alkyl (C ３ -C ７ ) Cycloalkyl, -C(=O)(C ３ -C ７ ) Heterocycloalkyl, -C(=O)(C １ -C ６ ) Alkyl (C ３ -C ７ ) Heterocycloalkyl, -C(=O)(C ６ -C １０ ) Aryl, -C (=O) (C １ -C ６ ) Alkyl (C ６ -C １０ ) Aryl, -C (=O) (C ５ -C ８ ) Heteroaryl, -C (=O) (C １ -C ６ ) Alkyl (C ５ -C ８ ) Heteroaryl, -C(=O)CH(NH ２ ) (C １ -C ６ ) Alkyl, -C(=O)CH(NH(C １ -C ６ )alkyl)(C １ -C ６ ) alkyl, -C(=O)CH(N((C １ -C ６ )alkyl) ２ ) (C １ -C ６ ) Alkyl, -C(=O)CH(NH ２ ) (C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -C(=O)CH(NH(C １ -C ６ )alkyl)(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -C(=O)CH(N((C １ -C ６ )alkyl) ２ ) (C １ -C ６ ) Alkyl (C ６ -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(C １ -C ６ ) alkyl, -P (=O) (OR １’ )NH(C １ -C ６ ) Heteroalkyl, -P(=O)(OR １’ )NH(C １ -C ６ ) Haloalkyl, -P(=O)(OR １’ )NH(C ３ -C ７ ) Cycloalkyl, -P(=O)(OR １’ )NH(C ３ -C ７ ) Heterocycloalkyl, -P(=O)(OR １’ )NH(C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C ５ -C ８ ) Heteroaryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Alkyl (C ５ -C ８ ) Heteroaryl, -P(=O)(NHR １’ )NH(C １ -C ６ ) alkyl, -P (=O) (NHR １’ )NH(C １ -C ６ ) Heteroalkyl, -P(=O)(NHR １’ )NH(C １ -C ６ ) Haloalkyl, -P(=O)(NHR １’ )NH(C ３ -C ７ ) Cycloalkyl, -P(=O)(NHR １’ )NH(C ３ -C ７ ) Heterocycloalkyl, -P(=O)(NHR １’ )NH(C ６ -C １０ )aryl, -P (=O) (NHR １’ )NH(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -P (=O) (NHR １’ )NH(C ５ -C ８ ) Heteroaryl, -P(=O)(NHR １’ )NH(C １ -C ６ ) Alkyl (C ５ -C ８ ) Heteroaryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Alkyl-C(=O)O-(C １ -C ６ ) alkyl, -P (=O) (OR １’ )NH(C １ -C ６ ) Heteroalkyl-C(=O)O-(C １ -C ６ ) alkyl, -P (=O) (OR １’ )NH(C １ -C ６ ) Haloalkyl-C(=O)O-(C １ -C ６ ) alkyl, -P (=O) (OR １’ )NH(C １ -C ６ ) Alkyl-C(=O)O-(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Heteroalkyl-C(=O)O-(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Haloalkyl-C(=O)O-(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Alkyl-C(=O)O-(C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Heteroalkyl-C(=O)O-(C ６ -C １０ )aryl, and -P(=O)(OR １’ )NH(C １ -C ６ ) Haloalkyl-C(=O)O-(C ６ -C １０ ) Selected from a group consisting of aryls, Each R １’ H, -(C) １ -C ６ ) alkyl, -(C １ -C ６ ) Heteroalkyl, -(C １ -C ６ ) Haloalkyl, -(C ２ -C ６ ) Alkenil, - (C ２ -C ６ ) Heteroalkenyl, -(C ２ -C ６ ) Haloalkenyl, -(C ２ -C ６ ) Alkinyl, -(C ２ -C ６ ) Heteroalkynyl, -(C ２ -C ６ ) Haloalkynyl, -(C ３ -C ７ ) Cycloalkyl, -(C ３ -C ７ ) Heterocycloalkyl, -(C ６ -C １０ ) Aryl, - (C １ -C ６ ) Alkyl (C ６ -C １０ ) Aryl, - (C ５ -C ８ ) heteroaryl, or -(C １ -C ６ ) Alkyl (C ５ -C ８ ) is a heteroaryl, R ２ H, (C １ -C ６ ) Alkyl, or -C≡CH, R ４ is, N ３ , halo, or -O(C １ -C ６ ) is alkyl, R ５ H, halo, -C≡N, hetero(C) １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkyl, N(R １’ ) ２ , -C(=O)NH ２ And, R ６ H, Halo, NH ２ , (C １ -C ６ ) alkyl, (C ２ -C ６ ) Alkenil, or (C ２ -C ６ ) is alkinyl, R ７ H, NH ２ OH, Halo, N(R) １’ ) ２ , or -O(C １ -C ６ ) is alkyl, and R ８ is H or halo, However, the compounds of formula II are (2S,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol, (2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-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]triazine-7-yl)-2-azido-2-(hydroxymethyl)tetrahydrofuran-3,4-diol, (2R,3S,4R,5S)-5 - (4-aminopyrrolo[2,1-f][1,2,4]triazine-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]triazine-7-yl)-2-azido-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate, or 2-ethylbutyl ((((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-2-azido-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate, The compound comprises an enantiomer, a racemic mixture, and a scaremic mixture, and further comprises a pharmaceutically acceptable salt thereof.

