Login| Sign Up| Help| Contact|

Patent Searching and Data


Title:
ANTIVIRAL PRODRUGS AND FORMULATIONS THEREOF
Document Type and Number:
WIPO Patent Application WO/2023/102472
Kind Code:
A1
Abstract:
Provided herein are compounds of Formula (I) as disclosed herein, pharmaceutical compositions comprising said compounds, and methods of using said compounds for the treatment and/or prevention of various viral infections, such as SARS-CoV-2 infections.

Inventors:
CHATTERJEE ARNAB (US)
GUPTA ANIL (US)
CHEN JIAN (US)
WILSON KATY (US)
GRABOBYI GENNADII (US)
PETRASSI HANK (US)
Application Number:
PCT/US2022/080740
Publication Date:
June 08, 2023
Filing Date:
December 01, 2022
Export Citation:
Click for automatic bibliography generation   Help
Assignee:
SCRIPPS RESEARCH INST (US)
International Classes:
A61K31/33; A61K31/395; A61K31/40; A61K31/407
Domestic Patent References:
WO2019129059A12019-07-04
WO2012012776A12012-01-26
WO2010002877A22010-01-07
WO2021216427A12021-10-28
Foreign References:
US20210161927A12021-06-03
US20210388019A12021-12-16
Other References:
DATABASE PUBCHEM COMPOUND ANONYMOUS : "2-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)oxolane-2-carbonitrile", XP093072231, retrieved from PUBCHEM
Attorney, Agent or Firm:
FITTING, Thomas et al. (US)
Download PDF:
View/Download PDF      PDF Help
Claims:
WHAT IS CLAIMED IS: 1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof; wherein: R1 is selected from the group consisting of hydrogen; -C(=O)-(C3-C7 cycloalkyl), wherein the C3-C7 cycloalkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of C1-C6 alkyl; -C(=O)-(5 to 6-membered heterocyclyl), wherein the 5 to 6-membered heterocyclyl is attached to the -C(=O) group through a ring carbon or ring heteroatom, and further wherein the 5 to 6-membered heterocyclyl is optionally substituted with a 5 to 6- membered heterocyclyl; -C(=O)-(C1-C20 alkyl), wherein the C1-C20 alkyl is optionally substituted with 1-3 substituents independently selected from C(=O)OH, C3-C7 cycloalkyl, and C6-C10 aryl; -C(=O)-(C6-C10 aryl); -P(=O)-(NH(C1-C6 alkyl))2; -P(=O)-(NH(C1-C6 alkyl)(N(C1-C6 alkyl)2); -P(=O)-(N(C1-C6 alkyl)2)2; -P(=O)-(NH(C1-C6 alkyl-C(=O)-O-C1-C6 alkyl))(O-C6-C10 aryl); and -P(=O)-(NH(C1-C6 alkyl-C(=O)-O-C1-C6 alkyl))(O-5 to 6-membered heteroaryl); R2 and R3 are each independently selected from the group consisting of hydrogen; -C(=O)-(C1-C10 alkyl), wherein the C1-C10 alkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of -NH2, -C(=O)-OH, and C6- C10 aryl; -C(=O)-(C3-C7 cycloalkyl), wherein the C3-C7 cycloalkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, C1-C6 alkyl, and -O- C1-C6 alkyl; and -C(=O)-(C6-C10 aryl); and R4 is selected from the group consisting of hydrogen, C3-C7 cycloalkyl; –(C=O)-O- C1-C10 alkyl; –(C=O)-(C1-C10 alkyl); and -C(=O)-(C3-C7 cycloalkyl); wherein in each instance, C6-C10 aryl and 5 to 6-membered heteroaryl are each optionally independently substituted with 1-3 substituents independently selected from the group consisting of halo, C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, and -O-C1- C6 alkyl; with the proviso that: (a) when only one of R1, R2, and R3 is independently hydrogen, -C(=O)-CH(CH3)2, -C(=O)- CH2CH3, -C(=O)-cyclopropyl, -C(=O)-C(CH3)3, -C(=O)-CH2C(CH3)3, or -C(=O)-CH(NH2)- CH(CH3)2, and the other two of R1, R2, and R3 are hydrogen, then R4 is not hydrogen; (b) when R1 = R2 = R3 and is selected from the group consisting of hydrogen, -C(=O)- CH(CH3)2, -C(=O)-CH2CH3, -C(=O)-CH3, and -C(=O)-cyclopropyl, then R4 is not hydrogen; (c) when R1 = R4 = hydrogen, then R2 and R3 cannot both be -C(=O)-(C1-C6)alkyl; when R4 = hydrogen, then R1, R2, and R3 cannot all be -C(=O)-CH(CH3)2 -C(=O)-CH3 - C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-(C1-C6)alkyl(C3-C7)cycloalkyl or -C(=O)- cyclopropyl; (d) when R1 = R2 and is selected from -C(=O)-CH(CH3)2 and -C(=O)-cyclopropyl, then R3 and R4 cannot both be hydrogen; (e) when R2 = R3 and is selected from hydrogen, -C(=O)-CH(CH3)2, -C(=O)-CH3 or -C(=O)- cyclopropyl, and R4 is hydrogen, -C(=O)-CH(CH3)2, -C(=O)-CH3 or -C(=O)-cyclopropyl, then R1 cannot be -C(=O)-CH(CH3)2 , -C(=O)-hetero(C1-C6)alkyl-C(=O)O-(C1-C6)alkyl, - C(=O)((C1-C6)alkylPh((NHC=OO(C1-C6)alkyl, -C(=O)((C1-C6)alkyl((NHC=OO(C1- C6)alkyl, -C(=O)-hetero(C1-C6)alkyl-C(=O)O-hetero(C1-C6)alkyl, -C(=O)-hetero(C1- C6)alkyl-C(=O)OH, or -C(=O)-hetero(C1-C6)alkyl; (f) when R1 is selected from the group consisting of -C(=O)-CH3, -C(=O)-CH2CH2CH3, -C(=O)-(CH2)7CH3, -C(=O)-phenyl, -C(=O)-cyclopropyl, -C(=O)-CH2CF3, -C(=O)-CH2CH(CH3)2, -C(=O)-CH(NH2)-CH(CH3)2, -C(=O)-CH(NH2)-benzyl, and -C(=O)-CH(NH2)-CH(CH3)-CH2CH3, then R2, R3, and R4 cannot all be hydrogen; and (g) when R2 = R3= R4= hydrogen, R1 cannot be selected from the group consisting of hydrogen, -C(=O)-(C1-C10)alkyl, -C(=O)-(C1-C10)alkyl-C(=O)-(C1-C6)alkyl, -C(=O)-(C1- C6)alkenyl, -C(=O)-(C1-C6)alkynyl, -C(=O)-halo(C1-C6)alkyl, -C(=O)-halo(C1-C6)alkenyl, - C(=O)-hetero(C1-C6)alkyl, -C(=O)-hetero(C1-C6)alkenyl, -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)-(C1-C6)alkyl-(C3-C7)heterocycloalkyl-(C1-C6)alkyl, -C(=O)- halo(C3-C7)cycloalkyl, -C(=O)-(C1-C6)alkyl-halo(C3-C7)cycloalkyl, -C(=O)-hydroxy(C3- C7)cycloalkyl, -C(=O)-(C1-C6)alkyl-hydroxy(C3-C7)cycloalkyl, -C(=O)-amino(C3- C7)cycloalkyl, -C(=O)-(C1-C6)alkyl-amino(C3-C7)cycloalkyl, -C(=O)-(C1-C6)heteroalkyl(C3- C7)cycloalkyl, and -C(=O)-(C1-C6)alkyl-(C1-C6)heteroalkyl(C3-C7)cycloalkyl, -C(=O)- halo(C3-C7)heterocycloalkyl, -C(=O)-(C1-C6)alkyl-halo(C3-C7)heterocycloalkyl, -C(=O)- hydroxy(C3-C7)heterocycloalkyl, -C(=O)-(C1-C6)alkyl-hydroxy(C3-C7)heterocycloalkyl, - C(=O)-amino(C3-C7)heterocycloalkyl, -C(=O)-(C1-C6)alkyl-amino(C3-C7)heterocycloalkyl, - C(=O)-(C1-C6)heteroalkyl(C3-C7)heterocycloalkyl, -C(=O)-(C1-C6)alkyl-(C1- C6)heteroalkyl(C3-C7)heterocycloalkyl, -C(=O)-(C1-C6)heteroalkyl-C(=O)-(C1-C6)alkyl, - C(=O)-(C1-C6)heteroalkyl-phenyl, and -C(=O)-(C1-C6)heteroalkyl-(C5-C8)heteroaryl. 2. The compound or a pharmaceutically acceptable salt thereof of claim 1 wherein in R1: the -C(=O)-(C3-C7 cycloalkyl) with the optional substituents of the C3-C7 cycloalkyl is selected from the group consisting of -C(=O)-cyclohexyl, -C(=O)-(1-methylcyclohexyl), and -C(=O)-(4,4-dimethylcyclohexyl); the -C(=O)-(5 to 6-membered heterocyclyl) with the optional substituents of the 5 to 6-membered heterocyclyl is the -C(=O)-(C1-C20 alkyl) with the optional substituents of the C1-C20 alkyl is selected from the group consisting of -C(=O)-CH(CH3)2, -C(=O)-CH(CH2CH3)2, -C(=O)-CH2CH(CH2CH3)2, -C(=O)-CH2-cyclopentyl, -C(=O)-benzyl, -C(=O)-CH(CH3)- benzyl, -C(=O)-CH(CH3)-phenyl, -C(=O)-C(CH3)3, -C(=O)-CH2-C(CH3)3, -C(=O)-CH2- CH(CH2CH3)2, -C(=O)-CH(CH3)(CH2CH2CH3), -C(=O)-CH(CH3)(CH2CH2CH2CH3), -C(=O)-CH(CH3)((CH2 )4CH3), -C(=O)-(CH2 )5CH3, -C(=O)-CH(CH3)((CH2 )5CH3), -C(=O)-(CH2 )8CH3, -C(=O)-CH(CH3)((CH2 )9CH3), -C(=O)-(CH2 )10CH3, -C(=O)-(CH2 )12CH3, -C(=O)-CH2-(2-fluorophenyl), -C(=O)-CH2-(4-fluorophenyl), -C(=O)- CH2-(3-fluorophenyl), -C(=O)-(CH2)2-C(=O)-OH, -C(=O)-CH2-(1-naphthyl), and -C(=O)- CH2-(2-Naphthyl); the -C(=O)-(C6-C10 aryl) is selected from the group consisting of -C(=O)-phenyl; the -P(=O)-(NH(C1-C6 alkyl-C(=O)-O-C1-C6 alkyl))(O-C6-C10 aryl) is selected from the group consisting of -P(=O)-(NH(CH(CH3)-C(=O)-O-CH2CH(CH3)2))(O-phenyl), -P(=O)-(NH(CH(CH(CH3)2)-C(=O)-O-CH2CH(CHCH3)2))(O-phenyl), -P(=O)-(NH(CH(benzyl)-C(=O)-O-CH2CH(CHCH3)2))(O-phenyl), -P(=O)-(NH(CH(phenyl)-C(=O)-O-CH2CH(CHCH3)2))(O-phenyl), -P(=O)-(NH(CH(CH3)-C(=O)-O-CH2CH(CH3)2))(O-(4-methoxyphenyl)), -P(=O)-(NH(CH(CH3)-C(=O)-O-CH2C(CH3)3))(O-(4-methoxyphenyl)), -P(=O)-(NH(CH(CH3)-C(=O)-O-CH2C(CH3)3))(O-(4-Bromophenyl)) -P(=O)-(NH(CH(CH3)-C(=O)-O-CH2CH(CH3)2))(O-1-naphthyl), and -P(=O)-(NH(CH(CH3)-C(=O)-O-CH2C(CH3)3))(O-2-naphthyl); and the -P(=O)-(NH(C1-C6 alkyl-C(=O)-O-C1-C6 alkyl))(O-5 to 6-membered heteroaryl) is -P(=O)-(NH(CH(CH3)-C(=O)-O-CH2C(CH3)3))(O-(3-pyridinyl)). 3. The compound or a pharmaceutically acceptable salt thereof of claim 1 or 2, wherein in R2 and R3: the -C(=O)-(C1-C10 alkyl) with the optional substituents of the C1-C10 alkyl is selected from the group consisting of -C(=O)-CH3, -C(=O)-(CH2)5-CH3, -C(=O)-benzyl, -C(=O)-CH(CH2CH3)2, -C(=O)-CH(NH2)CH(CH3)2, -C(=O)-CH(NH2)-phenyl, -C(=O)-CH(CH3)2, -C(=O)-CH(CH3)-phenyl, -C(=O)-CH2CH(CH2CH3)2, -C(=O)-CH2-(4-fluorophenyl), -C(=O)-CH2-(3-fluorophenyl), -C(=O)-CH2-(2-fluorophenyl), -C(=O)-(CH2)2-C(=O)-OH, -C(=O)-CH2-(1-naphthyl), and -C(=O)-CH2-(2-naphthyl); the -C(=O)-(C3-C7 cycloalkyl) with the optional substituents of the C3-C7 cycloalkyl is selected from the group consisting of -C(=O)-cyclohexyl, and -C(=O)-(4,4- dimethylcyclohexyl); and the -C(=O)-(C6-C10 aryl) is selected from the group consisting of - C(=O)-phenyl. 4. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1-3, wherein in R4: the C3-C7 cycloalkyl is selected from the group consisting of cyclopropyl; the –(C=O)-O-C1-C10 alkyl is selected from the group consisting of –(C=O)-O- (CH2)2CH3,and –(C=O)-O-(CH2)4CH3; the –(C=O)-(C1-C10 alkyl) is selected from the group consisting of –(C=O)-benzyl, and -C(=O)-(CH2)2CH3; and the -C(=O)-(C3-C7 cycloalkyl) is selected from the group consisting of -C(=O)-cyclobutyl. 5. The compound of any one of claims 1-4, selected from the group consisting of: , , , ,

