Nucleotide and nucleoside therapeutic compositions, combinations, and related uses

Abstract

The present disclosure relates to nucleotide and nucleoside therapeutic compositions and uses in the treatment of infectious diseases, viral infections, and cancers, where the base of the nucleotide or nucleoside comprises at least one thiol, thione, or thioether. The nucleotide and nucleoside therapeutic compositions can include at least one second antiviral agent, such as an antiviral agent for treating or preventing an enterovirus infection.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 184,609, filed May 5, 2021, which is incorporated by reference herein in its entirety.

[0002] The present disclosure relates to nucleotide and nucleoside therapeutic compositions and their associated uses. In certain embodiments, the present disclosure relates to sulfur-containing nucleosides or salts thereof, optionally complexed with phosphorus oxides. In certain embodiments, the present disclosure relates to complex compounds or salts thereof, including amino acid esters, lipids or sphingolipids, or derivatives linked to nucleotides or nucleosides by phosphorus oxides. In certain embodiments, the present disclosure contemplates pharmaceutical compositions comprising these compounds in combination for use in the treatment of infectious diseases, viral infections, and cancer. [Background technology]

[0003] Nucleoside and nucleotide phosphates and phosphonates are clinically useful as antiviral agents. Two examples are tenofovir disoproxil fumarate for the treatment of human immunodeficiency virus and adefovir dipivoxil for the treatment of hepatitis B virus infection. The administration of three or more antiretroviral drugs in combination, e.g., highly active antiretroviral therapy (HAART), has significantly reduced the morbidity and mortality associated with HIV infection. However, there is a growing need for new antiviral agents to address the critical issues of resistance and entry into viral sanctuaries (commonly referred to as privileged compartments). Penetration into privileged compartments may be partially responsible for the current inability of chemotherapy to completely eliminate patients with HIV infection and the emergence of resistance.

[0004] Antiviral agents that are non-phosphorylated nucleotides and nucleotide derivatives need to be phosphorylated to actively inhibit viral replication. Nucleoside analogs enter cells via two types of broad specificity transporters, concentrative nucleoside transporters (CNTs) and equilibrative nucleoside transporters (ENTs). Once inside the body, they utilize the host's nucleoside salvage pathways and are sequentially phosphorylated by deoxynucleoside kinases (dNKs), deoxynucleoside monophosphate kinases (dNMPKs), and nucleoside diphosphate kinases (NDPKs). However, the intracellular activation of these compounds is often compromised by the high substrate specificity of the host's endogenous kinases. In vitro and in vivo studies have demonstrated that the first and / or second phosphorylation catalyzed by dNKs and dNMPKs often represents the rate-limiting step for nucleoside analog activation. Thus, there is a need to identify improved antiviral nucleoside analogs that have structural features that allow them to be sufficiently activated by cellular kinases.

[0005] McGuigan et al., J Med Chem, 2005, 48(10), 3504-3515, reported that phenylmethoxyalanyl phosphoramidate of abacavir as a prodrug leads to enhanced antiviral efficacy. Painter et al., Antimicrob Agents Chemother, 2007, 51(10), 3505-3509, reported the use of a hexadecyloxypropyl prodrug ester named CMX157 to enhance the oral availability of tenofovir. PCT Patent Application No. 2014 / 054930 and PCT Publication No. 2015 / 038596A1 report nucleotide analogs that exhibit antiviral activity that were not developed into clinical trials.

[0006] Diverse viruses in the Enterovirus genus of the Picornaviridae family are positive-sense single-stranded RNA viruses known to cause a variety of diseases, including hand, foot and mouth disease (HFMD), encephalitis, aseptic meningitis, myocarditis, and various respiratory diseases. See Journal of Biomedical Science 28,10,(2021). Most EV infections are mild, but symptoms can be severe in young and immunocompromised individuals. In recent years, viruses such as EV-A71 and CV-A16 have emerged as serious public health threats, as they have caused HFMD outbreaks in China and Southeast Asia. In addition, EV-D68 caused a severe lower respiratory tract infection outbreak in North America in 2014. Therefore, broad-spectrum antiviral drugs that can inhibit multiple EVs across the genus would help overcome the public health burden caused by these EVs. (Ibid.). Five compounds that have been evaluated in Phase I and II clinical trials related to entrovirus infection include disoxalil, pleconaril, pirodavir, vapentavir, and pocapavir. Most of these inhibitors, despite promising in vitro efficacy, have shown insufficient efficacy and undesirable side effects at the doses tested in clinical trials. References cited herein are not admitted as prior art.

[0007] There is a need for compounds, compositions, and methods that are effective for treating and preventing viral infections, particularly infections caused by viruses of the Enterovirus genus. The compounds, compositions, and methods disclosed herein address these and other needs. Summary of the Invention

[0008] The present disclosure relates to nucleotide and nucleoside therapeutic compositions and uses related thereto. Included are conjugated compounds or salts thereof, including sulfur-containing nucleosides, optionally conjugated with a phosphorus oxide, prodrugs, or conjugated compounds or salts thereof, including amino acid esters, lipids, or sphingolipids, or derivatives linked to the nucleotide or nucleoside by a phosphorus oxide.

[0009] In some aspects of the disclosure, the composition comprises a compound having the following formula: [ka] (β-D or β-L) or a pharma- ceutically acceptable salt thereof, wherein U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; X is O, CH 2 , CHF, CF 2 , or CD 2 and R 1 is OH, monophosphate, diphosphate, or triphosphate; R 2 , R 3 , R 4 , R 6 , and R 7 However, each independently, H, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 9 C replaced with 1-22 alkyl, R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by R 6 and R 7 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9can be replaced by Each R 9 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R 5 is H or D, Q is a base such as: [ka] It is one of the wherein Z is OH, alkoxide, methoxide, ethoxide, halogen, thiol, alkylthio, alkyl, lipid, or geranyl, or a pharma- ceutically acceptable salt thereof; and a second antiviral agent.

[0010] In another aspect of the disclosure, the composition comprises a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein A is O or S; A' is OH or BH 3 - M + and R 5 is H or D, U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; Each X is independently O, S, NH, NR 8 , N.H.O.H., N.R. 8 OH,NHOR 8 , or NR 8 OR 8and R 1 But OH, SH, NH 2 , OR 8 , S.R. 8 , N.H.R. 8 , N.H.O.H., N.R. 8 OH,NHOR 8 , or NR 8 OR 8 and In formulae Ic and Id, any X is S or R 1 But, SR 8 or both X are S and R 1 But, SR 8 and In formula Ie, at least one X is S; Y is CH, N, or CR 2 and Z is CH, N, or CR 2 and R 3 , R 4 , R 6 , R 7 , and R 10 However, each independently, H, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 9 C replaced with 1-22 alkyl, R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by R 6 and R 7can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by R 8 is methyl, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 9 C replaced with 1-22 is alkyl, Each R 9 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R 2 is deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, optionally one or more of the same or different, R 9 C replaced with 1-22 or a pharma- ceutically acceptable salt thereof; and a second antiviral agent.

[0011] In some embodiments of the compounds or pharma- ceutically acceptable salts disclosed herein, A is O, A' is OH, U is O, and R 5 is H, Y and Z are CH, R 3 , R 4 , R 6 , R 7 , R 10 are each independently H, CH 3 , CD 3 , C.F. 3 , C.F. 2 H, CFH 2 , O.H., S.H., and N.H. 2 , N3 , CHO, CN, Cl, Br, F, or I.

[0012] In some embodiments of the compounds or pharma- ceutically acceptable salts disclosed herein, one X is S and the other X is O, and R 3 is H and R 4 is OH and R 6 But, CH 3 and R 7 is OH and R 10 But it's H.

[0013] In a further aspect of the disclosure, the composition has the following structure: [ka] , or a pharma- ceutically acceptable salt thereof, and a second antiviral agent.

[0014] In another further aspect of the present disclosure, the composition comprises a compound of the formula: [ka] (β-D or β-L) or a pharma- ceutically acceptable salt thereof, wherein U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; X is O, CH 2 , CHF, CF 2 , or CD 2 and R 5 is H or D, R 2 , R 3 , R 4 , R 8 , and R 9 However, each independently, H, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 10 C replaced with 1-22 alkyl, R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by R 6 and R 7 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by R 1 But the formula: [ka] It is one of the Y is O or S; Y 1 is Oaryl or BH 3 - M + and Y 2 But OH or BH 3 - M + and aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, 4-bromophenyl; Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, and Q is optionally substituted with one or more of the same or different alkyl, halogen, cycloalkyl; Each R 10are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; 6 optionally one or more, the same or different, R 10 or a pharma- ceutically acceptable salt thereof, and a second antiviral agent.

[0015] In some embodiments of the compounds or pharma- ceutically acceptable salts disclosed herein, U is O and X is CH. 2 Q is a pyrimidine having at least one thione, thiol, or thioether at the 2- and / or 4-position of the pyrimidine; R 5 is H and R 2 , R 3 , R 4 , R 8 , and R 9 are each independently H, CH 3 , CD 3 , C.F. 3 , C.F. 2 H, CFH 2 , O.H., S.H., and N.H. 2 , N 3 , CHO, CN, Cl, Br, F, or I.

[0016] In further embodiments of the compounds or pharma- ceutically acceptable salts disclosed herein, R 1 but, [ka] and Y is O and Y 1 is phenoxy, and R 6 iso-propyl.

[0017] In yet a further aspect of the disclosure, the composition comprises a compound having the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; R 5 is H or D, R 1 But the formula: [ka] It is one of the Y is O or S; Y 1 is Oaryl or BH 3 - M + and Y 2 But OH or BH 3 - M + and Each X is independently O, S, NH, NR 8 , N.H.O.H., N.R. 8 OH,NHOR 8 , or NR 8 OR 8 and R 2 But OH, SH, NH 2 , OR 8 , S.R. 8 , N.H.R. 8 , N.H.O.H., N.R. 8 OH,NHOR 8 , or NR 8OR 8 and In formulae Ig and Ih, one of X is S or R 2 But, SR 8 or both X are S and R 2 But, SR 8 and In formula Ii, at least one X is S; W is CH, N, or CR 8 and Z is CH, N, or CR 8 and R 3 , R 4 , R 7 , R 9 , and R 14 However, each independently, H, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 10 C replaced with 1-22 alkyl, R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by R 7 and R 14 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, 4-bromophenyl; R 8 is deuterium, methyl, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 10 C replaced with 1-22 is alkyl, R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; 6 optionally one or more, the same or different, R 10 or a pharma- ceutically acceptable salt thereof, and a second antiviral agent.

[0018] In other embodiments of the compounds or pharma- ceutically acceptable salts disclosed herein, U is O, W and Z are CH, and R 5 is H and R 1 but, [ka] wherein Y is O and Y 1 is phenoxy, and R 6 is an alkyl group.

[0019] In further embodiments of the compounds or pharma- ceutically acceptable salts disclosed herein, R 3 , R 4 , R 7 , R9 , and R 14 are each independently H, CH 3 , CD 3 , C.F. 3 , C.F. 2 H, CFH 2 , O.H., S.H., and N.H. 2 , N 3 , CHO, CN, Cl, Br, F, or I. In further embodiments of the compounds or pharma- ceutically acceptable salts disclosed herein, the compound has a structure represented by formula Ia, or a pharma- ceutically acceptable salt thereof, wherein one X is S and the other X is O.

[0020] In other further embodiments of the compounds or pharma- ceutically acceptable salts disclosed herein, R 6 iso-propyl.

[0021] In still further embodiments of the compounds or pharma- ceutically acceptable salts disclosed herein, R 5 is H and R 3 is H and R 4 is hydroxyl, and R 7 is hydroxyl, and R 14 is methyl, and R 1 but, [ka] and Y is O and Y 1 is phenoxy, and R 6 iso-propyl.

[0022] In a further aspect of the disclosure, the composition has the following structure: [ka] and one compound of and a second antiviral agent.

[0023] In some aspects of the disclosure, the composition comprises a compound having the following formula: [ka] or a pharma- ceutically acceptable salt thereof, U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; X is O, CH 2 , CHF, CF 2 , or CD 2 and R 5 is H or D, Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, and Q is optionally substituted with one or more of the same or different alkyl, halogen, or cycloalkyl; R 2 , R 3 , R 4 , R 8 , and R 9 However, each independently, H, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 10 C replaced with 1-22 alkyl, R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by R 8 and R 9 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10can be replaced by Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R 1 But the formula: [ka] It is one of the Y is O or S; Y 1 But OH or BH 3 _ M + and A compound or a pharma- ceutically acceptable salt thereof, wherein the lipid is as described herein; and a second antiviral agent.

[0024] In some embodiments of the compounds or pharma- ceutically acceptable salts disclosed herein, U is O, Q is a pyrimidine having at least one thione, thiol, or thioether at the 2- and / or 4-position of the pyrimidine, and R 5 But it's H.

[0025] In some embodiments of the compounds or pharma- ceutically acceptable salts disclosed herein, the lipid can be hexadecyloxypropyl, 2-aminohexadecyloxypropyl, 2-aminoarachidyl, lauryl, myristyl, palmityl, stearyl, arachidyl, behenyl, lignoceryl, or a sphingolipid described herein.

[0026] In a further aspect of the disclosure, the composition has the following structure: [ka] or a pharma- ceutically acceptable salt thereof, wherein R 5 is H or D, U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; E is CH 2 or CD 2 and R 1 But the formula: [ka] It is one of the Y is O or S; Y 1 But OH or BH 3 _ M + and the lipid is as described herein; Each X is independently O, S, NH, NR 8 , N.H.O.H., N.R. 8 OH,NHOR 8 , or NR 8 OR 8 and R 2 But OH, SH, NH 2 , OR 8 , S.R. 8 , N.H.R. 8 , N.H.O.H., N.R. 8 OH,NHOR 8 , or NR 8 OR 8 and In formulae Ip and Iq, one of X is S or R 2 But, SR 8 or both X are S and R 2 But, SR 8 and In formula Ir, at least one X is S; W is CH, N, or CR 8and Z is CH, N, or CR 8 and R 8 is deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 10 C replaced with 1-22 is alkyl, R 3 , R 4 , R 6 , R 7 , and R 14 However, each independently, H, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 10 C replaced with 1-22 alkyl, R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by R 7 and R 14 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2A compound or a pharma- ceutically acceptable salt thereof selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; and a second antiviral agent.

[0027] In some embodiments of the compounds or pharma- ceutically acceptable salts disclosed herein, E is CH 2 where U is O, and Y and Z are CH.

[0028] The second antiviral agent can be selected from disoxalil, pleconaril, pirodavir, vappendavir, pocapavir, or a combination thereof. In some examples, the second antiviral agent is selected from disoxalil, pleconaril, pirodavir, vappendavir, pocapavir, or a combination thereof, and the compound is [ka] is selected from.

[0029] Also described are pharmaceutical compositions for the treatment or prevention of a viral infection, comprising a composition described herein and a pharma- ceutical acceptable carrier. In some embodiments, the pharmaceutical formulation comprises EIDD-2023, or a pharma- ceutical acceptable salt thereof, and and a pharma- ceutically acceptable carrier.

[0030] Also described are liposome compositions comprising a composition described herein and a pharma- ceutically acceptable carrier.

[0031] Methods are described for treating infections caused by RNA and DNA viruses, comprising administering to a host in need thereof an effective amount of a composition described herein. The RNA or DNA viruses include picornaviruses, cardioviruses, enteroviruses, coxsackieviruses A, B, and C, coxsackievirus A16, EV-D68, EV-A71, rhinoviruses, polioviruses, echoviruses, erboviruses, hepatoviruses, kobuviruses, parechoviruses, teschoviruses, noroviruses, sapoviruses, lagoviruses, vesiviruses, caliciviruses, including astroviruses, togaviruses, flaviviruses, hepaciviruses, coronaviruses, arteriviruses, rhabdoviruses, filoviruses, paramiviruses, and the like. The virus may be a xovirus, orthomyxovirus, hantavirus, reovirus, rotavirus, birnavirus, chrysovirus, cystovirus, hypovirus, partivirus, totovirus, lentivirus, polyomavirus, papillomavirus, adenovirus, circovirus, parvovirus, erythrovirus, betaparvovirus, amdovirus, densovirus, iteravirus, brevidensovirus, pehudensovirus, herpesvirus 1, 2, 3, 4, 5, 6, 7, and 8, poxvirus, or hepadnavirus.

[0032] In some embodiments, the RNA or DNA virus is an enterovirus. Thus, methods of treating or preventing an enterovirus infection are provided, comprising administering to a host in need thereof a composition described herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the composition comprises EIDD-2023, or a pharmaceutically acceptable salt thereof, and and a pharmaceutically acceptable carrier. The enterovirus infection can be selected from the group consisting of Coxsackievirus A, B, and C, Coxsackie A16, EV-D68, EV-A71, rhinovirus, poliovirus, and echovirus. In some examples, the enterovirus infection is a Coxsackievirus, such as Coxsackie A16. In some embodiments of the methods disclosed herein, the host being treated can be immunosuppressed. [Brief description of the drawings]

[0033] [Figure 1] 1 illustrates certain embodiments of the present disclosure. [Diagram 2] Illustrated are exemplary thio-containing bases of certain embodiments provided herein. [Diagram 3] The in vivo unraveling of McGuigan prodrugs is illustrated. The metabolic unraveling of these prodrugs begins with esterase-catalyzed cleavage of the carboxylic acid ester, followed by several chemical rearrangement steps to yield an amino acid phosphoramidate. The final cleavage is carried out by one of several endogenous phosphoramidases, one of which has been identified as histidine triad nucleotide-binding protein 1 (hINT1). [Figure 4] Monophosphate and diphosphate structure type embodiments are illustrated. [Diagram 5] 1 illustrates a scheme for the synthesis of the conjugate. [Figure 6] 1 is the X-ray crystal structure of EIDD-02023 crystallized using the method of Example 86. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] The present disclosure relates to nucleotide and nucleoside therapeutic compositions and their associated uses. In certain embodiments, the present disclosure relates to sulfur-containing nucleosides or salts thereof, optionally complexed with a phosphorus oxide. In certain embodiments, the present disclosure relates to complex compounds or salts thereof, including amino acid esters, lipids or sphingolipids, or derivatives linked to a nucleotide or nucleoside by a phosphorus oxide. In certain embodiments, the present disclosure contemplates pharmaceutical compositions comprising these compounds for use in the treatment of infectious diseases, viral infections, and cancer.

[0035] In certain embodiments, the present disclosure relates to phosphorus oxide prodrugs of 2'-fluoro nucleosides containing sulfur-containing bases for the treatment of positive-sense and negative-sense RNA viral infections via targeting virally encoded RNA-dependent RNA polymerase (RdRp). The present disclosure also provides the general use of lipids and sphingolipids to deliver nucleoside analogs for the treatment of infectious diseases and cancer.

[0036] In certain embodiments, the present disclosure relates to a conjugate compound or salt thereof comprising a sphingolipid or derivative linked to a nucleotide or nucleoside by a phosphorus oxide, the nucleotide or nucleoside containing a sulfur-containing base. In certain embodiments, the phosphorus oxide is a phosphate, phosphonate, polyphosphate, or polyphosphonate, and the phosphate, phosphonate, or phosphate in the polyphosphate or polyphosphonate is optionally a phosphorothioate or phosphoroamidate. In certain embodiments, the lipid or sphingolipid is covalently bound to the phosphorus oxide via an amino group or a hydroxyl group.

[0037] A nucleotide or nucleoside is a heterocycle containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, which substituted heterocycle is optionally substituted with one or more, the same or different, alkyl, halogen, or cycloalkyl.

[0038] In certain embodiments, a heterocycle containing two or more nitrogen heteroatoms is substituted with at least one thione, thiol, or thioether, or is selected from pyrimidine-2-one-4-thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5-fluoropyrimidine-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4-dithione, or 4-amino-5-fluoropyrimidine-2-thione.

[0039] In certain embodiments, the sphingolipid is a saturated or unsaturated 2-amino alkyl or 2-amino octadecane, optionally substituted with one or more substituents. In certain embodiments, the sphingolipid derivative is a saturated or unsaturated 2-amino octadecane-3-ol, optionally substituted with one or more substituents. In certain embodiments, the sphingolipid derivative is a saturated or unsaturated 2-amino octadecane-3,5-diol, optionally substituted with one or more substituents.

[0040] In certain embodiments, the present disclosure contemplates a pharmaceutical composition comprising any compound disclosed herein and a pharma- ceutical acceptable excipient.In certain embodiments, the pharmaceutical composition is in the form of a pill, capsule, tablet, or saline buffer containing sugar.In certain embodiments, the composition may contain a second active agent, such as an analgesic, an anti-inflammatory, a nonsteroidal anti-inflammatory, an antiviral, an antibiotic, or an anticancer agent.

[0041] In certain embodiments, the present disclosure relates to a method of treating or preventing an infectious disease, comprising administering an effective amount of a compound disclosed herein to a subject in need thereof. Typically, the subject has been diagnosed with or is at risk for a viral, bacterial, fungal, protozoan, or parasitic infection.

[0042] In certain embodiments, the present disclosure relates to a method of treating a viral infection, comprising administering an effective amount of a pharmaceutical composition disclosed herein to a subject in need thereof. In certain embodiments, the subject is a mammal, such as a human. In certain embodiments, the subject has been diagnosed with a chronic viral infection. In certain embodiments, the administration is under conditions such that the viral infection is no longer detectable. In certain embodiments, the subject has been diagnosed with an RNA virus, a DNA virus, or a retrovirus infection. In certain embodiments, the subject has been diagnosed with a virus, i.e., a double-stranded DNA virus, a sense single-stranded DNA virus, a double-stranded RNA virus, a sense single-stranded RNA virus, an antisense single-stranded RNA virus, a sense single-stranded RNA retrovirus, or a double-stranded DNA retrovirus.

[0043] In certain embodiments, the subject is diagnosed with an infection caused by an enterovirus, including 15 serotypes: Enterovirus A (formerly human enterovirus A), Enterovirus B (formerly human enterovirus B), Enterovirus C (formerly human enterovirus C), Enterovirus D (formerly human enterovirus D), Enterovirus E (formerly bovine enterovirus A), Enterovirus F (formerly bovine enterovirus B), Enterovirus G (formerly porcine enterovirus B), Enterovirus H (formerly simian enterovirus A), Enterovirus I, Enterovirus J, Enterovirus K, Enterovirus L, Rhinovirus A (formerly human rhinovirus A), Rhinovirus B (formerly human rhinovirus B), Rhinovirus C (formerly human rhinovirus C). These 15 serotypes include: Enterovirus A: serotypes CVA-2, CVA-3, CVA-4, CVA-5, CVA-6, CVA-7, CVA-8, CVA-10, CVA-12, CVA-14, and CVA-16. Enterovirus B: serotypes CVB-1, CVB-2, CVB-3, CVB-4, CVB-5, CVB-6, and CVB-9. Enterovirus C: Coxsackieviruses, including serotypes CVA-1, CVA-11, CVA-13, CVA-17, CVA-19, CVA-20, CVA-21, CVA-22, and CVA-24. Enterovirus B: Echoviruses including serotypes E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-9, E-11 through E-21, E-24, E-25, E-26, E-27, E-29, E-30, E-31, E32, and E-33. Enterovirus A: serotypes EV-A71, EV-A76, EV-A89 to EV-A92, EV-A114, EV-A119, EV-A120, EV-A121, SV19, SV43, SV46, and BabEV-A13. Enterovirus B: serotypes EV-B69, EV-B73 to EV-B75, EV-B77 to EV-B88, EV-B93, EV-B97, EV-B98, EV-B100, EV-B101, EV-B106, EV-B107, EV-B110 to EV-B113, and SA5. Enterovirus C: serotypes EV-C95, EV-C96, EV-C99, EV-C102, EV-C104, EV-C105, EV-C109, EV-C113, EV-C116, EV-C117, and EV-C118. Enterovirus D: serotypes EV-D68, EV-D70, EV-D94, EV-D111, and EV-D120. Enterovirus E: serotypes EV-E1, EV-E2, EV-E3, EV-E4, and EV-E5. Enterovirus F: serotypes EV-F1, EV-F2, EV-F3, EV-F4, EV-F5, EV-F6, and EV-F7. Enterovirus G: serotypes EV-G1 to EV-G20. · Enterovirus H: serotype EV-H. Enterovirus I: serotypes EV-I1 and EV-I2. Enterovirus J: serotypes: EV-J1, EV-J103, and EV-J108. Enterovirus K: serotypes EV-K1 and EV-K2. Enterovirus L: Enteroviruses including serotype EV-L1. ·Rhinovirus A: Serotypes RV-A1, RV-A1B, RV-A2, RV-A7~RV-A13, RV-A15, RV-A16, RV-A18~RV-A25, RV-A28~RV-A34, RV-A36, RV-A38~RV-A41, RV-A43, RV-A45~ RV-A47, RV-A49~RV-A51, RV-A53~RV-A68, RV-A71, RV-A73~RV-A78, RV-A80~RV-A82, RV-A85, RV-A88~RV-A90, RV-A94, RV-A96, and RV-A100~RV-A108 Rhinovirus B: serotypes RV-B3 to RV-B6, RV-B14, RV-B17, RV-B26, RV-B27, RV-B35, RV-B37, RV-B42, RV-B48, RV-B52, RV-B69, RV-B70, RV-B72, RV-B79, RV-B83, RV-B84, RV-B86, RV-B91 to RV-B93, RV-B97, and RV-B99 to RV-B104 Rhinovirus C: Rhinoviruses including serotypes RV-C1 through RV-C51, RV-C54, RV-C55, and RV-C56. · Enterovirus C: Polioviruses including serotypes PV-1, PV-2, and PV-3.

[0044] In certain embodiments, the subject is diagnosed with influenza A virus, including subtypes H1N1, H3N2, H7N9, or H5N1, influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, human coronavirus, SARS coronavirus, MERS coronavirus, human adenovirus (HAdV-1-55), human papillomavirus (HPV) types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV), BK virus, Merkel cell polyomavirus, Coxsackie A virus, norovirus, rubella virus, lymphocytic choriomeningitis virus (LCV), lymphocytic choriomeningitis virus (HPV ... have been diagnosed with: CMV, chikungunya, Eastern equine encephalitis virus (EEEV), Western equine encephalitis virus (WEEV), Venezuelan equine encephalitis virus (VEEV), yellow fever virus, measles virus, mumps virus, respiratory syncytial virus, rinderpest virus, California encephalitis virus, hantavirus, rabies virus, Ebola virus, Marburg virus, herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), lymphotropic herpes virus, roseolovirus, or Kaposi's sarcoma-associated herpes virus, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, or human immunodeficiency virus (HIV).

[0045] In certain embodiments, the subject is diagnosed with influenza A, including subtypes H1N1, H3N2, H7N9, H5N1 (low pass), and H5N1 (high pass) influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, SARS coronavirus, MERS-CoV, human adenovirus types (HAdV-1-55), human papillomavirus (HPV) types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV), BK virus, Merkel cell polyomavirus, Coxsackie A virus, norovirus, rubella virus, lymphocytic choriomeningitis virus (LCMV), yellow fever virus, measles virus, mumps virus, respiratory syncytial virus, parainfluenza virus, Viruses 1 and 3, Rinderpest virus, Chikungunya, Eastern Equine Encephalitis virus (EEEV), Venezuelan Equine Encephalitis virus (VEEV), Western Equine Encephalitis virus (WEEV), California Encephalitis virus, Japanese Encephalitis virus, Rift Valley Fever virus (RVFV), Hantavirus, Dengue virus serotypes 1, 2, 3, and 4, West Nile virus, Tacaribe virus, Junin, Rabies virus, Ebola virus, Marble have been diagnosed with HIV, adenovirus, herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus, roseolovirus, or Kaposi's sarcoma-associated herpesvirus, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, or human immunodeficiency virus (HIV).

