Compounds and methods for treating viral infections

Abstract

Disclosed are compounds for treating viral infections and methods of using the compounds alone or in combination with additional pharmaceutical agents, as well as salts, crystalline forms, and pharmaceutical compositions of the compounds.

Description

[0001] Cross-referencing

[0002] This application claims priority to U.S. Provisional Application No. 63 / 071,134, filed August 27, 2020; U.S. Provisional Application No. 63 / 162,283, filed March 17, 2021; and U.S. Provisional Application No. 63 / 215,310, filed June 25, 2021, each of which is incorporated herein by reference in its entirety for all purposes. Background Technology

[0003] There is a need for compounds and methods for treating viral infections, such as those of the families Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Finoviridae, Arenaviridae, Orthomyxovirus, and Coronaviridae. This disclosure addresses the above and other needs. Summary of the Invention

[0004] This disclosure provides compounds of formula I:

[0005]

[0006] Or its pharmaceutically acceptable salt, wherein:

[0007] R 1 It is OH, OCOR 4 Or OC(O)OR 4 ;R 2 It is OH, OCOR 5 Or OC(O)OR 5 ;or

[0008] R 1 and R 2 Together they form -OC(O)O- or -OCHR 6 O-; where

[0009] R 6 It is H, C1-C6 alkyl or C6-C 10 Aryl;

[0010] R 3 It is H, COR 7 or COOR 7 ;

[0011] R 4 R 5 and R7 Each of these groups is independently a C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, or C6-C 10 Aryl, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S;

[0012] Where R 4 R 5 and R 7 Each of the groups is independently and optionally substituted by one, two, or three substituents, which are independently selected from the group consisting of: halogen, cyano, -N3, -OR. 8 -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three independent substituents selected from halogen, cyano, and C1-C6 alkyl groups; and

[0013] Each R 8 Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0014] Each R 9 Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0015] Each R 10 Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; and

[0016] The base is in

[0017] R 11 It is a C1-C6 alkyl group substituted with -OP(O)(OH)2;

[0018] The prerequisite is that when R 3 When it is H, then

[0019] R 1 It is OCOR 4 Or OC(O)OR 4 ;or

[0020] R 2 It is OCOR 5 Or OC(O)OR 5 ;or

[0021] R 1 and R 2 Together they form -OC(O)O- or -OCHR 6 O-.

[0022] This article also provides pharmaceutical compositions comprising the compounds disclosed herein or pharmaceutically acceptable salts thereof.

[0023] This disclosure also provides methods for treating or preventing viral infections in persons in need, wherein the method comprises administering to the person a compound of the disclosure or a pharmaceutically acceptable salt thereof.

[0024] This disclosure also provides a method for preparing a medicament for treating or preventing viral infections in people in need, characterized by using a compound of this disclosure or a pharmaceutically acceptable salt thereof.

[0025] This disclosure also provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment or prevention of viral infections in persons in need. Attached Figure Description

[0026] Figure 1: Shows the antiviral efficacy of compound 1. 1a-b: Viral yield reductions of the A, B.1.351, B.1.1.7, and P.1 lineages, and the SARS-CoV-2 clinical isolates WA1 / 2020, SA / 2020, CA / 2020, and BZ / 2021 on VeroE6 cells, represented by compound 1(a) and reference compound A(b), respectively. EC was specified. 50 Concentration. 1c-d: In vitro cytotoxicity profiles of compound 1 (c) and reference compound A (d) against VeroE6, HEp-2, BHK-21, HCT-8, and a group of primary HAE cells (“F2”, “F3”, “M2”, “M6”, “DF2”) from independent donors. In (ad), symbols denote single biological replicates (n=3), error bars indicate standard deviations, and lines depict nonlinear regression models. 1e: In vitro cytotoxicity profiles of remdesivir against VeroE6, HEp-2, BHK-21, HCT-8, and the same group of primary HAE cells (“F2”, “F3”, “M2”, “M6”, “DF2”). Symbols denote single biological replicates (n=3), error bars indicate standard deviations, and lines depict nonlinear regression models.

[0027] Figure 2: Demonstrates the prophylactic efficacy of compound 1 administered orally. 2a: Schematic diagram of the prophylactic efficacy study design. 2b: Viral titer from nasal lavage fluid; LoD, limit of detection. 2c: Temperature measurements collected daily. 2d: Body weight measured daily. 2e: Infectious titer of SARS-CoV-2 in nasal turbinates harvested four days post-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 infectious particles (h) and SARS-CoV-2 RNA copies (i) in the lungs four days post-infection. The number of independent biological replicates (individual animals) is shown in each subplot, with symbols indicating independent biological replicates. Lines (b, c, d, f) and bars (e, gi) connect or display sample mean values, and p-values ​​are expressed. Two-way ANOVA and Sidak's post-hoc multiple comparison test (b, c, d, f) or two-tailed t-test (e, g).

[0028] Figure 3: This illustrates 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 harvested four days post-infection. 3d: Temperature measurements collected daily. 3e: Body weight measured 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 subplot. Symbols indicate independent biological replicates, and lines (b, d, e, f) and bars (c, g) connect or display sample means, respectively, and p-values ​​are expressed. One-way (c, g) or two-way (b, d, e, f) ANOVA and Dunnett's (b, d, e, f) post-hoc multiple comparison tests.

[0029] Figure 4: This illustrates how 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 study design. 4b: Viral titer from nasal lavage fluid. 4c: SARS-CoV-2 RNA copies present in nasal lavage fluid. 4d: Infectious titer of SARS-CoV-2 in nasal turbinates harvested four days post-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 (bg), the number of independent biological replicates (individual animals) is shown in each subplot. Symbols represent independent biological replicates, and lines (b, c) and bars (d, e, f, g, h) connect or display sample mean values, respectively, and represent p-values. One-way (d, e) or two-way (b, c) ANOVA with Tukey's (d, e) or Sidak's (b, c) post-hoc multiple comparison tests. 4h: Metagenomic sequence analysis of inoculum WA1 / 2020 and BZ / 2021 viruses, viral populations extracted from the nasal turbinates of ferrets four days post-infection, and BZ / 2021 populations extracted from nasal lavage fluid of contact material from source animals treated with vectors. Relative allele frequencies of characteristic residues are shown. Symbols indicate independent biological replicates (viral populations of individual animals), and group means are listed.

[0030] Figure 5: Shows the source of infection with BZ / 2021 and the clinical signs of animals exposed to it. 5a: Temperature measurements were collected daily. 5b: Body weight was measured daily.

[0031] Figures 6a-6c The efficacy of compound 1, administered orally, against SARS-CoV-2 AGM was demonstrated.

[0032] Figures 7a-7c The efficacy of orally administered compound 15 against SARS-CoV-2 in mice was demonstrated. It is evident that treatment with compound 15 reduced the physiological effects of SARS-CoV-2 in mice.

[0033] Figure 8 The study showed that oral administration of compound 1 reduced the terminal SARS-CoV-2 infection titer in the lungs of mice.

[0034] Figures 9a-9c The study showed that orally administered compound 1 reduced the pathophysiological effects of SARS-CoV-2 in mice.

[0035] Figure 10 The XRPD pattern of compound 15 in its free base form I is shown.

[0036] Figure 11 The DSC thermogram of compound 15 in its free base form I is shown.

[0037] Figure 12 The TGA thermogram of compound 15 in its free base form I is shown.

[0038] Figure 13 : This shows the XRPD pattern of compound 15 in its free base form II.

[0039] Figure 14 The DSC thermogram of compound 15 in its free base form II is shown.

[0040] Figure 15 The TGA thermogram of compound 15 in its free base form II is shown.

[0041] Figure 16 : This shows the XRPD pattern of compound 15 in its free base form III.

[0042] Figure 17 The DSC thermogram of compound 15 in its free base form III is shown.

[0043] Figure 18 The TGA thermogram of compound 15 in its free base form III is shown.

[0044] Figure 19 The image shows the XRPD pattern of compound 15 benzonaphthalate material A.

[0045] Figure 20 The DSC thermogram of compound 15 naphthalate material A is shown.

[0046] Figure 21 The TGA thermogram of compound 15 naphthalate material A is shown.

[0047] Figure 22 The XRPD pattern of compound 15 HCl salt form I is shown.

[0048] Figure 23 The DSC thermogram of compound 15 HCl salt form I is shown.

[0049] Figure 24 The TGA thermogram of compound 15 HCl salt form I is shown.

[0050] Figure 25 The image shows the XRPD pattern of compound 15 HCl salt material A.

[0051] Figure 26 The DSC thermogram of compound 15 HCl salt material A is shown.

[0052] Figure 27 The TGA thermogram of compound 15 HCl salt material A is shown.

[0053] Figure 28 The image shows the XRPD pattern of compound 15 HCl salt material B.

[0054] Figure 29 The DSC thermogram of compound 15 HCl salt material B is shown.

[0055] Figure 30 The TGA thermogram of compound 15 HCl salt material B is shown.

[0056] Figure 31 The image shows the XRPD pattern of compound 15 HCl salt material C.

[0057] Figure 32 The DSC thermogram of compound 15 HCl salt material C is shown.

[0058] Figure 33 The TGA thermogram of compound 15 HCl salt material C is shown. Detailed Implementation

[0059] I. Overview

[0060] The present invention relates to methods and compounds for treating or preventing viral infections, such as those of the Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, Arenaviridae, Orthomyxoviridae, and Coronaviridae families.

[0061] II. Definition

[0062] Unless otherwise indicated, the following terms and phrases as used herein are intended to have the following meanings:

[0063] "Alkyl" refers to a saturated hydrocarbon chain that is unbranched or branched. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C1-C2). 20Alkyl groups, having 1 to 8 carbon atoms (i.e., C1-C8 alkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (I-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -C H(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, tert-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 (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 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(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), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3).

[0064] "Alkenyl" refers to a group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C24-C24-C24). 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C) 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C) 2-6 Alkenyl) or 2 to 4 carbon atoms (i.e., C) 2-4 Alkenyl groups are aliphatic groups. Examples of alkenyl groups include vinyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0065] "Alkyne" refers to a group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C64-C ... 2-20 acetylsyl group), 2 to 8 carbon atoms (i.e., C64) 2-8 alkynyl group), 2 to 6 carbon atoms (i.e., C64) 2-6 (alkynyl group) or 2 to 4 carbon atoms (i.e., C) 2-4 The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0066] "Haloalkyl" is an alkyl group as defined above, wherein one or more hydrogen atoms of the alkyl group are replaced by halogen atoms. The alkyl moiety of the haloalkyl group can have 1 to 20 carbon atoms (i.e., C1-C2). 20 Halogenated alkyl groups), 1 to 12 carbon atoms (i.e., C1-C1), 12 Halogenated alkyl groups, having 1 to 8 carbon atoms (i.e., C1-C8 alkyl groups), 1 to 6 carbon atoms (i.e., C1-C6 alkyl groups), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl groups). Examples of suitable alkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, -CH2CF3, etc.

[0067] "Aryl" refers to an aromatic hydrocarbon group derived by removing a hydrogen atom from a single carbon atom in a parent aromatic ring system. For example, aryl groups can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, groups derived from benzene (e.g., phenyl), substituted benzenes, naphthalenes, anthracene, biphenyls, etc.

[0068] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring atoms (i.e., 1 to 20-membered heteroaryl rings), 3 to 12 ring atoms (i.e., 3 to 12-membered heteroaryl rings), or 3 to 8 carbon ring atoms (i.e., 3 to 8-membered heteroaryl rings), or 5 to 6 ring atoms (i.e., 5 to 6-membered heteroaryl rings). Examples of heteroaryl groups include pyrimidinyl, purine, pyridinyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass aryl groups as defined above or overlaps with them.

[0069] A "carbocyclic group" or "carbocyclic ring" refers to a non-aromatic hydrocarbon ring composed of carbon and hydrogen atoms, having three to twenty carbon atoms, in some embodiments three to fifteen carbon atoms, and in some embodiments three to ten, three to eight, three to seven, or three to six carbon atoms, and is saturated or partially unsaturated and connected to the rest of the molecule by single bonds. Carbocyclic rings include, for example, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, and cyclooctane.

[0070] "Cycloalkyl" refers to a saturated cyclic alkyl group having a single ring or comprising multiple rings in fused, bridged, and spirocyclic systems. As used herein, cycloalkyl groups have 3 to 20 cyclic carbon atoms (i.e., C46, ​​C56, C6 ... 3-20 cycloalkyl groups), 3 to 12 cyclic carbon atoms (i.e., C12+ ... 3-12 cycloalkyl groups), 3 to 10 cyclic carbon atoms (i.e., C14 and C24). 3-10 cycloalkyl groups), 3 to 8 cyclic carbon atoms (i.e., C1646-C ... 3-8 cycloalkyl groups or 3 to 6 cyclic carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 3-6 (Cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0071] The term "optionally substituted" in relation to a specific portion (e.g., an optionally substituted aryl group) of a compound of formula I means a portion in which all substituents are hydrogen or in which one or more hydrogens of that portion may be replaced by the listed substituents.

[0072] Unless otherwise specified, the carbon atoms in compounds of Formula I are intended to have a tetravalent oxidation state. If, in some chemical structural representation, the carbon atom is not connected to a sufficient number of variables to produce a tetravalent oxidation state, it should be assumed that the remaining carbon substituents required to provide the tetravalent oxidation state are hydrogen.

[0073] Unless otherwise specified, as used herein, the term "treatment" means reversing, alleviating, or inhibiting the progression of a disease or condition to which the term applies, or one or more symptoms of such a disease or condition, or preventing the occurrence of one or more symptoms of such a disease or condition. As used herein, the term "treatment" refers to the act of treatment, as "treatment" is as defined above.

[0074] "Prevention" or "preventing" means any treatment for a disease or condition that prevents the development of clinical symptoms. In some embodiments, the compounds and compositions disclosed herein may be administered to subjects (including humans) at risk of developing a disease or condition. As used herein, the term "preventing / prevention" encompasses the administration of a compound, composition, or pharmaceutically acceptable salt according to the embodiments disclosed herein before or after an individual's exposure to a virus, but before the onset of symptoms of viral infection and / or before the virus is detected in the blood. The term also refers to the prevention of the onset of disease symptoms and / or the prevention of the virus from reaching detectable levels in the blood. The term includes pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) and event-driven or "on-demand" prophylaxis. The term also refers to the prevention of perinatal transmission of the virus from mother to infant by administration to the mother before delivery and to the infant during the first few days of life. The term also refers to the prevention of transmission of the virus via blood transfusion.

[0075] As used herein, the term "therapeutic effective amount" is the amount of a compound of formula I present in the compositions described herein that is required to deliver a desired level of the drug in the secretions and tissues of the airways and lungs, or alternatively, that is required to produce the desired physiological response or desired biological effect in the bloodstream of the subject to be treated when such a composition is administered via a chosen route of administration. The precise amount will depend on many 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 and its intended use, and patient considerations such as the severity of the disease, patient cooperation, etc., and this precise amount can be readily determined by those skilled in the art based on the information provided herein.

[0076] "DSC" refers to Differential Scanning Calorimetry.

[0077] "XRPD" refers to X-ray powder diffraction patterns in solid form.

[0078] "TGA" refers to thermogravimetric analysis.

[0079] When referring to, for example, XRPD patterns, DSC thermograms, or TGA plots, the term “substantially as shown” includes patterns, thermograms, or plots that may not necessarily be the same as those described herein, but which, when considered by a person of ordinary skill in the art, fall within the limits of experimental error or deviation.

[0080] A "protecting group" is a part of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. The chemical substructure of protecting groups varies considerably. One function of protecting groups is as intermediates in the synthesis of parent drugs. Chemical protecting groups and the strategies used for protection / deprotection are well known in the art. See: "Protective Groups in Organic Chemistry", Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. See also: Protective Groups in Organic Chemistry, Peter GMWuts and Theodora W. Greene, 4th ed., 2006. Protecting groups are often used to mask the reactivity of certain functional groups to contribute to the efficiency of desired chemical reactions, such as the orderly and planned formation and breaking of chemical bonds. Functional group protection of a compound alters other physical properties besides the reactivity of the protected functional group, such as polarity, lipophilicity (hydrophobicity), and other properties measurable by commonly used analytical tools. Chemically protected intermediates can themselves be biologically active or inactive. "Hydroxy protecting group" refers to those protecting groups that can be used to protect hydroxyl groups (-OH).

[0081] "Deprotecting agent" refers to any reagent capable of removing protecting groups. The deprotecting agent will depend 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 edition, mid-2006.

[0082] III. Compounds

[0083] Any reference to the compounds of the invention described herein also includes reference to their pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable bases such as alkali metals or alkaline earth metals (e.g., Na₂O₃). + Li + K + Ca +2 and Mg +2 ), ammonium and NR4 + (where R is defined in this paper) salt. Pharmaceutically acceptable salts of nitrogen atoms or amino groups include: (a) acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, etc.); (b) salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, ethanesulfonic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalactobionic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthyl ester, dihydroxynaphthyl salt, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine, etc.; and (c) salts formed by elemental anions such as chlorine, bromine, and iodine. Pharmaceutically acceptable salts of hydroxyl compounds include the anion of the compound with a suitable cation such as Na+. + and NR4 + The combination of .

[0084] 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 can exist as different polymorphs or pseudopolymorphs. As used herein, crystal polymorphism means the ability of a crystalline compound to exist in different crystal structures. Crystal polymorphism can be caused by differences in crystal packing (packing polymorphism) or by differences in packing between different conformational isomers of the same molecule (conformational polymorphism). As used herein, crystal pseudopolymorphism means the ability of a hydrated or solvated compound to exist in different crystal structures. The pseudopolymorphs of the present invention can exist due to differences in crystal packing (packing pseudopolymorphism) or due to differences in packing between different conformational isomers of the same molecule (conformational pseudopolymorphism). The present invention includes all polymorphs and pseudopolymorphs of compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, or IIIc and their pharmaceutically acceptable salts.

[0085] 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 in which the atomic positions are not long-range ordered. This definition also applies when the crystal size is two nanometers or less. Additives (including solvents) may be used to produce the amorphous forms of the present invention. The present invention includes all amorphous forms of compounds of formulas I, II, III, IV, V, Va, Vb, VI, VIa, and VIb and their pharmaceutically acceptable salts.

[0086] For therapeutic purposes, the salts of the active ingredients of the compounds of the present invention will be pharmaceutically acceptable, i.e., they will be salts derived from pharmaceutically acceptable acids or bases. However, salts of pharmaceutically unacceptable acids or bases may also be used, for example, to prepare or purify pharmaceutically acceptable compounds. All salts, whether or not derived from pharmaceutically acceptable acids or bases, are within the scope of the present invention.

[0087] It should also be understood that the compositions herein include the non-ionic and zwitterionic forms of the compounds of the present invention and a combination with a stoichiometric amount of water in the hydrate.

[0088] It should be noted that this invention covers all enantiomers, diastereomers, racemic mixtures, tautomers, polymorphs, and pseudopolymorphs of compounds and their pharmaceutically acceptable salts within the range of formulas I, II, III, IV, V, Va, Vb, VI, VIa, or VIb. All such mixtures of enantiomers and diastereomers are within the scope of this invention.

[0089] 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 comprise racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and transisomers. Furthermore, the compounds of the present invention comprise optical isomers enriched or resolved at any or all asymmetric, chiral atoms. In other words, the chiral center, as apparent from the description, is provided as a chiral isomer or a racemic mixture. Both racemic mixtures and diastereomer mixtures, as well as isolated or synthesized individual optical isomers (substantially free of their enantiomers or diastereomer conjugates), are within the scope of the present invention. Racemic mixtures are isolated into their individual, substantially optically pure isomers by suitable techniques, for example, by separating diastereomers formed with optically active auxiliaries (e.g., acids or bases), and then converting the diastereomers back into the optically active substance. In most cases, the desired optical isomers are synthesized via stereospecific reactions, starting with appropriate stereoisomers of the desired starting material.

[0090] The stereochemical definitions and conventions used in this article generally follow the SPParker editorial guidelines. 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 an optically active form, meaning they possess the ability to rotate the plane of polarization of light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule around its chiral center. The prefixes d and l, D and L, or (+) and (-) are used to indicate the plane-polarized rotation symbol of a compound, where S, (-), or 1 indicates that the compound is levorotatory, while compounds prefixed with R, (+), or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical, differing only in that they are mirror images of each other. Specific stereoisomers can also be called enantiomers, and mixtures of such isomers are generally called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur without stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that lacks optical activity.

[0091] In some cases, the compounds of the present invention may also exist as tautomers. Although only one delocalized resonance structure can be described, all such forms are considered within the scope of the present invention. For example, for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazolium systems, olefin-amine tautomers may exist, and all their possible tautomer forms are within the scope of the present invention.

[0092] 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 form and isotopically labeled form of the compound. Isotopically labeled compounds have the structure described by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, isotopes of these elements. 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 I. Various isotope-labeled compounds disclosed herein, such as those containing radioactive isotopes such as 3 H, 13 C and 14 C is incorporated. These isotope-labeled compounds can be used in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including tissue distribution assays of drugs or substrates, or for radiation therapy of patients.

[0093] This disclosure also includes compounds of Formula I, wherein one to x hydrogen atoms bonded to carbon atoms are replaced by deuterium, where x is the number of hydrogen atoms in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for extending the half-life of any compound of Formula I when administered to mammals, particularly humans. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. Vol. 5 (No. 12): pp. 524-527 (1984). In view of this disclosure, such compounds are synthesized by methods known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0094] The deuterium-labeled or substituted therapeutic compounds disclosed herein may have improved DMPK (drug metabolism and pharmacokinetics) properties, which involve distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope (such as deuterium) can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dose requirements, and / or improved therapeutic index. 18 F-labeled compounds can be used in PET or SPECT studies. The isotopically labeled compounds and their prodrugs disclosed herein can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents, or by following the procedures disclosed in the examples and formulations described below. It should be understood that, in this context, deuterium is considered a substituent in compounds of formula I.

[0095] The concentration of such heavier isotopes (particularly deuterium) can be defined by the isotope enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope means that atom represents any stable isotope. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," that position is understood to be hydrogen having its naturally occurring isotopic composition. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) means that deuterium is represented.

[0096] Whenever a compound described herein is substituted with more than one of the same designated groups (e.g., “R” or “R”), it should be understood that these groups may be the same or different, i.e., each group is chosen independently.

[0097] Waveform, Indicates the position where a covalent bond connects to an adjacent substructure, group, part, or atom.

[0098] IV. Compounds

[0099] In some embodiments, compounds of formula I are provided herein:

[0100]

[0101]

[0102] Or its pharmaceutically acceptable salt, wherein:

[0103] R 1 It is OH, OCOR 4 Or OC(O)OR 4 ;

[0104] R 2 It is OH, OCOR 5 Or OC(O)OR 5 ;or

[0105] R 1 and R 2 Together they form -OC(O)O- or -OCHR 6 O-; where

[0106] R 6 It is H, C1-C6 alkyl or C6-C 10 Aryl;

[0107] R 3 It is H, COR 7 or COOR 7 ;

[0108] R 4 R 5 and R 7 Each of these groups is independently a C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, or C6-C 10 Aryl, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S;

[0109] Where R 4 R 5 and R 7 Each of the groups is independently and optionally substituted by one, two, or three substituents, which are independently selected from the group consisting of: halogen, cyano, -N3, -OR. 8 -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three independent substituents selected from halogen, cyano, and C1-C6 alkyl groups; and

[0110] Each R 8 Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0111] Each R 9 Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0112] Each R 10 Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; and

[0113] The base is in

[0114] R 11 It is a C1-C6 alkyl group substituted with -OP(O)(OH)2;

[0115] The prerequisite is that when R 3 When it is H, then

[0116] R 1 It is OCOR 4 Or OC(O)OR 4 ;or

[0117] R 2 It is OCOR 5 Or OC(O)OR 5 ;or

[0118] R 1 and R 2 Together they form -OC(O)O- or -OCHR 6 O-.

[0119] In some embodiments of the compound of formula I or its pharmaceutically acceptable salt, the base is Where R 11 It is -CH2OP(O)(OH)2. In some embodiments, the base is Where R 11 It is a C1-C6 alkyl group substituted with -OP(O)(OH)2. In some embodiments, the base is... Where R 11 It is -CH2OP(O)(OH)2. In some embodiments, the base is Where R 11 It is a C1-C6 alkyl group substituted with -OP(O)(OH)2. In some embodiments, the base is... Where R 11 It is -CH2OP(O)(OH)2. In some embodiments of compounds of formula I or their pharmaceutically acceptable salts, the base is

[0120] In some embodiments, formula I is a compound of formula Ia:

[0121]

[0122] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 3 It is COR 7 or COOR 7 ;where R 7 It is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; and wherein R 7 The group may optionally be substituted by one, two, or three substituents, which are independently selected from the group consisting of: halogen, cyano, -N3, -OR.8 -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 3 It is COR 7 or COOR 7 ;where R 7 It is a C1-C8 alkyl, C3-C8 carbocyclic, C6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; and wherein R 7 The group may optionally be substituted by one, two, or three substituents, which are independently selected from the group consisting of: halogen, cyano, -N3, -OR. 8 -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 3 It is COR 7 or COOR 7 ;where R 7 It is a C1-C8 alkyl or C3-C8 carbocyclic group; and wherein R 7 The group may optionally be substituted by one, two, or three substituents, which are independently selected from the group consisting of: halogen, cyano, -N3, -OR. 8 -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 3 It is COR 7 or COOR 7 ;where R 7 It is a C1-C8 alkyl group optionally substituted with one, two, or three substituents, which are independently selected from the group consisting of: halogen, cyano, -N3, -OR. 8 -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 3 It is COR 7 or COOR 7 ;where R 7 It is a C1-C4 alkyl group optionally substituted with one, two, or three substituents, which are independently selected from the group consisting of: halogen, cyano, -N3, -OR. 8 -NR9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 9 and R 10 Both are H.

[0123] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 3 It is COR 7 or COOR 7 ;where R 7 It is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; and wherein R 7 The group may be optionally replaced by one, two, or three substituents, which are independently selected from the group consisting of: -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 3 It is COR 7 or COOR 7 ;where R 7 It is a C1-C8 alkyl, C3-C8 carbocyclic, C6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; and wherein R 7 The group may be optionally replaced by one, two, or three substituents, which are independently selected from the group consisting of: -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 3 It is COR 7 or COOR 7 ;where R 7 It is a C1-C8 alkyl or C3-C8 carbocyclic group; and wherein R 7 The group may be optionally replaced by one, two, or three substituents, which are independently selected from the group consisting of: -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 3 It is COR 7 or COOR 7 ;where R 7It is a C1-C8 alkyl group optionally substituted with one, two, or three substituents, which are independently selected from the group consisting of: -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 3 It is COR 7 or COOR 7 ;where R 7 It is a C1-C4 alkyl group optionally substituted with one, two, or three substituents, which are independently selected from the group consisting of: -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 9 and R 10 Both are H.

[0124] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 3 It is COR 7 or COOR 7 ;where R 7 It is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; and wherein R 7 The groups are optionally selected independently by one, two, or three free radicals. 9 R 10 Substituents in the group consisting of phenyl and ethyl groups are substituted. In some embodiments, R 3 It is COR 7 or COOR 7 ;where R 7 It is a C1-C8 alkyl, C3-C8 carbocyclic, C6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; and wherein R 7 The groups are optionally selected independently by one, two, or three free radicals. 9 R 10 Substituents in the group consisting of phenyl and ethyl groups are substituted. In some embodiments, R 3 It is COR 7 or COOR 7 ;where R 7 It is a C1-C8 alkyl or C3-C8 carbocyclic group; and wherein R 7 The groups are optionally selected independently by one, two, or three free radicals.9 R 10 Substituents in the group consisting of phenyl and ethyl groups are substituted. In some embodiments, R 3 It is COR 7 or COOR 7 ;where R 7 It is arbitrarily chosen by one, two, or three independent free agents -NR 9 R 10 The C1-C8 alkyl group consisting of phenyl groups and substituted groups. In some embodiments, R 3 It is COR 7 or COOR 7 ;where R 7 It is arbitrarily chosen by one, two, or three independent free agents -NR 9 R 10 The C1-C4 alkyl group consisting of phenyl groups and substituted groups. In some embodiments, R 9 and R 10 Both are H.

[0125] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 3 It is COR 7 or COOR 7 ;where R 7 It is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 Aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 3 It is COR 7 or COOR 7 ;where R 7 It is a C1-C8 alkyl, C3-C8 carbocyclic, C6-C 10 Aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 3 It is COR 7 or COOR 7 ;where R 7 It is a C1-C8 alkyl or C3-C8 carbocyclic group. In some embodiments, R 3 It is COR 7 or COOR 7 ;where R 7 It is a C1-C8 alkyl group. In some embodiments, R 3 It is COR 7 or COOR 7 ;where R 7 It is a C1-C4 alkyl group.

[0126] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 3 It is COR 7 or COOR 7 , where R 7 Choose from the following groups: -CH3, -CH2CH3, In some implementation schemes, R 3 It is COR 7 or COOR 7 , where R 7 Choose from the following groups: -CH3, -CH2CH3, In some implementation schemes, R 3 It is COR 7 or COOR 7 , where R 7 Choose from the following groups: -CH3, -CH2CH3,

[0127] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 3 It is COR 7 ;where R 7 It is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; and wherein R 7 The group may optionally be substituted by one, two, or three substituents, which are independently selected from the group consisting of: halogen, cyano, -N3, -OR. 8 -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 3 It is COR 7 ;where R 7 It is a C1-C8 alkyl, C3-C8 carbocyclic, C6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; and wherein R 7 The group may optionally be substituted by one, two, or three substituents, which are independently selected from the group consisting of: halogen, cyano, -N3, -OR. 8 -NR 9 R 10And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 3 It is COR 7 ;where R 7 It is a C1-C8 alkyl or C3-C8 carbocyclic group; and wherein R 7 The group may optionally be substituted by one, two, or three substituents, which are independently selected from the group consisting of: halogen, cyano, -N3, -OR. 8 -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 3 It is COR 7 ;where R 7 It is a C1-C8 alkyl group optionally substituted with one, two, or three substituents, which are independently selected from the group consisting of: halogen, cyano, -N3, -OR. 8 -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 3 It is COR 7 ;where R 7 It is a C1-C4 alkyl group optionally substituted with one, two, or three substituents, which are independently selected from the group consisting of: halogen, cyano, -N3, -OR. 8 -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 9 and R 10 Both are H.

[0128] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 3 It is COR 7 ;where R 7 It is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; and wherein R 7 The group may be optionally replaced by one, two, or three substituents, which are independently selected from the group consisting of: -NR 9 R 10And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 3 It is COR 7 ;where R 7 It is a C1-C8 alkyl, C3-C8 carbocyclic, C6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; and wherein R 7 The group may be optionally replaced by one, two, or three substituents, which are independently selected from the group consisting of: -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 3 It is COR 7 ;where R 7 It is a C1-C8 alkyl or C3-C8 carbocyclic group; and wherein R 7 The group may be optionally replaced by one, two, or three substituents, which are independently selected from the group consisting of: -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 3 It is COR 7 ;where R 7 It is a C1-C8 alkyl group optionally substituted with one, two, or three substituents, which are independently selected from the group consisting of: -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 3 It is COR 7 ;where R 7 It is a C1-C4 alkyl group optionally substituted with one, two, or three substituents, which are independently selected from the group consisting of: -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 9 and R 10 Both are H.

[0129] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 3 It is COR 7 ;where R 7It is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; and wherein R 7 The groups are optionally selected independently by one, two, or three free radicals. 9 R 10 Substituents in the group consisting of phenyl and ethyl groups are substituted. In some embodiments, R 3 It is COR 7 ;where R 7 It is a C1-C8 alkyl, C3-C8 carbocyclic, C6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; and wherein R 7 The groups are optionally selected independently by one, two, or three free radicals. 9 R 10 Substituents in the group consisting of phenyl and ethyl groups are substituted. In some embodiments, R 3 It is COR 7 ;where R 7 It is a C1-C8 alkyl or C3-C8 carbocyclic group; and wherein R 7 The groups are optionally selected independently by one, two, or three free radicals. 9 R 10 Substituents in the group consisting of phenyl and ethyl groups are substituted. In some embodiments, R 3 It is COR 7 ;where R 7 It is arbitrarily chosen by one, two, or three independent free agents -NR 9 R 10 The C1-C8 alkyl group consisting of phenyl groups and substituted groups. In some embodiments, R 3 It is COR 7 ;where R 7 It is arbitrarily chosen by one, two, or three independent free agents -NR 9 R 10 The C1-C4 alkyl group consisting of phenyl groups and substituted groups. In some embodiments, R 9 and R 10 Both are H.

