Compounds and methods for the 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 Application) This application claims priority to U.S. Provisional Patent Application No. 63 / 071,134 filed on August 27, 2020, U.S. Provisional Patent Application No. 63 / 162,283 filed on March 17, 2021, and U.S. Provisional Patent Application No. 63 / 215,310 filed on June 25, 2021, each of which is incorporated herein by reference in its entirety for all purposes. Background Art

[0002] There is a need for compounds and methods for treating viral infections, such as viral infections from Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, Arenaviridae, Orthomyxovirus, and Coronaviridae. 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, Chemical drawing or a pharmaceutically acceptable salt thereof, wherein, in the formula, R 1 is OH, OCOR 4 , or OC(O)OR 4 , and R 2 is OH, OCOR 5 , or OC(O)OR 5 , or R 1 and R 2 together form -OC(O)O- or -OCHR 6 O-, wherein, in the formula, R 6 is H, C1-C6 alkyl or C6-C 10It is Ariel, R 3 H, COR 7 Or COOR 7 And, R 4 , R 5 , and R 7 These are, independently, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocykyl, and C6-C 10 One, two, or three heteroatoms selected from aryl, N, O, and S It contains a 5-6 member heteroaryl compound. In the formula, R 4 , R 5 , and R 7 These are, independently, halogen, cyano, -N3, and -OR. 8 , -NR 9 R 10 , and optionally substituted with one, two, or three substituents independently selected from the group consisting of phenyl that is optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C1-C6 alkyl, Each R 8 These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl. Each R 9 These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl. Each R 10 These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl. Base is [ka] And, R 11 These are C1-C6 alkyl groups substituted with -OP(O)(OH)2. However, R 3 If H, R 1OCOR 4 Or OC(O)OR 4 is, or R 2 OCOR 5 Or OC(O)OR 5 is, or R 1 and R 2 These two combine to form -OC(O)O- or -OCHR 6 The present invention provides a compound of formula I that forms an O-, or a pharmaceutically acceptable salt thereof.

[0004] This specification also provides pharmaceutical compositions comprising the compounds disclosed herein, or pharmaceutically acceptable salts thereof.

[0005] This disclosure further provides a method for treating or preventing a viral infection in a person in need thereof, the method comprising administering a compound of this disclosure, or a pharmaceutically acceptable salt thereof, to a person.

[0006] This specification also provides a method for producing a pharmaceutical product for treating or preventing a viral infection in a person in need thereof, characterized in that a compound of the Disclosure or a pharmaceutically acceptable salt thereof is used.

[0007] This disclosure also provides the use of the compounds of this disclosure, or pharmaceutically acceptable salts thereof, for the manufacture of pharmaceuticals for treating or preventing viral infections in humans in need thereof. [Brief explanation of the drawing]

[0008] [Figure 1-1]The antiviral efficacy of compound 1 is shown. 1a-b: Reduction in viral yield of SARS-CoV-2 clinical isolates WA1 / 2020, SA / 2020, CA / 2020, and BZ / 2021, representing A, B.1.351, B.1.1.7, and P.1 strains, respectively, against VeroE6 cells by compound 1(a) and reference compound A(b). EC50 concentrations are specified. 1c-d: In vitro cytotoxicity profiles of compound 1(c) and reference compound A(d) against a panel of primary HAE cells from VeroE6, HEp-2, BHK-21, HCT-8, and independent donors ("F2", "F3", "M2", "M6", "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 profiles 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]The antiviral efficacy of compound 1 is shown. 1a-b: Reduction in viral yield of SARS-CoV-2 clinical isolates WA1 / 2020, SA / 2020, CA / 2020, and BZ / 2021, representing A, B.1.351, B.1.1.7, and P.1 strains, respectively, against VeroE6 cells by compound 1(a) and reference compound A(b). EC50 concentrations are specified. 1c-d: In vitro cytotoxicity profiles of compound 1(c) and reference compound A(d) against a panel of primary HAE cells from VeroE6, HEp-2, BHK-21, HCT-8, and independent donors ("F2", "F3", "M2", "M6", "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 profiles 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]The antiviral efficacy of compound 1 is shown. 1a-b: Reduction in viral yield of SARS-CoV-2 clinical isolates WA1 / 2020, SA / 2020, CA / 2020, and BZ / 2021, representing A, B.1.351, B.1.1.7, and P.1 strains, respectively, against VeroE6 cells by compound 1(a) and reference compound A(b). EC50 concentrations are specified. 1c-d: In vitro cytotoxicity profiles of compound 1(c) and reference compound A(d) against a panel of primary HAE cells from VeroE6, HEp-2, BHK-21, HCT-8, and independent donors ("F2", "F3", "M2", "M6", "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 profiles 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]The antiviral efficacy of compound 1 is shown. 1a-b: Reduction in viral yield of SARS-CoV-2 clinical isolates WA1 / 2020, SA / 2020, CA / 2020, and BZ / 2021, representing A, B.1.351, B.1.1.7, and P.1 strains, respectively, against VeroE6 cells by compound 1(a) and reference compound A(b). EC50 concentrations are specified. 1c-d: In vitro cytotoxicity profiles of compound 1(c) and reference compound A(d) against a panel of primary HAE cells from VeroE6, HEp-2, BHK-21, HCT-8, and independent donors ("F2", "F3", "M2", "M6", "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 profiles 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]The antiviral efficacy of compound 1 is shown. 1a-b: Reduction in viral yield of SARS-CoV-2 clinical isolates WA1 / 2020, SA / 2020, CA / 2020, and BZ / 2021, representing A, B.1.351, B.1.1.7, and P.1 strains, respectively, against VeroE6 cells by compound 1(a) and reference compound A(b). EC50 concentrations are specified. 1c-d: In vitro cytotoxicity profiles of compound 1(c) and reference compound A(d) against a panel of primary HAE cells from VeroE6, HEp-2, BHK-21, HCT-8, and independent donors ("F2", "F3", "M2", "M6", "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 profiles 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] This shows the prophylactic efficacy of orally administered compound 1. 2a: Schematic diagram of the prophylactic efficacy study design. 2b: Viral titer from nasal lavage fluid. LoD, limit of detection. 2c: Temperature measurements collected once daily. 2d: Body weight measured once daily. 2e: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 2f: SARS-CoV-2 RNA copies present in nasal lavage fluid. 2g: SARS-CoV-2 RNA copies detected in nasal turbinates. 2h~2i: SARS-CoV-2 infected particles (h) and SARS-CoV-2 RNA copies (i) in the lungs 4 days after infection. The number of independent biological replicates (individual animals) is shown in each subpanel, the symbols represent independent biological replicates, the lines (b, c, d, f) and bar graphs (e, g~i) connect or show the sample mean, respectively, and the P-value is indicated. Two-way ANOVA using Sidac's post-hoc multiple comparison tests (b, c, d, f) or two-tailed t-tests (e, g). [Figure 2-2]This shows the prophylactic efficacy of orally administered compound 1. 2a: Schematic diagram of the prophylactic efficacy study design. 2b: Viral titer from nasal lavage fluid. LoD, limit of detection. 2c: Temperature measurements collected once daily. 2d: Body weight measured once daily. 2e: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 2f: SARS-CoV-2 RNA copies present in nasal lavage fluid. 2g: SARS-CoV-2 RNA copies detected in nasal turbinates. 2h~2i: SARS-CoV-2 infected particles (h) and SARS-CoV-2 RNA copies (i) in the lungs 4 days after infection. The number of independent biological replicates (individual animals) is shown in each subpanel, the symbols represent independent biological replicates, the lines (b, c, d, f) and bar graphs (e, g~i) connect or show the sample mean, respectively, and the P-value is indicated. Two-way ANOVA using Sidac's post-hoc multiple comparison tests (b, c, d, f) or two-tailed t-tests (e, g). [Figure 2-3] This shows the prophylactic efficacy of orally administered compound 1. 2a: Schematic diagram of the prophylactic efficacy study design. 2b: Viral titer from nasal lavage fluid. LoD, limit of detection. 2c: Temperature measurements collected once daily. 2d: Body weight measured once daily. 2e: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 2f: SARS-CoV-2 RNA copies present in nasal lavage fluid. 2g: SARS-CoV-2 RNA copies detected in nasal turbinates. 2h~2i: SARS-CoV-2 infected particles (h) and SARS-CoV-2 RNA copies (i) in the lungs 4 days after infection. The number of independent biological replicates (individual animals) is shown in each subpanel, the symbols represent independent biological replicates, the lines (b, c, d, f) and bar graphs (e, g~i) connect or show the sample mean, respectively, and the P-value is indicated. Two-way ANOVA using Sidac's post-hoc multiple comparison tests (b, c, d, f) or two-tailed t-tests (e, g). [Figure 2-4]This shows the prophylactic efficacy of orally administered compound 1. 2a: Schematic diagram of the prophylactic efficacy study design. 2b: Viral titer from nasal lavage fluid. LoD, limit of detection. 2c: Temperature measurements collected once daily. 2d: Body weight measured once daily. 2e: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 2f: SARS-CoV-2 RNA copies present in nasal lavage fluid. 2g: SARS-CoV-2 RNA copies detected in nasal turbinates. 2h~2i: SARS-CoV-2 infected particles (h) and SARS-CoV-2 RNA copies (i) in the lungs 4 days after infection. The number of independent biological replicates (individual animals) is shown in each subpanel, the symbols represent independent biological replicates, the lines (b, c, d, f) and bar graphs (e, g~i) connect or show the sample mean, respectively, and the P-value is indicated. Two-way ANOVA using Sidac's post-hoc multiple comparison tests (b, c, d, f) or two-tailed t-tests (e, g). [Figure 2-5] This shows the prophylactic efficacy of orally administered compound 1. 2a: Schematic diagram of the prophylactic efficacy study design. 2b: Viral titer from nasal lavage fluid. LoD, limit of detection. 2c: Temperature measurements collected once daily. 2d: Body weight measured once daily. 2e: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 2f: SARS-CoV-2 RNA copies present in nasal lavage fluid. 2g: SARS-CoV-2 RNA copies detected in nasal turbinates. 2h~2i: SARS-CoV-2 infected particles (h) and SARS-CoV-2 RNA copies (i) in the lungs 4 days after infection. The number of independent biological replicates (individual animals) is shown in each subpanel, the symbols represent independent biological replicates, the lines (b, c, d, f) and bar graphs (e, g~i) connect or show the sample mean, respectively, and the P-value is indicated. Two-way ANOVA using Sidac's post-hoc multiple comparison tests (b, c, d, f) or two-tailed t-tests (e, g). [Figure 2-6]This shows the prophylactic efficacy of orally administered compound 1. 2a: Schematic diagram of the prophylactic efficacy study design. 2b: Viral titer from nasal lavage fluid. LoD, limit of detection. 2c: Temperature measurements collected once daily. 2d: Body weight measured once daily. 2e: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 2f: SARS-CoV-2 RNA copies present in nasal lavage fluid. 2g: SARS-CoV-2 RNA copies detected in nasal turbinates. 2h~2i: SARS-CoV-2 infected particles (h) and SARS-CoV-2 RNA copies (i) in the lungs 4 days after infection. The number of independent biological replicates (individual animals) is shown in each subpanel, the symbols represent independent biological replicates, the lines (b, c, d, f) and bar graphs (e, g~i) connect or show the sample mean, respectively, and the P-value is indicated. Two-way ANOVA using Sidac's post-hoc multiple comparison tests (b, c, d, f) or two-tailed t-tests (e, g). [Figure 2-7] This shows the prophylactic efficacy of orally administered compound 1. 2a: Schematic diagram of the prophylactic efficacy study design. 2b: Viral titer from nasal lavage fluid. LoD, limit of detection. 2c: Temperature measurements collected once daily. 2d: Body weight measured once daily. 2e: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 2f: SARS-CoV-2 RNA copies present in nasal lavage fluid. 2g: SARS-CoV-2 RNA copies detected in nasal turbinates. 2h~2i: SARS-CoV-2 infected particles (h) and SARS-CoV-2 RNA copies (i) in the lungs 4 days after infection. The number of independent biological replicates (individual animals) is shown in each subpanel, the symbols represent independent biological replicates, the lines (b, c, d, f) and bar graphs (e, g~i) connect or show the sample mean, respectively, and the P-value is indicated. Two-way ANOVA using Sidac's post-hoc multiple comparison tests (b, c, d, f) or two-tailed t-tests (e, g). [Figure 2-8]This shows the prophylactic efficacy of orally administered compound 1. 2a: Schematic diagram of the prophylactic efficacy study design. 2b: Viral titer from nasal lavage fluid. LoD, limit of detection. 2c: Temperature measurements collected once daily. 2d: Body weight measured once daily. 2e: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 2f: SARS-CoV-2 RNA copies present in nasal lavage fluid. 2g: SARS-CoV-2 RNA copies detected in nasal turbinates. 2h~2i: SARS-CoV-2 infected particles (h) and SARS-CoV-2 RNA copies (i) in the lungs 4 days after infection. The number of independent biological replicates (individual animals) is shown in each subpanel, the symbols represent independent biological replicates, the lines (b, c, d, f) and bar graphs (e, g~i) connect or show the sample mean, respectively, and the P-value is indicated. Two-way ANOVA using Sidac's post-hoc multiple comparison tests (b, c, d, f) or two-tailed t-tests (e, g). [Figure 2-9] This shows the prophylactic efficacy of orally administered compound 1. 2a: Schematic diagram of the prophylactic efficacy study design. 2b: Viral titer from nasal lavage fluid. LoD, limit of detection. 2c: Temperature measurements collected once daily. 2d: Body weight measured once daily. 2e: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 2f: SARS-CoV-2 RNA copies present in nasal lavage fluid. 2g: SARS-CoV-2 RNA copies detected in nasal turbinates. 2h~2i: SARS-CoV-2 infected particles (h) and SARS-CoV-2 RNA copies (i) in the lungs 4 days after infection. The number of independent biological replicates (individual animals) is shown in each subpanel, the symbols represent independent biological replicates, the lines (b, c, d, f) and bar graphs (e, g~i) connect or show the sample mean, respectively, and the P-value is indicated. Two-way ANOVA using Sidac's post-hoc multiple comparison tests (b, c, d, f) or two-tailed t-tests (e, g).

[0010] [Figure 3-1]This study demonstrates the therapeutic efficacy of orally administered compound 1 against SARS-CoV-2 in ferrets. 3a: Schematic diagram of the therapeutic efficacy study design. 3b: Viral titer from nasal lavage fluid. 3c: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 3d: Temperature measurements collected once daily. 3e: Body weight measured once daily. 3f: SARS-CoV-2 RNA copies present in nasal lavage fluid. 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 show the sample means, respectively, and P-values ​​are indicated. One-way (c, g) or two-way (b, d, e, f) ANOVA using Dunnett's (b, d, e, f) post-hoc multiple comparison test. [Figure 3-2] This study demonstrates the therapeutic efficacy of orally administered compound 1 against SARS-CoV-2 in ferrets. 3a: Schematic diagram of the therapeutic efficacy study design. 3b: Viral titer from nasal lavage fluid. 3c: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 3d: Temperature measurements collected once daily. 3e: Body weight measured once daily. 3f: SARS-CoV-2 RNA copies present in nasal lavage fluid. 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 show the sample means, respectively, and P-values ​​are indicated. One-way (c, g) or two-way (b, d, e, f) ANOVA using Dunnett's (b, d, e, f) post-hoc multiple comparison test. [Figure 3-3]This study demonstrates the therapeutic efficacy of orally administered compound 1 against SARS-CoV-2 in ferrets. 3a: Schematic diagram of the therapeutic efficacy study design. 3b: Viral titer from nasal lavage fluid. 3c: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 3d: Temperature measurements collected once daily. 3e: Body weight measured once daily. 3f: SARS-CoV-2 RNA copies present in nasal lavage fluid. 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 show the sample means, respectively, and P-values ​​are indicated. One-way (c, g) or two-way (b, d, e, f) ANOVA using Dunnett's (b, d, e, f) post-hoc multiple comparison test. [Figure 3-4] This study demonstrates the therapeutic efficacy of orally administered compound 1 against SARS-CoV-2 in ferrets. 3a: Schematic diagram of the therapeutic efficacy study design. 3b: Viral titer from nasal lavage fluid. 3c: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 3d: Temperature measurements collected once daily. 3e: Body weight measured once daily. 3f: SARS-CoV-2 RNA copies present in nasal lavage fluid. 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 show the sample means, respectively, and P-values ​​are indicated. One-way (c, g) or two-way (b, d, e, f) ANOVA using Dunnett's (b, d, e, f) post-hoc multiple comparison test. [Figure 3-5]This study demonstrates the therapeutic efficacy of orally administered compound 1 against SARS-CoV-2 in ferrets. 3a: Schematic diagram of the therapeutic efficacy study design. 3b: Viral titer from nasal lavage fluid. 3c: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 3d: Temperature measurements collected once daily. 3e: Body weight measured once daily. 3f: SARS-CoV-2 RNA copies present in nasal lavage fluid. 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 show the sample means, respectively, and P-values ​​are indicated. One-way (c, g) or two-way (b, d, e, f) ANOVA using Dunnett's (b, d, e, f) post-hoc multiple comparison test. [Figure 3-6] This study demonstrates the therapeutic efficacy of orally administered compound 1 against SARS-CoV-2 in ferrets. 3a: Schematic diagram of the therapeutic efficacy study design. 3b: Viral titer from nasal lavage fluid. 3c: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 3d: Temperature measurements collected once daily. 3e: Body weight measured once daily. 3f: SARS-CoV-2 RNA copies present in nasal lavage fluid. 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 show the sample means, respectively, and P-values ​​are indicated. One-way (c, g) or two-way (b, d, e, f) ANOVA using Dunnett's (b, d, e, f) post-hoc multiple comparison test. [Figure 3-7]This study demonstrates the therapeutic efficacy of orally administered compound 1 against SARS-CoV-2 in ferrets. 3a: Schematic diagram of the therapeutic efficacy study design. 3b: Viral titer from nasal lavage fluid. 3c: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 3d: Temperature measurements collected once daily. 3e: Body weight measured once daily. 3f: SARS-CoV-2 RNA copies present in nasal lavage fluid. 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 show the sample means, respectively, and P-values ​​are indicated. One-way (c, g) or two-way (b, d, e, f) ANOVA using Dunnett's (b, d, e, f) post-hoc multiple comparison test.