[0046] In certain embodiments, the subject has been diagnosed with: Acute poliomyelitis via the fecal route, etc. Polio-like syndrome, such as that seen in children who test positive for enterovirus 68; A nonspecific febrile illness is the most common symptom of enterovirus infection. Symptoms other than fever include myalgia, sore throat, gastrointestinal / abdominal pain, and headache. However, in neonates, the situation may be that of sepsis, which is severe and life-threatening; It may be aseptic meningitis. In the United States, enteroviruses cause 30,000 to 50,000 hospitalizations with meningitis annually, resulting in 10 to 15 million infections. Bornholm disease or epidemic pleurisy, characterized by severe paroxysmal pain in the chest and abdomen accompanied by fever and sometimes nausea, headache and vomiting; Pericarditis and / or myocarditis, usually caused by an enterovirus. Symptoms may include fever with difficulty breathing and chest pain. Cardiac arrhythmias, heart failure, and myocardial infarction have also been reported. Acute hemorrhagic conjunctivitis that may be caused by enteroviruses Herpangina can be caused by the Coxsackie A virus. Herpangina causes a vesicular rash in the mouth and throat accompanied by high fever, sore throat, fatigue, and often difficulty swallowing, loss of appetite, back pain, and headache.

[0047] Hand, foot and mouth disease, a childhood disease most commonly caused by infection with Coxsackie A virus or EV71; Encephalitis is a rare symptom of enterovirus infection. In general, when encephalitis occurs, the most common enterovirus known to cause it is echovirus 9. Myocarditis is characterized by inflammation of the heart muscle (cardiac muscle cells). Over the past few decades, enteroviruses have been identified as being involved in the development of myocarditis. One of the most common enteroviruses known to cause myocarditis is the Coxsackie B3 virus, acute respiratory or gastrointestinal infections associated with enteroviruses, which may be a contributing factor in chronic fatigue syndrome; or A combination of them.

[0048] In certain embodiments, the subject has been diagnosed with gastroenteritis, acute respiratory disease, severe acute respiratory syndrome, post-viral fatigue syndrome, viral hemorrhagic fever, acquired immune deficiency syndrome, or hepatitis.

[0049] In certain embodiments, the pharmaceutical compositions disclosed herein comprise 25-hydroxycholesterol, AN-12-H5, dioxalivir, pirodavir, bapentavir and pocapavir, abacavir, acyclovir, acyclovir, adefovir, amantadine, amiloride, amprenavir, ampligen, arbidol, atazanavir, atripla, aurintricarboxylic acid, BF738735, boceprevir, BPR-3P0128, buthionine sulfoximine, cidofovir, cyclosporine A, combivir, darunavir, DAS181, DC 07090, delavirdine, dibucaine, didanosine, docosanol, DTrip-22, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, enviroxime, famciclovir, fluoxetine, fomivirsen, fosamprenavir, foscarnet, phosphonet, ganciclovir, geldanamycin, gemcitabine, gliotoxin, GPC-N114, guanidine hydrochloride, GW5074, HBB, HL05100P2, ibacitabine, immunovir, idoxuridine, imiquimod, indinavir, inositol interferon type III, interferon type II, interferon type I, intrazonazole, lamivudine, lopinavir, loviride, maraviroc, moroxydine, methisazone, MRL-1237, nelfinavir, nevirapine, nexavir, NIM-811, oseltamivir, OSW-1, peginterferon alfa-2a, penciclovir, peramivir, PIK93, pirlindole, pleconaril (Picovir), podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, rupintrivir, pyramididine, and combinations thereof.

[0050] In certain embodiments, the present disclosure relates to the use of the compounds disclosed herein in the production or manufacture of a medicament for the treatment or prevention of infectious and / or viral infections.

[0051] In certain embodiments, the present disclosure relates to derivatives of any of the compounds disclosed herein or formulas thereof.

[0052] Additional advantages of the present disclosure are set forth in part in the following description: It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the present disclosure, as claimed.

[0053] It is to be understood that the present disclosure is not limited to the particular embodiments described. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present disclosure, which will be limited by the appended claims.

[0054] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of this disclosure, the preferred methods and materials are described here.

[0055] All publications and patents cited herein are incorporated by reference herein as if each individual publication or patent was specifically and individually indicated to be incorporated by reference, and are incorporated by reference herein to disclose and describe the methods and / or materials for which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure. Further, the publication dates provided may be different from the actual publication dates which may need to be independently confirmed.

[0056] As will be apparent to one of ordinary skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has distinct components and features which may be readily separated from or combined with any of the other several embodiments without departing from the scope or spirit of the disclosure. Any recited method may be carried out in the order of events recited or in any other order which is logically possible.

[0057] Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art. Such techniques are fully explained in the literature.

[0058] It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. In this specification and the following claims, reference will be made to a number of terms, which shall be defined to have the following meanings unless a contrary intention is apparent.

[0059] Prior to describing the various embodiments, the following definitions are provided and should be used unless otherwise indicated.

[0060] As used herein, the term "phosphorus oxide" refers to any of a variety of chemical moieties that contain a phosphorus-oxygen (PO or P=O) bond. When used herein as a linking group, the linked molecule may be attached to the oxygen or directly to the phosphorus atom. The term is intended to include, but is not limited to, phosphates, where the phosphorus is typically attached to four oxygens, and phosphonic acids, where the phosphorus is typically attached to one carbon and three oxygens. "Polyphosphate" generally refers to phosphates linked together by at least one phosphorus-oxygen-phosphorus (POP) bond. "Polyphosphonic acid" refers to polyphosphates that contain at least one phosphorus-carbon (CPOP) bond. In addition to containing phosphorus-oxygen bonds, phosphorus oxides may contain phosphorus-thiol (PS or P=S) bonds and / or phosphorus-amine (PN) bonds, referred to as phosphorothioates or phosphoramidates, respectively. In phosphorus oxides, the oxygen atom may form a double or single bond with phosphorus or a combination thereof, the oxygen may be further bonded to other atoms such as carbon, or may exist as an anion balanced with a cation, e.g., a metal or a quaternary amine.

[0061] As used herein, "alkyl" means an acyclic, cyclic, linear or branched, unsaturated or saturated hydrocarbon, such as those containing 1 to 22 carbon atoms, and specifically includes methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. The term includes both substituted and unsubstituted alkyl groups. The alkyl group can be optionally substituted with one or more moieties selected from, for example, hydroxyl, amino, halo, deuterium, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, or any other viable functional group that does not interfere with the pharmacological activity of the compound, either unprotected or protected as appropriate, as known to those of skill in the art, for example, as taught in TW Greene and PG M Huts, "Protective Groups in Organic Synthesis," 3rd ed., John Wiley & Sons, 1999, which is incorporated herein by reference.

[0062] The term "lower alkyl," as used herein, unless otherwise specified, refers to a C1-C4 saturated linear, branched, or, where appropriate, cyclic (e.g., cyclopropyl) alkyl group, including both substituted and unsubstituted forms. Unless otherwise specified in this application, when alkyl is a suitable moiety, lower alkyl is preferred.

[0063] The term "halo" or "halogen" as used herein includes chloro, bromo, iodo, and fluoro.

[0064] Non-aromatic monocyclic or polycyclic alkyls are referred to herein as "carbocyclic" or "carbocyclyl" groups containing from 3 to 30 carbon atoms. Representative saturated carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, and unsaturated carbocyclic rings include cyclopentenyl and cyclohexenyl, and the like.

[0065] A "heterocarbocycle" or "heterocarbocyclyl" group is a carbon ring containing from one to four heteroatoms independently selected from nitrogen, oxygen, and sulfur, which may be saturated or unsaturated (but not aromatic), monocyclic or polycyclic, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Heterocarbocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

[0066] "Aryl" means an aromatic carbocyclic monocyclic or polycyclic ring containing 6 to 32 carbon atoms, such as phenyl or naphthyl. Polycyclic ring systems can, but do not require, to contain one or more non-aromatic rings as long as one of the rings is aromatic.

[0067] As used herein, "heteroaryl" refers to an aromatic heterocarbocycle having 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur and containing at least one carbon atom, including both monocyclic and polycyclic ring systems. Polycyclic ring systems may, but need not, contain one or more non-aromatic rings, so long as one of the rings is aromatic. Representative heteroaryls are furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl. Use of the term "heteroaryl" is intended to include N-alkylated derivatives such as a 1-methylimidazol-5-yl substituent.

[0068] As used herein, "heterocycle" or "heterocyclyl" refers to monocyclic and polycyclic ring systems having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur and containing at least one carbon atom. The monocyclic and polycyclic ring systems can be aromatic, non-aromatic, or mixtures of aromatic and non-aromatic rings. Heterocycles include heterocarbocycles, heteroaryls, and the like.

[0069] "Alkylthio" refers to an alkyl group as defined above attached through a sulfur bridge. An example of an alkylthio group is methylthio (i.e., -S-CH 3 ).

[0070] "Alkoxy" refers to an alkyl group as defined above attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, and t-butoxy.

[0071] "Alkylamino" refers to an alkyl group as defined above attached through an amino bridge. An example of an alkylamino is methylamino (i.e., -NH-CH 3 ).

[0072] "Alkanoyl" refers to an alkyl as defined above attached through a carbonyl bridge.

[0073] "Alkylsulfonyl" refers to an alkyl, as defined above (i.e., -S(=O)), attached through a sulfonyl bridge, such as mesyl. 2 "Arylsulfonyl" refers to an aryl bonded through a sulfonyl bridge (i.e., -S(=O) 2 Aryl)

[0074] "Alkylsulfinyl" refers to an alkyl as defined above attached through a sulfinyl bridge (ie, --S(.dbd.O)alkyl).

[0075] The term "substituted" refers to a molecule in which at least one hydrogen atom has been replaced with a substituent. When substituted, one or more of the groups is a "substituent." A molecule may be multiply substituted. In the case of an oxo substituent ("=O"), two hydrogen atoms are replaced. Exemplary substituents in this context include halogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -NRaRb, -NRaC(=O)Rb, -NRaC(=O)NRaNRb, -NRaC(=O)ORb, -NRaSO 2 Rb, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRb, -OC(=O)NRaRb, -ORa, -SRa, -SORa, -S(=O) 2 Ra, -OS(=O) 2 Ra, and -S(=O) 2 ORa may be mentioned. Ra and Rb in this context may be the same or different and may be independently hydrogen, halogen hydroxyl, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl.

[0076] As used herein, the term "optionally substituted" means that the substitution is optional, and thus, the specified atom may not be substituted.

[0077] As used herein, "salt" refers to derivatives of the disclosed compounds, where the parent compound is modified to form its acid or base salt. Examples of salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkylamines, or dialkylamines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. In typical embodiments, the salts are conventional non-toxic pharma- ceutically acceptable salts, including quaternary ammonium salts of the parent compound formed, and non-toxic inorganic or organic acids. Preferred salts include those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and salts prepared from organic acids, such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and the like.

[0078] "Subject" refers to any animal, preferably a human patient, livestock, rodent, monkey, or household pet.

[0079] The term "prodrug" refers to an agent that is converted into a biologically active form in vivo. Prodrugs are often useful because, in some circumstances, they may be easier to administer than the parent compound. For example, they may be bioavailable by oral administration even if the parent compound is not. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis.

[0080] As used herein, the term "derivative" refers to a structurally similar compound that retains the full functional attributes of the identified analog. A derivative may be structurally similar because it lacks one or more substituents, one or more atoms replaced with a salt in a different hydration / oxidation state (e.g., replacing a single or double bond, replacing a hydroxyl group with a ketone), or one or more atoms in the molecule have been transformed (such as, but not limited to, replacing an oxygen atom with a sulfur or nitrogen atom, or replacing an amino group with a hydroxyl group, or vice versa). Substitution of carbon with nitrogen in an aromatic ring is a contemplated derivative. A derivative may be a prodrug. The derivatives can be prepared by any of the various synthetic methods or suitable adaptations presented in the chemical literature or in synthetic or organic chemistry textbooks, for example those provided in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, 6th Edition (2007) Michael B. Smith, or Domino Reactions in Organic Synthesis, Wiley (2006) Lutz F. Tietze, which are incorporated herein by reference.

[0081] As used herein, the terms "prevent" and "preventing" include complete or partial inhibition of the recurrence, spread, or onset of the referenced pathological condition or disease. It is not intended that the disclosure be limited to complete prevention. In some embodiments, onset is delayed or the severity of the disease is reduced.

[0082] As used herein, the terms "treat" and "treating" are not limited to cases where a subject (e.g., a patient) is cured and the disease is eradicated. Rather, embodiments of the present disclosure also contemplate treatment that merely alleviates symptoms and / or slows the progression of the disease.

[0083] As used herein, the term "in combination with" when used to describe administration with an additional therapy means that the agent may be administered before, together with, or after the additional therapy, or a combination thereof. The combination can be formulated, for example, as a single pharmaceutical formulation, such as a single pill, as separate formulations, such as two pills that are co-administered at the same time, or as separate formulations, such as two pills that are administered sequentially, but where the agents / compounds overlap in the body. The agents in the combination can be administered in any order. Generally, each agent is administered at a dose and / or time schedule determined for that agent. In general, it is expected that the additional therapeutic agent utilized in combination will be utilized at levels that do not exceed the levels utilized individually. In some embodiments, the levels utilized in combination will be lower than the levels utilized individually.

[0084] Nucleoside analogues as antiviral agents. Nucleoside analogs utilize the host's nucleoside salvage pathway and are sequentially phosphorylated by deoxynucleoside kinase (dNK), deoxynucleoside monophosphate kinase (dNMPK), and nucleoside diphosphate kinase (NDPK). However, the intracellular activation of these compounds is often compromised by the high substrate specificity of the host's endogenous kinases. In vitro and in vivo studies have demonstrated that the first and / or second phosphorylation catalyzed by dNK and dNMPK often represents the rate-limiting step of nucleoside analog activation. These significant inhibitions in the phosphorylation cascade of a given nucleoside analog result in the complete loss of observable activity in cellular assays. To circumvent these inhibitions, several kinase bypass strategies have been developed. For example, McGuigan phosphoramidates are chemical conjugates used for kinase bypass. See Serpi et al., J Med Chem, 2012, 55(10):4629-4639. Metabolism of these prodrugs begins with esterase-catalyzed cleavage of the carboxylic acid ester, followed by several chemical rearrangement steps to yield the amino acid phosphoramidate. The final cleavage is carried out by one of several endogenous phosphoramidases, one of which has been identified as histidine triad nucleotide-binding protein 1 (hINT1).

[0085] Another prodrug strategy to circumvent these inhibitions is to utilize sphingoid bases to mask nucleotide analog phosphates. Sphingoid bases have the potential to deliver nucleotide analog phosphates to important tissues such as the brain. The design concept driving the use of sphingoid bases to form nucleoside-lipid conjugates is based on the observation that sphingoid base analogs: (a) are well absorbed after oral administration, (b) are resistant to oxidative metabolism in enterocytes, and (c) achieve high concentrations in the brain. Based on data on the intestinal uptake of conventional phospholipid drug conjugates in mice and data on sphingoid base oral absorption in rats, sphingoid base conjugates are well absorbed and resist first-pass metabolism. After absorption, sphingoid bases, including sphingosine-1-phosphate, are transported into the blood via both lipoproteins and free plasma proteins such as albumin. Active epithelial cell uptake of sphingoid base phosphates has been demonstrated to occur via the ABC transporter CFTR, but passive protein trafficking and uptake by endocytosis are also possible, and drug conjugates delivered extracellularly are thought to be similarly processed by target cells in the central nervous system (CNS) and gut-associated lymphoid tissue (GALT). In the rat sphingolipid PK study mentioned above, 24-hour tissue concentrations exceeded plasma Cmax concentrations by more than 10-300 fold, with lung and brain levels being particularly high, without evidence of toxicity. This approach has significant potential for delivery of high drug concentrations of the conjugates to critical tissues.

[0086] compound In certain embodiments, the present disclosure relates to a nucleoside or a pharma- ceutically acceptable salt thereof having a sulfur-containing base complexed to a phosphorus moiety.

[0087] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; X is O, CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 and R 1 is a phosphonate, phosphonophosphate, phosphonodiphosphate, or phosphate, including monophosphate, diphosphate, triphosphate, and polyphosphate, or polyphosphonate; the phosphates in the phosphonate or polyphosphate are optionally phosphoroborates, phosphorothioates, or phosphoramidates; The phosphates, phosphoroborates, phosphorothioates, or phosphoramidates in the phosphonates or polyphosphates may optionally be linked to one or more of the same or different R 8 is replaced by the phosphate, phosphoroborate, phosphorothioate, or phosphoramidate in the phosphonate or polyphosphate optionally forms a phosphorus-containing heterocycle; A phosphonate, phosphonophosphate, phosphonodiphosphate, phosphate, polyphosphate, polyphosphonate, phosphorothiolate, or phosphoramidate is optionally represented by R 3 or R 4 Forming a carbon-phosphorus-containing heterocycle, R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 But independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, CH 3 , CD 3 , C.F. 3 , C.F.2 H, CFH 2 , O.H., S.H., and N.H. 2 , N 3 , CHO, CN, Cl, Br, F, I, NO 2 , C(O)O(C 1-22 alkyl), C(O)O(C 1-22 alkyl), C(O)O(C 1-22 alkynyl), C(O)O(C 1-22 alkenyl), O(C 1-22 acyl), O(C 1-22 alkyl), O(C 1-22 alkenyl), S(C 1-22 Acyl), S(C 1-22 alkyl), S(C 1-22 alkynyl), S(C 1-22 alkenyl), SO(C 1-22 acyl), SO(C 1-22 alkyl), SO(C 1-22 alkynyl), SO(C 1-22 alkenyl), SO 2 (C 1-22 Acyl), SO 2 (C 1-22 Alkyl), SO 2 (C 1-22 alkynyl), SO 2 (C 1-22 alkenyl), O 3 S(C 1-22 Acyl), O 3 S(C 1-22 Alkyl), O 3 S(C 1-22 alkenyl), NH 2 , NH(C 1-22 alkyl), NH(C 1-22 alkenyl), NH(C 1-22 alkynyl), NH(C 1-22 Acyl), N(C 1-22 Alkyl) 2 , N(C 1-22 Acyl) 2, sulfamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, or carbocyclyl; Alkyl, alkynyl, alkenyl, and vinyl are optionally selected from N 3 CN, 1-3 halogens (Cl, Br, F, I), deuterium, NO 2 , C(O)O(C 1-22 alkyl), C(O)O(C 1-22 alkyl), C(O)O(C 1-22 alkynyl), C(O)O(C 1-22 alkenyl), O(C 1-22 acyl), O(C 1-22 alkyl), O(C 1-22 alkenyl), S(C 1-22 Acyl), S(C 1-22 alkyl), S(C 1-22 alkynyl), S(C 1-22 alkenyl), SO(C 1-22 acyl), SO(C 1-22 alkyl), SO(C 1-22 alkynyl), SO(C 1-22 alkenyl), SO 2 (C 1-22 Acyl), SO 2 (C 1-22 Alkyl), SO 2 (C 1-22 alkynyl), SO 2 (C 1-22 alkenyl), O 3 S(C 1-22 Acyl), O 3 S(C 1-22 Alkyl), O 3 S(C 1-22 alkenyl), NH 2 , NH(C 1-22 alkyl), NH(C 1-22 alkenyl), NH(C1-22 alkynyl), NH(C 1-22 Acyl), N(C 1-22 Alkyl) 2 , N(C 1-22 Acyl) 2 , sulfamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, or carbocyclyl; R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by R 6 and R 7 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl, Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, and Q is optionally substituted with one or more of the same or different alkyl, halogen, cycloalkyl.

[0088] In certain exemplary embodiments of any of the formulas described herein, U is selected from the following: NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, and C=CF 2 is selected from the group consisting of:

[0089] In certain exemplary embodiments of any of the formulas described herein, X is selected from the following: CHMe, CMe 2 , CHF, and CF 2 is selected from the group consisting of:

[0090] In certain exemplary embodiments of any of the formulas described herein, R 3 and R 4 together with the carbon atom to which they are attached form a spiro ring containing carbon, oxygen, sulfur, or nitrogen, and optionally one or more, the same or different, R 9 can be replaced by In certain exemplary embodiments of any of the formulas described herein, R 6 and R 7 together with the carbon atom to which they are attached form a spiro ring containing carbon, oxygen, sulfur, or nitrogen, and optionally one or more, the same or different, R 9 can be replaced by In certain exemplary embodiments of any of the formulas described herein, R 5 is selected from the group consisting of: Me, CN, alkyl, alkenyl, and alkynyl.

[0091] In certain embodiments, Q heterocyclyl is selected from pyrimidine-2-one-4-thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5-fluoropyrimidine-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4-dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purine-6-thione, 2-amino-7-deaza-purine-6-thione, or 2-amino-7-deaza-7-substituted purine-6-thione.

[0092] In a preferred embodiment, U is O and Q is a pyrimidine having at least one thione, thiol, or thioether at position 2 and / or 4 of the pyrimidine. In another preferred embodiment, U is S and Q is a pyrimidine having at least one thione, thiol, or thioether at position 2 and / or 4 of the pyrimidine.

[0093] In a preferred embodiment, X is CH 2 It is.

[0094] In a preferred embodiment, the nucleoside or pharma- ceutically acceptable salt thereof conjugated to a phosphorus moiety has the following structure: [ka] or a pharma- ceutically acceptable salt thereof, wherein: U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; X is O, CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 and R 1 is OH, monophosphate, diphosphate, or triphosphate; R 2 , R 3 , R 4 , R 6 , and R 7 However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 9 C replaced with 1-22alkyl, Each R 9 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by R 6 and R 7 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl, Q is a base such as: [ka] It is one of the wherein Z is alkyl, alkenyl, acyl, lipid, or geranyl.

[0095] In certain embodiments, R 2 are H, D, and CH 3 , CD 3 , C.F. 3 , C.F. 2 H, CFH 2 , C.H. 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, or I. In one embodiment, R 2 is H.

[0096] In another particular embodiment, R 3 are H, D, and CH 3 , CD 3 , C.F. 3 , C.F. 2 H, CFH 2 , C.H. 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, or I.

[0097] In yet another particular embodiment, R 4 are H, D, and CH 3 , CD 3 , C.F. 3 , C.F. 2 H, CFH 2 , C.H. 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, or I.

[0098] In further particular embodiments, R 5 is selected from the group consisting of H and D.

[0099] In further particular embodiments, R 6 are H, D, and CH 3 , CD 3 , C.F. 3 , C.F. 2 H, CFH 2 , C.H. 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, or I.

[0100] In yet another particular embodiment, R 7 are H, D, and CH 3 , CD 3 , C.F. 3 , C.F.2 H, CFH 2 , C.H. 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, or I.

[0101] Lipids, as used herein, are defined as C 6-22 It is an alkyl, alkoxy, polyethylene glycol, or aryl substituted with an alkyl group.

[0102] In certain embodiments, the lipids are fatty alcohols, fatty amines, or fatty thiols derived from essential and non-essential fatty acids.

[0103] In certain embodiments, the lipids are unsaturated, polyunsaturated, omega-unsaturated, or omega-polyunsaturated fatty alcohols, fatty amines, or fatty thiols derived from essential and non-essential fatty acids.

[0104] In certain embodiments, the lipids are fatty alcohols, fatty amines, or fatty thiols derived from essential and non-essential fatty acids that have one or more of their carbon units replaced with oxygen, nitrogen, or sulfur.

[0105] In certain embodiments, the lipids are unsaturated, polyunsaturated, omega-unsaturated, or omega-polyunsaturated fatty alcohols, fatty amines, or fatty thiols derived from essential and non-essential fatty acids having one or more of their carbon units replaced with oxygen, nitrogen, or sulfur.

[0106] In certain embodiments, the lipids are fatty alcohols, fatty amines, or fatty thiols derived from essential and non-essential fatty acids, optionally substituted.

[0107] In certain embodiments, the lipids are unsaturated, polyunsaturated, omega-unsaturated, or omega-polyunsaturated fatty alcohols, fatty amines, or fatty thiols derived from essential and non-essential fatty acids, optionally substituted.

[0108] In certain embodiments, the lipids are fatty alcohols, fatty amines, or fatty thiols derived from essential and non-essential fatty acids with one or more of their carbon units optionally substituted with oxygen, nitrogen, or sulfur.

[0109] In certain embodiments, the lipids are unsaturated, polyunsaturated, omega-unsaturated, or omega-polyunsaturated fatty alcohols, fatty amines, or fatty thiols derived from essential and non-essential fatty acids having one or more of their carbon units optionally substituted with oxygen, nitrogen, or sulfur.

[0110] In certain embodiments, the lipid is hexadecyloxypropyl.

[0111] In certain embodiments, the lipid is 2-aminohexadecyloxypropyl.

[0112] In certain embodiments, the lipid is 2-aminoarachidyl.

[0113] In certain embodiments, the lipid is 2-benzyloxyhexadecyloxypropyl.

[0114] In certain embodiments, the lipid is lauryl, myristyl, palmityl, stearyl, arachidyl, behenyl, or lignoceryl.

[0115] In certain embodiments, the lipid is a sphingolipid having the formula: [ka] During the ceremony, Sphingolipid R 8is hydrogen, alkyl, C(=O)R 12 , C(=O)OR 12 , or C(=O)NHR 12 and Sphingolipid R 9 But hydrogen, fluoro, OR 12 ,OC(=O)R 12 ,OC(=O)OR 12 , or OC(=O)NHR 12 and Sphingolipid R 10 is a saturated or unsaturated alkyl chain having more than 6 and less than 22 carbon atoms, optionally containing one or more halogen or hydroxyl groups or one or more groups of the formula: [ka] The structure of a formula in which n is 8 to 14 or 8 or less to 14 or less, o is 9 to 15 or 9 or less to 15 or less, the sum of m and n is 8 to 14 or 8 or less to 14 or less, and the sum of m and o is 9 to 15 or 9 or less to 15 or less, or [ka] a formula in which n is 4 to 10 or 4 or less to 10 or less, o is 5 to 11 or 5 or less to 11 or less, the sum of m and n is 4 to 10 or 4 or less to 10 or less, and the sum of m and o is 5 to 11 or 5 or less to 11 or less, or [ka] And, n is 6 to 12, or n is 6 or less to 12 or less, and the sum of m and n is 6 to 12, or n is 6 or less to 12 or less, Sphingolipid R 11 But, OR 12 ,OC(=O)R 12 ,OC(=O)OR 12 , or OC(=O)NHR 12 and Sphingolipid R 12But hydrogen, branched or chain C 1-12 Alkyl, C 13-22 alkyl, cycloalkyl, or aryl selected from benzyl or phenyl, optionally having one or more, the same or different, R 13 is replaced by Sphingolipid R 13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

[0116] In certain embodiments, the R 12 is H, alkyl, methyl, ethyl, propyl, n-butyl, branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenyl, monosubstituted phenyl, disubstituted phenyl, trisubstituted phenyl, or saturated or unsaturated C12-C19 long chain alkyl.

