Compounds and methods for treatment of viral infections

Abstract

To provide compounds and methods of using the compounds, singly or in combination with additional agents, and salts, crystalline forms, pharmaceutical compositions of the compounds for the treatment of viral infections.SOLUTION: Provided herein are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof. The disclosure further provides methods of treating or preventing a viral infection in a human in need thereof, wherein the method comprises administering to the human a compound of the disclosure, or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 071,134, filed August 27, 2020, U.S. Provisional Patent Application No. 63 / 162,283, filed March 17, 2021, and U.S. Provisional Patent Application No. 63 / 215,310, filed June 25, 2021, each of which is incorporated herein in its entirety for all purposes. [Background technology]

[0002] There is a need for compounds and methods for treating viral infections, such as those of the Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, Arenaviridae, Orthomyxovirus, and Coronaviridae families. The present disclosure addresses these and other needs. Summary of the Invention [Means for solving the problem]

[0003] The present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 OH, OCOR 4 , or OC(O)OR 4 and R 2 OH, OCOR 5 , or OC(O)OR 5 or R 1 and R 2 together form -OC(O)O- or -OCHR 6 O-, wherein R 6 is H, C1-C6 alkyl or C6-C 10is aryl, R 3 H, COR 7 or COOR 7 and R 4 , R 5 , and R 7 are each independently C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C3 to C8 carbocyclyl, C6 to C 10 aryl or one, two, or three heteroatoms selected from N, O, and S; is a 5- to 6-membered heteroaryl containing In the formula, R 4 , R 5 , and R 7 are each independently halogen, cyano, -N3, -OR 8 , -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl; Each R 8 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 9 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 10 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Base is, [ka] and R 11 is a C1-C6 alkyl substituted with -OP(O)(OH), However, R 3 If is H, then R 1OCOR 4 Or OC(O)OR 4 or R 2 OCOR 5 Or OC(O)OR 5 or R 1 and R 2 together form -OC(O)O- or -OCHR 6 O-, or a pharmaceutically acceptable salt thereof.

[0004] Also provided herein are pharmaceutical compositions comprising the compounds disclosed herein, or pharmaceutically acceptable salts thereof.

[0005] The present disclosure further provides a method of treating or preventing a viral infection in a human in need thereof, the method comprising administering to the human a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0006] Also provided herein is a method for manufacturing a medicament for treating or preventing a viral infection in a human in need thereof, wherein a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used.

[0007] The present disclosure also provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing a viral infection in a human in need thereof. [Brief explanation of the drawings]

[0008] [Figure 1-1]Figure 1 shows the antiviral efficacy of compound 1. 1a-b: Reduction of viral yield of SARS-CoV-2 clinical isolates WA1 / 2020, SA / 2020, CA / 2020, and BZ / 2021, representing the A, B.1.351, B.1.1.7, and P.1 lineages, respectively, by compound 1 (a) and reference compound A (b) on VeroE6 cells. EC50 concentrations are indicated. 1c-d: In vitro cytotoxicity profiles of compound 1 (c) and reference compound A (d) on a panel of VeroE6, HEp-2, BHK-21, HCT-8, and primary HAE cells from independent donors ("F2," "F3," "M2," "M6," and "DF2"). In (a-d), symbols represent individual biological replicates (n=3), error bars indicate standard deviation, and lines indicate nonlinear regression models. 1e: In vitro cytotoxicity profile of remdesivir against a panel of VeroE6, HEp-2, BHK-21, HCT-8, and primary HAE cells ("F2", "F3", "M2", "M6", "DF2"). Symbols represent individual biological replicates (n=3), error bars indicate standard deviation, and lines indicate nonlinear regression models. [Figure 1-2]Figure 1 shows the antiviral efficacy of compound 1. 1a-b: Reduction of viral yield of SARS-CoV-2 clinical isolates WA1 / 2020, SA / 2020, CA / 2020, and BZ / 2021, representing the A, B.1.351, B.1.1.7, and P.1 lineages, respectively, by compound 1 (a) and reference compound A (b) on VeroE6 cells. EC50 concentrations are indicated. 1c-d: In vitro cytotoxicity profiles of compound 1 (c) and reference compound A (d) on a panel of VeroE6, HEp-2, BHK-21, HCT-8, and primary HAE cells from independent donors ("F2," "F3," "M2," "M6," and "DF2"). In (a-d), symbols represent individual biological replicates (n=3), error bars indicate standard deviation, and lines indicate nonlinear regression models. 1e: In vitro cytotoxicity profile of remdesivir against a panel of VeroE6, HEp-2, BHK-21, HCT-8, and primary HAE cells ("F2", "F3", "M2", "M6", "DF2"). Symbols represent individual biological replicates (n=3), error bars indicate standard deviation, and lines indicate nonlinear regression models. [Figure 1-3]Figure 1 shows the antiviral efficacy of compound 1. 1a-b: Reduction of viral yield of SARS-CoV-2 clinical isolates WA1 / 2020, SA / 2020, CA / 2020, and BZ / 2021, representing the A, B.1.351, B.1.1.7, and P.1 lineages, respectively, by compound 1 (a) and reference compound A (b) on VeroE6 cells. EC50 concentrations are indicated. 1c-d: In vitro cytotoxicity profiles of compound 1 (c) and reference compound A (d) on a panel of VeroE6, HEp-2, BHK-21, HCT-8, and primary HAE cells from independent donors ("F2," "F3," "M2," "M6," and "DF2"). In (a-d), symbols represent individual biological replicates (n=3), error bars indicate standard deviation, and lines indicate nonlinear regression models. 1e: In vitro cytotoxicity profile of remdesivir against a panel of VeroE6, HEp-2, BHK-21, HCT-8, and primary HAE cells ("F2", "F3", "M2", "M6", "DF2"). Symbols represent individual biological replicates (n=3), error bars indicate standard deviation, and lines indicate nonlinear regression models. [Figure 1-4]Figure 1 shows the antiviral efficacy of compound 1. 1a-b: Reduction of viral yield of SARS-CoV-2 clinical isolates WA1 / 2020, SA / 2020, CA / 2020, and BZ / 2021, representing the A, B.1.351, B.1.1.7, and P.1 lineages, respectively, by compound 1 (a) and reference compound A (b) on VeroE6 cells. EC50 concentrations are indicated. 1c-d: In vitro cytotoxicity profiles of compound 1 (c) and reference compound A (d) on a panel of VeroE6, HEp-2, BHK-21, HCT-8, and primary HAE cells from independent donors ("F2," "F3," "M2," "M6," and "DF2"). In (a-d), symbols represent individual biological replicates (n=3), error bars indicate standard deviation, and lines indicate nonlinear regression models. 1e: In vitro cytotoxicity profile of remdesivir against a panel of VeroE6, HEp-2, BHK-21, HCT-8, and primary HAE cells ("F2", "F3", "M2", "M6", "DF2"). Symbols represent individual biological replicates (n=3), error bars indicate standard deviation, and lines indicate nonlinear regression models. [Figure 1-5]Figure 1 shows the antiviral efficacy of compound 1. 1a-b: Reduction of viral yield of SARS-CoV-2 clinical isolates WA1 / 2020, SA / 2020, CA / 2020, and BZ / 2021, representing the A, B.1.351, B.1.1.7, and P.1 lineages, respectively, by compound 1 (a) and reference compound A (b) on VeroE6 cells. EC50 concentrations are indicated. 1c-d: In vitro cytotoxicity profiles of compound 1 (c) and reference compound A (d) on a panel of VeroE6, HEp-2, BHK-21, HCT-8, and primary HAE cells from independent donors ("F2," "F3," "M2," "M6," and "DF2"). In (a-d), symbols represent individual biological replicates (n=3), error bars indicate standard deviation, and lines indicate nonlinear regression models. 1e: In vitro cytotoxicity profile of remdesivir against a panel of VeroE6, HEp-2, BHK-21, HCT-8, and primary HAE cells ("F2", "F3", "M2", "M6", "DF2"). Symbols represent individual biological replicates (n=3), error bars indicate standard deviation, and lines indicate nonlinear regression models.

[0009] [Figure 2-1] Figure 2 shows the preventive efficacy of orally administered compound 1. 2a: Schematic of the preventive efficacy study design. 2b: Viral titers from nasal washes. LoD, limit of detection. 2c: Temperature measurements collected once daily. 2d: Body weights measured once daily. 2e: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 2f: SARS-CoV-2 RNA copies present in nasal washes. 2g: SARS-CoV-2 RNA copies detected in nasal turbinates. 2h-2i: SARS-CoV-2 infectious particles (h) and SARS-CoV-2 RNA copies (i) in the lungs 4 days post-infection. The number of independent biological replicates (individual animals) is shown in each subpanel; symbols represent independent biological replicates; lines (b, c, d, f) and bar graphs (e, g-i) connect or indicate sample means, respectively; P values ​​are provided. Two-way ANOVA with Sidak's post hoc multiple comparison test (b, c, d, f) or two-tailed t test (e, g). [Figure 2-2]Figure 2 shows the preventive efficacy of orally administered compound 1. 2a: Schematic of the preventive efficacy study design. 2b: Viral titers from nasal washes. LoD, limit of detection. 2c: Temperature measurements collected once daily. 2d: Body weights measured once daily. 2e: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 2f: SARS-CoV-2 RNA copies present in nasal washes. 2g: SARS-CoV-2 RNA copies detected in nasal turbinates. 2h-2i: SARS-CoV-2 infectious particles (h) and SARS-CoV-2 RNA copies (i) in the lungs 4 days post-infection. The number of independent biological replicates (individual animals) is shown in each subpanel; symbols represent independent biological replicates; lines (b, c, d, f) and bar graphs (e, g-i) connect or indicate sample means, respectively; P values ​​are provided. Two-way ANOVA with Sidak's post hoc multiple comparison test (b, c, d, f) or two-tailed t test (e, g). [Figure 2-3] Figure 2 shows the preventive efficacy of orally administered compound 1. 2a: Schematic of the preventive efficacy study design. 2b: Viral titers from nasal washes. LoD, limit of detection. 2c: Temperature measurements collected once daily. 2d: Body weights measured once daily. 2e: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 2f: SARS-CoV-2 RNA copies present in nasal washes. 2g: SARS-CoV-2 RNA copies detected in nasal turbinates. 2h-2i: SARS-CoV-2 infectious particles (h) and SARS-CoV-2 RNA copies (i) in the lungs 4 days post-infection. The number of independent biological replicates (individual animals) is shown in each subpanel; symbols represent independent biological replicates; lines (b, c, d, f) and bar graphs (e, g-i) connect or indicate sample means, respectively; P values ​​are provided. Two-way ANOVA with Sidak's post hoc multiple comparison test (b, c, d, f) or two-tailed t test (e, g). [Figure 2-4]Figure 2 shows the preventive efficacy of orally administered compound 1. 2a: Schematic of the preventive efficacy study design. 2b: Viral titers from nasal washes. LoD, limit of detection. 2c: Temperature measurements collected once daily. 2d: Body weights measured once daily. 2e: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 2f: SARS-CoV-2 RNA copies present in nasal washes. 2g: SARS-CoV-2 RNA copies detected in nasal turbinates. 2h-2i: SARS-CoV-2 infectious particles (h) and SARS-CoV-2 RNA copies (i) in the lungs 4 days post-infection. The number of independent biological replicates (individual animals) is shown in each subpanel; symbols represent independent biological replicates; lines (b, c, d, f) and bar graphs (e, g-i) connect or indicate sample means, respectively; P values ​​are provided. Two-way ANOVA with Sidak's post hoc multiple comparison test (b, c, d, f) or two-tailed t test (e, g). [Figure 2-5] Figure 2 shows the preventive efficacy of orally administered compound 1. 2a: Schematic of the preventive efficacy study design. 2b: Viral titers from nasal washes. LoD, limit of detection. 2c: Temperature measurements collected once daily. 2d: Body weights measured once daily. 2e: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 2f: SARS-CoV-2 RNA copies present in nasal washes. 2g: SARS-CoV-2 RNA copies detected in nasal turbinates. 2h-2i: SARS-CoV-2 infectious particles (h) and SARS-CoV-2 RNA copies (i) in the lungs 4 days post-infection. The number of independent biological replicates (individual animals) is shown in each subpanel; symbols represent independent biological replicates; lines (b, c, d, f) and bar graphs (e, g-i) connect or indicate sample means, respectively; P values ​​are provided. Two-way ANOVA with Sidak's post hoc multiple comparison test (b, c, d, f) or two-tailed t test (e, g). [Figure 2-6]Figure 2 shows the preventive efficacy of orally administered compound 1. 2a: Schematic of the preventive efficacy study design. 2b: Viral titers from nasal washes. LoD, limit of detection. 2c: Temperature measurements collected once daily. 2d: Body weights measured once daily. 2e: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 2f: SARS-CoV-2 RNA copies present in nasal washes. 2g: SARS-CoV-2 RNA copies detected in nasal turbinates. 2h-2i: SARS-CoV-2 infectious particles (h) and SARS-CoV-2 RNA copies (i) in the lungs 4 days post-infection. The number of independent biological replicates (individual animals) is shown in each subpanel; symbols represent independent biological replicates; lines (b, c, d, f) and bar graphs (e, g-i) connect or indicate sample means, respectively; P values ​​are provided. Two-way ANOVA with Sidak's post hoc multiple comparison test (b, c, d, f) or two-tailed t test (e, g). [Figure 2-7] Figure 2 shows the preventive efficacy of orally administered compound 1. 2a: Schematic of the preventive efficacy study design. 2b: Viral titers from nasal washes. LoD, limit of detection. 2c: Temperature measurements collected once daily. 2d: Body weights measured once daily. 2e: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 2f: SARS-CoV-2 RNA copies present in nasal washes. 2g: SARS-CoV-2 RNA copies detected in nasal turbinates. 2h-2i: SARS-CoV-2 infectious particles (h) and SARS-CoV-2 RNA copies (i) in the lungs 4 days post-infection. The number of independent biological replicates (individual animals) is shown in each subpanel; symbols represent independent biological replicates; lines (b, c, d, f) and bar graphs (e, g-i) connect or indicate sample means, respectively; P values ​​are provided. Two-way ANOVA with Sidak's post hoc multiple comparison test (b, c, d, f) or two-tailed t test (e, g). [Figure 2-8]Figure 2 shows the preventive efficacy of orally administered compound 1. 2a: Schematic of the preventive efficacy study design. 2b: Viral titers from nasal washes. LoD, limit of detection. 2c: Temperature measurements collected once daily. 2d: Body weights measured once daily. 2e: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 2f: SARS-CoV-2 RNA copies present in nasal washes. 2g: SARS-CoV-2 RNA copies detected in nasal turbinates. 2h-2i: SARS-CoV-2 infectious particles (h) and SARS-CoV-2 RNA copies (i) in the lungs 4 days post-infection. The number of independent biological replicates (individual animals) is shown in each subpanel; symbols represent independent biological replicates; lines (b, c, d, f) and bar graphs (e, g-i) connect or indicate sample means, respectively; P values ​​are provided. Two-way ANOVA with Sidak's post hoc multiple comparison test (b, c, d, f) or two-tailed t test (e, g). [Figure 2-9] Figure 2 shows the preventive efficacy of orally administered compound 1. 2a: Schematic of the preventive efficacy study design. 2b: Viral titers from nasal washes. LoD, limit of detection. 2c: Temperature measurements collected once daily. 2d: Body weights measured once daily. 2e: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 2f: SARS-CoV-2 RNA copies present in nasal washes. 2g: SARS-CoV-2 RNA copies detected in nasal turbinates. 2h-2i: SARS-CoV-2 infectious particles (h) and SARS-CoV-2 RNA copies (i) in the lungs 4 days post-infection. The number of independent biological replicates (individual animals) is shown in each subpanel; symbols represent independent biological replicates; lines (b, c, d, f) and bar graphs (e, g-i) connect or indicate sample means, respectively; P values ​​are provided. Two-way ANOVA with Sidak's post hoc multiple comparison test (b, c, d, f) or two-tailed t test (e, g).

[0010] [Figure 3-1]Figure 3 shows the therapeutic efficacy of orally administered Compound 1 against SARS-CoV2 in ferrets. 3a: Schematic of the therapeutic efficacy study design. 3b: Viral titers from nasal washes. 3c: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 3d: Temperature measurements collected daily. 3e: Body weight measured daily. 3f: SARS-CoV-2 RNA copies present in nasal washes. 3g: SARS-CoV-2 RNA copies detected in nasal turbinates. The number of independent biological replicates (individual animals) is shown in each subpanel. Symbols represent independent biological replicates. Lines (b, d, e, f) and bar graphs (c, g) connect or indicate sample means, respectively. P values ​​are listed. One-way (c, g) or two-way (b, d, e, f) ANOVA with Dunnett's (b, d, e, f) post-hoc multiple comparison test. [Figure 3-2] Figure 3 shows the therapeutic efficacy of orally administered Compound 1 against SARS-CoV2 in ferrets. 3a: Schematic of the therapeutic efficacy study design. 3b: Viral titers from nasal washes. 3c: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 3d: Temperature measurements collected daily. 3e: Body weight measured daily. 3f: SARS-CoV-2 RNA copies present in nasal washes. 3g: SARS-CoV-2 RNA copies detected in nasal turbinates. The number of independent biological replicates (individual animals) is shown in each subpanel. Symbols represent independent biological replicates. Lines (b, d, e, f) and bar graphs (c, g) connect or indicate sample means, respectively. P values ​​are listed. One-way (c, g) or two-way (b, d, e, f) ANOVA with Dunnett's (b, d, e, f) post-hoc multiple comparison test. [Figure 3-3]Figure 3 shows the therapeutic efficacy of orally administered Compound 1 against SARS-CoV2 in ferrets. 3a: Schematic of the therapeutic efficacy study design. 3b: Viral titers from nasal washes. 3c: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 3d: Temperature measurements collected daily. 3e: Body weight measured daily. 3f: SARS-CoV-2 RNA copies present in nasal washes. 3g: SARS-CoV-2 RNA copies detected in nasal turbinates. The number of independent biological replicates (individual animals) is shown in each subpanel. Symbols represent independent biological replicates. Lines (b, d, e, f) and bar graphs (c, g) connect or indicate sample means, respectively. P values ​​are listed. One-way (c, g) or two-way (b, d, e, f) ANOVA with Dunnett's (b, d, e, f) post-hoc multiple comparison test. [Figure 3-4] Figure 3 shows the therapeutic efficacy of orally administered Compound 1 against SARS-CoV2 in ferrets. 3a: Schematic of the therapeutic efficacy study design. 3b: Viral titers from nasal washes. 3c: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 3d: Temperature measurements collected daily. 3e: Body weight measured daily. 3f: SARS-CoV-2 RNA copies present in nasal washes. 3g: SARS-CoV-2 RNA copies detected in nasal turbinates. The number of independent biological replicates (individual animals) is shown in each subpanel. Symbols represent independent biological replicates. Lines (b, d, e, f) and bar graphs (c, g) connect or indicate sample means, respectively. P values ​​are listed. One-way (c, g) or two-way (b, d, e, f) ANOVA with Dunnett's (b, d, e, f) post-hoc multiple comparison test. [Figure 3-5]Figure 3 shows the therapeutic efficacy of orally administered Compound 1 against SARS-CoV2 in ferrets. 3a: Schematic of the therapeutic efficacy study design. 3b: Viral titers from nasal washes. 3c: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 3d: Temperature measurements collected daily. 3e: Body weight measured daily. 3f: SARS-CoV-2 RNA copies present in nasal washes. 3g: SARS-CoV-2 RNA copies detected in nasal turbinates. The number of independent biological replicates (individual animals) is shown in each subpanel. Symbols represent independent biological replicates. Lines (b, d, e, f) and bar graphs (c, g) connect or indicate sample means, respectively. P values ​​are listed. One-way (c, g) or two-way (b, d, e, f) ANOVA with Dunnett's (b, d, e, f) post-hoc multiple comparison test. [Figure 3-6] Figure 3 shows the therapeutic efficacy of orally administered Compound 1 against SARS-CoV2 in ferrets. 3a: Schematic of the therapeutic efficacy study design. 3b: Viral titers from nasal washes. 3c: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 3d: Temperature measurements collected daily. 3e: Body weight measured daily. 3f: SARS-CoV-2 RNA copies present in nasal washes. 3g: SARS-CoV-2 RNA copies detected in nasal turbinates. The number of independent biological replicates (individual animals) is shown in each subpanel. Symbols represent independent biological replicates. Lines (b, d, e, f) and bar graphs (c, g) connect or indicate sample means, respectively. P values ​​are listed. One-way (c, g) or two-way (b, d, e, f) ANOVA with Dunnett's (b, d, e, f) post-hoc multiple comparison test. [Figure 3-7]Figure 3 shows the therapeutic efficacy of orally administered Compound 1 against SARS-CoV2 in ferrets. 3a: Schematic of the therapeutic efficacy study design. 3b: Viral titers from nasal washes. 3c: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 3d: Temperature measurements collected daily. 3e: Body weight measured daily. 3f: SARS-CoV-2 RNA copies present in nasal washes. 3g: SARS-CoV-2 RNA copies detected in nasal turbinates. The number of independent biological replicates (individual animals) is shown in each subpanel. Symbols represent independent biological replicates. Lines (b, d, e, f) and bar graphs (c, g) connect or indicate sample means, respectively. P values ​​are listed. One-way (c, g) or two-way (b, d, e, f) ANOVA with Dunnett's (b, d, e, f) post-hoc multiple comparison test.

[0011] [Figure 4-1]Orally administered compound 1 blocks the replication and transmission of SARS-CoV-2 VoC BZ / 2021. 4a: Schematic of the efficacy and contact transmission study design. 4b: Viral titers from nasal washes. 4c: SARS-CoV-2 RNA copies present in nasal washes. 4d: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 4e: SARS-CoV-2 RNA copies detected in nasal turbinates. 4f: SARS-CoV-2 infectious titers in lung tissue. 4g: SARS-CoV-2 RNA copies present in lung tissue. In (b-g), the number of independent biological replicates (individual animals) is indicated in each subpanel. Symbols represent independent biological replicates, and lines (b, c) and bar graphs (d, e, f, g, h) connect or indicate sample means, respectively, with P values ​​noted. One-way (d, e) or two-way (b, c) ANOVA with Tukey's (d, e) or Sidak's (b, c) post hoc multiple comparison test. 4h: Metagenomic sequence analysis of inoculated WA1 / 2020 and BZ / 2021 viruses, virus populations extracted from ferret nasal turbinates 4 days post-infection, and BZ / 2021 populations extracted from nasal washes of contact animals of vehicle-treated source animals. Relative allele frequencies of signature residues are shown. Symbols represent independent biological replicates (virus populations from individual animals), and columns represent group means. [Figure 4-2]Orally administered compound 1 blocks the replication and transmission of SARS-CoV-2 VoC BZ / 2021. 4a: Schematic of the efficacy and contact transmission study design. 4b: Viral titers from nasal washes. 4c: SARS-CoV-2 RNA copies present in nasal washes. 4d: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 4e: SARS-CoV-2 RNA copies detected in nasal turbinates. 4f: SARS-CoV-2 infectious titers in lung tissue. 4g: SARS-CoV-2 RNA copies present in lung tissue. In (b-g), the number of independent biological replicates (individual animals) is indicated in each subpanel. Symbols represent independent biological replicates, and lines (b, c) and bar graphs (d, e, f, g, h) connect or indicate sample means, respectively, with P values ​​noted. One-way (d, e) or two-way (b, c) ANOVA with Tukey's (d, e) or Sidak's (b, c) post hoc multiple comparison test. 4h: Metagenomic sequence analysis of inoculated WA1 / 2020 and BZ / 2021 viruses, virus populations extracted from ferret nasal turbinates 4 days post-infection, and BZ / 2021 populations extracted from nasal washes of contact animals of vehicle-treated source animals. Relative allele frequencies of signature residues are shown. Symbols represent independent biological replicates (virus populations from individual animals), and columns represent group means. [Figure 4-3]Orally administered compound 1 blocks the replication and transmission of SARS-CoV-2 VoC BZ / 2021. 4a: Schematic of the efficacy and contact transmission study design. 4b: Viral titers from nasal washes. 4c: SARS-CoV-2 RNA copies present in nasal washes. 4d: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 4e: SARS-CoV-2 RNA copies detected in nasal turbinates. 4f: SARS-CoV-2 infectious titers in lung tissue. 4g: SARS-CoV-2 RNA copies present in lung tissue. In (b-g), the number of independent biological replicates (individual animals) is indicated in each subpanel. Symbols represent independent biological replicates, and lines (b, c) and bar graphs (d, e, f, g, h) connect or indicate sample means, respectively, with P values ​​noted. One-way (d, e) or two-way (b, c) ANOVA with Tukey's (d, e) or Sidak's (b, c) post hoc multiple comparison test. 4h: Metagenomic sequence analysis of inoculated WA1 / 2020 and BZ / 2021 viruses, virus populations extracted from ferret nasal turbinates 4 days post-infection, and BZ / 2021 populations extracted from nasal washes of contact animals of vehicle-treated source animals. Relative allele frequencies of signature residues are shown. Symbols represent independent biological replicates (virus populations from individual animals), and columns represent group means. [Figure 4-4]Orally administered compound 1 blocks the replication and transmission of SARS-CoV-2 VoC BZ / 2021. 4a: Schematic of the efficacy and contact transmission study design. 4b: Viral titers from nasal washes. 4c: SARS-CoV-2 RNA copies present in nasal washes. 4d: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 4e: SARS-CoV-2 RNA copies detected in nasal turbinates. 4f: SARS-CoV-2 infectious titers in lung tissue. 4g: SARS-CoV-2 RNA copies present in lung tissue. In (b-g), the number of independent biological replicates (individual animals) is indicated in each subpanel. Symbols represent independent biological replicates, and lines (b, c) and bar graphs (d, e, f, g, h) connect or indicate sample means, respectively, with P values ​​noted. One-way (d, e) or two-way (b, c) ANOVA with Tukey's (d, e) or Sidak's (b, c) post hoc multiple comparison test. 4h: Metagenomic sequence analysis of inoculated WA1 / 2020 and BZ / 2021 viruses, virus populations extracted from ferret nasal turbinates 4 days post-infection, and BZ / 2021 populations extracted from nasal washes of contact animals of vehicle-treated source animals. Relative allele frequencies of signature residues are shown. Symbols represent independent biological replicates (virus populations from individual animals), and columns represent group means. [Figure 4-5]Orally administered compound 1 blocks the replication and transmission of SARS-CoV-2 VoC BZ / 2021. 4a: Schematic of the efficacy and contact transmission study design. 4b: Viral titers from nasal washes. 4c: SARS-CoV-2 RNA copies present in nasal washes. 4d: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 4e: SARS-CoV-2 RNA copies detected in nasal turbinates. 4f: SARS-CoV-2 infectious titers in lung tissue. 4g: SARS-CoV-2 RNA copies present in lung tissue. In (b-g), the number of independent biological replicates (individual animals) is indicated in each subpanel. Symbols represent independent biological replicates, and lines (b, c) and bar graphs (d, e, f, g, h) connect or indicate sample means, respectively, with P values ​​noted. One-way (d, e) or two-way (b, c) ANOVA with Tukey's (d, e) or Sidak's (b, c) post hoc multiple comparison test. 4h: Metagenomic sequence analysis of inoculated WA1 / 2020 and BZ / 2021 viruses, virus populations extracted from ferret nasal turbinates 4 days post-infection, and BZ / 2021 populations extracted from nasal washes of contact animals of vehicle-treated source animals. Relative allele frequencies of signature residues are shown. Symbols represent independent biological replicates (virus populations from individual animals), and columns represent group means. [Figure 4-6]Orally administered compound 1 blocks the replication and transmission of SARS-CoV-2 VoC BZ / 2021. 4a: Schematic of the efficacy and contact transmission study design. 4b: Viral titers from nasal washes. 4c: SARS-CoV-2 RNA copies present in nasal washes. 4d: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 4e: SARS-CoV-2 RNA copies detected in nasal turbinates. 4f: SARS-CoV-2 infectious titers in lung tissue. 4g: SARS-CoV-2 RNA copies present in lung tissue. In (b-g), the number of independent biological replicates (individual animals) is indicated in each subpanel. Symbols represent independent biological replicates, and lines (b, c) and bar graphs (d, e, f, g, h) connect or indicate sample means, respectively, with P values ​​noted. One-way (d, e) or two-way (b, c) ANOVA with Tukey's (d, e) or Sidak's (b, c) post hoc multiple comparison test. 4h: Metagenomic sequence analysis of inoculated WA1 / 2020 and BZ / 2021 viruses, virus populations extracted from ferret nasal turbinates 4 days post-infection, and BZ / 2021 populations extracted from nasal washes of contact animals of vehicle-treated source animals. Relative allele frequencies of signature residues are shown. Symbols represent independent biological replicates (virus populations from individual animals), and columns represent group means. [Figure 4-7]Orally administered compound 1 blocks the replication and transmission of SARS-CoV-2 VoC BZ / 2021. 4a: Schematic of the efficacy and contact transmission study design. 4b: Viral titers from nasal washes. 4c: SARS-CoV-2 RNA copies present in nasal washes. 4d: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 4e: SARS-CoV-2 RNA copies detected in nasal turbinates. 4f: SARS-CoV-2 infectious titers in lung tissue. 4g: SARS-CoV-2 RNA copies present in lung tissue. In (b-g), the number of independent biological replicates (individual animals) is indicated in each subpanel. Symbols represent independent biological replicates, and lines (b, c) and bar graphs (d, e, f, g, h) connect or indicate sample means, respectively, with P values ​​noted. One-way (d, e) or two-way (b, c) ANOVA with Tukey's (d, e) or Sidak's (b, c) post hoc multiple comparison test. 4h: Metagenomic sequence analysis of inoculated WA1 / 2020 and BZ / 2021 viruses, virus populations extracted from ferret nasal turbinates 4 days post-infection, and BZ / 2021 populations extracted from nasal washes of contact animals of vehicle-treated source animals. Relative allele frequencies of signature residues are shown. Symbols represent independent biological replicates (virus populations from individual animals), and columns represent group means. [Figure 4-8-1]Orally administered compound 1 blocks the replication and transmission of SARS-CoV-2 VoC BZ / 2021. 4a: Schematic of the efficacy and contact transmission study design. 4b: Viral titers from nasal washes. 4c: SARS-CoV-2 RNA copies present in nasal washes. 4d: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 4e: SARS-CoV-2 RNA copies detected in nasal turbinates. 4f: SARS-CoV-2 infectious titers in lung tissue. 4g: SARS-CoV-2 RNA copies present in lung tissue. In (b-g), the number of independent biological replicates (individual animals) is indicated in each subpanel. Symbols represent independent biological replicates, and lines (b, c) and bar graphs (d, e, f, g, h) connect or indicate sample means, respectively, with P values ​​noted. One-way (d, e) or two-way (b, c) ANOVA with Tukey's (d, e) or Sidak's (b, c) post hoc multiple comparison test. 4h: Metagenomic sequence analysis of inoculated WA1 / 2020 and BZ / 2021 viruses, virus populations extracted from ferret nasal turbinates 4 days post-infection, and BZ / 2021 populations extracted from nasal washes of contact animals of vehicle-treated source animals. Relative allele frequencies of signature residues are shown. Symbols represent independent biological replicates (virus populations from individual animals), and columns represent group means. [Figure 4-8-2]Orally administered compound 1 blocks the replication and transmission of SARS-CoV-2 VoC BZ / 2021. 4a: Schematic of the efficacy and contact transmission study design. 4b: Viral titers from nasal washes. 4c: SARS-CoV-2 RNA copies present in nasal washes. 4d: SARS-CoV-2 infectious titers in nasal turbinates collected 4 days post-infection. 4e: SARS-CoV-2 RNA copies detected in nasal turbinates. 4f: SARS-CoV-2 infectious titers in lung tissue. 4g: SARS-CoV-2 RNA copies present in lung tissue. In (b-g), the number of independent biological replicates (individual animals) is indicated in each subpanel. Symbols represent independent biological replicates, and lines (b, c) and bar graphs (d, e, f, g, h) connect or indicate sample means, respectively, with P values ​​noted. One-way (d, e) or two-way (b, c) ANOVA with Tukey's (d, e) or Sidak's (b, c) post hoc multiple comparison test. 4h: Metagenomic sequence analysis of inoculated WA1 / 2020 and BZ / 2021 viruses, virus populations extracted from ferret nasal turbinates 4 days post-infection, and BZ / 2021 populations extracted from nasal washes of contact animals of vehicle-treated source animals. Relative allele frequencies of signature residues are shown. Symbols represent independent biological replicates (virus populations from individual animals), and columns represent group means.

