4'-Halogen-containing nucleotide and nucleoside therapeutic compositions and related uses

Abstract

Halogen-containing nucleotide and nucleoside therapeutic compositions and related uses are disclosed. In certain embodiments, the disclosure relates to the treatment or prevention of viral infections. Such viral infections may include enteroviruses, Tongaviridae, Bunyaviridae, Arenaviridae, Coronaviridae, Flaviviridae, Picornaviridae, Eastern equine encephalitis, Western equine encephalitis, and Venezuelan equine encephalitis (EEE, WEE, and VEE, respectively), Chikungunya fever (CHIK), Ebola, influenza, RSV, and Zika virus infections.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 500,416 filed on 5 May 2023, U.S. Provisional Application No. 63 / 534,748 filed on 25 August 2023, U.S. Provisional Application No. 63 / 588,255 filed on 5 October 2023, and U.S. Provisional Application No. 63 / 571,795 filed on 29 March 2024, the disclosures thereof being incorporated herein by reference.

[0002] Acknowledgment of government support This invention was made possible with government support through grants W15QKN-16-9-1002 granted by the Department of Defense and AI171403 granted by the National Institutes of Health. The government has certain rights to this invention.

[0003] This disclosure relates to halogen-containing nucleotide and nucleoside therapeutic compositions and related uses. In certain embodiments, this disclosure relates to viral infections, such as respiratory viruses, enteroviruses, Tongaviridae, Bunyaviridae, Arenaviridae, Coronaviridae, Flaviviridae, Picornaviridae, Eastern equine encephalitis, Western equine encephalitis, and Venezuelan equine encephalitis (EEE, WEE, and VEE, respectively), Chikungunya fever (CHIK), Ebola, influenza, RSV, and Zika virus infection, and the treatment or prevention of conditions caused by these viruses. [Background technology]

[0004] There is an urgent need for new antiviral agents to treat or prevent various viral infections. For example, the causative agents of eastern equine encephalitis, western equine encephalitis, and Venezuelan equine encephalitis (EEE, WEE, and VEE, respectively), as well as chikungunya fever (CHIK), are vector-borne viruses (Togaviridae, Alphavirus genus) that can be transmitted to humans via mosquito bites. Equine encephalitis viruses are CDC Class B pathogens, and CHIK viruses are Class C. There is great concern regarding the use of virulent strains of the VEE virus delivered via aerosols as biological weapons against soldiers. Animal studies have demonstrated that VEE virus infection via aerosol exposure leads to rapid, massive brain infections with high mortality and morbidity rates. See Roy et al., Pathogenesis of aerosolized Eastern equine encephalitis virus infection in guinea pigs. Virol J, 2009, 6:170.

[0005] Novel compounds and treatments are needed for viral infections. The compounds and methods disclosed herein address these needs.

[0006] References cited herein are not accepted as prior art. [Overview of the Initiative]

[0007] This disclosure relates to nucleotide and nucleoside therapeutic compositions containing halogens, such as 4'-halogens, and related uses. These include nucleosides, prodrugs, or complex compounds or salts thereof comprising amino acid esters, lipids, or sphingolipids or derivatives linked to nucleotides or nucleosides by phosphorus oxide or salts thereof.

[0008] In certain embodiments, this disclosure uses the formula defined herein. [ka] [ka] Compounds having the structure represented by, or the aforementioned subsets, The present invention relates to pharmaceutically acceptable salts, derivatives, or prodrugs thereof. In the above formula, the various substituent groups are understood to have the meanings further disclosed herein.

[0009] In certain embodiments, the disclosure intends to describe derivatives of the compounds disclosed herein, such as compounds containing one or more of the same or different substituents.

[0010] In certain embodiments, this disclosure envisions a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound disclosed herein. In certain embodiments, the pharmaceutical composition may be in the form of a tablet, capsule, pill, or aqueous buffer such as saline or phosphate buffer.

[0011] In certain embodiments, the disclosed pharmaceutical composition may include the compounds and propellants disclosed herein. In certain embodiments, the propellant may be a vaporizing propellant such as compressed air, ethanol, nitrogen, carbon dioxide, nitrous oxide, hydrofluoroalkane (HFA), 1,1,1,2,-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, or a combination thereof.

[0012] In certain embodiments, the Disclosure envisions a pressurized or non-pressurized vessel containing a compound or pharmaceutical composition as described herein. In certain embodiments, the vessel is a manual pump spray, inhaler, measuring inhaler, dry powder inhaler, atomizer, vibrating mesh atomizer, jet atomizer, or ultrasonic atomizer.

[0013] In certain embodiments, the present disclosure relates to a method for increasing bioavailability to treat or prevent a viral infection, comprising administering to a subject in need a pharmaceutical composition comprising an effective amount of a compound of formulas XXIX-XXXIVb disclosed herein, or a compound of formulas XXIX-XXXIVb and a pharmaceutically acceptable excipient.

[0014] In certain embodiments, the Disclosure relates to a method for treating or preventing a viral infection, comprising administering to a subject in need of it a pharmaceutical composition comprising an effective amount of a compound of formulas XXIX-XXXIVb disclosed herein, or a compound of formulas XXIX-XXXIVb and a pharmaceutically acceptable excipient. In certain embodiments, the viral infections are Tongan, Bunyaviridae, Arenaviridae, Coronaviridae, Flaviviridae, Picornaviridae, Zika virus infection, Eastern equine encephalitis, Western equine encephalitis, and Venezuelan equine encephalitis (EEE, WEE, and VEE, respectively), Chikungunya fever (CHIK), Ebola, influenza, and RSV.

[0015] In certain embodiments, the compound or pharmaceutical composition is administered orally, intravenously, or through the lungs, i.e., intrapulmonaryly.

[0016] In certain embodiments, this disclosure relates to the use of compounds as described herein in the production of agents for treating or preventing viral infections such as eastern equine encephalitis, western equine encephalitis, and Venezuelan equine encephalitis (EEE, WEE, and VEE, respectively), chikungunya fever (CHIK), Ebola, influenza, RSV, or Zika virus infection.

[0017] In certain embodiments, this disclosure relates to a method for producing compounds disclosed herein by mixing the starting materials and reagents disclosed herein under conditions such that the compounds are formed.

[0018] Additional advantages are some described in the following description, some are evident from that description, or can be learned by the implementation of the embodiments described below. The advantages described below will be realized and achieved by the elements and combinations specifically indicated in the attached claims. It should be understood that both the summary of the invention above and the embodiments for carrying out the invention below are merely illustrative and descriptive, and not limiting. [Brief explanation of the drawing]

[0019] [Figure 1] This demonstrates the stability of EIDD-2749 in methanol. [Figure 2] This demonstrates the stability of EIDD-2749 in water. [Figure 3] This demonstrates the stability of EIDD-2749 in 0.1N HCl. [Figure 4] This shows the stability of EIDD-2749 in PBS at pH 7.4. [Figure 5] This shows the stability of EIDD-2749 in a pH 9 buffer solution. [Figure 6] This shows the triphosphate concentrations in Huh-7 cells incubated with EIDD-2749 or a prodrug. [Figure 7] This shows the triphosphate concentrations in Vero cells incubated with EIDD-2749 or a prodrug. [Figure 8] The plasma PK curves from CD-1 mice that received single doses of EIDD-2749 at 50, 150, and 500 mg / kg PO or 10 mg / kg IP are shown. [Figure 9] This shows the changes in body weight of AG129 mice administered 10, 30, and 100 mg / kg of EIDD-2749 QD for 10 days. [Figure 10A]Representative data on the uptake and metabolism of EIDD-3232 in tissue culture experiments compared with EIDD-2749 are shown. Figure 10A shows data on the uptake and metabolism of EIDD-3232 in the indicated cell lines. Figure 10B shows data on the uptake and metabolism of EIDD-3232 in the indicated cell lines compared with EIDD-2749. [Figure 10B] Representative data on the uptake and metabolism of EIDD-3232 in tissue culture experiments compared with EIDD-2749 are shown. Figure 10A shows data on the uptake and metabolism of EIDD-3232 in the indicated cell lines. Figure 10B shows data on the uptake and metabolism of EIDD-3232 in the indicated cell lines compared with EIDD-2749. [Figure 11A] Representative pharmacokinetic data for EIDD-3232, EIDD-3321, and EIDD-2749 in mouse plasma after oral administration of 10 mg / kg of EIDD-3232 or 5 mg / kg of EIDD-2749 are shown. Figure 11A shows plasma concentrations versus time for the compounds shown. Figure 11B shows the plasma concentrations of EIDD-2749 after administration of either EIDD-3232 or EIDD-2749, as shown. [Figure 11B] Representative pharmacokinetic data for EIDD-3232, EIDD-3321, and EIDD-2749 in mouse plasma after oral administration of 10 mg / kg of EIDD-3232 or 5 mg / kg of EIDD-2749 are shown. Figure 11A shows plasma concentrations versus time for the compounds shown. Figure 11B shows the plasma concentrations of EIDD-2749 after administration of either EIDD-3232 or EIDD-2749, as shown. [Figure 12A] Representative data of tissue distribution after administration with EIDD-3232 are shown. Figure 12A shows the tissue concentration of EIDD-2749 after oral administration with EIDD-3232. Figure 12B shows the tissue concentration of EIDD-2991 after oral administration with EIDD-3232. [Figure 12B]Representative data of tissue distribution after administration with EIDD-3232 are shown. Figure 12A shows the tissue concentration of EIDD-2749 after oral administration with EIDD-3232. Figure 12B shows the tissue concentration of EIDD-2991 after oral administration with EIDD-3232. [Figure 13] Representative data regarding the stability of EIDD-3232 in simulated gastric juice (pH 1.3) is shown. [Figure 14] Representative data regarding the stability of EIDD-3232 in simulated intestinal fluid (pH 5.2) is shown. [Figure 15] As shown in the figure, the autopsy scoring (intestinal tissue) and changes in body weight of Sprague-Dawley rats administered with the indicated compounds are shown. [Figure 16] This demonstrates the efficacy of the compound shown (administered as shown in the figure) in a mouse survival model of IAV infection. [Figure 17] This shows the intracellular concentrations of EIDD-2991 in Calu3 or Huh7 cells incubated with EIDD-3639 or EIDD-3640. Results are shown as mean and standard deviation (n=3). [Figure 18] The mouse plasma concentrations and pharmacokinetic parameters of EIDD-2749 after a single oral administration of 16.5 mg / kg of EIDD-3639 or EIDD-3640 are shown. Results are presented as mean and standard deviation (n=4). [Figure 19A] The mouse tissue concentrations of EIDD-2749 (Figure 19A) and EIDD-2991 (Figure 19Bl) three hours after a single oral dose of 16.5 mg / kg of EIDD-3639 or EIDD-3640 are shown. Results are presented as mean and standard deviation. [Figure 19B] The mouse tissue concentrations of EIDD-2749 (Figure 19A) and EIDD-2991 (Figure 19Bl) three hours after a single oral dose of 16.5 mg / kg of EIDD-3639 or EIDD-3640 are shown. Results are presented as mean and standard deviation. [Figure 20]This shows the plasma concentrations (nmol / mL) of EIDD-2749 in mouse plasma after a single oral administration of 15 mg / kg EIDD-2749, 25 mg / kg EIDD-3519, or 25 mg / kg EIDD-2838. Results are shown as mean and standard deviation (n=3). [Figure 21] This chart shows the tissue concentrations (nmol / mL) of EIDD-2749 (Nuc; upper panel) and EIDD-2991 (TP; lower panel) in mouse tissue after a single oral administration of 15 mg / kg of EIDD-2749, 25 mg / kg of EIDD-3519, or 25 mg / kg of EIDD-2838. Black bars: EIDD-2749 administration, blue bars: EIDD-3519 administration, red bars: EIDD-2991 administration. Results are shown as mean and standard deviation (n=3). [Figure 22] Representative data on the stability of the EIDD-2749 prodrug in SGF at 10 μM, pH 1, and 37°C, as determined using the method described below in this specification, are shown. The prodrug numbers are shown in the figure and correspond to the same prodrug numbers and associated compound structures disclosed below in this specification. The t1 / 2 values ​​calculated for EIDD-2839 and EIDD-3509 are shown in the inserts adjacent to the figure. [Figure 23A] Representative data regarding the stability of EIDD-3509 in the presence of mouse intestinal microsomes (Figure 23A), mouse liver microsomes (Figure 23B), and mouse plasma (Figure 23C) are shown. Drug concentrations were determined using the assay methods disclosed below herein, and stability assays were performed as described below in the Examples. [Figure 23B] Representative data regarding the stability of EIDD-3509 in the presence of mouse intestinal microsomes (Figure 23A), mouse liver microsomes (Figure 23B), and mouse plasma (Figure 23C) are shown. Drug concentrations were determined using the assay methods disclosed below herein, and stability assays were performed as described below in the Examples. [Figure 23C]Representative data regarding the stability of EIDD-3509 in the presence of mouse intestinal microsomes (Figure 23A), mouse liver microsomes (Figure 23B), and mouse plasma (Figure 23C) are shown. Drug concentrations were determined using the assay methods disclosed below herein, and stability assays were performed as described below in the Examples. [Figure 24A] Representative data regarding the stability of prodrugs in the presence of mouse intestinal microsomes are shown. Figure 24A shows the time-course stability of EIDD-3051 and the co-release of EIDD-2749. Figure 24B shows the time-course stability of EIDD-3471 and the co-release of EIDD-2749. Figure 24C shows the time-course stability of EIDD-3469 and the co-release of EIDD-2749. Drug concentrations were determined using the assay methods disclosed below herein, and stability assays were performed as described below in the Examples. [Figure 24B] Representative data regarding the stability of prodrugs in the presence of mouse intestinal microsomes are shown. Figure 24A shows the time-course stability of EIDD-3051 and the co-release of EIDD-2749. Figure 24B shows the time-course stability of EIDD-3471 and the co-release of EIDD-2749. Figure 24C shows the time-course stability of EIDD-3469 and the co-release of EIDD-2749. Drug concentrations were determined using the assay methods disclosed below herein, and stability assays were performed as described below in the Examples. [Figure 24C] Representative data regarding the stability of prodrugs in the presence of mouse intestinal microsomes are shown. Figure 24A shows the time-course stability of EIDD-3051 and the co-release of EIDD-2749. Figure 24B shows the time-course stability of EIDD-3471 and the co-release of EIDD-2749. Figure 24C shows the time-course stability of EIDD-3469 and the co-release of EIDD-2749. Drug concentrations were determined using the assay methods disclosed below herein, and stability assays were performed as described below in the Examples. [Figure 25A]Representative data regarding the stability of prodrugs in the presence of mouse intestinal microsomes are shown. Figure 25A shows the time-course stability of EIDD-2838, as well as the co-release of EIDD-2749 and EIDD-2986. Figure 24B shows the time-course stability of EIDD-3519 and the co-release of EIDD-2729. Drug concentrations were determined using the assay methods disclosed below herein, and stability assays were performed as described below in the Examples. [Figure 25B] Representative data regarding the stability of prodrugs in the presence of mouse intestinal microsomes are shown. Figure 25A shows the time-course stability of EIDD-2838, as well as the co-release of EIDD-2749 and EIDD-2986. Figure 24B shows the time-course stability of EIDD-3519 and the co-release of EIDD-2729. Drug concentrations were determined using the assay methods disclosed below herein, and stability assays were performed as described below in the Examples. [Figure 26A] The protocols described in Figure 27A and Example 140 are used to illustrate representative in vivo tolerability of the indicated compounds and the indicated selected disclosed drugs when administered. Figure 26A shows body weight data collected for the indicated compounds. Figure 26B shows autopsy scores obtained for the indicated compounds. Figure 26C shows the probability of viability for the indicated compounds. [Figure 26B] The protocols described in Figure 27A and Example 140 are used to illustrate representative in vivo tolerability of the indicated compounds and the indicated selected disclosed drugs when administered. Figure 26A shows body weight data collected for the indicated compounds. Figure 26B shows autopsy scores obtained for the indicated compounds. Figure 26C shows the probability of viability for the indicated compounds. [Figure 26C]The protocols described in Figure 27A and Example 140 are used to illustrate representative in vivo tolerability of the indicated compounds and the indicated selected disclosed drugs when administered. Figure 26A shows body weight data collected for the indicated compounds. Figure 26B shows autopsy scores obtained for the indicated compounds. Figure 26C shows the probability of viability for the indicated compounds. [Figure 27A] The protocols described in Figure 27A and Example 140 are used to demonstrate representative in vivo tolerability of the indicated compounds and the indicated selected disclosed drugs when administered. Figure 27A shows the overall study protocol used to obtain the data shown in Figures 26A–26C and 27B–27G. Figure 27B shows body weight data for the indicated compounds obtained in the aforementioned study. Figure 27C shows autopsy scores obtained for the indicated compounds in the aforementioned study. Figure 27D shows body temperature data obtained for the indicated compounds in the aforementioned study. Figure 27E shows efficacy data obtained for the indicated compounds in an animal model of IAV, as described in the following examples herein. Figure 27F shows efficacy data obtained for the indicated compounds in an animal model of IAV, as described in the following examples herein. Figure 27G shows efficacy data obtained for the indicated compounds in an animal model of IAV, as described in the following examples herein. [Figure 27B]The protocols described in Figure 27A and Example 140 are used to demonstrate representative in vivo tolerability of the indicated compounds and the indicated selected disclosed drugs when administered. Figure 27A shows the overall study protocol used to obtain the data shown in Figures 26A–26C and 27B–27G. Figure 27B shows body weight data for the indicated compounds obtained in the aforementioned study. Figure 27C shows autopsy scores obtained for the indicated compounds in the aforementioned study. Figure 27D shows body temperature data obtained for the indicated compounds in the aforementioned study. Figure 27E shows efficacy data obtained for the indicated compounds in an animal model of IAV, as described in the following examples herein. Figure 27F shows efficacy data obtained for the indicated compounds in an animal model of IAV, as described in the following examples herein. Figure 27G shows efficacy data obtained for the indicated compounds in an animal model of IAV, as described in the following examples herein. [Figure 27C] The protocols described in Figure 27A and Example 140 are used to demonstrate representative in vivo tolerability of the indicated compounds and the indicated selected disclosed drugs when administered. Figure 27A shows the overall study protocol used to obtain the data shown in Figures 26A–26C and 27B–27G. Figure 27B shows body weight data for the indicated compounds obtained in the aforementioned study. Figure 27C shows autopsy scores obtained for the indicated compounds in the aforementioned study. Figure 27D shows body temperature data obtained for the indicated compounds in the aforementioned study. Figure 27E shows efficacy data obtained for the indicated compounds in an animal model of IAV, as described in the following examples herein. Figure 27F shows efficacy data obtained for the indicated compounds in an animal model of IAV, as described in the following examples herein. Figure 27G shows efficacy data obtained for the indicated compounds in an animal model of IAV, as described in the following examples herein. [Figure 27D]The protocols described in Figure 27A and Example 140 are used to demonstrate representative in vivo tolerability of the indicated compounds and the indicated selected disclosed drugs when administered. Figure 27A shows the overall study protocol used to obtain the data shown in Figures 26A–26C and 27B–27G. Figure 27B shows body weight data for the indicated compounds obtained in the aforementioned study. Figure 27C shows autopsy scores obtained for the indicated compounds in the aforementioned study. Figure 27D shows body temperature data obtained for the indicated compounds in the aforementioned study. Figure 27E shows efficacy data obtained for the indicated compounds in an animal model of IAV, as described in the following examples herein. Figure 27F shows efficacy data obtained for the indicated compounds in an animal model of IAV, as described in the following examples herein. Figure 27G shows efficacy data obtained for the indicated compounds in an animal model of IAV, as described in the following examples herein. [Figure 27E] The protocols described in Figure 27A and Example 140 are used to demonstrate representative in vivo tolerability of the indicated compounds and the indicated selected disclosed drugs when administered. Figure 27A shows the overall study protocol used to obtain the data shown in Figures 26A–26C and 27B–27G. Figure 27B shows body weight data for the indicated compounds obtained in the aforementioned study. Figure 27C shows autopsy scores obtained for the indicated compounds in the aforementioned study. Figure 27D shows body temperature data obtained for the indicated compounds in the aforementioned study. Figure 27E shows efficacy data obtained for the indicated compounds in an animal model of IAV, as described in the following examples herein. Figure 27F shows efficacy data obtained for the indicated compounds in an animal model of IAV, as described in the following examples herein. Figure 27G shows efficacy data obtained for the indicated compounds in an animal model of IAV, as described in the following examples herein. [Figure 27F]The protocols described in Figure 27A and Example 140 are used to demonstrate representative in vivo tolerability of the indicated compounds and the indicated selected disclosed drugs when administered. Figure 27A shows the overall study protocol used to obtain the data shown in Figures 26A–26C and 27B–27G. Figure 27B shows body weight data for the indicated compounds obtained in the aforementioned study. Figure 27C shows autopsy scores obtained for the indicated compounds in the aforementioned study. Figure 27D shows body temperature data obtained for the indicated compounds in the aforementioned study. Figure 27E shows efficacy data obtained for the indicated compounds in an animal model of IAV, as described in the following examples herein. Figure 27F shows efficacy data obtained for the indicated compounds in an animal model of IAV, as described in the following examples herein. Figure 27G shows efficacy data obtained for the indicated compounds in an animal model of IAV, as described in the following examples herein. [Figure 27G] The protocols described in Figure 27A and Example 140 are used to demonstrate representative in vivo tolerability of the indicated compounds and the indicated selected disclosed drugs when administered. Figure 27A shows the overall study protocol used to obtain the data shown in Figures 26A–26C and 27B–27G. Figure 27B shows body weight data for the indicated compounds obtained in the aforementioned study. Figure 27C shows autopsy scores obtained for the indicated compounds in the aforementioned study. Figure 27D shows body temperature data obtained for the indicated compounds in the aforementioned study. Figure 27E shows efficacy data obtained for the indicated compounds in an animal model of IAV, as described in the following examples herein. Figure 27F shows efficacy data obtained for the indicated compounds in an animal model of IAV, as described in the following examples herein. Figure 27G shows efficacy data obtained for the indicated compounds in an animal model of IAV, as described in the following examples herein. [Figure 28A]The stability data of EIDD-3621 in simulated gastric juice is shown using the protocol described below in this specification. The data on the release of EIDD-2749 from EIDD-3621 when incubated in the presence of mouse intestinal microsomes, mouse liver microsomes, and mouse plasma, using the protocol described below in this specification, is shown in Figure 28B. [Figure 28B] The stability data of EIDD-3621 in simulated gastric juice is shown using the protocol described below in this specification. The data on the release of EIDD-2749 from EIDD-3621 when incubated in the presence of mouse intestinal microsomes, mouse liver microsomes, and mouse plasma, using the protocol described below in this specification, is shown in Figure 28B. [Figure 29] This shows the survival of AG129 mice infected with Takaribe virus and treated with EIDD-02749 starting two hours before infection. [Figure 30] The viral titers on day 9 in serum (Graph A), liver tissue (Graph B), spleen tissue (Graph C), and brain tissue (Graph D) of AG129 mice infected with Takaribe virus and treated with EIDD-02749 are shown. [Figure 31] This shows the survival of AG129 mice infected with Takaribe virus and treated with EIDD-02749 starting at 2 hours, 1 day, 3 days, 5 days, and 7 days post-infection. [Figure 32] The viral titers on day 9 are shown in tissues from AG129 mice infected with Takaribe virus and treated with EIDD-02749 starting at 2 hours, 1 day, 3 days, 5 days, and 7 days post-infection. [Modes for carrying out the invention]

[0020] Before describing this disclosure in more detail, it should be understood that this disclosure is not limited to the specific embodiments described and is therefore naturally subject to change. It should also be understood that the terms used herein are solely for the purpose of describing specific embodiments and not to limit them, for the scope of this disclosure is limited only by the appended claims.

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this disclosure belongs. Any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of this disclosure, but preferred methods and materials are described below.

[0022] All documents and patents cited herein are incorporated herein by reference as if each individual document or patent were explicitly and individually indicated to be incorporated by reference, and are incorporated herein by reference to disclose and explain methods and / or materials relating to the cited documents. Any reference to a document is intended to indicate that the document was disclosed before the filing date, and should not be construed as acknowledging that this disclosure does not have prior rights to such document by prior disclosure. Furthermore, the publication dates indicated may differ from the actual publication dates and may require further verification.

[0023] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has distinct components and features that can be readily separated from or combined with any of several other embodiments without departing from the scope or spirit of this disclosure. Any of the methods described may be performed in the order described or in any other logically possible order.

[0024] Embodiments of this disclosure will, unless otherwise indicated, utilize techniques within the scope of the art, such as medicine, organic chemistry, biochemistry, molecular biology, and pharmacology. Such techniques are adequately described in the literature.

[0025] This disclosure relates to 4'-halogen-containing nucleotide and nucleoside therapeutic compositions and related uses. In certain embodiments, this disclosure relates to nucleosides optionally compounded with phosphorus oxidized or a salt thereof. In certain embodiments, this disclosure relates to complex compounds or salts thereof comprising amino acid esters, lipids, or sphingolipids or derivatives linked to nucleotides or nucleosides by phosphorus oxidized. In certain embodiments, this disclosure envisions pharmaceutical compositions comprising these compounds for use in the treatment of infectious diseases, viral infections, and cancer.

[0026] In certain embodiments, the disclosure relates to oxidized phosphorus prodrugs of 4'-halogen-containing nucleosides for the treatment of positive-sense and negative-sense RNA viral infections by targeting virus-encoded RNA-dependent RNA polymerase (RdRp). The disclosure also provides the common use of lipids and sphingolipids for delivering nucleoside analogs for the treatment of infectious diseases and cancer.

[0027] In certain embodiments, the disclosure relates to a complex compound or salt thereof comprising a sphingolipid or derivative linked to a nucleotide or nucleoside by oxidized phosphorus. In certain embodiments, the oxidized phosphorus is a phosphate, phosphonate, polyphosphate, or polyphosphonate, and the phosphate, phosphonate, or phosphate in the polyphosphate or polyphosphonate is optionally a phosphorothioate or phosphoramidate. In certain embodiments, the lipid or sphingolipid is covalently bonded to the oxidized phosphorus via an amino group or a hydroxyl group.

[0028] A nucleotide or nucleoside comprises a heterocycle containing two or more nitrogen heteroatoms, and the substituted heterocycle is optionally substituted with one or more identical or different alkyl, halogen, or cycloalkyl atoms.

[0029] In certain embodiments, the sphingolipid is a saturated or unsaturated 2-aminoalkyl or 2-aminooctadecane, optionally substituted with one or more substituents. In certain embodiments, the sphingolipid derivative is a saturated or unsaturated 2-aminooctadecane-3-ol, optionally substituted with one or more substituents. In certain embodiments, the sphingolipid derivative is a saturated or unsaturated 2-aminooctadecane-3,5-diol, optionally substituted with one or more substituents.

[0030] In certain embodiments, this disclosure envisions a pharmaceutical composition comprising any compound disclosed herein and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition is in the form of a pill, capsule, tablet, or saline buffer containing sugars. In certain embodiments, the composition may contain a second active agent such as an analgesic, anti-inflammatory agent, nonsteroidal anti-inflammatory agent, antiviral agent, antibiotic, or anticancer agent.

[0031] In certain embodiments, the present disclosure relates to a method for treating or preventing an infection, comprising administering to a subject in need of it a pharmaceutical composition comprising an effective amount of a compound of formulas XXIX-XXXIVb disclosed herein, or a compound of formulas XXIX-XXXIVb with a pharmaceutically acceptable excipient. Typically, the subject is diagnosed with or at risk of an infection caused by a virus, bacteria, fungus, protozoa, or parasite.

[0032] In certain embodiments, the present disclosure relates to a method for treating a viral infection, comprising administering to a subject in need of it a pharmaceutical composition comprising an effective amount of a compound of formula XXIX-XXXIVb disclosed herein, or a compound of formula XXIX-XXXIVb and a pharmaceutically acceptable excipient. In certain embodiments, the subject is a mammal, e.g., a human. In certain embodiments, the subject has been diagnosed with a chronic viral infection. In certain embodiments, the administration is performed 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. 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.

[0033] In certain embodiments, the subjects include influenza A virus, 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) types, 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, coxsackievirus A virus, coxsackievirus B virus, coxsackievirus A1~A16 subtypes (and in certain embodiments, A2-8, A10, A11, A12, A14, and A16 subtypes). (Type B), Norovirus, Rubella virus, Lymphocytic choriomeningitis virus (LCMV), Chikungunya, Eastern equine encephalitis virus (EEEV), Western equine encephalitis virus (WEEV), Venezuelan horse encephalitis virus (VEEV), Ross River virus, Berma Forest virus, Measles virus, Mumps virus, Respiratory syncytial virus, Rinderpest virus, California encephalitis virus, Hantavirus, Rabies virus, Ebola virus Diagnosed with Russus, 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 herpesvirus, roseolovirus, or Kaposi's sarcoma-associated herpesvirus, hepatitis A, hepatitis B, hepatitis D, hepatitis E, or human immunodeficiency virus (HIV).

[0034] In certain embodiments, the subjects include influenza A virus, influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, SARS coronavirus, MERS-CoV, human adenovirus (HAdV-1~55), and human papillomavirus (H PV) 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, coxsackie B virus, norovirus, rubella virus, lymphocytic choriomeningitis virus (LCMV), measles virus, mumps virus, respiratory syncytial virus, parainfluenza virus 1 Viruses including type 3, rinderpest virus, chikungunya, eastern equine encephalitis virus (EEEV), Venezuelan equine encephalitis virus (WEEV), western equine encephalitis virus (VEEV), California encephalitis virus, Rift Valley fever virus (RVFV), Heartland virus, Lacrosse virus, Malpol virus, severe fever with thrombocytopenia syndrome virus, Pichinde virus, hantavirus, Takaribe virus, Junin, rabies virus, Ebola virus, The patient has been diagnosed with Barburg virus, adenovirus, herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), lymphotropic herpesvirus, roseolovirus, or Kaposi's sarcoma-associated herpesvirus, hepatitis A, hepatitis B, hepatitis D, hepatitis E, or human immunodeficiency virus (HIV).

[0035] As used herein, “low pathogenic” virus, for example, “low pathogenic influenza” or “low pathogenic H5N1,” refers to a virus strain that causes mild or asymptomatic infection.

[0036] As used herein, “highly pathogenic” virus, for example, “highly pathogenic influenza” or “highly pathogenic H5N1” refers to a virus strain that results in a maximum morbidity and mortality rate of 50%, 60%, 70%, 80%, 90%, or 100%.

[0037] In certain embodiments, this disclosure relates to the use of compounds disclosed herein in the production or manufacture of agents for the treatment or prevention of infectious diseases, viral infections, or cancer.

[0038] In certain embodiments, this disclosure relates to a compound disclosed herein or a derivative of any of the formulas thereof.

[0039] Embodiments of this disclosure will, unless otherwise indicated, utilize techniques within the scope of the art, such as medicine, organic chemistry, biochemistry, molecular biology, and pharmacology. Such techniques are adequately described in the literature.

[0040] In certain embodiments, the drug may be in the form of a salt or prodrug, administered in the manner disclosed herein, and identified by weight. This refers to the weight of the enumerated compound. If it is in the form of a salt or prodrug, the weight is the molar equivalent of the corresponding salt or prodrug.

[0041] Where used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural nouns unless the context clearly indicates otherwise. In this specification and the following claims, certain terms are defined with reference to the following meanings, unless otherwise clearly intended.

[0042] definition Before describing the various embodiments, the following definitions are provided and should be used unless otherwise specified.

[0043] As used herein, the terms “deuterium” or “D” refer to a deuterium whose isotopic abundance relative to hydrogen (H) is at least 50%, at least 75%, or at least 90%.

[0044] As used herein, the term “phosphorus oxidized” refers to any various chemical moieties containing a phosphorus-oxygen (PO or P=O) bond. When used herein as a linking group, the linked molecule may be bonded to oxygen or directly to a phosphorus atom. The term is intended to include, but is not limited to, phosphoric acid, in which phosphorus is typically bonded to four oxygen atoms, and phosphonic acid, in which phosphorus is typically bonded to one carbon and three oxygen atoms. “Polyphosphate” generally refers to phosphoric acid linked to one another by at least one phosphorus-oxygen-phosphorus (POP) bond. “Polyphosphonic acid” refers to polyphosphate containing at least one phosphorus-carbon (CPOP) bond. In addition to containing a phosphorus-oxygen bond, phosphorus oxidized may also contain phosphorus-thiol (PS or P=S) bonds and / or phosphorus-amine (PN) bonds, which are referred to as phosphorothioates and phosphoramidates, respectively. In phosphorus oxide, the oxygen atom may form a double or single bond with phosphorus or a combination thereof, the oxygen may further bond with other atoms such as carbon, or it may exist as an anion in equilibrium with a cation, such as a metal or a quaternary amine.

[0045] As used herein, the term “subject” (or alternatively, “patient” or “participant,” such as a clinical trial participant) refers to a mammal being the object of treatment, observation, or experimentation. The mammal may be male or female. The mammal may be one or more selected from the group consisting of humans, bovines (e.g., cows), porcines (e.g., pigs), ovines (e.g., sheep), capras (e.g., goats), equines (e.g., horses), canines (e.g., domestic dogs), felines (e.g., house cats), lagomorphs (rabbits), rodents (e.g., rats or mice), and raccoons (Procyon lotors) (e.g., raccoons). In certain embodiments, the subject is human.

[0046] As used herein, the term “persons in need of it” (or alternatively, “patients in need of it”) refers to persons diagnosed with or suspected of having a viral infection, such as infection with SARS-CoV-2 (whether symptomatic or asymptomatic); persons at risk of exposure to a viral infection, such as infection with SARS-CoV-2 (e.g., healthcare workers who may be at risk of exposure to SARS-CoV-2); and persons exposed to a viral infection, such as infection with SARS-CoV-2, as defined herein (e.g., contact with family members of a COVID-19 patient or an asymptomatic patient infected with SARS-CoV-2).

[0047] As used herein, the terms “prevent” and “preventing” include prevention of recurrence, spread, or onset. This disclosure is not intended to be limited to complete prevention. In some embodiments, onset is delayed or the severity of the disease is reduced.

[0048] As used herein, the terms “to treat” and “to treat” are not limited to cases where the subject (e.g., a patient) is cured and the disease is eradicated. Rather, embodiments of the present disclosure may also intend to treat merely symptoms and / or slow the progression of the disease.

[0049] As used herein, the term “in combination with” means, when used to describe administration with additional treatment, that the drugs may be administered before, together with, or after, or in combination thereof, additional treatment.

[0050] As used herein, “alkyl” means a straight-chain or branched-chain saturated hydrocarbon moiety, such as those containing 1 to 24 carbon atoms. “Higher alkyl” refers to a saturated hydrocarbon having 24 or more carbon atoms. 16 " refers to alkyl groups containing 6 to 16 carbon atoms. Similarly, "C6-C 22 A "lower alkyl" group refers to an alkyl group containing 6 to 22 carbon atoms. Typical saturated linear alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-septyl, n-octyl, and n-nonyl, while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, and isopentyl. A "lower alkyl" group is an alkyl group containing 1 to 6 (for example, 1 to 4) carbon atoms. The term alkyl group is also used for C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, and C1-C 10 It can be alkyl, etc., up to C1-C 24 Contains alkyl.