[0011] [Figure 4-1]This shows that orally administered compound 1 blocks the replication and transmission of SARS-CoV-2 VoC BZ / 2021. 4a: Schematic diagram of the efficacy and contact transmission test design. 4b: Viral titer from nasal lavage. 4c: SARS-CoV-2 RNA copies present in nasal lavage. 4d: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 4e: SARS-CoV-2 RNA copies detected in nasal turbinates. 4f: Infectious titer of SARS-CoV-2 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 shown in each subpanel. Symbols represent independent biological replicates, lines (b, c) and bar graphs (d, e, f, g, h) connect or show the sample mean, respectively, and the P-value is indicated. One-way (d,e) or two-way (b,c) ANOVA using Tukey's (d,e) or Sidac's (b,c) post-hoc multiple comparison tests. 4h: Metagenomic sequencing analysis of inoculated WA1 / 2020 and BZ / 2021 viruses, viral populations extracted from ferret nasal turbinates 4 days after infection, and BZ / 2021 populations extracted from nasal lavage fluid of contact animals of vehicle-treated source animals. Relative allele frequencies of signature residues are shown. Symbols represent independent biological repeats (viral populations of individual animals), and columns show group means. [Figure 4-2]This shows that orally administered compound 1 blocks the replication and transmission of SARS-CoV-2 VoC BZ / 2021. 4a: Schematic diagram of the efficacy and contact transmission test design. 4b: Viral titer from nasal lavage. 4c: SARS-CoV-2 RNA copies present in nasal lavage. 4d: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 4e: SARS-CoV-2 RNA copies detected in nasal turbinates. 4f: Infectious titer of SARS-CoV-2 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 shown in each subpanel. Symbols represent independent biological replicates, lines (b, c) and bar graphs (d, e, f, g, h) connect or show the sample mean, respectively, and the P-value is indicated. One-way (d,e) or two-way (b,c) ANOVA using Tukey's (d,e) or Sidac's (b,c) post-hoc multiple comparison tests. 4h: Metagenomic sequencing analysis of inoculated WA1 / 2020 and BZ / 2021 viruses, viral populations extracted from ferret nasal turbinates 4 days after infection, and BZ / 2021 populations extracted from nasal lavage fluid of contact animals of vehicle-treated source animals. Relative allele frequencies of signature residues are shown. Symbols represent independent biological repeats (viral populations of individual animals), and columns show group means. [Figure 4-3]This shows that orally administered compound 1 blocks the replication and transmission of SARS-CoV-2 VoC BZ / 2021. 4a: Schematic diagram of the efficacy and contact transmission test design. 4b: Viral titer from nasal lavage. 4c: SARS-CoV-2 RNA copies present in nasal lavage. 4d: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 4e: SARS-CoV-2 RNA copies detected in nasal turbinates. 4f: Infectious titer of SARS-CoV-2 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 shown in each subpanel. Symbols represent independent biological replicates, lines (b, c) and bar graphs (d, e, f, g, h) connect or show the sample mean, respectively, and the P-value is indicated. One-way (d,e) or two-way (b,c) ANOVA using Tukey's (d,e) or Sidac's (b,c) post-hoc multiple comparison tests. 4h: Metagenomic sequencing analysis of inoculated WA1 / 2020 and BZ / 2021 viruses, viral populations extracted from ferret nasal turbinates 4 days after infection, and BZ / 2021 populations extracted from nasal lavage fluid of contact animals of vehicle-treated source animals. Relative allele frequencies of signature residues are shown. Symbols represent independent biological repeats (viral populations of individual animals), and columns show group means. [Figure 4-4]This shows that orally administered compound 1 blocks the replication and transmission of SARS-CoV-2 VoC BZ / 2021. 4a: Schematic diagram of the efficacy and contact transmission test design. 4b: Viral titer from nasal lavage. 4c: SARS-CoV-2 RNA copies present in nasal lavage. 4d: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 4e: SARS-CoV-2 RNA copies detected in nasal turbinates. 4f: Infectious titer of SARS-CoV-2 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 shown in each subpanel. Symbols represent independent biological replicates, lines (b, c) and bar graphs (d, e, f, g, h) connect or show the sample mean, respectively, and the P-value is indicated. One-way (d,e) or two-way (b,c) ANOVA using Tukey's (d,e) or Sidac's (b,c) post-hoc multiple comparison tests. 4h: Metagenomic sequencing analysis of inoculated WA1 / 2020 and BZ / 2021 viruses, viral populations extracted from ferret nasal turbinates 4 days after infection, and BZ / 2021 populations extracted from nasal lavage fluid of contact animals of vehicle-treated source animals. Relative allele frequencies of signature residues are shown. Symbols represent independent biological repeats (viral populations of individual animals), and columns show group means. [Figure 4-5]This shows that orally administered compound 1 blocks the replication and transmission of SARS-CoV-2 VoC BZ / 2021. 4a: Schematic diagram of the efficacy and contact transmission test design. 4b: Viral titer from nasal lavage. 4c: SARS-CoV-2 RNA copies present in nasal lavage. 4d: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 4e: SARS-CoV-2 RNA copies detected in nasal turbinates. 4f: Infectious titer of SARS-CoV-2 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 shown in each subpanel. Symbols represent independent biological replicates, lines (b, c) and bar graphs (d, e, f, g, h) connect or show the sample mean, respectively, and the P-value is indicated. One-way (d,e) or two-way (b,c) ANOVA using Tukey's (d,e) or Sidac's (b,c) post-hoc multiple comparison tests. 4h: Metagenomic sequencing analysis of inoculated WA1 / 2020 and BZ / 2021 viruses, viral populations extracted from ferret nasal turbinates 4 days after infection, and BZ / 2021 populations extracted from nasal lavage fluid of contact animals of vehicle-treated source animals. Relative allele frequencies of signature residues are shown. Symbols represent independent biological repeats (viral populations of individual animals), and columns show group means. [Figure 4-6]This shows that orally administered compound 1 blocks the replication and transmission of SARS-CoV-2 VoC BZ / 2021. 4a: Schematic diagram of the efficacy and contact transmission test design. 4b: Viral titer from nasal lavage. 4c: SARS-CoV-2 RNA copies present in nasal lavage. 4d: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 4e: SARS-CoV-2 RNA copies detected in nasal turbinates. 4f: Infectious titer of SARS-CoV-2 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 shown in each subpanel. Symbols represent independent biological replicates, lines (b, c) and bar graphs (d, e, f, g, h) connect or show the sample mean, respectively, and the P-value is indicated. One-way (d,e) or two-way (b,c) ANOVA using Tukey's (d,e) or Sidac's (b,c) post-hoc multiple comparison tests. 4h: Metagenomic sequencing analysis of inoculated WA1 / 2020 and BZ / 2021 viruses, viral populations extracted from ferret nasal turbinates 4 days after infection, and BZ / 2021 populations extracted from nasal lavage fluid of contact animals of vehicle-treated source animals. Relative allele frequencies of signature residues are shown. Symbols represent independent biological repeats (viral populations of individual animals), and columns show group means. [Figure 4-7]This shows that orally administered compound 1 blocks the replication and transmission of SARS-CoV-2 VoC BZ / 2021. 4a: Schematic diagram of the efficacy and contact transmission test design. 4b: Viral titer from nasal lavage. 4c: SARS-CoV-2 RNA copies present in nasal lavage. 4d: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 4e: SARS-CoV-2 RNA copies detected in nasal turbinates. 4f: Infectious titer of SARS-CoV-2 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 shown in each subpanel. Symbols represent independent biological replicates, lines (b, c) and bar graphs (d, e, f, g, h) connect or show the sample mean, respectively, and the P-value is indicated. One-way (d,e) or two-way (b,c) ANOVA using Tukey's (d,e) or Sidac's (b,c) post-hoc multiple comparison tests. 4h: Metagenomic sequencing analysis of inoculated WA1 / 2020 and BZ / 2021 viruses, viral populations extracted from ferret nasal turbinates 4 days after infection, and BZ / 2021 populations extracted from nasal lavage fluid of contact animals of vehicle-treated source animals. Relative allele frequencies of signature residues are shown. Symbols represent independent biological repeats (viral populations of individual animals), and columns show group means. [Figure 4-8-1]This shows that orally administered compound 1 blocks the replication and transmission of SARS-CoV-2 VoC BZ / 2021. 4a: Schematic diagram of the efficacy and contact transmission test design. 4b: Viral titer from nasal lavage. 4c: SARS-CoV-2 RNA copies present in nasal lavage. 4d: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 4e: SARS-CoV-2 RNA copies detected in nasal turbinates. 4f: Infectious titer of SARS-CoV-2 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 shown in each subpanel. Symbols represent independent biological replicates, lines (b, c) and bar graphs (d, e, f, g, h) connect or show the sample mean, respectively, and the P-value is indicated. One-way (d,e) or two-way (b,c) ANOVA using Tukey's (d,e) or Sidac's (b,c) post-hoc multiple comparison tests. 4h: Metagenomic sequencing analysis of inoculated WA1 / 2020 and BZ / 2021 viruses, viral populations extracted from ferret nasal turbinates 4 days after infection, and BZ / 2021 populations extracted from nasal lavage fluid of contact animals of vehicle-treated source animals. Relative allele frequencies of signature residues are shown. Symbols represent independent biological repeats (viral populations of individual animals), and columns show group means. [Figure 4-8-2]This shows that orally administered compound 1 blocks the replication and transmission of SARS-CoV-2 VoC BZ / 2021. 4a: Schematic diagram of the efficacy and contact transmission test design. 4b: Viral titer from nasal lavage. 4c: SARS-CoV-2 RNA copies present in nasal lavage. 4d: Infectious titer of SARS-CoV-2 in nasal turbinates collected 4 days after infection. 4e: SARS-CoV-2 RNA copies detected in nasal turbinates. 4f: Infectious titer of SARS-CoV-2 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 shown in each subpanel. Symbols represent independent biological replicates, lines (b, c) and bar graphs (d, e, f, g, h) connect or show the sample mean, respectively, and the P-value is indicated. One-way (d,e) or two-way (b,c) ANOVA using Tukey's (d,e) or Sidac's (b,c) post-hoc multiple comparison tests. 4h: Metagenomic sequencing analysis of inoculated WA1 / 2020 and BZ / 2021 viruses, viral populations extracted from ferret nasal turbinates 4 days after infection, and BZ / 2021 populations extracted from nasal lavage fluid of contact animals of vehicle-treated source animals. Relative allele frequencies of signature residues are shown. Symbols represent independent biological repeats (viral populations of individual animals), and columns show group means.

[0012] [Figure 5] This shows the clinical signs in source animals and contact animals infected with BZ / 2021. 5a: Temperature measurements collected once daily. 5b: Body weight measured once daily.

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

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

[0015] [Figure 8] This study demonstrates that orally administered compound 1 reduces the final SARS-CoV-2 infectivity titer in the lungs of mice.

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

[0017] [Figure 10] The XRPD pattern of free base form I of compound 15 is shown.

[0018] [Figure 11] The DSC thermogram of free base form I of compound 15 is shown.

[0019] [Figure 12] The TGA thermogram of compound 15 in free base form I is shown.

[0020] [Figure 13] The XRPD pattern of free base form II of compound 15 is shown.

[0021] [Figure 14] The DSC thermogram of compound 15 in free base form II is shown.

[0022] [Figure 15] The TGA thermogram of compound 15 in free base form II is shown.

[0023] [Figure 16] The XRPD pattern of free base form III of compound 15 is shown.

[0024] [Figure 17] The DSC thermogram of compound 15 in free base form III is shown.

[0025] [Figure 18] The TGA thermogram of compound 15 in free base form III is shown.

[0026] [Figure 19] The XRPD pattern of compound 15 xinafoate material A is shown.

[0027] [Figure 20] The DSC thermogram of compound 15 xinafoate material A is shown.

[0028] [Figure 21] The TGA thermogram of compound 15 xinafoate material A is shown.

[0029] [Figure 22] The XRPD pattern of compound 15 in HCl salt form I is shown.

[0030] [Figure 23]The DSC thermogram of compound 15 in HCl salt form I is shown.

[0031] [Figure 24] The TGA thermogram of compound 15 in HCl salt form I is shown.

[0032] [Figure 25] The XRPD pattern of material A, the HCl salt of compound 15, is shown.

[0033] [Figure 26] The DSC thermogram of material A, the HCl salt of compound 15, is shown.

[0034] [Figure 27] The TGA thermogram of material A, the HCl salt of compound 15, is shown.

[0035] [Figure 28] The XRPD pattern of material B, the HCl salt of compound 15, is shown.

[0036] [Figure 29] The DSC thermogram of material B, the HCl salt of compound 15, is shown.

[0037] [Figure 30] The TGA thermogram of material B, the HCl salt of compound 15, is shown.

[0038] [Figure 31] The XRPD pattern of material C, a HCl salt of compound 15, is shown.

[0039] [Figure 32] The DSC thermogram of compound 15's HCl salt material C is shown.

[0040] [Figure 33] The TGA thermogram of material C, the HCl salt of compound 15, is shown. [Modes for carrying out the invention]

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

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

[0043] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. For example, an alkyl group consists of 1 to 20 carbon atoms (i.e., C1 to C2). 20The alkyl group may have 1 to 8 carbon atoms (i.e., C1 to C8 alkyl), 1 to 6 carbon atoms (i.e., C1 to C6 alkyl), or 1 to 3 carbon atoms (i.e., C1 to C3 alkyl). Suitable examples of 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), and 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 2-methyl-1-butyl(-CH2CH2CH(CH3)2), 1-hexyl(-CH2CH2CH2CH2CH2CH3), 2-hexyl(-CH(CH3)CH2CH2CH2CH3), 3-hexyl(-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl(-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl(-CH(CH3)CH( Examples include, but are not limited to, CH3)CH2CH3), 4-methyl-2-pentyl(-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl(-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl(-CH(CH2CH3)CH(CH3)2), and 2,3-dimethyl-2-butyl(-C(CH3)2CH(CH3)2) and 3,3-dimethyl-2-butyl(-CH(CH3)C(CH3)3).

[0044] "Alkenyl" contains at least one carbon-carbon double bond and 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 This refers to an aliphatic group containing an alkenyl group. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

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

[0046] A "haloalkyl" is an alkyl group defined above in which one or more hydrogen atoms of the alkyl group are replaced by halogen atoms. The alkyl portion of a haloalkyl group consists of 1 to 20 carbon atoms (i.e., C1 to C2). 20 Haloalkyl), 1 to 12 carbon atoms (i.e., C1 to C 12 The haloalkyl group may have 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, and -CH2CF3.

[0047] The term "aryl" refers to an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom in an aromatic ring system. For example, an aryl group may 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 benzenes, naphthalenes, anthracenes, and biphenyls.

[0048] "Heteroaryl" refers to an aromatic group having a monocyclic, polycyclic, or fused polycyclic structure with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryls include 1 to 20 ring atoms (i.e., 1 to 20-membered heteroaryls), 3 to 12 ring atoms (i.e., 3 to 12-membered heteroaryls), 3 to 8 carbocyclic atoms (3 to 8-membered heteroaryls), or 5 to 6 ring atoms (5 to 6-membered heteroaryls). Examples of heteroaryl groups include pyrimidinyl, prinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryls do not include aryl as defined above, and do not overlap with aryl.

[0049] A "carbocyclyl" or "carbocyclic ring" refers to a non-aromatic hydrocarbon ring composed of carbon and hydrogen atoms, having 3 to 20 carbon atoms, in certain embodiments 3 to 15 carbon atoms, in certain embodiments 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 bonded to the rest of the molecule by single bonds. 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 monocyclic or polycyclic structures, including condensed ring systems, crosslinked ring systems, and spirocyclic systems. As used herein, cycloalkyl has 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 (Cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0051] The term "optionally substituted" (e.g., optionally substituted aryl group) with respect to a particular part of a compound of formula I means that all substituents are hydrogen atoms, or that one or more of the hydrogen atoms of the part are listed substituents.

[0052] Unless otherwise specified, the carbon atoms in compounds of formula I are intended to have a valency of 4. In some chemical structural representations where there are not enough variables for the carbon atom to produce a valency of 4, it should be assumed that the remaining carbon substituent needed to provide a valency of 4 is hydrogen.

[0053] As used herein, the term “to treat” means, unless otherwise indicated, to reverse, alleviate, inhibit the progression of, or prevent one or more symptoms of the disorder or condition to which such term applies. As used herein, the term “treatment” means the act of treating, as “to treat” is defined immediately before it.

[0054] "Prevention" or "prevention" means any treatment of a disease or condition that prevents the development of clinical symptoms of the disease or condition. The compounds and compositions disclosed herein may, in some embodiments, be administered to subjects (including humans) at risk of having a disease or condition. As used herein, the terms “prevention” and “prevention” encompass administering a compound, composition, or pharmaceutically acceptable salt according to the embodiments disclosed herein before an individual is exposed to a virus, or after exposure but before symptoms of viral infection appear and / or before the virus is detected in the blood. The term also means preventing the appearance of symptoms of a disease and / or preventing the virus from reaching detectable levels in the blood. The term includes pre-exposure prophylaxis (PrEP), as well as post-exposure prophylaxis (PEP) and event-driven or “on-demand” prophylaxis. This includes both. These terms also refer to preventing perinatal transmission of the virus from mother to infant by administering it to the mother before birth and to the child within a few days of birth. This term also refers to preventing transmission of the virus through blood transfusions.

[0055] As used herein, the term “therapeutic dose” means the amount of the compound of Formula I used herein required to deliver a desired level of the drug to the secretions and airway and lung tissues of the subject, or alternatively, to the bloodstream of the subject being treated, thereby producing an expected physiological response or desired biological effect when such a composition is administered via a selected route of administration. The exact amount depends on a number of factors, such as the specific 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 collaboration, and can be readily determined by a person skilled in the art based on the information provided herein.

[0056] "DSC" stands for Differential Scanning Calorimetry.

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

[0058] "TGA" refers to thermogravimetric analysis.

[0059] The term "substantially as shown herein" includes, for example, XRPD patterns, DSC thermograms, or TGA graphs, which do not necessarily have to be identical to those shown herein, but which, as considered by those skilled in the art, fall within the limits of experimental error or deviation.

[0060] A "protecting group" refers to a part of a compound that shields or alters the properties of a functional group or the compound as a whole. The chemical structures of protecting groups vary considerably. One function of protecting groups is to act as intermediates in the synthesis of the parent drug substance. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See "Organic Chemistry," Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991). Also see "Protective Groups in Organic Chemistry," Peter GMWuts and Theodora W. Greene, 4th Ed., 2006. Protecting groups are often used to shield the reactivity of a particular functional group, thereby assisting the effectiveness of a desired chemical reaction, for example, to create and break chemical bonds regularly and systematically. Protecting a functional group of a compound alters other physical properties of the protected functional group besides its reactivity, such as polarity, lipophilicity (hydrophobicity), and other properties that can be measured by common analytical tools. Chemically protected intermediates may be biologically active or inactive themselves. "Hydroxy protecting group" refers to a protecting group that is useful for protecting a hydroxyl group (-OH).

[0061] A "deprotecting agent" refers to any chemical that can remove 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 GMWuts and Theodora W. Greene, 4th Ed., 2006. III.Compound

[0062] Any reference to the compounds of the present invention described herein also includes references to their pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts of the compounds of the present invention include alkali metals or alkaline earth elements (e.g., Na + Li + , K + Ca +2 , and Mg +2 ), ammonium and NR4 + Examples of salts derived from suitable bases such as (wherein R is defined herein) include: (a) acid addition salts formed from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; and (b) for example, 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, and p-toluenesulfone. Examples include (c) salts formed from organic acids such as acids, benzenesulfonic 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 from elemental anions such as chlorine, bromine, and iodine. Examples of pharmaceutically acceptable salts of compounds with a hydroxyl group include Na + and NR4 + Examples include anions of the above compounds combined with suitable cations such as the following.

[0063] The compounds disclosed herein (e.g., compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb) and their pharmaceutically acceptable salts may exist as different polymorphs or pseudopolymorphs. As used herein, crystalline polymorphism means the ability of a crystalline compound to exist in different crystalline structures. Crystalline polymorphism may arise from differences in crystalline packing (packing polymorphism) or from differences in packing between different conformational isomers (conformational polymorphisms) of the same molecule. As used herein, crystalline pseudopolymorphism means the ability of a compound's hydrate or solvate to exist in different crystalline structures. Pseudopolymorphisms of the present invention may exist due to differences in crystalline packing (packing pseudopolymorphism) or from differences in packing between different conformational isomers (conformational pseudopolymorphisms) of the same molecule. The present invention comprises all polymorphs and pseudopolymorphs of 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 their pharmaceutically acceptable salts may also exist as amorphous solids. As used herein, an amorphous solid is a solid that lacks long-range order in the positions of atoms within the solid. This definition also applies when the crystal size is 2 nanometers or less. Amorphous forms of the present invention can be prepared using additives containing solvents. The present invention comprises all amorphous forms of the compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, and their pharmaceutically acceptable salts.

[0065] For therapeutic purposes, 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 pharmaceutically unacceptable acids or bases may also find uses, for example, in the preparation or purification of pharmaceutically acceptable compounds. All salts, whether derived from pharmaceutically acceptable acids or bases or not, are within the scope of the present invention.

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

[0067] It should be noted that all enantiomers, diastereomers, and racemic mixtures, tautomers, polymorphs, pseudopolymorphs, and pharmaceutically acceptable salts thereof of compounds within the range of formulas I, II, III, IV, V, Va, Vb, VI, VIa, or VIb 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 formulas I, II, III, IV, V, Va, Vb, VI, Via, or VIb, may have a chiral center, such as a chiral carbon or phosphorus atom. Therefore, the compounds of the present invention include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. In addition, the compounds of the present invention include optical isomers concentrated or decomposed into any or all asymmetric chiral atoms. In other words, chiral centers evident from the description are provided as chiral isomers or racemic mixtures. Both racemic mixtures and diastereomer mixtures, as well as individual isolated or synthesized optical isomers substantially free of their enantiomer or diastereomer partners, are all within the scope of the present invention. Racemic mixtures can be separated into their individual substantially optically pure isomers by appropriate techniques, such as the separation of diastereomer salts formed with an optical activity enhancer, e.g., an acid or base, followed by the reverse conversion to an optically active substance. In most cases, the desired optical isomer is synthesized by stereospecific reactions starting from a suitable stereoisomer of the desired starting material.

[0069] The stereochemical definitions and rules used herein generally follow those of SP. 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. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to its chiral center. The prefixes d and l, D and L, or (+) and (-) are used to indicate the rotation of plane-polarized light by the compound, and S, (-), or 1 means that the compound is levorotatory, while compounds with the prefixes R, (+), or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical to each other except that they are mirror images of each other. Certain stereoisomers may be called enantiomers, and mixtures of such isomers are often called enantiomer mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can result when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to equimolar mixtures of two enantiomer species that lack 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 described, all such forms are intended within the scope of the present invention. For example, en-amine tautomers may exist for purines, pyrimidines, imidazoles, guanidines, amidines, and tetrazoles, and all of their possible tautomers are within the scope of the present invention.

[0071] Any formula or structure given herein, including compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb, is also intended to represent the unlabeled and isotope-labeled forms of the compounds. The isotope-labeled compounds have the structure represented by the formulas given 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 the compounds of this 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 Isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as I, are included, but are not limited to these. Various isotope-labeled compounds of this disclosure include, for example, 3 H, 13 C and 14 These are compounds that incorporate radioactive isotopes such as 13C. Such isotope-labeled compounds are used in metabolic studies, reaction kinetic studies, positron emission tomography (PET), and single-photon emission computed tomography (SMT) including drug or substrate tissue distribution assays. In detection or imaging techniques such as tomography and SPECT, or in the radiation therapy of patients It may be useful in medical treatment.

[0072] This disclosure also includes compounds of formula I, in which 1 to x hydrogens bonded to a carbon atom are exchanged by deuterium, where x is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful in extending the half-life of any compound of formula I when administered to mammals, particularly humans. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). In consideration of this disclosure, such compounds are synthesized by means known in the art, for example, by using starting materials in which one or more hydrogens are exchanged by deuterium.

[0073] The deuterium-labeled or deuterium-substituted therapeutic compounds of this disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may result in certain therapeutic benefits due to greater metabolic stability, e.g., increased half-life in vivo, reduced dosage requirements, and / or improved therapeutic index. 18 1F-labeled compounds may be useful in PET or SPECT testing. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by substituting readily available isotope-labeling reagents with non-isotope-labeling reagents, by performing the procedures disclosed in the scheme or the examples and preparations described below. In this context, deuterium is understood to be a substituent in the compounds of formula I.

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

[0075] Whenever a compound described herein is substituted with, for example, more than one of the same groups denoting "R" or "R", it will be understood that the groups may be the same or different, that is, each group is selected independently.