[0012] [Figure 5] Clinical signs in source and contact animals infected with BZ / 2021. 5a: Temperature measurements collected once daily. 5b: Body weights measured once daily.

[0013] [Figure 6a] 1 shows the efficacy of orally administered Compound 1 against SARS-CoV-2 AGM. [Figure 6b] 1 shows the efficacy of orally administered Compound 1 against SARS-CoV-2 AGM. [Figure 6c] 1 shows the efficacy of orally administered Compound 1 against SARS-CoV-2 AGM.

[0014] [Figure 7a] This figure shows the efficacy of orally administered Compound 15 against SARS-CoV-2 in mice. As can be seen, treatment with Compound 15 reduces the physiological effects of SARS-CoV-2 in mice. [Figure 7b] This figure shows the efficacy of orally administered Compound 15 against SARS-CoV-2 in mice. As can be seen, treatment with Compound 15 reduces the physiological effects of SARS-CoV-2 in mice. [Figure 7c] This figure shows the efficacy of orally administered Compound 15 against SARS-CoV-2 in mice. As can be seen, treatment with Compound 15 reduces the physiological effects of SARS-CoV-2 in mice.

[0015] [Figure 8] Figure 1 shows that orally administered compound 1 reduces final SARS-CoV-2 infectious titers in the lungs of mice.

[0016] [Figure 9a] We show that orally administered compound 1 reduces the pathophysiological effects of SARS-CoV-2 in mice. [Figure 9b] We show that orally administered compound 1 reduces the pathophysiological effects of SARS-CoV-2 in mice. [Figure 9c] We show that orally administered compound 1 reduces the pathophysiological effects of SARS-CoV-2 in mice.

[0017] [Figure 10] 1 shows the XRPD pattern of the free base form I of compound 15.

[0018] [Figure 11] 1 shows the DSC thermogram of the free base form I of compound 15.

[0019] [Figure 12] 1 shows the TGA thermogram of the free base form I of Compound 15.

[0020] [Figure 13] 1 shows the XRPD pattern of the free base form II of compound 15.

[0021] [Figure 14] 1 shows the DSC thermogram of the free base Form II of Compound 15.

[0022] [Figure 15] 1 shows the TGA thermogram of the free base Form II of Compound 15.

[0023] [Figure 16] 1 shows the XRPD pattern of the free base form III of compound 15.

[0024] [Figure 17] 1 shows a DSC thermogram of the free base form III of compound 15.

[0025] [Figure 18] 1 shows the TGA thermogram of the free base form III of compound 15.

[0026] [Figure 19] 1 shows the XRPD pattern of Material A of the xinafoate salt of Compound 15.

[0027] [Figure 20] 1 shows the DSC thermogram of Material A of the xinafoate salt of Compound 15.

[0028] [Figure 21] 1 shows a TGA thermogram of Material A of the xinafoate salt of Compound 15.

[0029] [Figure 22] 1 shows the XRPD pattern of the HCl salt Form I of Compound 15.

[0030] [Figure 23]1 shows the DSC thermogram of the HCl salt Form I of Compound 15.

[0031] [Figure 24] 1 shows the TGA thermogram of HCl salt Form I of Compound 15.

[0032] [Figure 25] 1 shows the XRPD pattern of the HCl salt material A of compound 15.

[0033] [Figure 26] 1 shows the DSC thermogram of the HCl salt of Compound 15, Material A.

[0034] [Figure 27] 1 shows the TGA thermogram of Compound 15 HCl salt Material A.

[0035] [Figure 28] 1 shows the XRPD pattern of the HCl salt material B of compound 15.

[0036] [Figure 29] 1 shows the DSC thermogram of the HCl salt of Compound 15, Material B.

[0037] [Figure 30] 1 shows the TGA thermogram of Compound 15 HCl salt Material B.

[0038] [Figure 31] 1 shows the XRPD pattern of the HCl salt material C of compound 15.

[0039] [Figure 32] 1 shows the DSC thermogram of the HCl salt of Compound 15, Material C.

[0040] [Figure 33] 1 shows the TGA thermogram of Compound 15 HCl salt Material C. DETAILED DESCRIPTION OF THE INVENTION

[0041] I. Overview The present invention relates generally to methods and compounds for treating or preventing viral infections, such as those of the Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, Arenaviridae, Orthomyxovirus, and Coronaviridae families. II. Definition

[0042] Unless otherwise stated, the following terms and phrases are intended to have the following meanings as used herein:

[0043] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C1 to C6). 20The alkyl group may have 1 to 8 carbon atoms (i.e., C1-C8 alkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of suitable alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -C H(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH( These include, but are not limited to, 4-methyl-2-pentyl (-CH(CH)CHCH(CH)), 3-methyl-3-pentyl (-C(CH)(CHCH)), 2-methyl-3-pentyl (-CH(CHCH)CH(CH)), and 2,3-dimethyl-2-butyl (-C(CH)CH(CH)), 3,3-dimethyl-2-butyl (-CH(CH)C(CH)).

[0044] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2-4 Alkenyl refers to an aliphatic group having an alkyl group. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0045] "Alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2-4 The term "alkynyl" also includes alkynyl groups having one triple bond and one double bond.

[0046] A "haloalkyl" is an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group are replaced with a halogen atom. The alkyl portion of a haloalkyl group can have 1 to 20 carbon atoms (i.e., C1 to C6). 20 haloalkyl), 1 to 12 carbon atoms (i.e., C1 to C 12 haloalkyl), 1 to 8 carbon atoms (i.e., C1-C8 haloalkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of suitable haloalkyl groups include -CF3, -CHF2, -CFH2, -CH2CF3, and the like.

[0047] "Aryl" means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like.

[0048] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl contains 1 to 20 ring atoms (i.e., 1-20 membered heteroaryl), 3 to 12 ring atoms (i.e., 3-12 membered heteroaryl), or 3 to 8 carbon ring atoms (3-8 membered heteroaryl), or 5 to 6 ring atoms (5-6 membered heteroaryl). Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass and does not overlap with aryl, as defined above.

[0049] "Carbocyclyl" or "carbocyclic ring" refers to a non-aromatic hydrocarbon ring composed of carbon and hydrogen atoms, having from 3 to 20 carbon atoms, and in certain embodiments from 3 to 15 carbon atoms, and in certain embodiments from 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 7 carbon atoms, or 3 to 6 carbon atoms, which is saturated or partially unsaturated and is attached to the rest of the molecule by a single bond. Examples of carbocyclic rings include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, and cyclooctane.

[0050] "Cycloalkyl" refers to saturated cyclic alkyl groups having single or multiple rings, including fused, bridged, and spiro ring systems. As used herein, cycloalkyl refers to groups having 3 to 20 ring carbon atoms (i.e., C 3~20 cycloalkyl), having 3 to 12 ring carbon atoms (i.e., C 3~12 cycloalkyl), having 3 to 10 ring carbon atoms (i.e., C 3~10 cycloalkyl), having 3 to 8 ring carbon atoms (i.e., C 3~8 cycloalkyl), or having 3 to 6 ring carbon atoms (i.e., C 3~6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0051] The term "optionally substituted" with respect to a particular moiety in a compound of Formula I (e.g., an optionally substituted aryl group) means that all of the substituents are hydrogen, or one or more of the hydrogens on the moiety can be replaced with a substituent as listed.

[0052] Unless otherwise specified, the carbon atoms of the compounds of Formula I are intended to have a valence of 4. In some chemical structure representations where a carbon atom does not have a sufficient number of variables to produce a valence of 4, the remaining carbon substituents necessary to provide a valence of 4 should be assumed to be hydrogen.

[0053] As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. As used herein, the term "treatment" refers to the act of treating, as "treating" is defined immediately above.

[0054] "Prevention" or "preventing" refers to any treatment of a disease or condition that does not result in the development of clinical symptoms of the disease or condition. The compounds and compositions disclosed herein, in some embodiments, can be administered to subjects (including humans) at risk of having a disease or condition. As used herein, the terms "preventing" and "prevention" encompass administering a compound, composition, or pharmaceutically acceptable salt according to embodiments disclosed herein before or after an individual has been exposed to a virus, but before symptoms of viral infection appear and / or before the virus is detected in the blood. The term also refers to preventing symptoms of disease from appearing and / or preventing the virus from reaching detectable levels in the blood. The term refers to pre-exposure prophylaxis (PrEP), as well as post-exposure prophylaxis (PEP) and event-driven or "on-demand" prophylaxis. These terms also refer to the prevention of perinatal transmission of the virus from mother to infant by administration to the mother before birth and to the child within the first few days of life. The terms also refer to the prevention of transmission of the virus by blood transfusion.

[0055] As used herein, the term "therapeutically effective amount" refers to the amount of a compound of Formula I used herein required to provide a desired level of drug in the secretions and airway and lung tissues of a subject, or alternatively, in the bloodstream of a treated subject, that will produce an expected physiological response or desired biological effect when such a composition is administered by a selected route of administration. The exact amount will depend on numerous factors, such as the particular compound of Formula I, the specific activity of the composition, the delivery device used, the physical properties of the composition, its intended use, and patient considerations such as the severity of the disease state and patient interaction, and can be readily determined by one of ordinary skill in the art based on the information provided herein.

[0056] "DSC" refers to differential scanning calorimetry.

[0057] "XRPD" refers to the X-ray powder diffraction pattern of a solid form.

[0058] "TGA" refers to thermogravimetric analysis.

[0059] The term "substantially as shown in," when referring to, for example, an XRPD pattern, DSC thermogram, or TGA graph, includes a pattern, thermogram, or graph that may not necessarily be identical to that shown herein, but that falls within the limits of experimental error or variation as would be considered by one of ordinary skill in the art.

[0060] "Protecting Group" refers to a moiety of a compound that masks or alters the properties of a functional group or the compound as a whole. The chemical structures of protecting groups vary widely. One function of a protecting group is to serve as an intermediate in the synthesis of the parent drug substance. Chemical protecting groups and strategies for protection / deprotection are well known in the art. "Protective Groups in See, "Protective Groups in Organic Chemistry," by Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991; see also, Protective Groups in Organic Chemistry, Peter G.M.Wuts and Theodora W. Greene, 4th Ed., 2006. Protecting groups are often utilized to mask the reactivity of certain functional groups to aid in the efficiency of desired chemical reactions, e.g., to create and break chemical bonds in an orderly and deliberate manner. Protection of a functional group in a compound alters other physical properties beyond the reactivity of the protected functional group, such as polarity, lipophilicity (hydrophobicity), and other properties that can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive. A "hydroxy-protecting group" refers to a protecting group useful for protecting hydroxy groups (-OH).

[0061] "Deprotecting agent" refers to any agent capable of removing a protecting group. The deprotecting agent depends on the type of protecting group used. Representative deprotecting agents are known in the art and can be found in Protective Groups in Organic Chemistry, Peter G.M.Wuts and Theodora W. Greene, 4th Ed., 2006. III.Compound

[0062] Any reference to a compound of the invention described herein also includes a reference to a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable salts of the compounds of the invention include alkali metal or alkaline earth salts (e.g., Na + , Li + , K. + , Ca +2 , and Mg +2 ), ammonium and NR4 + (wherein R is as defined herein) Pharmaceutically acceptable salts of a nitrogen atom or an amino group include (a) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; (b) acid addition salts formed with acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like; (c) salts formed with organic acids such as benzoic acid, benzosulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, and leucine; and (c) salts formed with elemental anions such as chlorine, bromine, and iodine. Pharmaceutically acceptable salts of compounds with hydroxy groups include Na + and NR4 + Examples of suitable cations include the anions of the above compounds in combination with suitable cations such as:

[0063] The compounds disclosed herein (e.g., compounds of Formula I, II, III, IV, V, Va, Vb, VI, VIa, and VIb) and pharmaceutically acceptable salts thereof may exist as different polymorphs or pseudopolymorphs. As used herein, crystalline polymorphism refers to the ability of a crystalline compound to exist in different crystal structures. Crystalline polymorphism can result from differences in crystal packing (packing polymorphism) or differences in packing between different conformers of the same molecule (conformational polymorphism). As used herein, crystalline pseudopolymorphism refers to the ability of hydrates or solvates of a compound to exist in different crystal structures. The pseudopolymorphs of the present invention may exist due to differences in crystal packing (packing pseudopolymorphism) or differences in packing between different conformers of the same molecule (conformational pseudopolymorphism). The present invention includes all polymorphs and pseudopolymorphs of the compounds of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, or IIIc, and their pharmaceutically acceptable salts.

[0064] The compounds disclosed herein (e.g., compounds of Formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb) and pharmaceutically acceptable salts thereof can also exist as amorphous solids. As used herein, an amorphous solid is a solid in which there is no long-range order of the positions of atoms in the solid. This definition also applies when the crystal size is 2 nanometers or less. Additives, including solvents, can be used to create the amorphous forms of the present invention. The present invention includes all amorphous forms of the compounds of Formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, and pharmaceutically acceptable salts thereof.

[0065] For therapeutic use, salts of the active ingredients of the compounds of the present invention are pharmaceutically acceptable. That is, they are salts derived from pharmaceutically acceptable acids or bases. However, salts of non-pharmaceutically acceptable acids or bases may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether derived from pharmaceutically acceptable acids or bases, are within the scope of the present invention.

[0066] It should also be understood that the compositions herein include compounds of the present invention in their non-ionized as well as zwitterionic forms, as well as combinations with a stoichiometric amount of water in hydrates.

[0067] It should be noted that all enantiomers, diastereomers, and racemic mixtures, tautomers, polymorphs, pseudopolymorphs of compounds within the scope of Formula I, II, III, IV, V, Va, Vb, VI, VIa, or VIb, as well as pharmaceutically acceptable salts thereof, are encompassed by the present invention. All mixtures of such enantiomers and diastereomers are within the scope of the present invention.

[0068] The compounds of the present invention, exemplified by Formula I, II, III, IV, V, Va, Vb, VI, VIa, or VIb, may have chiral centers, such as chiral carbon or phosphorus atoms. Accordingly, the compounds of the present invention include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. Additionally, the compounds of the present invention include optical isomers enriched or resolved at any or all asymmetric chiral atoms. In other words, chiral centers apparent from the depiction are provided as chiral isomers or racemic mixtures. Both racemic and diastereomeric mixtures, as well as individual isolated or synthesized optical isomers substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the present invention. Racemic mixtures can be separated into their individual substantially optically pure isomers by suitable techniques, such as, for example, separation of diastereomeric salts formed with optically active auxiliaries, e.g., acids or bases, followed by conversion back to optically active materials. In most cases, the desired optical isomers are synthesized by stereospecific reactions beginning with the appropriate stereoisomer of the desired starting material.

[0069] Stereochemical definitions and rules used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994), John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d and l, D and L, or (+) and (-) are used to indicate the indication of rotation of plane-polarized light by the compound; S, (-), or 1 means that the compound is levorotatory, while a compound with an R, (+), or d prefix is ​​dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0070] The compounds of the present invention may also exist as tautomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the present invention. For example, ene-amine tautomers may exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems, and all of their possible tautomers are within the scope of the present invention.

[0071] Any formula or structure provided herein, including compounds of Formula I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, is also intended to represent unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structure shown by the formula provided herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include: 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 Isotopically labeled compounds of the present disclosure include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as I. 3 H, 13 C and 14 1C. Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetic studies, positron emission tomography (PET) or single-photon emission computed tomography (SPC) including drug or substrate tissue distribution assays. in detection or imaging techniques such as tomography, SPECT, or in the radiation treatment of patients These may be useful in the treatment of

[0072] The present disclosure also includes compounds of Formula I in which one to x hydrogens bonded to a carbon atom have been replaced by deuterium, where x is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for extending the half-life of any compound of Formula I when administered to a mammal, particularly a human. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). In light of the present disclosure, such compounds are synthesized by means known in the art, for example, by using starting materials in which one or more hydrogens have been replaced by deuterium.

[0073] Deuterium-labeled or deuterium-substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F-labeled compounds can be useful in PET or SPECT studies.The isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by replacing readily available isotopically labeled reagents with non-isotopically labeled reagents, and carrying out the procedures disclosed in the schemes or in the examples and preparations described below.In this context, it is understood that deuterium is considered to be a substituent in the compound of formula I.

[0074] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise noted, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at the natural abundance isotopic composition of hydrogen. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0075] Whenever a compound described herein is substituted with more than one of the same group, e.g., designated "R" or "R", it will be understood that the groups can be the same or different, i.e., each group is independently selected.

[0076] Wavy Lines [ka] indicates the site of covalent attachment to an adjacent substructure, group, moiety, or atom. IV.Compound

[0077] In certain embodiments, provided herein are compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 OH, OCOR 4 , or OC(O)OR 4 and R 2 OH, OCOR 5 , or OC(O)OR 5 or R 1 and R 2 together form -OC(O)O- or -OCHR 6O-, wherein R 6 is H, C1-C6 alkyl or C6-C 10 is aryl, R 3 H, COR 7 or COOR 7 and R 4 , R 5 , and R 7 are each independently C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C3 to C8 carbocyclyl, C6 to C 10 aryl or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; In the formula, R 4 , R 5 , and R 7 are each independently halogen, cyano, -N3, -OR 8 , -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl; Each R 8 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 9 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 10 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Base is, [ka] and R 11 is a C1-C6 alkyl substituted with -OP(O)(OH), However, R3 If is H, then R 1 OCOR 4 Or OC(O)OR 4 or R 2 OCOR 5 Or OC(O)OR 5 or R 1 and R 2 together form -OC(O)O- or -OCHR 6 O-, or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, Base is [ka] where R 11 is —CH 2 OP(O)(OH) 2 . In some embodiments, Base is [ka] where R 11 is a C1-C6 alkyl substituted with -OP(O)(OH). In some embodiments, Base is [ka] where R 11 is —CH 2 OP(O)(OH) 2 . In some embodiments, Base is [ka] where R 11 is a C1-C6 alkyl substituted with -OP(O)(OH). In some embodiments, Base is [ka] where R 11 is -CH2OP(O)(OH)2. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, Base is [ka] is.

[0079] In some embodiments, Formula I is a compound of Formula Ia: [ka]

[0080] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 3 is COR 7 or COOR 7 where R 7 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclyl, C6-C 10 aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 Groups include halogen, cyano, -N3, -OR 8 , -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 3 is COR 7 or COOR 7 where R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 Groups include halogen, cyano, -N3, -OR 8 , -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 3 is COR 7 or COOR 7 where R 7 is C1-C8 alkyl or C3-C8 carbocyclyl, and R 7 Groups include halogen, cyano, -N3, -OR 8 , -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 3 is COR 7 or COOR 7 where R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 3 is COR 7 or COOR 7 where R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 9 and R 10 are both H.

[0081] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 3 is COR 7 or COOR 7 where R 7 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclyl, C6-C 10 aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 The group is -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 3 is COR 7 or COOR 7 where R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 The group is -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 3 is COR 7 or COOR 7where R 7 is C1-C8 alkyl or C3-C8 carbocyclyl, and R 7 The group is -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 3 is COR 7 or COOR 7 where R 7 is -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 3 is COR 7 or COOR 7 where R 7 is -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 9 and R 10 are both H.

[0082] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 3 is COR 7 or COOR 7 where R 7 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclyl, C6-C 10 aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R7 The group is -NR 9 R 10 and phenyl. In some embodiments, R 3 is COR 7 or COOR 7 where R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 The group is -NR 9 R 10 and phenyl. In some embodiments, R 3 is COR 7 or COOR 7 and R 7 is C1-C8 alkyl or C3-C8 carbocyclyl, and R 7 The group is -NR 9 R 10 and phenyl. In some embodiments, R 3 is COR 7 or COOR 7 and R 7 is -NR 9 R 10 and phenyl. In some embodiments, R 3 is COR 7 or COOR 7 and R 7 is -NR 9 R 10 and phenyl. In some embodiments, R 9 and R 10 are both H.

[0083] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 3 is COR 7 or COOR 7 where R 7 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclyl, C6-C 10 aryl, or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 3 is COR 7 or COOR 7 where R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 3 is COR 7 or COOR 7 where R 7 is C1-C8 alkyl or C3-C8 carbocyclyl. In some embodiments, R 3 is COR 7 or COOR 7 where R 7 is C1-C8 alkyl. In some embodiments, R 3 is COR 7 or COOR 7 where R 7 is C1-C4 alkyl.

[0084] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 3 is COR 7 or COOR 7 where R 7 are -CH3, -CH2CH3, [ka] In some embodiments, R 3 is COR 7 or COOR 7 where R 7 are -CH3, -CH2CH3, [ka] In some embodiments, R 3 is COR 7 or COOR 7 where R 7 are -CH3, -CH2CH3, [ka] is selected from the group consisting of:

[0085] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 3 is COR 7 where R 7 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclyl, C6-C 10 aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 Groups include halogen, cyano, -N3, -OR 8 , -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 3 is COR 7 where R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 Groups include halogen, cyano, -N3, -OR 8 , -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 3 is COR 7 where R 7 is C1-C8 alkyl or C3-C8 carbocyclyl, and R 7 Groups include halogen, cyano, -N3, -OR 8 , -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 3 is COR 7 where R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 3 is COR 7 where R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 9 and R 10 are both H.

[0086] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 3 is COR 7 where R 7 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclyl, C6-C 10 aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 The group is -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 3 is COR 7 where R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 The group is -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 3 is COR 7 where R 7 is C1-C8 alkyl or C3-C8 carbocyclyl, and R 7The group is -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 3 is COR 7 where R 7 is -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 3 is COR 7 where R 7 is -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 9 and R 10 are both H.

[0087] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 3 is COR 7 where R 7 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclyl, C6-C 10 aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 The group is -NR 9 R 10 and phenyl. In some embodiments, R 3 is COR7 where R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 The group is -NR 9 R 10 and phenyl. In some embodiments, R 3 is COR 7 and R 7 is C1-C8 alkyl or C3-C8 carbocyclyl, and R 7 The group is -NR 9 R 10 and phenyl. In some embodiments, R 3 is COR 7 and R 7 is -NR 9 R 10 and phenyl. In some embodiments, R 3 is COR 7 and R 7 is -NR 9 R 10 and phenyl. In some embodiments, R 9 and R 10 are both H.

[0088] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 3 is COR 7 where R 7 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclyl, C6-C 10aryl, or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 3 is COR 7 where R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 3 is COR 7 where R 7 is C1-C8 alkyl or C3-C8 carbocyclyl. In some embodiments, R 3 is COR 7 where R 7 is C1-C8 alkyl. In some embodiments, R 3 is COR 7 where R 7 is C1-C4 alkyl.

[0089] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 3 is COR 7 where R 7 are -CH3, -CH2CH3, [ka] In some embodiments, R 3 is COR 7 where R 7 are -CH3, -CH2CH3, [ka] is selected from the group consisting of:

[0090] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R3 COOR 7 where R 7 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclyl, C6-C 10 aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 Groups include halogen, cyano, -N3, -OR 8 , -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 3 COOR 7 where R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 Groups include halogen, cyano, -N3, -OR 8 , -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 3 COOR 7 where R 7 is C1-C8 alkyl or C3-C8 carbocyclyl, and R 7 Groups include halogen, cyano, -N3, -OR 8 , -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl.3 COOR 7 where R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 3 COOR 7 where R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 9 and R 10 are both H.

[0091] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 3 COOR 7 where R 7 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclyl, C6-C 10 aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 The group is -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 3 COOR 7 where R 7is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 The group is -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 3 COOR 7 where R 7 is C1-C8 alkyl or C3-C8 carbocyclyl, and R 7 The group is -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 3 COOR 7 where R 7 is -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 3 COOR 7 where R 7 is -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 9 and R 10 are both H.

[0092] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 3 COOR 7 where R 7 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclyl, C6-C 10 aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 The group is -NR 9 R 10 and phenyl. In some embodiments, R 3 COOR 7 where R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 The group is -NR 9 R 10 and phenyl. In some embodiments, R 3 COOR 7 and R 7 is C1-C8 alkyl or C3-C8 carbocyclyl, and R 7 The group is -NR 9 R 10 and phenyl. In some embodiments, R 3 COOR 7 and R 7 is -NR 9 R 10 and phenyl. In some embodiments, R 3 COOR 7 and R 7is -NR 9 R 10 and phenyl. In some embodiments, R 9 and R 10 are both H.

[0093] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 3 COOR 7 where R 7 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclyl, C6-C 10 aryl, or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 3 COOR 7 where R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 3 COOR 7 where R 7 is C1-C8 alkyl or C3-C8 carbocyclyl. In some embodiments, R 3 COOR 7 where R 7 is C1-C8 alkyl. In some embodiments, R 3 COOR 7 where R 7 is C1-C4 alkyl.

[0094] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 3 COOR 7 where R 7 are -CH3, -CH2CH3, [ka] In some embodiments, R 3 COOR 7 where R 7 are -CH3, -CH2CH3, [ka] is selected from the group consisting of:

[0095] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 1 OH, OCOR 4 , or OC(O)OR 4 and R 2 OH, OCOR 5 , or OC(O)OR 5 In some embodiments, R 1 is OH and R 2 OH, OCOR 5 , or OC(O)OR 5 In some embodiments, R 1 is OH and R 2 OCOR 5 or OC(O)OR 5 In some embodiments, R 1 is OH and R 2 OCOR 5 In some embodiments, R 1 is OH and R 2 is OC(O)OR 5 is.

[0096] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 1 OH, OCOR 4 , or OC(O)OR 4 and R 2 is OH. In some embodiments, R 1 OCOR4 , or OC(O)OR 4 and R 2 is OH. In some embodiments, R 1 OCOR 4 and R 2 is OH. In some embodiments, R 1 is OC(O)OR 4 and R 2 is OH.

[0097] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 1 OCOR 4 or OC(O)OR 4 and R 2 OCOR 5 or OC(O)OR 5 In some embodiments, R 1 OCOR 4 and R 2 OCOR 5 or OC(O)OR 5 In some embodiments, R 1 is OC(O)OR 4 and R 2 OCOR 5 or OC(O)OR 5 is.