[0117] In certain embodiments, the sphingolipid has the formula: [ka] During the ceremony, Sphingolipid R 8is hydrogen, hydroxy, fluoro, OR 12 ,OC(=O)R 12 ,OC(=O)OR 12 , or OC(=O)NHR 12 and Sphingolipid R 9 is hydrogen, hydroxy, fluoro, OR 12 ,OC(=O)R 12 ,OC(=O)OR 12 , or OC(=O)NHR 12 and Sphingolipid R 10 is a saturated or unsaturated alkyl chain having more than 6 and less than 22 carbon atoms, and optionally one or more halogens or one or more of the following formula: [ka] The structure is n is 8 to 14 or 8 or less to 14 or less, and the sum of m and n is 8 to 14 or 8 or less to 14 or less, Sphingolipid R 12 Hydrogen, branched chain or weak chain C 1-12 Alkyl, C 13-22 alkyl, cycloalkyl, or aryl selected from benzyl or phenyl, optionally having one or more, the same or different, R 13 is replaced by Sphingolipid R 13is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

[0118] In certain embodiments, the R 12 is H, alkyl, methyl, ethyl, propyl, n-butyl, branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenyl, mono-substituted phenyl, di-substituted phenyl, tri-substituted phenyl, or saturated or unsaturated C 12 -C 19 It is a long chain alkyl.

[0119] Suitable sphingolipids include, but are not limited to, sphingosine, ceramide, or sphingomyelin, or 2-aminoalkyl, optionally substituted with one or more substituents.

[0120] Other suitable sphingolipids include 2-aminooctadecane-3,5-diol, (2S,3S,5S)-2-aminooctadecane-3,5-diol, (2S,3R,5S)-2-aminooctadecane-3,5-diol, 2-(methylamino)octadecane-3,5-diol, (2S,3R,5S)-2-(methylamino)octadecane-3,5-diol, 2-(dimethylamino)octadecane-3,5-diol, (2R,3S,5S)-2-(dimethylamino)octadecane-3,5-diol, which may be optionally substituted with one or more substituents. ol, 1-(pyrrolidin-2-yl)hexadecane-1,3-diol, (1S,3S)-1-((S)-pyrrolidin-2-yl)hexadecane-1,3-diol, 2-amino-11,11-difluorooctadecane-3,5-diol, (2S,3S,5S)-2-amino-11,11-difluorooctadecane-3,5-diol, 11,11-difluoro-2-(methylamino)octadecane-3,5-diol, (2S,3S,5S)-11,11-difluoro-2-(methylamino)octadecane-3,5-diol, N-((2S,3S ,5S)-3,5-dihydroxyoctadecane-2-yl)acetamide, N-((2S,3S,5S)-3,5-dihydroxyoctadecane-2-yl)palmitamide, 1-(1-aminocyclopropyl)hexadecane-1,3-diol, (1S,3R)-1-(1-aminocyclopropyl)hexadecane-1,3-diol, (1S,3S)-1-(1-aminocyclopropyl)hexadecane-1,3-diol, 2-amino-2-methyloctadecane-3,5-diol, (3S,5S)-2-amino-2-methyloctadecane-3,5-diol 2-amino-5-hydroxy-2-methyloctadecane-3-one, (Z)-2-amino-5-hydroxy-2-methyloctadecane-3-one oxime, (2S,3R,5R)-2-amino-6,6-difluorooctadecane-3,5-diol, (2S,3S,5R)-2-amino-6,6-difluorooctadecane-3,5-diol, (2S,3S,5S)-2-amino-6,These include, but are not limited to, 6-difluorooctadecane-3,5-diol, (2S,3R,5S)-2-amino-6,6-difluorooctadecane-3,5-diol, and (2S,3S,5S)-2-amino-18,18,18-trifluorooctadecane-3,5-diol.

[0121] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; Y is O or S; Y' is OH, OR", SR", NHR", or NR". 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, and Q is optionally substituted with one or more of the same or different alkyl, halogen, or cycloalkyl; R 3 , R 4 , R 6 , R 7 , and R 8 However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R9 C replaced with 1-22 alkyl, Each R 9 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by R 6 and R 7 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl.

[0122] In certain exemplary embodiments of any of the formulas described herein, Y' is one of the following: OR", SR", NHR", and NR". 2 is selected from the group consisting of:

[0123] In certain embodiments, Q is a heterocycle selected from the group consisting of pyrimidine-2-one-4-thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5-fluoropyrimidine-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4-dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purine-6-thione, 2-amino-7-deaza-purine-6-thione, or 2-amino-7-deaza-7-substituted purine-6-thione.

[0124] In a preferred embodiment, U is O and Q is a pyrimidine having at least one thione, thiol, or thioether at position 2 and / or 4 of the pyrimidine. In another preferred embodiment, U is S and Q is a pyrimidine having at least one thione, thiol, or thioether at position 2 and / or 4 of the pyrimidine.

[0125] In one embodiment, R 3 are H, D, and CH 3 , CD 3 , C.F. 3 , C.F. 2 H, CFH 2 , C.H. 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, or I.

[0126] In another embodiment, R 4 H, CH 3 , CD 3 , C.F. 3 , C.F. 2 H, CFH 2 , C.H. 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, or I.

[0127] In yet another embodiment, R 6 H, CH 3 , CD 3 , C.F. 3 , C.F. 2 H, CFH 2 , C.H. 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, or I.

[0128] In yet another embodiment, R 7 H, CH 3 , CD 3 , C.F. 3 , C.F. 2 H, CFH 2 , C.H. 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, or I.

[0129] In yet a further embodiment, R 8 H, CH 3 , CD 3 , C.F. 3 , C.F. 2 H, CFH 2 , C.H. 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, or I. In one embodiment, R 8 is H.

[0130] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein A is O or S; A', OH, OR", SR", NHR", NR" 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl, U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; Each X is independently O, S, NH, NR 8 , N.H.O.H., N.R. 8 OH,NHOR 8 , or NR 8 OR 8 and R 1 But OH, SH, NH 2 , OR 8 , S.R. 8 , N.H.R. 8 , N.H.O.H., N.R. 8 OH,NHOR 8 , or NR 8 OR 8 and In formulae Ic and Id, X is S or R 1 But, SR 8 or X is S and R 1 But, SR 8 and In formula Ie, at least one X is S; Y is CH, N, or CR 2 and Z is CH, N, or CR 2 and R 3 , R 4 , R 6 , R 7 , and R 10 However, independently, H, D, C 1-22Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 9 C replaced with 1-22 alkyl, R 8 is methyl, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 9 C replaced with 1-22 is alkyl, R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by R 6 and R 7 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by Each R 9 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R 2 is deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, optionally one or more of the same or different, R 9 C replaced with1-22 It is an alkyl.

[0131] In certain exemplary embodiments of any of the formulas described herein, A' is one of the following: OR", SR", NHR", and NR". 2 is selected from the group consisting of:

[0132] In certain exemplary embodiments of any of the formulas described herein, R 2 is deuterium.

[0133] In one embodiment, R 3 are H, D, and CH 3 , CD 3 , C.F. 3 , C.F. 2 H, CFH 2 , C.H. 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, or I.

[0134] In another embodiment, R 4 are H, D, and CH 3 , CD 3 , C.F. 3 , C.F. 2 H, CFH 2 , C.H. 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, or I.

[0135] In yet another embodiment, R 6 are H, D, and CH 3 , CD 3 , C.F. 3 , C.F. 2 H, CFH 2 , C.H. 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3, CHO, CN, Cl, Br, F, or I.

[0136] In yet another embodiment, R 7 are H, D, and CH 3 , CD 3 , C.F. 3 , C.F. 2 H, CFH 2 , C.H. 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, or I.

[0137] In yet a further embodiment, R 10 are H, D, and CH 3 , CD 3 , C.F. 3 , C.F. 2 H, CFH 2 , C.H. 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, or I. In one embodiment, R 8 is H.

[0138] In certain embodiments, U is S, and Y and Z are CH.

[0139] In other embodiments, U is O and Y and Z are CH.

[0140] In one embodiment, R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is methyl. In yet another embodiment, R 7 is fluoro. In still further embodiments, R 10 is H.

[0141] In another embodiment, the compound or a pharma- ceutically acceptable salt thereof is a compound in which A is O, A' is OH, U is O, and R 5 is H, Y and Z are CH, R 3 , R 4 , R 6 , R 7 , and R 10 are each independently H, CH 3 , CD 3 , C.F. 3 , C.F. 2 H, CFH 2 , O.H., S.H., and N.H. 2 , N 3 , CHO, CN, Cl, Br, F, or I.

[0142] In other embodiments, the compound is represented by formula Ie, or a pharma- ceutically acceptable salt thereof, wherein one X is S, the other X is O, and R 3 is H and R 4 is OH and R 6 But, CH 3 and R 7 is OH and R 10 But it's H.

[0143] In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0144] In one embodiment, R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 In yet another embodiment, R 7 is fluoro. In still further embodiments, R 10 is H. In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0145] In one embodiment, R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is C≡CH. In yet another embodiment, R 7 is fluoro. In still further embodiments, R 10 is H. In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0146] In one embodiment, R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is CH 2 In yet another embodiment, R 7 is fluoro. In still further embodiments, R 10 is H. In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0147] In one embodiment, R 3 is H. In another embodiment, R 4 is H. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is H. In yet another embodiment, R 7 is fluoro. In still further embodiments, R 10 is H. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0148] In one embodiment, R 3 is H. In another embodiment, R 4 is H. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is methyl. In yet another embodiment, R 7 is fluoro. In still further embodiments, R 10 is H. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0149] In one embodiment, R 3 is H. In another embodiment, R 4 is H. In a further embodiment, R 5 is H. In yet another embodiment, R 6 In yet another embodiment, R 7 is fluoro. In still further embodiments, R 10 is H. In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0150] In one embodiment, R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is methyl. In yet another embodiment, R 7 is hydroxyl. In still further embodiments, R 10 is H. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0151] In one embodiment, R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 In yet another embodiment, R 7 is hydroxyl. In still further embodiments, R 10 is H. In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0152] In one embodiment, R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is C≡CH. In yet another embodiment, R 7 is hydroxyl. In still further embodiments, R 10 is H. In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0153] In one embodiment, R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is CH 2 In yet another embodiment, R 7 is hydroxyl. In still further embodiments, R 10is H. In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0154] In one embodiment, R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is methyl. In yet another embodiment, R 7 is H. In still further embodiments, R 10 is H. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0155] In one embodiment, R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 In yet another embodiment, R 7 is H. In still further embodiments, R 10 is H. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0156] In one embodiment, R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In another embodiment, R 10 is N 3 In yet another embodiment, R 6 is H. In yet another embodiment, R7 is hydroxyl. In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0157] In one embodiment, R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In another embodiment, R 10 is C≡CH. In yet another embodiment, R 6 is H. In yet another embodiment, R 7 is hydroxyl. In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0158] In one embodiment, R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In another embodiment, R 10 is CH 2 In yet another embodiment, R 6 is H. In yet another embodiment, R 7 is hydroxyl. In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0159] In one embodiment, R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In another embodiment, R 10 is N 3 In yet another embodiment, R6 is H. In yet another embodiment, R 7 is fluoro. In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0160] In one embodiment, R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In another embodiment, R 10 is C≡CH. In yet another embodiment, R 6 is H. In yet another embodiment, R 7 is fluoro. In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0161] In one embodiment, R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In another embodiment, R 10 is CH 2 In yet another embodiment, R 6 is H. In yet another embodiment, R 7 is fluoro. In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0162] In one embodiment, R 3 is H. In another embodiment, R 4 is fluoro. In a further embodiment, R 5 is H. In another embodiment, R 10is H. In yet another embodiment, R 6 is H. In yet another embodiment, R 7 is hydroxyl. In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0163] In one embodiment, R 3 is H. In another embodiment, R 4 is fluoro. In a further embodiment, R 5 is H. In another embodiment, R 10 is H. In yet another embodiment, R 6 is methyl. In yet another embodiment, R 7 is hydroxyl. In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0164] In one embodiment, R 3 is H. In another embodiment, R 4 is fluoro. In a further embodiment, R 5 is H. In another embodiment, R 10 is H. In yet another embodiment, R 6 is C≡CH. In yet another embodiment, R 7 is hydroxyl. In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0165] In one embodiment, R 3 is H. In another embodiment, R 4 is fluoro. In a further embodiment, R 5 is H. In another embodiment, R 10is H. In yet another embodiment, R 6 is CH 2 In yet another embodiment, R 7 is hydroxyl. In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0166] In one embodiment, R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In another embodiment, R 10 is fluoro. In yet another embodiment, R 6 is methyl. In yet another embodiment, R 7 is hydroxyl. In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0167] In one embodiment, R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In another embodiment, R 10 is fluoro. In yet another embodiment, R 6 is C≡CH. In yet another embodiment, R 7 is hydroxyl. In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0168] In one embodiment, R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5is H. In another embodiment, R 10 is fluoro. In yet another embodiment, R 6 is CH 2 In yet another embodiment, R 7 is hydroxyl. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0169] In one embodiment, R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In another embodiment, R 10 is fluoro. In yet another embodiment, R 6 is methyl. In yet another embodiment, R 7 is fluoro. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0170] In one embodiment, R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In another embodiment, R 10 is fluoro. In yet another embodiment, R 6 is C≡CH. In yet another embodiment, R 7 is fluoro. In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0171] In one embodiment, R 3 is H. In another embodiment, R 4is hydroxyl. In a further embodiment, R 5 is H. In another embodiment, R 10 is fluoro. In yet another embodiment, R 6 is CH 2 In yet another embodiment, R 7 is fluoro. In an exemplary embodiment, the compound is [ka] In one embodiment, R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In another embodiment, R 10 is H. In yet another embodiment, R 6 is CH 3 In yet another embodiment, R 7 is chloro. In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0172] In one embodiment, R 3 is H. In another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is fluoro. In yet another embodiment, R 7 is H. In still further embodiments, R 10 is H. [ka]

[0173] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein A is O or S; A', OH, OR", SR", NHR", NR" 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl, U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; Each X is independently O, S, NH, NR 8 , N.H.O.H., N.R. 8 OH,NHOR 8 , or NR 8 OR 8 and R 1 But OH, SH, NH 2 , OR 8 , S.R. 8 , N.H.R. 8 , N.H.O.H., N.R. 8 OH,NHOR 8 , or NR 8 OR 8 and In formulae Ic' and Id', any X is S or R 1 But, SR 8 or both X are S and R 1 But, SR 8 and In formula Ie′, at least one X is S; Y is CH, N, or CR 2 and Z is CH, N, or CR 2 and R 3 , R 4 , R6 , R 7 , and R 10 However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 9 C replaced with 1-22 alkyl, R 8 is methyl, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 9 C replaced with 1-22 is alkyl, R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by R 6 and R 7 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by Each R 9 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R 2is deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, optionally one or more of the same or different, R 9 C replaced with 1-22 It is an alkyl.

[0174] In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0175] In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0176] In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0177] In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0178] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; X is O, CH 2 , CHMe, CMe2 , CHF, CF 2 , or CD 2 and R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl, R 2 , R 3 , R 4 , R 8 , and R 9 However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 10 C replaced with 1-22 alkyl, R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by R 8 and R 9 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by R 1 But the formula: [ka] It is one of the Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Y 2 OH, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, 4-bromophenyl; Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, and Q is optionally substituted with one or more of the same or different alkyl, halogen, cycloalkyl; Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; 6 optionally one or more, the same or different, R 10 is replaced by.

[0179] In certain exemplary embodiments, R 8 and R9 together with the carbon atom to which they are attached form a spiro ring containing carbon, oxygen, sulfur, or nitrogen, and optionally contain one or more, the same or different, R 10 can be substituted with

[0180] In a preferred embodiment, U is O and Q is a pyrimidine having at least one thione, thiol, or thioether at position 2 and / or 4 of the pyrimidine. In another preferred embodiment, U is S and Q is a pyrimidine having at least one thione, thiol, or thioether at position 2 and / or 4 of the pyrimidine.

[0181] In certain embodiments, R 2 , R 3 , R 4 , R 8 , and R 9 are each independently H, D, or CH 3 , CD 3 , C.F. 3 , C.F. 2 H, CFH 2 , C.H. 2 OH, CH 2 Cl, CCH, OH, SH, NH 2 , N 3 It is selected from CHO, CN, Cl, Br, F, or I.

[0182] In certain embodiments, U is O and X is CH 2 Q is a pyrimidine having at least one thione, thiol, or thioether at the 2- and / or 4-position of the pyrimidine; R 5 is H and R 2 , R 3 , R 4 , R 8 , and R 9 are each independently H, CH 3 , CD 3 , C.F. 3 , C.F. 2 H, CFH 2 , O.H., S.H., and N.H.2 , N 3 , CHO, CN, Cl, Br, F, or I.

[0183] In certain embodiments, R 1 teeth, [ka] wherein Y is O and Y 1 is phenoxy, and R 6 iso-propyl.

[0184] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl, R 1 But the formula: [ka] It is one of the Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Y 2 OH, OR”, SR”, NHR”, NR” 2 , or BH 3 -M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Each X is independently O, S, NH, NR 8 , N.H.O.H., N.R. 8 OH,NHOR 8 , or NR 8 OR 8 and R 2 But OH, SH, NH 2 , OR 8 , S.R. 8 , N.H.R. 8 , N.H.O.H., N.R. 8 OH,NHOR 8 , or NR 8 OR 8 and In formulae Ig and Ih, one of X is S or R 2 But, SR 8 or both X are S and R 2 But, SR 8 and In formula Ii, at least one X is S; W is CH, N, or CR 8 and Z is CH, N, or CR 8 and R 3 , R 4 , R 7 , R 9 , and R 14 However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 10 C replaced with 1-22 alkyl, R 3 and R4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by R 7 and R 14 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, 4-bromophenyl; R 8 is deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 10 C replaced with 1-22 is alkyl, R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; 6 optionally one or more, the same or different, R 10 is replaced by.

[0185] In certain embodiments, R 3 , R 4 , R 7 , R 9 , and R 14 are each independently H, CH 3 , CD 3 , C.F. 3 , C.F. 2 H, CFH 2 , O.H., S.H., and N.H. 2 , N 3 , CHO, CN, Cl, Br, F, or I.

[0186] In certain embodiments, R 6 is iso-propyl.

[0187] In certain exemplary embodiments, R 7 and R 14 together with the carbon atom to which they are attached form a spiro ring containing carbon, oxygen, sulfur, or nitrogen, and optionally contain one or more, the same or different, R 10 can be substituted with

[0188] In certain embodiments, U is S, and Y and Z are CH.

[0189] In other embodiments, U is O and Y and Z are CH.

[0190] In certain embodiments, one X is O and the other X is S.

[0191] In one embodiment, R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is H. In yet another embodiment, R 7 is F and R 14 is H. In a further embodiment, R 1 teeth [ka] wherein Y is O and Y 1 is phenoxy, and R 6 iso-propyl.

[0192] In certain embodiments, U is O, W and Z are CH, and R 5 is H and R 1 but, [ka] wherein Y is O and Y 1 is phenoxy, and R 6 is an alkyl group.

[0193] In certain embodiments, R 5 is H and R 3 is H and R 4 is hydroxyl, and R 7 is hydroxyl, and R 14 is methyl, and R 1 but, [ka] and Y is O and Y 1 is phenoxy, and R 6 iso-propyl.

[0194] In an exemplary embodiment, the compound is [ka] is selected from.

[0195] In one embodiment, R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is H. In yet another embodiment, R 7 is F and R 14 is methyl. In a further embodiment, R 1 teeth, [ka] wherein Y is O and Y 1 is phenoxy, and R 6 iso-propyl.

[0196] In an exemplary embodiment, the compound is selected from the following: [ka]

[0197] In one embodiment, R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is H. In yet another embodiment, R 7 is F and R 14 is trifluoromethyl. In a further embodiment, R 1 teeth, [ka] wherein Y is O and Y 1 is phenoxy, and R 6 iso-propyl.

[0198] In an exemplary embodiment, the compound is selected from the following: [ka]

[0199] In one embodiment, R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In yet another embodiment, R 7 is F. In another embodiment, R 14 is trifluoromethyl. In a further embodiment, R 1 teeth, [ka] wherein Y is O and Y 1 is phenoxy, and R 6 iso-propyl.

[0200] In an exemplary embodiment, the compound is selected from the following: [ka]

[0201] In one embodiment, R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In yet another embodiment, R 7 is F. In another embodiment, R 14 is methyl. In a further embodiment, R 1 teeth, [ka] wherein Y is O and Y 1 is phenoxy, and R 6 iso-propyl.

[0202] In an exemplary embodiment, the compound is selected from the following: [ka]

[0203] In one embodiment, R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is OH. In yet another embodiment, R 7 is F and R 14 is ethynyl. In a further embodiment, R 1 teeth, [ka] wherein Y is O and Y 1 is phenoxy, and R 6 iso-propyl.

[0204] In an exemplary embodiment, the compound is selected from the following: [ka]

[0205] In one embodiment, R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is OH. In yet another embodiment, R 7 is F and R 14 In a further embodiment, R 1 teeth, [ka] wherein Y is O and Y 1 is phenoxy, and R 6 iso-propyl.

[0206] In an exemplary embodiment, the compound is selected from the following: [ka]

[0207] In one embodiment, R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In yet another embodiment, R 7 is H. In another embodiment, R 14 is methyl. In a further embodiment, R 1 teeth, [ka] wherein Y is O and Y1 is phenoxy, and R 6 iso-propyl.

[0208] In an exemplary embodiment, the compound is selected from the following: [ka]

[0209] In one embodiment, R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is OH. In yet another embodiment, R 7 is H and R 14 is trifluoromethyl. In a further embodiment, R 1 teeth, [ka] wherein Y is O and Y 1 is phenoxy, and R 6 iso-propyl.

[0210] In an exemplary embodiment, the compound is selected from the following: [ka]

[0211] In one embodiment, R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In yet another embodiment, R 7 is hydroxyl. In another embodiment, R 14 is trifluoromethyl. In a further embodiment, R 1 teeth, [ka] wherein Y is O and Y 1is phenoxy, and R 6 iso-propyl.

[0212] In an exemplary embodiment, the compound is selected from the following: [ka]

[0213] In one embodiment, R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In yet another embodiment, R 7 is hydroxyl. In another embodiment, R 14 is methyl. In a further embodiment, R 1 teeth, [ka] wherein Y is O and Y 1 is phenoxy, and R 6 iso-propyl.

[0214] In an exemplary embodiment, the compound is selected from the following: [ka]

[0215] In one embodiment, R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In yet another embodiment, R 7 is hydroxyl. In another embodiment, R 14 is methyl. In a further embodiment, R 1 teeth, [ka] wherein Y is O.

[0216] In an exemplary embodiment, the compound is [ka] [ka] [ka] is selected from.

[0217] In more preferred embodiments, the compounds of the disclosure are selected from one or more of the following: [ka]

[0218] In one embodiment, R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In yet another embodiment, R 7 is hydroxyl. In another embodiment, R 14 is ethynyl. In a further embodiment, R 1 teeth, [ka] wherein Y is O and Y 1 is phenoxy, and R 6 iso-propyl.

[0219] In an exemplary embodiment, the compound is selected from the following: [ka]

[0220] In one embodiment, R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4is hydroxyl. In yet another embodiment, R 7 is hydroxyl. In another embodiment, R 14 In a further embodiment, R 1 teeth, [ka] wherein Y is O and Y 1 is phenoxy, and R 6 iso-propyl.

[0221] In an exemplary embodiment, the compound is [ka] is selected from.

[0222] In one embodiment, R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is fluoro. In yet another embodiment, R 7 is hydroxyl. In another embodiment, R 14 is H. In a further embodiment, R 1 teeth, [ka] wherein Y is O and Y 1 is phenoxy, and R 6 iso-propyl.

[0223] In an exemplary embodiment, the compound is: [ka] is selected from.

[0224] In one embodiment, R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4is fluoro. In yet another embodiment, R 7 is hydroxyl. In another embodiment, R 14 is methyl. In a further embodiment, R 1 teeth, [ka] wherein Y is O and Y 1 is phenoxy, and R 6 iso-propyl.

[0225] In an exemplary embodiment, the compound is: [ka] is selected from.

[0226] In one embodiment, R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is fluoro. In yet another embodiment, R 7 is hydroxyl. In another embodiment, R 14 is ethynyl. In a further embodiment, R 1 teeth, [ka] wherein Y is O and Y 1 is phenoxy, and R 6 iso-propyl.

[0227] In an exemplary embodiment, the compound is [ka] is selected from.

[0228] In one embodiment, R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4is fluoro. In yet another embodiment, R 7 is hydroxyl. In another embodiment, R 14 In a further embodiment, R 1 teeth, [ka] wherein Y is O and Y 1 is phenoxy, and R 6 iso-propyl.

[0229] In an exemplary embodiment, the compound is [ka] is selected from.

[0230] In an exemplary embodiment, the compound is [ka] is selected from.

[0231] In an exemplary embodiment, the compound is [ka] is selected from.

[0232] In an exemplary embodiment, the compound is [ka] is selected from.

[0233] In an exemplary embodiment, the compound is [ka] is selected from.

[0234] In an exemplary embodiment, the compound is [ka] is selected from.

[0235] In an exemplary embodiment, the compound is [ka] is selected from.

[0236] In an exemplary embodiment, the compound is [ka] is selected from.

[0237] In an exemplary embodiment, the compound is [ka] is selected from.

[0238] In an exemplary embodiment, the compound is [ka] is selected from.

[0239] In an exemplary embodiment, the compound is [ka] is selected from.

[0240] In an exemplary embodiment, the compound is [ka] is selected from.

[0241] In an exemplary embodiment, the compound is [ka] is selected from.

[0242] In an exemplary embodiment, the compound is [ka] is selected from.

[0243] In an exemplary embodiment, the compound is selected from the following: [ka]

[0244] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl, R 1 But the formula: [ka] It is one of the Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Y 2 OH, OR”, SR”, NHR”, NR” 2 , or BH 3 - M+ and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Each X is independently O, S, NH, NR 8 , N.H.O.H., N.R. 8 OH,NHOR 8 , or NR 8 OR 8 and R 2 But OH, SH, NH 2 , OR 8 , S.R. 8 , N.H.R. 8 , N.H.O.H., N.R. 8 OH,NHOR 8 , or NR 8 OR 8 and In formulae Ij and Ik, one of X is S or R 2 But, SR 8 or both X are S and R 2 But, SR 8 and In formula II, at least one X is S; W is CH, N, or CR 8 and Z is CH, N, or CR 8 and R 3 , R 4 , R 7 , R 9 , and R 14 However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 10 C replaced with 1-22 alkyl, R 3 and R4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by R 7 and R 14 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, 4-bromophenyl; R 8 is deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 10 C replaced with 1-22 is alkyl, R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; 6 optionally one or more, the same or different, R 10 is replaced by.

[0245] In certain embodiments, U is S, and Y and Z are CH.

[0246] In other embodiments, U is O and Y and Z are CH.

[0247] In one embodiment, R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In yet another embodiment, R 7 is hydroxyl. In another embodiment, R 14 is methyl. In a further embodiment, R 1 teeth, [ka] wherein Y is O and Y 1 is phenoxy, and R 6 iso-propyl.

[0248] In an exemplary embodiment, the compound is [ka] is selected from.

[0249] In one embodiment, R 5 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In yet another embodiment, R 7 is hydroxyl. In another embodiment, R 14 is methyl. In a further embodiment, R 1 teeth, [ka] wherein Y is O and Y 1 is O-aryl.

[0250] In an exemplary embodiment, the compound is selected from the following: [ka]

[0251] In an exemplary embodiment, the compound is selected from the following: [ka] [ka] [ka]

[0252] In an exemplary embodiment, the compound is selected from the following: [ka]

[0253] In an exemplary embodiment, the compound is selected from the following: [ka]

[0254] In a preferred embodiment, the nucleoside conjugated to the phosphorus moiety has the following structure: [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1 But the following: [ka] is selected from one of R 4 But, C 1-22 Alkoxy or C 1-22 is alkyl, alkyl, branched alkyl, cycloalkyl, or alkoxy; R5 Aryl, heteroaryl, substituted aryl, lipid, C 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 It is alkynyl, or substituted heteroaryl.