[0076] Wavy Line [ka] This indicates the site of covalent bonding to adjacent substructures, groups, parts, or atoms. IV.Compound

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

Chemical

[0078] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, the base is [ka] And in the formula, R 11 It is -CH2OP(O)(OH)2. In some embodiments, Base is [ka] And in the formula, R 11 is a C1-C6 alkyl group substituted with -OP(O)(OH)2. In some embodiments, the base is [ka] And in the formula, R 11 It is -CH2OP(O)(OH)2. In some embodiments, Base is [ka] And in the formula, R 11 is a C1-C6 alkyl group substituted with -OP(O)(OH)2. In some embodiments, the base is [ka] And in the formula, R 11 This is -CH2OP(O)(OH)2. In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, the base is [ka] That is the case.

[0079] In some embodiments, formula I is a compound of formula Ia. [ka]

[0080] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, R 3 COR 7 Or COOR 7 And in the formula, R 7 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyryl, and C6-C 10 A 5-6 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, O, and S, R 7 The base is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , and optionally substituted with one, two, or three substituents 3 COR 7 Or COOR 7 And in the formula, R 7 These are C1-C8 alkyl, C3-C8 carbocyric, and C6-C10 A 5-6 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, O, and S, R 7 The base is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , and optionally substituted with one, two, or three substituents 3 COR 7 Or COOR 7 And in the formula, R 7 R is a C1-C8 alkyl or C3-C8 carbocyric, 7 The base is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , and optionally substituted with one, two, or three substituents 3 COR 7 Or COOR 7 And in the formula, R 7 These are halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , and C1-C8 alkyl groups optionally substituted with one, two, or three substituents optionally substituted with phenyl 3 COR 7 Or COOR 7 And in the formula, R 7 These are halogen, cyano, -N3, -OR 8 , -NR 9 R 10, and C1-C4 alkyl groups optionally substituted with one, two, or three substituents optionally substituted with phenyl groups optionally substituted with one, two, or three substituents optionally substituted with halo, cyano, and C1-C6 alkyl groups. In some embodiments, R 9 and R 10 Both are H.

[0081] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, R 3 COR 7 Or COOR 7 And in the formula, R 7 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyryl, and C6-C 10 A 5-6 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, O, and S, R 7 The base is -NR 9 R 10 , and optionally substituted with one, two, or three substituents 3 COR 7 Or COOR 7 And in the formula, R 7 These are C1-C8 alkyl, C3-C8 carbocyric, and C6-C 10 A 5-6 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, O, and S, R 7 The base is -NR 9 R 10 , and optionally substituted with one, two, or three substituents 3 COR 7 Or COOR 7And in the formula, R 7 R is a C1-C8 alkyl or C3-C8 carbocyric, 7 The base is -NR 9 R 10 , and optionally substituted with one, two, or three substituents 3 COR 7 Or COOR 7 And in the formula, R 7 -NR 9 R 10 , and C1-C8 alkyl groups optionally substituted with one, two, or three substituents optionally substituted with phenyl 3 COR 7 Or COOR 7 And in the formula, R 7 -NR 9 R 10 , and C1-C4 alkyl groups optionally substituted with one, two, or three substituents optionally substituted with phenyl groups optionally substituted with one, two, or three substituents optionally substituted with halo, cyano, and C1-C6 alkyl groups. In some embodiments, R 9 and R 10 Both are H.

[0082] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, R 3 COR 7 Or COOR 7 And in the formula, R 7 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyryl, and C6-C 10 A 5-6 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, O, and S, R7 The base is -NR 9 R 10 It is optionally substituted with one, two, or three substituents independently selected from the group consisting of and phenyl. In some embodiments, R 3 COR 7 Or COOR 7 And in the formula, R 7 These are C1-C8 alkyl, C3-C8 carbocyric, and C6-C 10 A 5-6 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, O, and S, R 7 The base is -NR 9 R 10 It is optionally substituted with one, two, or three substituents independently selected from the group consisting of and phenyl. In some embodiments, R 3 COR 7 Or COOR 7 And R 7 R is a C1-C8 alkyl or C3-C8 carbocyric, 7 The base is -NR 9 R 10 It is optionally substituted with one, two, or three substituents independently selected from the group consisting of and phenyl. In some embodiments, R 3 COR 7 Or COOR 7 And R 7 -NR 9 R 10 A C1-C8 alkyl group optionally substituted with one, two, or three substituents independently selected from the group consisting of and phenyl. In some embodiments, R 3 COR 7 Or COOR 7 And R 7 -NR 9 R 10 A C1-C4 alkyl group optionally substituted with one, two, or three substituents independently selected from the group consisting of and phenyl. In some embodiments, R 9 and R 10 Both are H.

[0083] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, R 3 COR 7 Or COOR 7 And in the formula, R 7 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyryl, and C6-C 10 It is a 5-6 membered heteroaryl containing an aryl or one, two, or three heteroatoms selected from N, O, and S. In some embodiments, R 3 COR 7 Or COOR 7 And in the formula, R 7 These are C1-C8 alkyl, C3-C8 carbocyric, and C6-C 10 It is a 5-6 membered heteroaryl containing an aryl or one, two, or three heteroatoms selected from N, O, and S. In some embodiments, R 3 COR 7 Or COOR 7 And in the formula, R 7 is a C1-C8 alkyl or C3-C8 carbocyric. In some embodiments, R 3 COR 7 Or COOR 7 And in the formula, R 7 is a C1-C8 alkyl group. In some embodiments, R 3 COR 7 Or COOR 7 And in the formula, R 7 These are C1-C4 alkyl groups.

[0084] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, R 3 COR 7 Or COOR 7 And in the formula, R 7 -CH3, -CH2CH3, [ka] Selected from the group consisting of R 3 COR 7 Or COOR 7 And in the formula, R 7 -CH3, -CH2CH3, [ka] Selected from the group consisting of R 3 COR 7 Or COOR 7 And in the formula, R 7 -CH3, -CH2CH3, [ka] It is selected from the group consisting of the following.

[0085] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, R 3 COR 7 And in the formula, R 7 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyryl, and C6-C 10 A 5-6 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, O, and S, R 7 The bases are halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , and optionally substituted with one, two, or three substituents 3 COR 7 And in the formula, R 7 These are C1-C8 alkyl, C3-C8 carbocyric, and C6-C 10A 5-6 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, O, and S, R 7 The bases are halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , and optionally substituted with one, two, or three substituents 3 COR 7 And in the formula, R 7 R is a C1-C8 alkyl or C3-C8 carbocyric, 7 The bases are halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , and optionally substituted with one, two, or three substituents 3 COR 7 And in the formula, R 7 These are halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , and C1-C8 alkyl groups optionally substituted with one, two, or three substituents optionally substituted with phenyl 3 COR 7 And in the formula, R 7 These are halogen, cyano, -N3, -OR 8 , -NR 9 R 10, and C1-C4 alkyl groups optionally substituted with one, two, or three substituents optionally substituted with phenyl groups optionally substituted with one, two, or three substituents optionally substituted with halo, cyano, and C1-C6 alkyl groups. In some embodiments, R 9 and R 10 Both are H.

[0086] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, R 3 COR 7 And in the formula, R 7 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyryl, and C6-C 10 A 5-6 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, O, and S, R 7 The base is -NR 9 R 10 , and optionally substituted with one, two, or three substituents 3 COR 7 And in the formula, R 7 These are C1-C8 alkyl, C3-C8 carbocyric, and C6-C 10 A 5-6 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, O, and S, R 7 The base is -NR 9 R 10 , and optionally substituted with one, two, or three substituents 3 COR 7 And in the formula, R 7 R is a C1-C8 alkyl or C3-C8 carbocyric, 7The base is -NR 9 R 10 , and optionally substituted with one, two, or three substituents 3 COR 7 And in the formula, R 7 -NR 9 R 10 , and C1-C8 alkyl groups optionally substituted with one, two, or three substituents optionally substituted with phenyl 3 COR 7 And in the formula, R 7 -NR 9 R 10 , and C1-C4 alkyl groups optionally substituted with one, two, or three substituents optionally substituted with phenyl groups optionally substituted with one, two, or three substituents optionally substituted with halo, cyano, and C1-C6 alkyl groups. In some embodiments, R 9 and R 10 Both are H.

[0087] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, R 3 COR 7 And in the formula, R 7 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyryl, and C6-C 10 A 5-6 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, O, and S, R 7 The base is -NR 9 R 10 It is optionally substituted with one, two, or three substituents independently selected from the group consisting of and phenyl. In some embodiments, R 3 COR7 And in the formula, R 7 These are C1-C8 alkyl, C3-C8 carbocyric, and C6-C 10 A 5-6 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, O, and S, R 7 The base is -NR 9 R 10 It is optionally substituted with one, two, or three substituents independently selected from the group consisting of and phenyl. In some embodiments, R 3 COR 7 And R 7 R is a C1-C8 alkyl or C3-C8 carbocyric, 7 The base is -NR 9 R 10 It is optionally substituted with one, two, or three substituents independently selected from the group consisting of and phenyl. In some embodiments, R 3 COR 7 And R 7 -NR 9 R 10 A C1-C8 alkyl group optionally substituted with one, two, or three substituents independently selected from the group consisting of and phenyl. In some embodiments, R 3 COR 7 And R 7 -NR 9 R 10 A C1-C4 alkyl group optionally substituted with one, two, or three substituents independently selected from the group consisting of and phenyl. In some embodiments, R 9 and R 10 Both are H.

[0088] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, R 3 COR 7 And in the formula, R 7 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyryl, and C6-C 10It is a 5-6 membered heteroaryl containing an aryl or one, two, or three heteroatoms selected from N, O, and S. In some embodiments, R 3 COR 7 And in the formula, R 7 These are C1-C8 alkyl, C3-C8 carbocyric, and C6-C 10 It is a 5-6 membered heteroaryl containing an aryl or one, two, or three heteroatoms selected from N, O, and S. In some embodiments, R 3 COR 7 And in the formula, R 7 is a C1-C8 alkyl or C3-C8 carbocyric. In some embodiments, R 3 COR 7 And in the formula, R 7 is a C1-C8 alkyl group. In some embodiments, R 3 COR 7 And in the formula, R 7 These are C1-C4 alkyl groups.

[0089] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, R 3 COR 7 And in the formula, R 7 -CH3, -CH2CH3, [ka] Selected from the group consisting of R 3 COR 7 And in the formula, R 7 -CH3, -CH2CH3, [ka] It is selected from the group consisting of the following.

[0090] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, R3 COOR 7 And in the formula, R 7 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyryl, and C6-C 10 A 5-6 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, O, and S, R 7 The base is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , and optionally substituted with one, two, or three substituents 3 COOR 7 And in the formula, R 7 These are C1-C8 alkyl, C3-C8 carbocyric, and C6-C 10 A 5-6 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, O, and S, R 7 The base is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , and optionally substituted with one, two, or three substituents 3 COOR 7 And in the formula, R 7 R is a C1-C8 alkyl or C3-C8 carbocyric, 7 The base is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , and optionally substituted with one, two, or three substituents3 COOR 7 And in the formula, R 7 These are halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , and C1-C8 alkyl groups optionally substituted with one, two, or three substituents optionally substituted with phenyl 3 COOR 7 And in the formula, R 7 These are halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , and C1-C4 alkyl groups optionally substituted with one, two, or three substituents optionally substituted with phenyl groups optionally substituted with one, two, or three substituents optionally substituted with halo, cyano, and C1-C6 alkyl groups. In some embodiments, R 9 and R 10 Both are H.

[0091] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, R 3 COOR 7 And in the formula, R 7 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyryl, and C6-C 10 A 5-6 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, O, and S, R 7 The base is -NR 9 R 10 , and optionally substituted with one, two, or three substituents 3 COOR 7 And in the formula, R 7These are C1-C8 alkyl, C3-C8 carbocyric, and C6-C 10 A 5-6 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, O, and S, R 7 The base is -NR 9 R 10 , and optionally substituted with one, two, or three substituents 3 COOR 7 And in the formula, R 7 R is a C1-C8 alkyl or C3-C8 carbocyric, 7 The base is -NR 9 R 10 , and optionally substituted with one, two, or three substituents 3 COOR 7 And in the formula, R 7 -NR 9 R 10 , and C1-C8 alkyl groups optionally substituted with one, two, or three substituents optionally substituted with phenyl 3 COOR 7 And in the formula, R 7 -NR 9 R 10 , and C1-C4 alkyl groups optionally substituted with one, two, or three substituents optionally substituted with phenyl groups optionally substituted with one, two, or three substituents optionally substituted with halo, cyano, and C1-C6 alkyl groups. In some embodiments, R 9 and R 10 Both are H.

[0092] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, R 3 COOR 7 And in the formula, R 7 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyryl, and C6-C 10 A 5-6 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, O, and S, R 7 The base is -NR 9 R 10 It is optionally substituted with one, two, or three substituents independently selected from the group consisting of and phenyl. In some embodiments, R 3 COOR 7 And in the formula, R 7 These are C1-C8 alkyl, C3-C8 carbocyric, and C6-C 10 A 5-6 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, O, and S, R 7 The base is -NR 9 R 10 It is optionally substituted with one, two, or three substituents independently selected from the group consisting of and phenyl. In some embodiments, R 3 COOR 7 And R 7 R is a C1-C8 alkyl or C3-C8 carbocyric, 7 The base is -NR 9 R 10 It is optionally substituted with one, two, or three substituents independently selected from the group consisting of and phenyl. In some embodiments, R 3 COOR 7 And R 7 -NR 9 R 10 A C1-C8 alkyl group optionally substituted with one, two, or three substituents independently selected from the group consisting of and phenyl. In some embodiments, R 3 COOR 7 And R 7-NR 9 R 10 A C1-C4 alkyl group optionally substituted with one, two, or three substituents independently selected from the group consisting of and phenyl. In some embodiments, R 9 and R 10 Both are H.

[0093] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, R 3 COOR 7 And in the formula, R 7 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyryl, and C6-C 10 It is a 5-6 membered heteroaryl containing an aryl or one, two, or three heteroatoms selected from N, O, and S. In some embodiments, R 3 COOR 7 And in the formula, R 7 These are C1-C8 alkyl, C3-C8 carbocyric, and C6-C 10 It is a 5-6 membered heteroaryl containing an aryl or one, two, or three heteroatoms selected from N, O, and S. In some embodiments, R 3 COOR 7 And in the formula, R 7 is a C1-C8 alkyl or C3-C8 carbocyric. In some embodiments, R 3 COOR 7 And in the formula, R 7 is a C1-C8 alkyl group. In some embodiments, R 3 COOR 7 And in the formula, R 7 These are C1-C4 alkyl groups.

[0094] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, R 3 COOR 7 And in the formula, R 7 -CH3, -CH2CH3, [ka] Selected from the group consisting of R 3 COOR 7 And in the formula, R 7 -CH3, -CH2CH3, [ka] It is selected from the group consisting of the following.

[0095] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts 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 OH and R 2 OH, OCOR 5 , or OC(O)OR 5 In some embodiments, R 1 OH and R 2 OCOR 5 Or OC(O)OR 5 In some embodiments, R 1 OH and R 2 OCOR 5 In some embodiments, R 1 OH and R 2 , OC(O)OR 5 That is the case.

[0096] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts 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 , OC(O)OR 4 And R 2 It is OH.

[0097] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts 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 , OC(O)OR 4 And R 2 OCOR 5 Or OC(O)OR 5 That is the case.

[0098] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts 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 , OC(O)OR 5 That is the case.

[0099] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, R 1OCOR 4 And R 2 OCOR 5 In some embodiments, R 1 OCOR 4 And R 2 , OC(O)OR 5 That is the case.

[0100] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, R 1 , OC(O)OR 4 And R 2 OCOR 5 In some embodiments, R 1 , OC(O)OR 4 And R 2 , OC(O)OR 5 That is the case.

[0101] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, R 4 and R 5 Each of these is independently a C1-C8 alkyl group. In some embodiments, R 4 and R 5 Each of these is independently a C1-C6 alkyl group. In some embodiments, R 4 and R 5 Each of these is independently a C1-C3 alkyl group. In some embodiments, R 4 and R 5 These are, independently, methyl, ethyl, or isopropyl.

[0102] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, R 1 OH, OCOR 4 , or OC(O)OR 4 And R 2 OH, OCOR 5 , or OC(O)OR 5 And in the formula, R 4 and R 5 Each of these is independently a C1-C8 alkyl group. In some embodiments, R1 OH, OCOR 4 , or OC(O)OR 4 And R 2 OH, OCOR 5 , or OC(O)OR 5 And in the formula, R 4 and R 5 Each of these is independently a C1-C6 alkyl group. In some embodiments, R 1 OH, OCOR 4 , or OC(O)OR 4 And R 2 OH, OCOR 5 , or OC(O)OR 5 And in the formula, R 4 and R 5 Each of these is independently a C1-C3 alkyl group. In some embodiments, R 1 OH, OCOR 4 , or OC(O)OR 4 And R 2 OH, OCOR 5 , or OC(O)OR 5 And in the formula, R 4 and R 5 These are, independently, methyl, ethyl, or isopropyl.

[0103] In some embodiments, R 1 OH and R 2 OH, OCOR 5 , or OC(O)OR 5 And in the formula, R 5 is a C1-C8 alkyl group. In some embodiments, R 1 OH and R 2 OH, OCOR 5 , or OC(O)OR 5 And in the formula, R 5 is a C1-C6 alkyl group. In some embodiments, R 1 OH and R 2 OH, OCOR 5 , or OC(O)OR 5 And in the formula, R 5is a C1-C3 alkyl group. In some embodiments, R 1 OH and R 2 OH, OCOR 5 , or OC(O)OR 5 And in the formula, R 5 It is methyl, ethyl, or isopropyl.

[0104] In some embodiments, R 1 OH and R 2 OCOR 5 Or OC(O)OR 5 And in the formula, R 5 is a C1-C8 alkyl group. In some embodiments, R 1 OH and R 2 OCOR 5 Or OC(O)OR 5 And in the formula, R 5 is a C1-C6 alkyl group. In some embodiments, R 1 OH and R 2 OCOR 5 Or OC(O)OR 5 And in the formula, R 5 is a C1-C3 alkyl group. In some embodiments, R 1 OH and R 2 OCOR 5 Or OC(O)OR 5 And in the formula, R 5 It is methyl, ethyl, or isopropyl.

[0105] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, R 1 OH, OCOR 4 , or OC(O)OR 4 And R 2 OH is OH, and in the formula, R 4 is a C1-C8 alkyl group. In some embodiments, R 1 OH, OCOR 4 , or OC(O)OR 4 And R 2 OH is OH, and in the formula, R4 is a C1-C6 alkyl group. In some embodiments, R 1 OH, OCOR 4 , or OC(O)OR 4 And R 2 OH is OH, and in the formula, R 4 is a C1-C3 alkyl group. In some embodiments, R 1 OH, OCOR 4 , or OC(O)OR 4 And R 2 OH is OH, and in the formula, R 4 It is methyl, ethyl, or isopropyl.

[0106] In some embodiments, R 1 OCOR 4 , or OC(O)OR 4 And R 2 OH is OH, and in the formula, R 4 is a C1-C8 alkyl group. In some embodiments, R 1 OCOR 4 , or OC(O)OR 4 And R 2 OH is OH, and in the formula, R 4 is a C1-C6 alkyl group. In some embodiments, R 1 OCOR 4 , or OC(O)OR 4 And R 2 OH is OH, and in the formula, R 4 is a C1-C3 alkyl group. In some embodiments, R 1 OCOR 4 , or OC(O)OR 4 And R 2 OH is OH, and in the formula, R 4 It is methyl, ethyl, or isopropyl.

[0107] In some embodiments, R 1 OCOR 4 And R 2 OH is OH, and in the formula, R 4 is a C1-C8 alkyl group. In some embodiments, R1 OCOR 4 And R 2 OH is OH, and in the formula, R 4 is a C1-C6 alkyl group. In some embodiments, R 1 OCOR 4 And R 2 OH is OH, and in the formula, R 4 is a C1-C3 alkyl group. In some embodiments, R 1 OCOR 4 And R 2 OH is OH, and in the formula, R 4 It is methyl, ethyl, or isopropyl.

[0108] In some embodiments, R 1 , OC(O)OR 4 And R 2 OH is OH, and in the formula, R 4 is a C1-C8 alkyl group. In some embodiments, R 1 , OC(O)OR 4 And R 2 OH is OH, and in the formula, R 4 is a C1-C6 alkyl group. In some embodiments, R 1 , OC(O)OR 4 And R 2 OH is OH, and in the formula, R 4 is a C1-C3 alkyl group. In some embodiments, R 1 , OC(O)OR 4 And R 2 OH is OH, and in the formula, R 4 It is methyl, ethyl, or isopropyl.

[0109] Compounds of formula I or Ia, in some embodiments, R 1 OCOR 4 Or OC(O)OR 4 And R 2 OCOR 5 Or OC(O)OR 5 And in the formula, R 4 and R 5Each of these is independently a C1-C8 alkyl group. In some embodiments, R 1 OCOR 4 Or OC(O)OR 4 And R 2 OCOR 5 Or OC(O)OR 5 And in the formula, R 4 and R 5 Each of these is independently a C1-C6 alkyl group. In some embodiments, R 1 OCOR 4 Or OC(O)OR 4 And R 2 OCOR 5 Or OC(O)OR 5 And in the formula, R 4 and R 5 Each of these is independently a C1-C3 alkyl group. 1 OCOR 4 Or OC(O)OR 4 And R 2 OCOR 5 Or OC(O)OR 5 And in the formula, R 4 and R 5 These are, independently, methyl, ethyl, or isopropyl.