, ,

6. The compound of any one of claims 1-5, having the Formula: pharmaceutically acceptable salt thereof. 7. A pharmaceutical composition comprising an effect amount of at least one compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 8. A method of inhibiting an RNA-dependent RNA polymerase in a patient infected with a virus, comprising administering to the patient a therapeutically effective amount of at least one compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 9. A method of preventing or treating a viral infection in a patient comprising administering to the patient a therapeutically effective amount of at least one compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 10. The method of claim 8, wherein the virus is at least one virus selected from the group consisting of Ebola (Makona) virus, Ebola (Kikwit) virus, Bundibugyo virus, Sudan virus, Marburg virus, respiratory syncytial virus (RSV), Nipah virus, measles virus, parainfluenza virus, Middle Eastern Respiratory Syndrome (MERS) virus, South Asian Respiratory syndrome-Coronavirus (SARS-CoV), SARS-COV-2, hepatitis C virus (HCV), Dengue virus, Zika virus, West Nile virus, Lassa virus, and Junin virus,. 11. The method of claim 9, wherein the viral infection is caused by at least one virus selected from the group consisting of Ebola (Makona) virus, Ebola (Kikwit) virus, Bundibugyo virus, Sudan virus, Marburg virus, respiratory syncytial virus (RSV), Nipah virus, measles virus, parainfluenza virus, Middle Eastern Respiratory Syndrome (MERS) virus, South Asian Respiratory syndrome-Coronavirus (SARS-CoV), SARS-COV-2, hepatitis C virus (HCV), Dengue virus, Zika virus, West Nile virus, Lassa virus, and Junin virus. 12. The method of claim 11, wherein the viral infection is caused by SARS-COV-2 and its variants selected from the group consisting of delta, epsilon, kappa, zeta, UK SARS-COV-2 variant B.1.1.7 and South Africa SARS-CoV-2501.V2. 13. The method of any one of claims 8-12, further comprising administering at least one additional antiviral agent selected from the group consisting of nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, protease inhibitor, an integrase inhibitor and/or an entry inhibitor. 14. The method of claim 13, wherein the protease inhibitor comprises at least one selected from the group consisting of PF-07321332, islatravir and lenacapavir. 15. The method of claim 14, wherein the protease inhibitor is PF-07321332. 16. The method of any one of claims 8-15, wherein the compound is administered via a route selected from the group consisting of oral, inhalation, parenteral and implants. 17. The method of any one of claims 8-16, wherein the administration is for pre-exposure or post-exposure prophylaxis.
Description:
ANTIVIRAL PRODRUGS AND FORMULATIONS THEREOF CROSS REFERENCE TO RELATED APPLICATION This application claims priority to U.S. provisional patent application No.63/284,952, which was filed on December 1, 2021, and which is hereby incorporated by reference in its entirety. FIELD OF INVENTION This invention relates to antiviral compounds and compositions useful for the treatment of various viral infections, such as SARS-CoV-2 infections. BACKGROUND OF THE DISCLOSURE Nucleoside analogs have been utilized as small-molecule, broad-spectrum, direct- acting antivirals for the prevention and treatment of viral infections 1 . For RNA viruses, such compounds target the RNA-dependent RNA polymerase (RDRP) which carries out the key viral RNA synthesis reactions. RDRPs are attractive drug targets because they are essential for virus growth, are not encoded by the mammalian host cell and are well-conserved among viral families 2 . For SARS-CoV-2 the RDRP is non-structural protein (nsp) 12. Nsp12 associates with nsp7 and nsp8 in order to replicate the SARS-COV-2 genome. To date, nucleoside analogs that selectively target the RDRP have been the most promising approach to SARS-CoV-2 inhibition. Currently, there are ribonucleoside analogs that are approved by a stringent regulatory authority; such as Remdesivir (RDV; GS-5734, registered by Gilead Sciences as VEKLURY) (whose structure is show below) and are undergoing mid-stage clinical development 3-4 , for the treatment of SARS-CoV-2 infections. Remdesivir functions as a non-obligate or delayed RNA chain terminator. Delayed chain termination occurs when a nucleotide analogue has a free 3-OH group required for the addition of natural nucleotides. The incorporation of the delayed chain terminator, however, perturbs the RNA structure, and RNA synthesis is halted. In SARS-CoV-1, SARS-CoV-2, and MERS-CoV, remdesivir-TP incorporation consistently results in chain termination. Remdesivir (RDV, GS-5374), a nucleotide analog prodrug and an RNA-dependent RNA polymerase (RdRp) inhibitor with broad antiviral activity, demonstrated positive clinical endpoints in a Phase III Adaptive COVID-19 Treatment Trial (median time to recovery shortened from 15 to 11 days) 5 that justified its emergency use authorization by the US Food & Drug Administration for treatment of hospitalized COVID-19 patients 6 . However, its intravenous delivery makes the discovery of new or supplemental therapies that produce greater clinical improvements and can be administered outside of a hospital setting (i.e. orally) highly desirable. As mentioned, RDV is administered intravenously due to the drug’s poor hepatic stability and low plasma/serum stability, with each infusion taking up to two hours and requiring daily administration for either 5 or 10 days. Accordingly, alternative therapies that improve oral exposure is desirable. The present invention provides such alternatives. WO 2012/050961 and WO 2012/050956 refer to antiviral prodrugs and pharmaceutical compositions thereof. WO 2021/154687 refers to methods for treating SARS COV-2 infections. References: 1. Geraghty, R. J.; Aliota, M. T.; Bonnac, L. F., Broad-Spectrum Antiviral Strategies and Nucleoside Analogues. Viruses 2021, 13 (4). 2. Cannalire, R.; Cerchia, C.; Beccari, A. R.; Di Leva, F. S.; Summa, V., Targeting SARS-CoV-2 Proteases and Polymerase for COVID-19 Treatment: State of the Art and Future Opportunities. J Med Chem 2020. 3. Study of MK-4482 for Prevention of Coronavirus Disease 2019 (COVID-19) in Adults (MK-4482-013) (MOVe-AHEAD). https://clinicaltrials.gov/ct2/show/NCT04939428. 4. Study to Evaluate the Effects of RO7496998 (AT-527) in Non-Hospitalized Adult and Adolescent Participants With Mild or Moderate COVID-19 (MORNINGSKY). https://clinicaltrials.gov/ct2/show/NCT04889040. 5. Health, N. I. o., NIH clinical trial shows Remdesivir accelerates recovery from advanced COVID-19.2020. 6. Administration, U. S. F. D., Coronavirus (COVID-19) Update: FDA Issues Emergency Use Authorization for Potential COVID-19 Treatment. Administration, U. S. F. D., Ed. U.S. Food & Drug Administration: 2020. SUMMARY OF THE DISCLOSURE Some embodiments described herein relate to a compound of Formula (I): or a pharmaceutically acceptable salt thereof; wherein: R 1 is selected from the group consisting of hydrogen; -C(=O)-(C 3 -C 7 cycloalkyl), wherein the C 3 -C 7 cycloalkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 6 alkyl; -C(=O)-(5 to 6-membered heterocyclyl), wherein the 5 to 6-membered heterocyclyl is attached to the -C(=O) group through a ring carbon or ring heteroatom, and further wherein the 5 to 6-membered heterocyclyl is optionally substituted with a 5 to 6- membered heterocyclyl; -C(=O)-(C 1 -C 20 alkyl), wherein the C 1 -C 20 alkyl is optionally substituted with 1-3 substituents independently selected from C(=O)OH, C 3 -C 7 cycloalkyl, and C 6 -C 10 aryl; -C(=O)-(C 6 -C 10 aryl); -P(=O)-(NH(C 1 -C 6 alkyl)) 2 ; -P(=O)-(NH(C 1 -C 6 alkyl)(N(C 1 -C 6 alkyl) 2 ); -P(=O)-(N(C 1 -C 6 alkyl) 2 ) 2 ; -P(=O)-(NH(C 1 -C 6 alkyl-C(=O)-O-C 1 -C 6 alkyl))(O-C 6 -C 10 aryl); and -P(=O)-(NH(C 1 -C 6 alkyl-C(=O)-O-C 1 -C 6 alkyl))(O-5 to 6-membered heteroaryl); R 2 and R 3 are each independently selected from the group consisting of hydrogen; -C(=O)-(C 1 -C 10 alkyl), wherein the C 1 -C 10 alkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of -NH 2 , -C(=O)-OH, and C 6 - C 10 aryl; -C(=O)-(C 3 -C 7 cycloalkyl), wherein the C 3 -C 7 cycloalkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, C 1 -C 6 alkyl, and -O- C 1 -C 6 alkyl; and -C(=O)-(C 6 -C 10 aryl); and R 4 is selected from the group consisting of hydrogen, C 3 -C 7 cycloalkyl; –(C=O)-O- C 1 -C 10 alkyl; –(C=O)-(C 1 -C 10 alkyl); and -C(=O)-(C 3 -C 7 cycloalkyl); wherein in each instance, C 6 -C 10 aryl and 5 to 6-membered heteroaryl are each optionally independently substituted with 1-3 substituents independently selected from the group consisting of halo, C 1 -C 6 alkyl, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , and -O-C 1 - C 6 alkyl; with the proviso that: (a) when only one of R 1 , R 2 , and R 3 is independently hydrogen, -C(=O)-CH(CH 3 ) 2 , -C(=O)- CH 2 CH 3 , -C(=O)-cyclopropyl, -C(=O)-C(CH 3 ) 3 , -C(=O)-CH 2 C(CH 3 ) 3 , or -C(=O)-CH(NH 2 )- CH(CH 3 ) 2 , and the other two of R 1 , R 2 , and R 3 are hydrogen, then R 4 is not hydrogen; (b) when R 1 = R 2 = R 3 and is selected from the group consisting of hydrogen, -C(=O)- CH(CH 3 ) 2 , -C(=O)-CH 2 CH 3 , -C(=O)-CH 3 , and -C(=O)-cyclopropyl, then R 4 is not hydrogen; (c) when R 1 = R 4 = hydrogen, then R 2 and R 3 cannot both be -C(=O)-CH(CH 3 ) 2 ; (d) when R 1 = R 2 and is selected from -C(=O)-CH(CH 3 ) 2 and -C(=O)-cyclopropyl, then R 3 and R 4 cannot both be hydrogen; and (e) when R 1 is selected from the group consisting of -C(=O)-CH 3 , -C(=O)-CH 2 CH 2 CH 3 , -C(=O)-(CH 2 ) 7 CH 3 , -C(=O)-phenyl, -C(=O)-cyclopropyl, -C(=O)-CH 2 CF 3 , -C(=O)-CH 2 CH(CH 3 ) 2 , -C(=O)-CH(NH 2 )-CH(CH 3 ) 2 , -C(=O)-CH(NH 2 )-benzyl, and -C(=O)-CH(NH 2 )-CH(CH 3 )-CH 2 CH 3 , then R 2 , R 3 , and R 4 cannot all be hydrogen. The application further provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof; wherein: R 1 is selected from the group consisting of hydrogen; -C(=O)-(C 3 -C 7 cycloalkyl), wherein the C 3 -C 7 cycloalkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 6 alkyl; -C(=O)-(5 to 6-membered heterocyclyl), wherein the 5 to 6-membered heterocyclyl is attached to the -C(=O) group through a ring carbon or ring heteroatom, and further wherein the 5 to 6-membered heterocyclyl is optionally substituted with a 5 to 6- membered heterocyclyl; -C(=O)-(C 1 -C 20 alkyl), wherein the C 1 -C 20 alkyl is optionally substituted with 1-3 substituents independently selected from C(=O)OH, C 3 -C 7 cycloalkyl, and C 6 -C 10 aryl; -C(=O)-(C 6 -C 10 aryl); -P(=O)-(NH(C 1 -C 6 alkyl)) 2 ; -P(=O)-(NH(C 1 -C 6 alkyl)(N(C 1 -C 6 alkyl) 2 ); -P(=O)-(N(C 1 -C 6 alkyl) 2 ) 2 ; -P(=O)-(NH(C 1 -C 6 alkyl-C(=O)-O-C 1 -C 6 alkyl))(O-C 6 -C 10 aryl); and -P(=O)-(NH(C 1 -C 6 alkyl-C(=O)-O-C 1 -C 6 alkyl))(O-5 to 6-membered heteroaryl); R 2 and R 3 are each independently selected from the group consisting of hydrogen; -C(=O)-(C 1 -C 10 alkyl), wherein the C 1 -C 10 alkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of -NH 2 , -C(=O)-OH, and C 6 - C 10 aryl; -C(=O)-(C 3 -C 7 cycloalkyl), wherein the C 3 -C 7 cycloalkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, C 1 -C 6 alkyl, and -O- C 1 -C 6 alkyl; and -C(=O)-(C 6 -C 10 aryl); and R 4 is selected from the group consisting of hydrogen, C 3 -C 7 cycloalkyl; –(C=O)-O- C 1 -C 10 alkyl; –(C=O)-(C 1 -C 10 alkyl); and -C(=O)-(C 3 -C 7 cycloalkyl); wherein in each instance, C 6 -C 10 aryl and 5 to 6-membered heteroaryl are each optionally independently substituted with 1-3 substituents independently selected from the group consisting of halo, C 1 -C 6 alkyl, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , and -O-C 1 - C 6 alkyl; with the proviso that: (a) when only one of R 1 , R 2 , and R 3 is independently hydrogen, -C(=O)-CH(CH 3 ) 2 , -C(=O)- CH 2 CH 3 , -C(=O)-cyclopropyl, -C(=O)-C(CH 3 ) 3 , -C(=O)-CH 2 C(CH 3 ) 3 , or -C(=O)-CH(NH 2 )- CH(CH 3 ) 2 , and the other two of R 1 , R 2 , and R 3 are hydrogen, then R 4 is not hydrogen; (b) when R 1 = R 2 = R 3 and is selected from the group consisting of hydrogen, -C(=O)- CH(CH 3 ) 2 , -C(=O)-CH 2 CH 3 , -C(=O)-CH 3 , and -C(=O)-cyclopropyl, then R 4 is not hydrogen; (c) when R 1 = R 4 = hydrogen, then R 2 and R 3 cannot both be -C(=O)-(C 1 -C 6 )alkyl; when R 4 = hydrogen, then R 1 , R 2 , and R 3 cannot all be -C(=O)-CH(CH 3 ) 2 -C(=O)-CH 3 - C(=O)-CH 2 CH 3 , -C(=O)-CH 2 CH 2 CH 3 , -C(=O)-(C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkyl or -C(=O)- cyclopropyl; (d) when R 1 = R 2 and is selected from -C(=O)-CH(CH 3 ) 2 and -C(=O)-cyclopropyl, then R 3 and R 4 cannot both be hydrogen; (e) when R 2 = R 3 and is selected from hydrogen, -C(=O)-CH(CH 3 ) 2 , -C(=O)-CH 3 or -C(=O)- cyclopropyl, and R 4 is hydrogen, -C(=O)-CH(CH 3 ) 2 , -C(=O)-CH 3 or -C(=O)-cyclopropyl, then R 1 cannot be -C(=O)-CH(CH 3 ) 2 , -C(=O)-hetero(C 1 -C 6 )alkyl-C(=O)O-(C 1 -C 6 )alkyl, - C(=O)((C 1 -C 6 )alkylPh((NHC=OO(C 1 -C 6 )alkyl, -C(=O)((C 1 -C 6 )alkyl((NHC=OO(C 1 - C 6 )alkyl, -C(=O)-hetero(C 1 -C 6 )alkyl-C(=O)O-hetero(C 1 -C 6 )alkyl, -C(=O)-hetero(C 1 - C 6 )alkyl-C(=O)OH, or -C(=O)-hetero(C 1 -C 6 )alkyl; (f) when R 1 is selected from the group consisting of -C(=O)-CH 3 , -C(=O)-CH 2 CH 2 CH 3 , -C(=O)-(CH 2 ) 7 CH 3 , -C(=O)-phenyl, -C(=O)-cyclopropyl, -C(=O)-CH 2 CF 3 , -C(=O)-CH 2 CH(CH 3 ) 2 , -C(=O)-CH(NH 2 )-CH(CH 3 ) 2 , -C(=O)-CH(NH 2 )-benzyl, and -C(=O)-CH(NH 2 )-CH(CH 3 )-CH 2 CH 3 , then R 2 , R 3 , and R 4 cannot all be hydrogen; and (g) when R 2 = R 3 = R 4 = hydrogen, R 1 cannot be selected from the group consisting of hydrogen, -C(=O)-(C 1 -C 10 )alkyl, -C(=O)-(C 1 -C 10 )alkyl-C(=O)-(C 1 -C 6 )alkyl, -C(=O)-(C 1 - C 6 )alkenyl, -C(=O)-(C 1 -C 6 )alkynyl, -C(=O)-halo(C 1 -C 6 )alkyl, -C(=O)-halo(C 1 -C 6 )alkenyl, - C(=O)-hetero(C 1 -C 6 )alkyl, -C(=O)-hetero(C 1 -C 6 )alkenyl, -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 1 -C 6 )alkyl-(C 3 -C 7 )heterocycloalkyl-(C 1 -C 6 )alkyl, -C(=O)- halo(C 3 -C 7 )cycloalkyl, -C(=O)-(C 1 -C 6 )alkyl-halo(C 3 -C 7 )cycloalkyl, -C(=O)-hydroxy(C 3 - C 7 )cycloalkyl, -C(=O)-(C 1 -C 6 )alkyl-hydroxy(C 3 -C 7 )cycloalkyl, -C(=O)-amino(C 3 - C 7 )cycloalkyl, -C(=O)-(C 1 -C 6 )alkyl-amino(C 3 -C 7 )cycloalkyl, -C(=O)-(C 1 -C 6 )heteroalkyl(C 3 - C 7 )cycloalkyl, and -C(=O)-(C 1 -C 6 )alkyl-(C 1 -C 6 )heteroalkyl(C 3 -C 7 )cycloalkyl, -C(=O)- halo(C 3 -C 7 )heterocycloalkyl, -C(=O)-(C 1 -C 6 )alkyl-halo(C 3 -C 7 )heterocycloalkyl, -C(=O)- hydroxy(C 3 -C 7 )heterocycloalkyl, -C(=O)-(C 1 -C 6 )alkyl-hydroxy(C 3 -C 7 )heterocycloalkyl, - C(=O)-amino(C 3 -C 7 )heterocycloalkyl, -C(=O)-(C 1 -C 6 )alkyl-amino(C 3 -C 7 )heterocycloalkyl, - C(=O)-(C 1 -C 6 )heteroalkyl(C 3 -C 7 )heterocycloalkyl, -C(=O)-(C 1 -C 6 )alkyl-(C 1 - C 6 )heteroalkyl(C 3 -C 7 )heterocycloalkyl, -C(=O)-(C 1 -C 6 )heteroalkyl-C(=O)-(C 1 -C 6 )alkyl, - C(=O)-(C 1 -C 6 )heteroalkyl-phenyl, and -C(=O)-(C 1 -C 6 )heteroalkyl-(C 5 -C 8 )heteroaryl. Some embodiments described herein also provide a pharmaceutical composition comprising a compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. Some embodiments described herein also provide a method of inhibiting an RNA- dependent RNA polymerase in a patient infected with a virus, or a method of preventing or treating a viral infection in a patient comprising administering to the patient a therapeutically effective amount of at least one compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows in graphic form the Cyano/Rhesus PK data for compounds 19, 25, 39, 59, GS-441524, and GS-621763 following PO (oral) administration at 2.3-10 mg/kg equivalent dose of GS-441524. DETAILED DESCRIPTION OF THE DISCLOSURE Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meaning. All undefined technical and scientific terms used in this Application have the meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, “a” or “an” entity refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound unless stated otherwise. As such, the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein. “Patient” includes both human and animals. “Patient” and “subject” are used interchangeably herein. When a range of values is listed, it is intended to encompass each value and sub– range within the range. For example, “C 1–6 alkyl” is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1–6 , C 1–5 , C 1–4 , C 1–3 , C 1–2 , C 2–6 , C 2–5 , C 2–4 , C 2–3 , C 3–6 , C 3–5 , C 3–4 , C 4–6 , C 4–5 , and C 5–6 alkyl. “Alkyl” refers to a radical of a straight–chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C 1–20 alkyl”). In some embodiments, an alkyl group has 1 to 15 carbon atoms (“C 1–15 alkyl”). In some embodiments, an alkyl group has 1 to 14 carbon atoms (“C 1–14 alkyl”). In some embodiments, an alkyl group has 1 to 13 carbon atoms (“C 1–13 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C 1–12 alkyl”). In some embodiments, an alkyl group has 1 to 11 carbon atoms (“C 1–11 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C 1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1–9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1–8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1–7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1–6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1–5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1–2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2–6 alkyl”). Examples of C 1–6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), n–propyl (C 3 ), isopropyl (C 3 ), n–butyl (C 4 ), tert–butyl (C 4 ), sec–butyl (C 4 ), iso–butyl (C 4 ), n– pentyl (C 5 ), 3–pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3–methyl–2–butanyl (C 5 ), tertiary amyl (C 5 ), and n–hexyl (C 6 ). Additional examples of alkyl groups include n–heptyl (C 7 ), n– octyl (C 8 ) and the like. “Alkenyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 10 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds (“C 2–10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C 2–9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C 2–8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C 2–7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2–6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C 2–5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2–4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2–3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C 2 alkenyl”). The one or more carbon– carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1–butenyl). Examples of C 2–4 alkenyl groups include ethenyl (C 2 ), 1–propenyl (C 3 ), 2–propenyl (C 3 ), 1– butenyl (C 4 ), 2–butenyl (C 4 ), butadienyl (C 4 ), and the like. Examples of C 2–6 alkenyl groups include the aforementioned C 2–4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like. “Alkynyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 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 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2–9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2–8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2–7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C 2–6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2–5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2–4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2–3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C 2 alkynyl”). The one or more carbon– carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl). Examples of C 2–4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1–propynyl (C 3 ), 2–propynyl (C 3 ), 1–butynyl (C 4 ), 2–butynyl (C 4 ), and the like. Examples of C 2–6 alkenyl groups include the aforementioned C 2–4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (C 8 ), and the like. “Carbocyclyl” or “carbocyclic” refers to a radical of a non–aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C 3–14 carbocyclyl”) and zero heteroatoms in the non–aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C 3–10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3–8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C 3–7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3–6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C 4–6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C 5–6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5–10 carbocyclyl”). Exemplary C 3–6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like. Exemplary C 3–8 carbocyclyl groups include, without limitation, the aforementioned C 3–6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like. Exemplary C 3–10 carbocyclyl groups include, without limitation, the aforementioned C 3–8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro–1H–indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon–carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C 3–14 cycloalkyl”). In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C 3–10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C 3–8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3–6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C 4–6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C 5–6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5–10 cycloalkyl”). Examples of C 5–6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ). Examples of C 3–6 cycloalkyl groups include the aforementioned C 5–6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ). Examples of C 3–8 cycloalkyl groups include the aforementioned C 3–6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ). “Heterocyclyl” or “heterocyclic” refers to a group or radical of a 3– to 14– membered non–aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon– carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. In some embodiments, a heterocyclyl group is a 5–10 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–8 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–6 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Exemplary 3–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5–membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl–2,5–dione. Exemplary 5– membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5–membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6–membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6–membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6–membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro–1,8–naphthyridinyl, octahydropyrrolo[3,2–b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H–benzo[e][1,4]diazepinyl, 1,4,5,7–tetrahydropyrano[3,4–b]pyrrolyl, 5,6–dihydro–4H–furo[3,2–b]pyrrolyl, 6,7–dihydro– 5H–furo[3,2–b]pyranyl, 5,7–dihydro–4H–thieno[2,3–c]pyranyl, 2,3–dihydro–1H– pyrrolo[2,3–b]pyridinyl, 2,3–dihydrofuro[2,3–b]pyridinyl, 4,5,6,7–tetrahydro–1H–pyrrolo- [2,3–b]pyridinyl, 4,5,6,7–tetrahydrofuro[3,2–c]pyridinyl, 4,5,6,7–tetrahydrothieno[3,2– b]pyridinyl, 1,2,3,4–tetrahydro–1,6–naphthyridinyl, and the like. “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 pi electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6–14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1–naphthyl (α-naphthyl) and 2–naphthyl (β-naphthyl)). In some embodiments, an aryl group has 14 ring carbon atoms (“C 14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. “Heteroaryl” refers to a radical of a 5–14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl). In some embodiments, a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heteroaryl”). In some embodiments, the 5–6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Exemplary 5–membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5–membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5–membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5–membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6–membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6–membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6–membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7–membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6– bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6–bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl. “Saturated” refers to a ring moiety that does not contain a double or triple bond, i.e., the ring contains all single bonds. Alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may be optionally substituted. Optionally substituted refers to a group which may be substituted or unsubstituted. In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a non-hydrogen substituent, and which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Heteroatoms such as nitrogen, oxygen, and sulfur may have hydrogen substituents and/or non-hydrogen substituents which satisfy the valencies of the heteroatoms and results in the formation of a stable compound. Exemplary non-hydrogen substituents may be selected from the group consisting of halogen, –CN, –NO 2 , –N 3 , –SO 2 H, –SO 3 H, –OH, –OR aa , –N(R bb ) 2 , –N(OR cc )R bb , –SH, – SR aa , –C(=O)R aa , –CO 2 H, –CHO, –CO 2 R aa , –OC(=O)R aa , –OCO 2 R aa , –C(=O)N(R bb ) 2 , – OC(=O)N(R bb ) 2 , –NR bb C(=O)R aa , –NR bb CO 2 R aa , –NR bb C(=O)N(R bb ) 2 , –C(=NR bb )R aa , – C(=NR bb )OR aa , –OC(=NR bb )R aa , –OC(=NR bb )OR aa , –C(=NR bb )N(R bb ) 2 , –OC(=NR bb )N(R bb ) 2 , –NR bb C(=NR bb )N(R bb ) 2 , –C(=O)NR bb SO 2 R aa , –NR bb SO 2 R aa , –SO 2 N(R bb ) 2 , –SO 2 R aa , – S(=O)R aa , –OS(=O)R aa , -B(OR cc ) 2 , C 1–10 alkyl, C 2–10 alkenyl, C 2–10 alkynyl, C 3–14 carbocyclyl, 3– to 14- membered heterocyclyl, C 6–14 aryl, and 5– to 14- membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, or two geminal hydrogens on a carbon atom are replaced with the group =O; each instance of R aa is, independently, selected from the group consisting of C 1–10 alkyl, C 1–10 perhaloalkyl, C 2–10 alkenyl, C 2–10 alkynyl, C 3–14 carbocyclyl, 3– to 14- membered heterocyclyl, C 6–14 aryl, and 5– to 14- membered heteroaryl, or two R aa groups are joined to form a 3– to 14- membered heterocyclyl or 5– to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; each instance of R bb is, independently, selected from the group consisting of hydrogen, –OH, –OR aa , –N(R cc ) 2 , –CN, –C(=O)R aa , –C(=O)N(R cc ) 2 , –CO 2 R aa , –SO 2 R aa , – SO 2 N(R cc ) 2 , –SOR aa , C 1–10 alkyl, C 1–10 perhaloalkyl, C 2–10 alkenyl, C 2–10 alkynyl, C 3–14 carbocyclyl, 3– to 14- membered heterocyclyl, C 6–14 aryl, and 5– to 14- membered heteroaryl, or two R bb groups are joined to form a 3– to 14- membered heterocyclyl or 5– to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; each instance of R cc is, independently, selected from the group consisting of hydrogen, C 1–10 alkyl, C 1–10 perhaloalkyl, C 2–10 alkenyl, C 2–10 alkynyl, C 3–14 carbocyclyl, 3– to 14- membered heterocyclyl, C 6–14 aryl, and 5– to 14- membered heteroaryl, or two R cc groups are joined to form a 3– to 14- membered heterocyclyl or 5– to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; and each instance of R dd is, independently, selected from the group consisting of halogen, –CN, –NO 2 , –N 3 , –SO 2 H, –SO 3 H, –OH, –OC 1–6 alkyl, –ON(C 1–6 alkyl) 2 , –N(C 1–6 alkyl) 2 , – N(OC 1–6 alkyl)(C 1–6 alkyl), –N(OH)(C 1–6 alkyl), –NH(OH), –SH, –SC 1–6 alkyl, –C(=O)(C 1–6 alkyl), –CO 2 H, –CO 2 (C 1–6 alkyl), –OC(=O)(C 1–6 alkyl), –OCO 2 (C 1–6 alkyl), –C(=O)NH 2 , – 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), –NHCO 2 (C 1–6 alkyl), –NHC(=O)N(C 1–6 alkyl) 2 , –NHC(=O)NH(C 1– 6 alkyl), –NHC(=O)NH 2 , –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)NH 2 , –OC(=NH)N(C 1–6 alkyl) 2 , –OC(NH)NH(C 1–6 alkyl), –OC(NH)NH 2 , –NHC(NH)N(C 1–6 alkyl) 2 , – NHC(=NH)NH 2 , –NHSO 2 (C 1–6 alkyl), –SO 2 N(C 1–6 alkyl) 2 , –SO 2 NH(C 1–6 alkyl), –SO 2 NH 2 ,– SO 2 C 1–6 alkyl, -B(OH) 2 , -B(OC 1–6 alkyl) 2 ,C 1–6 alkyl, C 1–6 perhaloalkyl, C 2–6 alkenyl, C 2–6 alkynyl, C 3–10 carbocyclyl, C 6–10 aryl, 3–to 10- membered heterocyclyl, and 5- to 10- membered heteroaryl; or two geminal R dd substituents on a carbon atom may be joined to form =O. “Halo” or “halogen” refers to fluorine (fluoro, –F), chlorine (chloro, –Cl), bromine (bromo, –Br), or iodine (iodo, –I). It should be noted that in hetero-atom containing ring systems described herein, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring: there is no -OH attached directly to carbons marked 2 and 5. It should also be noted that tautomeric forms such as, for example, the moieties: are considered equivalent unless otherwise specified. As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. “Effective amount” or “therapeutically effective amount” is meant to describe an amount of compound or a composition described herein that is effective in inhibiting the above-noted enzyme, diseases or conditions, and thus producing the desired therapeutic, ameliorative, inhibitory and/or preventative effect. “Salt” includes any and all salts. “Pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes 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, nontoxic acid addition salts are salts of an amino group 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 using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2– naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1–4 alkyl) 4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC). Compounds described herein can be in the form of individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, replacement of a carbon by a 13 C- or 14 C- enriched carbon, and/or replacement of an oxygen atom with 18 O, are within the scope of the disclosure. Other examples of isotopes include 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 36 Cl and 123 I. Compounds with such isotopically enriched atoms are useful, for example, as analytical tools or probes in biological assays. Certain isotopically-labelled compounds of Formula (I), (e.g., those labeled with 3 H and 14 C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Certain isotopically-labelled compounds of Formula (I) can be useful for medical imaging purposes, for example, those labeled with positron-emitting isotopes like 11 C or 18 F can be useful for application in Positron Emission Tomography (PET) and those labeled with gamma ray emitting isotopes like 123 I can be useful for application in Single Photon Emission Computed Tomography (SPECT). Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and hence, may be preferred in some circumstances. Additionally, isotopic substitution at a site where epimerization occurs may slow or reduce the epimerization process and thereby retain the more active or efficacious form of the compound for a longer period of time. Isotopically labeled compounds of Formula (I), in particular those containing isotopes with longer half-lives (t 1/2 >1 day), can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent. The compounds described herein can also be used in combination with one or more additional therapeutic and/or prophylactic agents. As such, also provided herein are methods of treatment or prevention of the various viral infections provided herein, wherein the methods comprise administering to a subject in need thereof a compound of the disclosure and a therapeutically effective amount of one or more additional therapeutic and/or prophylactic agents (“therapeutic agent” is interchangeable with “prophylactic agent” as used herein). Accordingly, the compounds of the present invention and the additional therapeutic agents can be utilized for pre-exposure and post-exposure prophylaxis. In some embodiments, the additional therapeutic agent is an antiviral agent. Any suitable antiviral agent can be used in the methods described herein. In some embodiments, the antiviral agent is selected from the group consisting of 5-substituted 2' -deoxyuridine analogues, nucleoside analogues, pyrophosphate analogues, nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, entry inhibitors, acyclic guanosine analogues, acyclic nucleoside phosphonate analogues, HCV NS5A inhibitors, NS5B inhibitors, influenza virus inhibitors, interferons, immunostimulators, oligonucleotides, antimitotic inhibitors, and combinations thereof. In some embodiments, the additional therapeutic agent is a 5-substituted 2' - deoxyuridine analogue. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of idoxuridine, trifluridine, brivudine (bromo vinyl deoxyuridine or “BVDU”), and combinations thereof. In some embodiments, the additional therapeutic agent is a nucleoside analogue. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of vidarabine, entecavir (ETV), telbivudine, lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate (TDF) and combinations thereof. In some embodiments, the additional therapeutic agent is favipiravir, ribavirin, galidesivir, or a combination thereof. In some embodiments, the additional therapeutic agent is ~-D-N4-hydroxycytidine. In some embodiments, the additional therapeutic agent is a pyrophosphate analogue. For example, in some embodiments, the additional therapeutic agent is foscarnet or phosphonoacetic acid. In some embodiments, the additional therapeutic agent is foscarnet. In some embodiments, the additional therapeutic agent is nucleoside reverse transcriptase inhibitor. In some embodiments, the antiviral agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, and combinations thereof. In some embodiments, the additional therapeutic agent is sangivamycin, β-d-N4-Hydroxycytidine (NHC), EIDD-2801, EIDD-1931, or a combination thereof. In some embodiments, the antiviral agent is MK-4482 (EIDD-2801). In some embodiments, the additional therapeutic agent is a non-nucleoside reverse transcriptase inhibitor. In some embodiments, the antiviral agent is selected from the group consisting of nevirapine, delavirdine, efavirenz, etravirine, rilpivirine, and combinations thereof. In some embodiments, the additional therapeutic agent is a protease inhibitor. In some embodiments, the protease inhibitor is a HIV protease inhibitor. For example, in some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, and combinations thereof. In some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, and combinations thereof. In some embodiments, the protease inhibitor is a HCV NS3/4A protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, ribavirin, danoprevir, faldaprevir, vedroprevir, sovaprevir, deldeprevir, narlaprevir and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, and combinations thereof. In some embodiments, the protease inhibitor is PF-07321332, having the structure