[0051] As used herein, the term "alkenyl" refers to an unsaturated, linear, or branched hydrocarbon moiety containing a double bond. Unless otherwise specified, C2-C 24 (For example, C2-C 22 , C2-C 20、C2-C 18 、C2-C 16 、C2-C 14 、C2-C 12 、C2-C 10Alkenyl groups (C2-C8, C2-C6, or C2-C4) are intended. The alkenyl group may contain one or more unsaturated bonds.Examples include ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl 3-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl Examples include nyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, and 1-ethyl-2-methyl-2-propenyl.The term "vinyl" refers to a group having the structure -CH=CH2, 1-propenyl refers to a group having the structure -CH=CH-CH3, and 2-propenyl refers to a group having the structure -CH2-CH=CH2. (Z. 1 Z 2 )C=C(Z 3 Z 4 Asymmetric structures such as ) are intended to include both E and Z isomers. This can be assumed in the structural formulas herein if asymmetric alkenes are present, or it can be explicitly indicated by the bond symbol C=C.

[0052] As used herein, the term "alkynyl" refers to a straight-chain or branched-chain hydrocarbon moiety containing a triple bond. Unless otherwise specified, C2-C 24 (For example, C2-C 24 , C2-C 20 , C2-C 18 , C2-C 16 , C2-C 14 , C2-C 12 , C2-C 10Alkynyl groups (C2-C8, C2-C6, or C2-C4) are intended. Alkynyl groups may contain more than one unsaturated bond. Examples include ethynyl, 1-propynyl, 2-propynyl (or propargyl), 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-1-butynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 3-methyl-1-pentynyl, 4-methyl-1-pentynyl, 1- Examples of C2-C6 alkynyls include methyl-2-pentynyl, 4-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, and 1-ethyl-1-methyl-2-propynyl.

[0053] Non-aromatic monocyclic or polycyclic alkyl groups are referred to herein as "carbocyclic" or "carbocykyl" groups. Typical saturated carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, while unsaturated carbocyclic groups include cyclopentenyl and cyclohexenyl.

[0054] A "heterocarbocyclic" group is a carbon ring containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which can be saturated or unsaturated (but not aromatic), monocyclic or polycyclic, the nitrogen and sulfur heteroatoms can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized. Examples of heterocarbocyclic groups include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxyranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl.

[0055] The term "aryl" preferably refers to a monocyclic, bicyclic, or tricyclic ring-containing group of an aromatic homocyclic (i.e., hydrocarbon) having 6 to 12 members, such as phenyl, naphthyl, and biphenyl. Phenyl is a preferred aryl group. The term "substituted aryl" preferably refers to an aryl group substituted with one or more groups selected from alkyl, substituted alkyl, alkenyl (optionally substituted), aryl (optionally substituted), heterocyclo (optionally substituted), halo, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkanoyl (optionally substituted), aroyl (optionally substituted), alkyl ester (optionally substituted), aryl ester (optionally substituted), cyano, nitro, amino, substituted amino, amide, lactam, urea, urethane, sulfonyl, etc., wherein one or more substituents optionally form a 3 to 7-membered ring with the atom to which they are bonded.

[0056] As used herein, “heteroaryl” or “heteroaromatic” refers to an aromatic heterocarbon ring containing at least one carbon atom, having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and including both monocyclic and polycyclic ring systems. A polycyclic ring system may contain one or more nonaromatic rings, but is not required, as long as one of the rings is aromatic. Representative heteroaryls include furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, benzoxazolyl, pyrazolyl, pyrazolyl, imidazolyl, benzimimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridadinyl, pyrimidinyl, pyrazinyl, triazinyl, cinolinyl, phthalazinyl, and quinazolyl. The use of the term "heteroaryl" is intended to include N-alkylated derivatives such as 1-methylimidazole-5-yl substituents.

[0057] As used herein, “heterocyclic” refers to monocyclic and polycyclic systems having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and containing at least one carbon atom. Monocyclic and polycyclic systems may be aromatic rings, non-aromatic rings, or mixtures of aromatic and non-aromatic rings. Heterocyclic systems include heterocarbon rings, heteroaryl rings, and the like.

[0058] "Alkylthio" refers to an alkyl group, as defined above, having the indicated number of carbon atoms linked through a sulfur bridge. An example of alkylthio is methylthio (i.e., -S-CH3).

[0059] "Alkoxy" refers to an alkyl group having the indicated number of carbon atoms, as defined above, linked through an oxygen crosslink. Examples of alkoxys 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.

[0060] "Alkylamino" refers to an alkyl group, as defined above, having the indicated number of carbon atoms linked through an amino crosslink. An example of an alkylamino is methylamino (i.e., -NH-CH3).

[0061] "Alkanoyl" refers to an alkyl (i.e., -(C=O)alkyl) as defined above, having the indicated number of carbon atoms linked through a carbonyl crosslink.

[0062] "Alkylsulfonyl" refers to an alkyl (i.e., -S(=O)2 alkyl) having the indicated number of carbon atoms, as defined above, linked through a sulfonyl crosslink such as mesyl, while "arylsulfonyl" refers to an aryl (i.e., -S(=O)2 aryl) linked through a sulfonyl crosslink.

[0063] "Alkylsulfamoyl" refers to an alkyl group (i.e., -NHS(=O)2alkyl) having the indicated number of carbon atoms bonded through a sulfamoyl crosslink, as defined above, and "arylsulfamoyl" refers to an alkyl group (i.e., -NHS(=O)2aryl) bonded through a sulfamoyl crosslink.

[0064] "Alkyl sulfinyl" refers to an alkyl (i.e., -S(=O) alkyl) having the indicated number of carbon atoms bonded through a sulfinyl crosslink, as defined above.

[0065] The terms "cycloalkyl" and "cycloalkenyl" refer to monocyclic, dicyclic, or tricyclic homocyclic systems of 3 to 15 carbon atoms that are fully saturated and partially unsaturated, respectively. The term "cycloalkenyl" refers to bicyclic and tricyclic ring systems that are not aromatic as a whole but contain aromatic moieties (e.g., fluorene, tetrahydronaphthalene, dihydroindene, etc.). The rings of polycyclic cycloalkyl groups can be fused, crosslinked, and / or joined through one or more spirobonds. The terms "substituted cycloalkyl" and "substituted cycloalkenyl" refer, respectively, to cycloalkyl and cycloalkenyl groups substituted with one or more groups selected from, preferably, aryl, substituted aryl, heterocyclo, substituted heterocyclo, carbocyclo, substituted carbocyclo, halo, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkyl ester (optionally substituted), aryl ester (optionally substituted), alkanoyl (optionally substituted), ariol (optionally substituted), cyano, nitro, amino, substituted amino, amide, lactam, urea, urethane, sulfonyl, and the like.

[0066] The terms "halogen" and "halo" refer to fluorine, chlorine, bromine, and iodine.

[0067] The term "substituted" refers to a molecule in which at least one hydrogen atom is replaced by a substituent. When substituted, one or more of the groups are "substituents." Molecules can be multiple substituted. In the case of an oxo substituent ("=O"), two hydrogen atoms are substituted. Examples of substituents in this context include halogens, hydroxyls, alkyls, alkoxys, nitros, cyanos, oxos, carbocyclyls, carbocycloalkyls, heterocarbocyclyls, heterocarbocycloalkyls, aryls, arylalkyls, heteroaryls, heteroarylalkyls, -NRaRb, -NRaC(=O)Rb, -NRaC(=O)NRaNRb, -NRaC(=O)ORb, -NRaSO2Rb, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRb, -OC(=O)NRaRb, -ORa, -SRa, -SORa, -S(=O)2Ra, -OS(=O)2Ra, and -S(=O)2ORa. In this context, Ra and Rb may be the same or different, and independently can be hydrogen, halogen hydroxyl, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyryl, carbocyalkyl, heterocarbocyryl, heterocarbocyalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl.

[0068] As used herein, the term “optionally substituted” means that substitution at an additional group is optional, and therefore the specified atom may not be substituted. Thus, the use of the term “optionally substituted” means that this disclosure includes both examples where the group is substituted and examples where it is not.

[0069] When used herein, the designation of the multivalent part is intended to cover all possible arrangements without specifying a particular order of attachment. For example, formula Compounds represented by AXB are In the formula, X is NHC (=O), [ka] It encompasses both.

[0070] As used herein, the term “null” refers to the possible identity of a chemical part, indicating the absence of a group and the direct bonding of two adjacent groups. For example, in the genus of compounds having the formula CH3-X-CH3, if X is null, the resulting compound has the formula CH3-CH3. A group with the subscript “0” is similarly understood to represent a null group. For example, the compound CH3-(X) z In -CH3, if X is CH2 and z is 0, the compound has the formula CH3-CH3.

[0071] In certain cases, two or more variable groups can come together to form a ring. It should be understood that any indicated atom separated from the identified group itself forms part of the ring. [ka] When a variable group is substituted on an aromatic system, the new ring is a fused ring and, unless otherwise specified, can be aromatic or aromatic, carbocyclic or heterocyclic. [ka] A ring can be further defined by the number of carbon atoms in a particular ring formed by a variable group, which includes the atoms that separate the variable group. [ka] Except for the C2 heteroaryls mentioned above, each of the above is R 1 and R 2 However, when they come together, they form a six-membered (or six-atom) ring.

[0072] As used herein, “salt” refers to a derivative of a disclosed compound in which the parent compound has been modified to produce an acid or base salt thereof. Examples of salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkylamines, or dialkylamines, and alkali or organic salts of acidic residues such as carboxylic acids. In typical embodiments, the salt is a conventional, non-toxic, pharmaceutically acceptable salt, comprising a quaternary ammonium salt of the parent compound formed and a non-toxic inorganic or organic acid. Preferred salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, 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, and isethionic acid.

[0073] The term "prodrug" refers to a drug that is converted into a biologically active form in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than their 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 compared to their parent drugs. Prodrugs can be converted to their parent drugs by a variety of mechanisms, including enzymatic processes and metabolic hydrolysis.

[0074] Examples of prodrugs that can be used to improve bioavailability include esters, optionally substituted esters, branched esters, optionally substituted branched esters, carbonates, optionally substituted carbonates, carbamates, optionally substituted carbamates, thioesters, optionally substituted thioesters, branched thioesters, optionally substituted branched thioesters, thiocarbonates, optionally substituted thiocarbonates, S-thiocarbonates, optionally substituted S-thiocarbonates. - Carbonates, dithiocarbonates, optionally substituted dithiocarbonates, thiocarbamates, optionally substituted thiocarbamates, oxymethoxycarbonyl, optionally substituted oxymethoxycarbonyl, oxymethoxythiocarbonyl, optionally substituted oxymethoxythiocarbonyl, oxymethylcarbonyl, optionally substituted oxymethylcarbonyl, oxymethylthiocarbonyl, optionally substituted oxymethylthiocarbonyl, L-amino acid esters, D-amino acid esters, N-substituted L-amino acids No acid esters, N,N-disubstituted L-amino acid esters, N-substituted D-amino acid esters, N,N-disubstituted D-amino acid esters, sulfenyl, optionally substituted sulfenyl, imidate, optionally substituted imidate, hydrazonate, optionally substituted hydrazonate, oxymyl, optionally substituted oxymyl, imidinyl, optionally substituted imidinyl, imidyl, optionally substituted imidyl, aminal, optionally substituted aminal, hemiaminal, optionally substituted hemiaminal Acetal, optionally substituted acetal, hemiacetal, optionally substituted hemiacetal, carvonimidate, optionally substituted carvonimidate, thiocarboneimidate, optionally substituted thiocarboneimidate, carvonimidyl, optionally substituted carvonimidyl, carbamuimidate, optionally substituted carbamuimidate, carbamuimidyl, optionally substituted carbamuimidyl, thioacetal, optionally substituted thioacetal, S-acyl-2-thioethyl,Examples include optionally substituted S-acyl-2-thioethyl, bis-(acyloxybenzyl) esters, optionally substituted bis-(acyloxybenzyl) esters, (acyloxybenzyl) esters, optionally substituted (acyloxybenzyl) esters, and BAB esters. As used herein, the term “derivative” refers to a structurally similar compound that retains the full functional attributes of the identified analogue. Derivatives may be structurally similar because they lack one or more substituents, one or more atoms substituted with a salt in different hydrate / oxidation states (e.g., substituting a single or double bond, substituting a hydroxyl group with a ketone), or because one or more atoms in the molecule have been transposed (but not limited to substituting an oxygen atom with a sulfur or nitrogen atom, or substituting an amino group with a hydroxyl group, or vice versa). Substituting a carbon atom with nitrogen in an aromatic ring is an intended derivative. Derivatives may also be prodrugs. Derivatives can be prepared by any various synthetic methods or appropriate adaptations presented in chemical literature or textbooks on synthesis or organic chemistry, for example, 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.

[0075] The compounds described herein contain one or more double bonds and thus potentially give rise to cis / trans (E / Z) isomers and other stereoisomers. Unless otherwise stated, this disclosure includes all such possible isomers and mixtures of such isomers.

[0076] As used herein, the following three structural formulas represent the same compound. [ka] This rule applies to each of the nucleoside derivatives disclosed herein.

[0077] Except for the nucleoside rules exemplified above, formulas having chemical bonds shown only as solid lines and not as wedges or dashed lines intend each possible isomer, e.g., each enantiomer and diastereomer, as well as mixtures of isomers, e.g., racemic or scalemic mixtures. The compounds described herein may contain one or more asymmetric centers, thus potentially giving rise to diastereomers and optical isomers. Unless otherwise stated, this disclosure includes all such possible diastereomers, as well as their racemic mixtures, their substantially pure decomposed enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts. It also includes mixtures of stereoisomers and specific isolated stereoisomers. During the course of synthetic procedures used to prepare such compounds, or when using racemization or epimerization procedures known to those skilled in the art, the products of such procedures may be mixtures of stereoisomers. It is understood that the use of wedges or hashes is merely one representation of a stereochemical descriptor. All stereoisomers, including enantiomers and diastereomers, as well as their racemic and optically pure forms, and mixtures thereof, are provided in any proportion to formulas XXIX to XXXIb.

[0078] A “stereoisomer” refers to a compound that consists of the same atoms bonded together by the same bonds but has different three-dimensional structures that are not interchangeable. This disclosure intends various stereoisomers or mixtures thereof and includes “enantiomers,” which refer to two stereoisomers whose structures are mirror images of each other but cannot be superimposed. A “diastereomer” is a stereoisomer that has at least two asymmetric atoms but is not a mirror image of each other.

[0079] It is understood that when enantiomers and / or diastereomers of a given structure exist, and planar bonds indicate that all stereoisomers of the shown structure may exist. Furthermore, when enantiomers and / or diastereomers of a given structure exist, the presence of planar bonds and the "*" symbol indicates that the composition consists of at least 60% by weight, at least 70% by weight, at least 80% by weight, or at least 90% by weight of a single isomer having an unknown stereochemistry. Furthermore, when enantiomers and / or diastereomers of a given structure exist, it is understood that wedge-shaped or hash-shaped bonds indicate that the composition consists of at least 60% by weight, at least 70% by weight, at least 80% by weight, or at least 90% by weight of a single enantiomer or diastereomer having a known stereochemistry. Combinations of the above notations may be used as needed. Exemplary species may contain stereocenters having known stereochemistry and stereocenters having unknown stereochemistry.

[0080] Many organic compounds exist in optically active forms that have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to its chiral center(s). The prefixes d and l or (+) and (-) are used to indicate the rotation of plane-polarized light by the compound, with (-) or meaning that the compound is levorotatory. Compounds with (+) or d as prefixes are dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are incompatible mirror images of each other. Certain stereoisomers may also be called enantiomers, and mixtures of such isomers are often called enantiomer mixtures. A 50:50 mixture of enantiomers is called a racemic mixture. Many of the compounds described herein may have one or more chiral centers and therefore may exist in different enantiomer forms. If desired, chiral carbons may be indicated by an asterisk (*). When the bond to a chiral carbon is represented as a straight line in the disclosed formula, it is understood that both the (R) and (S) configurations of the chiral carbon, and therefore both enantiomers and mixtures thereof, are included in the formula. When it is desirable to specify the absolute configuration for a chiral carbon, as used in the art, one of the bonds to the chiral carbon can be represented as a wedge (bond to an atom above the plane), and the other as a series of short parallel lines or a wedge (bond to an atom below the plane). The Cahn-Inglod-Prelog system can be used to assign (R) or (S) configurations to chiral carbons.

[0081] The compounds described herein may contain atoms in both their naturally occurring and unnatural isotopic abundances. The disclosed compounds may be identically isotopically labeled or isotopically substituted compounds, due to the fact that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those typically found in nature. Examples of isotopes that can be incorporated into the compounds of this disclosure include, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, and 36 Examples include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine, such as Cl. Compounds further comprise their prodrugs, and pharmaceutically acceptable salts of such compounds, or of such prodrugs containing the aforementioned isotopes and / or other isotopes of other atoms, are within the scope of this disclosure. Certain isotope-labeled compounds of this disclosure, for example, 3 H and 14 Compounds incorporating radioactive isotopes such as 13C are useful in tissue distribution assays of drugs and / or substrates. Tritiated compounds, i.e., 3 H, and carbon-14, that is, 14 Isotopes of 1C are particularly preferred due to their ease of preparation and detectability. Furthermore, deuterium, i.e., 2 Substitution with heavier isotopes, such as 1H, can offer certain therapeutic advantages resulting from higher metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and may therefore be preferable in some situations. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by performing the following procedure, which involves substituting an unlabeled reagent with a readily available isotope-labeled reagent.

[0082] The compounds described herein may exist as solvates. In some cases, the solvent used to prepare the solvates is an aqueous solution, and the solvates are often called hydrates. The compounds may exist as hydrates, which can be obtained, for example, by crystallization from a solvent or aqueous solution. In this context, one, two, three, or any number of solvent or water molecules may, in combination with the compounds herein, form solvates and hydrates. Unless otherwise stated, this disclosure includes all such possible solvates.

[0083] The term "cocrystal" refers to the physical association of two or more molecules that bear their stability through non-covalent interactions. One or more components of this molecular complex provide a stable framework in the crystal lattice. In certain examples, guest molecules are incorporated into the crystal lattice as anhydrides or solvates; see, for example, "Crystal Engineering of the Composition Pharmaceutical Phase. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?" Almarasson, O., et al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of cocrystals include p-toluenesulfonic acid and benzenesulfonic acid.

[0084] It is also understood that certain compounds described herein may exist in equilibrium as tautomers. For example, ketones having an α-hydrogen may exist in equilibrium between keto and enol forms. [ka] Similarly, amides having an N-hydrogen can exist in equilibrium between amide and imido acid forms. Unless otherwise stated, this disclosure includes all such possible tautomers.

[0085] Chemical substances are known to form solids that exist in different ordered states, referred to as polymorphic forms or modifications. Different modifications of polymorphic substances can differ significantly in their physical properties. The compounds according to this disclosure can exist in different polymorphic forms, and certain modifications can be metastable. Unless otherwise stated, this disclosure includes all such possible polymorphic forms.

[0086] Certain materials, compounds, compositions, and components disclosed herein are commercially available or can be readily synthesized using techniques generally known to those skilled in the art. For example, the starting materials and reagents used in the preparation of the disclosed compounds and compositions are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis.), Acros Organics (Morris Plains, NJ), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.), or from Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers). It is either prepared by a method known to those skilled in the art, following the procedures described in references such as Inc., 1989.

[0087] Unless otherwise expressly stated, no method described herein is intended to be construed as requiring its steps to be performed in a specific order. Therefore, if a method claim does not actually enumerate the order in which its steps are followed, or if the claims or specification does not specifically state that the steps should be limited to a particular order, no order is ever intended to be inferred. This is reserved for any possible implicit grounds for interpretation, including the arrangement of steps or operational flows, the obvious meanings arising from grammatical structure or punctuation, and logical matters relating to the number or type of embodiments described in the specification.

[0088] The components used to prepare the compositions of this disclosure, as well as the compositions themselves used in the methods disclosed herein, are disclosed. These and other materials are disclosed herein, and where combinations, subsets, interactions, groups, etc., of these materials are disclosed, specific references to various individual and collective combinations and permutations of each of these compounds cannot be expressly disclosed, but each is understood to be specifically intended and described herein. For example, where a particular compound is disclosed and considered, and a number of modifications that can be made to several molecules containing the compound are considered, then, unless otherwise indicated, all possible combinations and permutations of the compound and possible modifications are specifically intended. Thus, if class molecules A, B, and C, and classes D, E, and F are disclosed, and an example of a combined molecule, A-D, is disclosed, then, even if each is not described individually, each is considered to disclose the combinations A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F individually and collectively. Similarly, any subset or combination of these is also disclosed. Therefore, for example, subgroups A-E, B-F, and C-E are considered to be disclosed. This concept applies to all embodiments of this application, including but not limited to steps in a method for preparing and using the compositions of this disclosure. Therefore, where there are various additional steps that can be performed, it is understood that each of these additional steps can be performed in any particular embodiment or combination of embodiments of the method of this disclosure.

[0089] Where used herein, the nomenclature of compounds, including organic compounds, may be given using the common nomenclature, IUPAC, IUBMB, or CAS recommendation. If one or more stereochemical features are present, the stereochemical priority, E / Z specification, etc., may be specified using the Cahn-Ingold-Prelog rules for stereochemistry. Those skilled in the art can easily verify the structure of a compound when naming it by systemically reducing the compound structure using the nomenclature rules, or by using commercially available software such as CHEMDRAW® (Cambridgesoft Corporation, USA).

[0090] compound In certain embodiments, this disclosure relates to nucleosides complexed with a phosphorus moiety and a pharmaceutically acceptable salt thereof.

[0091] In certain embodiments, the present disclosure relates to compounds of formula XXIX, [ka] or with respect to a pharmaceutically acceptable salt thereof, In the formula, R 1 However, the formula [ka] Selected from groups having a structure represented by, Y is either O or S, Y 1 However, OY 3 Or BH3 - M + Preferably, OY 3 And, Y 3 However, it is hydrogen, aryl, heteroaryl, or heterocyclyl, Y 3 However, you can choose to select one or more of the same or different R 10 Replaced with, preferably, Y 3 However, C6-C 12 Aryl or C1-C 12 It is a heteroaryl, R 2a and R 3a Each of these independently consists of hydrogen, C1-C6 alkyl, (C=O)C1-C6 alkyl, and (C=O)NR. 40 Selected from C1-C6 alkyl, (C=O)N(C1-C6 alkyl)2, or (C=O)OC1-C6 alkyl, where the alkyl group is optionally and independently one or more of the same or different R 10 Replaced by, R 40 However, in either case, hydrogen and C1-C6 alkyl are independently selected, and R is optionally selected. 10 Replaced by one or more times, R 2a and R 3a However, together they can form a 5- to 7-membered heterocyclic ring, for example, R 2a and R 3a However, when combined, they can become C(CH3)2, C(=O), or C(=S). R 5 However, R is hydrogen, alkyl, carbocykyl, heterocarbocykyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, or lipid. 5 However, you can choose to select one or more of the same or different R 10 Replaced with, preferably, R 5 However, hydrogen, C1-C8 alkyl, C6-C 12 Ariel, C1-C 12 These are heteroaryls, C2-C8 heterocyclyls, C3-C8 cycloalkyls, or C5-C8 cycloalkenyls, and R 5 However, you can choose to select one or more of the same or different R 10 Replaced by, R 7 and R 7’However, each is independently selected from hydrogen, deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocarbocykrill, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocykritolthio, heterocarbocykritolthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, R 7 and R 7’ However, you can choose to select one or more of the same or different R 10 Replaced with, preferably, R 7 and R 7’ However, independently, hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C 12 Ariel, C1-C 12 These are heteroaryls, C2-C8 heterocyclyls, C3-C8 cycloalkyls, or C5-C8 cycloalkenyls, and R 5 However, you can choose to select one or more of the same or different R 10 Replaced by, R 10is deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclicthio, heterocarbocyclicthio, arylthio, heteroarylthio, heterocyclicthio, cycloalkylthio, cycloalkenylthio, arenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, and R 10 is optionally substituted with one or more identical or different R 11 and R 11 is deuterium, hydroxy, azido, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocarbocyclic, aryl, heteroaryl, heterocyclic, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkylamino, cycloalkenylamino, alkylthio, carbocyclicthio, heterocarbocyclicthio, arylthio, heteroarylthio, heterocyclicthio, cycloalkylthio, cycloalkenylthio, arenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, polyethylene glycol, nitro, or carbonyl, and the lipid is independently C 11 -C 22 alkyl, C 11 -C 22 alkoxy, or C6-C 18It is an aryl substituted with an alkyl group.

[0092] In certain embodiments, R 7 and R 7’ One of them is hydrogen and the other is not hydrogen. In certain embodiments, R 7 is hydrogen and R 7’ is not hydrogen. In some embodiments, R 7 is not hydrogen and R 7’ is hydrogen.

[0093] In certain embodiments, the present disclosure relates to a compound of formula XXIX,

Chemical formula

Chemical formula

[0094] In a particular embodiment, R 7 and R 7’ One of them is hydrogen, and the other is not hydrogen. In a particular embodiment, R 7 is hydrogen, and R 7’ It is not hydrogen. In some embodiments, R 7 It is not hydrogen, but R 7’ It is hydrogen.

[0095] In exemplary embodiments of formula XXIX, the present disclosure relates to compounds of formula XXIXa, [ka] or with respect to a pharmaceutically acceptable salt thereof, In the formula, R 1 However, the formula [ka] Selected from groups having a structure represented by, Y is either O or S, Y 1 However, OY 3 Or BH3 - M + And, Y 3 However, it is hydrogen, aryl, heteroaryl, or heterocyclyl, and Y 3 However, you can choose to select one or more of the same or different R 10 Replaced by, R 2a and R 3a Each of these independently consists of hydrogen, C1-C6 alkyl, (C=O)C1-C6 alkyl, and (C=O)NR. 40 Selected from C1-C6 alkyl, (C=O)N(C1-C6 alkyl)2, or (C=O)OC1-C6 alkyl, polyethylene glycol, aryl, and lipids. R 2a and R 3a However, each can arbitrarily and independently select one or more identical or different Rs. 10 It can be replaced with, R 2a and R 3a However, together they can form a 5- to 7-membered heterocyclic ring, for example, R 2a and R 3a However, when combined, they can become C(CH3)2, C(=O), or C(=S). R 5 However, these are hydrogen, alkyl, carbocykyl, heterocarbocykyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, polyethylene glycol, alkyl-substituted aryl, lipids, and R 5 However, you can choose to select one or more of the same or different R 10 Replaced by, R 10However, it is deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocarbocykrill, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocykritolthio, heterocarbocykritolthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl, R 10 However, you can choose to select one or more of the same or different R 11 Replaced by, R 11 However, it is deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocarbocykrill, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocykritolthio, heterocarbocykritolthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl. Lipids, independently, C 11 -C 22 Alkyl, C 11 -C 22 Alkoxy, or C6-C18 It is an aryl substituted with an alkyl group.

[0096] In exemplary embodiments of formula XXIX, the present disclosure relates to compounds of formula XXIXa, [ka] or with respect to a pharmaceutically acceptable salt thereof, In the formula, R 1 However, the formula [ka] Selected from groups having a structure represented by, Y is either O or S, Y 1 However, OY 3 Or BH3 - M + And, Y 3 However, it is hydrogen, aryl, heteroaryl, or heterocyclyl, and Y 3 However, you can choose to select one or more of the same or different R 10 Replaced by, (C=O)C1-C6 alkyl, (C=O)NR 40 C1-C6 alkyl, (C=O)N(C1-C6 alkyl)2, or (C=O)OC1-C6 alkyl, wherein the alkyl group is optionally and independently one or more of the same or different R 10 Replaced by, R 40 However, in either case, hydrogen and C1-C6 alkyl are independently selected, and R is optionally selected. 10 Replaced by one or more times, R 5 However, R is hydrogen, alkyl, carbocykyl, heterocarbocykyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, or lipid. 5 However, you can choose to select one or more of the same or different R 10 Replaced by, R 7 and R 7’However, each is independently selected from hydrogen, deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocarbocykrill, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocykritolthio, heterocarbocykritolthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, R 7 However, you can choose to select one or more of the same or different R 10 Replaced by, R 10 However, it is deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocarbocykrill, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocykritolthio, heterocarbocykritolthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl, R 10 However, you can choose to select one or more of the same or different R 11 Replaced by, R 11However, it is deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocarbocykrill, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocykritolthio, heterocarbocykritolthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl. Lipids, independently, C 11 -C 22 Alkyl, C 11 -C 22 Alkoxy, or C6-C 18 It is an aryl substituted with an alkyl group.

[0097] In exemplary embodiments of formula XXIX, the present disclosure relates to a compound of formula XXIXb, [ka] or with respect to a pharmaceutically acceptable salt thereof, In the formula, R 1 However, the formula [ka] Selected from groups having a structure represented by, Y 3 However, it is hydrogen, aryl, heteroaryl, or heterocyclyl, and Y 3 However, you can choose to select one or more of the same or different R 10 Replaced by, R 2a and R 3aEach of these independently consists of hydrogen, C1-C6 alkyl, (C=O)C1-C6 alkyl, and (C=O)NR. 40 Selected from C1-C6 alkyl, (C=O)N(C1-C6 alkyl)2, or (C=O)OC1-C6 alkyl, polyethylene glycol, aryl, and lipids. R 2a and R 3a However, each can arbitrarily and independently select one or more identical or different Rs. 10 It can be replaced with, R 2a and R 3a However, together they can form a 5- to 7-membered heterocyclic ring, for example, R 2a and R 3a However, when combined, they can become C(CH3)2, C(=O), or C(=S). R 5 However, these are hydrogen, alkyl, carbocykyl, heterocarbocykyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, polyethylene glycol, alkyl-substituted aryl, lipids, and R 5 However, you can choose to select one or more of the same or different R 10 Replaced by, R 10 However, it is deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocarbocykrill, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocykritolthio, heterocarbocykritolthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl, R10 However, you can choose to select one or more of the same or different R 11 Replaced by, R 11 However, it is deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocarbocykrill, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocykritolthio, heterocarbocykritolthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl. Lipids, independently, C 11 -C 22 Alkyl, C 11 -C 22 Alkoxy, or C6-C 18 It is an aryl substituted with an alkyl group.

[0098] In exemplary embodiments of formula XXIX, the present disclosure relates to a compound of formula XXIXb, [ka] or relating to its pharmaceutical or physiological salt, In the formula, R 1 However, the formula [ka] Selected from groups having a structure represented by, Y 3 However, it is hydrogen, aryl, heteroaryl, or heterocyclyl, and Y 3 However, you can choose to select one or more of the same or different R10 Replaced by, R 5 However, R is hydrogen, alkyl, carbocykyl, heterocarbocykyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, or lipid. 5 However, you can choose to select one or more of the same or different R 10 Replaced by, R 10 However, it is deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocarbocykrill, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocykritolthio, heterocarbocykritolthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl, R 10 However, you can choose to select one or more of the same or different R 11 Replaced by, R 11However, it is deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocarbocykrill, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocykritolthio, heterocarbocykritolthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl. Lipids, independently, C 11 -C 22 Alkyl, C 11 -C 22 Alkoxy, or C6-C 18 It is an aryl substituted with an alkyl group.

[0099] In exemplary embodiments of formula XXIX, the present disclosure relates to a compound of formula XXIXc, [ka] or with respect to a pharmaceutically acceptable salt thereof, In the formula, R 1 but, [ka] Preferably, R 1 but, [ka] That is the case.

[0100] In some embodiments, R 1The portion has a stereochemical purity of at least 75 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the stereoisomers shown at the phosphorus atom. Those skilled in the art will understand that the above portion may be derived from alanine and is therefore essentially stereochemically pure at the methyl-supported carbon.

[0101] In a particular embodiment, Y 3 However, it is hydrogen, aryl, heteroaryl, or heterocyclyl, and Y 3 However, you can choose to select one or more of the same or different R 10 Replaced by, R 5 However, these are hydrogen, alkyl, carbocykyl, heterocarbocykyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, polyethylene glycol, alkyl-substituted aryl, lipids, and R 5 However, you can choose to select one or more of the same or different R 10 Replaced by, R 10 However, it is deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocarbocykrill, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocykritolthio, heterocarbocykritolthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl, R 10 However, you can choose to select one or more of the same or different R 11 Replaced by, R11 However, it is deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocarbocykrill, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocykritolthio, heterocarbocykritolthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl. Lipids, independently, C 11 -C 22 Alkyl, C 11 -C 22 Alkoxy, or C6-C 18 It is an aryl substituted with an alkyl group.

[0102] In exemplary embodiments of formula XXIX, the present disclosure relates to a compound of formula XXIXc, [ka] or relating to its pharmaceutical or physiological salt, In the formula, R 1 but, [ka] And, Preferably, R 1 but, [ka] That is the case.

[0103] In some embodiments, R 1The portion has a stereochemical purity of at least 75 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the stereoisomers shown at the phosphorus atom. Those skilled in the art will understand that the above portion may be derived from alanine and is therefore essentially stereochemically pure at the methyl-supported carbon.

[0104] In some embodiments, Y 3 However, it is hydrogen, aryl, heteroaryl, or heterocyclyl, and Y 3 However, you can choose to select one or more of the same or different R 10 Replaced by, R 5 However, R is hydrogen, alkyl, carbocykyl, heterocarbocykyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, or lipid. 5 However, you can choose to select one or more of the same or different R 10 Replaced by, R 10 However, it is deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocarbocykrill, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocykritolthio, heterocarbocykritolthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl, R 10 However, you can choose to select one or more of the same or different R 11 Replaced by, R 11However, it is deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocarbocykrill, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocykritolthio, heterocarbocykritolthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl. Lipids, independently, C 11 -C 22 Alkyl, C 11 -C 22 Alkoxy, or C6-C 18 It is an aryl substituted with an alkyl group.

[0105] In exemplary embodiments of formulas XXIX to XXIXc, R 1 is, formula [ka] It is a group having a structure represented by [this].

[0106] In exemplary embodiments of formulas XXIX to XXIXc, R 1 is, formula [ka] It is a group having a structure represented by [this].

[0107] In exemplary embodiments of formulas XXIX to XXIXc, R 1 is, formula [ka] It is a group having a structure represented by [this].

[0108] In exemplary embodiments of formulas XXIX to XXIXc, R 1 is, formula [ka] It is a group having a structure represented by [this].

[0109] In exemplary embodiments of formulas XXIX to XXIXc, R 1 is a group disclosed herein, however, R 1 teeth, [ka] This is conditional on the fact that it is not the case.

[0110] In exemplary embodiments of formulas XXIX to XXIXc, R 1 is, formula [ka] [ka] [ka] A group having a structure represented by, The stereochemical purity of the phosphorus atom is at least 75 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the indicated stereoisomers.

[0111] In exemplary embodiments of formulas XXIX to XXIXc, R 1 is, formula [ka] [ka] It is a group having a structure represented by [this].

[0112] In exemplary embodiments of formulas XXIX to XXIXc, R 1 is, formula [ka] [ka] A group having a structure represented by, The stereochemical purity of the phosphorus atom is at least 75 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the indicated stereoisomers.

[0113] In exemplary embodiments of formulas XXIX to XXIXc, R 1 is, formula [ka] It is a group having a structure represented by [this].