[0110] In some embodiments, R 1 OCOR 4 And R 2 OCOR 5 Or OC(O)OR 5 And in the formula, R 4 and R 5 Each of these is independently a C1-C8 alkyl group. In some embodiments, R 1 OCOR 4 And R 2 OCOR 5 Or OC(O)OR 5 And in the formula, R 4 and R 5 Each of these is independently a C1-C6 alkyl group. In some embodiments, R 1 OCOR 4 And R 2OCOR 5 Or OC(O)OR 5 And in the formula, R 4 and R 5 Each of these is independently a C1-C3 alkyl group. In some embodiments, R 1 OCOR 4 And R 2 OCOR 5 Or OC(O)OR 5 And in the formula, R 4 and R 5 These are, independently, methyl, ethyl, or isopropyl.

[0111] In some embodiments, R 1 , OC(O)OR 4 And R 2 OCOR 5 Or OC(O)OR 5 And in the formula, R 4 and R 5 Each of these is independently a C1-C8 alkyl group. In some embodiments, R 1 , OC(O)OR 4 And R 2 OCOR 5 Or OC(O)OR 5 And in the formula, R 4 and R 5 Each of these is independently a C1-C6 alkyl group. In some embodiments, R 1 , OC(O)OR 4 And R 2 OCOR 5 Or OC(O)OR 5 And in the formula, R 4 and R 5 Each of these is independently a C1-C3 alkyl group. In some embodiments, R 1 , OC(O)OR 4 And R 2 OCOR 5 Or OC(O)OR 5 And in the formula, R 4 and R 5 These are, independently, methyl, ethyl, or isopropyl.

[0112] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, R 1 OCOR 4 Or OC(O)OR 4 And R 2 OCOR 5 And in the formula, R 4 and R 5 Each of these is independently a C1-C8 alkyl group. In some embodiments, R 1 OCOR 4 Or OC(O)OR 4 And R 2 OCOR 5 And in the formula, R 4 and R 5 Each of these is independently a C1-C6 alkyl group. In some embodiments, R 1 OCOR 4 Or OC(O)OR 4 And R 2 OCOR 5 And in the formula, R 4 and R 5 Each of these is independently a C1-C3 alkyl group. In some embodiments, R 1 OCOR 4 Or OC(O)OR 4 And R 2 OCOR 5 And in the formula, R 4 and R 5 These are, independently, methyl, ethyl, or isopropyl.

[0113] In some embodiments, R 1 OCOR 4 Or OC(O)OR 4 And R 2 , OC(O)OR 5 And in the formula, R 4 and R 5 Each of these is independently a C1-C8 alkyl group. In some embodiments, R 1 OCOR 4 Or OC(O)OR 4 And R 2is OC(O)OR 5 and, in the formula, R 4 and R 5 are each independently C1-C6 alkyl. In some embodiments, R 1 is OCOR 4 or OC(O)OR 4 and, R 2 is OC(O)OR 5 and, in the formula, R 4 and R 5 are each independently C1-C3 alkyl. In some embodiments, R 1 is OCOR 4 or OC(O)OR 4 and, R 2 is OC(O)OR 5 and, in the formula, 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 is OCOR 4 and, R 2 is OCOR 5 and, in the formula, R 4 and R 5 are each independently C1-C8 alkyl. In some embodiments, R 1 is OCOR 4 and, R 2 is OCOR 5 and, in the formula, R 4 and R 5 are each independently C1-C6 alkyl. In some embodiments, R 1 is OCOR 4 and, R 2 is OCOR 5 and, in the formula, R 4 and R 5 are each independently C1-C3 alkyl. In some embodiments, R 1 is OCOR 4 and, R 2 is OCOR 5 and, in the formula, R4 and R 5 These are, independently, methyl, ethyl, or isopropyl.

[0115] In some embodiments, R 1 OCOR 4 And R 2 , OC(O)OR 5 And in the formula, R 4 and R 5 Each of these is independently a C1-C8 alkyl group. In some embodiments, R 1 OCOR 4 And R 2 , OC(O)OR 5 And in the formula, R 4 and R 5 Each of these is independently a C1-C6 alkyl group. In some embodiments, R 1 OCOR 4 And R 2 , OC(O)OR 5 And in the formula, R 4 and R 5 Each of these is independently a C1-C3 alkyl group. In some embodiments, R 1 OCOR 4 And R 2 , OC(O)OR 5 And in the formula, R 4 and R 5 These are, independently, methyl, ethyl, or isopropyl.

[0116] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, R 1 , OC(O)OR 4 And R 2 OCOR 5 And in the formula, R 4 and R 5 Each of these is independently a C1-C8 alkyl group. In some embodiments, R 1 , OC(O)OR 4 And R 2 OCOR 5 And in the formula, R 4 and R5 are each independently C1-C6 alkyl. In some embodiments, R 1 is OC(O)OR 4 and R 2 is OCOR 5 wherein 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 OCOR 5 wherein 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 wherein 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 wherein 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 wherein 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 wherein R 4 and R 5 are each independently methyl, ethyl or isopropyl.

[0118] Compounds of formula I or Ia, in some embodiments, R 6 H, C1-C3 alkyl or C6-C 10 It is an arrow. 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 It is an arrow. In some embodiments, R 6 It is phenyl.

[0119] Compounds of formula I or Ia, in some embodiments, R 1 and R 2 These two combine to form -OC(O)O- or -OCHR 6 Forms O-, and in the formula, R 6 is H, C1-C6 alkyl or C6-C 10 It is an arrow. In some embodiments, R 1 and R 2 These two combine to form -OC(O)O- or -OCHR 6 Forms O-, and in the formula, R 6 H, C1-C3 alkyl or C6-C 10 It is an arrow. In some embodiments, R 1 and R 2 These two combine to form -OC(O)O- or -OCHR 6 Forms O-, and in the formula, R 6 is H, C1-C6 alkyl, or phenyl. In some embodiments, R 1 and R 2 These two combine to form -OC(O)O- or -OCHR 6 Forms O-, and in the formula, R 6 is H, C1-C3 alkyl, or phenyl. In some embodiments, R 1 and R 2 These two combine to form -OC(O)O- or -OCHR 6 Forms O-, and in the formula, R 6 C6~C 10 It is an arrow. In some embodiments, R 1and R 2 These two combine to form -OC(O)O- or -OCHR 6 Forms O-, and in the formula, R 6 It is phenyl.

[0120] Compounds of formula I or Ia, in some embodiments, R 1 and R 2 They came together, -OCHR 6 Forms O-, and in the formula, R 6 is H, C1-C6 alkyl or C6-C 10 It is an arrow. In some embodiments, R 1 and R 2 They came together, -OCHR 6 Forms O-, and in the formula, R 6 H, C1-C3 alkyl or C6-C 10 It is an arrow. In some embodiments, R 1 and R 2 They came together, -OCHR 6 Forms O-, and in the formula, R 6 C6~C 10 It is an arrow. In some embodiments, R 1 and R 2 They came together, -OCHR 6 Forms O-, and in the formula, R 6 It is phenyl.

[0121] Compounds of formula I or Ia, in some embodiments, R 1 and R 2 They combine to form -OC(O)O-.

[0122] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, R 3 H is R 1 OCOR 4 , or OC(O)OR 4 In some embodiments, R 3 H is R 2 OCOR 5 , or OC(O)OR 5In some embodiments, R 3 H is R 1 and R 2 These two combine to form -OC(O)O- or -OCHR 6 Forms O-. In some embodiments, R 3 H is R 1 and R 2 They combine to form -OC(O)O-. In some embodiments, R 3 H is R 1 and R 2 They came together, -OCHR 6 Forms O-, and in the formula, R 6 is H, C1-C6 alkyl or C6-C 10 It is an arrow. In some embodiments, R 3 H is R 1 and R 2 They came together, -OCHR 6 Forms O-, and in the formula, R 6 H, C1-C3 alkyl or C6-C 10 It is an arrow. In some embodiments, R 3 H is R 1 and R 2 They came together, -OCHR 6 Forms O-, and in the formula, R 6 is H, C1-C6 alkyl, or phenyl. In some embodiments, R 3 H is R 1 and R 2 They came together, -OCHR 6 Forms O-, and in the formula, R 6 is H, C1-C3 alkyl, or phenyl. In some embodiments, R 3 H is R 1 and R 2 They came together, -OCHR 6 Forms O-, and in the formula, R 6 C6~C 10 It is an arrow. In some embodiments, R 3 H is R 1 and R 2 They came together, -OCHR 6Forms O-, and in the formula, R 6 It is phenyl.

[0123] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, each R 8 R is independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, each R 8 R is independently H or C1-C6 alkyl. In some embodiments, each R 8 R is independently H or C1-C3 alkyl. In some embodiments, each R 8 H is H.

[0124] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, each R 9 R is independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, each R 9 R is independently H or C1-C6 alkyl. In some embodiments, each R 9 R is independently H or C1-C3 alkyl. In some embodiments, each R 9 H is H.

[0125] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, each R 10 R is independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, each R 10 R is independently H or C1-C6 alkyl. In some embodiments, each R 10 R is independently H or C1-C3 alkyl. In some embodiments, each R 10 H is H.

[0126] In some embodiments of compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, each R 8 , R 9 and R 10 H is H.

[0127] In some embodiments of the compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, the compound is [ka] [ka] It is selected from the group consisting of the following.

[0128] In some embodiments of the compounds of formula I or Ia, or pharmaceutically acceptable salts thereof, the compound is [ka] That is the case.

[0129] In some embodiments of the compounds of formulas I and Ia, or their pharmaceutically acceptable salts, the compounds are: [ka] [ka] It is selected from the group consisting of the following.

[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]triazine-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (hereinafter, "reference compound A") (compound 13 described in International Publication No. 2009132135, compound 4 described in J.Med.Chem. 2017, 60, 1648-1661). Although not intended to be bound by any particular operating theory, the compounds of formula I and Ia are thought to be metabolized to reference compound A in vivo. In some embodiments, when administered orally, the compounds of formula I or Ia result in an increase in the bioavailability of reference compound A. In some embodiments, when administered orally, the compounds of formula I or Ia result in an increase of at least 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 25, or 30 times the bioavailability of reference compound A. [ka] V. Pharmaceutical preparations

[0131] The compounds disclosed herein can be formulated with conventional carriers and excipients. For example, tablets may contain excipients, lubricants, fillers, binders, etc. Aqueous formulations are generally isotonic when prepared in a sterile form and intended for delivery by means other than oral administration. All formulations may optionally contain excipients, such as those described in the "Handbook of Pharmaceutical Excipients" (1986). Examples of excipients 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 is in the range of about 3 to about 11, but is usually about 7 to 10. In some embodiments, the pH of the formulations is in the range of about 2 to about 5, but is usually about 3 to 4.

[0132] While the compounds of this disclosure ("active ingredients") can be administered alone, it may be preferable to present them as pharmaceutical formulations. Formulations for both animal and human use of the present invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers and optionally other additional therapeutic ingredients, in particular additional therapeutic active ingredients discussed herein. The carriers must be "acceptable" in the sense that they are compatible with the other components of the formulation and are physiologically harmless to their recipient.

[0133] The formulations include those suitable for the aforementioned routes of administration. The formulations may conveniently be presented in unit dosage forms and may be prepared by any suitable method known in the field of pharmacy. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods involve the step of associating the active ingredient with a carrier constituting one or more minor components. Generally, formulations are prepared by homogeneously and closely associating the active ingredient with a liquid carrier, a fine solid carrier, or both, and then, if necessary, shaping the product.

[0134] In some embodiments, the compounds of formula I or Ia described herein, or their pharmaceutically acceptable salts, 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 separate units such as capsules, cachetes, or tablets, each containing a predetermined amount of the active ingredient; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil liquid emulsions. The active ingredient may also be administered as a bolus, lick, or paste.

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

[0137] For infections of the eyes or other external tissues, such as the mouth and skin, the formulation is applied as a topical ointment or cream containing, for example, 0.075 to 20% by weight (containing active ingredient in the range of 0.1% to 20% in increments such as 0.1% by weight, 0.6% by weight, 0.7% by weight, etc.), preferably 0.2 to 15% by weight, and most preferably 0.5 to 10% by weight of the active ingredient. When formulated as an ointment, the active ingredient may be used with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream having an oil-in-water cream base.

[0138] If desired, the aqueous phase of the cream base may include, for example, at least 30% by weight of polyhydric alcohols, i.e., alcohols 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 preferably include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected area. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0139] The oily phase of the emulsion of the present invention may consist of known components in known forms. The phase may simply contain an emulsifier (alternatively known as an emulsion), but preferably contains at least one emulsifier and a mixture of fat or oil, or a mixture of both fat and oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferable to include both oil and fat. Together, the emulsifier, with or without a stabilizer, constitutes a so-called emulsifying wax, and the wax, together with the oil and fat, constitutes a so-called emulsifying ointment base that forms the oily dispersion phase of a cream formulation.

[0140] Suitable emulsions and emulsion stabilizers 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. Further suitable emulsions and emulsion stabilizers 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. The cream should preferably be a non-greasy, stain-free, washable product with a suitable consistency to avoid leakage from tubes or other containers. Linear or branched, mono- or dibasic alkyl esters, such as diisoadipates, isocetyl stearate, propylene glycol diesters of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or blends of branched esters known as Crodamol CAP may be used, with the latter three being preferred esters. These may be used alone or in combination, depending on the required properties. Alternatively, high-melting-point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils may be used.

[0142] A pharmaceutical formulation according to the present invention comprises the compound according to the present invention together with one or more pharmaceutically acceptable carriers or excipients and, optionally, other therapeutic agents. The pharmaceutical formulation containing the active ingredient may be in any form suitable for the intended method of administration. For example, when used for oral use, tablets, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs may be prepared. Compositions intended for oral use may 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, in order 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 include, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate 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. The tablets may be uncoated or coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period. For example, time-delaying substances such as glyceryl monostearate or glyceryl distearate may be used alone or with wax.

[0143] Formulations for oral use may also be presented as rigid gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as 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] The aqueous suspension of the present invention contains an active material mixed with excipients suitable for the production of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum, as well as dispersants or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxides and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxides and partial esters derived from fatty acids, and hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, 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 cases, the suspension agent is sulfobutyl ether β-cyclodextrin (SEB-β-CD), such as Captisol®.

[0145] Oil suspensions can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. Oral suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavorings as described above can be added to provide an oral preparation with a pleasant mouthfeel. These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0146] The dispersible powders and granules of the present invention, suitable for preparing aqueous suspensions by the addition of water, provide active ingredients when mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, such as sweeteners, flavoring agents, and colorants, may also be present.

[0147] The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oil phase may 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 soy lecithin, esters or partial esters derived from fatty acids, and hexitol anhydrides such as sorbitan monooleate, as well as condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweeteners and flavorings. Syrups and elixirs may be formulated with sweeteners such as glycerol, sorbitol, or sucrose. Such formulations may also contain lubricants, preservatives, flavorings, or colorings.

[0148] The pharmaceutical compositions of the present invention may be in the form of sterile injection preparations, such as sterile aqueous or oily suspensions for sterile injection. These suspensions may be formulated according to known techniques using the preferred dispersants or wetting agents and suspending agents described above. The sterile injection preparations may also be sterile injection solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as a solution in 1,3-butane-diol, or they may be prepared as lyophilized powders. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixative oils may conventionally be used as solvents or suspension media. For this purpose, any solvent-free fixative oil containing synthetic monoglycerides or diglycerides may be used. Furthermore, fatty acids such as oleic acid may also be used in the preparation of injections. Acceptable vehicles and solvents that may be used include 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 to produce a single dosage form will vary depending on the host being treated and the specific 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 combined with a suitable and convenient amount of carrier, which can vary from approximately 5 to approximately 95% (by weight) of the total composition. Pharmaceutical compositions can be prepared to provide an amount that is easily measurable for administration. For example, an aqueous solution intended for intravenous infusion may contain approximately 3 to 500 μg of active ingredient per milliliter of solution to allow for the injection of a suitable volume at a rate of approximately 30 mL / hour.

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

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

[0152] Formulations for rectal administration may be presented as suppositories having a suitable base, for example, containing cocoa butter or salicylate.

[0153] In some embodiments, the compounds disclosed herein are administered by inhalation. In some embodiments, formulations suitable for intrapulmonary or nasal administration have particle sizes, for example, in the range of 0.1 to 500 micrometers, such as 0.5, 1, 30, 35, and are administered by rapid inhalation through the nasal route 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 can be delivered together with other therapeutic agents. In some embodiments, the compounds used herein are formulated and administered as dry powder. In some embodiments, the compounds used herein are formulated and administered as a spray formulation. In some embodiments, the compounds used herein are formulated for delivery by face mask. In some embodiments, the compounds used herein are formulated for delivery by face tent.

[0154] Formulations suitable for intravaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations, each containing an active ingredient and a carrier known to be suitable in the art.

[0155] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile infusion solutions that may contain antioxidants, buffers, bacteriostads, and solutes to make the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners.

[0156] The formulations are presented in unit dose or multi-dose containers, such as sealed ampoules and vials, and can be stored in a freeze-dried state requiring only the addition of a sterile liquid carrier, such as sterile water for injection, immediately before use. Immediate injection solutions and suspensions are prepared from the sterile powders, granules, and tablets of the types described above. Preferred unit dose formulations contain the daily dose or unit daily subdose of the active ingredient as listed above herein, or appropriate fractions thereof.

[0157] In addition to the components specifically mentioned above, please understand that the formulations of the present invention may include other conventional drugs in the art with respect to the type of formulation in question, and for example, those suitable for oral administration may include flavoring agents.

[0158] The present invention further provides a veterinary composition comprising at least one of the above-mentioned active ingredients, as defined together with a veterinary carrier therefor.

[0159] Veterinary carriers are substances useful for administering compositions, and may be solid, liquid, or gaseous substances that are inert or acceptable in veterinary technology 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 of the compounds of the present invention as active ingredients, in which the release of the active ingredient is controlled and regulated to enable less frequent administration or to improve the pharmacokinetic or toxicity profile of a given active ingredient. VI. Kit

[0161] This specification also provides kits comprising the compounds disclosed herein, pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, or tautomers. In some embodiments, the kits described herein may include labels and / or instructions for use for the use of the compounds in the treatment of a disease or condition in a subject (e.g., a human) that requires them. In some embodiments, the disease or condition is a viral infection.

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

[0163] In some embodiments, the kits provided herein contain individual unit doses of the compound described herein, or pharmaceutically acceptable salts, racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs, amorphous forms, hydrates, or solvates. Examples of individual dose units include pills, tablets, capsules, pre-filled syringes, or syringe cartridges, IV bags, inhalers, nebulizers, etc., each of which may contain a therapeutically effective dose of the compound in question, or pharmaceutically acceptable salts, racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs, amorphous forms, hydrates, or solvates. In some embodiments, the kits may consist of a single dose unit and several other dose units, such as the number of dose units required for a particular regimen or period.

[0164] Products comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof, and a container are also provided. In some embodiments, the container for the product may be a vial, a bottle, an ampoule, a pre-filled syringe, a blister package, a tin can, a bottle, a box, an intravenous bag, an inhaler, or a sprayer. VII. Administration

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

[0166] In the present invention's method for treating a viral infection, the compounds of the present invention may be administered at any time to a person who may have been in contact with the virus or who is already suffering from the viral infection. In some embodiments, the compounds of the present invention may be administered prophylactically to a person who has been in contact with a person suffering from a viral infection or who is at risk of being in contact with a person suffering from a viral infection, such as a healthcare provider. In some embodiments, the administration of the compounds of the present invention may be 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 administration of the compounds of the present invention may be to a person at the onset of symptoms of a 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 terms “event-driven” or “event-driven administration” refer to the administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, (1) before an event that exposes an individual to the virus (or otherwise increases the risk of an individual becoming infected with the virus) (e.g., 2 hours, 1 day, 2 days, 5 days, or 7 days or more before the event), and / or (2) during an event (or two or more recurring events) that exposes an individual to the virus (or otherwise increases the risk of an individual becoming infected with the virus), and / or (3) after an event (or after the last event in a series of recurring events) that exposes an individual to the virus (or otherwise increases the risk of an individual becoming infected with the virus). In some embodiments, event-driven administration is performed before exposure to the virus of interest. In some embodiments, event-driven administration is performed after exposure to the virus of interest. In some embodiments, event-driven administration is performed both before and after exposure to the virus of interest.

[0169] In certain embodiments, the methods disclosed herein include administering, for example, pre-exposure prophylaxis (PrEP) and / or post-exposure prophylaxis (PEP) before and / or after an event that exposes an individual to the virus or an event that otherwise increases the risk of an individual becoming infected with the virus. 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 exposure to the virus in question.

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

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

[0173] An example of an event-driven dosing regimen includes administering compound I or a pharmaceutically acceptable salt thereof within 24 hours to 2 hours prior to exposure to the virus, followed by administration of compound I or a pharmaceutically acceptable salt thereof every 24 hours during the exposure period, followed by further administration of compound I or a pharmaceutically acceptable salt thereof after the last exposure, and finally one more administration of compound I or a pharmaceutically acceptable salt thereof 24 hours later.

[0174] Further examples of event-driven dosing regimens include administering a compound of formula I, or a pharmaceutically acceptable salt thereof, within 24 hours prior to exposure to the virus, followed by daily administration during the exposure period, and then a final dose (which may be an increased dose, such as a double dose) approximately 24 hours after the last exposure.

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

[0176] The daily dose may also be described as the total amount of the compound described herein administered per single dose or per day. The daily dose of the 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 the compounds disclosed herein may be adjusted throughout the course of treatment at the discretion of the administering physician.