PF-07321332 acts an orally active 3CL protease inhibitor, and the combination of PF- 07321332 with ritonavir is in phase III trials for the treatment of COVID-19. In some embodiments, the protease inhibitor is lenacapavir (GS-6207) that is being developed by Gilead Sciences for the treatment of HIV. It has the structure: . In some embodiments, the additional therapeutic agent is an integrase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of raltegravir, dolutegravir, elvitegravir, abacavir, lamivudine, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of bictegravir, raltegravir, dolutegravir, cabotegravir, elvitegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of bictegravir, dolutegravir, and cabotegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is bictegravir. In some embodiments, the additional therapeutic agent is an entry inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of docosanol, enfuvirtide, maraviroc, ibalizumab, fostemsavir, leronlimab, ibalizumab, fostemsavir, leronlimab, palivizumab, respiratory syncytial virus immune globulin, intravenous [RSV-IGIV], varicella-zoster immunoglobulin [VariZIG], varicella- zoster immune globulin [VZIG]), and combinations thereof. In some embodiments, the additional therapeutic agent is an acyclic guanosine analogue. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of acyclovir, ganciclovir, valacyclovir (also known as valaciclovir), valganciclovir, penciclovir, famciclovir, and combinations thereof. In some embodiments, the additional therapeutic agent is an acyclic nucleoside phosphonate analogues. For example, in some embodiments, the additional therapeutic agent is selected from a group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, emtricitabine, efavirenz, rilpivirine, elvitegravir, and combinations thereof. In some embodiment, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, and combinations thereof. In some embodiment, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir dipivoxil, TDF, and combinations thereof. In some embodiments, the additional therapeutic agent is a HCV NS5A or NS5B inhibitor. In some embodiments, the additional therapeutic agent is a NS3/4A protease inhibitor. In some embodiments, the additional therapeutic agent is a NS5A protein inhibitor. In some embodiments, the additional therapeutic agent is a NS5B polymerase inhibitor of the nucleoside/nucleotide type. In some embodiments, the additional therapeutic agent is a NS5B polymerase inhibitor of the nonnucleoside type. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, ribavirin, asunaprevir, simeprevir, paritaprevir, ritonavir, elbasvir, grazoprevir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, and combinations thereof. In some embodiments, the additional therapeutic agent is an influenza virus inhibitor. In some embodiments, the additional therapeutic agents is a matrix 2 inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, and combinations thereof. In some embodiments, the additional therapeutic agent is a neuraminidase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of zanamivir, oseltamivir, peramivir, laninamivir octanoate, and combinations thereof. In some embodiments, the additional therapeutic agent is a polymerase inhibitor distinct from the compounds of the present invention. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ribavirin, favipiravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, arbidol (umifenovir), baloxavir marboxil, oseltamivir, peramivir, ingavirin, laninamivir octanoate, zanamivir, favipiravir, ribavirin, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, zanamivir, oseltamivir, peramivir, laninamivir octanoate, ribavirin, favipiravir, and combinations thereof. In some embodiments, the additional therapeutic agent is DAS-181 or XC-221. In some embodiments, the additional therapeutic agent is an interferon. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon 1, interferon alfa lb, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfacon 1, pegylated interferon alfa lb, pegylated interferon alfa 2a (PegIFNα-2a), and PegIFNa-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon 1, pegylated interferon alfa 2a (PegIFNa-2a), PegIFNa-2b, and ribavirin. In some embodiments, the additional therapeutic agent is pegylated interferon alfa- 2a, pegylated interferon alfa-2b, or a combination thereof. In some examples, the additional therapeutic agent is interferon-beta. For example, the additional therapeutic agent ls interfernn- beta-1 a, such as SNG-001. In some embodiments, the additional therapeutic agent is an inteferon--inducing agent, such as tilorone hydrochloride. In some embodiments, the additional therapeutic agent is IL-17 antagonist such as ixekizumab. In some embodiments, the additional therapeutic agent is interferon alfa 2 ligand, secukinumab, IMU-838, or vidofludimus. In some embodiments, the additional therapeutic agent is an immunostimulatory agent. In some embodiments, the additional therapeutic agent is an oligonucleotide. In some embodiments, the additional therapeutic agent is an antimitotic inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of fomivirsen, podofilox, imiquimod, sinecatechins, and combinations thereof. In some embodiments, the additional therapeutic agent is azoximer bromide or IMM-101. In some embodiments, the additional therapeutic agent is selected from the group consisting of besifovir, nitazoxanide, REGN2222, doravirine, sofosbuvir, velpatasvir, daclatasvir, asunaprevir, beclabuvir, FVl00, and letermovir, and combinations thereof. In some embodiments, the additional therapeutic agent is an agent for treatment of RSV. For example, in some embodiments, the antiviral agent is ribavirin, ALS-8112 or presatovir. For example, in some embodiments, the antiviral agent is ALS-8112 or presatovir. In some embodiments, the antiviral agent is DFV890. In some embodiments, the antiviral agent is MAS825. In some embodiments, the antiviral agent is emetine. In some embodiments, the antiviral agent is protoporphyrin IX, SnPP protoporphyrin and verteporfin. In some embodiments, the antiviral agent is RBT-9. In some embodiments, the antiviral agent is thymosin. In some embodiments, the additional therapeutic agent is ivermectin. In some embodiments, the additional therapeutic agent is an agent for treatment of picomavirus. In some embodiments, the additional therapeutic agent is selected from the group consisting of hydantoin, guanidine hydrochloride, L-buthionine sulfoximine, Py-11, and combinations thereof. In some embodiments, the additional therapeutic agent is a picomavirus polymerase inhibitor. In some embodiments, the additional therapeutic agent is rupintrivir. In some embodiments, the additional therapeutic agent is an agent for treatment of malaria. For example, the additional therapeutic agent is dihydroartemisinin piperaquine. In some embodiments, the additional therapeutic agent is pyramax. In some embodiments, the additional therapeutic agent is selected from the group consisting of hydroxychloroquine, chloroquine, artemether, lumefantrine, atovaquone, proguanil, tafenoquine, pyronaridine, artesunate, artenimol, piperaquine, artesunate, amodiaquine, pyronaridine, artesunate, halofantrine, quinine sulfate, mefloquine, solithromycin, pyrimethamine, MMV-390048, ferroquine, artefenomel mesylate, ganaplacide, DSM-265, cipargamin, artemisone, and combinations thereof. In some embodiments, the additional therapeutic agent is an agent for treatment of coronavirus. In some embodiments, the additional therapeutic agent is selected from a group consisting of IFX-1, FM-201, CYNK-001, DPP4-Fc, ranpirnase, nafamostat, LB-2, AM-1, antiviroporins, and combinations thereof. In some embodiments, the additional therapeutic agent is an agent for treatment of ebola virus. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI- 557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola Convalescent Plasma (ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino- 5Hpyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine -3,4-diol), favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (l-N,7-N-bis[3-( dimethylamino )propyl]-3,9-dimethylquinolino[8, 7-h]quinolone- l,7-diamine), JK-05, TKM-Ebola, ZMapp, rNAPc2, VRC-EBOADC076-00-VP, OS-2966, MVA-BN filo, brincidofovir, Vaxart adenovirus vector 5-based ebola vaccine, Ad26-ZEBOV, Filo Vax vaccine, GOVX-E301, GOVX-E302, ebola virus entry inhibitors (NPCl inhibitors), rVSV-EBOV, and combinations thereof. In some embodiments, the additional therapeutic agent is ZMapp, mAB114, REGEN-EB3, and combinations thereof. In some embodiments, the additional therapeutic agent is an agent for treatment of HCV. In some embodiments, the additional therapeutic agent is a HCV polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of sofosbuvir, GS-6620, PSI-938 , ribavirin, tegobuvir, radalbuvir, MK-0608, and combinations thereof. In some embodiments, the additional therapeutic agent is a HCV protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of such as GS-9256, vedroprevir, voxilaprevir, and combinations thereof. In some embodiments, the additional therapeutic agent is a NS5A inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ledipasvir, velpatasvir, and combinations thereof. In some embodiments, the additional therapeutic agent is an anti HBV agent. For example, in some embodiments, the additional therapeutic agent is tenofovir disoproxil fumarate and emtricitabine, or a combination thereof. Examples of additional anti HBV agents include but are not limited to alpha-hydroxytropolones, amdoxovir, antroquinonol, beta- hydroxycytosine nucleosides,, ARB-199, CCC-0975, ccc-R08, elvucitabine, ezetimibe, cyclosporin A, gentiopicrin (gentiopicroside), HH-003, hepalatide, JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV-205 (molixan, BAM-205), oligotide, mivotilate, feron, GST-HG-131, levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN- co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5), HSK-11- 2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-006IA, Hepuyinfen, DasKloster 0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, hepulantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, QL- 007sofosbuvir, ledipasvir, UB-551, and ZH-2N, and the compounds disclosed in US20150210682, (Roche), US 2016/0122344 (Roche), WO2015173164, WO2016023877, US2015252057A (Roche), WO16128335Al (Roche), WO16120186Al (Roche), US2016237090A (Roche), WO16107833Al (Roche), WO16107832Al (Roche), US2016176899A (Roche), WO16102438Al (Roche), WO16012470Al (Roche), US2016220586A (Roche), and US2015031687A (Roche). In some embodiments, the additional therapeutic agent is a HBV polymerase inhibitor. Examples of HBV DNA polymerase inhibitors include, but are not limited to, adefovir (HEPSERA®), emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, tenofovir exalidex, besifovir, entecavir (BARACLUDE®), entecavir maleate, telbivudine (TYZEKA®), filocilovir, pradefovir, clevudine, ribavirin, lamivudine (EPIVIRHBV®), phosphazide, famciclovir, fusolin, metacavir, SNC-019754, FMCA, AGX-1009, AR-11-04- 26, HIP-1302, tenofovir disoproxil aspartate, tenofovir disoproxil orotate, and HS-10234. In some embodiments, the additional therapeutic agent is a HBV capsid inhibitor. In some embodiments, the additional therapeutic agent is an agent for treatment of HIV. In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, HIV integrase inhibitors, entry inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV nonnucleoside reverse transcriptase inhibitors, acyclic nucleoside phosphonate analogues, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, HIV non- nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody drug conjugates, gene modifiers, gene editors (such as CRISPR/Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs), and cell therapies (such as chimeric antigen receptor T-cell, CAR-T, and engineered T cell receptors, TCR-T, autologous T cell therapies). In some embodiments, the additional therapeutic agent is an immunotherapeutic peptides such as tertomotide. In some embodiments, the additional therapeutic agent is a CCL26 gene inhibitor, such as mosedipimod. In some embodiments, the additional therapeutic agent is selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof. In some embodiments, the additional therapeutic agent is a PI3K inhibitor, for example idelalisib or duvelisib. In some examples, the additional therapeutic agent is a HIV combination drug. Examples of the HIV combination drugs include, but are not limited to ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); BIKTARVY® (bictegravir, emtricitabine, and tenofovir alafenamide); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine ); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUV ADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); SYMTUZA® (darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat); SYMFI™ (efavirenz, lamivudine, and tenofovir disoproxil fumarate); CIMDU™ (lamivudine and tenofovir disoproxil fumarate); tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; COMBIVIR® (zidovudine and lamivudine; AZT +3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA ®; lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT +3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil; dapivirine + levonorgestrel, dolutegravir + lamivudine, dolutegravir + emtricitabine + tenofovir alafenamide, elsulfavirine + emtricitabine + tenofovir disoproxil, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir , ritonavir, zidovudine and lamivudine. In some embodiments, the additional therapeutic agent is a HIV protease inhibitor. For example, in some embodiments the additional therapeutic agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, ASC-09, AEBL-2, MK-8718, GS-9500, GS- 1156, and combinations thereof. For example, in some embodiments the additional therapeutic agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat. In some examples, the additional therapeutic agent is selected from the group consisting of amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, TMC-310911, and combinations thereof. In some embodiments, the additional therapeutic agent is a HIV integrase inhibitor. For example, in some embodiment, the additional therapeutic agent is selected from the group consisting of raltegravir, elvitegravir, dolutegravir, abacavir, lamivudine, bictegravir and combinations thereof. In some embodiment, the additional therapeutic agent is bictegravir. In some examples, the additional therapeutic agent is selected from a group consisting of bictegravir, elvitegravir, curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, BMS- 986197, cabotegravir (long acting injectable), diketo quinolin-4-1 derivatives, integrase- LEDGF inhibitor, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC- 642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbenedisulfonic acid, T- 169, VM-3500, cabotegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is a HIV entry inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of enfuvirtide, maraviroc, and combinations thereof. Further examples of HIV entry inhibitors include, but are not limited to, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, DS-003 (BMS-599793), gp120 inhibitors, and CXCR4 inhibitors. Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, leronlimab (PRO-140), adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120/CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu). Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu). In some embodiments, the additional therapeutic agent is a HIV nucleoside reverse transcriptase inhibitors. In some embodiments, the additional therapeutic agent is a HIV non- nucleoside reverse transcriptase inhibitors. In some embodiments, the additional therapeutic agent is an acyclic nucleoside phosphonate analogue. In some embodiments, the additional therapeutic agent is a HIV capsid inhibitor. In some embodiments, the additional therapeutic agent is a HIV nucleoside or nucleotide inhibitor of reverse transcriptase. For example, the additional therapeutic agent is selected from the group consisting of adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX® and VIDEX EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, islatravir, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, rovafovir etalafenamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, KP- 1461, and combinations thereof. In some examples, the additional therapeutic agent is a HIV non-nucleoside or nonnucleotide inhibitor of reverse transcriptase. For example, the additional agent is selected from the group consisting of dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA, ACC-007, AIC-292, KM- 023, PC-1005, elsulfavirine rilp (VM-1500), combinations thereof. In some embodiments, the additional therapeutic agents are selected from ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUV ADA® (tenofovir disoproxil fumarate and emtricitabine; TDF +FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; TRIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT +3TC); EPZICOM® (LIVEXA ®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT +3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazid; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate. In some embodiments, the additional therapeutic agent is selected from the group consisting of colistin, valrubicin, icatibant, bepotastine, epirubicin, epoprosetnol, vapreotide, aprepitant, caspofungin, perphenazine, atazanavir, efavirenz, ritonavir, acyclovir, ganciclovir, penciclovir, prulifloxacin, bictegravir, nelfinavir, tegobuvi, nelfinavir, praziquantel, pitavastatin, perampanel, eszopiclone, and zopiclone. In some embodiments, the additional therapeutic agent is an inhibitor of Bruton tyrosine kinase (BTK, AGMXI, AT, ATK, BPK, IGHD3, IMDl, PSCTKl, XLA; NCBI Gene ID: 695). For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of (S )-6-amino-9-( l -(but-2-ynoy l)pyrrolidin-3-y 1)-7-( 4-phenoxypheny l)-7H- purin-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib (Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, AZD6738, calquence, danvatirsen, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from a group consisting of tirabrutinib, ibrutinib, acalabrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from a group consisting of tirabrutinib, ibrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is a receptor tyrosine kinase inhibitor (RTKI). In some embodiments, the additional therapeutic agent is tyrphostin A9 (A9). In some embodiments, the additional therapeutic agent is a TEK receptor tyrosine kinase inhibitor. In some embodiments, the additional therapeutic agent is abivertinib maleate (STI-5656). In some embodiments, the additional therapeutic agent is a tyrosine kinase inhibitor, such as masitinib. In some embodiments, the additional therapeutic agent is a sphingosine kinase-2 (sk2)inhibitor, such as opaganib. In some embodiments, the additional therapeutic agent is a kinase inhibitor such as pacritinib. In some embodiments, the additional therapeutic agent is an Axl tyrosine kinase receptor inhibitor, such as bemcentinib. In some embodiments, the additional therapeutic agent is a FYVE finger phosphoinositide kinase inhibitor. In some embodiments, the additional therapeutic agent is a checkpoint kinase inhibitor, such as prexasertib. In some embodiments, the additional therapeutic agent is a MAP kinase inhibitor, such as KTH-222, ATI-450. In some embodiments, the additional therapeutic agent is a mTOR inhibitor, such as sirolimus. In some embodiments, the additional therapeutic agent is a pi3k/ mTOR inhibitor such as dactolisib. In some embodiments, the additional therapeutic agent is a Hsp90 inhibitor, such as ganetespib, ADX-1612. In some embodiments, the additional therapeutic agent is an MEK inhibitor such as ATR-002. In some embodiments, the additional therapeutic agent is a topoisomerase II inhibitor, such as etoposide. In some embodiments, the additional therapeutic agent is an exportin 1 inhibitor, such as selinexor, verdinexor. In some embodiments, the additional therapeutic agent is a dual inhibitor of PARPl/2 and Tankyrase 1/2, such as 2X-121. In some embodiments, the additional therapeutic agent is a cyclin dependent kinase inhibitor, such as CYC-065, CYC-202. In some embodiments, the additional therapeutic agent is a cytosine DNA methyltransferase inhibitor, such as decitabine. In some embodiments, the additional therapeutic agent is a DHFR inhibitor, such as methotrexate. In some embodiments, the additional therapeutic agent is a small ubiquitin related modifier inhibitor, such as TAK- 981. In some embodiments, the additional therapeutic agent is an integrin agonist such as 7HP- 349. In some embodiments, the additional therapeutic agent is a BET inhibitor, such as apabetalone. In some embodiments, the additional therapeutic agent is a BRD4 inhibitor, such as CPI-0610, ABBV-744. In some embodiments, the additional therapeutic agent is a ERl inhibitor, such as toremifene. In some embodiments, the additional therapeutic agent is a KRAS inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of AMG-510, COTI-219, MRTX-1257, ARS-3248, ARS-853, WDB-178, BI-3406, BI-1701963, ARS-1620 (Gl2C), SML-8-73-1 (Gl2C), Compound 3144 (Gl2D), Kobe0065/2602 (Ras GTP), RT11, MRTX-849 (Gl2C) and K-Ras(Gl2D)-selective inhibitory peptides, including KRpep-2 (Ac-RRCPLYISYDPVCRR-NH2), KRpep-2d (Ac-RRRRCPL YISYDPVCRRRR-NH2), and combinations thereof. In some embodiments, the additional therapeutic agent is an alkylating agent, such as melphalan. In some embodiments, the additional therapeutic agent is a proteasome inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from a group consisting of ixazomib, carfilzomib, marizomib, bortezomib, and combinations thereof. In some embodiments, the additional therapeutic agent is carfilzomib. In some embodiments, the additional therapeutic agent is a vaccine. For example, in some embodiments, the additional therapeutic agent is a DNA vaccine, RNA vaccine, live attenuated vaccine, therapeutic vaccine, prophylactic vaccine, protein based vaccine, or a combination thereof. In some embodiments, the additional therapeutic agent is mRNA-1273. In some embodiments, the additional therapeutic agent is INO-4800 or INO-4700. In some embodiments, the additional therapeutic agent is live-attenuated RSV vaccine MEDI-559, human monoclonal antibody REGN2222 against RSV, palivizumab, respiratory syncytial virus immune globulin, intravenous (RSV-IGIV), and combinations thereof. In some embodiments, the additional therapeutic agent is a HBV vaccine, for example pediarix, engerix-B, and recombivax HB. In some embodiments, the additional therapeutic agent is a VZV vaccine, for example zostavax and varivax. In some embodiments, the additional therapeutic agent is a HPV vaccine, for example cervarix, gardasil 9, and gardasil. In some embodiments, the additional therapeutic agent is an influenza virus vaccine. For example, a (i) monovalent vaccine for influenza A (e.g. influenza A (H5Nl) virus monovalent vaccine and influenza A (HlNl) 2009 virus monovalent vaccines), (ii) trivalent vaccine for influenza A and B viruses (e.g. Afluria, Agriflu, Fluad, Fluarix, Flublok, Flucelvax, FluLaval, Fluvirin, and Fluzone), and (iii) quadrivalent vaccine for influenza A and B viruses (FluMist, Fluarix, Fluzone, and FluLaval). In some embodiments, the additional therapeutic agent is a human adenovirus vaccine (e.g. Adenovirus Type 4 and Type 7 Vaccine, Live, Oral). In some embodiments, the additional therapeutic agent is a rotavirus vaccine (e.g. Rotarix for rotavirus serotype G 1, G3, G4, or G9 and RotaTeq for rotavirus serotype Gl, G2, G3, or G4). In some embodiments, the additional therapeutic agent is a hepatitis A virus vaccine (e.g. Havrix and Vaqta). In some embodiments, the additional therapeutic agent is poliovirus vaccines (e.g. Kinrix, Quadracel, and Ipol). In some embodiments, the additional therapeutic agent is a yellow fever virus vaccine (e.g. YFVax). In some embodiments, the additional