[0255] In an exemplified embodiment, the nucleoside conjugated to a phosphorus moiety, or a pharma- ceutically acceptable salt thereof, has the structure: [ka] [ka]

[0256] In other embodiments, R of formula Im 1 is the following: [ka] is selected from one of During the ceremony, R 2 is alkyl, branched alkyl, cycloalkyl; R 3 is aryl, biaryl, or substituted aryl; R 4 But, C 1-22 Alkoxy or C 1-22 is alkyl, alkyl, branched alkyl, cycloalkyl, or alkoxy; R 5 Aryl, heteroaryl, substituted aryl, lipid, C 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 It is alkynyl, or substituted heteroaryl.

[0257] In other embodiments, R of formula Im 1 is selected from one of the following: [ka] the lipid is as described herein; Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Y 2 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; R 5 is alkyl, branched alkyl, cycloalkyl; Aryl is as described herein; R 6 But, C 1-22 Alkoxy or C 1-22 is alkyl, alkyl, branched alkyl, cycloalkyl, or alkoxy; R 7 Aryl, heteroaryl, substituted aryl, lipid, C 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 It is alkynyl, or substituted heteroaryl.

[0258] In a preferred embodiment, the nucleoside or pharma- ceutically acceptable salt thereof conjugated to a phosphorus moiety has the following structure: [ka] having R 2But, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 , alkynyl, branched alkyl, or cycloalkyl; R 6 But lipids, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 , alkynyl, branched alkyl, cycloalkyl, or [ka] is selected from In the formula, R 4 But, C 1-22 Alkoxy or C 1-22 It is alkyl, branched alkyl, cycloalkyl, or alkoxy.

[0259] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; X is O, CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 and R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl, Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, and Q is optionally substituted with one or more of the same or different alkyl, halogen, or cycloalkyl; R 2 , R 3 , R 4 , R 8 , and R 9However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 10 C replaced with 1-22 alkyl, R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by R 8 and R 9 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R 1 But the formula: [ka] It is one of the Y is O or S; Y 1 OH, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; The lipid is as described herein.

[0260] In certain embodiments, Q heterocyclyl is selected from pyrimidine-2-one-4-thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5-fluoropyrimidine-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4-dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purine-6-thione, 2-amino-7-deaza-purine-6-thione, or 2-amino-7-deaza-7-substituted purine-6-thione.

[0261] In a preferred embodiment, U is O and Q is a pyrimidine having at least one thione, thiol, or thioether at the 2- and / or 4-position of the pyrimidine. In another preferred embodiment, U is S and Q is a pyrimidine having at least one thione, thiol, or thioether at the 2- and / or 4-position of the pyrimidine. In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl, U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; E is O, CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 and R 1 But the formula: [ka] It is one of the Y is O or S; Y 1 OH, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; the lipid is as described herein; Each X is independently O, S, NH, NR 8 , N.H.O.H., N.R. 8 OH,NHOR 8 , or NR 8 OR 8 and R 2 But OH, SH, NH 2 , OR 8 , S.R. 8 , N.H.R. 8 , N.H.O.H., N.R. 8 OH,NHOR 8 , or NR 8 OR 8 and In formulae Ip and Iq, one of X is S or R 2 But, SR 8 or both X are S and R 2 But, SR 8 and In formula Ir, at least one X is S; W is CH, N, or CR 8 and Z is CH, N, or CR 8 and R 8is deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 10 C replaced with 1-22 is alkyl, R 3 , R 4 , R 6 , R 7 , and R 14 However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 10 C replaced with 1-22 alkyl, R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by R 7 and R 14 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 It is selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.

[0262] In certain embodiments, U is S, and Y and Z are CH. In other embodiments, U is O and Y and Z are CH.

[0263] In certain embodiments, E is CH 2 where U is O, and Y and Z are CH.

[0264] In certain embodiments, the lipid is hexadecyloxypropyl, 2-aminohexadecyloxypropyl, 2-aminoarachidyl, lauryl, myristyl, palmityl, stearyl, arachidyl, behenyl, or lignoceryl.

[0265] In certain embodiments, the lipid is a sphingolipid having the formula: [ka] During the ceremony, Sphingolipid R 8 is hydrogen, alkyl, C(=O)R 12 , C(=O)OR 12 , or C(=O)NHR 12 and Sphingolipid R 9 But hydrogen, fluoro, OR 12 ,OC(=O)R 12 ,OC(=O)OR 12 , or OC(=O)NHR 12 and Sphingolipid R 10 is a saturated or unsaturated alkyl chain having more than 6 and less than 22 carbon atoms, optionally containing one or more halogen or hydroxyl groups or one or more groups of the formula: [ka] The structure is a formula in which n is 8 to 14 or 8 or less to 14 or less, o is 9 to 15 or 9 or less to 15 or less, the sum of m and n is 8 to 14 or 8 or less to 14 or less, and the sum of m and o is 9 to 15 or 9 or less to 15 or less, or [ka] And, a formula in which n is 4 to 10 or 4 or less to 10 or less, o is 5 to 11 or 5 or less to 11 or less, the sum of m and n is 4 to 10 or 4 or less to 10 or less, and the sum of m and o is 5 to 11 or 5 or less to 11 or less, or [ka] And, n is 6 to 12, or n is 6 or less to 12 or less, and the sum of m and n is 6 to 12, or n is 6 or less to 12 or less, Sphingolipid R 11 But, OR 12 ,OC(=O)R 12 ,OC(=O)OR 12 , or OC(=O)NHR 12 and Sphingolipid R 12 Hydrogen, branched chain or weak chain C 1-12 Alkyl, C 13-22 alkyl, cycloalkyl, or aryl selected from benzyl or phenyl, optionally having one or more, the same or different, R 13 is replaced by Sphingolipid R 13is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

[0266] In certain embodiments, the R 12 is H, alkyl, methyl, ethyl, propyl, n-butyl, branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenyl, monosubstituted phenyl, disubstituted phenyl, trisubstituted phenyl, or saturated or unsaturated C12-C19 long chain alkyl.

[0267] In certain embodiments, the sphingolipid has the formula: [ka] During the ceremony, Sphingolipid R 8 is hydrogen, hydroxy, fluoro, OR 12 ,OC(=O)R 12 ,OC(=O)OR 12 , or OC(=O)NHR 12 and Sphingolipid R 9 is hydrogen, hydroxy, fluoro, OR 12 ,OC(=O)R12 ,OC(=O)OR 12 , or OC(=O)NHR 12 and Sphingolipid R 10 is a saturated or unsaturated alkyl chain having more than 6 and less than 22 carbon atoms, and optionally one or more halogens or one or more of the following formula: [ka] The structure is n is 8 to 14 or 8 or less to 14 or less, and the sum of m and n is 8 to 14 or 8 or less to 14 or less, Sphingolipid R 12 Hydrogen, branched chain or weak chain C 1-12 Alkyl, C 13-22 alkyl, cycloalkyl, or aryl selected from benzyl or phenyl, optionally having one or more, the same or different, R 13 is replaced by Sphingolipid R 13 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

[0268] In certain embodiments, the R 12is H, alkyl, methyl, ethyl, propyl, n-butyl, branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenyl, mono-substituted phenyl, di-substituted phenyl, tri-substituted phenyl, or saturated or unsaturated C 12 -C 19 It is a long chain alkyl.

[0269] In one embodiment, R 5 is H. In another embodiment, R 4 is hydroxyl. In yet another embodiment, R 7 is hydroxyl. In yet another embodiment, R 14 is methyl. In a further embodiment, R 3 is hydrogen. In another embodiment, R 1 teeth, [ka] wherein Y is O and Y 1 In another embodiment, E is -OH and the lipid is a sphingolipid. 2 In an exemplary embodiment, the compound is selected from: [ka]

[0270] In one embodiment, R 5 is H. In another embodiment, R 4 is hydroxyl. In yet another embodiment, R 7 is hydroxyl. In yet another embodiment, R 14 is methyl. In a further embodiment, R 3 is hydrogen. In another embodiment, R 1 teeth, [ka] wherein Y is O and Y 1In another embodiment, E is -OH and the lipid is a sphingolipid. 2 In an exemplary embodiment, the compound is selected from: [ka]

[0271] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; X is CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 and R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl, R 1 is hydroxyl, Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, and Q is optionally substituted with one or more of the same or different alkyl, halogen, or cycloalkyl; R 2 , R 3 , R 4 , R 8 , and R 9 However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R10 C replaced with 1-22 alkyl, R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by R 8 and R 9 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 It is selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.

[0272] In certain embodiments, Q heterocyclyl is selected from pyrimidine-2-one-4-thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5-fluoropyrimidine-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4-dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purine-6-thione, 2-amino-7-deaza-purine-6-thione, or 2-amino-7-deaza-7-substituted purine-6-thione.

[0273] In a preferred embodiment, U is O and Q is a pyrimidine having at least one thione, thiol, or thioether at position 2 and / or 4 of the pyrimidine. In another preferred embodiment, U is S and Q is a pyrimidine having at least one thione, thiol, or thioether at position 2 and / or 4 of the pyrimidine.

[0274] In certain embodiments, R 8 and R 9 is selected from H, fluoro, methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, acetylenyl, ethyl, vinyl, and cyano.

[0275] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl, U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; Each X is independently O, S, NH, NR 8 , N.H.O.H., N.R. 8 OH,NHOR 8 , or NR 8 OR 8 and R 1 But OH, SH, NH 2 , OR 8 , S.R. 8 , N.H.R. 8 , N.H.O.H., N.R. 8 OH,NHOR 8 , or NR 8 OR 8 and In formulae It and Iu, one of X is S or R1 But, SR 8 or both X are S and R 1 But, SR 8 and In formula Iv, at least one X is S; Y is CH, N, or CR 8 and Z is CH, N, or CR 8 and R 7 and R 14 However, each independently, each independently H, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 10 C replaced with 1-22 alkyl, R 7 and R1 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by Each R 8 are independently deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 10 C replaced with 1-22 alkyl, Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2It is selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.

[0276] In certain embodiments, U is S, and Y and Z are CH.

[0277] In other embodiments, U is O and Y and Z are CH.

[0278] In certain embodiments, R 5 is H. In other embodiments, R 7 is F and R 14 is H. In an exemplary embodiment, the compound is [ka] is selected from.

[0279] In certain embodiments, R 5 is H. In other embodiments, R 7 is F and R 14 is methyl. In an exemplary embodiment, the compound is selected from: [ka]

[0280] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, and Q is optionally substituted with one or more of the same or different alkyl, halogen, cycloalkyl; R 2 , R 3 , R 4 , R 6 , and R 7 However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 9 C replaced with 1-22 alkyl, R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by R 6 and R 7 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by Each R 9 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl.

[0281] In certain embodiments, Q heterocyclyl is selected from pyrimidine-2-one-4-thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5-fluoropyrimidine-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4-dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purine-6-thione, 2-amino-7-deaza-purine-6-thione, or 2-amino-7-deaza-7-substituted purine-6-thione.

[0282] In a preferred embodiment, U is O and Q is a pyrimidine having at least one thione, thiol, or thioether at position 2 and / or 4 of the pyrimidine. In another preferred embodiment, U is S and Q is a pyrimidine having at least one thione, thiol, or thioether at position 2 and / or 4 of the pyrimidine.

[0283] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl, Each X is independently O, S, NH, NR 8 , N.H.O.H., N.R. 8 OH,NHOR 8 , or NR 8 OR 8 and R 1 But OH, SH, NH 2 , OR 8 , S.R.8 , N.H.R. 8 , N.H.O.H., N.R. 8 OH,NHOR 8 , or NR 8 OR 8 and In formulae Ix and Iy, one of X is S or R 1 But, SR 8 or both X are S and R 1 But, SR 8 and In formula Iz, at least one X is S; Y is CH, N, or CR 8 and Z is CH, N, or CR 8 and R 2 , R 3 , R 4 , R 6 , and R 7 However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 9 C replaced with 1-22 alkyl, R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by R 6 and R 7 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by Each R 8are independently deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 9 C replaced with 1-22 alkyl, Each R 9 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 It is selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.

[0284] In certain embodiments, U is S, and Y and Z are CH.

[0285] In other embodiments, U is O and Y and Z are CH.

[0286] In one embodiment, R 2 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is methyl. In yet a further embodiment, R 7 is fluoro.

[0287] In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0288] In one embodiment, R 2 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is trifluoromethyl. In yet a further embodiment, R 7 is fluoro. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0289] In one embodiment, R 2 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is C≡CH. In still further embodiments, R 7 is fluoro. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0290] In one embodiment, R 2 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is CH 2 In yet another embodiment, R 7 is fluoro. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0291] In one embodiment, R 2 is H. In another embodiment, R 3is H. In yet another embodiment, R 4 is H. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is H. In still further embodiments, R 7 is fluoro. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0292] In one embodiment, R 2 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is H. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is methyl. In yet a further embodiment, R 7 is fluoro. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0293] In one embodiment, R 2 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is H. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is trifluoromethyl. In yet a further embodiment, R 7 is fluoro. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0294] In one embodiment, R 2 is H. In another embodiment, R 3is H. In yet another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is methyl. In yet a further embodiment, R 7 is hydroxyl. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0295] In one embodiment, R 2 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is trifluoromethyl. In yet a further embodiment, R 7 is hydroxyl. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0296] In one embodiment, R 2 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is C≡CH. In still further embodiments, R 7 is hydroxyl. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0297] In one embodiment, R 2is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is CH 2 In yet a further embodiment, R 7 is hydroxyl. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0298] In one embodiment, R 2 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is methyl. In yet a further embodiment, R 7 is H. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0299] In one embodiment, R 2 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is trifluoromethyl. In yet a further embodiment, R 7 is H. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0300] In one embodiment, R 2 is N 3 In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is H. In still further embodiments, R 7 is hydroxyl. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0301] In one embodiment, R 2 is C≡CH. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is H. In still further embodiments, R 7 is hydroxyl. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0302] In one embodiment, R 2 is CH 2 In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is H. In still further embodiments, R 7 is hydroxyl. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0303] In one embodiment, R 2 is N 3 In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is H. In still further embodiments, R 7 is fluoro. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0304] In one embodiment, R 2 is C≡CH. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is H. In still further embodiments, R 7 is fluoro. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0305] In one embodiment, R 2 is CH 2 In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is H. In still further embodiments, R 7 is fluoro. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0306] In one embodiment, R 2 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is fluoro. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is H. In still further embodiments, R 7 is hydroxyl. In an exemplary embodiment, the compound is selected from the group consisting of: [ka]

[0307] In one embodiment, R 2 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is fluoro. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is methyl. In yet a further embodiment, R 7 is hydroxyl. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0308] In one embodiment, R 2 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is fluoro. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is C≡CH. In still further embodiments, R 7 is hydroxyl. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0309] In one embodiment, R 2 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is fluoro. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is CH 2 In yet a further embodiment, R 7 is hydroxyl. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0310] In one embodiment, R 2 is fluoro. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is methyl. In yet another embodiment, R 7 is hydroxyl. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0311] In one embodiment, R 2 is fluoro. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is C≡CH. In still further embodiments, R 7is hydroxyl. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0312] In one embodiment, R 2 is fluoro. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is CH 2 In yet a further embodiment, R 7 is hydroxyl. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0313] In one embodiment, R 2 is fluoro. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is methyl. In yet a further embodiment, R 7 is fluoro. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0314] In one embodiment, R 2 is fluoro. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6is C≡CH. In still further embodiments, R 7 is fluoro. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0315] In one embodiment, R 2 is fluoro. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is CH 2 In yet a further embodiment, R 7 is fluoro. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0316] In one embodiment, R 2 is H. In another embodiment, R 3 is H. In yet another embodiment, R 4 is hydroxyl. In a further embodiment, R 5 is H. In yet another embodiment, R 6 is fluoro. In still further embodiments, R 7 is H. In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0317] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, and Q is optionally substituted with one or more of the same or different alkyl, halogen, cycloalkyl; R 2 , R 3 , R 4 , R 6 , and R 7 However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 9 C replaced with 1-22 alkyl, R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by R 6 and R 7 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by Each R 9 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl.

[0318] In certain embodiments, Q heterocyclyl is selected from pyrimidine-2-one-4-thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5-fluoropyrimidine-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4-dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purine-6-thione, 2-amino-7-deaza-purine-6-thione, or 2-amino-7-deaza-7-substituted purine-6-thione.

[0319] In a preferred embodiment, U is O and Q is a pyrimidine having at least one thione, thiol, or thioether at position 2 and / or 4 of the pyrimidine. In another preferred embodiment, U is S and Q is a pyrimidine having at least one thione, thiol, or thioether at position 2 and / or 4 of the pyrimidine.

[0320] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl, Each X is independently O, S, NH, NR 8, N.H.O.H., N.R. 8 OH,NHOR 8 , or NR 8 OR 8 and R 1 But OH, SH, NH 2 , OR 8 , S.R. 8 , N.H.R. 8 , N.H.O.H., N.R. 8 OH,NHOR 8 , or NR 8 OR 8 and In formulae Ix and Iy, one of X is S or R 1 But, SR 8 or both X are S and R 1 But, SR 8 and In formula Iz, at least one X is S; Y is CH, N, or CR 8 and Z is CH, N, or CR 8 and R 2 , R 3 , R 4 , R 6 , and R 7 However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 9 C replaced with 1-22 alkyl, R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by R 6 and R7 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by Each R 8 are independently deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 9 C replaced with 1-22 alkyl, Each R 9 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 It is selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.

[0321] In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0322] In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0323] In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0324] In an exemplary embodiment, the compound is [ka] is selected from the group consisting of:

[0325] In one embodiment, the nucleoside conjugated to a phosphorus moiety has the following formula: [ka] or a pharma- ceutically acceptable salt thereof, R 1 is H, monophosphate, diphosphate, triphosphate, or [ka] is selected from one of U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; R 2’ is alkyl, branched alkyl, cycloalkyl; R 3 ' is aryl, biaryl, or substituted aryl; Z is CH, CD, or N; R 7 But H, D, N 3 , ethynyl, vinyl, fluoro, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, CD 3 , hydroxymethyl, or cyano; R 3 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, or vinyl; R 4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH; R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH; R6 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, or vinyl; In certain exemplary embodiments of any of the formulas described herein, Z is CD.

[0326] In certain embodiments, U is S and Z is CH.

[0327] In other embodiments, U is O and Z is CH.

[0328] In one embodiment, the nucleoside conjugated to a phosphorus moiety has the following formula: [ka] or a pharma- ceutically acceptable salt thereof, R 1 is H, monophosphate, diphosphate, triphosphate, or [ka] is selected from one of R 2’ is alkyl, branched alkyl, cycloalkyl; R 3 ' is aryl, biaryl, or substituted aryl; Z is CH, CD, or N; R 3 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl; R 4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH; R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH; R6 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl.

[0329] In certain embodiments, Z is CH.

[0330] In one embodiment, the nucleoside conjugated to a phosphorus moiety has the following formula: [ka] or a pharma- ceutically acceptable salt thereof, R 1 is H, monophosphate, diphosphate, triphosphate, or [ka] is selected from one of R 2’ is alkyl, branched alkyl, cycloalkyl; R 3’ is aryl, biaryl, or substituted aryl; Z is CH, CD, or N; R 3 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl; R 4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH; R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH; R 6 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl.

[0331] In certain embodiments, Z is CH.

[0332] In a preferred embodiment, the nucleoside conjugated to the phosphorus moiety has the following formula: [ka] or a pharma- ceutically acceptable salt thereof, R 1 is H, monophosphate, diphosphate, triphosphate, or [ka] is selected from one of R 2’ is alkyl, branched alkyl, cycloalkyl; R 3’ is aryl, biaryl, or substituted aryl; Z is CH, CD, or N; R 3 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl; R 4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH; R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH; R 6 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl.

[0333] In certain embodiments, Z is CH.

[0334] In one embodiment, the nucleoside conjugated to a phosphorus moiety has the following formula: [ka] or a pharma- ceutically acceptable salt thereof, R 1 is H, monophosphate, diphosphate, triphosphate, or [ka] is selected from one of R 2’ is alkyl, branched alkyl, cycloalkyl; R 3 ' is aryl, biaryl, or substituted aryl; Z is CH, CD, or N; R 3 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl; R 4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH; R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH; R 6 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl.

[0335] In certain embodiments, Z is CH.

[0336] In one embodiment, the nucleoside conjugated to a phosphorus moiety has the following formula: [ka] or a pharma- ceutically acceptable salt thereof, R 1is H, monophosphate, diphosphate, triphosphate, or [ka] is selected from one of R 2’ is alkyl, branched alkyl, cycloalkyl; R 3’ is aryl, biaryl, or substituted aryl; Z is CH, CD, or N; R 3 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl; R 4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH; R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH; R 6 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl.

[0337] In certain embodiments, Z is CH.

[0338] In one embodiment, the nucleoside conjugated to a phosphorus moiety has the following formula: [ka] or a pharma- ceutically acceptable salt thereof, R 1 is H, monophosphate, diphosphate, triphosphate, or [ka] is selected from one of R 2’ is alkyl, branched alkyl, cycloalkyl; R 3’ is aryl, biaryl, or substituted aryl; Z is CH, CD, or N; R 3 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl; R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH; R 6 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl.

[0339] In certain embodiments, Z is CH.

[0340] In one embodiment, the nucleoside conjugated to a phosphorus moiety has the following formula: [ka] or a pharma- ceutically acceptable salt thereof, R 1 is H, monophosphate, diphosphate, triphosphate, or [ka] is selected from one of R 2’ is alkyl, branched alkyl, cycloalkyl; R 3’ is aryl, biaryl, or substituted aryl; Z is CH, CD, or N; R 3 But H, D, methyl, CD 3, ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl; R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH; R 6 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl.

[0341] In certain embodiments, Z is CH.

[0342] In one embodiment, the nucleoside conjugated to a phosphorus moiety has the following formula: [ka] or a pharma- ceutically acceptable salt thereof, R 1 is H, monophosphate, diphosphate, triphosphate, or [ka] is selected from one of R 2’ is alkyl, branched alkyl, cycloalkyl; R 3’ is aryl, biaryl, or substituted aryl; Z is CH, CD, or N; R 3 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl; R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH; R 6 But H, D, methyl, CD 3, ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl.

[0343] In certain embodiments, Z is CH.

[0344] In one embodiment, the nucleoside conjugated to a phosphorus moiety has the following formula: [ka] or a pharma- ceutically acceptable salt thereof, R 1 is H, monophosphate, diphosphate, triphosphate, or [ka] is selected from one of R 2’ is alkyl, branched alkyl, cycloalkyl; R 3’ is aryl, biaryl, or substituted aryl; Z is CH, CD, or N; R 3 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl; R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH; R 6 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl.

[0345] In certain embodiments, Z is CH.

[0346] In one embodiment, the nucleoside conjugated to a phosphorus moiety has the following formula: [ka] or a pharma- ceutically acceptable salt thereof, R 1 is H, monophosphate, diphosphate, triphosphate, or [ka] is selected from one of R 2’ is alkyl, branched alkyl, cycloalkyl; R 3’ is aryl, biaryl, or substituted aryl; Z is CH, CD, or N; R 3 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl; R 4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH; R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH.

[0347] In certain embodiments, Z is CH.

[0348] In one embodiment, the nucleoside conjugated to a phosphorus moiety has the following formula: [ka] or a pharma- ceutically acceptable salt thereof, R 1 is H, monophosphate, diphosphate, triphosphate, or [ka] is selected from one of R 2’ is alkyl, branched alkyl, cycloalkyl; R 3’ is aryl, biaryl, or substituted aryl; Z is CH, CD, or N; R 3 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl; R 4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH; R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH.

[0349] In certain embodiments, Z is CH.

[0350] In one embodiment, the nucleoside conjugated to a phosphorus moiety has the following formula: [ka] or a pharma- ceutically acceptable salt thereof, R 1 is H, monophosphate, diphosphate, triphosphate, or [ka] is selected from one of R 2’ is alkyl, branched alkyl, cycloalkyl; R 3’ is aryl, biaryl, or substituted aryl; Z is CH, CD, or N; R 3 But H, D, methyl, CD 3, ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl; R 4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH; R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH.

[0351] In certain embodiments, Z is CH.

[0352] In one embodiment, the nucleoside conjugated to a phosphorus moiety has the following formula: [ka] or a pharma- ceutically acceptable salt thereof, R 1 is H, monophosphate, diphosphate, triphosphate, or [ka] is selected from one of R 2’ is alkyl, branched alkyl, cycloalkyl; R 3’ is aryl, biaryl, or substituted aryl; Z is CH, CD, or N; R 3 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl; R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH.

[0353] In certain embodiments, Z is CH.

[0354] In one embodiment, the nucleoside conjugated to a phosphorus moiety has the following formula: [ka] or a pharma- ceutically acceptable salt thereof, R 1 is H, monophosphate, diphosphate, triphosphate, or [ka] is selected from one of R 2’ is alkyl, branched alkyl, cycloalkyl; R 3’ is aryl, biaryl, or substituted aryl; Z is CH, CD, or N; R 3 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl; R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH.

[0355] In certain embodiments, Z is CH.

[0356] In one embodiment, the nucleoside conjugated to a phosphorus moiety has the following formula: [ka] or a pharma- ceutically acceptable salt thereof, R 1 is H, monophosphate, diphosphate, triphosphate, or [ka] is selected from one of R 2’is alkyl, branched alkyl, cycloalkyl; R 3’ is aryl, biaryl, or substituted aryl; Z is CH, CD, or N; R 3 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl; R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH.

[0357] In certain embodiments, Z is CH.

[0358] In one embodiment, the nucleoside conjugated to a phosphorus moiety has the following formula: [ka] or a pharma- ceutically acceptable salt thereof, R 1 is H, monophosphate, diphosphate, triphosphate, or [ka] is selected from one of R 2’ is alkyl, branched alkyl, cycloalkyl; R 3’ is aryl, biaryl, or substituted aryl; Z is CH, CD, or N; R 3 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl; R 4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH; R5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH.

[0359] In certain embodiments, Z is CH.

[0360] In one embodiment, the nucleoside conjugated to a phosphorus moiety has the following formula: [ka] or a pharma- ceutically acceptable salt thereof, R 1 is H, monophosphate, diphosphate, triphosphate, or [ka] is selected from one of R 2’ is alkyl, branched alkyl, cycloalkyl; R 3’ is aryl, biaryl, or substituted aryl; Z is CH, CD, or N; R 3 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl; R 4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH; R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH.

[0361] In certain embodiments, Z is CH.

[0362] In one embodiment, the nucleoside conjugated to a phosphorus moiety has the following formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is H, monophosphate, diphosphate, triphosphate, or [ka] is selected from one of R 2’ is alkyl, branched alkyl, cycloalkyl; R 3 ' is aryl, biaryl, or substituted aryl; Z is CH, CD, or N; R 3 But H, D, methyl, CD 3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl, or allyl; R 4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH; R 5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro, or SH.

[0363] In certain embodiments, Z is CH.

[0364] In one embodiment, the nucleoside conjugated to a phosphorus moiety has the following formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is H, monophosphate, diphosphate, triphosphate, or is selected from one of the following: [ka] R 2’ is alkyl, branched alkyl, cycloalkyl; R3’ is aryl, biaryl, or substituted aryl.

[0365] In another embodiment, R 1 is selected from one of the following: [ka] R 4 is alkyl, branched alkyl, cycloalkyl, or alkoxy; R 5 is aryl, heteroaryl, substituted aryl, or substituted heteroaryl.

[0366] In certain embodiments of formula I, X is methylene (CH 2 ) and R 1 is the following: [ka] It is one of the In the formula, R 12 C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, branched alkyl, or cycloalkyl, Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, 4-bromophenyl.

[0367] In certain embodiments, X is methylene (CH 2 ) and R 1 is the following: [ka] It is one of the During the ceremony, Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, 4-bromophenyl.