[0098] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 1 OCOR 4 or OC(O)OR 4 and R 2 OCOR 5 In some embodiments, R 1 OCOR 4 or OC(O)OR 4 and R 2 is OC(O)OR 5 is.

[0099] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 1OCOR 4 and R 2 OCOR 5 In some embodiments, R 1 OCOR 4 and R 2 is OC(O)OR 5 is.

[0100] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 1 is OC(O)OR 4 and R 2 OCOR 5 In some embodiments, R 1 is OC(O)OR 4 and R 2 is OC(O)OR 5 is.

[0101] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 4 and R 5 are each independently C1-C8 alkyl. In some embodiments, R 4 and R 5 are each independently C1-C6 alkyl. In some embodiments, R 4 and R 5 are each independently C1-C3 alkyl. In some embodiments, R 4 and R 5 are each independently methyl, ethyl, or isopropyl.

[0102] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 1 OH, OCOR 4 , or OC(O)OR 4 and R 2 OH, OCOR 5 , or OC(O)OR 5 where R 4 and R 5 are each independently C1-C8 alkyl. In some embodiments, R1 OH, OCOR 4 , or OC(O)OR 4 and R 2 OH, OCOR 5 , or OC(O)OR 5 where R 4 and R 5 are each independently C1-C6 alkyl. In some embodiments, R 1 OH, OCOR 4 , or OC(O)OR 4 and R 2 OH, OCOR 5 , or OC(O)OR 5 where R 4 and R 5 are each independently C1-C3 alkyl. In some embodiments, R 1 OH, OCOR 4 , or OC(O)OR 4 and R 2 OH, OCOR 5 , or OC(O)OR 5 where R 4 and R 5 are each independently methyl, ethyl, or isopropyl.

[0103] In some embodiments, R 1 is OH and R 2 OH, OCOR 5 , or OC(O)OR 5 where R 5 is C1-C8 alkyl. In some embodiments, R 1 is OH and R 2 OH, OCOR 5 , or OC(O)OR 5 where R 5 is C1-C6 alkyl. In some embodiments, R 1 is OH and R 2 OH, OCOR 5 , or OC(O)OR 5 where R 5is C1-C3 alkyl. In some embodiments, R 1 is OH and R 2 OH, OCOR 5 , or OC(O)OR 5 where R 5 is methyl, ethyl, or isopropyl.

[0104] In some embodiments, R 1 is OH and R 2 OCOR 5 or OC(O)OR 5 where R 5 is C1-C8 alkyl. In some embodiments, R 1 is OH and R 2 OCOR 5 or OC(O)OR 5 where R 5 is C1-C6 alkyl. In some embodiments, R 1 is OH and R 2 OCOR 5 or OC(O)OR 5 where R 5 is C1-C3 alkyl. In some embodiments, R 1 is OH and R 2 OCOR 5 or OC(O)OR 5 where R 5 is methyl, ethyl, or isopropyl.

[0105] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 1 OH, OCOR 4 , or OC(O)OR 4 and R 2 is OH, where R 4 is C1-C8 alkyl. In some embodiments, R 1 OH, OCOR 4 , or OC(O)OR 4 and R 2 is OH, where R4 is C1-C6 alkyl. In some embodiments, R 1 OH, OCOR 4 , or OC(O)OR 4 and R 2 is OH, where R 4 is C1-C3 alkyl. In some embodiments, R 1 OH, OCOR 4 , or OC(O)OR 4 and R 2 is OH, where R 4 is methyl, ethyl, or isopropyl.

[0106] In some embodiments, R 1 OCOR 4 , or OC(O)OR 4 and R 2 is OH, where R 4 is C1-C8 alkyl. In some embodiments, R 1 OCOR 4 , or OC(O)OR 4 and R 2 is OH, where R 4 is C1-C6 alkyl. In some embodiments, R 1 OCOR 4 , or OC(O)OR 4 and R 2 is OH, where R 4 is C1-C3 alkyl. In some embodiments, R 1 OCOR 4 , or OC(O)OR 4 and R 2 is OH, where R 4 is methyl, ethyl, or isopropyl.

[0107] In some embodiments, R 1 OCOR 4 and R 2 is OH, where R 4 is C1-C8 alkyl. In some embodiments, R1 OCOR 4 and R 2 is OH, where R 4 is C1-C6 alkyl. In some embodiments, R 1 OCOR 4 and R 2 is OH, where R 4 is C1-C3 alkyl. In some embodiments, R 1 OCOR 4 and R 2 is OH, where R 4 is methyl, ethyl, or isopropyl.

[0108] In some embodiments, R 1 is OC(O)OR 4 and R 2 is OH, where R 4 is C1-C8 alkyl. In some embodiments, R 1 is OC(O)OR 4 and R 2 is OH, where R 4 is C1-C6 alkyl. In some embodiments, R 1 is OC(O)OR 4 and R 2 is OH, where R 4 is C1-C3 alkyl. In some embodiments, R 1 is OC(O)OR 4 and R 2 is OH, where R 4 is methyl, ethyl, or isopropyl.

[0109] In some embodiments of the compounds of Formula I or Ia, R 1 OCOR 4 or OC(O)OR 4 and R 2 OCOR 5 or OC(O)OR 5 where R 4 and R 5are each independently C1-C8 alkyl. In some embodiments, R 1 OCOR 4 or OC(O)OR 4 and R 2 OCOR 5 or OC(O)OR 5 where R 4 and R 5 are each independently C1-C6 alkyl. In some embodiments, R 1 OCOR 4 or OC(O)OR 4 and R 2 OCOR 5 or OC(O)OR 5 where R 4 and R 5 are each independently a C1-C3 alkyl. 1 OCOR 4 or OC(O)OR 4 and R 2 OCOR 5 or OC(O)OR 5 where R 4 and R 5 are each independently methyl, ethyl, or isopropyl.

[0110] In some embodiments, R 1 OCOR 4 and R 2 OCOR 5 or OC(O)OR 5 where R 4 and R 5 are each independently C1-C8 alkyl. In some embodiments, R 1 OCOR 4 and R 2 OCOR 5 or OC(O)OR 5 where R 4 and R 5 are each independently C1-C6 alkyl. In some embodiments, R 1 OCOR 4 and R 2OCOR 5 or OC(O)OR 5 where R 4 and R 5 are each independently C1-C3 alkyl. In some embodiments, R 1 OCOR 4 and R 2 OCOR 5 or OC(O)OR 5 where R 4 and R 5 are each independently methyl, ethyl, or isopropyl.

[0111] In some embodiments, R 1 is OC(O)OR 4 and R 2 OCOR 5 or OC(O)OR 5 where R 4 and R 5 are each independently C1-C8 alkyl. In some embodiments, R 1 is OC(O)OR 4 and R 2 OCOR 5 or OC(O)OR 5 where R 4 and R 5 are each independently C1-C6 alkyl. In some embodiments, R 1 is OC(O)OR 4 and R 2 OCOR 5 or OC(O)OR 5 where R 4 and R 5 are each independently C1-C3 alkyl. In some embodiments, R 1 is OC(O)OR 4 and R 2 OCOR 5 or OC(O)OR 5 where R 4 and R 5 are each independently methyl, ethyl, or isopropyl.

[0112] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 1 OCOR 4 or OC(O)OR 4 and R 2 OCOR 5 where R 4 and R 5 are each independently C1-C8 alkyl. In some embodiments, R 1 OCOR 4 or OC(O)OR 4 and R 2 OCOR 5 where R 4 and R 5 are each independently C1-C6 alkyl. In some embodiments, R 1 OCOR 4 or OC(O)OR 4 and R 2 OCOR 5 where R 4 and R 5 are each independently C1-C3 alkyl. In some embodiments, R 1 OCOR 4 or OC(O)OR 4 and R 2 OCOR 5 where R 4 and R 5 are each independently methyl, ethyl, or isopropyl.

[0113] In some embodiments, R 1 OCOR 4 or OC(O)OR 4 and R 2 is OC(O)OR 5 where R 4 and R 5 are each independently C1-C8 alkyl. In some embodiments, R 1 OCOR 4 or OC(O)OR 4 and R 2is OC(O)OR 5 where R 4 and R 5 are each independently C1-C6 alkyl. In some embodiments, R 1 OCOR 4 or OC(O)OR 4 and R 2 is OC(O)OR 5 where R 4 and R 5 are each independently C1-C3 alkyl. In some embodiments, R 1 OCOR 4 or OC(O)OR 4 and R 2 is OC(O)OR 5 where R 4 and R 5 are each independently methyl, ethyl, or isopropyl.

[0114] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 1 OCOR 4 and R 2 OCOR 5 where R 4 and R 5 are each independently C1-C8 alkyl. In some embodiments, R 1 OCOR 4 and R 2 OCOR 5 where R 4 and R 5 are each independently C1-C6 alkyl. In some embodiments, R 1 OCOR 4 and R 2 OCOR 5 where R 4 and R 5 are each independently C1-C3 alkyl. In some embodiments, R 1 OCOR 4 and R 2 OCOR 5 where R4 and R 5 are each independently methyl, ethyl, or isopropyl.

[0115] In some embodiments, R 1 OCOR 4 and R 2 is OC(O)OR 5 where R 4 and R 5 are each independently C1-C8 alkyl. In some embodiments, R 1 OCOR 4 and R 2 is OC(O)OR 5 where R 4 and R 5 are each independently C1-C6 alkyl. In some embodiments, R 1 OCOR 4 and R 2 is OC(O)OR 5 where R 4 and R 5 are each independently C1-C3 alkyl. In some embodiments, R 1 OCOR 4 and R 2 is OC(O)OR 5 where R 4 and R 5 are each independently methyl, ethyl, or isopropyl.

[0116] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R 1 is OC(O)OR 4 and R 2 OCOR 5 where R 4 and R 5 are each independently C1-C8 alkyl. In some embodiments, R 1 is OC(O)OR 4 and R 2 OCOR 5 where R 4 and R5 are each independently C1-C6 alkyl. In some embodiments, R 1 is OC(O)OR 4 and R 2 OCOR 5 where R 4 and R 5 are each independently C1-C3 alkyl. In some embodiments, R 1 is OC(O)OR 4 and R 2 OCOR 5 where R 4 and R 5 are each independently methyl, ethyl, or isopropyl.

[0117] In some embodiments, R 1 is OC(O)OR 4 and R 2 is OC(O)OR 5 where R 4 and R 5 are each independently C1-C8 alkyl. In some embodiments, R 1 is OC(O)OR 4 and R 2 is OC(O)OR 5 where R 4 and R 5 are each independently C1-C6 alkyl. In some embodiments, R 1 is OC(O)OR 4 and R 2 is OC(O)OR 5 where R 4 and R 5 are each independently C1-C3 alkyl. In some embodiments, R 1 is OC(O)OR 4 and R 2 is OC(O)OR 5 where R 4 and R 5 are each independently methyl, ethyl, or isopropyl.

[0118] In some embodiments of the compounds of Formula I or Ia, R 6 is H, C1-C3 alkyl or C6-C 10 In some embodiments, R 6 is H, C1-C6 alkyl, or phenyl. In some embodiments, R 6 is H, C1-C3 alkyl, or phenyl. In some embodiments, R 6 C6~C 10 In some embodiments, R 6 is phenyl.

[0119] In some embodiments of the compounds of Formula I or Ia, R 1 and R 2 together form -OC(O)O- or -OCHR 6 O-, wherein R 6 is H, C1-C6 alkyl or C6-C 10 In some embodiments, R 1 and R 2 together form -OC(O)O- or -OCHR 6 O-, wherein R 6 is H, C1-C3 alkyl or C6-C 10 In some embodiments, R 1 and R 2 together form -OC(O)O- or -OCHR 6 O-, wherein R 6 is H, C1-C6 alkyl, or phenyl. In some embodiments, R 1 and R 2 together form -OC(O)O- or -OCHR 6 O-, wherein R 6 is H, C1-C3 alkyl, or phenyl. In some embodiments, R 1 and R 2 together form -OC(O)O- or -OCHR 6 O-, wherein R 6 C6~C 10 In some embodiments, R 1and R 2 together form -OC(O)O- or -OCHR 6 O-, wherein R 6 is phenyl.

[0120] In some embodiments of the compounds of Formula I or Ia, R 1 and R 2 Together, -OCHR 6 O-, wherein R 6 is H, C1-C6 alkyl or C6-C 10 In some embodiments, R 1 and R 2 Together, -OCHR 6 O-, wherein R 6 is H, C1-C3 alkyl or C6-C 10 In some embodiments, R 1 and R 2 Together, -OCHR 6 O-, wherein R 6 C6~C 10 In some embodiments, R 1 and R 2 Together, -OCHR 6 O-, wherein R 6 is phenyl.

[0121] In some embodiments of the compounds of Formula I or Ia, R 1 and R 2 together to form -OC(O)O-.

[0122] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, wherein R 3 is H and R 1 OCOR 4 , or OC(O)OR 4 In some embodiments, R 3 is H and R 2 OCOR 5 , or OC(O)OR 5In some embodiments, R 3 is H and R 1 and R 2 together form -OC(O)O- or -OCHR 6 In some embodiments, R 3 is H and R 1 and R 2 together form -OC(O)O-. In some embodiments, R 3 is H and R 1 and R 2 Together, -OCHR 6 O-, wherein R 6 is H, C1-C6 alkyl or C6-C 10 In some embodiments, R 3 is H and R 1 and R 2 Together, -OCHR 6 O-, wherein R 6 is H, C1-C3 alkyl or C6-C 10 In some embodiments, R 3 is H and R 1 and R 2 Together, -OCHR 6 O-, wherein R 6 is H, C1-C6 alkyl, or phenyl. In some embodiments, R 3 is H and R 1 and R 2 Together, -OCHR 6 O-, wherein R 6 is H, C1-C3 alkyl, or phenyl. In some embodiments, R 3 is H and R 1 and R 2 Together, -OCHR 6 O-, wherein R 6 C6~C 10 In some embodiments, R 3 is H and R 1 and R 2 Together, -OCHR 6O-, wherein R 6 is phenyl.

[0123] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, each R 8 is independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, each R 8 is independently H or C1-C6 alkyl. In some embodiments, each R 8 is independently H or C1-C3 alkyl. In some embodiments, each R 8 is H.

[0124] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, each R 9 is independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, each R 9 is independently H or C1-C6 alkyl. In some embodiments, each R 9 is independently H or C1-C3 alkyl. In some embodiments, each R 9 is H.

[0125] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, each R 10 is independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, each R 10 is independently H or C1-C6 alkyl. In some embodiments, each R 10 is independently H or C1-C3 alkyl. In some embodiments, each R 10 is H.

[0126] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, each R 8 , R 9 and R 10 is H.

[0127] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, the compound is [ka] [ka] is selected from the group consisting of:

[0128] In some embodiments of the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, the compound is [ka] is.

[0129] In some embodiments of the compounds of Formula I and Ia, or pharmaceutically acceptable salts thereof, the compound is [ka] [ka] is selected from the group consisting of:

[0130] In some embodiments, the compounds of Formula I or Ia disclosed herein can be considered prodrugs of (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (hereinafter "Reference Compound A") (Compound 13 described in WO 2009132135 and Compound 4 described in J. Med. Chem. 2017, 60, 1648-1661). While not intending to be bound by any particular theory of operation, it is believed that the compounds of Formula I and Ia are metabolized to Reference Compound A in vivo. In some embodiments, the compounds of Formula I or Ia, when administered orally, result in increased bioavailability of Reference Compound A. In some embodiments, a compound of Formula I or Ia, when administered orally, provides an increase in bioavailability of reference compound A of at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 8-fold, at least 10-fold, at least 12-fold, at least 14-fold, at least 16-fold, at least 18-fold, at least 20-fold, at least 25-fold, or at least 30-fold. [ka] V. Pharmaceutical Preparations

[0131] The compounds disclosed herein can be formulated with conventional carriers and excipients. For example, tablets contain excipients, lubricants, fillers, binders, etc. Aqueous formulations are prepared in sterile form and, if intended for delivery by routes other than oral administration, are generally isotonic. All formulations may optionally contain excipients such as those described in the "Handbook of Pharmaceutical Excipients" (1986). Excipients may include ascorbic acid and other antioxidants, chelating agents such as EDTA, and carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, and stearic acid. The pH of the formulations ranges from about 3 to about 11, but is typically about 7 to 10. In some embodiments, the pH of the formulations ranges from about 2 to about 5, but is typically about 3 to 4.

[0132] While it is possible for the compounds of the present disclosure ("active ingredients") to be administered alone, it may be preferable to present them as pharmaceutical formulations. The formulations of the present invention, both for veterinary and human use, comprise at least one active ingredient, as defined above, together with one or more acceptable carriers therefor and, optionally, other additional therapeutic ingredients, particularly the additional therapeutically active ingredients discussed herein. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically non-toxic to the recipient thereof.

[0133] Formulations include those suitable for the aforementioned routes of administration. Formulations may conveniently be presented in unit dosage form and may be prepared by any suitable method known in the art of pharmacy. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier, which constitutes one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0134] In some embodiments, the compounds of Formula I or Ia described herein, or pharmaceutically acceptable salts thereof, have optimized / improved pharmacokinetic properties and are suitable for oral administration. For example, the compounds of Formula I or Ia have improved bioavailability and can therefore be administered orally.

[0135] In some embodiments, formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary, or paste.

[0136] In some embodiments, tablets are made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant, in a suitable machine. Molded tablets can be made by molding a mixture of the powdered active ingredient moistened with an inert liquid diluent in a suitable machine. Tablets can optionally be coated or scored, and are optionally formulated to provide slow or controlled release of the active ingredient therefrom.

[0137] For infections of the eye or other external tissues, e.g., mouth and skin, formulations are applied as a topical ointment or cream containing, for example, 0.075 to 20% w / w (with active ingredient in the range of 0.1% to 20%, in increments of 0.1%, e.g., 0.6% w / w, 0.7% w / w, etc.), preferably 0.2 to 15% w / w, and most preferably 0.5 to 10% w / w. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base.

[0138] If desired, the aqueous phase of the cream base may contain, for example, at least 30% w / w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may desirably include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0139] The oily phase of the emulsion of the present invention can be composed of known ingredients in a known manner. The phase can simply contain an emulsifier (otherwise known as an emulsion), but desirably contains a mixture of at least one emulsifier with a fat or oil, or a mixture of both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier, with or without a stabilizer, constitutes the so-called emulsifying wax, which, together with the oil and fat, constitutes the so-called emulsifying ointment base that forms the oily dispersed phase of the cream formulation.

[0140] Emulgents and emulsion stabilizers suitable for use in the formulations of the present invention include TWEEN® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate. Additional emulgents and emulsion stabilizers suitable for use in the formulations of the present invention include TWEEN® 80.

[0141] The selection of suitable oils or fats for the formulation is based on achieving the desired aesthetic properties. Creams should preferably be non-greasy, non-staining, and washable products with a suitable consistency to avoid leakage from tubes or other containers. Linear or branched, mono- or dibasic alkyl esters, such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or a blend of branched esters known as Crodamol CAP, may also be used, the last three being preferred esters. These may be used alone or in combination, depending on the desired properties. Alternatively, high-melting-point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils may be used.

[0142] Pharmaceutical formulations according to the present invention comprise a compound according to the present invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient can be in any form suitable for the intended method of administration. For example, when used for oral administration, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs can be prepared. Compositions intended for oral administration can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or may be coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used alone or with a wax.

[0143] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

[0144] Aqueous suspensions of the present invention contain the active ingredient in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia, as well as dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearates), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids, and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoates, one or more colorants, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin. Further non-limiting examples of suspending agents include cyclodextrins. In some examples, the suspending agent is sulfobutyl ether β-cyclodextrin (SEB-β-CD), such as Captisol®.

[0145] Oil suspensions can be prepared by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oils such as liquid paraffin.Oral suspensions can contain thickening agents such as beeswax, hard paraffin or cetyl alcohol.Sweeteners and flavoring agents such as those mentioned above can be added to provide a palatable oral preparation.These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0146] Dispersible powders and granules of the present invention suitable for preparation of an aqueous suspension by adding water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0147] The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring gums such as acacia gum and tragacanth gum, naturally occurring phosphatides such as soybean lecithin, esters or partial esters derived from fatty acids, and hexitol anhydrides such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions can also contain sweeteners and flavoring agents. Syrups and elixirs can be formulated with sweeteners such as glycerol, sorbitol, or sucrose. Such formulations can also contain demulcents, preservatives, flavorings, or coloring agents.

[0148] The pharmaceutical compositions of the present invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. These suspensions may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol, or may be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any solvent-free fixed oil, including synthetic monoglycerides or diglycerides, may be used. Additionally, fatty acids such as oleic acid may also be used in the preparation of injectables. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution.

[0149] The amount of active ingredient that may be combined with a carrier material to produce a single dosage form will vary depending on the host treated and the particular mode of administration. For example, a sustained-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active ingredient, compounded with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 μg of active ingredient per milliliter of solution to allow infusion of a suitable volume at a rate of about 30 mL / hour.

[0150] Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, especially about 1.5% w / w.

[0151] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0152] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0153] In some embodiments, the compounds disclosed herein are administered by inhalation. In some embodiments, formulations suitable for pulmonary or nasal administration have particle sizes ranging from, for example, 0.1 to 500 micrometers, e.g., 0.5, 1, 30, 35, etc., and are administered by rapid inhalation through the nasal passage or by inhalation through the mouth to reach the alveoli. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and may be delivered with other therapeutic agents. In some embodiments, the compounds used herein are formulated and administered as dry powders. In some embodiments, the compounds used herein are formulated and administered as spray formulations. In some embodiments, the compounds used herein are formulated for delivery via a face mask. In some embodiments, the compounds used herein are formulated for delivery via a face tent.

[0154] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

[0155] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0156] The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind described above. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, of the active ingredient, or an appropriate fraction thereof.

[0157] It will be understood that in addition to the ingredients specifically mentioned above, the formulations of the present invention may include other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0158] The present invention further provides veterinary compositions comprising at least one active ingredient as defined above together with a veterinary carrier therefor.

[0159] A veterinary carrier is a substance useful for the purpose of administering the composition and may be a solid, liquid, or gaseous substance that is otherwise inert or acceptable in veterinary art and compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally, or by any other desired route.

[0160] The compounds of the present invention are used to provide controlled-release pharmaceutical formulations ("controlled-release formulations") containing one or more compounds of the present invention as the active ingredient, in which release of the active ingredient is controlled and regulated to allow less frequent administration or to improve the pharmacokinetic or toxicity profile of a given active ingredient. VI. Kit

[0161] Also provided herein are kits comprising the compounds disclosed herein, pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or tautomers thereof. In some embodiments, the kits described herein may include a label and / or instructions for use of the compound in treating a disease or condition in a subject (e.g., a human) in need thereof. In some embodiments, the disease or condition is a viral infection.

[0162] In some embodiments, the kit may also include one or more additional therapeutic agents and / or instructions for using the additional therapeutic agents in combination with the compound of Formula I in the treatment of a disease or condition in a subject (e.g., a human) in need thereof.

[0163] In some embodiments, the kits provided herein contain individual unit doses of a compound described herein, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate. Examples of individual dosage units include pills, tablets, capsules, pre-filled syringes or syringe cartridges, IV bags, inhalers, nebulizers, etc., each of which may contain a therapeutically effective amount of the compound of interest, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate. In some embodiments, the kits may contain a single dosage unit and other multiple dosage units, such as the number of dosage units required for a particular regimen or time period.

[0164] Also provided is an article of manufacture comprising a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, and a container. In some embodiments, the article of manufacture container can be a vial, bottle, ampoule, pre-filled syringe, blister package, tin, can, bottle, box, intravenous bag, inhaler, or nebulizer. VII. Administration

[0165] One or more compounds of the present invention are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, inhalation, pulmonary, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural), etc. In some embodiments, the compounds disclosed herein are administered by inhalation or intravenously. It will be understood that the preferred route may vary depending, for example, on the condition of the recipient.

[0166] In the method of the present invention for treating a viral infection, the compound of the present invention can be administered at any time to a person who may have come into contact with the virus or who is already suffering from the viral infection. In some embodiments, the compound of the present invention can be administered prophylactically to a person who has come into contact with a person suffering from a viral infection or who is at risk of coming into contact with a person suffering from a viral infection, such as a healthcare provider. In some embodiments, the compound of the present invention can be administered to a person who has tested positive for a viral infection but has not yet shown symptoms of the viral infection. In some embodiments, the compound of the present invention can be administered to a person at the onset of symptoms of the viral infection.

[0167] In some embodiments, the methods disclosed herein involve event-driven administration of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject.

[0168] As used herein, the term "event-driven" or "event-driven administration" refers to administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, (1) before an event (e.g., 2 hours, 1 day, 2 days, 5 days, or 7 days or more before the event) that exposes the individual to the virus (or otherwise increases the individual's risk of being infected with the virus), and / or (2) during an event (or two or more recurring events) that exposes the individual to the virus (or otherwise increases the individual's risk of being infected with the virus), and / or (3) after an event (or after the last event in a series of recurring events) that exposes the individual to the virus (or otherwise increases the individual's risk of being infected with the virus). In some embodiments, event-driven administration occurs before the subject's exposure to the virus. In some embodiments, event-driven administration occurs after the subject's exposure to the virus. In some embodiments, event-driven administration occurs before the subject's exposure to the virus and after the subject's exposure to the virus.

[0169] In certain embodiments, the methods disclosed herein involve administration before and / or after an event that exposes an individual to the virus or that otherwise increases the individual's risk of becoming infected with the virus, e.g., as pre-exposure prophylaxis (PrEP) and / or post-exposure prophylaxis (PEP). In some embodiments, the methods disclosed herein include pre-exposure prophylaxis (PrEP). In some embodiments, the methods disclosed herein include post-exposure prophylaxis (PEP).

[0170] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered prior to the subject's exposure to the virus.

[0171] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered before and after the subject's exposure to the virus.

[0172] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered after the subject's exposure to the virus.

[0173] An example of an event-driven dosing regimen includes administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, within 24 hours to 2 hours prior to the virus, followed by administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, every 24 hours for the duration of exposure, followed by another administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, after the final exposure, and finally another administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, 24 hours later.

[0174] A further example of an event-driven dosing regimen includes administering a compound of formula I, or a pharmaceutically acceptable salt thereof, within 24 hours before exposure to the virus, followed by daily dosing for the duration of exposure, followed by a final dose (which may be an increased dose, such as a double dose) about 24 hours after the last exposure.

[0175] The specific dose level of the compounds of the present disclosure for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combinations, and the severity of the particular disease in the subject being treated. For example, dosages may be expressed as milligrams of a compound described herein per kilogram of subject body weight (mg / kg). Doses of about 0.1 to 150 mg / kg may be appropriate. In some embodiments, doses of about 0.1 and 100 mg / kg may be appropriate. In other embodiments, doses of 0.5 to 60 mg / kg may be appropriate. Normalizing by subject body weight is particularly useful when adjusting dosages between subjects of widely different sizes, such as occurs when using drugs in both pediatric and adult humans, or when converting effective dosages in non-human subjects, such as dogs, to dosages suitable for human subjects.

[0176] A daily dose may also be described as the total amount of a compound described herein administered per administration or per day. The daily dose of a compound of Formula I, or a pharmaceutically acceptable salt thereof, may be about 1 mg to 4,000 mg, about 2,000 to 4,000 mg / day, about 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 20 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 15 to 150 mg / day.

[0177] The dosage or frequency of administration of a compound of the present disclosure may be adjusted over the course of treatment, based on the judgment of the administering physician.

[0178] The compounds of the present disclosure can be administered to an individual (e.g., a human) in a therapeutically effective amount. In some embodiments, the compounds are administered once daily.

[0179] The compounds provided herein can be administered by any useful route and means, such as oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of a compound can include from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, e.g., from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or from about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or from about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day. In some embodiments, a therapeutically effective amount of a compound provided herein can include from about 0.3 mg to about 30 mg per day, or from about 30 mg to about 300 mg per day, or from about 0.3 μg to about 30 mg per day, or from about 30 μg to about 300 μg per day.

[0180] The compounds of the present disclosure can be combined with one or more additional therapeutic agents at any dosage of the compound of the present disclosure (e.g., 1 mg to 1000 mg of compound). Therapeutically effective amounts may include from about 0.1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per dose, or from about 100 mg per dose to about 400 mg per dose, or from about 150 mg per dose to about 350 mg per dose, or from about 200 mg per dose to about 300 mg per dose, or from about 0.01 mg per dose to about 1000 mg per dose, or from about 0.01 mg per dose to about 100 mg per dose, or from about 0.1 mg per dose to about 100 mg per dose, or from about 1 mg per dose to about 100 mg per dose, or from about 1 mg per dose to about 10 mg per dose, or from about 1 mg per dose to about 1000 mg per dose. Other therapeutically effective amounts of a compound of formula I are about 1 mg per dose, or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg per dose. Other therapeutically effective amounts of compounds of the present disclosure are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or about 1000 mg per dose.

[0181] In some embodiments, the method includes administering to a subject an initial daily dose of about 1 to 500 mg of a compound provided herein, and increasing the dose incrementally until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dose can be increased daily, daily, twice weekly, weekly, every two weeks, every three weeks, or monthly.