[0114] In exemplary embodiments of formulas XXIX to XXIXc, R 5 The following are selected from lipids, methyl, ethyl, propyl, isopropyl, butyl, i-butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, and N,N-dipropylamino.

[0115] In exemplary embodiments of formulas XXIX to XXIXc, R 5The following are selected from lipids, ethyl, propyl, isopropyl, butyl, i-butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, and N,N-dipropylamino.

[0116] In exemplary embodiments of formulas XXIX to XXIXc, R 5 The following are selected from lipids, propyl, isopropyl, butyl, i-butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, and N,N-dipropylamino.

[0117] In exemplary embodiments of formulas XXIX to XXIXc, R 5 The following are selected from lipids, butyl, i-butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, and N,N-dipropylamino.

[0118] In exemplary embodiments of formulas XXIX to XXIXc, R 5The following are selected from lipids, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, and N,N-dipropylamino.

[0119] In exemplary embodiments of formulas XXIX to XXIXc, R 5 The compounds are selected from methyl, ethyl, propyl, isopropyl, butyl, i-butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and 2,6-dimethylphenyl.

[0120] In exemplary embodiments of formulas XXIX to XXIXc, R 5 The following are selected from ethyl, propyl, butyl, i-butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0121] In exemplary embodiments of formulas XXIX to XXIXc, R 5 It is selected from phenyl and 2,6-dimethylphenyl.

[0122] In exemplary embodiments of formulas XXIX to XXIXc, R 5 The compound is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0123] In exemplary embodiments of formulas XXIX to XXIXc, R 5The compound is selected from pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, and 4-septyl.

[0124] In exemplary embodiments of formulas XXIX to XXIXc, the compound is [ka] A selection will be made from these combinations.

[0125] In exemplary embodiments of formulas XXIX to XXIXc, the compound is [ka] A selection will be made from these combinations.

[0126] In exemplary embodiments of formulas XXIX to XXIXc, the compound is [ka] A selection will be made from these combinations.

[0127] In exemplary embodiments of formulas XXIX to XXIXc, the compound is [ka] A selection will be made from these combinations.

[0128] In exemplary embodiments of formulas XXIX to XXIXc, the compound is [ka] isn't it.

[0129] In certain embodiments, this disclosure relates to compounds of formula XXX, [ka] or with respect to a pharmaceutically acceptable salt thereof, in the formula, R1 but, [ka] It is a structure represented by an expression selected from, Q 2 is C(=O), O(C=O), S(C=O), NR 40 (C=O), C(=S), O(C=S), S(C=S), or NR 40 (C=S) Q 1 However, null, O, S, C(=O), O(C=O), S(C=O), NR 40 (C=O), C(=S), O(C=S), S(C=S), NR 40 (C=S), O(C=O)O, S(C=O)O, NR 40 (C=O)O, S(C=O)S, NR 40 (C=O)S, NR 40 (C=O)NR 40 , O(C=S)O, S(C=S)O, NR 40 (C=S)O, S(C=S)S, NR 40 (C=S)S, NR 40 (C=S)NR 40 , or NR 40 And, Q 3 However, C5-C8 cycloalkyl, C6-C 12 Ariel, C3-C 12 Heterocyclyl, or C3-C 12 It is a heteroaryl, Q 4 However, arbitrarily and independently, one or more identical or different R 10 It can be replaced with, Q 4 However, C5-C8 cycloalkyl, C6-C 12 Ariel, C3-C 12 Heterocyclyl, or C3-C 12 It is a heteroaryl, Q 4 However, arbitrarily and independently, one or more identical or different R 10 It can be replaced with, Y is either O or S, n is selected from 1, 2, and 3, and is preferably 1. A 1a , A 1b , A 1c , and A 1d Each of these independently consists of C, NR 40 Selected from S and O, R 21a However, in either case, hydrogen, deuterium, and C1-C are produced independently. 22 Alkyl, C1-C 22 Alkylamino, (C1-C 22 Alkyl)2-amino, (CH2) q -(C1-C 22 Alkoxy), C6-C 12 Ariel, C3-C 12 Heteroaryl, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, or C1-C 12 It is an alkoxy, R 21b However, in either case, hydrogen, deuterium, C1-C 22 Alkyl, C1-C 22 Alkylamino, (C1-C 22 Alkyl)2-amino, (CH2) q -(C1-C 22 Alkoxy), C6-C 12 Ariel, C3-C 12 Cycloalkyl, C3-C 12 Heteroaryl, C3-C 12 Heterocyclyl, or C1-C 12 It is an alkoxy, R 22 However, in either case, hydrogen, deuterium, C1-C 22 Alkyl, C1-C 22 Alkylamino, (C1-C 22 Alkyl)2-amino, (CH2) q -(C1-C 22 Alkoxy), C6-C 12 Ariel, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C3-C 12 Heteroaryl, or C1-C12 It is an alkoxy, R 21a , R 21b , and R 22 Each of them can optionally choose one or more of the same or different R 10 It can be replaced with, R 40 However, in either case, hydrogen and C1-C6 alkyl are independently selected, and R is optionally selected. 10 Replaced by one or more times, R 21a , R 21b , R 22 , and R 40 Any two or more of these together form a ring, for example, a C3-C8 cycloalkyl ring, a C6-C 12 It may form an aryl ring, a C3-C8 heteroaryl ring, or a C2-C8 heterocyclyl ring. R 2a and R 3a Each of these independently consists of hydrogen, C1-C6 alkyl, (C=O)C1-C6 alkyl, and (C=O)NR. 40 Selected from C1-C6 alkyl, (C=O)N(C1-C6 alkyl)2, and (C=O)OC1-C6 alkyl, the alkyl group is optionally and independently one or more of the same or different R 10 Replaced with R 2a and R 3a However, together they can form a 5-7 membered heterocyclic ring. R 10However, in each case, independently, the elements are deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocarbocykrill, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocycrylthio, heterocarbocycrylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl, R 10 However, you can choose to select one or more of the same or different R 11 Replaced by, R 11 However, it is deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocarbocykrill, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocykritolthio, heterocarbocykritolthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl. Lipids, independently, C 11 -C 22 Alkyl, C 11 -C 22Alkoxy, or C6-C 18 It is an aryl substituted with an alkyl group.

[0130] In a particular embodiment, Q 3 If A represents a phenyl ring, 1a and A 1b Neither of them is O.

[0131] In some embodiments, R 2a and R 3a Each of these is a (C=O)C1-C6 alkyl or (C=O)OC1-C6 alkyl, and the alkyl group can be optionally and independently one or more of the same or different R 10 It is replaced by R. In some embodiments, 2a and R 3a Together, they form C(=O), C(=S), or C(CH3)2.

[0132] In some embodiments, R 2a and R 3a Each of these is a (C=O)C1-C3 alkyl or (C=O)OC1-C3 alkyl, and the alkyl group can be optionally and independently one or more of the same or different R 10 Replaced with, or R 2a and R 3a These combine to form C(=O), C(=S), or C(CH3)2.

[0133] In a particular embodiment, R 10 The compound is F, Cl, OC1-C3 alkyl, CF3, OCF3, or phenyl, and the phenyl is optionally substituted one or more times with F, Cl, OC1-C3 alkyl, CF3, or OCF3.

[0134] In a particular embodiment, R 21a , R 21b , and R 22 Each of them independently consists of hydrogen, deuterium, and C1-C 12 Alkyl, C1-C 12 Alkylamino, (C1-C12 Alkyl)2-amino, (CH2) q -(C1-C 12 Alkoxy), C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, and C1-C 12 It is selected from alkoxys, and q is an integer selected from 1, 2, and 3.

[0135] In some embodiments, R 1 teeth, [ka] That is the case.

[0136] In a particular embodiment, Q 1 Q is null. In some embodiments, Q 1 is null, R 22 H is H. In some embodiments, Q 1 is null, R 22 H is R 21a and R 21b Each of them is a C1-C6 alkyl, and R is optionally selected. 10 It is replaced by Q. In some embodiments, Q 1 is null, R 21b H is R 21a and R 22 Each of them is a C1-C6 alkyl, and R is optionally selected. 10 It is replaced by Q. In some embodiments, Q 1 is null, R 22 H is R 21a and R 21b Each of them is methyl. In some embodiments, Q 1 is null, R 22 It is a C1-C6 alkyl group, and R is optionally selected. 10 Replaced by R 21a and R 21b Each of them is H.

[0137] In some embodiments, Q1 is O or NH. In some embodiments, Q 1 is O or NH, and Q 2 C(=O), O(C=O), NR 40 (C=O), or NR 40 (C=S). In some embodiments, Q 1 is O or NH, and Q 2 C(=O), O(C=O), NR 40 (C=O), or NR 40 (C=S) and R 22 , R 21a , and R 21b Independently, H and C1-C6 alkyl are selected, and optionally, R 10 It is replaced by. In some embodiments,

[0138] In some embodiments, Q 1 C(=O), O(C=O), NR 40 (C=O), C(=S), O(C=S), NR 40 (C=S), O(C=O)O, S(C=O)O, NR 40 (C=O)O, or NR 40 In some embodiments, Q 1 C(=O), O(C=O), NR 40 (C=O), C(=S), O(C=S), NR 40 (C=S), O(C=O)O, S(C=O)O, NR 40 (C=O)O, or NR 40 Q 2 C(=O), O(C=O), NR 40 (C=O), or NR 40 (C=S). In some embodiments, Q 1 C(=O), O(C=O), NR 40 (C=O), C(=S), O(C=S), NR 40 (C=S), O(C=O)O, S(C=O)O, NR 40 (C=O)O, or NR 40 Q 2 C(=O), O(C=O), NR 40(C=O), or NR 40 (C=S) and R 22 , R 21a , and R 21b Independently, H and C1-C6 alkyl are selected, and optionally, R 10 It has been replaced by.

[0139] In some embodiments, R 1 teeth, [ka] It could be, In the formula, n is 1, R 23 However, hydrogen, C1-C 12 Alkyl, C1-C 12 Alkylamino, (C1-C 12 Alkyl)2-amino, (CH2) q -(C1-C 12 Alkoxy), C3-C 12 Cycloalkyl, C6-C 12 Ariel, C3-C 12 Heterocyclyl, and C1-C 12 It is an alkoxy, where q is an integer selected from 1, 2, and 3, and R 23 However, R 10 Substituted one or more times by R 23 , R 21a , R 21b , and R 40 Any two or more of these can form a ring, Z 1 However, N or CR 20a And, Z 2 However, N or CR 20b And, Z 3 However, N or CR 20c And, Z 4 However, N or CR 20d And, R 20a , R 20b , R 20c , and R 20dHowever, each is independent of hydrogen, deuterium, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, OC1-C6 alkyl, (C=O)C1-C6 alkyl, and (C=O)NR 40 Selected from C1-C6 alkyl, (C=O)N(C1-C6 alkyl)2, (C=O)OC1-C6 alkyl, and lipids, wherein the alkyl group is optionally and independently one or more R 10 It has been replaced with.

[0140] In exemplary embodiments of formula XXX, the compound is [ka] It has structures represented by expressions selected from, and combinations thereof.

[0141] In exemplary embodiments of formula XXX, the compound is of formula [ka] It has a structure represented by [this].

[0142] In exemplary embodiments of formula XXX, the compound is of formula [ka] It has a structure represented by [this].

[0143] In an exemplary embodiment of formula XXX, R 2a and R 3a Both are (C=O)OC1-C6 alkyl groups substituted with aryl or heteroaryl groups, preferably phenyl or pyridinyl groups. In some embodiments, the compound is of the formula [ka] It has a structure represented by [this].

[0144] In some embodiments, R 1 teeth, [ka] That is the case. In some embodiments, A 1a / A1 c NH is A 1b / A 1d Is it O, or A? 1a / A1 c O is A 1b / A 1d is NH or A 1a / A1 c CH2 is, A 1b / A 1d is O. In some embodiments, Y is O.

[0145] In a particular embodiment, Q 3 R is a saturated cycloalkyl ring, and R is optionally and independently selected. 10 It is replaced by one or more times. In some embodiments, Q 3 Q is a saturated cycloheptyl, cyclohexyl, or cyclopentyl ring. In some embodiments, Q 3 Q is a saturated cycloheptyl, cyclohexyl, or cyclopentyl ring, the ring being further unsubstituted. In some embodiments, Q 3 is a saturated cycloheptyl, cyclohexyl, or cyclopentyl ring, wherein the ring has at least one R 10 It is replaced by R. In such embodiments, 10 The element is preferably a C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, or halo, preferably fluoro or chloro.

[0146] In a particular embodiment, Q 3 R is a phenyl ring, and optionally, independently, 10 It is replaced by one or more times. In some embodiments, Q 3 is a phenyl ring, and the ring is not further substituted. In some embodiments, Q 3is a phenyl ring, and the ring has at least one R 10 It is replaced by R. In such embodiments, 10 The element is preferably a C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, or halo, preferably fluoro or chloro.

[0147] In a particular embodiment, Q 3 is a pyridinyl ring, and optionally, independently, R 10 It is replaced by one or more times. In some embodiments, Q 3 is a pyridinyl ring, and the ring is not further substituted. In some embodiments, Q 3 is a pyridinyl ring, and the ring has at least one R 10 It is replaced by R. In such embodiments, 10 The element is preferably a C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, or halo, preferably fluoro or chloro.

[0148] In an exemplary embodiment of formula XXX, R 1 teeth, [ka] It is a structure represented by an expression selected from the given set.

[0149] In an exemplary embodiment of formula XXX, R 1 is, formula [ka] It is a group having a structure represented by [this].

[0150] In an exemplary embodiment of formula XXX, R 1 teeth, [ka] It is a structure represented by an expression selected from, The compound contains at least 75 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the indicated stereoisomer, preferably Y is O.

[0151] In an exemplary embodiment of formula XXX, R 1 teeth, [ka] It is a structure represented by an expression selected from, The compound contains at least 75 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the indicated stereoisomer, preferably Y is O.

[0152] In an exemplary embodiment, R 1 teeth, [ka] That is the case.

[0153] In a particular embodiment, Z 1 , Z 2 , Z 3 , Z 4 is N or CH, and preferably Y is O.

[0154] In an exemplary embodiment of formula XXX, R 1 is, formula [ka] A group having a structure represented by, The compound is at least 75 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the indicated stereoisomer. In certain embodiments, Z 1 , Z 2 , Z 3 , Z 4 is N or CH, and Y is O.

[0155] In an exemplary embodiment, R 1 teeth, [ka] And, The compound is at least 75 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the indicated stereoisomer. In certain embodiments, Z 1 , Z 2 , Z 3 , Z 4 is N or CH, and Y is O.

[0156] In an exemplary embodiment of formula XXX, R 1 teeth, [ka] That is the case.

[0157] In a particular embodiment, Z 1 , Z 2 , Z 3 , and Z 4 One of them is N. In a particular embodiment, Z 1 , Z 2 , Z 3 , and Z 4 One of them is N, and the other three are CH. In some embodiments, Z 1 However, N is Z 2 , Z 3 , and Z 4 But is it CH? Z 2 However, N is Z 2 , Z 3 , and Z 4 But is it CH? Z 3 However, N is Z 1 , Z 2 , and Z 4 However, is it CH or Z 4 However, N is Z1 , Z 2 , and Z 3 However, it is CH.

[0158] In an exemplary embodiment of formula XXX, R 20a , R 20b , R 20c , and R 20d At least one of them is not hydrogen. In an exemplary embodiment of formula XXX, R 20a , R 20b , R 20c , and R 20d The elements are independently selected from hydrogen, deuterium, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, hydroxyl, amino, cyano, F, Cl, Br, and I.

[0159] In an exemplary embodiment of formula XXX, R 20a , R 20b , R 20c , and R 20d These are independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, and halogen.

[0160] In an exemplary embodiment of formula XXX, R 20a , R 20b , R 20c , and R 20d These are independently selected from hydrogen, CH3, OCH3, CF3, OCF3, and halogens.

[0161] In exemplary embodiments of formula XXX, the halogen is selected from Cl, F, and I.

[0162] In exemplary embodiments of formula XXX, the halogen is Cl or F.

[0163] In an exemplary embodiment of formula XXX, the halogen is Cl.

[0164] In an exemplary embodiment of formula XXX, R 20a , R20b , R 20c , and R 20d At least one of them is a halogen.

[0165] In an exemplary embodiment of formula XXX, R 20a , R 20b , R 20c , and R 20d One or two of them are halogens, and the other is hydrogen.

[0166] In an exemplary embodiment of formula XXX, R 20a , R 20b , R 20c , and R 20d One or two of them are methyl, and the other is hydrogen.

[0167] In an exemplary embodiment of formula XXX, R 20a , R 20b , R 20c , and R 20d Three of them are methyl atoms, and the other is hydrogen.

[0168] In an exemplary embodiment of formula XXX, R 20a , R 20b , R 20c , and R 20d One or two of them are methoxy, and the other is hydrogen.

[0169] In an exemplary embodiment of formula XXX, R 20e , R 20f , R 20g , R 20h , and R 20i One or two of them are Cl, and the other is hydrogen.

[0170] In an exemplary embodiment of formula XXX, R 20e , R 20f , R 20g , R 20h , and R 20i One or two of them are F, and the other is hydrogen.

[0171] In some embodiments, R 1 teeth, [ka] It can be.

[0172] In some embodiments, A 1a / A1 c NH is A 1b / A 1d Is it O, or A? 1a / A1 c O is A 1b / A 1d is NH or A 1a / A1 c CH2 is, A 1b / A 1d It is O.

[0173] In exemplary embodiments of formula XXX, the compound is [ka] [ka] It has a structure represented by an expression selected from.

[0174] In exemplary embodiments of formula XXX, the compound is [ka] The compound has a structure represented by a formula selected from the above, and the compound is at least 75 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the stereoisomer shown at the phosphorus atom.

[0175] In an exemplary embodiment of formula XXX, R 1 but, [ka] And, In the formula, Z5 However, N and CR 20e Selected from, Z 6 However, N and CR 20f Selected from, Z 7 However, N and CR 20g Selected from, Z 8 However, N and CR 20h Selected from, Z 9 However, N and CR 20i Selected from, However, Z 5 , Z 6 , Z 7 , Z 8 , and Z 9 The condition is that three or fewer of them are N, R 20e , R 20f , R 20g , R 20h , R 20i , R 20o , sand R 20p However, each is independent of hydrogen, deuterium, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, OC1-C6 alkyl, (C=O)C1-C6 alkyl, and (C=O)NR 40 Selected from C1-C6 alkyl, (C=O)N(C1-C6 alkyl)2, (C=O)OC1-C6 alkyl, or lipids, wherein the alkyl group is optionally and independently one or more of the same or different R 10 Replaced by, R 20e , R 20f , R 20g , R 20h , and R 20i Two of these may combine to form a ring, for example, an optionally substituted 5- to 7-membered cycloalkyl or heterocyclyl ring. Z 10 However, N and CR 20j Selected from, Z 11 However, NR 20k and CR 20l R 20m Selected from, R 20j , R 20l , and R 20m However, each is independent of hydrogen, deuterium, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, OC1-C6 alkyl, (C=O)C1-C6 alkyl, and (C=O)NR 40 Selected from C1-C6 alkyl, (C=O)N(C1-C6 alkyl)2, (C=O)OC1-C6 alkyl, and lipids, wherein the alkyl is optionally and independently one or more of the same or different R 10 Replaced with R 20j , R 20k , R 20l , R 20m , R 20o , and R 20p Any two or more of these can come together to form a ring, R 20k However, it is hydrogen or a C1-C6 alkyl group, and optionally, independently, one or more of the same or different R 10 Replaced by, R 40 However, in either case, hydrogen and C1-C6 alkyl are independently selected, and R is optionally selected. 10 It has been replaced by one or more of these.

[0176] In an exemplary embodiment of formula XXX, R 20e , R 20f , R 20g , R 20h , and R 20i At least one of them is not hydrogen. In an exemplary embodiment of formula XXX, R 20e , R 20f , R 20g , R 20h , and R 20i The elements are independently selected from hydrogen, deuterium, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, hydroxyl, amino, cyano, F, Cl, Br, and I.

[0177] In an exemplary embodiment of formula XXX, R 20e , R 20f , R20g , R 20h , and R 20i These are independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, and halogen.

[0178] In an exemplary embodiment of formula XXX, R 20e , R 20f , R 20g , R 20h , and R 20i These are independently selected from hydrogen, CH3, OCH3, CF3, OCF3, and halogens.

[0179] In exemplary embodiments of formula XXX, the halogen is selected from Cl, F, and I.

[0180] In exemplary embodiments of formula XXX, the halogen is Cl or F.

[0181] In an exemplary embodiment of formula XXX, the halogen is Cl.

[0182] In an exemplary embodiment of formula XXX, R 20e , R 20f , R 20g , R 20h , and R 20i At least one of them is a halogen.

[0183] In an exemplary embodiment of formula XXX, R 20e , R 20f , R 20g , R 20h , and R 20i One or two of them are halogens, and the other is hydrogen.

[0184] In an exemplary embodiment of formula XXX, R 20e , R 20f , R 20g , R 20h , and R 20i One or two of them are methyl, and the other is hydrogen.

[0185] In an exemplary embodiment of formula XXX, R 20e , R 20f , R 20g , R 20h , and R 20i Three of them are methyl atoms, and the other is hydrogen.

[0186] In an exemplary embodiment of formula XXX, R 20e , R 20f , R 20g , R 20h , and R 20i One or two of them are methoxy, and the other is hydrogen.

[0187] In an exemplary embodiment of formula XXX, R 20e , R 20f , R 20g , R 20h , and R 20i One or two of them are Cl, and the other is hydrogen.

[0188] In an exemplary embodiment of formula XXX, R 20e , R 20f , R 20g , R 20h , and R 20i One or two of them are F, and the other is hydrogen.

[0189] In an exemplary embodiment of formula XXX, R 1 teeth, [ka] It is a structure represented by an expression selected from, In the formula, Z 5 However, N and CR 20e Selected from, Z 6 However, N and CR 20f Selected from, Z 7 However, N and CR 20g Selected from, Z 8 However, N and CR20h Selected from, Z 9 However, N and CR 20i Selected from, However, Z 5 , Z 6 , Z 7 , Z 8 , and Z 9 The condition is that three or fewer of them are N, R 20e , R 20f , R 20g , R 20h , and R 20i However, each is independent of hydrogen, deuterium, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, OC1-C6 alkyl, (C=O)C1-C6 alkyl, (C=O)NR 40 Selected from C1-C6 alkyl, (C=O)N(C1-C6 alkyl)2, (C=O)OC1-C6 alkyl, or lipids, R 20e , R 20f , R 20g , R 20h , and R 20i However, each can arbitrarily and independently select one or more identical or different Rs. 10 It can be replaced with, R 40 However, in either case, hydrogen and C1-C6 alkyl are independently selected, and R is optionally selected. 10 Replaced by one or more times, R 20e , R 20f , R 20g , R 20h , and R 20i Two of these may combine to form a ring, for example, an optionally substituted 5- to 7-membered cycloalkyl or heterocyclyl ring. Lipids, independently, C 11 -C 22 Alkyl, C 11 -C 22 Alkoxy, or C6-C 18 It is an aryl substituted with an alkyl group.

[0190] In a particular embodiment, Z 10 CH is, Z 11 is NH. In some embodiments, Z 10 is N, and Z 11 It is NH.

[0191] In exemplary embodiments of formula XXX, the compound is [ka] It has a structure represented by an expression selected from.

[0192] In exemplary embodiments of formula XXX, the compound is of formula [ka] It has a structure represented by [this].

[0193] In exemplary embodiments of formula XXX, the compound is of formula [ka] It has a structure represented by a.

[0194] In an exemplary embodiment of formula XXX, R 20e , R 20f , R 20g , R 20h , and R 20i At least one of them is not hydrogen. In an exemplary embodiment of formula XXX, R 20e , R 20f , R 20g , R 20h , and R 20i Each of these is independently selected from hydrogen, deuterium, hydroxyl, amino, cyano, halogen, and combinations thereof.

[0195] In an exemplary embodiment of formula XXX, R 20e , R 20f , R 20g , R 20h , and R 20iEach element is independently selected from hydrogen, halogens, and combinations thereof.

[0196] In a particular embodiment, R 20h and R 20i They come together to form a 6-membered ring. In a particular embodiment, R 20h and R 20i These combine to form a six-membered carbon-cyclic ring. In certain embodiments, R 20h and R 20i Together, they form a six-membered complex ring.

[0197] In a particular embodiment, R 20h and R 20g They come together to form a 6-membered ring. In a particular embodiment, R 20h and R 20g These combine to form a six-membered carbon-cyclic ring. In certain embodiments, R 20h and R 20g Together, they form a six-membered complex ring.

[0198] In exemplary embodiments of formula XXX, the halogen is selected from -Cl, -F, and -I.

[0199] In an exemplary embodiment of formula XXX, the halogen is -Cl.

[0200] In an exemplary embodiment of formula XXX, R 20e , R 20f , R 20g , R 20h , and R 20i At least one of them is a halogen.

[0201] In an exemplary embodiment of formula XXX, R 20e , R 20f , R 20g , R 20h , and R 20i One or two of them are halogens, and the other is hydrogen.

[0202] In an exemplary embodiment of formula XXX, R 20e , R 20f , R 20g , R 20h , and R 20i One or two of them are Cl, and the other is hydrogen.

[0203] In some embodiments, Q 4 teeth, [ka] And, In the formula, R h1 is CH3, OCH3, CF3, OCF3, I, Cl, or F, and R h2 is H, CH3, OCH3, CF3, OCF3, I, Cl, or F. In such embodiments, Q 2 This can be C(=O), C(=S), NH(C=O), or NH(C=S).

[0204] In exemplary embodiments of formula XXX, the compound is of formula [ka] [ka] A structure having these features, and a combination thereof, is selected.

[0205] In an exemplary embodiment of formula XXX, R 1 However, the formula [ka] It is a structure represented by, In the formula, Z 10 However, N and CR 20j Selected from, Z 11 However, NR 20k and CR 20l R 20m Selected from, R 20j , R 20l , and R20m However, each is independent of hydrogen, deuterium, hydroxyl, amino, cyano, halogen, -C1-C6 alkyl, (C=O)C1-C6 alkyl, and (C=O)NR 40 Selected from C1-C6 alkyl, (C=O)N(C1-C6 alkyl)2, (C=O)OC1-C6 alkyl, and lipids, R 20j , R 20l , and R 20m However, each can arbitrarily and independently select one or more identical or different Rs. 10 It can be replaced with, R 20k However, hydrogen, deuterium, C1-C6 alkyl, (C=O)C1-C6 alkyl, (C=O)NR 40 Selected from C1-C6 alkyl, (C=O)N(C1-C6 alkyl)2, and (C=O)OC1-C6 alkyl, R 40 However, in either case, hydrogen and C1-C6 alkyl are independently selected, and R is optionally selected. 10 It has been replaced by one or more of these.

[0206] In an exemplary embodiment of formula XXX, R 1 teeth, [ka] It is a structure represented by an expression selected from the given set.

[0207] In an exemplary embodiment of formula XXX, R 1 teeth, [ka] It is a structure represented by an expression selected from the given set.

[0208] In an exemplary embodiment of formula XXX, R 1 teeth, [ka] It is a structure represented by an expression selected from the given set.

[0209] In an exemplary embodiment of formula XXX, R 21a , R 21b , and R 23 Each of these is independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkylamino, (C1-C6 alkyl)2amino, and C1-C6 alkoxy.

[0210] In a particular embodiment, R 21a , R 21b , and R 23 Each of them is independently hydrogen, deuterium, C1-C8 alkyl, C1-C8 alkylamino, (C1-C8 alkyl)2amino, and C1-C8 alkoxy, R 21a , R 21b , and R 23 R is, arbitrarily and independently 10 It has been replaced by.

[0211] In some embodiments, R 21a and R 21b These elements combine to form a C3-C7 cycloalkyl or C1-C7 heterocyclyl ring.

[0212] In some embodiments, R 21a and R 23 They come together to form a ring, for example, a lactone, R 1 teeth, [ka] That is the case.

[0213] In some embodiments, R 21a and R 23 Together, they define butyrolactone, valerolactone, or caprolactone, and optionally, R 10 It has been replaced by one or more of these.

[0214] In some embodiments, R 21a and R 22They come together to form a ring, for example, a cyclic ether, R 1 The following applies: [ka]

[0215] In some embodiments, R 22 and R 23 Together, they define oxirane (3-membered ring), oxetane (4-membered ring), oxolane (5-membered ring), oxane (6-membered ring), and oxepan (7-membered ring), and arbitrarily select R 10 It is replaced by one or more times. In certain embodiments, Q 1 NH is R 21a and R 22 They can combine to form heterocyclines, such as aziridine, azetidine, pyrrolidine, piperidine, or azepane, as described above, and optionally, R 10 It has been replaced by one or more of these.

[0216] In an exemplary embodiment of formula XXX, R 21a , R 21b , and R 23 Each of these is independently selected from hydrogen, deuterium, C1-C3 alkyl, C1-C3 alkylamino, (C1-C3 alkyl)2amino, and C1-C3 alkoxy.

[0217] In an exemplary embodiment of formula XXX, R 22 is hydrogen and C1-C 20 Selected from alkyl groups. For example, R 22 C 12 -C 22 It can be alkyl.

[0218] In an exemplary embodiment of formula XXX, R 22 is hydrogen and C1-C 18 Selected from alkyl groups, or R 22 is hydrogen and C1-C 16 Selected from alkyl groups, or R 22is selected from hydrogen and C1-C 14 alkyl, or R 22 is selected from hydrogen and C1-C 12 alkyl, or R 22 is selected from hydrogen and C1-C 10 alkyl, or R 22 is selected from hydrogen and C1-C8 alkyl, or R 22 is selected from hydrogen and C1-C6 alkyl.

[0219] In an exemplary embodiment of formula XXX, R 40 is selected from hydrogen and C1-C3 alkyl.

[0220] In an exemplary embodiment of formula XXX, R 40 is selected from hydrogen, methyl, and ethyl.

[0221] In an exemplary embodiment of formula XXX, R 40 is selected from hydrogen and methyl.

[0222] In an exemplary embodiment of formula XXX, R 40 is hydrogen. In an exemplary embodiment of formula XXX, R 40 is methyl.

[0223] In certain embodiments, the disclosure provides a compound of formula XXXa, wherein

Chemical formula

[0224] In certain embodiments, the present disclosure relates to a compound of formula XXXb, [ka] In the formula, R 22 It is a C1-C6 alkyl group, and R 2a and R 3a As defined above, x and z are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, relating to the compound. In certain embodiments, R 22 The compound is methyl, ethyl, or isopropyl, and is preferably isopropyl.

[0225] In certain embodiments, the present disclosure relates to a compound of formula XXXc, [ka] In the formula, R 2a and R 3a Each of these independently consists of hydrogen, C1-C6 alkyl, (C=O)C1-C6 alkyl, and (C=O)NR. 40 Selected from C1-C6 alkyl, (C=O)N(C1-C6 alkyl)2, (C=O)OC1-C6 alkyl, and lipids, R 2a and R 3a Each of the alkyl groups can be optionally and independently one or more of the same or different R 10 It can be replaced with, R 2a and R 3a However, it can be covalently bonded in an optional manner, and together with the intermediate atom, it contains an optionally substituted 5-7 member cycloheteralkyl group. R 22 However, hydrogen and C1-C 22 Alkyl groups, for example, C1-C3 alkyl, C1-C6 alkyl, C1-C 12 Alkyl, or C 12 -C 22 This relates to compounds selected from alkyl groups.

[0226] In certain embodiments, the present disclosure relates to a compound of formula XXXI, [ka] or with respect to a pharmaceutically acceptable salt thereof, In the formula, each of m and y is independently selected from 1, 2, 3, and 4. R 2a and R 3a Each of these independently consists of hydrogen, C1-C6 alkyl, (C=O)C1-C6 alkyl, and (C=O)NR. 40 Selected from C1-C6 alkyl, (C=O)N(C1-C6 alkyl)2, (C=O)OC1-C6 alkyl, and lipids, R 2a and R 3a Each of the alkyl groups can be optionally and independently one or more of the same or different R 10 It can be replaced with, R 2a and R 3a However, it can be covalently bonded in an optional manner, and together with the intermediate atom, it contains an optionally substituted 5-7 member heterocycline. In an exemplary embodiment of formula XXXI, the compound is of formula XXXIa [ka] It has a structure represented by [this].

[0227] In an exemplary embodiment of formula XXXI, the compound is of formula XXXIb [ka] It has a structure represented by [this]. In an exemplary embodiment of formula XXXI, the compound is of formula XXXI. [ka] It has a structure represented by [this].

[0228] In certain embodiments, the present disclosure relates to a compound of formula XXXII, [ka] or with respect to a pharmaceutically acceptable salt thereof, In the formula, A 2 However, it is selected from CH2, O, S, NC1-C3 alkyl, and NH. R 2a and R 3a Each of these independently consists of hydrogen, C1-C6 alkyl, (C=O)C1-C6 alkyl, and (C=O)NR. 40 Selected from C1-C6 alkyl, (C=O)N(C1-C6 alkyl)2, (C=O)OC1-C6 alkyl, and lipids, R 40 However, in either case, hydrogen and C1-C6 alkyl are independently selected, and R is optionally selected. 10 Replaced by one or more times, R 2a and R 3a Each of the alkyl groups can be optionally and independently one or more of the same or different R 10 It can be replaced with, R 2a and R 3a However, it can be covalently bonded in an optional manner, and together with the intermediate atom, it contains an optionally substituted 5-7 member heterocycline. R 30 However, it is selected from hydrogen, deuterium, C1-C6 alkyl, and C1-C6 alkoxy.

[0229] In certain embodiments, the present disclosure relates to a compound of formula XXXIIa, [ka] In the formula, R 30 However, this relates to compounds selected from hydrogen, deuterium, and C1-C6 alkyl groups.

[0230] In certain embodiments, the present disclosure relates to a compound of formula XXXIIb, [ka] In the formula, R 30 However, this relates to compounds selected from hydrogen, deuterium, and C1-C6 alkyl groups.

[0231] In certain embodiments, the present disclosure relates to a compound of formula XXXIIc, [ka] In the formula, R 30 However, this relates to compounds selected from hydrogen, deuterium, and C1-C6 alkyl groups.

[0232] In certain embodiments, the present disclosure relates to a compound of formula XXXIId, [ka] or with respect to a pharmaceutically acceptable salt thereof, In the formula, R 30 However, it is selected from hydrogen, deuterium, and C1-C6 alkyl groups.

[0233] In exemplary embodiments of formulas XXXII to XXXIId, R 30 This is selected from hydrogen and C1-C6 alkyl groups.

[0234] In exemplary embodiments of formulas XXXII to XXXIId, R 30 This is selected from hydrogen, methyl, and ethyl.

[0235] In exemplary embodiments of formulas XXXII to XXXIId, R 30 It is selected from hydrogen and methyl.

[0236] In exemplary embodiments of formulas XXXII to XXXIId, R 30 It is hydrogen.

[0237] In exemplary embodiments of formulas XXXII to XXXIId, R 30 It is methyl.