3. A compound of formula (IIIa) or (IIIb), 【Transformation 3】 During the ceremony, R １ is H, -C (=O) (C １ -C ６ ) alkyl, -C (=O) (C １ -C ６ ) Heteroalkyl, -C(=O)(C ３ -C ７ ) Cycloalkyl, -C(=O)(C １ -C ６ ) Alkyl (C ３ -C ７ ) Cycloalkyl, -C(=O)(C ３ -C ７ ) Heterocycloalkyl, -C(=O)(C １ -C ６ ) Alkyl (C ３ -C ７ ) Heterocycloalkyl, -C(=O)(C ６ -C １０ ) Aryl, -C (=O) (C １ -C ６ ) Alkyl (C ６ -C １０ ) Aryl, -C (=O) (C ５ -C ８ ) Heteroaryl, -C (=O) (C １ -C ６ ) Alkyl (C ５ -C ８ ) Heteroaryl, -C(=O)CH(NH ２ ) (C １ -C ６ ) Alkyl, -C(=O)CH(NH(C １ -C ６ )alkyl)(C １ -C ６ ) alkyl, -C(=O)CH(N((C １ -C ６ )alkyl) ２ ) (C １ -C ６ ) Alkyl, -C(=O)CH(NH ２ ) (C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -C(=O)CH(NH(C １ -C ６ )alkyl)(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -C(=O)CH(N((C １ -C ６ )alkyl) ２ ) (C １ -C ６ ) Alkyl (C ６ -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(C １ -C ６ ) alkyl, -P (=O) (OR １’ )NH(C １ -C ６ ) Heteroalkyl, -P(=O)(OR １’ )NH(C １ -C ６ ) Haloalkyl, -P(=O)(OR １’ )NH(C ３ -C ７ ) Cycloalkyl, -P(=O)(OR １’ )NH(C ３ -C ７ ) Heterocycloalkyl, -P(=O)(OR １’ )NH(C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C ５ -C ８ ) Heteroaryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Alkyl (C ５ -C ８ ) Heteroaryl, -P(=O)(NHR １’ )NH(C １ -C ６ ) alkyl, -P (=O) (NHR １’ )NH(C １ -C ６ ) Heteroalkyl, -P(=O)(NHR １’ )NH(C １ -C ６ ) Haloalkyl, -P(=O)(NHR １’ )NH(C ３ -C ７ ) Cycloalkyl, -P(=O)(NHR １’ )NH(C ３ -C ７ ) Heterocycloalkyl, -P(=O)(NHR １’ )NH(C ６ -C １０ )aryl, -P (=O) (NHR １’ )NH(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -P (=O) (NHR １’ )NH(C ５ -C ８ ) Heteroaryl, -P(=O)(NHR １’ )NH(C １ -C ６ ) Alkyl (C ５ -C ８ ) Heteroaryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Alkyl-C(=O)O-(C １ -C ６ ) alkyl, -P (=O) (OR １’ )NH(C １ -C ６ ) Heteroalkyl-C(=O)O-(C １ -C ６ ) alkyl, -P (=O) (OR １’ )NH(C １ -C ６ ) Haloalkyl-C(=O)O-(C １ -C ６ ) alkyl, -P (=O) (OR １’ )NH(C １ -C ６ ) Alkyl-C(=O)O-(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Heteroalkyl-C(=O)O-(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Haloalkyl-C(=O)O-(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Alkyl-C(=O)O-(C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Heteroalkyl-C(=O)O-(C ６ -C １０ )aryl, and -P(=O)(OR １’ )NH(C １ -C ６ ) Haloalkyl-C(=O)O-(C ６ -C １０ ) Selected from a group consisting of aryls, Each R １’ H, -(C) １ -C ６ ) alkyl, -(C １ -C ６ ) Heteroalkyl, -(C １ -C ６ ) Haloalkyl, -(C ２ -C ６ ) Alkenil, - (C ２ -C ６ ) Heteroalkenyl, -(C ２ -C ６ ) Haloalkenyl, -(C ２ -C ６ ) Alkinyl, -(C ２ -C ６ ) Heteroalkynyl, -(C ２ -C ６ ) Haloalkynyl, -(C ３ -C ７ ) Cycloalkyl, -(C ３ -C ７ ) Heterocycloalkyl, -(C ６ -C １０ ) Aryl, - (C １ -C ６ ) Alkyl (C ６ -C １０ ) Aryl, - (C ５ -C ８ ) heteroaryl, or -(C １ -C ６ ) Alkyl (C ５ -C ８ ) is a heteroaryl, R ２ａ H, OH, halo, (C １ -C ６ ) Alkyl, or -C≡CH, R ２ｂ is H, OH, halo, or (C １ -C ６ ) is alkyl, R ３ａ is H, OH, halo, or (C １ -C ６ ) is alkyl, R ３ｂ is H, OH, halo, or (C １ -C ６ ) is alkyl, R ４ is, N ３ , Halo, -C≡N, (C １ -C ３ ) Haloalkyl, or -O(C １ -C ６ ) is alkyl, R ６ and R ６’ These are separate entities: Hello and NH. ２ NH(C １ -C ６ ) alkyl, N((C １ -C ６ )alkyl) ２ -OH, -O(C) １ -C ６ ) alkyl, -oxo, or -C≡CH, and R ８ is H or halo, However, the compound of formula III is (((2R,3S,4R,5R)-5-(2,6-diamino-9H-purine-9-yl)-2-(difluoromethyl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl) triphosphate, (((2S,3S,4R,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-4-ethynyl-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl Not (2S,3S,4R,5R)-5-(2,6-diamino-9H-purine-9-yl)-2-fluoro-2-(hydroxymethyl)-4-methyltetrahydrofuran-3,4-diol, or (2S,3S,4R,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-4-ethynyl-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol, The compound comprises an enantiomer, a racemic mixture, and a scaremic mixture, and further comprises a pharmaceutically acceptable salt thereof.