[0130] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 3 It is COR 7 ;where R 7 It is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10Aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 3 It is COR 7 ;where R 7 It is a C1-C8 alkyl, C3-C8 carbocyclic, C6-C 10 Aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 3 It is COR 7 ;where R 7 It is a C1-C8 alkyl or C3-C8 carbocyclic group. In some embodiments, R 3 It is COR 7 ;where R 7 It is a C1-C8 alkyl group. In some embodiments, R 3 It is COR 7 ;where R 7 It is a C1-C4 alkyl group.

[0131] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 3 It is COR 7 , where R 7 Choose from the following groups: -CH3, -CH2CH3, In some implementation schemes, R 3 It is COR 7 , where R 7 Choose from the following groups: -CH3, -CH2CH3,

[0132] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 3 It is COOR 7 ;where R 7 It is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; and wherein R 7 The group may optionally be substituted by one, two, or three substituents, which are independently selected from the group consisting of: halogen, cyano, -N3, -OR. 8 -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 3 It is COOR7 ;where R 7 It is a C1-C8 alkyl, C3-C8 carbocyclic, C6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; and wherein R 7 The group may optionally be substituted by one, two, or three substituents, which are independently selected from the group consisting of: halogen, cyano, -N3, -OR. 8 -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 3 It is COOR 7 ;where R 7 It is a C1-C8 alkyl or C3-C8 carbocyclic group; and wherein R 7 The group may optionally be substituted by one, two, or three substituents, which are independently selected from the group consisting of: halogen, cyano, -N3, -OR. 8 -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 3 It is COOR 7 ;where R 7 It is a C1-C8 alkyl group optionally substituted with one, two, or three substituents, which are independently selected from the group consisting of: halogen, cyano, -N3, -OR. 8 -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 3 It is COOR 7 ;where R 7 It is a C1-C4 alkyl group optionally substituted with one, two, or three substituents, which are independently selected from the group consisting of: halogen, cyano, -N3, -OR. 8 -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 9 and R 10 Both are H.

[0133] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 3 It is COOR7 ;where R 7 It is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; and wherein R 7 The group may be optionally replaced by one, two, or three substituents, which are independently selected from the group consisting of: -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 3 It is COOR 7 ;where R 7 It is a C1-C8 alkyl, C3-C8 carbocyclic, C6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; and wherein R 7 The group may be optionally replaced by one, two, or three substituents, which are independently selected from the group consisting of: -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 3 It is COOR 7 ;where R 7 It is a C1-C8 alkyl or C3-C8 carbocyclic group; and wherein R 7 The group may be optionally replaced by one, two, or three substituents, which are independently selected from the group consisting of: -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 3 It is COOR 7 ;where R 7 It is a C1-C8 alkyl group optionally substituted with one, two, or three substituents, which are independently selected from the group consisting of: -NR 9 R 10 And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 3 It is COOR 7 ;where R 7 It is a C1-C4 alkyl group optionally substituted with one, two, or three substituents, which are independently selected from the group consisting of: -NR 9 R 10And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R 9 and R 10 Both are H.

[0134] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 3 It is COOR 7 ;where R 7 It is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; and wherein R 7 The groups are optionally selected independently by one, two, or three free radicals. 9 R 10 Substituents in the group consisting of phenyl and ethyl groups are substituted. In some embodiments, R 3 It is COOR 7 ;where R 7 It is a C1-C8 alkyl, C3-C8 carbocyclic, C6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; and wherein R 7 The groups are optionally selected independently by one, two, or three free radicals. 9 R 10 Substituents in the group consisting of phenyl and ethyl groups are substituted. In some embodiments, R 3 It is COOR 7 ;where R 7 It is a C1-C8 alkyl or C3-C8 carbocyclic group; and wherein R 7 The groups are optionally selected independently by one, two, or three free radicals. 9 R 10 Substituents in the group consisting of phenyl and ethyl groups are substituted. In some embodiments, R 3 It is COOR 7 ;where R 7 It is arbitrarily chosen by one, two, or three independent free agents -NR 9 R 10 The C1-C8 alkyl group consisting of phenyl groups and substituted groups. In some embodiments, R 3 It is COOR 7 ;where R 7 It is arbitrarily chosen by one, two, or three independent free agents -NR 9 R 10 The C1-C4 alkyl group consisting of phenyl groups and substituted groups. In some embodiments, R 9 and R10 Both are H.

[0135] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 3 It is COOR 7 ;where R 7 It is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 Aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 3 It is COOR 7 ;where R 7 It is a C1-C8 alkyl, C3-C8 carbocyclic, C6-C 10 Aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 3 It is COOR 7 ;where R 7 It is a C1-C8 alkyl or C3-C8 carbocyclic group. In some embodiments, R 3 It is COOR 7 , where R 7 It is a C1-C8 alkyl group. In some embodiments, R 3 It is COOR 7 , where R 7 It is a C1-C4 alkyl group.

[0136] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 3 It is COOR 7 , where R 7 Choose from the following groups: -CH3, -CH2CH3, In some implementation schemes, R 3 It is COOR 7 , where R 7 Choose from the following groups: -CH3, -CH2CH3,

[0137] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 1 It is OH, OCOR 4 Or OC(O)OR 4 And R 2 It is OH, OCOR 5 Or OC(O)OR 5 In some implementations, R 1 It is OH and R2 It is OH, OCOR 5 Or OC(O)OR 5 In some implementations, R 1 It is OH and R 2 It is OCOR 5 Or OC(O)OR 5 In some implementations, R 1 It is OH and R 2 It is OCOR 5 In some implementations, R 1 It is OH and R 2 It is OC(O)OR 5 .

[0138] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 1 It is OH, OCOR 4 Or OC(O)OR 4 And R 2 It is OH. In some implementations, R 1 It is OCOR 4 Or OC(O)OR 4 And R 2 It is OH. In some implementations, R 1 It is OCOR 4 And R 2 It is OH. In some implementations, R 1 It is OC(O)OR 4 And R 2 It is OH.

[0139] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 1 It is OCOR 4 Or OC(O)OR 4 And R 2 It is OCOR 5 Or OC(O)OR 5 In some implementations, R 1 It is OCOR 4 And R 2 It is OCOR 5 Or OC(O)OR 5 In some implementations, R 1 It is OC(O)OR 4 And R 2 It is OCOR 5 Or OC(O)OR 5 .

[0140] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 1 It is OCOR 4 Or OC(O)OR 4 And R 2 It is OCOR 5 In some implementations, R 1 It is OCOR 4 Or OC(O)OR 4 And R 2 It is OC(O)OR 5 .

[0141] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 1 It is OCOR 4 And R 2 It is OCOR 5 In some implementations, R 1 It is OCOR 4 And R 2 It is OC(O)OR 5 .

[0142] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 1 It is OC(O)OR 4 And R 2 It is OCOR 5 In some implementations, R 1 It is OC(O)OR 4 And R 2 It is OC(O)OR 5 .

[0143] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 4 and R 5 Each is independently a C1-C8 alkyl group. In some embodiments, R 4 and R 5 Each is independently a C1-C6 alkyl group. In some embodiments, R 4 and R 5 Each is independently a C1-C3 alkyl group. In some embodiments, R 4 and R 5 Each can be methyl, ethyl, or isopropyl.

[0144] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 1 It is OH, OCOR 4 Or OC(O)OR 4 And R2 It is OH, OCOR 5 Or OC(O)OR 5 ;where R 4 and R 5 Each is independently a C1-C8 alkyl group. In some embodiments, R 1 It is OH, OCOR 4 Or OC(O)OR 4 And R 2 It is OH, OCOR 5 Or OC(O)OR 5 ;where R 4 and R 5 Each is independently a C1-C6 alkyl group. In some embodiments, R 1 It is OH, OCOR 4 Or OC(O)OR 4 And R 2 It is OH, OCOR 5 Or OC(O)OR 5 ;where R 4 and R 5 Each is independently a C1-C3 alkyl group. In some embodiments, R 1 It is OH, OCOR 4 Or OC(O)OR 4 And R 2 It is OH, OCOR 5 Or OC(O)OR 5 ;where R 4 and R 5 Each can be methyl, ethyl, or isopropyl.

[0145] In some implementation schemes, R 1 It is OH and R 2 It is OH, OCOR 5 Or OC(O)OR 5 ;where R 5 It is a C1-C8 alkyl group. In some embodiments, R 1 It is OH and R 2 It is OH, OCOR 5 Or OC(O)OR 5 ;where R 5 It is a C1-C6 alkyl group. In some embodiments, R 1 It is OH and R 2 It is OH, OCOR 5 Or OC(O)OR 5 ;where R 5 It is a C1-C3 alkyl group. In some embodiments, R 1 It is OH and R2 It is OH, OCOR 5 Or OC(O)OR 5 ;where R 5 It is methyl, ethyl, or isopropyl.

[0146] In some implementation schemes, R 1 It is OH and R 2 It is OCOR 5 Or OC(O)OR 5 ;where R 5 It is a C1-C8 alkyl group. In some embodiments, R 1 It is OH and R 2 It is OCOR 5 Or OC(O)OR 5 ;where R 5 It is a C1-C6 alkyl group. In some embodiments, R 1 It is OH and R 2 It is OCOR 5 Or OC(O)OR 5 ;where R 5 It is a C1-C3 alkyl group. In some embodiments, R 1 It is OH and R 2 It is OCOR 5 Or OC(O)OR 5 ;where R 5 It is methyl, ethyl, or isopropyl.

[0147] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 1 It is OH, OCOR 4 Or OC(O)OR 4 And R 2 It is OH; where R 4 It is a C1-C8 alkyl group. In some embodiments, R 1 It is OH, OCOR 4 Or OC(O)OR 4 And R 2 It is OH; where R 4 It is a C1-C6 alkyl group. In some embodiments, R 1 It is OH, OCOR 4 Or OC(O)OR 4 And R 2 It is OH; where R 4 It is a C1-C3 alkyl group. In some embodiments, R 1 It is OH, OCOR 4 Or OC(O)OR 4 And R 2 It is OH; where R4 It is methyl, ethyl, or isopropyl.

[0148] In some implementation schemes, R 1 It is OCOR 4 Or OC(O)OR 4 And R 2 It is OH; where R 4 It is a C1-C8 alkyl group. In some embodiments, R 1 It is OCOR 4 Or OC(O)OR 4 And R 2 It is OH; where R 4 It is a C1-C6 alkyl group. In some embodiments, R 1 It is OCOR 4 Or OC(O)OR 4 And R 2 It is OH; where R 4 It is a C1-C3 alkyl group. In some embodiments, R 1 It is OCOR 4 Or OC(O)OR 4 And R 2 It is OH; where R 4 It is methyl, ethyl, or isopropyl.

[0149] In some implementation schemes, R 1 It is OCOR 4 And R 2 It is OH; where R 4 It is a C1-C8 alkyl group. In some embodiments, R 1 It is OCOR 4 And R 2 It is OH; where R 4 It is a C1-C6 alkyl group. In some embodiments, R 1 It is OCOR 4 And R 2 It is OH; where R 4 It is a C1-C3 alkyl group. In some embodiments, R 1 It is OCOR 4 And R 2 It is OH; where R 4 It is methyl, ethyl, or isopropyl.

[0150] In some implementation schemes, R 1 It is OC(O)OR 4 And R 2 It is OH; where R 4 It is a C1-C8 alkyl group. In some embodiments, R 1 It is OC(O)OR4 And R 2 It is OH; where R 4 It is a C1-C6 alkyl group. In some embodiments, R 1 It is OC(O)OR 4 And R 2 It is OH; where R 4 It is a C1-C3 alkyl group. In some embodiments, R 1 It is OC(O)OR 4 And R 2 It is OH; where R 4 It is methyl, ethyl, or isopropyl.

[0151] In some embodiments of compounds of formula I or Ia, R 1 It is OCOR 4 Or OC(O)OR 4 And R 2 It is OCOR 5 Or OC(O)OR 5 ;where R 4 and R 5 Each is independently a C1-C8 alkyl group. In some embodiments, R 1 It is OCOR 4 Or OC(O)OR 4 And R 2 It is OCOR 5 Or OC(O)OR 5 ;where R 4 and R 5 Each is independently a C1-C6 alkyl group. In some embodiments, R 1 It is OCOR 4 Or OC(O)OR 4 And R 2 It is OCOR 5 Or OC(O)OR 5 ;where R 4 and R 5 Each is independently a C1-C3 alkyl group. R 1 It is OCOR 4 Or OC(O)OR 4 And R 2 It is OCOR 5 Or OC(O)OR 5 ;where R 4 and R 5 Each can be methyl, ethyl, or isopropyl.

[0152] In some implementation schemes, R 1 It is OCOR 4 And R 2It is OCOR 5 Or OC(O)OR 5 ;where R 4 and R 5 Each is independently a C1-C8 alkyl group. In some embodiments, R 1 It is OCOR 4 And R 2 It is OCOR 5 Or OC(O)OR 5 ;where R 4 and R 5 Each is independently a C1-C6 alkyl group. In some embodiments, R 1 It is OCOR 4 And R 2 It is OCOR 5 Or OC(O)OR 5 ;where R 4 and R 5 Each is independently a C1-C3 alkyl group. In some embodiments, R 1 It is OCOR 4 And R 2 It is OCOR 5 Or OC(O)OR 5 ;where R 4 and R 5 Each can be methyl, ethyl, or isopropyl.

[0153] In some implementation schemes, R 1 It is OC(O)OR 4 And R 2 It is OCOR 5 Or OC(O)OR 5 ;where R 4 and R 5 Each is independently a C1-C8 alkyl group. In some embodiments, R 1 It is OC(O)OR 4 And R 2 It is OCOR 5 Or OC(O)OR 5 ;where R 4 and R 5 Each is independently a C1-C6 alkyl group. In some embodiments, R 1 It is OC(O)OR 4 And R 2 It is OCOR 5 Or OC(O)OR 5 ;where R 4 and R 5 Each is independently a C1-C3 alkyl group. In some embodiments, R 1It is OC(O)OR 4 And R 2 It is OCOR 5 Or OC(O)OR 5 ;where R 4 and R 5 Each can be methyl, ethyl, or isopropyl.

[0154] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 1 It is OCOR 4 Or OC(O)OR 4 And R 2 It is OCOR 5 ;where R 4 and R 5 Each is independently a C1-C8 alkyl group. In some embodiments, R 1 It is OCOR 4 Or OC(O)OR 4 And R 2 It is OCOR 5 ;where R 4 and R 5 Each is independently a C1-C6 alkyl group. In some embodiments, R 1 It is OCOR 4 Or OC(O)OR 4 And R 2 It is OCOR 5 ;where R 4 and R 5 Each is independently a C1-C3 alkyl group. In some embodiments, R 1 It is OCOR 4 Or OC(O)OR 4 And R 2 It is OCOR 5 ;where R 4 and R 5 Each can be methyl, ethyl, or isopropyl.

[0155] In some implementation schemes, R 1 It is OCOR 4 Or OC(O)OR 4 And R 2 It is OC(O)OR 5 ;where R 4 and R 5 Each is independently a C1-C8 alkyl group. In some embodiments, R 1 It is OCOR 4 Or OC(O)OR 4 And R 2 It is OC(O)OR5 ;where R 4 and R 5 Each is independently a C1-C6 alkyl group. In some embodiments, R 1 It is OCOR 4 Or OC(O)OR 4 And R 2 It is OC(O)OR 5 ;where R 4 and R 5 Each is independently a C1-C3 alkyl group. In some embodiments, R 1 It is OCOR 4 Or OC(O)OR 4 And R 2 It is OC(O)OR 5 ;where R 4 and R 5 Each can be methyl, ethyl, or isopropyl.

[0156] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 1 It is OCOR 4 And R 2 It is OCOR 5 ;where R 4 and R 5 Each is independently a C1-C8 alkyl group. In some embodiments, R 1 It is OCOR 4 And R 2 It is OCOR 5 ;where R 4 and R 5 Each is independently a C1-C6 alkyl group. In some embodiments, R 1 It is OCOR 4 And R 2 It is OCOR 5 ;where R 4 and R 5 Each is independently a C1-C3 alkyl group. In some embodiments, R 1 It is OCOR 4 And R 2 It is OCOR 5 ;where R 4 and R 5 Each can be methyl, ethyl, or isopropyl.

[0157] In some implementation schemes, R 1 It is OCOR 4 And R 2 It is OC(O)OR 5 ;where R 4and R 5 Each is independently a C1-C8 alkyl group. In some embodiments, R 1 It is OCOR 4 And R 2 It is OC(O)OR 5 ;where R 4 and R 5 Each is independently a C1-C6 alkyl group. In some embodiments, R 1 It is OCOR 4 And R 2 It is OC(O)OR 5 ;where R 4 and R 5 Each is independently a C1-C3 alkyl group. In some embodiments, R 1 It is OCOR 4 And R 2 It is OC(O)OR 5 ;where R 4 and R 5 Each can be methyl, ethyl, or isopropyl.

[0158] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, R 1 It is OC(O)OR 4 And R 2 It is OCOR 5 ;where R 4 and R 5 Each is independently a C1-C8 alkyl group. In some embodiments, R 1 It is OC(O)OR 4 And R 2 It is OCOR 5 ;where R 4 and R 5 Each is independently a C1-C6 alkyl group. In some embodiments, R 1 It is OC(O)OR 4 And R 2 It is OCOR 5 ;where R 4 and R 5 Each is independently a C1-C3 alkyl group. In some embodiments, R 1 It is OC(O)OR 4 And R 2 It is OCOR 5 ;where R 4 and R 5 Each can be methyl, ethyl, or isopropyl.

[0159] In some implementation schemes, R 1It is OC(O)OR 4 And R 2 It is OC(O)OR 5 ;where R 4 and R 5 Each is independently a C1-C8 alkyl group. In some embodiments, R 1 It is OC(O)OR 4 And R 2 It is OC(O)OR 5 ;where R 4 and R 5 Each is independently a C1-C6 alkyl group. In some embodiments, R 1 It is OC(O)OR 4 And R 2 It is OC(O)OR 5 ;where R 4 and R 5 Each is independently a C1-C3 alkyl group. In some embodiments, R 1 It is OC(O)OR 4 And R 2 It is OC(O)OR 5 ;where R 4 and R 5 Each can be methyl, ethyl, or isopropyl.

[0160] In some embodiments of compounds of formula I or Ia, R 6 It is H, C1-C3 alkyl or C6-C 10 Aryl. In some implementations, R 6 It is H, C1-C6 alkyl, or phenyl. In some embodiments, R 6 It is H, C1-C3 alkyl, or phenyl. In some embodiments, R 6 It is C6-C 10 Aryl. In some implementations, R 6 It is phenyl.

[0161] In some embodiments of compounds of formula I or Ia, R 1 and R 2 Together they form -OC(O)O- or -OCHR 6 O-; where R 6 It is H, C1-C6 alkyl or C6-C 10 Aryl. In some implementations, R 1 and R 2 Together they form -OC(O)O- or -OCHR 6 O-; where R 6 It is H, C1-C3 alkyl or C6-C 10Aryl. In some implementations, R 1 and R 2 Together they form -OC(O)O- or -OCHR 6 O-; where R 6 It is H, C1-C6 alkyl, or phenyl. In some embodiments, R 1 and R 2 Together they form -OC(O)O- or -OCHR 6 O-; where R 6 It is H, C1-C3 alkyl, or phenyl. In some embodiments, R 1 and R 2 Together they form -OC(O)O- or -OCHR 6 O-; where R 6 It is C6-C 10 Aryl. In some implementations, R 1 and R 2 Together they form -OC(O)O- or -OCHR 6 O-; where R 6 It is phenyl.

[0162] In some embodiments of compounds of formula I or Ia, R 1 and R 2 Together to form - OCHR 6 O-; where R 6 It is H, C1-C6 alkyl or C6-C 10 Aryl. In some implementations, R 1 and R 2 Together to form - OCHR 6 O-; where R 6 It is H, C1-C3 alkyl or C6-C 10 Aryl. In some implementations, R 1 and R 2 Together to form - OCHR 6 O-; where R 6 It is C6-C 10 Aryl. In some implementations, R 1 and R 2 Together to form - OCHR 6 O-; where R 6 It is phenyl.

[0163] In some embodiments of compounds of formula I or Ia, R 1 and R 2 Together they form -OC(O)O-.

[0164] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, wherein R3 It is H and R 1 It is OCOR 4 Or OC(O)OR 4 In some implementations, R 3 It is H and R 2 It is OCOR 5 Or OC(O)OR 5 In some implementations, R 3 It is H and R 1 and R 2 Together they form -OC(O)O- or -OCHR 6 O-. In some implementations, R 3 It is H and R 1 and R 2 Together they form -OC(O)O-. In some implementations, R 3 It is H and R 1 and R 2 Together to form - OCHR 6 O-; where R 6 It is H, C1-C6 alkyl or C6-C 10 Aryl. In some implementations, R 3 It is H and R 1 and R 2 Together to form - OCHR 6 O-; where R 6 It is H, C1-C3 alkyl or C6-C 10 Aryl. In some implementations, R 3 It is H and R 1 and R 2 Together to form - OCHR 6 O-; where R 6 It is H, C1-C6 alkyl, or phenyl. In some embodiments, R 3 It is H and R 1 and R 2 Together to form - OCHR 6 O-; where R 6 It is H, C1-C3 alkyl, or phenyl. In some embodiments, R 3 It is H and R 1 and R 2 Together to form - OCHR 6 O-; where R 6 It is C6-C 10 Aryl. In some implementations, R 3 It is H and R 1 and R 2 Together to form - OCHR 6 O-; where R 6It is phenyl.

[0165] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, each R 8 Independently, it is H, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, each R 8 Independently, it is an H or C1-C6 alkyl group. In some embodiments, each R... 8 Independently, it is an H or C1-C3 alkyl group. In some embodiments, each R... 8 It is H.

[0166] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, each R 9 Independently, it is H, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, each R 9 Independently, it is an H or C1-C6 alkyl group. In some embodiments, each R... 9 Independently, it is an H or C1-C3 alkyl group. In some embodiments, each R... 9 It is H.

[0167] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, each R 10 Independently, it is H, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, each R 10 Independently, it is an H or C1-C6 alkyl group. In some embodiments, each R... 10 Independently, it is an H or C1-C3 alkyl group. In some embodiments, each R... 10 It is H.

[0168] In some embodiments of compounds of formula I or Ia or their pharmaceutically acceptable salts, each R 8 R 9 and R 10 It is H.

[0169] In some embodiments of the compound of formula I or Ia or a pharmaceutically acceptable salt thereof, the compound is selected from the group consisting of:

[0170]

[0171]

[0172]

[0173] In some embodiments of the compound of formula I or Ia or a pharmaceutically acceptable salt thereof, wherein the compound is

[0174] In some embodiments of compounds of formulas I and Ia, or pharmaceutically acceptable salts thereof, wherein the compound is selected from the group consisting of:

[0175]

[0176]

[0177] In some embodiments, the compounds of formula I or Ia disclosed herein can be considered as prodrugs of (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carboxynitrile (hereinafter referred to as "Reference Compound A") (compound 13 in WO2009132135; compound 4 in J. Med. Chem. 2017, 60, 1648-1661). While not wishing to be bound by any particular operational theory, it is believed that compounds of formula I and Ia are metabolized in vivo to Reference Compound A. In some embodiments, when administered orally, compounds of formula I or Ia provide increased bioavailability of Reference Compound A. In some embodiments, when administered orally, the compound of formula I or Ia provides at least 2, at least 3, at least 4, at least 5, at least 6, at least 8, at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, at least 25, or at least 30 times the bioavailability of the reference compound A.

[0178]

[0179] V. Pharmaceutical preparations

[0180] The compounds disclosed herein can be formulated with conventional carriers and excipients. For example, tablets will contain excipients, flow aids, fillers, binders, etc. Aqueous formulations are prepared aseptically and are typically isotonic when intended for delivery by non-oral administration. All formulations may optionally contain excipients, such as those described in the "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc. The pH range of the formulation is from about 3 to about 11, but is typically from about 7 to 10. In some embodiments, the pH range of the formulation is from about 2 to about 5, but is typically from about 3 to 4.

[0181] While the compounds of this disclosure (“active ingredients”) can be administered alone, they are preferably provided as pharmaceutical formulations. Both veterinary and human formulations of the present invention comprise at least one active ingredient as defined above, together with one or more of its acceptable carriers and optional other therapeutic ingredients, particularly those additional therapeutic ingredients discussed herein. The carrier must be “acceptable,” meaning compatible with the other components of the formulation and physiologically harmless to the recipient.

[0182] These formulations include those suitable for the aforementioned routes of administration. Formulations are readily available in unit dosage forms and can be prepared by any suitable method known in the pharmaceutical field. Techniques and formulations are commonly 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 auxiliary ingredients. Generally, formulations are prepared by uniformly and tightly associating the active ingredient with a liquid carrier or a finely divided solid carrier, or both, and then, if desired, shaping the product.

[0183] 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, compounds of formula I or Ia have improved bioavailability and are therefore administerable by oral administration.

[0184] In some embodiments, the formulations of the present invention suitable for oral administration may be provided as discrete units such as capsules, granules, 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 pills, granules, or pastes.

[0185] In some embodiments, tablets are prepared by compression or molding, optionally with one or more excipients. Compressed tablets are prepared by compressing an active ingredient in a free-flowing form (such as powder or granules) in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant. Molded tablets are prepared by molding a mixture of powdered active ingredients moistened with an inert liquid diluent in a suitable machine. Tablets may optionally be coated or scored, and optionally formulated to provide a slow or controlled release of the active ingredient therefrom.

[0186] For infections of the eyes or other external tissues (e.g., the mouth and skin), the formulation is applied as a topical ointment or cream containing active ingredients in amounts, for example, from 0.075% w / w to 20% w / w (including active ingredients in increments of 0.1% w / w, such as 0.6% w / w, 0.7% w / w, etc.), preferably from 0.2% w / w to 15% w / w, and most preferably from 0.5% w / w to 10% w / w. When formulated as an ointment, the active ingredient may be used with a paraffin base or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with an oil-in-water emulsion base.

[0187] If desired, the aqueous phase of the cream matrix may contain, for example, at least 30% w / w polyols, i.e., alcohols having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerin, and polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may ideally include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0188] The oil phase of the emulsion of the present invention can be composed of known components in a known manner. While this phase may consist only of emulsifiers (or simply emulsifiers), it ideally includes at least one emulsifier with fats or oils, or a mixture of both. Preferably, hydrophilic emulsifiers are included together with lipophilic emulsifiers that act as stabilizers. It is also preferable to include both oils and fats. Emulsifiers, with or without stabilizers, together constitute a so-called emulsified wax, and the wax, together with the oils and fats, constitutes a so-called emulsified ointment matrix, which forms the oily dispersed phase of the ointment formulation.

[0189] Emulsifiers and emulsion stabilizers suitable for the formulations of this invention include 60. 80. Cetearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate. Other emulsifiers and emulsion stabilizers suitable for the formulations of this invention include: 80.

[0190] The appropriate oil or fat is selected for the formulation based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, non-staining, and washable product with a suitable consistency to prevent leakage from tubes or other containers. Straight-chain or branched monoalkyl or dialkyl esters can be used, such as diisohexyl adipate, isohexadecanoyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or mixtures of branched esters known as Crodamol CAP, the last three being preferred esters. These esters can be used alone or in combination, depending on the desired properties. Alternatively, high-melting-point lipids, such as white soft paraffin and / or liquid paraffin or other mineral oils, can be used.

[0191] Pharmaceutical formulations according to the invention comprise compounds according to the invention, as well as one or more pharmaceutically acceptable carriers or excipients and optional other therapeutic agents. Pharmaceutical formulations containing the active ingredient can be in any form suitable for the intended method of administration. For example, when intended for oral use, they can be prepared as tablets, lozenges, tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions intended for oral use can be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more pharmaceutical agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable formulation. Tablets containing the active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for manufacturing tablets are acceptable. These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated using known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing sustained action over a longer period. For example, delaying materials such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with waxes.

[0192] Formulations intended for oral use may also be provided as hard 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 an aqueous or oily medium (such as peanut oil, liquid paraffin, or olive oil).

[0193] The aqueous suspension of the present invention contains an active substance mixed with excipients suitable for manufacturing aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; and dispersants or wetting agents such as naturally occurring phospholipids (e.g., lecithin), condensation products of olefinic oxygen and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecanethoxycetyl alcohol), and condensation products of ethylene oxide and esters derived from fatty acids and hexyl anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives, such as ethylparaben or n-propylparaben, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose or saccharin. Other non-limiting examples of suspending agents include cyclodextrin. In some examples, the suspending agent is sulfobutyl ether β-cyclodextrin (SEB-β-CD), for example...

[0194] Oily suspensions can be prepared by suspending the active ingredients in vegetable oils (such as peanut oil, olive oil, sesame oil, or coconut oil) or mineral oils (such as liquid paraffin). Oral suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners (such as those mentioned above) and flavoring agents may be added to provide palatable oral formulations. These compositions may be preserved by adding antioxidants (such as ascorbic acid).

[0195] The dispersible powders and granules of the present invention, suitable for preparing aqueous suspensions by adding water, provide an active ingredient that can be 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 coloring agents, may also be present.

[0196] The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. 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 gum arabic and tragacanth; naturally occurring phospholipids, such as soybean lecithin; esters or metaesters derived from fatty acids and hexitan anhydrides, such as sorbitan monooleate; and condensation products of these metaesters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents. Syrups and elixirs may be formulated with sweeteners such as glycerin, sorbitol, or sucrose. Such formulations may also contain modifiers, preservatives, flavoring agents, or coloring agents.

[0197] The pharmaceutical compositions of the present invention may be in the form of sterile injectable formulations, such as sterile injectable aqueous or oily suspensions. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents mentioned above, according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents (such as solutions in 1,3-butanediol), or prepared as lyophilized powders. Acceptable solvents and media are water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils are generally used as solvents or suspension media. For this purpose, any mild non-volatile oil may be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid may also be used in the preparation of injectable formulations. Acceptable solvents and media are water, Ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution.

[0198] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific route of administration. For example, a sustained-release formulation intended for oral administration to humans may contain approximately 1 mg to 1000 mg of the active material, compounded with an appropriate and convenient amount of carrier material, which may vary between approximately 5% to approximately 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable dosages. For example, an aqueous solution intended for intravenous infusion may contain approximately 3 μg to 500 μg of the active ingredient per milliliter to allow for the infusion of an appropriate volume at a rate of approximately 30 mL / hr.

[0199] Formulations suitable for topical application to the eyes also include eye drops, wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly in an aqueous solution of the active ingredient. The active ingredient is preferably present in such formulations at a concentration of 0.5% to 20%, advantageously 0.5% to 10%, and particularly about 1.5% w / w.

[0200] Preparations suitable for topical application in the oral cavity include lozenges containing flavoring active ingredients, typically sucrose and gum arabic or tragacanth; tablets containing inert active ingredients, such as gelatin and glycerin, or sucrose and gum arabic; and mouthwashes containing the active ingredients in a suitable liquid carrier.

[0201] Formulations for rectal administration may be provided as suppositories with a suitable matrix, including, for example, cocoa butter or salicylates.

[0202] In some embodiments, the compounds disclosed herein are administered by inhalation. In some embodiments, formulations suitable for intrapulmonary or intranasal administration have particle sizes, such as 0.5 micrometers, 1 micrometer, 30 micrometers, 35 micrometers, etc., in the range of 0.1 micrometers to 500 micrometers, and are administered by rapid inhalation through the nasal passage or by inhalation through the mouth to reach the alveolar sacs. 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 powders. In some embodiments, the compounds used herein are formulated and administered as nebulized formulations. In some embodiments, the compounds used herein are formulated for delivery via a face mask. In some embodiments, the compounds used herein are formulated for delivery via a face mask inhaler.