[0238] In exemplary embodiments of Formulas XXXII to XXXIId, the compound has a structure selected from

Chemical formula

[0239] In certain embodiments, the present disclosure is a compound of Formula XXXIII,

Chemical formula

[0240] In certain embodiments, the present disclosure relates to a compound of formula XXXIV, [ka] In the formula, R 2a and R 3a Each of these independently consists of deuterium, hydrogen, C1-C6 alkyl, (C=O)C1-C6 alkyl, and (C=O)NR. 40 Selected from C1-C6 alkyl, (C=O)N(C1-C6 alkyl)2, (C=O)OC1-C6 alkyl, and lipids, R 2a and R 3a However, each can arbitrarily and independently select one or more identical or different Rs. 10 It can be replaced with, R 2a and R 3a However, it can be covalently bonded in an optional manner, and together with the intermediate atom, it contains an optionally substituted 5-7 member heterocycline. R 6 , R 6’ , R 6’’ , and R 6’’’ However, each is independent of hydrogen, deuterium, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, (C=O)C1-C6 alkyl, and (C=O)NR. 40 Selected from C1-C6 alkyl, (C=O)N(C1-C6 alkyl)2, (C=O)OC1-C6 alkyl, or lipids, R 6 , R 6’ , R 6’’ , and R 6’’’ However, each can arbitrarily and independently select one or more identical or different Rs. 10 It can be replaced with, however, R 6 , R 6’ , R 6’’ , and R 6’’’On the condition that at least one of them is not hydrogen, R 10 However, R is deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, (alkyl)2amino, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl. 10 However, arbitrarily and independently, one or more identical or different R 11 Replaced by, R 11 However, these are deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, (alkyl)2amino, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl. Lipids, independently, C 11 -C 22 Alkyl, C 11 -C 22 Alkoxy, or C6-C 18 Compounds that are aryl compounds substituted with alkyl groups, or relating to a pharmaceutically acceptable salt thereof.

[0241] In certain embodiments, the present disclosure relates to a compound of formula XXXIVa, [ka] The compound is composed of at least 75 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the stereoisomers shown at the phosphorus atom. In the formula, R 6 , R 6’ , R 6’’ , and R 6’’’ However, each is independent of hydrogen, deuterium, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, (C=O)C1-C6 alkyl, and (C=O)NR. 40Selected from C1-C6 alkyl, (C=O)N(C1-C6 alkyl)2, (C=O)OC1-C6 alkyl, or lipids, R 6 , R 6’ , R 6’’ , and R 6’’’ However, each can arbitrarily and independently select one or more identical or different Rs. 10 It can be replaced with, R 10 However, R is deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, (alkyl)2amino, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl. 10 However, arbitrarily and independently, one or more identical or different R 11 Replaced by, R 11 However, these are deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, (alkyl)2amino, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl. Lipids, independently, C 11 -C 22 Alkyl, C 11 -C 22 Alkoxy, or C6-C 18 Compounds that are aryl compounds substituted with alkyl groups, or relating to a pharmaceutically acceptable salt thereof.

[0242] In certain embodiments, the present disclosure relates to a compound of formula XXXIVa, [ka] The compound is composed of at least 75 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the stereoisomers shown at the phosphorus atom. In the formula, R 6 , R 6’ , R6’’ , and R 6’’’ However, each is independent of hydrogen, deuterium, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, (C=O)C1-C6 alkyl, and (C=O)NR. 40 Selected from C1-C6 alkyl, (C=O)N(C1-C6 alkyl)2, (C=O)OC1-C6 alkyl, or lipids, R 6 , R 6’ , R 6’’ , and R 6’’’ However, each can arbitrarily and independently select one or more identical or different Rs. 10 It can be replaced with, R 10 However, R is deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, (alkyl)2amino, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl. 10 However, arbitrarily and independently, one or more identical or different R 11 Replaced by, R 11 However, these are deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, (alkyl)2amino, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl. Lipids, independently, C 11 -C 22 Alkyl, C 11 -C 22 Alkoxy, or C6-C 18 Compounds that are aryl compounds substituted with alkyl groups, or relating to a pharmaceutically acceptable salt thereof.

[0243] In exemplary embodiments of formulas XXXIV to XXXIVb, R 6 , R 6’ , R 6’’ , and R 6’’’ One of them is not hydrogen.

[0244] In exemplary embodiments of formulas XXXIV to XXXIVb, R 6 , R 6’ , R 6’’ , and R 6’’’ Two of them are not hydrogen.

[0245] In exemplary embodiments of formulas XXXIV to XXXIVb, R 6 , R 6’ , R 6’’ , and R 6’’’ Three of them are not hydrogen.

[0246] In exemplary embodiments of formulas XXXIV to XXXIVb, R 6 It is not hydrogen.

[0247] In exemplary embodiments of formulas XXXIV to XXXIVb, R 6’ It is not hydrogen.

[0248] In exemplary embodiments of formulas XXXIV to XXXIVb, R 6’’ It is not hydrogen.

[0249] In exemplary embodiments of formulas XXXIV to XXXIVb, R 6’’’ It is not hydrogen.

[0250] In exemplary embodiments of formulas XXXIV to XXXIVb, R 6 , R 6’ , and R 6’’ Each of them is hydrogen.

[0251] In exemplary embodiments of formulas XXXIV to XXXIVb, R 6’ , R 6’’ , and R 6’’’ Each of them is hydrogen.

[0252] In exemplary embodiments of formulas XXXIV to XXXIVb, R 6 , R 6’ , and R 6’’’ Each of them is hydrogen.

[0253] In exemplary embodiments of formulas XXXIV to XXXIVb, R 6 , R 6’’ , and R 6’’’ Each of them is hydrogen.

[0254] In an exemplary embodiment of formula XXXIVa, R 6 , R 6’ , R 6’’ , and R 6’’’ Each of them is hydrogen.

[0255] In an exemplary embodiment of formula XXXIVb, R 6 , R 6’ , R 6’’ , and R 6’’’ Each of them is hydrogen.

[0256] In exemplary embodiments, the compounds of formulas XXXIV to XXXIVb are [ka] The combination is selected from the aforementioned options.

[0257] In exemplary embodiments, the compound is [ka] A selection will be made from these combinations.

[0258] In exemplary embodiments, the compound is [ka] A selection will be made from these combinations.

[0259] In exemplary embodiments, the compound is [ka] [ka] [ka] Selected from.

[0260] In exemplary embodiments, the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] It is selected from the pharmaceutically acceptable salts.

[0261] infectious disease The compounds and pharmaceutical formulations provided herein can be used to treat viral infectious diseases.

[0262] Disclosed herein are methods for treating or preventing a viral infection, comprising administering to a subject in need of treatment or prevention of a viral infection an effective amount of a compound of formula XXIX-XXXIVb, or a pharmaceutical composition comprising a compound of formula XXIX-XXXIVb and a pharmaceutically acceptable excipient.

[0263] Also disclosed herein are methods for treating or preventing a viral infection, comprising administering to a subject in need of treatment or prevention of a viral infection an effective amount of a compound of formula XXIX-XXXIVb, or a pharmaceutical composition comprising a compound of formula XXIX-XXXIVb and a pharmaceutically acceptable excipient.

[0264] The use of disclosed compounds, for example, one or more compounds of formulas XXIX to XXXIVb, or pharmaceutically acceptable salts thereof, in the manufacture of a drug for the treatment of viral infectious diseases is disclosed.

[0265] The use of the disclosed compounds, for example, one or more compounds of formulas XXIX-XXXIVb, or pharmaceutically acceptable salts thereof, in the manufacture of agents for the treatment of viral infectious diseases is also disclosed.

[0266] A method for treating or preventing a viral infection is disclosed, comprising administering to a subject in need of treatment or prevention of a viral infection an effective amount of a compound of formula XXIX-XXXIVb, or a pharmaceutical composition comprising a compound of formula XXIX-XXXIVb and a pharmaceutically acceptable excipient, wherein the subject is administered a loading dose of the pharmaceutical composition during a first treatment period, and a therapeutic dose of the pharmaceutical composition during a second treatment period following the first treatment period.

[0267] Also disclosed is a method for treating or preventing a viral infection, comprising administering to a subject in need of treatment or prevention of a viral infection an effective amount of a compound of formula XXIX-XXXIVb, or a pharmaceutical composition comprising a compound of formula XXIX-XXXIVb and a pharmaceutically acceptable excipient, wherein the subject is administered a loading dose of the pharmaceutical composition during a first treatment period, and a therapeutic dose of the pharmaceutical composition during a second treatment period following the first treatment period.

[0268] In exemplary embodiments, the first treatment period is 1 to 5 days after diagnosis of viral infection or presentation for prevention of viral infection, the first treatment period is 1 to 2 days after diagnosis of viral infection or presentation for prevention of viral infection, the first treatment period is 1 day after diagnosis of viral infection or presentation for prevention of viral infection, and other periods are as described above.

[0269] In exemplary embodiments, the first treatment period is 1, 2, 4, 8, 12, 18, or 24 hours before infection or exposure to the virus, and the second treatment period is a post-infection treatment period, including treatment 1 to 7 days after infection, for example, 1, 2, 3, 4, 5, 6, or 7 days after the initial viral infection. As disclosed elsewhere in this specification, post-infection medication may be daily, every other day, etc.

[0270] In exemplary embodiments, the loading dose is approximately 1.1 to 10 times the therapeutic dose, approximately 1.5 to 5 times the therapeutic dose, approximately 1.5 to 2.5 times the therapeutic dose, and other loading doses are as described above.

[0271] In exemplary embodiments, the loading dose is administered once, twice, three times, or four times daily, or alternatively, every other day, every two days, etc., with other administration intervals as intended above. In some embodiments, the loading dose is administered at least twice daily. In further embodiments, the loading dose is divided evenly among the number of times it is administered per day. As described above with respect to the daily dose, the administration of the loading dose may occur repeatedly over 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more days.

[0272] In exemplary embodiments, treatment is delayed or staggered after the initial diagnosis or presentation of a viral infection, i.e., treatment is initiated several days after the diagnosis or presentation of a viral infection, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days or more, and then continues for a preferred period thereafter, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days or more.

[0273] 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 viruses and DNA viruses are considered herein.

[0274] Examples of RNA viruses include aftviruses (e.g., foot-and-mouth disease viruses O, A, C, Asia1, SAT1, SAT2, and SAT3), cardioviruses (e.g., encephalomyelitis virus and Tyler's mouse encephalomyelitis virus), and enteroviruses (e.g., poliovirus 1, 2, and 3, human enteroviruses A-D, bovine enteroviruses 1 and 2, human coxsackieviruses A1-A22 and A24, human coxsackieviruses B1-B5, and human echoviruses 1-7, 9, 11-12, and 24). 27, 29-33, human enterovirus 68-71, porcine enterovirus 8-10 and monkey enterovirus 1-18), elbovirus (e.g., equine rhinitis virus), hepatovirus (e.g., human hepatitis A virus and monkey hepatitis A virus), cobb virus (e.g., bovine cobb virus and Aichi virus), parechovirus (e.g., human parechovirus 1 and human parechovirus 2), rhinovirus (e.g., rhinovirus A, rhinovirus B, rhinovirus C, HRV) 16 HRV 16 (VR-11757), HRV 14 (VR-284), or HRV 1AExamples include, but are not limited to, picornaviruses, including (VR-1559), human rhinovirus 1-100 and bovine rhinovirus 1-3), and Tessowvirus (e.g., porcine Tessowvirus).

[0275] Further examples of RNA viruses include norovirus (e.g., Norwalk virus), sapovirus (e.g., Sapporo virus), lagovirus (e.g., rabbit hemorrhagic disease virus and European brown hares syndrome), and caliciviruses, including vesiviruses (e.g., porcine varicella virus and feline calicivirus). Other RNA viruses include astroviruses, including mamastoru virus and abastrovirus. Togaviruses are also RNA viruses. Examples of togaviruses include alphaviruses (e.g., chikungunya virus, Sindbis virus, Semlik Forest virus, Western equine encephalitis virus, Eastern getavirus, Everglades virus, Venezuelan encephalitis virus, Ross River virus, Berma Forest virus, and Auravirus), and rubella virus.

[0276] Other examples of RNA viruses include coronaviruses, such as SARS-CoV (including, but not limited to, SARS-CoV-2 and its variants, as well as more virulent strains recently found in Brazil (known as P.1), the United Kingdom (known as 20I / 501Y.V1, VOC 202012 / 01, or B.1.1.7), and South Africa (known as 20H / 501Y.V2 or B.1.351), as well as further variants and lineages derived from them), human respiratory coronaviruses such as HCoV-229E, HCoV-NL63, and HCoV-OC43. Coronaviruses also include bat SARS-like CoV, Middle East Respiratory Syndrome Coronavirus (MERS), turkey coronavirus, chicken coronavirus, feline coronavirus, and canine coronavirus. Coronaviruses are enveloped, positive-sense RNA viruses that cause a fair number of respiratory illnesses in humans. The two previous coronaviruses to emerge and cause disease in humans were SARS and MERS. There have been over 8,000 human cases of SARS, resulting in 774 deaths. Since 2012, there have been over 2,500 cases of MERS, resulting in 919 deaths. In 2019, the novel coronavirus, SARS-CoV-2, was discovered in humans in Wuhan, China, and is currently causing a pandemic with significant loss of life. SARS-CoV-2 is a highly pathogenic human pathogen. SARS-CoV-2 causes a disease called COVID-19. COVID-19 can include severe respiratory illness in humans, endothelial disorders including stroke, and neurological disorders including dizziness, impaired consciousness, acute cerebrovascular disease, epilepsy, olfactory impairment, visual impairment, and neuralgia (medRxiv, 2020, 1-26). SARS-CoV-2 entry into the CNS may be facilitated through viral interaction with the ACE2 receptor after the virus spreads in the systemic circulation or across the cribriform plate.

[0277] Further RNA viruses include arteriviruses (e.g., equine arterivirus, porcine genital respiratory syndrome virus, mouse lactate dehygrogenase elevation virus, and monkey hemorrhagic fever virus). Other RNA viruses include lyssaviruses (e.g., rabies virus, Lagos bat virus, Mokola virus, Dubenhage virus, and European bat lyssavirus), becycloviruses (e.g., VSV-Indiana, VSV-New Jersey, VSV-Alagoas, Piri virus, Cocal virus, Maraba virus, Isfahan virus, and Chandipla virus), and rhabdoviruses, including ephemeral viruses (e.g., bovine epidemic fever virus, Adelaide River virus, and Belimer virus). Further examples of RNA viruses include filoviruses, which include Marburg and Ebola viruses (e.g., EBOV-Z, EBOV-S, EBOV-IC, and EBOV-R).

[0278] Paramyxoviruses are also RNA viruses. Examples of these viruses include rubraviruses (e.g., mumps, parainfluenza virus type 5, human parainfluenza virus type 2, Mapuella virus and butalbra virus), abrasive viruses (e.g., Newcastle disease virus), respoviruses (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, ruminant zoonotic virus, seal distemper virus and rinderpest virus), pneumoviruses (e.g., human respiratory syncytial virus (RSV) A2, B1 and S2, bovine respiratory syncytial virus and mouse pneumonia virus), and metapneumoviruses (e.g., human metapneumovirus and trimetaphenovirus). Additional paramyxoviruses include feldlance virus, tree shrew paramyxovirus, menangle virus, tioman virus, bayron virus, J virus, Mothman virus, Salem virus, and narib virus.

[0279] Additional RNA viruses include orthomyxoviruses. These viruses include influenza viruses and strains (e.g., influenza A, influenza A A / Victoria / 3 / 75 strain, influenza A A / Puerto Rico / 8 / 34 strain, influenza A H1N1 (including, but not limited to, A / WS / 33, A / NWS / 33 and A / California / 04 / 2009 strains), influenza B, influenza B Lee strain, 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), togotovirus and isavirus. Orthobuniyaviruses (e.g., Akabane virus, California encephalitis, Cash 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., Hantan, Dobrava, Soul, Pumara, Sin Nombre, Bayou, Black Creek Canal, Andes, and Sotapalayang) 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.

[0280] Additional RNA viruses include reovirus, rotavirus, birnavirus, krysovirus, cystvirus, hypovirus partitivirus, and totovirus. Orbiviruses such as African horse plague virus, blue tang virus, changuinora virus, chenuda virus, Chobar Gorge Corriparta virus, epidemic hemorrhagic fever virus, equine encephalitis virus, euvenanzi virus, yeri virus, great island virus, levombovirus, orungovirus, pariam virus, Peruvian horse plague virus, St. Croix River virus, horse tyravirus, wadmedani virus, warral virus, warrego virus, and wongor virus are also RNA viruses. Retroviruses include alpha-retroviruses (e.g., Rous sarcoma virus and avian leukemia virus), beta-retroviruses (e.g., mouse mammary cancer virus, Mason-Pfizer monkey virus and Jersey-Kte sheep retrovirus), gamma-retroviruses (e.g., mouse leukemia virus and feline leukemia virus), deltra-retroviruses (e.g., human T-cell leukemia virus (HTLV-1, HTLV-2), bovine leukemia virus, STLV-1 and STLV-2), and epsilon-retrivirus (e.g., Examples include walleye dermatosarcoma virus and walleye epidermal hyperplastic virus1), reticular endotheliosis 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, canine arthritis encephalitis virus, and Visna maedi virus), and spumaviruses (e.g., human foam virus and feline syncytial virus).

[0281] Viral-encoded RNA-dependent RNA polymerase (RdRp) forms replication complexes with other viral-encoded proteins as well as host cell proteins, catalyzing RNA template-directed RNA synthesis. This protein is involved in the synthesis of anti-genomic complementary RNA, progeny viral genomic RNA, and capped, non-polyadenylated viral mRNA. Ribonucleoside analogs selectively inhibit the primary pathway of genetic information flow in these viruses (RNA-to-RNA copying) by acting on viral-encoded RdRp either via their active 5'-triphosphate metabolites or by acting via viral-encoded RdRp. Ribonucleoside analogs (after phosphorylation to the corresponding 5'-triphosphate by host intracellular kinases) function as competitive alternative substrate inhibitors of RdRp, either halting nascent RNA synthesis after integration or being utilized as a substrate by RdRp, integrated into nascent RNA, and rendered nonfunctional by disrupting its secondary structure.

[0282] Examples of DNA viruses include polyomaviruses (e.g., simian virus 40), simian agent 12, BK virus, JC virus, Merkel cell polyomavirus, bovine polyomavirus, lymphocytotropic 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), beta-parvovirus, amdovirus, densovirus, iteravirus, brevidensovirus, pephdensovirus, herpesviruses 1, 2, 3, 4 Examples include types 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 cercopa herpesvirus type 1 (B virus)), poxviruses (e.g., smallpox, cowpox, monkeypox, vaccinia, uasin-gishu, camelpox, pseudocowpox, pigeonpox, horsepox, fowlpox, turkeypox, and swinepox), and hepadnaviruses (e.g., hepatitis B and hepatitis B-like viruses). Chimeric viruses containing more than one portion of the viral genome are also intended herein.

[0283] In certain embodiments, RNA viruses that can be treated with the compounds and compositions of this disclosure include enteroviruses. The genus Enterovirus (EV), belonging to the family Picornaviridae, comprises 13 species, seven of which 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 rhinoviruses RV-A, RV-B, and RV-C, which consist of more than 100 different RV numbers. EV RNA contains a single open reading frame (ORF) flanked by two untranslated regions (UTRs), the 5'UTR and the 3'UTR. ORF encodes a single polyprotein that is cleaved into P1, P2, and P3 proteins. The P1 protein is cleaved by proteolysis to produce capsid proteins VP1-4. P2 and P3 are cleaved to produce non-structural (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 cell receptors upon viral entry. NS proteins are essential for replication, translation, and disruption of host cell mechanisms. Due to their role in cell entry and decoating of genetic material, capsid proteins are desirable targets for antiviral drug development.

[0284] The diverse viruses of the EV genus are known to cause a variety of diseases, including hand, foot, and mouth disease (HFMD), encephalitis, aseptic meningitis, myocarditis, and various respiratory illnesses. While some EV infections are mild, symptoms can be severe in young and immunocompromised individuals. In recent years, viruses such as EV-A71 and CV-A16 have emerged as a serious public health threat, causing 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 capable of inhibiting multiple EVs across the entire genus would help overcome the public health burden caused by these EVs.

[0285] The compounds and compositions of this disclosure can be used to treat or prevent diseases caused by enteroviruses and to reduce enterovirus loads. In addition, the compounds and compositions of this disclosure can be combined with other drugs to treat enteroviruses 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.

[0286] In certain embodiments, the Disclosure relates to a method for treating or preventing a viral infection, comprising administering to a subject in need of such treatment or prevention a pharmaceutical composition comprising an effective amount of a compound of formulas XXIX-XXXIVb disclosed herein, or a compound of formulas XXIX-XXXIVb and a pharmaceutically acceptable excipient. In certain exemplary embodiments, a method is provided for treating or preventing a Zika virus infection, comprising administering to a subject in need of such treatment or prevention a pharmaceutical composition comprising an effective amount of a compound of formulas XXIX-XXXIVb disclosed herein, or a compound of formulas XXIX-XXXIVb and a pharmaceutically acceptable excipient.

[0287] In certain embodiments, the viral infection is or caused by an alphavirus, a flavivirus, or a coronavirus of the orthomyxoviridae or paramyxoviridae family, or RSV, influenza, Poissant virus, or filoviridae family, or Ebola.

[0288] In certain embodiments, the viral infection is or is caused by a virus selected from MERS coronavirus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Ross River virus, Berma Forest virus, Poissant virus, Zika virus, and Chikungunya virus. In certain exemplary embodiments, the viral infection is or is caused by the Zika virus.

[0289] In certain embodiments, the compound is administered by inhalation through the lungs.

[0290] In some embodiments, the subjects include influenza A virus, influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, human coronavirus, SARS coronavirus (recently known as Brazil (P.1), the United Kingdom (20I / 501Y.V1, VOC 202012 / 01, or B.1.1.7), and South Africa (20H / 501Y.V2 or B.1).This includes, but is not limited to, more virulent strains of SARS-CoV-2 and its variants (including, but not limited to, the more virulent strains found in SARS-CoV-2 (known as 351), as well as further variants and lineages derived therefrom), MERS coronavirus, human adenovirus (HAdV-1~55) types, 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), dengue virus, Zika virus, chikungunya, eastern equine encephalitis virus (EEEV), western equine encephalitis virus (WEEV), Venezuelan equine encephalitis virus (VEEV), Ross River virus, and Berma Forest virus. You are at risk of, have symptoms of, or have been diagnosed with any of the following: 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), herpestropous virus, roseolovirus, or Kaposi's sarcoma-associated herpesvirus, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, or human immunodeficiency virus (HIV), human T-lymphotropic virus type 1 (HTLV-1), friend splenic fociform virus (SFFV), or heterotropic mouse leukemia virus-associated virus (XMRV). In some embodiments, the subjects are at risk of Zika virus infection, exhibiting symptoms of it, or have been diagnosed with it.

[0291] In certain embodiments, the subjects include influenza A virus, influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, SARS coronavirus (recently known as Brazil (P.1), UK (20I / 501Y.V1, VOC)), and subtypes H1N1, H3N2, H7N9, H5N1 (low pathogenic), and H5N1 (high pathogenic). This includes, but is not limited to, the more virulent strains found in SARS-CoV-2 and its variants (including, but not limited to, SARS-CoV-2 and its variants, such as 202012 / 01 (known as B.1.1.7) and South Africa (known as 20H / 501Y.V2 or B.1.351), as well as further variants and lineages derived therefrom), MERS-CoV, human adenovirus (HAdV-1~55) types, 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 types 1 and 3, and cattle. Epidemic viruses, Chikungunya, Eastern Equine Encephalitis Virus (EEEV), Venezuelan Equine Encephalitis Virus (WEEV), Western Equine Encephalitis Virus (VEEV), California Encephalitis Virus, Japanese Encephalitis Virus, Rift Valley Fever Virus (RVFV), Hantavirus, Dengue Virus Serotypes 1, 2, 3, and 4, Zika Virus, West Nile Virus, Takaribe Virus, Junin, Rabies Virus, Ebola Virus, Marburg Virus, The patient has been diagnosed with adenovirus, herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), lymphotropic herpesvirus, roseolovirus, or Kaposi's sarcoma-associated herpesvirus, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, or human immunodeficiency virus (HIV).In a particular embodiment, the subject is diagnosed with a Zika virus infection.

[0292] In certain embodiments, the subject is diagnosed with gastroenteritis, acute respiratory disease, severe acute respiratory syndrome, post-viral fatigue syndrome, viral hemorrhagic fever, acquired immunodeficiency syndrome, or hepatitis.

[0293] In exemplary embodiments, the present disclosure relates to treating or preventing infections caused by viruses, bacteria, fungi, protozoa, and parasites, and includes, for example, administering to a subject in need of treatment or prevention of an infection caused by viruses, bacteria, fungi, protozoa, and parasites an effective amount of a compound of formula XXIX-XXXIVb, or a compound of formula XXIX-XXXIVb and a pharmaceutically acceptable excipient.

[0294] In some embodiments, the disclosure relates to a method for treating a viral infection, which includes administering the compounds of this specification to a subject who has been diagnosed with, is suspected of having, or is exhibiting symptoms of a viral infection.

[0295] Viruses are typically infectious agents that can replicate inside the living cells of an organism. Viral particles (virions) usually consist of nucleic acids, a protein coat, and, in some cases, a lipid envelope surrounding the protein coat. Virus shapes range from simple helical and icosahedral forms to more complex structures. Protein subunits encoded by a virus self-assemble to form a capsid, generally requiring the presence of a viral genome. More complex viruses may encode proteins that assist in the construction of their capsids. Proteins associated with nucleic acids are known as nucleoproteins, and the association of viral capsid proteins with viral nucleic acids is called a nucleocapsid.

[0296] Viruses are transmitted in various ways, including direct contact or contact with bodily fluids, such as blood, tears, semen, pre-semen, saliva, milk, vaginal secretions, lesions, droplet contact, fecal-oral contact, or as a result of animal bites or childbirth. Viruses have genes in either DNA or RNA, and are called DNA viruses 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, the strands are said to be either positive-sense (called the + strand) or negative-sense (called the - strand) depending on whether they are complementary to the viral messenger RNA (mRNA). Positive-sense viral RNA is identical to viral mRNA and can therefore be immediately 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. DNA nomenclature is similar to RNA nomenclature in that the coding strand of viral mRNA is complementary to it (negative), and the non-coding strand is a (positive) copy of it.

[0297] Antigen shifts or reassortments can give rise to new strains. Viruses undergo genetic changes through several mechanisms. These include a process called genetic drift, in which individual bases in DNA or RNA mutate to other bases. Antigen shifts occur when there are significant changes in the viral genome. This can be a result of recombination or reassortment. RNA viruses often exist as pseudospecies or clusters of the same virus, but with slightly different genomic nucleoside sequences.

[0298] The genetic material within viruses and the methods by which this material is replicated vary among different viral species. In most DNA viruses, genome replication occurs in the cell nucleus. If the cell surface has appropriate receptors, 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 mechanisms, as well as the RNA processing mechanisms. Replication usually occurs in the cytoplasm. RNA viruses typically use their own RNA replicase enzymes to make copies of their genome.

[0299] The Baltimore classification of viruses is based on the mechanism of mRNA production. Viruses must produce mRNA from their genome in order to produce proteins and replicate themselves, but different mechanisms are used to achieve this. The viral genome may be single-stranded (ss) or double-stranded (ds), may be RNA or DNA, and may or may not use reverse transcriptase (RT). In addition, ssRNA viruses may be either sense (+) or antisense (-). This classification divides 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, having a DNA intermediate in their life cycle (e.g., retroviruses); and VII. dsDNA-RT viruses (e.g., hepadnaviruses).

[0300] Human immunodeficiency virus (HIV) is a lentivirus (a member of the retroviridae family) that causes acquired immunodeficiency syndrome (AIDS). Lentiviruses are transmitted as single-stranded positive-sense enveloped RNA viruses. Upon reaching target cells, the viral RNA genome is converted to double-stranded DNA by the virus-encoded reverse transcriptase. This viral DNA is then integrated into the cell's DNA by the virus-encoded integrase, along with host cell cofactors. There are two types of HIV. HIV-1 is sometimes called LAV or HTLV-III.

[0301] HIV primarily infects key cells within 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 gradually becomes more susceptible to infections by other viruses or bacteria. Individuals with HIV typically develop malignant lesions associated with progressive failure of the immune system.

[0302] The viral envelope consists of two layers of phospholipids that newly formed viral particles acquire from the human cell membrane when they bud from the cell. The viral envelope is embedded with host cell-derived proteins and HIV proteins 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 sometimes a tenth gene, tev, which is a fusion of tat, env, and rev), encoding 19 proteins. Three of these genes, gag, pol, and env, contain the information necessary to construct the structural proteins of a new viral particle. HIV-1 diagnosis is typically performed by antibody-based ELISA, Western blotting, or immunoaffinity assays, or by nucleic acid testing (e.g., viral RNA or DNA amplification).

[0303] HIV is typically treated with antiviral agents, such as a combination of two nucleoside analog reverse transcription inhibitors and one non-nucleoside analog reverse transcription inhibitor or protease inhibitor. A combination of three drugs is commonly known as a triple cocktail. In certain embodiments, this disclosure relates to treating a subject diagnosed with HIV by administering a pharmaceutical composition disclosed herein in combination with two nucleoside analog reverse transcription inhibitors and one non-nucleoside analog reverse transcription inhibitor or protease inhibitor.

[0304] In certain embodiments, this disclosure relates to treating a subject by administering the compounds disclosed herein, emtricitabine, tenofovir, and efavirenz. In certain embodiments, this disclosure relates to treating a subject by administering the compounds disclosed herein, emtricitabine, tenofovir, and raltegravir. In certain embodiments, this disclosure relates to treating a subject by administering the compounds disclosed herein, emtricitabine, tenofovir, ritonavir, and darunavir. In certain embodiments, this disclosure relates to treating a subject by administering the compounds disclosed herein, emtricitabine, tenofovir, ritonavir, and atazanavir.

[0305] Banana lectin (BanLec or BanLec-1) is one of the main proteins in the pulp of ripe bananas and has binding specificity to mannose and mannose-containing oligosaccharides. BanLec binds to the HIV-1 envelope protein gp120. In certain embodiments, this disclosure relates to treating viral infections such as HIV by administering the compounds disclosed herein in combination with banana lectin.

[0306] Therapeutic agents can, in some cases, suppress the virus for extended periods. A typical drug therapy is a combination of interferon alfa and ribavirin. The subject may receive injections of PEGylated interferon alfa. Genotypes 1 and 4 are less responsive to interferon-based treatment than the other genotypes (2, 3, 5, and 6). In certain embodiments, this disclosure relates to treating a subject having HCV by administering the compounds disclosed herein to a subject exhibiting or diagnosed with HCV. In certain embodiments, the compounds are administered in combination with interferon alfa 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.

[0307] In certain embodiments, the subject is diagnosed with a virus by nucleic acid detection or viral antigen detection. Cytomegalovirus (CMV) belongs to the betaherpesvirinae subfamily of the Herpesviridae family. In humans, it is commonly known as HCMV or human herpesvirus 5 (HHV-5). Herpesviruses typically share the characteristic of remaining dormant in the body for a long period of time. HCMV infection can be life-threatening for immunocompromised patients. In certain embodiments, this disclosure relates to a method for treating a subject diagnosed with cytomegalovirus or a method for preventing 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 immunosuppressant drugs, and / or diagnosed with HIV infection. In certain embodiments, the subject may be diagnosed with cytomegalovirus hepatitis causing fulminant hepatitis, cytomegalovirus retinitis (inflammation of the retina may be detected by ophthalmoscopic examination), cytomegalovirus colitis (inflammation of the large intestine), cytomegalovirus pneumonia, cytomegalovirus esophagitis, cytomegalovirus mononucleosis, polyradiculopathy, transverse myelitis, and subacute encephalitis. 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 periodic serological monitoring.

[0308] HCMV infection in pregnant subjects can cause birth defects. Congenital HCMV infection occurs when the mother suffers a primary infection (or reactivation) during pregnancy. In certain embodiments, this disclosure relates to a method for treating a pregnant subject diagnosed with cytomegalovirus by administering a compound disclosed herein, or a method for preventing cytomegalovirus infection in subjects at risk of pregnancy, planning to become pregnant, or currently pregnant.

[0309] Subjects infected with CMV typically express antibodies against the virus. Several laboratory tests have been developed to detect these antibodies against CMV. The virus can be cultured from specimens obtained from urine, pharyngeal swabs, bronchial lavage, and tissue samples to detect active infection. PCR may be used to monitor the viral load in CMV-infected subjects. The CMV pp65 antigenemia test is an immunoaffinity-based assay for identifying the cytomegalovirus pp65 protein in peripheral blood leukocytes. CMV should be suspected when a patient has symptoms of infectious mononucleosis but tests for mononucleosis and Epstein-Barr virus are negative, or when they show signs of hepatitis but tests for hepatitis A, B, and C are negative. Culture of hepatitis A virus can be performed whenever the subject is symptomatic. Laboratory testing for antibodies against CMV can be performed to determine whether a subject already has a CMV infection.

[0310] Enzyme-linked immunosorbent assay (ELISA) is the most commonly available serological test for measuring antibodies against CMV. The results can be used to determine whether acute infection, previous infection, or passively acquired maternal antibodies are present in infants. Other tests include various fluorescence assays, indirect hemagglutination (PCR), and latex agglutination. ELISA techniques for CMV-specific IgM are available.

[0311] Hepatitis B virus is a hepadnavirus. The viral particle (virion) consists of an outer lipid envelope and an icosahedral nucleocapsid core composed of proteins. The HBV genome is made of circular DNA, but the DNA is not perfectly double-stranded. One end of the strand is bound to the viral DNA polymerase. The virus replicates through the form of RNA intermediates via reverse transcription. Replication typically occurs in the liver, where inflammation (hepatitis) occurs. The virus spreads into the bloodstream, and virus-specific proteins and their corresponding antibodies are found in infected individuals. Blood tests for these proteins and antibodies are used to diagnose infection.

[0312] Hepatitis B virus enters cells via endocytosis. Since the virus replicates via RNA produced by host enzymes, the viral genomic DNA must be transferred to the cell nucleus by a host chaperone. The partially double-stranded viral DNA is then transformed into fully double-stranded, covalently bound closed circular DNA (cccDNA) that serves as a template for viral mRNA transcription. Based on the antigenic epitopes present on its envelope protein, the virus is divided into four main serotypes (adr, adw, ayr, ayw) and into eight genotypes (A-H) based on variations in the overall nucleotide sequence of the genome.

[0313] The surface antigen of hepatitis B (HBcAg) is typically used to screen for the presence of this infection. It is the first detectable viral antigen to appear during infection. However, this antigen may be absent in the early stages of infection, or it may be undetectable later in the infection if it is cleared by the host. Infectious virions contain an internal "core particle" that encapsulates the viral genome. The icosahedral core particle is made up of core proteins and is also known as the hepatitis B core antigen or HBcAg. IgM antibodies against the hepatitis B core antigen (anti-HBc IgM) can be used as a serological marker. The hepatitis B e antigen (HBeAg) may also appear. The presence of HBeAg in the host serum is associated with a high rate of viral replication. Certain variants of the hepatitis B virus do not produce the "e" antigen.