[0182] When administered orally, the total daily dosage for a human subject may be about 1-4,000 mg / day, about 1-3,000 mg / day, 1-2,000 mg / day, about 1-1,000 mg / day, about 10-500 mg / day, about 50-300 mg / day, about 75-200 mg / day, or about 100-150 mg / day. In some embodiments, the total daily dosage for a human subject can be about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject can be about 200, 300, 400, 500, 600, 700, or 800 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 300, 400, 500, or 600 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, or 4000 mg / day.In some embodiments, the total daily dosage for a human subject is about 100-200, 100-300, 100-400, 100-500, 100-600, 100-700, 100-800, 100-900, 100-1000, 500-1100, 500-1200, 500-1300, 500-1400, 500-1500, 500-1600, 500-1700, 500-1800, 500-1900, 500-2000, 1500-2100, It may be 1500 to 2200, 1500 to 2300, 1500 to 2400, 1500 to 2500, 2000 to 2600, 2000 to 2700, 2000 to 2800, 2000 to 2900, 2000 to 3000, 2500 to 3100, 2500 to 3200, 2500 to 3300, 2500 to 3400, 2500 to 3500, 3000 to 3600, 3000 to 3700, 3000 to 3800, 3000 to 3900, or 3000 to 4000 mg / day.

[0183] In some embodiments, the total daily dosage for a human subject may be about 100 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 150 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 200 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 250 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 300 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 350 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 400 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 450 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 500 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 550 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 600 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 650 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 700 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 750 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 800 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 850 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 900 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 950 mg / day administered in a single dose.In some embodiments, the total daily dosage for a human subject may be about 1000 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 1500 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 2000 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 2500 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 3000 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 4000 mg / day administered in a single dose.

[0184] A single dose can be administered hourly, daily, weekly, or monthly. For example, a single dose can be administered once every 1, 2, 3, 4, 6, 8, 12, 16 hours, or once every 24 hours. A single dose can also be administered once every 1, 2, 3, 4, 5, 6 days, or once every 7 days. A single dose can also be administered once every 1, 2, 3 weeks, or once every 4 weeks. In some embodiments, a single dose can be administered once weekly. A single dose can also be administered once monthly. In some embodiments, a compound disclosed herein is administered once daily in a method disclosed herein. In some embodiments, a compound disclosed herein is administered twice daily in a method disclosed herein. In some embodiments, a compound disclosed herein is administered three times daily in a method disclosed herein.

[0185] In some embodiments, the compounds disclosed herein are administered once daily at a total daily dose of 100-4000 mg / day. In some embodiments, the compounds disclosed herein are administered twice daily at a total daily dose of 100-4000 mg / day. In some embodiments, the compounds disclosed herein are administered three times daily at a total daily dose of 100-4000 mg / day.

[0186] The frequency of administration of the compounds of the present disclosure is determined by the needs of each individual patient and can be, for example, once a day or twice a day or more. Administration of the compounds continues as long as necessary to treat the viral infection. For example, the compounds can be administered to a human infected with a virus for a period of 20 to 180 days, or for example, for a period of 20 to 90 days, or for example, for a period of 30 to 60 days.

[0187] Administration can be intermittent, with the patient receiving a daily dose of a compound of the present disclosure for a period of several days or more, followed by a period of several days or more during which the patient does not receive a daily dose of the compound. For example, the patient can receive a dose of the compound every other day or three times per week. As a further example, the patient can receive a dose of the compound daily for a period of 1 to 14 days, followed by a period of 7 to 21 days during which the patient does not receive a dose of the compound, followed by a subsequent period (e.g., 1 to 14 days) during which the patient again receives a daily dose of the compound. The alternating periods of compound administration followed by non-compound administration can be repeated as clinically needed to treat the patient.

[0188] The compounds of the present disclosure or pharmaceutical compositions thereof may be administered once, twice, three times, or four times daily using any suitable method described above. Administration or treatment with the compound may also continue for several days; for example, treatment will typically continue for at least 7, 14, or 28 days per treatment cycle. Treatment cycles are well known in cancer chemotherapy and frequently alternate with rest periods of about 1 to 28 days, typically about 7 days or about 14 days, between cycles. Treatment cycles may also be continuous in other embodiments. VIII.How to use

[0189] The present disclosure also provides a method of treating or preventing a viral infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject a compound described herein.

[0190] In some embodiments, the present disclosure provides a method of treating a viral infection in a subject (e.g., a human) in need thereof, comprising administering to the subject in need thereof a compound described herein.

[0191] In some embodiments, the present disclosure provides a method of treating or preventing a viral infection in a subject (e.g., a human) in need thereof, comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic agent.

[0192] In some embodiments, the present disclosure provides a method of treating a viral infection in a subject (e.g., a human) in need thereof, comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic agent.

[0193] In one embodiment, the present disclosure provides a method of inhibiting a viral polymerase in a cell, comprising contacting a virally infected cell with a compound disclosed herein, thereby inhibiting the viral polymerase.

[0194] In one embodiment, the present disclosure provides a method of inhibiting a viral polymerase in a cell, comprising contacting a virally infected cell with a compound disclosed herein and at least one additional active therapeutic agent, thereby inhibiting the viral polymerase.

[0195] Also provided are methods of using the compounds disclosed herein for use in treating or preventing a viral infection in a subject in need thereof. For example, provided herein are methods of using the compounds disclosed herein for use in treating a viral infection in a subject in need thereof.

[0196] In some embodiments, the viral infection is a Paramyxoviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method for treating a Paramyxoviridae virus infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject a compound disclosed herein. Paramyxoviridae viruses include, but are not limited to, Nipah virus, Hendra virus, measles virus, mumps virus, and parainfluenza virus.

[0197] In some embodiments, the viral infection is a Pneumoviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method of treating a Pneumoviridae virus infection in a human in need thereof, the method comprising administering a compound provided herein to the human. Pneumoviridae viruses include, but are not limited to, respiratory syncytial virus and human metapneumovirus. In some embodiments, the Pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the Pneumoviridae virus infection is a human metapneumovirus infection.

[0198] In some embodiments, the present disclosure provides a compound disclosed herein for use in treating a Pneumoviridae virus infection in a human in need thereof. In some embodiments, the Pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the Pneumoviridae virus infection is a human metapneumovirus infection.

[0199] In some embodiments, the present disclosure provides a method for treating a RSV infection in a human in need thereof, the method comprising administering a compound provided herein to the human. In some embodiments, the human is suffering from a chronic respiratory syncytial virus infection. In some embodiments, the human is acutely infected with RSV.

[0200] In some embodiments, a method of inhibiting RSV replication is provided, comprising administering to a human in need thereof a compound disclosed herein, wherein the administration is by inhalation.

[0201] In some embodiments, the present disclosure provides a method for reducing the viral load associated with a RSV infection, the method comprising administering to a human infected with RSV a compound disclosed herein.

[0202] In some embodiments, the viral infection is a Picornaviridae virus infection. In some embodiments, the disclosure provides a method of treating a Picornaviridae virus infection in a human in need thereof, the method comprising administering a compound of the disclosure to the human. Picornaviridae viruses are enteroviruses that cause a heterogeneous group of infections, including herpangina, aseptic meningitis, common cold-like syndrome (human rhinovirus infection), non-paralytic polio-like syndrome, epidemic pleurodynia (an acute, febrile, infectious illness that typically occurs during epidemics), hand, foot, and mouth disease, pediatric and adult pancreatitis, and severe myocarditis. In some embodiments, the Picornaviridae virus infection is a human rhinovirus infection (HRV). In some embodiments, the Picornaviridae virus infection is an HRV-A, HRV-B, or HRV-C infection.

[0203] In some embodiments, the present disclosure provides a compound for use in treating a Picornaviridae virus infection in a human in need thereof, hi some embodiments, the Picornaviridae virus infection is a human rhinovirus infection.

[0204] In some embodiments, the viral infection is a Flaviviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method of treating a Flaviviridae virus infection in a human in need thereof, the method comprising administering to the human a compound described herein. Representative Flaviviridae viruses include dengue fever, yellow fever, West Nile, Zika, Japanese encephalitis virus, and hepatitis C (HCV). In some embodiments, the Flaviviridae virus infection is a dengue virus infection. In some embodiments, the Flaviviridae virus infection is a yellow fever virus infection. In some embodiments, the Flaviviridae virus infection is a West Nile virus infection. In some embodiments, the Flaviviridae virus infection is a Zika virus infection. In some embodiments, the Flaviviridae virus infection is a Japanese encephalitis virus infection. In some embodiments, the Flaviviridae virus infection is a hepatitis C virus infection.

[0205] In some embodiments, the disclosure provides use of a compound of the disclosure for the treatment of a Flaviviridae virus infection in a human in need thereof. In some embodiments, the Flaviviridae virus infection is a Dengue virus infection. In some embodiments, the Flaviviridae virus infection is a Yellow Fever virus infection. In some embodiments, the Flaviviridae virus infection is a West Nile virus infection. In some embodiments, the Flaviviridae virus infection is a Zika virus infection. In some embodiments, the Flaviviridae virus infection is a Hepatitis C virus infection.

[0206] In some embodiments, the viral infection is a Filoviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method of treating a Filoviridae virus infection in a human in need thereof, the method comprising administering to the human a compound disclosed herein. Representative Filoviridae viruses include, but are not limited to, Ebola virus (Zaire, Bundibugyo, Sudan, Tai Forest, or Reston variant) and Marburg virus. In some embodiments, the Filoviridae virus infection is an Ebola virus infection. In some embodiments, the Filoviridae virus infection is a Marburg virus infection.

[0207] In some embodiments, the present disclosure provides a compound for use in treating a Filoviridae virus infection in a human in need thereof. In some embodiments, the Filoviridae virus infection is an Ebola virus infection. In some embodiments, the Filoviridae virus infection is a Marburg virus infection.

[0208] In some embodiments, the viral infection is a coronavirus infection. Accordingly, in some embodiments, provided herein are methods of treating a coronavirus infection in a human in need thereof, the method comprising administering a compound provided herein to the human. In some embodiments, the coronavirus infection is a severe acute respiratory syndrome (SARS-CoV) infection, a Middle East respiratory syndrome (MERS) infection, a SARS-CoV-2 infection, another human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infection, or a zoonotic coronavirus (PEDV or HKU CoV isolate, e.g., HKU3, HKU5, or HKU9) infection. In some embodiments, the viral infection is a severe acute respiratory syndrome (SARS) infection. In some embodiments, the viral infection is a Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is a SARS-CoV-2 infection. In some embodiments, the viral infection is a zoonotic coronavirus infection, and in some embodiments, the viral infection is caused by a virus having at least 70% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 80% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 90% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 95% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2.

[0209] In some embodiments, the viral infection is caused by a SARS-CoV-2 variant, such as the B.1.1.7 variant (UK variant), the B.1.351 variant (South African variant), the P.1 variant (Brazilian variant), the B.1.1.7 with the E484K mutation, the B.1.1.207 variant, the B.1.1.317 variant, the B.1.1.318 variant, the B.1.429 variant, the B.1.525 variant, or the P.3 variant. In some embodiments, the viral infection is caused by the B.1.1.7 variant of SARS-CoV-2. In some embodiments, the viral infection is caused by the B.1.351 variant of SARS-CoV-2. In some embodiments, the viral infection is caused by the P.1 variant of SARS-CoV-2.

[0210] In some embodiments, the disclosure provides compounds for use in treating a coronavirus infection in a human in need thereof. In some embodiments, the coronavirus infection is a severe acute respiratory syndrome (SARS) infection, a Middle East respiratory syndrome (MERS) infection, a SARS-CoV-2 infection, another human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infection, or a zoonotic coronavirus (PEDV or HKUCoV isolate, e.g., HKU3, HKU5, or HKU9) infection. In some embodiments, the viral infection is a severe acute respiratory syndrome (SARS) infection. In some embodiments, the viral infection is a Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is a SARS-CoV-2 infection (COVID19).

[0211] In some embodiments, the viral infection is an Arenaviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method of treating an Arenaviridae virus infection in a human in need thereof, the method comprising administering to the human a compound disclosed herein. In some embodiments, the Arenaviridae virus infection is a Lassa infection or a Junin infection.

[0212] In some embodiments, the present disclosure provides a compound for use in treating an Arenaviridae virus infection in a human in need thereof, hi some embodiments, the Arenaviridae virus infection is a Lassa infection or a Junin infection.

[0213] In some embodiments, the viral infection is an orthomyxovirus infection, such as an influenza virus infection. In some embodiments, the viral infection is an influenza virus A, influenza virus B, or influenza virus C infection.

[0214] As described more fully herein, the compounds described herein can be administered to an individual (e.g., a human) infected with a viral infection along with one or more additional therapeutic agents. The additional therapeutic agents can be administered to the infected individual simultaneously with the compounds of the present disclosure, or before or after administration of the compounds of the present disclosure. IX. Combination Therapy

[0215] The compounds described herein can also be used in combination with one or more additional therapeutic agents. Accordingly, also provided herein is a method of treating a viral infection in a subject in need thereof, the method comprising administering to the subject a compound disclosed herein and a therapeutically effective amount of one or more additional therapeutic agents.

[0216] In some embodiments, the additional therapeutic agent comprises an antiviral agent. Any suitable antiviral agent can be used in the methods described herein. In some embodiments, the antiviral agent is selected from the group consisting of a 5-substituted 2'-deoxyuridine analog, a nucleoside analog, a pyrophosphate analog, a nucleoside reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor, an integrase inhibitor, an entry inhibitor, an acyclic guanosine analog, an acyclic nucleoside phosphonate analog, an HCV NS5A / NS5B inhibitor, an influenza virus inhibitor, an interferon, an immunostimulant, an oligonucleotide, a mitotic inhibitor, and combinations thereof.

[0217] In some embodiments, the additional therapeutic agent is a 5-substituted 2'-deoxyuridine analog, e.g., in some embodiments, the additional therapeutic agent is selected from the group consisting of idoxuridine, trifluridine, brivudine [BVDU], and combinations thereof.

[0218] In some embodiments, the additional therapeutic agent is a nucleoside analog. For example, in some embodiments, the additional therapeutic agent is vidarabine, entecavir (ETV), or the like. In some embodiments, the additional therapeutic agent is selected from the group consisting of telbivudine, lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate (TDF), and combinations thereof. In some embodiments, the additional therapeutic agent is favipiravir, ribavirin, galidesivir, β-D-N4-hydroxycytidine, or a combination thereof.

[0219] In some embodiments, the additional therapeutic agent is a pyrophosphate analog. For example, in some embodiments, the additional therapeutic agent is foscarnet or phosphonoacetic acid. In some embodiments, the additional therapeutic agent is foscarnet.

[0220] In some embodiments, the additional therapeutic agent is a nucleoside reverse transcriptase inhibitor, hi some embodiments, the antiviral agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, and combinations thereof.

[0221] In some embodiments, the additional therapeutic agent is a non-nucleoside reverse transcriptase inhibitor. In some embodiments, the antiviral agent is selected from the group consisting of nevirapine, delavirdine, efavirenz, etravirine, rilpivirine, and combinations thereof.

[0222] In some embodiments, the additional therapeutic agent is a protease inhibitor. In some embodiments, the protease inhibitor is an HIV protease inhibitor. For example, in some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, and combinations thereof. In some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, and combinations thereof. In some embodiments, the protease inhibitor is an HCV NS3 / 4A protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, ribavirin, danoprevir, faldaprevir, bedroprevir, sovaprevir, deldeprevir, naraprevir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, and combinations thereof.

[0223] In some embodiments, the additional therapeutic agent is an integrase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of raltegravir, dolutegravir, elvitegravir, abacavir, lamivudine, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of bictegravir, raltegravir, dolutegravir, cabotegravir, elvitegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of bictegravir, dolutegravir, and cabotegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is bictegravir.

[0224] In some embodiments, the additional therapeutic agent is an entry inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of docosanol, enfuvirtide, maraviroc, ibalizumab, fostemsavir, leronlimab, ibalizumab, fostemsavir, leronlimab, palivizumab, respiratory syncytial virus immune globulin, intravenous [RSV-IGIV], varicella zoster immune globulin [VariZIG], varicella zoster immune globulin [VZIG], and combinations thereof.

[0225] In some embodiments, the additional therapeutic agent is an acyclic guanosine analog, for example, in some embodiments, the additional therapeutic agent is selected from the group consisting of acyclovir, ganciclovir, valacyclovir (also known as valaciclovir), valganciclovir, penciclovir, famciclovir, and combinations thereof.

[0226] In some embodiments, the additional therapeutic agent is an acyclic nucleoside phosphonate analog. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, emtricitabine, efavirenz, rilpivirine, elvitegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir dipivoxil, TDF, and combinations thereof.

[0227] In some embodiments, the additional therapeutic agent is an HCV NS5A / NS5B inhibitor. In some embodiments, the additional therapeutic agent is an NS3 / 4A protease inhibitor. In some embodiments, the additional therapeutic agent is an NS5A protein inhibitor. In some embodiments, the additional therapeutic agent is a nucleoside / nucleotide-based NS5B polymerase inhibitor. In some embodiments, the additional therapeutic agent is a non-nucleoside-based NS5B polymerase inhibitor. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, ribavirin, asunaprevir, simeprevir, paritaprevir, ritonavir, elbasvir, grazoprevir, AT-527, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, and combinations thereof.

[0228] In some embodiments, the additional therapeutic agent is an influenza virus inhibitor. In some embodiments, the additional therapeutic agent is a matrix 2 inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, and combinations thereof. In some embodiments, the additional therapeutic agent is a neuraminidase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of zanamivir, oseltamivir, peramivir, laninamivir octanoate, and combinations thereof. In some embodiments, the additional therapeutic agent is a polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ribavirin, favipiravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, arbidol (umifenovir), baloxavir marboxil, oseltamivir, peramivir, ingavirin, laninamivir octanoate, zanamivir, favipiravir, ribavirin, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, zanamivir, oseltamivir, peramivir, laninamivir octanoate, ribavirin, favipiravir, and combinations thereof.

[0229] In some embodiments, the additional therapeutic agent is an interferon. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon1, interferon alfa lb, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfacon1, pegylated interferon alfa lb, pegylated interferon alfa 2a (PegIFNα-2a), and PegIFNα-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon1, interferon alfa lb, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfa 2a (PegIFNα-2a), and PegIFNα-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon1, pegylated interferon alfa 2a (PegIFNα-2a), PegIFNα-2b, and ribavirin. In some embodiments, the additional therapeutic agent is pegylated interferon alpha-2a, pegylated interferon alpha-2b, or a combination thereof.

[0230] In some embodiments, the additional therapeutic agent is an immunostimulant. In some embodiments, the additional therapeutic agent is an oligonucleotide. In some embodiments, the additional therapeutic agent is a mitotic inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of fomivirsen, podofilox, imiquimod, sinecatechin, and combinations thereof.

[0231] In some embodiments, the additional therapeutic agent is selected from the group consisting of besifovir, nitazoxanide, REGN2222, doravirine, sofosbuvir, velpatasvir, daclatasvir, asunaprevir, beclabuvir, FV100, and letermovir, and combinations thereof.

[0232] In some embodiments, the additional therapeutic agent is an agent for the treatment of RSV. For example, in some embodiments, the antiviral agent is ribavirin, ALS-8112, or presatovir. For example, in some embodiments, the antiviral agent is ALS-8112 or presatovir.

[0233] In some embodiments, the additional therapeutic agent is an agent for the treatment of picornavirus. In some embodiments, the additional therapeutic agent is selected from the group consisting of hydantoin, guanidine hydrochloride, l-buthionine sulfoximine, Py-11, and combinations thereof. In some embodiments, the additional therapeutic agent is a picornavirus polymerase inhibitor. In some embodiments, the additional therapeutic agent is rupintrivir.

[0234] In some embodiments, the additional therapeutic agent is an agent for the treatment of malaria, hi some embodiments, the additional therapeutic agent is chloroquine.

[0235] In some embodiments, the additional therapeutic agent is selected from the group consisting of hydroxychloroquine, chloroquine, artemether, lumefantrine, atovaquone, proguanil, tafenoquine, pyronaridine, artesunate, artenimol, piperaquine, artesunate, amodiaquine, pyronaridine, artesunate, halofantrine, quinine sulfate, mefloquine, solithromycin, pyrimethamine, MMV-390048, ferroquine, artefenomer mesylate, ganaplacid, DSM-265, cypargamine, artemisone, and combinations thereof.

[0236] In some embodiments, the additional therapeutic agent is an agent for the treatment of coronavirus, hi some embodiments, the additional therapeutic agent is selected from the group consisting of IFX-1, FM-201, CYNK-001, DPP4-Fc, ranpirnase, nafamostat, LB-2, AM-1, antiviroporin, and combinations thereof.

[0237] In some embodiments, the additional therapeutic agent is an agent for the treatment of Ebola virus. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola Convalescent Plasma, and the like. Plasma, ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol), favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9-dimethylquinolin[8,7- h]quinolone-1,7-diamine), JK-05, TKM-Ebola, ZMapp, rNAPc2, VRC-EBOADC076-00-VP, OS-2966, MVA-BN Filo, brincidofovir, Vaxart adenoviral vector 5-based Ebola vaccine, Ad26-ZEBOV, FiloVax vaccine, GOVX-E301, GOVX-E302, Ebola virus entry inhibitor (NPC1 inhibitor), rVSV-EBOV, and combinations thereof. In some embodiments, the additional therapeutic agent is ZMapp, mAB114, REGEN-EB3, and combinations thereof.

[0238] In some embodiments, the additional therapeutic agent is an agent for the treatment of HCV. In some embodiments, the additional therapeutic agent is an HCV polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of sofosbuvir, GS-6620, PSI-938, ribavirin, tegobuvir, ladarbuvir, MK-0608, and combinations thereof. In some embodiments, the additional therapeutic agent is an HCV protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of GS-9256, vedroprevir, voxilaprevir, and combinations thereof.

[0239] In some embodiments, the additional therapeutic agent is an NS5A inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ledipasvir, velpatasvir, and combinations thereof.

[0240] In some embodiments, the additional therapeutic agent is an anti-HBV agent, for example, in some embodiments, the additional therapeutic agent is tenofovir disoproxil fumarate and emtricitabine, or a combination thereof. Examples of additional anti-HBV agents include α-hydroxytropolone, amdoxovir, antroquinonol, β-hydroxycytosine nucleosides, ARB-199, CCC-0975, ccc-R08, elvucitabine, ezetimibe, cyclosporine A, gentiopicrin (gentiopicroside), HH-003, heparatide, JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV-205 (Mollixan, BAM-205), oligotide, mibotylate, Feron, GST-HG-131, levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-006IA, Hepuyinfen, DasKloster0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, Heplantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, QL-007 sofosbuvir, ledipasvir, UB-551, and ZH-2N, as well as U.S. Patent Application Publication Nos. 20150210682 (Roche), 2016 / 0122344 (Roche), WO 2015173164, WO 2016023877, U.S. Patent Application Publication No. 2015252057(A) (Roche), WO 2015252057(B) (Roche), WO 2015252057(C) (Roche), WO 2015252057(D) (Roche), WO 2015252057(E) (Roche), WO 2015252057(F) (Roche), WO 2015252057(G) (Roche), WO 2015252057(H) (Roche), WO 2015252057(I ... Examples of additional therapeutic agents include, but are not limited to, compounds disclosed in Publication Nos. 16128335(A1) (Roche), 16120186(A1) (Roche), U.S. Patent Application Publication Nos. 2016237090(A) (Roche), WO 16107833(A1) (Roche), WO 16107832(A1) (Roche), U.S. Patent Application Publication Nos. 2016176899(A) (Roche), WO 16102438(A1) (Roche), WO 16012470(A1) (Roche), U.S. Patent Application Publication Nos. 2016220586(A) (Roche), and 2015031687(A) (Roche). In some embodiments, the additional therapeutic agent is an HBV polymerase inhibitor. HBVExamples of DNA polymerase inhibitors include adefovir (HEPSERA®), emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, tenofovir exalidex, bicifovir, and entecavir. In some embodiments, the additional therapeutic agent includes, but is not limited to, HBV capsid inhibitors, such as HBV cyclosporine, ...

[0241] In some embodiments, the additional therapeutic agent is an agent for the treatment of HIV, hi some embodiments, the additional therapeutic agent is selected from the group consisting of an HIV protease inhibitor, an HIV integrase inhibitor, an entry inhibitor, an HIV nucleoside reverse transcriptase inhibitor, an HIV non-nucleoside reverse transcriptase inhibitor, an acyclic nucleoside phosphonate analog, and combinations thereof.

[0242] In some embodiments, the additional therapeutic agent is selected from the group consisting of an HIV protease inhibitor, a non-nucleoside or non-nucleotide inhibitor of HIV reverse transcriptase, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry inhibitor, an HIV maturation inhibitor, an immune modulator, an immunotherapeutic agent, an antibody-drug conjugate, a gene modulating agent, a gene editing agent (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), and a cell therapy (e.g., chimeric antigen receptor T cells, CAR-T, and engineered T cell receptors, TCR-T, autologous T cell therapy).

[0243] In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV combination drugs, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reactivators, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0244] In some embodiments, the additional therapeutic agent is an HIV combination medication. Examples of HIV combination medications include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); BIKTARVY® (bictegravir, emtricitabine, and tenofovir alafenamide); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine). TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); SYMTUZA® (darunavir, tenofovir alafenamide hemifumarate, emtricitabine) , and cobicistat; SYMFI™ (efavirenz, lamivudine, and tenofovir disoproxil fumarate); CIMDU™ (lamivudine and tenofovir disoproxil fumarate); tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and ervivir Tegravir; COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA®; lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); atazanavir and cobicistat;Atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil; dapivirine and levonorgestrel, dolutegravir and lamivudine, dolutegravir and emtricitabine and tenofovir alafena These include, but are not limited to, elsulfavirine + emtricitabine + tenofovir disoproxil, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine, and lamivudine;

[0245] In some embodiments, the additional therapeutic agent is an HIV protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, ASC-09, AEBL-2, MK-8718, GS-9500, GS-1156, and combinations thereof. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, and cobicistat. In some embodiments, the additional therapeutic agent is selected from the group consisting of amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, TMC-310911, and combinations thereof.

[0246] In some embodiments, the additional therapeutic agent is an HIV integrase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of raltegravir, elvitegravir, dolutegravir, abacavir, lamivudine, bictegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is bictegravir. In some embodiments, the additional therapeutic agent is selected from the group consisting of bictegravir, elvitegravir, curcumin, curcumin derivatives, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, A Selected from the group consisting of VX-15567, BMS-986197, cabotegravir (long-acting injectable), diketoquinoline 4-1 derivatives, integrase-LEDGF inhibitors, ledgin, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, VM-3500, cabotegravir, and combinations thereof.

[0247] In some embodiments, the additional therapeutic agent is an HIV entry inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of enfuvirtide, maraviroc, and combinations thereof. Further examples of HIV entry inhibitors include, but are not limited to, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 adhesion inhibitors, DS-003 (BMS-599793), gp120 inhibitors, and CXCR4 inhibitors. Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, leronlimab (PRO-140), adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu). Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0248] In some embodiments, the additional therapeutic agent is an HIV nucleoside reverse transcriptase inhibitor. In some embodiments, the additional therapeutic agent is an HIV non-nucleoside reverse transcriptase inhibitor. In some embodiments, the additional therapeutic agent is an acyclic nucleoside phosphonate analog. In some embodiments, the additional therapeutic agent is an HIV capsid inhibitor.

[0249] In some embodiments, the additional therapeutic agent is a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, for example, adefovir, adefovir dipivoxil, azuvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX®, and VIDEX EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, islatravir, lamivudine, phosphazide, stavudine, zalcitabine, zidovudine, lobafovir etalafenamid (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, KP-1461, and combinations thereof.

[0250] In some embodiments, the additional therapeutic agent is a non-nucleoside or non-nucleotide inhibitor of HIV reverse transcriptase, for example, the additional agent is selected from the group consisting of dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA, ACC-007, AIC-292, KM-023, PC-1005, elsulfavirin rilp (VM-1500), and combinations thereof.

[0251] In some embodiments, the additional therapeutic agent is ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FT C); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); Adefovir; Adefovir dipivoxil; Cobicistat; Emtricitabine; Tenofovir; Tenofovir disoproxil; Tenofovir disoproxil fumarate; Tenofovir alafenamide; Tenofovir alafenamide hemifumarate; T RIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavir sulfate) acid salt, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine;Selected from stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (Receptor); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0252] In some embodiments, the additional therapeutic agent is selected from the group consisting of colistin, barbicin, icatibant, bepotastine, epirubicin, epoprocetonol, vapreotide, aprepitant, caspofungin, perphenazine, atazanavir, efavirenz, ritonavir, acyclovir, ganciclovir, penciclovir, prulifloxacin, bictegravir, nelfinavir, tegovyne, nelfinavir, praziquantel, pitavastatin, perampanel, eszopiclone, and zopiclone.

[0253] In some embodiments, the additional therapeutic agent is an inhibitor of Bruton's tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA, NCBI gene ID: 695). For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib (Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, becabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, AZD6738, calquence, dambatrisen, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of tirabrutinib, ibrutinib, acalabrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of tirabrutinib, ibrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is tyrphostin A9 (A9).