4. A compound of formula (IV), 【Chemistry 4】 During the ceremony, R １ is H, -C (=O) (C １ -C ６ ) alkyl, -C (=O) (C １ -C ６ ) Heteroalkyl, -C(=O)(C ３ -C ７ ) Cycloalkyl, -C(=O)(C １ -C ６ ) Alkyl (C ３ -C ７ ) Cycloalkyl, -C(=O)(C ３ -C ７ ) Heterocycloalkyl, -C(=O)(C １ -C ６ ) Alkyl (C ３ -C ７ ) Heterocycloalkyl, -C(=O)(C ６ -C １０ ) Aryl, -C (=O) (C １ -C ６ ) Alkyl (C ６ -C １０ ) Aryl, -C (=O) (C ５ -C ８ ) Heteroaryl, -C (=O) (C １ -C ６ ) Alkyl (C ５ -C ８ ) Heteroaryl, -C(=O)CH(NH ２ ) (C １ -C ６ ) Alkyl, -C(=O)CH(NH(C １ -C ６ )alkyl)(C １ -C ６ ) alkyl, -C(=O)CH(N((C １ -C ６ )alkyl) ２ ) (C １ -C ６ ) Alkyl, -C(=O)CH(NH ２ ) (C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -C(=O)CH(NH(C １ -C ６ )alkyl)(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -C(=O)CH(N((C １ -C ６ )alkyl) ２ ) (C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C １ -C ６ ) alkyl, -P (=O) (OR １’ )NH(C １ -C ６ ) Heteroalkyl, -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(C １ -C ６ ) Haloalkyl, -P(=O)(OR １’ )NH(C ３ -C ７ ) Cycloalkyl, -P(=O)(OR １’ )NH(C ３ -C ７ ) Heterocycloalkyl, -P(=O)(OR １’ )NH(C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C ５ -C ８ ) Heteroaryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Alkyl (C ５ -C ８ ) Heteroaryl, -P(=O)(NHR １’ )NH(C １ -C ６ ) alkyl, -P (=O) (NHR １’ )NH(C １ -C ６ ) Heteroalkyl, -P(=O)(NHR １’ )NH(C １ -C ６ ) Haloalkyl, -P(=O)(NHR １’ )NH(C ３ -C ７ ) Cycloalkyl, -P(=O)(NHR １’ )NH(C ３ -C ７ ) Heterocycloalkyl, -P(=O)(NHR １’ )NH(C ６ -C １０ )aryl, -P (=O) (NHR １’ )NH(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -P (=O) (NHR １’ )NH(C ５ -C ８ ) Heteroaryl, -P(=O)(NHR １’ )NH(C １ -C ６ ) Alkyl (C ５ -C ８ ) Heteroaryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Alkyl-C(=O)O-(C １ -C ６ ) alkyl, -P (=O) (OR １’ )NH(C １ -C ６ ) Heteroalkyl-C(=O)O-(C １ -C ６ ) alkyl, -P (=O) (OR １’ )NH(C １ -C ６ ) Haloalkyl-C(=O)O-(C １ -C ６ ) alkyl, -P (=O) (OR １’ ) NH(C １ -C ６ ) alkyl-C(=O)O-(C １ -C ６ ) alkyl(C ６ -C １０ ) aryl, -P(=O)(OR １’ ) NH(C １ -C ６ ) heteroalkyl-C(=O)O-(C １ -C ６ ) alkyl(C ６ -C １０ ) aryl, -P(=O)(OR １’ ) NH(C １ -C ６ ) haloalkyl-C(=O)O-(C １ -C ６ ) alkyl(C ６ -C １０ ) aryl, -P(=O)(OR １’ ) NH(C １ -C ６ ) alkyl-C(=O)O-(C ６ -C １０ ) aryl, -P(=O)(OR １’ ) NH(C １ -C ６ ) heteroalkyl-C(=O)O-(C ６ -C １０ ) aryl, and -P(=O)(OR １’ ) NH(C １ -C ６ ) haloalkyl-C(=O)O-(C ６ -C １０ ) selected from the group consisting of aryl, Each R １’ H, -(C) １ -C ６ ) alkyl, -(C １ -C ６ ) Heteroalkyl, -(C １ -C ６ ) Haloalkyl, -(C ２ -C ６ ) Alkenil, - (C ２ -C ６ ) Heteroalkenyl, -(C ２ -C ６ ) Haloalkenyl, -(C ２ -C ６ ) Alkinyl, -(C ２ -C ６ ) Heteroalkynyl, -(C ２ -C ６ ) Haloalkynyl, -(C ３ -C ７ ) Cycloalkyl, -(C ３ -C ７ ) Heterocycloalkyl, -(C ６ -C １０ ) Aryl, - (C １ -C ６ ) Alkyl (C ６ -C １０ ) Aryl, - (C ５ -C ８ ) heteroaryl, or -(C １ -C ６ ) Alkyl (C ５ -C ８ ) is a heteroaryl, R ４ is, N ３ , halo, or -O(C １ -C ６ ) is alkyl, and R ６ is H, halo, (C １ -C ６ )alkyl, (C ２ -C ６ )alkenyl, or (C ２ -C ６ )alkynyl, and The compound comprises an enantiomer, a racemic mixture, and a scaremic mixture, and further comprises a pharmaceutically acceptable salt thereof.