[0314] When a host can clear the infection, typically HBsAg becomes undetectable, and IgG antibodies against hepatitis B surface and core antigens (anti-HBs and anti-HBc IgG) develop. The time between HBsAg clearance and the appearance of anti-HBs is called the gap period. Individuals who are negative for HBsAg and positive for anti-HBs are either cleared of the infection or have been previously vaccinated. Individuals who remain HBsAg positive for at least six months are considered hepatitis B carriers. Viral carriers may have chronic hepatitis B, which would be reflected by elevated serum alanine aminotransferase levels and liver inflammation that may be identified by biopsy. Nucleic acid (PCR) testing has been developed to detect and measure the amount of HBV DNA in clinical specimens.

[0315] Acute infection with the hepatitis B virus is associated with acute viral hepatitis. Acute viral hepatitis typically begins with symptoms of general malaise, loss of appetite, nausea, vomiting, body aches, low-grade fever, and dark urine, and then progresses to the development of jaundice. Chronic infection with the hepatitis B virus can be either asymptomatic or associated with chronic inflammation of the liver (chronic hepatitis), which may lead to cirrhosis. Having a chronic hepatitis B infection increases the incidence of hepatocellular carcinoma (liver cancer).

[0316] During HBV infection, the host immune response triggers both liver cell damage and viral clearance. Adaptive immune responses, particularly virus-specific cytotoxic T lymphocytes (CTLs), contribute significantly to many cases of liver damage associated with HBV infection. CTLs eliminate the virus by killing infected cells and producing antiviral cytokines capable of clearing HBV from viable liver cells. While liver damage is initiated and mediated by CTLs, antigen-nonspecific inflammatory cells can exacerbate CTL-induced immunopathology, and activated platelets at the site of infection can promote CTL accumulation in the liver.

[0317] The therapeutic agent can stop the virus from replicating and thus minimize liver damage. In certain embodiments, this disclosure relates to a method for treating a subject diagnosed with HBV by administering a compound disclosed herein. In certain embodiments, the subject is immunocompromised. In certain embodiments, the compound is administered in combination with another antiviral agent such as lamivudine, adefovir, tenofovir, terbivudine, and entecavir, as well as / or an immune system modifier such as interferon alpha-2a and PEGylated interferon alpha-2a (Pegasys). In certain embodiments, this disclosure relates to preventing HBV infection in an immunocompromised subject at risk of infection by administering a pharmaceutical composition disclosed herein and one or more antiviral agents optionally. In certain embodiments, the subject is at risk of infection because the subject's sexual partner has been diagnosed with HBV.

[0318] In certain embodiments, the pharmaceutical compositions disclosed herein include ABT-450, ABT-267, ABT-333, ABT-493, ABT-530, abacavir, acyclovir, adefovir, amantadine, amprenavir, amprigen, arbidol, atazanavir, atripra, boceprevir, cidofovir, combivir, daclatasvir, darunavir, dasabuvir, delavirdin, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, phosphonet, ganciclovir, ivacitabine, immunovir, doxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I It is administered in combination with a second antiviral agent such as lamivudine, ledipasvir, lopinavir, rovirid, maraviroc, moloxidine, methisazone, nelfinavir, nevirapine, nexavir, ombitasvir, oseltamivir, paritaprevir, pegylated interferon alfa-2a, penciclovir, peramivir, preconalil, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, simeprevir, sofosbuvir, stabudine, telaprevir, terbivudine, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valacyclovir, valganciclovir, bicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, or zidovudine, or combinations thereof.

[0319] In certain embodiments, the pharmaceutical compositions disclosed herein can be co-formulated and administered in combination with a second antiviral agent selected from the following: [ka]

[0320] In a particular embodiment, [ka] This can be co-formulated and administered in combination with a second antiviral agent selected from the following: [ka]

[0321] In a particular embodiment, [ka] This can be co-formulated and administered in combination with a second antiviral agent selected from the following: [ka]

[0322] In certain embodiments, the pharmaceutical compositions disclosed herein can be co-formulated and administered in combination with a second antiviral agent selected from WO2016 / 106050 or WO2017 / 156380.

[0323] In a particular embodiment, [ka] This can be co-formulated and administered in combination with a second antiviral agent selected from WO2016 / 106050 or WO2017 / 156380.

[0324] In a particular embodiment, [ka] This can be co-formulated and administered in combination with a second antiviral agent selected from WO2016 / 106050 or WO2017 / 156380.

[0325] In an exemplary embodiment, [ka] teeth, [ka] It can be combined with this.

[0326] In an exemplary embodiment, [ka] teeth, [ka] It can be combined with this.

[0327] In an exemplary embodiment, [ka] teeth, [ka] It can be combined with this.

[0328] In an exemplary embodiment, [ka] teeth, [ka] It can be combined with this.

[0329] In an exemplary embodiment, [ka] teeth, [ka] It can be combined with this.

[0330] In an exemplary embodiment, [ka] teeth, [ka] It can be combined with this.

[0331] In an exemplary embodiment, [ka] teeth, [ka] It can be combined with this.

[0332] In an exemplary embodiment, [ka] teeth, [ka] It can be combined with this.

[0333] In an exemplary embodiment, [ka] The pharmacological or physiological salt, [ka] These pharmaceutical or physiological salts can be found in combination in virus-infected and uninfected host cells, tissues, and / or organs.

[0334] In an exemplary embodiment, [ka] The pharmaceutical or physiological salt is released into the host's plasma or whole blood. [ka] It may be found in combination with its pharmacological or physiological salt.

[0335] In an exemplary embodiment, [ka] The pharmaceutical or physiological salt is released into the host's plasma or whole blood. [ka] It may be found in combination with its pharmacological or physiological salt.

[0336] In an exemplary embodiment, [ka] The pharmaceutical or physiological salt is released into the host's plasma or whole blood. [ka] It may be found in combination with its pharmacological or physiological salt.

[0337] In an exemplary embodiment, [ka] The pharmaceutical or physiological salt is released into the host's plasma or whole blood. [ka] It may be found in combination with its pharmacological or physiological salt.

[0338] In an exemplary embodiment, [ka] The pharmaceutical or physiological salt is released into the host's plasma or whole blood. [ka] It may be found in combination with its pharmacological or physiological salt.

[0339] In an exemplary embodiment, [ka] The pharmaceutical or physiological salt is released into the host's plasma or whole blood. [ka] It may be found in combination with its pharmacological or physiological salt.

[0340] In an exemplary embodiment, [ka] The pharmaceutical or physiological salt is released into the host's plasma or whole blood. [ka] It may be found in combination with its pharmacological or physiological salt.

[0341] In an exemplary embodiment, [ka] The pharmaceutical or physiological salt is released into the host's plasma or whole blood. [ka] It may be found in combination with its pharmacological or physiological salt.

[0342] In yet another embodiment, at least two direct-acting antiviral agents are one or more of ABT-450 and / or ABT-267 and / or ABT-333 and / or ABT-493 and / or ABT-530 and the compound of the present invention; US2010 / 0144608, US61 / 339,964, US2011 / 0312973, WO2009 / 039127, US2010 / 0317568, 2012 / 151158, US2012 / 0172290, WO2012 / 092411, WO2012 / 087833, WO2012 Compounds disclosed in any of / 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 and the compounds of the present invention; one of simeprevir and / or GSK805 The above and the compound of the present invention; one or more of asunaprevir, and / or dacrustavir, and / or BMS-325 and the compound of the present invention; one or more of GS-9451, and / or regisasvir, and / or sofosbuvir, and / or GS-9669 and the compound of the present invention; one or more of ACH-2684, and / or ACH-3102, and / or ACH-3422 and the compound of the present invention; one or more of boseprevir, and / or MK-8742 and the compound of the present invention; faldaprevir, and / or dereobubi One or more of the following and the compound of the present invention; PPI-668 and the compound of the present invention; one or more of telaprevir and / or VX-135 and the compound of the present invention; one or more of samatasvir and / or IDX-437 and the compound of the present invention; PSI-7977 and / or PSI-938 and the compound of the present invention; BMS-790052 and / or BMS-650032 and the compound of the present invention; GS-5885 and / or GS-9451 and the compound of the present invention; GS-5885, GS-9190 and / or GS-9451 and the compound of the present invention;This includes combinations of drugs selected from the group consisting of BI-201335 and / or BI-27127 and the compound of the present invention; telaprevir and / or VX-222 and the compound of the present invention; PSI-7977 and / or TMC-435 and the compound of the present invention; and danoprevir and / or R7128 and the compound of the present invention.

[0343] In one aspect of this disclosure, “infection” or “bacterial infection” means Acinetobacter spp, Bacteroides spp, Burkholderia spp, Campylobacter spp, Chlamydia spp, Chlamydophila spp, Clostridium spp, Enterobacter spp, Enterococcus spp, Escherichia spp, Fusobacterium spp, Gardnerella spp, Haemophilus spp, Helicobacter spp, Klebsiella spp, Legionella spp, Moraxella spp, Morganella spp, Mycoplasma spp, Neisseria spp, Peptococcus spp, Peptostreptococcus spp, Proteus spp, Pseudomonas spp, Salmonella This refers to infections caused by spp, Serratia spp, Staphylococcus spp, Streptococcus spp, Stenotrophomonas spp, or Ureaplasma spp.

[0344] In one aspect of this disclosure, ``infection'' or ``bacterial infection'' means, Acinetobacter baumanii, Acinetobacter haemolyticus, Acinetobacter junii, Acinetobacter johnsonii, Acinetobacter lwoffi, Bacteroides bivius, Bacteroides fragilis, Burkholderia cepacia, Campylobacter jejuni, Chlamydia pneumoniae, Chlamydia urealyticus, Chlamydophila pneumoniae, Clostridium difficile, Enterobacter aerogenes, Enterobacter cloacae、Enterococcus faecalis、Enterococcus faecium、Escherichia coli、Gardnerella vaginalis、Haemophilus par influenzae、Haemophilus influenzae、Helicobacter pylori、Klebsiella pneumoniae、Legionella pneumophila、resistant Staphylococcus aureus、susceptible Staphylococcus aureus、Moraxella catarrhalis、Morganella morganii、Mycoplasma pneumoniae、Neisseria gonorrhoeae、penis resistant Streptococcus pneumoniae, ペニシリン susceptibility, Streptococcus pneumoniae, Peptostreptococcus, Peptostreptococcus magnus, Peptostreptococcus micros, Peptostreptococcus anaerobius, Peptostreptococcus asaccharolyticus, Peptostreptococcus prevotii, Peptostreptococcus tetradius, Peptostreptococcus vaginalis, Proteusmirabilis, Pseudomonas aeruginosa, quinolone-resistant Staphylococcus aureus, quinolone-resistant Staphylococcus epidermis, Salmonella, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Salmonella typhimurium, Serratia marcescens, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Stenotrophomonas maltophilia, Ureaplasma urealyticum, vancomycin-resistant Enterococcus faecium, vancomycin-resistant Enterococcus faecalis, vancomycin-resistant Staphylococcus aureus, vancomycin-resistant Staphylococcus epidermis, Mycobacterium This refers to infections caused by tuberculosis, Clostridium perfringens, Klebsiella oxytoca, Neisseria miningitidis, Proteus vulgaris, or coagulase-negative Staphylococcus (including Staphylococcus lugdunensis, Staphylococcus capitis, Staphylococcus hominis, or Staphylococcus saprophytic).

[0345] In one aspect of this disclosure, “infection” or “bacterial infection” means aerobic bacteria, obligate anaerobic bacteria, facultative anaerobic bacteria, Gram-positive bacteria, Gram-negative bacteria, Gram-variable bacteria, or atypical respiratory pathogens.

[0346] In some embodiments, this disclosure relates to treating bacterial infections such as gynecological infections, respiratory tract infections (RTIs), sexually transmitted diseases, or urinary tract infections.

[0347] In some embodiments, this disclosure relates to treating bacterial infections, such as those caused by drug-resistant bacteria.

[0348] In some embodiments, the disclosure relates to treating bacterial infections such as community-acquired pneumonia, hospital-acquired pneumonia, cutaneous and cutaneous structural infections, gonococcal cervicitis, gonococcal urethritis, febrile neutropenia, osteomyelitis, endocarditis, and urinary tract infections, as well as infections caused by drug-resistant bacteria such as penicillin-resistant penicillin-resistant streptococcus pneumoniae, methicillin-resistant staphylococcus aureus, methicillin-resistant staphylococcus epidermidis, and vancomycin-resistant enterococci, syphilis, ventilator-associated pneumonia, intraperitoneal infections, gonorrhoeae, meningitis, tetanus, or tuberculosis.

[0349] In some embodiments, the disclosure relates to the treatment of fungal infections such as tinea versicolor, microsporum, trichophyton, epidermophyton, candidiasis, cryptococcosis, or aspergillosis.

[0350] In some embodiments, the present disclosure relates to treating infections caused by protozoa, including but not limited to malaria, amoebiasis, giardiasis, toxoplasmosis, cryptosporidiosis, trichomoniasis, leishmaniasis, sleeping sickness, or Shigella.

[0351] Certain compounds disclosed herein are useful for preventing or treating malaria parasite infection in a subject, and / or for preventing, treating, and / or alleviating associated complications and / or symptoms, and can therefore be used in the preparation of agents for treating and / or preventing such diseases. Malaria may be caused by the malaria parasites Plasmodium falciparum, P. vivax, P. ovale, or P. malariae.

[0352] In one embodiment, the compound is administered to a subject after exposure to a malaria parasite. In another embodiment, the compound disclosed herein is administered to a subject before traveling to a country where malaria is endemic.

[0353] The compound or the above-described pharmaceutical composition may also be used in combination with one or more other therapeutically useful substances, selected from the group including antimalarial agents such as quinoline (e.g., quinine, chloroquine, amodiaquine, mefloquine, primaquine, tafenoquine); peroxide antimalarial agents (e.g., artemisinin, artemether, artesunate); pyrimethamine-sulfadoxine antimalarial agents (e.g., Fansidal); hydroxynaphthoquinone (e.g., atovaquone); acrolin-type antimalarial agents (e.g., pyronarizine); and antiparasitic agents such as ethylstibamin, hydroxystilbamidine, pentamidine, stilbamidine, quinapyramine, puromycin, propamidine, nifurtimox, meralsoprol, nimorazole, nifloxime, aminitrozole.

[0354] In one embodiment, the compounds disclosed herein can be used in combination with one additional drug, such as chloroquine, artemesin, tinhaos, 8-aminoquinoline, amodiaquine, arteether, artemether, artemisinin, artesunate, artesunic acid, artenic acid, atbocone, azithromycin, biguanide, chloroquine phosphate, chlorproguanil, cycloguanil, dapsone, desbutylhalofantrin, desipramine, doxycycline, and dihyphenate. Selected from the group consisting of folate reductase inhibitors, dipyridamole, halofantrine, haloperidol, hydroxychloroquine sulfate, imipramine, mefloquine, penfluridol, phospholipid inhibitors, primaquine, proguanil, pyrimethamine, pyronalizine, kinin, quinidine, quinacrine artemisinin, sulfonamide, sulfone, sulfadoxine, sulfarene, tafenoquine, tetracycline, tetrazidine, triazine, salts, or mixtures thereof.

[0355] The compounds of this disclosure may be administered in combination with a second agent, including, but not limited to, antiviral agents such as direct-acting antivirals, indirect-acting antivirals, and host-targeted antivirals. In various embodiments, the compounds of this disclosure may be administered in combination with a second agent, including, but not limited to, immunomodulators such as interleukin-6 (IL-6) inhibitors, corticosteroids, TNF inhibitors, and other immuno-dependent therapies; antibody therapies such as convalescent plasma therapy, hyperimmunoglobulin therapy, monoclonal antibodies, polyclonal antibodies, and neutralizing antibodies; soluble guanylate cyclase stimulants such as riociguat; cannibidiol; and vaccines. Additional therapies that may be considered include biological products that are biosimilars to any biological product or therapy expressly listed herein.

[0356] In various embodiments, the compounds of this disclosure include 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide, 3',4'-didehydro-4'deoxy-8'-norbin-caloicoblastin, 47D11, 5-fluorouracil, abatacept, abacavir, abiraterone acetate, ABT-450 and / or ABT-267 and / or ABT-333, ABX464, avivertinib, acalabrutinib, and ACE2. -Fc, ACE-MAB (STI-4920, CMAB020), acetylsalicylic acid, acetaminophen, ACT-20, Actemra, Actemra / Ro Actemra, acyclovir, adefovir, adalimumab, adipocyte mesenchymal cells, AdMSC (autologous adipose-derived stem cells), ADR-001, adrecizumab (HAM8101), ADX-629 / Reproxalap, AK-119, Alferon N, Alocetra (leukocyte cell therapy), Alostim, Alox stem cells, AL T-100 (enamptocumab), AL T-803, altretamine, amantadine, amnioboost, amiodarone, ampion, amprigen, amprenavir, arbidol, asunaprevir, atazanavir, atripra, anaferon, anakinra, AMG-3777, anhydrovinblastine, anti-nCoV nanovirus drug, aprepitant, AP-003 (anticovir), APL-9 (pegylated synthetic cyclic peptide), APX-115 AQCH, AR-701, ARO-COV, AS-1411, ascorbic acid, asnercept, atobakon / azithromycin, AT-100 (rhSP-D), AT-301, AT-H201, ATI-450, ATR-002, orlistatin, avdralimab (IPH5401), axatirimab, AZD-1061, AZD-7442, alberestat (AZD-9668), AZD-8895, azubudine, azubudine / tetrandrin, azithromycin, baloxivir, BI-201335, BI-27127, boceprevir, bardoxolone, bardoxolone Methyl, baricitinib, BBT-032, bemcentinib, BGE-175, BIO-300, BIOMEDIVR, bevacizumab, bexarotene, bicalutamide, BIO-1106, BLD-2660, BLD-2736,BOLD-I 00, Brekinal sodium, Brilacidine, Bromhexine hydrochloride, BTL-TML00l, Bleomycin, BMS-986253, BMS 184476, BT-086, BT-588, BXCL501, BXT-25, Bucillamine, Budesonide, Sidofovir, Combivir, Daclatasvir, Kaketin, Acalabrutinib, Camrelizumab, Camrelizumab / Thymosine, Captopril, CardioIRx, Kalimycin, Cavaltinib, Comostat, Camostat mesylate, Canakinumab, CAP-1002, Carboplatin, Carmustine, CB5064 analog, CD24Fc (recombinant fusion protein) ), Cepharanthine, Semadotine, Cenicliviroc, Canthaquin, CERC-002, Chlorambucil, Chloropromazine, Cholecalciferol, Ciclesonide, Cisplatin, Citrimoxazole, CK-0802, Clazakizumab, Clarithromycin, CLBS-119, CM4620-IE, Colchicine, CorLiCyte (umbilical cord inner layer stem cells), COVID-19 aptamer therapy, COVID-19 human mAb, COVID-19 neutralizing antibody, COVID-19 siRNA therapy, COVID-HIG, COVID-EIG, spike glycoprotein, cobiglobulin, COVI-GUARD (STI-1499) CPI-006, chryzanlizumab, cryptophysin, CSL-324, CT-P59, CTAP-101, CV-15, CVL-218, cyclosporine, cell replacement therapy, cyclophosphamide, CYNK-001, cytarabine, danoprevir, darunavir, delavirdin, dereobvir, didanosine, disoxalil, docosanol, dacarbazine, dactricib, dactinomycin, dalargin, DAS-181, dapagliflozin, dapansultril, daunorubicin, decitabine, dexamethasone, DNL 758 (SAR443122, RIPK1 inhibitor), dipyridamole, DMX-200, DS-2319, dupirfenidone duvelisib, DV-890, DWRX-2003, docetaxol, dorastatin, doxetaxel, doxorubicin (adriamycin), DP-710, edoxudine, efavirenz, enfuvirtide, encitrelvir, entecavir, EB-05, EB-201, ebastine, eculizumab, EDP-1815,Efineptakin alfa, emaparmab, emtricitabine, encifentrin, ENU-200, enoxaparin, enzalutanide, Epaspire, etanercept, etoposide, ellabacycline, favipiravir, famciclovir, hominivirsen, fosamprenavir, foscarnet, phosphonet, famotidine, finasteride, fingolimod, phlevogamma (IGIV31), fluvoxamine, foralumab (NI-0401, TZLS-401), fo Stamatinib, Flutanide, FSD-201, FW1022, FT516, Ganciclovir, GS-5882, GS-9190, GS-9451, Gumnex (IGIV-C), Ganetespib, GC-376, Diapreza, GLS-1200, Galadasimab, GC-5131A (hyperimmune globulin), GIGA-2050 (rCIG), Gymcirumab, GNS561, GP1681, GSK-2586881 / APN-l, GSK-4182136, GTB-3550 (Trike 161533), haNK:CD-16, HB-adMSC, HFB30132A, HLCM-051, heparin, hydrocortisone, hydroxyurea, ibuprofen, ibudilast (MN-166), icosapent ethyl, IC14, IDB-003, IFX-l / BDB-1, IgY-110, IMM101, IMS00l, IMS002, ibacitabine, immunovir, idoxuridine, imiquimod, indinavir, inosine, ifosfarnide, imatinib, infliximab, INM-005, interferon alpha, interferon alpha 1B, interferon alpha 2B, interferon Lonbeta IA, Interferon Beta 1B, Interleukin-6, Interleukin-7, Isoquercetin, Itanaplaced (CHF-5074), Itorizumab, Ivermectin, IVIG, JS012 (Monoclonal Antibody, LY-CoV016), Jactinib, Kagocel, KB109, K-NK-1D101, KTH-222, Lamivudine, Laninamivir Octanoate, Resisavir, Lopinavir or Lopinavir / Ritonavir, Lobilid, Lactoferrin, LAM-002A (Apirimod Dimesylate), Lanadermab, Lamelosome, LB-1148, Larazotide, Leflunornide, Rezilumab,Leronlimab (monoclonal antibody), lebilimab (BCD-089), revalnizole, rialozol, linagliptin, lipocluc, losartan, ribilimab, lomustine (CCNU), ronidamine, rosmapimod, losartan, LY-CoV555 (LY-3819253), LY-3127804, mornupiravir, moloxidine, methisazone, mannitol, maraviroc, mastinib, maprilimumab, MDV3100, mechloretamine, MEDI-3506, melatonin, melphalan, meplasmab, melemepodib, mesenchymal stem cells (MS) C) Mesencure (cell replacement therapy), Metablock (anti-inflammatory drug), metformin, methotrexate, methylprednisolone, mitomycin, mibobrine isethionate, mosedipimod (EC-18), MP-0420, MP-0423, MRx4DP0004, N-acetylcysteine, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-1-L-proline-t-butylamide, nelfinavir, nevirapine, nexavir, namilumab (IZN-101), nangibotide, narsoprimab, nebulizer Mazefafa, NED-260, Niagen (nicotinamide riboside; vitamin B3), NK cell therapy, niclosamide, nilutamide, nintedanib, nitric oxide, nivolumab, NL-CVXl, NLP-21, NP-02, N-120 (ifenprodil), Novaferon, NT-17 (efineptakin alfa), NTR-441, oseltamivir, octagum, olokizumab, omeprazole, onapristone, opaganib, OP-101, OT-101 (travedersen), ocilimab, ozanimod, paxlovide, penciclovir, peramivir Lu, pirodavir, preconalil, pokapavir, podophyllotoxin, PPI-668, PSI-7977, PSI-938, paclitaxel, pacritinib, Panafix, pamrebulumab, paracetamol, PAXLOVID (trademark), PB1046, PTC299, pegylated interferon alpha, pegylated interferon alpha 2b, pegylated interferon lambda, pembrolizumab, PL-8177, pirfenidone, pristicepsin (apridine), pneumoblast, polyoxidenium, prazosin, prednimustine, prednisolone,Prednisone, Pritumumab, Procarbazine, Prolastin, PTC-299, Pyronarizine / Artesunate, Radotinib, RAPA-501, Raltegravir, Remdesivir, Ribavirin, Rimantadine, Ritonavir, Rabulizumab, Razprotafib, Interferon Beta-1 agonist, RECC327, REGN-COV2 (antibody cocktail), Reparixin, Lintatrimod (Amprigen), RLF-100 (Aviptadil), RLS-0071, STI-5656 (Avivertinib), Rhu-pGSN (Gelsolin), Rizoxin, RPR109881, Ro Actemra, RUCONEST (Conestat Alpha), Ruxolitinib, SAB-185, SAR443122, Sarilumab, SARS-CoV-2 antibody, SARS-CoV-2 monoclonal antibody, SARS-CoV-2 polyclonal antibody, SARS-CoV-2 neutral pyramidine, Samatasvir, Saquinavir, Simeprevir, Sofosbuvir, Stabuzin, SCTA0l, Leukin (Salglamostim), Serenexol, Sevoflurane, Certenef, Siltuximab, Sildenafil citrate, Silymarin, Simvastatin, Sirolimus, Silkumab, SIW A-318, Solunatide, SNG-001, ST-266, Stem Cell Educational Therapy, STI-1499, STI-2020dna (COVI-MAB), STI-4398 (Covidtrap), Stramustine Phosphate, Streptozocin, T-cell Therapy (TargNaturTa), TAK-671, TAK-888, TATX-36, TATX-99, TCB-007, TJ003234 / TJM-2, TP508, TRV027, TD-0903, TLC19, TMC-435, Telaprevir, Tenofovir, Tenofovir Disoproxil Tipranavir, trifluridine, trizivir, tromantadine, Truvada, Thekuruma, tafenoquin, tamoxifen, tazonelmin, taxane, taxol, tetradrine, thalidomide, thimerosal, thymalfacin, tinzaparin, tocilizumab, tofacitinib, toremifene, trazipitant, tranexamic acid, transcrocetinate sodium (TSC), tramadol, tretinoin, TXA127 (antiotensin-(1-7) peptide), TY027, TZLS-501, UNI-911, urinastatin,Upamostat, valacyclovir, valganciclovir, bapendavir, bicriviroc, vidarabine, pyramidinezalcitabine, bafidemstat, valsartan, icosapentoethyl, bazegepant, VBI-S, VERU-111, VHH72-Fc, vinblastine, vincristine, vinosulfate, Decine, Vinflunin, VIR-2703 (ALN-COV), VIR-7831, VIR-7832, Vitamin C, Vitamin D, VX-135, VX-222, XAV-19, Xpro-1595, XRx-101, Zanamivir, Zidovudine, Zing antibody, Zanubrutinib, Zircoplan, Zinc; and / or US2010 / 0144608, US61 / 339,964, U S2011 / 0312973, WO2009 / 039127, US2010 / 0317568, 2012 / 151158, US2012 / 0172290, WO2012 / 092411, WO2012 / 087833, WO2012 / 083170, WO2009 / 039135, US2012 / 0115918, WO2012 / 05136 1. Compounds disclosed in any of WO2012 / 009699, WO2011 / 156337, US2011 / 0207699, WO2010 / 075376, US7,9105,95, WO2010 / 120935, WO2010 / 111437, WO2010 / 111436, US2010 / 0168384, or US2004 / 0167123, as well as their salts and / or prodrugs, and combinations thereof, or, where appropriate, the aforementioned prodrugs, and / or, where appropriate, their physiological or pharmaceutically active salts, and / or combinations thereof, may be administered in combination with a second agent.

[0357] In certain embodiments, the compounds of the Disclosure include abacavir, acyclovir, adefovir, amantadine, amprenavir, amprigen, arbidol, atazanavir, atripra, baloxivir, BI-201335, BI-27127, boceprevir, cidofovir, combivir, daclatasvir, danoprevir, darunavir, delavirdin, dereobvir, didanosine, disoxalil, docosanol, edoxidin, efavirenz, emtricitabine, enfuvirtide, encitrelvir, entecavir, and f Avipiravir, famciclovir, homivirsen, fosamprenavir, foscarnet, phosphonet, ganciclovir, GS-5882, GS-9190, GS-9451, ibacitabine, immunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, laninamivir octanoate, resisavir (ledisavir), lopinavir, or lopinavir / ritonavir, rovilid, maraviroc, mornupiravir, moloxidine Methisazone, nelfinavir, nevirapine, nexavir, oseltamivir, pachyrovid, pegylated interferon alfa-2a, penciclovir, peramivir, pyrodavir, preconalil, pokapavir, podophyllotoxin, PPI-668, PSI-7977, PSI-938, raltegravir, remdesivir, ribavirin, rimantadine, ritonavir, pyramidine, samatasvir, saquinavir, simeprevir, sofosbuvir, stabudine, TMC-435, telaprevir, tenofovir, tenofovir disoproxil, Pranavir, Trifluridine, Trizivir, Tromantadine, Truvada, Valacyclovir, Valganciclovir, Bapendavir, Bicriviroc, Vidarabine, Viramidine, Zalcitabine, Zanamivir, Zidovudine, US2010 / 0144608, US61 / 339,964, US2011 / 0312973, WO2009 / 039127, US2010 / 0317568, 2012 / 151158, US2012 / 0172290, WO2012 / 092411, WO2012 / 087833, WO2012 / 083170,Compounds described in any of 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, VX-135, VX-222, as well as their salts and / or prodrugs, and combinations thereof, may be administered in combination with a second antiviral agent.

[0358] In certain embodiments, the compounds of the Disclosure include IFN-α-2a (including its pegylated form; and used alone or in combination with ribavirin), IFN-α-2b (including its pegylated form; and used alone or in combination with ribavirin), IFN-α-N3, IFN-β-1a (including its pegylated form; and used alone or in combination with ribavirin), IFN-β-1b (including its pegylated form; and used alone or in combination with ribavirin), podophyllox, interferon alphacon-1, imiquimod, one or more syncatechins, maraviroc, and DAS1. 81, R448 (cabozantinib), ezetimibe, ovatocrax, glycirihidin, concanamycin, daptomycin, LJ001, tapsigargin, dinosaur, MLS000394177, MLS000733230, MLS000730532, bisindolylmalid I, califostine C, cherislin, enzasparalaurin, staurosinaurin, fativeracin, lintatrimod, GS9620, RO6864018, RO7020531, AL-034, imiquimod, GS9688, CL097, PF-04878691, or 852A, CPG10101, IMO-2125, SD-101, inarigivir (SB It can be administered in combination with a second antiviral agent, such as a host-directed antiviral agent, including but not limited to 9200), quercetin, A23187, phorbol myristate acetate, CI1033, SIP agonists, PPAR agonists, and combinations thereof.

[0359] In certain embodiments, the second agent disclosed herein, for example, an antiviral agent, is the following compound: [ka] It is administered with one of these, or in combination thereof.

[0360] In certain embodiments, the second agent disclosed herein, for example, an antiviral agent, is the following compound: [ka] It is administered with one of these, or in combination thereof.

[0361] In certain embodiments, the second agent disclosed herein, for example, an antiviral agent, is the following compound: [ka] It is administered in combination with one of the above, or the aforementioned combination.

[0362] In certain embodiments, the second agent disclosed herein, for example, an antiviral agent, is the following compound: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] It is administered with one of these, or with a pharmaceutically acceptable salt, solvate, or polymorph thereof.

[0363] Methods for treating viral infections disclosed herein, such as enteroviruses, RSV, influenza, VEEV, EEEV, HCV, and other viruses provided herein, are also provided in subjects. The method comprises administering the compounds of the disclosure to provide at least two direct-acting antiviral agents (DAAs), such as mornupiravir or ribavirin, for a period not exceeding 12 weeks, or another period as described herein, such as less than one week, for example, five days. Preferably, the two or more direct-acting antiviral agents (DAAs) are administered in amounts effective to provide a sustained virological response (SVR) or to achieve another desired measure of efficacy in the subject. In some embodiments, the method further comprises administering a cytochrome P-450 inhibitor (such as ritonavir) to the subject to improve the pharmacokinetics or bioavailability of one or more DAAs.

[0364] In another embodiment, a method for treating a subject with a viral infection disclosed herein, such as enterovirus, RSV, influenza, VEEV, EEEV, HCV, and other viruses provided herein, comprises administering (a) a protease inhibitor, (b) at least one polymerase inhibitor, at least one of which is (c) a polymerase of the Disclosure, with or without mornupiravir, and combinations thereof. Preferably, the compound is administered in an amount effective to provide the subject with a high percentage of sustained viability rate (SVR) or another measure of efficacy. In a non-limiting example, the compound may be co-formulated and administered once daily, and the treatment regimen preferably lasts for 1 to 5 days to 1 week.

[0365] In yet another embodiment, a method for treating a viral infection disclosed herein, such as enterovirus, RSV, influenza, VEEV, EEEV, HCV, and other viruses provided herein, comprises administering at least two DAAs, one of which is a compound of the Disclosure. Preferably, at least two DAAs are administered to the subject in an amount effective to produce a sustained viral response (SVR) or another measure of efficacy in at least about 70% of the population, preferably at least 90% of the population.

[0366] In the methods described above and in the methods described below herein, the DAA can be selected from the group consisting of protease inhibitors, nucleoside or nucleotide polymerase inhibitors (one of which is provided herein), non-nucleoside polymerase inhibitors, NS3B inhibitors, NS4A inhibitors, NS5A inhibitors, NS5B inhibitors, cyclophylline inhibitors, and any combination thereof. For example, in some embodiments, the DAA used in the method comprises or consists of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor provided herein.

[0367] In some embodiments, at least two DAAs include at least one viral inhibitor, e.g., an inhibitor of enterovirus, RSV, influenza, VEEV, EEEV, HCV, and other viruses provided herein, and at least one NS5A inhibitor. For example, the polymerase inhibitors of this disclosure may be administered in a total daily dose of about 100 mg to about 250 mg, and the NS5A inhibitors may be administered in a total daily dose of about 25 mg to about 200 mg. Ritonavir (or another cytochrome P-450 3A4 inhibitor) may be co-administered to improve the pharmacokinetics and bioavailability of the compound.

[0368] In the methods described above and in the methods described herein, DAAs can be administered in any effective dosing scheme 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.

[0369] In some embodiments, the technology provides a method for treating a subject with a viral infection disclosed herein, such as enterovirus, RSV, influenza, VEEV, EEEV, HCV, and other viruses provided herein, comprising administering at least two DAAs to a subject in need of viral treatment, wherein the subject is not administered interferon during the period. In some embodiments, at least two DAAs, with or without ribavirin, are administered in amounts effective to produce a sustained viral response (SVR). Some methods further include administering a cytochrome P450 inhibitor to the subject.

[0370] In some embodiments, the duration of the treatment regimen does not exceed 16 weeks (for example, the duration is 16 weeks, or the duration is 14, 12, or 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 week, or 1 to 7 days, for example, 1, 2, 3, 4, 5, 6, or 7 days daily). The treatment includes administration of ribavirin but does not include administration of interferon. If one of the DAAs requires pharmacokinetic enhancement, the treatment may include administration of 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 daily and the other DAA twice daily. In another example, both DAAs are administered once daily. In yet another example, the two DAAs are co-formulated into a single composition and administered simultaneously (e.g., once daily).

[0371] In a further embodiment, a method for treating enteroviruses in a subject is provided. The method comprises administering a nucleoside or nucleotide compound of the Disclosure. In addition, the method comprises administering the nucleoside or nucleotide compound of the Disclosure in combination with a second antiviral agent active against enteroviruses. In certain embodiments, the Disclosure relates to a method for treating a subject diagnosed with an enterovirus-induced infection, or a method for preventing enterovirus infection, by administration of a compound or composition disclosed herein. In certain embodiments, the subject is immunocompromised, immunodeficient, or immunosuppressed (i.e., a subject in which any part of the immune system is not functioning properly or is functioning below normal, in other words, a subject in which any part of the immune response or immune activity is reduced or impaired, whether by disease, clinical intervention, other treatment, or in any other way). In certain embodiments, the nucleoside or nucleotide compound of the Disclosure may be combined with a second antiviral agent provided in Anasir et al., J Biomed Sci (2021) 28, 10:5-12. Anasir et al. provide a review of antiviral agents for the treatment of enteroviruses, the disclosure of which is incorporated herein by reference in its entirety.