[0203] Preparations suitable for vaginal application may be provided in the form of pessaries, tampons, creams, gels, pastes, foams or sprays, and contain, in addition to the active ingredient, a suitable carrier known in the art.

[0204] Preparations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents, and solutes to make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners.

[0205] The formulation is present in single-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Temporary injectable solutions and suspensions are prepared from sterile powders, granules, and tablets of the aforementioned types. Preferred single-dose formulations are those containing a daily dose or a sub-daily dose of the active ingredient as described above, or a suitable portion thereof.

[0206] It should be understood that, in addition to the ingredients specifically mentioned above, the formulations of the present invention may include other agents conventional in the art related to the type of formulation discussed, such as flavoring agents suitable for oral administration.

[0207] The present invention further provides a veterinary drug composition comprising at least one active ingredient as defined above and its veterinary drug carrier.

[0208] Veterinary drug carriers are materials that can be used to administer compositions and can be solid, liquid, or gaseous materials. They are otherwise inert or acceptable in the veterinary field and compatible with the active ingredient. These veterinary drug compositions can be administered orally, parenterally, or via any other desired route.

[0209] 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, wherein the release of the active ingredient is controlled and regulated to allow administration at a lower frequency or to improve the pharmacokinetic or toxicological characteristics of a given active ingredient.

[0210] VI. Reagent Kit

[0211] This document 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 labeling and / or instructions for use to treat a disease or condition in a subject (e.g., a human) of need. In some embodiments, the disease or condition is a viral infection.

[0212] In some embodiments, the kit may also contain instructions for use of one or more additional therapeutic agents and / or instructions for using additional therapeutic agents in combination with compounds of Formula I to treat a disease or condition of a subject (e.g., a person) in need.

[0213] In some embodiments, the kits provided herein contain a single dose unit of the compound as described herein, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvation thereof. Examples of single dose units may include pills, tablets, capsules, pre-filled syringes or syringes, IV bags, inhalers, nebulizers, etc., each comprising a therapeutically effective amount of the compound in question, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvation thereof. In some embodiments, the kit may contain a single dose unit, and in other embodiments, multiple dose units are present, e.g., the number of dose units required for a specified regimen or cycle.

[0214] Articles of manufacture are also provided, 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. In some embodiments, the container for the article of manufacture is a vial, can, ampoule, pre-filled syringe, blister pack, can, canister, bottle, box, intravenous bag, inhaler, or nebulizer.

[0215] VII. Application

[0216] One or more compounds of the present invention may be administered via any route suitable for the condition to be treated. Suitable routes include oral, rectal, inhalation, pulmonary, local (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 intravenous administration. It should be understood that preferred routes may vary depending on, for example, the recipient's condition.

[0217] In the method of treating viral infection of the present invention, the compounds of the present invention can be administered at any time to persons who may be exposed to the virus or who already have a viral infection. In some embodiments, the compounds of the present invention can be administered prophylactically to persons who have been in contact with or are at risk of contact with persons who have been in ...

[0218] In some implementations, the methods disclosed herein include event-driven administration of a compound of formula I or a pharmaceutically acceptable salt thereof to a subject.

[0219] As used herein, the terms “event-driven” or “event-driven administration” mean that a compound of formula I or a pharmaceutically acceptable salt thereof is administered (1) prior to an event that will expose an individual to the virus (or otherwise increase the individual’s risk of acquiring a viral infection) (e.g., 2 hours, 1 day, 2 days, 5 days, or 7 days or more prior to the event); and / or (2) during an event that will expose an individual to the virus (or otherwise increase the individual’s risk of acquiring a viral infection) (or more than one repeated event); and / or (3) after an event that will expose an individual to the virus (or otherwise increase the individual’s risk of acquiring a viral infection) (or after the final event in a series of repeated events). In some embodiments, event-driven administration is performed before the subject is exposed to the virus. In some embodiments, event-driven administration is performed after the subject is exposed to the virus. In some embodiments, event-driven administration is performed both before and after the subject is exposed to the virus.

[0220] In some embodiments, the methods disclosed herein involve administration, for example as pre-exposure prophylaxis (PrEP) and / or post-exposure prophylaxis (PEP), before and / or after an event that will expose an individual to a virus or otherwise increase the individual's risk of acquiring a viral infection. In some embodiments, the methods disclosed herein include pre-exposure prophylaxis (PrEP). In some embodiments, the methods disclosed herein include post-exposure prophylaxis (PEP).

[0221] In some implementations, a compound of formula I or a pharmaceutically acceptable salt thereof is administered to the subject prior to exposure to the virus.

[0222] In some implementations, a compound of formula I or a pharmaceutically acceptable salt thereof is administered to the subject before and after exposure to the virus.

[0223] In some implementations, a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a subject after exposure to the virus.

[0224] Examples of event-driven dosing regimens include administering a compound of Formula I or a pharmaceutically acceptable salt thereof 24 hours to 2 hours before exposure to the virus, followed by administering a compound of Formula I or a pharmaceutically acceptable salt thereof every 24 hours during exposure, followed by further administration of a compound of Formula I or a pharmaceutically acceptable salt thereof after the last exposure, and a final administration of a compound of Formula I or a pharmaceutically acceptable salt thereof 24 hours later.

[0225] Another example of an event-driven dosing regimen involves administering a compound of Formula I or a pharmaceutically acceptable salt thereof 24 hours prior to viral exposure, followed by daily administration during exposure, and then a final administration approximately 24 hours after the last exposure (which may be an increased dose, such as a double dose).

[0226] The specific dose level of the compounds disclosed herein for any particular subject will depend on a variety of factors, including the activity of the specific compound used, the age, weight, general health condition, sex, diet, time of administration, route of administration and excretion rate, drug combination, and severity of the specific disease. For example, the dose may be expressed as milligrams (mg / kg) of the compound described herein per kilogram of subject body weight. A dose between about 0.1 mg / kg and 150 mg / kg may be appropriate. In some embodiments, a dose between about 0.1 mg / kg and 100 mg / kg may be appropriate. In other embodiments, a dose between 0.5 mg / kg and 60 mg / kg may be appropriate. Normalization based on the subject's weight is particularly useful when adjusting doses among subjects with large differences in size (such as when using the drug in children and adults, or when converting an effective dose for a non-human subject, such as a dog, to a dose suitable for a human subject).

[0227] The daily dose can also be described as the total amount of the compound described herein administered per dose or per day. The daily dose of the compound of Formula I or a pharmaceutically acceptable salt thereof may be between about 1 mg and 4,000 mg, between about 2,000 mg / day and 4,000 mg / day, between about 1 mg / day and 2,000 mg / day, between about 1 mg / day and 1,000 mg / day, between about 10 mg / day and 500 mg / day, between about 20 mg / day and 500 mg / day, between about 50 mg / day and 300 mg / day, between about 75 mg / day and 200 mg / day, or between about 15 mg / day and 150 mg / day.

[0228] The dosage or frequency of administration of the disclosed compounds may be adjusted during treatment based on the judgment of the physician administering the medication.

[0229] The compounds disclosed herein can be administered in therapeutically effective amounts to an individual (e.g., a human). In some embodiments, the compounds are administered once daily.

[0230] The compounds provided herein may be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration. Therapeutic amounts of the compounds may include from about 0.00001 mg / kg body weight / day to about 10 mg / kg body weight / day, such as from about 0.0001 mg / kg body weight / day to about 10 mg / kg body weight / day, or such as from about 0.001 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as from about 0.01 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as from about 0.05 mg / kg body weight / day to about 0.5 mg / kg body weight / day. In some embodiments, therapeutic amounts of the compounds provided herein include from about 0.3 mg to about 30 mg / day, or from about 30 mg to about 300 mg / day, or from about 0.3 μg to about 30 mg / day, or from about 30 μg to about 300 μg / day.

[0231] The compounds disclosed herein may be combined with one or more additional therapeutic agents at any dose of the disclosed compounds (e.g., 1 mg to 1000 mg of the compound). Therapeuticly effective doses may include about 0.1 mg / dose to about 1000 mg / dose, such as about 50 mg / dose to about 500 mg / dose, or such as about 100 mg / dose to about 400 mg / dose, or such as about 150 mg / dose to about 350 mg / dose, or such as about 200 mg / dose to about 300 mg / dose, or such as about 0.01 mg / dose to about 100 mg / dose, or such as about 0.01 mg / dose to about 100 mg / dose, or such as about 0.1 mg / dose to about 100 mg / dose, or such as about 1 mg / dose to about 100 mg / dose, or such as about 1 mg / dose to about 100 mg / dose, or such as about 1 mg / dose to about 1000 mg / dose. Other therapeutically effective doses of the compounds of Formula I are about 1 mg / dose, or about 2 mg / dose, 3 mg / dose, 4 mg / dose, 5 mg / dose, 6 mg / dose, 7 mg / dose, 8 mg / dose, 9 mg / dose, 10 mg / dose, 15 mg / dose, 20 mg / dose, 25 mg / dose, 30 mg / dose, 35 mg / dose, 40 mg / dose, 45 mg / dose, 50 mg / dose, 55 mg / dose, 60 mg / dose, 65 mg / dose, 70 mg / dose, 75 mg / dose, 80 mg / dose, 85 mg / dose, 90 mg / dose, 95 mg / dose, or about 100 mg / dose. Other therapeutically effective doses of the compounds disclosed herein are approximately 100 mg / dose, 125 mg / dose, 150 mg / dose, 175 mg / dose, 200 mg / dose, 225 mg / dose, 250 mg / dose, 275 mg / dose, 300 mg / dose, 325 mg / dose, 350 mg / dose, 375 mg / dose, 400 mg / dose, 425 mg / dose, 450 mg / dose, 475 mg / dose, 500 mg / dose, 525 mg / dose. mg / dose, 550mg / dose, 575mg / dose, 600mg / dose, 625mg / dose, 650mg / dose, 675mg / dose, 700mg / dose, 725mg / dose, 750mg / dose, 775mg / dose, 800mg / dose, 825mg / dose, 850mg / dose, 875mg / dose, 900mg / dose, 925mg / dose, 950mg / dose, 975mg / dose or approximately 1000mg / dose.

[0232] In some embodiments, the method described herein involves administering an initial daily dose of about 1 mg to 500 mg of the compound provided herein to a subject, and gradually increasing the dose until clinical efficacy is achieved. Increments of about 5 mg, 10 mg, 25 mg, 50 mg, or 100 mg may be used to increase the dose. The dose may be increased daily, every other day, twice a week, once a week, once every two weeks, once every three weeks, or once a month.

[0233] When administered orally, the total daily dose for human subjects may range from about 1 mg / day to 4,000 mg / day, from about 1 mg / day to 3,000 mg / day, from 1 mg / day to 2,000 mg / day, from about 1 mg / day to 1,000 mg / day, from about 10 mg / day to 500 mg / day, from about 50 mg / day to 300 mg / day, from about 75 mg / day to 200 mg / day, or from about 100 mg / day to 150 mg / day. In some implementations, the total daily dose for human subjects may be approximately 100 mg / day, 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, 800 mg / day, 900 mg / day, 1000 mg / day, 1100 mg / day, 1200 mg / day, 1300 mg / day, or 1400 mg / day, administered as a single dose. The daily doses for human subjects may be approximately 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, or 800 mg / day, administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, or 600 mg / day, administered as a single dose. In some implementations, the total daily dose for human subjects may be approximately 100 mg / day, 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, 800 mg / day, 900 mg / day, 1000 mg / day, 1100 mg / day, 1200 mg / day, 1300 mg / day, 1400 mg / day, 1500 mg / day, 1600 mg / day, 1700 mg / day, 1800 mg / day, 1900 mg / day, 20... 00mg / day, 2100mg / day, 2200mg / day, 2300mg / day, 2400mg / day, 2500mg / day, 2600mg / day, 2700mg / day, 2800mg / day, 2900mg / day, 3000mg / day, 3100mg / day, 3200mg / day, 3300mg / day, 3400mg / day, 3500mg / day, 3600mg / day, 3700mg / day, 3800mg / day, 3900mg / day, or 4000mg / day.In some implementations, the total daily dose for human subjects may be approximately 100 mg / day - 200 mg / day, 100 mg / day - 300 mg / day, 100 mg / day - 400 mg / day, 100 mg / day - 500 mg / day, 100 mg / day - 600 mg / day, 100 mg / day - 700 mg / day, 100 mg / day - 800 mg / day, 100 mg / day - 900 mg / day, 100 mg / day - 1000 mg / day, or 500 mg / day. -1100mg / day, 500mg / day-1200mg / day, 500mg / day-1300mg / day, 500mg / day-1400mg / day, 500mg / day-1500mg / day, 500mg / day-1600mg / day, 500mg / day-1700mg / day, 500mg / day-1800mg / day, 500mg / day-1900mg / day, 500mg / day-2000mg / day, 1500mg / day-21 00mg / day, 1500mg / day-2200mg / day, 1500mg / day-2300mg / day, 1500mg / day-2400mg / day, 1500mg / day-2500mg / day, 2000mg / day-2600mg / day, 2000mg / day-2700mg / day, 2000mg / day-2800mg / day, 2000mg / day-2900mg / day, 2000mg / day-3000mg / day, 2500mg / day 3100mg / day, 2500mg / day-3200mg / day, 2500mg / day-3300mg / day, 2500mg / day-3400mg / day, 2500mg / day-3500mg / day, 3000mg / day-3600mg / day, 3000mg / day-3700mg / day, 3000mg / day-3800mg / day, 3000mg / day-3900mg / day, or 3000mg / day-4000mg / day.

[0234] In some embodiments, the total daily dose for a human subject may be about 100 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 150 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 200 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 250 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 300 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 350 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 400 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 450 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 500 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 550 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 600 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 650 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 700 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 750 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 800 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 850 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 900 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 950 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 1000 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 1500 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 2000 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 2500 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 3000 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 4000 mg / day, administered as a single dose.

[0235] A single dose may be administered hourly, daily, weekly, or monthly. For example, a single dose may be administered every 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, or every 24 hours. A single dose may also be administered every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or every 7 days. A single dose may also be administered every 1 week, 2 weeks, 3 weeks, or every 4 weeks. In some embodiments, a single dose may be administered weekly. A single dose may also be administered monthly. In some embodiments, the compounds disclosed herein are administered once daily using the methods disclosed herein. In some embodiments, the compounds disclosed herein are administered twice daily using the methods disclosed herein. In some embodiments, the compounds disclosed herein are administered three times daily using the methods disclosed herein.

[0236] In some embodiments, the compounds disclosed herein are administered once daily at a total daily dose of 100 mg / day to 4000 mg / day. In some embodiments, the compounds disclosed herein are administered twice daily at a total daily dose of 100 mg / day to 4000 mg / day. In some embodiments, the compounds disclosed herein are administered three times daily at a total daily dose of 100 mg / day to 4000 mg / day.

[0237] The frequency of dosage of the disclosed compound will be determined by the individual patient's needs and may be, for example, once daily or twice daily or more. Administration of the compound will continue as long as treatment of the viral infection is required. For example, the compound may be administered to a person infected with the virus for a period of 20 to 180 days, or for a period of, for example, 20 to 90 days, or for example, 30 to 60 days.

[0238] Administration may be intermittent, with the patient receiving a daily dose of the disclosed compound for periods of several days or more, followed by periods of not receiving the same daily dose for several days or more. For example, the patient may receive a dose of the compound every other day or three times a week. Again, by way of example, the patient may receive a daily dose of the compound for periods of 1 to 14 days, followed by periods of not receiving the compound for periods of 7 to 21 days, followed by periods of receiving the same daily dose of the compound again for subsequent periods (e.g., 1 to 14 days). The alternating periods of administration followed by non-administration of the compound may be repeated as needed to treat the patient's clinical needs.

[0239] The compounds or pharmaceutical compositions thereof disclosed herein may be administered once, twice, three times, or four times daily in any of the suitable modes described above. Furthermore, administration of the compound or treatment may continue for multiple days; for example, for a treatment cycle, treatment typically continues for at least 7, 14, or 28 days. Treatment cycles are well known in cancer chemotherapy and typically alternate with rest periods of approximately 1 to 28 days, typically approximately 7 or 14 days, between cycles. In other embodiments, treatment cycles may also be continuous.

[0240] VIII. Usage Instructions

[0241] This disclosure also provides a method for treating or preventing viral infection in a subject (e.g., a person) in need, the method comprising administering the compound described herein to the subject.

[0242] In some embodiments, this disclosure provides a method for treating a viral infection in a subject (e.g., a person) in need, the method comprising administering the compound described herein to the subject in need.

[0243] In some embodiments, this disclosure provides a method for treating or preventing viral infection in a subject (e.g., a person) in need, the method comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic agent.

[0244] In some embodiments, this disclosure provides a method for treating a viral infection in a subject (e.g., a person) in need, the method comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic agent.

[0245] In one embodiment, this disclosure provides a method for inhibiting viral polymerase in cells, the method comprising contacting virus-infected cells with a compound disclosed herein, thereby inhibiting the viral polymerase.

[0246] In one embodiment, this disclosure provides a method for inhibiting viral polymerase in cells, the method comprising contacting virus-infected cells with the compounds disclosed herein and at least one additional active therapeutic agent, thereby inhibiting the viral polymerase.

[0247] This document also provides for the use of the disclosed compounds in treating or preventing viral infections in subjects in need. For example, this document provides for the use of the disclosed compounds in treating viral infections in subjects in need.

[0248] In some embodiments, the viral infection is a paramyxoviridae virus infection. Therefore, in some embodiments, this disclosure provides a method for treating a paramyxoviridae infection in a subject (e.g., a human) in need, the method comprising administering the disclosed compound to the subject. Paramyxoviridae viruses include, but are not limited to, Nipah virus, Hendra virus, measles virus, mumps virus, and parainfluenza virus.

[0249] In some embodiments, the viral infection is a pulmonaviridae virus infection. Therefore, in some embodiments, this disclosure provides a method for treating a person in need of a pulmonaviridae virus infection, the method comprising administering to the person a compound provided herein. Pulmonaviridae viruses include, but are not limited to, respiratory syncytial virus (RSV) and human metapneumovirus (HMV). In some embodiments, the pulmonaviridae virus infection is a respiratory syncytial virus (RSV) infection. In some embodiments, the pulmonaviridae virus infection is a human metapneumovirus (HMV) infection.

[0250] In some embodiments, this disclosure provides compounds disclosed herein for treating pulmonary viral infections in persons of need. In some embodiments, the pulmonary viral infection is respiratory syncytial virus infection. In some embodiments, the pulmonary viral infection is human metapneumovirus infection.

[0251] In some embodiments, this disclosure provides a method for treating RSV infection in a person of need, the method comprising administering to the person a compound provided herein. In some embodiments, the person has a chronic respiratory syncytial virus infection. In some embodiments, the person is acutely infected with RSV.

[0252] In some embodiments, a method for inhibiting RSV replication is provided, wherein the method includes administering the disclosed compound to a person in need, wherein the administration is by inhalation.

[0253] In some embodiments, this disclosure provides a method for reducing viral load associated with RSV infection, wherein the method includes administering the disclosed compounds to a person infected with RSV.

[0254] In some embodiments, the viral infection is a picornaviridae virus infection. Therefore, in some embodiments, this disclosure provides a method for treating a person in need of a picornaviridae virus infection, the method comprising administering the compound of this disclosure to the person. Picornaviridae viruses are heterogeneous enteroviruses that cause a wide range of infections, including herpetic pharyngitis, aseptic meningitis, common cold-like syndrome (human rhinovirus infection), nonparalytic poliomyelitis-like syndrome, epidemic pleuropneumonia (an acute, febrile, infectious disease that typically occurs during epidemics), hand-foot-mouth disease, pancreatitis in children and adults, and severe myocarditis. In some embodiments, the picornaviridae virus infection is a human rhinovirus infection (HRV). In some embodiments, the picornaviridae virus infection is an HRV-A, HRV-B, or HRV-C infection.

[0255] In some embodiments, this disclosure provides compounds for treating microribonucleoviridae virus infections in people of need. In some embodiments, the microribonucleoviridae virus infection is a human rhinovirus infection.

[0256] In some embodiments, the viral infection is a flaviviridae virus infection. Therefore, in some embodiments, this disclosure provides a method of treating a person in need of a flaviviridae virus infection, the method comprising administering the compound described herein to that person. Representative flaviviridae viruses include, but are not limited to, dengue fever, yellow fever, West Nile virus, Zika virus, Japanese encephalitis virus, and hepatitis C virus (HCV). In some embodiments, the flaviviridae virus infection is dengue virus infection. In some embodiments, the flaviviridae virus infection is yellow fever virus infection. In some embodiments, the flaviviridae virus infection is West Nile 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.

[0257] In some embodiments, this disclosure provides the use of the compounds disclosed herein for treating flaviviridae virus infections in persons of need. In some embodiments, the flaviviridae virus infection is dengue virus infection. In some embodiments, the flaviviridae virus infection is yellow fever virus infection. In some embodiments, the flaviviridae virus infection is West Nile virus infection. In some embodiments, the flaviviridae virus infection is Zika virus infection. In some embodiments, the flaviviridae virus infection is hepatitis C virus infection.

[0258] In some embodiments, the viral infection is a filoviridae virus infection. Therefore, in some embodiments, this document provides a method for treating a person in need of a filoviridae virus infection, the method comprising administering to that person a compound disclosed herein. Representative filoviridae viruses include, but are not limited to, Ebola virus (variants Zaire, Bundibugio, Sudan, Tai Forest, or Reston) and Marburg virus. In some embodiments, the filoviridae virus infection is an Ebola virus infection. In some embodiments, the filoviridae virus infection is a Marburg virus infection.

[0259] In some embodiments, this disclosure provides compounds for treating filoviridae virus infections in persons in need. In some embodiments, the filoviridae virus infection is Ebola virus infection. In some embodiments, the filoviridae virus infection is Marburg virus infection.

[0260] In some embodiments, the viral infection is a coronavirus infection. Therefore, in some embodiments, this document provides a method for treating a person in need of a coronavirus infection, wherein the method comprises administering to the person a compound provided herein. 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 coronaviruses (229E, NL63, OC43, HKU1, or WIV1) infection, or zoonotic coronavirus (PEDV or HKU CoV isolates, such as 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 with a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, viral infection is caused by a virus having at least 80% sequence homology with a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, viral infection is caused by a virus having at least 90% sequence homology with a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, viral infection is caused by a virus having at least 95% sequence homology with a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2.

[0261] In some embodiments, viral infection is caused by a variant of SARS-CoV-2, such as variant B.1.1.7 (UK variant), variant B.1.351 (South African variant), variant P.1 (Brazilian variant), variants B.1.1.7 and E484K, variant B.1.1.207, variant B.1.1.317, variant B.1.1.318, variant B.1.429, variant B.1.525, or variant P.3. In some embodiments, viral infection is caused by variant B.1.1.7 of SARS-CoV-2. In some embodiments, viral infection is caused by variant B.1.351 of SARS-CoV-2. In some embodiments, viral infection is caused by variant P.1 of SARS-CoV-2.

[0262] In some embodiments, this disclosure provides compounds for treating coronavirus infections in people of 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 coronaviruses (229E, NL63, OC43, HKU1, or WIV1) infection, or zoonotic coronavirus (PEDV or HKU CoV isolates, such as 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).

[0263] In some embodiments, the viral infection is an infection of a arenaviridae virus. Therefore, in some embodiments, this disclosure provides a method for treating an arenaviridae virus infection in a person of need, the method comprising administering to the person a compound disclosed herein. In some embodiments, the arenaviridae virus infection is a lassa virus infection or a juniper virus infection.

[0264] In some embodiments, this disclosure provides compounds for treating arenaviridae virus infections in persons in need. In some embodiments, the arenaviridae virus infection is lassa virus infection or Junin virus infection.

[0265] In some implementations, the viral infection is an orthomyxovirus infection, such as an influenza virus infection. In some implementations, the viral infection is an influenza A virus, influenza B virus, or influenza C virus infection.

[0266] As described more fully herein, the compounds described herein can be administered to an individual (e.g., a human) infected with a virus, together with one or more adjunctive therapeutic agents. The adjunctive therapeutic agents can be administered to the infected individual simultaneously with, before, or after the administration of the compounds of this disclosure.

[0267] IX. Combination Therapy

[0268] The compounds described herein can also be used in combination with one or more additional therapeutic agents. Therefore, this document also provides methods for treating viral infections in subjects in need, wherein these methods include administering to the subject the disclosed compounds and a therapeutically effective amount of one or more additional therapeutic agents.

[0269] In some embodiments, the additional therapeutic agent is an antiviral agent. Any suitable antiviral agent may be used in the methods 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, antimitotic inhibitors, and combinations thereof.

[0270] In some embodiments, the adjunctive therapeutic agent is a 5-substituted 2'-deoxyuridine analogue. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of iodouridine, trifluorouridine, brovudine [BVDU], and combinations thereof.

[0271] In some embodiments, the adjunctive therapeutic agent is a nucleoside analog. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: vidarabine, entecavir (ETV), telmivudine, lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate (TDF), and combinations thereof. In some embodiments, the adjunctive therapeutic agent is favipiravir, ribavirin, galidivir, β-D-N4-hydroxycytidine, or combinations thereof.

[0272] In some embodiments, the adjunctive therapeutic agent is a pyrophosphate analog. For example, in some embodiments, the adjunctive therapeutic agent is phosphonoformic acid or phosphonoacetic acid. In some embodiments, the adjunctive therapeutic agent is phosphonoformic acid.

[0273] In some implementations, the adjunctive therapeutic agent is a nucleoside reverse transcriptase inhibitor. In some implementations, the antiviral agent is zidovudine, didanoxin, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, or combinations thereof.

[0274] In some implementations, the adjunctive therapeutic agent is a non-nucleoside reverse transcriptase inhibitor. In some implementations, the antiviral agent is selected from the group consisting of: nevirapine, delavudine, efavirenz, etravirine, rilpivirine, and combinations thereof.

[0275] In some embodiments, the adjunctive treatment 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, ampravir, lopinavir, atazanavir, fossavir, drenellavir, telanavir, cobistat, and combinations thereof. In some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, ampravir, lopinavir, atazanavir, fossavir, drenellavir, telanavir, and combinations thereof. In some embodiments, the protease inhibitor is an HCV NS3 / 4A protease inhibitor. For example, in some embodiments, the adjunctive treatment agent is selected from the group consisting of: voxiprevir, anavipiravir, boprevir, paliprevir, cimetidine, telaprevir, vaniprevir, gzopiclone, ribavirin, danoprevir, fadaprevir, vedoprevir, sovaprevir, deldeprefir, nalaprevir, and combinations thereof. In some embodiments, the adjunctive treatment agent is selected from the group consisting of: voxiprevir, anavipiravir, boprevir, paliprevir, cimetidine, telaprevir, vaniprevir, gzopiclone, and combinations thereof.

[0276] In some embodiments, the adjunctive therapeutic agent is an integrase inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: ritagvir, dulutegravir, erteiravir, abacavir, lamivudine, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: bicagvir, ritagvir, dulutegravir, cabotevir, erteiravir, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: bicagvir, dulutegravir, and cabotevir, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is bicagvir.

[0277] In some implementations, the adjunctive therapeutic agent is an entry inhibitor. For example, in some implementations, the adjunctive therapeutic agent is selected from the group consisting of: docosanol, entfuvirtide, maraviro, ipalizumab, fosetexavir, leronlimab, ipalizumab, fosetexavir, leronlimab, palizumab, intravenous respiratory syncytial virus immunoglobulin [RSV-IGIV], varicella-zoster immunoglobulin [VariZIG], varicella-zoster immunoglobulin [VZIG], and combinations thereof.

[0278] In some embodiments, the adjunctive therapeutic agent is an acyclovir analogue. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of acyclovir, ganciclovir, valacyclovir (also known as valacyclovir), valganciclovir, penciclovir, famciclovir, and combinations thereof.

[0279] In some embodiments, the adjunctive therapeutic agent is an acyclic nucleoside phosphonate analog. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, emtricitabine, efavirenz, rilpivirine, erteiravir, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: cidofovir, adefovir dipivoxil, tenofovir, TDF, and combinations thereof.

[0280] In some embodiments, the adjunctive therapeutic agent is an HCV NS5A / NS5B inhibitor. In some embodiments, the adjunctive therapeutic agent is an NS3 / 4A protease inhibitor. In some embodiments, the adjunctive therapeutic agent is an NS5A protease inhibitor. In some embodiments, the adjunctive therapeutic agent is a nucleoside / nucleotide type NS5B polymerase inhibitor. In some embodiments, the adjunctive therapeutic agent is a non-nucleoside type NS5B polymerase inhibitor. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, obbitasvir, elbasvir, sofosbuvir, dasabuvir, ribavirin, anavipiravir, cimetidine, paliprevir, ritonavir, elbasvir, gzopivir, AT-527, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, obbitasvir, elbasvir, sofosbuvir, dasabuvir, and combinations thereof.

[0281] In some embodiments, the adjunctive therapeutic agent is an influenza virus inhibitor. In some embodiments, the adjunctive therapeutic agent is a matrix 2 inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: amantadine, adalimumidine, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is a neuraminidase inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: zanamivir, oseltamivir, peramivir, lanimivir caprylate, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is a polymerase inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: ribavirin, favipiravir, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: amantadine, adalimumidine, arbidol (uminovir), baloxavirmabosiform, oseltamivir, peramivir, ingavirin, lanimivir caprylate, zanamivir, favipiravir, ribavirin, and combinations thereof. In some implementations, the adjunctive treatment agent is selected from the group consisting of: amantadine, adalimumab, zanamivir, oseltamivir, peramivir, lanimivir caprylate, ribavirin, favipiravir, and combinations thereof.

[0282] In some embodiments, the adjunctive therapeutic agent is interferon. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: interferon alfacon 1, interferon α1b, interferon α2a, interferon α2b, pegylated interferon alfacon 1, pegylated interferon α1b, pegylated interferon α2a (PegIFNα-2a), and PegIFNα-2b. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: interferon alfacon 1, interferon α1b, interferon α2a, interferon α2b, pegylated interferon α2a (PegIFNα-2a), and PegIFNα-2b. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: interferon alfacon 1, pegylated interferon α2a (PegIFNα-2a), PegIFNα-2b, and ribavirin. In some implementations, the additional therapeutic agent is pegylated interferon α-2a, pegylated interferon α-2b, or a combination thereof.

[0283] In some embodiments, the adjunctive therapeutic agent is an immunostimulant. In some embodiments, the adjunctive therapeutic agent is an oligonucleotide. In some embodiments, the adjunctive therapeutic agent is an antimitotic inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: fomivirex, prodafiloyl, imiquimod, phenelzine, and combinations thereof.

[0284] In some implementations, the adjunctive treatment agent is selected from the group consisting of: bexifovir, nitrozonide, REGN2222, doravirin, sofosbuvir, velpatasvir, daclatasvir, anavipiravir, becabuvir, FV100, and lemetmovir, as well as combinations thereof.

[0285] In some embodiments, the adjunctive treatment is a pharmaceutical agent used to treat RSV. For example, in some embodiments, the antiviral agent is ribavirin, ALS-8112, or pretovir.

[0286] In some embodiments, the adjunctive therapeutic agent is a drug for treating piconemaviruses. In some embodiments, the adjunctive therapeutic agent is selected from the group consisting of hydantoin, guanidine hydrochloride, L-butyrosine sulfoxide, Py-11, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is a piconemavirus polymerase inhibitor. In some embodiments, the adjunctive therapeutic agent is rupinetrivir.

[0287] In some implementations, the adjunctive treatment is a drug used to treat malaria. In some implementations, the adjunctive treatment is chloroquine.

[0288] In some implementations, the adjunctive therapeutic agent is selected from the group consisting of: hydroxychloroquine, chloroquine, artemether, benzyl fluorene, atovaquinone, chloroguanidine, tafenoxanol, phenazine, artemisinin ester, dihydroartemisinin, piperaquine, artemisinin ester, amodiaquine, phenazine, artemisinin ester, halofantroline, quinine sulfate, mefloquine, sorimycin, pyrimethamine, MMV-390048, ferrocene chloroquine, artemisinin mesylate, ganaplacide, DSM-265, cipargamine, artemisinone, and combinations thereof.