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

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

[0180] The compounds of this disclosure can be combined with one or more additional therapeutic agents at any dose of the compounds of this disclosure (e.g., 1 mg to 1000 mg of the compounds). The therapeutically effective dose may include approximately 0.1 mg to approximately 1000 mg per dose, for example, approximately 50 mg to approximately 500 mg per dose, or for example, approximately 100 mg to approximately 400 mg per dose, or for example, approximately 150 mg to approximately 350 mg per dose, or for example, approximately 200 mg to approximately 300 mg per dose, or for example, approximately 0.01 mg to approximately 1000 mg per dose, or for example, approximately 0.01 mg to approximately 100 mg per dose, or for example, approximately 0.1 mg to approximately 100 mg per dose, or for example, approximately 1 mg to approximately 100 mg per dose, or for example, approximately 1 mg to approximately 100 mg per dose. Other therapeutically effective doses of the compound of formula I are approximately 1 mg per dose, or approximately 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 approximately 100 mg per dose. Other therapeutically effective doses of the compounds disclosed herein are approximately 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 approximately 1000 mg per dose.

[0181] In some embodiments, the method comprises administering a target compound provided herein in an initial daily dose of about 1 to 500 mg, and incrementally increasing the dose until clinical efficacy is achieved. The dose can be increased using increments of about 5, 10, 25, 50, or 100 mg. The dose can be increased daily, every day, twice a week, once a week, every two weeks, every three weeks, or once a month.

[0182] When administered orally, the total daily dose for human subjects may be approximately 1-4,000 mg / day, approximately 1-3,000 mg / day, 1-2,000 mg / day, approximately 1-1,000 mg / day, approximately 10-500 mg / day, approximately 50-300 mg / day, approximately 75-200 mg / day, or approximately 100-150 mg / day. In some embodiments, the total daily dose for human subjects may be approximately 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, or 3000 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 200, 300, 400, 500, 600, 700, or 800 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be about 300, 400, 500, or 600 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects 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 dose for human subjects is approximately 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, The dosage may be 1500-2200, 1500-2300, 1500-2400, 1500-2500, 2000-2600, 2000-2700, 2000-2800, 2000-2900, 2000-3000, 2500-3100, 2500-3200, 2500-3300, 2500-3400, 2500-3500, 3000-3600, 3000-3700, 3000-3800, 3000-3900, or 3000-4000 mg / day.

[0183] In some embodiments, the total daily dose for human subjects may be about 100 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be about 150 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be about 200 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be about 250 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be about 300 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be about 350 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be about 400 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be about 450 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be about 500 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 550 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 600 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 650 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 700 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 750 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 800 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 850 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 900 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 950 mg / day administered as a single dose.In some embodiments, the total daily dose for human subjects may be about 1000 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be about 1500 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be about 2000 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be about 2500 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be about 3000 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be about 4000 mg / day administered as 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, or 16 hours, or once every 24 hours. A single dose can also be administered once every 1, 2, 3, 4, 5, or 6 days, or once every 7 days. A single dose can also be administered once every 1, 2, or 3 weeks, or once every 4 weeks. In some embodiments, a single dose may be administered once every week. A single dose can also be administered once every month. In some embodiments, the compounds disclosed herein are administered once daily in the manner disclosed herein. In some embodiments, the compounds disclosed herein are administered twice daily in the manner disclosed herein. In some embodiments, the compounds disclosed herein are administered three times daily in the manner disclosed herein.

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

[0186] The frequency of administration of the compounds disclosed herein is determined by the individual patient's needs and may be, for example, once daily, twice daily, or more. Administration of the compounds is continued for as long as necessary to treat the viral infection. For example, the compounds may be administered to a person infected with a virus over a period of 20 to 180 days, or, for example, 20 to 90 days, or, for example, 30 to 60 days.

[0187] Administration may be intermittent, involving periods of several days or more during which the patient receives a daily dose of the compound, followed by periods of several days or more during which the patient does not receive a daily dose of the compound. For example, a patient may receive a certain dose of the compound every other day or three times per week. As another example, a patient may receive a certain 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 certain dose of the compound, and then for a subsequent period (e.g., 1 to 14 days) during which the patient may again receive a daily dose of the compound. Alternating periods of administration and subsequent non-administration of the compound may be repeated as clinically necessary to treat the patient.

[0188] The compounds or pharmaceutical compositions thereof of this disclosure may be administered once, twice, three times, or four times daily using any preferred form described above. Administration or treatment with the compounds may also be continued for several days; for example, treatment would typically last at least 7, 14, or 28 days for one treatment cycle. Treatment cycles are well known in cancer chemotherapy and frequently alternate with rest periods of approximately 1 to 28 days, generally about 7 or 14 days. Treatment cycles may also be continuous in other embodiments. VIII.How to use

[0189] This disclosure also provides a method for treating or preventing a viral infection in a subject that requires it (e.g., a human), the method comprising administering a compound described herein to the subject.

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

[0191] In some embodiments, the Disclosure provides a method for treating or preventing a viral infection in a subject (e.g., a human) that requires such treatment, comprising administering a compound disclosed herein along with at least one additional active therapeutic agent to the subject.

[0192] In some embodiments, the Disclosure provides a method for treating a viral infection in a subject (e.g., a human) that requires such treatment, comprising administering a compound disclosed herein along with at least one additional active therapeutic agent to the subject.

[0193] In one embodiment, the present disclosure provides a method for inhibiting viral polymerase in cells, wherein virus-infected cells are brought into contact with a compound disclosed herein, thereby inhibiting viral polymerase.

[0194] In one embodiment, the present disclosure provides a method for inhibiting viral polymerase in cells, wherein virus-infected cells are brought into contact with the compounds disclosed herein and at least one additional active therapeutic agent, thereby inhibiting viral polymerase.

[0195] Methods of use of the compounds disclosed herein for use in treating or preventing viral infections in subjects where such treatment is needed are also provided. For example, methods of use of the compounds disclosed herein for use in treating viral infections in subjects where such treatment is needed are provided.

[0196] In some embodiments, the viral infection is a paramyxoviridae virus infection. Accordingly, in some embodiments, the disclosure provides a method for treating a paramyxoviridae virus infection in a subject (e.g., a human) that requires such treatment, the method comprising administering a compound disclosed herein to the subject. Examples of 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 for treating a Pneumoviridae virus infection in a person in need thereof, the method comprising administering a compound provided herein to a person. Examples of Pneumoviridae viruses include, but are not limited to, respiratory syncytial viruses and human metapneumoviruses. 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 compounds disclosed herein for use in treating Pneumoviridae virus infections in humans 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 Disclosure provides a method for treating RSV infection in a person in need thereof, the method comprising administering a compound provided herein to the person. In some embodiments, the person has chronic respiratory syncytial virus infection. In some embodiments, the person has acute RSV infection.

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

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

[0202] In some embodiments, the viral infection is a picornaviridae virus infection. In some embodiments, the disclosure provides a method for treating a picornaviridae virus infection in a person in need thereof, the method comprising administering a compound of the disclosure to a person. Picornaviridae viruses are enteroviruses that cause a mixed group of infections, including herpangina, aseptic meningitis, flu-like syndrome (human rhinovirus infection), nonparalytic polio-like syndrome, epidemic pleuritic pain (an acute, febrile, infectious disease 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 human rhinovirus infection (HRV). In some embodiments, the picornaviridae virus infection is HRV-A, HRV-B, or HRV-C infection.

[0203] In some embodiments, the present disclosure provides compounds for use in treating picornaviridae virus infections in humans in need. In some embodiments, the picornaviridae virus infection is human rhinovirus infection.

[0204] In some embodiments, the viral infection is a flavivirid virus infection. Therefore, in some embodiments, the disclosure provides a method for treating a flavivirid virus infection in a person in need, the method comprising administering a compound described herein to a person. Representative flavivirid viruses include dengue fever, yellow fever, West Nile virus, Zika virus, Japanese encephalitis virus, and hepatitis C (HC). V) is one example, but is not limited to these. In some embodiments, the flaviviridae virus infection is dengue fever virus infection. In some embodiments, the flaviviridae virus infection is yellow fever virus infection. In some embodiments, the flaviviridae virus infection is West Nile fever virus infection. In some embodiments, the flaviviridae virus infection is Zika virus infection. In some embodiments, the flaviviridae virus infection is Japanese encephalitis virus infection. In some embodiments, the flaviviridae virus infection is hepatitis C virus infection.

[0205] In some embodiments, the Disclosure provides the use of the compounds of the Disclosure for the treatment of flavivirid virus infections in humans in need. In some embodiments, the flavivirid virus infection is dengue fever virus infection. In some embodiments, the flavivirid virus infection is yellow fever virus infection. In some embodiments, the flavivirid virus infection is West Nile fever virus infection. In some embodiments, the flavivirid virus infection is Zika virus infection. In some embodiments, the flavivirid virus infection is hepatitis C virus infection.

[0206] In some embodiments, the viral infection is a filoviral virus infection. Accordingly, in some embodiments, this specification provides a method for treating a filoviral virus infection in a person in need, the method comprising administering a compound disclosed herein to the person. Representative filoviral viruses include, but are not limited to, Ebola virus (Zaire, Bundibugyo, Sudan, Taiforest, or Reston variants) and Marburg virus. In some embodiments, the filoviral virus infection is an Ebola virus infection. In some embodiments, the filoviridae virus infection is Marburg virus infection.

[0207] In some embodiments, the present disclosure provides compounds for use in treating filoviral virus infections in humans in need. In some embodiments, the filoviral virus infection is Ebola virus infection. In some embodiments, the filoviral virus infection is Marburg virus infection.

[0208] In some embodiments, the viral infection is a coronavirus infection. Accordingly, in some embodiments, the Specified provides a method for treating a coronavirus infection in a person in need thereof, the method comprising administering a compound provided herein to the person. In some embodiments, the coronavirus infection is severe acute respiratory syndrome (SARS-CoV) infection, Middle East respiratory syndrome (MERS) infection, SARS-CoV-2 infection, other human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infection, or zoonotic coronavirus (PEDV or HKU CoV isolates, e.g., HKU3, HKU5, or HKU9) infection. In some embodiments, the viral infection is severe acute respiratory syndrome (SARS) infection. In some embodiments, the viral infection is Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is 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 SARS-CoV-2 variants, such as the B.1.1.7 variant (UK variant), the B.1.351 variant (South Africa variant), the P.1 variant (Brazil variant), the B.1.1.7 variant 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 present disclosure provides compounds for use in treating coronavirus infections in humans in need. In some embodiments, the coronavirus infection is severe acute respiratory syndrome (SARS) infection, Middle East respiratory syndrome (MERS) infection, SARS-CoV-2 infection, other human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infection, or zoonotic coronavirus (PEDV or HKUCoV isolates, e.g., HKU3, HKU5, or HKU9) infection. In some embodiments, the viral infection is severe acute respiratory syndrome (SARS) infection. In some embodiments, the viral infection is Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is SARS-CoV-2 infection (COVID-19).

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

[0212] In some embodiments, the present disclosure provides compounds for use in treating arenaviridae virus infections in humans in need thereof. In some embodiments, the arenaviridae virus infection is Lassa infection or 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 will be more fully described herein, the compounds described herein can be administered to an individual (e.g., a human) infected with a viral infection, together with one or more additional therapeutic agents. The additional therapeutic agents can be administered to the infected individual simultaneously with the compounds disclosed herein, or before or after administration of the compounds disclosed herein. IX. Combination Therapy

[0215] The compounds described herein can also be used in combination with one or more additional therapeutic agents. Accordingly, methods for treating viral infections in subjects in need thereof are also provided herein, the methods comprising administering the compounds disclosed herein and one or more additional therapeutic agents in therapeutically effective amounts to the subject.

[0216] In some embodiments, additional therapeutic agents include antiviral agents. Any suitable antiviral agent can be used in the method described herein. In some embodiments, the antiviral agent is selected from the group consisting of 5-substituted 2'-deoxyuridine analogs, nucleoside analogs, pyrophosphate analogs, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, entry inhibitors, acyclic guanosine analogs, acyclic nucleoside phosphonate analogs, HCV NS5A / NS5B inhibitors, influenza virus inhibitors, interferons, immunostimulants, oligonucleotides, mitotic inhibitors, and combinations thereof.

[0217] In some embodiments, the additional therapeutic agent is a 5-substituted 2'-deoxyuridine analog. For example, 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) The following are selected from the group consisting of terbivudine, lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate (TDF), and combinations thereof. In some embodiments, additional therapeutic agents are favipiravir, ribavirin, galidesivir, β-D-N4-hydroxycytidine, or combinations 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 phosphonoacetate. In some embodiments, the additional therapeutic agent is foscarnet.

[0220] In some embodiments, additional therapeutic agents are nucleoside reverse transcriptase inhibitors. In some embodiments, antiviral agents include zidovudine, didanosine, zalcitabine, stabudine, lamivudine, abacavir, emtricitabine, and combinations thereof.

[0221] In some embodiments, additional therapeutic agents are non-nucleoside reverse transcriptase inhibitors. In some embodiments, antiviral agents are selected from the group consisting of nevirapine, delaviridine, 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 boxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, ribavirin, danoprevir, faldaprevir, pedroprevir, sobaprevir, deldeprevir, naraprevir, 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, ivalizumab, fostemsavir, leronlimab, ivalizumab, fostemsavir, leronlimab, palivizumab, respiratory syncytial virus immunoglobulin, intravenous [RSV-IGIV], varicella-zoster immunoglobulin [VariZIG], varicella-zoster immunoglobulin [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 valacyclovir), 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-type NS5B polymerase inhibitor. In some embodiments, the additional therapeutic agent is a non-nucleoside-type 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, additional therapeutic agents are 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 interferon. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alphacon 1, interferon alpha 1b, interferon alpha 2a, interferon alpha 2b, pegylated interferon alphacon 1, pegylated interferon alpha 1b, pegylated interferon alpha 2a (PegIFNα-2a), and PegIFNα-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alphacon 1, interferon alpha 1b, interferon alpha 2a, interferon alpha 2b, pegylated interferon alpha 2a (PegIFNα-2a), and PegIFNα-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alphacon 1, pegylated interferon alpha 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 homivirsen, podophyllox, imiquimod, synecatechin, and combinations thereof.

[0231] In some embodiments, additional therapeutic agents are 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, additional therapeutic agents are drugs for the treatment of RSV. For example, in some embodiments, the antiviral agent is ribavirin, ALS-8112, or presatovir.

[0233] In some embodiments, the additional therapeutic agent is a drug for treating picornavirus. In some embodiments, the additional therapeutic agent is selected from the group consisting of hydantoin, guanidine hydrochloride, l-butionine 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 lupintrivir.

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

[0235] In some embodiments, additional therapeutic agents are selected from the group consisting of hydroxychloroquine, chloroquine, artemether, lumefantrine, atovaquone, proguanil, tafenoquine, pyronarizine, artesunate, artenimol, piperaquine, artesunate, amodiaquine, pyronarizine, artesunate, halofantrine, quinine sulfate, mefloquine, solithromycin, pyrimethamine, MMV-390048, ferroquine, artefenomemesylate, ganapraside, DSM-265, sipalgamin, artemison, and combinations thereof.

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

[0237] In some embodiments, additional therapeutic agents are drugs for the treatment of the Ebola virus. For example, in some embodiments, additional therapeutic agents are ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, doronedarone, verapamil, and Ebola convalescent plasma. Plasma, ECP), TKM-100201, BCX4430((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidine-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-dimethylquinolino[8,7- The following are selected from the group consisting of [h]quinolone-1,7-diamine), JK-05, TKM-Ebola, ZMapp, rNAPc2, VRC-EBOADC076-00-VP, OS-2966, MVA-BN Filo, brincidofovir, Vaxart adenovirus vector 5-based Ebola vaccine, Ad26-ZEBOV, FiloVax vaccine, GOVX-E301, GOVX-E302, Ebola virus entry inhibitors (NPC1 inhibitors), rVSV-EBOV, and combinations thereof. In some embodiments, additional therapeutic agents are ZMapp, mAB114, REGEN-EB3, and combinations thereof.

[0238] In some embodiments, the additional therapeutic agent is a drug 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, radarbuvir, 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, boxilaprevir, 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 nucleoside, ARB-199, CCC-0975, ccc-R08, erbucitabine, ezetimibe, cyclosporine A, gentiopicrin (gentiopicroside), HH-003, heparatide, JNJ-56136379, nitazoxanide, virinapant, NJK14047, NOV-205 (molixan, BAM-205), oligotide, mibotylate, Ferron, GST-HG-131, Levamisosol, 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 No. 20150210682 (Roche), No. 2016 / 0122344 (Roche), International Publication No. 2015173164, No. 2016023877, U.S. Patent Application Publication No. 2015252057(A) (Roche), International Examples of compounds disclosed in Publication No. 16128335(A1) (Roche), No. 16120186(A1) (Roche), U.S. Patent Application Publication No. 2016237090(A) (Roche), International Publication No. 16107833(A1) (Roche), No. 16107832(A1) (Roche), U.S. Patent Application Publication No. 2016176899(A) (Roche), International Publication No. 16102438(A1) (Roche), No. 16012470(A1) (Roche), U.S. Patent Application Publication No. 2016220586(A) (Roche), and No. 2015031687(A) (Roche) include, but are not limited to, those disclosed in. In some embodiments, additional therapeutic agents are HBV polymerase inhibitors.Examples 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, bisifovir, and enteca Examples include, but are not limited to, BARACLUDE®, entecavir maleate, terbivudine (TYZEKA®), filosilovir, pradefovir, crevudine, ribavirin, lamivudine (EPIVIR-HBV®), phosphazide, famciclovir, fusolin, metakavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil aspartate, tenofovir disoproxil asparagine orote, and HS-10234. In some embodiments, additional therapeutic agents are HBV capsid inhibitors.

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

[0242] In some embodiments, additional therapeutic agents are selected from the group consisting of HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editing agents (CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), and cell therapies (e.g., chimeric antigen receptor T cells, CAR-T and engineered T cell receptors, TCR-T, autologous T cell therapy).

[0243] In some embodiments, additional therapeutic agents are 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 (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latent infection reactivators, capsid inhibitors, immunotherapy, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and “antibody-like” therapeutic proteins, as well as combinations thereof.

[0244] In some embodiments, additional therapeutic agents are HIV concomitant medications. Examples of HIV concomitant medications include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); BIKTARVY® (bictegravir, emtricitabine, and tenofovir alafenamide); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); and STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine). TRUVADA (registered trademark) (Tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY (registered trademark) (Tenofovir alafenamide and emtricitabine); ODEFSEY (registered trademark) (Tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA (registered trademark) (Tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); SYMTUZA (registered trademark) (Darunavir, tenofovir alafenamide hemifumarate, emtricitabine) , and cobicistat); SYMFI (trademark) (efavirenz, lamivudine, and tenofovir disoproxil fumarate); CIMDU (trademark) (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 eruby 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; Dapivine + levonorgestrel, Dolutegravir + lamivudine, Dolutegravir + emtricitabine + tenofovir alafena Examples include, but are not limited to, Mid, el-sulfavirine + 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, additional therapeutic agents are selected from the group consisting of amprenavir, atazanavir, blekanavir, 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 bictegravir, elvitegravir, curcumin, curcumin derivatives, chicolinic acid, derivatives of chicolinic 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, tilphostine, derivatives of tilphostine, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, A The following are selected from the group consisting of VX-15567, BMS-986197, cabotegravir (long-acting injection), 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, stilbendesulfonic acid, T-169, VM-3500, cabotegravir, and combinations thereof.

[0247] In some embodiments, additional therapeutic agents are HIV entry inhibitors. For example, in some embodiments, additional therapeutic agents are selected from the group consisting of enfvirtide, maraviroc, and combinations thereof. Further examples of HIV entry inhibitors include, but are not limited to, cenicliviroc, CCR5 inhibitors, gp41 inhibitors, CD4 adhesion inhibitors, DS-003 (BMS-599793), gp120 inhibitors, and CXCR4 inhibitors. Examples of CCR5 inhibitors include aplaviroc, bicliviroc, maraviroc, cenicliviroc, leronrimab (PRO-140), adaptervir (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 prelixafor, 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, additional therapeutic agents are nucleoside or nucleotide inhibitors of HIV reverse transcriptase. For example, additional therapeutic agents include 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 Selected from the group consisting of EC(registered trademark) (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, sensabudine, didanosine, erbucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fodivudine tidoxil, islatravir, lamivudine, phosphazide, stabudine, zalcitabine, zidovudine, lovahovir etalafenamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, KP-1461, and combinations thereof.

[0250] In some embodiments, additional therapeutic agents are non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase. For example, additional agents are selected from the group consisting of dapivine, delaviridine, delaviridine mesylate, doravirine, efavirenz, etravirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA, ACC-007, AIC-292, KM-023, PC-1005, el-sulfavirine rilup (VM-1500), and combinations thereof.

[0251] In some embodiments, additional therapeutic agents include 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 (registered trademark) (tenofovir alafenamide and emtricitabine); ODEFSEY (registered trademark) (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA (registered trademark) (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; T RIUMEQ(registered trademark) (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA(registered trademark) (KALETRA(registered trademark); lopinavir and ritonavir); COMBIVIR(registered trademark) (zidovudine and lamivudine; AZT+3TC); EPZICOM(registered trademark) (LIVEXA(registered trademark); abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR(registered trademark) (abacavir sulfate) Salts, 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; prolastine; fosanprenavir; fosanprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine;Selected from: stabudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirudine; delavirudine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0252] In some embodiments, additional therapeutic agents are selected from the group consisting of colistin, barbicin, icatibant, bepotastine, epirubicin, epoprosetonol, bapreotide, aprepitant, caspofungin, perphenazine, atazanavir, efavirenz, ritonavir, acyclovir, ganciclovir, penciclovir, prulifloxacin, bictegravir, nelfinavir, tegobubi, nelfinavir, praziquantel, pitavastatin, perampanel, eszopiclone, and zopiclone.