[0372] Combination therapy can provide "synergistic effects," that is, effects achieved when the combined active ingredients are greater than the combined effects of the compounds used separately. Synergistic effects can be achieved when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combination formulation, (2) delivered alternately or in parallel as separate formulations, or (3) in several other regimens. In alternating therapy, synergistic effects can be achieved when the compounds are administered or delivered sequentially, for example, in separate tablets, pills, or capsules, or by different injections in separate syringes. Generally, in alternating therapy, effective doses of each active ingredient are administered sequentially, i.e., sequentially, whereas in combination therapy, effective doses of two or more active ingredients are administered together.

[0373] Also disclosed is a method for producing a drug triphosphate, comprising: providing a plurality of cells; contacting the plurality of cells with a disclosed compound, e.g., compound formula XXIXc; and incubating the plurality of cells and the amount thereof of the compound or pharmaceutical composition for a period of time effective for forming a drug triphosphate. In some examples, the plurality of cells are in vivo. In some examples, the contact is intended to be administered to a subject requiring it.

[0374] cancer In a typical embodiment, this disclosure relates to a method for treating cancer, comprising administering a compound disclosed herein to a patient. In some embodiments, this disclosure relates to a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[0375] In some embodiments, this disclosure relates to the compounds disclosed herein or pharmaceutically acceptable salts thereof, as defined herein for use in the treatment of breast cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer, and bronchoalveolar carcinoma) and prostate cancer.

[0376] In some embodiments, this disclosure relates to the compounds disclosed herein or pharmaceutically acceptable salts thereof, as defined herein, for use in the treatment of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, endometrium, pancreas, skin, testes, thyroid gland, uterus, cervix and vulva, as well as cancers of leukemia (including ALL and CML), multiple myeloma and lymphoma.

[0377] In some embodiments, this disclosure relates to the compounds disclosed herein or pharmaceutically acceptable salts thereof, as defined herein for use in the treatment of lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcoma, head and neck cancer, tumors of the central nervous system, and their metastases, as well as glioblastoma.

[0378] In some embodiments, the compounds disclosed herein may be used in a clinical setting, either alone or in combination with other clinically relevant agents. These compounds can also inhibit potential cancer resistance mechanisms that may result from mutations in a set of genes.

[0379] The anticancer treatments defined herein may be applied as monotherapy, or may include conventional surgery or radiotherapy or chemotherapy in addition to the compounds of this disclosure. Such chemotherapy may include one or more antitumor agents from the following categories: (i) Antiproliferative / antineoplastic drugs and combinations thereof used in medical oncology, e.g., alkylating agents (e.g., cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, and nitrosourea); antimetabolites (e.g., fluoropyrimidines such as 5-fluorouracil and gemcitabine, folate antimetabolites such as tegafur, larcitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumor antibiotics (e.g., adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, myrrhizin, sylvestrexate); Anthracyclines such as tomycin C, dactinomycin, and mithramycin; antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxoids such as taxol and taxotere); topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide, teniposide, amsacrin, topotecan, and camptothecin); proteasome inhibitors (e.g., bortezomib [Velcade®]); the drug anegrilid [Agrylin®]; and the drug alpha-interferon; (ii) Cell division inhibitors, such as anti-estrogen agents (e.g., tamoxifen, toremifene, raloxifene, doroxifene, and iodoxifene), estrogen receptor down regulators (e.g., fulvestrant), anti-androgens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, borazole, and exemestane), and 5α-reductase inhibitors such as finasteride; (iii) Drugs that inhibit the invasion of cancer cells (e.g., metalloproteinase inhibitors such as marimastat and inhibitors of urokinase-type plasminogen activator receptor function); (iv) Inhibitors of growth factor function, for example, such inhibitors include growth factor antibodies, growth factor receptor antibodies (e.g., anti-erbb2 antibody trastuzumab [Herceptin®] and anti-erbb1 antibody cetuximab), farnesyltransferase inhibitors, tyrosine kinase inhibitors and serine / threonine kinase inhibitors, for example, inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, e.g., N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazoline-4-amine (erlotinib), and 6-acrylamide-N-(3-chloro (L-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoline-4-amine (CI1033), for example, inhibitors of the platelet-derived growth factor family, as well as inhibitors of the hepatocyte growth factor family, such as phosphatidylinositol 3-kinase (PI3K), as well as inhibitors of mitogen-activated protein kinase kinase (MEK1 / 2), as well as inhibitors of protein kinase B (PKB / Akt), such as the Src tyrosine kinase family, and / or inhibitors of the (AbI) Abelson tyrosine kinase family, such as dasatinib (BMS-354825) and imatinib mesylate (Gleevec®), and any agents that modify STAT signaling; (v) Anti-angiogenic agents that inhibit the effects of vascular endothelial growth factor (e.g., the anti-vascular endothelial growth factor antibody bevacizumab [Avastin®]), and compounds that act by other mechanisms (e.g., linamide, inhibitors of integrin °Cvβ3 function, and angiostatins); (vi) Vascular irritants such as combretastatin A4; (vii) Antisense therapies, such as anti-ras antisense, that target the targets listed above; (viii) Gene therapy approaches, such as those that replace abnormal genes like abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy), approaches that use cytosine deaminase, thymidine kinase or bacterial nitroreductase enzymes, and approaches that increase a patient's resistance to chemotherapy or radiotherapy, such as multidrug resistance gene therapy; and (ix) Immunotherapy approaches include, for example, ex vivo and in vivo approaches that increase the immunogenicity of patient tumor cells, approaches that reduce T cell anergy, such as transfection with cytokines such as interleukin-2, interleukin-4 or granulocyte-macrophage colony-stimulating factor, approaches that use transfected immune cells such as cytokine-transfected dendritic cells, approaches that use cytokine-transfected tumor cell lines, and approaches that use anti-idiotype antibodies, as well as approaches that use immunomodulatory drugs such as thalidomide and lenalidomide [Revlimid®].

[0380] Such conjoint treatment may be achieved by administering the individual components of the treatment simultaneously, sequentially, or individually. Such combination products use the compounds of the Disclosure or pharmaceutically acceptable salts thereof within the aforementioned dosage ranges, and other pharmaceutically active agents within their approved dosage ranges.

[0381] In one aspect of this disclosure, “infection” or “bacterial infection” means Acinetobacter spp, Bacteroides spp, Burkholderia spp, campylobacter spp, chlamydia spp, chlamydophila spp, clostridium spp, enterobacter spp, enterococcus spp, escherichia spp, fusobacterium spp, gardnerella spp, haemophilus spp, helicobacter spp, klebsiella spp, legionella spp, moraxella spp, morganella spp, mycoplasma spp, neisseria spp, peptococcus spp, Peptostreptococcus spp, proteus spp, pseudomonas spp, Salmonella spp, serratia spp, Staphylococcus This refers to infections caused by SPP, Streptococcus SPP, Stenotrophomonas SPP, or Ureaplasma SPP.

[0382] Acinetobacter baumanii, Acinetobacter haemolyticus Acinetobacter and Acinetobacter junii, Acinetobacter johnsonii, Acinetobacter Iwoffi, Bacteroides bivius, Bacteroides fragilis, Burkholderia cepacia, campylobacter jejuni, chlamydia pneumoniae, chlamydia urealyticus, and pneumonia difficile、enterobacter aerogenes、enterobacter cloacae、enterococcus faecalis、enterococcus faecium、escherichia coli、gardnerella vaginalis、haemophilus par influenzae、haemophilus influenzae、helicobacter pylori pneumoniae, legionella pneumophila, Staphylococcus aureus, Staphylococcus aureus, moraxella catarrhalis, morganella plasma morganism pneumoniae, neisseria gonorrhoeae, streptococcus pneumoniae, streptococcus pneumoniae magnus、Peptostreptococcus micros、Peptostreptococcus anaerobius、Peptostreptococcus asaccharolyticus、Peptostreptococcus prevotii、Peptostreptococcus tetradius、Peptostreptococcus vaginalis、proteusmirabilis, pseudomonas aeruginosa, quinolone-resistant Staphylococcus aureus, quinolone-resistant Staphylococcus epidermis, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Salmonella typhimurium, serratia marcescens, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, streptoccocus agalactiae, streptococcus pneumoniae, streptococcus pyogenes, stenotrophomonas maltophilia, ureaplasma urealyticum, vancomycin-resistant enterococcus faecium, vancomycin-resistant enterococcus faecalis, vancomycin-resistant Staphylococcus aureus, vancomycin-resistant Staphylococcus epidermis, mycobacterium This refers to infections caused by tuberculosis, Clostridium perfringens, Klebsiella oxytoca, Neisseria miningitidis, Proteus vulgaris, or coagulase-negative Staphylococcus (including Staphylococcus lugdunensis, Staphylococcus capitis, Staphylococcus hominis, or Staphylococcus saprophytic).

[0383] In one aspect of this disclosure, “infection” or “bacterial infection” means aerobic bacteria, obligate anaerobic bacteria, facultative anaerobic bacteria, Gram-positive bacteria, Gram-negative bacteria, Gram-variable bacteria, or atypical respiratory pathogens.

[0384] In some embodiments, this disclosure relates to treating bacterial infections such as gynecological infections, respiratory tract infections (RTIs), sexually transmitted diseases, or urinary tract infections.

[0385] In some embodiments, this disclosure relates to treating bacterial infections, such as those caused by drug-resistant bacteria.

[0386] In some embodiments, the disclosure relates to treating bacterial infections such as community-acquired pneumonia, hospital-acquired pneumonia, cutaneous and cutaneous structural infections, gonococcal cervicitis, gonococcal urethritis, febrile neutropenia, osteomyelitis, endocarditis, and urinary tract infections, as well as infections caused by drug-resistant bacteria such as penicillin-resistant penicillin-resistant streptococcus pneumoniae, methicillin-resistant staphylococcus aureus, methicillin-resistant staphylococcus epidermidis, and vancomycin-resistant enterococci, syphilis, ventilator-associated pneumonia, intraperitoneal infections, gonorrhoeae, meningitis, tetanus, or tuberculosis.

[0387] In some embodiments, the disclosure relates to the treatment of fungal infections such as tinea versicolor, microsporum, trichophyton, epidermophyton, candidiasis, cryptococcosis, or aspergillosis.

[0388] In some embodiments, the present disclosure relates to treating infections caused by protozoa, including but not limited to malaria, amoebiasis, giardiasis, toxoplasmosis, cryptosporidiosis, trichomoniasis, leishmaniasis, sleeping sickness, or Shigella.

[0389] Certain compounds disclosed herein are useful for preventing or treating malaria parasite infection in a subject, and / or for preventing, treating, and / or alleviating associated complications and / or symptoms, and can therefore be used in the preparation of agents for treating and / or preventing such diseases. Malaria may be caused by the malaria parasites Plasmodium falciparum, P. vivax, P. ovale, or P. malariae.

[0390] formulation The pharmaceutical compositions disclosed herein may be in the form of pharmaceutically acceptable salts, as generally described below. Some preferred non-limiting examples of suitable pharmaceutically acceptable organic and / or inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, and citric acid, as well as other pharmaceutically acceptable acids known by themselves (see references cited below).

[0391] If the compounds of the Disclosure contain acidic and basic groups, the compounds of the Disclosure may also contain intramolecular salts, and such compounds are within the scope of the Disclosure. If the compounds of the Disclosure contain a hydrogen-donating heteroatom (e.g., NH), the Disclosure also covers salts and / or isomers formed by the transfer of a hydrogen atom to a basic group or an intramolecular atom.

[0392] pharmaceutically acceptable salts of a compound include its acid addition salts and base salts. Preferred acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, cansylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodine / iodine, and isethionene. Examples include methyl sulfate, lactate, maleate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xynowheate salts. Preferred base salts are formed from bases that form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts. Hemi salts of acids and bases, such as hemisulfate and hemicalcium salts, may also be formed. For an overview of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002) (incorporated herein by reference).

[0393] The compounds disclosed herein may be administered in the form of prodrugs. Prodrugs may contain a covalently bonded carrier that, when administered to a mammalian subject, releases an active parent drug. Prodrugs may be prepared by modifying functional groups present in the compound in such a way that the modification is cleaved into the parent compound, either in a routine procedure or in vivo. Prodrugs include, for example, compounds bonded to any group, where, when administered to a mammalian subject, the hydroxyl group is cleaved to form a free hydroxyl group. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol functional groups in the compound. Methods for constructing compounds as prodrugs are well known and can be found in Testa and Mayer, Hydrolysis in Drug and Prodrug Metabolism, Wiley (2006). Typical prodrugs form active metabolites by hydrolysis of the prodrug by hydrolysis of hydrolases, amides, lactams, peptides, carboxylic acid esters, epoxides, or transformation of the prodrug by cleavage of esters of inorganic acids. Ester prodrugs have been shown to be readily broken down in the body, releasing the corresponding alcohol. For example, see Imai, Drug Metab Pharmacokinet. (2006) 21(3):173-85, titled "Human carboxylesterase isozymes: catalytic properties and rational drug design".

[0394] Pharmaceutical compositions for use in this disclosure typically comprise an effective amount of a compound of formula XXIX–XXXIVb and a pharmaceutically acceptable excipient, or an effective amount of a disclosed compound and a suitable pharmaceutically acceptable carrier. Preparations can be prepared by methods known in themselves, which typically involve mixing at least one compound according to this disclosure with one or more pharmaceutically acceptable carriers, and optionally in combination with other pharmaceutically active compounds, and, if necessary, under sterile conditions. See U.S. Patents 6,372,778, 6,369,086, 6,369,087, and 6,372,733, as well as the further references mentioned above, and standard handbooks, e.g., the latest edition of Remington's Pharmaceutical Sciences.

[0395] In general, with respect to pharmaceutical use, the compound can be formulated as a pharmaceutical product comprising at least one of the compound and at least one pharmaceutically acceptable carrier, diluent, or excipient, and optionally comprising one or more further pharmaceutically active compounds.

[0396] The pharmaceutical products of this disclosure are preferably in unit dosage forms and may optionally be suitably packaged in, for example, boxes, blisters, vials, bottles, sachets, ampoules, or any other suitable single-dose or multi-dose holders or containers (which may be appropriately labeled), together with one or more booklets containing product information and / or instructions for use. Generally, such unit doses would contain 1 to 1000 mg, typically 5 to 500 mg, of at least one compound of this disclosure, for example, about 10, 25, 50, 100, 200, 300, or 400 mg per unit dose.

[0397] This compound may be administered via various routes, including oral, ocular, rectal, transdermal, subcutaneous, sublingual, intravenous, intramuscular, or intranasal routes, depending on the specific preparation primarily used. The compound is generally administered in an "effective dose," which means any amount of the compound sufficient to achieve the desired therapeutic or prophylactic effect in the subject to which it is administered, at a suitable time of administration. Typically, depending on the condition being prevented or treated and the route of administration, such an effective dose is 0.01 to 1000 mg per kilogram of body weight of the patient, daily, every other day, twice a week, or weekly, and more frequently, 0.1 to 500 mg, for example, 1 to 250 mg, daily, every other day, twice a week, or weekly, for example, about 5, 10, 20, 50, 100, 150, 200, or 250 mg per kilogram of body weight of the patient, daily, every other day, twice a week, or weekly, as a single dose daily, every other day, twice a week, or weekly, or as one or more divided doses daily, every other day, twice a week, or weekly. The dosage(s), route of administration, and further treatment regimens may be determined by the treating clinician depending on factors such as the patient's age, sex, and general health, as well as the nature and severity of the disease / symptom being treated. See U.S. Patent Nos. 6,372,778, 6,369,086, 6,369,087, and 6,372,733, as well as the further references mentioned above, and standard handbooks, e.g., the latest edition of Remington's Pharmaceutical Sciences.

[0398] Regarding oral administration forms, the compound can be mixed with suitable additives, such as excipients, stabilizers, or inert diluents, and prepared by conventional methods in suitable dosage forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic, or oily solutions. Examples of suitable inert carriers include gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, particularly corn starch. In this case, preparations can be carried out in both dry and wet granules. Suitable oily excipients or solvents include vegetable or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions, or mixtures thereof. Polyethylene glycol and polypropylene glycol are also useful as further adjuvants for other dosage forms. As immediate-release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, and lactose, and / or other excipients, binders, fillers, disintegrants, diluents, and lubricants known in the art.

[0399] When administered by nasal aerosol or inhalation, the composition may be prepared according to techniques known in the art of pharmaceutical formulations, and may be prepared as a solution in physiological saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and / or other solubilizers or dispersants known in the art. Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds of the disclosure or physiologically tolerable salts thereof in a pharmaceutically acceptable solvent, such as ethanol or water, or a mixture of such solvents. If necessary, the formulation may also contain other pharmaceutical adjuvants, such as surfactants, emulsifiers and stabilizers, and propellants.

[0400] For subcutaneous or intravenous administration, the compound may be prepared as a solution, suspension, or emulsion, optionally with conventional substances, such as solubilizers, emulsifiers, or further adjuvants. The compound may also be lyophilized, and the resulting lyophilized product can be used, for example, to produce injection or infusion preparations. Suitable solvents are, for example, water, physiological saline solution, or alcohol, such as ethanol, propanol, glycerol, glucose or mannitol solution, or a mixture of the various solvents mentioned. Injectable solutions or suspensions may be formulated according to known techniques using suitable non-toxic, parenterally tolerable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, or isotonic sodium chloride solution, or suitable dispersants or wetting agents and suspending agents, such as sterile, non-irritating, non-volatile oils containing synthetic mono or diglycerides, and fatty acids containing oleic acid.

[0401] When administered rectally in the form of a suppository, the formulation may be prepared by mixing the compound of formula I with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride ester, or polyethylene glycol, which is solid at room temperature but liquefies and / or dissolves in the rectal lumen to release the drug.

[0402] In certain embodiments, these compositions are intended to be sustained-release formulations. Typical sustained-release formulations utilize enteric coatings. Typically, a barrier is applied to the oral drug to control the location in the digestive system where it is absorbed. The enteric coating prevents the drug from being released before it reaches the small intestine. Enteric coatings include polysaccharide polymers such as maltodextrin, xanthan gum, scleroglucandextran, starch, alginate, pullulan, hyaluronic acid, chitin, and chitosan; proteins (such as albumin and gelatin), other natural polymers such as poly-L-lysine; sodium poly(acrylate); poly(hydroxyalkyl methacrylate) (e.g., poly(hydroxyethyl methacrylate)); carboxypolymethylene (e.g., Carbopol®), carbomer, polyvinylpyrrolidone; gums such as guar gum, gum arabic, karaya gum, ghati gum, locust bean gum, tamarind gum, gellan gum, tragacanth gum, agar, pectin, and gluten; and poly(vinyl alcohol) ); ethylene vinyl alcohol; polyethylene glycol (PEG); and cellulose ethers, such as hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), methylcellulose (MC), ethylcellulose (EC), carboxyethylcellulose (CEC), ethyl hydroxyethylcellulose (EHEC), carboxymethyl hydroxyethylcellulose (CMHEC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl ethylcellulose (HPEC), and sodium carboxymethylcellulose (Na-CMC); and copolymers and / or (simple) mixtures of any of the above polymers. Certain above polymers may be further crosslinked by standard techniques.

[0403] The choice of polymer is determined by the properties of the active ingredient / drug used in the composition of the present disclosure, as well as the desired release rate. In particular, it will be understood by those skilled in the art that, for example, in the case of HPMCs, the higher the molecular weight, the slower the drug release rate from the composition generally becomes. Furthermore, in the case of HPMCs, different degrees of substitution of methoxyl and hydroxypropoxyl groups result in variations in the drug release rate from the composition. In this regard, and as described above, it may be desirable to provide the compositions of the present disclosure in the form of a coating provided, for example, by a blend of two or more polymers of different molecular weights, in order to give a specific required or desired release profile.

[0404] Poly(lactide-co-glycolide) microspheres of polylactides, polyglycolides, and their copolymers can be used to form sustained-release protein delivery systems. Proteins can be encapsulated in poly(lactide-co-glycolide) microsphere depots by several methods, including the formation of water-in-oil emulsions using water-mediated proteins and organic solvent-mediated polymers (emulsion method), the formation of solid-in-oil suspensions using solid proteins dispersed in solvent-based polymer solutions (suspension method), or by dissolving the proteins in solvent-based polymer solutions (dissolution method). Poly(ethylene glycol) can be PEGylated to proteins to increase the in vivo half-life of circulating therapeutic proteins and reduce the opportunity for immune response.

[0405] Liposome suspensions (containing liposomes targeting viral antigens) can also be prepared by conventional methods to generate pharmaceutically acceptable carriers. This may be suitable for the delivery of free nucleoside, acyl nucleoside, or phosphate ester prodrug forms of the nucleoside compounds according to the present invention.

[0406] It is understood that the nucleosides of the present invention have several chiral centers, exist in optically active and racemic forms, and can be isolated in those forms. Some compounds may exhibit polymorphism. It is understood that the present invention encompasses any racemic, optically active, diastereomer, polymorphic, or stereoisomeric form, or mixture thereof, of the compounds of the present invention that have the useful properties described herein. How the optically active form is prepared is known (e.g., by separation of the racemic form by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).

[0407] The carbon atoms of nucleosides are chiral, and their non-hydrogen substituents (base and CHOR group, respectively) can be either cis (same side) or trans (opposite side) relative to the sugar ring system. Thus, the four optical isomers are represented by the following configurations (when the sugar portion is oriented horizontally with the oxygen atom at the rear): cis (both groups are "up," corresponding to the configuration of the naturally occurring β-D nucleoside), cis (both groups are "down," which is the unnatural β-L configuration), trans (C2' substituent is "up" and C4' substituent is "down"), and trans (C2' substituent is "down" and C4' substituent is "up"). "D-nucleoside" is the cis nucleoside of the naturally occurring configuration, and "L-nucleoside" is the cis nucleoside of the unnatural configuration.

[0408] Similarly, most amino acids are chiral (referred to as L or D, with the L enantiomer being the naturally occurring configuration) and can exist as distinct enantiomers.

[0409] Examples of methods for obtaining optically active materials are known in the art and include at least the following: i) physical separation of crystals - techniques for manually separating macroscopic crystals of individual enantiomers. This technique can be used when crystals of separate enantiomers exist, i.e., the material is an aggregate and the crystals are visually distinct; ii) Co-crystallization - a technique in which individual enantiomers are crystallized separately from a racemic solution, which is only possible if the latter is a solid aggregate; iii) Enzymatic resolution - a technique in which a racemic mixture is partially or completely separated by the different reaction rates of the enantiomers by enzymes; iv) Enzymatic asymmetric synthesis - a synthetic technique that uses an enzymatic reaction in at least one step of synthesis to obtain a enantiomerically pure or concentrated synthetic precursor of the desired enantiomer; v) Chemical asymmetric synthesis - a synthetic technique in which the desired enantiomer is synthesized from an achiral precursor under conditions that can be achieved using a chiral catalyst or chiral auxiliary, resulting in asymmetry (i.e., chirality) in the product; vi) Diastereomer separation - a technique in which a racemic compound is reacted with an enantiomerically pure reagent (chiral auxiliary) to convert individual enantiomers into diastereomers. Next, the obtained diastereomers are separated by chromatography or crystallization due to their now clear structural differences, and the chiral auxiliaries are subsequently removed to obtain the desired enantiomer; vii) Primary and secondary asymmetric conversion - This technique involves equilibrating the diastereomers derived from the racemic mixture, either by making the diastereomer derived from the desired enantiomer dominant in solution, or by disrupting the equilibrium by preferentially crystallizing the diastereomer derived from the desired enantiomer, and in principle, ultimately converting all materials from the desired enantiomer to a crystalline diastereomer.The desired enantiomer is then separated from the diastereomer; viii) Kinetic resolution - this technique refers to achieving partial or complete resolution of a racemate (or further resolution of a partially resolved compound) by uneven reaction rates between the enantiomer and a chiral non-racemic reagent or catalyst under kinetic conditions; ix) Enantiospecific synthesis from non-racemic precursors - a synthetic technique in which the desired enantiomer is obtained from non-chiral starting materials and stereochemical integrity is not lost, or only minimally lost, throughout the synthetic process; x) Chiral liquid chromatography - a technique in which enantiomers of a racemate are separated in a liquid mobile phase due to their different interactions with the stationary phase. The stationary phase may be made of chiral material, or the mobile phase may contain additional chiral material to induce different interactions; xi) Chiral gas chromatography - a technique for separating enantiomers by volatilizing a racemate and their different interactions with a column containing an immobilized non-racemic chiral adsorbent phase in the gas mobile phase; xii) Extraction in chiral solvents - a technique for separating enantiomers by the preferential dissolution of one enantiomer in a particular chiral solvent; xiii) Transport across chiral membranes, i.e., a technique in which the racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure difference results in preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral properties of the membrane, allowing only one enantiomer of the racemate to pass through. Chiral chromatography, including pseudo-moving bed chromatography, is used in one embodiment. A wide variety of chiral stationary phases are commercially available.

[0410] Some of the compounds described herein contain olefinic double bonds, and unless otherwise specified, this means that both E and Z geometric isomers are present.

[0411] In addition, some of the nucleosides described herein may exist as tautomers, such as keto-enol tautomers. Individual tautomers and mixtures thereof are intended to be incorporated within the compounds of the present invention.

[0412] Combination therapy The compounds described herein may be administered adjunctly in conjunction with other active compounds. These compounds include, but are not limited to, analgesics, anti-inflammatory agents, antipyretics, antidepressants, antiepileptic agents, antihistamines, anti-migraine agents, anti-muscarinic agents, anxiolytics, sedatives, hypnotics, antipsychotics, bronchodilators, anti-asthmatic agents, cardiovascular agents, corticosteroids, dopamine agonists, electrolytes, gastrointestinal agents, muscle relaxants, nutritional supplements, vitamins, parasympathomimetic agents, stimulants, appetite suppressants, anti-narcolepsy agents, and antiviral agents. In certain embodiments, the antiviral agent is a non-CNS-targeted antiviral compound. As used herein, “adjunct administration” means that the compound may be administered in the same dosage form or in a separate dosage form with one or more other active agents. Additional active agents may be formulated for immediate release, controlled release, or combinations thereof.

[0413] Specific examples of compounds that can be administered adjunctly with this compound include aceclofenac, acetaminophen, admexetine, almotriptan, alprazolam, amantadine, amcinonide, aminocyclopropane, amitriptyline, amorodipine, amoxapine, amphetamine, aripiprazole, aspirin, atomoxetine, azasetron, azatadine, beclomethasone, benactidine, benoxaprofen, belmoprofen, betamethasone, bicifadine, bromocriptine, budesonide, buprenorphine, bupropion, and buprenorphine. Pyrone, butorphanol, buttriptyline, caffeine, carbamazepine, carbidopa, carisoprodol, celecoxib, chlordiazepoxide, chlorpromazine, choline salicylate, citalopram, clomipramine, clonazepam, clonidine, clonitazen, clorazepate, clotiazepam, cloxazolam, clozapine, codeine, corticosterone, cortisone, cyclobenzaprine, cyproheptadine, demexiptyline, desipramine, desomorphine, dexamethasone, dexanabinol, dextroamphetamine sulfate, Dextromoramide, dextropropoxifen, dezosin, diazepam, dibenzepine, diclofenac sodium, diflunisal, dihydrocodeine, dihydroergotamine, dihydromorphine, dimethacrine, divalproex, disatriptan, drasetron, donepezil, dotiepin, doxepin, duloxetine, ergotamine, escitalopram, estazolam, ethosuximide, etodolac, femoxetine, fenamete, fenoprofen, fentanyl, fludiazepam, fluoxetine, fluphenazine, flurazepam, flu Lubiprofen, flutazolam, fluvoxamine, flovatriptan, gabapentin, galantamine, gepilone, ginkgo biloba, granisetron, haloperidol, huperzine A, hydrocodone, hydrocortisone, hydromorphone, hydroxyzine, ibuprofen, imipramine, indipron, indomethacin, indoprofen, iprendol, ipsapirone, ketaselin, ketoprofen, ketrolac, resopitron, levodopa, lipase, lofepramine, lorazepam, roxapine, maprotiline, mazindol, mefenamic acid, melatonin,Melitracene, memantine, meperidine, meprobamate, mesalamine, metapramine, metaxalon, methadone, methadone, methamphetamine, methocarbamol, methyldopa, methylphenidate, methyl salicylate, methyserzide, metoclopramide, mianserin, mifepristone, milnacipran, minaprin, mirtazapine, moclobemide, modafinil (anti-narcolepsy), morindone, morphine, morphine hydrochloride, nabumetone, nadolol, naproxen, naratriptan, nefazodone, ni eurontin, nomifensin, nortriptyline, olanzapine, olsalazine, ondansetron, opipramol, orphenadrine, oxafrozan, oxaprazine, oxazepam, oxytriptan, oxycodone, oxymorphone, pancrelipase, parecoxib, paroxetine, pemoline, pentazocine, pepsin, perphenazine, phenacetin, fendimethrazine, fenmetrazine, phenylbutazone, phenytoin, phosphatidylserine, pimozide, pyrrindol, pyroxy Cam, Pizotifen, Pizotirine, Pramipexole, Prednisolone, Prednisone, Pregabalin, Propanolol, Propizepine, Propoxifen, Protriptyline, Quazepam, Quinupramine, Leboxitine, Reserpine, Risperidone, Ritasserine, Rivastigmine, Rizatriptan, Lofecoxib, Ropinirole, Rotigotine, Salsalat, Sertraline, Sibutramine, Sildenafil, Sulfasalazine, Sulindac, Sumatriptan, Tacrine, Temazepam, Tetrabenodine, Thia This includes, but is not limited to, zide, thioridazine, thiothixene, tiapride, thiacipyrone, tizanidine, tofenacin, tolmetine, troxatone, topiramate, tramadol, trazodone, triazolam, trifluoperazine, trimethobenzamide, trimipramine, tropisetron, valdecoxib, valproic acid, venlafaxine, piroxazine, vitamin E, zimelzine, ziprasidone, zolmitriptan, zolpidem, zopiclone, and isomers, salts, and combinations thereof.

[0414] In certain embodiments, exemplary compounds and pharmaceutical compositions include abacavir, acyclovir, adefovir, amantadine, amprenavir, amprigen, arbidol, atazanavir, atripra, parapiravir, BCX4430, boceprevir, cidofovir, combivir, daclatasvir, darunavir, dasabuvir, delavirdin, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, phosphonet, ganciclovir, GS-5734, ibasitabine, immunovir, doxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, ledipasvir, and ro It may be administered in combination with other antiviral agents such as pinavir, roviride, maraviroc, moloxidine, methisazone, nelfinavir, nevirapine, nexavir, NITD008, ombitasvir, oseltamivir, paritaprevir, pegylated interferon alfa-2a, penciclovir, peramivir, preconalil, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, simeprevir, sofosbuvir, stabudine, telaprevir, terbivudine, tenofovir, tenofovir disoproxil, tenofovir exalidex, tipranavir, trifluridine, trizivir, tromantadine, truvada, valacyclovir, valganciclovir, bicriviroc, vidarabine, viramidine, zalcitabine, or zidovudine, as well as combinations thereof.

[0415] In exemplary embodiments, exemplary compounds and pharmaceutical compositions are: [ka] It can be administered in combination with [another drug].

[0416] In an exemplary embodiment, [ka] teeth, [ka] It can be administered in combination with [another drug].

[0417] In an exemplary embodiment, [ka] teeth, [ka] It can be administered in combination with [another drug].

[0418] In an exemplary embodiment, [ka] teeth, [ka] It can be administered in combination with [another drug].

[0419] In an exemplary embodiment, [ka] teeth, [ka] It can be administered in combination with [another drug].

[0420] In exemplary embodiments, the pharmaceutical composition comprises one compound from formulas XXIX to XXXIVb and a pharmaceutically acceptable excipient.

[0421] In exemplary embodiments, the pharmaceutical composition comprises a compound of formulas XXIX to XXXIVb, or any compound species or combination thereof disclosed herein, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable excipient, the formulation being intended for oral delivery.

[0422] In exemplary embodiments, the pharmaceutical composition comprises a compound of formulas XXIX to XXXIVb, or any compound species or combination thereof disclosed herein, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable excipient, which may be a capsule, tablet, cachet, pill, powder, granule, elixir, tincture, suspension, syrup, or emulsion.

[0423] In exemplary embodiments, the pharmaceutical composition comprises a compound of formulas XXIX to XXXIVb, or any compound species or combination thereof disclosed herein, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable excipient, the formulation being for oral delivery and in solid dosage form.

[0424] In exemplary embodiments, the pharmaceutical composition comprises a compound of formulas XXIX to XXXIVb, or any compound species or combination thereof disclosed herein, or a pharmaceutically acceptable salt, solvate or polymorph thereof, and a pharmaceutically acceptable excipient, which is a formulation for parenteral delivery.

[0425] In exemplary embodiments, the pharmaceutical composition comprises compounds of formulas XXIX to XXXIVb, or any compound species or combination thereof disclosed herein, or pharmaceutically acceptable salts, solvates, or polymorphs thereof, and pharmaceutically acceptable excipients, which are formulations for parenteral delivery such as bolus injection or infusion, as well as for administration by intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subarticular, subarachnoid, intramedullary, epidural, and intrapleural injection and infusion.

[0426] In exemplary embodiments, the pharmaceutical composition comprises compounds of formulas XXIX to XXXIVb, or any compound species or combination thereof disclosed herein, or pharmaceutically acceptable salts, solvates, or polymorphs thereof, and pharmaceutically acceptable excipients, which are formulations for parenteral delivery such as subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intrafocal, and intracranial injection or infusion techniques.

[0427] In exemplary embodiments, the pharmaceutical composition comprises one compound from formulas XXIX to XXXIVb, or any compound species or combination thereof disclosed herein, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable excipient, which is a formulation for pulmonary delivery.

[0428] In exemplary embodiments, the pharmaceutical composition comprises a compound of formulas XXIX to XXXIVb, or any compound species or combination thereof disclosed herein, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable excipient, which is a formulation for lung delivery including a propellant.

[0429] In exemplary embodiments, a pharmaceutical composition comprises a compound of formulas XXIX to XXXIVb, or any compound species or combination thereof disclosed herein, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable excipient, which is a formulation for lung delivery comprising a propellant such as compressed air, ethanol, nitrogen, carbon dioxide, nitrous oxide, hydrofluoroalkane (HFA), 1,1,1,2,-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, or a combination thereof.

[0430] manner The following list of exemplary embodiments is supported and endorsed by the disclosures provided herein.