[0289] In some implementations, the adjunctive therapeutic agent is a drug for treating coronavirus. In some implementations, the adjunctive therapeutic agent is selected from the group consisting of: IFX-1, FM-201, CYNK-001, DPP4-Fc, leopard frog enzyme, naftomostat, LB-2, AM-1, antiviral porin, and combinations thereof.

[0290] In some implementations, the adjunctive treatment is an agent used to treat Ebola virus. For example, in some implementations, the adjunctive treatment is selected from the group consisting of: ribavirin, palilizumab, motavizumab, RSV-IGIV. MEDI-557, A-60444, MDT-637, BMS-433771, Amiodarone, Dronedarone, Verapamil, Ebola Convalescent Plasma (ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol), Favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9-dimethylquinoline[8,7-h]quinolone-1,7-diamine), JK-05, TKM-Ebola, ZMapp, rNAPc2, VRC-EBOADC076-00-VP, OS-2966, MVA-BN filo, bromidedofovir, Ebola vaccines based on Vaxart adenovirus vector 5, 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.

[0291] In some embodiments, the adjunctive therapeutic agent is a pharmaceutical agent for treating HCV. In some embodiments, the adjunctive therapeutic agent is an HCV polymerase inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: sofosbuvir, GS-6620, PSI-938, ribavirin, tegobvir, redabuvir, MK-0608, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is an HCV protease inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: such as GS-9256, vedoprevir, voxiprevir, and combinations thereof.

[0292] In some implementations, the adjunctive therapy is an NS5A inhibitor. For example, in some implementations, the adjunctive therapy is selected from the group consisting of: ledipasvir, velpatasvir, and combinations thereof.

[0293] In some implementations, the adjunctive treatment is an anti-HBV agent. For example, in some implementations, the adjunctive treatment is tenofovir disoproxil fumarate and emtricitabine or a combination thereof. Examples of adjunctive anti-HBV agents include, but are not limited to, α-hydroxytophenone, amadoxovir, duroquinol, β-hydroxycytosine nucleoside, ARB-199, CCC-0975, ccc-R08, evitabine, ezetimibe, cyclosporine A, gentiopicroside, HH-003, hapratide, JNJ-56136379, nitrozonide, birenapa, NJK14047, NOV-205 (molixan, BAM-205), oligonucleotides, mirtovalidone, feron, GST-HG-131, levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, caryophyllin, HepB-nRNA, cTP-5(rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-006IA, Hepuyinfen, DasKloster 0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, berberine, DasKloster-0039, hepulantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, QL-007, sofosbuvir, ledipasvir, UB-551, and ZH-2N, as well as US20150210682 (Roche), US The compounds disclosed in Roche's patents 2016 / 0122344, WO2015173164, WO2016023877, US2015252057A, WO16128335A1, WO16120186A1, US2016237090A, WO16107833A1, WO16107832A1, US2016176899A, WO16102438A1, WO16012470A1, US2016220586A, and US2015031687A are included. In some embodiments, the additional therapeutic agent is an HBV polymerase inhibitor. Examples of HBV DNA polymerase inhibitors include, but are not limited to, adefovir. Enqutabin Tenofovir disoproxil fumarate Tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir alafenamide diterpenoid, tenofovir alafenamide diterpenoid, tenofovir octadecyloxyethyl ester, CMX-157, tenofovir exalidex, besifovir, entecavir Entecavir maleate, telbivudine Felosivir, Pradefovir, Clavudine, Ribavirin, Lamivudine Azidoxime, famciclovir, fusolin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil fumarate aspartate, tenofovir disoproxil fumarate orotate, and HS-10234. In some implementations, the additional treatment agent is an HBV capsid inhibitor.

[0294] In some embodiments, the adjunctive therapeutic agent is a pharmaceutical agent used to treat HIV. In some embodiments, the adjunctive 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.

[0295] In some implementations, the adjunctive therapeutic agent is selected from the group consisting of: HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editing agents (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), and cell therapies (such as chimeric antigen receptor T cells, CAR-T and engineered T cell receptors, TCR-T, autologous T cell therapy).

[0296] In some implementations, the adjunctive therapeutic agent is selected from the group consisting of: combination drugs for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0297] In some implementations, the adjunctive treatment is an HIV combination drug. Examples of HIV combination drugs include, but are not limited to, those mentioned above. (Efavirenz, tenofovir disoproxil fumarate and emtricitabine); (Bicagvir, Emtricitabine and Tenofovir Alaminamide); ( Rilpivirine, tenofovir disoproxil fumarate, and emtricitabine; (Ertiravir, Cobistat, Tenofovir disoproxil fumarate and Emtricitabine); (Tenofovir dipivoxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (Tenofovir alafenamide, emtricitabine, and rilpivirine); (Tenofovir alafenamide, emtricitabine, cobistat and erteiravir); (Direravir, Tenofovir disoproxil fumarate, Emtricitabine, and Cobistat); SYMFI TM (Efavirenz, Lamivudine, and Tenofovir disoproxil fumarate); CIMDU TM (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, cobistat and erteiravir; (Zidovudine and Lamivudine; AZT+3TC); ( Abacavir sulfate and lamivudine; ABC+3TC); ( Lopinavir and ritonavir); (Durutvir, Abacavir and Lamivudine); (Abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); Atazanavir and cobistat; Atazanavir sulfate and cobistat; Atazanavir sulfate and ritonavir; Deruravir and cobistat; Dulutegravir and rilpivirine; Dulutegravir and rilpivirine hydrochloride; Dulutegravir, abacavir sulfate, and lamivudine; Lamivudine, nevirapine, and zidovudine; Rettagvir and lamivudine; Doravirine, lamivudine, and tenofovir disoproxil fumarate; Doravirine, lamivudine, and tenofovir disoproxil fumarate; Dapivirine + levonorgestrel, Dulutegravir + lamivudine Durutvir + Emtricitabine + Tenofovir Alamenosamine, Alfavirine + Emtricitabine + Tenofovir Disoproxil Fumarate, Lamivudine + Abacavir + Zidovudine, Lamivudine + Abacavir, Lamivudine + Tenofovir Disoproxil Fumarate, Lamivudine + Zidovudine + Nevirapine, Lopinavir + Ritonavir, Lopinavir + Ritonavir + Abacavir + Lamivudine, Lopinavir + Ritonavir + Zidovudine + Lamivudine, Tenofovir + Lamivudine, Tenofovir Disoproxil Fumarate + Emtricitabine + Rilpivirine Hydrochloride, Lopinavir, Ritonavir, Zidovudine, and Lamivudine.

[0298] In some implementations, the adjunctive treatment is an HIV protease inhibitor. For example, in some implementations, the adjunctive treatment is selected from the group consisting of: saquinavir, ritonavir, indinavir, nelfinavir, ampravir, lopinavir, atazanavir, fossavir, drenellavir, telanavir, cobistat, ASC-09, AEBL-2, MK-8718, GS-9500, GS-1156, and combinations thereof. For example, in some implementations, the adjunctive treatment is selected from the group consisting of: saquinavir, ritonavir, indinavir, nelfinavir, ampravir, lopinavir, atazanavir, fossavir, drenellavir, telanavir, and cobistat. In some implementations, the adjunctive treatment agent is selected from the group consisting of: ampravir, atazanavir, becanavir, deriravir, fossavir, fossavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, telanavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, TMC-310911, and combinations thereof.

[0299] In some implementations, the adjunctive treatment is an HIV integrase inhibitor. For example, in some implementations, the adjunctive treatment is selected from the group consisting of: retigvir, ertirapvir, dulutegravir, abacavir, lamivudine, bicagvir, and combinations thereof. In some implementations, the adjunctive treatment is bicagvir. In some implementations, the adjunctive treatment is selected from the group consisting of: bicagvir, ertirapvir, curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, ginsenoside tricarboxylic acid, ginsenoside tricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrosine kinase inhibitors, tyrosine kinase inhibitor derivatives, quercetin, quercetin derivatives, retigvir, dulutegravir, JTK-351, bicagvir, AVX-15567, BM. S-986197, Cabotevir (long-acting injectable), diketoquinoline-4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, VM-3500, Cabotevir, and combinations thereof.

[0300] In some implementations, the adjunctive therapy is an HIV entry inhibitor. For example, in some implementations, the adjunctive therapy is selected from the group consisting of entreviride, maraviro, and combinations thereof. Other examples of HIV entry inhibitors include, but are not limited to, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 linker inhibitors, DS-003 (BMS-599793), gp120 inhibitors, and CXCR4 inhibitors. Examples of CCR5 inhibitors include apravirone, vevicvirone, maraviro, cenicriviroc, leronlimab (PRO-140), adatabvir (RAP-101), nifevirone (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, peptide C25P, TD-0680, and vMIP (Haimipu). Examples of CXCR4 inhibitors include praxavir, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0301] In some embodiments, the adjunctive therapeutic agent is an HIV nucleoside reverse transcriptase inhibitor. In some embodiments, the adjunctive therapeutic agent is an HIV non-nucleoside reverse transcriptase inhibitor. In some embodiments, the adjunctive therapeutic agent is an acyclic nucleoside phosphonate analog. In some embodiments, the adjunctive therapeutic agent is an HIV capsid inhibitor.

[0302] In some implementations, the adjunctive therapy is an HIV nucleoside or nucleotide reverse transcriptase inhibitor. For example, the adjunctive therapy is selected from the group consisting of: adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, and VIDEX (Didanoxin, DDL), Abacavir, Abacavir sulfate, Alovudine, Alitabin, Cinovine, Didanoxin, Avtabin, Fetinavivir, Fosalvudine Tidoxil, CMX-157, Dapivirine, Doravirine, Etravirine, OCR-5753, Tenofovir disoproxil orotate, Fosalvudine Tidoxil, Islatravir, Lamivudine, Phosphazid, Stavudine, Zacitabine, Zidovudine, Rovafovir-Etalaflavinamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, KP-1461, and combinations thereof.

[0303] In some implementations, the adjunctive therapy is an HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitor. For example, the adjunctive therapy is selected from the group consisting of: dapirine, delavudine, delavudine mesylate, doravirine, efavirenz, ectrevirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA, ACC-007, AIC-292, KM-023, PC-1005, favirine rilp (VM-1500), and combinations thereof.

[0304] In some implementations, the additional therapeutic agent is selected from... (Efavirenz, tenofovir disoproxil fumarate and emtricitabine); ( Rilpivirine, tenofovir disoproxil fumarate, and emtricitabine; (Ertiravir, Cobistat, Tenofovir disoproxil fumarate and Emtricitabine); (Tenofovir dipivoxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (Tenofovir alafenamide, emtricitabine, and rilpivirine); (Tenofovir alafenamide, emtricitabine, cobistatin and ertiravir); Adefovir; Adefovir dipyridamole; Cobistatin; Emtricitabine; Tenofovir; Tenofovir disoproxil fumarate; Tenofovir disoproxil fumarate; Tenofovir alafenamide hemifumarate; (Durutexvir, Abacavir and Lamivudine); Durutvir, Abacavir Sulfate and Lamivudine; Rettagvir; Rettagvir and Lamivudine; Maraviro; Enfuvirtide; ( Lopinavir and ritonavir); (Zidovudine and Lamivudine; AZT+3TC); ( Abacavir sulfate and lamivudine; ABC+3TC); (Abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); Rilpivirine; Rilpivirine hydrochloride; Atazanavir sulfate and cobistat; Atazanavir and cobistat; Derreravir and cobistat; Atazanavir; Atazanavir sulfate; Dulutevir; Ertirapvir; Ritonavir; Atazanavir sulfate and Ritonavir; Derreravir; Lamivudine; Prandine; Fosanavir; Fosanavir calcium efavirenz; Etravirine; Nefernavir; Nefernavir mesylate; Interferon; Didanoxin; Stavudine; Indinavir; Indinavir sulfate; Tenofovir and Lamivudine; Zidovudine; Nevirapine; Saquinavir; Saquinavir mesylate; Aldehyde interleukin; Zacitabine; Telanavir; Ampravir; Delavudine; Delavudine mesylate; Radha-108 (receptor alcohol); Lamivudine and Tenofovir disoproxil fumarate; Efaviraxyl, Lamivudine and Tenofovir disoproxil fumarate; Aziphosphonate; Lamivudine, Nevirapine and Zidovudine; Abacavir; and Abacavir sulfate.

[0305] In some implementation schemes, the adjunctive treatment agent is selected from the group consisting of: colistin, penrubocin, ateband, betasine, epirubocin, epoprosetnol, vaportide, aprepitant, caspofungin, perphenazine, atazanavir, efavirenz, ritonavir, acyclovir, ganciclovir, penciclovir, prulifloxacin, bicagvir, nelfinavir, tegobuvi, nelfinavir, praziquantel, pitavastatin, perampanel, eszopiclone, and zopiclone.

[0306] In some implementations, the adjunctive therapeutic agent is an inhibitor of Bruton's tyrosine kinases (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI gene ID: 695). For example, in some implementations, the adjunctive therapeutic agent is selected from the group consisting of: (S)-6-amino-9-(1-(but-2-ethynyl)pyrrolidone-3-yl)-7-(4-phenoxyphenyl)-7H-purine-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib (Imbruvica), M-2951 (ibubrutinib (evobr) The adjunctive therapy includes teirabrutinib (ONO-4059), sipetinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, AZD6738, acalabrutinib, danvastatin, and combinations thereof. In some embodiments, the adjunctive therapy is selected from the group consisting of teirabrutinib, ibrutinib, acalabrutinib, and combinations thereof. In some embodiments, the adjunctive therapy is selected from the group consisting of teirabrutinib, ibrutinib, and combinations thereof. In some embodiments, the adjunctive therapy is a tyrosine kinase inhibitor A9 (A9).

[0307] In some embodiments, the adjunctive therapeutic agent is a KRAS inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of: AMG-510, COTI-219, MRTX-1257, ARS-3248, ARS-853, WDB-178, BI-3406, BI-1701963, ARS-1620 (G12C), SML-8-73-1 (G12C), compound 3144 (G12D), Kobe0065 / 2602 (Ras GTP), RT11, MRTX-849 (G12C), and K-Ras (G12D) selective inhibitory peptides, including KRpep-2 (Ac-RRCPLYISYDPVCRR-NH2), KRpep-2d (Ac-RRRRCPLYISYDPVCRRRR-NH2), and combinations thereof.

[0308] In some embodiments, the adjunctive therapeutic agent is a proteasome inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of ixazomib, carfilzomib, marizomib, bortezomib, and combinations thereof. In some embodiments, the adjunctive therapeutic agent is carfilzomib.

[0309] In some embodiments, the adjunctive therapeutic agent is a vaccine. For example, in some embodiments, the adjunctive therapeutic agent is a DNA vaccine, an RNA vaccine, a live attenuated vaccine, a therapeutic vaccine, a prophylactic vaccine, a protein-based vaccine, or a combination thereof. In some embodiments, the adjunctive therapeutic agent is mRNA-1273. In some embodiments, the adjunctive therapeutic agent is INO-4800 or INO-4700. In some embodiments, the adjunctive therapeutic agent is the live attenuated RSV vaccine MEDI-559, the anti-RSV human monoclonal antibody REGN2222, palizumab, respiratory syncytial virus immunoglobulin, intravenous respiratory syncytial virus immunoglobulin [RSV-IGIV], and combinations thereof. In some embodiments, the adjunctive therapeutic agent is an HBV vaccine, such as pediarix, engerix-B, and recombivax HB. In some embodiments, the adjunctive therapeutic agent is a VZV vaccine, such as zostavax and varivax. In some embodiments, the adjunctive therapeutic agent is an HPV vaccine, such as cervarix, gardasil9, and gardasil. In some implementations, the adjunctive therapeutic agent is an influenza virus vaccine. For example, (i) a monovalent influenza A vaccine (e.g., a monovalent influenza A [H5N1] virus vaccine and a monovalent influenza A [H1N1]2009 virus vaccine), (ii) a trivalent influenza A and B virus vaccine (e.g., Afluria, Agriflu, Fluad, Fluarix, Flublok, Flucelvax, FluLaval, Fluvirin, and Fluzone), and (iii) a quadrivalent influenza A and B virus vaccine (FluMist, Fluarix, Fluzone, and FluLaval). In some implementations, the adjunctive therapeutic agent is a human adenovirus vaccine (e.g., adenovirus type 4 and 7 vaccines, live, oral). In some implementations, the adjunctive 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 adjunctive therapeutic agent is a hepatitis A virus vaccine (e.g., Havrix and Vaqta). In some embodiments, the adjunctive therapeutic agent is a polio virus vaccine (e.g., Kinrix, Quadracel, and Ipol). In some embodiments, the adjunctive therapeutic agent is a yellow fever virus vaccine (e.g., YF-Vax). In some embodiments, the adjunctive therapeutic agent is a Japanese encephalitis virus vaccine (e.g., Ixiaro and JE-Vax). In some embodiments, the adjunctive therapeutic agent is a measles vaccine (e.g., MMR II and ProQuad). In some embodiments, the adjunctive therapeutic agent is a mumps vaccine (e.g., MMR II and ProQuad).In some embodiments, the adjunctive therapeutic agent is a rubella vaccine (e.g., MMR II and ProQuad). In some embodiments, the adjunctive therapeutic agent is a varicella vaccine (e.g., ProQuad). In some embodiments, the adjunctive therapeutic agent is a rabies vaccine (e.g., Imovax and RabAvert). In some embodiments, the adjunctive therapeutic agent is a smallpox virus (smallpox) vaccine (ACAM2000). In some embodiments, the adjunctive therapeutic agent is a hepatitis E virus (HEV) vaccine (e.g., HEV239). In some embodiments, the adjunctive therapeutic agent is a 2019-nCoV vaccine.

[0310] In some embodiments, the adjunctive therapeutic agent is an antibody, such as a monoclonal antibody. For example, the adjunctive therapeutic agent is an anti-2019-nCoV antibody selected from the group consisting of: Regeneron antibodies, Wuxi antibodies, Vir Biotechnology antibodies, antibodies targeting the SARS-CoV-2 spike protein, antibodies that neutralize SARS-CoV-2 (SARS-CoV-2 neutralizing antibodies), and combinations thereof. In some embodiments, the adjunctive therapeutic agent is the anti-SARS-CoV antibody CR-3022. In some embodiments, the adjunctive therapeutic agent is an aPD-1 antibody.

[0311] In some implementations, the adjunctive therapeutic agent is an injectable protein derived from a recombinant cytokine gene.

[0312] In some embodiments, the adjunctive therapeutic agent is a polymerase inhibitor. In some embodiments, the adjunctive therapeutic agent is a DNA polymerase inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is cidofovir. In some embodiments, the adjunctive therapeutic agent is an RNA polymerase inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is selected from the group consisting of ribavirin, favipiravir, lamivudine, pimodevir, and combinations thereof.

[0313] In some implementations, the adjunctive treatment agent is selected from the group consisting of: lopinavir, ritonavir, interferon alpha-2b, ritonavir, arbidol, hydroxychloroquine, direravir and cobistat, arbidol hydrochloride, oseltamivir, litonavir, emtricitabine, tenofovir alafenamide fumarate, baloxavir macozide, ruxotetinib, and combinations thereof.

[0314] In some implementations, the adjunctive therapeutic agent is selected from the group consisting of: 6'-fluorinated monexin analogues, acyclovir fleximer analogues, disulfiram, thiopurine analogues, ASC09F, GC376, GC813, phenylisoserine derivatives, neuraminidase inhibitor analogues, pyrimethamine derivatives, basilin and 5-hydroxytryptamine derivatives, SSYA10-001, griffithsin, HR2P-M1, HR2P-M2, P21S10, dihydrotanshinone E-64-C and E-64-D, OC43-HR2P, ME RS-5HB, 229E-HR1P, 229E-HR2P, resveratrol, 1-thiophene-4-azaspiro[4.5]dec-3-one derivatives, gemcitabine hydrochloride, loperamide, recombinant interferon, cyclosporine A, arapovir, imatinib mesylate, dasatinib, sumetinib, trametinib, rapamycin, zicatinib, chlorpromazine, trifluprozine, fluphenazine, thiophene, promethazine, cyclophilin inhibitors, K11777, carmostat, K22, teicoplanin derivatives, benzo[a]heterocyclic amine derivative N30, mycophenolic acid, silvestrol, and combinations thereof.

[0315] In some embodiments, the adjunctive therapeutic agent is an antibody. In some embodiments, the adjunctive therapeutic agent is an antibody that binds to a coronavirus, such as an antibody that binds to SARS-CoV or MERS-CoV. In some embodiments, the adjunctive therapeutic agent is an antibody against the 2019-nCoV virus.

[0316] The compositions of the present invention are also used in combination with other active ingredients. For the treatment of 2019-nCoV virus infection, preferably, the other active therapeutic agents have anti-coronavirus infection activity, such as anti-2019-nCoV virus infection activity. The compounds and compositions of the present invention are also intended for use in providing general care to patients suffering from 2019-nCoV virus infection, including parenteral fluids (including glucose saline and Ringer's lactate) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylaxis, fever and pain medications, 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, immunomodulatory drugs (e.g., dry eye), and other similar medications. This includes interferon, other small molecule or biological antiviral agents targeting 2019-nCoV (such as, but not limited to, lopinavir / ritonavir, EIDD-1931, favipiravir, ribavirin, neutralizing antibodies, etc.), vaccines, pain medications, and medications for other common diseases in the patient population, such as antimalarial agents (including artemether and artemisinin-benfluridine combination therapy), typhoid vaccines (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin) or Shigella vaccines. In some embodiments, the adjunctive therapeutic agent is dihydroartemisinin / piperaquine. In some embodiments, the adjunctive therapeutic agent is EIDD-2801 (MH-4482, monoupivir).

[0317] In some implementations, the adjunctive therapeutic agent is an immunomodulator. Examples of immunomodulatory therapies include Toll-like receptor modulators such as TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13; programmed cell death protein 1 (Pd-1) modulators; programmed death ligand 1 (Pd-L1) modulators; IL-15 modulators; DermaVir; interleukin-7; plaquenil (hydroxychloroquine); prazolam (aldeleukin, IL-2); interferon α; interferon α-2b; interferon α-n3; pegylated interferon α; interferon γ; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivatives. The formulation includes mycophenolate mofetil (MMF); ribavirin; polymeric polyethyleneimine (PEI); geopon; 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; nifedipine; 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, the adjunctive therapeutic agent refers to fingolimod, leflunomide, or a combination thereof. In some embodiments, the adjunctive therapeutic agent is thalidomide.

[0318] In some implementations, the adjunctive treatment is an IL-6 inhibitor, such as tocilizumab, thalidomab, or a combination thereof.

[0319] In some implementations, the adjunctive therapy is an anti-TNF inhibitor. For example, the adjunctive therapy is adalimumab, etanercept, golimumab, infliximab, or a combination thereof.

[0320] In some implementations, the adjunctive therapy is a JAK inhibitor, such as baricitinib, filgortinib, baricitinib, or a combination thereof.

[0321] In some implementations, the additional therapeutic agent is an inflammation inhibitor, such as pirfenidone.

[0322] In some implementations, the adjunctive therapeutic agent is an antibiotic used for secondary bacterial pneumonia. For example, the adjunctive therapeutic agent is a macrolide antibiotic (e.g., azithromycin, clarithromycin, and mycoplasma pneumoniae), a fluoroquinolone (e.g., ciprofloxacin and levofloxacin), a tetracycline (e.g., doxycycline and tetracycline), or a combination thereof.

[0323] In some implementations, the compounds disclosed herein are used in combination with standards of care for pneumonia (see, for example, Pediatric Community Pneumonia Guidelines, CID 2011:53 (October 1)). Treatment of pneumonia typically involves curing the infection and preventing complications. Specific treatment will depend on several factors, including the type and severity of pneumonia, the individual's age, and overall health. Options include: (i) antibiotics, (ii) cough medicines, and (iii) antipyretics / analgesics (e.g., aspirin, ibuprofen (Advil, Motrin IB, etc.), and acetaminophen (Tylenol, etc.)). In some implementations, an additional treatment is bromhexine cough suppressant.

[0324] In some embodiments, the compounds disclosed herein are used in combination with immunoglobulins from recovered COVID-19 patients. In some embodiments, the compounds disclosed herein are used in combination with plasma infusion. In some embodiments, the compounds disclosed herein are used in combination with stem cells.

[0325] In some implementations, the additional treatment agent is a TLR agonist. Examples of TLR agonists include, but are not limited to, vesamimod (GS-9620), GS-986, IR-103, lefemod, tilsotolimod, rintatlimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, telratolimod, and RO-7020531.

[0326] In some implementations, the adjunctive treatment agent is selected from the group consisting of bortezomib, flurazepam, ponatinib, sorafenib, peramisone, clotropone, flucloxacillin, serindole, clovidipine, atorvastatin, sinusizine, clofazimine, fosapiram, and combinations thereof.

[0327] In some implementations, the adjunctive therapeutic agent is azithromycin, suramin, triazolene, dipyridamole, bevacizumab, meperizumab, GD31 (Rhizobium spp.), an NLRP inflammasome inhibitor, or α-ketoamine. In some implementations, the adjunctive therapeutic agent is recombinant human angiotensin-converting enzyme 2 (rhACE2). In some implementations, the adjunctive therapeutic agent is viral macrophage inflammatory protein (vMIP).

[0328] In some embodiments, the adjunctive therapeutic agent is an antiviral porin therapeutic agent. For example, the adjunctive therapeutic agent is BIT-314 or BIT-225. In some embodiments, the adjunctive therapeutic agent is a coronavirus E protein inhibitor. For example, the adjunctive therapeutic agent is BIT-009. Further examples of adjunctive therapeutic agents include those described in WO-2004112687, WO-2006135978, WO-2018145148, and WO-2009018609.

[0329] Any compound of the present invention can also be combined with one or more additional active therapeutic agents in a single dosage form for simultaneous or sequential administration to a patient. Combination therapy can be administered as a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in two or more doses.

[0330] Co-administration of the compound of the present invention with one or more other active therapeutic agents generally refers to the simultaneous or sequential administration of the compound of the present invention and one or more other active therapeutic agents, such that therapeutically effective amounts of the compound of the present invention and one or more other active therapeutic agents are present in the patient.

[0331] Co-administration includes administering a unit dose of the compound of the present invention before or after administering a unit dose of one or more other active therapeutic agents, for example, administering the compound of the present invention within seconds, minutes, or hours of administering 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 over several 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 over several seconds or minutes. In some cases, it may be necessary 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 hour to 12 hours). In other cases, it may be necessary 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 hour to 12 hours).

[0332] Combination therapy can provide “synergistic” or “synergistic” effects, meaning that the combined effect of active ingredients is greater than the sum of the effects of using the compounds alone. Synergistic effects are achieved when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combination formulation; (2) delivered alternately or in parallel as individual formulations; or (3) through some other protocol. Synergistic effects are achieved when delivered in alternating therapy, such as in separate tablets, pills, or capsules, or by different injection sequences in separate syringes. Generally, in alternating therapy, each active ingredient is administered in an effective dose sequentially (i.e., consecutively), while in combination therapy, two or more active ingredients are administered together in effective doses. A synergistic antiviral effect indicates that the antiviral effect is greater than the predicted additive effect of the individual compounds in the combination.

[0333] 1. Combination therapy for treating pulmonary virology

[0334] The compounds described herein can also be used in combination with other active therapeutic agents. For the treatment of pulmonary viral infections, preferably, the other active therapeutic agents have activity against pulmonary viral infections, particularly respiratory syncytial virus (RSV) and / or metapneumovirus (MRV) infections. Non-limiting examples of these other active therapeutic agents with anti-RSV activity are ribavirin, palilizumab, mavitizumab, and RSV-IGIV. MEDI-557, A-60444 (also known as RSV604), MDT-637, BMS-433771, ALN-RSV0, ALX-0171, and mixtures thereof. Other non-limiting examples of other active therapeutic agents with activity 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 pretovir; 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 nitrozonide.

[0335] In some implementations, other active therapeutic agents may be vaccines for the treatment or prevention of RSV, including but not limited to MVA-BN RSV, RSV-F, MEDI-8897, JNJ-64400141, DPX-RSV, SynGEM, GSK-3389245A, GSK-300389-1A, RSV-MEDI deltaM2-2 vaccine, VRC-RSVRGP084-00VP, Ad35-RSV-FA2, Ad26-RSV-FA2, and RSV fusion glycoprotein subunit vaccines.

[0336] Non-limiting examples of other active therapeutic agents that are active against metapneumovirus infection include sialidase modulators, such as DAS-181; RNA polymerase inhibitors, such as ALS-8112; and antibodies for the treatment of metapneumovirus infection, such as EV-046113.

[0337] In some implementations, other active therapeutic agents may be vaccines used to treat or prevent metapneumovirus infection, including but not limited to mRNA-1653 and rHMPV-Pa vaccines.

[0338] 2. Combination therapy for treating microribonucleoviridae

[0339] The compounds described herein can also be used in combination with other active therapeutic agents. For the treatment of picornaviridae virus infections, preferably, the other active therapeutic agents have activity against picornaviridae virus infections, particularly enterovirus infections. Non-limiting examples of these other active therapeutic agents are capsid binding inhibitors, such as pracetamyl, BTA-798 (vapendavir), and other compounds disclosed by Wu et al. (US 7,078,403) and Watson (US 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.

[0340] In some implementations, other active therapeutic agents may be vaccines for the treatment or prevention of infection with microribonucleoviridae viruses, including but not limited to EV71 vaccines, TAK-021, and vaccines based on the EV-D68 adenovirus vector.

[0341] 3. Combination therapy for respiratory tract infections

[0342] Infections caused by many viruses of the Pneumoviridae, Picornaviridae, and Coronaviridae families are respiratory infections. Therefore, adjunctive active therapeutic agents for the treatment of respiratory symptoms and post-infectious sequelae can be used in combination with the compounds provided herein. The adjunctive agents are preferably administered orally or by direct inhalation. Other preferred adjunctive therapeutic agents, for example, for the treatment of viral respiratory infections in combination with the compounds provided herein include, but are not limited to, bronchodilators and corticosteroids.

[0343] Glucocorticoids

[0344] First introduced as a treatment for asthma in 1950 (Carryer, Journal of Allergy, 21, 282-287, 1950), glucocorticoids remain the most effective and consistently effective treatment for this disease, but their mechanisms of action are not fully understood (Morris, J. Allergy Clin. Immunol., 75(1Pt)1-13, 1985). Unfortunately, oral glucocorticoid therapy is associated with serious adverse side effects such as truncal obesity, hypertension, glaucoma, impaired glucose tolerance, accelerated cataract formation, bone mineral loss, and psychological effects, all of which limit its use as a long-term treatment (Goodman and Gilman, 10th ed., 2001). A solution to systemic side effects is the direct delivery of steroid medications to the site of inflammation. Inhaled corticosteroids (ICS) have been developed to alleviate the severe side effects of oral steroids. Non-limiting examples of corticosteroids that may be used in combination with the compounds provided herein are dexamethasone, dexamethasone sodium phosphate, flumethonone, flumethonone acetate, clotipreno, clotipreno ecaprate, hydrocortisone, prednisolone, fludrocortisone, triamcinolone, triamcinolone, betamethasone, beclomethasone dipropionate, methylprednisolone, fluocinolone acetonide, flunisolone, flucodone-21-butyrate, flumethasone, flumethasone valerate, budesonide, halobetasol propionate, mometasone furoate, fludioxonone, AZD-7594, cyclosporine; or pharmaceutically acceptable salts thereof.