5. A compound of formula (V), 【Transformation 5】 During the ceremony, R １ is H, -C (=O) (C １ -C ６ ) alkyl, -C (=O) (C １ -C ６ ) Heteroalkyl, -C(=O)(C ３ -C ７ ) Cycloalkyl, -C(=O)(C １ -C ６ ) Alkyl (C ３ -C ７ ) Cycloalkyl, -C(=O)(C ３ -C ７ ) Heterocycloalkyl, -C(=O)(C １ -C ６ ) Alkyl (C ３ -C ７ ) Heterocycloalkyl, -C(=O)(C ６ -C １０ ) Aryl, -C (=O) (C １ -C ６ ) Alkyl (C ６ -C １０ ) Aryl, -C (=O) (C ５ -C ８ ) Heteroaryl, -C (=O) (C １ -C ６ ) Alkyl (C ５ -C ８ ) Heteroaryl, -C(=O)CH(NH ２ ) (C １ -C ６ ) Alkyl, -C(=O)CH(NH(C １ -C ６ )alkyl)(C １ -C ６ ) alkyl, -C(=O)CH(N((C １ -C ６ )alkyl) ２ ) (C １ -C ６ ) Alkyl, -C(=O)CH(NH ２ ) (C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -C(=O)CH(NH(C １ -C ６ )alkyl)(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -C(=O)CH(N((C １ -C ６ )alkyl) ２ ) (C １ -C ６ ) Alkyl (C ６ -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(C １ -C ６ ) alkyl, -P (=O) (OR １’ )NH(C １ -C ６ ) Heteroalkyl, -P(=O)(OR １’ )NH(C １ -C ６ ) Haloalkyl, -P(=O)(OR １’ )NH(C ３ -C ７ ) Cycloalkyl, -P(=O)(OR １’ )NH(C ３ -C ７ ) Heterocycloalkyl, -P(=O)(OR １’ )NH(C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C ５ -C ８ ) Heteroaryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Alkyl (C ５ -C ８ ) Heteroaryl, -P(=O)(NHR １’ )NH(C １ -C ６ ) alkyl, -P (=O) (NHR １’ )NH(C １ -C ６ ) Heteroalkyl, -P(=O)(NHR １’ )NH(C １ -C ６ ) Haloalkyl, -P(=O)(NHR １’ )NH(C ３ -C ７ ) Cycloalkyl, -P(=O)(NHR １’ )NH(C ３ -C ７ ) Heterocycloalkyl, -P(=O)(NHR １’ )NH(C ６ -C １０ )aryl, -P (=O) (NHR １’ )NH(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -P (=O) (NHR １’ )NH(C ５ -C ８ ) Heteroaryl, -P(=O)(NHR １’ )NH(C １ -C ６ ) Alkyl (C ５ -C ８ ) Heteroaryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Alkyl-C(=O)O-(C １ -C ６ ) alkyl, -P (=O) (OR １’ )NH(C １ -C ６ ) Heteroalkyl-C(=O)O-(C １ -C ６ ) alkyl, -P (=O) (OR １’ )NH(C １ -C ６ ) Haloalkyl-C(=O)O-(C １ -C ６ ) alkyl, -P (=O) (OR １’ )NH(C １ -C ６ ) Alkyl-C(=O)O-(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Heteroalkyl-C(=O)O-(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Haloalkyl-C(=O)O-(C １ -C ６ ) Alkyl (C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Alkyl-C(=O)O-(C ６ -C １０ )aryl, -P (=O) (OR １’ )NH(C １ -C ６ ) Heteroalkyl-C(=O)O-(C ６ -C １０ )aryl, and -P(=O)(OR １’ )NH(C １ -C ６ ) Haloalkyl-C(=O)O-(C ６ -C １０ ) Selected from a group consisting of aryls, Each R １’ H, -(C) １ -C ６ ) alkyl, -(C １ -C ６ ) Heteroalkyl, -(C １ -C ６ ) Haloalkyl, -(C ２ -C ６ ) Alkenil, - (C ２ -C ６ ) Heteroalkenyl, -(C ２ -C ６ ) Haloalkenyl, -(C ２ -C ６ ) Alkinyl, -(C ２ -C ６ ) Heteroalkynyl, -(C ２ -C ６ ) Haloalkynyl, -(C ３ -C ７ ) Cycloalkyl, -(C ３ -C ７ ) Heterocycloalkyl, -(C ６ -C １０ ) Aryl, - (C １ -C ６ ) Alkyl (C ６ -C １０ ) Aryl, - (C ５ -C ８ ) heteroaryl, or -(C １ -C ６ ) Alkyl (C ５ -C ８ ) is a heteroaryl, R ２ H, Halo, (C １ -C ６ ) Alkyl, or -C≡CH, R ４ is, N ３ , Halo, -C≡N, (C １ -C ３ ) Haloalkyl, or -O(C １ -C ６ ) is alkyl, R ５ H, halo, -C≡N, hetero(C) １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkyl, halo(C １ -C ６ ) alkyl, N(R １’ ) ２ , -(C(=O)NH ２ And, R ６ H, Halo, NH ２ , (C １ -C ６ ) alkyl, (C ２ -C ６ ) Alkenil, or (C ２ -C ６ ) is alkinyl, R ７ H, NH ２ OH, Halo, N(R) １’ ) ２ , or -O(C １ -C ６ ) is alkyl, and R ８ is H or halo, The compound comprises an enantiomer, a racemic mixture, and a scaremic mixture, and further comprises a pharmaceutically acceptable salt thereof.