therapeutic agent is a Japanese encephalitis virus vaccines ( e.g. Ixiaro and JE-Vax). In some embodiments, the additional therapeutic agent is a measles vaccine (e.g. M-M-R II and ProQuad). In some embodiments, the additional therapeutic agent is a mumps vaccine (e.g. M-M-R II and ProQuad). In some embodiments, the additional therapeutic agent is a rubella vaccine (e.g. M-M-R II and ProQuad). In some embodiments, the additional therapeutic agent is a varicella vaccine (e.g. ProQuad). In some embodiments, the additional therapeutic agent is a rabies vaccine (e.g. Imovax and RabAvert). In some embodiments, the additional therapeutic agent is a variola virus (smallpox) vaccine (ACAM2000). In some embodiments, the additional therapeutic agent is a and hepatitis E virus (HEV) vaccine (e.g. HEV239). In some embodiments, the additional therapeutic agent is a 2019-nCov vaccine. In some embodiments, the additional therapeutic agent is Ad5-nCoV. In some embodiments, the additional therapeutic agents in the mRNA vaccine BNT-162. In some embodiments, the additional therapeutic agent is a BCG vaccine. In some embodiments, the additional therapeutic agent is Pfizer-BioNTech COVID-19 vaccine. In some embodiments, the additional therapeutic agent is Moderna Covid-19 vaccine. In some embodiments, the additional therapeutic agent is AZD1222 (astrazeneca Covid-19 vaccine). In some embodiments, the additional therapeutic agent is a poliovirus vaccine, e.g. OPV. In some embodiments, the additional therapeutic agent is BNT162al, BNT162bl, BNT162b2, or BNT162c2 (prime/boost, single or multiple doses). In some embodiments, the additional agent is AZD1222 (ChAdOxl nCov-19) vaccine. In some embodiments, the additional agent is Gam-COVID-Vac (Ad26), Gam-COVID-Vac (Ad5), Gam-COVID-Vac (Ad26 Prime-boost), Covax-19, or Naso VAX. In some embodiments, the additional therapeutic agents is LUNAR-COV19 (ARCT-021). In some embodiments, the additional agent is TerraCoV2. In some embodiments, the additional agent is COVID-19 S-Trimer. In some embodiments, the additional agent is TNX-1810, TNX-1820, or TNX-1830. In some embodiments, the additional agent is VaxiPatch COVID-19 vaccine. In some embodiments, the additional agent is VBI-2901. In some embodiments, the additional agent is VLA-2001. In some embodiments, the additional agent is exoVACC-SARS-CoV2CoV-2. In some embodiments, the additional agent is SCB-2019. In some embodiments, the additional agent is MV-SARS-CoV-2. In some embodiments, the additional agent is NVX-CoV2373, Matrix-Mor NVX-CoV2373. In some embodiments, the additional agent is BBV152A, B, C, PicoVacc, KBP-COVID-19, MF59 adjuvanted SARS-CoV-2 Sclamp, MVC-COV1901, SCB-2019 (COVID-19 S-Trimer + CpG1018+AS03), TMV-083, V-591, VPM1002, or V-SARS. In some embodiments, the additional therapeutic agent is an antibody, for example a monoclonal antibody. For example, the additional therapeutic agent is an antibody against 2019-nCov selected from the group consisting of the Regeneron antibodies, the Wuxi Antibodies, the Vir Biotechnology Antibodies, antibodies that target the SARS-CoV-2 spike protein, antibodies that can neutralize SARS-CoV-2 (SARS-CoV-2 neutralizing antibodies), and combinations thereof. In some embodiments, the additional therapeutic agent is anti-SARS CoV antibody CR- 3022. In some embodiments, the additional therapeutic agent is aPD-1 antibody. In some embodiments, the additional therapeutic agent is anti-IL-6R mAb. For example, the additional therapeutic agent is TZLS-501 or siltuximab. In some embodiments, the additional therapeutic agent is an antibody that targets specific sites on ACE2. In some embodiments, the additional therapeutic agent is a polypeptide targeting SARS-CoV-2 spike protein (S-protein). In some embodiments, the additional therapeutic agent is a virus suppressing factor (VSF, HzVSFv13). In some embodiments, the additional therapeutic agent is an anti-CD147 antibody. For example, the additional therapeutic agent is meplazumab. In some embodiments, the additional therapeutic agent is a phosphodiesterase type 4 (PDE4) or phosphodiesterase type 5 (PDE5) inhibitor. In some embodiments, the additional therapeutic agent is a PDE5 inhibitor, for example, the additional therapeutic agent is sildenafil. In some embodiments, the additional therapeutic agent is a PDE4 inhibitor, for example, the additional therapeutic agent is brilacidin. In some embodiments, the additional therapeutic agent is an agent targeting NKGA2. In some embodiments, the additional therapeutic agent is a checkpoint inhibitor. In some embodiments, the additional therapeutic agent is NKG2 A B activating NK receptor antagonist, such as monalizumab. In some examples, the additional therapeutic agent is a CTLA-4 checkpoint inhibitor, such as BPI-002. In some embodiments, the additional therapeutic agent is a CD73 antagonist, such as CPI-006. In some embodiments, the additional therapeutic agent is recombinant cytokine gene derived protein injection. In some embodiments, the additional therapeutic agent is a polymerase inhibitor. In some embodiments, the additional therapeutic agent is a DNA polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is cidofovir. In some embodiments, the additional therapeutic agent is lamivudine. In some embodiments, the additional therapeutic agent is a RNA polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ribavirin, favipiravir, lamivudine, pimodivir and combination thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of ribavirin, favipiravir, pimodivir and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of lopinavir, ritonavir, interferon-alpha-2b, ritonavir, arbidol, hydroxychloroquine, darunavir and cobicistat, abidol hydrochloride, oseltamivir, litonavir, emtricitabine, tenofovir alafenamide fumarate, baloxavir marboxil, ruxolitinib, and combinations thereof. In some embodiments, the additional therapeutic agent is a beta-catenin inhibitor. For example, the additional therapeutic agent is tetrandrine. In some embodiments, the additional therapeutic agent is a trypsin inhibitor, for example the additional therapeutic agent is ulinastatin. In some embodiments, the additional therapeutic agent is TAK-671. In some embodiments, the additional therapeutic agent is selected from the group consisting of ABBV-744, dBET6, MZl, CPI-0610, Sapanisertib, Rapamycin, Zotatifin, Verdinexor, Chloroquine, Dabrafenib, WDB002, Sanglifehrin A, FK-506, Pevonedistat, Ternatin 4, 4E2RCat, Tomivosertib, PS3061, IHVR-19029, Captopril, Lisinopril, Camostat, N afamostat, Chloramphenicol, Tigecycline, Linezolid, and combinations thereof. In some embodiments, the additional therapeutic agent is selected form the group consisting of JQ-1, RVX-208,silmitasertib, TMCB, apicidin, valproic acid, Bafilomycin Al, E- 52862, PD-144418, RS-PPCC, PD28, haloperidol, entacapone, indomethacin, Metformin, Ponatinib, H-89, Merimepodib, Migalastat, Mycophenolic acid, Ribavirin, XL413, CCT 365623, Midostaurin, Ruxolitinib, ZINC I 775962367, ZINC4326719, ZINC4511851, ZINC95559591, AC-55541, AZ8838, Daunorubicin, GB llO, S-verapamil, AZ3451, and combinations thereof. In some embodiments, the additional therapeutic agent is selected form a group consisting of tilorone, cyclosporine, loperamide, mefloquine, amodiaquine, proscillaridin, digitoxin, digoxin, hexachlorophene, hydroxyprogesterone caproate, salinomycin, ouabain, cepharanthine, ciclesonide, oxyclozanide, anidulafungin, gilteritinib, berbamine, tetrandrine, abemaciclib, ivacaftor, bazedoxifene, niclosamide, eltrombopag, and combinations thereof. In some embodiments, the additional therapeutic agent is a drug targeting the coronavirus main protease 3CLpro (e.g. lopinavir). In some embodiments the additional therapeutic agent is a drug targeting the papain-like protease PLpro (e.g., lopinavir). In some examples, the additional therapeutic agent is a drug that functions as a virus-host cell fusion inhibitor to prevent viral entry into host cells (e.g. arbidol). In some embodiments, the additional therapeutic agent is a TMPRSS2 inhibitor (e.g. camostat mesylate). In some embodiments, the additional therapeutic agent is a serine protease inhibitor, such as LB ll 48, upamostat, RHB-107, or alpha- I antitrypsin. In some embodiments, the additional therapeutic agent is an inhibitor of neutrophil elastase, such as lonodelestat. In some embodiments, the additional therapeutic agent is an a-ketoamide. In some examples, the additional therapeutic agent is a poly-ADP-ribose polymerase 1 (PARPl) inhibitor, for example, the additional therapeutic agent is CVL218. In some embodiments, the additional therapeutic agent is selected from the group consisting of 6' -fluorinated aristeromycin analogues, acyclovir fleximer analogues, disulfiram, thiopurine analogues, ASC09F, GC376, GC813, phenylisoserine derivatives, neuroiminidase inhibitor analogues, pyrithiobac derivatives, bananins and 5-hydroxychromone derivatives, SSYAl0-001, griffithsin, HR2P-Ml, HR2P-M2, P21S10, Dihydrotanshinone E-64-C and E-64- D, OC43-HR2P, MERS-5HB, 229E-HR1P, 229E-HR2P, resveratrol, l-thia-4- azaspiro[4.5]decan-3-one derivatives, gemcitabine hydrochloride, loperamide, recombinant interferons, cyclosporine A, alisporivir, imatinib mesylate, dasatinib, selumetinib, trametinib, rapamycin, saracatinib, chlorpromazine, triflupromazine, fluphenazine, thiethylperazine, promethazine, cyclophilin inhibitors, Kll 777, camostat, k22, teicoplanin derivatives, benzo- heterocyclic amine derivatives N30, mycophenolic acid, silvestrol, and combinations thereof. In some embodiments, the additional therapeutic agent is an antibody. In some embodiments, the additional therapeutic agent is an antibody that binds to a coronavirus, for example an antibody that binds to SARS or MERS. In some embodiments, the additional therapeutic agent is a of 2019-nCoV virus antibody. In some embodiments, the additional therapeutic agent is LY-CoV555. In some embodiments, the additional therapeutic agent is S309. In some embodiments, the additional therapeutic agent is SAB-185. In some embodiments, the additional therapeutic agent is CB6. In some embodiments, the additional therapeutic agent is STI-1499. In some embodiments, the additional therapeutic agent is JS016. In some embodiments, the additional therapeutic agent is VNAR. In some embodiments, the additional therapeutic agent is VIR-7832 and/or VIR- 7831. In some embodiments, the additional therapeutic agent is REGN-COV2 (REGN10933 + RGN10987) In some embodiments, the additional therapeutic agent is BAT2020, BAT2019. In some embodiments, the additional therapeutic agent is 47D 11. In some embodiments, the additional therapeutic agent is COVI-SHIELD. In some embodiments, the additional therapeutic agent is BRII-196, BRII-198. In some embodiments, the additional therapeutic agent is INM-005, SCTA0l, TY-027, XAV-19. Compositions of the invention are also used in combination with other active ingredients. For the treatment of 2019-nCoV virus infections, preferably, the other active therapeutic agent is active against coronavirus infections, for example 2019-nCoV virus infections. The compounds and compositions of the present invention are also intended for use with general care provided patients with 2019-nCoV viral infections, including parenteral fluids (including dextrose saline and Ringer's lactate) and nutrition, antibiotic (including metronidazole and cephalosporin antibiotics, such as ceftriaxone and cefuroxime) and/or antifungal prophylaxis, fever and pain medication, antiemetic (such as metoclopramide) and/or antidiarrheal agents, vitamin and mineral supplements (including Vitamin Kand zinc sulfate), anti-inflammatory agents ( such as ibuprofen or steroids), corticosteroids such as methylprednisolone, immonumodulatory medications (eg interferon), other small molecule or biologics antiviral agents targeting 2019-nCoV (such as but not limited to lopinavir/ritonavir, EIDD-1931, favipiravir, ribavirine, neutralizing antibodies, etc), vaccines, pain medications, and medications for other common diseases in the patient population, such anti-malarial agents (including artemether and artesunate-lumefantrine combination therapy), typhoid (including quinolone antibiotics, such as ciprofloxacin, macrolide antibiotics, such as azithromycin, cephalosporin antibiotics, such as ceftriaxone, or aminopenicillins, such as ampicillin), or shigellosis. In some embodiments, the additional therapeutic agent is dihydroartemisinin/piperaquine. In some embodiments, the additional therapeutic agent is a corticosteroid, for example the additional therapeutic agent is ciclesonide. In some embodiments, the compounds disclosed herein are used in combination with amoxicillin/clavulanate, trimethoprim/sulfamethoxazole, cholecalciferol, vitamin C, prednisone, mometasone, or budenoside. In some embodiments, the compounds disclosed herein are used in combination with inhibitors such as Panaphix (PAX-1), which inhibit production of pro-inflammatory cytokines. In some embodiments, the compounds disclosed herein are used in combination with inhibitors such as NCP-112 which inhibit excessive immune response such as cytokine storm. In some embodiments, the additional therapeutic agent is an antifungal agent, for example itraconazole or 17-0H- itraconazole. In some examples, the additional therapeutic agent is an immunomodulator. Examples of immune-based therapies include toll-like receptors modulators such as tlrl, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlrlO, tlrll, tlr12, and tlr13; programmed cell death protein 1 (Pd-1) modulators; programmed death-ligand 1 (Pd-Ll) modulators; IL-15 modulators; DermaVir; interleukin-7; plaquenil (hydroxychloroquine); proleukin (aldesleukin, IL-2); interferon alfa; interferon alfa-2b; interferon alfa-n3; pegylated interferon alfa; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; polymer polyethyleneimine (PEI); gepon; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15/Fc fusion protein, AM-0015, ALT-803, NIZ-985, NKTR-255, NKTR-262, NKTR-214, normferon, peginterferon alfa-2a, peginterferon alfa-2b, recombinant interleukin-15, Xmab-24306, RPI-MN, STING modulators, RIG-I modulators, NOD2 modulators, SB-9200, and IR-103. In some embodiments, the additional therapeutic agent is fingolimod, leflunomide, or a combination thereof. In some embodiments, the additional therapeutic agent is thalidomide. In some embodiments, the additional therapeutic agent is CD24Fc. In some embodiments, the additional therapeutic agent is a type I IL-1 receptor antagonists, such as anakinra. In some embodiments, the additional therapeutic agent is a TLR4 antagonist, such as EB-05. In some embodiments, the additional therapeutic agent is nivolumab, efineptakin alfa, lactoferrin, ozanimod, astegolimab (MSTT1041A, RG-6149), or UTTR1147 A. In some embodiments, the additional therapeutic agent is Ampligen. In some embodiments, the additional therapeutic agent is lefitolimod. In some embodiments, the additional therapeutic agent is RPH-104. In some embodiments, the additional therapeutic agent is canakinumab. In some embodiments, the additional therapeutic agent is an IL-33 ligand inhibitor such as MEDI3506. In some embodiments, the additional therapeutic agent is an IL-5 receptor antagonist, such as mepolizumab. In some embodiments, the additional therapeutic agent is an IL-12 inhibitor, such as apilimod. In some embodiments, the additional therapeutic agent is a IL-15 receptor agonist, such as N-803. In some embodiments, the additional therapeutic agent is an interferon gamma ligand inhibitor, such as emapalumab. In some embodiments, the additional therapeutic agent is an IL-6 inhibitor, for example tocilizumab, sarilumab, or a combination thereof. In some embodiments, the additional therapeutic agent is tocilizumab. In some embodiments, the additional therapeutic agent is an IL-6 inhibitor, for example tocilizumab, sarilumab, olokizumab, sirukumab, clazakizumab, levilimab or a combination thereof. In some embodiments, the additional therapeutic agent is a nicotinamide phosphoribosyltransferase inhibitors. For example, the additional therapeutic agent is enamptcumab. In some embodiments, the additional therapeutic agent is a di peptidase 1 (DPEP-1) inhibitor. For example, the additional therapeutic agent is Metablok (LSALT peptide). In some embodiments, the additional therapeutic agent is an anti-TNF inhibitor. For example, the additional therapeutic agent is adalimumab, etanercept, golirnurnab, infliximab, or a combination thereof. In some embodiments, the additional therapeutic agent is a TNF alpha ligand inhibitor, such as XPro1595. In some embodiments, the additional therapeutic agent is a JAK inhibitor, for example the additional therapeutic agent is baricitinib, filgotinib, olumiant, or a combination thereof. In some examples, the additional therapeutic agent is jaktinib. In some embodiments, the additional therapeutic agent is tofacitinib or TD-0903. In some embodiments, the additional therapeutic agent is an inflammation inhibitor, for example pirfenidone. In some embodiments, the additional therapeutic agent is L YT-100. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, such as dociparstat sodium. In some embodiments, the additional agent is used in the treatment of septic shock, such as nangibotide. In some embodiments, the additional therapeutic agent is a CCRl antagonist, such as MLN-3897. In some embodiments, the additional therapeutic agent targets IKKβ and NFKβ, such as OP-101. In some embodiment, the additional therapeutic agent is a glucocorticoid receptor agonist, such as hydrocortisone or dexamethasone. In some embodiments, the additional therapeutic agent is an immunosuppressant, such as tacrolimus, BXT-10, ibudilast, FP-025, apremilast, abatacept, crizanlizumab, itolizumab, bardoxolone methyl, M-5049. In some embodiments, the additional therapeutic agent is a RIP-1 kinase inhibitor, such as DNL-758. In some embodiments, the additional therapeutic agent is a IL-8 receptor antagonist, such as BMS-986253 (HuMax-IL8). In some embodiments, the additional therapeutic agent is a CD 14 inhibitor, such as IC-14. In some embodiments, the additional therapeutic agent is a Dihydroorotate dehydrogenase (DHODH) inhibitor, such as brequinar, PCT-299. In some embodiments, the additional therapeutic is anti-fibrotic, such as RT- 1840,nintedanib, GB-0139, nintedanib, pamrevlumab. In some embodiments, the additional therapeutic is a hepatocyte growth factor (HGF) mimetic, such as SNV-003 (ANG-3777). In some embodiments, the additional therapeutic agent is an A3 adenosine receptor (A3AR) antagonist, for example the additional therapeutic agent is piclidenoson. In some embodiments, the additional therapeutic agent is an antibiotic for secondary bacterial pneumonia. For example, the additional therapeutic agent is macrolide antibiotics (e.g. azithromycin, clarithromycin, and mycoplasma pneumoniae), fluoroquinolones (e.g. ciprofloxacin and levofloxacin), tetracyclines (e.g. doxycycline and tetracycline), or a combination thereof. In some embodiments, the additional therapeutic agent is XEL 1004. In some embodiments, the additional therapeutic agent is eravacycline. In some embodiments, the compounds disclosed herein are used in combination with pneumonia standard of care (see e.g. Pediatric Community Pneumonia Guidelines, CID 2011:53 (1 October)). Treatment for pneumonia generally involves curing the infection and preventing complications. Specific treatment will depend on several factors, including the type and severity of pneumonia, age and overall health of the individuals. The options include: (i) antibiotics, (ii) cough medicine, and (iii) fever reducers/pain relievers (for e.g. aspirin, ibuprofen (Advil, Motrin IB, others) and acetaminophen (Tylenol, others)). In some embodiments, the additional therapeutic agent is bromhexine anti-cough. In some embodiments, the compounds disclosed herein are used in combination with immunoglobulin from cured COVID-19 patients. In some embodiments, the compounds disclosed herein are used in combination with plasma transfusion. In some examples, the compounds disclosed herein are used in combination with TAK-888 (anti-SARS-CoV-2 polyclonal hyperimmune globulin (H-IG)). In some embodiments, the compounds disclosed herein are used in combination with COVID-19 convalescent plasma or immunoglobulin. In some embodiments, the compounds described herein are used in combination with COVID- EIG or COVID-HIG. In some embodiments, the compounds disclosed herein are used in combination with stem cells. For example, in some embodiments, the compounds disclosed herein are used in combination with MultiStem or Remestemcel-L (mesenchymal stem cells). In some embodiments, the compounds described herein are used in combination with allogenic mesenchymal-like cells, for example in combination with PLX cells. In some embodiments, the compounds described herein are used in combination with allogenic cell therapy, for example in combination with CK-0802. In some embodiments, the compounds described herein are used in combination with Pluristem or ACT-20. In some examples, the additional therapeutic agent is an TLR agonist. Examples of TLR agonists include, but are not limited to, vesatolimod (GS-9620), GS-986, IR-103, lefitolimod, tilsotolimod, rintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, telratolimod.RO-7020531. In some embodiments the additional therapeutic agent is PUL-042. In some embodiments, the additional therapeutic agent is polyinosinic-polycytidylic acid (poly I:C). In some examples, the additional therapeutic agent is selected from the group consisting of bortezomid, flurazepam, ponatinib, sorafenib, paramethasone, clocortolone, flucloxacillin, sertindole, clevidipine, atorvastatin, cinolazepam, clofazimine, fosaprepitant, and combinations thereof. In some examples, the additional therapeutic agent is simvastatin or rosuvastatin. In some examples, the additional therapeutic agent is carrimycin, suramin, triazavirin, dipyridamole, bevacizumab, meplazumab, GD31 (rhizobium), NLRP inflammasome inhibitor, or a-ketoamine. In some embodiments, the additional therapeutic agent is recombinant human angiotensin-converting enzyme 2 (rhACE2). In some embodiments, the additional therapeutic agent is viral macrophage inflammatory protein (vMIP). In some embodiments, the additional therapeutic agent is a recombinant human angiotensin-converting enzyme 2 (rhACE2), for example APN-01. In some embodiments, the additional therapeutic agent is an angiotensin II receptor agonist. In some examples, the additional therapeutic agent is a partial agonist of A T2 or a partial antagonist of AT 1. In some embodiments, the additional therapeutic agent is L-163491. In some embodiments, the additional therapeutic agent is ACE2-Fc fusion protein, for example the additional therapeutic agent is STI-4398. In some embodiments, the additional therapeutic agent is valsartan, losartan, candesartan, eprosartan, irbesartan, olmesartan. In some embodiments, the additional therapeutic agent is VP-01, TXA-127. In some embodiments, the additional therapeutic agent is telmisartan. In some embodiments, the additional therapeutic agent is an ACE inhibitor, such as ramipril, captopril, enalapril, or lisonopril. In some embodiments, the additional therapeutic agent is an aldose reductase inhibitor, such as AT-001. In some embodiments, the additional therapeutic agent is a platelet inhibitor. For example, the additional therapeutic agent is dipyridamole. In some embodiments, the additional therapeutic agent is an anti-coagulant, such as heparins (heparin and low molecular weight heparin), aspirin, apixaban, dabigatran, edoxaban, argatroban, enoxaparin, fondaparinux. In some embodiments, the additional therapeutic agent is a tissue factor inhibitor, such as AB-201. In some embodiments, the additional therapeutic is a Factor Xlla antagonist, such as garadacimab. In some embodiments, the additional therapeutic agent is a VE-PTP inhibitor, such as razuprotafib. In some embodiments, the additional therapeutic agent is a VIP 2 receptor