[0368] In another embodiment, R 1 is selected from one of the following: [ka] the lipid is as described herein; Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Y 2 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; R 5is alkyl, branched alkyl, cycloalkyl; Aryl is as described herein; R 6 But, C 1-22 Alkoxy or C 1-22 is alkyl, alkyl, branched alkyl, cycloalkyl, or alkoxy; R 7 Aryl, heteroaryl, substituted aryl, lipid, C 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 It is alkynyl, or substituted heteroaryl.

[0369] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; Y 2 is O or S, Y 3 But, OH, OR 10 , S.R. 10 , N.H.R. 10 , N.R. 10 2 , lipid, BH 3 _ M + or [ka] is selected from E is CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 and R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl, Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, and Q is optionally substituted with one or more of the same or different alkyl, halogen, cycloalkyl; R 2 , R 3 , R 6 , and R 7 However, each independently, each independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 11 C replaced with 1-22 alkyl, R 6 and R 7 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 11 can be replaced by R 10 Aryl, heteroaryl, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 , alkynyl, branched alkyl, or cycloalkyl; R 4 But, C 1-22 Alkyl, C 1-22 Alkoxy, C 2-22 Alkenyl, C 2-22 alkynyl, branched alkyl, or cycloalkyl; Each R 11 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2It is selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.

[0370] In certain embodiments, Y 3 , OH, SR 10 , N.H.R. 10 , and N.R. 10 2 is selected from the group consisting of:

[0371] In certain embodiments, E is CHMe, CMe 2 , CHF, and CF 2 is selected from the group consisting of:

[0372] In certain embodiments, Q heterocyclyl is selected from pyrimidine-2-one-4-thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5-fluoropyrimidine-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4-dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purine-6-thione, 2-amino-7-deaza-purine-6-thione, or 2-amino-7-deaza-7-substituted purine-6-thione.

[0373] In a preferred embodiment, U is O and Q is a pyrimidine having at least one thione, thiol, or thioether at position 2 and / or 4 of the pyrimidine. In another preferred embodiment, U is S and Q is a pyrimidine having at least one thione, thiol, or thioether at position 2 and / or 4 of the pyrimidine.

[0374] In certain other embodiments, R 2 , R 3 , R 6 , and R 7 are each independently H, D, or CH 3 , CD 3 , C.F. 3, C.F. 2 H, CFH 2 , O.H., S.H., and N.H. 2 , N 3 , CHO, CN, Cl, Br, F, or I.

[0375] In yet other certain embodiments, R 10 is alkyl, methyl, ethyl, propyl, n-butyl, branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or 2-butyl.

[0376] In certain embodiments, the present disclosure provides a compound of the formula: [ka] For compounds of the formula (I), U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; In the formula, R 1 and R 2 However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 8 C replaced with 1-22 alkyl, Each R 8 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; Q, [ka] is selected from Y is O or S; R is linear or branched alkyl, for example, methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, or C 12-19 long chain alkyl; cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; benzyl, aryl, or heteroaryl.

[0377] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; R 1 and R 9 However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 10 C replaced with 1-22 alkyl, Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; Q, [ka] is selected from Y is O or S; Lipids, [ka] and In the formula, R 2 is H: alkyl, e.g., methyl, C(O)R', C(O)OR', or C(O)NHR'; R 3 is H, hydrogen, fluoro, OR', OC(O)R', OC(O)OR', OC(O)NHR', R' is H; linear or branched alkyl, such as methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, or C 12-19 long chain alkyl; cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; benzyl, phenyl; mono-substituted phenyl; di-substituted phenyl; or tri-substituted phenyl; R 4 But, C 11-17 Long alkyl chains, e.g. [ka] wherein n is 8 to 14; o is 9 to 15, or [ka] and "m+n" is 8 to 14 and "m+o" is 9 to 15; or [ka] where n is 4 to 10 and o is 5 to 11; or [ka] "m+n" is 4 to 10 and "m+o" is 5 to 11; or [ka] and n is 6 to 12; or [ka] and "m+n" is between 6 and 12.

[0378] R 5 is H, hydrogen, fluoro, OR', OC(O)R', OC(O)OR', OC(O)NHR'.

[0379] In an alternative embodiment, the lipid is [ka] and In the formula, R 6 is H, hydrogen, fluoro, OR', OC(O)R', OC(O)OR', OC(O)NHR', R 7 is H, hydrogen, fluoro, OR', OC(O)R', OC(O)OR', OC(O)NHR', R' is H; linear or branched alkyl, such as methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, or C 12-19 long chain alkyl; cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; benzyl, phenyl; monosubstituted phenyl; disubstituted phenyl; trisubstituted phenyl; R 8 But, C 9-15 Alkyl chains, e.g. [ka] wherein n is 8 to 14; or [ka] In the formula, “m+n” is 8 to 14.

[0380] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl, E is CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 and U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; Y is O or S; Y 1 But, OH, OR 40 , S.R. 40 , N.H.R. 40 , N.R. 40 2 , lipid, BH 3 _ M + or [ka] is selected from Each X is independently O, S, NH, NR 8 , N.H.O.H., N.R. 8 OH,NHOR 8 , or NR 8 OR 8 and R 1 But OH, SH, NH 2 , OR 8 , S.R. 8 , N.H.R. 8 , N.H.O.H., N.R. 8 OH,NHOR 8, or NR 8 OR 8 and In formula IIc and IId, one of X is S or R 1 But, SR 8 or both X are S and R 1 But, SR 8 and In formula IIe, at least one X is S; W is CH, N, or CR 8 and Z is CH, N, or CR 8 and R 6 , R 7 , and R 9 However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 8 C replaced with 1-22 alkyl, R 6 and R 7 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 8 can be replaced by Each R 8 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R 40 Aryl, heteroaryl, C 1-22 Alkyl, C 2-22Alkenyl, C 2-22 , alkynyl, branched alkyl, or cycloalkyl; R 4 But, C 1-22 Alkyl, C 1-22 Alkoxy, C 2-22 Alkenyl, C 2-22 It is alkynyl, branched alkyl, or cycloalkyl.

[0381] In certain embodiments, U is S, and Y and Z are CH.

[0382] In other embodiments, U is O and Y and Z are CH.

[0383] In an exemplary embodiment, the compound is [ka] is selected from.

[0384] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl, U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; E is CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 and Y 2 is O or S, R 2 , R 3 , R 6 , and R 7 However, independently, H, D, C 1-22Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 8 C replaced with 1-22 alkyl, R 6 and R 7 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 8 can be replaced by Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, and Q is optionally substituted with one or more of the same or different alkyl, halogen, or cycloalkyl; Each R 8 is independently selected from alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R 19 But, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 , alkynyl, branched alkyl, or cycloalkyl.

[0385] In a preferred embodiment, U is O and Q is a pyrimidine having at least one thione, thiol, or thioether at position 2 and / or 4 of the pyrimidine. In another preferred embodiment, U is S and Q is a pyrimidine having at least one thione, thiol, or thioether at position 2 and / or 4 of the pyrimidine.

[0386] In certain embodiments, R 6 is selected from hydrogen, methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, acetylenyl, ethyl, vinyl, or cyano.

[0387] In certain embodiments, R 19 is selected from alkyl, methyl, ethyl, propyl, n-butyl, branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or 2-butyl.

[0388] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; R 6 and R 7 However, each independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 10 C replaced with 1-22 alkyl, R 6 and R 7 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; Q, [ka] is selected from Y is O or S; R is linear or branched alkyl, for example, methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, or C 12-19 A long chain alkyl; a cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or benzyl.

[0389] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl, E is CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 and U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; Y is O or S; Each X is independently O, S, NH, NR 8 , N.H.O.H., N.R. 8 OH,NHOR8 , or NR 8 OR 8 and R 1 But OH, SH, NH 2 , OR 8 , S.R. 8 , N.H.R. 8 , N.H.O.H., N.R. 8 OH,NHOR 8 , or NR 8 OR 8 and In formula IIIb and IIIc, one of X is S or R 1 But, SR 8 or both X are S and R 1 But, SR 8 and In formula IIId, at least one X is S; W is CH, N, or CR 8 and Z is CH, N, or CR 8 and R 6 , R 7 , and R 10 However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 9 C replaced with 1-22 alkyl, R 6 and R 7 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by R 8is deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 9 C replaced with 1-22 is alkyl, Each R 9 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R 50 But, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 , alkynyl, branched alkyl, or cycloalkyl.

[0390] In certain embodiments, U is S and W and Z are CH. In other embodiments, U is O and W and Z are CH.

[0391] In certain embodiments, R 5 is H. In other embodiments, R 6 is methyl. In yet other embodiments, R 7 is hydroxyl. In a preferred embodiment, R 5 is H and R 6 is methyl, R 7 is hydroxyl.

[0392] In certain embodiments, R 50 is alkyl, methyl, ethyl, propyl, n-butyl, branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or 2-butyl.

[0393] In an exemplary embodiment, the compound is selected from the following: [ka]

[0394] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein X is O, CH 2 , or CD 2 and R 1 is a phosphate, phosphonate, polyphosphate, polyphosphonate substituent, and the phosphate or polyphosphonate in the phosphate or polyphosphate is optionally a phosphoroborate, phosphorothioate, or phosphoroamidate, and the substituent is optionally one or more, the same or different, R 6 further substituted with an amino acid ester or lipid or derivative, Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, and Q is optionally substituted with one or more of the same or different alkyl, halogen, or cycloalkyl; R 6 are the same or different, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; 6 optionally one or more, the same or different, R 7 is replaced by R 7is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

[0395] In certain embodiments, Q heterocyclyl is pyrimidine-2-one-4-thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5-fluoropyrimidine-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4-dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purine-6-thione, 2-amino-7-deaza-purine-6-thione, or 2-amino-7-deaza-7-substituted purine-6-thione.

[0396] In a preferred embodiment, U is O and Q is a pyrimidine having at least one thione, thiol, or thioether at position 2 and / or 4 of the pyrimidine. In another preferred embodiment, U is S and Q is a pyrimidine having at least one thione, thiol, or thioether at position 2 and / or 4 of the pyrimidine.

[0397] In certain embodiments, the lipid is a sphingolipid of any of the formulas described above or herein.

[0398] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein each Y is independently O or S; X is O, S, NH, NR 24 and R 23 is O or NH, R 4 and R 7 However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 9 C replaced with 1-22 alkyl, Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, and Q is optionally substituted with one or more of the same or different alkyl, halogen, or cycloalkyl; Each R 9 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R 20 optionally one or more, the same or different, R 26 is an alkyl group having 6 to 22 carbon atoms substituted with R 21 and R 22are each independently selected from hydrogen, alkyl, or alkanoyl; R 21 and R 22 each optionally containing one or more of the same or different R 26 is replaced by R 24 and R 25 are each independently selected from hydrogen, alkyl, or aryl; R 24 and R 25 each optionally containing one or more of the same or different R 26 is replaced by Each R 26 are independently alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 It is selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.

[0399] In certain embodiments, R 4 and R 7 is independently hydrogen, hydroxy, alkoxy, azido, or halogen.

[0400] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein The dotted lines represent the presence of a single or double bond; Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, and Q is optionally substituted with one or more of the same or different alkyl, halogen, cycloalkyl; X is O, S, NH, NR 24 and R 23 is O or NH, R 4 and R 7However, each independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 26 C replaced with 1-22 alkyl, R 20 optionally one or more, the same or different, R 26 is an alkyl group having 6 to 22 carbon atoms substituted with R 21 , R 22 , and R 25 is independently selected from hydrogen, alkyl, or alkanoyl; R 21 , R 22 , and R 25 each optionally containing one or more of the same or different R 26 is replaced by Each R 24 is independently selected from hydrogen, alkyl, or aryl; 24 optionally, one or more, the same or different, R 26 is replaced by Each R 26 are independently alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl

[0401] In certain embodiments, Q heterocyclyl is pyrimidine-2-one-4-thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5-fluoropyrimidine-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4-dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purine-6-thione, 2-amino-7-deaza-purine-6-thione, or 2-amino-7-deaza-7-substituted-purine-6-thione.

[0402] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein X is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; Y is O or S; Z is O, S, NH, NR 24 and R 23 is O or NH, Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, and Q is optionally substituted with one or more of the same or different alkyl, halogen, or cycloalkyl; R 20 optionally one or more, the same or different, R 37 is an alkyl group having 6 to 22 carbon atoms substituted with R 21 and R 22 are each independently selected from hydrogen, alkyl, or alkanoyl; R 21 and R 22 each optionally containing one or more of the same or different R 37 is replaced by R 24is hydrogen, alkyl, or aryl, and each R 24 optionally, one or more, the same or different, R 37 is replaced by R 26 is alkyl, Each R 37 are independently alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 It is selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.

[0403] In certain embodiments, Q heterocyclyl is pyrimidine-2-one-4-thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5-fluoropyrimidine-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4-dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purine-6-thione, 2-amino-7-deaza-purine-6-thione, or 2-amino-7-deaza-7-substituted purine-6-thione.

[0404] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein X is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; Y is O or S; Z is O, S, NH, NR 24 and R 23 is O or NH, Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, and Q is optionally substituted with one or more of the same or different alkyl, halogen, or cycloalkyl; R 27 optionally one or more, the same or different, R 37 is an alkyl group having 6 to 22 carbon atoms substituted with R 21 , R 22 , R 28 , and R 29 are each independently selected from hydrogen, alkyl, or alkanoyl; R 21 , R 22 , R 28 , and R 29 each optionally containing one or more of the same or different R 37 is replaced by R 24 is hydrogen, alkyl, or aryl, and each R 24 optionally, one or more, the same or different, R 37 is replaced by R 26 is alkyl, Each R 37 are independently alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 It is selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.

[0405] In certain embodiments, Q heterocyclyl is pyrimidine-2-one-4-thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5-fluoropyrimidine-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4-dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purine-6-thione, 2-amino-7-deaza-purine-6-thione, or 2-amino-7-deaza-7-substituted purine-6-thione.

[0406] In a preferred embodiment, U is O and Q is a pyrimidine having at least one thione, thiol, or thioether at position 2 and / or 4 of the pyrimidine. In another preferred embodiment, U is S and Q is a pyrimidine having at least one thione, thiol, or thioether at position 2 and / or 4 of the pyrimidine.

[0407] In certain embodiments, R 23 -R 27The fragment defined by the formula (I) is a sphingolipid. Suitable sphingolipids include 2-aminooctadecane-3,5-diol, (2S,3S,5S)-2-aminooctadecane-3,5-diol, (2S,3R,5S)-2-aminooctadecane-3,5-diol, 2-(methylamino)octadecane-3,5-diol, (2S,3R,5S)-2-(methylamino)octadecane-3,5-diol, 2-(dimethylamino)octadecane-3,5-diol, (2R,3S,5S)-2-(dimethylamino)octadecane- 3,5-diol, 1-(pyrrolidin-2-yl)hexadecane-1,3-diol, (1S,3S)-1-((S)-pyrrolidin-2-yl)hexadecane-1,3-diol, 2-amino-11,11-difluorooctadecane-3,5-diol, (2S,3S,5S)-2-amino-11,11-difluorooctadecane-3,5-diol, 11,11-difluoro-2-(methylamino)octadecane-3,5-diol, (2S,3S,5S)-11,11-difluoro-2-(methylamino)octadecane-3,5-diol ol, N-((2S,3S,5S)-3,5-dihydroxyoctadecane-2-yl)acetamide, N-((2S,3S,5S)-3,5-dihydroxyoctadecane-2-yl)palmitamide, 1-(1-aminocyclopropyl)hexadecane-1,3-diol, (1S,3R)-1-(1-aminocyclopropyl)hexadecane-1,3-diol, (1S,3S)-1-(1-aminocyclopropyl)hexadecane-1,3-diol, 2-amino-2-methyloctadecane-3,5-diol, (3S,5S)-2-amino- 2-Methyloctadecane-3,5-diol, (3S,5R)-2-amino-2-methyloctadecane-3,5-diol, (3S,5S)-2-methyl-2-(methylamino)octadecane-3,5-diol, 2-amino-5-hydroxy-2-methyloctadecane-3-one, (Z)-2-amino-5-hydroxy-2-methyloctadecane-3-one oxime, (2S,3R,5R)-2-amino-6,6-difluorooctadecane-3,5-diol, (2S,3S,5R)-2-amino-6,6-difluorooctadecane-3,5-diol, (2S,3S,5S)-2-amino-6,6-difluorooctadecane-3,5-diol, (2S,3R,5S)-2-amino-6,6-difluorooctadecane-3,5-diol, and (2S,3S,5S)-2-amino-18,18,18-trifluorooctadecane-3,5-diol.

[0408] In a preferred embodiment, the nucleoside conjugate has the following structure: [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1 is H, monophosphate, diphosphate, triphosphate, or [ka] is selected from one of R 2 is alkyl, branched alkyl, cycloalkyl; R 3 is aryl, biaryl, or substituted aryl; In an exemplified embodiment, the nucleoside conjugated to a phosphorus moiety, or a pharma- ceutically acceptable salt thereof, has the structure: [ka]

[0409] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein A is absent or CH 2 , CHF, CF 2 , CD 2 , O, C.H. 2 O, CHFO, CF 2 O, C.D. 2 O, OCH2 , OCHF, OCF 2 , or OCD 2 is selected from R 1 But the following: [ka] and X is selected from O, S, NH, CH 2 , CD 2 , CHF, CF 2 , C=CH 2 , C=CHF, or C=CF 2 and Each U is independently O, S, NH, or NR 9 , N.H.O.H., N.R. 9 OH,NHOR 9 , or NR 9 OR 9 and R 8 However, independently, OH, SH, NH 2 , OR 9 , S.R. 9 , N.H.R. 9 , N.H.O.H., N.R. 9 OH,NHOR 9 , or NR 9 OR 9 and In formulas Xa and Xb, one of U is S or R 8 But, SR 9 or both U are S and R 8 But, SR 9 and In formula Xc, at least one U is S; W is CH, N, or CR 9 and Z is CH, N, or CR 9 and Each R 9 are independently deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 10 C replaced with1-22 is alkyl, Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; Each R 2 is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, fluoro, methyl, ethynyl, vinyl, allyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, azido, methoxy, or amino; Each R 3 is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, fluoro, methyl, ethynyl, vinyl, allyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, or azido; Each R 4 is independently selected from hydrogen, deuterium, hydroxyl, halogen, fluoro, azido, methoxy, or amino; the lipid is as described herein; Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Y 2 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; R 5 is alkyl, branched alkyl, cycloalkyl; Aryl is as described herein; R 6 But, C 1-22 Alkoxy or C 1-22 is alkyl, alkyl, branched alkyl, cycloalkyl, or alkoxy; R 7 Aryl, heteroaryl, substituted aryl, lipid, C 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 It is alkynyl, or substituted heteroaryl.

[0410] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein A is absent or CH 2 , CHF, CF 2 , CD 2 , O, C.H. 2 O, CHFO, CF 2 O, C.D. 2 O, OCH 2 , OCHF, OCF 2 , or OCD 2 is selected from R 1 is selected from one of the following: [ka] X is O, S, NH, CH 2 , CD 2 , CHF, CF 2 , C=CH 2 , C=CHF, or C=CF 2 and Each R 2 are independently hydrogen, deuterium, hydroxyl, cyano, halogen, fluoro, methyl, ethynyl, vinyl, allyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, azido, methoxy, or amino; Each R 3 are independently hydrogen, deuterium, hydroxyl, cyano, halogen, fluoro, methyl, ethynyl, vinyl, allyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, or azido; Each R 4 is independently hydrogen, deuterium, hydroxyl, halogen, fluoro, azido, methoxy, or amino; the lipid is as described herein; Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Y 2 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; R 5 is alkyl, branched alkyl, cycloalkyl; Aryl is as described herein; R 6 But, C 1-22 Alkoxy or C 1-22 is alkyl, alkyl, branched alkyl, cycloalkyl, or alkoxy; R7 Aryl, heteroaryl, substituted aryl, lipid, C 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 It is alkynyl, or substituted heteroaryl.

[0411] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein A is absent or CH 2 , CHF, CF 2 , CD 2 , O, C.H. 2 O, CHFO, CF 2 O, C.D. 2 O, OCH 2 , OCHF, OCF 2 , or OCD 2 is selected from R 1 But the following: [ka] and X is selected from O, S, NH, CH 2 , CD 2 , CHF, CF 2 , C=CH 2 , C=CHF, or C=CF 2 and Each R 2 are independently hydrogen, deuterium, hydroxyl, cyano, halogen, fluoro, methyl, ethynyl, vinyl, allyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, azido, methoxy, or amino; Each R 3 are independently hydrogen, deuterium, hydroxyl, cyano, halogen, fluoro, methyl, ethynyl, vinyl, allyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, or azido; Each R 4is independently hydrogen, deuterium, hydroxyl, halogen, fluoro, azido, methoxy, or amino; the lipid is as described herein; Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Y 2 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; R 5 is alkyl, branched alkyl, cycloalkyl; Aryl is as described herein; R 6 But, C 1-22 Alkoxy or C 1-22 is alkyl, alkyl, branched alkyl, cycloalkyl, or alkoxy; R 7 Aryl, heteroaryl, substituted aryl, lipid, C 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 It is alkynyl, or substituted heteroaryl.

[0412] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein A is absent or CH 2 , CHF, CF 2 , CD 2 , O, C.H. 2 O, CHFO, CF 2 O, C.D. 2 O, OCH 2 , OCHF, OCF 2 , or OCD 2 is selected from X is O, S, NH, CH 2 , CD 2 , CHF, CF 2 , C=CH 2 , C=CHF, or C=CF 2 and Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, and Q is optionally substituted with one or more of the same or different alkyl, halogen, cycloalkyl; Each R 2 are independently hydrogen, deuterium, hydroxyl, cyano, halogen, fluoro, methyl, ethynyl, vinyl, allyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, azido, methoxy, or amino; Each R 3 are independently hydrogen, deuterium, hydroxyl, cyano, halogen, fluoro, methyl, ethynyl, vinyl, allyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, or azido; Each R 4 is independently hydrogen, deuterium, hydroxyl, halogen, fluoro, azido, methoxy, or amino; Y is O or S; R 5 Aryl, heteroaryl, substituted aryl, lipid, C 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 It is alkynyl, or substituted heteroaryl.

[0413] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein A is absent or CH 2 , CHF, CF 2 , CD 2 , O, C.H. 2 O, CHFO, CF 2 O, C.D. 2 O, OCH 2 , OCHF, OCF 2 , or OCD 2 is selected from R 1 is selected from one of the following: [ka] X is O, S, NH, CH 2 , CD 2 , CHF, CF 2 , C=CH 2 , C=CHF, or C=CF 2 and Each U is independently O, S, NH, or NR 9 , N.H.O.H., N.R. 9 OH,NHOR 9 , or NR 9 OR 9 and R 8 But OH, SH, NH 2 , OR 9 , S.R. 9 , N.H.R. 9 , N.H.O.H., N.R. 9 OH,NHOR 9 , or NR 9 OR 9 and In formulas XIIIa and XIIIb, one of U is S or R 8 But, SR 9 or both U are S and R 8 But, SR 9 and In formula XIIIc, at least one U is S; W is CH, N, or CR 9 and Z is CH, N, or CR 9 and Each R 9 are independently deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 10 C replaced with 1-22 is alkyl, Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; the lipid is as described herein; Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Y 2 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; R 5is alkyl, branched alkyl, cycloalkyl; Aryl is as described herein; R 6 But, C 1-22 Alkoxy or C 1-22 is alkyl, alkyl, branched alkyl, cycloalkyl, or alkoxy; R 7 Aryl, heteroaryl, substituted aryl, lipid, C 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 It is alkynyl, or substituted heteroaryl.

[0414] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is selected from one of the following: [ka] Each U is independently O, S, NH, or NR 9 , N.H.O.H., N.R. 9 OH,NHOR 9 , or NR 9 OR 9 and R 8 But OH, SH, NH 2 , OR 9 , S.R. 9 , N.H.R. 9 , N.H.O.H., N.R. 9 OH,NHOR 9 , or NR 9 OR 9 and In formulae XIVa and XIVb, one of U is S or R 8 But, SR 9 or both U are S and R 8 But, SR 9 and In formula XIVc, at least one U is S; W is CH, N, or CR 9 and Z is CH, N, or CR 9 and Each R 9 are independently methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 10 C replaced with 1-22 is alkyl, Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; the lipid is as described herein; Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Y 2 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; R 5is alkyl, branched alkyl, cycloalkyl; Aryl is as described herein; R 6 But, C 1-22 Alkoxy or C 1-22 is alkyl, alkyl, branched alkyl, cycloalkyl, or alkoxy; R 7 Aryl, heteroaryl, substituted aryl, lipid, C 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 It is alkynyl, or substituted heteroaryl.

[0415] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein A is absent or CH 2 , CHF, CF 2 , CD 2 , O, C.H. 2 O, CHFO, CF 2 O, C.D. 2 O, OCH 2 , OCHF, OCF 2 , or OCD 2 is selected from R 1 is selected from one of the following: [ka] X is O, S, NH, CH 2 , CD 2 , CHF, CF 2 , C=CH 2 , C=CHF, or C=CF 2 and Each U is independently O, S, NH, or NR 9 , N.H.O.H., N.R. 9 OH,NHOR 9 , or NR 9 OR9 and R 8 But OH, SH, NH 2 , OR 9 , S.R. 9 , N.H.R. 9 , N.H.O.H., N.R. 9 OH,NHOR 9 , or NR 9 OR 9 and In formulas XVa and XVb, one of U is S or R 8 But, SR 9 or both U are S and R 8 But, SR 9 and In formula XVc, at least one U is S; W is CH, N, or CR 9 and Z is CH, N, or CR 9 and Each R 9 is deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 10 C replaced with 1-22 is alkyl, Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; the lipid is as described herein; Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Y 2 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; R 5 is alkyl, branched alkyl, cycloalkyl; Aryl is as described herein; R 6 But, C 1-22 Alkoxy or C 1-22 is alkyl, alkyl, branched alkyl, cycloalkyl, or alkoxy; R 7 Aryl, heteroaryl, substituted aryl, lipid, C 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 It is alkynyl, or substituted heteroaryl. In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is selected from one of the following: [ka] Each U is independently O, S, NH, or NR 9 , N.H.O.H., N.R. 9 OH,NHOR 9 , or NR 9 OR 9 and R 8But OH, SH, NH 2 , OR 9 , S.R. 9 , N.H.R. 9 , N.H.O.H., N.R. 9 OH,NHOR 9 , or NR 9 OR 9 and In formulas XVIa and XVIb, one of U is S or R 8 But, SR 9 or both U are S and R 8 But, SR 9 and In formula XVIc, at least one U is S; W is CH, N, or CR 9 and Z is CH, N, or CR 9 and Each R 9 are independently deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 10 C replaced with 1-22 is alkyl, Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; the lipid is as described herein; Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Y 2 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; R 5 is alkyl, branched alkyl, cycloalkyl; Aryl is as described herein; R 6 But, C 1-22 Alkoxy or C 1-22 is alkyl, alkyl, branched alkyl, cycloalkyl, or alkoxy; R 7 Aryl, heteroaryl, substituted aryl, lipid, C 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 It is alkynyl, or substituted heteroaryl.