6. R ２ｂ The compound according to claim 1, wherein the compound is an OH group or a halo.

7. R ２ｂ The compound according to claim 3, which is a halo.

8. R ２ａ The compound according to claim 7, wherein the compound is Me or a halo.

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

10. R ２ａ However, (C １ -C ６ The compound according to any one of claims 6 to 8, wherein it is alkyl.

11. R ２ａ The compound according to claim 10, wherein Me.

12. R ２ａ The compound according to any one of claims 6 to 8, wherein the compound is a halo.

13. R ２ａ The compound according to claim 12, wherein the compound is Cl.

14. R ２ The compound according to any one of claims 2 or 5, wherein H is present.

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

16. R ２ The compound according to claim 15, wherein F.

17. R ２ However, (C １ -C ６ The compound according to any one of claims 2 or 5, wherein it is alkyl.

18. R ２ The compound according to claim 17, wherein Me.

19. R ５ The compound according to any one of claims 1 to 2 or 5, wherein H is present.

20. R ５ However, -CH ２ The compound according to any one of claims 1 to 2 or 5, wherein it is an OH group.

21. R ５ is -C(=O)NH ２ The compound according to any one of claims 1 to 2 or 5.

22. R ３ The compound according to any one of claims 1, 6 to 13, or 19 to 21, wherein the compound is an OH group.

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

24. R ４ The compound according to any one of claims 1 to 23, wherein the compound is a halo.

25. R ４ However, the compound according to claim 24 is F.

26. R ４ The compound according to claim 24, wherein the compound is Cl.

27. R ４ However, N ３ The compound according to any one of claims 1 to 23.

28. R ４ However, -O(C １ -C ６ The compound according to any one of claims 1 to 23, wherein it is alkyl.

29. R ４ The compound according to claim 28, wherein the compound is -OMe.

30. R ６ However, H or NH ２ And R ６’ However, -NH(C １ -C ６ ) alkyl or -O(C １ -C ６ The compound according to any one of claims 1 to 29, wherein it is alkyl.