agonist, such as PB-1046. In some embodiments, the additional therapeutic agent is an anti-thrombotic, such as defibrotide, rivaroxaban, alteplase, tirofiban, clopidogrel, prasugrel, bemiparin, bivalirudin, sulodexide, tranexamic acid. In some embodiments, the additional therapeutic agent is a vasodilator, such as iloprost, ventaprost, vazegepant, angiotensin 1-7, ambrisentan, NORS, pentoxifylline, propranolol, RESP301, sodium nitrite, TRV-027. In some embodiments, the additional therapeutic agent is a blood clotting modulator, such as lanadelumab. In some embodiments, the additional therapeutic agent is a diuretic, such as an aldosterone antagonist, such as spironolactone. In some embodiments, the additional therapeutic agent is antihypoxic, such as trans-sodium crocetinate. In some embodiments, the additional therapeutic agent is MK-5475. In some embodiments, the additional therapeutic agent is a hypoxia-inducible factor (HF) prolyl hydroxylase-2 (PHD-2) inhibitor such as desidustat or vadadustat. In some embodiments, the additional therapeutic agent is a renin inhibitor, such as aliskiren. In some embodiments, the additional therapeutic agent is a calcium channel inhibitor such as nifedipine. In some embodiments, the additional therapeutic agent is a chelating agent, such as desferal, deferiprone, deferoxamine. In some embodiments, the additional therapeutic agent is a retinoic acid receptor agonist, such as isotretinoin or fenretinide. In some embodiments, the additional therapeutic agent is an AMPA receptor modulator, such as traneurocin. In some embodiments, the additional therapeutic agent is a human antimicrobial peptide, such as LL-37i. In some embodiments, the additional therapeutic agent is a microbiome modulator, such as EDP-1815, KB-109. In some embodiments, the additional therapeutic agent is an estrogen receptor antagonist, such as tamoxifen. In some embodiments, the additional therapeutic agent is an androgen receptor antagonist such as bicalutamide, enzalutamide. In some embodiments, the additional therapeutic agent is a GNRH receptor antagonist, such as degarelix. In some embodiments, the additional therapeutic agent is a sex hormone modulator, such as dutasteride. In some embodiments, the additional therapeutic agent is a calpain inhibitor, such as BLD-2660. In some embodiments, the additional therapeutic agent is a GM-CSF ligand inhibitor such as gimsilumab, lenzilumab, namilumab, TJM2 or otilimab. In some embodiments, the additional therapeutic agent is a GM-CSF receptor antagonist, such as mavrilimumab. In some embodiments, the additional therapeutic agent is a GM-CSF receptor agonist, such as sargramostim. In some embodiments, the additional therapeutic agent is an alpha 1 adrenoreceptor antagonist such as prazosin. In some embodiments, the additional therapeutic agent is a neuropilin 2 inhibitor, such as ATYR-1923. In some embodiments, the additional therapeutic agent is an activated calcium (CRAC) channel inhibitor, such as CM- 4620. In some embodiments, the additional therapeutic agent is a proto-oncogene Mas agonist, such as BIO101. In some embodiments, the additional therapeutic agent is a DPP4 inhibitor, such as saxagliptin, sitagliptin, alogliptin, linagliptin. In some embodiments, the additional therapeutic agent is a sodium glucose cotransporter type 2 (SGLT-2) inhibitor such as dapagliflozin propanediol. In some embodiments, the additional therapeutic agent is a fractalkine receptor inhibitor such as KAND-567. In some embodiments, the additional therapeutic agent is an alpha2-receptor agonist. For example, the additional therapeutic agent is dexmedetomidine. In some embodiments, the additional therapeutic agent is a mCBM40 (multivalent carbohydrate-binding module Family 40 domain) product, for example the additional therapeutic agent is neumifil. In some embodiments, the additional therapeutic agent is a histamine H1 receptor antagonist, such as ebastine. In some embodiments, the additional therapeutic agent is tranilast. In some embodiments, the additional therapeutic agent is a histamine H2 receptor antagonist. In some embodiments, the additional therapeutic agent is famotidine. In some embodiments, the additional therapeutic agent is anti-histamine. In some embodiments, the additional therapeutic agent is cloroperastine or clemastine. In some embodiments, the additional therapeutic agent is a vasoactive intestinal peptide receptor 1 agonists, such as aviptadil. In some embodiments, the additional therapeutic agent is a drug that treats acute respiratory distress syndrome (ARDS). In some embodiments, the additional therapeutic agent is a peptide, for example the additional therapeutic agent is BIO-11006. In some embodiments, the additional therapeutic agent is aliposomal formulation, for example the additional therapeutic agent is LEAF-4L6715, LEAF-4L7520. In some embodiments, the additional therapeutic agent is a respiratory stimulant, such as almitrine. In some embodiments, the additional therapeutic agent is a bronchodilator, such as brensocatib or formoterol. In some embodiments, the additional therapeutic agent is an anti-LIGHT antibody, such as CERC-002. In some embodiments, the additional therapeutic agent is a CRAC (calcium release-activated calcium) channel inhibitor, such as CM-4620-IE. In some embodiments, the compounds described herein are used in combination with respiratory-specific small interfering RNA therapies. In some embodiments, these therapies are delivered by a nebulizer. In some embodiments, the additional therapeutic agent is a vimentin modulators. For example, the additional therapeutic agent is pritumumab. In some embodiments, the additional therapeutic agent is hzVSF-v13. In some embodiments, the additional therapeutic agent is a modulator of Nspl5 (nonstructural protein 15) such as benzopurpurin B, C-467929, C-473872, NSC-306711 and N-65828. In some embodiments, the additional therapeutic agent is a xanthine dehydrogenase inhibitor, such as oxypurinol (XRx-101). In some embodiments, the additional therapeutic agent is a cathepsin L-inhibitor. In some embodiments, the additional therapeutic agent is a cathepsin inhibitor, such as VBY-825 or ONO-5334. In some embodiments, the additional therapeutic agent is a Transforming growth factor beta (TGF-~) inhibitor. For example, the additional therapeutic agent is OT-101. In some embodiments, the additional therapeutic agent is a N-methyl-D-aspartate (NMDA) receptor antagonist. For example, the additional therapeutic agent is ifenprodil. In some embodiments, the additional therapeutic agent is a glycolysis inhibitor. For example, the additional therapeutic agent is WP-1122. In some embodiments, the additional therapeutic is a Leukotriene D4 antagonist, such as montelukast. In some embodiments, the additional therapeutic is a Leukotriene BLT receptor antagonist, such as ebselen. In some embodiments, the additional therapeutic is a tubulin inhibitor, such as VERU-111 or colchicine. In some embodiments, the additional therapeutic agent is a glucosylceramide synthase inhibitor such as miglustat. In some embodiments, the additional therapeutic agent is a Nrf2 activator, such as PB 125. In some embodiments, the additional therapeutic agent is a Rev protein modulator, such as ABX464. In some embodiments, the additional therapeutic agent is a nuclear import inhibitor, such as iCP-NI (CV-15). In some embodiments, the additional therapeutic agent is a cannabinoid CB2 receptor agonist, such as PPP003. In some embodiments, the additional therapeutic agent is a dehydropeptidase-1 modulator, such as LSALT peptide. In some embodiments, the additional therapeutic agent is a cyclooxygenase inhibitor, such as celecoxib, naproxen, aspirin/dipyridamole. In some embodiments, the additional therapeutic agent is an antitoxin such as CAL02. In some embodiments, the additional therapeutic agent is a nitric oxide stimulant, such as GLS-1200. In some embodiments, the additional therapeutic agent is an apelin receptor agonist, such as CB-5064. In some embodiments, the additional therapeutic agent is a complement inhibitor, such as ravulizumab. In some embodiments, the additional therapeutic agent is a colony-stimulating factor 1 receptor (CSFlR) inhibitor, such as avdoralimab. In some embodiments, the additional therapeutic agent is a complement C5 factor inhibitor, such as eculizumab, zilucoplan, and C5a such as BDB-001, IFX-1, advoralimab, In some embodiments, the additional therapeutic agent is a complement C 1 s inhibitor, such as cone stat alpha. In some embodiments, the additional therapeutic agent is a C3 inhibitor, such as APL-9 or AMY-101. In some embodiments, the additional therapeutic agent is an anti-C5aR antibody, such as advoralimab. In some embodiments, the additional therapeutic agent is an anti-elongation factor 1 alpha 2 inhibitor, such as plitidepsin. In some embodiments, the additional therapeutic agent is an angiopoietin ligand-2 inhibitor, such as L Y-3127804. In some embodiments, the additional therapeutic agent is a lysine specific histone demethylase 1 inhibitor, such as vafidemstat. In some embodiments, the additional therapeutic agent is a hyaluronan inhibitor. In some embodiments, the additional therapeutic agent is a proton pump inhibitor, such as omeprazole. In some embodiments, the additional therapeutic agent is an anti-viroporin therapeutic. For example, the additional therapeutic agent is BIT-314 or BIT-225. In some embodiments, the additional therapeutic agent is coronavirus E protein inhibitor. For example, the additional therapeutic agent is BIT-009. Further examples of additional therapeutic agents include those described in WO-2004112687, WO-2006135978, WO-2018145148, and WO-2009018609. In some embodiments, the compounds disclosed herein are used in combination with cell therapy, such as allogeneic natural killer cells, BM-Allo.MSC, CAStem, IL-15-NK cells, NKG2D- CAR-NK cells, ACE2 CAR-NK cells, partially HLA-matched Virus Specific T cells (VSTs), RAPA-501, or SARS-CoV-2 Specific T Cells. It is also possible to combine any compound of the invention with one or more additional active therapeutic agents in a unitary dosage form for simultaneous or sequential administration to a patient. The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations. Co-administration of a compound of the invention with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound of the invention and one or more other active therapeutic agents, such that therapeutically effective amounts of the compound of the invention and one or more other active therapeutic agents are both present in the body of the patient. Co-administration includes administration of unit dosages of the compounds of the invention before or after administration of unit dosages of one or more other active therapeutic agents, for example, administration of the compounds of the invention within seconds, minutes, or hours of the administration of one or more other active therapeutic agents. For example, a unit dose of a compound of the invention can be administered first, followed within seconds or minutes by administration of a unit dose of one or more other active therapeutic agents. Alternatively, a unit dose of one or more other therapeutic agents can be administered first, followed by administration of a unit dose of a compound of the invention within seconds or minutes. In some cases, it may be desirable to administer a unit dose of a compound of the invention first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more other active therapeutic agents. In other cases, it may be desirable to administer a unit dose of one or more other active therapeutic agents first, followed, after a period of hours ( e.g., 1-12 hours), by administration of a unit dose of a compound of the invention. The combination therapy may provide "synergy" and "synergistic", i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately. A synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g. in separate tablets, pills or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e. serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. A synergistic anti-viral effect denotes an antiviral effect which is greater than the predicted purely additive effects of the individual compounds of the combination. Embodiments Examples of embodiments of the present application include the following: Embodiment 1 A compound of Formula or a pharmaceutically acceptable salt thereof; wherein: R 1 is selected from the group consisting of hydrogen; -C(=O)-(C 3 -C 7 cycloalkyl), wherein the C 3 -C 7 cycloalkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 6 alkyl; -C(=O)-(5 to 6-membered heterocyclyl), wherein the 5 to 6-membered heterocyclyl is attached to the -C(=O) group through a ring carbon or ring heteroatom, and further wherein the 5 to 6-membered heterocyclyl is optionally substituted with a 5 to 6- membered heterocyclyl; -C(=O)-(C 1 -C 20 alkyl), wherein the C 1 -C 20 alkyl is optionally substituted with 1-3 substituents independently selected from C(=O)OH, C 3 -C 7 cycloalkyl, and C 6 -C 10 aryl; -C(=O)-(C 6 -C 10 aryl); -P(=O)-(NH(C 1 -C 6 alkyl)) 2 ; -P(=O)-(NH(C 1 -C 6 alkyl)(N(C 1 -C 6 alkyl) 2 ); -P(=O)-(N(C 1 -C 6 alkyl) 2 ) 2 ; -P(=O)-(NH(C 1 -C 6 alkyl-C(=O)-O-C 1 -C 6 alkyl))(O-C 6 -C 10 aryl); and -P(=O)-(NH(C 1 -C 6 alkyl-C(=O)-O-C 1 -C 6 alkyl))(O-5 to 6-membered heteroaryl); R 2 and R 3 are each independently selected from the group consisting of hydrogen; -C(=O)-(C 1 -C 10 alkyl), wherein the C 1 -C 10 alkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of -NH 2 , -C(=O)-OH, and C 6 - C 10 aryl; -C(=O)-(C 3 -C 7 cycloalkyl), wherein the C 3 -C 7 cycloalkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, C 1 -C 6 alkyl, and -O- C 1 -C 6 alkyl; and -C(=O)-(C 6 -C 10 aryl); and R 4 is selected from the group consisting of hydrogen, C 3 -C 7 cycloalkyl; –(C=O)-O- C 1 -C 10 alkyl; –(C=O)-(C 1 -C 10 alkyl); and -C(=O)-(C 3 -C 7 cycloalkyl); wherein in each instance, C 6 -C 10 aryl and 5 to 6-membered heteroaryl are each optionally independently substituted with 1-3 substituents independently selected from the group consisting of halo, C 1 -C 6 alkyl, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , and -O-C 1 - C 6 alkyl; with the proviso that: (a) when only one of R 1 , R 2 , and R 3 is independently hydrogen, -C(=O)-CH(CH 3 ) 2 , -C(=O)- CH 2 CH 3 , -C(=O)-cyclopropyl, -C(=O)-C(CH 3 ) 3 , -C(=O)-CH 2 C(CH 3 ) 3 , or -C(=O)-CH(NH 2 )- CH(CH 3 ) 2 , and the other two of R 1 , R 2 , and R 3 are hydrogen, then R 4 is not hydrogen; (b) when R 1 = R 2 = R 3 and is selected from the group consisting of hydrogen, -C(=O)- CH(CH 3 ) 2 , -C(=O)-CH 2 CH 3 , -C(=O)-CH 3 , and -C(=O)-cyclopropyl, then R 4 is not hydrogen; (c) when R 1 = R 4 = hydrogen, then R 2 and R 3 cannot both be -C(=O)-CH(CH 3 ) 2 ; (d) when R 1 = R 2 and is selected from -C(=O)-CH(CH 3 ) 2 and -C(=O)-cyclopropyl, then R 3 and R 4 cannot both be hydrogen; and (e) when R 1 is selected from the group consisting of -C(=O)-CH 3 , -C(=O)-CH 2 CH 2 CH 3 , -C(=O)-(CH 2 ) 7 CH 3 , -C(=O)-phenyl, -C(=O)-cyclopropyl, -C(=O)-CH 2 CF 3 , -C(=O)-CH 2 CH(CH 3 ) 2 , -C(=O)-CH(NH 2 )-CH(CH 3 ) 2 , -C(=O)-CH(NH 2 )-benzyl, and -C(=O)-CH(NH 2 )-CH(CH 3 )-CH 2 CH 3 , then R 2 , R 3 , and R 4 cannot all be hydrogen. The application further provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof; wherein: R 1 is selected from the group consisting of hydrogen; -C(=O)-(C 3 -C 7 cycloalkyl), wherein the C 3 -C 7 cycloalkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 6 alkyl; -C(=O)-(5 to 6-membered heterocyclyl), wherein the 5 to 6-membered heterocyclyl is attached to the -C(=O) group through a ring carbon or ring heteroatom, and further wherein the 5 to 6-membered heterocyclyl is optionally substituted with a 5 to 6- membered heterocyclyl; -C(=O)-(C 1 -C 20 alkyl), wherein the C 1 -C 20 alkyl is optionally substituted with 1-3 substituents independently selected from C(=O)OH, C 3 -C 7 cycloalkyl, and C 6 -C 10 aryl; -C(=O)-(C 6 -C 10 aryl); -P(=O)-(NH(C 1 -C 6 alkyl)) 2 ; -P(=O)-(NH(C 1 -C 6 alkyl)(N(C 1 -C 6 alkyl) 2 ); -P(=O)-(N(C 1 -C 6 alkyl) 2 ) 2 ; -P(=O)-(NH(C 1 -C 6 alkyl-C(=O)-O-C 1 -C 6 alkyl))(O-C 6 -C 10 aryl); and -P(=O)-(NH(C 1 -C 6 alkyl-C(=O)-O-C 1 -C 6 alkyl))(O-5 to 6-membered heteroaryl); R 2 and R 3 are each independently selected from the group consisting of hydrogen; -C(=O)-(C 1 -C 10 alkyl), wherein the C 1 -C 10 alkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of -NH 2 , -C(=O)-OH, and C 6 - C 10 aryl; -C(=O)-(C 3 -C 7 cycloalkyl), wherein the C 3 -C 7 cycloalkyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, C 1 -C 6 alkyl, and -O- C 1 -C 6 alkyl; and -C(=O)-(C 6 -C 10 aryl); and R 4 is selected from the group consisting of hydrogen, C 3 -C 7 cycloalkyl; –(C=O)-O- C 1 -C 10 alkyl; –(C=O)-(C 1 -C 10 alkyl); and -C(=O)-(C 3 -C 7 cycloalkyl); wherein in each instance, C 6 -C 10 aryl and 5 to 6-membered heteroaryl are each optionally independently substituted with 1-3 substituents independently selected from the group consisting of halo, C 1 -C 6 alkyl, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , and -O-C 1 - C 6 alkyl; with the proviso that: (a) when only one of R 1 , R 2 , and R 3 is independently hydrogen, -C(=O)-CH(CH 3 ) 2 , -C(=O)- CH 2 CH 3 , -C(=O)-cyclopropyl, -C(=O)-C(CH 3 ) 3 , -C(=O)-CH 2 C(CH 3 ) 3 , or -C(=O)-CH(NH 2 )- CH(CH 3 ) 2 , and the other two of R 1 , R 2 , and R 3 are hydrogen, then R 4 is not hydrogen; (b) when R 1 = R 2 = R 3 and is selected from the group consisting of hydrogen, -C(=O)- CH(CH 3 ) 2 , -C(=O)-CH 2 CH 3 , -C(=O)-CH 3 , and -C(=O)-cyclopropyl, then R 4 is not hydrogen; (c) when R 1 = R 4 = hydrogen, then R 2 and R 3 cannot both be -C(=O)-(C 1 -C 6 )alkyl; when R 4 = hydrogen, then R 1 , R 2 , and R 3 cannot all be -C(=O)-CH(CH 3 ) 2 -C(=O)-CH 3 - C(=O)-CH 2 CH 3 , -C(=O)-CH 2 CH 2 CH 3 , -C(=O)-(C 1 -C 6 )alkyl(C 3 -C 7 )cycloalkyl or -C(=O)- cyclopropyl; (d) when R 1 = R 2 and is selected from -C(=O)-CH(CH 3 ) 2 and -C(=O)-cyclopropyl, then R 3 and R 4 cannot both be hydrogen; (e) when R 2 = R 3 and is selected from hydrogen, -C(=O)-CH(CH 3 ) 2 , -C(=O)-CH 3 or -C(=O)- cyclopropyl, and R 4 is hydrogen, -C(=O)-CH(CH 3 ) 2 , -C(=O)-CH 3 or -C(=O)-cyclopropyl, then R 1 cannot be -C(=O)-CH(CH 3 ) 2 , -C(=O)-hetero(C 1 -C 6 )alkyl-C(=O)O-(C 1 -C 6 )alkyl, - C(=O)((C 1 -C 6 )alkylPh((NHC=OO(C 1 -C 6 )alkyl, -C(=O)((C 1 -C 6 )alkyl((NHC=OO(C 1 - C 6 )alkyl, -C(=O)-hetero(C 1 -C 6 )alkyl-C(=O)O-hetero(C 1 -C 6 )alkyl, -C(=O)-hetero(C 1 - C 6 )alkyl-C(=O)OH, or -C(=O)-hetero(C 1 -C 6 )alkyl; (f) when R 1 is selected from the group consisting of -C(=O)-CH 3 , -C(=O)-CH 2 CH 2 CH 3 , -C(=O)-(CH 2 ) 7 CH 3 , -C(=O)-phenyl, -C(=O)-cyclopropyl, -C(=O)-CH 2 CF 3 , -C(=O)-CH 2 CH(CH 3 ) 2 , -C(=O)-CH(NH 2 )-CH(CH 3 ) 2 , -C(=O)-CH(NH 2 )-benzyl, and -C(=O)-CH(NH 2 )-CH(CH 3 )-CH 2 CH 3 , then R 2 , R 3 , and R 4 cannot all be hydrogen; and (g) when R 2 = R 3 = R 4 = hydrogen, R 1 cannot be selected from the group consisting of hydrogen, -C(=O)-(C 1 -C 10 )alkyl, -C(=O)-(C 1 -C 10 )alkyl-C(=O)-(C 1 -C 6 )alkyl, -C(=O)-(C 1 - C 6 )alkenyl, -C(=O)-(C 1 -C 6 )alkynyl, -C(=O)-halo(C 1 -C 6 )alkyl, -C(=O)-halo(C 1 -C 6 )alkenyl, - C(=O)-hetero(C 1 -C 6 )alkyl, -C(=O)-hetero(C 1 -C 6 )alkenyl, -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 1 -C 6 )alkyl-(C 3 -C 7 )heterocycloalkyl-(C 1 -C 6 )alkyl, -C(=O)- halo(C 3 -C 7 )cycloalkyl, -C(=O)-(C 1 -C 6 )alkyl-halo(C 3 -C 7 )cycloalkyl, -C(=O)-hydroxy(C 3 - C 7 )cycloalkyl, -C(=O)-(C 1 -C 6 )alkyl-hydroxy(C 3 -C 7 )cycloalkyl, -C(=O)-amino(C 3 - C 7 )cycloalkyl, -C(=O)-(C 1 -C 6 )alkyl-amino(C 3 -C 7 )cycloalkyl, -C(=O)-(C 1 -C 6 )heteroalkyl(C 3 - C 7 )cycloalkyl, and -C(=O)-(C 1 -C 6 )alkyl-(C 1 -C 6 )heteroalkyl(C 3 -C 7 )cycloalkyl, -C(=O)- halo(C 3 -C 7 )heterocycloalkyl, -C(=O)-(C 1 -C 6 )alkyl-halo(C 3 -C 7 )heterocycloalkyl, -C(=O)- hydroxy(C 3 -C 7 )heterocycloalkyl, -C(=O)-(C 1 -C 6 )alkyl-hydroxy(C 3 -C 7 )heterocycloalkyl, - C(=O)-amino(C 3 -C 7 )heterocycloalkyl, -C(=O)-(C 1 -C 6 )alkyl-amino(C 3 -C 7 )heterocycloalkyl, - C(=O)-(C 1 -C 6 )heteroalkyl(C 3 -C 7 )heterocycloalkyl, -C(=O)-(C 1 -C 6 )alkyl-(C 1 - C 6 )heteroalkyl(C 3 -C 7 )heterocycloalkyl, -C(=O)-(C 1 -C 6 )heteroalkyl-C(=O)-(C 1 -C 6 )alkyl, - C(=O)-(C 1 -C 6 )heteroalkyl-phenyl, and -C(=O)-(C 1 -C 6 )heteroalkyl-(C 5 -C 8 )heteroaryl. Embodiment 2 The compound and/or pharmaceutically acceptable salt thereof of Embodiment 1, wherein in R 1 : the -C(=O)-(C 3 -C 7 cycloalkyl) with the optional substituents of the C 3 -C 7 cycloalkyl is selected from the group consisting of -C(=O)-cyclohexyl, -C(=O)-(1-methylcyclohexyl), and -C(=O)-(4,4-dimethylcyclohexyl); the -C(=O)-(5 to 6-membered heterocyclyl) with the optional substituents of the 5 to 6-membered heterocyclyl is the -C(=O)-(C 1 -C 20 alkyl) with the optional substituents of the C 1 -C 20 alkyl is selected from the group consisting of -C(=O)-CH(CH 3 ) 2 , -C(=O)-CH(CH 2 CH 3 ) 2 , -C(=O)-CH 2 CH(CH 2 CH 3 ) 2 , -C(=O)-CH 2 -cyclopentyl, -C(=O)-benzyl, -C(=O)-CH(CH 3 )- benzyl, -C(=O)-CH(CH 3 )-phenyl, -C(=O)-C(CH 3 ) 3, -C(=O)-CH 2 -C(CH 3 ) 3 , -C(=O)-CH 2 - CH(CH 2 CH 3 ) 2 , -C(=O)-CH(CH 3 )(CH 2 CH 2 CH 3 ), -C(=O)-CH(CH 3 )(CH 2 CH 2 CH 2 CH 3 ), -C(=O)-CH(CH 3 )((CH 2 ) 4 CH 3 ), -C(=O)-(CH 2 ) 5 CH 3 , -C(=O)-CH(CH 3 )((CH 2 ) 5 CH 3 ), -C(=O)-(CH 2 ) 8 CH 3 , -C(=O)-CH(CH 3 )((CH 2 ) 9 CH 3 ), -C(=O)-(CH 2 ) 10 CH 3 , -C(=O)-(CH 2 ) 12 CH 3 , -C(=O)-CH 2 -(2-fluorophenyl), -C(=O)-CH 2 -(4-fluorophenyl), -C(=O)- CH 2 -(3-fluorophenyl), -C(=O)-(CH 2 ) 2 -C(=O)-OH, -C(=O)-CH 2 -(1-naphthyl), and -C(=O)- CH 2 -(2-Naphthyl); the -C(=O)-(C 6 -C 10 aryl) is selected from the group consisting of -C(=O)-phenyl; the -P(=O)-(NH(C 1 -C 6 alkyl-C(=O)-O-C 1 -C 6 alkyl))(O-C 6 -C 10 aryl) is selected from the group consisting of -P(=O)-(NH(CH(CH 3 )-C(=O)-O-CH 2 CH(CH 3 ) 2 ))(O-phenyl), -P(=O)-(NH(CH(CH(CH 3 ) 2 )-C(=O)-O-CH 2 CH(CHCH 3 ) 2 ))(O-phenyl), -P(=O)-(NH(CH(benzyl)-C(=O)-O-CH 2 CH(CHCH 3 ) 2 ))(O-phenyl), -P(=O)-(NH(CH(phenyl)-C(=O)-O-CH 2 CH(CHCH 3 ) 2 ))(O-phenyl), -P(=O)-(NH(CH(CH 3 )-C(=O)-O-CH 2 CH(CH 3 ) 2 ))(O-(4-methoxyphenyl)), -P(=O)-(NH(CH(CH 3 )-C(=O)-O-CH 2 C(CH 3 ) 3 ))(O-(4-methoxyphenyl)), -P(=O)-(NH(CH(CH 3 )-C(=O)-O-CH 2 C(CH 3 ) 3 ))(O-(4-Bromophenyl)) -P(=O)-(NH(CH(CH 3 )-C(=O)-O-CH 2 CH(CH 3 ) 2 ))(O-1-naphthyl), and -P(=O)-(NH(CH(CH 3 )-C(=O)-O-CH 2 C(CH 3 ) 3 ))(O-2-naphthyl); and the -P(=O)-(NH(C 1 -C 6 alkyl-C(=O)-O-C 1 -C 6 alkyl))(O-5 to 6-membered heteroaryl) is -P(=O)-(NH(CH(CH 3 )-C(=O)-O-CH 2 C(CH 3 ) 3 ))(O-(3-pyridinyl)). Embodiment 3 The compound or a pharmaceutically acceptable salt thereof of Embodiment 1 or 2, wherein in R 2 and R 3 : the -C(=O)-(C 1 -C 10 alkyl) with the optional substituents of the C 1 -C 10 alkyl is selected from the group consisting of -C(=O)-CH 3 , -C(=O)-(CH 2 ) 5 -CH 3 , -C(=O)-benzyl, -C(=O)-CH(CH 2 CH 3 ) 2 , -C(=O)-CH(NH 2 )CH(CH 3 ) 2 , -C(=O)-CH(NH 2 )-phenyl, -C(=O)-CH(CH 3 ) 2 , -C(=O)-CH(CH 3 )-phenyl, -C(=O)-CH 2 CH(CH 2 CH 3 ) 2 , -C(=O)-CH 2 -(4-fluorophenyl), -C(=O)-CH 2 -(3-fluorophenyl), -C(=O)-CH 2 -(2-fluorophenyl), -C(=O)-(CH 2 ) 2 -C(=O)-OH, -C(=O)-CH 2 -(1-naphthyl), and -C(=O)-CH 2 -(2-naphthyl); the -C(=O)-(C 3 -C 7 cycloalkyl) with the optional substituents of the C 3 -C 7 cycloalkyl is selected from the group consisting of -C(=O)-cyclohexyl, and -C(=O)-(4,4- dimethylcyclohexyl); and the -C(=O)-(C 6 -C 10 aryl) is selected from the group consisting of - C(=O)-phenyl. Embodiment 4 The compound or a pharmaceutically acceptable salt thereof of any one of Embodiments 1-3, wherein in R 4 : the C 3 -C 7 cycloalkyl is selected from the group consisting of cyclopropyl; the –(C=O)-O-C 1 -C 10 alkyl is selected from the group consisting of –(C=O)-O- (CH 2 ) 2 CH 3 ,and –(C=O)-O-(CH 2 ) 4 CH 3 ; the –(C=O)-(C 1 -C 10 alkyl) is selected from the group consisting of –(C=O)-benzyl, and -C(=O)-(CH 2 ) 2 CH 3 ; and the -C(=O)-(C 3 -C 7 cycloalkyl) is selected from the group consisting of -C(=O)-cyclobutyl. Embodiment 5 The compound of any one of Embodiments 1-4, selected from the group consisting of:

, ,

,

Embodiment 6 The compound of any one of Embodiments 1-5, having the Formula: pharmaceutically acceptable salt thereof. Embodiment 7 A pharmaceutical composition comprising at least one compound of any one of Embodiments 1-6, or a pharmaceutical acceptable salt thereof, and a pharmaceutically acceptable carrier. Embodiment 8 A method of inhibiting an RNA-dependent RNA polymerase in a patient infected with a virus, comprising administering to the patient a therapeutically effective amount of at least one compound of any one of Embodiments 1-6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Embodiment 9 A method of preventing or treating a viral infection in a patient comprising administering to the patient a therapeutically effective amount of at least one compound of any one of Embodiments 1-6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Embodiment 10 The method of Embodiment 8 or 9, wherein the virus of Embodiment 8 comprises, or the viral infection of Embodiment 9 is caused by at least one virus selected from the table below listing the virus families and the respective viruses thereunder:

Embodiment 11 The method of Embodiment 9, wherein the viral infection is caused by at least one virus selected from the group consisting of Ebola (Makona) virus, Ebola (Kikwit) virus, Bundibugyo virus, Sudan virus, Marburg virus, respiratory syncytial virus (RSV), Nipah virus, measles virus, parainfluenza virus, Middle Eastern Respiratory Syndrome (MERS) virus, South Asian Respiratory syndrome-Coronavirus (SARS-CoV), SARS-COV-2, hepatitis C virus (HCV), Dengue virus, Zika virus, West Nile virus, Lassa virus, and Junin virus. Embodiment 12 The method of Embodiment 11, wherein the viral infection is caused by SARS-COV- 2 and its variants selected from the group consisting of delta, epsilon, kappa, zeta, UK SARS- COV-2 variant B.1.1.7 and South Africa SARS-CoV-2501.V2. Embodiment 13 The method of any one of claims 8-12, further comprising administering at least one additional antiviral agent selected from the group consisting of nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, protease inhibitor, an integrase inhibitor and/or an entry inhibitor. Embodiment 14 The method of Embodiment 13, wherein the protease inhibitor comprises at least one selected from the group consisting of PF-07321332, islatravir and lenacapavir. Embodiment 15 The method of Embodiment 14, wherein the protease inhibitor is PF-07321332. Embodiment 16 The method of any one of Embodiment s 8-15, wherein the compound is administered via a route selected from the group consisting of oral, inhalation, parenteral and implants. Embodiment 17 The method of any one of Embodiment s 8-16, wherein the administration is for pre- exposure or post-exposure prophylaxis. Administration and Pharmaceutical Composition In general, the compounds described herein will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Therapeutically effective amounts of a compound described herein may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. A suitable dosage level may be from about 0.1 to about 250 mg/kg per day; about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day. For oral administration, the compositions can be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient. The actual amount of the compound, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors. In general, compounds described herein will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), parenteral (e.g., intramuscular, intravenous, intrasternal or subcutaneous) topical (e.g., application to skin) administration, or through an implant. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions. The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules, including enteric coated or delayed release tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No.4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No.5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability. The compositions are comprised of in general, a compound described herein in combination with at least one pharmaceutically acceptable carrier/excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art. Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be chosen from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols. Compressed gases may be used to disperse a compound described herein in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000). The level of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound described based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt %. A compound described herein may be used in combination with one or more other drugs in the treatment of diseases or conditions for which a compound described herein or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound described herein. When a compound described herein is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and a compound described herein is preferred. However, the combination therapy may also include therapies in which a compound described herein and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, a compound described herein and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, a pharmaceutical composition described herein also can include those that contain one or more other active ingredients, in addition to a compound described herein. EXAMPLES Synthetic Examples Abbreviations The following abbreviations are used: tetrahydrofuran (THF), dichloromethane (DCM), Acetonitrile (MeCN), N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), trifluoroacetic acid (TFA), triethylamine (TEA), diisopropylethylamine (DIPEA), methanol (MeOH), Ethyl acetate (EtOAc), 4-Dimethylaminopyridine (DMAP), N-(3- Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC•HCl), N,N'- Dicyclohexylcarbodiimide (DCC). General Examples for the Preparation of Compounds of the Invention The starting materials and intermediates for the compounds of this invention may be prepared by the application or adaptation of the methods described below, their obvious chemical equivalents, or, for example, as described in literature such as The Science of Synthesis, Volumes 1-8. Editors E. M. Carreira et al. Thieme publishers (2001-2008). Details of reagent and reaction options are also available by structure and reaction searches using commercial computer search engines such as Scifinder (www.cas.org) or Reaxys (www.reaxys.com). Part I: Preparation of Intermediates Example 1 Synthesis of intermediate-1, -2: Synthesis o ,4]triazin-7-yl)-6- (hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol e-4-carbonitrile (Intermediate 1) To a solution of (2R,3R,4S,5R)‑2‑(4‑aminopyrrolo[1,2‑f][1,2,4]triazin ‑7‑yl)‑3,4‑dihydroxy ‑ 5‑(hydroxymethyl)tetrahydrofuran‑2‑carbonitrile (2.0 g, 6.86 mmol) in acetone (20 mL), were added H 2 SO 4 (0.5 mL) and compound 2,2-dimethoxypropane (4.2 g, 34.33 mmol) at room temperature. The reaction mixture was stirred at 60 °C for 45 min. After completion of reaction by TLC, solvent was evaporated and dried under reduced pressure to give a residue. The residue was basified by saturated sodium bicarbonate solution (50 mL) and extracted with EtOAc (2 X 50 mL). Then organic layer was washed with cold water (50 mL) and brine (50 mL). Organic layer was dried over anhydrous sodium sulfate and evaporated to get crude compound which was purified by column chromatography over silica gel (Davisil) (using 0- 5% MeOH in DCM as an eluent) to afford 2.0 g (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahy drofuro[3,4-d][1,3]dioxole-4- carbonitrile (Intermediate 1) as off white solid. [TLC system: MeOH:DCM (0.5:9.5); R f value: 0.2]. LC-MS: m/z= 332.3 (M + H + ). Synthesis of (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5 -(((tert- butyldimethylsilyl)oxy)methyl)-3,4-dihydroxytetrahydrofuran- 2-carbonitrile (Intermediate 2) I ntermediate 2 To a solution of tert-Butyldimethylsilyl chloride (TBSCl) (778 mg, 5.16 mmol) in pyridine (10 mL) was added (2R,3R,4S,5R)‑2‑(4‑aminopyrrolo[1,2‑f][1,2,4]triazin ‑7‑yl)‑3,4‑ dihydroxy‑5‑(hydroxymethyl)tetrahydrofuran‑2‑carboni trile (1 g, 3.43 mmol) followed by 4-dimethylaminopyridine (42 mg, 0.343 mmol). The reaction was stirred at room temperature till SM was no longer observed by LCMS (~24 hrs). The reaction was concentrated by blowing under a N 2 stream, then diluted with 0.5N HCl (30 mL) and extracted with EtOAc (3 x 55 mL). The combined organic layer was dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH), affording compound X (340 mg, 24%). LC-MS: m/z= 406.7 (M + H + ). Part II: Preparation of Example Compounds Examples 1-3 Compounds 1-3 were prepared by using the procedure followed for the compound 4 as shown below. Example 4 Synthesis of ( 5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-phenylacetate (Compound 4) Preparation of A: Intermediate 1 (450 mg, 1.36 mmol) and 4-dimethylaminopyridine (17 mg, 0.139 mmol) were dissolved in DCM (15 mL) under argon and chilled to 0° C. After 30 min at 0° C, phenylacetic acid (236 mg, 1.73 mmol) and DCC (395 mg, 1.91 mmol) were added to the reaction, and then the mixture was stirred at room temperature for an hour. The mixture was filtered and the solid was rinsed with DCM (2 x 10 mL). The filtrate was concentrated, then purified by silica gel column chromatography (100% hexanes-100% EtOAc), affording ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4] triazin-7-yl) -6-cyano-2,2-dimethyl tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-phenylacetate (A) (529 mg, 87%). LC-MS: m/z= 450.8 (M + H + ). Preparation of Compound 4: 1:1 TFA/H 2 O (9 mL) was chilled to 0° C then added to ((3aR,4R,6R,6aR)-6-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyl tetrahydrofuro[3,4- d][1,3]dioxol-4-yl)methyl 2-phenylacetate (A) (529 mg, 1.18 mmol) with stirring in an ice bath. The reaction was stirred at room temperature and monitored by LCMS until completion (~2-3 hrs). The reaction was concentration in vacuo then diluted with EtOAc (50 mL) and H 2 O (50 mL), before adding saturated aqueous NaHCO 3 (20 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL), then the combined organic layer was dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by silica gel column chromatography (0- 5% MeOH in DCM), affording ((2R,3S,4R,5R)-5-(4-aminopyrrolo [2,1-f][1,2,4]triazin -7-yl)- 5-cyano -3,4-dihydroxy tetrahydrofuran-2-yl)methyl 2-phenylacetate (Compound 4) (337 mg, 70%). LC-MS: m/z= 410.4 (M + H + ). 1 H NMR (500 MHz, DMSO) δ 7.93 (m, 3H), 7.33 – 7.18 (m, 5H), 6.92 (d, J = 4.5 Hz, 1H), 6.78 (d, J = 4.5 Hz, 1H), 6.30 (d, J = 5.8 Hz, 1H), 5.39 (d, J = 5.8 Hz, 1H), 4.66 (t, J = 5.3 Hz, 1H), 4.38 – 4.33 (m, 1H), 4.22 (ddt, J = 17.4, 11.8, 6.0 Hz, 2H), 3.94 (q, J = 5.7 Hz, 1H), 3.67 (s, 2H). Alternate Procedure for Preparation of Compound 4: A solution of ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl )-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-phenylacetate (A) (1.1 g, 2.44 mmol) in formic acid (11 mL) was stirred at room temperature for 16 h. After completion of reaction by TLC, reaction mixture was evaporated and dried under reduced pressure to get residue. The residue was basified by saturated solution of sodium bicarbonate (30 mL) and extracted with EtOAc (2 X 50 mL). Then organic layer was washed with cold water (50 mL) and Brine (50 mL). Organic layer was dried over anhydrous sodium sulfate and evaporated to get crude which was purified by column chromatography over silica gel (Davisil) (using 0-5% MeOH in DCM as an eluent) to afford 0.75 g of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran- 2-yl)methyl 2-phenyl acetate (Compound 4) as off white solid. LC-MS: m/z= 410.4 (M + H + ). Examples 5-28 Compounds 5-28 were prepared by using the procedure followed for the compound 4. Example 29 Compounds 29 was prepared by using the procedure followed for the compound 30. Examples 30 Synthesis of (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2 -cyano-5- (hydroxymethyl)tetrahydrofuran-3,4-diyl bis(2-phenylacetate) (Compound 30) Preparation of B: Intermediate 2 (335 mg, 0.826 mmol) and 4-dimethylaminopyridine (10.3 mg, 0.084 mmol) were dissolved in DCM (12 mL) and MeCN (3.5 mL) under argon and chilled to 0°C. After 30 min at 0° C, phenylacetic acid (227 mg, 1.67 mmol) and DCC (392 mg, 1.90 mmol) were added to the reaction, and then the mixture was stirred at room temperature for 2 hrs. The mixture was filtered and the solid was rinsed with MeCN (2 x 10 mL). The filtrate was concentrated, then purified by silica gel column chromatography (100% hexanes-100% EtOAc), affording (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5 -(((tert- butyldimethylsilyl)oxy)methyl)-2-cyanotetrahydrofuran-3,4-di yl bis(2-phenylacetate) (B) (470 mg, 89%). LC-MS: m/z= 642.8 (M + H + ). Preparation of Compound 30: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5 -(((tert- butyldimethylsilyl)oxy)methyl)-2-cyanotetrahydrofuran-3,4-di yl bis(2-phenylacetate) (B) (315 mg, 0.491 mmol) was dissolved in THF (2.8 mL) under N 2 . Acetic acid (34 mL, 0.594 mmol) was added, then the reaction was chilled to 0°C. A 1M solution of TBAF in THF (0.539 mL, 0,539 mmol) was added dropwise to the reaction at 0°C, and then the mixture was stirred at room temperature overnight. The reaction was concentrated, then purified by silica gel column chromatography (0-5% MeOH in DCM) affording (2R,3R,4R,5R)-2-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-(hydroxyme thyl)tetrahydrofuran-3,4-diyl bis(2-phenylacetate) (Compound 30) (219 mg, 85%). LC-MS: m/z= 528.5 (M + H + ). 1 H NMR (500 MHz, DMSO) δ 7.92 (m, 3H), 7.33 (d, J = 4.4 Hz, 4H), 7.31 – 7.20 (m, 4H), 7.18 – 7.12 (m, 2H), 6.90 (d, J = 4.6 Hz, 1H), 6.76 (d, J = 4.6 Hz, 1H), 5.99 (d, J = 5.9 Hz, 1H), 5.43 (dd, J = 5.8, 3.6 Hz, 1H), 5.15 (t, J = 5.6 Hz, 1H), 4.40 (q, J = 3.6 Hz, 1H), 3.71 – 3.52 (m, 4H), 3.40 (d, J = 16.1 Hz, 1H). Examples 31-37 Compounds 31-37 were prepared by using the procedure followed for the compound 30. Example 38 Compounds 38 was prepared by using the procedure followed for the compound 39. Example 39 and 56 Synthesis of ,4]triazin-7-yl)-2-cyano-5-((2- phenylacetoxy)methyl)tetrahydrofuran-3,4-diyl bis(2-phenylacetate) (Compound 39) (2R,3R,4S,5R)‑2‑(4‑aminopyrrolo[1,2‑f][1,2,4]triazin ‑7‑yl)‑3,4‑dihydroxy‑ 5‑(hydroxymethyl)tetrahydrofuran‑2‑carbonitrile (1 g, 3.43 mmol), 4- dimethylaminopyridine (127 mg, 1.04 mmol), and phenylacetic acid (1.43 g, 10.5 mmol) were combined with DMF (7.5 mL) and MeCN (34 mL) under argon and chilled to 0°C. After 20 min at 0° C, DCC (2.34 g, 11.3 mmol) was added to the reaction, and then the mixture was stirred at room temperature overnight. The mixture was filtered and the solid was rinsed with MeCN (2 x 10 mL), and EtOAc (10 mL). The filtrate was concentrated, then purified by silica gel column chromatography (100% hexanes-100% EtOAc), affording (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2 -cyano-5-((2- phenylacetoxy)methyl)tetrahydrofuran-3,4-diyl bis(2-phenylacetate) (Compound 39) (1.61 g, 73%). LC-MS: m/z= 646.8 (M + H + ). 1 H NMR (500 MHz, DMSO) δ 8.07 – 7.92 (m, 2H), 7.91 (s, 1H), 7.43 – 7.05 (m, 15H), 6.92 (d, J = 4.6 Hz, 1H), 6.74 (d, J = 4.6 Hz, 1H), 6.08 (d, J = 6.0 Hz, 1H), 5.45 (dd, J = 6.0, 4.4 Hz, 1H), 4.61 (q, J = 4.2 Hz, 1H), 4.40 (dd, J = 12.4, 3.3 Hz, 1H), 4.27 (dd, J = 12.4, 4.8 Hz, 1H), 3.70 – 3.56 (m, 5H), 3.46 (d, J = 16.1 Hz, 1H). Synthesis of (2R,3R,4R,5R)-2-cyano-2-(4-(2-phenylacetamido)pyrrolo[2,1-f] [1,2,4]triazin-7- yl)-5-((2-phenylacetoxy)methyl)tetrahydrofuran-3,4-diyl bis(2-phenylacetate) (Compound 56) (2R,3R,4R,5R)-2-cyano-2-(4-(2-phenylacetamido)pyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-((2- phenylacetoxy)methyl)tetrahydrofuran-3,4-diyl bis(2-phenylacetate) was a byproduct formed under reaction conditions to generate (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin- 7-yl)-2-cyano-5-((((S)-(((S)-1-(2-ethylbutoxy)-1-oxopropan-2 - yl)amino)(phenoxy)phosphoryl)oxy) methyl)tetrahydrofuran-3,4-diyl bis(2-phenylacetate). Isolation of Compound 56 from Compound 39 was possible by separation with silica gel column chromatography (100% hexanes-100% EtOAc). LC-MS: m/z= 764.3 (M + H + ). 1 H NMR (400 MHz, DMSO) δ 8.37 (s, 1H), 7.38 – 7.12 (m, 22H), 6.94 (d, J = 4.9 Hz, 1H), 6.02 (d, J = 6.1 Hz, 1H), 5.47 (dd, J = 5.9, 4.1 Hz, 1H), 4.67 (m, 1H), 4.40 (dd, J = 12.4, 3.3 Hz, 1H), 4.28 (dd, J = 12.4, 4.7 Hz, 1H), 4.05 (s, 2H), 3.72 – 3.54 (m, 5H), 3.48 (d, J = 16.0 Hz, 1H). Example 40 Compounds 40 was prepared by using the procedure followed for the compound 41. Example 41