[0416] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is selected from one of the following: [ka] Each U is independently O, S, NH, or NR 9 , N.H.O.H., N.R. 9 OH,NHOR 9 , or NR 9 OR 9 and R 8 But OH, SH, NH 2 , OR 9 , S.R. 9 , N.H.R. 9 , N.H.O.H., N.R. 9 OH,NHOR 9 , or NR 9 OR 9 and In formulae XVIIa and XVIIb, one of U is S or R 8 But, SR 9 or both U are S and R 8 But, SR 9 and In formula XVIIc, at least one U is S; W is CH, N, or CR 9 and Z is CH, N, or CR 9 and Each R 9 are independently deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 10 C replaced with 1-22 is alkyl, Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; the lipid is as described herein; Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Y 2 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; R 5 is alkyl, branched alkyl, cycloalkyl; Aryl is as described herein; R 6 But, C 1-22 Alkoxy or C 1-22 is alkyl, alkyl, branched alkyl, cycloalkyl, or alkoxy; R 7 Aryl, heteroaryl, substituted aryl, lipid, C 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 It is alkynyl, or substituted heteroaryl.

[0417] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein A is absent or CH 2 , CHF, CF 2 , CD 2 , O, C.H. 2 O, CHFO, CF 2 O, C.D. 2 O, OCH 2 , OCHF, OCF 2 , or OCD 2 is selected from R 1is selected from one of the following: [ka] X is O, S, NH, CH 2 , CD 2 , CHF, CF 2 , C=CH 2 , C=CHF, or C=CF 2 and Each U is independently O, S, NH, or NR 9 , N.H.O.H., N.R. 9 OH,NHOR 9 , or NR 9 OR 9 and R 8 But OH, SH, NH 2 , OR 9 , S.R. 9 , N.H.R. 9 , N.H.O.H., N.R. 9 OH,NHOR 9 , or NR 9 OR 9 and In formulae XVIIIa and XVIIIb, one of U is S or R 8 But, SR 9 or both U are S and R 8 But, SR 9 and In formula XVIIIc, at least one U is S; W is CH, N, or CR 9 and Z is CH, N, or CR 9 and Each R 9 are independently deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 10 C replaced with 1-22 is alkyl, Each R 10are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; the lipid is as described herein; Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Y 2 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; R 5 is alkyl, branched alkyl, cycloalkyl; Aryl is as described herein; R 6 But, C 1-22 Alkoxy or C 1-22 is alkyl, alkyl, branched alkyl, cycloalkyl, or alkoxy; R 7 Aryl, heteroaryl, substituted aryl, lipid, C 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 It is alkynyl, or substituted heteroaryl.

[0418] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is selected from one of the following: [ka] Each U is independently O, S, NH, or NR 9 , N.H.O.H., N.R. 9 OH,NHOR 9 , or NR 9 OR 9 and R 8 But OH, SH, NH 2 , OR 9 , S.R. 9 , N.H.R. 9 , N.H.O.H., N.R. 9 OH,NHOR 9 , or NR 9 OR 9 and In formulas XIXa and XIXb, one of U is S or R 8 But, SR 9 or both U are S and R 8 But, SR 9 and In formula XIXc, at least one U is S; W is CH, N, or CR 9 and Z is CH, N, or CR 9 and R 9 is deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 10 C replaced with 1-22 is alkyl, Each R 10are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; the lipid is as described herein; Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Y 2 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; R 5 is alkyl, branched alkyl, cycloalkyl; Aryl is as described herein; R 6 But, C 1-22 Alkoxy or C 1-22 is alkyl, alkyl, branched alkyl, cycloalkyl, or alkoxy; R 7 Aryl, heteroaryl, substituted aryl, lipid, C 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 It is alkynyl, or substituted heteroaryl.

[0419] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein A is absent or CH 2 , CHF, CF 2 , CD 2 , O, C.H. 2 O, CHFO, CF 2 O, C.D. 2 O, OCH 2 , OCHF, OCF 2 , or OCD 2 is selected from R 1 is selected from one of the following: [ka] X is O, S, NH, CH 2 , CD 2 , CHF, CF 2 , C=CH 2 , C=CHF, or C=CF 2 and Each U is independently O, S, NH, or NR 9 , N.H.O.H., N.R. 9 OH,NHOR 9 , or NR 9 OR 9 and R 8 But OH, SH, NH 2 , OR 9 , S.R. 9 , N.H.R. 9 , N.H.O.H., N.R. 9 OH,NHOR 9 , or NR 9 OR 9 and In formulae XXa and XXb, one of U is S or R 8 But, SR 9 or both U are S and R 8 But, SR 9 and In formula XXc, at least one U is S; W is CH, N, or CR 9 and Z is CH, N, or CR 9 and Each R 9 are independently deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 10 C replaced with 1-22 is alkyl, Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; the lipid is as described herein; Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Y 2 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; R 5is alkyl, branched alkyl, cycloalkyl; Aryl is as described herein; R 6 But, C 1-22 Alkoxy or C 1-22 is alkyl, alkyl, branched alkyl, cycloalkyl, or alkoxy; R 7 Aryl, heteroaryl, substituted aryl, lipid, C 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 It is alkynyl, or substituted heteroaryl.

[0420] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is selected from one of the following: [ka] Each U is independently O, S, NH, or NR 9 , N.H.O.H., N.R. 9 OH,NHOR 9 , or NR 9 OR 9 and R 8 But OH, SH, NH 2 , OR 9 , S.R. 9 , N.H.R. 9 , N.H.O.H., N.R. 9 OH,NHOR 9 , or NR 9 OR 9 and In formulas XXIa and XXIb, one of U is S or R 8 But, SR 9 or both U are S and R 8 But, SR 9 and In formula XXIc, at least one U is S; W is CH, N, or CR 9 and Z is CH, N, or CR 9 and Each R 9 are independently deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 10 C replaced with 1-22 is alkyl, Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; the lipid is as described herein; Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Y 2 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; R 5is alkyl, branched alkyl, cycloalkyl; Aryl is as described herein; R 6 But, C 1-22 Alkoxy or C 1-22 is alkyl, alkyl, branched alkyl, cycloalkyl, or alkoxy; R 7 Aryl, heteroaryl, substituted aryl, lipid, C 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 It is alkynyl, or substituted heteroaryl.

[0421] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein A is absent or CH 2 , CHF, CF 2 , CD 2 , O, C.H. 2 O, CHFO, CF 2 O, C.D. 2 O, OCH 2 , OCHF, OCF 2 , or OCD 2 is selected from R 1 is selected from one of the following: [ka] X is O, S, NH, CH 2 , CD 2 , CHF, CF 2 , C=CH 2 , C=CHF, or C=CF 2 and Each U is independently O, S, NH, or NR 9 , N.H.O.H., N.R. 9 OH,NHOR 9 , or NR 9 OR9 and R 8 But OH, SH, NH 2 , OR 9 , S.R. 9 , N.H.R. 9 , N.H.O.H., N.R. 9 OH,NHOR 9 , or NR 9 OR 9 and In formulae XXIIa and XXIIb, one of U is S or R 8 But, SR 9 or both U are S and R 8 But, SR 9 and In formula XXIIc, at least one U is S; W is CH, N, or CR 9 and Z is CH, N, or CR 9 and Each R 9 are independently deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 10 C replaced with 1-22 is alkyl, Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; the lipid is as described herein; Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M+ and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Y 2 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; R 5 is alkyl, branched alkyl, cycloalkyl; Aryl is as described herein; R 6 But, C 1-22 Alkoxy or C 1-22 is alkyl, alkyl, branched alkyl, cycloalkyl, or alkoxy; R 7 Aryl, heteroaryl, substituted aryl, lipid, C 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 It is alkynyl, or substituted heteroaryl.

[0422] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is selected from one of the following: [ka] Each U is independently O, S, NH, or NR 9 , N.H.O.H., N.R. 9 OH,NHOR 9 , or NR 9 OR9 and R 8 But OH, SH, NH 2 , OR 9 , S.R. 9 , N.H.R. 9 , N.H.O.H., N.R. 9 OH,NHOR 9 , or NR 9 OR 9 and In formulae XXIIIa and XXIIIb, one of U is S or R 8 But, SR 9 or both U are S and R 8 But, SR 9 and In formula XXIIIc, at least one U is S; W is CH, N, or CR 9 and Z is CH, N, or CR 9 and Each R 9 are independently deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 10 C replaced with 1-22 is alkyl, Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; the lipid is as described herein; Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M+ and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Y 2 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; R 5 is alkyl, branched alkyl, cycloalkyl; Aryl is as described herein; R 6 But, C 1-22 Alkoxy or C 1-22 is alkyl, alkyl, branched alkyl, cycloalkyl, or alkoxy; R 7 Aryl, heteroaryl, substituted aryl, lipid, C 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 It is alkynyl, or substituted heteroaryl.

[0423] In a preferred embodiment, the nucleoside or pharma- ceutically acceptable salt thereof conjugated to a phosphorus moiety has the following structure: [ka] or a pharma- ceutically acceptable salt thereof, wherein: A is S, NH, NR 8 and U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; X is OCH 2, OCHMe, OCMe 2 , OCHF, OCF 2 , OCD 2 , C.H. 2 O, CHFO, CF 2 O, C.D. 2 O, R 1 is selected from one of the following: [ka] R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 12 C replaced with 1-22 alkyl, Each R 12 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 12 can be replaced by R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl, the lipid is as described herein; Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Y 2 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; R 9 is alkyl, branched alkyl, cycloalkyl; Aryl is as described herein; R 10 But, C 1-22 Alkyl, C 1-22 Alkoxy, C 2-22 Alkenyl, C 2-22 alkynyl, branched alkyl, cycloalkyl, or alkoxy; R 11 Aryl, heteroaryl, substituted aryl, lipid, C 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 alkynyl, or substituted heteroaryl; Q is thymine, uracil, cytosine, adenine, guanine, or a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether.

[0424] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein A is S, NH, or NR 8 and U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; Y 2 is O or S, Y 3 But, OH, OR 10 , S.R. 10 , N.H.R. 10 , N.R. 10 2 , or BH 3 - M + or [ka] is selected from E is CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 and R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl, Q is thymine, uracil, cytosine, adenine, guanine, or heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether; R 2 , R 3 , R 6 , R 7 , and R 8 But independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3, CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 11 C replaced with 1-22 alkyl, R 10 But, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 alkynyl, branched alkyl, cycloalkyl, H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Aryl is as described herein; the lipid is as described herein; R 4 But, C 1-22 Alkyl, C 1-22 Alkoxy, C 2-22 Alkenyl, C 2-22 alkynyl, branched alkyl, cycloalkyl, or alkoxy; Each R 11 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 It is selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.

[0425] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; A is S, NH, or NR 3 and R 1 , R2 , and R 3 However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 4 C replaced with 1-22 alkyl, Each R 4 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; Q is thymine, uracil, cytosine, adenine, guanine, or heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether; Y is O or S; R is linear or branched alkyl, for example, methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, or C 12-19 long chain alkyl; cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or benzyl, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 alkynyl, H, aryl, heteroaryl, phenyl, benzyl, naphthyl; Aryl is as described herein.

[0426] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; A is S, NH, or NR 3 and R 1 , R 2 , and R 3 However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 4 C replaced with 1-22 alkyl, Each R 4 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; Q is thymine, uracil, cytosine, adenine, guanine, or heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether; Y is O or S; The lipid is as described herein.

[0427] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein: A is S, NH, or NR 9 and R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl, U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; E is CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 and Y 2 is O or S, R 2 , R 3 , R 6 , R 7 , R 9 However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 10 C replaced with 1-22 alkyl, Q is thymine, uracil, cytosine, adenine, guanine, or heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether; Each R 10 is independently selected from alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R 8 But, C 1-22 Alkyl, C 2-22Alkenyl, C 2-22 , alkynyl, branched alkyl, or cycloalkyl.

[0428] In a preferred embodiment, the nucleoside or pharma- ceutically acceptable salt thereof conjugated to a phosphorus moiety has the following structure: [ka] or a pharma- ceutically acceptable salt thereof, wherein: X is OCH 2 , OCHMe, OCMe 2 , OCHF, OCF 2 , OCD 2 , C.H. 2 O, CHFO, CF 2 O, C.D. 2 O, R 1 is selected from one of the following: [ka] R 2 , R 3 , R 4 , and R 8 However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 12 C replaced with 1-22 alkyl, Each R 12 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 12 can be replaced by R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl, the lipid is as described herein; Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Y 2 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; R 9 is alkyl, branched alkyl, cycloalkyl; Aryl is as described herein; R 10 But, C 1-22 Alkyl, C 1-22 Alkoxy, C 2-22 Alkenyl, C 2-22 alkynyl, branched alkyl, cycloalkyl, or alkoxy; R 11 Aryl, heteroaryl, substituted aryl, lipid, C 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22alkynyl, or substituted heteroaryl; Q is thymine, uracil, cytosine, adenine, guanine, or a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether.

[0429] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein Y 2 is O or S, Y 3 But, OH, OR 10 , S.R. 10 , N.H.R. 10 , N.R. 10 2 , or BH 3 - M + or [ka] is selected from E is CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 and R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl, Q is thymine, uracil, cytosine, adenine, guanine, or heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether; R 2 , R 3 , and R 8 But independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 11 C replaced with 1-22 alkyl, R 10 But, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 alkynyl, branched alkyl, cycloalkyl, H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Aryl is as described herein; the lipid is as described herein; R 4 But, C 1-22 Alkyl, C 1-22 Alkoxy, C 2-22 Alkenyl, C 2-22 alkynyl, branched alkyl, cycloalkyl, or alkoxy; Each R 11 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 It is selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.

[0430] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein Q is thymine, uracil, cytosine, adenine, guanine, or heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether; Y is O or S; R is linear or branched alkyl, for example, methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, or C 12-19 long chain alkyl; cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or benzyl, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 alkynyl, H, aryl, heteroaryl, phenyl, benzyl, naphthyl; Aryl is as described herein.

[0431] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein Q is thymine, uracil, cytosine, adenine, guanine, or heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether; Y is O or S; The lipid is as described herein.

[0432] In certain embodiments, the present disclosure provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein Y 2 is O or S, Q is thymine, uracil, cytosine, adenine, guanine, or heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether; R 8 But, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22In a preferred embodiment, the nucleoside conjugated to the phosphorus moiety or a pharma- ceutically acceptable salt thereof has the following structure: [ka] or a pharma- ceutically acceptable salt thereof, wherein: A is S, NH, NR 8 and U is NH, CH 2 , CHF, CF 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; X is OCH 2 , OCHMe, OCMe 2 , OCHF, OCF 2 , OCD 2 , C.H. 2 O, CHFO, CF 2 O, C.D. 2 O, R 1 is selected from one of the following: [ka] R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 12 C replaced with 1-22 alkyl, Each R 12are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 12 can be replaced by R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl, the lipid is as described herein; Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Y 2 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; R 9 is alkyl, branched alkyl, cycloalkyl; Aryl is as described herein; R 10 But, C 1-22 Alkyl, C 1-22 Alkoxy, C2-22 Alkenyl, C 2-22 alkynyl, branched alkyl, cycloalkyl, or alkoxy; R 11 Aryl, heteroaryl, substituted aryl, lipid, C 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 alkynyl, or substituted heteroaryl; T is OH, SH, NH 2 , OR 13 , S.R. 13 , N.H.R. 13 , N.H.O.H., N.R. 13 OH,NHOR 13 , or NR 13 OR 13 and W is O or S; V is CH, N, or CR 13 and Z is CH, N, or CR 13 and Each R 13 are independently deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 9 C replaced with 1-22 alkyl, Each R 14 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 It is selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl. In a preferred embodiment, the nucleoside or pharma- ceutically acceptable salt thereof conjugated to a phosphorus moiety has the following structure: [ka] or a pharma- ceutically acceptable salt thereof, wherein: X is OCH 2 , OCHMe, OCMe 2 , OCHF, OCF 2 , OCD 2 , C.H. 2 O, CHFO, CF 2 O, C.D. 2 O, R 1 is selected from one of the following: [ka] R 2 , R 3 , R 4 , and R 8 However, independently, H, D, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 12 C replaced with 1-22 alkyl, Each R 12 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 12 can be replaced by R 5 is H, D, Me, CN, alkyl, alkenyl, alkynyl, the lipid is as described herein; Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Y 2 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; R 9 is alkyl, branched alkyl, cycloalkyl; Aryl is as described herein; R 10 But, C 1-22 Alkyl, C 1-22 Alkoxy, C 2-22 Alkenyl, C 2-22 alkynyl, branched alkyl, cycloalkyl, or alkoxy; R 11 Aryl, heteroaryl, substituted aryl, lipid, C 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 alkynyl, or substituted heteroaryl; T is OH, SH, NH 2 , OR 13 , S.R. 13 , N.H.R. 13 , N.H.O.H., N.R. 13 OH,NHOR 13 , or NR 13 OR 13 and W is O or S; V is CH, N, or CR 13 and Z is CH, N, or CR 13 and Each R 13 are independently deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 9 C replaced with 1-22 alkyl, Each R 14 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 It is selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.

[0433] In a preferred embodiment, the nucleoside or pharma- ceutically acceptable salt thereof conjugated to a phosphorus moiety has the following structure: [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1 is selected from one of the following: [ka] the lipid is as described herein; Y is O or S; Y 1 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; Y 2 OH, Oaryl, OR”, SR”, NHR”, NR” 2 , or BH 3 - M + and R″ is H, methyl, ethyl, isopropyl, butyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, phenyl, benzyl, naphthyl; R 9 is alkyl, branched alkyl, cycloalkyl; Aryl is as described herein; R 10 But, C 1-22 Alkyl, C 1-22 Alkoxy, C 2-22 Alkenyl, C 2-22 alkynyl, branched alkyl, cycloalkyl, or alkoxy; R 11 Aryl, heteroaryl, substituted aryl, lipid, C 1-22 Alkoxy, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 alkynyl, or substituted heteroaryl; T is OH, SH, NH 2 , OR 13 , S.R. 13 , N.H.R. 13 , N.H.O.H., N.R. 13 OH,NHOR 13 , or NR 13 OR 13 and W is O or S; V is CH, N, or CR 13 and Z is CH, N, or CR 13 and Each R 13are independently deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 9 C replaced with 1-22 alkyl, Each R 14 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 It is selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.

[0434] In an exemplary embodiment, the compound is [ka] In an exemplary embodiment, the compound is selected from the group consisting of: [ka] In an exemplary embodiment, the compound is selected from the group consisting of: [ka] In an exemplary embodiment, the compound is selected from the group consisting of: [ka] is selected from the group consisting of:

[0435] As provided herein, a nucleotide or nucleoside compound (containing a heterocycle containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether) can be formulated in combination with a second antiviral agent.In certain embodiments, the second antiviral agent is 25-hydroxycholesterol, AN-12-H5, dioxalivir, pirodavir, bapentavir and pocapavir, abacavir, acyclovir, acyclovir, adefovir, amantadine, amiloride, amprenavir, ampligen, arbidol, atazanavir, atripla, aurintricarboxylic acid, BF738735, boceprevir, BPR-3P0128, buthionine sulfoximine, cidofovir, cyclosporine A, combivir, darunavir, DAS181, DC0 7090, delavirdine, dibucaine, didanosine, docosanol, DTrip-22, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, enviroxime, famciclovir, fluoxetine, fomivirsen, fosamprenavir, foscarnet, phosphonet, ganciclovir, geldanamycin, gemcitabine, gliotoxin, GPC-N114, guanidine hydrochloride, GW5074, HBB, HL05100P2, ibacitabine, immunovir, idoxuridine, imiquimod, indinavir, Inosine, Interferon III, Interferon II, Interferon I, Intrazonazole, Lamivudine, Lopinavir, Loviride, Maraviroc, Moroxydine, Methisazone, MRL-1237, Nelfinavir, Nevirapine, Nexavir, NIM-811, Oseltamivir, OSW-1, Peginterferon alfa-2a, Penciclovir, Peramivir, PIK93, Pirlindole, Pleconaril (Picovir), Podophyllotoxin, Raltegravir, Ribavirin, Rimantadine, Ritonavir, Lupinto The medicament may be selected from livir, pyramidine, saquinavir, sovosbuvir, stavudine, T-00127-HEV1, T-00127-HEV2, TBZE-029, telaprevir, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, TP-219, TTP-8307, V-7404, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine, or zuclopenthixol, as well as combinations thereof.

[0436] In certain instances, the second antiviral compound used in combination with the above compounds of the present disclosure includes disoxalil, pleconaril, pirodavir, vapentavir, and pocapavir. Vapendivir, its analogs, and related compounds that can be used in combination with the compounds / compositions / medicaments of the present disclosure are described in U.S. Patent Nos. 8,415,309, 8,501,699, 7,579,465, 7,829,705, 8,217,171, 8,624,025, 8,580,791, 9,447,080, 9,675,694, 9,163,029, 7,504,434, 9,802,926, 9,452,991, 9,974,779, 8,440,833, 9,670,159, and 9,908,858.

[0437] infectious disease The compounds and compositions provided herein can be used to treat viral infections.Examples of viral infections include, but are not limited to, infections caused by RNA viruses (negative strand RNA viruses, positive strand RNA viruses, double-strand RNA viruses, and retroviruses) or DNA viruses.All strains, types, and subtypes of RNA and DNA viruses are contemplated herein.

[0438] Examples of RNA viruses include aphthoviruses (e.g., foot and mouth disease viruses O, A, C, Asia1, SAT1, SAT2, and SAT3), cardioviruses (e.g., encephalomyocarditis virus and Theiler's murine encephalomyelitis virus), enteroviruses (e.g., polioviruses 1, 2, and 3, human enteroviruses A to D, bovine enteroviruses 1 and 2, human coxsackieviruses A1 to A22 and A24, human coxsackieviruses B1 to B5, human echoviruses 1 to 7, 9, 11 to 12, 24, 27, 29 to 33, human enteroviruses 68 to 71, porcine enteroviruses 8 to 10, and simian enteroviruses 1 to 18), erboviruses (e.g., , equine rhinitis virus), hepatoviruses (e.g., human hepatitis A virus and simian hepatitis A virus), kobuviruses (e.g., bovine kobuvirus and Aichi virus), parechoviruses (e.g., human parechovirus 1 and human parechovirus 2), rhinoviruses (e.g., rhinovirus A, rhinovirus B, rhinovirus C, HRV16, HRV16(VR-11757), HRV14(VR-284), or HRV1A(VR-1559), human rhinoviruses 1-100 and bovine rhinoviruses 1-3), and picornaviruses (e.g., porcine teschovirus).

[0439] In certain embodiments, RNA viruses that can be treated by the compounds and compositions of the present disclosure include enteroviruses. The genus Enterovirus (EV), which belongs to the Picornaviridae family, includes 13 species, of which 7 are human viruses. Four of the species are (1) EV-A, such as Coxsackievirus (CV)-A6, CV-A10, CV-A16, and EV-A71; (2) EV-B, such as CV-B virus, echovirus (ECHO), and CV-A9; (3) EV-C, such as poliovirus (PV) and CV-A21; and (4) EV-D, such as EV-D68 and EV-D70. Other species include rhinovirus RV-A, RV-B, and RV-C, which are composed of over 100 different numbers of RVs. EV RNA includes a single open reading frame (ORF) flanked by two untranslated regions (UTRs), 5'UTR and 3'UTR. The ORF encodes a single polyprotein that is cleaved into P1, P2, and P3 proteins. The P1 protein is proteolytically cleaved to generate capsid proteins VP1-4. P2 and P3 are cleaved to generate nonstructural (NS) proteins 2A, 2B, 2C, and 3A, 3B, 3C, 3D, respectively. The role of the capsid proteins is to surround the genetic material and to recognize cellular receptors during viral entry. The NS proteins are essential for replication, translation, and subversion of the host cell machinery. Due to their role in cell entry and uncoating the genetic material, the capsid proteins are good targets for antiviral drug development.

[0440] Diverse viruses in the EV genus are known to cause a variety of diseases, such as hand, foot and mouth disease (HFMD), encephalitis, aseptic meningitis, myocarditis, and various respiratory diseases. Some EV infections are mild, but symptoms can be severe in young and immunocompromised individuals. In recent years, viruses such as EV-A71 and CV-A16 have emerged as serious public health threats, as they have caused HFMD outbreaks in China and Southeast Asia. In addition, EV-D68 caused a severe lower respiratory tract infection outbreak in North America in 2014. Therefore, broad-spectrum antiviral drugs that can inhibit multiple EVs across the genus would be helpful in overcoming the public health burden caused by these EVs.

[0441] The compounds and compositions of the present disclosure can be used to treat or prevent diseases caused by enteroviruses and to reduce enterovirus load. In addition, the compounds and compositions of the present disclosure can be combined with other drugs to treat enteroviruses as provided herein. Anasir et al., J Biomed Sci (2021) 28, 10:5-12 provides a review of enteroviruses and antiviral agents for treating them, the disclosure of which is incorporated herein by reference in its entirety.

[0442] Additional examples of RNA viruses that can be treated or prevented using the compounds and compositions herein include noroviruses (e.g., Norwalk virus), sapoviruses (e.g., Sapporo virus), lagoviruses (e.g., rabbit hemorrhagic disease virus and European brown hare syndrome), and caliciviruses, including vesiviruses (e.g., swine vesicular rash virus and feline calicivirus). Other RNA viruses include astroviruses, including mamastreviruses and avastroviruses. Togaviruses are also RNA viruses. Togaviruses include alphaviruses (e.g., chikungunya virus, sindbis virus, semliki forest virus, western equine encephalitis virus, eastern getah virus, everglades virus, Venezuelan equine encephalitis virus, and aura virus), and rubella virus. Additional examples of RNA viruses include flaviviruses (e.g., tick-borne encephalitis virus, Tyurenii virus, Arroa virus, M virus (types 1-4), Kedougou virus, Japanese encephalitis virus (JEV), West Nile virus (WNV), Dengue virus (including genotypes 1-4), Kokobera virus, Ntaya virus, Spongeweni virus, Yellow fever virus, Entebbe bat virus, Modoc virus, Rio Bravo virus, cell fusion agent virus, Pestivirus, GB virus A, GBV-A-like virus, GB virus C, Hepatitis G virus, Hepacivirus (all 6 genotypes of Hepatitis C virus (HCV)), Bovine viral diarrhea virus (BVDV) types 1 and 2, and GB virus B).

[0443] Other examples of RNA viruses are coronaviruses, including human respiratory coronaviruses such as SARS-CoV, HCoV-229E, HCoV-NL63, and HCoV-OC43. Coronaviruses also include bat SARS-like CoVs, Middle East Respiratory Syndrome Coronavirus (MERS), turkey coronavirus, chicken coronavirus, feline coronavirus, and canine coronavirus. Additional RNA viruses include arteriviruses (e.g., equine arterivirus, porcine reproductive and respiratory syndrome virus, mouse lactate dehydrogenase elevated virus, and simian hemorrhagic fever virus). Other RNA viruses include lyssaviruses (e.g., rabies virus, Lagos bat virus, Mokola virus, Duvenhage virus, and European bat lyssavirus), vesiculoviruses (e.g., VSV-Indiana, VSV-New Jersey, VSV-Alagoas, Pirie virus, Cocal virus, Maraba virus, Isfahan virus, and Chandipura virus), and rhabdoviruses including ephemeroviruses (e.g., Bovine ephemeral fever virus, Adelaide River virus, and Berimer virus). Additional examples of RNA viruses include filoviruses. These include Marburg and Ebola viruses (e.g., EBOV-Z, EBOV-S, EBOV-IC, and EBOV-R).

[0444] Paramyxoviruses are also RNA viruses. Examples of these viruses are rubulaviruses (e.g., mumps, parainfluenza virus type 5, human parainfluenza virus type 2, mapuera virus and butalubula virus), abulaviruses (e.g., Newcastle disease virus), lespoviruses (e.g., Sendai virus, human parainfluenza virus types 1 and 3, bovine parainfluenza virus type 3), henipaviruses (e.g., Hendra virus and Nipah virus), morbiloviruses (e.g., measles, whale morbillivirus, canine distemper virus, peste des petits ruminants virus, seal distemper virus and rinderpest virus), pneumoviruses (e.g., human respiratory syncytial virus (RSV) A2, B1 and S2, bovine respiratory syncytial virus and pneumonia virus of mice), metapneumoviruses (e.g., human metapneumovirus and avian metapneumovirus). Additional paramyxoviruses include Ferdransvirus, Tupaiparamyxovirus, Menanglevirus, Tiomanvirus, Beironvirus, Jvirus, Mossmanvirus, Salemvirus, and Narivavirus.