[0254] In some embodiments, the additional therapeutic agent is a KRAS inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of MRTX-849(G12C) and K-Ras(G12D) selective inhibitory peptides, including AMG-510, COTI-219, MRTX-1257, ARS-3248, ARS-853, WDB-178, BI-3406, BI-1701963, ARS-1620(G12C), SML-8-73-1(G12C), compound 3144(G12D), Kobe0065 / 2602 (Ras GTP), RT11, KRpep-2(Ac-RRCPLYISYDPVCRR-NH2), KRpep-2d(Ac-RRRRCPLYISYDPVCRRRR-NH2), and combinations thereof.

[0255] In some embodiments, the additional therapeutic agent is a proteasome inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ixazomib, carfilzomib, marizomib, bortezomib, and combinations thereof. In some embodiments, the additional therapeutic agent is carfilzomib.

[0256] In some embodiments, the additional therapeutic agent is a vaccine. For example, in some embodiments, the additional therapeutic agent is a DNA vaccine, an RNA vaccine, a live attenuated vaccine, a therapeutic vaccine, a prophylactic vaccine, a protein-based vaccine, or a combination thereof. In some embodiments, the additional therapeutic agent is mRNA-1273. In some embodiments, the additional therapeutic agent is INO-4800 or INO-4700. In some embodiments, the additional therapeutic agent is a live attenuated RSV vaccine MEDI-559, a human monoclonal antibody against RSV REGN2222, palivizumab, respiratory syncytial virus immune globulin intravenous [RSV-IGIV], and combinations thereof. In some embodiments, the additional therapeutic agent is an HBV vaccine, e.g., Pedialix, Engelix-B, and RecombiVax HB. In some embodiments, the additional therapeutic agent is a VZV vaccine, e.g., Zostavix and Varivax. In some embodiments, the additional therapeutic agent is an HPV vaccine, e.g., cervical, Gardasil 9, and Gardasil. In some embodiments, the additional therapeutic agent is an influenza virus vaccine, such as (i) a monovalent vaccine for influenza A (e.g., an influenza A [H5N1] virus monovalent vaccine and an influenza A [H1N1] 2009 virus monovalent vaccine), (ii) a trivalent vaccine for influenza A and B viruses (e.g., Afluria, Agriflu, Flude, Fluarix, Flublox, Flucervax, Flulaval, Fluvirin, and Fluzone), and (iii) a tetravalent vaccine for influenza A and B viruses (Flumist, Fluarix, Fluzone, and Flulaval). In some embodiments, the additional therapeutic agent is a human adenovirus vaccine (e.g., adenovirus types 4 and 7 vaccine, live, oral). In some embodiments, the additional therapeutic agent is a rotavirus vaccine (e.g., Rotarix for rotavirus serotypes G1, G3, G4, or G9, and RotaTeq for rotavirus serotypes G1, G2, G3, or G4). In some embodiments, the additional therapeutic agent is a hepatitis A virus vaccine (eg, Havrix and Vaqta).In some embodiments, the additional therapeutic agent is a poliovirus vaccine (e.g., Kinrix, Quadracel, and Ipol). In some embodiments, the additional therapeutic agent is a yellow fever virus vaccine (e.g., YF-Vax). In some embodiments, the additional therapeutic agent is a Japanese encephalitis virus vaccine (e.g., Ixiaro and JE-Vax). In some embodiments, the additional therapeutic agent is a measles vaccine (e.g., MMR II and ProQuad). In some embodiments, the additional therapeutic agent is a mumps vaccine (e.g., MMR II and ProQuad). In some embodiments, the additional therapeutic agent is a rubella vaccine (e.g., MMR II and ProQuad). In some embodiments, the additional therapeutic agent is a varicella vaccine (e.g., ProQuad). In some embodiments, the additional therapeutic agent is a rabies vaccine (e.g., Imovax and RabAvert). In some embodiments, the additional therapeutic agent is a variola virus (smallpox) vaccine (ACAM2000). In some embodiments, the additional therapeutic agent is a Hepatitis E Virus (HEV) vaccine (e.g., HEV239). In some embodiments, the additional therapeutic agent is a 2019-nCov vaccine.

[0257] In some embodiments, the additional therapeutic agent is an antibody, e.g., a monoclonal antibody. For example, the additional therapeutic agent is an antibody against 2019-nCov selected from the group consisting of a Regeneron antibody, a Wuxi antibody, a Vir Biotechnology antibody, an antibody targeting the SARS-CoV-2 spike protein, an antibody capable of neutralizing SARS-CoV-2 (a SARS-CoV-2 neutralizing antibody), and combinations thereof. In some embodiments, the additional therapeutic agent is the anti-SARS-CoV antibody CR-3022. In some embodiments, the additional therapeutic agent is an aPD-1 antibody.

[0258] In some embodiments, the additional therapeutic agent is a recombinant cytokine gene-derived protein injection.

[0259] In some embodiments, the additional therapeutic agent is a polymerase inhibitor. In some embodiments, the additional therapeutic agent is a DNA polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is cidofovir. In some embodiments, the additional therapeutic agent is an RNA polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ribavirin, favipiravir, lamivudine, pimodivir, and combinations thereof.

[0260] In some embodiments, the additional therapeutic agent is selected from the group consisting of lopinavir, ritonavir, interferon-alpha-2b, ritonavir, arbidol, hydroxychloroquine, darunavir and cobicistat, abidol hydrochloride, oseltamivir, ritonavir, emtricitabine, tenofovir alafenamide fumarate, baloxavir marboxil, ruxolitinib, and combinations thereof.

[0261] In some embodiments, the additional therapeutic agent is a 6'-fluorinated aristemicin analog, an acyclovir fleximer analog, disulfiram, a thiopurine analog, ASC09F, GC376, GC813, a phenylisoserine derivative, a neuroimidase inhibitor analog, a pyrithiobac derivative, a vananin and a 5-hydroxychromone derivative, SSYA10-001, a griffithsin, a HR2P-M1, a HR2P-M2, a P21S10, dihydrotanshinones E-64-C and E-64-D, an OC43-HR2P, a MERS-5HB, a 229E-HR1P, a 229E-HR2P, a resveratrol, a hydroxybenzoate, a benzocaine, a benzodiazepine ... rol, 1-thia-4-azaspiro[4.5]decan-3-one derivatives, gemcitabine hydrochloride, loperamide, recombinant interferon, cyclosporin A, alisporivir, imatinib mesylate, dasatinib, selumetinib, trametinib, rapamycin, saracatinib, chlorpromazine, triflupromazine, fluphenazine, thiethylperazine, promethazine, cyclophilin inhibitors, K11777, camostat, k22, teicoplanin derivatives, benzoheterocyclic amine derivative N30, mycophenolic acid, silvestrol, and combinations thereof.

[0262] In some embodiments, the additional therapeutic agent is an antibody. In some embodiments, the additional therapeutic agent is an antibody that binds to a coronavirus, e.g., an antibody that binds to SARS-CoV or MERS-CoV. In some embodiments, the additional therapeutic agent is a viral antibody of 2019-nCoV.

[0263] The compositions of the invention may also be used in combination with other active ingredients. For the treatment of 2019-nCoV viral infection, preferably, the other active therapeutic agent is active against coronavirus infection, e.g., 2019-nCoV viral infection. The compounds and compositions of the invention may also be used in combination with parenteral fluids (including dextrose saline and lactated Ringer's solution) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics, such as ceftriaxone and cefuroxime) and / or antifungal prophylactics, fever and analgesics, antiemetics (such as metoclopramide) and / or antidiarrheal medications, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen or steroids), corticosteroids such as methylprednisolone, immunomodulatory agents (e.g., interferons), and other small molecule or biological antivirals targeting 2019-nCoV. The additional therapeutic agent is intended for use in conjunction with general care provided to patients with 2019-nCoV virus infection, including other common illnesses in the patient population, such as antivirals (including, but not limited to, lopinavir / ritonavir, EIDD-1931, favipiravir, ribavirin, neutralizing antibodies, etc.), vaccines, analgesics, and drugs for other common illnesses in the patient population, such as antimalarials (including artemether and artemether-lumefantrine combination therapy), typhoid fever (quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or shigellosis. In some embodiments, the additional therapeutic agent is dihydroartemisinin / piperaquine. In some embodiments, the additional therapeutic agent is EIDD-2801 (MH-4482, molnupiravir).

[0264] In some embodiments, the additional therapeutic agent is an immune modulator. Examples of immune system therapeutic agents include toll-like receptor modulators such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (Pd-1) modulators; programmed death-ligand 1 (Pd-L1) modulators; IL-15 modulators, DermaVir; interleukin-7; Plaquenil (hydroxychloroquine); Proleukin (aldesleukin, IL-2); interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its derivatives. tert-Butyl derivatives mycophenolate mofetil (MMF); ribavirin; polymerpolyethyleneimine (PEI); gepon; Examples of additional therapeutic agents include IL-12, WF-10, VGV-1, MOR-22, BMS-936559, CYT-107, interleukin-15 / Fc fusion protein, AM-0015, ALT-803, NIZ-985, NKTR-255, NKTR-262, NKTR-214, normferon, pegylated interferon alfa-2a, pegylated interferon alfa-2b, recombinant interleukin-15, Xmab-24306, RPI-MN, STING modulators, RIG-I modulators, NOD2 modulators, SB-9200, and IR-103. In some embodiments, the additional therapeutic agent is fingolimod, leflunomide, or a combination thereof. In some embodiments, the additional therapeutic agent is thalidomide.

[0265] In some embodiments, the additional therapeutic agent is an IL-6 inhibitor, e.g., tocilizumab, sarilumab, or a combination thereof.

[0266] In some embodiments, the additional therapeutic agent is an anti-TNF inhibitor, e.g., the additional therapeutic agent is adalimumab, etanercept, golimumab, infliximab, or a combination thereof.

[0267] In some embodiments, the additional therapeutic agent is a JAK inhibitor, for example, the additional therapeutic agent is baricitinib, filgotinib, Olumiant, or a combination thereof.

[0268] In some embodiments, the additional therapeutic agent is an inflammation inhibitor, eg, pirfenidone.

[0269] In some embodiments, the additional therapeutic agent is an antibiotic for secondary bacterial pneumonia, for example, the additional therapeutic agent is a macrolide antibiotic (e.g., azithromycin, clarithromycin, and mycoplasma pneumoniae), a fluoroquinolone (e.g., ciprofloxacin and levofloxacin), a tetracycline (e.g., doxycycline and tetracycline), or a combination thereof.

[0270] In some embodiments, the compounds disclosed herein are used in combination with standard of care treatments for pneumonia (e.g., Pediatric Community Pneumonia). Guidelines, CID 2011:53 (1 October). Treatment of pneumonia generally involves curing the infection and preventing complications. The specific treatment depends on several factors, including the type and severity of the pneumonia, the age, and the overall health of the individual. Options include: (i) antibiotics, (ii) cough suppressants, and (iii) antipyretics / pain relievers (e.g., aspirin, ibuprofen (Advil, Motrin IB, etc.), and acetaminophen (Tylenol, etc.)). In some embodiments, the additional therapeutic agent is a bromhexine cough suppressant.

[0271] In some embodiments, the compounds disclosed herein are used in combination with immunoglobulin from cured COVID-19 patients. In some embodiments, the compounds disclosed herein are used in combination with plasma transfusions. In some embodiments, the compounds disclosed herein are used in combination with stem cells.

[0272] In some embodiments, the additional therapeutic agent is a TLR agonist. Examples of TLR agonists include, but are not limited to, vesatolimod (GS-9620), GS-986, IR-103, lefitolimod, tilsotolimod, lintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, tellulatorimod, and RO-7020531.

[0273] In some embodiments, the additional therapeutic agent is selected from the group consisting of bortezomib, flurazepam, ponatinib, sorafenib, paramethasone, clocortolone, flucloxacillin, sertindole, crividipine, atorvastatin, cinolazepam, clofazimine, fosaprepitant, and combinations thereof.

[0274] In some embodiments, the additional therapeutic agent is kalimycin, suramin, triazavirine, dipyridamole, bevacizumab, meplasmab, GD31 (Rhizobium), an NLRP inflammasome inhibitor, or an alpha-ketoamine. In some embodiments, the additional therapeutic agent is recombinant human angiotensin-converting enzyme 2 (rhACE2). In some embodiments, the additional therapeutic agent is It is viral macrophage inflammatory protein (vMIP).

[0275] In some embodiments, the additional therapeutic agent is an anti-viroporin therapeutic agent. For example, the additional therapeutic agent is BIT-314 or BIT-225. In some embodiments, the additional therapeutic agent is a coronavirus E protein inhibitor. For example, the additional therapeutic agent is BIT-009. Further examples of additional therapeutic agents include those described in WO 2004 / 112687, WO 2006 / 135978, WO 2018 / 145148, and WO 2009 / 018609.

[0276] Any compound of the present invention can also be combined with one or more additional active therapeutic agents in a single dosage form for simultaneous or sequential administration to a patient. The combination therapy can be administered as a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in two or more doses.

[0277] Co-administration of a compound of the invention with one or more other active therapeutic agents generally refers to the simultaneous or sequential administration of a compound of the invention with one or more other active therapeutic agents such that therapeutically effective amounts of both the compound of the invention and the one or more other active therapeutic agents are present in the patient's body.

[0278] Co-administration includes administration of a unit dose of a compound of the invention before or after administration of a unit dose of one or more other active therapeutic agents, e.g., within seconds, minutes, or hours of administration of a compound of the invention. For example, a unit dose of a compound of the invention can be administered first, followed within seconds or minutes by administration of a unit dose of one or more other active therapeutic agents. Alternatively, a unit dose of one or more other therapeutic agents can be administered first, followed within seconds or minutes by administration of a unit dose of a compound of the invention. In some cases, it may be desirable to administer a unit dose of a compound of the invention first, followed several hours (e.g., 1-12 hours) later by administration of a unit dose of one or more other active therapeutic agents. In other embodiments, it may be desirable to administer a unit dose of one or more other active therapeutic agents first, followed several hours (e.g., 1-12 hours) later by administration of a unit dose of a compound of the invention.

[0279] Combination therapy can provide "synergistic" and "synergistic" effects, i.e., effects achieved when the active ingredients used together are greater than the sum of the effects resulting from using the compounds separately. Synergistic effects can be achieved when the active ingredients are (1) co-formulated and administered or delivered simultaneously in a combined formulation, (2) delivered alternately or in parallel as separate formulations, or (3) by some other regimen. When delivered in alternation therapy, synergistic effects can be achieved when the compounds are administered or delivered sequentially, for example, by separate tablets, pills, capsules, or different injections in separate syringes. Generally, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., consecutively, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. A synergistic antiviral effect indicates an antiviral effect that is greater than the expected purely additive effect of the individual compounds of the combination. 1. Combination therapy for the treatment of Pneumoviridae

[0280] The compounds provided herein may also be used in combination with other active therapeutic agents. In the case of treating Pneumoviridae virus infections, preferably, the other active therapeutic agent is active against Pneumoviridae virus infections, particularly respiratory syncytial virus infections and / or metapneumovirus infections. Non-limiting examples of these other active therapeutic agents against RSV include ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI-557, A-60444 (also known as RSV604), MDT-637, BMS-433771, ALN-RSV0, ALX-0171, and mixtures thereof. Other non-limiting examples of other active therapeutic agents active against respiratory syncytial virus infection include respiratory syncytial virus protein F inhibitors such as AK-0529; RV-521, ALX-0171, JNJ-53718678, BTA-585, and presatovir; RNA polymerase inhibitors such as lumicitabine and ALS-8112; anti-RSV G protein antibodies such as anti-G protein mAb; and viral replication inhibitors such as nitazoxanide.

[0281] In some embodiments, the other active therapeutic agent can be a vaccine for the treatment or prevention of RSV, including, but not limited to, MVA-BN RSV, RSV-F, MEDI-8897, JNJ-64400141, DPX-RSV, SynGEM, GSK-3389245A, GSK-300389-1A, RSV-MEDI δM2-2 vaccine, VRC-RSVRGP084-00VP, Ad35-RSV-FA2, Ad26-RSV-FA2, and RSV fusion glycoprotein subunit vaccines.

[0282] Non-limiting examples of other active therapeutic agents active against metapneumovirus infection include sialidase modulators such as DAS-181; RNA polymerase inhibitors such as ALS-8112; and antibodies for the treatment of metapneumovirus infection, such as EV-046113.

[0283] In some embodiments, the other active therapeutic agent can be a vaccine for the treatment or prevention of metapneumovirus infection, including but not limited to mRNA-1653 and rHMPV-Pa vaccines. 2. Combination therapy for the treatment of Picornaviridae

[0284] The compounds provided herein can also be used in combination with other active therapeutic agents.When treating Picornaviridae virus infections, preferably, the other active therapeutic agents are active against Picornaviridae virus infections, particularly enterovirus infections.Non-limiting examples of these other active therapeutic agents include capsid binding inhibitors, such as pleconaril, BTA-798 (vapendavir), and other compounds disclosed by Wu et al. (U.S. Patent No. 7,078,403) and Watson (U.S. Patent No. 7,166,604); fusion sialidase proteins such as DAS-181; capsid protein VP1 inhibitors such as VVX-003 and AZN-001; viral protease inhibitors such as CW-33; phosphatidylinositol 4 kinase β inhibitors such as GSK-480 and GSK-533; anti-EV71 antibodies.

[0285] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of Picornaviridae virus infection, including but not limited to, EV71 vaccine, TAK-021, and EV-D68 adenovector-based vaccine. 3. Combination therapy for respiratory infections

[0286] Many infections caused by Pneumoviridae, Picornaviridae, and Coronaviridae viruses are respiratory infections. Therefore, additional active therapeutic agents used to treat respiratory symptoms and sequelae of infections can be used in combination with the compounds provided herein. The additional agents are preferably administered orally or by direct inhalation. For example, other preferred additional therapeutic agents combined with the compounds provided herein for the treatment of viral respiratory infections include, but are not limited to, bronchodilators and corticosteroids. Glucocorticoids

[0287] Glucocorticoids, first introduced as a treatment for asthma in 1950 (Carryer, Journal of Allergy, 21, 282-287, 1950), remain the most potent and consistently effective therapy for this disease, although their mechanism of action is not yet fully understood (Morris, J. Allergy Clin. Immunol., 75(1 Pt)1-13, 1985). Unfortunately, oral glucocorticoid therapy is associated with significant undesirable side effects, including truncal obesity, hypertension, glaucoma, glucose intolerance, accelerated cataract formation, bone mineral loss, and psychological effects, all of which limit their use as long-term treatment (Goodman and Gilman, 10th (Edition, 2001). A solution to systemic side effects is to deliver steroid medications directly to the site of inflammation. Inhaled corticosteroids (ICS) have been developed to alleviate the severe adverse effects of oral steroids. Non-limiting examples of corticosteroids that may be used in combination with the compounds provided herein include dexamethasone, dexamethasone sodium phosphate, fluorometholone, fluorometholone acetate, loteprednol, loteprednol etabonate, hydrocortisone, prednisolone, fludrocortisone, triamcinolone, triamcinolone acetonide, betamethasone, beclomethasone dipropionate, methylprednisolone ... donisolone, fluocinolone, fluocinolone acetonide, flunisolide, fluocortin-21-butyrate, flumethasone, flumethasone pivalate, budesonide, halobetasol propionate, mometasone furoate, fluticasone, AZD-7594, ciclesonide, or a pharmaceutically acceptable salt thereof. anti-inflammatory agents

[0288] Other anti-inflammatory agents that act through anti-inflammatory cascade mechanisms are also useful as additional therapeutic agents combined with the compounds provided herein for the treatment of viral respiratory infections.The application of "anti-inflammatory signaling modulators" (referred to herein as AISTMs), such as phosphodiesterase inhibitors (e.g., PDE-4, PDE-5, or PDE-7 specific), transcription factor inhibitors (e.g., blocking NFκB through IKK inhibition), or kinase inhibitors (e.g., P38 MAP, JNK, PI3K, EGFR, or Syk), is a logical approach to stop inflammation because these small molecules target a limited number of common intracellular pathways, signaling pathways that are key points for anti-inflammatory therapeutic intervention (see review by PJBarnes, 2006).These additional therapeutic agents include, but are not limited to, 5-(2,4-difluoro-phenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (2-dimethylamino-ethyl)-amide (P38 MAP kinase inhibitor ARRY-797; 3-cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4-difluoromethoxy-benzamide (PDE-4 inhibitor Roflumilast); 4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4 inhibitor CDP-840); N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)-8-[(methylsulfonyl)amino]-1-dibenzofurancarboxamide (PDE-4 inhibitor Oglemilast); N-(3,5-dichloro-pyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxo-acetamide (PDE-4 inhibitor AWD 12-281; ​​8-Methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid (3,5-dichloro-1-oxy-pyridin-4-yl)-amide (PDE-4 inhibitor Sch 351591); 4-[5-(4-fluorophenyl)-2-(4-methanesulfinyl-phenyl)-1H-imidazol-4-yl]-pyridine (P38 inhibitor SB-203850); 4-[4-(4-fluoro-phenyl)-1-(3-phenyl-propyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-but-3-yn-1-ol (P38 inhibitor RWJ-67657); 4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-cyclohexanecarboxylic acid 2-diethyl 2-diethyl-ethyl ester prodrug of cilomilast, a PDE-4 inhibitor; (3-chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (gefinib, an EGFR inhibitor); and 4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (imatinib, an EGFR inhibitor). Beta-2 adrenergic receptor agonist bronchodilators

[0289] Combinations including an inhaled β2-adrenergic receptor agonist bronchodilator, such as formoterol, albuterol, or salmeterol, together with a compound provided herein are also suitable, but non-limiting, combinations useful for treating respiratory viral infections.

[0290] Combinations of inhaled β2-adrenergic receptor agonist bronchodilators, such as formoterol or salmeterol, with ICS are also used to treat both bronchial constriction and inflammation (Symbicort® and Advair®, respectively). Combinations including these ICS and β2-adrenergic receptor agonists with the compounds provided herein are also suitable, but not limited to, combinations useful for treating respiratory viral infections.

[0291] Other examples of β2 adrenergic receptor agonists are bedoradrine, vilanterol, indacaterol, olodaterol, tulobuterol, formoterol, abesiterol, salbutamol, arformoterol, levalbuterol, fenoterol, and TD-5471. Anticholinergic drugs

[0292] Anticholinergic agents may be useful for the treatment or prevention of pulmonary bronchoconstriction and, therefore, are useful as additional therapeutic agents in combination with the compounds provided herein for the treatment of viral respiratory infections. These anticholinergic agents include muscarinic receptor antagonists (especially of the M3 subtype) that have shown therapeutic efficacy in humans for controlling cholinergic tone in COPD (Witek, 1999); 1-{4-hydroxy-1-[3,3,3-tris-(4-fluoro-phenyl)-propionyl]-pyrrolidine-2-carbonyl}-pyrrolidine-2-carboxylic acid (1-methyl-piperidin-4-ylmethyl)-amide; 3-[3-(2-diethylamino-acetoxy)-2-phenyl-propionyloxy]-8-isopropyl-8-methyl-8-azonia-bicyclo[3.2.1]octane (ipratropium-N,N-diethylglycinate); 1-cyclohexyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (solifenacin); );2-hydroxymethyl-4-methanesulfinyl-2-phenyl-butyric acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (revatropate);2-{1-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-pyrrolidin-3-yl}-2,2-diphenyl-acetamide (darifenacin);4-azepan-1-yl-2,2-diphenyl-butyramide (buzepide);7-[3-( 2-Diethylamino-acetoxy)-2-phenyl-propionyloxy]-9-ethyl-9-methyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane (oxitropium-N,N-diethylglycinate);7-[2-(2-diethylamino-acetoxy)-2,2-di-thiophen-2-yl-acetoxy]-9,9-dimethyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane (tiotropium-N,N-diethylglycinate);Dimethylaminoacetic acid 2-(3-diisopropylamino-1-phenyl-propyl)-4-methyl-phenyl ester (tolterodine-N,N-dimethylglycinate);3-[4,4-bis-(4-fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-1-methyl-1-(2-oxo-2-pyridin-2-yl-ethyl)-pyrrolidinium;1-[1-(3-fluoro-benzyl)-piperidin-4-yl]-4,4-bis-(4-fluoro-phenyl)-imidazolidin-2-one;1-cyclooctyl-3-(3-methoxy-1-aza-bicyclo[2.2.2] 3-[2-(2-diethylamino-acetoxy)-2,2-dithiophen-2-yl-acetoxy]-1-(3-phenoxy-propyl)-1-azonia-bicyclo[2.2.2]octane (acridinium-N,N-diethylglycinate); or (2-diethylamino-acetoxy)-dithiophen-2-yl-acetic acid 1-methyl-1-(2-phenoxy-ethyl)-piperidin-4-yl ester; rebefenacin, glycopyrronium bromide, umeclidinium bromide, tiotropium bromide, acridinium bromide, bencycloquidium bromide, but are not limited to these. mucolytics

[0293] The compounds provided herein can also be combined with mucolytic agents to treat both the infection and symptoms of respiratory infections. A non-limiting example of a mucolytic agent is ambroxol. Similarly, the compounds can be combined with expectorants to treat both the infection and symptoms of respiratory infections. A non-limiting example of an expectorant is guaifenesin.

[0294] Nebulized hypertonic saline is used to improve the immediate and long-term clearance of small airways in patients with lung disease (Kuzik, J. Pediatrics 2007, 266). Therefore, the compounds provided herein can also be combined with nebulized hypertonic saline, especially when viral infections are coexisting with bronchiolitis. The combination of the compounds provided herein and hypertonic saline can also include any of the additional agents discussed above. In one embodiment, about 3% nebulized hypertonic saline is used. 4. Combination therapy for the treatment of Flaviviridae infections

[0295] The compounds and compositions provided herein are also used in combination with other active therapeutic agents. In the case of treating Flaviviridae infections, preferably the other active therapeutic agent is active against Flaviviridae infections.

[0296] For the treatment of dengue virus infection, non-limiting examples of other active therapeutic agents include host cell factor modulators such as GBV-006; fenretinide ABX-220, BRM-211; alpha-glucosidase 1 inhibitors such as celgosivir; platelet activating factor receptor (PAFR) antagonists such as modipafant; cadherin-5 / factor Ia modulators such as X-06; NS4B inhibitors such as JNJ-8359; viral RNA splicing modulators such as ABX-202; NS5 polymerase inhibitors; NS3 protease inhibitors; and TLR modulators.

[0297] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of dengue fever, including, but not limited to, TetraVax-DV, Dengvaxia®, DPIV-001, TAK-003, live attenuated dengue vaccine, tetravalent dengue vaccine, tetravalent DNA vaccine, rDEN2δ30-7169; and DENV-1 PIV. 5. Combination therapy for the treatment of Flaviviridae infections

[0298] The compounds provided herein may also be used in combination with other active therapeutic agents. In the case of treatment of Filoviridae infections, preferably, the other active therapeutic agent is active against Filoviridae infections, particularly Marburg virus infection, Ebola virus infection, and Cueva virus infection. Non-limiting examples of these other active therapeutic agents include ribavirin, amiodarone, dronedarone, verapamil, Ebola Convalescent Plasma (ECP), TKM-100201, BCX4430 ((2S,3S, 4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol), TKM-Ebola, T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9-dimethylquinolino[8,7-h]quinolone-1,7-diamine), rNAP c2, OS-2966, brincidofovir, remdesivir; RNA polymerase inhibitors such as galidesivir, favipiravir (also known as T-705 or Avigan), JK-05; host cell factor modulators such as GMV-006; cadherin-5 / factor Ia modulators such as FX-06; and antibodies for the treatment of Ebola such as REGN-3470-3471-3479 and ZMapp.

[0299] Other non-limiting active therapeutic agents active against Ebola include alpha-glucosidase 1 inhibitors, cathepsin B inhibitors, CD29 antagonists, dendritic ICAM-3 binding nonintegrin 1 inhibitors, estrogen receptor antagonists, factor VII antagonists HLA class II antigen modulators, host cell factor modulators, interferon alpha ligands, neutral alpha-glucosidase AB inhibitors, Niemann-Pick C1 protein inhibitors, nucleoprotein inhibitors, polymerase cofactor VP35 inhibitors, serine protease inhibitors, tissue factor inhibitors, TLR-3 agonists, viral envelope glycoprotein inhibitors, and Ebola virus entry inhibitors (NPC1 inhibitors).

[0300] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of Ebola, including, but not limited to, VRC-EBOADC076-00-VP, adenovirus-based Ebola vaccine, rVSV-EBOV, rVSVN4CT1-EBOVGP, MVA-BN Filo+Ad26-ZEBOV regimen, INO-4212, VRC-EBODNA023-00-VP, VRC-EBOADC069-00-VP, GamEvac-combi vaccine, SRC VB vector, HPIV3 / EboGP vaccine, MVA-EBOZ, Ebola recombinant glycoprotein vaccine, Vaxart adenovirus vector 5-based Ebola vaccine, FiloVax vaccine, GOVX-E301, and GOVX-E302.

[0301] The compounds provided herein also include phosphoramidate morpholino oligomers, which are synthetic antisense oligonucleotide analogs designed to interfere with the translation process by forming base-paired duplexes with specific RNA sequences. An example of a PMO is AVI-72. 87, AVI-7288, AVI-7537, AVI-7539, AVI-6002 and AVI-6003.