Synthesis of (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2 -cyano-5-((2- phenylacetoxy)methyl)tetrahydrofuran-3,4-diyl dibenzoate (Compound 41) ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-phenylacetate (Compound 4) (152 mg, 0.371 mmol) and 4-dimethylaminopyridine (5 mg, 0.041 mmol) were dissolved in DCM (5 mL) and MeCN (2 mL) under argon and chilled to 0° C. After 30 min at 0° C, benzoic acid (93 mg, 0.762 mmol) and DCC (178 mg, 0.863 mmol) were added to the reaction, and then the mixture was stirred at room temperature for 4 hrs. The mixture was filtered and the solid was rinsed with DCM (2 x 5 mL). The filtrate was concentrated, then purified by silica gel column chromatography (100% hexanes-100% EtOAc), affording (2R,3R,4R,5R)-2-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-((2-phenyl acetoxy)methyl)tetrahydrofuran- 3,4-diyl dibenzoate (Compound 41) (170 mg, 74%). LC-MS: m/z= 618.6 (M + H + ). 1 H NMR (500 MHz, DMSO) δ 8.10 – 7.93 (m, 4H), 7.93 – 7.84 (m, 3H), 7.72 – 7.61 (m, 2H), 7.54 – 7.41 (m, 4H), 7.31 – 7.19 (m, 5H), 6.95 (d, J = 4.6 Hz, 1H), 6.87 (d, J = 4.6 Hz, 1H), 6.45 (d, J = 6.0 Hz, 1H), 5.86 (dd, J = 6.0, 3.6 Hz, 1H), 4.91 (q, J = 3.7 Hz, 1H), 4.52 (dd, J = 12.3, 3.5 Hz, 1H), 4.43 (dd, J = 12.3, 4.6 Hz, 1H), 3.77 – 3.64 (m, 2H). Example 42 Compound 42 was prepared by using the procedure followed for the compound 41. Example 43 Compound 43 was prepared by using the procedure followed for the compound 39. Example 44 Compound 44 was prepared by using the procedure followed for the compound 41. Example 45 Compound 45 was prepared by using the procedure followed for the compound 39. Example 46 Compound 46 was prepared by using the procedure followed for the compound 41. Example 47 Compound 47 was prepared by using the procedure followed for the compound 39. Examples 48-49 Compounds 48-49 were prepared by using the procedure followed for the compound 41. Examples 50-52 Compounds 50-52 were prepared by using the procedure followed for the compound 39. Example 53 Synthesis of (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5 -cyano-4-hydroxy- 2-(hydroxymethyl)tetrahydrofuran-3-yl 2-phenylacetate (Compound 8) Preparation of C: To a stirred solution of (2R,3R,4S,5R)‑2‑(4‑aminopyrrolo[1,2‑f][1,2,4]triazin ‑7‑yl)‑3,4‑ dihydroxy‑ 5‑(hydroxymethyl)tetrahydrofuran‑2‑carbonitrile (2.0 g, 6.87 mmol) in DMF (40 mL) was added t-Bu 2 Si(OTf) 2 (2.5 mL, 7.56 mmol) at 0 o C. Reaction mixture was stirred at 0°C for 3 h. After depletion of starting material, the reaction mixture was quenched with water (25 mL) and extracted with EtOAc (2 X 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get crude compound. The crude compound was purified using column chromatography (silica gel 100- 200 mesh, 0-15% EtOAc in hexanes as an eluent) to afford (4aR,6R,7R,7aS)-6-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,2-di-tert-butyl-7- hydroxytetrahydro-4H-furo[3,2- d][1,3,2]dioxasiline-6-carbonitrile (C) (2.0 g) as an off white solid. [TLC system: EtOAc:hexanes (1:1); R f value: 0.5]. LC-MS: m/z= 432.2 (M + H + ). Preparation of D: To a stirred solution of (4aR,6R,7R,7aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl) -2,2-di- tert-butyl-7-hydroxytetrahydro-4H-furo[3,2-d][1,3,2]dioxasil ine-6-carbonitrile (C) (1.4 g, 3.24 mmol) and phenylacetic acid (0.53 g, 3.89 mmol) in DCM (30 mL) was added DCC (1.3 g, 6.48 mmol) followed by DMAP (0.040 g, 0.32 mmol) at 0 0 C and reaction mixture was stirred at room temperature for 16 h. After completion of starting material, the reaction mixture was quenched with water (50 mL) and extracted with DCM (2 X 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get crude compound. The crude compound was purified using column chromatography (silica gel 100-200 mesh, 0-10% EtOAc in hexanes as an eluent) to afford 0.8 g of (4aR,6R,7R,7aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl) -2,2-di-tert- butyl-6-cyanotetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-7-yl 2-phenylacetate (D) as an off white solid. [TLC system: EtOAc:hexanes (3:7); R f value: 0.5]. Preparation of Compound 53: To a stirred solution of (4aR,6R,7R,7aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl) -2,2-di- tert-butyl-6-cyanotetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin -7-yl 2-phenylacetate (D) (0.2 g, 0.36 mmol) in THF (5 mL) was added Et 3 N.3HF (0.29 g, 1.80 mmol) at 0 °C and reaction mixture was stirred at room temperature for 2 h. After completion of starting material, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 X 20 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get crude compound. The crude compound was purified by reverse phase preparative-HPLC to afford (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-(hydroxymethyl)te trahydrofuran-3-yl 2- phenylacetate (Compound 53) (0.092 g, 62%) as an off-white solid. [TLC system: MeOH:DCM (1:9); R f value: 0.2]. LC-MS m/z= 408.32 (M-1). 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.94-7.90 (m, 3H), 7.34-7.26 (m, 5H), 6.91 (dd, J = 14.0, 4.4 Hz, 2H), 6.53 (d, J = 6.5 Hz, 1H), 5.20 (q, J = 3.1 Hz, 1H), 5.00 (t, J = 6.0 Hz, 2H), 4.27 (q, J = 3.7 Hz, 1H), 3.76 (q, J = 13.9 Hz, 2H), 3.63-3.52 (m, 2H). Example 54 Compound 54 was prepared by using the procedure followed for the compound 53. Example 55 Synthesis of (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5 -cyano-4-hydroxy- 2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl 2-phenylacetate (Compound 55) To a solution of ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)- 5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methyl 2-phenylacetate (Compound 4) (0.6 g, 1.46 mmol) in DCM (10 mL), were added DCC (0.44 g, 2.19 mmol) and DMAP (0.018 g, 0.14 mmol) at 0 °C. phenylacetic acid (0.2 g, 1.46 mmol) was added and stirred at room temperature for 16 h. After completion of reaction by TLC, reaction mixture was quenched with cold water (20 mL) and extracted with DCM (30 mL). Then organic layer was washed with cold water (50 mL) and brine (50 mL). Organic layer was dried over anhydrous sodium sulfate and evaporated to get crude compound which was purified by column chromatography over silica gel (Davisil) (using 0-5% MeOH in DCM as an eluent) to afford 0.4 g of crude product as an off white solid. Crude compound was further purified by Reverse Phase Prep-HPLC purification to get 0.1 g of (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5 - cyano-4-hydroxy-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3 -yl 2-phenylacetate (Compound 55) as white solid. [TLC system: MeOH:DCM (1:9); R f value: 0.5]. LC-MS: m/z= 528.56 (M+H + ). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.93 (br. s, 3H), 7.32 (d, J = 4.4 Hz, 4H), 7.29-7.23 (m, 4H), 7.19-7.17 (m, 2H), 6.94 (d, J = 4.6 Hz, 1H), 6.83 (d, J = 4.6 Hz, 1H), 6.66 (d, J = 6.4 Hz, 1H), 5.14 (t, J = 5.2 Hz, 1H), 5.05 (t, J = 6.0 Hz, 1H), 4.47 (t, J = 4.2 Hz, 1H), 4.34 (dd, J = 12.4, 3.6 Hz, 1H), 4.23 (dd, J = 12.4, 5.2 Hz, 1H), 3.76 (q, J = 13.0 Hz, 2H), 3.64 (d, J = 1.1 Hz, 2H). Example 56 Compound 56 was prepared as a byproduct during the synthesis of the compound 39. Example 57 Step 1: (2R,3R,4R,5R)-2-cyano-2-(4-(cyclopropylamino)pyrrolo[2,1-f][ 1,2,4]triazin-7-yl)-5- ((2-phenylacetoxy)methyl)tetrahydrofuran-3,4-diyl bis(2-phenylacetate) A mixture of DCC (71 mg, 0.344 mmol), DMAP (2 mg, 0.018 mmol), phenylacetic acid (43 mg, 0.317 mmol ) and (2R,3R,4S,5R)-2-(4-(cyclopropylamino)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrah ydrofuran-2-carbonitrile (30 mg, 0.091 mmol) in DCM (4 mL) was stirred at room temperature overnight. Filtered and the filtrated was concentrated in vacuo to give the crude, which was purified by Prep-HPLC (Daisogel-C18-10-100, 30 x 250 mm, 5 um, mobile phase: ACN--H2O (0.1%FA), gradient: 5 ~ 95) to afford (2R,3R,4R,5R)-2-cyano-2-(4-(cyclopropylamino)pyrrolo[2,1-f][ 1,2,4]triazin- 7-yl)-5-((2-phenylacetoxy)methyl)tetrahydrofuran-3,4-diyl bis(2-phenylacetate) (Compound 57, 26 mg, 39.78% yield) as white solid. MS (ESI): mass calcd. for C 39 H 35 N 5 O 7 685.25, m/z found 685.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.62 (s, 1H), 8.02 (s, 1H), 7.30- 7.19 (m, 11H), 7.16-7.12 (m, 4H), 6.88 (d, J = 4.8 Hz, 1H), 6.70 (d, J = 4.4 Hz, 1H), 6.04 (d, J = 5.6 Hz, 1H), 5.43-5.40 (m, 1H), 4.63- 4.55 (m, 1H), 4.36 (dd, J = 3.2, 12.4 Hz, 1H), 4.23 (m, dd, J = 4.8, 12.4 Hz, 1H), 3.64-3.54 (m, 5H), 3.45-3.39 (m, 1H), 2.99-2.92 (m, 1H), 0.80- 0.75 (m, 2H), 0.62-0.58 (m, 2H). Example 58 Step 1: (2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-(4- chloropyrrolo[2,1- f][1,2,4]triazin-7-yl)tetrahydrofuran-2-carbonitrile (X) (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3 ,4-bis(benzyloxy)-5- ((benzyloxy)methyl)tetrahydrofuran-2-carbonitrile (400 mg, 0.712 mmol) and Isoamyl nitrite (417 mg, 3.561 mmol) was dissolved in MeCN (20 mL) and cooled to 0 o C, then TMSCl (387 mg, 3.561 mmol) in MeCN (3 mL) was added and the mixture was heated to refluxed for 3 hours under N 2 . After the reaction was finished, the solvent was removed in vacuo to give the crude and the crude was purified by chromatography on silica gel, eluting (PE : EA = 1:1) to give (2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-(4- chloropyrrolo[2,1- f][1,2,4]triazin-7-yl)tetrahydrofuran-2-carbonitrile (200 mg, 45.9% yield) as yellow oil. MS (ESI): mass calcd. for C 33 H 29 ClN 4 O 4 580.19, m/z found 580.6 [M+H] + . Step 2: (2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-(4- (cyclopropylamino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahyd rofuran-2-carbonitrile (Y) (2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-(4- chloropyrrolo[2,1- f][1,2,4]triazin-7-yl)tetrahydrofuran-2-carbonitrile (200 mg, 0.344 mmol) was dissolved in MeCN (10 mL), Cs 2 CO 3 (168 mg, 0.516 mmol) was added, cyclopropanamine in MeCN (2 mL) was added. The mixture was stirred at room temperature overnight, after the reaction was finished, the solvent was remove in vacuo to give the crude, which was purified by chromatography on silica gel, eluting (PE : EA = 1:1) to give (2R,3R,4R,5R)-3,4- bis(benzyloxy)-5-((benzyloxy)methyl)-2-(4-(cyclopropylamino) pyrrolo[2,1-f][1,2,4]triazin- 7-yl)tetrahydrofuran-2-carbonitrile (200 mg, 91.7% yield) as colorless oil. MS (ESI): mass calcd. for C 36 H 35 N 5 O 4 601.27, m/z found 601.6 [M+H] + . Step 3: (2R,3R,4S,5R)-2-(4-(cyclopropylamino)pyrrolo[2,1 triazin-7-yl)-3,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-(4- (cyclopropylamino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahyd rofuran-2-carbonitrile (150 mg, 0.249 mmol) was dissolved in DCM (10 mL) and cooled to -78 o C under N 2 , then boron trichloride (146 mg, 1.245 mmol) was added and the mixture was stirred at -78 o C for 1 hour. After the reaction was finished, the mixture was quenched by a solution of Et 3 N in MeOH (Et 3 N:MeOH=1:5, 6 mL), then removed solvent in vactuo to give the crude, which was purified by chromatography on silica gel, eluting (DCM : MeOH = 10:1) to give (2R,3R,4S,5R)-2-(4-(cyclopropylamino)pyrrolo[2,1-f][1,2,4]tr iazin-7-yl)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-carbonitrile as white solid. MS (ESI): mass calcd. for C 15 H 17 N 5 O 4 331.13, m/z found 331.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.43 (d, J = 3.2 Hz, 1H), 8.04 (s, 1H), 6.91-6.83 (m, 2H), 6.12 (d, J = 6.0 Hz, 1H), 5.21 (d, J = 4.8 Hz, 1H), 4.92 (t, J = 5.2 Hz, 1H), 4.63 (t, J = 5.2 Hz, 1H), 4.08-4.03 (m, 1H), 3.99 -3.84 (m, 1H), 3.71-3.60 (m, 1H), 3.55-3.43 (m, 1H), 3.04-2.96 (m, 1H), 0.85-0.76 (m, 2H), 0.66-0.60 (m, 2H). Example 59 Compound 59 was prepared by using the procedure followed for the compound 60. Example 60 Synthesis of (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2 -cyano-5-((((S)- (((S)-1-(2-ethylbutoxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran-3,4- diyl bis(2-phenylacetate) (Compound 60) 4-Dimethylaminopyridine (5.2 mg, 0.043 mmol), EDC-HCl (199 mg, 1.04 mmol), and phenylacetic acid (141 mg, 1.04) were dissolved in DCM (10 mL) under argon at 0° C. After 20 min at 0° C, 2-ethylbutyl ((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin- 7- yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(pheno xy)phosphoryl)-L-alaninate (250 mg, 0.415 mmol) was added to the reaction, and then the mixture was stirred at room temperature for 2 hrs. The reaction was diluted with DCM (50 mL), then washed with saturated sodium bicarbonate (2 x 25 mL). The combined aqueous layer was back extracted with EtOAc (50 mL), then the combined organic layer was dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by silica gel column chromatography (100% hexanes- 100% EtOAc), affording (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2 - cyano-5-((((S)-(((S)-1-(2-ethylbutoxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran-3,4- diyl bis(2-phenylacetate) (Compound 60, 257 mg, 74%). LC-MS: m/z= 839.8 (M + H + ). 1 H NMR (400 MHz, DMSO) δ 8.12 – 7.93 (m, 2H), 7.91 (s, 1H), 7.35 – 7.20 (m, 10H), 7.19 – 7.07 (m, 5H), 6.88 (d, J = 4.6 Hz, 1H), 6.70 (d, J = 4.5 Hz, 1H), 6.15 – 6.04 (m, 1H), 6.00 (d, J = 5.8 Hz, 1H), 5.46 (s, 1H), 4.62 (s, 1H), 4.31 – 4.14 (m, 2H), 3.93 (dd, J = 11.0, 5.8 Hz, 1H), 3.82 (dd, J = 11.0, 5.7 Hz, 1H), 3.81 – 3.69 (m, 1H), 3.72 – 3.55 (m, 3H), 3.41 (d, J = 16.1 Hz, 2H), 1.40 (p, J = 6.3 Hz, 1H), 1.23 (m, 4H), 1.15 (d, J = 7.1 Hz, 3H), 0.78 (t, J = 7.5 Hz, 6H). Examples 61-64 Compounds 61-64 were prepared by using the procedure followed for the compound 60. Example 65 Step 1: (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5 -cyano-2-((((S)-(((S)-1- (2-ethylbutoxy)-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)o xy)methyl)-4- hydroxytetrahydrofuran-3-yl tert-butyl succinate (Z) To a solution of 2-ethylbutyl (2S)-2-[({[(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl}-5-cyano-3,4-dihydroxyoxolan-2- yl]methoxy}(phenoxy)phosphoryl)amino]propanoate (1 g, 1.7 mmol), 4-(tert-butoxy)-4- oxobutanoic acid [0.44 g, 2.5 mmol], 4-Dimethylaminopyridine (0.04 g, 0.3 mmol) in MeCN stirred under nitrogen at room temperature was added a solution of DCC (0.7 g, 3.4 mmol) in MeCN dropwise over 1 minute. The reaction mixture was stirred at room temperature for 4h, The mixture was filteredthrough Celite pad to remove by-product. The filtrate was concentrated to give crude product. The residue was purified by chromatography on silica gel, eluting (MeOH:DCM = 5%) to give (2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-2-((((S)-(((S)-1-(2-ethylbuto xy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)oxy)methyl)-4-hydroxytetrahydro furan-3-yl tert-butyl succinate (400 mg, 90%) as a white solid, . MS (ESI): mass calcd. for C35H47N6O11P 758.30, m/z found 759.31 [M+H] + . Step 2: 4-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-y l)-5-cyano-2-((((S)- (((S)-1-(2-ethylbutoxy)-1-oxopropan-2-yl)amino)(phenoxy)phos phoryl)oxy)methyl)-4- hydroxytetrahydrofuran-3-yl)oxy)-4-oxobutanoic acid (65) A solution of (2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5 -cyano-2- {[({[(2S)-1-(2-ethylbutoxy)-1-oxopropan-2-yl]amino}(phenoxy) phosphoryl)oxy]methyl}-4- hydroxyoxolan-3-yl 1-tert-butyl butanedioate (600 mg, 0.79 mmol) in TFA/DCM=3:1 (10 mL) was stirred at room temperature for 2h. The mixture was concentrated and purified by Prep-HPLC (Gemini-C18150 x 21.2 mm, 5um, mobile phase: ACN-H 2 O, gradient: 30 ~ 70%) to give 4-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-y l)-5-cyano-2- ((((S)-(((S)-1-(2-ethylbutoxy)-1-oxopropan-2-yl)amino)(pheno xy)phosphoryl) oxy)methyl)- 4-hydroxytetrahydrofuran-3-yl)oxy)-4-oxobutanoic acid (130 mg, 95%) as a white solid. MS (ESI): mass calcd. for C31H39N6O11P 702.24, m/z found 703.24 [M+H] + . 1 H NMR (301 MHz, CD 3 OD) δ 7.98 (d, J = 3.7 Hz, 1H), 7.29 (t, J = 7.1 Hz, 2H), 7.19 – 7.10 (m, 3H), 7.02 – 6.97 (m, 1H), 5.31 (dd, J = 7.0, 2.9 Hz, 1H), 5.05 (dd, J = 5.7, 1.5 Hz, 1H), 4.57 (s, 1H), 4.36 (dd, J = 6.2, 3.4 Hz, 2H), 4.09 – 3.78 (m, 4H), 2.78 – 2.65 (m, 4H), 1.47 (dd, J = 11.4, 6.0 Hz, 1H), 1.40 – 1.33 (m, 3H), 1.32 – 1.26 (m, 4H), 0.88 (m, 6H). Example 66 and 67 Step1: 2-ethylbutyl((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1, 2,4]triazin-7-yl)-3-((R)-2-((tert- butoxycarbonyl)amino)-2-phenylacetoxy)-5-cyano-4-hydroxytetr ahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate & 2-ethylbutyl ((S)-(((2R,3R,4R,5R)-5-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-((R)-2-((tert-buto xycarbonyl)amino)-2- phenylacetoxy)-5-cyano-3-hydroxytetrahydrofuran-2-yl)methoxy )(phenoxy)phosphoryl)-L- alaninate (Z1 and Z2) To a solution of 2-ethylbutyl (2S)-2-[({[(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl}-5-cyano-3,4-dihydroxyoxolan-2- yl]methoxy}(phenoxy)phosphoryl)amino]propanoate (700 mg, 1.16 mmol), (R)-2-((tert- butoxycarbonyl)amino)-2-phenylacetic acid (439 mg, 1.74 mmol), 4-Dimethylaminopyridine (28 mg, 0.23 mmol) in MeCN stirred under nitrogen at room temperature was added a solution of DCC (359 mg, 1.74 mmol) in MeCN dropwise over 1 minute. The reaction mixture was stirred at room temperature for 2h, The mixture was filteredthrough Celite pad to remove by-product. The filtrate was concentrated to give crude product. The residue was purified by chromatography on silica gel, eluting (MeOH:DCM = 5%) to give a mixture of 2- ethylbutyl((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2, 4]triazin-7-yl)-3-((R)-2-((tert- butoxycarbonyl)amino)-2-phenylacetoxy)-5-cyano-4-hydroxytetr ahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (Z1) and 2-ethylbutyl ((S)-(((2R,3R,4R,5R)- 5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-((R)-2-((tert -butoxycarbonyl)amino)-2- phenylacetoxy)-5-cyano-3-hydroxytetrahydrofuran-2-yl)methoxy )(phenoxy)phosphoryl)-L- alaninate (Z2) (450 mg, 90%) as a yellow solid. ES MS M/Z = 836.33 (M+1). Step 2: 2-ethylbutyl ((S)-(((2R,3S,4R,5R)-3-((R)-2-amino-2-phenylacetoxy)-5-(4-am inopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (66) 2-ethylbutyl((S)-(((2R,3R,4R,5R)-4-((R)-2-amino-2-phenylacet oxy)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3-hydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate(67) A mixture of 2-ethylbutyl (2S)-2-{[(S)-{[(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl}-3-{[(2R)-2-{[(tert-butoxy)carbonyl]am ino}-2-phenylacetyl]oxy}-5- cyano-4-hydroxyoxolan-2-yl]methoxy}(phenoxy)phosphoryl]amino }propanoate (Z1) and 2- ethylbutyl ((S)-(((2R,3R,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin- 7-yl)-4-((R)-2-((tert- butoxycarbonyl)amino)-2-phenylacetoxy)-5-cyano-3-hydroxytetr ahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (Z2) (600 mg, 0.66 mmol) in TFA/DCM=3:1 (10 mL) was stirred at room temperature for 2h, The mixture was concentrated and purified by Prep-HPLC (Gemini-C18150 x 21.2 mm, 5um, mobile phase: ACN-H 2 O, gradient: 30 ~ 70%) to give 2-ethylbutyl ((S)-(((2R,3S,4R,5R)-3-((R)-2-amino-2-phenylacetoxy)-5-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxytet rahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (66, 128.3 mg, 95%) as a white solid, 2- ethylbutyl((S)-(((2R,3R,4R,5R)-4-((R)-2-amino-2-phenylacetox y)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3-hydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (67, 87.5 mg 95%) as a white soild .ES MS M/Z = 736.28 (M+1). Comp 66: 1 H NMR (400 MHz, CD 3 OD) δ 7.96 (d, J = 11.1 Hz, 1H), 7.60 – 7.53 (m, 2H), 7.47 (dd, J = 6.0, 2.7 Hz, 3H), 7.30 (s, 2H), 7.17 (s, 3H), 7.06-7.00 (m, 1H), 6.96 (d, J = 4.7 Hz, 1H), 5.49 – 5.42 (m, 1H), 5.30 (s, 1H), 5.14 (d, J = 5.9 Hz, 1H), 4.60 (d, J = 3.8 Hz, 1H), 4.38-4.30 (m, 2H), 4.04 – 3.95 (m, 2H), 3.88 (dd, J = 11.0, 5.7 Hz, 1H), 3.81-3.79 (m, 1H), 1.49 – 1.41 (m, 1H), 1.33 – 1.27 (m, 4H), 1.25 (d, J = 7.2 Hz, 3H), 0.85-0.80 (m, 6H). Comp 67: 1 H NMR (400 MHz, MeOD) δ 8.01 – 7.97 (m, 1H), 7.59 – 7.54 (m, 2H), 7.50-7.45 (m, 3H), 7.29 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 11.8 Hz, 3H), 7.12 (d, J = 1.0 Hz, 1H), 7.02- 7.00 (m, 1H), 5.57 (dd, J = 5.5, 2.2 Hz, 1H), 5.32 (s, 1H), 5.27 – 5.21 (m, 1H), 4.43 – 4.32 (m, 1H), 4.32 – 4.23 (m, 2H), 4.22 – 4.14 (m, 1H), 4.00-3.95 (m, 5.7 Hz, 1H), 3.90 (dd, J = 10.9, 5.7 Hz, 1H), 3.80 – 3.73 (m, 1H), 1.43 (dd, J = 12.4, 6.2 Hz, 1H), 1.33 – 1.28 (m, 4H), 1.24 (d, J = 7.2 Hz, 3H), 0.85 (t, J = 7.4 Hz, 6H). Example 68 Compound 68 was prepared by using the procedure followed for the compound 69. Example 69 Synthesis of 2-ethylbutyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl )-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(naphthalen- 1-yloxy)phosphoryl)-L- alaninate (Compound 69) Preparation of E: To a solution of naphthalen-1-ol (5.0 g, 34.7 mmol) and phosphoryl trichloride (5.3 g, 34.7 mmol) in Et 2 O (50 mL) under nitrogen at -78 ℃ was added a solution of TEA (3.5 g, 34.7 mmol) in Et 2 O (10 mL) dropwise. The reaction mixture was stirred at room temperature for 2h. The mixture was filtered through a Celite pad, and the filtrate was concentrated to give the crude naphthalen-1-yloxy)phosphonoyl dichloride (E) (9.0 g, 100%) as a colorless oil. MS (ESI): m/z= 262 [M+H] + . Preparation of F: To a solution of (naphthalen-1-yloxy) phosphonoyl dichloride (A) (2.0 g, 7.7 mmol) and 2- ethylbutyl (2R)-2-aminopropanoate (1.33 g, 7.7 mmol) in DCM (200 mL) was added TEA (3.12g, 30.8 mmol) at -78 o C under nitrogen. The mixture was stirred at room temperature for 2h, then 2,3,4,5,6-pentafluorophenol (2.83 g, 15.4 mmol) was added to the reaction mixture at 0 o C. The mixture was stirred at room temperature for 2h. The mixture was concentrated and purified by chromatography on silica gel, eluting (PE:EA = 10:1) to give 2-ethylbutyl ((naphthalen-1-yloxy) (perfluorophenoxy)phosphoryl)-L-alaninate (F) (3.8 g, 81.8%) as a yellow oil. MS (ESI): m/z= 546 [M+H] + . Preparation of Compound 69: A solution of 2-ethylbutyl (2S)-2-{[(naphthalen-1-yloxy) (2,3,4,5,6-pentafluorophenoxy) phosphoryl]amino}propanoate (F) (2.0 g, 3.708 mmol), (2R,3R,4S,5R)-2-{4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-3,4-dihydroxy-5-(hyd roxymethyl)oxolane-2- carbonitrile (0.72 g, 2.472 mmol) in THF (30 mL) and was added tert-butyl magnesium chloride (4.89 mL, 4.89 mmol) dropwise at 0 o C, then the reaction mixture was stirred at 25℃ for 12 hrs. Concentrated and the residue was purified by chromatography on silica gel, eluting (DCM: MeOH = 20:1) to give 2-ethylbutyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran- 2-yl)methoxy)(naphthalen-1- yloxy)phosphoryl)-L-alaninate (Compound 69) (0.42 g, 17.6%) as a white solid. MS (ESI): m/z= 653.8. 1 H NMR (400 MHz, DMSO) δ 8.14 – 8.06 (m, 1H), 8.03 – 7.82 (m, 4H), 7.73 (dd, J = 8.6, 4.7 Hz, 1H), 7.60 – 7.50 (m, 2H), 7.47 – 7.39 (m, 2H), 6.88 (t, J = 5.1 Hz, 1H), 6.82 (dd, J = 4.5, 1.6 Hz, 1H), 6.32 (dd, J = 16.3, 6.1 Hz, 1H), 6.27 – 6.18 (m, 1H), 5.43 – 5.36 (m, 1H), 4.63 (m, 1H), 4.38 – 4.25 (m, 2H), 4.25 – 4.12 (m, 1H), 4.03 – 3.77 (m, 4H), 1.43 – 1.32 (m, 1H), 1.26 – 1.13 (m, 7H), 0.80 – 0.71 (m, 6H). Example 70 Synthesis of neopentyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl )-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(naphthalen- 1-yloxy)phosphoryl)-L- alaninate (Compound 9) mCMQ720 Preparation of G: To a solution of (tert-butoxycarbonyl)-L-alanine (20 g,105.1 mmol) , 2,2-dimethylpropan-1- ol (11.1 g,126 mmol) and DMAP (1.28 g,10.5 mmol) in DCM (200 mL) under nitrogen at 0℃ was added a EDCI (30.2 g,157.6 mmol) portionwise . The reaction mixture was stirred at room temperature for 18h. The mixture was diluted with water (500 mL) and extracted with DCM (100 mL x 3). The DCM layers were washed with brine (100 mL), then dried over Na2SO4, concentrated to afford 26 g crude product (G) as a yellow oil. MS (ESI): m/z= 281.9 [M+Na] + . Preparation of H: A solution of neopentyl (tert-butoxycarbonyl)-L-alaninate (G) (26 g, 99.9 mmol) in dioxane/HCl (4 M, 250 mL) was stirred under nitrogen at room temperature for 18hrs. The mixture was concentrated. The residue was treated with EA (200 mL). The solid was filtered and dried to afford 15 g product (H) as a white solid (90% purity, 69.1 % yield). MS (ESI): m/z= 160.0 [M+H] + . Preparation of I: Neopentyl L-alaninate hydrochloride (H) (1.0 g, 5.12 mmol) was added to a stirred solution of naphthalen-1-yl phosphorodichloridate (2.0 g, 7.69 mmol) in DCM (30 mL) at -78 o C, then TEA (4.01 g, 39.9 mmol) was added slowly. The reaction mixture was stirred at -78 o C for 1h, then pentafluorophenol (1.8 g 10.2 mmol) was added dropwise. The reaction mixture was stirred at 0 o C for 2hrs. Filtered the reaction system and collected the filtrate.The filtrate was concentrated and purified by chromatography on silica gel, eluting (PE:EA = 10:1) to give neopentyl ((naphthalen-1-yloxy)(perfluorophenoxy)phosphoryl)-L-alanina te (I) (1.8 g, 66.6%) as a white solid. MS (ESI): m/z= 532.5 [M+H] + . Preparation of Compound 70: A solution of neopentyl ((naphthalen-1-yloxy)(perfluorophenoxy)phosphoryl)-L-alanina te (I) (1.0 g, 1.88 mmol), (2R,3R,4S,5R)-2-(4-aminopyrrolo [2,1-f][1,2,4]triazin-7-yl)-3,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (365 mg, 1.25 mmol) and tert- butyl magnesium chloride (2.5 mL, 2.5 mmol) in THF (30 mL) was stirred at 25℃ for 12 hrs. Concentrated and the residue was purified by chromatography on silica gel, eluting (DCM:MeOH = 20:1) to give neopentyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran- 2-yl)methoxy)(naphthalen-1- yloxy)phosphoryl)-L-alaninate (Compound 70) (0.26 g, 21.6%) as a white solid. MS (ESI): m/z= 639.8 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.16 – 8.05 (m, 1H), 8.00 – 7.80 (m, 4H), 7.73 (dd, J = 7.8, 4.5 Hz, 1H), 7.55 (m, 2H), 7.48 – 7.38 (m, 2H), 6.88 (t, J = 4.0 Hz, 1H), 6.82 (d, J = 4.5 Hz, 1H), 6.32 (dd, J = 17.2, 6.2 Hz, 1H), 6.28 – 6.20 (m, 1H), 5.41 (t, J = 6.3 Hz, 1H), 4.67 – 4.58 (m, 1H), 4.38 – 4.26 (m, 2H), 4.20 (dd, J = 10.3, 4.4 Hz, 1H), 4.03 – 3.95 (m, 1H), 3.94 – 3.83 (m, 1H), 3.68 (m, 2H), 1.24 (d, J = 7.0 Hz, 1H), 1.19 (d, J = 7.1 Hz, 2H), 0.83 (s, 9H). Examples 71-73 Compounds 71-73 were prepared by using the procedure followed for the compound 70. Example 74 Compound 74 was prepared by using the procedure followed for the compound 75. Example 75 Synthesis of 2-ethylbutyl ((((2R,3S,4R,5R)-5-(4-butyramidopyrrolo[2,1 triazin-7-yl)- 5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)p hosphoryl)-L-alaninate (Compound 75) Preparation of K: A mixture of 2-ethylbutyl ((((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7- yl)-6- cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)meth oxy)(phenoxy)phosphoryl)-L- alaninate (J) (800 mg, 1.24 mmol) and butanoyl butanoate (295.4mg,1.87 mmol) in pyridine was stirred at 60 ℃ for 8h. The mixture was concentrated to give crude product. The residue was purified by chromatography on silica gel, eluting (MeOH:DCM = 5%) to give 2- ethylbutyl((((3aR,4R,6R,6aR)-6-(4-butyramidopyrrolo[2,1-f][1 ,2,4]triazin-7-yl)-6-cyano-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(pheno xy)phosphoryl)-L-alaninate (K) (600 mg, 80%) as a yellow solid. MS (ESI): m/z= 723.0 (M+1). Preparation of Compound 75: A solution of 2-ethylbutyl (2S)-2-[({[(3aR,4R,6R,6aR)-6-{4-butanamidopyrrolo[2,1- f][1,2,4]triazin-7-yl}-6-cyano-2,2-dimethyl-dihydro-3aH-furo [3,4-d][1,3]dioxol-4- yl]methoxy}(phenoxy)phosphoryl)amino]propanoate (A) (600 mg, 0.84 mmol) in acetone/H 2 O (4:1) (10 mL) was stirred at rt for 12h. The mixture was concentrated and purified by chromatography on silica gel, eluting (MeOH:DCM = 5%) to give 2- ethylbutyl((((2R,3S,4R,5R)-5-(4-butyramidopyrrolo[2,1-f][1,2 ,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L -alaninate (Compound 75) (200 mg, 85%) as a white solid. MS (ESI): m/z= 673.27 (M+1). 1 H NMR (300 MHz, CD 3 OD) δ 8.25 (s, 1H), 7.32 (t, J = 7.9 Hz, 2H), 7.17-7.10 (m, 5H), 4.78 (d, J = 5.3 Hz, 1H), 4.46 – 4.35 (m, 2H), 4.30 (dd, J = 11.2, 5.5 Hz, 1H), 4.14 (t, J = 5.7 Hz, 1H), 4.02 (dd, J = 10.9, 5.7 Hz, 1H), 3.96 – 3.84 (m, 2H), 2.65 (t, J = 7.3 Hz, 2H), 1.85 – 1.69 (m, 2H), 1.45 (m, 1H), 1.31 (m, 7H), 1.04 (t, J = 7.4 Hz, 3H), 0.85 (t, J = 7.4 Hz, 6H). Example 76 Compound 76 was prepared by using the procedure followed for the compound 75. Example 77 Compound 77 was prepared by using the procedure followed for the compound 78. Example 78 Synthesis of 2-ethylbutyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl )-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)pho sphoryl)-L-phenylalaninate (Compound 78) Preparation of A1: (tert-butoxycarbonyl)-L-phenylalanine (5.0 g, 24.6 mmol) was added to a stirred solution of 2-ethylbutan-1-ol (3.01 g, 29.5 mmol) in DCM (50 mL) at 0 o C, then EDCI (9.40 g, 49.2 mmol) and DMAP (0.3 g.2.46 mmol) was added slowly. The reaction mixture was stirred at 25 o C for 12h. The residue was then purified by chromatography on silica gel, eluting (PE:EA = 10:1) to afford 2-ethylbutyl (tert-butoxycarbonyl)-L-phenylalaninate (A1) (4.4 g, 68.3%) as a colorless oil. MS (ESI): m/z= 372.5 [M+Na] + . Preparation of B1: A solution of 2-ethylbutyl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate (A1) (4.4 g, 12.6 mmol) in HCl/dioxiane (4M/L, 40 mL) was stirred at 25℃ for 12 hrs. The reaction mixture was concentrated to give 2-ethylbutyl L-phenylalaninate (B1) (2.9 g, 93.1%) as a white solid. MS (ESI): m/= 272.2 [M+Na] + . Preparation of C1: 2-ethylbutyl L-phenylalaninate (B1) (600 mg, 2.4 mmol) was added to a stirred solution of phenyl phosphorodichloridate (607 mg, 2.89 mmol) in DCM (10 mL) at -78 o C, then TEA (969.6 mg, 9.6 mmol) was added slowly. The reaction mixture was stirred at -78 o C for 1h, then pentafluorophenol (878 mg, 4.8 mmol) was added slowly. The reaction mixture was stirred at 0 o C for 2hrs. Filter the reaction system and collect the filtrate.The filtrated was concentrated and purified by chromatography on silica gel, eluting (PE:EA = 10:1) to give 2- ethylbutyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-phenylalaninate (C1) (840 mg, 54.5%) as a white solid. MS (ESI): m/z= 572 [M+H] + . Preparation of Compound 78: A solution of 2-ethylbutyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-phenylalaninate (C1) (840 mg, 1.47 mmol), (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3 ,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (285 mg, 0.98 mmol) and tert- butyl magnesium chloride (1.96 mL, 1.96 mmol) in THF (20 mL) was stirred at 25℃ for 12 hrs. Concentrated and the residue was purified by chromatography on silica gel, eluting (DCM:MeOH = 20:1) to give 2-ethylbutyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran- 2- yl)methoxy)(phenoxy)phosphoryl)-L-phenylalaninate (Compound 78) (300 mg, 17.2%) as a white solid. MS (ESI): m/z= 679.6 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.92 (d, J = 3.8 Hz, 3H), 7.34 – 7.09 (m, 8H), 7.00 (t, J = 9.0 Hz, 2H), 6.90 (t, J = 4.5 Hz, 1H), 6.82 (dd, J = 4.5, 2.6 Hz, 1H), 6.32 (dd, J = 13.1, 6.2 Hz, 1H), 6.26 – 6.12 (m, 1H), 5.36 (s, 1H), 4.61 (t, J = 4.9 Hz, 1H), 4.14 (d, J = 4.0 Hz, 1H), 4.02 – 3.75 (m, 6H), 2.98 – 2.88 (m, 1H), 2.80 (dd, J = 13.4, 8.4 Hz, 1H), 1.31 (m, 1H), 1.21 – 1.09 (m, 4H), 0.77 – 0.70 (m, 6H). Example 79 Compound 79 was prepared by using the procedure followed for the compound 78. Biological Examples Virus generation. Vero E6 cells (ATCC CRL-1586) were plated in a T225 flask with complete DMEM (Corning 15-013-CV) containing 10% FBS, 1×PenStrep (Corning 20-002- CL), 2 mM L-Glutamine (Corning 25-005-CL) overnight at 37℃ 5% CO 2 . The media in the flask was removed and 2 mL of SARS-CoV-2 strain USA-WA1/2020 (BEI Resources NR- 52281) in complete DMEM was added to the flask at an MOI of 0.5 and was allowed to incubate for 30 minutes at 34℃ 5% CO 2 . After incubation, 30 mL of complete DMEM was added to the flask. The flask was then placed in a 34℃ incubator at 5% CO 2 for 5 days. On day 5 post infection the supernatant was harvested and centrifuged at 1,000×g for 5 minutes. The supernatant was filtered through a 0.22 µM filter and stored at -80℃. HeLa-ACE2 stable cell line. HeLa-ACE2 cells were generated through transduction of human ACE2 lentivirus. The lentivirus was created by co-transfection of HEK293T cells with pBOB-hACE2 construct and lentiviral packaging plasmids pMDL, pREV, and pVSV-G (Addgene) using Lipofectamine 2000 (Thermo Fisher Scientific, 11668019). Supernatant was collected 48 h after transfection then used to transduce pre-seeded HeLa cells.12 h after transduction stable cell lines were collected, scaled up and stored. Cells were maintained in DMEM (Gibco, 11965-092) with 10% FBS (Gibco, 10438026) and 1× sodium pyruvate (Gibco, 11360070) at 37℃ 5% CO 2 . SARS-CoV-2/HeLa-ACE2 high-content screening assay. Compounds were acoustically transferred into 384-well µclear-bottom plates (Greiner, Part. No.781090-2B). HeLa-ACE2 cells were seeded in 13 µL DMEM with 2% FBS at a density of 1.0×10 3 cells per well. Plated cells were transported to the BSL3 facility where 13 µL of SARS-CoV-2 diluted in assay media was added to achieve ~30 – 50% infected cells. Plates were incubated for 24 h at 34℃ 5% CO 2 , and then fixed with final concentration of 4% formaldehyde for 1 h at 34℃ 5% CO 2. Plates were washed with 1xPBS 0.05% Tween 20 in between fixation and subsequent primary and secondary antibody staining. Human polyclonal plasma diluted 1:500 in Perm/Wash buffer (BD Biosciences 554723) was added to the plate and incubated at RT for 2 h. Six µg/mL of goat anti-human H+L conjugated Alexa 488 (Thermo Fisher Scientific A11013) together with 8 µM of antifade-46-diamidino-2-phenylindole (DAPI; Thermo Fisher Scientific D1306) in SuperBlock T20 (PBS) buffer (Thermo Fisher Scientific 37515) was added to the plate and incubated at RT for 1.5-2hr h in the dark. Plates were imaged using the ImageXpress Micro Confocal High-Content Imaging System (Molecular Devices) with a 10× objective, with 4 fields imaged per well. Images were analyzed using the Multi-Wavelength Cell Scoring Application Module (MetaXpress), with DAPI staining identifying the host-cell nuclei (the total number of cells in the images) and the SARS-CoV-2 immunofluorescence signal leading to identification of infected cells. Calu-3 high-content screening assay. The assay is carried out as outlined for the HeLa- ACE2 assay, with the following exceptions. Calu-3 cells (ATCC HTB-55), a kind gift from Dr. Catherine Chen at NCATS/NIH and Dr. Juan Carlos de la Torre at Scripps Research, were seeded at a density of 5,000 cells per 20 µL per well in assay media (MEM with 2% FBS) before SARS-CoV-2 diluted in assay media was added to achieve ~30 – 60% infected cells. Plates were incubated for 48 h at 34℃ 5% CO 2 , and then fixed with a final concentration of 4% formaldehyde. Fixed cells were stained and imaged as in the HeLa- ACE2 assay. Uninfected host cell cytotoxicity counter screens. For both the HeLa-ACE2 and Calu3 cells, compounds were acoustically transferred into 1,536-well µclear plates (Greiner Part. No.789091). HeLa-ACE2 cells were seeded in the assay-ready plates at 400 cells/well in DMEM with 2% FBS and plates were incubated for 24 h at 37℃ 5% CO 2 . Calu-3 cells were seeded in MEM with 2% FBS at a density of 600 cells per 5 µL per well and plates were incubated for 48 h at 37℃ 5% CO 2 . To assess cell viability, 2 µL of 50% Cell-Titer Glo (Promega No G7573) diluted in water was added to the cells and luminescence measured on an EnVision Plate Reader (Perkin Elmer). Example 80 Results from the assays and characterizing data on exemplary compounds are presented in Table 2 below.