[0445] Additional RNA viruses include orthomyxoviruses, which include influenza viruses and strains (e.g., influenza A, influenza A strain A / Victoria / 3 / 75, influenza A strain A / Puerto Rico / 8 / 34, influenza A strain H1N1 (including but not limited to strains A / WS / 33, A / NWS / 33, and A / California / 04 / 2009), influenza B, influenza B strain Lee, and influenza C viruses) H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, and H10N7), as well as avian influenza (e.g., H5N1, H5N1 Duck / MN / 1525 / 81, H5N2, H7N1, H7N7, and H9N2 strains), Thogotoviruses, and Isaviruses. Orthobunyaviruses (e.g., Akabane virus, California encephalitis, Cache Valley virus, Snowshoe rabbit virus), Nairoviruses (e.g., Nairobi sheep disease virus, Crimean-Congo hemorrhagic fever virus group, and Hughes virus), Phleboviruses (e.g., Candiru, Punta Toro, Rift Valley fever, Sandfly fever, Naples, Tuscany, Sicily, and Chagres), and Hantaviruses (e.g., Hantaan, Dobrava, Seoul, Puumala, Sin Nombre, Bayou, Black Creek Canal, Andean, and Sotapalayam) are also RNA viruses. Arenaviruses such as lymphocytic choriomeningitis virus, Lujo virus, Lassa fever virus, Argentine hemorrhagic fever virus, Bolivian hemorrhagic fever virus, Venezuelan hemorrhagic fever virus, SABV, and WWAV are also RNA viruses. Borna disease virus is also an RNA virus. Hepatitis D (delta) virus and hepatitis E are also RNA viruses.

[0446] Additional RNA viruses include reoviruses, rotaviruses, birnaviruses, charysoviruses, cystoviruses, hypoviruses, partitiviruses, and totoviruses. Orbiviruses, such as African horse sickness virus, bluetongue virus, Changuinola virus, Chenuda virus, Chobar Canyon virus, epizootic hemorrhagic fever virus, equine encephalitis virus, euvenangivirus, Yeri virus, Great Island virus, Lebombo virus, Olungo virus, Paliam virus, Peruvian horse sickness virus, St. Croix virus, Umatilla virus, Wadmedani virus, Wallar virus, Warrego virus, and Wongoa virus, are also RNA viruses. Retroviruses include alpharetroviruses (e.g., Rous sarcoma virus and avian leukosis virus), betaretroviruses (e.g., mouse mammary tumor virus, Mason-Pfizer monkey virus, and Jaagsiegte sheep retrovirus), gammaretroviruses (e.g., murine leukemia virus and feline leukemia virus), deltora retroviruses (e.g., human T-cell leukemia viruses (HTLV-1, HTLV-2), bovine leukemia virus (STLV-1 and STLV-2), epsilon retrovirus ( Examples include walleye cutaneous sarcoma virus, walleye epidermal hyperplasia virus 1), reticuloendotheliosis viruses (e.g., chicken syncytial virus), lentiviruses (e.g., human immunodeficiency virus (HIV) type 1, human immunodeficiency virus (HIV) type 2, human immunodeficiency virus (HIV) type 3, simian immunodeficiency virus, equine infectious anemia virus, feline immunodeficiency virus, caprine arthritis-encephalitis virus, visna-maedi virus), and spumaviruses (e.g., human foamy virus and feline syncytial virus).

[0447] Examples of DNA viruses include polyomaviruses (e.g., simian virus 40), simian agent 12, BK virus, JC virus, Merkel cell polyomavirus, bovine polyomavirus, lymphotropic papovavirus), papillomaviruses (e.g., human papillomavirus, bovine papillomavirus), adenoviruses (e.g., adenoviruses A-F, canine adenovirus type 1, canine adenovirus type 2), circoviruses (e.g., porcine circovirus, beak and feather disease virus (BFDV)), parvoviruses (e.g., canine parvovirus), erythroviruses (e.g., adeno-associated viruses types 1-8), and betaparvoviruses, amdoviruses, densoviruses, iteraviruses, brevidensoviruses, and the like. Examples of viruses that may be present include, but are not limited to, pephdensoviruses, herpesviruses 1, 2, 3, 4, 5, 6, 7, and 8 (e.g., herpes simplex virus type 1, herpes simplex virus type 2, varicella zoster virus, Epstein-Barr virus, cytomegalovirus, Kaposi's sarcoma-associated herpesvirus, human herpesvirus-6 variant A, human herpesvirus-6 variant B, and cercopithecian herpesvirus type 1 (B virus)), poxviruses (e.g., smallpox (variola), cowpox, monkeypox, vaccinia, ouassin-guishou, camelpox, pseudocowpox, pigeonpox, horsepox, fowlpox, turkeypox, swinepox), and hepadnaviruses (e.g., hepatitis B, hepatitis B-like viruses). Chimeric viruses containing portions of more than one viral genome are also contemplated herein.

[0448] In some embodiments, the disclosure relates to the treatment or prevention of viral, bacterial, fungal, protozoal, and parasitic infections. In some embodiments, the disclosure relates to a method of treating a viral infection comprising administering a compound herein to a subject diagnosed with, suspected of having, or exhibiting symptoms of a viral infection.

[0449] Viruses are typically infectious agents capable of replicating inside living cells of an organism. A virus particle (virion) usually consists of nucleic acid, a protein coat, and sometimes a lipid envelope surrounding the protein coat. Virus shapes range from simple helical and icosahedral forms to more complex structures. Virus-encoded protein subunits self-assemble to form capsids, which generally require the presence of a viral genome. Complex viruses may encode proteins that aid in the construction of their capsids. Proteins associated with nucleic acid are known as nucleoproteins, and the association of viral capsid proteins with viral nucleic acid is called nucleocapsid.

[0450] Viruses are transmitted in a variety of ways, including direct contact or contact with bodily fluids, such as blood, tears, semen, pre-sperm, saliva, milk, vaginal secretions, lesions, droplet contact, fecal-oral contact, or as a result of animal bites or childbirth. Viruses have either DNA or RNA genes and are referred to as DNA or RNA viruses, respectively. Viral genomes are either single-stranded or double-stranded. Some viruses contain genomes that are partially double-stranded and partially single-stranded. With respect to RNA or single-stranded DNA viruses, they are said to be either positive-sense (called the plus strand) or negative-sense (called the minus strand), depending on whether the strand is complementary to the viral messenger RNA (mRNA). Positive-sense viral RNA is identical to viral mRNA and therefore can be readily translated by the host cell. Negative-sense viral RNA is complementary to mRNA and therefore must be converted to positive-sense RNA by RNA polymerase before translation. The DNA nomenclature is similar to the RNA nomenclature in that the coding strand of the viral mRNA is its (negative) complement and the non-coding strand is its (positive) copy.

[0451] Antigenic shift or reassortment can give rise to new strains. Viruses undergo genetic change by several mechanisms. These include the mutation of individual bases in DNA or RNA to other bases, a process called genetic drift. Antigenic shift occurs when there are large changes in the genome of a virus. This can be the result of recombination or reassortment. RNA viruses often exist as quasi-species or swarms of viruses of the same kind, but with slightly different genomic nucleoside sequences.

[0452] The genetic material within a virus and the way in which that material is replicated varies between different species of virus. For most DNA viruses, genome replication occurs in the nucleus of the cell. If the appropriate receptor is present on the cell's surface, these viruses enter the cell by fusing with the cell membrane or by endocytosis. Most DNA viruses are entirely dependent on the host DNA and RNA synthesis and RNA processing machinery. Replication usually occurs in the cytoplasm. RNA viruses typically use their own RNA replicase enzyme to make copies of their genome.

[0453] The Baltimore classification of viruses is based on the mechanism of mRNA production. Viruses must generate mRNA from their genome to produce proteins and replicate themselves, but they use different mechanisms to accomplish this. Viral genomes can be single-stranded (ss) or double-stranded (ds), can be RNA or DNA, and may or may not use reverse transcriptase (RT). In addition, ssRNA viruses can be either sense (+) or antisense (-). This classification separates viruses into seven groups: I. dsDNA viruses (e.g., adenoviruses, herpesviruses, poxviruses); II. ssDNA viruses (+) sense DNA (e.g., parvoviruses); III. dsRNA viruses (e.g., reoviruses); IV. (+) ssRNA viruses (+) sense RNA (e.g., picornaviruses, togaviruses); V. (-) ssRNA viruses (-) sense RNA (e.g., orthomyxoviruses, rhabdoviruses); VI. ssRNA-RT viruses (+) sense RNA, with a DNA intermediate in the life cycle (e.g., retroviruses); and VII. dsDNA-RT viruses (e.g., hepadnaviruses).

[0454] Human immunodeficiency virus (HIV) is a lentivirus (a member of the retrovirus family) that causes acquired immune deficiency syndrome (AIDS). Lentiviruses are transmitted as single-stranded positive-sense enveloped RNA viruses. Once in a target cell, the viral RNA genome is converted to double-stranded DNA by virally encoded reverse transcriptase. This viral DNA is then integrated into the cell's DNA by virally encoded integrase, along with host cell cofactors. There are two species of HIV. HIV-1 is sometimes called LAV or HTLV-III.

[0455] HIV infects the main key cells in the human immune system, such as helper T cells (CD4+ T cells), macrophages, and dendritic cells. HIV infection results in low levels of CD4+ T cells. When the number of CD4+ T cells falls below a critical level, cell-mediated immunity is lost and the body becomes gradually more susceptible to other viral or bacterial infections. Subjects with HIV typically develop malignancies associated with the progressive failure of the immune system.

[0456] The viral envelope is composed of two layers of phospholipids that are snatched from the human cell membrane as the newly formed virus particle buds from the cell. Embedded in the viral envelope are proteins from the host cell and an HIV protein known as Env. Env contains the glycoproteins gp120 and gp41. The RNA genome consists of structural landmarks (LTR, TAR, RRE, PE, SLIP, CRS, and INS) and nine genes (gag, pol, and env, tat, rev, nef, vif, vpr, vpu, and a tenth tev, which is sometimes a fusion of tat, env, and rev), encoding 19 proteins. Three of these genes, gag, pol, and env, contain the information necessary to make the structural proteins of new virus particles. HIV-1 diagnosis is typically performed by ELISA, Western blot, or immunoaffinity assays using antibodies, or by nucleic acid tests (e.g., viral RNA or DNA amplification).

[0457] HIV is typically treated with a combination of antiviral drugs, such as two nucleoside analog reverse transcription inhibitors and one non-nucleoside analog reverse transcription inhibitor or protease inhibitor. The combination of three drugs is generally known as a triple cocktail. In certain embodiments, the present disclosure relates to treating a subject diagnosed with HIV by administering the pharmaceutical composition disclosed herein in combination with two nucleoside analog reverse transcription inhibitors and one non-nucleoside analog reverse transcription inhibitor or protease inhibitor.

[0458] In certain embodiments, the present disclosure relates to treating a subject by administering a compound disclosed herein, emtricitabine, tenofovir, and efavirenz. In certain embodiments, the present disclosure relates to treating a subject by administering a compound disclosed herein, emtricitabine, tenofovir, and raltegravir. In certain embodiments, the present disclosure relates to treating a subject by administering a compound disclosed herein, emtricitabine, tenofovir, ritonavir, and darunavir. In certain embodiments, the present disclosure relates to treating a subject by administering a compound disclosed herein, emtricitabine, tenofovir, ritonavir, and atazanavir.

[0459] Banana lectin (BanLec or BanLec-1) is one of the major proteins in the pulp of ripe bananas and has binding specificity for mannose and mannose-containing oligosaccharides. BanLec binds to the HIV-1 envelope protein gp120. In certain embodiments, the present disclosure relates to treating viral infections, such as HIV, by administering the compounds disclosed herein in combination with banana lectin.

[0460] Hepatitis C virus is a single-stranded, positive-sense RNA virus. It is the only known member of the genus Hepacivirus in the family Flaviviridae. There are six major genotypes of hepatitis C virus, designated numerically. Hepatitis C virus particles consist of a core of genetic material (RNA) surrounded by an icosahedral protective shell, which is further enveloped in a lipid envelope. Two viral envelope glycoproteins, E1 and E2, are embedded in the lipid envelope. The genome consists of a single open reading frame that is translated to produce a single protein. This large preprotein is subsequently cleaved by cellular and viral proteases into smaller proteins that either allow replication of the virus in the host cell or assemble into mature viral particles, e.g., E1, E2, NS2, NS3, NS4, NS4A, NS4B, NS5, NS5A, and NS5B.

[0461] HCV causes inflammation of the liver, and chronic infection leads to cirrhosis. Most patients with hepatitis C infection have the chronic form. Diagnosis of HCV can be performed by nucleic acid analysis of the 5' non-coding region. ELISA assays can be performed to detect hepatitis C antibodies, and RNA assays can be performed to determine viral load. Subjects infected with HCV may show symptoms of abdominal pain, ascites, dark urine, fatigue, generalized itching, jaundice, fever, nausea, white or clay-colored stools, and vomiting.

[0462] Therapeutic agents may suppress the virus for extended periods of time in some cases. A typical drug therapy is a combination of interferon alpha and ribavirin. The subject may receive injections of pegylated interferon alpha. Genotypes 1 and 4 are less responsive to interferon-based therapy than other genotypes (2, 3, 5, and 6). In certain embodiments, the present disclosure relates to treating a subject with HCV by administering a compound disclosed herein to a subject who is symptomatic or diagnosed with HCV. In certain embodiments, the compound is administered in combination with interferon alpha and another antiviral agent, such as ribavirin, and / or a protease inhibitor, such as telaprevir or boceprevir. In certain embodiments, the subject is diagnosed with genotype 2, 3, 5, or 6. In other embodiments, the subject is diagnosed with genotype 1 or 4.

[0463] In certain embodiments, the subject has been diagnosed with the virus by nucleic acid detection or viral antigen detection. Cytomegalovirus (CMV) belongs to the betaherpesvirus subfamily of the Herpesviridae family. In humans, it is commonly known as HCMV or human herpesvirus 5 (HHV-5). Herpesviruses typically share the property of remaining dormant in the body for long periods of time. HCMV infection can be life-threatening for immunocompromised patients. In certain embodiments, the disclosure relates to methods of treating a subject diagnosed with a cytomegalovirus infection or preventing a cytomegalovirus infection by administration of a compound disclosed herein. In certain embodiments, the subject is immunocompromised. In typical embodiments, the subject is an organ transplant recipient, undergoing hemodialysis, diagnosed with cancer, receiving immunosuppressive drugs, and / or diagnosed with HIV infection. In certain embodiments, the subject may be diagnosed with cytomegalovirus hepatitis, cytomegalovirus retinitis (inflammation of the retina can be detected by ophthalmoscopy), cytomegalovirus colitis (inflammation of the large intestine), cytomegalovirus pneumonia, cytomegalovirus esophagitis, cytomegalovirus mononucleosis, polyradiculopathy, transverse myelitis, and subacute encephalitis, which are the causes of fulminant hepatic failure.In certain embodiments, the compounds disclosed herein are administered in combination with an antiviral agent, such as valganciclovir or ganciclovir.In certain embodiments, the subject undergoes regular serological monitoring.

[0464] HCMV infection in pregnant subjects can cause congenital abnormalities. Congenital HCMV infection occurs when the mother suffers from primary infection (or reactivation) during pregnancy. In certain embodiments, the present disclosure relates to methods of treating pregnant subjects diagnosed with cytomegalovirus or preventing cytomegalovirus infection in subjects at risk of, planning to, or currently pregnant by administering a compound disclosed herein.

[0465] Subjects infected with CMV typically develop antibodies to the virus. Several laboratory tests have been developed to detect these antibodies to CMV. The virus can be cultured from specimens obtained from urine, throat swabs, bronchial washings, and tissue samples to detect active infection. PCR may be used to monitor viral load in CMV-infected subjects. The CMV pp65 antigenemia test is an immunoaffinity-based assay to identify the pp65 protein of cytomegalovirus in peripheral blood leukocytes. CMV should be suspected when patients have symptoms of infectious mononucleosis but test results for mononucleosis and Epstein-Barr virus are negative, or when they show signs of hepatitis but test results for hepatitis A, B, and C are negative. Cultures for hepatitis A virus can be performed whenever a subject is symptomatic. Laboratory tests for antibodies to CMV can be performed to determine if a subject already has a CMV infection.

[0466] The enzyme-linked immunosorbent assay (or ELISA) is the most commonly available serological test for measuring antibodies to CMV. Results can be used to determine whether acute infection in the infant, prior infection, or passively acquired maternal antibodies are present. Other tests include various fluorescent assays, indirect hemagglutination, (PCR), and latex agglutination. ELISA techniques for CMV-specific IgM are available.

[0467] Hepatitis B virus is a hepadnavirus. The virus particle (virion) consists of an outer lipid envelope and an icosahedral nucleocapsid core made of proteins. The genome of HBV is made of circular DNA, but the DNA is not completely double-stranded. One end of the strand is bound to the viral DNA polymerase. The virus replicates through the formation of an RNA intermediate by reverse transcription. Replication typically occurs in the liver, where inflammation (hepatitis) is caused. The virus spreads to the blood, where virus-specific proteins and their corresponding antibodies are found in infected individuals. Blood tests for these proteins and antibodies are used to diagnose the infection.

[0468] Hepatitis B virus enters cells by endocytosis. Because the virus propagates via RNA made by host enzymes, the viral genomic DNA must be transferred to the cell nucleus by host chaperones. The partially double-stranded viral DNA is then transformed into a covalently closed circular DNA (cccDNA) that makes a complete double strand and serves as a template for the transcription of viral mRNA. The virus is divided into four main serotypes (adr, adw, ayr, ayw) based on antigenic epitopes present on its envelope protein, and into eight genotypes (A-H) based on the variation in the overall nucleotide sequence of the genome.

[0469] Hepatitis B surface antigen (HBsAg) is typically used to screen for the presence of this infection. It is the first detectable viral antigen that appears during infection. However, early in infection this antigen may be absent and may be undetectable later in infection when it is eliminated by the host. Infectious virions contain an internal "core particle" in which the viral genome is encapsulated. The icosahedral core particle is made of core protein and is also known as hepatitis B core antigen or HBcAg. IgM antibodies against hepatitis B core antigen (anti-HBc IgM) may be used as a serological marker. Hepatitis B e antigen (HBeAg) may appear. The presence of HBeAg in the host's serum is associated with a high rate of viral replication. Certain variants of the hepatitis B virus do not produce the "e" antigen.

[0470] If the host is able to clear the infection, HBsAg typically becomes undetectable and IgG antibodies against hepatitis B surface and core antigens (anti-HBs and anti-HBc IgG) arise. The time between the clearance of HBsAg and the appearance of anti-HBs is called the gap time. Individuals who are HBsAg negative and anti-HBs positive have either cleared the infection or have previously been vaccinated. Individuals who remain HBsAg positive for at least 6 months are considered hepatitis B carriers. Carriers of the virus may have chronic hepatitis B, which will be reflected by elevated serum alanine aminotransferase levels and liver inflammation that can be identified on biopsy. Nucleic acid (PCR) tests have been developed to detect and measure the amount of HBV DNA in clinical specimens.

[0471] Acute infection with hepatitis B virus is associated with acute viral hepatitis. Acute viral hepatitis typically begins with symptoms of general ill health, loss of appetite, nausea, vomiting, body aches, low-grade fever, dark urine, and then progresses to the development of jaundice. Chronic infection with hepatitis B virus may be either asymptomatic or associated with chronic inflammation of the liver (chronic hepatitis), possibly leading to cirrhosis. Having chronic hepatitis B infection increases the incidence of hepatocellular carcinoma (liver cancer).

[0472] During HBV infection, the host immune response leads to both hepatocyte damage and viral clearance. The adaptive immune response, particularly virus-specific cytotoxic T lymphocytes (CTLs), contributes to much of the liver damage associated with HBV infection. CTLs eliminate the virus by killing infected cells and producing antiviral cytokines that can clear HBV from viable hepatocytes. Although liver damage is initiated and mediated by CTLs, antigen-nonspecific inflammatory cells can exacerbate CTL-induced immunopathology, and platelets activated at the site of infection can promote the accumulation of CTLs in the liver.

[0473] The therapeutic agent can stop the virus from replicating, thus minimizing liver damage. In certain embodiments, the present disclosure relates to a method of treating a subject diagnosed with HBV by administering the compounds disclosed herein disclosed herein. In certain embodiments, the subject is immunocompromised. In certain embodiments, the compounds are administered in combination with another antiviral agent, such as lamivudine, adefovir, tenofovir, telbivudine and entecavir, and / or immune system regulators interferon alpha-2a and pegylated interferon alpha-2a (Pegasys). In certain embodiments, the present disclosure relates to preventing HBV infection in an immunocompromised subject at risk of infection by administering a pharmaceutical composition disclosed herein and, optionally, one or more antiviral agents. In certain embodiments, the subject is at risk of infection because the subject's sexual partner has been diagnosed with HBV.

[0474] The compounds of the present disclosure include disoxalil, pleconaril, pirodavir, vapentavir, pocapavir, abacavir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, phosphonet, ganciclovir, ibacitabine, immunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, laminidine, ramiclovir ... It can be administered in combination with a second antiviral agent, such as vudine, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, oseltamivir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, sovosbuvir, stavudine, telaprevir, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, or zidovudine, as well as combinations thereof.

[0475] In certain embodiments, one of the following compounds is administered with the second antiviral agent described above: [ka] .

[0476] Also provided is a method for treating enterovirus and HCV infections in a subject. The method includes administering a compound of the present disclosure to provide at least two direct acting antiviral agents (DAAs), with or without ribavirin, for a period not exceeding 12 weeks, or another period as described herein. In one embodiment, the period of treatment does not exceed 12 weeks. In another embodiment, the period of treatment does not exceed 8 weeks. Preferably, the two or more direct acting antiviral agents (DAAs), with or without ribavirin, are administered in an amount effective to provide sustained virologic response (SVR) or achieve another desired measure of efficacy in the subject. The subject is not administered interferon during the treatment regimen. In other words, in one embodiment, the method precludes administration of interferon to the subject, thereby avoiding side effects associated with interferon. In some embodiments, the method further includes administering an inhibitor of cytochrome P-450 (such as ritonavir) to the subject to improve the pharmacokinetics or bioavailability of one or more DAAs.

[0477] In another embodiment, a method for treating enterovirus and HCV infections in a subject is provided. The method includes administering to the subject (a) a protease inhibitor, (b) at least one polymerase inhibitor, at least one of which is a polymerase of the present disclosure, and combinations thereof, with or without (c) ribavirin and / or (d) an inhibitor or cytochrome P-450, for a period not exceeding 12 weeks, or another period as described herein (e.g., the treatment regimen can last for a period not exceeding 8 weeks). Preferably, the compound is administered in an amount effective to provide a high rate of SVR or another measure of efficacy in the subject. As a non-limiting example, the compound can be co-formulated and administered once a day, and the treatment regimen preferably lasts for 8 weeks or 6 weeks.

[0478] In yet another aspect, a method is provided for treating a population of subjects with enterovirus or HCV infection. The method includes administering to the subject at least two DAAs, one of which is a compound of the present disclosure, with or without ribavirin for a period of 12 weeks or 8 weeks or 6 weeks or less. Preferably, the at least two DAAs are administered to the subject in an amount effective to induce SVR or another measure of efficacy in at least about 70% of the population, preferably at least 90% of the population.

[0479] In the methods described above and below herein, the DAA can be selected from the group consisting of a protease inhibitor, a nucleoside or nucleotide polymerase inhibitor (one of which is provided herein), a non-nucleoside polymerase inhibitor, an NS3B inhibitor, an NS4A inhibitor, an NS5A inhibitor, an NS5B inhibitor, a cyclophilin inhibitor, and a combination of any of the foregoing. For example, in some embodiments, the DAA used in the methods comprises or consists of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor provided herein.

[0480] At least one of the enterovirus and / or HCV polymerase inhibitors is one of the compounds of the present disclosure (described herein). By way of example, the compounds of the present disclosure can be administered in a total daily dose of about 100 mg to about 250 mg, or can be administered once a day in a dose of about 150 mg to about 250 mg.

[0481] In some embodiments, the at least two DAAs include at least one enterovirus and / or HCV polymerase inhibitor of the present disclosure and at least one NS5A inhibitor. By way of example, the polymerase inhibitor of the present disclosure can be administered at a total daily dose of about 100 mg to about 250 mg, and the NS5A inhibitor can be administered at a total daily dose of about 25 mg to about 200 mg. Ritonavir (or another cytochrome P-450 3A4 inhibitor) can be co-administered to improve the pharmacokinetics and bioavailability of the compound.

[0482] In the above-mentioned method and the method described herein, the DAA can be administered with or without ribavirin in any effective dosing schedule and / or frequency, for example, each can be administered daily.Each DAA can be administered individually or in combination, and each DAA can be administered at least once a day, at least twice a day, or at least three times a day.Similarly, ribavirin can be administered separately or in combination with one or more DAAs at least once a day, at least twice a day, or at least three times a day.In some preferred embodiments, the compound is administered once a day.

[0483] In some embodiments, the present technology provides a method for treating enterovirus and / or HCV infection, comprising administering at least two DAAs, with or without ribavirin, to a subject in need thereof for a period not exceeding 12 weeks, 8 weeks, or 6 weeks, wherein the subject is not administered interferon during the period. In some embodiments, the at least two DAAs, with or without ribavirin, are administered in an amount effective to induce SVR. Some methods further comprise administering to the subject an inhibitor of cytochrome P450. In some embodiments, the period is not exceeding 8 weeks.

[0484] In yet another embodiment, the at least two direct acting antiviral agents are one or more of disoxalil, pleconaril, pirodavir, vapentavir, pocapavir, ABT-450, and / or ABT-267, and / or ABT-333 and a compound of the disclosure; US2010 / 0144608, US61 / 339,964, US2011 / 0312973, WO2009 / 039127, US2010 / 0317568, 2012 / 151158, US2012 / 0172290, WO2012 / 092411, WO2012 / 087833, WO2012 a compound disclosed in any of US2012 / 0115918, WO2012 / 051361, WO2012 / 009699, WO2011 / 156337, US2011 / 0207699, WO2010 / 075376, US7,9105,95, WO2010 / 120935, WO2010 / 111437, WO2010 / 111436, US2010 / 0168384, or US2004 / 0167123 with a compound of the present disclosure; Compounds of the disclosure; one or more of asunaprevir, and / or daclusteravir, and / or BMS-325 and compounds of the disclosure; one or more of GS-9451, and / or redisusvir, and / or sofosbuvir, and / or GS-9669 and compounds of the disclosure; one or more of ACH-2684, and / or ACH-3102, and / or ACH-3422 and compounds of the disclosure; one or more of boceprevir and / or MK-8742 and compounds of the disclosure; one or more of faldaprevir and / or deleobvir and compounds of the disclosure; PPIs -668 and a compound of the disclosure; one or more of telaprevir, and / or VX-135 and a compound of the disclosure; one or more of samatasvir, and / or IDX-437 and a compound of the disclosure; PSI-7977 and / or PSI-938 and a compound of the disclosure; BMS-790052 and / or BMS-650032 and a compound of the disclosure; GS-5885 and / or GS-9451 and a compound of the disclosure; GS-5885, GS-9190, and / or GS-9451 and a compound of the disclosure; BI-201335 and / or BI-27127 and a compound of the disclosure;The combination of drugs includes those selected from the group consisting of telaprevir, and / or VX-222 and a compound of the disclosure; PSI-7977, and / or TMC-435 and a compound of the disclosure; and danoprevir, and / or R7128 and a compound of the disclosure;

[0485] In yet another embodiment, the at least two direct-acting antiviral agents include a compound of the present disclosure in combination with PSI-7977 and / or BMS-790052 (daclatasvir). In yet another embodiment, the at least two direct-acting antiviral agents include a compound of the present disclosure in combination with PSI-7977 and / or BMS-650032 (asunaprevir). In yet another embodiment, the at least direct-acting antiviral agents include a compound of the present disclosure in combination with PSI-7977, BMS-650032 (asunaprevir) and / or BMS-790052 (daclatasvir). Compounds of the present disclosure can also be used to add to these combinations or to replace the listed polymerases.