[0302] The compounds provided herein are also intended for use in combination with the general care provided to patients with Filoviridae virus infections, including parenteral fluids (including dextrose saline and lactated Ringer's solution) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylaxis, antipyretics and analgesics, antiemetics (such as metoclopramide) and / or antidiarrheal medications, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen), analgesics, and antimalarials (including artemether and artesunate-lumefantrine combination therapy), typhoid (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or medications for other common illnesses in the patient population, such as shigellosis. X. Compound Preparation

[0303] In some embodiments, the present disclosure provides processes and intermediates useful for preparing the compounds provided herein, or pharmaceutically acceptable salts thereof.

[0304] The compounds described herein can be purified by any of the techniques known in the art, including chromatographic techniques such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reverse phase and ionic resins. Most typically, the disclosed compounds are purified by silica gel and / or alumina chromatography.

[0305] During any of the processes for the preparation of the compounds provided herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is further discussed in T.W. Greene and P.G.M. Buts, "Protective Groups in Organic Synthesis," 4 th This can be achieved by conventional protecting groups, as described in standard works such as "Protective Groups for the Synthesis of Novel Compounds," ed., Wiley, New York 2006. The protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0306] Exemplary chemicals useful in the methods of the embodiments will now be described by reference to exemplary synthetic schemes for their general preparation herein and the specific examples below. To obtain the various compounds herein, those skilled in the art will recognize that starting materials can be appropriately selected to obtain the desired product such that the ultimately desired substituents are carried through the reaction scheme, with or without protection as necessary. Alternatively, it may be necessary or desirable to use, in place of the ultimately desired substituent, a suitable group that is carried through the reaction scheme and can be appropriately replaced with the desired substituent. Furthermore, those skilled in the art will understand that the transformations shown in the following schemes can be performed in any order that is compatible with the functionality of the particular pendant groups.

[0307] Although the methods of the present disclosure generally provide a particular enantiomer or diastereomer as the desired product, the stereochemistry of the enantiomer or diastereomer has not been determined in all cases. When the stereochemistry of a particular stereocenter in an enantiomer or diastereomer is not determined, the compound is derived without indicating the stereochemistry at that particular stereocenter, even though the compound may be substantially enantiomerically or diastereomerically pure.

[0308] Representative syntheses of compounds of the present disclosure are described in the following schemes and specific examples below.

[0309] The compounds of the present disclosure may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent to those skilled in the art in light of the disclosures herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. Synthesis of exemplary compounds described herein can be achieved as illustrated in the following examples. Where available, reagents may be purchased commercially, for example, from Sigma-Aldrich or other chemical suppliers. In general, the compounds described herein are typically stable and isolatable at room temperature and pressure. The compounds prepared herein can be purified using methods known to those skilled in the art, including those described herein. Those skilled in the art will understand that if an acid (e.g., TFA) is present in the purification solvent, the final product may be isolated as a salt (e.g., a TFA salt). Methods for preparing compounds of formula Ib

[0310] In some embodiments, the disclosure provides a method of making a compound of formula Ib: [ka] During the ceremony, R 7 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclyl, C6-C 10 aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 Groups include halogen, cyano, -N3, -OR 8 , -NR 9 R 10 and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl; Each R 8are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 9 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 10 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; The method comprises reacting a compound of formula A [ka] [In the formula, each R A are independently hydroxy protecting groups, or two R A The group is bonded to -C(R B )2-group, wherein R B is H, C1-C8 alkyl, phenyl or substituted phenyl] the coupling partner of formula B [ka] [In the formula, R X is chloro, hydroxy, -OCOR Y and R Y is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclyl, C6-C 10 aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R Y Groups include halogen, cyano, -N3, -OR 8’ , -NR 9’ R 10’ and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl; Each R 8’are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 9’ are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 10’ are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl.

[0311] In some embodiments, the disclosure provides a method of making a compound of formula Ib: [ka] In the formula, R 7 is a C1-C8 alkyl, The method comprises reacting a compound of formula A [ka] [In the formula, each R A are independently hydroxy protecting groups, or two R A The group is bonded to -C(R B )2-group, wherein R B is H or C1-C8 alkyl] the coupling partner of formula B [ka] [In the formula, R X is chloro, hydroxy, -OCOR Y and R Y is C1 to C8 alkyl or C6 to C 10 aryl, and R Y The group is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen.

[0312] In some embodiments, the disclosure provides a method of making a compound of formula Ib: [ka] In the formula, R 7 is a C1-C3 alkyl, The method comprises reacting a compound of formula A [ka] [In the formula, each R A are independently hydroxy protecting groups, or two R A The group is bonded to -C(R B )2-group, wherein R B is H or C1-C8 alkyl] the coupling partner of formula B [ka] [In the formula, R X is chloro, hydroxy, -OCOR Y and R Y is C1-C3 alkyl or phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen.

[0313] In some embodiments, the disclosure provides a method of making a compound of formula Ib: [ka] In the formula, R 7 is a C3 alkyl, The method comprises reacting a compound of formula A [ka] [In the formula, each R A are independently hydroxy protecting groups, or two R A The group is bonded to -C(R B )2-group, wherein R B is H or C1-C8 alkyl] the coupling partner of formula B [ka] [In the formula, R X is chloro, hydroxy, -OCOR Y and R Y is a C alkyl or phenyl, wherein the phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen.

[0314] In some embodiments, the disclosure provides a method of making a compound of formula Ib: [ka] In the formula, R 7 is isopropyl, The method comprises reacting a compound of formula A [ka] [Wherein, two R A The group is bonded to -C(R B )2-group, wherein R B is H or C1-C3 alkyl] the coupling partner of formula B [ka] [In the formula, R Xis chloro, hydroxy, -OCOR Y and R Y is isopropyl or phenyl, wherein phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen.

[0315] In some embodiments, the disclosure provides a method of making a compound of formula Ib: [ka] In the formula, R 7 is isopropyl, The method comprises reacting a compound of formula A [ka] [Wherein, two R A The group is bonded to -C(R B )2-group, wherein R B is H or methyl] the coupling partner of formula B [ka] [In the formula, R X is chloro, hydroxy, -OCOR Y and R Y is isopropyl or phenyl, wherein the phenyl is optionally substituted with one, two, or three chloro groups.

[0316] In some embodiments, coupling of a compound of formula A with a coupling partner of formula B is carried out by coupling a compound of formula C [ka] brings about In the formula, R A and R 7 are each as defined herein for the various embodiments of the methods of making compounds of formula Ib.

[0317] In some embodiments, the method of making a compound of Formula Ib further comprises deprotecting a compound of Formula C to obtain a compound of Formula Ib. In some embodiments, deprotecting a compound of Formula C comprises the use of an acid. In some embodiments, using an acid of general structure HX (wherein X is a conjugate base) to deprotect a compound of Formula C results in a salt of a compound of Formula Ib (Formula Ib·HX). If the deprotected compound is obtained as a salt, optionally, a freebasing step can be performed. In some embodiments, the freebasing step comprises treatment with a base. Coupling reaction of formula A and formula B [ka]

[0318] The method of making a compound of formula Ib provided herein comprises coupling a compound of formula A with a coupling partner of formula B.

[0319] In some embodiments of the coupling partner of Formula B, R X is chloro. In some embodiments, R X is hydroxy. In some embodiments, R X -OCOR Y In some embodiments, R X Ha-OCOR Y where R Y is R 7 is the same as or R Y is halogen, cyano, -N3, -OR 8’ , -NR 9’ R 10’and phenyl optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, and C1-C6 alkyl. 10 In some embodiments, R X Ha-OCOR Y where R Y is R 7 is the same as or R Y is a C6-C optionally substituted with one, two, or three substituents 10 aryl, and each substituent is independently a halogen. In some embodiments, R X Ha-OCOR Y where R Y is R 7 is the same as or R Y is phenyl optionally substituted with 1, 2, or 3 substituents, each of which is independently a halogen. X Ha-OCOR Y where R Y is R 7 In some embodiments, R X Ha-OCOR Y where R Y is phenyl optionally substituted with 1, 2, or 3 substituents, each of which is independently a halogen. X Ha-OCOR Y where R Y is R 7 is the same as or R Y is phenyl optionally substituted with one, two, or three chloro groups.

[0320] The coupling partner of Formula B can be used in any suitable amount. In some embodiments, the amount of Formula B is at least 1.0 equivalent (mol / mol) relative to the compound of Formula A. In some embodiments, the amount of Formula B is 0.1 to 10.0 equivalents (mol / mol) relative to the compound of Formula A. In some embodiments, the amount of Formula B is 0.5 to 5.0 equivalents (mol / mol) relative to the compound of Formula A. In some embodiments, the amount of Formula B is 1.0 to 2.0 equivalents (mol / mol) relative to the compound of Formula A. In some embodiments, the amount of Formula B is 1.0 to 1.5 equivalents (mol / mol) relative to the compound of Formula A. In some embodiments, the amount of Formula B is 1.2 equivalents (mol / mol) relative to the compound of Formula A.

[0321] In some embodiments, the coupling of Formula A with a coupling partner of Formula B is carried out in the presence of a catalyst. Any suitable catalyst can be used. In some embodiments, the catalyst is a nitrogenated heterocycle, an azodicarboxylate, a guanidinium or uronium type coupling reagent, triphenylphosphine, tri-n-butylphosphine, or S,S-bis(4,6-dimethyl-2-pyrimidinyl)carbodithioate.

[0322] In some embodiments, the coupling of Formula A with a coupling partner of Formula B is carried out in the presence of a catalyst, and the catalyst is a nitrogenated heterocycle. In some embodiments, the catalyst is 4-dimethylaminopyridine (DMAP), 1-methylimidazole, imidazole, or pyridine. In some embodiments, the catalyst is 1-methylimidazole. In some embodiments, the catalyst is imidazole. In some embodiments, the catalyst is pyridine. In some embodiments, the catalyst is DMAP.

[0323] In some embodiments, the coupling of Formula A with a coupling partner of Formula B is carried out in the presence of a catalyst, and the catalyst is azodicarboxylate. In some embodiments, the catalyst is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicyclohexylcarbodiimide, diethylazodicarboxylate, or diisopropylazodicarboxylate. In some embodiments, the catalyst is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. In some embodiments, the catalyst is dicyclohexylcarbodiimide. In some embodiments, the catalyst is diethylazodicarboxylate. In some embodiments, the catalyst is diisopropylazodicarboxylate.

[0324] In some embodiments, the coupling of Formula A with a coupling partner of Formula B is carried out in the presence of a catalyst, and the catalyst is a guanidinium and uronium type coupling reagent. In some embodiments, the catalyst is N-[dimethylamino)-1H-1,2,3-triazolo[4,5-b]-pyridin-1-ylmethylene]-N-methylmethanaminium Hexafluorophosphate N-oxide (HATU), N-[(1H-benzotriazol-1-yl)-(dimethylamino)-methylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HBTU), N-[(1H-benzotriazol-1-yl)-(dimethylamino)-methylene]-N-methylmethanaminium tetrafluoroborate N-oxide (TBTU), 2-(2-oxo-1(2H)-pyridyl-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), O-[(cyano(ethoxycarbonyl)methyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOT In some embodiments, the catalyst is N-[dimethylamino)-1H-1,2,3-triazolo[4,5-b]-pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU). In some embodiments, the catalyst is HBTU. In some embodiments, the catalyst is TBTU. In some embodiments, the catalyst is TPTU. In some embodiments, the catalyst is TOTU. In some embodiments, the catalyst is COMU.

[0325] In some embodiments, the coupling of Formula A with a coupling partner of Formula B is carried out in the presence of a catalyst, and the catalyst is triphenylphosphine, tri-n-butylphosphine, or S,S-bis(4,6-dimethyl-2-pyrimidinyl)carbodithioate. In some embodiments, the catalyst is triphenylphosphine. In some embodiments, the catalyst is tri-n-butylphosphine. In some embodiments, the catalyst is S,S-bis(4,6-dimethyl-2-pyrimidinyl)carbodithioate.

[0326] The catalyst can be used in any suitable amount. In some embodiments, the amount of catalyst is 1 to 100 mol % relative to the compound of Formula A. In some embodiments, the amount of catalyst is 1 to 50 mol % relative to the compound of Formula A. In some embodiments, the amount of catalyst is 1 to 10 mol % relative to the compound of Formula A. In some embodiments, the amount of catalyst is 1 to 5 mol % relative to the compound of Formula A. In some embodiments, the amount of catalyst is 3 mol % relative to the compound of Formula A. In some embodiments, no catalyst is used.

[0327] In some embodiments, 1-10 mol % DMAP is used as a catalyst for the coupling of Formula A with Formula B. In some embodiments, 1-5 mol % DMAP is used as a catalyst for the coupling of Formula A with Formula B. In some embodiments, 3 mol % DMAP is used as a catalyst for the coupling of Formula A with Formula B.

[0328] In some embodiments, the coupling of Formula A with a coupling partner of Formula B is further carried out in the presence of a base. Any suitable base can be used. In some embodiments, the base used is an inorganic base. In some examples, the base is a carbonate, bicarbonate, metal dibasic phosphate, metal tribasic phosphate, or nitrogen-containing base.

[0329] In some embodiments, the base is bicarbonate. In some embodiments, the base is lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, or a combination thereof. In some embodiments, the base is sodium bicarbonate, potassium bicarbonate, or a combination thereof. In some embodiments, the base is lithium bicarbonate. In some embodiments, the base is sodium bicarbonate. In some examples, the base is potassium bicarbonate.

[0330] In some embodiments, the base is a carbonate. In some embodiments, the base is lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, or a combination thereof. In some embodiments, the base is lithium carbonate, sodium carbonate, potassium carbonate, or a combination thereof. In some embodiments, the base is sodium carbonate, potassium carbonate, cesium carbonate, or a combination thereof. In some embodiments, the base is sodium carbonate, potassium carbonate, or a combination thereof. In some embodiments, the base is lithium carbonate. In some embodiments, the base is sodium carbonate. In some embodiments, the base is potassium carbonate. In some embodiments, the base is cesium carbonate.

[0331] In some embodiments, the base is a metal dibasic phosphate. In some embodiments, the base is dibasic sodium phosphate, dibasic potassium phosphate, or a combination thereof. In some embodiments, the base is dibasic sodium phosphate. In some embodiments, the base is dibasic potassium phosphate.

[0332] In some embodiments, the base is a metal tribasic phosphate. In some embodiments, the base is tribasic sodium phosphate, tribasic potassium phosphate, or a combination thereof. In some embodiments, the base is tribasic sodium phosphate. In some embodiments, the base is tribasic potassium phosphate.

[0333] In some embodiments, the base is a nitrogen-containing base. In some examples, the base is an azaarene, an amine, or an amidine. In some embodiments, the base is pyridine, 2,6-lutidine, triethylamine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, or a combination thereof. In some embodiments, the base is an azaarene. In some embodiments, the catalyst is pyridine or 2,6-lutidine. In some embodiments, the base is an amine. In some embodiments, the base is triethylamine, N,N-diisopropylethylamine, or 1,4-diazabicyclo[2.2.2]octane. In some embodiments, the base is an amidine. In some embodiments, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0334] Any suitable amount of base can be used. In some embodiments, the amount of base used is about 0.0 to 10.0 equivalents (mol / mol) relative to the compound of Formula A. In some embodiments, the amount of base used is about 0.0, 0.1, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, or 10.0 equivalents (mol / mol) relative to the compound of Formula A. In some embodiments, the amount of base used is about 0.0 to 1.0 equivalents (mol / mol) relative to the compound of Formula A. In some embodiments, the amount of base used is about 0.0 to 2.0 equivalents (mol / mol) relative to the compound of Formula A. In some embodiments, the amount of base used is about 0.0 to 3.0 equivalents (mol / mol) relative to the compound of Formula A. In some embodiments, the amount of base used is about 0.0 to 0.5 equivalents (mol / mol) relative to the compound of Formula A. In some embodiments, no base is used.

[0335] The coupling of the compound of formula A with the coupling partner of formula B can be carried out in the presence of a solvent. Any suitable solvent can be used. In some embodiments, the solvent is an organic ether solvent, a halogenated solvent, a polar aprotic solvent, an organic ketone solvent, an organic ester solvent, a hydrocarbon solvent, or a nitrile solvent. In some embodiments, the solvent further comprises water.

[0336] In some embodiments, the solvent is an organic ether. In some examples, the solvent is diethyl ether, tert-butyl methyl ether, tetrahydrofuran (THF), methyl tetrahydrofuran (MeTHF), or a combination thereof. In some embodiments, the solvent is diethyl ether. In some embodiments, the solvent is tert-butyl methyl ether. In some embodiments, the solvent is THF. In some embodiments, the solvent is MeTHF. In some embodiments, the solvent is a combination of an organic ether and water. In some embodiments, the solvent comprises diethyl ether, tert-butyl methyl ether, tetrahydrofuran (THF), methyl tetrahydrofuran (MeTHF), or a combination thereof and water. In some embodiments, the solvent comprises water and diethyl ether. In some embodiments, the solvent comprises water and tert-butyl methyl ether. In some embodiments, the solvent comprises water and THF. In some embodiments, the solvent comprises water and MeTHF.

[0337] In some embodiments, the solvent is a halogenated solvent. In some embodiments, the solvent is dichloromethane (DCM), 1,2-dichloroethane, or chlorobenzene. In some embodiments, the solvent is DCM. In some embodiments, the solvent is 1,2-dichloroethane. In some embodiments, the solvent is chlorobenzene. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and chlorobenzene. In some embodiments, the solvent comprises water and dichloromethane (DCM). In some embodiments, the solvent comprises water and 1,2-dichloroethane.

[0338] In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the solvent is N,N-dimethylformamide, N,N-dimethylacetamide, or N-methyl-2-pyrrolidone. In some embodiments, the solvent is N,N-dimethylformamide. In some embodiments, the solvent is N,N-dimethylacetamide. In some embodiments, the solvent is N-methyl-2-pyrrolidone. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and N,N-dimethylformamide. In some embodiments, the solvent comprises water and N,N-dimethylacetamide. In some embodiments, the solvent comprises water and N-methyl-2-pyrrolidone.

[0339] In some embodiments, the solvent is an organic ketone solvent. In some embodiments, the solvent is acetone, 2-butanone, or 4-methyl-2-pentanone. In some embodiments, the solvent is acetone. In some embodiments, the solvent is 2-butanone. In some embodiments, the solvent is 4-methyl-2-pentanone. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and acetone. In some embodiments, the solvent comprises water and 2-butanone. In some embodiments, the solvent comprises water and 4-methyl-2-pentanone.

[0340] In some embodiments, the solvent is an organic ester. In some embodiments, the solvent is ethyl acetate or isopropyl acetate. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is isopropyl acetate. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and ethyl acetate. In some embodiments, the solvent comprises water and isopropyl acetate.

[0341] In some embodiments, the solvent is a hydrocarbon. In some embodiments, the solvent is hexane, n-heptane, pentane, or toluene. In some embodiments, the solvent is toluene or n-heptane. In some embodiments, the solvent is toluene. In some embodiments, the solvent is n-heptane. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and toluene. In some embodiments, the solvent comprises water and n-heptane.

[0342] In some embodiments, the solvent is a nitrile solvent. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and acetonitrile.

[0343] The coupling reaction can be carried out at any suitable temperature. In some embodiments, the coupling reaction is carried out at a temperature of about -35°C to 60°C. In some examples, the coupling reaction is carried out at a temperature of about -25°C to 50°C. In some examples, the coupling reaction is carried out at a temperature of about -15°C to 40°C. In some examples, the coupling reaction is carried out at a temperature of about -5°C to 30°C. In some examples, the coupling reaction is carried out at a temperature of about 5°C to 20°C. In some examples, the coupling reaction is carried out at a temperature of about 5°C to 15°C. In some examples, the coupling reaction is carried out at a temperature of about 0°C to 10°C. In some examples, the coupling reaction is carried out at a temperature of about 5°C. Deprotection of Compound of Formula C [ka]

[0344] In some embodiments, coupling of Formula A with a coupling partner of Formula B results in a compound of Formula C, and the method of making a compound of Formula Ib further comprises deprotecting the compound of Formula C. Any suitable deprotecting agent can be used for deprotection. In some embodiments, the deprotecting agent is an acid. In some embodiments, the deprotecting agent is an inorganic acid, a carboxylic acid, or a sulfonic acid.

[0345] In some embodiments, the deprotecting agent is an inorganic acid. In some embodiments, the deprotecting agent is hydrochloric acid, hydrobromic acid, sulfuric acid, or a combination thereof. In some embodiments, the deprotecting agent is hydrochloric acid. In some embodiments, the deprotecting agent is hydrobromic acid. In some embodiments, the deprotecting agent is sulfuric acid. In some embodiments, the deprotecting agent is phosphoric acid.

[0346] In some embodiments, the deprotecting agent is a solid-supported acidic resin. In some embodiments, the deprotecting agent is a strong cation exchange resin containing sulfonic acid groups or the corresponding salt. In some embodiments, the deprotecting agent is Amberlite® / Amberlyst® / Amberjet® (sulfonic acid) IR-120 Plus(H), IR-120 Plus, IRP-69, 15, or 1200(H). In some embodiments, the deprotecting agent is Dowex® (sulfonic acid), 50WX2-100, 50WX2-200, 50WX2-400, 50WX4-50, 50WX4-100, 50WX4-200, 50WX4-200R, 50WX4-400, 50WX8-100, 50WX8-200, 50WX8-400, HCR-S, HCR-W2, 88, 650C, Marathon C, or MSC-1. In some embodiments, the deprotecting agent is Duolite® (sulfonic acid) C-26. In some embodiments, the deprotecting agent is a weak cation exchange resin containing carboxylic acid groups or the corresponding salt. In some embodiments, the deprotecting agent is Amberlite® (carboxylic acid) CG-50 Type I, IRC-50, IRC-50s, or IRP-64.

[0347] In some embodiments, the deprotecting agent is a carboxylic acid. In some embodiments, the deprotecting agent is formic acid, maleic acid, oxalic acid, butyric acid, isobutyric acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, or a combination thereof. In some embodiments, the deprotecting agent is acetic acid. In some embodiments, the deprotecting agent is trifluoroacetic acid. In some embodiments, the deprotecting agent is trichloroacetic acid. In some embodiments, the deprotecting agent is propionic acid. In some embodiments, the deprotecting agent is formic acid. In some embodiments, the deprotecting agent is maleic acid. In some embodiments, the deprotecting agent is oxalic acid. In some embodiments, the deprotecting agent is butyric acid. In some embodiments, the deprotecting agent is isobutyric acid. In some embodiments, the deprotecting agent is an amino acid. In some embodiments, the deprotecting agent is L-aspartic acid.

[0348] In some embodiments, the deprotecting agent is a sulfonic acid. In some embodiments, the deprotecting agent is methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, or a combination thereof. In some embodiments, the deprotecting agent is benzenesulfonic acid. In some embodiments, the deprotecting agent is p-toluenesulfonic acid. In some embodiments, the deprotecting agent is pyridinium p-toluenesulfonate. In some embodiments, the deprotecting agent is methanesulfonic acid. In some embodiments, the deprotecting agent is ethanesulfonic acid.

[0349] In some embodiments, the deprotecting agent is a Lewis acid. In some embodiments, the deprotecting agent is trimethylsilyl triflate, boron trichloride, magnesium bromide, cerium chloride, or a combination thereof. In some embodiments, the deprotecting agent is boron trichloride. In some embodiments, the deprotecting agent is magnesium bromide. In some embodiments, the deprotecting agent is cerium chloride. In some embodiments, the deprotecting agent is trimethylsilyl triflate.

[0350] Any suitable amount of deprotecting agent can be used. In some embodiments, the amount of deprotecting agent used is about 0.01 to 10.0 equivalents (mol / mol) relative to the compound of Formula A. In some embodiments, the amount of deprotecting agent used is about 0.1 to 5.0 equivalents (mol / mol) relative to the compound of Formula A. In some embodiments, the amount of deprotecting agent used is about 1.0 to 5.0 equivalents (mol / mol) relative to the compound of Formula A. In some embodiments, the amount of deprotecting agent used is about 2.0 to 4.0 equivalents (mol / mol) relative to the compound of Formula A. In some embodiments, the amount of deprotecting agent used is about 3.0 equivalents (mol / mol) relative to the compound of Formula A. In some embodiments, the amount of deprotecting agent used is about 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, or 10.0 equivalents (mol / mol) relative to the compound of Formula A.

[0351] In some embodiments, the deprotecting agent is an inorganic acid, and the amount of the deprotecting agent used is about 1.0 to 5.0 equivalents (mol / mol) relative to the compound of Formula A. In some embodiments, the deprotecting agent is hydrochloric acid, and the amount of the deprotecting agent used is about 1.0 to 5.0 equivalents (mol / mol) relative to the compound of Formula A. In some embodiments, the deprotecting agent is hydrochloric acid, and the amount of the deprotecting agent used is about 3.0 equivalents (mol / mol) relative to the compound of Formula A.

[0352] The deprotection step can be carried out in any suitable solvent, hi some embodiments, the solvent for the deprotection step comprises an ether solvent, a polar aprotic solvent, an alcohol, an ester solvent, a halogenated solvent, a hydrocarbon, a nitrile solvent, or a combination thereof.

[0353] In some embodiments, the solvent for the deprotection step is an ethereal solvent. In some embodiments, the solvent for the deprotection step is THF, MeTHF, tert-butyl methyl ether, or a combination thereof. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and THF. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and MeTHF. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and tert-butyl methyl ether.

[0354] In some embodiments, the solvent for the deprotection step is a polar aprotic solvent. In some embodiments, the solvent for the deprotection step is N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or a combination thereof. In some embodiments, the solvent for the deprotection step is N,N-dimethylformamide. In some embodiments, the solvent for the deprotection step is N,N-dimethylacetamide. In some embodiments, the solvent for the deprotection step is N-methyl-2-pyrrolidone. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and N,N-dimethylformamide. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and N,N-dimethylacetamide. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and N-methyl-2-pyrrolidone.

[0355] In some embodiments, the solvent for the deprotection step is an alcohol. In some embodiments, the solvent is methanol, ethanol, 2-propanol, or a combination thereof. In some embodiments, the solvent is methanol. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is 2-propanol. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and methanol, ethanol, 2-propanol, or a combination thereof. In some embodiments, the solvent comprises water and methanol. In some embodiments, the solvent comprises water and ethanol. In some embodiments, the solvent comprises water and 2-propanol.

[0356] In some embodiments, the solvent for the deprotection step is an organic ester. In some embodiments, the solvent is ethyl acetate or isopropyl acetate. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is isopropyl acetate. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and ethyl acetate. In some embodiments, the solvent comprises water and isopropyl acetate.

[0357] In some embodiments, the solvent for the deprotection step is a halogenated solvent. In some embodiments, the solvent is dichloromethane (DCM), 1,2-dichloroethane, or chlorobenzene. In some embodiments, the solvent is DCM. In some embodiments, the solvent is 1,2-dichloroethane. In some embodiments, the solvent is chlorobenzene. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and chlorobenzene. In some embodiments, the solvent comprises water and dichloromethane (DCM). In some embodiments, the solvent comprises water and 1,2-dichloroethane.

[0358] In some embodiments, the solvent for the deprotection step is a hydrocarbon. In some embodiments, the solvent is hexane, heptane, pentane, or toluene. In some embodiments, the solvent is toluene or n-heptane. In some embodiments, the solvent is toluene. In some embodiments, the solvent is n-heptane. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and toluene. In some embodiments, the solvent comprises water and n-heptane.

[0359] In some embodiments, the solvent for the deprotection step is a nitrile solvent. In some embodiments, the solvent is acetonitrile, propionitrile, butyronitrile, benzonitrile, or a combination thereof. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is propionitrile. In some embodiments, the solvent is butyronitrile. In some embodiments, the solvent is benzonitrile. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and acetonitrile. In some embodiments, the solvent comprises water and propionitrile. In some embodiments, the solvent comprises water and butyronitrile. In some embodiments, the solvent comprises water and benzonitrile.

[0360] The deprotection reaction can be carried out at any suitable temperature. In some embodiments, the deprotection reaction is carried out at about -20°C to 50°C. In some embodiments, the deprotection reaction is carried out at about -10°C to 40°C. In some embodiments, the deprotection reaction is carried out at about 0°C to 30°C. In some embodiments, the deprotection reaction is carried out at about 10°C to 30°C. In some embodiments, the deprotection reaction is carried out at about 15°C to 25°C. In some embodiments, the deprotection reaction is carried out at about 10°C to 30°C. In some embodiments, the deprotection reaction is carried out at about 20°C. Free Base Formation

[0361] In some embodiments, the use of an acid of general structure HX (where X is a conjugate base) to deprotect a compound of formula C results in a salt of a compound of formula Ib (formula Ib·HX). If the deprotected compound is obtained as a salt, an additional freebasing step can optionally be performed. [ka]

[0362] In some embodiments, freebasing involves treatment with a base. Any suitable base can be used. In some embodiments, the base used is an inorganic base. For example, bicarbonate. In some examples, the base is lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, or a combination thereof. In some examples, the base is sodium bicarbonate, potassium bicarbonate, or a combination thereof. In some examples, the base is lithium bicarbonate. In some examples, the base is sodium bicarbonate. In some examples, the base is potassium bicarbonate.