31. R ６ The compound according to any one of claims 1 to 29, wherein the compound is a halo.

32. R ６ The compound according to claim 31, wherein F.

33. R ６ The compound according to any one of claims 1 to 29, wherein -C≡CH.

34. R １ The compound according to any one of claims 1 to 33, wherein H is present.

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

36. R １ is -P(=O)(OR １’ )NH(C １ -C ６ ) Alkyl-C(=O)O-(C １ -C ６ The compound according to any one of claims 1 to 33, wherein it is alkyl.

37. A compound having one of the following formulas selected from the group: (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-azido-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-2-(hydroxymethyl)-2-methoxy-4-methyltetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3S,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3R,4S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-4-chloro-2,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol; (2R,3R,4S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-azido-4-chloro-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol; (2R,3R,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-5-azido-5-(hydroxymethyl)tetrahydrofuran-3-ol; (2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-2-azido-2-(hydroxymethyl)-4-methyltetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)-4-methyltetrahydrofuran-3,4-diol; (2R,3R,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-5-fluoro-5-(hydroxymethyl)tetrahydrofuran-3-ol; (2R,3R,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-5-fluoro-5-(hydroxymethyl)tetrahydrofuran-3-ol; (2S,3S,4R,5R)-2-fluoro-5-(4-fluoro-7H-pyrrolo[2,3-d]pyrimidine-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]pyrimidine-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]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(6-amino-2-ethynyl-9H-purine-9-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5S)-5-(4-aminoimidazo[2,1-f][1,2,4]triazine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-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]pyrimidine-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-2-fluoro-2-(hydroxymethyl)-5-(7H-pyrrolo[2,3-d]pyrimidine-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]pyrimidine-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-carbonitriel; (2S,3S,4R,5R)-5-(2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-2-fluoro-2-(hydroxymethyl)-5-(6-(methylthio)-9H-purine-9-yl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(4-chloro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (1S,2S,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3-fluoro-3-(hydroxymethyl)cyclopentan-1,2-diol; (2S,3S,4R,5R)-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydrofuran-2-carbonitrile; (2S,3S,4R,5R)-5-(4-amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; ((2S,3S,4R,5S)-5-(4-amino-5-carbamoylpyrrolo[2,1-f][1,2,4]triazine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl benzoate; (2S,3S,4R,5R)-2-fluoro-5-(5-fluoro-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(5-chloro-7H-pyrrolo[2,3-d]pyrimidine-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]pyrimidine-7-yl)tetrahydrofuran-3-ol; (2S,3S,4R,5R)-2-fluoro-2-(hydroxymethyl)-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidine-7-yl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(4-amino-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(6-amino-2-chloro-9H-purine-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)pyrimidine-2(1H)-one; (2S,3S,4R,5R)-2-((benzoyloxy)methyl)-5-(3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)-2-fluorotetrahydrofuran-3,4-diyldiacetate; ((2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate; (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-((isobutyryloxy)methyl)tetrahydrofuran-3,4-diylbis(methyl 2-propionate); Isopropyl((S)-(((2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; Isopropyl((R)-(((2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; ((2S,3S,4R,5R)-4-(benzoyloxy)-5-(4-cyano-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3-hydroxytetrahydrofuran-2-yl)methyl