[0486] In another aspect, the technology features a combination of at least two DAAs for use in treating enterovirus and / or HCV infection, where the duration of the treatment regimen is not more than 12 weeks (e.g., the duration is 12 weeks, or the duration is 11, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). The treatment includes administering at least two DAAs to a subject infected with HCV. The duration of the treatment can be 12 weeks, and can last for example not more than 8 weeks (e.g., the duration is 8 weeks, or the duration is 7, 6, 5, 4, or 3 weeks). The treatment can include administering ribavirin, but not interferon. If one of the DAAs requires pharmacokinetic enhancement, the treatment can also include administering ritonavir or another CYP3A4 inhibitor (e.g., cobicistat). The at least two DAAs can be administered simultaneously or sequentially. For example, one DAA can be administered once a day and another DAA can be administered twice a day. In another example, two DAAs are administered once a day. As yet another example, two DAAs are co-formulated into a single composition and administered simultaneously (e.g., once a day). As a non-limiting example, the patient being treated may be infected with HCV genotype 1, such as genotype 1a or 1b. As another non-limiting example, the patient may be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient may be an HCV treatment-naive patient, an HCV treatment-experienced patient, an interferon non-responder (e.g., a non-responder, a partial responder, or a relapser), or may not be a candidate for interferon treatment.

[0487] In another aspect, the present technology features a combination of at least two DAAs for use in treating an enterovirus and / or HCV infection, the combination comprising a compound of the present disclosure, particularly EIDD-2023 and its prodrugs, Combinations of PSI-7977 and / or PSI-938, Combinations of BMS-790052 and / or BMS-650032, Combination of GS-5885 and / or GS-9451, Combinations of GS-5885, GS-9190, and / or GS-9451; combinations of BI-201335 and / or BI-27127, combination of telaprevir and / or VX-222, Combination of PSI-7977 and / or TMC-435, combination of danoprevir and / or R7128, combinations of ABT-450 and / or ABT-267 and / or ABT-333; A combination of baperivir and / or dioxalivir, A combination of vapenavir and / or pleconaril, combination of baperivir and / or pirodavir; combination of vapenavir and / or pocapavir, bapentil and / or a combination of one or more of the following: dioxalivir, pleconaril, pirodavir, and pirodavir; one or more of the following protease inhibitors: ABT450, simeprevir, asunaprevir, GS-9451, ACH-2684, boceprevir, MK-5172, faldaprevir, and telaprevir; one or more of the following NS5A inhibitors: ABT-267, GSK805, daclusteravir, dedipasvir, GS-5816, ACH-3102, MK-8742, PPI-668, and samatasvir; In combination with a compound selected from one or more of the following non-nuc NS5B inhibitors: ABT-333, TMC055, BMS-325, GS-9669, and deleobvir.

[0488] In one embodiment, the compound of the present disclosure used in the above combination therapy is EIDD-1911, EIDD-2023, or EIDD-2024. In a currently preferred embodiment, the compound of the present disclosure used in the above combination therapy is EIDD-2023. One or more of EIDD-1911, EIDD-2023, and EIDD-2024 may be combined with one or more of dioxalivir, pleconaril, pirodavir, bapentavir, pocapavir, ABT-450, ABT-267, and / or ABT-333, and / or one or more of US 2010 / 0144608, US61 / 339,964, US2011 / 0312973, WO2009 / 039127, US2010 / 0317568, 2012 / 151158, US2012 / 0172290, WO2012 / 092411, WO20

[0033] The compounds may be combined with compounds disclosed in WO2012 / 087833, WO2012 / 083170, WO2009 / 039135, US2012 / 0115918, WO2012 / 051361, WO2012 / 009699, WO2011 / 156337, US2011 / 0207699, WO2010 / 075376, US7,9105,95, WO2010 / 120935, WO2010 / 111437, WO2010 / 111436, US2010 / 0168384, or US2004 / 0167123.

[0489] In yet another aspect, the present technology features a combination of at least two DAAs for use in treating an enterovirus or HCV infection, the combination comprising a compound of the present disclosure: ABT-450 and / or ABT-267 and / or ABT-333, and / or US2010 / 0144608, US61 / 339,964, US2011 / 0312973, WO2009 / 039127, US2010 / 0317568, 2012 / 151158, US2012 / 0172290, WO2012 / 092411, WO2012 / 087833, WO2012 / 083170, WO2009 / 039135, US2012 / 0115918, WO2012 / 051361, WO2012 / 009699, WO2011 / 156337, US2011 / 0207699, WO2010 / 075376, US7,9105,95, WO2010 / 120935, WO2010 / 111437, WO2010 / 111436, US2010 / 0168384, or compounds disclosed in US2004 / 0167123; Combination of PSI-797 and / or BMS-790052, Combination of PSI-7977 and / or BMS-650032, Combinations of PSI-7977, BMS-790052, and / or BMS-650032; Combinations of INX-189 and / or BMS-790052, A combination of INX-189 and / or BMS-650032, or The combinations include those selected from the group consisting of INX-189, BMS-790052, and / or BMS-650032.

[0490] In yet another aspect, the present technology features PSI-7977, or a combination of at least two DAAs for use in treating HCV infection, the combination comprising a compound of the present disclosure and: combination of mericitabine and / or danoprevir; A combination of daclatasvir and / or BMS-791325, and The combination includes a compound selected from the group consisting of PSI-7977 and / or GS-5885.

[0491] The treatment involves administering PSI-7977 or a DAA combination to a subject infected with HCV or an enterovirus.

[0492] In yet another aspect, the technology features a combination of PSI-7977 and a compound of the disclosure, or at least two DAAs, for use in treating an HCV or enterovirus infection, the combination comprising: combination of mericitabine and / or danoprevir; combinations of INX-189, daclatasvir, and / or BMS-791325, and The combination includes those selected from the combination of PSI-7977 and / or GS-5885.

[0493] The treatment involves administering PSI-7977 or a DAA combination to a subject infected with HCV. In yet another aspect, the present technology features a combination of at least two DAAs for use in treating HCV infection, the combination being selected from the compounds disclosed herein, and combination of tegobuvir and / or GS-9256, A combination of BMS-791325, asunaprevir, and / or daclatasvir, and Includes combinations of TMC-435 and / or daclatasvir.

[0494] The treatment involves administering to a subject infected with HCV a DAA combination.

[0495] In yet another aspect, the present technology features a combination of a compound of the present disclosure with PSI-7977 and / or BMS-790052 for use in treating HCV infection, the treatment comprising administering a DAA combination to a subject infected with HCV or an enterovirus.

[0496] In yet another aspect, the technology features a combination of a compound of the present disclosure with PSI-7977 and / or TMC-435 for use in treating an HCV infection or an enterovirus.

[0497] In yet another aspect, the present technology features a combination of a compound of the present disclosure with danoprevir and / or mericitabine for use in treating HCV enterovirus infection.

[0498] In yet another aspect, the present technology features a combination of a compound of the present disclosure with daclatasvir and / or BMS-791325 for use in treating HCV infection, the treatment comprising administering to a subject infected with HCV or an enterovirus a DAA combination.

[0499] In yet another aspect, the present technology features a combination of a compound of the present disclosure with PSI-7977 and / or GS-5885 for use in treating HCV infection, the treatment comprising administering a DAA combination to a subject infected with HCV or an enterovirus.

[0500] The duration of the treatment regimen in some embodiments is not more than 16 weeks (e.g., the duration is 16 weeks, or the duration is 14, 12, or 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 week). The treatment includes administering ribavirin, but does not include administering interferon. If one of the DAAs requires pharmacokinetic enhancement, the treatment may include administering ritonavir or another CYP3A4 inhibitor (e.g., cobicistat). The two DAAs can be administered simultaneously or sequentially. For example, one DAA can be administered once a day and the other DAA can be administered twice a day. In another example, the two DAAs are administered once a day. As yet another example, the two DAAs are co-formulated into a single composition and administered simultaneously (e.g., once a day). As a non-limiting example, the patient being treated may be infected with HCV genotype 1, such as genotype 1a or 1b. As another non-limiting example, the patient may be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient may be an HCV treatment naive patient, an HCV treatment experienced patient, an interferon non-responder (e.g., a non-responder), or may not be a candidate for interferon treatment.

[0501] In yet another embodiment of this aspect of the disclosure, the at least two DAAs include an HCV or enterovirus protease inhibitor and an HCV polymerase inhibitor of the disclosure. The treatment can last for no more than 12 weeks, for example, but not limited to, 8, 9, 10, 11, or 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatment can also last for 8 weeks. The subject being treated can be, for example, a treatment-naive patient. The subject can also be a treatment-experienced patient, or an interferon non-responder (e.g., a non-responder). Preferably, the subject being treated is infected with HCV genotype 1, for example HCV genotype 1a. As another non-limiting example, the subject being treated is infected with HCV genotype 3.

[0502] In yet another embodiment of this aspect of the disclosure, the at least two DAAs include an HCV or enterovirus protease inhibitor and a non-nucleoside or non-nucleotidic HCV polymerase inhibitor, and a compound of the disclosure. The treatment can last for no more than 12 weeks, for example, but not limited to, 8, 9, 10, 11, or 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatment can also last for 8 weeks. The subject being treated can be, for example, a treatment-naive patient. The subject can also be a treatment-experienced patient, or an interferon non-responder (e.g., a non-responder). Preferably, the subject being treated is infected with HCV genotype 1, for e...

Claims

1. The following formula: 【Chemistry 1】 (β-D or β-L) or a pharma- ceutically acceptable salt thereof, U is NH, CH 2 , C.H.F., C.F. 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; X is O, CH 2 , C.H.F., C.F. 2 , or CD 2 and R 1 is OH, monophosphate, diphosphate, or triphosphate; R 2 , R 3 , R 4 , R 6 , and R 7 Each independently represents H, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 9 C substituted with 1-22 alkyl, R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by R 6 and R 7 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by Each R 9 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R 5 is H or D, Q is a base such as: 【Chemistry 2】 It is one of the wherein Z is OH, alkoxide, methoxide, ethoxide, halogen, thiol, alkylthio, alkyl, lipid, or geranyl, or a pharma- ceutically acceptable salt thereof; and a second antiviral agent.

2. The following formula: 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof, wherein A is O or S; A' is OH or BH 3 - M + and R 5 is H or D, U is NH, CH 2 , C.H.F., C.F. 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; Each X is independently O, S, NH, NR 8 , N.H.O.H., N.R. 8 OH, N.H.O.R. 8 , or NR 8 OR 8 and R 1 But OH, SH, NH 2 , OR 8 , S.R. 8 , N.H.R. 8 , N.H.O.H., N.R. 8 OH, N.H.O.R. 8 , or NR 8 OR 8 and In formulae Ic and Id, any X is S or R 1 But, S.R. 8 or both X are S and R 1 But, S.R. 8 and In formula Ie, at least one X is S; Y is CH, N, or CR 2 and Z is CH, N, or CR 2 and R 3 , R 4 , R 6 , R 7 , and R 10 Each independently represents H, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 9 C substituted with 1-22 alkyl, R 3 and R 4 can, together with the carbon atom to which they are attached, form a spiro ring containing carbon, oxygen, sulfur, or nitrogen, and optionally can contain one or more of the same or different R 9 can be replaced by R 6 and R 7 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 9 can be replaced by R 8 is methyl, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 9 C substituted with 1-22 is alkyl, Each R 9 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R 2 is deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, optionally one or more of the same or different, R 9 C substituted with 1-22 or a pharma- ceutically acceptable salt thereof; and a second antiviral agent.

3. The compound or a pharma- ceutically acceptable salt thereof is A is O, A' is OH; U is O; R 5 is H, Y and Z are CH; R 3 , R 4 , R 6 , R 7 , and R 10 each independently represents H, CH 3 , C.D. 3 , C.F. 3 , C.F. 2 H, C.F.H. 2 , O.H., S.H., and N.H. 2 , N 3 3. The composition of claim 2, wherein said alkyl group is selected from the group consisting of aryl, aryloxy ...

4. The compound is represented by formula Ie, or a pharma- ceutically acceptable salt thereof, wherein: one X is S and the other X is O; R 3 is H, R 4 is OH, R 6 But, CH 3 and R 7 is OH, R 10 The composition of claim 2 , wherein is H.

5. The structure: 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof, and a second antiviral agent.

6. The following formula: 【Chemistry 5】 (β-D or β-L) or a pharma- ceutically acceptable salt thereof, U is NH, CH 2 , C.H.F., C.F. 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; X is O, CH 2 , C.H.F., C.F. 2 , or CD 2 and R 5 is H or D, R 2 , R 3 , R 4 , R 8 , and R 9 Each independently represents H, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 10 C substituted with 1-22 alkyl, R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by R 6 and R 7 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by R 1 But the formula: 【Chemistry 6】 It is one of the Y is O or S; Y 1 is Oaryl or BH 3 - M + and Y 2 OH or BH 3 - M + and aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, 4-bromophenyl; Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, and Q is optionally substituted with one or more of the same or different alkyl, halogen, cycloalkyl; Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; 6 optionally one or more, the same or different, R 10 or a pharma- ceutically acceptable salt thereof, and a second antiviral agent.

7. U is O; X is CH 2 and Q is a pyrimidine having at least one thione, thiol, or thioether at the 2- and / or 4-position of the pyrimidine; R 5 is H, R 2 , R 3 , R 4 , R 8 , and R 9 each independently represents H, CH 3 , C.D. 3 , C.F. 3 , C.F. 2 H, C.F.H. 2 , O.H., S.H., and N.H. 2 , N 3 7. The composition of claim 6, wherein the alkyl group is selected from the group consisting of CHO, CN, Cl, Br, F, and I.

8. R 1 but, 【Chemistry 7】 and wherein Y is O; Y 1 is phenoxy, R 6 The composition of claim 6, wherein is iso-propyl.

9. The following formula: 【Chemistry 8】 or a pharma- ceutically acceptable salt thereof, wherein U is NH, CH 2 , C.H.F., C.F. 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; R 5 is H or D, R 1 But the formula: 【Chemistry 9】 It is one of the Y is O or S; Y 1 is Oaryl or BH 3 - M + and Y 2 OH or BH 3 - M + and Each X is independently O, S, NH, NR 8 , N.H.O.H., N.R. 8 OH, N.H.O.R. 8 , or NR 8 OR 8 and R 2 But OH, SH, NH 2 , OR 8 , S.R. 8 , N.H.R. 8 , N.H.O.H., N.R. 8 OH, N.H.O.R. 8 , or NR 8 OR 8 and In formulae Ig and Ih, one of X is S or R 2 But, S.R. 8 or both X are S and R 2 But, S.R. 8 and In formula Ii, at least one X is S; W is CH, N, or CR 8 and Z is CH, N, or CR 8 and R 3 , R 4 , R 7 , R 9 , and R 14 Each independently represents H, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 10 C substituted with 1-22 alkyl, R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by R 7 and R 14 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, 4-bromophenyl; R 8 is deuterium, methyl, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 10 C substituted with 1-22 is alkyl, R 6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; 6 optionally one or more, the same or different, R 10 or a pharma- ceutically acceptable salt thereof, and a second antiviral agent.

10. U is O; W and Z are CH; R 5 is H, R 1 but, 【Chemistry 10】 wherein Y is O and Y 1 is phenoxy, R 6 The composition of claim 9 , wherein is alkyl.

11. R 3 , R 4 , R 7 , R 9 , and R 14 each independently represents H, CH 3 , C.D. 3 , C.F. 3 , C.F. 2 H, C.F.H. 2 , O.H., S.H., and N.H. 2 , N 3 10. The composition of claim 9, wherein the alkyl group is selected from the group consisting of aryl, aryloxy ...

12. having a structure represented by formula Ia, or a pharma- ceutically acceptable salt thereof; 12. The composition of claim 11, wherein one X is O and the other X is S.

13. R 6 The composition of claim 12, wherein is iso-propyl.

14. R 5 is H, R 3 is H, R 4 is hydroxyl, R 7 is hydroxyl, R 14 is methyl, R 1 but, 【Chemistry 11】 and Y is O; Y 1 is phenoxy, R 6 The composition of claim 9, or a pharma- ceutically acceptable salt thereof, wherein is iso-propyl.

15. The structure: 【Chemistry 12】 and a compound having one of and a second antiviral agent.

16. The following formula: 【Chemistry 13】 (β-D or β-L) or a pharma- ceutically acceptable salt thereof, U is NH, CH 2 , C.H.F., C.F. 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; X is O, CH 2 , C.H.F., C.F. 2 , or CD 2 and R 5 is H or D, Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, and Q is optionally substituted with one or more of the same or different alkyl, halogen, or cycloalkyl; R 2 , R 3 , R 4 , R 8 , and R 9 Each independently represents H, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 10 C substituted with 1-22 alkyl, R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by R 8 and R 9 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; R 1 But the formula: 【Chemistry 14】 It is one of the Y is O or S; Y 1 OH or BH 3 # M + and A compound or a pharma- ceutically acceptable salt thereof, wherein the lipid is as described herein; and a second antiviral agent.

17. U is O; Q is a pyrimidine having at least one thione, thiol, or thioether at the 2- and / or 4-position of the pyrimidine; R 5 The composition of claim 16 , wherein is H.

18. 17. The composition of claim 16, wherein the lipid is hexadecyloxypropyl.

19. The composition of claim 16, wherein the lipid is 2-aminohexadecyloxypropyl.

20. The composition of claim 16, wherein the lipid is 2-aminoarachidyl.

21. 17. The composition of claim 16, wherein the lipid is selected from the group consisting of lauryl, myristyl, palmityl, stearyl, arachidyl, behenyl, and lignoceryl.

22. The lipid has the formula: 【Chemistry 15】 is a sphingolipid of the formula: R 13 is hydrogen, fluoro, OR 17 , OC(=O)R 17 , OC(=O)OR 17 or OC(=O)NHR 17 and R 15 is hydrogen, alkyl, C(=O)R 17 , C(=O)OR 17 or C(=O)NHR 17 and R 14 is a saturated or unsaturated alkyl chain having more than 6 and less than 22 carbon atoms, optionally containing one or more halogen or hydroxyl groups or one or more groups of the formula: 【Chemistry 16】 The structure of n is 8 to 14 or ≦8 to ≦14; o is 9 to 15 or ≦9 to ≦15; the sum or m and n is 8 to 14 or ≦8 to ≦14; the sum of m and o is 9 to 15 or ≦9 to ≦15; or 【Chemistry 17】 And, n is 4 to 10 or ≦4 to ≦10; o is 5 to 11 or ≦5 to ≦11; the sum of m and n is 4 to 10 or ≦4 to ≦10; the sum of m and o is 5 to 11 or ≦5 to ≦11; or 【Chemistry 18】 And, n is 6 to 12 or n is ≦6 to ≦12; the sum of m and n is 6 to 12, or n is ≦6 to ≦12; R 17 is hydrogen, branched or linear C 1-12 Alkyl, C 13-22 alkyl, cycloalkyl, or aryl selected from benzyl or phenyl, said aryl optionally having one or more, the same or different, R 11 is replaced by R 11 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

23. 23. The composition of claim 22, wherein the sphingolipid is an optionally substituted sphingosine, ceramide, or sphingomyelin, or a 2-aminoalkyl optionally substituted with one or more substituents.

24. The following formula: 【Chemistry 19】 or a pharma- ceutically acceptable salt thereof, In the formula, R 5 is H or D, U is NH, CH 2 , C.H.F., C.F. 2 , C=CH 2 , C=CHF, C=CF 2 , O, or S; E is CH 2 or CD 2 and R 1 But the formula: 【Chemistry 20】 It is one of the Y is O or S; Y 1 OH or BH 3 # M + and the lipid is as described herein; Each X is independently O, S, NH, NR 8 , N.H.O.H., N.R. 8 OH, N.H.O.R. 8 , or NR 8 OR 8 and R 2 But OH, SH, NH 2 , OR 8 , S.R. 8 , N.H.R. 8 , N.H.O.H., N.R. 8 OH, N.H.O.R. 8 , or NR 8 OR 8 and In formulae Ip and Iq, one of X is S or R 2 But, S.R. 8 or both X are S and R 2 But, S.R. 8 and In formula Ir, at least one X is S; W is CH, N, or CR 8 and Z is CH, N, or CR 8 and R 8 is deuterium, methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, optionally one or more of the same or different, R 10 C substituted with 1-22 is alkyl, R 3 , R 4 , R 6 , R 7 , and R 14 Each independently represents H, C 1-22 Alkyl, C 2-22 Alkenyl, C 2-22 Alkynyl, allyl, ethynyl, vinyl, C 1-22 Alkoxy, OH, SH, NH 2 , N 3 , CHO, CN, Cl, Br, F, I, or optionally one or more of the same or different, R 10 C substituted with 1-22 alkyl, R 3 and R 4 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by R 7 and R 14 can form a spiro ring containing carbon, oxygen, sulfur, or nitrogen together with the carbon atom to which they are attached, and optionally can contain one or more, the same or different, R 10 can be replaced by Each R 10 are independently alkyl, deuterium, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 A compound or a pharma- ceutically acceptable salt thereof selected from amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl; and a second antiviral agent.

25. E is CH 2 and U is O; 25. The composition of claim 24, wherein Y and Z are CH.

26. 25. The composition of claim 24, wherein the lipid is hexadecyloxypropyl.

27. 25. The composition of claim 24, wherein the lipid is 2-aminohexadecyloxypropyl.

28. 25. The composition of claim 24, wherein the lipid is 2-aminoarachidyl.

29. 25. The composition of claim 24, wherein the lipid is selected from the group consisting of lauryl, myristyl, palmityl, stearyl, arachidyl, behenyl, and lignoceryl.

30. The lipid has the formula: 【Chemistry 21】 is a sphingolipid of the formula: R 13 is hydrogen, fluoro, OR 17 , OC(=O)R 17 , OC(=O)OR 17 or OC(=O)NHR 17 and R 15 is hydrogen, alkyl, C(=O)R 17 , C(=O)OR 17 or C(=O)NHR 17 and R 14 is a saturated or unsaturated alkyl chain having more than 6 and less than 22 carbon atoms, optionally containing one or more halogen or hydroxyl groups or one or more groups of the formula: 【Chemical 22】 The structure of n is 8 to 14 or ≦8 to ≦14; o is 9 to 15 or ≦9 to ≦15; the sum or m and n is 8 to 14 or ≦8 to ≦14; the sum of m and o is 9 to 15 or ≦9 to ≦15; or 【Chemistry 23】 And, n is 4 to 10 or ≦4 to ≦10; o is 5 to 11 or ≦5 to ≦11; the sum of m and n is 4 to 10 or ≦4 to ≦10; the sum of m and o is 5 to 11 or ≦5 to ≦11; or 【Chemistry 24】 And, n is 6 to 12 or n is ≦6 to ≦12; the sum of m and n is 6 to 12, or n is ≦6 to ≦12; R 17 is hydrogen, branched or linear C 1-12 Alkyl, C 13-22 R is an alkyl, cycloalkyl, or aryl selected from benzyl or phenyl, wherein the aryl is optionally selected from one or more, the same or different, 11 is replaced by R 11 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

31. 31. The composition of claim 30, wherein the sphingolipid is an optionally substituted sphingosine, ceramide, or sphingomyelin, or a 2-aminoalkyl optionally substituted with one or more substituents.

32. 2. The composition of claim 1, wherein the second antiviral agent is selected from disoxalil, pleconaril, pirodavir, vapentavir, pocapavir, or combinations thereof.

33. 2. The composition of claim 1, wherein the second antiviral agent is selected from disoxalil, pleconaril, pirodavir, vapentavir, pocapavir, or a combination thereof, and the compound is selected from the following: 【Chemistry 25】

34. A pharmaceutical composition for the treatment or prevention of a viral infection, comprising the composition of any one of claims 1 to 33 and a pharma- ceutically acceptable carrier.

35. 35. The pharmaceutical composition of claim 34, wherein the viral infection is caused by an infectious agent comprising an RNA or DNA virus.

36. The RNA or DNA virus is selected from the group consisting of picornaviruses, cardioviruses, enteroviruses, coxsackieviruses A, B, and C, coxsackievirus A16, EV-D68, EV-A71, rhinoviruses, polioviruses, echoviruses, erboviruses, hepatoviruses, kobuviruses, parechoviruses, teschoviruses, noroviruses, sapoviruses, lagoviruses, caliciviruses including vesiviruses, astroviruses, togaviruses, flaviviruses, hepaciviruses, coronaviruses, arteriviruses, rhabdoviruses, filoviruses, and paramyxoviruses. , orthomyxovirus, hantavirus, reovirus, rotavirus, birnavirus, chrysovirus, cystovirus, hypovirus, partivirus, totovirus, lentivirus, polyomavirus, papillomavirus, adenovirus, circovirus, parvovirus, erythrovirus, betaparvovirus, amdovirus, densovirus, iteravirus, brevidensovirus, pehudensovirus, herpesvirus 1, 2, 3, 4, 5, 6, 7, and 8, poxvirus, or hepadnavirus.

37. A liposome composition comprising the composition of any one of claims 1 to 33 and a pharma- ceutically acceptable carrier.

38. 35. The pharmaceutical composition of claim 34, wherein the second antiviral agent selected from disoxaril, pleconaril, pirodavir, bapentavir and pocapavir, and combinations thereof, is administered with one or more of the following compounds: 【Chemistry 26】

39. 36. The pharmaceutical composition of claim 35, wherein the RNA and DNA virus is an enterovirus.

40. 40. The pharmaceutical composition of claim 39, wherein the enterovirus infection is selected from the group consisting of Coxsackievirus A, B, and C, Coxsackievirus A16, EV-D68, EV-A71, rhinovirus, poliovirus, and echovirus.

41. 40. The pharmaceutical composition of claim 39, wherein the enterovirus infection is a Coxsackievirus.

42. 42. The pharmaceutical composition of claim 41, wherein the Coxsackievirus is Coxsackie A16.

43. The pharmaceutical composition of claim 35, wherein the host is immunosuppressed.

44. 【Catalogue 27】 (EIDD-2023) or a pharma- ceutically acceptable salt thereof; bapendavir or a pharma- ceutically acceptable salt thereof; and a pharma- ceutically acceptable carrier.

45. 45. A pharmaceutical formulation as claimed in claim 44 for treating or preventing an enterovirus infection.

46. 46. ​​The pharmaceutical preparation of claim 45, wherein the enterovirus infection is selected from the group consisting of Coxsackievirus A, B, and C, Coxsackie A16, EV-D68, EV-A71, rhinovirus, poliovirus, and echovirus.

47. 46. ​​The pharmaceutical preparation of claim 45, wherein the enterovirus infection is a Coxsackievirus.

48. 48. The pharmaceutical preparation of claim 47, wherein the Coxsackievirus is Coxsackie A16.

49. 45. The pharmaceutical preparation of claim 44, wherein the host is immunosuppressed.

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