[0253] In some embodiments, additional therapeutic agents are inhibitors of Bruton's tyrosine kinases (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA, NCBI gene ID:695). For example, in some embodiments, additional therapeutic agents are selected from the group consisting of (S)-6-amino-9-(1-(buta-2-inoyl)pyrrolidine-3-yl)-7-(4-phenoxyphenyl)-7H-purine-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib (Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebratinib (CC-292), TAK-020, becabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, AZD6738, calkens, dambatrichen, 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 tilfostine 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-RRRRCPLYISYDPVCRR-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, RNA vaccine, attenuated live vaccine, therapeutic vaccine, prophylactic vaccine, protein-based vaccine, or a combination thereof. In some embodiments, the additional therapeutic agent is mRNA-1273. In some embodiments, the additional therapeutic agent is INO-4800 or INO-4700. In some embodiments, the additional therapeutic agent is an attenuated live RSV vaccine MEDI-559, a human monoclonal antibody against RSV REGN2222, palivizumab, respiratory syncytial virus immunoglobulin, intravenous [RSV-IGIV], and a combination thereof. In some embodiments, the additional therapeutic agent is an HBV vaccine, e.g., Pedialix, Engerix-B, and Recomvivax 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. For example, (i) a monovalent vaccine for influenza A (e.g., a monovalent influenza A[H5N1] virus vaccine and a monovalent influenza A[H1N1]2009 virus vaccine), (ii) a trivalent vaccine for influenza A and B viruses (e.g., Afluria, Agriflu, Fluud, Flualix, Flublock, Flucellvax, Fluraval, Fluvirin, and Fluzon), and (iii) a quadrivalent vaccine for influenza A and B viruses (FluMist, Flualix, Fluzon, and Fluraval). In some embodiments, the additional therapeutic agent is a human adenovirus vaccine (e.g., adenovirus type 4 and type 7 vaccines, 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 (e.g., 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 smallpox virus 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, such as a monoclonal antibody. For example, the additional therapeutic agent is an antibody against 2019-nCoV selected from the group consisting of Regeneron antibody, Wuxi antibody, Vir Biotechnology antibody, antibody targeting the SARS-CoV-2 spike protein, antibody capable of neutralizing SARS-CoV-2 (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 the aPD-1 antibody.

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

[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, pimozivir, and combinations thereof.

[0260] In some embodiments, additional therapeutic agents are 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, additional therapeutic agents include 6'-fluorinated aristemycin analogs, acyclovir fleximer analogs, disulfiram, thiopurine analogs, ASC09F, GC376, GC813, phenylisoserine derivatives, neuroimidase inhibitor analogs, pyrithiobac derivatives, bananin and 5-hydroxychromone derivatives, SSYA10-001, griffiscin, HR2P-M1, HR2P-M2, P21S10, dihydrotancinone E-64-C and E-64-D, OC43-HR2P, MERS-5HB, 229E-HR1P, 229E-HR2P, resverat The following are selected from the group consisting of lol, 1-thia-4-azaspiro[4.5]decan-3-one derivatives, gemcitabine hydrochloride, loperamide, recombinant interferon, cyclosporine A, arisporivir, imatinib mesylate, dasatinib, selumetinib, trametinib, rapamycin, salakatinib, chlorpromazine, triflupromazine, fluphenazine, thiethylperazine, promethazine, cyclophylline inhibitors, K11777, camostat, k22, teicoplanin derivatives, benzoheterocyclic amine derivatives 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, for example, an antibody that binds to SARS-CoV or MERS-CoV. In some embodiments, the additional therapeutic agent is a viral antibody against 2019-nCoV.

[0263] The compositions of the present invention are also used in combination with other active ingredients. For the treatment of 2019-nCoV virus infection, preferably other active therapeutic agents are active against coronavirus infections, e.g., 2019-nCoV virus infection. The compounds and compositions of the present invention are also parenteral fluids (including dextrose saline and Ringer's lactate solution) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylactic agents, fever and analgesics, antiemetics (such as metoclopramide) and / or antidiarrheals, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen or steroids), corticosteroids such as methylprednisolone, immunomodulators (e.g., interferon), other small molecules or biological antivirals that target 2019-nCoV. It is intended for use in conjunction with general care provided to patients with 2019-nCoV virus infection, including drugs (not limited to lopinavir / ritonavir, EIDD-1931, favipiravir, ribavirin, neutralizing antibodies, etc.), vaccines, analgesics, and antimalarial agents (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 drugs for other common diseases in the patient population such as bacterial dysentery. In some embodiments, an additional therapeutic agent is dihydroartemisinin / piperaquine. In some embodiments, an additional therapeutic agent is EIDD-2801 (MH-4482, mornupiravir).

[0264] In some embodiments, additional therapeutic agents are immunomodulators. Examples of immunotherapeutic 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 cell death ligand 1 (Pd-L1) modulators; IL-15 modulators, DermaVir; interleukin-7; Plaquenil (hydroxychloroquine); proleukin (aldesleukin, IL-2); interferon α; interferon α-2b; interferon α-n3; PEGylated interferon α; interferon γ; hydroxyurea; mycophenolate mofetil (MPA) and its es Mycophenolate mofetil (MMF), ribavirin; polymer polyethyleneimine (PEI); gepon; Examples 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, normuferon, pegylated interferon α-2a, pegylated interferon α-2b, recombinant interleukin-15, Xmab-24306, RPI-MN, STING modulator, RIG-I modulator, NOD2 modulator, SB-9200, and IR-103. In some embodiments, additional therapeutic agents are fingolimod, leflunomide, or a combination thereof. In some embodiments, additional therapeutic agents are thalidomide.

[0265] In some embodiments, additional therapeutic agents are IL-6 inhibitors, such as tocilizumab, sarilumab, or a combination thereof.

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

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

[0268] In some embodiments, additional therapeutic agents include anti-inflammatory drugs, such as pirfenidone.

[0269] In some embodiments, additional therapeutic agents are antibiotics for secondary bacterial pneumonia. For example, additional therapeutic agents may be macrolide antibiotics (e.g., azithromycin, clarithromycin, and mycoplasma pneumoniae), fluoroquinolones (e.g., ciprofloxacin and levofloxacin), tetracyclines (e.g., doxycycline and tetracycline), or combinations thereof.

[0270] In some embodiments, the compounds disclosed herein are used in combination with standard treatments for pneumonia (e.g., Pediatric Community Pneumonia). See Guidelines, CID 2011:53(1 October). Treatment of pneumonia generally involves curing the infection and preventing complications. Specific treatments depend on several factors, including the type and severity of the pneumonia, age, and the individual's overall health. These options include (i) antibiotics, (ii) antitussives, and (iii) antipyretics / analgesics (e.g., aspirin, ibuprofen (Advil, Motrin IB, etc.), and acetaminophen (Tylenol, etc.)). In some embodiments, an additional therapeutic agent is the bromhexine antitussive.

[0271] In some embodiments, the compounds disclosed herein are used in combination with immunoglobulin derived from recovered 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, additional therapeutic agents are TLR agonists. Examples of TLR agonists include, but are not limited to, besatrimod (GS-9620), GS-986, IR-103, refitrimod, chilsotrimod, lintatrimod, DSP-0509, AL-034, G-100, covitrimod, AST-008, motrimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, tellatrimod, and RO-7020531.

[0273] In some embodiments, additional therapeutic agents are selected from the group consisting of bortezomid, flurazepam, ponatinib, sorafenib, paramethasone, crocoltrone, flucloxacillin, certindol, clibidipine, atorvastatin, cinorazepam, clofazimine, fosaprepitant, and combinations thereof.

[0274] In some embodiments, additional therapeutic agents are kalimycin, suramin, triazavirin, dipyridamole, bevacizumab, meplasmab, GD31 (Rhizobium), NLRP inflammasome inhibitors, or α-ketoamines. In some embodiments, additional therapeutic agents are recombinant human angiotensin-converting enzyme 2 (rhACE2). In some embodiments, additional therapeutic agents are This is a viral macrophage inflammatory protein (vMIP).

[0275] In some embodiments, the additional therapeutic agent is an anti-biloporin 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 are described in International Publication Nos. 2004 / 112687, 2006 / 135978, 2018 / 145148, and 2009 / 018609.

[0276] Furthermore, any compound of the present invention can be combined with one or more additional active therapeutic agents in single dosage forms for simultaneous or sequential administration to patients. Combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more doses.

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

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

[0279] Combination therapy can provide a "synergistic" effect, meaning that the combined active ingredients used together produce a greater effect than the combined effect of the compounds used individually. A synergistic effect 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 several other regimens. In the case of alternating therapy, a synergistic effect can be achieved when the compounds are administered or delivered sequentially, for example, by different injections in separate tablets, pills, capsules, or syringes. Generally, during alternating therapy, the effective dose of each active ingredient is administered sequentially, i.e., consecutively, whereas in combination therapy, the effective doses of two or more active ingredients are administered together. A synergistic antiviral effect exhibits a greater antiviral effect than the predicted pure additive effect of the individual compounds in the combination. 1. Combination therapy for the treatment of Pneumoviridae

[0280] The compounds provided herein are also used in combination with other active therapeutic agents. In the case of treating Pneumoviridae virus infections, preferably the other active therapeutic agents are 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 active therapeutic agents effective 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 mAbs; and viral replication inhibitors such as nitazoxanide.

[0281] In some embodiments, other active therapeutic agents may include, but are 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, as vaccines for the treatment or prevention of RSV.

[0282] Other active therapeutic agents effective 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, other active therapeutic agents may be vaccines for the treatment or prevention of metapneumovirus infections, including but not limited to mRNA-1653 and rHMPV-Pa vaccines. 2. Combination therapy for the treatment of Picornaviridae

[0284] The compounds provided herein are also used in combination with other active therapeutic agents. In the case of 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, e.g., preconalil, BTA-798 (bapendavir), 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; and anti-EV71 antibodies.

[0285] In some embodiments, other active therapeutic agents may include, but are not limited to, EV71 vaccine, TAK-021, and EV-D68 adenovector-based vaccines, as vaccines for the treatment or prevention of picornaviridae virus infections. 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 may be used in combination with the compounds provided herein. These additional agents are preferably administered orally or by direct inhalation. Other preferred additional therapeutic agents to be 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 in 1950 as an asthma treatment (Carryer, Journal of Allergy, 21, 282-287, 1950), remain the most potent, consistent, and effective therapies for this disease, although their mechanisms of action are 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 such as trunk obesity, hypertension, glaucoma, glucose intolerance, accelerated cataract formation, bone mineral loss, and psychological effects, all of which limit its use as a long-term treatment (Goodman and Gilman, 10th (edition, 2001). The solution to systemic side effects is to deliver steroid drugs directly to the site of inflammation. Inhaled corticosteroids (ICS) have been developed to mitigate 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 etavonate, hydrocortisone, prednisolone, fludrocortisone, triamcinolone, triamcinolone acetonide, betamethasone, beclomethasone dipropionate, methylpre The drug is donisolone, fluocinolone, fluocinolone acetonide, flunisolide, fluocortin-21-butyrate, flumetasone, flumetasone pivalate, budesonide, halobetazole propionate, mometasone furoate, fluticasone, AZD-7594, ciclesonide, or a pharmaceutically acceptable salt thereof. Anti-inflammatory drugs

[0288] Other anti-inflammatory agents acting through anti-inflammatory cascade mechanisms are also useful as additional therapeutic agents to be combined with the compounds provided herein for the treatment of viral respiratory infections. Applying “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 stopping inflammation because these small molecules target a limited number of common intracellular pathways, i.e., signaling pathways that are key points of anti-inflammatory therapeutic intervention (see review by PJBarnes, 2006).These non-limiting additional therapeutic agents include 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (2-dimethylaminoethyl)-amide (P38 Map kinase inhibitor ARRY-797); 3-cyclopropylmethoxy-N-(3,5-dichloropyridine-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-dichloropyridine-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indole-3-yl]-2-oxoacetamide (PDE-4 inhibitor AWD) 12-281); 8-Methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid (3,5-dichloro-1-oxypyridine-4-yl)amide (PDE-4 inhibitor Sch 351591); 4-[5-(4-fluorophenyl)-2-(4-methanesulfinylphenyl)-1H-imidazole-4-yl]pyridine (P38 inhibitor SB-203850); 4-[4-(4-fluorophenyl)-1-(3-phenyl-propyl)-5-pyridine-4-yl-1H-imidazole-2-yl]buta-3-in-1-ol (P38 inhibitor RWJ-67657); 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexanecarboxylic acid 2-dieth Examples include diaminoethyl ester (shiromilast, a 2-diethyl-ethyl ester prodrug for PDE-4 inhibitors); (3-chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholine-4-ylpropoxy)-quinazoline-4-yl]amine (gefinib, an EGFR inhibitor); and 4-(4-methyl-piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridine-3-ylpyrimidine-2-ylamino)-phenyl]-benzamide (imatinib, an EGFR inhibitor). β2-adrenergic receptor agonist bronchodilator

[0289] Combinations of inhaled β2-adrenergic receptor agonist bronchodilators, such as formoterol, albuterol, or salmeterol, with the compounds provided herein are also preferred, but not limited, combinations useful for the treatment of respiratory viral infections.

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

[0291] Other examples of β2 adrenergic receptor agonists include vedradrine, vilanterol, indacaterol, olodaterol, tulobuterol, formoterol, avesiderol, salbutamol, alformoterol, revalbuterol, fenoterol, and TD-5471. Anticholinergic drugs

[0292] Anticholinergics may be useful for the treatment or prevention of pulmonary bronchoconstriction and are therefore useful as additional therapeutic agents to be combined with the compounds provided herein for the treatment of viral respiratory infections. These anticholinergic drugs have shown therapeutic efficacy in humans for controlling cholinergic tones in COPD (Witek, 1999): muscarinic receptor antagonists (especially of the M3 subtype); 1-{4-hydroxy-1-[3,3,3-tris-(4-fluorophenyl)-propionyl]-pyrrolidine-2-carbonyl}pyrrolidine-2-carboxylic acid (1-methyl-piperidine-4-ylmethyl)amide; 3-[3-(2-diethylaminoacetoxy)-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]octa-3-yl ester (solifenacin). );2-Hydroxymethyl-4-methanesulfinyl-2-phenyl-butyrate 1-aza-bicyclo[2.2.2]octa-3-yl ester (levatropate);2-{1-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-pyrrolidine-3-yl}-2,2-diphenyl-acetamide (dalifenacin);4-azepan-1-yl-2,2-diphenyl-butylamide (buzepide);7-[3-( 2-Diethylaminoacetoxy)-2-phenylpropionyloxy]-9-ethyl-9-methyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane(oxytropium-N,N-diethylglycinate); 7-[2-(2-diethylaminoacetoxy)-2,2-di-thiophen-2-ylacetoxy]-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-fluorophenyl)-2-oxo-imidazolidined-1-yl]-1-methyl-1-(2-oxo-2-pyridine-2-yl-ethyl)-pyrrolidinium; 1-[1-(3-fluorobenzyl)-piperidine-4-yl]-4,4-bis-(4-fluorophenyl)-imidazolidined-2-one; 1-cyclooctyl-3-(3-methoxy-1-aza-bicyclo[2.2.2] Octa-3-yl)-1-phenyl-propa-2-in-1-ol; 3-[2-(2-diethylamino-acetoxy)-2,2-di-thiophen-2-yl-acetoxy]-1-(3-phenoxy-propyl)-1-azonia-bicyclo[2.2.2]octane(acridinium-N,N-diethylglycinate); or (2-diethylamino-acetoxy)-di-thiophen-2-yl-acetate 1-methyl-1-(2-phenoxyethyl)-piperidine-4-yl ester; lebefenacin, glycopyrronium bromide, umeclidinium bromide, tiotropium bromide, acridinium bromide, and bencycloxium bromide are examples, but are not limited to these. Mucus dissolving agent

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

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

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

[0296] Other active therapeutic agents for the treatment of dengue virus infection include, but are not limited to, host cell factor modulators such as GBV-006; fenretinide ABX-220, BRM-211; alpha-glucosidase 1 inhibitors such as cergocivir; platelet activating factor receptor (PAFR) antagonists such as modipafant; F These include 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, other active therapeutic agents may include, but are not limited to, TetraVax-DV, Dengvaxia®, DPIV-001, TAK-003, live attenuated dengue vaccine, quadrivalent dengue vaccine, quadrivalent DNA vaccine, rDEN2δ30-7169; and DENV-1 PIV, as vaccines for the treatment or prevention of dengue fever. 5. Combination therapy for the treatment of flaviviral virus infections

[0298] The compounds provided herein are also used in combination with other active therapeutic agents. In the case of treating filoviral infections, preferably the other active therapeutic agents are active against filoviral infections, particularly Marburg virus infection, Ebola virus infection, and Queva virus infection. Non-limiting examples of these other active therapeutic agents include ribavirin, amiodarone, doronedarone, verapamil, Ebola convalescent plasma (ECP), TKM-100201, BCX4430((2S,3S, 4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidine-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 RNA polymerase inhibitors such as c2, OS-2966, brincidofovir, remdesivir; 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-limited therapeutic agents active against Ebola include α-glucosidase 1 inhibitors, cathepsin B inhibitors, CD29 antagonists, dendritic ICAM-3-binding nonintegrin 1 inhibitors, estrogen receptor antagonists, factor VII antagonist HLA class II antigen modulators, host cell factor modulators, interferon α-ligands, neutral α-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, other active therapeutic agents may be vaccines for the treatment or prevention of Ebola, including, but not limited to, VRC-EBOADC076-00-VP, adenovirus-based Ebola vaccines, 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 Ebola vaccine, FiloVax vaccine, GOVX-E301, and GOVX-E302.

[0301] The compounds provided herein are also synthetic antisense oligonucleotide analogs, phosphoramidate morpholino oligomers, designed to interfere with the translation process by forming base-paired double helices with specific RNA sequences. It can be used in combination with oligomers (PMOs). An example of a PMO is AVI-72. Examples include, but are not limited to, 87, AVI-7288, AVI-7537, AVI-7539, AVI-6002, and AVI-6003.

[0302] The compounds provided herein are also intended for use in conjunction with general care provided to patients with filoviral infections, including parenteral fluids (including dextrose saline and Ringer's lactate 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 antidiarrheals, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen), analgesics, and antimalarial drugs (including artemether and artesunate-mefantrine combination therapy), typhoid fever (including quinolone antibiotics such as ciprofloxacin, macrolid antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or drugs for other common diseases in patient populations such as bacterial dysentery. X. Preparation of Compounds

[0303] In some embodiments, the 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 chromatographic technique known in the art, such as high-performance liquid chromatography (HPLC), preparative thin-layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase, such as normal-phase, reverse-phase, and ionic resins, can be used. Most typically, the disclosed compounds are purified by silica gel and / or alumina chromatography.

[0305] During any of the processes for preparing the compounds provided herein, it may be necessary and / or desirable to protect the sensitive or reactive groups in any of the molecules involved. This is as described in TWGreene and PGMWuts, "Protective Groups in Organic Synthesis," 4 th This can be achieved by conventional protecting groups, as described in standard studies such as Wiley, New York 2006. The protecting groups can be removed in a convenient subsequent step using methods known from the art.

[0306] Here, exemplary chemicals useful in the methods of the embodiments are described by reference to the exemplary synthesis schemes for their general preparations herein and the specific examples below. Those skilled in the art will recognize that to obtain the various compounds herein, the desired products can be obtained by suitably selecting the starting materials such that the ultimately desired substituent is supported through the reaction scheme, with or without protection as necessary. Alternatively, it may be necessary or desirable to use a suitable group that is supported through the reaction scheme and can be appropriately replaced with the desired substituent instead of the ultimately desired substituent. Furthermore, those skilled in the art will understand that the transformations shown in the following schemes can be carried out in any order that is suitable for the functionality of the particular pendant group.

[0307] The methods of this disclosure generally provide specific enantiomers or diastereomers as desired products, but the stereochemistry of the enantiomers or diastereomers is not determined in all cases. When the stereochemistry of a particular stereocenter in an enantiomer or diastereomer is not determined, the compound is drawn without exhibiting stereochemistry at that particular stereocenter, even if the compound may be substantially enantiomerically or diastereomerically pure.

[0308] Typical synthesis methods of the compounds of this disclosure are described in the following scheme and in the following specific examples.

[0309] The compounds of this disclosure may be prepared using the methods disclosed herein and their routine modifications, which will be apparent to those skilled in the art given the disclosure herein and methods well known in the art. In addition to the teachings herein, conventional and well known synthetic methods may be used. The synthesis of typical compounds described herein can be achieved as described 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 isolateable at room temperature and pressure. 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 can be isolated as a salt (e.g., a TFA salt). Method for preparing the compound of formula Ib

[0310] In some embodiments, the present disclosure provides a method for preparing compounds of formula Ib, [ka] During the ceremony, R 7 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyryl, and C6-C 10 A 5-6 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, O, and S, R 7 The base is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , and optionally substituted with one, two, or three substituents optionally selected from the group consisting of phenyl that is optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C1-C6 alkyl, Each R 8These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl. Each R 9 These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl. Each R 10 These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl. This method is used for the compound of formula A. [ka] [In the formula, each R A is independently a hydroxy protecting group, or two R A The group is bonded to -C(R B ) forms a 2-group, in the formula, R B [These are 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 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyryl, and C6-C 10 A 5-6 membered heteroaryl containing an aryl, or one, two, or three heteroatoms selected from N, O, and S, R Y The base is halogen, cyano, -N3, -OR 8’ , -NR 9’ R 10’ , and optionally substituted with one, two, or three substituents optionally selected from the group consisting of phenyl that is optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C1-C6 alkyl, Each R 8’These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl. Each R 9’ These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl. Each R 10’ This involves coupling with H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl, independently of H.