benzoate; (2R,3R,4S,5S)-2-(4-aminoimidazo[2,1-f][1,2,4]triazine-7-yl)-5-fluoro-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile; (2S,3S,4R,5R)-5-(4-amino-1H-pyrazolo[3,4-d]pyrimidine-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]pyrimidine-7-yl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-5-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol; (2S,3R,5R)-5-(4-amino-5-(benzo[d]thiazole-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2,4,4-trifluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol; ((2S,3S,4R,5R)-5-(2-amino-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl benzoate; (2S,3R,4S,5R)-5-(2-amino-6-(methylamino)-9H-purine-9-yl)-4-chloro-2,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol; Isopropyl((R)-(((2S,3R,4S,5R)-5-(2-amino-6-(methylamino)-9H-purine-9-yl)-4-chloro-2,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; Isopropyl((S)-(((2S,3R,4S,5R)-5-(2-amino-6-(methylamino)-9H-purine-9-yl)-4-chloro-2,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; (2S,3R,5R)-5-(2-amino-6-ethoxy-9H-purine-9-yl)-2,4,4-trifluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol; Isopropyl((((2S,3R,5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purine-9-yl)-2,4,4-trifluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; 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-purine-9-yl)-4-chloro-2-fluoro-2-(hydroxymethyl)-4-methyltetrahydrofuran-3-ol; Isopropyl((((2S,3R,4R,5R)-5-(2-amino-6-ethoxy-9H-purine-9-yl)-4-chloro-2-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; Neopentyl ((((2S,3S,4R,5R)-5-(4-aminoimidazo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(naphthalene-1-yloxy)phosphoryl)-L-alaninate; (2S,3R,4S,5R)-5-(2-amino-6-ethoxy-9H-purine-9-yl)-4-chloro-2,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol; Isopropyl((((2S,3R,4S,5R)-5-(2-amino-6-ethoxy-9H-purine-9-yl)-4-chloro-2,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; (2S,3R,4S,5R)-5-(2-amino-6-ethoxy-9H-purine-9-yl)-4-bromo-2,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol; Isopropyl((((2S,3R,5R)-5-(2-amino-6-ethoxy-9H-purine-9-yl)-2,4,4-trifluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; (2S,3S,4R,5R)-4-ethynyl-2-fluoro-2-(hydroxymethyl)-5-(4-(propylamino)-7H-pyrrolo[2,3-d]pyrimidine-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]pyrimidine-7-yl)tetrahydrofuran-3,4-diol; ((2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyl L-valinate; Neopentyl ((((2S,3S,4R,5R)-5-(4-amino-1H-pyrazolo[3,4-d]pyrimidine-1-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(naphthalene-1-yloxy)phosphoryl)-L-alaninate; ((2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyltetrahydrogen triphosphate; ((2S,3S,4R,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyltetrahydrogen triphosphate; ((2S,3S,4R,5R)-2-fluoro-3,4-dihydroxy-5-(4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)tetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate; ((2S,3S,4R,5R)-5-(5-carbamoyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyltetrahydrogen triphosphate; ((2S,3S,4R,5R)-5-(5-bromo-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyltetrahydrogen triphosphate; ((2S,3S,4R,5R)-2-fluoro-5-(5-fluoro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyltetrahydrogen triphosphate; ((2S,3S,4R,5R)-5-(4-aminoimidazo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyltetrahydrogen triphosphate; ((2S,3S,4R,5R)-5-(4-amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyltetrahydrogen triphosphate; ((2S,3S,4R,5R)-5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxytetrahydrofuran-2-yl)methyltetrahydrogen triphosphate; ((2S,3R,4R,5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purine-9-yl)-4-chloro-2-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate; and ((2S,3S,4S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate.