[0345] anti-inflammatory agents

[0346] Other anti-inflammatory agents that act through an anti-inflammatory cascade mechanism can also be used as adjunctive therapies in combination with the compounds presented herein for the treatment of viral respiratory infections. The application of “anti-inflammatory signal transduction modulators” (referred to as AISTMs in this text), such as phosphodiesterase inhibitors (e.g., PDE-4, PDE-5, or PDE-7 specific), transcription factor inhibitors (e.g., blocking NFκB via IKK inhibition), or kinase inhibitors (e.g., blocking p38 MAP, JNK, PI3K, EGFR, or Syk), is a logical approach to cutting off inflammation because these small molecules target a limited number of common intracellular pathways—those signal transduction pathways that are key points of intervention for anti-inflammatory therapies (see the review in PJ Barnes, 2006). These non-restrictive adjunctive therapeutic agents include: 5-(2,4-difluoro-phenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (2-dimethylamino-ethyl)-amide (P38 Map kinase inhibitor ARRY-797); 3-cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4-difluoromethoxy-benzamide (PDE-4 inhibitor roflumilast); 4-[2-(3-cyclopentoxy-4-methoxyphenyl)-2-benzyl] [3,5-dichloro-4-pyridinyl]-pyridine (PDE-4 inhibitor CDP-840); N-(3,5-dichloro-4-pyridinyl)-4-difluoromethoxy-8-[(methanesulfonyl)amino]-1-dibenzofuran carboxamide (PDE-4 inhibitor Oglemilast); N-(3,5-dichloro-pyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxo-acetamide (PDE-4 inhibitor AWD 12-281); 8-methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid (3,5-dichloro-1-oxy-pyridin-4-yl)-amide (PDE-4 inhibitor Sch 351591); 4-[5-(4-fluorophenyl)-2-(4-methanesulfinyl-phenyl)-1H-imidazol-4-yl]-pyridine (P38 inhibitor SB-203850); 4-[4-(4-fluorophenyl)-1-(3-phenylpropyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-but-3-yn-1-ol (P38 inhibitor RWJ-67657); 4-cyano-4-(3-cyclopentoxy-4-methoxy-phenyl)-cyclohexanecarboxylic acid 2 -Diethylamino-ethyl ester (2-diethyl-ethyl ester prodrug of silostabrine, a PDE-4 inhibitor); (3-chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (gefitinib, an EGFR inhibitor); and 4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (imatinib, an EGFR inhibitor).

[0347] β2-adrenergic receptor agonists and bronchodilators

[0348] Combinations of inhaled β2-adrenergic receptor agonists and bronchodilators such as formoterol, salbutamol, or salmeterol with the compounds provided herein are also suitable, but not limiting, combinations for the treatment of respiratory viral infections.

[0349] Inhaled β2-adrenergic receptor agonists and bronchodilators such as formoterol or salmeterol, in combination with ICS, are also used to treat bronchoconstriction and inflammation (respectively). and Combinations of these ICS and β2-adrenergic receptor agonists, as well as combinations of the compounds presented herein, are also suitable, but not limiting, combinations for the treatment of respiratory viral infections.

[0350] Other examples of β2-adrenergic receptor agonists are bedoradine, vilanterol, indacaterol, olodaterol, tuloterrol, formoterol, abidilol, salbutamol, afortrol, levosalbutamol, fenoterol, and TD-5471.

[0351] Anticholinergic agents

[0352] Anticholinergic agents have potential use in the treatment or prevention of bronchoconstriction and can therefore be used as adjunctive therapy in combination with the compounds described herein for the treatment of viral respiratory infections.These anticholinergic agents include, but are not limited to, antagonists of muscarinic receptors (especially the M3 subtype), which have been shown to be effective in controlling cholinergic tension in humans for COPD (Witek, 1999); 1-{4-hydroxy-1-[3,3,3-tris-(4-fluorophenyl)propionyl]pyrrolidine-2-carbonyl}-pyrrolidine-2-carboxylic acid (1-methylpiperidin-4-ylmethyl)-amide; 3-[3-(2-diethylamino-acetoxy)-2-phenyl-propionyloxy]-8-isopropyl-8-methyl-8-aza-onium-bicyclo[3.2.1]octane (ipratropium-N,N-diethylglycine ester); 1-cyclohexyl-3,4-dihydro-1H-isoquinoline-2- 1-aza-bicyclo[2.2.2]oct-3-yl formate (sofenadine); 1-aza-bicyclo[2.2.2]oct-3-yl 2-hydroxymethyl-4-methanesulfinyl-2-phenyl-butyric acid (revatropide); 2-{1-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-pyrrolidine-3-yl}-2,2-diphenyl-acetamide (dapoxetine); 4-azacycloheptane-1-yl-2,2-diphenyl-butyramide (Buzepide); 7-[3-(2-diethylamino-acetoxy)-2-phenyl-propionyloxy]-9-ethyl-9-methyl-3-oxa-9-aza-tricyclo[3.3.1.02,4]nonane (oxytropine-N) ,N-diethylglycine ester); 7-[2-(2-diethylamino-acetoxy)-2,2-di-thiophene-2-yl-acetoxy]-9,9-dimethyl-3-oxa-9-aza-tricyclo[3.3.1.02,4]nonane (tiotropium-N,N-diethylglycine ester); dimethylamino-acetic acid 2-(3-diisopropylamino-1-phenyl-propyl)-4-methyl-phenyl ester (tolterodine-N,N-dimethylglycine ester); 3-[4,4-bis-(4-fluorophenyl)-2-oxo-imidazolidine-1-yl]-1-methyl-1-(2-oxo-2-pyridin-2-yl-ethyl)-pyrrolidineonium; 1-[1-(3-fluorobenzyl)-piperidin-4-yl]- 4,4-Bis-(4-fluorophenyl)-imidazolidine-2-one; 1-Cyclooctyl-3-(3-methoxy-1-aza-bicyclo[2.2.2]oct-3-yl)-1-phenyl-prop-2-yn-1-ol; 3-[2-(2-diethylamino-acetoxy)-2,2-dithiophene-2-yl-acetoxy]-1-(3-phenoxy-propyl)-1-aza-bicyclo[2.2.2]octane (aldecanedinium bromide-N,N-diethylglycine ester); or (2-diethylamino-acetoxy)-dithiophene-2-yl-acetic acid 1-methyl-1-(2-phenoxy-ethyl)-piperidin-4-yl ester; refenapyridine, ganroammonium bromide, wudiammonium bromide, tiotropium bromide, adicanedinium bromide, benzylquinoline bromide.

[0353] Mucus Dissolving Agent

[0354] The compounds described herein can also be combined with mucolytics to treat symptoms of infections and respiratory tract infections. A non-limiting example of a mucolytic is ambroxol. Similarly, these compounds can be combined with expectorants to treat symptoms of infections and respiratory tract infections. A non-limiting example of an expectorant is guaiacol.

[0355] Nebulized hypertonic saline is used to improve the immediate and long-term clearance of small airways in patients with lung disease (Kuzik, J. Pediatrics 2007, 266). Therefore, the compounds described herein can also be combined with nebulized hypertonic saline, particularly when viral infection is complicated by bronchiolitis. The combination of the compounds described herein with hypertonic saline may also include any additional agents discussed above. In one embodiment, approximately 3% hypertonic saline is used via nebulization.

[0356] 4. Combination therapy for treating infections caused by Flaviviridae viruses.

[0357] The compounds and compositions provided herein can also be used in combination with other active therapeutic agents. For the treatment of flaviviridae virus infections, preferably, the other active therapeutic agents have activity against flaviviridae virus infections.

[0358] Non-limiting examples of other active therapeutic agents for the treatment of dengue virus infection include host cytokine modulators such as GBV-006; fenivel-Amin ABX-220 and BRM-211; α-glucosidase 1 inhibitors such as celgosivir; platelet-activating factor receptor (PAFR) antagonists such as modepapanan; cadherin-5 / factor Ia modulators such as FX-06; NS4B inhibitors such as JNJ-8359; viral RNA splicing modulators such as ABX-202; NS5 polymerase inhibitors; NS3 protease inhibitors; and TLR modulators.

[0359] In some implementations, other active therapeutic agents may be vaccines used to treat or prevent dengue fever, including but not limited to TetraVax-DV. DPIV-001, TAK-003, live attenuated dengue vaccine, quadrivalent dengue vaccine, quadrivalent DNA vaccine, rDEN2delta30-7169 and DENV-1PIV.

[0360] 5. Combination therapy for treating infections caused by filoviridae viruses.

[0361] The compounds provided herein can also be used in combination with other active therapeutic agents. For the treatment of filoviridae virus infections, preferably, the other active therapeutic agents have activity against filoviridae virus infections, particularly Marburg virus, Ebola virus, and Cueva virus infections. Non-limiting examples of these other active therapeutic agents are: ribavirin, amiodarone, dronedarone, verapamil, Ebola convalescent plasma (ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol), TKM-Ebola, T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(di- [methylamino]propyl]-3,9-dimethylquinolino[8,7-h]quinolone-1,7-diamine), rNAPc2, OS-2966, brinzidofovir, remdesivir; RNA polymerase inhibitors, such as galidivir, favipiravir (also known as T-705 or Avigan), JK-05; host cytokine modulators, such as GMV-006; cadherin-5 / factor Ia modulators, such as FX-06; and antibodies used to treat Ebola, such as REGN-3470-3471-3479 and ZMapp.

[0362] Other non-restricted active therapeutic agents with anti-Ebola activity include alpha-glucosidase 1 inhibitors, cathepsin B inhibitors, CD29 antagonists, dendritic ICAM-3 grasping integrin 1 inhibitors, estrogen receptor antagonists, factor VII antagonists, HLA class II antigen modulators, host cytokine modulators, interferon alpha ligands, neutral alpha-glucosidase AB inhibitors, Niemann-Pick C1 protein inhibitors, nucleoprotein inhibitors, polymerase cofactor VP35 inhibitors, serine protease inhibitors, tissue factor inhibitors, TLR-3 agonists, viral envelope glycoprotein inhibitors, and Ebola virus entry inhibitors (NPC1 inhibitors).

[0363] In some implementations, 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, recombinant Ebola glycoprotein vaccine, Vaxart adenovirus vector 5-based Ebola vaccine, FiloVax vaccine, GOVX-E301, and GOVX-E302.

[0364] The compounds described herein can also be used in combination with aminophosphate morpholino oligomers (PMOs), which are synthetic antisense oligonucleotide analogs designed to interfere with translation by forming base-pair duplexes with specific RNA sequences. Examples of PMOs include, but are not limited to, AVI-7287, AVI-7288, AVI-7537, AVI-7539, AVI-6002, and AVI-6003.

[0365] The compounds described herein are also intended for use with general care provided to patients with filoviridae virus infections, which include parenteral fluids (including glucose saline and Ringer's lactate) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylaxis, fever and pain medications, antiemetics (such as metoclopramide) and / or antidiarrheals, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen), pain medications, and medications for other common illnesses in the patient population, such as antimalarial agents (including artemether and artemisinin-benfluridine combination therapy), typhoid vaccines (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin) or Shigella vaccines.

[0366] X. Compound Preparation

[0367] In some embodiments, this disclosure provides methods and intermediates for preparing the compounds provided herein or pharmaceutically acceptable salts thereof.

[0368] The compounds described herein can be purified by any method known in the art, including chromatographic methods such as high-performance liquid chromatography (HPLC), preparative thin-layer chromatography, rapid column chromatography, and ion-exchange chromatography. Any suitable stationary phase can be used, including normal-phase and reversed-phase, as well as ion exchange resins. Most typically, the disclosed compounds are purified by silica gel and / or alumina chromatography.

[0369] During any method used to prepare the compounds provided herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any molecule of interest. This can be achieved with conventional protecting groups as described in standard works such as TW Greene and PGM Uts, “Protective Groups in Organic Synthesis,” 4th edition, Wiley, New York 2006. Protecting groups can be removed at convenient subsequent stages using methods known in the art.

[0370] Exemplary chemical entities that can be used to implement the methods will now be described with reference to the general preparation described herein and the illustrative synthetic schemes of specific examples below. Those skilled in the art will recognize that, in order to obtain the various compounds described herein, starting materials can be suitably selected such that a reaction scheme, carried out as appropriate or without protection, will carry the final desired substituent to produce the desired product. Alternatively, it may be necessary or desirable to substitute a suitable group for the final desired substituent, which can be carried out in the reaction scheme and, as appropriate, substituted with the desired substituent. Furthermore, those skilled in the art will recognize that the transformations shown in the following schemes can be performed in any order compatible with the functionality of the particular side groups.

[0371] The methods disclosed herein typically provide a specific enantiomer or diastereomer as the desired product, although the stereochemistry of the enantiomer or diastereomer is not determined in all cases. When the stereochemistry of a specific stereocenter in the enantiomer or diastereomer is not determined, the compound is drawn without any stereochemistry being shown at that specific stereocenter, even if the compound may be substantially enantiomerically pure or diastereomerically pure.

[0372] Representative syntheses of the compounds disclosed herein are described in the following schemes and in subsequent specific examples.

[0373] The compounds disclosed herein can be prepared using the methods disclosed herein and their conventional modifications, as will be apparent to those skilled in the art given the disclosure and methods well known in the art. In addition to the teachings herein, conventional and well-known synthetic methods may also be used. The synthesis of typical compounds described herein can be carried out as illustrated in the following examples. Reagents, if available, can be purchased commercially available, for example from Sigma Aldrich or other chemical suppliers. Generally, the compounds described herein are typically stable and separable at room temperature and pressure. The compounds prepared herein can be purified using methods known to those skilled in the art, including those described herein. Those skilled in the art will understand that when an acid (e.g., TFA) is present in the purification solvent, the final product can be separated as a salt (e.g., a TFA salt).

[0374] Methods for preparing compounds of formula Ib

[0375] In some embodiments, this disclosure provides a method for preparing compounds of formula Ib:

[0376]

[0377] in:

[0378] R 7 It is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; and wherein R 7 The group may optionally be substituted by one, two, or three substituents, which are independently selected from the group consisting of: halogen, cyano, -N3, -OR. 8 -NR 9 R 10 And phenyl groups optionally substituted with one, two or three independent substituents selected from halogen, cyano and C1-C6 alkyl groups;

[0379] Each R 8 Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0380] Each R 9 Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; and

[0381] Each R 10 Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; the method includes making a compound of formula A:

[0382] Each RA Independently, it is the hydroxyl protecting group or the two R groups thereon. A Group bonding forms -C(R) B )2-group, wherein R B It is H, C1-C8 alkyl, phenyl, or substituted phenyl;

[0383] Coupled with the coupling partner of formula B:

[0384] Where R X It is chlorine, hydroxyl, -OCOR Y ;

[0385] R Y It is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; and wherein R Y The group may optionally be substituted by one, two, or three substituents, which are independently selected from the group consisting of: halogen, cyano, -N3, -OR. 8' -NR 9' R 10' And phenyl groups optionally substituted with one, two or three independent substituents selected from halogen, cyano and C1-C6 alkyl groups;

[0386] Each R 8' Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0387] Each R 9' Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; and

[0388] Each R 10' Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl.

[0389] In some embodiments, this disclosure provides a method for preparing compounds of formula Ib:

[0390]

[0391] Where R 7 It is a C1-C8 alkyl group;

[0392] This method involves making a compound of formula A:

[0393] Each R A Independently, it is the hydroxyl protecting group or the two R groups thereon.A Group bonding forms -C(R) B )2-group, wherein R B It is H or C1-C8 alkyl;

[0394] Coupled with the coupling partner of formula B:

[0395] Where R X It is chlorine, hydroxyl, -OCOR Y ;

[0396] R Y It is a C1-C8 alkyl or C6-C 10 Aryl; and R in which Y The group may be optionally substituted by one, two or three substituents independently selected from the group consisting of halogens.

[0397] In some embodiments, this disclosure provides a method for preparing compounds of formula Ib:

[0398]

[0399]

[0400] Where R 7 It is a C1-C3 alkyl group;

[0401] This method involves making a compound of formula A:

[0402] Each R A Independently, it is the hydroxyl protecting group or the two R groups thereon. A Group bonding forms -C(R) B )2-group, wherein R B It is H or C1-C8 alkyl;

[0403] Coupled with the coupling partner of formula B:

[0404] Where R X It is chlorine, hydroxyl, -OCOR Y ;

[0405] R Y It is a C1-C3 alkyl or phenyl; and wherein the phenyl is optionally substituted by one, two or three substituents independently selected from the group consisting of halogens.

[0406] In some embodiments, this disclosure provides a method for preparing compounds of formula Ib:

[0407]

[0408] Where R 7 It is a C3 alkyl group;

[0409] This method involves making a compound of formula A:

[0410] Each R A Independently, it is the hydroxyl protecting group or the two R groups thereon. A Group bonding forms -C(R) B )2-group, wherein R B It is H or C1-C8 alkyl;

[0411] Coupled with the coupling partner of formula B:

[0412] Where R X It is chlorine, hydroxyl, -OCOR Y ;

[0413] R Y It is a C3 alkyl or phenyl; and wherein the phenyl is optionally substituted by one, two or three substituents independently selected from the group consisting of halogens.

[0414] In some embodiments, this disclosure provides a method for preparing compounds of formula Ib:

[0415]

[0416] Where R 7 It is isopropyl;

[0417] This method involves making a compound of formula A:

[0418] Among them, the two R's A Group bonding forms -C(R) B )2-group, wherein R B It is an H or C1-C3 alkyl group;

[0419] Coupled with the coupling partner of formula B:

[0420] Where R X It is chlorine, hydroxyl, -OCOR Y ;

[0421] R Y It is isopropyl or phenyl; and wherein the phenyl is optionally substituted by one, two or three substituents independently selected from the group consisting of halogens.

[0422] In some embodiments, this disclosure provides a method for preparing compounds of formula Ib:

[0423]

[0424] Where R 7 It is isopropyl;

[0425] This method involves making a compound of formula A:

[0426] Among them, the two R's A Group bonding forms -C(R) B )2-group, wherein R B It is H or methyl;

[0427] Coupled with the coupling partner of formula B:

[0428] Where R X It is chlorine, hydroxyl, -OCOR Y ;

[0429] R Y It is isopropyl or phenyl; and wherein the phenyl group is optionally substituted with one, two or three chlorine groups.

[0430] In some embodiments, coupling of a compound of formula A with a coupling partner of formula B produces a compound of formula C:

[0431]

[0432] Where R A and R 7 Each is as defined herein in various embodiments of the method for preparing compounds of formula Ib.

[0433] In some embodiments, the method for preparing the compound of formula Ib further includes deprotecting the compound of formula C to obtain the compound of formula Ib. In some embodiments, deprotection of the compound of formula C includes using an acid. In some embodiments, the compound of formula C is deprotected using an acid of the general formula HX (where X is a conjugate base) to produce a salt of the compound of formula Ib (formula Ib·HX). When the deprotected compound is obtained in salt form, a free basification step may optionally be performed. In some embodiments, the free basification step includes treatment with a base.

[0434] Coupling reaction of formula A and formula B

[0435]

[0436] The method for preparing compounds of formula Ib provided herein includes coupling a compound of formula A with a coupling partner of formula B.

[0437] In some implementations of the coupling partner of formula B, R X It is chlorine. In some implementations, R X It is a hydroxyl group. In some embodiments, R X It is -OCOR Y In some implementations, R X It is -OCOR Y ;where R Y With R 7 Same or R Y It is a C6-C that is optionally substituted with one, two or three substituents. 10 aryl, the substituent being independently selected from the group consisting of: halogen, cyano, -N3, -OR 8' -NR 9' R 10' And phenyl groups optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl groups. In some embodiments, R X It is -OCOR Y ;where R Y With R 7 Same or R Y It is a C6-C that is optionally substituted with one, two or three substituents. 10 Aryl; wherein each substituent is independently a halogen. In some embodiments, R X It is -OCOR Y ;where R Y With R 7 Same or R Y It is a phenyl group optionally substituted with one, two, or three substituents; wherein each substituent is independently a halogen. In some embodiments, R X It is -OCOR Y ;where R Y With R 7 The same. In some implementations, R X It is -OCOR Y ;where R Y It is a phenyl group optionally substituted with one, two, or three substituents; wherein each substituent is independently a halogen. In some embodiments, R X It is -OCOR Y ;where R Y With R 7 Same or R Y It is a phenyl group that is optionally substituted with one, two, or three chlorine groups.

[0438] The coupling partner of Formula B can be used in any suitable amount. In some embodiments, the amount of Formula B is at least 1.0 equivalents (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.

[0439] In some embodiments, the coupling of the coupling pair of Formula A and Formula B is carried out in the presence of a catalyst. Any suitable catalyst can be used. In some embodiments, the catalyst is a nitrided heterocyclic compound, an azodicarboxylic acid ester, a guanidinium and ureonium-type coupling agent, triphenylphosphine, tri-n-butylphosphine, or S,S-bis(4,6-dimethyl-2-pyrimidinyl)carbodisulfate.

[0440] In some embodiments, the coupling of the coupling partners of Formula A and Formula B is carried out in the presence of a catalyst, wherein the catalyst is a nitrided heterocyclic ring. 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.

[0441] In some embodiments, the coupling of the coupling pair of Formula A and Formula B is carried out in the presence of a catalyst, wherein the catalyst is an azodicarboxylic acid ester. In some embodiments, the catalyst is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicyclohexylcarbodiimide, diethyl azodicarboxylic acid, or diisopropyl azodicarboxylic acid. 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 diethyl azodicarboxylic acid. In some embodiments, the catalyst is diisopropyl azodicarboxylic acid.

[0442] In some embodiments, the coupling of the coupling partners of Formula A and Formula B is carried out in the presence of a catalyst, wherein the catalyst is a guanidinium and ureon-type coupling agent. In some embodiments, the catalyst is N-[(dimethylamino)-1H-1,2,3-triazol[4,5-b]-pyridin-1-ylmethylene]-N-methylmethylammonium hexafluorophosphate N-oxide (HATU), N-[(1H-benzotriazol-1-yl)-(dimethylamino)-methylene]-N-methylmethylammonium hexafluorophosphate N-oxide (HBTU), N-[(1H-benzotriazol-1-yl)-(dimethylamino)-methylene]-N-methylmethylammonium tetrafluoroborate N-oxide (TBTU), 2-(2-oxo-1(2H)-pyridinyl-1,1,3,3-tetramethylurea tetrafluoroborate (TPTU), O-[(cyano(ethoxycarbonyl)methyleneamino] ...carbonyl)methylenecarbonyl]-[(cyano(ethoxycarbonyl)methylenecarbonyl)methylenecarbonyl]-[(cyano(ethoxycarbonyl)methylenecarbonyl)methylenecarbonyl]-[(cyano(ethoxycarbonyl)methylenecarbonyl)methylenecarbonyl]-[(cyano The catalyst is [[dimethylamino]-1H-1,2,3-triazolo[4,5-b]-pyridin-1-ylmethylene]-N-methylmethylammonium 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.

[0443] In some embodiments, the coupling of the coupling partners of Formula A and Formula B is carried out in the presence of a catalyst, wherein the catalyst is triphenylphosphine, tri-n-butylphosphine, or S,S-bis(4,6-dimethyl-2-pyrimidinyl)carbodisulfate. 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)carbodisulfate.

[0444] The catalyst can be used in any suitable amount. In some embodiments, the amount of catalyst is 1 mol% to 100 mol% relative to the compound of formula A. In some embodiments, the amount of catalyst is 1 mol% to 50 mol% relative to the compound of formula A. In some embodiments, the amount of catalyst is 1 mol% to 10 mol% relative to the compound of formula A. In some embodiments, the amount of catalyst is 1 mol% 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.

[0445] In some embodiments, 1 mol% to 10 mol% of DMAP is used as a catalyst for coupling formula A and formula B. In some embodiments, 1 mol% to 5 mol% of DMAP is used as a catalyst for coupling formula A and formula B. In some embodiments, 3 mol% of DMAP is used as a catalyst for coupling formula A and formula B.

[0446] In some embodiments, the coupling of the coupling partners of Formula A and Formula B is further carried out in the presence of a base. Any suitable base can be used. In some embodiments, the base used is an inorganic base. In some examples, the base is a carbonate, bicarbonate, metal hydrogen phosphate disalt, metal triphosphate, or a nitrogen-containing base.

[0447] In some embodiments, the base is a bicarbonate salt. 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.

[0448] 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.

[0449] In some embodiments, the base is a metal dihydrogen phosphate. In some embodiments, the base is disodium hydrogen phosphate, dipotassium hydrogen phosphate, or a combination thereof. In some embodiments, the base is disodium hydrogen phosphate. In some embodiments, the base is dipotassium hydrogen phosphate.

[0450] In some embodiments, the base is a metal triphosphate. In some embodiments, the base is trisodium phosphate, tripotassium phosphate, or a combination thereof. In some embodiments, the base is trisodium phosphate. In some embodiments, the base is tripotassium phosphate.

[0451] In some embodiments, the base is a nitrogen-containing base. In some examples, the base is a nitrogen-containing aromatic hydrocarbon, an amine, or an amidine. In some embodiments, the base is pyridine, 2,6-dimethylpyridine, triethylamine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, or a combination thereof. In some embodiments, the base is a nitrogen-containing aromatic hydrocarbon. In some embodiments, the base is pyridine or 2,6-dimethylpyridine. In some embodiments, the base is an amine. In some embodiments, the base is triethylamine, N,N-diisopropylethylamine, or 1,4-diazabicyclo[2.2.2]octane. In some embodiments, the base is an amidine. In some embodiments, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0452] Any suitable amount of base can be used. In some embodiments, the amount of base used is about 0.0 equivalents 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 equivalents, 0.1 equivalents, 0.5 equivalents, 1.0 equivalents, 2.0 equivalents, 3.0 equivalents, 4.0 equivalents, 5.0 equivalents, 6.0 equivalents, 7.0 equivalents, 8.0 equivalents, 9.0 equivalents, 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 equivalents to 1.0 equivalents (mol / mol) relative to the compound of formula A. In some embodiments, the amount of base used is about 0.0 equivalents 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 equivalents 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.

[0453] The coupling of the compound of formula A with the coupling pair 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 also includes water.

[0454] In some embodiments, the solvent is an organic ether. In some examples, the solvent is diethyl ether, tert-butyl methyl ether, tetrahydrofuran (THF), methyltetrahydrofuran (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), methyltetrahydrofuran (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.

[0455] 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 includes water. In some embodiments, the solvent includes water and chlorobenzene. In some embodiments, the solvent includes water and dichloromethane (DCM). In some embodiments, the solvent includes water and 1,2-dichloroethane.

[0456] 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 includes water. In some embodiments, the solvent includes water and N,N-dimethylformamide. In some embodiments, the solvent includes water and N,N-dimethylacetamide. In some embodiments, the solvent includes water and N-methyl-2-pyrrolidone.

[0457] 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 includes water. In some embodiments, the solvent includes water and acetone. In some embodiments, the solvent includes water and 2-butanone. In some embodiments, the solvent includes water and 4-methyl-2-pentanone.

[0458] 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 includes water. In some embodiments, the solvent includes water and ethyl acetate. In some embodiments, the solvent includes water and isopropyl acetate.

[0459] 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 includes water. In some embodiments, the solvent includes water and toluene. In some embodiments, the solvent includes water and n-heptane.

[0460] In some embodiments, the solvent is a nitrile solvent. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent further includes water. In some embodiments, the solvent includes both water and acetonitrile.

[0461] The coupling reaction can be carried out at any suitable temperature. In some embodiments, the coupling reaction is carried out at a temperature of about -35°C to 60°C. In some examples, the coupling reaction is carried out at a temperature of about -25°C to 50°C. In some examples, the coupling reaction is carried out at a temperature of about -15°C to 40°C. In some examples, the coupling reaction is carried out at a temperature of about -5°C to 30°C. In some examples, the coupling reaction is carried out at a temperature of about 5°C to 20°C. In some examples, the coupling reaction is carried out at a temperature of about 5°C to 15°C. In some examples, the coupling reaction is carried out at a temperature of about 0°C to 10°C. In some examples, the coupling reaction is carried out at a temperature of about 5°C.

[0462] Deprotection of compounds of formula C

[0463]

[0464] In some embodiments, coupling of formula A with a coupling partner of formula B yields a compound of formula C, and the method for preparing 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.

[0465] 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.

[0466] In some embodiments, the deprotecting agent is a solid-supported acidic resin. In some embodiments, the deprotecting agent is a strong cation exchange resin containing sulfonic acid groups or corresponding salts. In some embodiments, the deprotecting agent is... (Sulfonic acid) IR-120Plus(H), IR-120Plus, IRP-69, 15, or 1200(H). In some embodiments, the deprotecting agent is... (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... (Sulfonic acid) C-26. In some embodiments, the deprotecting agent is a weak cation exchange resin containing a carboxylic acid group or the corresponding salt. In some embodiments, the deprotecting agent is... (Carboxylic acid) CG-50I type, IRC-50, IRC-50s or IRP-64.

[0467] 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 combinations 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.

[0468] 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.

[0469] In some embodiments, the deprotecting agent is a Lewis acid. In some embodiments, the deprotecting agent is trimethylsilyl trifluoromethanesulfonate, 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 trifluoromethanesulfonate.

[0470] 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 deprotectant used is about 1.0 equivalent, 2.0 equivalent, 3.0 equivalent, 4.0 equivalent, 5.0 equivalent, 6.0 equivalent, 7.0 equivalent, 8.0 equivalent, 9.0 equivalent, or 10.0 equivalent (mol / mol) relative to the compound of formula A.

[0471] 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.

[0472] The deprotection step can be carried out in any suitable solvent. In some embodiments, the solvent used for the deprotection step includes ether solvents, polar aprotic solvents, alcohols, ester solvents, halogenated solvents, hydrocarbons, nitrile solvents, or combinations thereof.

[0473] In some embodiments, the solvent used in the deprotection step is an ether solvent. In some embodiments, the solvent used in the deprotection step is THF, MeTHF, tert-butyl methyl ether, or a combination thereof. In some embodiments, the solvent further includes water. In some embodiments, the solvent includes water and THF. In some embodiments, the solvent further includes water. In some embodiments, the solvent includes water and MeTHF. In some embodiments, the solvent further includes water. In some embodiments, the solvent includes water and tert-butyl methyl ether.

[0474] In some embodiments, the solvent used in the deprotection step is a polar aprotic solvent. In some embodiments, the solvent used in the deprotection step is N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or a combination thereof. In some embodiments, the solvent used in the deprotection step is N,N-dimethylformamide. In some embodiments, the solvent used in the deprotection step is N,N-dimethylacetamide. In some embodiments, the solvent used in the deprotection step is N-methyl-2-pyrrolidone. In some embodiments, the solvent further includes water. In some embodiments, the solvent includes water and N,N-dimethylformamide. In some embodiments, the solvent further includes water. In some embodiments, the solvent includes water and N-methyl-2-pyrrolidone.

[0475] In some embodiments, the solvent used in 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 includes water. In some embodiments, the solvent includes water and methanol, ethanol, 2-propanol, or a combination thereof. In some embodiments, the solvent includes water and methanol. In some embodiments, the solvent includes water and ethanol. In some embodiments, the solvent includes water and 2-propanol.

[0476] In some embodiments, the solvent used in 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 includes water. In some embodiments, the solvent includes water and ethyl acetate. In some embodiments, the solvent includes water and isopropyl acetate.

[0477] In some embodiments, the solvent used in the deprotection step is a halogenated solvent. In some embodiments, the solvent is dichloromethane (DCM), 1,2-dichloroethane, or chlorobenzene. In some embodiments, the solvent is DCM. In some embodiments, the solvent is 1,2-dichloroethane. In some embodiments, the solvent is chlorobenzene. In some embodiments, the solvent further includes water. In some embodiments, the solvent includes water and chlorobenzene. In some embodiments, the solvent includes water and dichloromethane (DCM). In some embodiments, the solvent includes water and 1,2-dichloroethane.

[0478] In some embodiments, the solvent used in 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 includes water. In some embodiments, the solvent includes water and toluene. In some embodiments, the solvent includes water and n-heptane.

[0479] In some embodiments, the solvent used in 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 includes water. In some embodiments, the solvent includes water and acetonitrile. In some embodiments, the solvent includes water and propionitrile. In some embodiments, the solvent includes water and butyronitrile. In some embodiments, the solvent includes water and benzonitrile.

[0480] The deprotection reaction can be carried out at any suitable temperature. In some embodiments, the deprotection reaction is carried out at about -20°C to 50°C. In some embodiments, the deprotection reaction is carried out at about -10°C to 40°C. In some embodiments, the deprotection reaction is carried out at about 0°C to 30°C. In some embodiments, the deprotection reaction is carried out at about 10°C to 30°C. In some embodiments, the deprotection reaction is carried out at about 20°C.

[0481] Free base formation

[0482] In some embodiments, an acid of the general formula HX (where X is a conjugate base) is used to deprotect the compound of formula C to produce a salt of the compound of formula Ib (formula Ib·HX). When the deprotected compound is obtained in salt form, an additional free basification step may optionally be performed.