[0431] Embodiment 1. A method for treating or preventing a viral infection, comprising an effective amount of a pharmaceutically acceptable excipient and a compound of formula XXIXc, [ka] Or, administering a pharmaceutical composition comprising a pharmaceutically or physiological salt thereof to a subject in need of treatment or prevention of a viral infection, In the formula, R 1 However, the formula [ka] Selected from groups having a structure represented by, Y 3 However, it is hydrogen, aryl, heteroaryl, or heterocyclyl, and Y 3 However, you can choose to select one or more of the same or different R 10 Replaced by, R 5 However, R is hydrogen, alkyl, alkenyl, alkynyl, carbocykyl, heterocarbocykyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, allenyl, or lipid. 5 However, you can choose to select one or more of the same or different R 10 Replaced by, R 10However, it is deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocarbocykrill, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocykritolthio, heterocarbocykritolthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, R 10 However, you can choose to select one or more of the same or different R 11 Replaced by, R 11 The method is characterized by the presence of deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyryl, heterocarbocyryl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyramino, heterocarbocyramino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyrylthio, heterocarbocyrylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl.

[0432] Appearance 2.R 1 However, the formula [ka] [ka] [ka] The method according to claim 1, wherein the group has a structure represented by [the given expression].

[0433] Appearance 3.R 1 However, the formula [ka] The method according to claim 2, wherein the group is a group having the structure represented by

[0434] Appearance 4.R 5 The method according to any one of claims 1 to 3, wherein the selected material is a lipid, methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, and N,N-dipropylamino.

[0435] Appearance 5.R 5 The method according to claim 4, wherein the selected element is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0436] Appearance 6.R 5 The method according to claim 4, wherein the selected element is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, and 4-septyl.

[0437] Appearance 7.R 5 The method according to claim 4, wherein the selected element is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, and 3-pentyl.

[0438] Embodiment 8. The compound is of the formula [ka] A method according to any one of claims 1, comprising structures represented by, and combinations thereof, selected from.

[0439] Embodiment 9. The compound is of the formula [ka] The method according to claim 1, which is a structure represented by, or a combination thereof.

[0440] Embodiment 10. The method according to any one of Claims 1 to 9, further comprising administering a second antiviral agent.

[0441] Embodiment 11. The second antiviral agent is remdesivir, favipiravir, darunavir, nelfinavir, saquinavir, lopinavir, ritonavir, remdesivir, paxlovide, mornupiravir, ABX464, faviravir, niclosamide, laninamivir, oseltamivir, zanamivir, peramivir, CS-8958, ribavirin, amantadine, rimantadine, tamiphosphoguanidine monoester, or phosphazanamivir or its monoester, disoxalil, preconalil, pyrodavir, bapendavir, pokapavir, azaglutamine, S-nitroso-N-acetyl - The method according to claim 10, selected from penicillamine (SNAP), glyceryl trinitrate (GTN), isosorbide disnitrate (ISDN), glycerillidine, 5-(3,4-dichlorophenyl)methylhydantoin, AG7088, preconalil, 3-methylthio-5-aryl-4-isothiazole carbonitride, pyridylimidazolidinone, ribavirin, mycophenolic acid, 6-azauridine, pyrazofrine, and 3-methylcaenferol, as well as their derivatives, physiological or pharmaceutical salts, or prodrugs, and combinations thereof.

[0442] Embodiment 12. The method according to Claim Embodiment 11, wherein the second antiviral agent is selected from remdesivir, favipiravir, darunavir, nelfinavir, saquinavir, lopinavir, ritonavir, remdesivir, paxlovide, mornupiravir, ABX464, faviravir, and niclosamide, as well as their derivatives, physiological or pharmaceutical salts, or prodrugs, and combinations thereof.

[0443] Embodiment 13. The method according to Claim Embodiment 11, wherein the second antiviral agent is selected from laninamivir, oseltamivir, zanamivir, peramivir, CS-8958, ribavirin, amantadine, rimantadine, tamiphosphoguanidine monoester, and phosphazanamivir or its monoester, as well as derivatives, physiological or pharmaceutical salts, or prodrugs thereof, and combinations thereof.

[0444] Embodiment 14. The method according to any one of Claim Embodiments 1 to 13, wherein the virus does not infect or substantially does not infect the liver.

[0445] Embodiment 15. The method according to Claim Embodiment 14, wherein the viral infection does not include a flavivirus infection.

[0446] Embodiment 16. The method according to Claim Embodiment 15, wherein the flavivirus infection does not include a hepatitis virus.

[0447] Embodiment 17. The method according to Claim Embodiment 16, wherein the hepatitis virus is hepatitis C virus.

[0448] Embodiment 18. The method according to any one of Claim Embodiments 1 to 16, wherein the viral infection includes an RNA virus infection.

[0449] Embodiment 19. The viral infection includes coxsackievirus A, B, and C, coxsackievirus A16, EV-D68, EV-A71, rhinovirus, poliovirus, echovirus, picornavirus, cardiovirus, enterovirus, elbovirus, hepatovirus, cobvirus, parechovirus, tesshouvirus, norovirus, sapovirus, lagowvirus, calicivirus including vesivirus, astrovirus, togavirus, flavivirus, hepacivirus, coronavirus, arterivirus, rhabdovirus, paramyxovirus, orthomyxovirus, hantavirus, reovirus, rotavirus, birnavirus, chrysovirus, cystvirus, hypovirus partitivirus, totovirus, lentivirus, polyomavirus, papillomavirus, adenovirus, circovirus, parvovirus, erythrovirus, and beta-parvovirus. The method according to any one of claims 1 to 18, comprising viruses selected from, amdovirus, densovirus, iteravirus, brevidensovirus, pephdensovirus, herpesvirus 1, 2, 3, 4, 5, 6, 7, and 8, poxvirus, hepadnavirus, pneumonia virus, bunyavirus, arenavirus, orthomyxovirus, human coronavirus, SARS coronavirus, MERS coronavirus, eastern equine encephalitis virus, western equine encephalitis virus, Venezuelan equine encephalitis virus, chikungunya virus, Ross River virus, RSV, influenza virus, takaribe virus, pichinde virus, Junin virus, Lassa fever virus, lymphocytic choriomeningitis virus, Rift Valley fever virus, Punta Torovirus, Lacrosse virus, Maporal virus, Heartland virus, and severe fever with thrombocytopenia syndrome virus, as well as combinations thereof.

[0450] Embodiment 20. The method according to Claim Embodiment 19, wherein the viral infection includes an enterovirus.

[0451] Embodiment 21. The method according to claim embodiment 20, wherein the enterovirus is a non-polioenterovirus.

[0452] Embodiment 22. The method according to Claim Embodiment 20 or 21, wherein the enterovirus or coxsackievirus is selected from bovine enterovirus, human enterovirus A, human enterovirus B, human enterovirus C, human enterovirus D, porcine enterovirus B, monkey enterovirus A, human rhinovirus A, human rhinovirus B, rhinovirus C, coxsackievirus A16, EV-D68, EV-A71, rhinovirus, poliovirus, and echovirus, and combinations thereof.

[0453] Embodiment 23. The method according to Claim Embodiment 20, wherein the enterovirus comprises an enterovirus selected from the group consisting of coxsackievirus A, B, and C, coxsackie A16, EV-D68, EV-A71, rhinovirus, poliovirus, and echovirus.

[0454] Embodiment 24. The method according to Claim Embodiment 23, wherein the enterovirus includes a coxsackievirus.

[0455] Embodiment 25. The method according to Claim Embodiment 23, wherein the enterovirus comprises Coxsackie A16.

[0456] Embodiment 26. The method according to Claim Embodiment 19, wherein the viral infection is of the Togaviridae family.

[0457] Embodiment 27. The method according to claim embodiment 26, wherein the virus is selected from Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus, and Ross River virus.

[0458] Embodiment 28. The method according to claim embodiment 19, wherein the viral infection is a human coronavirus, SARS coronavirus, and MERS coronavirus infection.

[0459] Embodiment 29. The method according to claim embodiment 28, wherein the viral infection is a SARS-CoV-2 infection.

[0460] The method according to claim 29, wherein the variants of SARS-CoV-2 are, but are not limited to, a more toxic strain originating from Brazil, known as Embodiment 30.P.1; a variant originating from the United Kingdom, known as 20I / 501Y.V1, VOC 202012 / 01, or B.1.1.7; and a variant originating from South Africa, known as 20H / 501Y.V2 or B.1.351; and further variants and lines derived therefrom.

[0461] Embodiment 31. The method according to claim embodiment 19, wherein the viral infection is an orthomyxovirus.

[0462] Embodiment 32. The method according to claim 33, wherein the orthomyxovirus is selected from alpha influenza virus, beta influenza virus, gamma influenza virus, delta influenza virus, isa virus, togot virus, and quaranja virus.

[0463] Embodiment 33. The method according to claim embodiment 31, wherein the viral infection is influenza A virus and influenza B virus.

[0464] Embodiment 34. The method according to Claim Embodiment 19, wherein the viral infection is of the Pneumoviridae family.

[0465] Embodiment 35. The method according to claim embodiment 34, wherein the viral infection is RSV.

[0466] Embodiment 36. The method according to Claim Embodiment 19, wherein the viral infection is of the Arenaviridae family.

[0467] Embodiment 37. The method according to claim embodiment 36, wherein the viral infection is Takaribe virus, Pichinde virus, Junin virus, Lassa fever virus, and lymphocytic choriomeningitis virus.

[0468] Embodiment 38. The method according to Claim Embodiment 19, wherein the viral infection is of the Bunyaviridae family.

[0469] Embodiment 39. The method according to claim 38, wherein the viral infection is Rift Valley fever virus, Punta Toro virus, Lacrosse virus, Maporal virus, Heartland virus, and Severe Fever with Thrombocytopenia Syndrome virus.

[0470] Embodiment 40. The method according to Claim Embodiment 19, wherein the viral infection is of the Flaviviridae family.

[0471] Embodiment 41. The method according to claim embodiment 40, wherein the viral infection is Zika virus, dengue virus 1, dengue virus 2, dengue virus 3, dengue virus 4, West Nile virus, yellow fever virus, Japanese encephalitis virus, Poissant virus, Usutu virus, and tick-borne encephalitis virus.

[0472] Embodiment 42. The method according to Claim Embodiment 19, wherein the viral infection is of the Picornaviridae family.

[0473] Embodiment 43. The method according to claim embodiment 42, wherein the viral infection is poliovirus, coxsackievirus, or enterovirus.

[0474] Embodiment 44. A method for treating or preventing a viral infection, comprising administering an effective amount of a pharmaceutical composition, a pharmaceutically acceptable excipient, and a compound of formula XXIXc to a subject in need of treatment or prevention of a viral infection, In the subject, a loading dose of the pharmaceutical composition is administered during the first treatment period. In the subject, a therapeutic dose of the pharmaceutical composition is administered during a second treatment period following the first treatment period. The compound of formula XXIXc is, [ka] A compound having the structure given by, or a pharmaceutically or physiological salt thereof, In the formula, R 1 However, the formula [ka] Selected from groups having a structure represented by, Y 3 However, it is hydrogen, aryl, heteroaryl, or heterocyclyl, and Y 3 However, you can choose to select one or more of the same or different R 10 Replaced by, R 5 However, R is hydrogen, alkyl, alkenyl, alkynyl, carbocykyl, heterocarbocykyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, allenyl, or lipid. 5 However, you can choose to select one or more of the same or different R 10 Replaced by, R 10 However, it is deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocarbocykrill, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocykritolthio, heterocarbocykritolthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, R 10 However, you can choose to select one or more of the same or different R 11 Replaced by, R 11The method is characterized by the presence of deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyryl, heterocarbocyryl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyramino, heterocarbocyramino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyrylthio, heterocarbocyrylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl.

[0475] Appearance 45.R 1 However, the formula [ka] [ka] [ka] The method according to claim 44, wherein the group has a structure represented by [the specified method].

[0476] Appearance 46.R 1 However, the formula [ka] The method according to claim 45, wherein the group has a structure represented by [the specified method].

[0477] Appearance 47.R 5The method according to any one of claims 44 to 46, wherein the selected lipid is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, and N,N-dipropylamino.

[0478] Appearance 48.R 5 The method according to claim 47, wherein the selected element is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0479] Appearance 49.R 5 The pharmaceutical composition according to claim 47, wherein the active ingredient is selected from methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, and 4-septyl.

[0480] Appearance 50.R 5 The method according to claim 47, wherein the selected element is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, and 3-pentyl.

[0481] Embodiment 51. The compound is of the formula [ka] A method according to any one of claims 44 to 50, which is a structure represented by, and a combination thereof.

[0482] Embodiment 52. The compound is of the formula [ka] The method according to claim 51, which is a structure represented by, or a combination thereof.

[0483] Embodiment 53. The method according to any one of Claims 44 to 52, wherein the first treatment period is 1 to 5 days after the diagnosis of the viral infection or after presentation for the prevention of the viral infection.

[0484] Embodiment 54. The method according to claim 53, wherein the first treatment period is 1 to 2 days after the diagnosis of the viral infection or after presentation for the prevention of the viral infection.

[0485] Embodiment 55. The method according to claim 53, wherein the first treatment period is the first day after the diagnosis of the viral infection or the first day after presentation for the prevention of the viral infection.

[0486] Embodiment 56. The method according to any one of the embodiments 44 to 55, wherein the loading dose is approximately 1.1 to approximately 10 times the therapeutic dose.

[0487] Embodiment 57. The method according to claim 56, wherein the loading dose is approximately 1.5 to approximately 5 times the therapeutic dose.

[0488] Embodiment 58. The method according to Claim Embodiment 56, wherein the loading dose is approximately 1.5 to approximately 2.5 times the therapeutic dose.

[0489] Embodiment 59. The method according to any one of Claims 44 to 58, wherein the loading dose is administered once a day, twice a day, three times a day, or four times a day.

[0490] Embodiment 60. The method according to any one of the embodiments 44 to 58, wherein the loading dose is administered at least twice a day.

[0491] Embodiment 61. The method according to claim embodiment 59 or 60, wherein the loading dose is divided equally among the number of times it is administered per day.

[0492] Embodiment 62. A method for producing a drug triphosphate, wherein the method is To provide multiple cells, The aforementioned plurality of cells are brought into contact with the compound of formula XXIXc, The process includes incubating the plurality of cells and the amount of the compound or pharmaceutical composition for a period of time effective for forming the drug triphosphate, The compound of formula XXIXc is, [ka] A compound having the structure given by, or a pharmaceutically or physiological salt thereof, In the formula, R 1 However, the formula [ka] Selected from groups having a structure represented by, Y 3 However, it is hydrogen, aryl, heteroaryl, or heterocyclyl, and Y 3 However, you can choose to select one or more of the same or different R 10 Replaced by, R 5 However, R is hydrogen, alkyl, alkenyl, alkynyl, carbocykyl, heterocarbocykyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, allenyl, or lipid. 5 However, you can choose to select one or more of the same or different R 10 Replaced by, R 10However, it is deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocarbocykrill, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocykritolthio, heterocarbocykritolthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, R 10 However, you can choose to select one or more of the same or different R 11 Replaced by, R 11 The method is characterized by the presence of deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyryl, heterocarbocyryl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl)2amino, carbocyramino, heterocarbocyramino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyrylthio, heterocarbocyrylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl.

[0493] Appearance 63.R 1 However, the formula [ka] [ka] [ka] The method according to claim 62, wherein the group is having a structure represented by

[0494] Appearance 64.R 1 However, the formula [ka] The method according to claim 63, wherein the group is a group having the structure represented by

[0495] Appearance 65.R 5 The method according to any one of claims 62 to 64, wherein the selected lipid is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2,6-dimethylphenyl, isopropoxide, tert-butoxide, N-propylamino, N-isopropylamino, N-tert-butylamino, N,N-dimethylamino, N,N-diethylamino, and N,N-dipropylamino.

[0496] Appearance 66.R 5 The method according to claim 65, wherein the selected element is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0497] Appearance 67.R 5 The method according to claim 66, wherein the selected element is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, and 4-septyl.

[0498] Appearance 68.R 5 The method according to claim embodiment 66, wherein the selected element is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, and 3-pentyl.

[0499] Embodiment 69. The compound is of the formula [ka] A method according to any one of claims 62 to 68, which is selected from structures represented by these, and combinations thereof.

[0500] Embodiment 70. The compound is of the formula [ka] The method according to claim 69, which is a structure represented by, and a combination thereof.

[0501] Embodiment 71. The method according to any one of the embodiments 62 to 70, wherein the plurality of cells are in vivo.

[0502] Embodiment 72. The method according to any one of the embodiments 62 to 71, wherein the contact is administered to an object requiring it.

[0503] Appearance 73. Formula [ka] A compound having a structure represented by, Q 1 However, null, O, S, C(=O), O(C=O), S(C=O), NR 40 (C=O), C(=S), O(C=S), S(C=S), NR 40 (C=S), O(C=O)O, S(C=O)O, NR 40 (C=O)O, S(C=O)S, NR 40 (C=O)S, NR40 (C=O)NR 40 , or O(C=S)O, S(C=S)O, NR 40 (C=S)O, S(C=S)S, NR 40 (C=S)S, NR 40 (C=S)NR 40 , or NR 40 And, Q 1 is C(=O), O(C=O), S(C=O), NR 40 (C=O), C(=S), O(C=S), S(C=S), or NR 40 (C=S) Q 3 However, C5-C8 carbocyclyl, C6-C 12 Ariel, C3-C 12 Heterocyclyl, or C3-C 12 Represents a heteroaryl, Y is either O or S, n is selected from 1, 2, and 3, preferably 1. A 1a , A 1b , A 1c , and A 1d Each of these independently consists of C, NR 40 Selected from S and O, R 40 However, in either case, hydrogen and C1-C6 alkyl are independently selected, and R is optionally selected. 10 It is replaced one or more times by, However, Q 3 If A represents a phenyl ring, 1a and A 1b Both are conditional on the fact that they cannot be O. Ar 1 However, selected from 3-12 membered carbon rings, 3-12 membered heterorings, 6-12 membered aryls, and 5-12 membered heteroaryls, Ar 1 However, arbitrarily and independently, one or more identical or different R 10 It can be replaced with, R 2a and R 3aEach of these independently consists of deuterium, hydrogen, C1-C6 alkyl, (C=O)C1-C6 alkyl, and (C=O)NR. 40 Selected from C1-C6 alkyl, (C=O)N(C1-C6 alkyl)2, (C=O)OC1-C6 alkyl, polyethylene glycol, aryls optionally substituted with alkyl groups, and lipids. R 2a and R 3a However, each can arbitrarily and independently select one or more identical or different Rs. 10 It can be replaced with, R 2a and R 3a However, together they can form a 5- to 7-membered heterocyclic ring, for example, R 2a and R 3a However, when combined, they can become C(CH3)2, C(=O), or C(=S). R 10 However, it is deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, or alkenyl, Lipids, as described herein, C 11 -C 22 High-grade alkyl, C 11 -C 22 It is a higher alkoxy or lipid. R 21a , R 21b , and R 22 Each of these independently consists of hydrogen, deuterium, and C1-C 12 Alkyl, C1-C 12 Alkylamino, (C1-C 12 Alkyl)2-amino, (CH2) q -(C1-C 12 Alkoxy), C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, and C1-C 12 Selected from alkoxy, q is an integer selected from 1, 2, and 3. R 21a , R 21b , and R 22 Each of them can optionally choose one or more of the same or different R10 It can be replaced with, R 21a and R 21b However, it contains a 3-7 member spirocycloalkyl or spirocycloheterocyl that is optionally covalently bonded and optionally substituted with an intermediate atom, R 22 However, R 21a or R 21b It contains a 3-7 member cycloalkyl or heterocycline that is optionally covalently bonded to and optionally substituted with an intermediate atom, R 22 However, you can choose to select one or more of the same or different R 10 It can be replaced with, R 10 However, in each case, independently, the elements are alkynyl, alkoxy, alkylamino, (alkyl)2amino, aryl, heteroaryl, allenyl, sulfinyl, sulfamoyl, sulfonyl, polyethylene glycol, lipid, nitro, or carbonyl, and R 10 However, arbitrarily and independently, one or more identical or different R 11 Replaced by, R 11 However, the compound is deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, (alkyl)2amino, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or oxo. or a pharmaceutically acceptable salt, solvate, or polymorph thereof.

[0504] Appearance 74.R 1 but, [ka] It is a structure represented by an expression selected from, n is selected from 1, 2, and 3. Y is either O or S, Z 1 However, N and CR 20a Selected from, Z 2 However, N and CR 20b’ Selected from, Z 3 However, N and CR 20c Selected from, Z 4 However, N and CR 20d Selected from, However, Z 1 , Z 2 , Z 3 , and Z 4 The condition is that three or fewer of them are N, A 1a , A 1b , A 1c , and A 1d Each of these independently consists of C, NR 40 Selected from S and O, R 40 However, hydrogen and C1-C6 are selected, However, Z 1 , Z 2 , Z 3 , and Z 4 If at least one of them is not N, then A 1a and A 1b Both are conditional on the fact that they cannot be O. Ar 1 However, they are selected from 3-12 membered carbon rings, 3-12 membered heterocarbon rings, 5-12 membered aryl groups, and 5-12 membered heteroaryl groups. R 2a and R 3a Each of these is independently selected from deuterium, hydrogen, -Ac, C1-C6 alkyl, C1-C6 carboxamide, C1-C6 carboxylate, polyethylene glycol, alkyl-substituted aryl, and lipids. R 2a and R 3a However, each can arbitrarily and independently select one or more identical or different Rs. 10 It can be replaced with, R 2a and R 3aHowever, it can be covalently bonded in any way, and together with the intermediate atom, it comprises an optionally substituted 3-7 member cycloalkyl or cycloheterocyl group. R 20a , R 20b , R 20c , and R 20d However, each is independently selected from hydrogen, deuterium, hydroxyl, amino, cyano, halogen, -OAc, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, (C1-C3 alkyl)2-amino, C1-C3 carboxamide, and lipids. R 20a , R 20b , R 20c , and R 20d However, each can arbitrarily and independently select one or more identical or different Rs. 10 It can be replaced with, R 10 However, R is deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, (alkyl)2amino, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl. 10 However, arbitrarily and independently, one or more identical or different R 11 Replaced by, R 11 However, these are deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, (alkyl)2amino, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl. Lipids, as described herein, C 11 -C 22 High-grade alkyl, C 11 -C 22 It is a higher alkoxy or lipid. R 21a , R 21b , and R 23 Each of these independently consists of hydrogen, deuterium, and C1-C 12 Alkyl, C1-C 12 Alkylamino, (C1-C12 Alkyl)2-amino, (CH2) q -(C1-C 12 Alkoxy, and C1-C 12 Selected from alkoxy, q is an integer selected from 1, 2, and 3. R 21a , R 21b , and R 23 Each of them can optionally choose one or more of the same or different R 10 It can be replaced with, R 21a and R 21b However, it contains a 5-7 member spirocycloalkyl or spirocycloheterocyl that is optionally covalently bonded and optionally substituted with an intermediate atom, R 23 However, R 21a or R 21b It contains a 5-7 member cycloalkyl or heterocycloalkyl group that is optionally covalently bonded to and optionally substituted with an intermediate atom, R 22 However, hydrogen, deuterium, and C1-C 22 Selected from alkyl groups, R 22 However, you can choose to select one or more of the same or different R 10 It can be replaced with, R 22 However, R 21a or R 21b The compound according to claim 73, comprising a 3- to 7-membered cycloalkyl or heterocycloalkyl group optionally covalently bonded to and together with an intermediate atom, optionally substituted.

[0505] Embodiment 75. The compound is [ka] A compound according to claim 73 or 74, having a structure represented by a formula selected from, and combinations thereof.

[0506] Embodiment 76. The compound is of the formula [ka] The compound according to claim 73 or 74, having a structure represented by [the given formula].

[0507] Embodiment 77. The compound is of the formula [ka] The compound according to claim 73 or 74, having a structure represented by [the given formula].

[0508] Embodiment 78. The compound is of the formula [ka] The compound according to claim 73 or 74, having a structure represented by [the given formula].

[0509] Appearance 79.R 1 but, [ka] A compound according to any one of claims 73 to 78, wherein the structure is represented by a formula selected from the following.

[0510] Appearance 80.R 1 However, the formula [ka] The compound according to claim embodiment 79, having a structure represented by [the given formula / symbol].

[0511] Appearance 81.R 1 but, [ka] The compound according to claim 80, wherein the structure is represented by a formula selected from the following.

[0512] Appearance 82.R 1 However, the formula [ka] The compound according to claim embodiment 79, having a structure represented by [the given formula / symbol].

[0513] Appearance 83.R 1 However, the formula [ka] The compound according to claim embodiment 82, having a structure represented by [the given formula / symbol].

[0514] Appearance 84.R 1 However, the formula [ka] The compound according to claim embodiment 79, having a structure represented by [the given formula / symbol].

[0515] Embodiment 85. The compound is of the formula [ka] [ka] A compound according to any one of claims 73 to 84, having a structure represented by, or a combination thereof.

[0516] Appearance 86.Ar 1 but, [ka] It has a structure represented by an expression selected from, In the formula, Z 5 However, N and CR 20e Selected from, Z 6 However, N and CR 20f Selected from, Z 7 However, N and CR 20g Selected from, Z 8 However, N and CR 20h Selected from, Z 9 However, N and CR 20i Selected from, However, Z 5 , Z 6 , Z 7 , Z 8 , and Z 9 The condition is that three or fewer of them are N, R 20e , R 20f , R 20g , R 20h , and R 20i However, each is independently selected from hydrogen, deuterium, hydroxyl, amino, cyano, halogen, -OAc, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, (C1-C3 alkyl)2-amino, C1-C3 carboxamide, and lipids. R 20e , R 20f , R 20g , R 20h , and R 20i However, each can arbitrarily and independently select one or more identical or different Rs. 10 It can be replaced with, R 20e , R 20f , R 20g , R 20h , and R 20i Two of these are optionally covalentl...

Claims

1. Formula XXX: 【Chemistry 1】 A compound having, or a pharmaceutically acceptable salt thereof, R １ but, 【Chemistry 2】 It is a structure represented by an expression selected from, Q ２ are C(=O), O(C=O), S(C=O), NR ４０ (C=O), C(=S), O(C=S), S(C=S), or NR ４０ (C = S) Q １ is null, O, S, C(=O), O(C=O), S(C=O), NR ４０ (C=O), C(=S), O(C=S), S(C=S), NR ４０ (C=S), O(C=O)O, S(C=O)O, NR ４０ (C=O)O, S(C=O)S, NR ４０ (C=O)S, NR ４０ (C=O)NR ４０ or O(C=S)O, S(C=S)O, NR ４０ (C=S)O, S(C=S)S, NR ４０ (C=S)S, NR ４０ (C=S)NR ４０ or NR ４０ and Q ３ However, C ５ -C ８ Cycloalkyl, C ６ -C １２ Ariel, C ３ -C １２ Heterocyclyl, or C ３ -C １２ It is a heteroaryl, Q ４ However, one or more identical or different Rs can be selected independently and arbitrarily. １０ It can be replaced with, Q ４ However, C ５ -C ８ Cycloalkyl, C ６ -C １２ Ariel, C ３ -C １２ Heterocyclyl, or C ３ -C １２ It is a heteroaryl, Q ４ However, one or more identical or different Rs can be selected independently and arbitrarily. １０ It can be replaced with, Y is either O or S, n is selected from 1, 2, and 3, preferably 1. A １ａ A １ｂ A １ｃ , and A １ｄ Each of these independently, C, NR ４０ Selected from S and O, R ４０ However, in either case, hydrogen and C １ -C ６ Selected from alkyl groups, optionally, R １０ Replaced by one or more times, R ２ａ and R ３ａ Each of them independently produces hydrogen and C １ -C ６ Alkyl, (C=O)C １ -C ６ Alkyl, (C=O)NR ４０ C １ -C ６ Alkyl, (C=O)N(C １ -C ６ Alkyl) ２ (C=O)OC １ -C ６ Selected from alkyl groups, wherein the alkyl group is optionally and independently one or more of the same or different R １０ Replaced with R ２ａ and R ３ａ However, together they can form a 5- to 7-membered heterocyclic ring. R ２１ａ However, in either case, hydrogen, deuterium, and C are produced independently. １ -C ２２ Alkyl, C １ -C ２２ Alkylamino, (C １ -C ２２ Alkyl) ２ Amino, (CH ２ ) ｑ - (C １ -C ２２ Alkoxy), C ６ -C １２ Ariel, C ３ -C １２ Cycloalkyl, C ３ -C １２ Heterocyclyl, C ３ -C １２ Heteroaryl, or C １ -C １２ It is an alkoxy, R ２１ｂ in each case, independently, is hydrogen, deuterium, C １ -C ２２ -alkyl, C １ -C ２２ -alkylamino, (C １ -C ２２ -alkyl) ２ -amino, (CH ２ ) ｑ -(C １ -C ２２ -alkoxy), C ６ -C １２ -aryl, C ３ -C １２ -cycloalkyl, C ３ -C １２ -heterocyclyl, C ３ -C １２ -heteroaryl, or C １ -C １２ -alkoxy, and R ２２ However, in either case, hydrogen, deuterium, and C are produced independently. １ -C ２２ Alkyl, C １ -C ２２ Alkylamino, (C １ -C ２２ Alkyl) ２ Amino, (CH ２ ) ｑ - (C １ -C ２２ Alkoxy), C ６ -C １２ Ariel, C ３ -C １２ Cycloalkyl, C ３ -C １２ Heterocyclyl, C ３ -C １２ Heteroaryl, or C １ -C １２ It is an alkoxy, and q is 1, 2, or 3. R ２１ａ , R ２１ｂ , and R ２２ Each of them can optionally choose one or more of the same or different R １０ It can be replaced with, R ２１ａ , R ２１ｂ , R ２２ , and R ４０ Any two or more of these can come together to form a ring. R １０ However, in each case, independently, deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyrill, heterocarbocyrill, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ２ Amino, carbocyclamino, heterocarboclamino, arylamino, heteroarylamino, heterocyclamino, cycloalcamino, cycloalkenamino, alkylthio, carbocyclilthio, heterocarboclilthio, arylthio, heteroarylthio, heterocyclilthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl, R １０ However, you can choose to select one or more identical or different R １１ Replaced by, R １１ However, in each case, independently, deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocyrill, heterocarbocyrill, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ２ Amino, carbocyclamino, heterocarboclamino, arylamino, heteroarylamino, heterocyclamino, cycloalcamino, cycloalkenamino, alkylthio, carbocyclilthio, heterocarboclilthio, arylthio, heteroarylthio, heterocyclilthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, polyethylene glycol, or carbonyl. Lipids, independently, C １１ -C ２２ Alkyl, C １１ -C ２２ Alkoxy, or C ６ -C １８ A compound, or a pharmaceutically acceptable salt thereof, that is an aryl substituted with an alkyl group.

2. R １ but, 【Transformation 3】 And, During the ceremony, Z １ However, N and C-R ２０ａ Selected from, Z ２ However, N and C-R ２０ｂ’ Selected from, Z ３ However, N and C-R ２０ｃ Selected from, Z ４ However, N and C-R ２０ｄ Selected from, However, Z １ Z ２ Z ３ , and Z ４ The condition is that three or fewer of them are N, R ２０ａ , R ２０ｂ , R ２０ｃ , and R ２０ｄ However, each is independent of hydrogen, deuterium, hydroxyl, amino, cyano, halogen, and C. １ -C ６ Alkyl, OC １ -C ６ Alkyl, (C=O)C １ -C ６ Alkyl, (C=O)NR ４０ C １ -C ６ Alkyl, (C=O)N(C １ -C ６ Alkyl) ２ (C=O)OC １ -C ６ Selected from alkyls and lipids, wherein the alkyl group is optionally and independently one or more R １０ Replaced by, R ２３ However, hydrogen, C １ -C １２ Alkyl, C １ -C １２ Alkylamino, (C １ -C １２ Alkyl) ２ Amino, (CH ２ ) ｑ - (C １ -C １２ Alkoxy), C ３ -C １２ Cycloalkyl, C ６ -C １２ Ariel, C ３ -C １２ Heterocyclyl, C ３ -C １２ Heteroaryls, and C １ -C １２ It is an alkoxy, where q is an integer selected from 1, 2, and 3, and R ２３ However, R is optional. １０ Replaced by one or more times, R ２３ , R ２１ａ , R ２１ｂ , and R ４０ The compound according to claim 1, wherein any two or more of these can form a ring.

3. R １ but, 【Chemistry 4】 The compound according to claim 1.

4. R １ but, 【Transformation 5】 The compound according to claim 1.

5. R １ but, 【Transformation 6】 It is a structure represented by an expression selected from, The compound according to claim 1, wherein the compound is at least 75 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the stereoisomer represented at the phosphorus atom.

6. R １ but, 【Transformation 7】 And, The compound according to claim 1, wherein the compound is at least 75 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the stereoisomer represented at the phosphorus atom.

7. R １ but, 【Transformation 8】 And, The compound according to claim 1, wherein the compound is at least 75 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the stereoisomer represented at the phosphorus atom.

8. Z １ However, N is Z ２ Z ３ , and Z ４ But is it CH? Z ２ However, N is Z ２ Z ３ , and Z ４ But is it CH? Z ３ However, N is Z １ Z ２ , and Z ４ However, is it CH or Z ４ However, N is Z １ Z ２ , and Z ３ The compound according to any one of claims 3 to 7, wherein the compound is CH.

9. R ２０ａ , R ２０ｂ , R ２０ｃ , and R ２０ｄ The compound according to any one of claims 2 to 8, wherein the compound is independently hydrogen, deuterium, hydroxyl, amino, cyano, or halogen.

10. R ２０ａ , R ２０ｂ , R ２０ｃ , and R ２０ｄ However, independently, hydrogen, C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkyl, C １ -C ３ A compound according to any one of claims 2 to 8, selected from haloalkoxys and halogens.

11. R ２０ａ , R ２０ｂ , R ２０ｃ , and R ２０ｄ The compound according to any one of claims 2 to 8, wherein the compound is independently selected from hydrogen, F, and Cl.

12. R ２０ａ , R ２０ｂ , R ２０ｃ , and R ２０ｄ The compound according to any one of claims 2 to 8, wherein two of the elements are hydrogen and the other two are independently F or Cl.

13. R ２０ａ The compound according to any one of claims 2 to 12, wherein the compound is F or Cl.

14. R ２０ｂ The compound according to any one of claims 2 to 12, wherein the compound is F or Cl.

15. R ２０ｄ The compound according to any one of claims 2 to 12, wherein the compound is F or Cl.

16. R ２０ｅ The compound according to any one of claims 2 to 12, wherein the compound is F or Cl.

17. R ２０ａ , R ２０ｂ , R ２０ｃ , and R ２０ｄ However, independently, hydrogen, deuterium, CH ３ CF ３ , OCH ３ OCF ３ The compound according to any one of claims 2 to 8, which is hydroxyl, amino, cyano, or halogen.

18. R ２０ａ , R ２０ｂ , R ２０ｃ , and R ２０ｄ The compound according to any one of claims 2 to 8, wherein the compound is independently hydrogen, F, or Cl.

19. R ２０ａ , R ２０ｂ , R ２０ｃ , R ２０ｄ , and R ２０ｅ However, independently, hydrogen, F, Cl, CH ３ CF ３ , OCH ３ , or OCF ３ The compound according to claim 1.