[0363] In some embodiments, the base is a carbonate. In some embodiments, the base is lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, or a combination thereof. In some embodiments, the base is lithium carbonate, sodium carbonate, potassium carbonate, or a combination thereof. In some embodiments, the base is sodium carbonate, potassium carbonate, cesium carbonate, or a combination thereof. In some embodiments, the base is sodium carbonate, potassium carbonate, or a combination thereof. In some embodiments, the base is lithium carbonate. In some embodiments, the base is sodium carbonate. In some embodiments, the base is potassium carbonate. In some embodiments, the base is cesium carbonate.

[0364] In some embodiments, the base is an alkoxide. In some embodiments, the base is sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium tert-pentoxide, lithium tert-butoxide, potassium tert-butoxide, or a combination thereof. In some embodiments, the base is sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium tert-pentoxide, lithium tert-butoxide, or potassium tert-butoxide. In some embodiments, the base is sodium methoxide. In some embodiments, the base is sodium ethoxide. In some embodiments, the base is sodium tert-butoxide. In some embodiments, the base is sodium tert-pentoxide. In some embodiments, the base is lithium tert-butoxide. In some embodiments, the base is potassium tert-butoxide.

[0365] In some embodiments, the base is a metal hydroxide. In some embodiments, the base is lithium hydroxide, sodium hydroxide, potassium hydroxide, or a combination thereof. In some embodiments, the base is lithium hydroxide. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide.

[0366] In some embodiments, the base is a metal dibasic phosphate. In some embodiments, the base is dibasic sodium phosphate, dibasic potassium phosphate, or a combination thereof. In some embodiments, the base is dibasic sodium phosphate. In some embodiments, the base is dibasic potassium phosphate.

[0367] In some embodiments, the base is a metal tribasic phosphate. In some embodiments, the base is tribasic sodium phosphate, tribasic potassium phosphate, or a combination thereof. In some embodiments, the base is tribasic sodium phosphate. In some embodiments, the base is tribasic potassium phosphate.

[0368] In some embodiments, the base is a nitrogen-containing base. In some examples, the base is an azaarene, an amine, or an amidine. In some embodiments, the base is pyridine, 2,6-lutidine, triethylamine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, or a combination thereof. In some embodiments, the base is an azaarene. In some embodiments, the catalyst is pyridine or 2,6-lutidine. In some embodiments, the base is an amine. In some embodiments, the base is triethylamine, N,N-diisopropylethylamine, or 1,4-diazabicyclo[2.2.2]octane. In some embodiments, the base is an amidine. In some embodiments, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0369] The free basing step can be carried out in any suitable solvent, hi some embodiments, the solvent for the free basing step comprises an ether solvent, a polar aprotic solvent, an alcohol, an ester solvent, a halogenated solvent, a hydrocarbon, a nitrile solvent, or a combination thereof.

[0370] In some embodiments, the solvent for the free basing step is an ethereal solvent. In some embodiments, the solvent for the free basing step is THF, MeTHF, tert-butyl methyl ether, or a combination thereof. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and THF. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and MeTHF. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and tert-butyl methyl ether.

[0371] In some embodiments, the solvent for the free basing step is a polar aprotic solvent. In some embodiments, the solvent for the free basing step is N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or a combination thereof. In some embodiments, the solvent for the free basing step is N,N-dimethylformamide. In some embodiments, the solvent for the free basing step is N,N-dimethylacetamide. In some embodiments, the solvent for the free basing step is N-methyl-2-pyrrolidone. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and N,N-dimethylformamide. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and N,N-dimethylacetamide. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and N-methyl-2-pyrrolidone.

[0372] In some embodiments, the solvent for the freebasing step is an alcohol. In some embodiments, the solvent is methanol, ethanol, 2-propanol, or a combination thereof. In some embodiments, the solvent is methanol. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is 2-propanol. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and methanol, ethanol, 2-propanol, or a combination thereof. In some embodiments, the solvent comprises water and methanol. In some embodiments, the solvent comprises water and ethanol. In some embodiments, the solvent comprises water and 2-propanol.

[0373] In some embodiments, the solvent for the freebasing step is an organic ester. In some embodiments, the solvent is ethyl acetate or isopropyl acetate. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is isopropyl acetate. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and ethyl acetate. In some embodiments, the solvent comprises water and isopropyl acetate.

[0374] In some embodiments, the solvent for the freebasing step is a halogenated solvent. In some embodiments, the solvent is dichloromethane (DCM), 1,2-dichloroethane, or chlorobenzene. In some embodiments, the solvent is DCM. In some embodiments, the solvent is 1,2-dichloroethane. In some embodiments, the solvent is chlorobenzene. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and chlorobenzene. In some embodiments, the solvent comprises water and dichloromethane (DCM). In some embodiments, the solvent comprises water and 1,2-dichloroethane.

[0375] In some embodiments, the solvent for the freebasing step is a hydrocarbon. In some embodiments, the solvent is hexane, heptane, pentane, or toluene. In some embodiments, the solvent is toluene or n-heptane. In some embodiments, the solvent is toluene. In some embodiments, the solvent is n-heptane. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and toluene. In some embodiments, the solvent comprises water and n-heptane.

[0376] In some embodiments, the solvent for the free basing step is a nitrile solvent. In some embodiments, the solvent is acetonitrile, propionitrile, butyronitrile, benzonitrile, or a combination thereof. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is propionitrile. In some embodiments, the solvent is butyronitrile. In some embodiments, the solvent is benzonitrile. In some embodiments, the solvent further comprises water. In some embodiments, the solvent comprises water and acetonitrile. In some embodiments, the solvent comprises water and propionitrile. In some embodiments, the solvent comprises water and butyronitrile. In some embodiments, the solvent comprises water and benzonitrile.

[0377] The free basing can be carried out at any suitable temperature. In some embodiments, the coupling reaction is carried out at about 10° C. to 30° C. In some embodiments, the coupling reaction is carried out at about 20° C. XI. Crystalline Form of Compound 15

[0378] Polymorphic forms or polymorphs may have properties such as bioavailability and stability under certain conditions that may be suitable for medical or pharmaceutical use. Crystalline forms of compound 15 may offer bioavailability and stability advantages suitable for use as an active ingredient in pharmaceutical compositions. Variations in the crystalline structure of a pharmaceutical drug substance or active ingredient may affect the dissolution rate (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ability to consistently prepare doses of known strength), and stability (e.g., thermal stability, shelf life, etc.) of the pharmaceutical drug product or active ingredient. Such variations may affect the preparation or formulation of pharmaceutical compositions for different dosage or delivery forms, such as solid oral dosage forms including tablets and capsules. Compared to other forms, such as non-crystalline or amorphous forms, crystalline forms may provide desirable or suitable hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, and / or process control. Thus, the crystalline form of compound 15 may provide advantages such as improving the manufacturing process of the active agent or the stability or storage of the drug product form of the compound or active ingredient, and / or having suitable bioavailability and / or stability as an active agent. Compound 15, Form I

[0379] In some embodiments, crystalline Form I of Compound 15 (crystalline Compound 15 Form I) is provided, wherein the crystalline structure exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 10. Crystalline Compound 15 Form I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 11. Crystalline Compound 15 Form I may exhibit a thermogravimetric analysis (TGA) graph substantially as shown in Figure 12.

[0380] In some embodiments of crystalline Compound 15 Form I, at least one, at least two, or all of the following apply: (a) crystalline Compound 15 Form I has an XRPD pattern substantially as shown in FIG. 10; (b) crystalline Compound 15 Form I has a DSC thermogram substantially as shown in FIG. 11; and (c) crystalline Compound 15 Form I has a TGA graph substantially as shown in FIG. 12.

[0381] In some embodiments, crystalline Compound 15 Form I has the following properties: (a) XRPD pattern substantially as shown in Figure 10; (b) a DSC thermogram substantially as shown in Figure 11; and (a) TGA graph substantially as shown in Figure 12.

[0382] In some embodiments, crystalline Compound 15 Form I has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, or at least six of the 2θ reflectances with maximal intensities as an XRPD pattern substantially as shown in FIG. 10.

[0383] In some embodiments, crystalline Compound 15 Form I has an XRPD pattern comprising 2θ reflectances at 8.5°, 22.1°, and 23.8° (+ / −0.2 2θ°). In some embodiments, crystalline Compound 15 Form I has an XRPD pattern comprising one, two, or three of 2θ reflectances at 8.5°, 22.1°, and 23.8° (+ / −0.2 2θ°), and 2θ reflectances at 15.4°, 16.9°, and 28.1° (+ / −0.2 2θ°). In some embodiments, crystalline Compound 15 Form I has an XRPD pattern comprising one or two of 2θ reflectances at 8.5°, 22.1°, and 23.8° (+ / −0.2 2θ°), and 2θ reflectances at 15.4°, 16.9°, and 28.1° (+ / −0.2 2θ°). In some embodiments, crystalline Compound 15 Form I has an XRPD pattern comprising one or two of 2θ reflectances at 8.5°, 22.1°, and 23.8° (+ / −0.2 2θ°). 2θ), and one of the 2θ reflectances at 15.4°, 16.9°, and 28.1° (+ / −0.2 2θ). In some embodiments, crystalline Compound 15 Form I has an XRPD pattern that includes the 2θ reflectances at 8.5°, 22.1°, and 23.8° (+ / −0.2 2θ), and two of the 2θ reflectances at 15.4°, 16.9°, and 28.1° (+ / −0.2 2θ). In some embodiments, crystalline Compound 15 Form I has an XRPD pattern that includes the 2θ reflectances at 8.5°, 15.4°, 16.9°, 22.1°, 23.8°, and 28.1° (+ / −0.2 2θ). In some embodiments, crystalline Compound 15 Form I has an XRPD pattern comprising any three 2θ reflectances (+ / −0.2 2θ degrees) selected from the group consisting of 8.5°, 15.4°, 16.9°, 22.1°, 23.8°, and 28.1°.

[0384] In some embodiments, crystalline Compound 15 Form I has an XRPD pattern that includes one, two, or three of the following: 2θ reflectances at 8.5°, 15.4°, 16.9°, 22.1°, 23.8°, and 28.1° (+ / −0.2 2θ°), and 2θ reflectances at 10.5°, 17.5°, and 27.5° (+ / −0.2 2θ°). In some embodiments, crystalline Compound 15 Form I has an XRPD pattern that includes one or two of the following: 2θ reflectances at 8.5°, 15.4°, 16.9°, 22.1°, 23.8°, and 28.1° (+ / −0.2 2θ°), and 2θ reflectances at 10.5°, 17.5°, and 27.5° (+ / −0.2 2θ°). In some embodiments, crystalline Compound 15 Form I has an XRPD pattern comprising one of the following 2θ reflectances: 8.5°, 15.4°, 16.9°, 22.1°, 23.8°, and 28.1° (+ / −0.2 2θ°), and 10.5°, 17.5°, and 27.5° (+ / −0.2 2θ°). In some embodiments, crystalline Compound 15 Form I has an XRPD pattern comprising two of the following 2θ reflectances: 8.5°, 15.4°, 16.9°, 22.1°, 23.8°, and 28.1° (+ / −0.2 2θ°), and 10.5°, 17.5°, and 27.5° (+ / −0.2 2θ°). In some embodiments, crystalline Compound 15 Form I has an XRPD pattern comprising 2θ reflectances at 8.5°, 10.5°, 15.4°, 16.9°, 17.5°, 22.1°, 23.8°, 27.5°, and 28.1° (+ / −0.2 2θ°). In some embodiments, crystalline Compound 15 Form I has an XRPD pattern comprising three of the 2θ reflectances at 8.5°, 10.5°, 15.4°, 16.9°, 17.5°, 22.1°, 23.8°, 27.5°, and 28.1° (+ / −0.2 2θ°). Compound 15, Form II

[0385] In some embodiments, crystalline Form II of Compound 15 (crystalline Compound 15 Form II) is provided, wherein the crystalline structure exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 13. Crystalline Compound 15 Form II may exhibit a DSC thermogram substantially as shown in Figure 14. Crystalline Compound 15 Form II may exhibit a TGA graph substantially as shown in Figure 15.

[0386] In some embodiments of crystalline Compound 15 Form II, at least one, at least two, or all of the following apply: (a) crystalline Compound 15 Form II has an XRPD pattern substantially as shown in FIG. 13; (b) crystalline Compound 15 Form II has a DSC thermogram substantially as shown in FIG. 14; and (c) crystalline Compound 15 Form II has a TGA graph substantially as shown in FIG. 15.

[0387] In some embodiments, crystalline Compound 15 Form II has the following properties: (a) An XRPD pattern substantially as shown in Figure 13; (b) a DSC thermogram substantially as shown in Figure 14; and (c) TGA graph substantially as shown in FIG.

[0388] In some embodiments, crystalline Compound 15 Form II has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, or at least six of the 2θ reflectances with maximal intensities as an XRPD pattern substantially as shown in FIG. 13.

[0389] In some embodiments, crystalline Compound 15 Form II has an XRPD pattern comprising 2θ reflectances at 6.4°, 13.7°, and 16.3° (+ / −0.2 2θ°). In some embodiments, crystalline Compound 15 Form II has an XRPD pattern comprising one, two, or three of 2θ reflectances at 6.4°, 13.7°, and 16.3° (+ / −0.2 2θ°), and 18.4°, 20.8°, and 23.3° (+ / −0.2 2θ°). In some embodiments, crystalline Compound 15 Form II has an XRPD pattern comprising one or two of the 2θ reflectances at 6.4°, 13.7°, and 16.3° (+ / −0.2 2θ°), and the 2θ reflectances at 18.4°, 20.8°, and 23.3° (+ / −0.2 2θ°). In some embodiments, crystalline Compound 15 Form II has an XRPD pattern comprising one of the 2θ reflectances at 6.4°, 13.7°, and 16.3° (+ / −0.2 2θ°), and the 2θ reflectances at 18.4°, 20.8°, and 23.3° (+ / −0.2 2θ°). In some embodiments, crystalline Compound 15 Form II has an XRPD pattern comprising two of the 2θ reflectances at 6.4°, 13.7°, and 16.3° (+ / −0.2 2θ°) and two of the 2θ reflectances at 18.4°, 20.8°, and 23.3° (+ / −0.2 2θ°). In some embodiments, crystalline Compound 15 Form II has an XRPD pattern comprising the 2θ reflectances at 6.4°, 13.7°, 16.3°, 18.4°, 20.8°, and 23.3° (+ / −0.2 2θ°). In some embodiments, crystalline Compound 15 Form II has an XRPD pattern comprising any three 2θ reflectances (+ / −0.2 2θ°) selected from the group consisting of 6.4°, 13.7°, 16.3°, 18.4°, 20.8°, and 23.3°.

[0390] In some embodiments, crystalline Compound 15 Form II has an XRPD pattern comprising any three 2θ reflectances (+ / −0.2 2θ) selected from the group consisting of 6.4°, 13.7°, 16.3°, 18.4°, 20.8°, 23.3°, and 25.4°. In some embodiments, crystalline Compound 15 Form II has an XRPD pattern comprising 2θ reflectances (+ / −0.2 2θ) at 6.4°, 13.7°, 16.3°, 18.4°, 20.8°, 23.3°, and 25.4°. Compound 15, Form III

[0391] In some embodiments, crystalline Form III of Compound 15 (crystalline Compound 15 Form III) is provided, wherein the crystalline structure exhibits an XRPD pattern substantially as shown in Figure 16. Crystalline Compound 15 Form III may exhibit a DSC thermogram substantially as shown in Figure 17. Crystalline Compound 15 Form III may exhibit a TGA graph substantially as shown in Figure 18.

[0392] In some embodiments of crystalline Compound 15 Form III, at least one, at least two, or all of the following apply: (a) crystalline Compound 15 Form III has an XRPD pattern substantially as shown in FIG. 16; (b) crystalline Compound 15 Form III has a DSC thermogram substantially as shown in FIG. 17; and (c) crystalline Compound 15 Form III has a TGA graph substantially as shown in FIG. 18.

[0393] In some embodiments, crystalline Compound 15 Form III has the following properties: (a) An XRPD pattern substantially as shown in Figure 16; (b) a DSC thermogram substantially as shown in Figure 17; and (c) TGA graph substantially as shown in FIG.

[0394] In some embodiments, crystalline Compound 15 Form III has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, or at least six of the 2θ reflectances with maximal intensities as an XRPD pattern substantially as shown in FIG. 16.

[0395] In some embodiments, crystalline Compound 15 Form III has an XRPD pattern comprising 2θ reflectances at 9.8°, 16.0°, and 25.4° (+ / −0.2 2θ°). In some embodiments, crystalline Compound 15 Form III has an XRPD pattern comprising one, two, or three of 2θ reflectances at 9.8°, 16.0°, and 25.4° (+ / −0.2 2θ°), and 10.2°, 19.1°, and 26.9° (+ / −0.2 2θ°). In some embodiments, crystalline Compound 15 Form III has an XRPD pattern comprising one or two of the following: 2θ reflectances at 9.8°, 16.0°, and 25.4° (+ / −0.2 2θ degrees), and 2θ reflectances at 10.2°, 19.1°, and 26.9° (+ / −0.2 2θ degrees). In some embodiments, crystalline Compound 15 Form III has an XRPD pattern comprising one of the following: 2θ reflectances at 9.8°, 16.0°, and 25.4° (+ / −0.2 2θ degrees), and 2θ reflectances at 10.2°, 19.1°, and 26.9° (+ / −0.2 2θ degrees). In some embodiments, crystalline Compound 15 Form III has an XRPD pattern comprising two of the 2θ reflectances at 9.8°, 16.0°, and 25.4° (+ / −0.2 2θ°) and two of the 2θ reflectances at 10.2°, 19.1°, and 26.9° (+ / −0.2 2θ°). In some embodiments, crystalline Compound 15 Form III has an XRPD pattern comprising two of the 2θ reflectances at 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9° (+ / −0.2 2θ°). In some embodiments, crystalline Compound 15 Form III has an XRPD pattern comprising any three of the 2θ reflectances at 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9° (+ / −0.2 2θ°).

[0396] In some embodiments, crystalline Compound 15 Form III has 2θ reflectances at 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9° (+ / −0.2 2θ°), and 2θ reflectances at 10.4°, 19.8°, and 20.7° (+ / −0.2 In some embodiments, crystalline Compound 15 Form III has an XRPD pattern that includes one, two, or three of the following 2θ reflectances: 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9° (+ / −0.2 2θ degrees). In some embodiments, crystalline Compound 15 Form III has an XRPD pattern that includes one or two of the following 2θ reflectances: 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9° (+ / −0.2 2θ degrees), and 10.4°, 19.8°, and 20.7° (+ / −0.2 2θ degrees). In some embodiments, crystalline Compound 15 Form III has an XRPD pattern comprising one of the following 2θ reflectances: 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9° (+ / −0.2 2θ°), and the following 2θ reflectances: 10.4°, 19.8°, and 20.7° (+ / −0.2 2θ°). In some embodiments, crystalline Compound 15 Form III has an XRPD pattern comprising two of the following 2θ reflectances: 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9° (+ / −0.2 2θ°), and the following 2θ reflectances: 10.4°, 19.8°, and 20.7° (+ / −0.2 2θ°). In some embodiments, crystalline Compound 15 Form III has an XRPD pattern comprising 2θ reflectances at 9.8°, 10.2°, 10.4°, 16.0°, 19.1°, 19.8°, 20.7°, 25.4°, and 26.9° (+ / −0.2 2θ°). In some embodiments, crystalline Compound 15 Form III has an XRPD pattern comprising any three of 2θ reflectances at 9.8°, 10.2°, 10.4°, 16.0°, 19.1°, 19.8°, 20.7°, 25.4°, and 26.9° (+ / −0.2 2θ°). XII. Salt of Compound 15 Compound 15 xinafoate salt

[0397] In some embodiments, the disclosure provides a xinafoate salt of Compound 15 (Compound 15 xinafoate). In some embodiments, Compound 15 xinafoate is unsolvated.

[0398] In some embodiments, the present disclosure provides a crystalline form of Compound 15 xinafoate. In some embodiments, the crystalline form of Compound 15 xinafoate exhibits an XRPD pattern substantially as shown in Figure 19. In some embodiments, the crystalline form of Compound 15 xinafoate may exhibit a DSC thermogram substantially as shown in Figure 20. In some embodiments, the crystalline form of Compound 15 xinafoate may exhibit a TGA graph substantially as shown in Figure 21.

[0399] In some embodiments of the crystalline form of Compound 15 xinafoate, at least one, at least two, at least three, or all of the following (a)-(c) apply: (a) the crystalline form of Compound 15 xinafoate has an XRPD pattern substantially as shown in Figure 19; (b) the crystalline form of Compound 15 xinafoate has a DSC thermogram substantially as shown in Figure 20; and (c) the crystalline form of Compound 15 xinafoate has a TGA graph substantially as shown in Figure 21.

[0400] In some embodiments, the crystalline form of Compound 15 xinafoate salt has the following properties: : (a) An XRPD pattern substantially as shown in Figure 19; (b) a DSC thermogram substantially as shown in Figure 20; and (c) TGA graph substantially as shown in FIG.

[0401] In some embodiments, a crystalline form of compound 15 xinafoate salt has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, or at least six of the 2θ reflectances with maximal intensities as an XRPD pattern substantially as shown in FIG. 19.

[0402] In some embodiments, a crystalline form of compound 15 xinafoate has an XRPD pattern that includes 2θ reflectances at 4.0°, 12.2°, and 14.8° (+ / −0.2 2θ°). In some embodiments, a crystalline form of compound 15 xinafoate has an XRPD pattern that includes one, two, or three of 2θ reflectances at 4.0°, 12.2°, and 14.8° (+ / −0.2 2θ°), and 2θ reflectances at 6.2°, 12.9°, and 26.6° (+ / −0.2 2θ°). In some embodiments, a crystalline form of compound 15 xinafoate has an XRPD pattern that includes one or two of the following: 2θ reflectances at 4.0°, 12.2°, and 14.8° (+ / −0.2 2θ), and 2θ reflectances at 6.2°, 12.9°, and 26.6° (+ / −0.2 2θ). In some embodiments, a crystalline form of compound 15 xinafoate has an XRPD pattern that includes one of the following: 2θ reflectances at 4.0°, 12.2°, and 14.8° (+ / −0.2 2θ), and 2θ reflectances at 6.2°, 12.9°, and 26.6° (+ / −0.2 2θ). In some embodiments, the crystalline form of compound 15 xinafoate has an XRPD pattern that includes two of the 2θ reflectances at 4.0°, 12.2°, and 14.8° (+ / −0.2 2θ), and two of the 2θ reflectances at 6.2°, 12.9°, and 26.6° (+ / −0.2 2θ). In some embodiments, the crystalline form of compound 15 xinafoate has an XRPD pattern that includes two of the 2θ reflectances at 4.0°, 6.2°, 12.2°, 12.9°, 14.8°, and 26.6° (+ / −0.2 2θ). In some embodiments, the crystalline form of compound 15 xinafoate has an XRPD pattern that includes any three of the 2θ reflectances at 4.0°, 6.2°, 12.2°, 12.9°, 14.8°, and 26.6° (+ / −0.2 2θ).

[0403] In some embodiments, the crystalline form of compound 15 xinafoate salt has 2θ reflectances at 4.0°, 6.2°, 12.2°, 12.9°, 14.8°, and 26.6° (+ / −0.2 2θ°), and 2θ reflectances at 7.8°, 10.3°, and 15.7° (+ / −0.2 In some embodiments, a crystalline form of compound 15 xinafoate has an XRPD pattern that includes one, two, or three of the following 2θ reflectances: 4.0°, 6.2°, 12.2°, 12.9°, 14.8°, and 26.6° (+ / −0.2 2θ°); and one or two of the 2θ reflectances at 7.8°, 10.3°, and 15.7° (+ / −0.2 2θ°). In some embodiments, a crystalline form of compound 15 xinafoate has an XRPD pattern that includes one of the following 2θ reflectances: 4.0°, 6.2°, 12.2°, 12.9°, 14.8°, and 26.6° (+ / −0.2 2θ), and the following 2θ reflectances: 7.8°, 10.3°, and 15.7° (+ / −0.2 2θ). In some embodiments, a crystalline form of compound 15 xinafoate has an XRPD pattern that includes two of the following 2θ reflectances: 4.0°, 6.2°, 12.2°, 12.9°, 14.8°, and 26.6° (+ / −0.2 2θ), and the following 2θ reflectances: 7.8°, 10.3°, and 15.7° (+ / −0.2 2θ). In some embodiments, a crystalline form of compound 15 xinafoate has an XRPD pattern comprising 2θ reflectances at 4.0°, 6.2°, 7.8°, 10.3°, 12.2°, 12.9°, 14.8°, 15.7°, and 26.6° (+ / −0.2 2θ°). In some embodiments, a crystalline form of compound 15 xinafoate has an XRPD pattern comprising any three of 2θ reflectances at 4.0°, 6.2°, 7.8°, 10.3°, 12.2°, 12.9°, 14.8°, 15.7°, and 26.6° (+ / −0.2 2θ°). Compound 15HCl salt

[0404] In some embodiments, the present disclosure provides an HCl salt of compound 15 (compound 15 HCl salt).

[0405] In some embodiments, the present disclosure provides a crystalline form of Compound 15 HCl salt. Compound 15 HCl Salt Form I

[0406] In some embodiments, the present disclosure provides crystalline Form I of Compound 15HCl salt ("Compound 15HCl salt Form I"). In some embodiments, Compound 15HCl salt Form I exhibits an XRPD pattern substantially as shown in Figure 22. In some embodiments, Compound 15HCl salt Form I may exhibit a DSC thermogram substantially as shown in Figure 23. In some embodiments, Compound 15HCl salt Form I may exhibit a TGA graph substantially as shown in Figure 24.

[0407] In some embodiments of Compound 15 HCl salt Form I, at least one, at least two, or all of the following apply: (a) Compound 15 HCl salt Form I has an XRPD pattern substantially as shown in FIG. 22; (b) Compound 15 HCl salt Form I has a DSC thermogram substantially as shown in FIG. 23; and (c) Compound 15 HCl salt Form I has a TGA graph substantially as shown in FIG. 24.

[0408] In some embodiments, Compound 15 HCl salt Form I has the following properties: (a) An XRPD pattern substantially as shown in Figure 22; (b) a DSC thermogram substantially as shown in Figure 23; and (c) TGA graph substantially as shown in FIG.

[0409] In some embodiments, Compound 15 HCl salt Form I has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, or at least six of the 2θ reflectances with maximal intensities as an XRPD pattern substantially as shown in FIG. 22.

[0410] In some embodiments, Compound 15 HCl salt Form I has an XRPD pattern comprising 2θ reflectances at 5.9°, 14.0°, and 24.3° (+ / −0.2 2θ°). In some embodiments, Compound 15 HCl salt Form I has an XRPD pattern comprising one, two, or three of 2θ reflectances at 5.9°, 14.0°, and 24.3° (+ / −0.2 2θ°), and 11.7°, 16.7°, and 23.9° (+ / −0.2 2θ°). In some embodiments, Compound 15 HCl salt Form I has an XRPD pattern comprising one or two of the 2θ reflectances at 5.9, 14.0, and 24.3° (+ / −0.2 2θ degrees), and the 2θ reflectances at 11.7, 16.7, and 23.9° (+ / −0.2 2θ degrees). In some embodiments, Compound 15 HCl salt Form I has an XRPD pattern comprising one of the 2θ reflectances at 5.9, 14.0, and 24.3° (+ / −0.2 2θ degrees), and the 2θ reflectances at 11.7, 16.7, and 23.9° (+ / −0.2 2θ degrees). In some embodiments, Compound 15 HCl salt Form I has an XRPD pattern that includes two of the 2θ reflectances at 5.9°, 14.0°, and 24.3° (+ / −0.2 2θ), and two of the 2θ reflectances at 11.7°, 16.7°, and 23.9° (+ / −0.2 2θ). In some embodiments, Compound 15 HCl salt Form I has an XRPD pattern that includes two of the 2θ reflectances at 5.9°, 11.7°, 14.0°, 16.7°, 23.9°, and 24.3° (+ / −0.2 2θ). In some embodiments, Compound 15 HCl salt Form I has an XRPD pattern that includes any three of the 2θ reflectances at 5.9°, 11.7°, 14.0°, 16.7°, 23.9°, and 24.3° (+ / −0.2 2θ).