[0483]

[0484] In some embodiments, free alkalization involves treatment with an alkali. Any suitable alkali can be used. In some embodiments, the alkali used is an inorganic alkali, such as a bicarbonate. In some examples, the alkali is lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, or a combination thereof. In some examples, the alkali is sodium bicarbonate, potassium bicarbonate, or a combination thereof. In some examples, the alkali is lithium bicarbonate. In some examples, the alkali is sodium bicarbonate. In some examples, the alkali is potassium bicarbonate.

[0485] 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.

[0486] In some embodiments, the base is an alkoxide. In some embodiments, the base is sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium tert-amyloxide, lithium tert-butoxide, potassium tert-butoxide, or combinations thereof. 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-amyloxide. In some embodiments, the base is lithium tert-butoxide. In some embodiments, the base is potassium tert-butoxide.

[0487] 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.

[0488] In some embodiments, the base is a metal dihydrogen phosphate. In some embodiments, the base is disodium hydrogen phosphate, dipotassium hydrogen phosphate, or a combination thereof. In some embodiments, the base is disodium hydrogen phosphate. In some embodiments, the base is dipotassium hydrogen phosphate.

[0489] In some embodiments, the base is a metal triphosphate. In some embodiments, the base is trisodium phosphate, tripotassium phosphate, or a combination thereof. In some embodiments, the base is trisodium phosphate. In some embodiments, the base is tripotassium phosphate.

[0490] In some embodiments, the base is a nitrogen-containing base. In some examples, the base is a nitrogen-containing aromatic hydrocarbon, an amine, or an amidine. In some embodiments, the base is pyridine, 2,6-dimethylpyridine, triethylamine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, or a combination thereof. In some embodiments, the base is a nitrogen-containing aromatic hydrocarbon. In some embodiments, the base is pyridine or 2,6-dimethylpyridine. In some embodiments, the base is an amine. In some embodiments, the base is triethylamine, N,N-diisopropylethylamine, or 1,4-diazabicyclo[2.2.2]octane. In some embodiments, the base is an amidine. In some embodiments, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0491] The free alkalization step can be carried out in any suitable solvent. In some embodiments, the solvents used for free alkalization include ether solvents, polar aprotic solvents, alcohols, ester solvents, halogenated solvents, hydrocarbons, nitrile solvents, or combinations thereof.

[0492] In some embodiments, the solvent used for the free alkalization step is an ether solvent. In some embodiments, the solvent used for the free alkalization step is THF, MeTHF, tert-butyl methyl ether, or a combination thereof. In some embodiments, the solvent further includes water. In some embodiments, the solvent includes water and THF. In some embodiments, the solvent further includes water. In some embodiments, the solvent includes water and MeTHF. In some embodiments, the solvent further includes water. In some embodiments, the solvent includes water and tert-butyl methyl ether.

[0493] In some embodiments, the solvent used for the free alkalization step is a polar aprotic solvent. In some embodiments, the solvent used for the free alkalization step is N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or a combination thereof. In some embodiments, the solvent used for the free alkalization step is N,N-dimethylformamide. In some embodiments, the solvent used for the free alkalization step is N,N-dimethylacetamide. In some embodiments, the solvent used for the free alkalization step is N-methyl-2-pyrrolidone. In some embodiments, the solvent further includes water. In some embodiments, the solvent includes water and N,N-dimethylformamide. In some embodiments, the solvent further includes water. In some embodiments, the solvent includes water and N-methyl-2-pyrrolidone.

[0494] In some embodiments, the solvent used for the free alkalization 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 includes water. In some embodiments, the solvent includes water and methanol, ethanol, 2-propanol, or a combination thereof. In some embodiments, the solvent includes water and methanol. In some embodiments, the solvent includes water and ethanol. In some embodiments, the solvent includes water and 2-propanol.

[0495] In some embodiments, the solvent used in the free alkalization 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 includes water. In some embodiments, the solvent includes water and ethyl acetate. In some embodiments, the solvent includes water and isopropyl acetate.

[0496] In some embodiments, the solvent used in the free alkalization 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 includes water. In some embodiments, the solvent includes water and chlorobenzene. In some embodiments, the solvent includes water and dichloromethane (DCM). In some embodiments, the solvent includes water and 1,2-dichloroethane.

[0497] In some embodiments, the solvent used in the free alkalization 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 includes water. In some embodiments, the solvent includes water and toluene. In some embodiments, the solvent includes water and n-heptane.

[0498] In some embodiments, the solvent used in the free alkalization 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 includes water. In some embodiments, the solvent includes water and acetonitrile. In some embodiments, the solvent includes water and propionitrile. In some embodiments, the solvent includes water and butyronitrile. In some embodiments, the solvent includes water and benzonitrile.

[0499] Free alkalization can be carried out at any suitable temperature. In some embodiments, the coupling reaction is carried out at about 10°C to 30°C. In some embodiments, the coupling reaction is carried out at about 20°C.

[0500] XI. Crystalline form of compound 15

[0501] Polymorphic forms or polymorphs can possess properties such as bioavailability and stability under certain conditions suitable for medical or pharmaceutical use. The crystalline form of Compound 15 offers the advantages of bioavailability and stability suitable for use as an active ingredient in pharmaceutical compositions. Variations in the crystal structure of a pharmaceutical substance or active ingredient can affect the dissolution rate of the pharmaceutical product or active ingredient (which can 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.). Such variations can affect the preparation or formulation of pharmaceutical compositions in different dosage or delivery forms, such as solid oral dosage forms, including tablets and capsules. Compared to other forms such as amorphous or non-crystalline forms, crystalline forms offer desired or suitable 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 can provide advantages such as improved preparation methods of the active agent or stability or storability of the pharmaceutical product form of the compound or active ingredient, and / or suitable bioavailability and / or stability as an active agent.

[0502] Compound 15, Form I

[0503] In some embodiments, crystalline form I of compound 15 (crystalline compound 15 form I) is provided, wherein the crystal structure exhibits substantially as follows: Figure 10 The X-ray powder diffraction (XRPD) pattern is shown. Crystalline compound 15, form I, can exhibit essentially the same characteristics. Figure 11 The differential scanning calorimetry (DSC) thermogram shown. Crystalline compound 15, form I, exhibits essentially the same characteristics. Figure 12 The thermogravimetric analysis (TGA) graph is shown.

[0504] In some embodiments of crystalline compound form I 15, at least one, at least two, or all of the following (a)-(c) are applicable: (a) crystalline compound form I 15 has substantially as Figure 10 The XRPD pattern shown; (b) Crystalline compound 15 form I has essentially the same Figure 11 The DSC thermogram shown; (c) Crystalline compound 15, form I, has essentially the same... Figure 12 The TGA diagram shown.

[0505] In some embodiments, crystalline compound 15 form I has the following properties:

[0506] (a) Basically as Figure 10 The XRPD pattern shown;

[0507] (b) Basically as Figure 11 The DSC thermogram shown; and

[0508] (c) Basically as Figure 12 The TGA diagram shown.

[0509] In some embodiments, crystalline compound 15 form I has at least two, at least three, at least four, at least five, or at least six [symbols] substantially as shown in the original text. Figure 10 The XRPD pattern shown is an XRPD pattern with the highest intensity of 2θ reflection.

[0510] In some embodiments, crystalline compound 15 form I has an XRPD pattern including 2θ reflection (+ / -0.2°2θ) at 8.5°, 22.1°, and 23.8°. In some embodiments, crystalline compound 15 form I has an XRPD pattern including one, two, or three of the following: 2θ reflection (+ / -0.2°2θ) at 8.5°, 22.1°, and 23.8°; and 2θ reflection (+ / -0.2°2θ) at 15.4°, 16.9°, and 28.1°. In some embodiments, crystalline compound 15 form I has an XRPD pattern including one or two of the following: 2θ reflection (+ / -0.2°2θ) at 8.5°, 22.1°, and 23.8°; and 2θ reflection (+ / -0.2°2θ) at 15.4°, 16.9°, and 28.1°. In some embodiments, crystalline compound 15 form I has an XRPD pattern including one of degree 2θ reflection (+ / -0.2 degrees 2θ) at 8.5°, 22.1°, and 23.8° and degree 2θ reflection (+ / -0.2 degrees 2θ) at 15.4°, 16.9°, and 28.1°. In some embodiments, crystalline compound 15 form I has an XRPD pattern including both of degree 2θ reflection (+ / -0.2 degrees 2θ) at 8.5°, 22.1°, and 23.8° and degree 2θ reflection (+ / -0.2 degrees 2θ) at 15.4°, 16.9°, and 28.1°. In some embodiments, crystalline compound 15 form I has an XRPD pattern including 2θ reflectance (+ / -0.2 degrees 2θ) at 8.5°, 15.4°, 16.9°, 22.1°, 23.8°, and 28.1°. In some embodiments, crystalline compound 15 form I has an XRPD pattern including any three 2θ reflectances (+ / -0.2 degrees 2θ) selected from 8.5°, 15.4°, 16.9°, 22.1°, 23.8°, and 28.1°.

[0511] In some embodiments, crystalline compound 15 form I has an XRPD pattern including one, two, or three of the following: 2θ reflection (+ / -0.2°2θ) at 8.5°, 15.4°, 16.9°, 22.1°, 23.8°, and 28.1°; and 2θ reflection (+ / -0.2°2θ) at 10.5°, 17.5°, and 27.5°. In some embodiments, crystalline compound 15 form I has an XRPD pattern including one or two of the following: 2θ reflection (+ / -0.2°2θ) at 8.5°, 15.4°, 16.9°, 22.1°, 23.8°, and 28.1°; and 2θ reflection (+ / -0.2°2θ) at 10.5°, 17.5°, and 27.5°. In some embodiments, crystalline compound 15 form I has an XRPD pattern including one of degree 2θ reflection (+ / -0.2 degrees 2θ) at 8.5°, 15.4°, 16.9°, 22.1°, 23.8°, and 28.1° and one of degree 2θ reflection (+ / -0.2 degrees 2θ) at 10.5°, 17.5°, and 27.5°. In some embodiments, crystalline compound 15 form I has an XRPD pattern including two of degree 2θ reflection (+ / -0.2 degrees 2θ) at 8.5°, 15.4°, 16.9°, 22.1°, 23.8°, and 28.1° and one of degree 2θ reflection (+ / -0.2 degrees 2θ) at 10.5°, 17.5°, and 27.5°. In some embodiments, crystalline compound 15 form I has an XRPD pattern including 2θ reflectance (+ / -0.2 degrees 2θ) at 8.5°, 10.5°, 15.4°, 16.9°, 17.5°, 22.1°, 23.8°, 27.5°, and 28.1°. In some embodiments, crystalline compound 15 form I has an XRPD pattern including three of the following: 2θ reflectance (+ / -0.2 degrees 2θ) at 8.5°, 10.5°, 15.4°, 16.9°, 17.5°, 22.1°, 23.8°, 27.5°, and 28.1°.

[0512] Compound 15, Form II

[0513] In some embodiments, crystalline form II of compound 15 (crystalline compound 15 form II) is provided, wherein the crystal structure exhibits substantially as follows: Figure 13 The X-ray powder diffraction (XRPD) pattern is shown. Crystalline compound 15, form II, can exhibit essentially the same characteristics. Figure 14 The DSC thermogram shown. Crystalline compound 15, form II, can exhibit essentially the same characteristics as... Figure 15 The TGA diagram shown.

[0514] In some embodiments of crystalline compound form II, at least one, at least two, or all of the following (a)-(c) are applicable: (a) crystalline compound form II has substantially the following characteristics: Figure 13 The XRPD pattern shown; (b) Crystalline compound 15 form II has essentially the same Figure 14 The DSC thermogram shown; (c) Crystalline compound 15, form II, has essentially the same... Figure 15 The TGA diagram shown.

[0515] In some embodiments, crystalline compound 15 form II has the following properties:

[0516] (a) Basically as Figure 13 The XRPD pattern shown;

[0517] (b) Basically as Figure 14 The DSC thermogram shown; and

[0518] (c) Basically as Figure 15 The TGA diagram shown.

[0519] In some embodiments, crystalline compound 15 form II has at least two, at least three, at least four, at least five, or at least six [symbols] substantially as shown in the original text. Figure 13 The XRPD pattern shown is an XRPD pattern with the highest intensity of 2θ reflection.

[0520] In some embodiments, crystalline compound 15 form II has an XRPD pattern including 2θ reflection (+ / -0.2°2θ) at 6.4°, 13.7°, and 16.3°. In some embodiments, crystalline compound 15 form II has an XRPD pattern including one, two, or three of the following: 2θ reflection (+ / -0.2°2θ) at 6.4°, 13.7°, and 16.3°; and 2θ reflection (+ / -0.2°2θ) at 18.4°, 20.8°, and 23.3°. In some embodiments, crystalline compound 15 form II has an XRPD pattern including one or two of the following: 2θ reflection (+ / -0.2°2θ) at 6.4°, 13.7°, and 16.3°; and 2θ reflection (+ / -0.2°2θ) at 18.4°, 20.8°, and 23.3°. In some embodiments, crystalline compound 15 form II has an XRPD pattern including one of degree 2θ reflection (+ / -0.2 degrees 2θ) at 6.4°, 13.7°, and 16.3° and one of degree 2θ reflection (+ / -0.2 degrees 2θ) at 18.4°, 20.8°, and 23.3°. In some embodiments, crystalline compound 15 form II has an XRPD pattern including both of degree 2θ reflection (+ / -0.2 degrees 2θ) at 6.4°, 13.7°, and 16.3° and one of degree 2θ reflection (+ / -0.2 degrees 2θ) at 18.4°, 20.8°, and 23.3°. In some embodiments, crystalline compound 15 form II has an XRPD pattern including 2θ reflectance (+ / -0.2 degrees 2θ) at 6.4°, 13.7°, 16.3°, 18.4°, 20.8°, and 23.3°. In some embodiments, crystalline compound 15 form II has an XRPD pattern including any three 2θ reflectance (+ / -0.2 degrees 2θ) selected from 6.4°, 13.7°, 16.3°, 18.4°, 20.8°, and 23.3°.

[0521] In some embodiments, crystalline compound 15 form II has an XRPD pattern including any three degrees 2θ reflectance (+ / -0.2 degrees 2θ) selected from 6.4°, 13.7°, 16.3°, 18.4°, 20.8°, 23.3°, and 25.4°. In some embodiments, crystalline compound 15 form II has an XRPD pattern including degrees 2θ reflectance (+ / -0.2 degrees 2θ) at 6.4°, 13.7°, 16.3°, 18.4°, 20.8°, 23.3°, and 25.4°.

[0522] Compound 15, Form III

[0523] In some embodiments, crystalline form III of compound 15 (crystalline compound 15 form III) is provided, wherein the crystal structure exhibits substantially as follows: Figure 16 The XRPD pattern shown. Crystalline compound 15, form III, can exhibit essentially the same characteristics. Figure 17 The DSC thermogram shown. Crystalline compound 15, form III, can exhibit essentially the same characteristics as... Figure 18 The TGA diagram shown.

[0524] In some embodiments of crystalline compound form III, at least one, at least two, or all of the following (a)-(c) are applicable: (a) crystalline compound form III has substantially the following characteristics: Figure 16 The XRPD pattern shown; (b) Crystalline compound 15, form III, has essentially the same... Figure 17 The DSC thermogram shown; (c) Crystalline compound 15, form III, has essentially the same... Figure 18 The TGA diagram shown.

[0525] In some embodiments, crystalline compound 15 form III has the following properties:

[0526] (a) Basically as Figure 16 The XRPD pattern shown;

[0527] (b) Basically as Figure 17 The DSC thermogram shown; and

[0528] (c) Basically as Figure 18 The TGA diagram shown.

[0529] In some embodiments, crystalline compound 15 form III has at least two, at least three, at least four, at least five, or at least six [symbols] substantially as shown in the original text. Figure 16 The XRPD pattern shown is an XRPD pattern with the highest intensity of 2θ reflection.

[0530] In some embodiments, crystalline compound form III has an XRPD pattern including 2θ reflection (+ / -0.2°2θ) at 9.8°, 16.0°, and 25.4°. In some embodiments, crystalline compound form III has an XRPD pattern including one, two, or three of the following: 2θ reflection (+ / -0.2°2θ) at 9.8°, 16.0°, and 25.4°; and 2θ reflection (+ / -0.2°2θ) at 10.2°, 19.1°, and 26.9°. In some embodiments, crystalline compound form III has an XRPD pattern including one or two of the following: 2θ reflection (+ / -0.2°2θ) at 9.8°, 16.0°, and 25.4°; and 2θ reflection (+ / -0.2°2θ) at 10.2°, 19.1°, and 26.9°. In some embodiments, crystalline compound 15 form III has an XRPD pattern including one of degree 2θ reflection (+ / -0.2 degrees 2θ) at 9.8°, 16.0°, and 25.4° and one of degree 2θ reflection (+ / -0.2 degrees 2θ) at 10.2°, 19.1°, and 26.9°. In some embodiments, crystalline compound 15 form III has an XRPD pattern including both of degree 2θ reflection (+ / -0.2 degrees 2θ) at 9.8°, 16.0°, and 25.4° and one of degree 2θ reflection (+ / -0.2 degrees 2θ) at 10.2°, 19.1°, and 26.9°. In some embodiments, crystalline compound 15 form III has an XRPD pattern including 2θ reflectance (+ / -0.2 degrees 2θ) at 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9°. In some embodiments, crystalline compound 15 form III has an XRPD pattern including any three of the following at 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9°: 2θ reflectance (+ / -0.2 degrees 2θ).

[0531] In some embodiments, crystalline compound 15 form III has an XRPD pattern including one, two, or three of the following: 2θ reflection (+ / -0.2°2θ) at 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9°; and 2θ reflection (+ / -0.2°2θ) at 10.4°, 19.8°, and 20.7°. In some embodiments, crystalline compound 15 form III has an XRPD pattern including one or two of the following: 2θ reflection (+ / -0.2°2θ) at 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9°; and 2θ reflection (+ / -0.2°2θ) at 10.4°, 19.8°, and 20.7°. In some embodiments, crystalline compound 15 form III has an XRPD pattern including 2θ reflection (+ / -0.2°2θ) at 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9°, and including 2θ reflection (+ / -0.2°2θ) at 10.4°, 19.8°, and 20.7°. In some embodiments, crystalline compound 15 form III has an XRPD pattern including 2θ reflection (+ / -0.2°2θ) at 9.8°, 10.2°, 16.0°, 19.1°, 25.4°, and 26.9°, and including 2θ reflection (+ / -0.2°2θ) at 10.4°, 19.8°, and 20.7°. In some embodiments, crystalline compound 15 form III has an XRPD pattern including 2θ reflection (+ / -0.2 degrees 2θ) at 9.8°, 10.2°, 10.4°, 16.0°, 19.1°, 19.8°, 20.7°, 25.4°, and 26.9°. In some embodiments, crystalline compound 15 form III has an XRPD pattern including any three of the following at 9.8°, 10.2°, 10.4°, 16.0°, 19.1°, 19.8°, 20.7°, 25.4°, and 26.9°: 2θ reflection (+ / -0.2 degrees 2θ).

[0532] XII. Salt of Compound 15

[0533] Compound 15 sine naphthalate

[0534] In some embodiments, this disclosure provides a chloronaphthate of compound 15 (compound 15 chloronaphthate). In some embodiments, compound 15 chloronaphthate is unsolvated.

[0535] In some embodiments, this disclosure provides a crystalline form of compound 15-chloronaphthyl salt. In some embodiments, the crystalline form of compound 15-chloronaphthyl salt exhibits essentially as follows: Figure 19The XRPD pattern is shown. In some embodiments, the crystalline form of compound 15 chloronaphthate can exhibit essentially the following characteristics. Figure 20 The DSC thermogram is shown. In some embodiments, the crystalline form of compound 15-naphthyl salt can exhibit essentially the following characteristics. Figure 21 The TGA diagram shown.

[0536] In some embodiments of the crystalline form of compound 15 benzonatate, at least one, at least two, at least three, or all of the following (a)-(c) are applicable: (a) the crystalline form of compound 15 benzonatate has substantially the following characteristics: Figure 19 The XRPD pattern shown; (b) the crystalline form of compound 15 sine naphthate has essentially the same as Figure 20 The DSC thermogram shown; (c) The crystalline form of compound 15 sine naphthate has essentially the following characteristics. Figure 21 The TGA diagram shown.

[0537] In some embodiments, the crystalline form of compound 15 naphthalate has the following characteristics:

[0538] (a) Basically as Figure 19 The XRPD pattern shown;

[0539] (b) Basically as Figure 20 The DSC thermogram shown; and

[0540] (c) Basically as Figure 21 The TGA diagram shown.

[0541] In some embodiments, the crystalline form of compound 15 sine naphthate has at least two, at least three, at least four, at least five, or at least six crystalline forms substantially as shown in the figure. Figure 19 The XRPD pattern shown is an XRPD pattern with the highest intensity of 2θ reflection.

[0542] In some embodiments, the crystalline form of compound 15 benzonaphthyl salt has an XRPD pattern including 2θ reflection (+ / -0.2°2θ) at 4.0°, 12.2°, and 14.8°. In some embodiments, the crystalline form of compound 15 benzonaphthyl salt has an XRPD pattern including one, two, or three of the following: 2θ reflection (+ / -0.2°2θ) at 4.0°, 12.2°, and 14.8°; and 2θ reflection (+ / -0.2°2θ) at 6.2°, 12.9°, and 26.6°. In some embodiments, the crystalline form of compound 15 benzonaphthyl salt has an XRPD pattern including one or two of the following: 2θ reflection (+ / -0.2°2θ) at 4.0°, 12.2°, and 14.8°; and 2θ reflection (+ / -0.2°2θ) at 6.2°, 12.9°, and 26.6°. In some embodiments, the crystalline form of compound 15-benzodiazepine has an XRPD pattern including one of 2θ reflectance (+ / -0.2°2θ) at 4.0°, 12.2°, and 14.8° and 2θ reflectance (+ / -0.2°2θ) at 6.2°, 12.9°, and 26.6°. In some embodiments, the crystalline form of compound 15-benzodiazepine has an XRPD pattern including both of 2θ reflectance (+ / -0.2°2θ) at 4.0°, 12.2°, and 14.8° and 2θ reflectance (+ / -0.2°2θ) at 6.2°, 12.9°, and 26.6°. In some embodiments, the crystalline form of compound 15 benzonaphthyl salt has an XRPD pattern including 2θ reflectance (+ / -0.2 degrees 2θ) at 4.0°, 6.2°, 12.2°, 12.9°, 14.8°, and 26.6°. In some embodiments, the crystalline form of compound 15 benzonaphthyl salt has an XRPD pattern including any three of the following 2θ reflectance (+ / -0.2 degrees 2θ): 4.0°, 6.2°, 12.2°, 12.9°, 14.8°, and 26.6°.

[0543] In some embodiments, the crystalline form of compound 15-benzodiazepine has an XRPD pattern comprising one, two, or three of the following: 2θ reflectance (+ / -0.2°2θ) at 4.0°, 6.2°, 12.2°, 12.9°, 14.8°, and 26.6°; and 2θ reflectance (+ / -0.2°2θ) at 7.8°, 10.3°, and 15.7°. In some embodiments, the crystalline form of compound 15-benzodiazepine has an XRPD pattern comprising one or two of the following: 2θ reflectance (+ / -0.2°2θ) at 4.0°, 6.2°, 12.2°, 12.9°, 14.8°, and 26.6°; and 2θ reflectance (+ / -0.2°2θ) at 7.8°, 10.3°, and 15.7°. In some embodiments, the crystalline form of compound 15-benzodiazepine has an XRPD pattern including 2θ reflection (+ / -0.2°2θ) at 4.0°, 6.2°, 12.2°, 12.9°, 14.8°, and 26.6°, and including 2θ reflection (+ / -0.2°2θ) at 7.8°, 10.3°, and 15.7°. In some embodiments, the crystalline form of compound 15-benzodiazepine has an XRPD pattern including 2θ reflection (+ / -0.2°2θ) at 4.0°, 6.2°, 12.2°, 12.9°, 14.8°, and 26.6°, and including 2θ reflection (+ / -0.2°2θ) at 7.8°, 10.3°, and 15.7°. In some embodiments, the crystalline form of compound 15-benzodiazepine has an XRPD pattern including 2θ reflectance (+ / -0.2 degrees 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-benzodiazepine has an XRPD pattern including any three of the following 2θ reflectance (+ / -0.2 degrees 2θ): 4.0°, 6.2°, 7.8°, 10.3°, 12.2°, 12.9°, 14.8°, 15.7°, and 26.6°.

[0544] Compound 15 HCl salt

[0545] In some embodiments, this disclosure provides an HCl salt of compound 15 (compound 15 HCl salt).

[0546] In some embodiments, this disclosure provides the crystalline form of the HCl salt of compound 15.

[0547] Compound 15 HCl salt form I

[0548] In some embodiments, this disclosure provides a crystalline form I of the 15 HCl salt (“Compound 15 HCl Salt Form I”). In some embodiments, Compound 15 HCl Salt Form I exhibits substantially the following characteristics: Figure 22 The XRPD pattern is shown. In some embodiments, compound 15 HCl salt form I can exhibit essentially the same characteristics. Figure 23 The DSC thermogram is shown. In some embodiments, compound 15 HCl salt form I can exhibit essentially the same characteristics. Figure 24 The TGA diagram shown.

[0549] In some embodiments of compound 15 HCl salt form I, at least one, at least two, or all of the following (a)-(c) are applicable: (a) compound 15 HCl salt form I has substantially the following characteristics: Figure 22 The XRPD pattern shown; (b) Compound 15HCl salt form I has essentially the same Figure 23 The DSC thermogram shown; (c) Compound 15 HCl salt form I has essentially the same... Figure 24 The TGA diagram shown.

[0550] In some embodiments, compound 15 HCl salt form I has the following properties:

[0551] (a) Basically as Figure 22 The XRPD pattern shown;

[0552] (b) Basically as Figure 23 The DSC thermogram shown; and

[0553] (c) Basically as Figure 24 The TGA diagram shown.

[0554] In some embodiments, compound 15 HCl salt form I has at least two, at least three, at least four, at least five, or at least six salts that are substantially as shown in the original text. Figure 22 The XRPD pattern shown is an XRPD pattern with the highest intensity of 2θ reflection.

[0555] In some embodiments, compound 15 HCl salt form I has an XRPD pattern including degree 2θ reflection (+ / -0.2 degrees 2θ) at 5.9°, 14.0°, and 24.3°. In some embodiments, compound 15 HCl salt form I has an XRPD pattern including degree 2θ reflection (+ / -0.2 degrees 2θ) at 5.9°, 14.0°, and 24.3°, and degree 2θ reflection (+ / -0.2 degrees 2θ) at 11.7°, 16.7°, and 23.9°, or both. In some embodiments, compound 15 HCl salt form I has an XRPD pattern including degree 2θ reflection (+ / -0.2 degrees 2θ) at 5.9°, 14.0°, and 24.3°, and degree 2θ reflection (+ / -0.2 degrees 2θ) at 11.7°, 16.7°, and 23.9°, or both. In some embodiments, the 15HCl salt form I of compound has an XRPD pattern including one of degree 2θ reflection (+ / -0.2 degrees 2θ) at 5.9°, 14.0°, and 24.3° and degree 2θ reflection (+ / -0.2 degrees 2θ) at 11.7°, 16.7°, and 23.9°. In some embodiments, the 15HCl salt form I of compound has an XRPD pattern including both of degree 2θ reflection (+ / -0.2 degrees 2θ) at 5.9°, 14.0°, and 24.3° and degree 2θ reflection (+ / -0.2 degrees 2θ) at 11.7°, 16.7°, and 23.9°. In some embodiments, compound 15HCl salt form I has an XRPD pattern including 2θ reflection (+ / -0.2 degrees 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 the following at 5.9°, 11.7°, 14.0°, 16.7°, 23.9°, and 24.3°: 2θ reflection (+ / -0.2 degrees 2θ).

[0556] In some embodiments, compound 15 HCl salt form I has an XRPD pattern including one, two, or three of the following: 2θ reflection (+ / -0.2°2θ) at 5.9°, 11.7°, 14.0°, 16.7°, 23.9°, and 24.3°; and 2θ reflection (+ / -0.2°2θ) at 14.2°, 19.7°, and 22.4°. In some embodiments, compound 15 HCl salt form I has an XRPD pattern including one or two of the following: 2θ reflection (+ / -0.2°2θ) at 5.9°, 11.7°, 14.0°, 16.7°, 23.9°, and 24.3°; and 2θ reflection (+ / -0.2°2θ) at 14.2°, 19.7°, and 22.4°. In some embodiments, compound 15 HCl salt form I has an XRPD pattern including 2θ reflection (+ / -0.2°2θ) at 5.9°, 11.7°, 14.0°, 16.7°, 23.9°, and 24.3°, and including 2θ reflection (+ / -0.2°2θ) at 14.2°, 19.7°, and 22.4°. In some embodiments, compound 15 HCl salt form I has an XRPD pattern including 2θ reflection (+ / -0.2°2θ) at 5.9°, 11.7°, 14.0°, 16.7°, 23.9°, and 24.3°, and including 2θ reflection (+ / -0.2°2θ) at 14.2°, 19.7°, and 22.4°. In some embodiments, compound 15 HCl salt form I has an XRPD pattern including 2θ reflection (+ / -0.2 degrees 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 15 HCl salt form I has an XRPD pattern including any three of the following at 5.9°, 11.7°, 14.0°, 14.2°, 16.7°, 19.7°, 22.4°, 23.9°, and 24.3°: 2θ reflection (+ / -0.2 degrees 2θ).

[0557] Compound 15 HCl salt material A

[0558] In some embodiments, this disclosure provides a crystalline material A of a compound 15 HCl salt (“Compound 15 HCl Salt Material A”). In some embodiments, Compound 15 HCl Salt Material A exhibits substantially the following characteristics: Figure 25 The XRPD pattern shown. In some embodiments, compound 15 HCl salt material A can exhibit essentially the same characteristics as... Figure 26 The DSC thermogram is shown. In some embodiments, compound 15 HCl salt material A can exhibit essentially the following characteristics. Figure 27The TGA diagram shown.

[0559] In some embodiments of Compound 15 HCl salt material A, at least one, at least two, or all of the following (a)-(c) are applicable: (a) Compound 15 HCl salt material A has substantially the following characteristics: Figure 25 The XRPD pattern shown; (b) Compound 15HCl salt material A has essentially the same as Figure 26 The DSC thermogram shown; (c) Compound 15 HCl salt material A has essentially the same properties as Figure 27 The TGA diagram shown.

[0560] In some embodiments, compound 15 HCl salt material A has the following properties:

[0561] (a) Basically as Figure 25 The XRPD pattern shown;

[0562] (b) Basically as Figure 26 The DSC thermogram shown; and

[0563] (c) Basically as Figure 27 The TGA diagram shown.

[0564] In some embodiments, compound 15 HCl salt material A has at least two, at least three, at least four, at least five, or at least six components substantially as shown. Figure 25 The XRPD pattern shown is an XRPD pattern with the highest intensity of 2θ reflection.

[0565] In some embodiments, Compound 15 HCl salt material A has an XRPD pattern including 2θ reflection (+ / -0.2°2θ) at 4.0°, 15.0°, and 25.8°. In some embodiments, Compound 15 HCl salt material A has an XRPD pattern including one, two, or three of the following: 2θ reflection (+ / -0.2°2θ) at 4.0°, 15.0°, and 25.8°; and 2θ reflection (+ / -0.2°2θ) at 10.6°, 16.3°, and 26.7°. In some embodiments, Compound 15 HCl salt material A has an XRPD pattern including one or two of the following: 2θ reflection (+ / -0.2°2θ) at 4.0°, 15.0°, and 25.8°; and 2θ reflection (+ / -0.2°2θ) at 10.6°, 16.3°, and 26.7°. In some embodiments, Compound 15 HCl salt material A has an XRPD pattern including one of degree 2θ reflection (+ / -0.2 degrees 2θ) at 4.0°, 15.0°, and 25.8° and degree 2θ reflection (+ / -0.2 degrees 2θ) at 10.6°, 16.3°, and 26.7°. In some embodiments, Compound 15 HCl salt material A has an XRPD pattern including both of degree 2θ reflection (+ / -0.2 degrees 2θ) at 4.0°, 15.0°, and 25.8° and degree 2θ reflection (+ / -0.2 degrees 2θ) at 10.6°, 16.3°, and 26.7°. In some embodiments, compound 15HCl salt material A has an XRPD pattern including 2θ reflection (+ / -0.2 degrees 2θ) at 4.0°, 10.6°, 15.0°, 16.3°, 25.8°, and 26.7°. In some embodiments, compound 15HCl salt material A has an XRPD pattern including any three of the following 2θ reflections (+ / -0.2 degrees 2θ) at 4.0°, 10.6°, 15.0°, 16.3°, 25.8°, and 26.7°.