38. The compound according to claim 37, having the formula (2S,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2-fluoro-2-(hydroxymethyl)tetrahydrofuran-3,4-diol or isopropyl((R)-(((2S,3R,4S,5R)-5-(2-amino-6-(methylamino)-9H-purine-9-yl)-4-chloro-2,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate.

39. A pharmaceutical composition comprising a compound according to any one of claims 1 to 38, which is mixed with a pharmaceutically acceptable carrier, diluent, or excipient.

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

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

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

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

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

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

46. The method according to claim 45, wherein the RNA virus infection is at least one virus selected from the group consisting of dengue virus, South Asian respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, Zika virus, yellow fever virus, Ebola (Makona) virus, Ebola (Kikwit) virus, Bundibugyo virus, Sudan virus, Marburg virus, respiratory fusion 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 according to claim 46, wherein the RNA virus infection is caused by the dengue virus.

48. The method according to claim 46, wherein the RNA virus infection is caused by the SARS-CoV-2 virus.

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

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

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

52. The method according to claim 51, wherein at least one of the one or more therapeutic compounds or compositions is a drug effective in treating or improving RNA virus infections.

53. The method according to claim 52, wherein the drug for treating the RNA virus infection is selected from the group consisting of remdesivir, mornupiravir, or pachyrovid.

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

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