[0411] In some embodiments, Compound 15 HCl salt Form I has an XRPD pattern that includes one, two, or three of the following: 2θ reflectances at 5.9°, 11.7°, 14.0°, 16.7°, 23.9°, and 24.3° (+ / −0.2 2θ degrees), and 2θ reflectances at 14.2°, 19.7°, and 22.4° (+ / −0.2 2θ degrees). In some embodiments, Compound 15 HCl salt Form I has an XRPD pattern that includes one or two of the following: 2θ reflectances at 5.9°, 11.7°, 14.0°, 16.7°, 23.9°, and 24.3° (+ / −0.2 2θ degrees), and 2θ reflectances at 14.2°, 19.7°, and 22.4° (+ / −0.2 2θ degrees). In some embodiments, Compound 15 HCl salt Form I has an XRPD pattern comprising one of the following 2θ reflectances: 5.9°, 11.7°, 14.0°, 16.7°, 23.9°, and 24.3° (+ / −0.2 2θ°); and the following 2θ reflectances: 14.2°, 19.7°, and 22.4° (+ / −0.2 2θ°). In some embodiments, Compound 15 HCl salt Form I has an XRPD pattern comprising two of the following 2θ reflectances: 5.9°, 11.7°, 14.0°, 16.7°, 23.9°, and 24.3° (+ / −0.2 2θ°); and the following 2θ reflectances: 14.2°, 19.7°, and 22.4° (+ / −0.2 2θ°). In some embodiments, Compound 15 HCl salt Form I has an XRPD pattern comprising 2θ reflectances at 5.9°, 11.7°, 14.0°, 14.2°, 16.7°, 19.7°, 22.4°, 23.9°, and 24.3° (+ / −0.2 2θ°). In some embodiments, Compound 15 HCl salt Form I has an XRPD pattern comprising any three of 2θ reflectances at 5.9°, 11.7°, 14.0°, 14.2°, 16.7°, 19.7°, 22.4°, 23.9°, and 24.3° (+ / −0.2 2θ°). Compound 15HCl Salt Material A

[0412] In some embodiments, the present disclosure provides a crystalline Compound 15HCl salt, Material A ("Compound 15HCl salt Material A"). In some embodiments, Compound 15HCl salt Material A exhibits an XRPD pattern substantially as shown in Figure 25. In some embodiments, Compound 15HCl salt Material A may exhibit a DSC thermogram substantially as shown in Figure 26. In some embodiments, Compound 15HCl salt Material A may exhibit a TGA graph substantially as shown in Figure 27.

[0413] In some embodiments of Compound 15 HCl salt material A, at least one, at least two, or all of the following (a)-(c) apply: (a) Compound 15 HCl salt material A has an XRPD pattern substantially as shown in FIG. 25; (b) Compound 15 HCl salt material A has a DSC thermogram substantially as shown in FIG. 26; and (c) Compound 15 HCl salt material A has a TGA graph substantially as shown in FIG. 27.

[0414] In some embodiments, Compound 15 HCl salt Material A has the following properties: (a) An XRPD pattern substantially as shown in Figure 25; (b) a DSC thermogram substantially as shown in Figure 26; and (c) TGA graph substantially as shown in FIG.

[0415] In some embodiments, Compound 15 HCl salt material A has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, or at least six of the 2θ reflectances with maximal intensities as an XRPD pattern substantially as shown in FIG. 25.

[0416] In some embodiments, Compound 15 HCl salt material A has an XRPD pattern comprising 2θ reflectances at 4.0°, 15.0°, and 25.8° (+ / −0.2 2θ°). In some embodiments, Compound 15 HCl salt material A has an XRPD pattern comprising one, two, or three of 2θ reflectances at 4.0°, 15.0°, and 25.8° (+ / −0.2 2θ°), and 2θ reflectances at 10.6°, 16.3°, and 26.7° (+ / −0.2 2θ°). In some embodiments, Compound 15 HCl salt material A has an XRPD pattern that includes one or two of the 2θ reflectances at 4.0°, 15.0°, and 25.8° (+ / −0.2 2θ degrees), and the 2θ reflectances at 10.6°, 16.3°, and 26.7° (+ / −0.2 2θ degrees). In some embodiments, Compound 15 HCl salt material A has an XRPD pattern that includes one of the 2θ reflectances at 4.0°, 15.0°, and 25.8° (+ / −0.2 2θ degrees), and the 2θ reflectances at 10.6°, 16.3°, and 26.7° (+ / −0.2 2θ degrees). In some embodiments, compound 15HCl salt material A has an XRPD pattern that includes two of the 2θ reflectances at 4.0°, 15.0°, and 25.8° (+ / −0.2 2θ°) and the 2θ reflectances at 10.6°, 16.3°, and 26.7° (+ / −0.2 2θ°). In some embodiments, compound 15HCl salt material A has an XRPD pattern that includes two of the 2θ reflectances at 4.0°, 10.6°, 15.0°, 16.3°, 25.8°, and 26.7° (+ / −0.2 2θ°). In some embodiments, compound 15HCl salt material A has an XRPD pattern that includes any three of the 2θ reflectances at 4.0°, 10.6°, 15.0°, 16.3°, 25.8°, and 26.7° (+ / −0.2 2θ°).

[0417] In some embodiments, compound 15HCl salt material A has an XRPD pattern that includes one, two, or three of the following: 2θ reflectances at 4.0°, 10.6°, 15.0°, 16.3°, 25.8°, and 26.7° (+ / −0.2 2θ degrees), and 2θ reflectances at 12.2°, 15.7°, and 31.5° (+ / −0.2 2θ degrees). In some embodiments, compound 15HCl salt material A has an XRPD pattern that includes one or two of the following: 2θ reflectances at 4.0°, 10.6°, 15.0°, 16.3°, 25.8°, and 26.7° (+ / −0.2 2θ degrees), and 2θ reflectances at 12.2°, 15.7°, and 31.5° (+ / −0.2 2θ degrees). In some embodiments, Compound 15HCl salt material A has an XRPD pattern that includes one of the following 2θ reflectances: 4.0°, 10.6°, 15.0°, 16.3°, 25.8°, and 26.7° (+ / −0.2 2θ°), and the following 2θ reflectances: 12.2°, 15.7°, and 31.5° (+ / −0.2 2θ°). In some embodiments, Compound 15HCl salt material A has an XRPD pattern that includes two of the following 2θ reflectances: 4.0°, 10.6°, 15.0°, 16.3°, 25.8°, and 26.7° (+ / −0.2 2θ°), and the following 2θ reflectances: 12.2°, 15.7°, and 31.5° (+ / −0.2 2θ°). In some embodiments, Compound 15 HCl salt material A has an XRPD pattern comprising 2θ reflectances at 4.0°, 10.6°, 12.2°, 15.0°, 15.7°, 16.3°, 25.8°, 26.7°, and 31.5° (+ / −0.2 2θ°). In some embodiments, Compound 15 HCl salt material A has an XRPD pattern comprising any three of 2θ reflectances at 4.0°, 10.6°, 12.2°, 15.0°, 15.7°, 16.3°, 25.8°, 26.7°, and 31.5° (+ / −0.2 2θ°). Compound 15HCl Salt Material B

[0418] In some embodiments, the present disclosure provides crystalline Compound 15HCl salt Material B ("Compound 15HCl salt Material B"). In some embodiments, Compound 15HCl salt Material B exhibits an XRPD pattern substantially as shown in Figure 28. In some embodiments, Compound 15HCl salt Material B may exhibit a DSC thermogram substantially as shown in Figure 29. In some embodiments, Compound 15HCl salt Material B may exhibit a TGA graph substantially as shown in Figure 30.

[0419] In some embodiments of Compound 15 HCl salt Material B, at least one, at least two, or all of the following (a)-(c) apply: (a) Compound 15 HCl salt Material B has an XRPD pattern substantially as shown in FIG. 28; (b) Compound 15 HCl salt Material B has a DSC thermogram substantially as shown in FIG. 29; and (c) Compound 15 HCl salt Material B has a TGA graph substantially as shown in FIG. 30.

[0420] In some embodiments, Compound 15HCl salt Material B has the following properties: (a) An XRPD pattern substantially as shown in Figure 28; (b) a DSC thermogram substantially as shown in Figure 29; and (c) TGA graph substantially as shown in FIG.

[0421] In some embodiments, Compound 15 HCl salt Material B has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, or at least six of the 2θ reflectances with maximal intensities as an XRPD pattern substantially as shown in FIG. 28.

[0422] In some embodiments, Compound 15 HCl salt Material B has an XRPD pattern comprising 2θ reflectances at 4.3°, 15.9°, and 26.6° (+ / −0.2 2θ°). In some embodiments, Compound 15 HCl salt Material B has an XRPD pattern comprising one, two, or three of 2θ reflectances at 4.3°, 15.9°, and 26.6° (+ / −0.2 2θ°), and 2θ reflectances at 7.1°, 16.8°, and 25.7° (+ / −0.2 2θ°). In some embodiments, Compound 15 HCl salt material B has an XRPD pattern that includes one or two of the 2θ reflectances at 4.3°, 15.9°, and 26.6° (+ / −0.2 2θ degrees), and the 2θ reflectances at 7.1°, 16.8°, and 25.7° (+ / −0.2 2θ degrees). In some embodiments, Compound 15 HCl salt material B has an XRPD pattern that includes one of the 2θ reflectances at 4.3°, 15.9°, and 26.6° (+ / −0.2 2θ degrees), and the 2θ reflectances at 7.1°, 16.8°, and 25.7° (+ / −0.2 2θ degrees). In some embodiments, compound 15HCl salt material B has an XRPD pattern that includes two of the 2θ reflectances at 4.3°, 15.9°, and 26.6° (+ / −0.2 2θ degrees) and the 2θ reflectances at 7.1°, 16.8°, and 25.7° (+ / −0.2 2θ degrees). In some embodiments, compound 15HCl salt material B has an XRPD pattern that includes two of the 2θ reflectances at 4.3°, 7.1°, 15.9°, 16.8°, 25.7°, and 26.6° (+ / −0.2 2θ degrees). In some embodiments, compound 15HCl salt material B has an XRPD pattern that includes any three of the 2θ reflectances at 4.3°, 7.1°, 15.9°, 16.8°, 25.7°, and 26.6° (+ / −0.2 2θ degrees).

[0423] In some embodiments, Compound 15 HCl salt material B has an XRPD pattern that includes one, two, or three of the following: 2θ reflectances at 4.3°, 7.1°, 15.9°, 16.8°, 25.7°, and 26.6° (+ / −0.2 2θ degrees), and 2θ reflectances at 14.3°, 18.7°, and 27.0° (+ / −0.2 2θ degrees). In some embodiments, Compound 15 HCl salt material B has an XRPD pattern that includes one or two of the following: 2θ reflectances at 4.3°, 7.1°, 15.9°, 16.8°, 25.7°, and 26.6° (+ / −0.2 2θ degrees), and 2θ reflectances at 14.3°, 18.7°, and 27.0° (+ / −0.2 2θ degrees). In some embodiments, Compound 15 HCl salt material B has an XRPD pattern comprising one of 2θ reflectances at 4.3°, 7.1°, 15.9°, 16.8°, 25.7°, and 26.6° (+ / −0.2 2θ°), and 2θ reflectances at 14.3°, 18.7°, and 27.0° (+ / −0.2 2θ°). In some embodiments, Compound 15 HCl salt material B has an XRPD pattern comprising one of 2θ reflectances at 4.3°, 7.1°, 15.9°, 16.8°, 25.7°, and 26.6° (+ / −0.2 2θ°). 2θ), and two of the 2θ reflectances at 14.3°, 18.7°, and 27.0° (+ / −0.2 2θ). In some embodiments, Compound 15 HCl salt material B has an XRPD pattern that includes 2θ reflectances at 4.3°, 7.1°, 14.3°, 15.9°, 16.8°, 18.7°, 25.7°, 26.6°, and 27.0° (+ / −0.2 2θ). In some embodiments, Compound 15 HCl salt material B has an XRPD pattern that includes any three of the 2θ reflectances at 4.3°, 7.1°, 14.3°, 15.9°, 16.8°, 18.7°, 25.7°, 26.6°, and 27.0° (+ / −0.2 2θ). Compound 15HCl Salt Material C

[0424] In some embodiments, the present disclosure provides crystalline Compound 15HCl salt Material C ("Compound 15HCl salt Material C"). In some embodiments, Compound 15HCl salt Material C exhibits an XRPD pattern substantially as shown in Figure 31. In some embodiments, Compound 15HCl salt Material C may exhibit a DSC thermogram substantially as shown in Figure 32. In some embodiments, Compound 15HCl salt Material C may exhibit a TGA graph substantially as shown in Figure 33.

[0425] In some embodiments of Compound 15 HCl salt material C, at least one, at least two, or all of the following (a)-(c) apply: (a) Compound 15 HCl salt material C has an XRPD pattern substantially as shown in FIG. 31; (b) Compound 15 HCl salt material C has a DSC thermogram substantially as shown in FIG. 32; and (c) Compound 15 HCl salt material C has a TGA graph substantially as shown in FIG. 33.

[0426] In some embodiments, Compound 15HCl salt material C has the following properties: (a) An XRPD pattern substantially as shown in Figure 31; (b) a DSC thermogram substantially as shown in Figure 32; and (c) TGA graph substantially as shown in FIG.

[0427] In some embodiments, Compound 15 HCl salt material C has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, or at least six of the 2θ reflectances with maximal intensities as an XRPD pattern substantially as shown in FIG. 31.

[0428] In some embodiments, Compound 15 HCl salt material C has an XRPD pattern comprising 2θ reflectances at 4.3°, 14.7°, and 31.4° (+ / −0.2 2θ°). In some embodiments, Compound 15 HCl salt material C has an XRPD pattern comprising one, two, or three of 2θ reflectances at 4.3°, 14.7°, and 31.4° (+ / −0.2 2θ°), and 2θ reflectances at 12.8°, 17.3°, and 35.1° (+ / −0.2 2θ°). In some embodiments, Compound 15 HCl salt material C has an XRPD pattern comprising one or two of the 2θ reflectances at 4.3°, 14.7°, and 31.4° (+ / −0.2 2θ degrees), and the 2θ reflectances at 12.8°, 17.3°, and 35.1° (+ / −0.2 2θ degrees). In some embodiments, Compound 15 HCl salt material C has an XRPD pattern comprising one of the 2θ reflectances at 4.3°, 14.7°, and 31.4° (+ / −0.2 2θ degrees), and the 2θ reflectances at 12.8°, 17.3°, and 35.1° (+ / −0.2 2θ degrees). In some embodiments, compound 15HCl salt material C has an XRPD pattern that includes two of the 2θ reflectances at 4.3°, 14.7°, and 31.4° (+ / −0.2 2θ°) and the 2θ reflectances at 12.8°, 17.3°, and 35.1° (+ / −0.2 2θ°). In some embodiments, compound 15HCl salt material C has an XRPD pattern that includes two of the 2θ reflectances at 4.3°, 12.8°, 14.7°, 17.3°, 31.4°, and 35.1° (+ / −0.2 2θ°). In some embodiments, compound 15HCl salt material C has an XRPD pattern that includes any three of the 2θ reflectances at 4.3°, 12.8°, 14.7°, 17.3°, 31.4°, and 35.1° (+ / −0.2 2θ°).

[0429] In some embodiments, Compound 15 HCl salt material C has an XRPD pattern that includes one, two, or three of the following: 2θ reflectances at 4.3°, 12.8°, 14.7°, 17.3°, 31.4°, and 35.1° (+ / −0.2 2θ degrees), and 2θ reflectances at 16.6°, 24.9°, and 27.2° (+ / −0.2 2θ degrees). In some embodiments, Compound 15 HCl salt material C has an XRPD pattern that includes one or two of the following: 2θ reflectances at 4.3°, 12.8°, 14.7°, 17.3°, 31.4°, and 35.1° (+ / −0.2 2θ degrees), and 2θ reflectances at 16.6°, 24.9°, and 27.2° (+ / −0.2 2θ degrees). In some embodiments, Compound 15 HCl salt material C has an XRPD pattern comprising one of the following 2θ reflectances: 4.3°, 12.8°, 14.7°, 17.3°, 31.4°, and 35.1° (+ / −0.2 2θ°), and the following 2θ reflectances: 16.6°, 24.9°, and 27.2° (+ / −0.2 2θ°). In some embodiments, Compound 15 HCl salt material C has an XRPD pattern comprising two of the following 2θ reflectances: 4.3°, 12.8°, 14.7°, 17.3°, 31.4°, and 35.1° (+ / −0.2 2θ°), and the following 2θ reflectances: 16.6°, 24.9°, and 27.2° (+ / −0.2 2θ°). In some embodiments, Compound 15 HCl salt material C has an XRPD pattern comprising 2θ reflectances at 4.3°, 12.8°, 14.7°, 16.6°, 17.3°, 24.9°, 27.2°, 31.4°, and 35.1° (+ / −0.2 2θ°). In some embodiments, Compound 15 HCl salt material C has an XRPD pattern comprising any three of 2θ reflectances at 4.3°, 12.8°, 14.7°, 16.6°, 17.3°, 24.9°, 27.2°, 31.4°, and 35.1° (+ / −0.2 2θ°). XIII. Working Examples Intermediate A: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate [ka]

[0430] (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (Compound 13 described in International Publication No. 2009132135 and Compound 4 described in J. Med. Chem. 2017, 60, 1648-1661) and 2-((Tert-butoxycarbonyl)amino)-2-methylpropanoic acid (209 mg, 1.03 mmol) were dissolved in anhydrous DMF (3 mL). N,N'-diisopropylcarbodiimide (177 μL, 1.13 mmol) was added to the mixture and stirred for 20 minutes. Subsequently, the nucleoside (150 mg, 0.52 mmol) and triethylamine (180 μL, 1.29 mmol) were added. The resulting mixture was stirred for 16 hours. Additional 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (1 equivalent) and N,N'-diisopropylcarbodiimide (1 equivalent) were added at this point and heated at 60°C for 4 hours, followed by stirring at room temperature for an additional 16 hours. Diluted with ethyl acetate and washed with saturated NaHCO3 and saturated brine. The organic layer was dried over Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with ethyl acetate in hexanes (0% to 100%) to give Intermediate A.

[0431] MS m / z=475.1 [M-1]. Intermediate B: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(tert-butoxycarbonyl)-L-valinate [ka]

[0432] Intermediate B was prepared in a similar manner to Intermediate A, except that (tert-butoxycarbonyl)-L-valine (55 mg, 0.26 mmol) was used in place of 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid. Example 1: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-((isobutyryloxy)methyl)tetrahydrofuran-3,4-diylbis(2-methylpropanoate) [ka]

[0433] (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (29 mg, 0.1 mmol) was dissolved in anhydrous DMF (1 mL). Isobutyric acid (46 μL, 0.5 mmol) was added in one portion. N,N'-Diisopropylcarbodiimide (78 μL, 0.5 mmol) was added dropwise. The reaction was stirred for 15 minutes. 4-(Dimethylamino)pyridine (12.2 mg, 0.1 mmol) was added. The reaction was then stirred for 16 hours. Diluted with acetonitrile (1 mL) and the solid was filtered off. The filtrate was purified by preparative HPLC (0-95% acetonitrile in water). The fractions were combined and lyophilized to give the title compound.

[0434] 1 H NMR(300MHz,CDCl3)δ11.15(bs,1H),8.27(bs,1H),7.95(s,1H),7.32(m,1H),7.07(m,1H),6.05(d,J=6.0 Hz,1H), 5.44(t,J=5.1Hz,1H),4.66(t,J=3.6Hz,1H),4.32(m,2H),2.73-2.52(m,3H),1.27-1.14(m,18H).

[0435] LC / MS:t R= 2.60 min, MS m / z = 502.2 [M+1], 500.1 [M-1]; LC / MS system: Thermo LCQ Advantage; Phenomenex Gemini, C 18 , 5u, 110A, 30x4.6mm; Buffer A: 0.1% acetic acid in water; Buffer B: 0.1% acetic acid in acetonitrile; 5 to 100% Buffer B in 2.5 min at 2mL / min, then 100% for 0.9 min.

[0436] HPLC:t R = 3.33 min; HPLC system: Agilent 1100; Phenomenex Gemini, C 18 , 5u, 110A, 50x4.6mm; Buffer A: 0.05% TFA in water; Buffer B: 0.05% TFA in acetonitrile; 2 to 98% Buffer B in 5 min at 2 mL / min. Example 2: (2R,3R,4R,5R)-5-(acetoxymethyl)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyanotetrahydrofuran-3,4-diyl diacetate [ka]

[0437] The title compound was prepared in a similar manner to compound 1, except that acetic acid (29 uL, 0.50 mmol) was used in place of isobutyric acid.

[0438] 1 H NMR(300MHz,CDCl3)δ11.15(bs,1H),8.08(bs,1H),7.97(s,1H),7.35(m,1H),7.12(d,J=4.8Hz,1H),6.06(d, J=5.7Hz,1H), 5.40(t,J=6.0Hz,1H),4.67(m,1H),4.48-4.32(m,2H),2.20(s,3H),2.17(s,3H),2.09(s,3H).

[0439] LC / MS:t R=2.00 min, MS m / z=418.0[M+1], 416.0[M-1]. Example 3: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-((propionyloxy)methyl)tetrahydrofuran-3,4-diyl dipropionate [ka]

[0440] The title compound was prepared in a similar manner to compound 1, except that propionic acid (37 uL, 0.50 mmol) was used in place of isobutyric acid.

[0441] 1 H NMR:(400MHz,methanol-d4)δ8.04(s,1H),7.23(d,J=4.7Hz,1H),7.03(d,J=4.7Hz,1H),6.20(d,J=5.7Hz,1H),5.51(dd,J=5.7,4.6Hz,1H),4.67(td, J=4.5,3.5Hz,1H),4.49(dd,J=12.3,3.6Hz,1H),4.38(dd,J=12.3,4.6Hz,1H),2.56-2.40(m,4H),2.36(qd,J=7.6,5.1Hz,2H),1.30-1.06(m,9H).

[0442] LC / MS:t R =0.89 min, MS m / z=460.2[M+1]. Example 4: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2-phenyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile [ka]

[0443] (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (58 mg, 0.20 mmol) was combined with benzaldehyde (3 mL), followed by the addition of zinc(II) chloride (41 mg, 0.3 mmol). The resulting reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was then diluted with ethyl acetate and washed with saturated NaHCO and saturated brine. The organic layer was dried over NaSO, concentrated in vacuo, and purified by column chromatography eluting with ethyl acetate in hexanes (0% to 30% to 50%) to give the desired product.

[0444] 1 H NMR (400 MHz, methanol-d₄) δ 7.90 (s, 1H), 7.80-7.70 (m, 2H), 7.51-7.39 (m, 3H), 7.03-6.91 (m, 2H), 6.14 (s, 1H), 5.55 (d, J = 7.2 Hz, 1H), 5.09 (dd, J = 7.2, 3.8 Hz, 1H), 4.60 (q, J = 4.4 Hz, 1H), 3.89-3.77 (m, 2H).

[0445] LC / MS:t R =-0.77 min, MS m / z=380.1[M+1]. Example 5: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2-phenyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate [ka]

[0446] The title compound was prepared in a manner similar to that of compound 1, except that compound 4 (32 mg, 0.084 mmol) was used in place of (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile.

[0447] 1 H NMR (400MHz, methanol-d4) δ8.05(s,1H),7.77-7.70(m,2H),7.52-7.40(m,3H),7.2 4(d,J=4.7Hz,1H),7.04(d,J=4.7Hz,1H),6.13(s,1H),5.50(d,J=7.0Hz,1H),5. 07(dd,J=6.9,3.6Hz,1H),4.78(dt,J=5.4,4.0Hz,1H),4.42(dd,J=12.0,4.2Hz, 1H),4.30(dd,J=12.1,5.5Hz,1H),2.49(hept,J=7.0Hz,1H),1.18-1.05(m,6H).

[0448] LC / MS:t R =0.94 min, MS m / z=450.2[M+1]. Example 6: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2-phenyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl L-valinate [ka]

[0449] (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2-phenyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile (32 mg, 0.084 mmol) was dissolved in anhydrous DMF (1 mL). (tert-Butoxycarbonyl)-L-valine (37 mg, 0.168 mmol) and N,N'-diisopropylcarbodiimide (26 μL, 0.168 mmol) were added. The resulting mixture was stirred for 20 minutes. 4-(Dimethylamino)pyridine (10 mg, 0.084 mmol) was then added, and the reaction mixture was stirred at room temperature for 16 hours. After dilution with acetonitrile, the solid was filtered off. The filtrate was purified by preparative HPLC. The fractions were combined and concentrated in vacuo. The residue was dissolved in 20% trifluoroacetic acid in dichloromethane (3 mL) and stirred for 45 min. The mixture was then concentrated and purified by preparative HPLC to give the title compound.

[0450] 1 H NMR (400MHz, methanol-d4) δ8.00(s,1H),7.60-7.49(m,2H),7.50-7.39(m,3H),7.12(d,J=4.7Hz,1H),7.05(d,J=4.7Hz,1H),6.44(s,1H),5.56(d,J=6) .7Hz,1H),5.23(dd,J=6.7,5.6Hz,1H),4.74(q,J=5.6Hz,1H),4.70-4.55( m,2H),4.01-3.92(m,1H),2.31(pd,J=7.0,4.5Hz,1H),1.09-0.94(m,6H).

[0451] LC / MS:t R =0.85 min, MS m / z=479.2[M+1]. Example 7: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl 2-amino-2-methylpropanoate [ka]

[0452] The title compound was prepared in a similar manner to compound 6, except that 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (80 mg, 0.40 mmol) was used instead of (tert-butoxycarbonyl)-L-valine, and the deprotection step was stirred at room temperature for 3 hours instead of 45 minutes.

[0453] 1 H NMR (400MHz, methanol-d4) δ7.98(s,1H),7.13(d,J=4.7Hz,1H),7.01(d,J=4.7Hz,1H),4.89(s,1H),4. 57(d,J=5.1Hz,2H),4.44(dt,J=7.2,5.1Hz,1H),4.14(dd,J=7.0,5.4Hz,1H),1.58(d,J=6.7Hz,6H).

[0454] LC / MS:t R =0.20 min, MS m / z=377.2[M+1]. Example 8: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl L-valinate [ka]

[0455] (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile and (tert-butoxycarbonyl)-L-valine (55 mg, 0.56 mmol) were dissolved in anhydrous DMF (2 mL). To this mixture was added N,N'-diisopropylcarbodiimide (40 μL, 0.26 mmol) and stirred for 15 minutes, followed by the addition of the nucleoside (50 mg, 0.17 mmol) and triethylamine (47 μL, 0.34 mmol). The resulting mixture was stirred for 16 hours. At this time, additional (tert-butoxycarbonyl)-L-valine (55 mg, 0.56 mmol) and N,N'-diisopropylcarbodiimide (40 μL, 0.25 mmol) were added, and the mixture was stirred at room temperature for an additional 5 hours. The reaction was then heated at 50°C for 3 hours, followed by stirring at room temperature for an additional 72 hours. It was diluted with ethyl acetate and washed with saturated NaHCO3 and saturated brine. The organic layer was dried over Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with ethyl acetate in hexanes (0% to 70%), then further purified by reverse-phase HPLC. The fractions were combined and concentrated in vacuo. The residue was dissolved in 20% trifluoroacetic acid in dichloromethane and stirred for 30 minutes. The mixture was then concentrated and purified by preparative HPLC to give the title compound.

[0456] 1 H NMR (400MHz, methanol-d4) δ7.92(s,1H),7.05(s,2H),5.57(dd,J=5.8,2.3Hz,1H),5.31(d,J=5.8Hz,1H),4.49(q ,J=3.0Hz,1H),4.18-4.04(m,1H),3.93-3.77(m,2H),2.53(qd,J=7.0,4.5Hz,1H),1.16(dd,J=7.0,4.9Hz,6H).

[0457] LC / MS:t R =0.48 min, MS m / z=391.2[M+1]. Example 9: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl D-valinate [ka]

[0458] The title compound was prepared in a manner similar to that of Compound 8, except that (tert-butoxycarbonyl)-D-valine (75 mg, 0.34 mmol) was used in place of (tert-butoxycarbonyl)-L-valine.

[0459] 1 H NMR (400MHz, methanol-d4) δ7.90(s,1H),7.02(q,J=4.7Hz,2H),5.60(ddd,J=19.1,5.9,2.3Hz,1H),5.31(dd,J=18.0,5.9Hz,1H) ,4.56-4.47(m,1H),4.11(dd,J=4.2,2.4Hz,1H),3.97-3.75(m,2H),2.68(pd,J=7.1,3.8Hz,1H),1.17(dt,J=7.0,4.8Hz,6H).

[0460] LC / MS:t R =0.44 min, MS m / z=391.2[M+1]. Example 10: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl L-phenylalaninate [ka]

[0461] The title compound was prepared in a manner similar to that of Compound 8, except that (tert-butoxycarbonyl)-L-phenylalanine (55 mg, 0.26 mmol) was used in place of (tert-butoxycarbonyl)-L-valine.

[0462] 1 H NMR (400MHz, methanol-d4) δ7.94(s,1H),7.48-7.28(m,5H),7.12-7.03(m,2H),5.53(dd,J=5.8,2.1Hz,1H),5.29(d,J=5.7Hz,1H),4 .48(dd,J=8.1,6.1Hz,1H),4.24(q,J=3.0Hz,1H),3.77(qd,J=12.4,3.2Hz,2H),3.46(dd,J=14.3,6.2Hz,1H),3.29-3.24(m,1H).

[0463] LC / MS:t R =0.58 min, MS m / z=439.2[M+1]. Example 11: (2R,3R,4R,5R)-5-(((2-amino-2-methylpropanoyl)oxy)methyl)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyanotetrahydrofuran-3,4-diylbis(2-methylpropanoate) [ka]

[0464] Intermediate A (45 mg, 0.094 mmol) was dissolved in anhydrous DMF (3 mL). Isobutyric acid (26 μL, 0.28 mmol) and N,N'-diisopropylcarbodiimide (44 μL, 0.28 mmol) were added. The reaction was stirred for 15-20 minutes, followed by the addition of 4-(dimethylamino)pyridine (11.6 mg, 0.09 mmol). The reaction was then stirred for 4 hours. At this point, additional isobutyric acid (3 equiv.) and N,N'-diisopropylcarbodiimide (3 equiv.) and 4-(dimethylamino)pyridine (1 eq...

Claims

[Claim 1] The invention described in this specification.

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