[0311] In some embodiments, the present disclosure provides a method for preparing compounds of formula Ib, [ka] In the formula, R 7 These are C1-C8 alkyl groups, This method is used for the compound of formula A. [ka] [In the formula, each R A is independently a hydroxy protecting group, or two R A The group is bonded to -C(R B ) forms a 2-group, in the formula, 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 C1-C8 alkyl or C6-C 10 It is aryl, R Y The group is coupled with one, two, or three substituents, which are optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens.

[0312] In some embodiments, the present disclosure provides a method for preparing compounds of formula Ib, [ka] In the formula, R 7 These are C1-C3 alkyl groups, This method is used for the compound of formula A. [ka] [In the formula, each R A is independently a hydroxy protecting group, or two R A The group is bonded to -C(R B ) forms a 2-group, in the formula, 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 This involves coupling with a C1-C3 alkyl or phenyl molecule, where the phenyl molecule is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens.

[0313] In some embodiments, the present disclosure provides a method for preparing compounds of formula Ib, [ka] In the formula, R 7 It is a C3 alkyl group, This method is used for the compound of formula A. [ka] [In the formula, each R A is independently a hydroxy protecting group, or two R A The group is bonded to -C(R B ) forms a 2-group, in the formula, 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 The process involves coupling with a C3 alkyl or phenyl molecule, where the phenyl molecule is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens.

[0314] In some embodiments, the present disclosure provides a method for preparing compounds of formula Ib, [ka] In the formula, R 7 It is isopropyl, This method is used for the compound of formula A. [ka] [In the formula, two R A The group is bonded to -C(R B ) forms a 2-group, in the formula, R B [It 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 The process involves coupling with isopropyl or phenyl, where phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens.

[0315] In some embodiments, the present disclosure provides a method for preparing compounds of formula Ib, [ka] In the formula, R 7 It is isopropyl, This method is used for the compound of formula A. [ka] [In the formula, two R A The group is bonded to -C(R B ) forms a 2-group, in the formula, R B is H or It is methyl. The coupling partner of formula B [ka] [In the formula, R X is chloro, hydroxy, -OCOR Y And, R Y The method involves coupling with isopropyl or phenyl, where phenyl is optionally substituted with one, two, or three chloro groups.

[0316] In some embodiments, the coupling of a compound of formula A with a coupling partner of formula B is performed on a compound of formula C. [ka] Bringing about, In the formula, R A and R 7 Each of these is defined herein for various embodiments of the method for preparing the compound of formula Ib.

[0317] In some embodiments, the method for producing the compound of formula Ib further includes deprotecting the compound of formula C to obtain the compound of formula Ib. In some embodiments, the deprotection of the compound of formula C includes the use of an acid. In some embodiments, the use of an acid of general structure HX (wherein X is a conjugate base) for deprotection of the compound of formula C results in a salt of the compound of formula Ib (formula Ib·HX). If the deprotected compound is obtained as a salt, a liberation basification step may be optionally performed. In some embodiments, the liberation basification step includes treatment with a base. Coupling reaction of formulas A and B [ka]

[0318] A method for producing the compound of formula Ib provided herein comprises coupling the 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 hydroxyl. In some embodiments, R X is, -OCOR Y In some embodiments, R X ha-OCOR Y And in the formula, R Y is R 7 It is the same as, or R Y These are halogen, cyano, -N3, -OR 8’ , -NR 9’ R 10’, and C6-C6 alkyl phenyl molecules optionally substituted with one, two, or three substituents 10 It is an arrow. In some embodiments, R X ha-OCOR Y And in the formula, R Y is R 7 It is the same as, or R Y C6~C is a C6~C molecule that is optionally substituted with one, two, or three substituents. 10 It is aryl, and each substituent is independently a halogen. In some embodiments, R X ha-OCOR Y And in the formula, R Y is R 7 It is the same as, or R Y R is a phenyl molecule optionally substituted with one, two, or three substituents, each substituent independently being a halogen. In some embodiments, R X ha-OCOR Y And in the formula, R Y is R 7 It is the same as R X ha-OCOR Y And in the formula, R Y R is a phenyl molecule optionally substituted with one, two, or three substituents, each substituent independently being a halogen. In some embodiments, R X ha-OCOR Y And in the formula, R Y is R 7 It is the same as, or R Y This is a phenyl molecule optionally substituted with one, two, or three chloro groups.

[0320] The coupling partner of formula B can be used in any preferred 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 nitrated heterocycle, an azodicarboxylate, a guanidinium and uronium type coupling reagent, triphenylphosphine, tri-n-butylphosphine, or S,S-bis(4,6-dimethyl-2-pyrimidinyl)carboditiote.

[0322] In some embodiments, the coupling of formula A with the coupling partner of formula B is carried out in the presence of a catalyst, which 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, the catalyst being an 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 the coupling partner of formula B is carried out in the presence of a catalyst, which is a guanidinium- and uronium-type coupling reagent. In some embodiments, the catalyst is N-[dimethylamino)-1H-1,2,3-triazolo[4,5-b]-pyridine-1-ylmethylene]-N-methylmethaneaminium Hexafluorophosphate N-oxide (HATU), N-[(1H-benzotriazole-1-yl)-(dimethylamino)-methylene]-N-methylmethaneaminium hexafluorophosphate N-oxide (HBTU), N-[(1H-benzotriazole-1-yl)-(dimethylamino)-methylene]-N-methylmethaneaminium 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 The catalyst is U), or (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU). In some embodiments, the catalyst is N-[dimethylamino)-1H-1,2,3-triazolo[4,5-b]-pyridine-1-ylmethylene]-N-methylmethaneaminium 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 the coupling partner of formula B is carried out in the presence of a catalyst, which is triphenylphosphine, tri-n-butylphosphine, or S,S-bis(4,6-dimethyl-2-pyrimidinyl)carboditiote. 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)carboditiote.

[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 to 10 mol% of DMAP is used as a catalyst for the coupling of formula A with formula B. In some embodiments, 1 to 5 mol% of DMAP is used as a catalyst for the coupling of formula A with formula B. In some embodiments, 3 mol% of 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 the coupling partner of formula B is 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 a 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 tribasic metal 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 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]undeca-7-ene, or a combination thereof. In some embodiments, the base is 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]undeca-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 equivalent (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 includes diethyl ether, tert-butyl methyl ether, tetrahydrofuran (THF), methyl tetrahydrofuran (MeTHF), or a combination thereof and water. In some embodiments, the solvent includes water and diethyl ether. In some embodiments, the solvent includes water and tert-butyl methyl ether. In some embodiments, the solvent includes water and THF. In some embodiments, the solvent includes 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 preferred temperature. In some embodiments, the coupling reaction is carried out at approximately -35°C to 60°C. In some examples, the coupling reaction is carried out at a temperature of approximately -25°C to 50°C. In some examples, the coupling reaction is carried out at a temperature of approximately -15°C to 40°C. In some examples, the coupling reaction is carried out at a temperature of approximately -5°C to 30°C. In some examples, the coupling reaction is carried out at a temperature of approximately 5°C to 20°C. In some examples, the coupling reaction is carried out at a temperature of approximately 5°C to 15°C. In some examples, the coupling reaction is carried out at a temperature of approximately 0°C to 10°C. In some examples, the coupling reaction is carried out at a temperature of approximately 5°C. Deprotection of the compound of formula C [ka]

[0344] In some embodiments, the coupling of formula A with a coupling partner of formula B yields a compound of formula C, and the method for producing a compound of formula Ib further includes deprotection of 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 deprotectant is a solid-supported acidic resin. In some embodiments, the deprotectant is a strong cation exchange resin containing a sulfonic acid group or a corresponding salt. In some embodiments, the deprotectant 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 a carboxylic acid group or a corresponding salt. In some embodiments, the deprotective 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 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 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 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. In some embodiments, the solvent for the deprotection step includes ether solvents, polar aprotic solvents, alcohols, ester solvents, halogenated solvents, hydrocarbons, nitrile solvents, or combinations thereof.

[0353] In some embodiments, the solvent for the deprotection step is an ether 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 halogenating 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 preferred temperature. In some embodiments, the deprotection reaction is carried out at approximately -20°C to 50°C. In some embodiments, the deprotection reaction is carried out at approximately -10°C to 40°C. In some embodiments, the deprotection reaction is carried out at approximately 0°C to 30°C. In some embodiments, the deprotection reaction is carried out at approximately 10°C to 30°C. In some embodiments, the deprotection reaction is carried out at approximately 15°C to 25°C. In some embodiments, the deprotection reaction is carried out at approximately 10°C to 30°C. In some embodiments, the deprotection reaction is carried out at approximately 20°C. Free base formation

[0361] In some embodiments, the use of an acid of general structure HX (wherein X is a conjugate base) for deprotection of the compound of formula C results in a salt of the compound of formula Ib (formula Ib·HX). If the deprotected compound is obtained as a salt, an additional free basification step may be optionally performed. [ka]

[0362] In some embodiments, free basification involves treatment with a base. Any suitable base can be used. In some embodiments, the base used is an inorganic base, for example, a bicarbonate. In some examples, the base is lithium bicarbonate, 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 tribasic metal 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 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]undeca-7-ene, or a combination thereof. In some embodiments, the base is 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]undeca-7-ene.

[0369] The free basification step can be carried out in any suitable solvent. In some embodiments, the solvent for the free basification step includes ether solvents, polar aprotic solvents, alcohols, ester solvents, halogenated solvents, hydrocarbons, nitrile solvents, or combinations thereof.

[0370] In some embodiments, the solvent for the free basing step is an ether 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 free basement 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 free basement 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 free basification 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 free basement 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 basement 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] Free basement can be carried out at any suitable temperature. In some embodiments, the coupling reaction is carried out at approximately 10°C to 30°C. In some embodiments, the coupling reaction is carried out at approximately 20°C. XI. Crystalline form of compound 15

[0378] Polymorphic forms or polymorphs may possess properties such as bioavailability and stability under specific conditions that make them suitable for medical or pharmaceutical use. The crystalline form of compound 15 may offer advantages in bioavailability and stability that make it suitable for use as an active ingredient in pharmaceutical compositions. Variations in the crystalline structure of a pharmaceutical 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 product or active ingredient. Such variations may affect the preparation or formulation of pharmaceutical compositions in different dosing or delivery forms, such as solid oral dosage forms including tablets and capsules. Compared to other forms such as amorphous or noncrystalline forms, crystalline forms may offer desired or preferred hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, and / or process control. Therefore, the crystalline form of compound 15 may offer advantages such as improving the manufacturing process of the active drug or the stability or storability of the drug product form of the compound or active ingredient, and / or having suitable bioavailability and / or stability as an active drug. Compound 15, Form I

[0379] In some embodiments, a crystalline form I of compound 15 (crystalline compound 15 form I) is provided, in which 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 (a) to (c) apply: (a) crystalline compound 15 form I has an XRPD pattern substantially as shown in Figure 10; (b) crystalline compound 15 form I has a DSC thermogram substantially as shown in Figure 11; (c) crystalline compound 15 form I has a TGA graph substantially as shown in Figure 12.

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

[0382] In some embodiments, the crystalline compound 15 form I has an XRPD pattern that exhibits at least two, at least three, at least four, at least five, or at least six of the 2θ reflectances that have maximum intensity as an XRPD pattern substantially as shown in Figure 10.

[0383] In some embodiments, the crystalline compound 15 form I has an XRPD pattern that includes 2θ reflectances (+ / -0.2 2θ°) at 8.5°, 22.1°, and 23.8°. In some embodiments, the crystalline compound 15 form I has an XRPD pattern that includes one, two, or three of the following: 2θ reflectances (+ / -0.2 2θ°) at 8.5°, 22.1°, and 23.8°, and 2θ reflectances (+ / -0.2 2θ°) at 15.4°, 16.9°, and 28.1°. In some embodiments, the crystalline compound 15 form I has an XRPD pattern that includes one or two of the following: 2θ reflectances (+ / -0.2 2θ°) at 8.5°, 22.1°, and 23.8°, and 2θ reflectances (+ / -0.2 2θ°) at 15.4°, 16.9°, and 28.1°. The XRPD pattern includes a 2θ reflectance (+ / -0.2 2θ°) at 8.5°, 22.1°, and 23.8°, as well as two of the 2θ reflectances (+ / -0.2 2θ°) at 15.4°, 16.9°, and 28.1°. In some embodiments, the crystalline compound 15 form I has an XRPD pattern including a 2θ reflectance (+ / -0.2 2θ°) at 8.5°, 22.1°, and 23.8°, as well as two of the 2θ reflectances (+ / -0.2 2θ°) at 15.4°, 16.9°, and 28.1°. In some embodiments, the crystalline compound 15 form I has an XRPD pattern including a 2θ reflectance (+ / -0.2 2θ°) at 8.5°, 15.4°, 16.9°, 22.1°, 23.8°, and 28.1°. In some embodiments, the crystalline compound 15 form I has an XRPD pattern that includes any three 2θ reflectances (+ / -0.2 2θ°) selected from the group consisting of 8.5°, 15.4°, 16.9°, 22.1°, 23.8°, and 28.1°.

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

[0385] In some embodiments, a crystalline form II of compound 15 (crystalline compound 15 form II) is provided, in which 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 (a) to (c) apply: (a) crystalline compound 15 form II has an XRPD pattern substantially as shown in Figure 13; (b) crystalline compound 15 form II has a DSC thermogram substantially as shown in Figure 14; (c) crystalline compound 15 form II has a TGA graph substantially as shown in Figure 15.

[0387] In some embodiments, crystalline compound 15 form II has the following properties: (a) XRPD patterns essentially as shown in Figure 13, (b) A DSC thermogram substantially as shown in Figure 14, and (c) A TGA graph essentially as shown in Figure 15.

[0388] In some embodiments, the 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 that have maximum intensity as an XRPD pattern substantially as shown in Figure 13.

[0389] In some embodiments, the crystalline compound 15 form II has an XRPD pattern that includes 2θ reflectances (+ / -0.2 2θ°) at 6.4°, 13.7°, and 16.3°. In some embodiments, the crystalline compound 15 form II has an XRPD pattern that includes one, two, or three of the 2θ reflectances (+ / -0.2 2θ°) at 6.4°, 13.7°, and 16.3°, as well as 2θ reflectances (+ / -0.2 2θ°) at 18.4°, 20.8°, and 23.3°. In some embodiments, the crystalline compound 15 form II has an XRPD pattern that includes one or two of the following 2θ reflectances: 6.4°, 13.7°, and 16.3° (+ / -0.2 2θ°), and 18.4°, 20.8°, and 23.3° (+ / -0.2 2θ°). In some embodiments, the crystalline compound 15 form II has an XRPD pattern including 2θ reflectances (+ / -0.2 2θ°) at 6.4°, 13.7°, and 16.3°, and two of 2θ reflectances (+ / -0.2 2θ°) at 18.4°, 20.8°, and 23.3°. In some embodiments, the crystalline compound 15 form II has an XRPD pattern including 2θ reflectances (+ / -0.2 2θ°) at 6.4°, 13.7°, 16.3°, 18.4°, 20.8°, and 23.3°. In some embodiments, the crystalline compound 15 form II has an XRPD pattern including 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, the crystalline compound 15 form II has an XRPD pattern including 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°. Compound 15, Form III

[0391] In some embodiments, a crystalline form III of compound 15 (crystalline compound 15 form III) is provided, in which 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 (a) to (c) apply: (a) crystalline compound 15 form III has an XRPD pattern substantially as shown in Figure 16; (b) crystalline compound 15 form III has a DSC thermogram substantially as shown in Figure 17; (c) crystalline compound 15 form III has a TGA graph substantially as shown in Figure 18.

[0393] In some embodiments, crystalline compound 15 form III has the following properties: (a) XRPD patterns essentially as shown in Figure 16, (b) A DSC thermogram substantially as shown in Figure 17, and (c) A TGA graph essentially as shown in Figure 18.

[0394] In some embodiments, the 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 that have maximum intensity as an XRPD pattern substantially as shown in Figure 16.

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

[0396] In some embodiments, the crystalline compound 15 form III has a 2θ reflectance (+ / -0.2 2θ°) at 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9°, and a 2θ reflectance (+ / -0.2 2θ°) at 10.4°, 19.8°, and 20.7°. The XRPD pattern includes one, two, or three of the 2θ reflectances (+ / -0.2 2θ°). In some embodiments, the crystalline compound 15 form III has an XRPD pattern including one or two of the 2θ reflectances (+ / -0.2 2θ°) at 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9°, and at 10.4°, 19.8°, and 20.7°. In some embodiments, the crystalline compound 15 form III has an XRPD pattern that includes one of the following 2θ reflectances (+ / -0.2 2θ°) at 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9°, and 2θ reflectances (+ / -0.2 2θ°) at 10.4°, 19.8°, and 20.7°. In some embodiments, the crystalline compound 15 form III has an XRPD pattern that includes 2θ reflectances (+ / -0.2 2θ°) at 9.8°, 10.2°, 10.4°, 16.0°, 19.1°, 19.8°, 20.7°, 25.4°, and 26.9°. In some embodiments, the crystalline compound 15 form III has an XRPD pattern that includes any three of the 2θ reflectances (+ / -0.2 2θ°) at 9.8°, 10.2°, 10.4°, 16.0°, 19.1°, 19.8°, 20.7°, 25.4°, and 26.9°. XII. Salts of Compound 15 Compound 15 xinafoate

[0397] In some embodiments, the disclosure provides xinafoate of compound 15 (compound 15 xinafoate). In some embodiments, compound 15 xinafoate is nonsolvable.

[0398] In some embodiments, the disclosure provides crystalline forms of compound 15 xinafoate. In some embodiments, the crystalline form of compound 15 xinafoate exhibits a substantially XRPD pattern as shown in Figure 19. In some embodiments, the crystalline form of compound 15 xinafoate may exhibit a DSC thermogram as shown in Figure 20. In some embodiments, the crystalline form of compound 15 xinafoate may exhibit a TGA graph 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) to (c) apply: (a) the crystalline form of compound 15 xinafoate has a substantially XRPD pattern as shown in Figure 19; (b) the crystalline form of compound 15 xinafoate has a substantially DSC thermogram as shown in Figure 20; (c) the crystalline form of compound 15 xinafoate has a TGA graph as shown in Figure 21.

[0400] In some embodiments, the crystalline form of compound 15 xinafoate has the following properties : (a) A substantially XRPD pattern as shown in Figure 19, (b) A DSC thermogram substantially as shown in Figure 20, and (c) A TGA graph essentially as shown in Figure 21.

[0401] In some embodiments, the crystalline form of compound 15 xinafoate has an XRPD pattern that exhibits at least two, at least three, at least four, at least five, or at least six of the 2θ reflectances that have maximum intensity as an XRPD pattern substantially as shown in Figure 19.

[0402] In some embodiments, the crystalline form of compound 15 xinafoate has an XRPD pattern including 2θ reflectances (+ / -0.2 2θ°) at 4.0°, 12.2°, and 14.8°. In some embodiments, the crystalline form of compound 15 xinafoate has an XRPD pattern including 2θ reflectances (+ / -0.2 2θ°) at 4.0°, 12.2°, and 14.8°, as well as one, two, or three of 2θ reflectances (+ / -0.2 2θ°) at 6.2°, 12.9°, and 26.6°. In some embodiments, the crystalline form of compound 15 xinafoate has an XRPD pattern that includes one or two of the following: 2θ reflectances (+ / -0.2 2θ°) at 4.0°, 12.2°, and 14.8°, and 2θ reflectances (+ / -0.2 2θ°) at 6.2°, 12.9°, and 26.6°. In some embodiments, the crystalline form of compound 15 xinafoate has an XRPD pattern that includes two of the following 2θ reflectances: 4.0°, 12.2°, and 14.8° (+ / -0.2 2θ°), and 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 2θ reflectances: 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 following 2θ reflectances: 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 has a 2θ reflectance (+ / -0.2 2θ°) at 4.0°, 6.2°, 12.2°, 12.9°, 14.8° and 26.6°, and a 2θ reflectance (+ / -0.2 2θ°) at 7.8°, 10.3° and 15.7°. The XRPD pattern has one, two, or three of the 2θ reflectances (+ / -0.2 2θ°). In some embodiments, the crystalline form of compound 15 xinafoate has an XRPD pattern that has one or two of the 2θ reflectances (+ / -0.2 2θ°) at 4.0°, 6.2°, 12.2°, 12.9°, 14.8° and 26.6°, and at 7.8°, 10.3° and 15.7°. In some embodiments, the crystalline form of compound 15 xinafoate has an XRPD pattern that includes one of the following 2θ reflectances (+ / -0.2 2θ°) at 4.0°, 6.2°, 12.2°, 12.9°, 14.8°, and 26.6°, and one of the following 2θ reflectances (+ / -0.2 2θ°) at 7.8°, 10.3°, and 15.7°. In some embodiments, the crystalline form of compound 15 xinafoate has an XRPD pattern that includes two of the following 2θ reflectances (+ / -0.2 2θ°) at 4.0°, 6.2°, 12.2°, 12.9°, 14.8°, and 26.6°, and two of the following 2θ reflectances (+ / -0.2 2θ°) at 7.8°, 10.3°, and 15.7°. In some embodiments, the crystalline form of compound 15 xinafoate has an XRPD pattern including 2θ reflectances (+ / -0.2 2θ°) at 4.0°, 6.2°, 7.8°, 10.3°, 12.2°, 12.9°, 14.8°, 15.7°, and 26.6°. In some embodiments, the crystalline form of compound 15 xinafoate has an XRPD pattern including any three of 2θ reflectances (+ / -0.2 2θ°) at 4.0°, 6.2°, 7.8°, 10.3°, 12.2°, 12.9°, 14.8°, 15.7°, and 26.6°. Compound 15HCl salt

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

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

[0406] In some embodiments, the Disclosure provides a crystalline form I of the 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 15HCl salt form I, at least one, at least two, or all of the following (a) to (c) apply: (a) compound 15HCl salt form I has an XRPD pattern substantially as shown in Figure 22; (b) compound 15HCl salt form I has a DSC thermogram substantially as shown in Figure 23; (c) compound 15HCl salt form I has a TGA graph substantially as shown in Figure 24.