[0566] In some embodiments, Compound 15 HCl salt material A has an XRPD pattern including one, two, or three of the following: 2θ reflection (+ / -0.2°2θ) at 4.0°, 10.6°, 15.0°, 16.3°, 25.8°, and 26.7°; and 2θ reflection (+ / -0.2°2θ) at 12.2°, 15.7°, and 31.5°. In some embodiments, Compound 15 HCl salt material A has an XRPD pattern including one or two of the following: 2θ reflection (+ / -0.2°2θ) at 4.0°, 10.6°, 15.0°, 16.3°, 25.8°, and 26.7°; and 2θ reflection (+ / -0.2°2θ) at 12.2°, 15.7°, and 31.5°. In some embodiments, Compound 15 HCl salt material A has an XRPD pattern including 2θ reflection (+ / -0.2°2θ) at 4.0°, 10.6°, 15.0°, 16.3°, 25.8°, and 26.7°, and including 2θ reflection (+ / -0.2°2θ) at 12.2°, 15.7°, and 31.5°. In some embodiments, Compound 15 HCl salt material A has an XRPD pattern including 2θ reflection (+ / -0.2°2θ) at 4.0°, 10.6°, 15.0°, 16.3°, 25.8°, and 26.7°, and including 2θ reflection (+ / -0.2°2θ) at 12.2°, 15.7°, and 31.5°. In some embodiments, Compound 15 HCl salt material A has an XRPD pattern including 2θ reflection (+ / -0.2 degrees 2θ) at 4.0°, 10.6°, 12.2°, 15.0°, 15.7°, 16.3°, 25.8°, 26.7°, and 31.5°. In some embodiments, Compound 15 HCl salt material A has an XRPD pattern including any three of the following at 4.0°, 10.6°, 12.2°, 15.0°, 15.7°, 16.3°, 25.8°, 26.7°, and 31.5°: 2θ reflection (+ / -0.2 degrees 2θ).

[0567] Compound 15 HCl salt material B

[0568] In some embodiments, this disclosure provides a crystalline material B of compound 15 HCl salt (“Compound 15 HCl Salt Material B”). In some embodiments, Compound 15 HCl Salt Material B exhibits substantially the following characteristics: Figure 28 The XRPD pattern is shown. In some embodiments, compound 15 HCl salt material B can exhibit essentially the same characteristics as... Figure 29 The DSC thermogram is shown. In some embodiments, compound 15 HCl salt material B can exhibit essentially the same characteristics as... Figure 30The TGA diagram shown.

[0569] In some embodiments of Compound 15 HCl salt material B, at least one, at least two, or all of the following (a)-(c) are applicable: (a) Compound 15 HCl salt material B has substantially the following characteristics: Figure 28 The XRPD pattern shown; (b) Compound 15HCl salt material B has essentially the same as Figure 29 The DSC thermogram shown; (c) Compound 15 HCl salt material B has essentially the same properties as Figure 30 The TGA diagram shown.

[0570] In some embodiments, compound 15 HCl salt material B has the following properties:

[0571] (a) Basically as Figure 28 The XRPD pattern shown;

[0572] (b) Basically as Figure 29 The DSC thermogram shown; and

[0573] (c) Basically as Figure 30 The TGA diagram shown.

[0574] In some embodiments, compound 15 HCl salt material B has at least two, at least three, at least four, at least five, or at least six components substantially as shown. Figure 28 The XRPD pattern shown is an XRPD pattern with the highest intensity of 2θ reflection.

[0575] In some embodiments, Compound 15 HCl salt material B has an XRPD pattern including 2θ reflection (+ / -0.2°2θ) at 4.3°, 15.9°, and 26.6°. In some embodiments, Compound 15 HCl salt material B has an XRPD pattern including one, two, or three of the following: 2θ reflection (+ / -0.2°2θ) at 4.3°, 15.9°, and 26.6°; and 2θ reflection (+ / -0.2°2θ) at 7.1°, 16.8°, and 25.7°. In some embodiments, Compound 15 HCl salt material B has an XRPD pattern including one or two of the following: 2θ reflection (+ / -0.2°2θ) at 4.3°, 15.9°, and 26.6°; and 2θ reflection (+ / -0.2°2θ) at 7.1°, 16.8°, and 25.7°. In some embodiments, Compound 15 HCl salt material B has an XRPD pattern including one of 2θ reflection (+ / -0.2°2θ) at 4.3°, 15.9°, and 26.6° and 2θ reflection (+ / -0.2°2θ) at 7.1°, 16.8°, and 25.7°. In some embodiments, Compound 15 HCl salt material B has an XRPD pattern including both of 2θ reflection (+ / -0.2°2θ) at 4.3°, 15.9°, and 26.6° and 2θ reflection (+ / -0.2°2θ) at 7.1°, 16.8°, and 25.7°. In some embodiments, compound 15HCl salt material B has an XRPD pattern including 2θ reflection (+ / -0.2 degrees 2θ) at 4.3°, 7.1°, 15.9°, 16.8°, 25.7°, and 26.6°. In some embodiments, compound 15HCl salt material B has an XRPD pattern including any three of the following 2θ reflections (+ / -0.2 degrees 2θ) at 4.3°, 7.1°, 15.9°, 16.8°, 25.7°, and 26.6°.

[0576] In some embodiments, Compound 15 HCl salt material B has an XRPD pattern including one, two, or three of the following: 2θ reflection (+ / -0.2°2θ) at 4.3°, 7.1°, 15.9°, 16.8°, 25.7°, and 26.6°; and 2θ reflection (+ / -0.2°2θ) at 14.3°, 18.7°, and 27.0°. In some embodiments, Compound 15 HCl salt material B has an XRPD pattern including one or two of the following: 2θ reflection (+ / -0.2°2θ) at 4.3°, 7.1°, 15.9°, 16.8°, 25.7°, and 26.6°; and 2θ reflection (+ / -0.2°2θ) at 14.3°, 18.7°, and 27.0°. In some embodiments, Compound 15 HCl salt material B has an XRPD pattern including 2θ reflection (+ / -0.2°2θ) at 4.3°, 7.1°, 15.9°, 16.8°, 25.7°, and 26.6° and including 2θ reflection (+ / -0.2°2θ) at 14.3°, 18.7°, and 27.0°. In some embodiments, Compound 15 HCl salt material B has an XRPD pattern including 2θ reflection (+ / -0.2°2θ) at 4.3°, 7.1°, 15.9°, 16.8°, 25.7°, and 26.6° and including 2θ reflection (+ / -0.2°2θ) at 14.3°, 18.7°, and 27.0°. In some embodiments, Compound 15 HCl salt material B has an XRPD pattern including 2θ reflection (+ / -0.2 degrees 2θ) at 4.3°, 7.1°, 14.3°, 15.9°, 16.8°, 18.7°, 25.7°, 26.6°, and 27.0°. In some embodiments, Compound 15 HCl salt material B has an XRPD pattern including any three of the following at 4.3°, 7.1°, 14.3°, 15.9°, 16.8°, 18.7°, 25.7°, 26.6°, and 27.0°: 2θ reflection (+ / -0.2 degrees 2θ).

[0577] Compound 15 HCl salt material C

[0578] In some embodiments, this disclosure provides a crystalline material C of a compound 15 HCl salt (“Compound 15 HCl Salt Material C”). In some embodiments, Compound 15 HCl Salt Material C exhibits substantially the following characteristics: Figure 31 The XRPD pattern is shown. In some embodiments, compound 15 HCl salt material C can exhibit essentially the same characteristics as... Figure 32 The DSC thermogram is shown. In some embodiments, compound 15 HCl salt material C can exhibit essentially the same characteristics as... Figure 33The TGA diagram shown.

[0579] In some embodiments of Compound 15 HCl salt material C, at least one, at least two, or all of the following (a)-(c) are applicable: (a) Compound 15 HCl salt material C has substantially the following characteristics: Figure 31 The XRPD pattern shown; (b) Compound 15HCl salt material C has essentially the same as Figure 32 The DSC thermogram shown; (c) Compound 15 HCl salt material C has essentially the same properties as Figure 33 The TGA diagram shown.

[0580] In some embodiments, compound 15 HCl salt material C has the following properties:

[0581] (a) Basically as Figure 31 The XRPD pattern shown;

[0582] (b) Basically as Figure 32 The DSC thermogram shown; and

[0583] (c) Basically as Figure 33 The TGA diagram shown.

[0584] In some embodiments, compound 15 HCl salt material C has at least two, at least three, at least four, at least five, or at least six components substantially as shown. Figure 31 The XRPD pattern shown is an XRPD pattern with the highest intensity of 2θ reflection.

[0585] In some embodiments, Compound 15 HCl salt material C has an XRPD pattern including 2θ reflection (+ / -0.2°2θ) at 4.3°, 14.7°, and 31.4°. In some embodiments, Compound 15 HCl salt material C has an XRPD pattern including one, two, or three of the following: 2θ reflection (+ / -0.2°2θ) at 4.3°, 14.7°, and 31.4°; and 2θ reflection (+ / -0.2°2θ) at 12.8°, 17.3°, and 35.1°. In some embodiments, Compound 15 HCl salt material C has an XRPD pattern including one or two of the following: 2θ reflection (+ / -0.2°2θ) at 4.3°, 14.7°, and 31.4°; and 2θ reflection (+ / -0.2°2θ) at 12.8°, 17.3°, and 35.1°. In some embodiments, the compound 15 HCl salt material C has an XRPD pattern including one of 2θ reflection (+ / -0.2°2θ) at 4.3°, 14.7°, and 31.4° and 2θ reflection (+ / -0.2°2θ) at 12.8°, 17.3°, and 35.1°. In some embodiments, the compound 15 HCl salt material C has an XRPD pattern including both of 2θ reflection (+ / -0.2°2θ) at 4.3°, 14.7°, and 31.4° and 2θ reflection (+ / -0.2°2θ) at 12.8°, 17.3°, and 35.1°. In some embodiments, the compound 15HCl salt material C has an XRPD pattern including 2θ reflection (+ / -0.2 degrees 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 including any three of the following 2θ reflections (+ / -0.2 degrees 2θ) at 4.3°, 12.8°, 14.7°, 17.3°, 31.4°, and 35.1°.

[0586] In some embodiments, the compound 15 HCl salt material C has an XRPD pattern including one, two, or three of the following: 2θ reflection (+ / -0.2°2θ) at 4.3°, 12.8°, 14.7°, 17.3°, 31.4°, and 35.1°; and 2θ reflection (+ / -0.2°2θ) at 16.6°, 24.9°, and 27.2°. In some embodiments, the compound 15 HCl salt material C has an XRPD pattern including one or two of the following: 2θ reflection (+ / -0.2°2θ) at 4.3°, 12.8°, 14.7°, 17.3°, 31.4°, and 35.1°; and 2θ reflection (+ / -0.2°2θ) at 16.6°, 24.9°, and 27.2°. In some embodiments, the compound 15 HCl salt material C has an XRPD pattern including 2θ reflection (+ / -0.2°2θ) at 4.3°, 12.8°, 14.7°, 17.3°, 31.4°, and 35.1°, and including 2θ reflection (+ / -0.2°2θ) at 16.6°, 24.9°, and 27.2°. In some embodiments, the compound 15 HCl salt material C has an XRPD pattern including 2θ reflection (+ / -0.2°2θ) at 4.3°, 12.8°, 14.7°, 17.3°, 31.4°, and 35.1°, and including 2θ reflection (+ / -0.2°2θ) at 16.6°, 24.9°, and 27.2°. In some embodiments, the compound 15 HCl salt material C has an XRPD pattern including 2θ reflection (+ / -0.2 degrees 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 15 HCl salt material C has an XRPD pattern including any three of the following 2θ reflections (+ / -0.2 degrees 2θ) at 4.3°, 12.8°, 14.7°, 16.6°, 17.3°, 24.9°, 27.2°, 31.4°, and 35.1°.

[0587] XIII. Implementation Examples

[0588] Intermediate A: 2-((tert-butoxycarbonyl)amino)-2-methylpropionic acid ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ester

[0589]

[0590] (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carboxynitrile (compound 13 in WO2009132135; compound s4 in J.Med.Chem.2017,60,1648-1661) and 2-((tert-butoxycarbonyl)amino)-2-methylpropionic acid (209 mg, 1.03 mmol) were dissolved in anhydrous DMF (3 mL). N,N'-diisopropylcarbodiimide (177 μL, 1.13 mmol) was added to the mixture and stirred for 20 min, followed by the addition of a nucleoside (150 mg, 0.52 mmol) and triethylamine (180 μL, 1.29 mmol). The resulting mixture was stirred for 16 hours. At this point, more 2-((tert-butoxycarbonyl)amino)-2-methylpropionic acid (1 equivalent) and N,N'-diisopropylcarbodiimide (1 equivalent) were added, and the mixture was heated at 60°C for 4 hours, followed by stirring at room temperature for another 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 with ethyl acetate / hexane (0%-100%) to give intermediate A.

[0591] MS m / z = 475.1 [M-1].

[0592] Intermediate B: (tert-butoxycarbonyl)-L-valine ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ester

[0593]

[0594] Intermediate B was prepared in a similar manner to intermediate A, except that (tert-butoxycarbonyl)-L-valine (55 mg, 0.26 mmol) was used instead of 2-((tert-butoxycarbonyl)amino)-2-methylpropionic acid.

[0595] 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-dimethylbis(2-methylpropionate)

[0596]

[0597] (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carboxynitrile (29 mg, 0.1 mmol) was dissolved in anhydrous DMF (1 mL). Isobutyric acid (46 μL, 0.5 mmol) was added in a single addition. N,N'-diisopropylcarbodiimide (78 μL, 0.5 mmol) was added dropwise. The reaction was stirred for 15 min. 4-(dimethylamino)pyridine (12.2 mg, 0.1 mmol) was added. The reaction was then stirred for 16 h. The solid was diluted with acetonitrile (1 mL) and filtered off. The filtrate was purified by preparative HPLC (0-95% aqueous acetonitrile). The fractions were combined and lyophilized to give the title compound.

[0598] 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).

[0599] LC / MS: t R =2.60min, MS m / z=502.2[M+1],500.1[M-1]; LC / MS system

[0600] System: Thermo LCQ Advantage; Phenomenex Gemini, C 18 , 5u, 110A, 30×4.6mm; Buffer A: 0.1% aqueous solution of acetic acid; Buffer B: 0.1% acetic acid in acetonitrile solution; 5%-100% Buffer B over 2.5 min, then continue at 2 mL / min for 0.9 min at 100% Buffer B.

[0601] HPLC: t R = 3.33 min; HPLC system: Agilent 1100; Phenomenex Gemini, C 18 , 5u, 110A, 50×4.6mm; Buffer A: 0.05% TFA aqueous solution; Buffer B: 0.05% TFA acetonitrile solution; 2%-98% Buffer B at 2mL / min over 5 minutes.

[0602] Example 2: (2R,3R,4R,5R)-5-(acetoxymethyl)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-2-cyanotetrahydrofuran-3,4-dimethyldiacetate

[0603]

[0604] The title compound was prepared in a similar manner to that of compound 1, except that acetic acid (29 μL, 0.50 mmol) was used instead of isobutyric acid.

[0605] 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).

[0606] LC / MS: t R =2.00min, MS m / z=418.0[M+1], 416.0[M-1].

[0607] 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-dimethyldipropionate

[0608]

[0609] The title compound was prepared in a similar manner to compound 1, except that propionic acid (37 μL, 0.50 mmol) was used instead of isobutyric acid.

[0610] 1H 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).

[0611] LC / MS: t R =0.89min, MS m / z=460.2[M+1].

[0612] Example 4: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-6-(hydroxymethyl)-2-phenyltetrahydrofuran[3,4-d][1,3]m-dioxacyclopentene-4-carboxynitrile

[0613]

[0614] (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carboxynitrile (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 by elution with ethyl acetate / hexane (0%–30%–50%) to give the desired product.

[0615] 1 ¹H NMR (400 MHz, methanol-d⁴) δ 7.90 (s, 1H), 7.80–7.70 (m, 2H), 7.51–7.39 (m, 3H), 7.03–6.91 (m, 2H), 6.14 (s, 1H), 5.55 (d, J = 7.2 Hz, 1H), 5.09 (dd, J = 7.2, 3.8 Hz, 1H), 4.60 (q, J = 4.4 Hz, 1H), 3.89–3.77 (m, 2H).

[0616] LC / MS: t R=-0.77min, MS m / z=380.1[M+1].

[0617] Example 5: Isobutyric acid ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-6-cyano-2-phenyltetrahydrofuran[3,4-d][1,3]m-dioxacyclopenten-4-yl) methyl ester

[0618]

[0619] The title compound was prepared in a similar manner to 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-carboxynitrile.

[0620] 1 H NMR(400MHz, methanol-d4)δ8.05(s,1H),7.77–7.70(m,2H),7.52–7.40(m,3H),7.24( d,J=4.7Hz,1H),7.04(d,J=4.7Hz,1H),6.13(s,1H),5.50(d,J=7.0Hz,1H),5.0 7(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).

[0621] LC / MS: t R =0.94min, MS m / z=450.2[M+1].

[0622] Example 6: L-valine ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-6-cyano-2-phenyltetrahydrofuran[3,4-d][1,3]m-dioxacyclopenten-4-yl) methyl ester

[0623]

[0624] (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-6-(hydroxymethyl)-2-phenyltetrahydrofuran[3,4-d][1,3]m-dioxane-4-carboxynitrile (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 min. Then, 4-(dimethylamino)pyridine (10 mg, 0.084 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. 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 a 20% trifluoroacetic acid solution in dichloromethane (3 mL) and stirred for 45 min. The mixture was then concentrated and purified by preparative HPLC to obtain the title compound.

[0625] 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=6.7 Hz,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).

[0626] LC / MS: t R =0.85min, MS m / z=479.2[M+1].

[0627] Example 7: Methyl 2-amino-2-methylpropionic acid ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) ester

[0628]

[0629] The title compound was prepared in a similar manner to compound 6, except that 2-((tert-butoxycarbonyl)amino)-2-methylpropionic acid (80 mg, 0.40 mmol) was used instead of (tert-butoxycarbonyl)-L-valine, and the deprotection step was performed by stirring at room temperature for 3 hours instead of 45 min.

[0630] 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).

[0631] LC / MS: t R =0.20min, MS m / z=377.2[M+1].

[0632] Example 8: L-valine ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ester

[0633]

[0634] (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carboxynitrile 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 the mixture and stirred for 15 min, followed by the addition of a nucleoside (50 mg, 0.17 mmol) and triethylamine (47 μL, 0.34 mmol). The resulting mixture was stirred for 16 h. At this point, more (tert-butoxycarbonyl)-L-valine (55 mg, 0.56 mmol) and N,N'-diisopropylcarbodiimide (40 μL, 0.25 mmol) were added, and the mixture was stirred at room temperature for another 5 h. The reaction was then heated at 50 °C for 3 hours, followed by stirring at room temperature for 72 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 with ethyl acetate / hexane (0%–70%) as elution, followed by further purification by reversed-phase HPLC. The fractions were combined and concentrated under vacuum. The residue was dissolved in a 20% trifluoroacetic acid solution in dichloromethane and stirred for 30 min. The mixture was then concentrated and purified by preparative HPLC to give the title compound.

[0635] 1H NMR (400MHz, methanol-d4) δ7.92(s,1H),7.05(s,2H),5.57(dd,J=5.8,2.3Hz,1H),5.31(d,J=5.8Hz,1H),4.49(q,J =3.0Hz,1H),4.18–4.04(m,1H),3.93–3.77(m,2H),2.53(qd,J=7.0,4.5Hz,1H),1.16(dd,J=7.0,4.9Hz,6H).

[0636] LC / MS: t R =0.48min, MS m / z=391.2[M+1].

[0637] Example 9: D-valine ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ester

[0638]

[0639] The title compound was prepared in a similar manner to compound 8, except that (tert-butoxycarbonyl)-D-valine (75 mg, 0.34 mmol) was used instead of (tert-butoxycarbonyl)-L-valine.

[0640] 1 H NMR (400MHz, methanol-d4) δ7.90 (s, 1H), 7.02 (q, J = 4.7Hz, 2H), 5.60 (ddd, J = 19.1, 5.9, 2.3Hz, 1H), 5.31 (dd, J = 18.0, 5.9Hz, 1H), 4.56–4.47(m,1H),4.11(dd,J=4.2,2.4Hz,1H),3.97–3.75(m,2H),2.68(pd,J=7.1,3.8Hz,1H),1.17(dt,J=7.0,4.8Hz,6H).

[0641] LC / MS: t R =0.44min, MS m / z=391.2[M+1].

[0642] Example 10: L-phenylalanine ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ester

[0643]

[0644] The title compound was prepared in a similar manner to compound 8, except that (tert-butoxycarbonyl)-L-phenylalanine (55 mg, 0.26 mmol) was used instead of (tert-butoxycarbonyl)-L-valine.

[0645] 1 H NMR (400MHz, methanol-d4) δ7.94(s,1H),7.48–7.28(m,5H),7.12–7.03(m,2H),5.53(dd,J=5.8,2.1Hz,1H),5.29(d,J=5.7Hz,1H),4. 48(dd,J=8.1,6.1Hz,1H), 4.24(q,J=3.0Hz,1H), 3.77(qd,J=12.4,3.2Hz,2H), 3.46(dd,J=14.3,6.2Hz,1H), 3.29-3.24(m,1H).

[0646] LC / MS: t R =0.58min, MS m / z=439.2[M+1].

[0647] Example 11: (2R,3R,4R,5R)-5-(((2-amino-2-methylpropionyl)oxy)methyl)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-2-cyanotetrahydrofuran-3,4-dimethylbis(2-methylpropionate)

[0648]

[0649] Intermediate A (45 mg, 0.094 mmol) was dissolved in anhydrous DMF (3 mL). Isobutyric acid (26 μL, 0.28 mmol) and N,N'-diisopropylcarbodiimide (44 μL, 0.28 mmol) were added. The reaction was stirred for 15–20 min, followed by the addition of 4-(dimethylamino)pyridine (11.6 mg, 0.09 mmol). The reaction was then stirred for 4 h. At this point, more isobutyric acid (3 equivalents), N,N'-diisopropylcarbodiimide (3 equivalents), and 4-(dimethylamino)pyridine (1 equivalent) were added. The resulting mixture was stirred at ambient temperature for another 16 h. 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 reversed-phase HPLC. The fractions were combined and concentrated under vacuum. The residue was dissolved in a 20% trifluoroacetic acid solution in dichloromethane (3 mL) and stirred for 45 min. The mixture was then concentrated and purified by preparative HPLC to give the title compound (32 mg, 66%).

[0650] 1H NMR (400MHz, methanol-d4) δ7.96 (s, 1H), 7.08 (d, J = 4.7Hz, 1H), 6.97 (d, J = 4.7Hz, 1H), 6.39 (d, J = 5.6Hz, 1H), 5.68 (dd, J = 5.6, 2.9Hz, 1H), 4.74 (q, J=3.9Hz, 1H), 4.58–4.39 (m, 2H), 2.62 (ddq, J=37.5, 14.0, 7.0Hz, 2H), 1.73 (d, J=2.9Hz, 6H), 1.28–1.05 (m, 12H).

[0651] LC / MS: t R =0.77min, MS m / z=517.3[M+1].

[0652] Example 12: (2R,3R,4R,5R)-5-(((L-valinel)oxy)methyl)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-2-cyanotetrahydrofuran-3,4-dimethylbis(2-methylpropionate)

[0653]

[0654] The title compound was prepared in a similar manner to that of compound 11, except that intermediate B (61 mg, 0.12 mmol) was used instead of intermediate A.

[0655] 1 H NMR (400MHz, methanol-d4) δ7.96(s,1H),7.09(d,J=4.7Hz,1H),6.99(d,J=4.7Hz,1H ),6.32(d,J=5.8Hz,1H),5.69(dd,J=5.8,4.1Hz,1H),4.71(q,J=4.0Hz,1H),4. 48(qd,J=12.4,3.9Hz,2H),4.08(d,J=4.1Hz,1H),2.81–2.67(m,1H),2.68–2. 45 (m, 2H), 1.23 (d, J = 7.0Hz, 6H), 1.16 (d, J = 7.3Hz, 6H), 1.12 (d, J = 6.6Hz, 6H).

[0656] LC / MS: t R =0.79min, MS m / z=531.2[M+1].

[0657] Example 13: (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-6-(hydroxymethyl)-2-oxotetrahydrofuran[3,4-d][1,3]m-dioxacyclopentene-4-carboxynitrile

[0658]

[0659] (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carboxynitrile (50 mg, 0.17 mmol) was dissolved in anhydrous DMF (3 mL). Diphenyl carbonate (37 mg, 0.17 mmol) was added to this solution, and the resulting reaction mixture was stirred at 130 °C for 1 hour. Triethylamine (60 μL, 0.43 mmol) was then added, and the mixture was heated at 130 °C for another 2 hours. The reaction mixture was cooled, 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 by elution with methanol / dichloromethane (0%–5%) to give the desired product.

[0660] LC / MS: t R =0.56min, MS m / z=318.0[M+1].

[0661] Example 14: (S)-3-amino-4-phenylbutyric acid ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ester

[0662]

[0663] The title compound was prepared in a similar manner to compound 8, except that L-β-homophenylalanine (96 mg, 0.34 mmol) was used instead of (tert-butoxycarbonyl)-L-valine.

[0664] 1H NMR 1H NMR (400MHz, methanol-d4) δ7.96(s,1H),7.49–7.28(m,5H),7.17–7.02(m,2H),5.59(dd,J=6.0,2.4Hz,1H),5.27(d,J=6.0Hz,1H ), 4.46 (q, J = 3.0Hz, 1H), 4.08 (dt, J = 12.8, 7.6Hz, 1H), 3.92–3.74 (m, 2H), 3.15–2.91 (m, 4H), 2.76 (dd, J = 16.8, 8.1Hz, 1H).

[0665] LC / MS: t R =0.63min.

[0666] Example 15: Isobutyric acid ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ester

[0667]

[0668] N,N'-diisopropylcarbodiimide (914 mg, 7.2 mmol) was slowly added to a solution of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]m-dioxane-4-carboxynitrile (2000 mg, 6.0 mmol) (Siegel et al. J. Med. Chem. 2017, 60, 1648-1661) and isobutyric acid (638 ng, 7.2 mmol) in DMF (5 mL), followed by the addition of 4-dimethylaminopyridine (737 mg, 6.0 mmol) at room temperature and stirring for 4 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried, and concentrated. The obtained product was purified by rapid chromatography using DCM / methanol (20% methanol / DCM) as the eluent to obtain the intermediate isobutyric acid ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]m-dioxacyclopenten-4-yl) methyl ester.

[0669] MS m / z = 402.2(M+1).

[0670] A solution of the intermediate acetone compound (1500 mg) in THF (10 mL) was added with concentrated HCl (2 mL) and stirred at room temperature for 4 h. LC-MS showed that the product formed together with SM. After 4 h, the reaction was stopped, the reaction mixture was diluted with dichloromethane, washed with water, saturated bicarbonate and brine, dried over sodium sulfate, concentrated and purified by rapid chromatography using DCM / methanol (30% methanol / DCM) as eluent to give the title compound.

[0671] 1 H NMR(400MHz, methanol-d4)δ7.88(s,1H),6.96–6.85(m,2H),4.50–4.27(m,4H),4.1 6(dd,J=6.2,5.3Hz,1H), 2.56(p,J=7.0Hz,1H), 1.14(dd,J=7.0,3.8Hz,6H).

[0672] MS m / z:362.1(M+1).

[0673] Alternative synthesis of compound 15:

[0674]

[0675] Add N,N-dimethylaminopyridine (0.03 equivalents) to a solution of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]m-dioxacyclopentene-4-carboxynitrile (2000 mg, 6.0 mmol) in THF. Slowly add isobutyric anhydride (1.1 equivalents) to the reaction mixture. After the starting materials were obtained, the reaction mixture was concentrated and purified by rapid chromatography using DCM / methanol (20% methanol / DCM) as the eluent to give the intermediate isobutyric acid ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofurano[3,4-d][1,3]m-dioxacyclopenten-4-yl) methyl ester. MS m / z = 402.2 (M+1).

[0676] A solution of the intermediate acetone compound (1000 mg) in acetonitrile (10 mL) was added with concentrated HCl (5 equivalents, 1 mL) and stirred at room temperature for 2 h. LC-MS showed product formation. After 4 h, the reaction mixture was stopped, diluted with ethyl acetate, and quenched with saturated bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by rapid chromatography using DCM / methanol (30% methanol / DCM) as eluent, and the fraction was concentrated to give the title compound. 1 ¹H NMR (400 MHz, methanol-d⁴) δ 7.88 (s, 1H), 6.96–6.85 (m, 2H), 4.50–4.27 (m, 4H), 4.16 (dd, J = 6.2, 5.3 Hz, 1H), 2.56 (p, J = 7.0 Hz, 1H), 1.14 (dd, J = 7.0, 3.8 Hz, 6H); MS m / z: 362.1 (M+1). The obtained compound was identified as compound 15, form II.

[0677] Example 16: Methylbutyric acid ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ester

[0678]

[0679] Intermediate: 3-Methylbutyric acid ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran[3,4-d][1,3]m-dioxacyclopenten-4-yl) methyl ester

[0680] N,N′-diisopropylcarbodiimide (0.14 mL, 0.91 mmol) was added to a mixture of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]m-dioxane-4-carboxynitrile (200 mg, 0.6 mmol) and 3-methylbutyric acid (92 mg, 0.91 mmol) in DMF (2 mL). The mixture was stirred at room temperature for 20 min and DMAP (74 mg, 0.6 mmol) was added. The resulting mixture was stirred at room temperature for 2 h and purified by reversed-phase HPLC (10% to 100% aqueous ACN for 15 min, then 100% ACN for 3 min) to give an intermediate (188 mg, 75%). LCMS: MS m / z = 416.16 [M+1]; t R= 1.56 min; LC system: Thermo Accela 1250U HPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μXB-C18 100A, 50×3.0 mm; Solvent: Acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN, 1800 μl / min.

[0681] At room temperature, concentrated HCl (0.2 mL) was added to a solution of the above intermediate (188 mg, 0.226 mmol) in ACN (2 mL). The mixture was stirred for 3 h, neutralized with TEA, and purified by reversed-phase HPLC (10% to 100% aqueous ACN for 15 min, then 100% ACN for 3 min) to give title compound 16 (146 mg, 86%).

[0682] Compound 16 :

[0683] 1 H NMR (400MHz, acetonitrile-d3) δ7.97(s,1H),6.87(d,J=4.6Hz,1H),6.81(d,J=4.6Hz,1H),6.38(s,2H),4.93–4.72(m,2H),4.43– 4.30(m,2H),4.28–4.16(m,2H),3.71(d,J=5.0Hz,1H),2.14(dd,J=7.2,2.5Hz,2H),1.99(m,1H),0.90(d,J=6.7Hz,6H).

[0684] LCMS: MS m / z = 376.14 [M+1]; t R = 1.21 min; LC system: Thermo

[0685] Accela 1250U HPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μXB-C18 100A, 50×3.0mm; Solvent: Acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; Gradient: 0min-1.8min 2-100% acetonitrile, 1.8min-1.85min 100%-2% acetonitrile, 1.85min-2.00min 2% ACN, 1800μl / min.

[0686] HPLC: tR = 3.69 min; HPLC system: 1290 Infinity II; Column: Phenomenex 2.6μC18100A, 100×4.6 mm; Solvent: Acetonitrile containing 0.1% TFA, water containing 0.1% TFA; Gradient: 0 min-8.5 min 2%-98% ACN, 1.5 mL / min.