Table 2.

General formulations of Compounds of the Invention F1: 5% ethanol, 30% propylene glycol, 45% PEG 400, 20% water (pH 1.9 with conc HCl) F2: 5% EtOH, 40% PEG 400, 55% 50 mM citrate buffer, pH 4-5 F3: 5% EtOH, 40% PEG 400, 55% 50 mM citrate buffer containing 0.5% Tween80, pH 4-5 F4: 15% Transcutol P, 20% Kolliphor HS-15, 65% water, pH 5.8 Pharmacokinetic Studies 1. Animals Animals (Male Cyno monkeys ~ 2-3 kg and Male rhesus macaques ~6.1-6.3 kg) were obtained from an approved vendor (SLAC Laboratory Animal Co. Ltd., Shanghai, China and/or Topgene Biotechnology, Wuhan city, Hubei Province, China and/or Suzhou Xishan Zhongke Drug R&D Co.,Ltd, Suzhou, Jiangsu, China) Acclimation/Quarantine: Following arrival, animals were assessed as to their general health by a member of the veterinary staff or other authorized personnel. Animals were acclimated for at least 3 days before being placed on study. Animal Husbandry: Animals were group housed during acclimation and individually housed during the study. The animal room environment will be controlled (target conditions: temperature 18 to 26°C, relative humidity 30 to 70%, 12 hours artificial light and 12 hours dark). Temperature and relative humidity were monitored daily. Animal Cannulation: No Animals were fasted at least 12 hours prior to the administration. All animals had access to Certified Rodent and non-Rodent Diet (Catalog # M01-F, SLAC Laboratory Animal Cl. Ltd., Shanghai, China) ad libitum 4 hours post dosing. Water was autoclaved before provided to the animals ad libitum. Periodic analyses of the water were performed and the results archived. There are no known contaminants in the diet or water that, at the levels of detection, is expected to interfere with the purpose, conduct or outcome of the study. 2. Dose Formulation Formulation: The formulations were prepared on the day of dosing. Animals were dosed within four hours after the formulation is prepared. Two 20 μL aliquots of each formulation were removed from each of the formulation solutions, transferred into 1.5 mL of polypropylene microcentrifuge tubes and run dose validation by LC/UV or LC-MS/MS. 3. Dose Administration The dose formulation was administered following facility SOPs. 4. Sample Collection Approximately 200 μL blood was collected from saphenous vein at each time point for rats and 0.5 mL for rhesus macaques. All blood samples were transferred into microcentrifuge tubes containing 4μL of K 2 EDTA (0.5M) as anti-coagulant and placed on wet ice until processed for plasma. 5. Blood/Plasma processing Blood: Blood samples were processed for plasma by centrifugation at approximately 4 °C, 3000 g 15 min within half an hour of collection. Plasma samples was stored in polypropylene tubes, quick frozen over dry ice and kept at −70±10 °C until LC/MS/MS analysis. 6. Sample Analysis Dose formulation concentration verification ^ Aliquots of the formulations were collected in the middle position of each dose formulation in duplicate ^ The concentrations of the test compound in dose formulation samples were determined by the LC/UV or LC/MS/MS method Bioanalytical method and sample analysis ^ LC-MS/MS methods for the quantitative determination of test compound in corresponded biological matrix was developed under non-GLP compliance. ^ A calibration curve with 8 non-zero calibration standards was applied for the method including LLOQ. ^ A set of QC samples consisting of low, middle, and high concentration was applied for the method. ^ The study sample analysis will be performed concurrently with a set of calibration standards and two sets of QC samples using the LC-MS/MS method (If sample numbers were more than 48, then two calibration curves with 2 sets of QC samples were applied). ^ Acceptance criteria: Linearity: a minimum of 6 calibration standards was back calculated to within ±20% of their nominal values in plasma Accuracy: A minimum of 4 out of 6 QC samples was back calculated to within ±20% of their nominal values in plasma. Specificity: The mean calculated concentration in the single blank matrix should be 0.5 times the LLOQ. Sensitivity: the LLOQ will be tried to target 1~3 ng/mL. Carryover: the mean calculated carry-over concentration in the single blank matrix immediately after the highest standard injection should be £ LLOQ. If the carryover couldn’t meet the criteria, then the percent of carryover should be estimated following in-house bioanalytical SOP. 7. Data Analysis Plasma concentration versus time data was analyzed by non-compartmental approaches using the Phoenix WinNonlin 6.3 software program. C max , T max , T ½ , AUC (0-t) , AUC (0-inf) , MRT (0-t) , MRT (0-inf) , %F and graphs of plasma concentration versus time profile were reported. Example 81: Compounds 19, 25, 39, 59, GS-441524, GS-5734 and GS-621763 were subjected to a single dose Cyno/rhesus macaque PK studies via oral route of administration with equivalent doses of 2.3-10 mg/kg of GS-441524. Oral administration of comp 39 shows ~9x increase in dose-normalized (DN) area under curve (AUC) exposure vs. GS-441524 in Rhesus; ~5.2x better DN AUC and 4x better MRT than GS-621763. Comp 39 is 3-fold more stable in a human primary hep assay than GS-5734 (t1/2: 21.5 vs 7.5 min) and has improved permeability Caco-2 Papp A-B/B-A than GS-5734 (2.2 vs 0.1). In addition, compounds 19, 25, 59 have shown improved DN AUC by 1.8x, 3.8x and 2.2x fold respectively when compared to GS-441524 in Cyno PK studies. Compounds 19 and 25 have higher Cmax than compound 39, but faster elimination and lower AUC. Table 3 shows the Cyno/Rhesus PK data for compounds 19, 25, 39, 59, GS-441524, GS- 5734 and GS-621763 (structure shown below) following PO administration at 2.3-10 mg/kg equivalent dose of GS-441524. The data are shown in graphic form in Figure 1.

As set forth above, the present invention provides an approach to improve oral exposure by modifying RDV or its parent nucleoside (GS-441524) to increase absorption. This patent application discloses various molecules that are ester prodrugs of GS-441524 that show increased absorption and exposure. The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the disclosure should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled. This application refers to various issued patents, published patent applications, journal articles, and other publications, each of which is incorporated herein by reference.




 
Previous Patent: HUMAN CORTICAL ORGANOIDS WITH ENGINEERED MICROGLIA-LIKE CELLS

Next Patent: SYSTEM FOR REMOVING POLYMER PELLETS AND OTHER CONTAMINANTS FROM WATER RESERVOIRS