[0408] In some embodiments, compound 15HCl salt form I has the following properties: (a) XRPD patterns essentially as shown in Figure 22, (b) A DSC thermogram substantially as shown in Figure 23, and (c) A TGA graph essentially as shown in Figure 24.

[0409] In some embodiments, compound 15HCl salt form I has an XRPD pattern that exhibits at least two, at least three, at least four, at least five, or at least six of the 2θ reflectances that have maximum intensity as an XRPD pattern substantially as shown in Figure 22.

[0410] In some embodiments, compound 15HCl salt form I has an XRPD pattern including 2θ reflectances (+ / -0.2 2θ°) at 5.9°, 14.0°, and 24.3°. In some embodiments, compound 15HCl salt form I has an XRPD pattern including one, two, or three of the following: 2θ reflectances (+ / -0.2 2θ°) at 5.9°, 14.0°, and 24.3°, and 2θ reflectances (+ / -0.2 2θ°) at 11.7°, 16.7°, and 23.9°. In some embodiments, compound 15HCl salt form I has an XRPD pattern that includes one or two of the following: 2θ reflectances (+ / -0.2 2θ°) at 5.9°, 14.0°, and 24.3°, and 2θ reflectances (+ / -0.2 2θ°) at 11.7°, 16.7°, and 23.9°. In some embodiments, compound 15HCl salt form I has an XRPD pattern including 2θ reflectances (+ / -0.2 2θ°) at 5.9°, 14.0°, and 24.3°, and two of 2θ reflectances (+ / -0.2 2θ°) at 11.7°, 16.7°, and 23.9°. In some embodiments, compound 15HCl salt form I has an XRPD pattern including 2θ reflectances (+ / -0.2 2θ°) at 5.9°, 11.7°, 14.0°, 16.7°, 23.9°, and 24.3°. In some embodiments, compound 15HCl salt form I has an XRPD pattern including any three of 2θ reflectances (+ / -0.2 2θ°) at 5.9°, 11.7°, 14.0°, 16.7°, 23.9°, and 24.3°.

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

[0412] In some embodiments, the Disclosure provides a crystalline material A of the compound 15HCl salt ("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 15HCl salt material A, at least one, at least two, or all of the following (a) to (c) apply: (a) compound 15HCl salt material A has an XRPD pattern substantially as shown in Figure 25; (b) compound 15HCl salt material A has a DSC thermogram substantially as shown in Figure 26; (c) compound 15HCl salt material A has a TGA graph substantially as shown in Figure 27.

[0414] In some embodiments, the compound 15HCl salt material A has the following properties: (a) XRPD patterns essentially as shown in Figure 25, (b) A DSC thermogram substantially as shown in Figure 26, and (c) A TGA graph essentially as shown in Figure 27.

[0415] In some embodiments, the compound 15HCl 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 that have maximum intensity as an XRPD pattern substantially as shown in Figure 25.

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

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

[0418] In some embodiments, the Disclosure provides a crystalline material B of the compound 15HCl salt ("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 15HCl salt material B, at least one, at least two, or all of the following (a) to (c) apply: (a) compound 15HCl salt material B has an XRPD pattern substantially as shown in Figure 28; (b) compound 15HCl salt material B has a DSC thermogram substantially as shown in Figure 29; (c) compound 15HCl salt material B has a TGA graph substantially as shown in Figure 30.

[0420] In some embodiments, compound 15HCl salt material B has the following properties: (a) XRPD patterns essentially as shown in Figure 28, (b) A DSC thermogram substantially as shown in Figure 29, and (c) A TGA graph essentially as shown in Figure 30.

[0421] In some embodiments, the compound 15HCl salt material B has an XRPD pattern that exhibits at least two, at least three, at least four, at least five, or at least six of the 2θ reflectances that have maximum intensity as an XRPD pattern substantially as shown in Figure 28.

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

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

[0424] In some embodiments, the Disclosure provides a crystalline material C of a compound 15HCl salt ("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 15HCl salt material C, at least one, at least two, or all of the following (a) to (c) apply: (a) compound 15HCl salt material C has an XRPD pattern substantially as shown in Figure 31; (b) compound 15HCl salt material C has a DSC thermogram substantially as shown in Figure 32; (c) compound 15HCl salt material C has a TGA graph substantially as shown in Figure 33.

[0426] In some embodiments, the compound 15HCl salt material C has the following properties: (a) XRPD patterns essentially as shown in Figure 31, (b) A DSC thermogram substantially as shown in Figure 32, and (c) A TGA graph essentially as shown in Figure 33.

[0427] In some embodiments, the compound 15HCl 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 that have maximum intensity as an XRPD pattern substantially as shown in Figure 31.

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

[0429] In some embodiments, the compound 15HCl salt material C has an XRPD pattern that includes one, two, or three of the following 2θ reflectances (+ / -0.2 2θ°): at 4.3°, 12.8°, 14.7°, 17.3°, 31.4°, and 35.1°, and at 16.6°, 24.9°, and 27.2°. In some embodiments, the compound 15HCl salt material C has an XRPD pattern that includes one of the following 2θ reflectances (+ / -0.2 2θ°) at 4.3°, 12.8°, 14.7°, 17.3°, 31.4°, and 35.1°, and 2θ reflectances (+ / -0.2 2θ°) at 16.6°, 24.9°, and 27.2°. In some embodiments, the compound 15HCl salt material C has an XRPD pattern that includes two of the following 2θ reflectances (+ / -0.2 2θ°) at 4.3°, 12.8°, 14.7°, 17.3°, 31.4°, and 35.1°, and 2θ reflectances (+ / -0.2 2θ°) at 16.6°, 24.9°, and 27.2°. In some embodiments, the compound 15HCl salt material C has an XRPD pattern that includes 2θ reflectances (+ / -0.2 2θ°) at 4.3°, 12.8°, 14.7°, 16.6°, 17.3°, 24.9°, 27.2°, 31.4°, and 35.1°. In some embodiments, the compound 15HCl salt material C has an XRPD pattern that includes any three of the 2θ reflectances (+ / -0.2 2θ°) at 4.3°, 12.8°, 14.7°, 16.6°, 17.3°, 24.9°, 27.2°, 31.4°, and 35.1°. XIII. Examples Intermediate A: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-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]triazine-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (compound 13 described in International Publication No. 2009132135, 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 this mixture and stirred for 20 minutes, followed by the addition of nucleoside (150 mg, 0.52 mmol) and triethylamine (180 μL, 1.29 mmol). The resulting mixture was stirred for 16 hours. Further 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (1 equivalent) and N,N'-diisopropylcarbodiimide (1 equivalent) were added at this point, and the mixture was heated at 60°C for 4 hours, followed by stirring at room temperature for a further 16 hours. The mixture was diluted with ethyl acetate and washed with saturated NaHCO3 and saturated brine. The organic layer was dried over Na2SO4, concentrated under vacuum, and purified by column chromatography eluting with ethyl acetate (0%~100%) in hexane to obtain 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]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(tert-butoxycarbonyl)-L-valinate [ka]

[0432] Intermediate B was prepared using the same method as for intermediate A, except that (tert-butoxycarbonyl)-L-valine (55 mg, 0.26 mmol) was used instead of 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid. Example 1: (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-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]triazine-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 all at once. N,N'-diisopropylcarbodiimide (78 μL, 0.5 mmol) was added dropwise. The reaction mixture was stirred for 15 minutes. 4-(dimethylamino)pyridine (12.2 mg, 0.1 mmol) was added. The reaction mixture was then stirred for 16 hours. The mixture was 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 freeze-dried to obtain the labeled 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; 5-100% Buffer B at 2 mL / min for 2.5 minutes, then 100% for 0.9 minutes.

[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; Buffer B is injected at 2 mL / min for 5 minutes until 2-98% of Buffer B is dissolved. Example 2: (2R,3R,4R,5R)-5-(acetoxymethyl)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-2-cyanotetrahydrofuran-3,4-diyldiacetate [ka]

[0437] The indicated compound was prepared using the same method as for compound 1, except that acetic acid (29 μL, 0.50 mmol) was used instead 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]triazine-7-yl)-2-cyano-5-((propionyloxy)methyl)tetrahydrofuran-3,4-diyl=dipropionate [ka]

[0440] The indicated compound was prepared in the same manner as compound 1, except that propionic acid (37 uL, 0.50 mmol) was used instead 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]triazine-7-yl)-6-(hydroxymethyl)-2-phenyltetrahydrofl[3,4-d][1,3]dioxol-4-carbonitrile [ka]

[0443] (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-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 NaHCO3 and saturated brine. The organic layer was dried over Na2SO4, concentrated under vacuum, and purified by column chromatography eluting with ethyl acetate in hexane (0%~30%~50%) to obtain the desired product.

[0444] 1 ¹H NMR (400MHz, 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=7.2Hz, 1H), 5.09 (dd, J=7.2, 3.8Hz, 1H), 4.60 (q, J=4.4Hz, 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]triazine-7-yl)-6-cyano-2-phenyltetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)methylisobutyrate [ka]

[0446] The indicated compound was prepared in the same manner as compound 1, except that compound 4 (32 mg, 0.084 mmol) was used instead of (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-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]triazine-7-yl)-6-cyano-2-phenyltetrahydrofluoro[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]triazine-7-yl)-6-(hydroxymethyl)-2-phenyltetrahydrofl[3,4-d][1,3]dioxol-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. Then, 4-(dimethylamino)pyridine (10 mg, 0.084 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with acetonitrile, and the solid was filtered off. The filtrate was purified by preparative HPLC. The fractions were combined and concentrated under vacuum. The residue was dissolved in 20% trifluoroacetic acid in 3 mL of dichloromethane and stirred for 45 minutes. The mixture was then concentrated and purified by preparative HPLC to obtain the labeled 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]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl 2-amino-2-methylpropanoate [ka]

[0452] The marked compound was prepared in the same manner as 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 performed at room temperature with stirring 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]triazine-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]triazine-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). N,N'-diisopropylcarbodiimide (40 μL, 0.26 mmol) was added to this mixture and stirred for 15 minutes, followed by the addition of nucleoside (50 mg, 0.17 mmol) and triethylamine (47 μL, 0.34 mmol). The resulting mixture was stirred for 16 hours. At this point, additional (tert-butoxycarbonyl)-L-valine (55 mg, 0.56 mmol) and N,N'-diisopropylcarbodiimide (40 uL, 0.25 mmol) were added, and the mixture was stirred at room temperature for a further 5 hours. The reaction was then heated at 50°C for 3 hours, followed by stirring at room temperature for a further 72 hours. The mixture was...

Claims

1. formula: 【Chemistry 1】 A crystal of a compound, wherein the crystal is characterized by an XRPD pattern having 2θ reflectances (+ / -0.2° 2θ) at 8.5°, 22.1°, and 23.8°.

2. The crystal according to claim 1, wherein the XRPD pattern further includes one of the 2θ reflectances (+ / -0.2° 2θ) at 15.4°, 16.9°, and 28.1°.

3. The crystal according to claim 1 or 2, wherein the XRPD pattern includes 2θ reflectances (+ / -0.2° 2θ) at 8.5°, 15.4°, 16.9°, 22.1°, 23.8°, and 28.1°.

4. The crystal according to any one of claims 1 to 3, wherein the XRPD pattern includes 2θ reflectances (+ / -0.2° 2θ) at 8.5°, 10.5°, 15.4°, 16.9°, 17.5°, 22.1°, 23.8°, 27.5°, and 28.1°.

5. The aforementioned XRPD pattern is Table 5 The crystal according to claim 1, comprising a 2θ reflectance (+ / - 0.2° 2θ) at a given point.

6. The crystal according to any one of claims 1 to 5, wherein the crystal exhibits one endothermic transition at 169°C.

7. The crystal according to any one of claims 1 to 6, wherein the crystal has not been solvated.

8. formula: 【Transformation 8】 A crystal of the compound, wherein the crystal is characterized by an XRPD pattern having 2θ reflectances (+ / -0.2° 2θ) at 6.4°, 13.7°, and 16.3°; and Here, the crystal exhibits two endothermic events at 165°C and 176°C, and an exothermic event at 169°C.

9. The crystal according to claim 8, wherein the XRPD pattern further includes one of the 2θ reflectances (+ / -0.2° 2θ) at 18.4°, 20.8°, and 23.3°.

10. The crystal according to claim 8 or 9, wherein the XRPD pattern includes 2θ reflectances (+ / -0.2° 2θ) at 6.4°, 13.7°, 16.3°, 18.4°, 20.8°, and 23.3°.

11. The crystal according to any one of claims 8 to 10, wherein the XRPD pattern further includes a 2θ reflectance at 25.4°.

12. The aforementioned XRPD pattern is Table 12 The crystal according to claim 8, comprising a 2θ reflectance (+ / - 0.2° 2θ) at a given point.

13. The crystal according to any one of claims 8 to 12, wherein the crystal has not been solvated.

14. formula: 【Chemistry 15】 The compound xinafoate.

15. A xinafoate crystal according to claim 14, wherein the crystal is characterized by an XRPD pattern having 2θ reflectances (+ / -0.2° 2θ) at 4.0°, 6.2°, 12.2°, and 14.8°.

16. The crystal according to claim 15, wherein the XRPD pattern further includes one of the 2θ reflectances (+ / -0.2° 2θ) at 12.9° and 26.6°.

17. The crystal according to claim 15 or 16, wherein the XRPD pattern includes 2θ reflectances (+ / -0.2° 2θ) at 4.0°, 6.2°, 12.2°, 12.9°, 14.8° and 26.6°.

18. The XRPD pattern has a 2θ reflectance (+ / - 0.2°) at 4.0°, 6.2°, 7.8°, 10.3°, 12.2°, 12.9°, 14.8°, 15.7°, and 26.6°. A crystal according to any one of claims 15 to 17, comprising 2θ).

19. The aforementioned XRPD pattern is Table 20 The crystal according to claim 15, comprising a 2θ reflectance (+ / - 0.2° 2θ) at .

20. The crystal according to any one of claims 15 to 19, wherein the crystal exhibits an endothermic event at 154°C.

21. The crystal according to any one of claims 15 to 20, wherein the crystal is not solvated.

22. formula: 【Chemistry 23】 The HCl salt of the compound.

23. A crystal of an HCl salt according to claim 22, wherein the crystal is characterized by an XRPD pattern having 2θ reflectances (+ / -0.2° 2θ) at 5.9°, 14.0°, and 24.3°.

24. The crystal according to claim 23, wherein the XRPD pattern further includes one of the 2θ reflectances (+ / -0.2° 2θ) at 11.7°, 16.7°, and 23.9°.

25. The crystal according to claim 23 or 24, wherein the XRPD pattern includes 2θ reflectances (+ / -0.2° 2θ) at 5.9°, 11.7°, 14.0°, 16.7°, 23.9°, and 24.3°.

26. The crystal according to any one of claims 23 to 25, wherein the XRPD pattern includes 2θ reflectances (+ / -0.2° 2θ) at 5.9°, 11.7°, 14.0°, 14.2°, 16.7°, 19.7°, 22.4°, 23.9°, and 24.3°.

27. The aforementioned XRPD pattern is Table 28 The crystal according to claim 23, comprising a 2θ reflectance (+ / - 0.2° 2θ) at .

28. The crystal according to any one of claims 23 to 27, wherein the crystal exhibits two endothermic transitions at 115°C and 187°C and an exothermic event at 140°C.

29. The crystal according to any one of claims 23 to 28, wherein the crystal exhibits a 1.1% by weight weight loss event that begins between 20°C and 100°C, a 3.4% by weight weight loss event that begins between 100°C and 135°C, and a 31% by weight weight loss event that begins between 135°C and 265°C.

30. A crystal of an HCl salt according to claim 22, wherein the crystal is characterized by an XRPD pattern having 2θ reflectances (+ / -0.2° 2θ) at 4.0°, 10.6°, 15.0°, and 25.8°.

31. The crystal according to claim 30, wherein the XRPD pattern further includes one of the 2θ reflectances (+ / -0.2° 2θ) at 16.3° and 26.7°.

32. The crystal according to claim 30 or 31, wherein the XRPD pattern includes 2θ reflectances (+ / -0.2° 2θ) at 4.0°, 10.6°, 15.0°, 16.3°, 25.8°, and 26.7°.

33. The crystal according to any one of claims 30 to 32, wherein the XRPD pattern includes 2θ reflectances (+ / -0.2° 2θ) at 4.0°, 10.6°, 12.2°, 15.0°, 15.7°, 16.3°, 25.8°, 26.7°, and 31.5°.

34. The aforementioned XRPD pattern is Table 35 The crystal according to claim 30, comprising a 2θ reflectance (+ / - 0.2° 2θ) at a given point.

35. The crystal according to any one of claims 30 to 34, wherein the crystal exhibits two endothermic transitions at 155°C and 195°C.

36. The crystal according to any one of claims 30 to 35, wherein the crystal exhibits a 35% by weight loss that begins between 100°C and 260°C.

37. A crystal of an HCl salt according to claim 22, wherein the crystal is characterized by an XRPD pattern having 2θ reflectances (+ / -0.2° 2θ) at 4.3°, 7.1°, 15.9°, and 26.6°.

38. The crystal according to claim 37, wherein the XRPD pattern further includes one of the 2θ reflectances (+ / -0.2° 2θ) at 16.8° and 25.7°.

39. The crystal according to claim 37 or 38, wherein the XRPD pattern includes 2θ reflectances (+ / -0.2° 2θ) at 4.3°, 7.1°, 15.9°, 16.8°, 25.7°, and 26.6°.

40. The crystal according to any one of claims 37 to 39, wherein the XRPD pattern includes 2θ reflectances (+ / -0.2° 2θ) at 4.3°, 7.1°, 14.3°, 15.9°, 16.8°, 18.7°, 25.7°, 26.6°, and 27.0°.

41. The aforementioned XRPD pattern is Table 42 The crystal according to claim 37, comprising a 2θ reflectance (+ / - 0.2° 2θ) at a given point.

42. The crystal according to any one of claims 37 to 41, wherein the crystal exhibits a single endothermic transition at 178°C.

43. The crystal according to any one of claims 37 to 42, wherein the crystal exhibits a weight loss of 1.2% by weight that begins between 20°C and 100°C and a weight loss of 28% by weight that begins between 100°C and 240°C.

44. A crystal of an HCl salt according to claim 22, wherein the crystal is characterized by an XRPD pattern having 2θ reflectances (+ / -0.2° 2θ) at 4.3°, 12.8°, 14.7°, and 31.4°.

45. The crystal according to claim 44, wherein the XRPD pattern further includes one of 2θ reflectances of 17.3° and 35.1° (+ / -0.2° 2θ).

46. The crystal according to claim 44 or 45, wherein the XRPD pattern includes 2θ reflectances (+ / -0.2° 2θ) at 4.3°, 12.8°, 14.7°, 17.3°, 31.4°, and 35.1°.

47. The crystal according to any one of claims 44 to 46, wherein the XRPD pattern includes 2θ reflectances (+ / -0.2° 2θ) at 4.3°, 12.8°, 14.7°, 16.6°, 17.3°, 24.9°, 27.2°, 31.4°, and 35.1°.

48. The aforementioned XRPD pattern is Table 49 The crystal according to claim 44, comprising a 2θ reflectance (+ / - 0.2° 2θ) at .

49. The crystal according to any one of claims 44 to 48, wherein the crystal exhibits one endothermic transition at 186°C.

50. The crystal according to any one of claims 44 to 49, wherein the crystal exhibits a 30% by weight loss that begins between 100°C and 250°C.

51. A pharmaceutical composition, (a) The crystal according to any one of claims 1 to 13, 15 to 21, and 23 to 50 or the salt according to claim 14 or 22; and (b) Pharmaceutically acceptable excipients A pharmaceutical composition containing the following:

52. The pharmaceutical composition according to claim 51, wherein the pharmaceutical composition is for subcutaneous, intramuscular, intravenous, oral, or inhalation administration.

53. The pharmaceutical composition according to claim 51, wherein the pharmaceutical composition is for oral administration.

54. A pharmaceutical formulation comprising a crystal according to any one of claims 1 to 13, 15 to 21, and 23 to 50, or a salt according to claim 14 or 22, for treating or preventing a viral infection in a person who needs to treat or prevent a viral infection.

55. The pharmaceutical preparation according to claim 54, wherein the viral infection is SARS-CoV-2 infection (COVID-19).

56. The pharmaceutical preparation according to claim 54, wherein the viral infection is a Pneumoviridae virus infection, a Picornaviridae virus infection, a Flaviviridae virus infection, a Filoviridae virus infection, an orthomyxovirus infection, or a Paramyxoviridae virus infection.

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