[0687] Example 17: Cyclohexanecarboxylic acid ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ester

[0688]

[0689] As described in Example 16, the title compound was synthesized using cyclohexanoic acid instead of 3-methylbutyric acid as the starting material.

[0690] Intermediate 17a: Cyclohexanecarboxylic acid ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran[3,4-d][1,3]m-dioxacyclopenten-4-yl) methyl ester: LCMS: MS m / z = 442.16 [M+1]; t R = 1.64 min.

[0691] Compound 17 :

[0692] 1 H NMR(400MHz,DMSO-d6)δ8.03-7.75(m,3H),6.92(d,J=4.5Hz,1H),6.81(d,J=4.5 Hz,1H),6.33(d,J=5.9Hz,1H),5.37(d,J=5.9Hz,1H),4.70(t,J=5.4Hz,1H),4.3 1(dd,J=12.1,2.8Hz,1H),4.23(ddd,J=7.2,4.8,2.7Hz,1H),4.15(dd,J=12.0,4 .9Hz,1H),4.03–3.92(m,1H),2.25(m,1H),1.82–1.51(m,4H),1.37–1.03(m,6H).

[0693] LCMS: MS m / z = 402.17 [M+1]; t R =1.29min.

[0694] HPLC: t R=4.05min.

[0695] Example 18: Methyl 2-propylvalerate ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) ester

[0696]

[0697] As described in Example 16, the title compound was synthesized using 2-propylvaleric acid instead of 3-methylbutyric acid as the starting material.

[0698] Intermediate: 2-Propylvaleric acid ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran[3,4-d][1,3]m-dioxacyclopenten-4-yl) methyl ester: LCMS: MSm / z = 458.19 [M+1]; t R =1.81min.

[0699] Compound 18 :

[0700] 1 H NMR (400MHz, methanol-d4) δ7.88(s,1H),6.92(s,2H),4.90(d,J=5.3Hz,1H),4.45–4.33(m,3H),4.16(t,J =5.5Hz,1H),2.38(m,1H),1.54(m,2H),1.40(m,2H),1.31–1.19(m,4H),0.86(td,J=7.3,5.4Hz,6H).

[0701] LCMS: MS m / z = 418.20 [M+1]; t R = 1.43 min.

[0702] HPLC: t R = 4.60 min.

[0703] Example 19: 2-Ethylbutyric acid ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ester

[0704] As described in Example 16, the title compound was synthesized using 2-ethylbutyric acid instead of 3-methylbutyric acid as the starting material.

[0705]

[0706] Intermediate: 2-Ethylbutyric acid ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran[3,4-d][1,3]m-dioxacyclopenten-4-yl) methyl ester: LCMS: MSm / z = 430.18 [M+1]; t R = 1.64 min.

[0707] Compound 19 :

[0708] 1 H NMR (400MHz, DMSO-d6) δ8.05-7.72(m,3H),6.92(d,J=4.5Hz,1H),6.82(d,J=4.5Hz,1H),6.33(d,J=6.0Hz,1H),5.38(d, J=5.9Hz,1H),4.70(dd,J=6.0,4.9Hz,1H),4.35–4.18(m,3H),3.96(m,1H),2.17(m,1H),1.57–1.34(m,4H),0.79(m,6H).

[0709] LCMS: MS m / z = 390.15 [M+1]; t R =1.27min.

[0710] HPLC: t R =3.95min.

[0711] Example 20: Caprylic acid ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methyl octanoate

[0712] As described in Example 16, the title compound was synthesized using octanoic acid instead of 3-methylbutyric acid as the starting material.

[0713]

[0714] Intermediate: Caprylic acid ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran[3,4-d][1,3]m-dioxacyclopenten-4-yl) methyl ester: LCMS: MS m / z = 458.17 [M+1]; t R =1.83min.

[0715] Compound 20 :

[0716] 1 H NMR (400MHz, DMSO-d6): δ8.08-7.78(m,3H),6.92(d,J=4.5Hz,1H),6.81(d,J=4.5Hz,1H ),6.32(d,J=6.0Hz,1H),5.38(d,J=5.9Hz,1H),4.69(dd,J=6.0,4.9Hz,1H),4.32(dd,J= 11.9,2.6Hz,1H),4.27–4.20(m,1H),4.17(dd,J=11.8,5.5Hz,1H),3.94(td,J=6.2,4.9 Hz,1H),2.28(td,J=7.4,2.0Hz,2H),1.48(m,2H),1.29–1.15(m,8H),0.88–0.78(m,3H).

[0717] LCMS: MS m / z = 418.21 [M+1]; t R =1.48min.

[0718] HPLC: t R =3.97min.

[0719] Example 21: 3,3-Dimethylbutyric acid ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ester

[0720] As described in Example 16, the title compound was synthesized using 3,3-dimethylbutyric acid instead of 3-methylbutyric acid as the starting material.

[0721]

[0722] Intermediate: methyl 3,3-dimethylbutyric acid ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran[3,4-d][1,3]m-dioxacyclopenten-4-yl) ester: LCMS: MS m / z = 430.16 [M+1]; t R = 1.63 min.

[0723] Compound 21 :

[0724] 1H NMR (400MHz, DMSO-d6) δ8.04-7.71(m,3H),6.92(d,J=4.5Hz,1H),6.82(d,J=4.5Hz,1H),6.33(d,J=6.0Hz,1H),5.38(d,J=5.9Hz,1H),4.71(dd,J=6. 0,4.9Hz,1H),4.30(dd,J=11.9,2.7Hz,1H),4.26-4.21(m,1H),4.16(dd,J =11.8,5.7Hz,1H),3.94(td,J=6.3,4.9Hz,1H),2.16(s,2H),0.94(s,9H).

[0725] LCMS: MS m / z = 390.19 [M+1]; t R =1.28min.

[0726] HPLC: t R =4.84min.

[0727] Example 22: Methyl 2-phenylacetic acid ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) ester

[0728] As described in Example 16, the title compound was synthesized using 2-phenylacetic acid instead of 3-methylbutyric acid as the starting material.

[0729]

[0730] Intermediate: methyl 2-phenylacetic acid ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran[3,4-d][1,3]m-dioxacyclopenten-4-yl) ester: LCMS: MSm / z = 450.24 [M+1]; t R =1.52min.

[0731] Compound 22 :

[0732] 1H NMR (400MHz, DMSO-d6) δ8.00-7.77(m,3H),7.37–7.18(m,5H),6.98–6.88(m,1H),6.79(d,J=4.5Hz,1H),6.31(d,J=6.0Hz,1 H), 5.39 (d, J = 5.8Hz, 1H), 4.67 (t, J = 5.5Hz, 1H), 4.36 (dd, J = 11.6, 2.3Hz, 1H), 4.28–4.17 (m, 2H), 3.95 (m, 1H), 3.68 (s, 2H).

[0733] LCMS: MS m / z = 410.18 [M+1]; t R =1.23min.

[0734] HPLC: t R =3.80min.

[0735] Example 23: 4-Methylbenzoic acid ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ester

[0736] As described in Example 16, the title compound was synthesized using 4-methylbenzoic acid instead of 3-methylbutyric acid as the starting material.

[0737]

[0738] Intermediate: 4-Methylbenzoic acid ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran[3,4-d][1,3]m-dioxacyclopenten-4-yl) methyl ester: LCMS: MS m / z = 450.12 [M+1]; t R =1.55min.

[0739] Compound 23 :

[0740] 1H NMR (400MHz, DMSO-d6) δ8.03-7.82 (m, 3H), 7.79 (dt, J = 8.1, 1.8Hz, 2H), 7.32 (d,J=7.8Hz,2H),6.92–6.87(m,1H),6.80(dd,J=4.5,1.5Hz,1H),6.36(dd,J= 6.0,1.5Hz,1H),5.44(dd,J=5.9,1.5Hz,1H),4.87–4.73(m,1H),4.57(dd,J= 11.8, 2.6Hz, 1H), 4.46–4.33 (m, 2H), 4.12 (q, J=6.4, 5.8Hz, 1H), 2.40 (s, 3H).

[0741] LCMS: MS m / z = 410.09 [M+1]; t R =1.25min.

[0742] HPLC: t R = 3.86 min.

[0743] Example 24: Octahydropentaenoic acid-2-carboxylic acid ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methyl ester

[0744] As described in Example 16, the title compound was synthesized using octahydropentaenoic-2-carboxylic acid instead of 3-methylbutyric acid as the starting material, providing a mixture of cis and trans isomers.

[0745]

[0746] Intermediate: Octahydropentaenoic acid-2-carboxylic acid ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran[3,4-d][1,3]m-dioxacyclopenten-4-yl) methyl ester: LCMS: MS m / z = 468.20 [M+1]; t R =1.73min.

[0747] Compound 24 :

[0748] 1H NMR(400MHz,DMSO-d6)δ8.04-7.71(m,3H),6.92(m,1H),6.81(m,1H),6.33(m, 1H),5.37(d,J=5.9Hz,1H),4.74–4.62(m,1H),4.39-4.27(m,1H),4.28–4.10( m,2H),4.01–3.90(m,1H),2.72–2.52(m,1H),2.42(m,2H),2.13–1.85(m,2H), 1.84–1.67(m,2H),1.65–1.42(m,4H),1.33(m,1H),1.26–0.95(m,1H); LCMS:MS m / z = 428.19[M+1]; t R =1.40 min; HPLC: t R =4.47min (85%), 4.56min (15%).

[0749] Example 25: Butyric acid ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ester

[0750] As described in Example 16, the title compound was synthesized using butyric acid instead of 3-methylbutyric acid as the starting material.

[0751]

[0752] Intermediate: Butyric acid ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran[3,4-d][1,3]m-dioxacyclopenten-4-yl) methyl ester: LCMS: MS m / z = 402.12 [M+1]; t R =0.76min.

[0753] Compound 25 :

[0754] 1H NMR(400MHz, DMSO-d6)δ8.05-7.78(m,3H),6.92(d,J=4.5Hz,1H),6.81(d,J=4.5H z,1H),6.32(d,J=6.0Hz,1H),5.38(d,J=5.9Hz,1H),4.70(t,J=5.5Hz,1H),4.34(d d,J=11.9,2.7Hz,1H),4.23(td,J=6.1,2.6Hz,1H),4.16(dd,J=11.9,5....

Claims

1. A crystalline form of a compound of the following formula: The crystalline form is characterized by XRPD patterns with 2θ reflection (±0.2 degrees 2θ) at 8.5°, 22.1° and 23.8°.

2. The crystalline form according to claim 1, wherein the XRPD pattern further comprises one, two, or three of the 2θ reflections (±0.2 degrees 2θ) at 15.4°, 16.9°, and 28.1°.

3. The crystalline form according to claim 1 or 2, wherein the XRPD pattern further includes one or both of the 2θ reflections (±0.2 degrees 2θ) at 15.4°, 16.9°, and 28.1°.

4. The crystalline form according to claim 1 or 2, wherein the XRPD pattern further comprises one of the 2θ reflections (±0.2 degrees 2θ) at 15.4°, 16.9° and 28.1°.

5. The crystalline form according to claim 1 or 2, wherein the XRPD pattern includes 2θ reflections (±0.2 degrees 2θ) at 8.5°, 15.4°, 16.9°, 22.1°, 23.8° and 28.1°.

6. The crystalline form according to claim 1, wherein the XRPD pattern further comprises one, two, or three of the 2θ reflections (±0.2 degrees 2θ) at 10.5°, 17.5°, and 27.5°.

7. The crystalline form according to claim 5, wherein the XRPD pattern further comprises one, two, or three of the 2θ reflections (±0.2 degrees 2θ) at 10.5°, 17.5°, and 27.5°.

8. The crystalline form according to claim 1, wherein the XRPD pattern further comprises one or both of the 2θ reflections (±0.2 degrees 2θ) at 10.5°, 17.5° and 27.5°.

9. The crystalline form according to claim 5, wherein the XRPD pattern further comprises one or both of the 2θ reflections (±0.2 degrees 2θ) at 10.5°, 17.5°, and 27.5°.

10. The crystalline form according to claim 1, wherein the XRPD pattern includes 2θ reflections (±0.2 degrees 2θ) at 8.5°, 10.5°, 15.4°, 16.9°, 17.5°, 22.1°, 23.8°, 27.5° and 28.1°.

11. The crystalline form according to claim 5, wherein the XRPD pattern includes 2θ reflections (±0.2 degrees 2θ) at 8.5°, 10.5°, 15.4°, 16.9°, 17.5°, 22.1°, 23.8°, 27.5° and 28.1°.

12. The crystalline form according to claim 1, wherein the XRPD pattern comprises 2θ reflection (±0.2 degrees 2θ) as follows:

13. The crystalline form according to claim 1 or 12, wherein the crystalline form exhibits an endothermic transformation at about 169°C.

14. The crystalline form according to claim 1 or 12, wherein the crystalline form is unsolvated.

15. The crystalline form of a compound of the following formula: The crystalline form is characterized by XRPD patterns with 2θ reflection (±0.2 degrees 2θ) at 6.4°, 13.7° and 16.3°.

16. The crystalline form of claim 15, wherein the XRPD pattern further comprises one, two, or three of the 2θ reflections (±0.2 degrees 2θ) at 18.4°, 20.8°, and 23.3°.

17. The crystalline form according to claim 15 or 16, wherein the XRPD pattern further comprises one or both of the 2θ reflections (±0.2 degrees 2θ) at 18.4°, 20.8°, and 23.3°.

18. The crystalline form according to claim 15 or 16, wherein the XRPD pattern further comprises one of the 2θ reflections (±0.2 degrees 2θ) at 18.4°, 20.8° and 23.3°.

19. The crystalline form according to claim 15 or 16, wherein the XRPD pattern includes 2θ reflections (±0.2 degrees 2θ) at 6.4°, 13.7°, 16.3°, 18.4°, 20.8° and 23.3°.

20. The crystalline form of claim 15, wherein the XRPD pattern further includes 2θ reflection at 25.4°.

21. The crystalline form of claim 19, wherein the XRPD pattern further includes 2θ reflection at 25.4°.

22. The crystalline form according to claim 15, wherein the XRPD pattern comprises 2θ reflection (±0.2 degrees 2θ) as follows: 。 23. The crystalline form according to claim 15 or 22, wherein the crystalline form exhibits two endothermic events at about 165°C and 176°C and an exothermic event at about 169°C.

24. The crystalline form according to claim 15 or 22, wherein the crystalline form is unsolvated.

25. A naphthalene salt of a compound of the following formula:

26. A crystalline form of the sine naphthate according to claim 25, wherein the crystalline form is characterized by having an XRPD pattern with 2θ reflection (±0.2 degrees 2θ) at 4.0°, 12.2° and 14.8°.

27. The crystalline form of claim 26, wherein the XRPD pattern further comprises one, two, or three of the 2θ reflections (±0.2 degrees 2θ) at 6.2°, 12.9°, and 26.6°.

28. The crystalline form according to claim 26 or 27, wherein the XRPD pattern further comprises one or both of the 2θ reflections (±0.2 degrees 2θ) at 6.2°, 12.9°, and 26.6°.

29. The crystalline form according to claim 26 or 27, wherein the XRPD pattern further comprises one of the 2θ reflections (±0.2 degrees 2θ) at 6.2°, 12.9° and 26.6°.

30. The crystalline form according to claim 26 or 27, wherein the XRPD pattern includes 2θ reflections (±0.2 degrees 2θ) at 4.0°, 6.2°, 12.2°, 12.9°, 14.8° and 26.6°.

31. The crystalline form according to claim 26, wherein the XRPD pattern further comprises one, two, or three of the 2θ reflections (±0.2 degrees 2θ) at 7.8°, 10.3°, and 15.7°.

32. The crystalline form of claim 30, wherein the XRPD pattern further comprises one, two, or three of the 2θ reflections (±0.2 degrees 2θ) at 7.8°, 10.3°, and 15.7°.

33. The crystalline form according to claim 26, wherein the XRPD pattern further comprises one or both of the 2θ reflections (±0.2 degrees 2θ) at 7.8°, 10.3°, and 15.7°.

34. The crystalline form of claim 30, wherein the XRPD pattern further comprises one or both of the 2θ reflections (±0.2 degrees 2θ) at 7.8°, 10.3°, and 15.7°.

35. The crystalline form according to claim 26, wherein the XRPD pattern includes 2θ reflections (±0.2 degrees 2θ) at 4.0°, 6.2°, 7.8°, 10.3°, 12.2°, 12.9°, 14.8°, 15.7° and 26.6°.

36. The crystalline form according to claim 30, wherein the XRPD pattern includes 2θ reflections (±0.2 degrees 2θ) at 4.0°, 6.2°, 7.8°, 10.3°, 12.2°, 12.9°, 14.8°, 15.7° and 26.6°.

37. The crystalline form according to claim 26, wherein the XRPD pattern comprises 2θ reflection (±0.2 degrees 2θ) as follows:

38. The crystalline form according to claim 26 or 37, wherein the crystalline form exhibits an endothermic event at about 154°C.

39. The crystalline form according to claim 26 or 37, wherein the crystalline form is unsolvated.

40. An HCl salt of a compound of the following formula:

41. A crystalline form of the HCl salt according to claim 40, wherein the crystalline form is characterized by having an XRPD pattern with 2θ reflection (±0.2 degrees 2θ) at 5.9°, 14.0° and 24.3°.

42. The crystalline form according to claim 41, wherein the XRPD pattern further comprises one, two, or three of the 2θ reflections (±0.2 degrees 2θ) at 11.7°, 16.7°, and 23.9°.

43. The crystalline form according to claim 41 or 42, wherein the XRPD pattern further comprises one or both of the 2θ reflections (±0.2 degrees 2θ) at 11.7°, 16.7° and 23.9°.

44. The crystalline form according to claim 41 or 42, wherein the XRPD pattern further comprises one of the 2θ reflections (±0.2 degrees 2θ) at 11.7°, 16.7° and 23.9°.

45. The crystalline form according to claim 41 or 42, wherein the XRPD pattern includes 2θ reflections (±0.2 degrees 2θ) at 5.9°, 11.7°, 14.0°, 16.7°, 23.9° and 24.3°.

46. ​​The crystalline form according to claim 41, wherein the XRPD pattern further comprises one, two, or three of the 2θ reflections (±0.2 degrees 2θ) at 14.2°, 19.7°, and 22.4°.

47. The crystalline form of claim 45, wherein the XRPD pattern further comprises one, two, or three of the 2θ reflections (±0.2 degrees 2θ) at 14.2°, 19.7°, and 22.4°.

48. The crystalline form according to claim 41, wherein the XRPD pattern further comprises one or both of the 2θ reflections (±0.2 degrees 2θ) at 14.2°, 19.7°, and 22.4°.

49. The crystalline form according to claim 45, wherein the XRPD pattern further comprises one or both of the 2θ reflections (±0.2 degrees 2θ) at 14.2°, 19.7°, and 22.4°.

50. The crystalline form according to claim 41, wherein the XRPD pattern includes 2θ reflections (±0.2 degrees 2θ) at 5.9°, 11.7°, 14.0°, 14.2°, 16.7°, 19.7°, 22.4°, 23.9° and 24.3°.

51. The crystalline form according to claim 45, wherein the XRPD pattern includes 2θ reflections (±0.2 degrees 2θ) at 5.9°, 11.7°, 14.0°, 14.2°, 16.7°, 19.7°, 22.4°, 23.9° and 24.3°.

52. The crystalline form according to claim 41, wherein the XRPD pattern comprises 2θ reflection (±0.2 degrees 2θ) as follows:

53. The crystalline form according to claim 41 or 52, wherein the crystalline form exhibits two endothermic transitions at about 115°C and 187°C and an exothermic event at about 140°C.

54. The crystalline form according to claim 41 or 52, wherein the crystalline form exhibits three weight loss events of about 1.1 wt%, about 3.4 wt%, and about 31 wt%, respectively, starting between 20°C and 100°C, between 100°C and 135°C, and between 135°C and 265°C.

55. A crystalline form of the HCl salt according to claim 40, wherein the crystalline form is characterized by having an XRPD pattern with 2θ reflection (±0.2 degrees 2θ) at 4.0°, 15.0° and 25.8°.

56. The crystalline form according to claim 55, wherein the XRPD pattern further comprises one, two, or three of the 2θ reflections (±0.2 degrees 2θ) at 10.6°, 16.3°, and 26.7°.

57. The crystalline form according to claim 55 or 56, wherein the XRPD pattern further comprises one or both of the 2θ reflections (±0.2 degrees 2θ) at 10.6°, 16.3°, and 26.7°.

58. The crystalline form according to claim 55 or 56, wherein the XRPD pattern further comprises one of the 2θ reflections (±0.2 degrees 2θ) at 10.6°, 16.3° and 26.7°.

59. The crystalline form according to claim 55 or 56, wherein the XRPD pattern includes 2θ reflections (±0.2 degrees 2θ) at 4.0°, 10.6°, 15.0°, 16.3°, 25.8° and 26.7°.

60. The crystalline form according to claim 55, wherein the XRPD pattern further comprises one, two, or three of the 2θ reflections (±0.2 degrees 2θ) at 12.2°, 15.7°, and 31.5°.

61. The crystalline form according to claim 59, wherein the XRPD pattern further comprises one, two, or three of the 2θ reflections (±0.2 degrees 2θ) at 12.2°, 15.7°, and 31.5°.

62. The crystalline form according to claim 55, wherein the XRPD pattern further comprises one or both of the 2θ reflections (±0.2 degrees 2θ) at 12.2°, 15.7°, and 31.5°.

63. The crystalline form according to claim 59, wherein the XRPD pattern further comprises one or both of the 2θ reflections (±0.2 degrees 2θ) at 12.2°, 15.7°, and 31.5°.

64. The crystalline form according to claim 55, wherein the XRPD pattern includes 2θ reflections (±0.2 degrees 2θ) at 4.0°, 10.6°, 12.2°, 15.0°, 15.7°, 16.3°, 25.8°, 26.7° and 31.5°.

65. The crystalline form according to claim 59, wherein the XRPD pattern includes 2θ reflections (±0.2 degrees 2θ) at 4.0°, 10.6°, 12.2°, 15.0°, 15.7°, 16.3°, 25.8°, 26.7° and 31.5°.

66. The crystalline form according to claim 55, wherein the XRPD pattern comprises 2θ reflection (±0.2 degrees 2θ) as follows:

67. The crystalline form according to claim 55 or 66, wherein the crystalline form exhibits two endothermic transitions at about 155°C and 195°C.

68. The crystalline form according to claim 55 or 66, wherein the crystalline form exhibits a weight loss of approximately 35% by weight between 100°C and 260°C.

69. A crystalline form of the HCl salt according to claim 40, wherein the crystalline form is characterized by having an XRPD pattern with 2θ reflection (±0.2 degrees 2θ) at 4.3°, 15.9° and 26.6°.

70. The crystalline form according to claim 69, wherein the XRPD pattern further comprises one, two, or three of the 2θ reflections (±0.2 degrees 2θ) at 7.1°, 16.8°, and 25.7°.

71. The crystalline form according to claim 69 or 70, wherein the XRPD pattern further comprises one or both of the 2θ reflections (±0.2 degrees 2θ) at 7.1°, 16.8°, and 25.7°.

72. The crystalline form according to claim 69 or 70, wherein the XRPD pattern further comprises one of the 2θ reflections (±0.2 degrees 2θ) at 7.1°, 16.8°, and 25.7°.

73. The crystalline form according to claim 69 or 70, wherein the XRPD pattern includes 2θ reflections (±0.2 degrees 2θ) at 4.3°, 7.1°, 15.9°, 16.8°, 25.7° and 26.6°.

74. The crystalline form according to claim 69, wherein the XRPD pattern further comprises one, two, or three of the 2θ reflections (±0.2 degrees 2θ) at 14.3°, 18.7°, and 27.0°.

75. The crystalline form according to claim 73, wherein the XRPD pattern further comprises one, two, or three of the 2θ reflections (±0.2 degrees 2θ) at 14.3°, 18.7°, and 27.0°.

76. The crystalline form according to claim 69, wherein the XRPD pattern further comprises one or both of the 2θ reflections (±0.2 degrees 2θ) at 14.3°, 18.7°, and 27.0°.

77. The crystalline form according to claim 73, wherein the XRPD pattern further comprises one or both of the 2θ reflections (±0.2 degrees 2θ) at 14.3°, 18.7°, and 27.0°.

78. The crystalline form according to claim 69, wherein the XRPD pattern includes 2θ reflections (±0.2 degrees 2θ) at 4.3°, 7.1°, 14.3°, 15.9°, 16.8°, 18.7°, 25.7°, 26.6° and 27.0°.

79. The crystalline form according to claim 73, wherein the XRPD pattern includes 2θ reflections (±0.2 degrees 2θ) at 4.3°, 7.1°, 14.3°, 15.9°, 16.8°, 18.7°, 25.7°, 26.6° and 27.0°.

80. The crystalline form according to claim 69, wherein the XRPD pattern comprises 2θ reflection (±0.2 degrees 2θ) as follows:

81. The crystalline form according to claim 69 or 80, wherein the crystalline form exhibits an endothermic transformation at about 178°C.

82. The crystalline form according to claim 69 or 80, wherein the crystalline form exhibits a weight loss of about 1.2 wt% and 28 wt% respectively between 20°C and 100°C and between 100°C and 240°C.

83. A crystalline form of the HCl salt according to claim 40, wherein the crystalline form is characterized by having an XRPD pattern with 2θ reflection (±0.2 degrees 2θ) at 4.3°, 14.7° and 31.4°.

84. The crystalline form according to claim 83, wherein the XRPD pattern further comprises one, two, or three of the 2θ reflections (±0.2 degrees 2θ) at 12.8°, 17.3°, and 35.1°.

85. The crystalline form according to claim 83 or 84, wherein the XRPD pattern further comprises one or both of the 2θ reflections (±0.2 degrees 2θ) at 12.8°, 17.3°, and 35.1°.

86. The crystalline form according to claim 83 or 84, wherein the XRPD pattern further comprises one of the 2θ reflections (±0.2 degrees 2θ) at 12.8°, 17.3° and 35.1°.

87. The crystalline form according to claim 83 or 84, wherein the XRPD pattern includes 2θ reflections (±0.2 degrees 2θ) at 4.3°, 12.8°, 14.7°, 17.3°, 31.4° and 35.1°.

88. The crystalline form according to claim 83, wherein the XRPD pattern further comprises one, two, or three of the 2θ reflections (±0.2 degrees 2θ) at 16.6°, 24.9°, and 27.2°.

89. The crystalline form according to claim 87, wherein the XRPD pattern further comprises one, two, or three of the 2θ reflections (±0.2 degrees 2θ) at 16.6°, 24.9°, and 27.2°.

90. The crystalline form according to claim 83, wherein the XRPD pattern further comprises one or both of the 2θ reflections (±0.2 degrees 2θ) at 16.6°, 24.9°, and 27.2°.

91. The crystalline form according to claim 87, wherein the XRPD pattern further comprises one or both of the 2θ reflections (±0.2 degrees 2θ) at 16.6°, 24.9°, and 27.2°.

92. The crystalline form according to claim 83, wherein the XRPD pattern includes 2θ reflections (±0.2 degrees 2θ) at 4.3°, 12.8°, 14.7°, 16.6°, 17.3°, 24.9°, 27.2°, 31.4° and 35.1°.

93. The crystalline form according to claim 87, wherein the XRPD pattern includes 2θ reflections (±0.2 degrees 2θ) at 4.3°, 12.8°, 14.7°, 16.6°, 17.3°, 24.9°, 27.2°, 31.4° and 35.1°.

94. The crystalline form according to claim 83, wherein the XRPD pattern comprises 2θ reflection (±0.2 degrees 2θ) as follows:

95. The crystalline form according to claim 83 or 94, wherein the crystalline form exhibits an endothermic transition at about 186°C.

96. The crystalline form according to claim 83 or 94, wherein the crystalline form exhibits a weight loss of approximately 30% by weight between 100°C and 250°C.

97. A pharmaceutical composition comprising: (a)(i) the crystalline form according to any one of claims 1 to 24, 26 to 39 and 41 to 96 or (ii) the salt according to claim 25 or 40; and (b) Pharmaceutically acceptable excipients.

98. The pharmaceutical composition of claim 97, wherein the pharmaceutical composition is for subcutaneous, intramuscular, intravenous, oral, or inhalation administration.

99. The pharmaceutical composition according to claim 97, wherein the pharmaceutical composition is for oral administration.

100. Use of the crystalline form according to any one of claims 1 to 24, 26 to 39 and 41 to 96, or the salt according to claim 25 or 40, in the preparation of a medicament for treating or preventing viral infections in persons in need.

101. The use according to claim 100, wherein the drug is formulated for oral, intramuscular, intravenous, subcutaneous or inhalation administration.

102. The use according to claim 100 or 101, wherein the drug is used in conjunction with at least one additional therapeutic or preventative agent.

103. The use according to claim 100 or 101, wherein the viral infection is a coronavirus infection.

104. The use according to claim 100 or 101, wherein the viral infection is a zoonotic coronavirus infection.

105. The use according to claim 100 or 101, wherein the viral infection is caused by a virus having at least 70% sequence homology with a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase and SARS-CoV-2.

106. The use according to claim 100 or 101, wherein the viral infection is caused by a virus having at least 80% sequence homology with a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase and SARS-CoV-2.

107. The use according to claim 100 or 101, wherein the viral infection is caused by a virus having at least 90% sequence homology with a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase and SARS-CoV-2.

108. The use according to claim 100 or 101, wherein the viral infection is caused by a virus having at least 95% sequence homology with a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase and SARS-CoV-2.

109. The use according to claim 100 or 101, wherein the viral infection is selected from the group consisting of: 229E virus infection, NL63 virus infection, OC43 virus infection and HKU1 virus infection.

110. The use according to claim 100 or 101, wherein the viral infection is SARS-CoV-2 infection (COVID-19).

111. The use according to claim 100 or 101, wherein the viral infection is a SARS-CoV virus infection.

112. The use according to claim 100 or 101, wherein the viral infection is a MERS-CoV viral infection.

113. The use according to claim 100 or 101, wherein the viral infection is a pulmonary virus infection.

114. The use according to claim 113, wherein the pulmonary virus infection is a respiratory syncytial virus infection.

115. The use according to claim 113, wherein the pulmonaryviridae virus infection is human metapneumovirus infection.

116. The use according to claim 100 or 101, wherein the viral infection is a piconerivirus infection.

117. The use according to claim 116, wherein the viral infection is an enterovirus infection.

118. The use according to claim 100 or 101, wherein the viral infection is selected from the group consisting of: Coxsackie A virus infection, Coxsackie A virus infection, Enterovirus D68 infection, Enterovirus B69 infection, Enterovirus D70 infection, Enterovirus A71 infection, and poliovirus infection.

119. The use according to claim 116, wherein the microribonucleoviridae virus infection is a human rhinovirus infection (HRV).

120. The use according to claim 116, wherein the microribonucleovir infection is HRV-A, HRV-B, or HRV-C infection.

121. The use according to claim 100 or 101, wherein the viral infection is a flaviviridae virus infection.

122. The use according to claim 121, wherein the Flaviviridae virus infection is dengue virus infection, yellow fever virus infection, West Nile virus infection, tick-borne encephalitis, Kunzin Japanese encephalitis, St. Louis encephalitis, Murray Valley encephalitis, Omsk hemorrhagic fever, bovine viral diarrhea, Zika virus infection, or HCV infection.

123. The use according to claim 100 or 101, wherein the viral infection is a filoviridae virus infection.

124. The use according to claim 123, wherein the filoviridae virus infection is an Ebola virus infection or a Marburg virus infection.

125. The use according to claim 100 or 101, wherein the viral infection is an orthomyxovirus infection.

126. The use according to claim 125, wherein the viral infection is an influenza virus infection.

127. The use according to claim 125, wherein the viral infection is an influenza A virus infection or an influenza B virus infection.

128. The use according to claim 100 or 101, wherein the viral infection is a paramyxoviridae virus infection.

129. The use according to claim 128, wherein the viral infection is human parainfluenza virus, Nipah virus, Hendra virus, measles or mumps infection.

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