20. R １ but, 【Chemistry 9】 And, During the ceremony, Z ５ However, N and C-R ２０ｅ Selected from, Z ６ However, N and C-R ２０ｆ Selected from, Z ７ However, N and C-R ２０ｇ Selected from, Z ８ However, N and C-R ２０ｈ Selected from, Z ９ However, N and C-R ２０ｉ Selected from, However, Z ５ Z ６ Z ７ Z ８ , and Z ９ The condition is that three or fewer of them are N, R ２０ｅ , R ２０ｆ , R ２０ｇ , R ２０ｈ , R ２０ｉ , R ２０ｏ , and R ２０ｐ However, each is independent of hydrogen, deuterium, hydroxyl, amino, cyano, and halogen C １ -C ６ Alkyl, OC １ -C ６ Alkyl, (C=O)C １ -C ６ Alkyl, (C=O)NR ４０ C １ -C ６ Alkyl, (C=O)N(C １ -C ６ Alkyl) ２ (C=O)OC １ -C ６ Selected from alkyl or lipids, wherein the alkyl is optionally R １０ Replaced by one or more times, R ２０ｅ , R ２０ｆ , R ２０ｇ , R ２０ｈ , and R ２０ｉ Two or more of them can come together to form a ring. Z １０ However, N and C-R ２０ｊ Selected from, Z １１ However, N-R ２０ｋ and CR ２０ｌ R ２０ｍ Selected from, R ２０ｊ , R ２０ｌ , and R ２０ｍ However, each is independent of hydrogen, deuterium, hydroxyl, amino, cyano, halogen, and C. １ -C ６ Alkyl, OC １ -C ６ Alkyl, (C=O)C １ -C ６ Alkyl, (C=O)NR ４０ C １ -C ６ Alkyl, (C=O)N(C １ -C ６ Alkyl) ２ (C=O)OC １ -C ６ Selected from alkyls and lipids, wherein the alkyl is optionally R １０ Substituted once or more by R ２０ｊ , R ２０ｋ , R ２０ｌ , R ２０ｍ , R ２０ｏ , and R ２０ｐ Any two or more of these can come together to form a ring. R ２０ｋ However, hydrogen, or optionally, R １０ C substituted one or more times by １ -C ６ The compound according to claim 1, wherein it is alkyl.

21. R ２０ｅ , R ２０ｆ , R ２０ｇ , R ２０ｈ , and R ２０ｉ However, each independently, hydrogen, C １－３ Alkyl, C １－３ The compound according to claim 20, wherein the compound is an alkoxy, F, or Cl.

22. R ２０ｅ , R ２０ｆ , R ２０ｇ , R ２０ｈ , and R ２０ｉ The compound according to claim 20, wherein one or two of them are F or Cl, and the other is H.

23. R ２０ｅ , R ２０ｆ , R ２０ｇ , R ２０ｈ , and R ２０ｉ The compound according to claim 20, wherein one of them is F or Cl, and the other is H.

24. R ２０ｅ , R ２０ｆ , R ２０ｇ , R ２０ｈ , and R ２０ｉ The compound according to claim 20, wherein two of the elements are F or Cl and the other is H.

25. R ２０ｅ , R ２０ｆ , R ２０ｇ , R ２０ｈ , and R ２０ｉ The compound according to claim 20, wherein two of the atoms are Cl and the other is H.

26. R １ but, 【Chemistry 10】 The compound according to claim 1.

27. R １ but, 【Chemistry 11】 The compound according to claim 1.

28. R ２１ａ , R ２１ｂ , and R ２３ However, independently, hydrogen, deuterium, C １ -C ８ Alkyl, C １ -C ８ Alkylamino, (C １ -C ８ Alkyl) ２ Amino, and C １ -C ８ It is an alkoxy, R ２１ａ , R ２１ｂ , and R ２３ However, R can be selected independently and arbitrarily. １０ The compound according to claim 26 or 27, which is substituted by...

29. R ２１ａ and R ２１ｂ But together, C ３ -C ７ Cycloalkyl or C １ -C ７ A compound according to any one of claims 26 to 28, which forms a heterocyclyl ring.

30. R ２１ａ and R ２３ The compound according to any one of claims 26 to 28, wherein the compounds come together to form a ring.

31. R ２２ However, C １ -C ６ Alkyl or C １ -C ６ It is an alkoxy, R ２２ However, R can be selected independently and arbitrarily. １０ The compound according to any one of claims 26 to 28, which is substituted once or more by [a specific agent].

32. R ２２ However, C １２ -C ２２ Alkyl or C １２ -C ２２ The compound according to claim 31, which is an alkoxy.

33. formula 【Chemistry 12】 It has, in the formula, R ２２ However, C １ -C ６ It is alkyl, and each R ２１ａ and R ２１ｂ However, independently, (CH ２ ) ｑ - (C １ -C １２ The compound according to claim 1, selected from alkoxys, wherein q is 1, 2, or 3.

34. formula 【Chemistry 13】 It has, in the formula, R ２２ However, C １ -C ２２ The compound according to claim 1, wherein x and z are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

35. The compound according to claim 34, wherein both z and x are 0.

36. formula 【Chemistry 14】 The compound according to claim 1, wherein each of m and y is independently selected from 1, 2, 3, and 4.

37. The compound according to claim 36, wherein y is 1.

38. The compound according to claim 36, wherein m is 1.

39. formula 【Chemistry 15】 It has, in the formula, A ２ However, CH ２ O, S, NC １ -C ３ Selected from alkyl and NH, R ３０ However, hydrogen, deuterium, C １ -C ６ Alkyl, or C １ -C ６ The compound according to claim 1, wherein it is an alkoxy.

40. A is CH ２ And R ３０ However, hydrogen, deuterium, or C １ -C ６ The compound according to claim 39, wherein it is alkyl.

41. A is O, R ３０ However, hydrogen, deuterium, or C １ -C ６ The compound according to claim 39, wherein it is alkyl.

42. A is S, and R ３０ However, hydrogen, deuterium, or C １ -C ６ The compound according to claim 39, wherein it is alkyl.

43. A is NH, and R ３０ However, hydrogen, deuterium, or C １ -C ６ The compound according to claim 39, wherein it is alkyl.

44. A is NC １ -C ３ It is alkyl, R ３０ However, hydrogen, deuterium, or C １ -C ６ The compound according to claim 39, wherein it is alkyl.

45. R ３０ The compound according to any one of claims 39 to 44, wherein the compound is hydrogen, methyl, or ethyl.

46. R ３０ The compound according to any one of claims 39 to 44, wherein the compound is hydrogen.

47. R ３０ The compound according to any one of claims 39 to 44, wherein the compound is methyl.

48. R ３０ The compound according to any one of claims 39 to 44, wherein the compound is ethyl.

49. formula 【Chemistry 16】 It has, During the ceremony, R ４１ and R ４２ Each of them independently contains hydrogen and C １ -C １２ Selected from alkyl groups, R ４１ and R ４２ Each of them, at their own discretion and independently, chooses one or more identical or different R １０ It can be replaced with R ４１ and R ４２ The compound according to claim 1, wherein the compounds can come together to form a ring.

50. formula 【Chemistry 17】 It has, In the formula, R ６ , R ６’ , R ６’’ , and R ６’’’ However, each is independent of hydrogen, deuterium, hydroxyl, amino, cyano, halogen, and C. １ -C ６ Alkyl, (C=O)C １ -C ６ Alkyl, (C=O)NR ４０ C １ -C ６ Alkyl, (C=O)N(C １ -C ６ Alkyl) ２ (C=O)OC １ -C ６ Selected from alkyl or lipids, R ６ , R ６’ , R ６’’ , and R ６’’’ However, each can arbitrarily and independently select one or more identical or different Rs. １０ It can be replaced with, However, R ６ , R ６’ , R ６’’ , and R ６’’’ The compound according to claim 1, provided that at least one of them is not hydrogen.

51. formula [Chemistry 18] It has, In the formula, R ６ , R ６’ , R ６’’ , and R ６’’’ However, each is independent of hydrogen, deuterium, hydroxyl, amino, cyano, halogen, and C. １ -C ６ Alkyl, (C=O)C １ -C ６ Alkyl, (C=O)NR ４０ C １ -C ６ Alkyl, (C=O)N(C １ -C ６ Alkyl) ２ (C=O)OC １ -C ６ Selected from alkyl or lipids, R ６ , R ６’ , R ６’’ , and R ６’’’ However, each can arbitrarily and independently select one or more identical or different Rs. １０ It can be replaced with, The compound according to claim 1, wherein the compound is at least 75 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the stereoisomer represented at the phosphorus atom.

52. formula 【Chemistry 19】 It has, In the formula, R ６ , R ６’ , R ６’’ , and R ６’’’ However, each is independent of hydrogen, deuterium, hydroxyl, amino, cyano, halogen, and C. １ -C ６ Alkyl, (C=O)C １ -C ６ Alkyl, (C=O)NR ４０ C １ -C ６ Alkyl, (C=O)N(C １ -C ６ Alkyl) ２ (C=O)OC １ -C ６ Selected from alkyl or lipids, R ６ , R ６’ , R ６’’ , and R ６’’’ However, each can arbitrarily and independently select one or more identical or different Rs. １０ It can be replaced with, The compound according to claim 1, wherein the compound is at least 75 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the stereoisomer represented at the phosphorus atom.

53. R ６ , R ６’ , R ６’’ , and R ６’’’ A compound according to any one of claims 50 to 52, wherein one of the compounds is not hydrogen.

54. R ６ , R ６’ , R ６’’ , and R ６’’’ A compound according to any one of claims 50 to 52, wherein two of the compounds are not hydrogen.

55. R ６ , R ６’ , R ６’’ , and R ６’’’ A compound according to any one of claims 50 to 52, wherein three of the compounds are not hydrogen.

56. R ６ However, the compound according to any one of claims 50 to 52, which is not hydrogen.

57. R ６’ However, the compound is not hydrogen, as described in any one of claims 50 to 52.

58. R ６’’ However, the compound according to any one of claims 50 to 52, which is not hydrogen.

59. R ６’’’ However, the compound is not hydrogen, as described in any one of claims 50 to 52.

60. R ６ , R ６’ , and R ６’’ The compound according to any one of claims 50 to 52, wherein each of them is hydrogen.

61. R ６’ , R ６’’ , and R ６’’’ The compound according to any one of claims 50 to 52, wherein each of them is hydrogen.

62. R ６ , R ６’ , and R ６’’’ The compound according to any one of claims 50 to 52, wherein each of them is hydrogen.

63. R ６ , R ６’ , R ６’’ , and R ６’’’ Each of the compounds according to any one of claims 50 to 52 is hydrogen.

64. R ６ , R ６’ , R ６’’ , and R ６’’’ The compound according to any one of claims 50 to 52, wherein one of the elements is a halogen.

65. R ６ , R ６’ , R ６’’ , and R ６’’’ The compound according to any one of claims 50 to 52, wherein two of the elements are halogens.

66. R ６ , R ６’ , R ６’’ , and R ６’’’ The compound according to any one of claims 50 to 52, wherein three of the elements are halogens.

67. R ６ , R ６’ , R ６’’ , and R ６’’’ The compound according to any one of claims 50 to 52, wherein one of the is Cl.

68. R ６ , R ６’ , R ６’’ , and R ６’’’ The compound according to any one of claims 50 to 52, wherein two of the members are Cl.

69. R ６ , R ６’ , R ６’’ , and R ６’’’ The compound according to any one of claims 50 to 52, wherein three of the components are Cl.

70. R ６ , R ６’ , R ６’’ , and R ６’’’ The compound according to any one of claims 50 to 52, wherein one of them is F.

71. R ６ , R ６’ , R ６’’ , and R ６’’’ The compound according to any one of claims 50 to 52, wherein two of the compounds are F.

72. R ６ , R ６’ , R ６’’ , and R ６’’’ The compound according to any one of claims 50 to 52, wherein three of them are F.

73. R １ but, 【Chemistry 20】 The compound according to claim 1.

74. R １ but, 【Chemistry 21】 The compound according to claim 1.

75. A １ａ However, it is NH and A １ｂ The compound according to any one of claims 1 to 74, wherein the compound is O.

76. A １ａ However, O and A １ｂ The compound according to any one of claims 1 to 74, wherein the compound is NH.

77. A １ａ However, CH ２ A １ｂ The compound according to any one of claims 1 to 74, wherein the compound is O.

78. A １ｃ However, it is NH and A １ｄ The compound according to any one of claims 1 to 74, wherein the compound is O.

79. A １ｃ However, O and A １ｄ The compound according to any one of claims 1 to 74, wherein the compound is NH.

80. A １ｃ However, CH ２ A １ｄ The compound according to any one of claims 1 to 74, wherein the compound is O.

81. Q ４ but, 【Chemistry 22】 And, In the formula, R ｈ１ However, CH ３ , OCH ３ CF ３ OCF ３ , I, Cl, or F, R ｈ２ However, H, CH ３ , OCH ３ CF ３ OCF ３ The compound according to claim 1, wherein the compound is I, Cl, or F.

82. R ｈ１ However, it is Cl, and R ｈ２ The compound according to claim 81, wherein H is present.

83. R ｈ１ However, F is R ｈ２ The compound according to claim 81, wherein H is present.

84. R ｈ１ However, I is R ｈ２ The compound according to claim 81, wherein H is present.

85. R ｈ１ However, it is Cl, and R ｈ２ However, the compound according to claim 81 is F.

86. R ｈ１ However, F is R ｈ２ However, the compound according to claim 81 is F.

87. R ｈ１ However, it is Cl, and R ｈ２ The compound according to claim 81, wherein the compound is Cl.

88. R ｈ１ However, F is R ｈ２ The compound according to claim 81, wherein the compound is Cl.

89. Q ２ The compound according to any one of claims 81 to 88, wherein the compound is C(=O), C(=S), NH(C=O), or NH(C=S).

90. R ２ａ and R ３ａ Each of them is (C=O)C １ -C ６ Alkyl or (C=O)OC １ -C ６ It is an alkyl group, and the alkyl group is optionally R １０ A compound according to any one of claims 1 to 89, which is substituted once or more by [a specific agent].

91. R ２ａ and R ３ａ Each of them is (C=O)C １ -C ６ It is an alkyl group, and the alkyl group is optionally R １０ A compound according to any one of claims 1 to 90, which is substituted once or more by [a specific agent].

92. R ２ａ and R ３ａ Each of them is (C=O)OC １ -C ６ It is an alkyl group, and the alkyl group is optionally R １０ A compound according to any one of claims 1 to 90, which is substituted once or more by [a specific agent].

93. R ２ａ and R ３ａ Each of them is (C=O)C １ -C ６ A compound according to any one of claims 1 to 90, wherein the alkyl group is unsubstituted.

94. R ２ａ and R ３ａ Each of them is (C=O)OC １ -C ６ It is an alkyl group, and each of the alkyl groups is R １０ A compound according to any one of claims 1 to 90, which is substituted once or more by [a specific agent].

95. R ２ａ and R ３ａ Each of them is (C=O)OCH ２ A compound according to any one of claims 1 to 90, wherein the pH is [value missing].

96. R ２ａ and R ３ａ Each of them is (C=O)C １ -C ３ The compound according to any one of claims 1 to 90, which is alkyl.

97. R ２ａ and R ３ａ Each of them is (C=O)CH ３ The compound according to any one of claims 1 to 90.

98. R ２ａ and R ３ａ The compound according to any one of claims 1 to 90, wherein each of them is (C=O)i-Pr.

99. R ２ａ and R ３ａ However, both are C(CH ３ ) ２ The compound according to any one of claims 1 to 90, wherein the compound is C(=O) or C(=S).

100. R １０ However, independently, deuterium, hydroxyl, amino, halogen, C １ -C ８ Alkyl, C ２ -C ８ Alkenil, C ２ -C ８ Alkinyl, Carbocyclyl, C ６ -C １２ Ariel, C １ -C ８ Heteroaryl, C ２ -C ８ Heterocyclyl, C ３ -C ８ Cycloalkyl, C ５ -C ８ Cycloalkenyl, C １ -C ８ If selected from alkoxy, R １０ However, you can choose to select one or more identical or different R １１ Replaced by, R １１ However, deuterium, C ６ Aryl, hydroxy, halogen, C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C １ -C ３ Alkylamino, (C １ -C ３ Alkyl) ２ A compound according to any one of claims 1 to 99, which is an amino acid.

101. R １０ However, independently, hydroxyl, halogen, C １ -C ８ Alkyl and C １ -C ８ If selected from alkoxy, R １０ However, you can choose to select one or more identical or different R １１ A compound according to any one of claims 1 to 99, which is substituted with

102. R １０ However, independently, F, Cl, CH ３ , OCH ３ , or if selected from OH, the CH ３ and OCH ３ However, R is optional. １１ A compound according to any one of claims 1 to 101, which is substituted with

103. R １０ However, CF ３ OCF ３ ,CH ２ Ph, or OCH ２ A compound according to any one of claims 1 to 102, wherein the pH is [value missing].

104. Q ３ If A is phenyl, １ａ and A １ｂ The compound according to claim 1, wherein neither is oxygen.

105. Formula XXIX: 【Chemistry 23】 A compound thereof, or a pharmaceutically acceptable salt thereof, In the formula, R １ However, the formula 【Chemistry 24】 Selected from groups having a structure represented by, Y is either O or S, Y １ However, OY ３ or BH ３ － M ＋ And M ＋ However, it is an alkali cation or an ammonium cation. Y ３ However, it is hydrogen, aryl, heteroaryl, or heterocyclyl, Y ３ However, you can choose to select one or more identical or different R １０ Replaced by, R ２ａ and R ３ａ Each of them independently produces hydrogen and C １ -C ６ Alkyl, (C=O)C １ -C ６ Alkyl, (C=O)NR ４０ C １ -C ６ Alkyl, (C=O)N(C １ -C ６ Alkyl) ２ , or (C=O)OC １ -C ６ Selected from alkyl groups, wherein the alkyl group is optionally and independently one or more of the same or different R １０ Replaced with R ４０ However, in either case, hydrogen and C １ -C ６ Selected from alkyl groups, optionally, R １０ Replaced by one or more times, R ２ａ and R ３ａ However, together they can form a 5- to 7-membered complex ring. R ５ However, R is hydrogen, alkyl, carbocykyl, heterocarbocykyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, or lipid. ５ However, you can choose to select one or more identical or different R １０ Replaced by, R ７ and R ７’ However, each independently, hydrogen, deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocykyl, heterocarbocykyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ２ Selected from amino, carbocyclamino, heterocarboclamino, arylamino, heteroarylamino, heterocyclamino, cycloalcamino, cycloalkenamino, alkylthio, carbocyclilthio, heterocarboclthio, arylthio, heteroarylthio, heterocyclilthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, R ７ However, you can choose to select one or more identical or different R １０ Replaced by, R １０ However, deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocykyl, heterocarbocykyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ２ Amino, carbocyclamino, heterocarboclamino, arylamino, heteroarylamino, heterocyclamino, cycloalcamino, cycloalkenamino, alkylthio, carbocyclilthio, heterocarboclitolthio, arylthio, heteroarylthio, heterocyclilthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, R １０ However, you can choose to select one or more identical or different R １１ Replaced by, R １１ However, deuterium, hydroxy, azide, thiol, amino, cyano, halogen, alkyl, alkenyl, alkynyl, carbocykyl, heterocarbocykyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocyoxy, heterocarbocyoxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ２ Amino, carbocyclamino, heterocarboclamino, arylamino, heteroarylamino, heterocyclamino, cycloalcamino, cycloalkenamino, alkylthio, carbocyclilthio, heterocarboclthio, arylthio, heteroarylthio, heterocyclilthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl. Lipids, independently, C １１ -C ２２ Alkyl, C １１ -C ２２ Alkoxy, or C ６ -C １８ A compound, or a pharmaceutically acceptable salt thereof, that is an aryl substituted with an alkyl group.

106. R ２ａ and R ３ａ However, both are C(CH ３ ) ２ The compound according to claim 105, wherein the compound is C(=O) or C(=S).

107. R ２ａ and R ３ａ However, each of them is (C=O)C １ -C ６ Alkyl or (C=O)OC １ -C ６ It is an alkyl group, and each is optionally R １０ The compound according to claim 105, which is substituted by

108. R ２ａ and R ３ａ The compound according to claim 105, wherein each of them is hydrogen.

109. R ７ and R ７’ However, independently, hydrogen, C １ -C ８ Alkyl, C ２ -C ８ Alkenil, C ２ -C ８ Alkinyl, C ６ -C １２ Ariel, C １ -C １２ Heteroaryl, C ２ -C ８ Heterocyclyl, C ３ -C ８ Cycloalkyl, or C ５ -C ８ It is a cycloalkenyl, R ５ However, you can choose to select one or more identical or different R １０ A compound according to any one of claims 105 to 108, which is substituted with

110. R ７ However, it is hydrogen, R ７’ However, R is optional. １０ C replaced by １ -C ８ A compound according to any one of claims 105 to 109, wherein it is alkyl.

111. R ７ However, it is hydrogen, R ７’ However, R １０ C replaced by １ -C ８ A compound according to any one of claims 105 to 109, wherein it is alkyl.

112. R ７ However, C １ -C ８ It is alkyl, and optionally R １０ Replaced by R ７’ The compound according to any one of claims 105 to 109, wherein the compound is hydrogen.

113. R ７ However, R １０ C replaced by １ -C ８ It is alkyl, R ７’ The compound according to any one of claims 105 to 109, wherein the compound is hydrogen.

114. R ７ and R ７’ The compound according to any one of claims 105 to 109, wherein each of them is hydrogen.

115. R ７ and R ７’ However, each is independent of C １ -C ８ It is an alkyl group, and each is optionally R １０ A compound according to any one of claims 105 to 109, which is substituted by...

116. R ７ and R ７’ However, each is independent of C １ -C ８ It is an alkyl group, and each is R １０ A compound according to any one of claims 105 to 109, which is substituted by...

117. R ７ However, R １０ C replaced by １ -C ８ It is alkyl, R ７’ However, C １ -C ８ A compound according to any one of claims 105 to 109, wherein it is alkyl.

118. R ７ However, C １ -C ８ It is alkyl, R ７’ However, R １０ C replaced by １ -C ８ A compound according to any one of claims 105 to 109, wherein it is alkyl.

119. R ５ However, hydrogen, C １ -C ８ Alkyl, C ６ -C １２ Ariel, C １ -C １２ Heteroaryl, C ２ -C ８ Heterocyclyl, C ３ -C ８ Cycloalkyl, or C ５ -C ８ It is a cycloalkenyl, R ５ However, you can choose to select one or more identical or different R １０ A compound according to any one of claims 105 to 118, which is substituted with

120. R ５ However, hydrogen, C １ -C ８ Alkyl, or C ３ -C ８ It is a cycloalkyl group, and optionally contains one or more of the same or different R groups. １０ A compound according to any one of claims 105 to 118, which is substituted with

121. Y is O, and Y １ is OY ３ and Y ３ is hydrogen, C ６ -C １２ -aryl, or C １ -C １２ -heteroaryl, a compound according to any one of claims 105 to 118.

122. Y is O, Y １ However, OY ３ Y ３ However, it is hydrogen or phenyl, and optionally one or more of the same or different R １０ A compound according to any one of claims 105 to 118, which is substituted by...

123. Y is O, and Y １ is OY ３ and Y ３ is hydrogen or unsubstituted phenyl, a compound according to any one of claims 105 to 118.

124. Y is O, Y １ However, OY ３ Y ３ However, it is hydrogen or phenyl, and one or more of the same or different R １０ A compound according to any one of claims 105 to 118, which is substituted by...

125. R １ but, 【Chemistry 25】 The compound according to any one of claims 105 to 124.

126. R １ but, 【Chemistry 26】 And, The compound according to any one of claims 105 to 124, wherein the stereochemical purity of the phosphorus atom is at least 75 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the indicated stereoisomer.

127. R １ but, 【Chemistry 27-1】 【Chemistry 27-2】 The compound according to any one of claims 105 to 124.

128. R １ but, 【Chemistry 28-1】 【Chemistry 28-2】 And, The compound according to any one of claims 105 to 124, wherein the stereochemical purity of the phosphorus atom is at least 75 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the stereoisomer shown in the phosphorus atom.

129. R ５ The compound according to any one of claims 105 to 124, wherein the compound is methyl, ethyl, propyl, isopropyl, butyl, i-butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or 2,6-dimethylphenyl.

130. R ５ The compound according to any one of claims 105 to 124, wherein the compound is methyl, ethyl, propyl, butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, 4-septyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or 2,6-dimethylphenyl.

131. R ５ The compound according to any one of claims 105 to 124, wherein the compound is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

132. R ５ The compound according to any one of claims 105 to 124, wherein the compound is butyl, i-butyl, s-butyl, t-butyl, pentyl, s-pentyl, t-pentyl, neopentyl, 3-pentyl, hexyl, t-hexyl, or 4-septyl.

133. R ５ The compound according to any one of claims 105 to 124, wherein the compound is phenyl or 2,6-dimethylphenyl.

134. R ５ The compound according to any one of claims 105 to 124, wherein the compound is methyl or ethyl.

135. The following formula: 【Chemistry 29】 The compound according to claim 105, having or a pharmaceutically acceptable salt thereof.

136. R １ but, 【Transformation 30】 The compound described in any one of claims 105 to 134, not the compound described in any one of claims 105 to 134.

137. The following formula: 【Chemistry 31-1】 【Chemistry 31-2】 Compounds having, or a pharmaceutically acceptable salt thereof.

138. The following formula: 【Chemistry 32】 A compound having, A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is at least 75 mol%, at least 85 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the stereoisomer represented at the phosphorus atom.

139. formula 【Chemistry 33-1】 【Chemistry 33-2】 【Chemistry 33-3】 Compounds having, or a pharmaceutically acceptable salt thereof.

140. The following formula: 【Transformation 34】 A compound having any of the following: or a pharmaceutically acceptable salt thereof.

141. The following formula: 【Chemistry 35】 A compound having any of the following: or a pharmaceutically acceptable salt thereof.

142. The following formula 【Transformation 36】 Compounds having, or a pharmaceutically acceptable salt thereof.

143. The following formula: 【Chemistry 37-1】 【Chemistry 37-2】 【Chemistry 37-3】 A compound having any of the above, or a pharmaceutically acceptable salt thereof.

144. The following formula: 【Chemistry 38-1】 【Chemistry 38-2】 【Chemistry 38-3】 【Chemistry 38-4】 【Chemistry 38-5】 【Chemistry 38-6】 【Chemistry 38-7】 【Chemistry 38-8】 【Chemistry 38-9】 Compounds having, or a pharmaceutically acceptable salt thereof.

145. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound according to any one of claims 1 to 144.

146. The pharmaceutical composition according to claim 145, further comprising a propellant.

147. The pharmaceutical composition according to claim 146, wherein the propellant is compressed air, ethanol, nitrogen, carbon dioxide, nitrous oxide, hydrofluoroalkane (HFA), 1,1,1,2,-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, or a combination thereof.

148. A pressurized vessel comprising the pharmaceutical composition described in claim 145.

149. The container according to claim 148, wherein the container is a manual pump sprayer, inhaler, measuring inhaler, dry powder inhaler, atomizer, vibrating mesh atomizer, jet atomizer, or ultrasonic atomizer.

150. A method for treating or preventing a viral infection, comprising administering an effective amount of a compound according to any one of claims 1 to 149.

151. The method according to claim 150, wherein the viral infection is a Togaviridae infection.

152. The method according to claim 151, wherein the Togaviridae infection is caused by an infection with a virus selected from Eastern Equine Encephalitis Virus, Western Equine Encephalitis Virus, Venezuelan Equine Encephalitis Virus, Chikungunya Virus, and Ross River Virus.

153. The method according to claim 150, wherein the viral infection is of the Coronavirus family.

154. The method according to claim 153, wherein the viral infection is a human coronavirus infection, a SARS coronavirus infection, or a MERS coronavirus infection.

155. The method according to claim 154, wherein the SARS coronavirus infection is an infection caused by the SARS-CoV2 virus.

156. The method according to claim 155, wherein the SARS-CoV-2 virus comprises a more virulent strain of SARS-CoV-2, known as P. 1, a variant of the United Kingdom known as 20I / 501Y.V1, VOC 202012 / 01, or B. 1.1.7, and a variant of the South African virus known as 20H / 501Y.V2 or B. 1.351, and further variants and strains derived therefrom, but not limited to, SARS-CoV-2 variants.

157. The method according to claim 150, wherein the viral infection is an orthomyxoviridae virus.

158. The method according to claim 150, wherein the viral infection is influenza A virus and influenza B virus.

159. The method according to claim 150, wherein the viral infection is of the Pneumoviridae family.

160. The method according to claim 150, wherein the viral infection is RSV.

161. The method according to claim 150, wherein the viral infection is of the Arenaviridae family.

162. The method according to claim 150, wherein the viral infection is Takaribe virus, Pichinde virus, Junin virus, Lassa fever virus, and lymphocytic choriomeningitis virus.

163. The method according to claim 150, wherein the viral infection is of the Bunyaviridae family.

164. The method according to claim 150, wherein the viral infection is Rift Valley fever virus, Punta Torovirus, Lacrosse virus, Maporal virus, Heartland virus, and Severe Fever with Thrombocytopenia Syndrome virus.

165. The method according to claim 150, wherein the viral infection is of the Flaviviridae family.

166. The method according to claim 150, wherein the viral infection is Zika virus, dengue virus 1, dengue virus 2, dengue virus 3, dengue virus 4, West Nile virus, yellow fever virus, Japanese encephalitis virus, Poissant virus, Usutu virus, and tick-borne encephalitis virus.

167. The method according to claim 150, wherein the viral infection is of the Picornaviridae family.

168. The method according to claim 151, wherein the viral infection is poliovirus, coxsackievirus, or enterovirus.

169. The aforementioned viral infections include human coronavirus, SARS coronavirus, MERS coronavirus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan horse encephalitis virus, Chikungunya virus, Ross River virus, RSV, influenza A virus, influenza B virus, Takalibe virus, Pichinde virus, Junin virus, Lassa fever virus, lymphocytic choriomeningitis virus, Rift Valley fever virus, Punta Torovirus, Lacrosse virus, Maporal virus, Heartland virus, and severe fever with thrombocytopenia syndrome virus, poliovirus, norovirus, enterovirus, coxsackievirus A, B, and C, coxsackie A16, EV-D68, EV-A71, rhinovirus, poliovirus, echovirus, picornavirus, cardiovirus, enterovirus, elbowvirus, hepatovirus, cobbvirus, parechovirus, and Tesshou virus. The method according to claim 150, comprising infection by a virus, including norovirus, sapovirus, lagow virus, calicivirus including vesivirus, astrovirus, togavirus, flavivirus, hepacivirus, coronavirus, arterivirus, rhabdovirus, paramyxovirus, orthomyxovirus, hantavirus, reovirus, rotavirus, birnavirus, chrysovirus, cystvirus, hypovirus partitivirus, totovirus, lentivirus, polyomavirus, papillomavirus, adenovirus, circovirus, parvovirus, erythrovirus, betaparvovirus, amdovirus, densovirus, iteravirus, brevidensovirus, pephdensovirus, herpesvirus 1, 2, 3, 4, 5, 6, 7, and 8, poxvirus, hepadnavirus, pneumonia virus, bunyavirus, arenavirus, or orthomyxovirus.

170. The method according to any one of claims 150 to 169, further comprising administering a second antiviral agent.

171. The second antiviral agent is remdesivir, favipiravir, darunavir, nelfinavir, saquinavir, lopinavir, ritonavir, remdesivir, paxlovide, mornupiravir, ABX464, faviravir, niclosamide, laninamivir, oseltamivir, zanamivir, peramivir, CS-8958, ribavirin, amantadine, rimantadine, tamiphosphoguanidine monoester, or phosphazanamivir or its monoester, disoxalil, preconalil, pyrodavir, bapendavir, pokapavir, azaglutamine, S-nitroso-N-acetyl The method according to claim 170, selected from penicillamine (SNAP), glyceryl trinitrate (GTN), isosorbide disnitrate (ISDN), glycerillidine, 5-(3,4-dichlorophenyl)methylhydantoin, AG7088, preconalil, 3-methylthio-5-aryl-4-isothiazole carbonitride, pyridylimidazolidinone, ribavirin, mycophenolic acid, 6-azauridine, pyrazofrine, 3-methylcaenferol, and derivatives thereof, physiological or pharmaceutical salts, or prodrugs, and combinations thereof.

172. The method according to claim 170, wherein the second antiviral agent is selected from remdesivir, favipiravir, darunavir, nelfinavir, saquinavir, lopinavir, ritonavir, remdesivir, paxlovide, mornupiravir, ABX464, faviravir, and niclosamide, as well as their derivatives, physiological or pharmaceutical salts, or prodrugs, and combinations thereof.

173. The method according to claim 170, wherein the second antiviral agent is selected from laninamivir, oseltamivir, zanamivir, peramivir, CS-8958, ribavirin, amantadine, rimantadine, tamiphosphoguanidine monoester, and phosphazanamivir or its monoester, as well as derivatives, physiological or pharmaceutical salts, or prodrugs thereof, and combinations thereof.

174. A method for treating or preventing a viral infection, comprising administering an effective amount of any one of claims 1 to 144 to a subject in need of treatment or prevention of a viral infection, In the subject, a loading dose of the compound or pharmaceutical composition is administered during the first treatment period. A method comprising administering a therapeutic dose of the pharmaceutical composition to the subject during a second treatment period following the first treatment period.

175. The method according to claim 174, wherein the first treatment period is 1 to 5 days after the diagnosis of the viral infection or after presentation for the prevention of the viral infection.

176. The method according to claim 174, wherein the first treatment period is one to two days after the diagnosis of the viral infection or after presentation for the prevention of the viral infection.

177. The method according to claim 174, wherein the first treatment period is the first day after the diagnosis of the viral infection or the first day after presentation for the prevention of the viral infection.

178. The method according to any one of claims 174 to 177, wherein the loading dose is approximately 1.1 to approximately 10 times the therapeutic dose.

179. The method according to claim 178, wherein the loading dose is approximately 1.5 to approximately 5 times the therapeutic dose.

180. The method according to claim 179, wherein the loading dose is approximately 1.5 to approximately 2.5 times the therapeutic dose.

181. The method according to any one of claims 174 to 180, wherein the loading dose is administered once a day, twice a day, three times a day, or four times a day.

182. The method according to any one of claims 174 to 180, wherein the loading dose is administered at least twice a day.

183. The method according to claim 181 or 182, wherein the loading dose is divided equally among the number of times administered per day.

184. The compound has the following structure: 【Chemistry 39】 The method according to any one of claims 150 to 183, or a combination thereof.

185. The method according to claims 174 to 184, wherein the first treatment period is 1 to 5 days after the diagnosis of the viral infection or after presentation for the prevention of the viral infection.

186. The method according to claims 174 to 184, wherein the first treatment period is one to two days after the diagnosis of the viral infection or after presentation for the prevention of the viral infection.

187. The method according to claims 174 to 184, wherein the first treatment period is the first day after the diagnosis of the viral infection or the first day after presentation for the prevention of the viral infection.

188. The method according to any one of claims 174 to 184, wherein the loading dose is approximately 1.1 to approximately 10 times the therapeutic dose.

189. The method according to claims 174 to 184, wherein the loading dose is approximately 1.5 to approximately 5 times the therapeutic dose.

190. The method according to claims 174 to 184, wherein the loading dose is approximately 1.5 to approximately 2.5 times the therapeutic dose.

191. The method according to any one of claims 174 to 190, wherein the loading dose is administered once a day, twice a day, three times a day, or four times a day.

192. The method according to any one of claims 174 to 190, wherein the loading dose is administered at least twice a day.

193. The method according to claims 174 to 192, wherein the loading dose is divided equally among the number of times administered per day.

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